Clinical trial NCT03615066
Conditions: Chronic Hepatitis B
Sponsor: Gilead Sciences
Start date: 2018-08-28; Completion date: 2021-04-12
Enrollment: 67 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The primary objectives of this study are to evaluate the safety and tolerability of multiple oral doses of selgantolimod and to evaluate the antiviral activity of selgantolimod in adult participants with chronic hepatitis B (CHB) who are viremic and not currently being treated.

Detailed description:

Arms: arm 1: Participants with Hepatitis B e antigen (HBeAg)-positive CHB or HBeAg-negative CHB currently not on oral antiviral (OAV) treatment, will receive selgantolimod 3 mg (2 x 1.5 mg tablet) on the same day once weekly for 24 doses along with tenofovir alafenamide (TAF) 25 mg once daily for 24 weeks. After the 24th dose, selgantolimod will be discontinued, and participants will continue to receive TAF until Week 48/early discontinuation (ED). At Week 48, per Principal Investigator's (PI's) discretion, participants can continue in the Treatment Free Follow-Up (TFFU) phase for up to an additional 48 weeks. arm 2: Participants with HBeAg-positive CHB or HBeAg-negative CHB currently not on OAV treatment, will receive selgantolimod 1.5 mg (1 x 1.5 mg tablet) and placebo (1 tablet) on the same day once weekly for 24 doses along with TAF 25 mg once daily for 24 weeks. After the 24th dose, selgantolimod will be discontinued, and participants will continue to receive TAF until Week 48/ED. At Week 48, per PI's discretion, participants can continue in the TFFU phase for up to an additional 48 weeks. arm 3: Participants with HBeAg-positive CHB or HBeAg-negative CHB currently not on OAV treatment, will receive 2 tablets of placebo on the same day once weekly for 24 doses along with TAF 25 mg once daily for 24 weeks. After the 24th dose, placebo will be discontinued, and participants will continue to receive TAF until Week 48/ED. At Week 48, per PI's discretion, participants can continue in the TFFU phase for up to an additional 48 weeks.
Interventions: intervention 1: Placebo intervention 2: Selgantolimod intervention 3: TAF
Intervention descriptions: intervention 1: Tablet(s) administered orally every 7 days for 24 doses in fasted state intervention 2: Tablet(s) administered orally every 7 days for 24 doses in fasted state intervention 3: Tablet(s) administered orally once daily with food

Protocol documents:
Prot_000.pdf: 
(rJ GILEAU 
CLINICAL STUDY PROTOCOL 
Study Title: 
A Phase 2, Randomized, Double-Blind, Placebo-Controlled, 
Multi-center Study to Evaluate the Safety, Tolerability and 
Antiviral Activity of GS-9688 in Viremic Adult Subjects with 
Chronic Hepatitis B who are not cmTently on Treatment 
Sponsor: 
Gilead Sciences, Inc. 
333 Lakeside Drive 
Foster City, CA 94404 
IND Number: 
Non-IND Study 
EudraCT Number: 
Not Applicable 
Clinical Trials.gov 
Identifier: 
NCT03615066 
Indication: 
Chronic Hepatitis B 
Protocol ID: 
GS-US-389-2025 
Gilead Medical Monitor: 
Name: 
Telephone: 
Fax: 
Protocol Version/Date: 
Original: 
23 March 2018 
Amendment 1: 
27 August 2019 
CONFIDENTIALITY STATEMENT 
The info1m ation 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 Boai·d 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 necessa1y to obtain infonned consent from those 
persons to whom the dmg may be administered. 


GS-9688 
Protocol GS-US-389-2025 
Gilead Sciences, Inc. 
Final 
Amendment 1 
TABLE OF CONTENTS 
TABLE OF CONTENTS .............................................................................................................................................. 2 
LIST OF IN-TEXT TABLES ........................................................................................................................................ 5 
LIST OF IN-TEXT FIGURES ...................................................................................................................................... 6 
PROTOCOL SYNOPSIS .............................................................................................................................................. 7 
GLOSSARY OF ABBREVIATIONS AND DEFINITION OF TERMS .................................................................... 24 
1. 
INTRODUCTION .............................................................................................................................................. 29 
1.1. 
Backgrowid ............................................................................................................................................ 29 
1.2. 
GS-9688 ................................................................................................................................................. 30 
1.2.1. 
General Infonnation ............................................................................................................. 30 
1.2.2. 
Preclinical Phannacology and Toxicology ........................................................................... 30 
1.2.3. 
Genotoxicity ......................................................................................................................... 32 
1.2.4. 
Safety Pharmacology ............................................................................................................ 32 
1.2.5. 
Nonclinical Pha1macology ................................................................................................... 33 
1.2.6. 
Clinical Trials of GS-9688 ................................................................................................... 34 
1.3. 
Rationale for This Study ........................................................................................................................ 42 
1.3.1. 
GS-9688 for Virernic Subjects with Chronic Hepatitis B Not Cwl'ently on 
Treatnlent ............................................................................................................................. 42 
1.3.2. 
Rationale for the Dose Selection .......................................................................................... 42 
1.3.3. 
Rationale for Treatinent Dw·ation ........................................................................................ 43 
1.4. 
TAF (GS-7340) ...................................................................................................................................... 43 
1.4.1. 
General Infonnation ............................................................................................................. 43 
1.4.2. 
Clinical Trials ofTAF .......................................................................................................... 44 
1.5. 
Risk/Benefit Assessment for the Study .................................................................................................. 53 
1.6. 
Compliance ............................................................................................................................................ 55 
2. 
OBJECTIVES ..................................................................................................................................................... 56 
3. 
STUDY DESIGN ................................................................................................................................................ 58 
3.1. 
3.2. 
3.3. 
3.4. I 
Study Design .......................................................................................................................................... 58 
Study Treatnlents ................................................................................................................................... 58 
Duration ofTreatnlent ............................................................................................................................ 60 
Pha1macokinetic Assessment ................................................................................................................. 60 
3.7. 
End ofStudy ........................................................................................................................................... 61 
4. 
SUBJECT POPULATION .................................................................................................................................. 62 
4.1. 
Number of Subjects and Subject Selection ............................................................................................ 62 
4.2. 
Inclusion Criteria .................................................................................................................................... 62 
4.3. 
Exclusion Criteria ................................................................................................................................... 62 
5. 
INVESTIGATIONAL MEDICINAL PRODUCTS ........................................................................................... 65 
5.1. 
Rando1nization, Blinding and Treatment Codes .................................................................................... 65 
5.1.1. 
Procedures for Breaking Treatnlent Codes ........................................................................... 65 
5.2. 
Description and Handling of GS-9688!PTM and TAF .......................................................................... 66 
5.2.1. 
Foimulation .......................................................................................................................... 66 
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5.2.2. 
Packaging and Labeling ....................................................................................................... 66 
5.2.3. 
Storage and Handling ........................................................................................................... 67 
5.3. 
Dosage and Administrntion ofGS-9688/PTM and TAF ........................................................................ 67 
5.4. 
Fasting State Dosing .............................................................................................................................. 68 
5.5. 
Concomitant and Prohibited Medications .............................................................................................. 68 
5.6. 
Other Protocol Restrictions .................................................................................................................... 70 
5.7. 
Accountability for GS-9688/PTM and TAF ........................................................................................... 71 
5.8. 
Investigational Medicinal Product Retum or Disposal.. ......................................................................... 71 
6. 
STUDY PROCEDURES .................................................................................................................................... 72 
6.1. 
Subject Enrollment and Treatment Assignment ..................................................................................... 72 
6.2. 
Preti·eatinent Assessments ...................................................................................................................... 72 
6.2.1. 
Screening Visit (Window of -30 Days) ................................................................................ 72 
6.2.2. 
Randomization/ Baseline Assessments ................................................................................ 73 
6.3. 
Treatment Assessments (All Visits Have Window of± 1 Days) ........................................................... 75 
6.4. 
Post GS-9688/PTM Treatlnent Assessments (All Visits Have Window of± 3 Days except 
Week 24 ± 1 Day) .................................................................................................................................. 77 
6.5. 
Treatment Free Follow-Up (TFFU) aBer ED ......................................................................................... 78 
6.5.1. 
TFFU aBer ED Visit Assessments(± 7 Days) ..................................................................... 78 
6.6. 
TFFU Post Study Completion (Week 48) .............................................................................................. 79 
6.6.1. 
TFFU Post Study Completion Visit Assessments (± 7 Days) .............................................. 79 
6.7. 
Unscheduled Visits ................................................................................................................................. 80 
6.8. 
Phannacokinetic Assessments ................................................................................................................ 80 
6.10. 
-
6.12. 
6.13. 
6.14. 
6.15. 
6.16. 
Sa ety Assess1nents ................................................................................................................................ 83 
6.10.1. 
Elect1·ocardiogra1n Assess1nent ............................................................................................ 83 
6.10.2. 
Holter Monitoring ................................................................................................................ 83 
6.10.3. 
Physical Examination ........................................................................................................... 84 
6.10.4. 
Vital Signs ............................................................................................................................ 84 
6.10.5. 
Clinical Laborat01y Tests/ Assessments for Safety Evaluations ........................................... 84 
6 .10. 6. 
Creatinine Clearance ............................................................................................................ 85 
6.10.7. 
Ophthal1nic Exainination ...................................................................................................... 86 
6.10.8. 
Adverse Events/Concomitant Medications/Protocol Restl-ictions ........................................ 86 
Assessments or Premature D1scontmuatlon ·om Stu y ....................................................................... 86 
Criteria for Discontinuation of Study Treatment. ................................................................................... 86 
Resistance Swveillance .......................................................................................................................... 87 
End of Study ........................................................................................................................................... 87 
Post Study Care ...................................................................................................................................... 87 
7. 
ADVERSE EVENTS AND TOXICITY MANAGEMENT ............................................................................... 88 
7 .1. 
Definitions of Adverse Events, Adverse Reactions, and Serious Adverse Events ................................. 88 
7 .1.1. 
Adverse Events ..................................................................................................................... 88 
7.1.2. 
Serious Adverse Events ........................................................................................................ 88 
7.2. 
Assessment of Adverse Events and Serious Adverse Events ................................................................. 89 
7.2.1. 
Assessment of Causality for Study Drngs and Procedw-es ................................................... 89 
7.2.2. 
Assess1nent ofSeverity ........................................................................................................ 90 
7.3. 
Investigator Requirements and Instrnctions for Reporting Adverse Events and Serious 
Adverse Events to Gilead ....................................................................................................................... 90 
7 .3 .1. 
Adverse Events ..................................................................................................................... 90 
7.3.2. 
Serious Adverse Events ........................................................................................................ 90 
7.4. 
Gilead Reporting Requirements ............................................................................................................. 92 
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7.5.
Clinical Laboratory Abnormalities and Other Abnormal Assessments as Adverse Events or 
Serious Adverse Events..........................................................................................................................92
7.6.
Toxicity Management ............................................................................................................................93
7.6.1.
ALT Elevation or Flare Management...................................................................................93
7.6.2.
Management of GS-9688/PTM Dose Limiting Toxicities ...................................................94
7.6.3.
TAF Dose Modification and Monitoring .............................................................................94
7.6.4.
Management of Neutropenia................................................................................................95
7.6.5.
Grades 1 and 2 Laboratory Abnormality or Clinical Event..................................................95
7.6.6.
Grades 3 and 4 Laboratory Abnormality or Clinical Event..................................................96
7.7.
Other Criteria for Discontinuation of Study Drug..................................................................................96
7.8.
Subject Withdrawal Criteria...................................................................................................................97
7.9.
Study Specific Stopping Criteria............................................................................................................97
7.9.1.
Laboratory Abnormalities and Treatment-Emergent Adverse Events..................................97
7.9.2.
Virologic Criteria .................................................................................................................97
7.10.
Special Situations Reports......................................................................................................................98
7.10.1.
Definitions of Special Situations..........................................................................................98
7.10.2.
Instructions for Reporting Special Situations.......................................................................99
8.
STATISTICAL CONSIDERATIONS..............................................................................................................101
8.1.
Analysis Objectives and Endpoints......................................................................................................101
8.1.1.
Analysis Objectives............................................................................................................101
8.1.2.
Primary Efficacy Endpoint.................................................................................................102
8.1.3.
Secondary Efficacy Endpoints ...........................................................................................102
8.2.
Analysis Conventions...........................................................................................................................103
8.2.1.
Analysis Sets ......................................................................................................................103
8.3.
Data Handling Conventions .................................................................................................................103
8.4.
Demographic Data and Baseline Characteristics .................................................................................103
8.5.
Efficacy Analysis .................................................................................................................................104
8.5.1.
Primary Analysis................................................................................................................104
8.5.2.
Secondary Analyses ...........................................................................................................104
8.5.3.
Analysis of Other Endpoints of Interest .............................................................................104
8.6.
Safety Analysis.....................................................................................................................................105
8.6.1.
Extent of Exposure.............................................................................................................105
8.6.2.
Adverse Events...................................................................................................................105
8.6.3.
Laboratory Evaluations ......................................................................................................106
8.6.4.
Other Safety Evaluations....................................................................................................106
8.7.
Pharmacokinetic Analysis....................................................................................................................106
8.9.
Sample Size..........................................................................................................................................107
8.10.
Data Monitoring Committee ................................................................................................................107
8.11.
Internal Data Review Team..................................................................................................................108
9.
RESPONSIBILITIES........................................................................................................................................109
9.1.
Investigator Responsibilities ................................................................................................................109
9.1.1.
Good Clinical Practice........................................................................................................109
9.1.2.
Institutional Review Board (IRB)/Independent Ethics Committee (IEC) 
Review and Approval.........................................................................................................109
9.1.3.
Informed Consent...............................................................................................................109
9.1.4.
Confidentiality....................................................................................................................110
9.1.5.
Study Files and Retention of Records ................................................................................110
9.1.6.
Case Report Forms.............................................................................................................111
9.1.7.
Study Drug Accountability and Return ..............................................................................112
9.1.8.
Inspections..........................................................................................................................112
9.1.9.
Protocol Compliance..........................................................................................................112
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9.2.
Sponsor Responsibilities ......................................................................................................................113
9.2.1.
Protocol Modifications.......................................................................................................113
9.2.2.
Study Report and Publications ...........................................................................................113
9.3.
Joint Investigator/Sponsor Responsibilities .........................................................................................113
9.3.1.
Payment Reporting.............................................................................................................113
9.3.2.
Access to Information for Monitoring................................................................................113
9.3.3.
Access to Information for Auditing or Inspections ............................................................113
9.3.4.
Study Discontinuation........................................................................................................114
10.
REFERENCES .................................................................................................................................................115
11.
APPENDICES ..................................................................................................................................................119
Appendix 1.
Investigator Signature Page..................................................................................................120
Appendix 2.
Study Procedures Tables ......................................................................................................121
Appendix 3.
Pregnancy Precautions, Definition for Female of Childbearing Potential, and 
Contraceptive Requirements.................................................................................................127
Appendix 4.
GSI Grading Scale for Severity of Adverse Events and Laboratory Abnormalities.............130
LIST OF IN-TEXT TABLES
Table 1-1.
GS-US-389-2021: GS-9688 Plasma Pharmacokinetic Parameters by Treatment 
Following Single-Dose Administration of GS-9688 in the Fasted State (Cohorts 1 to 
4) (GS-9688 PK Analysis Set)................................................................................................35
Table 1-2.
GS-US-389-2021: GS-9688 Plasma Pharmacokinetic Parameters by Treatment 
Following Single-Dose Administration of GS-9688 in the Fasted and Fed States 
(Cohort 6) (GS-9688 PK Analysis Set) ..................................................................................36
Table 1-3.
GS-US-389-2022: Summary Statistics of GS-9688 Plasma Pharmacokinetic 
Parameters by Treatment Following Single- or Multiple-Dose (2 or 4 Doses QW) 
Administration of GS-9688 in Subjects Who Were Virally Suppressed or Viremic 
(PK Analysis Set). ..................................................................................................................38
Table 1-4.
GS-US-389-3979: Statistical comparison of GS-9688 Pharmacokinetic Parameters 
following single dose administration of GS-9688 in the presence of probe drug (Day 
8) and GS-9688 alone (Day 1)................................................................................................40
Table 1-5.
Clinical Studies to Support Efficacy for the TAF Marketing Applications............................45
Table 1-6.
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) ........................................46
Table 1-7.
GS-US-320-0110: Proportion of Subjects with HBeAg Loss or Seroconversion at 
Week 48, Missing = Failure (Serologically Evaluable Full Analysis Set) .............................47
Table 1-8.
GS-US-320-0108 and GS-US-320-0110: Overall Summary of Adverse Events in 
the TAF Phase 3 Safety Population (Safety Analysis Set) .....................................................48
Table 1-9.
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)...........................................................................................................................49
Table 1-10.
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)...........50
Table 1-11.
GS-US-320-0108 and GS-US-320-0110: Treatment-Emergent Grade 3 or 4 
Laboratory Abnormalities Reported for at Least 1% of Subjects in Either Treatment 
Group in the Overall TAF Phase 3 Safety Population (Safety Analysis Set) .........................51
Table 5-1.
List of Agents Disallowed while on GS-9688/PTM treatment (+7 days)...............................69
Table 5-2.
Disallowed Concomitant Medications while on TAF ............................................................70
Table 7-1.
TAF Dose Modification and Monitoring................................................................................95


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LIST OF IN-TEXT FIGURES
Figure 3-1.
Study Schema.........................................................................................................................58


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PROTOCOL SYNOPSIS
Gilead Sciences, Inc.
333 Lakeside Drive
Foster City, CA 94404
Study Title: 
A Phase 2, Randomized, Double-Blind, Placebo-Controlled, 
Multi-center Study to Evaluate the Safety, Tolerability and Antiviral 
Activity of GS-9688 in Viremic Adult Subjects with Chronic 
Hepatitis B who are not currently on Treatment
IND Number:
EudraCT Number:
Clinical Trials.gov 
Identifier:
Non-IND Study
Not Applicable
NCT03615066
Study Centers Planned:
Approximately 12 centers in Canada, South Korea, and Taiwan
Objectives:
The primary objectives of this study are as follows:

To evaluate the safety and tolerability of multiple oral doses of
GS-9688 at Week 24 in chronic hepatitis B (CHB) adult subjects 
who are viremic and not currently not being treated 

To evaluate the antiviral activity of GS-9688 as measured by the 
proportion of subjects with ≥1 log10 IU/mL decline from baseline 
in serum quantitative hepatitis B surface antigen (qHBsAg) at 
Week 24
The secondary objectives of this study are as follows:

To evaluate the antiviral activity of GS-9688 at Weeks 4, 8, 
12 and 48 as measured by the proportion of subjects with 
≥1 log10 IU/mL decline from baseline in serum qHBsAg

To evaluate the change in serum qHBsAg (log10 IU/mL) from 
baseline to Weeks 4, 8, 12, 24 and 48

To evaluate the proportion of subjects with HBV DNA <LLOQ 
at Weeks 12, 24, and 48

To evaluate the proportion of subjects with HBsAg loss at 
Weeks 12, 24 and 48

To evaluate the proportion of subjects with Hepatitis B e-Antigen 
(HBeAg) loss and seroconversion at Weeks 12, 24 and 48


GS-9688 
Protocol GS-US-389-2025 
Gilead Sciences, Inc. 
Study Design: 
CONFIDENTIAL 
Final 
Amendment 1 
• 
To characterize the phannacokinetics (PK) of GS-9688 
• 
To evaluate the propo1iion of subjects experiencing Hepatitis B 
vims (HBV) virologic breakthrough (2 consecutive visits of 
HBV DNA~ 69 IU/mL) 
• 
To evaluate the incidence of diug resistance mutations 
This is a multicenter, randomized, double-blind, placebo-controlled 
Phase 2 study of GS-9688 in viremic CHB subjects who are not 
cmTently being treated. 
Approximately 65 viremic subjects who are not cmTently being 
treated for CHB will be emolled into two coho1is within this study 
that will rnn in parallel. 
• 
Coho1i 1 (n = 40): HBeAg-positive CHB subjects 
• 
Coho1i 2 (n = 25): HBeAg-negative CHB subjects 
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Within each cohort, subjects will be randomized in a 1:2:2 in ratio to 
one of the three treatment arms (A: B: C) for weekly dosing of 
GS-9688/Placebo to Match (PTM) for 24 doses. All subjects will 
also be treated with tenofovir alafenamide (TAF) 25 mg oral daily 
for 48 weeks, in addition to the following treatments:
Treatment Arm A: Approximately 8 subjects in Cohort 1 and 
approximately 5 subjects in Cohort 2 will be administered 
placebo-to-match (PTM) orally on the same day once a week 
(every 7 days) for 24 doses 
Treatment Arm B: Approximately 16 subjects in Cohort 1 and 
approximately 10 subjects in Cohort 2 will be administered 
GS-9688/PTM 1.5 mg orally on the same day once a week 
(every 7 days) for 24 doses
Treatment Arm C: Approximately 16 subjects in Cohort 1 and 
approximately 10 subjects in Cohort 2 will be administered 
GS-9688/PTM 3 mg orally on the same day once a week 
(every 7 days) for 24 doses
All GS-9688/PTM study drug doses will be administered in fasted 
state.
After the 24th dose (Week 23 visit), GS-9688/PTM will be 
discontinued. Subjects will continue being treated with TAF and will 
be followed until Week 48/ED. The total study duration for each 
subject will be 48 weeks with up to an additional 48 weeks if 
continued into the Treatment Free Follow-up (TFFU) phase.
Subjects should take TAF and other commercially available 
medications no earlier than 2 hours after GS-9688/PTM dosing.
Ondansetron dosing is allowed around GS-9688/PTM dosing; 
dosing of other antiemetics should be discussed with the Gilead 
medical monitor (MM) for approval.
Following completion of the 48-week study period the Investigators 
will be responsible for assessing the need to continue study subjects 
on treatment for CHB. At Week 48, at Principal Investigator (PI) 
discretion, subjects will be managed in one of two ways:
1) Continue in the study for 48 weeks following the discontinuation
of TAF (Treatment Free Follow-Up, TFFU, window of ± 7 days) 
or until an alternative commercially approved CHB treatment is 
started, whichever occurs first
2) Initiate other standard of care CHB therapy immediately at end 
of study. 


GS-9688 
Protocol GS-US-389-2025 
Gilead Sciences, Inc. 
CONFIDENTIAL 
Final 
Amendment 1 
At the PI's discretion, subject(s) in the TFFU phase may initiate 
other standard of care CHB therapy at any time per local treatment 
guidelines. If a subject initiates other standard of care CHB therapy 
for their CHB, TFFU visits will continue for 2 more TFFU visits or 
until the end of the TFFU phase (Week 96), whichever comes first. 
The primaiy analysis will occur after all subjects have completed 
Week 24 assessment post last dose of GS-9688/PTM or prematurely 
discontinued with the prima1y endpoints being the safety and 
tolerability of GS-9688/PTM, as well as assessment of the antiviral 
activity of GS-9688/PTM at Week 24 as measured by the propo1iion 
of subjects with ~l log10 (IU/mL) decline from baseline in sernm 
qHBsAg. 
The study will be unblinded to appropriate Gilead Sciences Inc. 
(GSI) study team personnel at the time of prima1y analysis (Week 24 
assessment). An Internal Data Review, external to the study team, 
may be unblinded at Week 12 assessment visit to review the 
unblinded safety and efficacy data in order to guide strntegic 
decisions regarding the future of the program. Investigators and 
subjects will remain blinded through the end of the study. 
Pharmacokinetic (PK) Assessments 
Spai·se (pre-identified) PK plasma sampling will occur on Day 1 and 
Week 23 at pre-dose, 1, 4, and 24 hours post-dose and at Week 11 at 
pre-dose, 1, and 4 hours post-dose. 
Spai·se (timed) plasma PK samples will be obtained on any two of 
the following visits: Weeks 2, 4, 8, 12, 16, and/or 20 at pre-dose and 
any time between 30 minutes to 4 hours post-dose. 
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Gilead Sciences, Inc. 
Amendment 1
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Number of Subjects 
Planned:
Approximately 65 subjects
Cohort 1 will enroll approximately 40 subjects and Cohort 2 will 
enroll approximately 25 subjects (within each cohort, enrollment 
will be PTM: GS-9688 1.5 mg: GS-9688 3 mg at a ratio of 1:2:2)
Target Population:
Adult subjects with CHB who are viremic and not currently on 
treatment for CHB for at least 3 months.
Duration of 
Treatment:
GS-9688 or PTM will be administered once a week (every 7 days) 
for 24 treatment doses. All subjects will take TAF 25 mg oral daily 
through Week 48.
At Week 48, per PI’s discretion, subjects can continue in the TFFU
phase for up to an additional 48 weeks.
Diagnosis and Main 
Eligibility Criteria:
Inclusion Criteria
Subjects must meet all of the following inclusion criteria to be 
eligible for participation in this study:
1) Must have the ability to understand and sign a written informed 
consent form, which must be obtained prior to initiation of study 
procedures.
2) Adult male and non-pregnant, non-lactating female subjects, 
18-65 years of age inclusive based on the date of the Screening 
visit.
3) Documented evidence of chronic HBV infection 
(e.g., HBsAg positive for more than 6 months) with detectable 
HBsAg levels at Screening.
4) Females of childbearing potential (as defined in Appendix 3) 
must have a negative serum pregnancy test at Screening and a 
negative urine pregnancy test at Baseline prior to enrollment.
5) Male and female subjects of childbearing potential who engage 
in heterosexual intercourse must agree to use protocol specified 
method(s) of contraception as described in Appendix 3
6) Screening HBV Deoxyribonucleic acid (DNA) ≥ 2000 IU/mL.
7) Screening Electrocardiogram (ECG) without clinically 
significant abnormalities and with 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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Exclusion Criteria
Subjects who meet any of the following exclusion criteria are not to 
be enrolled in this study:
1) 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 3 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
2) Received a commercially available HBV OAV treatment(s) 
(tenofovir alafenamide, tenofovir disoproxil fumarate, entecavir,
adefovir dipivoxil, lamivudine, telbivudine, either as single 
agents or in combination) within the 3 months prior to screening.
3) Received prolonged therapy with immunomodulators 
(e.g., corticosteroids) or biologics (e.g., monoclonal antibody, 
interferon) within 3 months of screening
4) Subjects meeting any of the following laboratory parameters at 
screening:
a) Hemoglobin < 12 g/dL (for males) or <11 g/dL (for females)
b) White Blood cell count < 2500 cells/mm3
c) Neutrophil count < 1500 cells/mm3 (or < 1000 cells/mm3 if 
considered a physiological variant in a subject of African 
descent)
d) Alanine aminotransferase (ALT) >5x ULN 
e) International normalized ratio (INR) > ULN unless the 
subject is stable on an anticoagulant regimen affecting INR
f)
Albumin < 3.5 g/dL
g) Direct bilirubin >1.5x ULN


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Gilead Sciences, Inc. 
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h) Platelet Count < 100,000/L
i)
Estimated creatinine clearance (CrCl) < 60 mL/min (using 
the Cockcroft-Gault method) based on serum creatinine and 
actual body weight as measured at the screening evaluation, 
i.e.,
Male:
(140 – Age [years]) (Weight [kg])
CrCl (mL/min)
72 (Serum Creatinine [mg/dL])
Female: (140 – Age [years]) (Weight [kg]) 0.85 CrCl (mL/min)
72 (Serum Creatinine [mg/dL])
5) Co-infection with human immunodeficiency virus (HIV), 
hepatitis C virus (HCV) or hepatitis D virus (HDV)

Subjects who are HCV Ab positive, but have a documented 
negative HCV RNA, are eligible
6) Prior history of hepatocellular carcinoma (HCC) 
(e.g., as evidenced by prior imaging) or screening 
alpha-fetoprotein (AFP) ≥ 50 ng/mL without imaging to rule out 
HCC.
7) 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.
8) Significant cardiovascular, pulmonary, or neurological disease in 
the opinion of the investigator.
9) Diagnosis of autoimmune disease (e.g., systemic lupus 
erythematosus, rheumatoid arthritis, inflammatory bowel 
disease, autoimmune hepatitis, sarcoidosis, psoriasis of greater 
than mild severity, autoimmune uveitis), poorly controlled 
diabetes mellitus, significant psychiatric illness, severe chronic 
obstructive pulmonary disease (COPD), hemoglobinopathy, 
retinal disease, or are immunosuppressed.
10) Chronic liver disease of a non-HBV etiology 
(e.g., Wilson’s disease, hemochromatosis, alpha-1-antitrypsin 
deficiency, cholangitis, nonalcoholic steatohepatitis), except for 
non-alcoholic fatty liver disease.
11) Received solid organ or bone marrow transplant.
12) Use of another investigational agent within 90 days of screening, 
unless allowed by the Sponsor.


GS-9688 
Protocol GS-US-389-2025 
Gilead Sciences, Inc. 
Study Procedures/ 
Frequency: 
CONFIDENTIAL 
Final 
Amendment 1 
13) CmTent alcohol or substance abuse judged by the investigator to 
potentially interfere with subject compliance. 
14) Known hypersensitivity to study drngs or fo1mulation excipients. 
15) Women who are breastfeeding, pregnant or who wish to become 
pregnant during the course of the study. 
16) Female subjects unwilling to refrain from egg donation and in 
vitro fe1iilization dming and until at least 30 days after the last 
study dmg dose. 
17) Male subjects unwilling to refrain from spenn donation dming 
and until at least 90 days after the last study dmg dose. 
18) Use of any prohibited concomitant medications as described in 
Section 5.5 and Table 5-1. 
Believed by the Study Investigator to be inappropriate for study 
pa1iicipation for any reason not othe1wise listed. 
All subjects will be required to participate in the following visits: 
• 
Screening Visit (up to -30 days of Baseline visit) 
• 
On-Treatment Period Visits: Day 1 (includes post-dose 1 and 
4 hom assessments), Day 1 + 24 hours (Day 2), Weeks 2, 4, 8, 
11 (includes post-dose 1 and 4 hom assessments), 12, 16, 20, 
23 (includes post-dose 1 and 4 hour assessments), and 
23 + 24 homs 
• 
Post GS-9688/PTM Study Treatment Period: Weeks 24, 28, 36, 
and48 
Screening assessments include: 
• 
Review of inclusion/exclusion criteria 
• 
Obtain medical histo1y (including HBV disease and treatment 
histo1y) 
• 
Review concomitant medications 
• 
Complete Physical examination (including weight, height, BMI, 
vital signs) 
• 
Safety laborato1y tests (sernm chemistiy, hematology, and 
coagulation) 
• 
12-lead ECG 
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27 August 2019 


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Final
Gilead Sciences, Inc. 
Amendment 1
CONFIDENTIAL
Page 15
27 August 2019

Ophthalmologic exam (Days -10 to -1)

Qualitative HBV serology (HBeAg [reflex Hepatitis B e-Antigen 
(HBeAb) if HBeAg is negative] and HBsAg [reflex Hepatitis B 
surface Antigen (HBsAb) if HBsAg is negative])

HBV DNA levels and resistance surveillance sample

HBV Genotyping by history (if known) and laboratory testing 

Quantitative HBsAg

HCV, HDV and HIV Ab testing (with reflex testing performed if 
positive)

FibroTest 

AFP (Imaging test required to rule out HCC for subjects with 
AFP ≥ 50 ng/mL)

Urinalysis and urine drug screen

For all female subjects of child-bearing potential, serum beta 
human chorionic gonadotropin (β-hCG) 

For female subjects post-menopausal for less than two years, 
serum follicle-stimulating hormone (FSH) testing (if FSH 
< 40 mIU/mL a serum pregnancy test will be required)

Record any serious adverse events and all adverse events related 
to protocol mandated procedures occurring after signing of the 
consent form
On-treatment assessments
All Day 1 (Baseline) tests and procedures must be completed prior 
to the receipt of the first dose of study drug. 
All On-Treatment Assessments (Day 1 through Week 23 +24 hours) 
should be obtained pre-dose unless otherwise indicated:

Review of inclusion/exclusion criteria and confirm medical 
history on Day 1

Complete pre-dose physical examination (includes weight, 
height, BMI, vital signs, concomitant medications and adverse 
events [AEs]) on Day 1 and Weeks 2, 4, 8, and 12. 

Symptom directed physical exam (includes weight, vital signs, 
concomitant medications and AEs) on Day 2, Weeks 11, 16, 20, 
23 and 23 + 24 hours.
CCI


GS-9688 
Protocol GS-US-389-2025 
Gilead Sciences, Inc. 
CONFIDENTIAL 
Final 
Amendment 1 
• 
Ophthahnologic exam on Week 12 (Days -4 to +10) 
• 
In clinic GS-9688/PTM study drng dosing on Day 1 and 
Weeks 2, 4, 8, 11, 12, 16, 20, and 23. Self/Home GS-9688/PTM 
study drng dosing on Weeks 1, 3, 5, 6, 7, 9, 10, 13, 14, 15, 17, 
18, 19, 21, and 22. Study drng will be taken orally at 
approximately the same time on the same day once a week 
(eve1y 7 days) for 24 doses. 
• 
TAF is to be dosed at approximately the same time daily with 
food or, in jurisdictions in which T AF has been approved, 
consult the local prescribing infonnation for T AF dose 
recommendations with concomitant medications. Day 2 through 
Week 23, T AF dosing will be no earlier than 2 hours post 
GS-9688/PTM weekly dose. 
• 
Safety laborato1y tests (sernm chemistiy, hematology, and 
coagulation) on Day 1 and Weeks 2, 4, 8, 11, 12, 16, 20, and 23 
• 
Urinalysis on Day 1 and Weeks 2, 4, 8, 11, 12, 16, 20, and 23 
• 
FibroTest on Day 1 
• 
Sernm P-hCG, for all female subjects of child-bearing potential 
on Day 1 and Weeks 4, 8, 12, 16, and 20 
• 
Urine Pregnancy Test, for all female subjects of child-bearing 
potential on Day 1 and Weeks 2 and 11 
• 
HBV DNA and resistance surveillance on Day 1 and Weeks 2, 4, 
8, 11, 12, 16, 20, and23 
• 
Qualitative HBV serology (HBeAg [reflex HBeAb if HBeAg is 
negative] and HBsAg [reflex HBsAb ifHBsAg is negative]) on 
Day 1 and Week 12 
• 
Quantitative HBsAg on Day 1 and Weeks 2, 4, 8, 11, 12, 16, 20, 
I 
I 
I 
and23 
Page 16 
27 August 2019 


GS-9688 
Protocol GS-US-389-2025 
Gilead Sciences, Inc. 
CONFIDENTIAL 
I 
Final 
Amendment 1 
• 
Whole blood gene expression (Paxgene RNA) samples on 
Days 1 Pre-dose, 1 +4 hour, 1 + 24 hours (Day 2) and Weeks 11 
Pre-dose, 11 +4 hours, 12, 23, 23 +4 hours, and 23 + 24 hours 
• 
PBMC samples will be collected on Days 1, 1 + 4 hours, 
I 
1 + 24 hours (Day 2) and Weeks 11 Pre-dose, 11 + 4 hours, 12, 
23, 23 + 4 hours, and 23 + 24 hours 
• 
Sparse (pre-identified) PK plasma sampling will occur on Day 1 
and Week 23 at pre-dose, 1, 4, and 24 hours post-dose and 
Week 11 at pre-dose, 1, and 4 hours post-dose. 
• 
Sparse (timed) plasma PK samples will be obtained on any 
two of the following visits: Weeks 2, 4, 8, 12, 16, and/or 20 at 
pre-dose and any time between 30 minutes to 4 hours post-dose. 
• 
Holter Monitoring: 
I 
I 
Day 1: Pre-dose (:S 5 minutes of dose) through 4 hours, and 
24 hours 
Week 11 : Pre-dose (:S 5 minutes of dose) through 4 hours 
Week 23: Pre-dose (:S 5 minutes of dose) through 4 hours, 
and 24 hours 
• 
Randomization on Day 1 
If a subject chooses to tenninate the study anytime during the 
treatment period, all subjects should complete all of the above 
assessments at the ED visit except for the sparse (pre-identified) 
plasma PK sample. 
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GS-9688 
Protocol GS-US-389-2025 
Gilead Sciences, Inc. 
CONFIDENTIAL 
Final 
Amendment 1 
Post GS-9688/PTM treatment assessments include the following, 
perfonned at all visits from Week 24 through Week 48, or in event 
of ED, unless specifically noted: 
• 
Complete physical examination (includes weight, height, BMI, 
vital signs, concomitant medications and AEs) 
• 
Ophthalmologic exam on Week 24 (Days -4 to +10) 
• 
Safety laborato1y tests (senun chemistiy, hematology, and 
coagulation) 
• 
Urinalysis 
• 
FibroTest on Weeks 24 and 48/ED 
• 
Senun P-hCG, for all female subjects of child-bearing potential 
• 
HBV DNA levels and resistance surveillance samples 
• 
Qualitative HBV serology (HBeAg [reflex HBeAb if HBeAg is 
negative] and HBsAg [reflex HBsAb ifHBsAg is negative]) on 
Weeks 24, 36, and 48/ED 
• 
Quantitative HBsAg 
I 
I 
I 
• 
Whole blood gene expression (P AXgene RNA) samples on 
Weeks 24 and 48/ED 
• 
PBMC samples will be collected on Weeks 24 and 48/ED 
I 
• 
If a subject chooses to tenninate the study anytime during the 
post GS-9688/PTM ti·eatinent period, all subjects should 
complete all of the above assessments at the ED visit. 
Page 18 
27 August 2019 


GS-9688
Protocol GS-US-389-2025
Final
Gilead Sciences, Inc. 
Amendment 1
CONFIDENTIAL
Page 19
27 August 2019
Test Product, Dose, and 
Mode of 
Administration:
GS-9688 will be supplied as tablets in strengths of 1.5 mg. 
Treatment Arm A (PTM): No GS-9688 tablets
Treatment Arm B (GS-9688 1.5 mg): 1 x GS-9688 1.5 mg tablet
Treatment Arm C (GS-9688 3 mg): 2 x GS-9688 1.5 mg tablets 
Study drug(s) will be orally administered at approximately the same 
time, on the same day, once weekly, following an overnight fast 
(no food or drinks, except water, for at least 8 hours with no food or 
drinks, including water, for the 1 hour before dosing). After dosing, 
subjects will continue to fast (no food or drinks, including water) for 
2 hours. After 2 hours postdose, water is allowed and after 4 hours 
postdose, patients are allowed to eat any food or drinks. Subjects 
should take their other prescribed medications no earlier than 
2 hours after GS-9688/PTM dosing or, if medications require dosing 
with food, no earlier than 4 hours after GS-9688/PTM dosing.
Ondansetron dosing is allowed around GS-9688/PTM dosing; 
dosing of other antiemetics should be discussed with the Gilead MM 
for approval.
TAF will be supplied as a tablet (25 mg) to be given orally at 
approximately the same time once daily with food or, in jurisdictions
in which TAF has been approved, consult the local prescribing 
information for TAF dose recommendations with concomitant 
medications for 48 weeks.
Reference Therapy, 
Dose, and Mode of 
Administration:
PTM GS-9688 tablets will also be supplied and will be identical in 
size, shape, color and appearance to the active GS-9688 tablets.
Treatment Arm A (PTM): 2 x PTM tablets
Treatment Arm B (GS-9688 1.5 mg): 1 x PTM tablet
Treatment Arm C (GS-9688 3 mg): No PTM tablets 
All study treatments will be administered in the same manner, as 
described above. 
Criteria for Evaluation:
Safety:
Safety will be evaluated by assessment of clinical laboratory tests, 
ECGs/Holter monitoring, periodic physical examinations including 
vital signs at various time points during the study, including the 
TFFU Phase, and by documentation of AEs and concomitant 
medications.
An independent, external Data Monitoring Committee (DMC) will 
review the progress of the study and perform safety data review after


GS-9688 
Protocol GS-US-389-2025 
Gilead Sciences, Inc. 
CONFIDENTIAL 
Final 
Amendment 1 
20 subjects have completed randomization. Subsequent meetings 
may be held approximately eve1y 3 months until the last subject 
enrolled has completed the GS-9688/PTM study diug dosing period. 
The DMC will provide recommendations as needed regarding study 
conduct and the need for additional meetings or an alternative 
meeting schedule. The DMC will be immediately notified in the 
event of any dose limiting toxicities (DLT). 
Grade 3 and 4 clinically significant laborato1y abnonnalities, ALT 
elevations meeting definition of ALT flare or dose-limiting flare, 
and Grade 2 neutropenia should be confnmed by repeat testing 
within 7 calendar days of receipt of results. 
Management of Dose Limiting Toxicities 
In the event of any DLT, the investigator should discuss with the 
Gilead Medical Monitor the subject's status until the DLT has 
resolved. 
GS-9688/PTM dosing for a subject will be held if the subject 
experiences at least one of the following DLTs: 
• 
A confin ned, clinically significant lab abno1mality ( other than 
ALT) :::: Grade 3 considered dmg-related by the investigator or 
Sponsor 
• 
Dose-limiting ALT flare defined as confnmed ALT :::: lOx ULN 
Page 20 
27 August 2019 


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Final
Gilead Sciences, Inc. 
Amendment 1
CONFIDENTIAL
Page 21
27 August 2019
If a subject experiences any of the above DLTs, then GS-9688/PTM 
will be held until repeat labs demonstrate that the lab abnormality 
returns to ≤ Grade 2 levels. Once the lab abnormality returns to 
≤Grade 2, GS-9688/PTM can be restarted with Gilead Medical 
Monitor consultation. Subjects who experience a dose interruption 
DLT will continue to be monitored at least once a week, or more 
frequently as clinically needed, until resolution.
GS-9688/PTM dosing for a subject will be permanently discontinued
if the subject experiences at least one of the following DLTs:

A confirmed ALT increase (i.e., grade shift or 2x previous value) 
with evidence of worsened hepatic function (e.g., Total Bilirubin 
> 2mg/dL above BL, elevated INR ≥ 1.7 or > 0.5 over BL, 
abnormal serum albumin > 1g/dL decrease from BL)

Prolonged (2 sequential), confirmed, clinically significant lab 
abnormality (other than ALT) ≥ Grade 3 considered drug-related 
by the investigator

Any confirmed recurrence of study drug-related Grade 3 or 
4 clinically significant laboratory adverse event following dose 
interruption mandates permanent discontinuation of study drug.

A confirmed ≥ Grade 3 AE (excluding ALT) considered 
drug-related by the investigator
Subjects who experience a permanent discontinuation DLT will be 
monitored at least once a week, or more frequently as clinically 
needed, until resolution.
Refer to Section 7.6.3 for TAF dose modification and monitoring 
guidelines.
Other Criteria for Discontinuation of Study Drug

Intercurrent illness that would, in the judgment of the 
investigator, affect assessments of clinical status to a significant 
degree

Unacceptable toxicity, as defined in the toxicity management
Section 7.6 of the protocol, or toxicity that, in the judgment of 
the investigator, compromises the ability to continue 
study-specific procedures or is considered not to be in the 
subject’s best interest

Subject requests to discontinue for any reason

Subject noncompliance

Pregnancy during the study; refer to Appendix 3


GS-9688
Protocol GS-US-389-2025
Final
Gilead Sciences, Inc. 
Amendment 1
CONFIDENTIAL
Page 22
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
Investigator discretion

Discontinuation of the study at the request of Gilead, a 
regulatory agency or an institutional review board (IRB) or 
independent ethics committee (IEC).

Continuation of dosing will be suspended if three or more 
Grade 3 or two or more Grade 4 treatment-emergent, drug 
related AEs or laboratory abnormalities occur. Decisions to 
reinitiate continuation of dosing will be made by the Sponsor 
upon review of all safety data generated by subjects dosed to 
date.
Efficacy:
The primary efficacy endpoint is:

Proportion of subjects with ≥1 log10 IU/mL decline in serum 
qHBsAg from baseline at Week 24
The secondary efficacy endpoints are: 

Proportion of subjects with ≥ 1 log10 IU/mL decline in serum 
qHBsAg from baseline at Weeks 4, 8, 12 and 48

Change in serum qHBsAg (log10 IU/mL) from baseline at 
Weeks 4, 8, 12, 24 and 48

To evaluate the proportion of subjects with HBV DNA <LLOQ 
at Weeks 12, 24, and 48

Proportion of subjects with HBsAg loss at Weeks 12, 24 and 48

Proportion of subjects with HBeAg loss and seroconversion at 
Weeks 12, 24 and 48

Proportion of subjects with virologic breakthrough
(2 consecutive visits of HBV DNA ≥ 69 IU/mL)

Proportion of subjects with drug resistance mutations
Statistical Methods:
Safety endpoints will be analyzed by treatment arm by the number 
and percentage of subjects with AE or laboratory abnormalities for 
categorical values or by the 8-number summary (n, mean, SD, 
median, Q1, Q3, minimum, and maximum) for continuous data.
The primary efficacy endpoint is the proportion of subjects with 
≥1 log10 IU/mL decline in qHBsAg from Baseline at Week 24. The 
primary analysis will be performed in all randomized and treated 
subjects after the last subject has completed Week 24 assessments or 
discontinued prematurely. To compare the GS-9688 1.5 mg group 
and the GS-9688 3 mg group to the PTM group for HBeAg positive


GS-9688
Protocol GS-US-389-2025
Final
Gilead Sciences, Inc. 
Amendment 1
CONFIDENTIAL
Page 23
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and negative subjects separately, the 95% confidence intervals (CI)
on the proportion difference (1.5 mg – PTM, 3 mg - PTM) will be 
constructed, by baseline HBeAg status (positive, negative), based on 
the standardized statistic and inverting 2 1-sided tests. 
The secondary endpoints include the proportion of subjects with 
≥1 log10 IU/mL decline in HBsAg from baseline at Weeks 4, 8, 
12 and 48; the proportion of subjects with HBV DNA <LLOQ at 
Weeks 12, 24, and 48; the proportion of subjects with HBsAg loss; 
the proportion of subjects with HBeAg loss and seroconversion; the 
change in log10 qHBsAg from baseline; the proportion of subjects 
with virologic breakthrough; the proportion of subjects with drug 
resistance mutations; and the PK parameters. Analysis of secondary 
efficacy endpoints will be performed by treatment group by baseline 
HBeAg status (positive, negative). 
All continuous efficacy endpoints will be summarized using an 
8-number summary (n, mean, standard deviation (SD), median, 
Quartile (Q1, Q3, minimum, and maximum). All categorical 
secondary endpoints will be summarized by number and percentage 
of subjects who meet the endpoint.
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 arm 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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Final
Gilead Sciences, Inc. 
Amendment 1
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Page 24
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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
%AUCexp
percentage of AUC extrapolated between AUClast and AUCinf
C 
degrees Celsius
F
degrees Fahrenheit
Ab
Antibody
AE
adverse event
AFP
alpha-fetoprotein
ALT
alanine aminotransferase (previously serum glutamic pyruvic transaminase)
ANOVA
analysis of variance
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
BCRP
breast cancer resistance protein
BID
twice daily, two a day
BL
baseline
BLQ
below limit of quantitation
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
CL/F
apparent oral clearance after administration of the drug:
CL/F = Dose/AUCinf, where “Dose” is the dose of the drug
Clast
last observed quantifiable concentration of the drug
CrCl
creatinine clearance
Cmax
maximum observed concentration of drug
COPD
chronic obstructive pulmonary disease
CPN
chronic progressive nephropathy
CRF
case report form
CRO
clinical research organization
CSR
clinical study report


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Gilead Sciences, Inc. 
Amendment 1
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Ctau
observed drug concentration at the end of the dosing interval
CYP
cytochrome
cccDNA
covalently closed circular DNA
DDI
drug-drug interaction
DLT
dose limiting toxicity
DMC
Data Monitoring Committee
DNA
Deoxyribonucleic acid
DSPH
Drug Safety and Public Health
EASL
European Association for the Study of the Liver
ECG
electrocardiogram
eCRF
electronic case report form
ED
early discontinuation
EDC
electronic data capture
eGFR
estimated glomerular filtration rate
ELISPOT
enzyme-linked immunosorbent spot assay
eSAE
electronic serious adverse event
ET
early termination
EU
European Union
FDA
Food and Drug Administration
FE
food effect
FIH
first-in-human
FSH
Follicle-Stimulating Hormone
GCP
Good Clinical Practice
Gilead
Gilead Sciences, Inc.
GLSM
geometric least-squares mean
GLP
Good Laboratory Practice
GSI
Gilead Sciences, Inc.
HAV
hepatitis A virus
HBcrAg
hepatitis B core-related antigen 
HBeAg
hepatitis B e antigen
HBsAg
hepatitis B surface antigen
HBeAb
hepatitis B e antibody
HBsAb
hepatitis B surface antibody
HBV
Hepatitis B virus
HCC
hepatocellular carcinoma
HCV
hepatitis C virus
HDV
hepatitis D virus
HED
human equivalent doses
HEV
hepatitis E virus
HDL
high-density lipoprotein


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Final
Gilead Sciences, Inc. 
Amendment 1
CONFIDENTIAL
Page 26
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HDPE
high-density polyethylene
HIV
human immunodeficiency virus
HLGT
high-level group term
HLT
high-level term
HRQoL
Health Related Quality of Life
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 
IgM
immunoglobulin M
IL
interleukin
IMP
investigational medicinal product
IND
investigational new drug (application)
IRB
institutional review board
IMRS
Interactive Mobile Response System
IUD
intrauterine device
IWRS
Interactive Web Response System
IXRS
Interactive Response System
kg
kilogram
LDH
Lactic acid dehydrogenase
LDL
low-density lipoprotein
LLT
lower-level term
LLOQ
lower limit of quantitation
MARCO
macrophage receptor with collagenous structure
MCV
mean corpuscular volume
mDC
myeloid dendritic cells
MedDRA
Medical Dictionary for Regulatory Activities
MM
medical monitor
NDA
new drug application
NK
natural killer
NOAEL
no observed adverse effect level
NSAID
Nonsteroidal Anti Inflammatory Drug
OAV
oral antiviral
PBMC
peripheral blood mononuclear cell
PCTFE
Polychlorotrifluoroethylene
PD
pharmacodynamic(s)
PD-1
programmed cell death protein 1


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Protocol GS-US-389-2025
Final
Gilead Sciences, Inc. 
Amendment 1
CONFIDENTIAL
Page 27
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PEG
pegylated interferon-α
PG
Pharmacogenomics
P-gp
p-glycoprotein
PHH
primary human hepatocytes
PI
principal investigator
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
PVC
Polyvinyl chloride
PVE
Pharmacovigilance and Epidemiology
QD
One a day, once daily
qHBsAg
quantitative hepatitis B surface antigen
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
RNA
Ribonucleic acid
SAD
single ascending dose
SADR
serious adverse drug reaction
SAE
serious adverse event
SNP
single nucleotide polymorphism
SOC
system organ class
SOP
standard operating procedure
SUSAR
suspected unexpected serious adverse reaction
TAF 
tenofovir alafenamide /Vemlidy®
TEAE
treatment-emergent adverse event
TFFU
Treatment Free Follow-Up
Tlast
time (observed time point) of Clast
Tmax
the time (observed time point) of Cmax
TG
Triglyceride
TLR
Toll-like receptor
TNF
Tumor necrosis factor
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)
UGT
UDP glucoronosyl transferase 


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ULN
upper limit of normal
Vz/F
apparent volume of distribution of the drug
WBC
white blood cell
WHO
World Health Organization
WHV
Woodchuck hepatitis virus
WHsAg
Woodchuck hepatitis surface antigen


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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 {World Health 
Organization (WHO) 2015, 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 2015, an 
estimated 654,000 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 2016}.
The loss of HBsAg, accompanied by seroconversion to anti-HBsAg, is the accepted endpoint for
anti-HBV therapy endorsed by the American Association for the Study of Liver Diseases, the
European Association for the Study of the Liver, and the Asian Pacific Association for the Study
of the Liver allowing for cessation of therapy {European Association for the Study of the Liver 
2017, European Association for the Study of the Liver (EASL) 2012, Lok 2009, Sarin 2015, 
Terrault 2016}. Clearance of HBsAg has been associated with improvements in liver histology, 
including the reversal of cirrhosis, a decreased risk of HCC, and prolonged survival, and is 
considered evidence of a functional cure {Benias 2011, Fattovich 1998, Kim 2013}.
Nucleos(t)ide analogs are the standard-of-care for CHB treatment, providing durable suppression
of viral replication that results in long-term clinical benefits with a reduced risk of liver
complications {Dienstag 2003, Liaw 2011, Lok 2013}. However, treatment with nucleos(t)ide
inhibitors rarely results in clearance of HBsAg and seroconversion to anti-HBsAg {Kwon 2011}.
Thus, new treatment options that enhance rates of HBsAg clearance and seroconversion are
needed; such treatments will allow patients to discontinue life-long oral antiviral therapy and
provide a finite-duration treatment option for a functional cure. A finite therapy is expected to be
applicable to a broader population of those chronically infected with HBV, including
immunotolerant patients who are currently untreated.


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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 natural killer (NK) cell antiviral function {Peppa 
2010, Rehermann 2005}.
Toll-like receptors (TLRs) are a family of membrane-bound pattern recognition receptors that
play a central role in both innate and adaptive immunity by recognition of pathogen-associated
molecular patterns from microorganisms {O'Neill 2013}. TLR8 is a transmembrane receptor
located in the endosomal membrane of a subset of immune cells and recognizes single-stranded
RNA. Published studies have demonstrated that TLR8 activates innate and adaptive effector cell
immune responses {Du 2010, Gorski 2006, Jo 2014, Lu 2012, Peng 2005, Wille-Reece 2006}.
Activation of TLR8 by a selective, oral, small-molecule agonist with good absorption and high
first-pass hepatic clearance to limit systemic activation is therefore a rational approach to safely
induce effective antiviral immunity in CHB patients and drive functional cure.
1.2.
GS-9688
1.2.1.
General Information
GS-9688 is a novel, potent, and selective small molecule agonist of TLR8. GS-9688 directly 
binds the ectodomain of TLR8 and activates human TLR8 with > 100-fold selectivity over 
human TLR7. In human peripheral blood mononuclear cells (PBMCs), GS-9688 induces the 
production of the cellular immune mediator interleukin (IL)-12 and the antiviral cytokines tumor 
necrosis factor (TNF)-α and interferon (IFN)-γ, but has minimal effects on the levels of IFN-α, a 
TLR7-induced cytokine. GS-9688 induces cytokine production in myeloid dendritic cells (mDC)
and monocytes, but not plasmacytoid dendritic cells; activates natural killer (NK) cells and total 
CD8+ T cells in vitro in PBMCs isolated from both healthy donors and CHB patients; and 
increases IFN-γ production and reduces expression of the inhibitory receptor programmed cell 
death protein 1 (PD-1) by HBV-specific CD8+ T cells. Collectively, these data demonstrate the 
selectivity and activity of GS-9688 for TLR8 in human primary immune cells.
For further information on GS-9688 refer to the Investigator’s Brochure (IB).
1.2.2.
Preclinical Pharmacology and Toxicology
GS-9688 has been characterized in repeat-dose oral (once weekly) toxicity studies of up to 
26-weeks (27 doses) in mice and 39-weeks (40 doses) in cynomolgus monkeys, genetic 
toxicology, and phototoxicity studies. The mouse was selected based on its PK properties and 
previous experience with TLR agonists. In rodents, TLR8 agonists activate TLR7 but not TLR8, 
and induce a broader immune response than is expected in humans {Hemmi 2002, Liu 2010}. 
Female mice were used in nonpivotal studies as TLR8 is X-linked {Chuang 2000}; however, no 
gender-specific toxicities have been observed in repeat-dose toxicity studies with GS-9688. The 
monkey is the closest pharmacologically relevant species to human for TLR8 activity. Consistent 
with the intended route of administration in humans, in vivo toxicity studies were conducted by 


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the oral route of administration. Study designs and parameters evaluated were consistent with 
accepted principles and practices as outlined by the International Conference on Harmonization 
(ICH), Organization for Economic Cooperation and Development, and national regulations 
United States (US) Food and Drug Administration [FDA] and European Community Directives). 
Unless otherwise noted, all studies were conducted in accordance with US FDA Good 
Laboratory Practice (GLP) regulations.
In the initial dose range-finding study (2 doses, on Days 1 and 8) studies, mortality in mice was 
observed following a single dose at 1000 mg/kg due to general debilitation. In the chronic 27 dose 
study in mice, early mortality was observed in 6 mice administered 30 mg/kg/week, which 
correlated to an exposure margin of >1400-fold the projected 3 mg clinically efficacious dose.
Ocular
In the 4 week, 5 dose, study in monkeys, early termination (Day 11) of the 300 mg/kg/week group 
was due to GS-9688-related ocular toxicity and clinical signs of pain/distress associated with these 
findings. A dose-related bilateral inflammation of the anterior segment of the eyes was observed 
in 2 of 8 animals in each of the 30 and 100 mg/kg/week groups following ophthalmic evaluation. 
Changes were partially or completely resolved between each dose at 30 mg/kg/week and in 
1 of the 2 animals administered 100 mg/kg/week. In one male at 100 mg/kg/week the 
inflammatory response progressively worsened and was considered adverse. In the 39 week, 
40 dose (30 mg/kg), study in monkeys, 3 of 20 animals administered 30 mg/kg presented with 
findings consistent with an intraocular inflammatory response. The findings were generally mild, 
occurred at a low incidence, and/or were self-limiting. In addition, no findings were observed in 
any animals after the 13-week interim necropsy. The no observed adverse effect level (NOAEL)
for ocular findings in the monkey was 30 mg/kg/week. Similar findings have previously been 
described for another small molecule TLR8 agonist (VTX-2337; motolimod) in non-human 
primates, but have not been observed clinically {Northfelt 2014}.
No ocular findings were noted in mice at any dose level. 
Immunomodulation
Adverse, GS 9688-related, histopathology changes were observed in the kidney, esophagus, 
thymus, spleen, mesenteric lymph node, mandibular salivary gland, Harderian gland, and/or 
lacrimal gland of mice administered 30 mg/kg/week in the 27 dose study. Findings with marked 
severity included: mononuclear cell infiltrates in the kidney, Harderian gland, mandibular 
salivary gland, and lacrimal gland; fibroplasia in the esophagus; vessel inflammation in the 
mandibular salivary gland; lymphoid cellularity in thymus and spleen; lymphocyte necrosis in 
the mesenteric lymph node (males); and moderate and marked severity of chronic progressive 
nephropathy (CPN) in the kidney. In addition, glomerulonephritis was noted in 2 females. With 
the exception of CPN, all findings were partially reversed or not observed at the end of the 
4-week recovery. As a result of inflammatory findings in the 27 dose study, the NOAEL was 
10 mg/kg/week.


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In monkeys, multisystemic inflammatory cell infiltrates were noted in the 4-week, 5 dose study 
in the brain and liver at ≥30 mg/kg/week. In the brain, findings of perivascular mononuclear cell 
infiltrates and/or choroid plexus inflammation at 30 mg/kg/week were of increased incidence 
and/or severity compared with vehicle administered animals. In addition, microgliosis was noted 
in females administered 100 mg/kg/week. These findings were considered adverse in the 
monkeys at ≥100 mg/kg/week. Inflammatory cellular infiltrates were limited to the liver, 
gastrointestinal tract, and/or thymus following chronic dosing in the 40 dose study. All changes 
were considered non-adverse and exhibited reversibility at the end of the recovery phase. Due to 
the progressive inflammatory infiltrates in the brain at the 100mg/kg/week in the 4-week study 
and the lack of adverse changes in the 40 dose study, the NOAEL for immumodulation was 
considered to be 30 mg/kg/week.
GS-9688 is intended for oral administration and evaluation of local tolerance for this route was 
conducted during the repeat dose studies. There were no treatment-related gastrointestinal effects 
observed in mice. Emesis was noted at ≥ 10 mg/kg in cynomolgus monkeys; however these 
observations had no adverse effect on the health of the animals. In addition sporadic findings 
from male monkeys administered 300 mg/kg/week (terminated early) that were potentially 
GS-9688 related included occasional fibrin thrombi in the villus lymphatics of the duodenum, 
jejunum, and/or ileum.
GS-9688 administration is not considered to result in phototoxicity.
At the projected efficacious clinical dose of 3 mg, the anticipated margin of exposure based on 
the NOAELs in mice and cynomolgus monkey compared to the estimated human exposure 
AUC0-24 (0.56 ng•h/mL) in virally suppressed CHB subjects is 332- and 64-fold, respectively.
1.2.3.
Genotoxicity
GS-9688 was negative in the bacterial reverse mutation (Ames) assay. GS-9688 was considered 
negative for inducing chromosomal aberrations when tested with and without metabolic 
activation up to the limit dose level or limits of cytotoxicity. In addition, GS-9688 was negative 
in the in vivo rat bone marrow micronucleus assay at exposures of up to 5400-fold the human 
exposure (AUC0-24) of 0.56 ng•h/mL at the projected 3 mg clinically efficacious dose; therefore, 
GS-9688 was considered non-genotoxic.
1.2.4.
Safety Pharmacology
To support the proposed clinical development plan, the nonclinical safety profile of GS-9688 
was characterized in studies evaluating the potential pharmacologic effects on specific organ 
systems. Study designs and parameters evaluated were consistent with accepted principles and 
practices as outlined by the ICH and the US FDA Center for Drug Evaluation and Research. All 
studies were conducted in accordance with ICH GLP regulations.
In safety pharmacology studies, there were no clinically-relevant effects on the central nervous
and respiratory systems in mice at exposures approximately 2900-fold above the estimated 
human protein-free Cmax of 0.015 ng/mL at the projected 3 mg clinical efficacious dose.


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In telemetered cynomolgus monkeys, no adverse cardiovascular effects were noted at doses up to 
100 mg/kg. A non-dose dependent increase in heart rate (up to 43%) was noted 2-4 hours post 
dose. These changes in heart rate can be correlated with elevated inflammatory biomarkers
associated with TLR8 agonists {Northfelt 2014} and have been associated with increased resting 
heart rate {Whelton 2014}. Minimal body temperature changes at 100 mg/kg, resulting from a 
lack of decrease during the post dose dark cycle were noted at 100 mg/kg and are possibly an 
exacerbation of stress associated with emesis noted at this dose level (2 of 4 animals). Changes 
were not considered adverse and could potentially be secondary pharmacodynamic effects of 
TLR8 stimulation with GS-9688. Based on the Day 1 protein-free Cmax (1.0 ng/mL, males) in the 
4-week (5 dose) study in cynomolgus monkeys, the NOAEL dose was at least 67-fold above the 
estimated human protein-free Cmax of 0.015 ng/mL at the projected 3 mg dose.
There was no evidence of significant inhibition of the hERG potassium channel current by 
GS-9688.
Pretreatment with anti-emetic agents (ondansetron or compazine) or a Nonsteroidal 
Anti-Inflammatory Drug (NSAID) (ibuprofen) did not substantially alter the PD response to 
GS-9688 in healthy cynomolgus monkeys.
1.2.5.
Nonclinical Pharmacology 
GS-9688 activates NK cells in vitro in PBMCs from healthy donors and CHB patients. GS-9688 
also increases the expression of the activation marker CD40 in human mDCs and monocytes in 
vitro, suggesting that GS-9688 has the potential to augment antigen-specific CD8+ T cell 
responses by enhancing antigen presentation. GS-9688 activates total CD8+ T cells in vitro in 
PBMCs from healthy donors and CHB patients. GS-9688 increases IFN-γ production while 
reducing expression of PD-1 by HBV-specific CD8+ T cells in vitro, suggesting that GS-9688 
has the potential to restore the functionality of HBV specific CD8+ T cells in vivo.
In HBV-infected primary human hepatocytes (PHH), GS-9688 does not have direct antiviral 
activity, consistent with the lack of TLR8 expression in this cell type. In contrast, cytokines 
produced by GS-9688-treated PBMCs reduce the levels of HBV DNA, RNA, HBsAg, and 
hepatitis B e antigen (HBeAg). This antiviral activity is comparable for all HBV genotypes 
tested (A, B, and D) and in PHH from multiple donors. GS-9688 induced cytokines do not 
reduce viral cccDNA levels in PHH with established HBV infection, but treatment of PHH prior 
to HBV infection blocks cccDNA establishment. These data suggest that GS-9688 has the 
potential to produce cytokines that inhibit established HBV infection and prevent HBV infection 
of hepatocytes in vivo.
GS-9688 is a selective agonist of woodchuck TLR8. Administration of 3 mg/kg GS-9688 to 
woodchucks chronically infected with Woodchuck hepatitis virus (WHV) led to a reduction of 
serum WHV DNA (2.8 to 7.4 log10) and Woodchuck hepatitis surface antigen (WHsAg)
(2.2 to > 4.6 log10) in 4 of 6 animals. This response was sustained in 3 animals until the end of 
the study (24 weeks after the end of treatment). These 3 animals had > 95% reduction in 
intrahepatic WHV covalently closed circular DNA (cccDNA), DNA, and RNA at the end of the 
study. These 3 animals also had detectable anti-WHsAg antibodies and an enhanced 


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WHV-specific T cell response upon GS-9688 treatment. Doses of 3 mg/kg GS-9688 were 
generally well tolerated in WHV infected woodchucks.
GS-9688 induces a comparable cytokine response in PBMCs from cynomolgus monkeys and 
humans, albeit with 10-fold lower potency in cynomolgus monkey PBMCs. In healthy 
cynomolgus monkeys, oral administration of GS-9688 induces dose-dependent induction of 
serum IL-12p40, as well as whole-blood macrophage receptor with collagenous structure 
(MARCO) mRNA. The minimum pharmacologically active dose for oral GS-9688 in 
cynomolgus monkeys is 0.3 mg/kg.
GS-9688 exhibits minimal cytotoxicity (CC50 from 4.6 to > 44 μM) in human MT-4 
lymphoblastoid T-cells, hepatoma-derived Huh7 cells, galactose-adapted HepG2 cells, galactose 
adapted PC-3 prostate cancer cells, normal human fetal lung fibroblast MRC5 cells, primary rat 
NRVMs, PHHs, and human PBMCs from healthy donors. This corresponds to a selectivity index 
of 49-fold to > 473-fold relative to the IL-12p40 EC50 in PBMCs. GS-9688 did not show any 
mitochondria-specific inhibition.
Molecular target screening studies showed that GS-9688 had no activity against a panel of 
87 receptors, ion channels, and transporters when tested at a concentration of 10 μM.
In summary, the preclinical pharmacology profile of GS-9688 supports its clinical investigation 
as a novel agent for the treatment of CHB.
1.2.6.
Clinical Trials of GS-9688
1.2.6.1.
GS-US-389-2021
Study GS-US-389-2021 was a first-in-human (FIH), randomized, blinded, placebo-controlled, 
single ascending dose study of GS-9688 in healthy male and female subjects. The primary 
objective of the study was to evaluate the safety, tolerability and PK of escalating doses of 
GS-9688 as well as evaluate the effect of food on GS-9688 PK. The effect of GS-9688 on PD 
markers was also explored.
This FIH study comprised four single ascending dose cohorts (each cohort with 12 active/3 placebo)
and one food effect cohort that assessed GS-9688 PK administered under fasted and fed 
conditions (N=12 active subjects). Doses evaluated were 0.5, 1.5, 3, and 5 mg GS-9688 and the 
food effect cohort evaluated 1.5 mg GS-9688. For all cohorts, subjects were followed for 14 days 
following the last dose of GS-9688 and evaluated for safety through the reporting of AEs, 
physical examination and clinical laboratory test findings, and measurement of
electrocardiograms (ECGs), vital signs, and ophthalmologic exams.
The treatment was generally safe. There were no Grade 3 or 4 AEs or serious adverse events 
(SAEs) reported. No significant alterations in vital signs, ECGs, or ophthalmologic exams were 
noted in any cohort. No individual subject discontinued due to AEs or laboratory abnormalities 
and most AEs were mild (Grade 1). The single treatment-emergent, treatment-related Grade 2 
AE was exacerbation of intermittent diarrhea in one subject who received GS-9688 1.5 mg as a 
single dose. 


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There were no Grade 3 or higher laboratory abnormalities in any cohort. In the 0.5 mg single 
dose cohort, there were 3 treatment-emergent transient Grade 2 lab abnormalities (lipase in a 
single subject and cholesterol and low density lipoprotein (LDL) in another subject). In the 
1.5 mg single dose cohort, there were 2 treatment-emergent Grade 2 lab abnormalities (LDL and 
cholesterol, all in a single subject). In the 5 mg single dose cohort, there were 2 subjects with 
treatment-emergent transient Grade 2 ALT elevation and 1 subject with treatment-emergent 
transient Grade 1 ALT elevation. 
PK data following administration of single doses of GS-9688 at 0.5 mg, 1.5 mg, 3 mg and 5 mg 
under fasted conditions are shown in Table 1-1. GS-9688 was absorbed quickly following single 
fasted oral doses with the maximum plasma concentrations (Cmax) occurring between 0.5 and 
1.25 hours (median Tmax). Less than dose proportional increases in exposure were observed 
between 0.5 and 1.5 mg dose levels; GS-9688 exhibited dose proportional PK between 1.5 mg 
and 5 mg doses. Median t1/2 at 1.5 mg, 3 mg and 5 mg doses was approximately 5 hours. 
Table 1-1.
GS-US-389-2021: GS-9688 Plasma Pharmacokinetic Parameters by 
Treatment Following Single-Dose Administration of GS-9688 in the 
Fasted State (Cohorts 1 to 4) (GS-9688 PK Analysis Set)
GS-9688 PK 
Parameter
Mean (%CV)
GS-9688
0.5 mg
(N = 12)
GS-9688
1.5 mg
(N = 12)
GS-9688
3 mg
(N = 12)
GS-9688
5 mg
(N = 12)
AUClast (h•pg/mL)
97.4 (44.4)
152.6 (75.8)
494.9 (53.2)
825.3 (37.6)
AUCinf (h•pg/mL)
124.2 (39.4)
160.3 (72.9)
507.5 (52.2)
847.9 (38.0)
Cmax (pg/mL)
36.4 (111.5)
52.9 (83.0)
165.3 (92.6)
258.1 (55.9)
Tmax (h)a
0.50 (0.50, 1.00)
0.75 (0.50, 1.00)
0.75 (0.50, 1.01)
1.00 (0.50, 2.25)
t1/2 (h)a
11.28 (8.37, 19.94)
4.28 (2.94, 5.03)
4.91 (4.22, 5.55)
5.05 (4.66, 5.81)
a
Values are presented as median (Q1, Q3). Means presented are unadjusted arithmetic means. N is the number of subjects in 
the PK Analysis Set.
PK data summarizing the effect of moderate fat meal on the pharmacokinetics of GS-9688 
1.5 mg are shown in Table 1-2.
Food slowed the rate of absorption of GS-9688 (median Tmax: 05 hours versus 1.5 hours) without 
a substantial change in bioavailability, as evidenced by comparable plasma exposures (AUC and 
Cmax) upon fed and fasted administration. These results suggest that pharmacokinetics of 
GS-9688 is not substantially altered by food.


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Table 1-2.
GS-US-389-2021: GS-9688 Plasma Pharmacokinetic Parameters by 
Treatment Following Single-Dose Administration of GS-9688 in the 
Fasted and Fed States (Cohort 6) (GS-9688 PK Analysis Set)
GS-9688 PK Parameter
Mean (%CV)
GS-9688
1.5 mg Fed
(N = 12)
GS-9688
1.5 mg Fasted
(N = 12)
AUClast (h•pg/mL)
268.0 (65.0)
220.8 (76.2)
AUCinf (h•pg/mL)
279.0 (62.9)
236.9 (70.2)
Cmax (pg/mL)
87.2 (83.8)
92.5 (129.9)
Tmax (h)a
1.50 (0.75, 1.75)
0.50 (0.50, 1.00)
t1/2 (h)a
5.18 (4.00, 5.78)
4.91 (4.66, 6.84)
a
Values are presented as median (Q1, Q3). Means presented are unadjusted arithmetic means. N is the number of subjects in 
the PK Analysis Set.
IL-12p40, IL-1RA, and MARCO gene expression were evaluated as PD markers of GS-9688 
pharmacological activity. IL-12p40 and IL-1RA serum concentrations increased after GS-9688 
treatment, with peak concentrations occurring approximately 4 hours postdose. Generally, 
IL-12p40 and IL-1RA concentrations increased with increasing GS-9688 dose. Increases in 
IL-12p40 and IL-1RA concentrations were smaller following fed-state treatment compared with 
fasted-state treatment. Whole blood MARCO gene expression following administration of 
GS-9688 0.5 mg remained generally constant, with a transient dose-dependent decrease in 
expression 2 hours postdose.
1.2.6.2.
GS-US-389-2022
Study GS-US-389-2022 is a randomized, blinded, placebo-controlled, multiple-dose, 
dose-escalation Phase 1b study evaluating the safety, tolerability, pharmacokinetics and 
pharmacodynamics of GS-9688 in Patients with CHB. 
This study consisted of four cohorts: Cohort 1 (evaluating 1.5 mg/placebo to match (PTM), 
n=10), Cohort 2 (evaluating 1.5 mg/PTM, n=9) and Cohort 4 (evaluating 3 mg/PTM, 
n=10),GS-9688 or placebo to match was administered in the fasted state once a week 
(every 7 days) for 2 treatment doses; Cohort 5 (evaluating 3 mg/PTM, n=9), GS-9688 or placebo 
to match was administered in the fasted state once a week (every 7 days) for 4 treatment doses. 
Cohorts 3 and 6 were not initiated. For Cohorts 1,2, and 4, subjects were followed for up to 
28 days and for Cohort 5 subjects were followed for up to 21 days following the last dose of 
GS-9688 and evaluated for safety by assessment of clinical laboratory tests, electrocardiograms 
(ECGs), periodic physical examinations including vital signs, ophthalmic examinations, and by 
documentation of AEs and concomitant medications.
Single and multiple doses of GS-9688 were generally safe when administered to subjects with 
CHB who were virally suppressed or viremic. Roughly half of subjects (20 of 38 subjects, 
52.6%) had at least 1 AE, the majority of these subjects (15 subjects, 75%) reported only Grade 1 
AEs. AEs were observed in all treatment groups except for the viremic (2 doses) placebo group.


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Across all subjects, the most commonly reported AEs (ie, AEs reported in ≥ 3 subjects overall) 
were headache, nausea, dizziness, and chills. More AEs were observed in subjects who received 
GS-9688 3 mg compared with GS-9688 1.5 mg or placebo and more AEs were observed for 
virally suppressed subjects who received 4 doses of GS-9688 compared with 2 doses.
Six Grade 2 AEs, including headache, cough, herpes virus infection, nausea, and vomiting, were 
reported for 5 subjects (13.2%) who were virally suppressed (2 subjects, placebo [2 or 4 doses] 
and 3 subjects, GS-9688 3 mg [4 doses]). Fifteen of 38 subjects (39.5%) had an AE considered 
related to study drug by the investigator; of these treatment-related AEs, 4 subjects who were 
virally suppressed (4 doses) had AEs with severity Grade 2 (herpes virus infection [1 subject, 
placebo], nausea and vomiting [reported in 1 subject, GS-9688 3 mg], headache and cough 
[1 subject each, GS-9688 3 mg]).
No Grade 3 or 4 AEs, SAEs, AEs that led to discontinuation or interruption of study drug, or 
deaths were reported.
Overall, 32 of 38 subjects (84.2%) had a graded laboratory abnormality; the majority of these 
subjects (18 subjects, 56.3%) had only Grade 1 laboratory abnormalities and 36.8% (14 of 38) 
had Grade 2 laboratory abnormalities, which were observed in all treatment groups. The most 
frequently reported Grade 2 laboratory abnormalities were increased low-density lipoprotein 
(LDL) cholesterol and hyperglycemia (5 subjects overall for both). All other Grade 2 laboratory 
abnormalities were reported for ≤ 2 subjects overall. No Grade 3 or 4 abnormalities were 
observed.
Two of 8 viremic subjects who received GS-9688 3 mg reported treatment-related Grade 1 AEs 
of pyrexia; no other notable changes in vital signs (systolic blood pressure, diastolic blood 
pressure, pulse, respiration rate, and temperature) or ECGs were reported. One Grade 1 
ophthalmic AE of anterior cell trace was incidentally found on eye exam on Day 9 with no other 
corresponding ophthalmic AE; the AE was considered study drug-related and resolved by 
Day 21.
Table 1-3 presents GS-9688 plasma PK parameters following multiple-dose administration 
(2 or 4 doses QW) of GS-9688 1.5 or 3 mg in subjects who were either virally suppressed or 
viremic in the fasted state.
GS-9688 was rapidly absorbed following single- or multiple-dose administration of GS-9688 
1.5 or 3 mg on Day 1 and Day 8. Mean GS-9688 plasma concentrations and exposure 
(as measured by AUClast, AUCinf, and Cmax) increased with increasing GS-9688 dose on Day 1 
and Day 8. Analysis using the ANOVA model indicated that exposure was approximately dose 
proportional between the GS-9688 1.5 mg cohort and the pooled GS-9688 3 mg cohorts.


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Table 1-3.
GS-US-389-2022: Summary Statistics of GS-9688 Plasma
Pharmacokinetic Parameters by Treatment Following Single- or
Multiple-Dose (2 or 4 Doses QW) Administration of GS-9688 in
Subjects Who Were Virally Suppressed or Viremic (PK Analysis Set).
GS-9688 PK 
Parameter
Mean (%CV)
Virally Suppressed (2 Doses)
GS-9688
1.5 mg
GS-9688
3 mg
Day 1 (N=8)
Day 8 (N=8)
Day 1 (N=7)
Day 8 (N=7)
AUClast (h•pg/mL)
304.9 (35.8)
351.4 (37.7)
624.7 (76.5)
434.0 (44.0)
AUCinf (h•pg/mL)
315.9 (36.1)
364.5 (38.1)
641.5 (74.2)
444.5 (43.5)
Cmax (pg/mL)
105.4 (32.2)
140.3 (34.2)
266.5 (83.2)
234.8 (68.3)
Tmax (h)a
1.00 (0.75, 1.00)
0.50 (0.50, 1.00)
0.50 (0.25, 2.00)
0.50 (0.50, 0.50)
t1/2 (h)a
5.63 (5.16, 6.11)
5.54 (4.64, 6.26)
5.26 (3.86, 6.19)
5.32 (4.60, 6.05)
GS-9688 PK 
Parameter
Mean (%CV)
Virally Suppressed (4 Doses)
Viremic (2 Doses)
GS-9688
3 mg
GS-9688
1.5 mg
Day 1 (N=8)
Day 8 (N=8)
Day 1 (N=8)
Day 8 (N=8)
AUClast 
(h•pg/mL)
932.4 (53.0)
967.4 (61.1)
944.0 (65.1)
899.9 (61.2)
AUCinf 
(h•pg/mL)
950.4 (52.5)
986.4 (60.8)
959.5 (64.5)
918.8 (60.9)
Cmax (pg/mL)
627.8 (84.7)
621.0 (71.0)
627.0 (132.3)
433.4 (79.1)
Tmax (h)a
0.75 (0.50, 1.00)
0.50 (0.50, 0.50)
0.38 (0.25, 1.00)
0.50 (0.50, 1.50)
t1/2 (h)a
4.77 (3.96, 5.73)
5.76 (4.69, 6.00)
4.59 (4.15, 5.05)
4.98 (4.60, 5.95)
a
Values are presented as median (Q1, Q3). Means presented are unadjusted arithmetic means. N is the number of subjects in 
the PK Analysis Set.
1.2.6.3.
Ophthalmologic Evaluation in GS-US-389-2021 and GS-US-389-2022
Based on nonclinical ophthalmologic finding in monkeys (Section 1.2.2), multiple, sequential 
ophthalmologic exams were assessed in subjects receiving GS-9688 in GS-US-389-2021 and 
GS-US-389-2022. In the FIH study in healthy volunteers, GS-US-389-2021, there were 
3 treatment-emergent ophthalmologic abnormalities (1 each in 1.5 mg, 3 mg, and placebo 
groups). The subject receiving 1.5 mg had the abnormality of pupils partially dilated noted on 
Day 7 and was considered study procedure related; the subject had a corresponding TEAE of 
visual impairment (with reported term of intermittent visual disturbance) starting on Day 4 and 
ending on Day 14. It was in the opinion of the onsite ophthalmologist that the visual impairment 
symptoms were related to the dilated ophthalmic assessments performed during the study. The 
subject in the 3 mg group had a small conjunctival scar noted on Day 2 exam and the placebo 
subject had a slight increase in pigment cells in the left eye on Day 7. Neither of these 2 subjects 
had a corresponding ophthalmologic TEAE. 


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In study GS-US-389-2022, three treatment-emergent ophthalmic abnormalities were reported, all
Grade 1 in severity as follows:

One subject (GS-9688 1.5 mg [2 doses], virally suppressed) reported Grade 1 eye pruritus 
starting on Day 13 and ending on Day 26; this was assessed by the clinical investigator as not 
related to study drug or study procedures. At screening, the subject was noted to have dry eye 
signs and there were no changes noted on ophthalmologic exams; on the final visit on Day 
15, the ophthalmologist noted “punctate epitheliopathy noted in right cornea [that] was seen 
previously”.

The second subject (GS-9688 3 mg [4 doses], virally suppressed), with a medical history of 
mild cataract (Listing 16.2.4.3), had a reported AE term of Grade 1 anterior chamber cell 
trace (Listing 16.2.7.1). At the Day 9 ophthalmologic exam (one day after the second 
GS-9688 dose), the subject was diagnosed to have trace cells in the anterior chamber, which 
was evaluated as study drug-related. The subject reported no other corresponding 
ophthalmologic treatment-emergent AE. The subject was started on fluorometholone acetate 
drops and the AE was resolved by Day 21 at the time of the next ophthalmologic exam as 
well as on Day 28.

The third subject (GS-9688 3 mg [2 doses], viremic) reported Grade 1 dry eye on Day 9 that 
resolved on Day 10 with no intervention; this AE was considered not related to study drug. 
There were no changes noted on any ophthalmologic exams.
Ophthalmologic exams for all other subjects in Study GS-US-389-2022 showed no significant
abnormalities.
1.2.6.4.
GS-US-389-3979
Study GS-US-389-3979 is a Phase 1 study in healthy volunteers to evaluate UDP glucoronosyl 
transferase (UGT) and cytochrome (CYP) P450 – mediated drug-drug interactions between 
GS-9688 and probe drugs. The primary objectives were to evaluate the effects of probe inhibitor 
and inducer on the PK of GS-9688. The secondary objective was to assess the safety of GS-9688 
when administered with probe drugs. Exploratory assessment of PD biomarkers was also 
conducted. 
This study consisted of cohort 1 (CYP3A inhibitor - voriconazole 200 mg BID), cohort 2 
(UGT inhibitor – probenecid 500 mg BID), cohort 3 (CYP1A2/CYP3A inhibitor – ciprofloxacin 
500 mg BID), and cohort 4 (CYP450/UGT inducer – rifampin 600 mg QD). For cohorts 1-3, a 
dose of 1 mg GS-9688 was given on Day 1 followed by a washout, administration of probe 
inhibitor on Day 7, and coadministration of 1 mg GS-9688 + probe inhibitor on Day 8. For 
cohort 4, 2 mg of GS-9688 was administered on Day 1, followed by 600 mg of rifampin on 
Days 2-7 and administration of GS-9688 + rifampin administered (12 hours after GS-9688 dose) 
on Day 8. For all cohorts, subjects were followed for 14 days after last dose of study drug and 
evaluated for safety through the reporting of AEs, physical examination and clinical laboratory 
test findings, and measurement of ECGs and vital signs.


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Safety data from GS-US-389-3979 indicate that GS-9688 was generally safe. There were no 
SAEs or Grade 4 AEs. There were two discontinuations, both considered study drug related. 
Both discontinuations were in Cohort 4, one subject with transient neutropenia (Grade 3) and one 
subject with transient elevated liver function tests (Grade 1 ALT and AST on Day 7). The most 
common Grade 2 AE observed was nausea in 3 subjects (all in cohort 2) with other Grade 2 AEs 
observed in one subject each with headache (cohort 1), syncope (cohort 4) and vomiting (cohort 
4). Overall, most treatment-emergent treatment-related AEs were Grade 1 with the most common 
AE being nausea. No Grade 4 laboratory abnormalities were observed and Grade 3 lab 
abnormalities included creatine kinase (CK) (one subject in cohort 1), LDL (one subject each in 
cohorts 2 and 4), lipase (one subject in cohort 3), cholesterol (one subject in cohort 4), and 
neutropenia (one subject in cohort 4, as discussed previously).
PD biomarkers IL-12p40 and IL-1RA showed minimal change (~20-37% increase in cohort 1-3 
and ~16% decrease in cohort 4) when GS-9688 was co-administered in the presence of probe 
inhibitors or inducer compared to administration of GS-9688 alone. PD biomarker levels were 
similar to those observed in study GS-398-2021. PK data (Table 1-4) for this study showed a 
3-fold increase in AUCinf and 8-fold increase in Cmax in GS-9688 exposure when co-administered 
with a potent CYP3A4 inhibitor voriconazole. Smaller increases in the systemic exposure of 
GS-9688 with a pan-UGT inhibitor probenecid or a potent CYP1A2/moderate CYP3A4 inhibitor 
ciprofloxacin were noted. Co-administration with probenecid showed a 45% and 12% increase in 
AUCinf and Cmax, respectively. Co-administration with ciprofloxacin showed a 40% and 
77% increase in AUCinf and Cmax, respectively, likely due to CYP3A inhibition. The 
coadministration of the inducer rifampin showed a 47% and 50% decrease in AUCinf and Cmax of 
GS-9688, respectively. 
The data suggest that GS-9688 metabolism is primarily mediated by CYP3A4 with CYP1A2 and 
UGT playing a less important role. Based on these data, the use of strong inhibitors or inducers 
of CYP3A with GS-9688 is not currently recommended. GS-9688 may be co-administered with 
CYP1A2 or UGT inhibitors or inducers. 
Table 1-4.
GS-US-389-3979: Statistical comparison of GS-9688 Pharmacokinetic 
Parameters following single dose administration of GS-9688 in the 
presence of probe drug (Day 8) and GS-9688 alone (Day 1).
Parameter
Cohort 1 (VORI)
Cohort 2 (PBC)
Cohort 3 (CIPRO)
Cohort 4 (RIF)
AUCinf
340.5 
(262.3, 442.0)
144.3 
(123.8, 168.2)
139.6
(125.2,155.6)
47.0
(39.6,55.6)
Cmax
801.1 
(583.3, 1100.2)
112.8 
(94.5, 134.5)
176.77
(142.2,219.8)
50.27
(39.6, 63.8)
Data are: GLSM ratio (90% CI). GLSM = geometric least-squares mean; CI = Confidence Interval
GLSM ratio = Day 8 / Day 1, Day 8 = GS-9688+probe, Day 1 = GS-9688
VORI = voriconazole (200 mg BID), PBC = probenecid (500 mg BID), CIPRO = ciprofloxacin (500 mg BID), RIF = rifampin 
(600 mg QD).


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1.2.6.5.
GS-US-389-4564
Study GS-US-389-4564 is a Phase 1 study in healthy volunteers to evaluate the PK, PD, safety, 
and tolerability of GS-9688 in smoking and nonsmoking subjects. 
Nonclinical and clinical DDI data (Study GS-US-389-3979) suggested that GS-9688 metabolism 
in humans is mediated primarily by oxidation via CYP3A4 with minor contribution of 
glucuronidation via UGT, and negligible to no contribution by CYP1A2. GS-9688 is also a 
substrate for human CYP1A1 in vitro (Study AD-389-2035). CYP1A1 is expressed in lung tissue 
and is known to be induced by smoking {Ding 2003, Kim 2004, Thum 2006}. According to the 
Centers for Disease Control and Prevention, the prevalence of cigarette smoking among adults in 
the US has remained approximately 15% to 20% in recent years. Smoking is more prevalent in 
other regions of the world and in certain ethnic populations, and can be even more prevalent in 
HBV infected subjects {Yi 2018}. Therefore, it was important to understand the in vivo impact 
of smoking on GS-9688 PK and provide guidance on GS-9688 administration in smokers. 
Subjects were defined as smokers if they consumed ≥ 20 cigarettes per day for at least 6 months 
prior to enrolling in the study and had a urine cotinine level > 500 ng/mL at screening, and as 
nonsmokers if they had not smoked during the 6 months prior to dosing and had a urine cotinine 
level ≤ 20 ng/mL at screening. Following single-dose administration of GS-9688, lower GS-9688 
plasma exposures were observed in smoking subjects compared with nonsmoking subjects, as 
reflected in the 23% and 26% decrease in GS-9688 AUCinf and Cmax, respectively. The Tmax and 
t1/2 were similar in smoking and nonsmoking subjects. These data suggest that CYP1A1 does not 
play an important role in GS-9688 metabolism and are in agreement with the clinical DDI study 
results (Study GS-US-389-3979).
Mean IL-12p40 and IL-1RA serum concentrations increased following single-dose 
administration of GS-9688 2 mg, with similar concentration profiles observed in smokers and 
nonsmokers. Serum concentrations of IL-12p40 and IL-1RA reached peaks at 4 hours postdose 
and returned to approximate baseline levels 24 hours postdose. There were numerically higher 
mean concentration ratios for IL-12p40 in smokers and for IL-1RA in nonsmokers at all postdose 
time points following GS-9688 administration. The variability in the magnitudes of the PD 
responses, together with the lack of a systematically higher PD response in 1 cohort versus the 
other, led us to conclude that there was no substantive difference in the PD responses when 
GS-9688 was administered in smoking and nonsmoking subjects.
GS-9688 was well tolerated by smoking and nonsmoking subjects. There were no SAEs, AEs 
that led to premature discontinuation of study drug, or deaths reported during this study. All AEs 
and the majority of graded laboratory abnormalities were Grade 1 or 2 in severity. There were no 
notable trends in vital signs measurements and no clinically significant ECG abnormalities.
Overall, a slight decrease in GS-9688 plasma exposures and no substantive difference in 
biomarker responses were observed in smoking subjects compared with nonsmoking subjects. 
These data suggest a minimal impact of smoking on GS-9688 PK/PD and support GS9688 
administration without regard to smoking status.


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1.3.
Rationale for This Study
1.3.1.
GS-9688 for Viremic Subjects with Chronic Hepatitis B Not Currently on 
Treatment
Given the low rate of HBsAg loss/seroconversion 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/seroconversion with finite 
treatment duration. The primary objective is to evaluate the safety, tolerability and efficacy of 
GS-9688 in association with an oral nucleotide HBV polymerase inhibitor, TAF, for the 
treatment of CHB subjects, and secondary objectives include evaluating the changes in HBV 
specific immune responses following treatment with GS-9688.
This Phase 2 study will be conducted in viremic CHB subjects not currently on treatment. 
Subjects with CHB generally have a rapid decline in viremia in response to beginning antiviral 
treatment. The decrease in viral burden may allow for increased responsiveness to immune 
stimulation and forms the basis for the design of this study. Of note, only subjects with sufficient 
hepatic reserve will be included in this study to further maximize safety.
1.3.2.
Rationale for the Dose Selection
Selection of the weekly administration of 1.5 mg and 3 mg is based on preclinical data and the 
safety, tolerability, PK, and PD data from the single ascending dose first in human (FIH) study in 
healthy volunteers (GS-US-389-2021) and the preliminary data from the ongoing Phase 1b study 
(GS-US-389-2022) in virologically suppressed (on OAV treatment) patients with CHB. 
From available clinical data, a dose of 1.5 mg was chosen as it has resulted in quantifiable and 
consistent increases in PD biomarkers IL-12 and IL-1RA in both the FIH study and the ongoing 
Phase 1b study. In the Phase 1b study with CHB subjects, the 1.5 mg dose was well-tolerated and 
safe as discussed in (Section 1.2.6.2). 
The highest GS-9688 dose planned to be developed in clinical studies is 3 mg. This maximum 
dose has been defined based on the available safety and tolerability data and PK and PD results 
from the FIH study and the ongoing Phase 1b study. The FIH study GS-US-389-2021 showed 
that GS-9688 was generally safe with single doses up to 5 mg (Section 1.2.6.1). At the highest 
dose evaluated, 5 mg, two subjects had a grade 2 laboratory abnormality of elevated ALT. 
Accordingly, GS-9688 doses of 1.5 mg and 3 mg have been selected for subsequent evaluation. 
Further, the FIH study showed dose dependent systemic exposure (AUC and Cmax) and PD 
increases (IL-12p40 and IL-1RA) peripheral cytokine induction with GS-9688 doses ranging 
from 0.5 mg up to 5 mg. Dosing with food resulted in smaller increases in IL-12p40 and 
IL-1RA serum concentration compared with fasted state dosing; therefore dosing will be in the 
fasted state. 
In GS-US-389-2022, two or four weekly doses of 1.5 or 3 mg have been evaluated in HBV 
infected patients. Safety demonstrated that GS-9688 is generally well-tolerated as discussed 
previously (Section 1.2.6.2). There were no SAEs, no treatment discontinuations due to AEs, and 
no Grade 3 or higher treatment-emergent laboratory abnormalities in either cohort. Similar to 


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data from the FIH study, data shows evidence of biological activity with dose dependent 
induction of IL-12p40 and IL-1RA and PK data shows a similar profile in patients compared to 
healthy volunteers in the FIH study, with minimal to no accumulation with time 
(Section 1.2.6.2).
Thus, based on preclinical data, safety and tolerability and available PD and PK data from both 
the FIH study and Phase 1b trial, GS-9688 doses of 1.5 mg and a maximal dose of 3 mg is 
supported to explore safety, tolerability and efficacy in viremic CHB patients not currently on 
treatment.
1.3.3.
Rationale for Treatment Duration
As no reductions in HBsAg levels were anticipated or observed with 2 once-weekly doses, 
longer treatment duration of 24 weeks is being explored. This duration is based on nonclinical 
data with GS-9688 that demonstrated efficacy in the woodchuck animal model of CHB. In this 
model, 8-12 weeks of exposure induced persistent reduction in WHsAg to undetectable levels in 
a subgroup of animals with response rate increasing over time. Given the preclinical efficacy 
data that suggests longer treatment duration may be required to achieve higher rates of antiviral 
response, this study will evaluate a 24 week treatment duration. 
More frequent observation and safety labs at the start of treatment, along with clear management 
of dose limiting toxicities (Section 7.6.2) will allow an adequate assessment of safety with 
repeated dosing and a rigorous evaluation of efficacy based on reductions in serum 
HBsAg levels.
1.4.
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.
1.4.1.
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


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1.4.2.
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:

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 (OAV) 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 1-5. 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 OAV 
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 1-5.
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%).
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 1-6 presents HBV DNA outcomes for
Studies GS-US-320-0108 {Buti 2016} and GS-US-320-0110 {Chan 2016} for subjects at 


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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 1-6.
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. 
Serological Analyses
In Study GS-US-320-0108, no subject in either treatment group experienced HBsAg loss by
Week 48. In Study GS-US-320-0110, 4 subjects (0.7%) in the TAF group and 1 subject (0.3%)
in the TDF group experienced HBsAg loss at Week 48. Three of the 4 subjects in the TAF group
and none in the TDF group also experienced HBsAg seroconversion at Week 48.


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In Study GS-US-320-0110, the proportion of subjects with HBeAg loss or seroconversion to
anti-HBe at Week 48 was also evaluated; these data are presented on Table 1-7. 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 1-7.
GS-US-320-0110: Proportion of Subjects with HBeAg Loss or 
Seroconversion at Week 48, Missing = Failure 
(Serologically Evaluable Full Analysis Set)
GS-US-320-0110
TAF 25 mg
(N = 565)
TDF 300 mg
(N = 285)
TAF 25 mg vs TDF 300 mg
p-value
Prop Diff
(95% CI)
HBeAg Loss, n (%)
78/565 (13.8%)
34/285 (11.9%)
0.47
1.8%
(−3.0% to 6.5%)
HBeAg Seroconversion, n (%)
58/565 (10.3%)
23/285 (8.1%)
0.32
2.1%
(−2.0% to 6.3%)
P-values were from the Cochran-Mantel-Haenszel test stratified by baseline HBV DNA categories and oral antiviral treatment 
status. Differences in the proportion between treatment groups and its 95% CI were calculated based on the Mantel-Haenszel 
proportions adjusted by baseline HBV DNA categories and oral antiviral treatment status strata.
Serologically Evaluable Full Analysis Set for HBeAg loss/seroconversion included subjects who were HBeAg positive and 
HBeAb negative/missing at baseline. HBeAg loss was defined as changes from HBeAg-positive at baseline to HBeAg-negative 
at a post-baseline visit with baseline anti-HBe negative/missing. HBeAg seroconversion was defined as HBeAg loss and 
anti-HBe change from negative/missing at baseline to positive at a post-baseline visit.
Source: GS-US-320-0110 Week 48 CSR, Section 15.1, Table 19.1
Virologic Resistance Analysis
In an integrated analysis of Studies GS-US-320-0108 and GS-US-320-0110, 24 subjects (2.8%)
in the TAF group and 14 subjects (3.2%) in the TDF group qualified for population-based
sequence analysis after up to 48 weeks of treatment. Among the 24 subjects in the TAF group
who qualified for population-based sequence analysis, 15 had no changes detected in the pol/RT
sequence from baseline, 4 were unable to be sequenced, and 5 had polymorphic site
substitutions. Among the 14 subjects in the TDF treatment group who qualified for
population-based sequence analysis, 6 had no changes detected in the pol/RT sequence from
baseline, 4 were unable to be sequenced, 2 had polymorphic site substitutions, and 2 had a 
conserved site substitution. Overall, no HBV pol/RT amino acid substitutions associated with 
resistance to TFV were detected by sequencing and phenotypic analysis through 48 weeks of the 
study in either treatment group.
Safety of TAF in CHB Subjects
The principal sources of safety data for TAF are presented in Table 1-5 and consist of 2 Phase 3 
studies in subjects with CHB, Study GS-US-320-0108 and GS-US-320-0110. Subjects included 
in the Safety Analysis Set received at least 1 dose of study drug.


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Adverse Events for the TAF Phase 3 Safety Population
Summary of Adverse Events
Table 1-8 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 1-8.
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 1-9 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 1-9.
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 1-10 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 1-10.
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 1-11 presents a summary of the subject incidence of Grade 3 or 4 serum chemistry or 
urinalysis abnormalities reported for ≥ 1% in either treatment group for the overall TAF Phase 3 
Safety Population. The only Grade 3 or 4 serum chemistry laboratory abnormality that occurred 
in > 5% of subjects overall in each of the treatment groups individually was ALT elevation 
(TAF 8.1%, 70 subjects; TDF 9.3%, 40 subjects). In the TDF group, Grade 3 or 4 elevations of 
AST also occurred in > 5% of subjects overall (TAF 3.3%, 28 subjects; TDF 5.4%, 23 subjects). 
Grade 3 urinalysis abnormalities included occult blood (TAF 7.7%, 66 subjects; TDF 7.0%, 
30 subjects), urine erythrocytes (TAF 7.7%, 59 subjects; TDF 9.1%, 35 subjects), and urine 
glucose (TAF 4.8%, 41 subjects; TDF 1.2%, 5 subjects). The majority of subjects 
(88.6%; 124 of 140 subjects) who had Grade 3 urine occult blood or urine erythrocytes were 
women of child bearing potential (defined as age ≤ 54 years). The abnormalities were generally 
asymptomatic and not associated with AEs; none of the events were considered related to study 


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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 1-11.
GS-US-320-0108 and GS-US-320-0110: Treatment-Emergent 
Grade 3 or 4 Laboratory Abnormalities Reported for at Least 
1% of Subjects in Either Treatment Group in the Overall TAF 
Phase 3 Safety Population (Safety Analysis Set)
TAF 25 mg
(N = 866)
TDF 300 mg
(N = 432)
Maximum Postbaseline Toxicity Grade (N)
859
428
Grade 3
225 (26.2%)
96 (22.4%)
Grade 4
44 (5.1%)
30 (7.0%)
Chemistry
Alanine Aminotransferase (N)
859
428
Grade 3
52 (6.1%)
27 (6.3%)
Grade 4
18 (2.1%)
13 (3.0%)
Amylase (N)
859
427
Grade 3
22 (2.6%)
9 (2.1%)
Aspartate Aminotransferase (N)
859
428
Grade 3
25 (2.9%)
18 (4.2%)
Grade 4
3 (0.3%)
5 (1.2%)
Creatine Kinase (N)
859
428
Grade 3
16 (1.9%)
7 (1.6%)
Grade 4
9 (1.0%)
6 (1.4%)
Fasting Glucose (Hyperglycemia) (N)
857
425
Grade 3
9 (1.1%)
0
Fasting LDL Cholesterol (N)
837
417
Grade 3
37 (4.4%)
1 (0.2%)
Nonfasting Glucose (Hyperglycemia) (N)
856
426
Grade 3
25 (2.9%)
7 (1.6%)
Urinalysis
Occult Blood (N)
859
426
Grade 3
66 (7.7%)
30 (7.0%)
Urine Erythrocytes (N)
768
386
Grade 3
59 (7.7%)
35 (9.1%)
Urine Glucose (N)
859
426
Grade 3
41 (4.8%)
5 (1.2%)
Denominator for percentage (N) is the number of subjects in the safety analysis set with at least 1 postbaseline laboratory value 
for the test.
Subjects were counted once for the maximum postbaseline severity for each laboratory test. For urinalysis (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’ means low.
Source: TAF Week 48 ISS, Table 20


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In Studies GS-US-320-0108 and GS-US-320-0110 the incidence of graded hepatic laborato1y 
abnonnalities 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 bilimbin 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 laborato1y abnonnalities in both treatment groups were generally Grade 1 or 2 at 
maximum severity; Grade 3 or 4 ALT abnonnalities and Grade 3 or 4 AST abno1malities were 
observed in lower percentages of subjects in the T AF 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 bilimbin 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 laborato1y abno1malities were generally not associated with hepatic AEs. 
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 (QI, 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.
1.5.
Risk/Benefit Assessment for the Study
GS-9688 is being developed to provide patients with CHB with a finite duration, curative 
treatment option and for beneficial antiviral response without inducing a significant systemic 
immune response. Published studies have demonstrated that TLR8 activates innate and adaptive
effector cell immune responses {Du 2010, Gorski 2006, Jo 2014, Lu 2012, Peng 2005, Wille-
Reece 2006}. Activation of TLR8 by a selective, oral, small-molecule agonist with good 
absorption and high first-pass hepatic clearance to limit systemic activation is therefore a rational 
approach to safely induce effective antiviral immunity in CHB patients and drive functional cure.
The loss of HBsAg with seroconversion is the gold standard endpoint for anti-HBV therapy and 
allows for cessation of treatment {European Association for the Study of the Liver 2017, Liaw 
2012, Sarin 2015, Terrault 2016}. 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 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 after multiple
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 with 
seroconversion are needed. Through effects on both innate and adaptive immune effectors 
(including HBV-specific T cells), agonist-induced activation of TLR8 may provide a novel 
component of treatment for patients with chronic HBV infection. 


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In human studies, dose escalation in healthy volunteers demonstrated dose-dependency of AEs
with the highest evaluated dose of 5 mg demonstrating significant increases in nausea and 
vomiting and with several subjects experiencing transient ALT elevations at the highest dose. 
Importantly, at doses of 1.5 and 3 mg evaluated in the Phase 1b study in CHB patients 
(GS-US-389-2022), rates of nausea, vomiting, and laboratory abnormalities have been limited. 
Nonclinical data in cynomolgus monkeys suggest that vomiting AEs are sporadic with no 
persistence and no morbidity or mortality associated with vomiting was noted. Currently, it is not 
known if there will be any treatment effects associated with longer treatment duration.
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 7.6.2 and 7.9. Based on safety data from 3 clinical trials (completed or ongoing), a 
number of dose limiting toxicities (DLTs), including ALT elevation and neutropenia, are 
identified that would determine if treatment should be discontinued in a patient. In addition, risk 
will be further minimized with the inclusion of a data safety monitoring committee that will 
periodically evaluate the safety of the entire study and verify independently if the benefits of the 
trial continue to outweigh any risks observed. In summary, the goal of the GS-9688 program is to 
address a major unmet need for CHB patients, namely to enhance rates of serum HBsAg loss 
with seroconversion with a finite duration treatment regimen. Study GS-US-389-2025 will 
investigate the efficacy of 24 doses of GS-9688 at two dose levels (1.5 and 3 mg) administered 
weekly, in association with TAF administered daily, to viremic CHB patients not currently on 
treatment.
The risks of treatment with GS-9688 in pregnancy have not been evaluated. Pre-clinical data has 
shown that the potential for GS-9688 to affect the PK of other drugs via CYP450, or UGT
enzymes or drug transporter (p-glycoprotein [P-gp]/ Breast Cancer Resistance Protein [BCRP])
is low. Oral contraceptives are mainly metabolized by CYP450 enzymes and may be substrates 
for P-gp/BCRP. If females are using hormonal agents for contraception, the likelihood for 
substantial changes in safety and/or efficacy of the contraceptive via drug-drug interaction (DDI) 
is low. Please refer to the current Investigator’s Brochure for additional information about 
GS-9688.
Based on in vitro data and preliminary data from the DDI study (GS-US-389-3979), GS-9688 is 
mainly metabolized by CYP450 enzymes. In this study, the inhibition or induction of CYP3A 
showed a decrease in GS-9688 exposure, thus drugs that are known to be potent CYP3A 
inhibitors/inducers of CYP3A are prohibited in this study.
Further, pre-clinical data showed that GS-9688 is unlikely to be a perpetrator of DDIs (based on 
inhibition and induction studies of CYP450 enzymes and drug transporters). OAVs used in the 
treatment of HBV are not metabolized CYP450 enzymes. Thus, it is not expected that GS-9688 
will result in DDIs with OAVs used to treat HBV. 
Based on available information, the benefit/risk balance for this study is considered positive.


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1.6.
Compliance
This study will be conducted in compliance with this protocol, Good Clinical Practice (GCP), 
and all applicable regulatory requirements.


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2.
OBJECTIVES
The primary objectives of this study are as follows:

To evaluate the safety and tolerability of multiple oral doses of GS-9688 at Week 24 in CHB 
adult subjects who are viremic and not currently not being treated 

To evaluate the antiviral activity of GS-9688 as measured by the proportion of subjects with 
≥1 log10 IU/mL decline from baseline in serum quantitative hepatitis B surface antigen 
(qHBsAg) at Week 24
The secondary objectives of this study are as follows:

To evaluate the antiviral activity of GS-9688 at Weeks 4, 8, 12 and 48 as measured by the 
proportion of subjects with ≥1 log10 IU/mL decline from baseline in serum qHBsAg

To evaluate the change in serum qHBsAg (log10 IU/mL) from baseline to Weeks 4, 8, 12, 24 
and 48

To evaluate the proportion of subjects with HBV DNA <LLOQ at Weeks 12, 24, and 48

To evaluate the proportion of subjects with HBsAg loss at Weeks 12, 24 and 48

To evaluate the proportion of subjects with Hepatitis B e-Antigen (HBeAg) loss and 
seroconversion at Weeks 12, 24 and 48

To characterize the PK of GS-9688

To evaluate the proportion of subjects experiencing HBV virologic breakthrough 
(2 consecutive visits of HBV DNA ≥69 IU/mL)

To evaluate the incidence of drug resistance mutations
CCI


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CCI


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3.
STUDY DESIGN
3.1.
Study Design
This is a multicenter, randomized, double-blinded, placebo-controlled Phase 2 study of 
GS-9688/PTM in viremic adult CHB subjects not currently on OAV treatment.
Figure 3-1.
Study Schema
a
At Week 48, per PI’s discretion, subjects will be managed in one of two ways:
1.
Continue in the study for 48 weeks following the discontinuation of TAF (TFFU, window of ± 7 days) or until an 
alternative commercially approved CHB treatment is started, whichever occurs first
2.
Initiate other standard of care CHB therapy with Week 48 representing the last study visit
3.2.
Study Treatments
Approximately 65 viremic subjects who are not currently being treated for CHB will be enrolled 
into two cohorts within this study that will run in parallel. 

Cohort 1 (n = 40): HBeAg-positive CHB subjects

Cohort 2 (n = 25): HBeAg-negative CHB subjects
Within each cohort, subjects will be randomized in a 1:2:2 in ratio to one of the three treatment 
arms (A: B: C) for weekly dosing of GS-9688/PTM for 24 doses. 
Baseline 
(Day 1) 
Arm A 
N=8 
ArmB 
N=16 
ArmC 
N=16 
HBeAg-positive CHB subjects 
N=40 
Cohort 2: 
HBeAg-negative CH B subjects 
N=25 
'Cohorl 1 and Cohort 2 will run In parallel 
Week 23 (Last GS-9688/PTM Dose) 
Week 48/rn 
i 
TAF 
Placebo To Match 
I 
Weekly x 24 doses 
TAF 
GS-9688 1.5 mg 
I 
Weekly x 24 dose, 
TAF 
GS-9688 3 mg 
I 
Weekly x 24 dose, 
Baseline 
(Day 1) 
Arm A 
N=S 
ArmB 
N=lO 
ArmC 
N=lO 
Week 23 (Last GS-9688/PTM Dose) Week 48/fD 
i 
TAF 
Pl ace bo To Match 
I 
Weekly x 24 dose, 
TAF 
GS-9688 1.5 mg 
I 
Weekly x 24 dose, 
TAF 
GS-9688 3 mg 
I 
Weekly x 24 dose, 


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All subjects will also be treated with TAF 25 mg oral daily for the duration of the study, 
48 weeks, in addition to the following treatments:
Treatment Arm A: Approximately 8 subjects in Cohort 1 and approximately 5 subjects in 
Cohort 2 will be administered placebo-to-match (PTM) orally on the same day once a week 
(every 7 days) for 24 doses 
Treatment Arm B: Approximately 16 subjects in Cohort 1 and approximately 10 subjects in 
Cohort 2 will be administered GS-9688 1.5 mg orally on the same day once a week (every 
7 days) for 24 doses
Treatment Arm C: Approximately 16 subjects in Cohort 1 and approximately 10 subjects in 
Cohort 2 will be administered GS-9688 3 mg orally on the same day once a week (every 7 days) 
for 24 doses
All GS-9688 study drug doses will be administered in fasted state.
After the 24th dose (Week 23 visit), GS-9688/PTM will be discontinued. Subjects will continue 
being treated with TAF and will be followed until Week 48/ED. The total study duration for each 
subject will be 48 weeks with up to an additional 48 weeks if continued into the Treatment Free 
Follow-up (TFFU) phase. Subjects should take TAF and other commercially available 
medications no earlier than 2 hours after GS-9688/PTM dosing. Ondansetron dosing is allowed 
around GS-9688/PTM dosing; dosing of other antiemetics should be discussed with the Gilead 
MM for approval.
Following completion of the 48-week study period the Investigators will be responsible for 
assessing the need to continue study subjects on treatment for CHB. At Week 48, at Principal 
Investigator (PI) discretion, subjects will be managed in one of two ways:
1) Continue in the study for 48 weeks following the discontinuation of TAF (Treatment Free 
Follow-Up, TFFU, window of ± 7 days) or until an alternative commercially approved CHB 
treatment is started, whichever occurs first
2) Initiate other standard of care CHB therapy immediately at end of study.
At the PI’s discretion, subject(s) in the TFFU phase may initiate other standard of care CHB 
therapy at any time per local treatment guidelines. If a subject initiates other standard of care 
CHB therapy for their CHB, TFFU visits will continue for 2 more TFFU visits or until the end of 
the TFFU phase (Week 96), whichever comes first.
The primary analysis will occur after all subjects have completed Week 24 assessment post last 
dose of GS-9688/PTM or prematurely discontinued with the primary endpoints being the safety 
and tolerability of GS-9688, as well as assessment of the antiviral activity of GS-9688 at
Week 24 as measured by the proportion of subjects with ≥1 log10 (IU/mL) decline from baseline 
in serum qHBsAg.


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The study will be unblinded to appropriate Gilead Sciences Inc., (GSI) study team personnel at 
the time of prima1y analysis (Week 24 assessment). An Internal Data Review, external to the 
study team, may be unblinded at Week 12 assessment visit to review the unblinded safety and 
efficacy data in order to guide strategic decisions regarding the future of the program. 
Investigators and subjects will remain blinded through Week 48. 
3.3. 
Duration of Treatment 
The total study duration for each subject will be 48 weeks with up to an additional 48 weeks if 
continued into the TFFU phase. Coho1i 1 and 2 consist of24 doses (Week 23) of treatment of 
GS-9688 study drng/PTM, and 48 weeks of T AF treatment. 
3.4. 
Pharmacokinetic Assessment 
Sparse (pre-identified) PK plasma sampling will occur on Day 1 and Week 23 at pre-dose, 1, 4, 
and 24 hours post-dose and at Week 11 at pre-dose, 1, and 4 hours post-dose. Sparse (timed) 
plasma PK samples will be obtained on any two of the following visits: Weeks 2, 4, 8, 12, 16, 
and/or 20 at pre-dose and any time between 30 minutes to 4 hours post-dose. See details in 
Section 6.8. 
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3.7. 
End of Study 
Final 
Amendment 1 
The end of this study will be the last subject's last completed study visit at Week 48. If the 
subject emolls in the TFFU phase, the subject will be observed for up to an additional 48 weeks 
(Week 96). 
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4.
SUBJECT POPULATION
4.1.
Number of Subjects and Subject Selection
A total of approximately 65 subjects will be enrolled in the study, aged 18-65 years inclusive, 
with CHB and not currently on OAV treatment. 
4.2.
Inclusion Criteria
Subjects must meet all of the following inclusion criteria to be eligible for participation in this 
study.
1) Must have the ability to understand and sign a written informed consent form, which must be 
obtained prior to initiation of study procedures.
2) Adult male and non-pregnant, non-lactating female subjects, 18-65 years of age inclusive 
based on the date of the Screening visit.
3) Documented evidence of chronic HBV infection (e.g., HBsAg positive for more than 
6 months) with detectable HBsAg levels at Screening.
4) Females of childbearing potential (as defined in Appendix 3) must have a negative serum 
pregnancy test at Screening and a negative urine pregnancy test at Baseline prior to 
enrollment.
5) Male and female subjects of childbearing potential who engage in heterosexual intercourse 
must agree to use protocol specified method(s) of contraception as described in Appendix 3.
6) Screening HBV Deoxyribonucleic acid (DNA) ≥ 2000 IU/mL.
7) Screening Electrocardiogram (ECG) without clinically significant abnormalities and with 
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.
4.3.
Exclusion Criteria
Subjects who meet any of the following exclusion criteria are not to be enrolled in this study:
1) 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 3 years of screening, or, 
in the absence of an appropriate liver biopsy, either:
b) Screening FibroTest score of > 0.48 and APRI > 1, or


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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
2) Received a commercially available HBV OAV treatment(s) (tenofovir alafenamide, tenofovir 
disoproxil fumarate, entecavir, adefovir dipivoxil, lamivudine, telbivudine, either as single 
agents or in combination) within the 3 months prior to screening.
3) Received prolonged therapy with immunomodulators (e.g., corticosteroids) or biologics 
(e.g., monoclonal antibody, interferon) within 3 months of screening
4) Subjects meeting any of the following laboratory parameters at screening:
a) Hemoglobin < 12 g/dL (for males) or <11 g/dL (for females)
b) White Blood cell count < 2500 cells/mm3
c) Neutrophil count < 1500 cells/mm3 (or < 1000 cells/mm3 if considered a physiological 
variant in a subject of African descent)
d) Alanine aminotransferase (ALT) >5x ULN 
e) International normalized ratio (INR) > ULN unless the subject is stable on an 
anticoagulant regimen affecting INR
f)
Albumin < 3.5 g/dL
g) Direct bilirubin >1.5x ULN
h) Platelet Count < 100,000/L
i)
Estimated creatinine clearance (CrCl) < 60 mL/min (using the Cockcroft-Gault method) 
based on serum creatinine and actual body weight as measured at the screening 
evaluation, i.e.,
Male:
(140 – Age [years]) (Weight [kg])
CrCl (mL/min)
72 (Serum Creatinine [mg/dL])
Female:
(140 – Age [years]) (Weight [kg]) 0.85 
CrCl (mL/min)
72 (Serum Creatinine [mg/dL])


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5) Co-infection with human immunodeficiency virus (HIV), hepatitis C virus (HCV) or 
hepatitis D virus (HDV)

Subjects who are HCV Ab positive, but have a documented negative HCV RNA, are 
eligible
6) Prior history of hepatocellular carcinoma (HCC) (e.g., as evidenced by prior imaging) or 
screening alpha-fetoprotein (AFP) ≥ 50 ng/mL without imaging to rule out HCC.
7) 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.
8) Significant cardiovascular, pulmonary, or neurological disease in the opinion of the 
investigator.
9) Diagnosis of autoimmune disease (e.g., systemic lupus erythematosus, rheumatoid arthritis, 
inflammatory bowel disease, autoimmune hepatitis, sarcoidosis, psoriasis of greater than 
mild severity, autoimmune uveitis), poorly controlled diabetes mellitus, significant 
psychiatric illness, severe chronic obstructive pulmonary disease (COPD), 
hemoglobinopathy, retinal disease, or are immunosuppressed.
10) Chronic liver disease of a non-HBV etiology (e.g., Wilson’s disease, hemochromatosis, 
alpha-1-antitrypsin deficiency, cholangitis, nonalcoholic steatohepatitis), except for 
non-alcoholic fatty liver disease.
11) Received solid organ or bone marrow transplant. 
12) Use of another investigational agent within 90 days of screening, unless allowed by the 
Sponsor.
13) Current alcohol or substance abuse judged by the investigator to potentially interfere with 
subject compliance.
14) Known hypersensitivity to study drugs or formulation excipients.
15) Women who are breastfeeding, pregnant or who wish to become pregnant during the course 
of the study.
16) Female subjects unwilling to refrain from egg donation and in vitro fertilization during and 
until at least 30 days after the last study drug dose.
17) Male subjects unwilling to refrain from sperm donation during and until at least 90 days after 
the last study drug dose.
18) Use of any prohibited concomitant medications as described in Section 5.5 and Table 5-1.
19) 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, Blinding and Treatment Codes
It is the responsibility of the investigator to ensure that the subject is eligible for the study prior 
to enrollment. Subjects will be assigned a screening number at the time of consent.
All screening procedures must be completed and reviewed by the investigator for eligibility prior 
to the administration of the first dose of study drug on Day 1. Once informed consent is obtained 
subjects will be randomized in a 1:2:2 ratio to receive either PTM, blinded GS-9688 1.5 mg, or 
GS-9688 3 mg. Once a subject number has been assigned to a subject, it will not be reassigned to 
another subject. If necessary, replacement subjects may be enrolled after discussion and approval 
from sponsor. A new unique subject number will be assigned to the replacement subject. 
The randomization will be performed via an Interactive Mobile Response System (IMRS) or 
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.
Investigators and subjects will remain blinded through Week 48 except in instances of 
emergency treatment unblinding.
5.1.1.
Procedures for Breaking Treatment Codes
In the event of a medical emergency where breaking the blind is required to provide medical care 
to the subject, the investigator may obtain treatment assignment directly from the Interactive 
Response System (IXRS) for that subject. In the event of a system or technology failure, the 
IXRS provider should be contacted via phone. Gilead recommends but does not require that the 
investigator contact the Gilead medical monitor before breaking the blind. Treatment assignment 
should remain blinded unless that knowledge is necessary to determine subject emergency 
medical care. The rationale for unblinding must be clearly explained in source documentation 
and on the case report form/ electronic case report form (CRF/eCRF), along with the date on 
which the treatment assignment was obtained. The investigator is requested to contact the Gilead 
medical monitor promptly in case of any treatment unblinding.
Blinding of study treatment is critical to the integrity of this clinical trial and therefore, if a 
subject’s treatment assignment is disclosed to the investigator, the subject will have study 
treatment discontinued. All subjects will be followed until study completion unless consent to do 
so is specifically withdrawn by the subject.
In addition, Gilead Pharmacovigilance and Epidemiology (PVE) may independently unblind 
cases for expedited reporting of suspected unexpected serious adverse reactions (SUSARs).


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5.2.
Description and Handling of GS-9688/PTM and TAF
5.2.1.
Formulation
5.2.1.1.
GS-9688
GS-9688 is provided as 1.5 mg strength tablets. GS-9688 tablets are round, plain-faced, 
film-coated white tablets. In addition to the active ingredient, GS-9688 tablets contain the 
following inactive ingredients: microcrystalline cellulose, mannitol, crospovidone, and 
magnesium stearate. The white tablet film-coating contains polyvinyl alcohol, titanium dioxide, 
polyethylene glycol (PEG) 3350, and talc.
PTM GS-9688 tablets contain the following inactive ingredients: microcrystalline cellulose, 
lactose monohydrate, croscarmellose sodium, and magnesium stearate. The white tablet 
film-coating contains polyvinyl alcohol, titanium dioxide, PEG 3350, and talc. PTM GS-9688 
tablets are identical in size, shape, color and appearance to the active GS-9688 tablets.
5.2.1.2.
Vemlidy (TAF Tablets)
Vemlidy (TAF) 25 mg tablets contain 28 mg of tenofovir alafenamide fumarate, which is 
equivalent to 25 mg of TAF. The tablets are yellow, round-shaped, and film-coated. The tablets 
are debossed with “GSI” on one side and “25” on the other side. In addition to the active 
ingredient, each film-coated tablet contains the following inactive ingredients: lactose 
monohydrate, microcrystalline cellulose, croscarmellose sodium, magnesium stearate, 
polyethylene glycol, polyvinyl alcohol, talc, titanium dioxide, and yellow iron oxide.
5.2.2.
Packaging and Labeling
All study drugs are to be distributed to centers in participating countries and shall be labeled to 
meet applicable requirements of the local regulations.
5.2.2.1.
GS-9688
GS-9688 1.5 mg tablets and PTM tablets are packaged in clear Polyvinyl chloride (PVC) /
Polychlorotrifluoroethylene (PCTFE) film blister strips and sealed with aluminum foil lidding 
material. Each blister strip contains 4 round tablets sealed with an aluminum push through 
lidding material. GS-9688 active and placebo blister strips in the quantity needed for a 4 week 
supply of GS-9688 (i.e., 2 strips/8 ct) are placed into a paperboard child resistant wallet system 
in accordance with the dosage strategy.
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, aluminum-faced liner.


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5.2.3.
Storage and Handling
To ensure the stability and proper identification, study drugs 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.
5.2.3.1.
GS-9688
The recommended storage condition for GS-9688 active and PTM tablets packaged in blister 
strips/wallet system is as follows: “Store below 30°C.” Storage conditions are specified on the 
label. Until dispensed to the subjects, all study drugs should be stored in a securely locked area, 
accessible only to authorized site personnel.
5.2.3.2.
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. 
5.3.
Dosage and Administration of GS-9688/PTM and TAF
Approximately 65 viremic subjects who are not currently being treated for CHB will be enrolled 
into two cohorts depending on HBeAg status. 

Cohort 1 (n = 40): HBeAg-positive CHB subjects

Cohort 2 (n = 25): HBeAg-negative CHB subjects
5.3.1.1.
GS-9688
Within each cohort, subjects will be randomized in a 1:2:2 in ratio to one of the three treatment 
arms (A: B: C) for weekly dosing of GS-9688/PTM for 24 doses. Study drug will be taken orally 
at approximately the same time on the same day once a week (every 7 days). All GS-9688 study 
drug doses will be administered in fasted state. 
Treatment Arm A: Approximately 8 subjects in Cohort 1 and approximately 5 subjects in 
Cohort 2 will be administered placebo-to-match (PTM) orally on the same day once a week 
(every 7 days) for 24 doses 
Treatment Arm B: Approximately 16 subjects in Cohort 1 and approximately 10 subjects in 
Cohort 2 will be administered GS-9688 1.5 mg orally on the same day once a week (every 
7 days) for 24 doses
Treatment Arm C: Approximately 16 subjects in Cohort 1 and approximately 10 subjects in 
Cohort 2 will be administered GS-9688 3 mg orally on the same day once a week (every 7 days) 
for 24 doses


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5.3.1.2.
TAF
All subjects will also be treated with TAF 25 mg oral at approximately the same time daily with 
food or, in jurisdictions in which TAF has been approved, consult the local prescribing 
information for TAF dose recommendations with concomitant medications for 48 weeks. For 
Baseline through Week 23, TAF dosing will be no earlier than 2 hours post GS-9688/PTM 
weekly dose.
5.4.
Fasting State Dosing 
GS-9688/PTM will be orally administered at approximately the same time, on the same day, 
once weekly, following an overnight fast (no food or drinks, except water, for at least 8 hours 
with no food or drinks, including water, for the 1 hour before dosing). After dosing, subjects will 
continue to fast (no food or drinks, including water) for 2 hours. After 2 hours postdose, water is 
allowed and after 4 hours postdose, patients are allowed to eat any food or drinks. Subjects 
should take their other prescribed medications no earlier than 2 hours after GS-9688/PTM dosing 
or, if medications require dosing with food, no earlier than 4 hours after GS-9688/PTM dosing.
Ondansetron dosing is allowed around GS-9688/PTM dosing; dosing of other antiemetics should 
be discussed with the Gilead MM for approval.
5.5.
Concomitant and Prohibited Medications
Concomitant medications taken within 30 days prior to Screening, up to and including 30 days 
after the last administration of study drug need to be recorded in the source documents and 
eCRFs. Further, any concomitant medications taken during TFFU should also be recorded in the 
source documents and eCRFs.
Data from the drug-drug interaction study GS-US-389-3979 indicate that CYP3A plays a major 
role in GS-9688 metabolism and therefore the administration of potent CYP3A 
inhibitors/inducers is not permitted in this study (see Section 1.2.6.4). 
During treatment with GS-9688/PTM, use of the following medications on Table 5-1 are 
prohibited for a minimum of 21 days prior to the Baseline/Day 1 visit through the last dose of 
GS-9688/PTM study treatment plus 7 days (except where noted).
This is not an exhaustive list of agents. Any medications not in Table 5-1 should be reviewed 
with the Sponsor prior to randomization and during the study treatment period with 
GS-9688/PTM.


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Table 5-1.
List of Agents Disallowed while on GS-9688/PTM treatment (+7 days)
Drug Class
Agents Disallowed
Acid Reducing Agentsa
Proton-Pump Inhibitors, H2-Receptor Antagonists, Antacids, Sucralfate
Antibiotics
clarithromycin, rifabutin, rifampin, rifapentin, telithromycin, troleandomycin 
Anticonvulsants
carbamazepine, enzalutamide, oxcarbazepine, phenobarbital, phenytoin
Antidepressants
Nefazodone
Antifungals
fluconazole, itraconazole, ketoconazole, posaconazole, voriconazole
Antiviral
VIEKIRA PAK (ombitasvir/paritaprevir/ritonavir & dasabuvir), telaprevir, 
danoprevir, boceprevir
Cardiac Medications
Mifefradil
Diuretics
Conivaptan
GI Motility Agentsb
Cisapride, metoclopramide, domperidone, mosapride citrate, pruclopride, 
itopride hydrochloride, levosulpiride
Hematologic stimulating agents
erythropoiesis-stimulating agents; granulocyte colony stimulating factor 
[GCSF]; and thrombopoietin [TPO] mimetics
Herbal/Natural Supplements
St. John’s Wort, Echinaccea. Milk thistle (ie, silymarin), 
Chinese herb sho-saiko-to (or Xiao-Shai-Hu-Tang)
Other
Avasimive, enzalutamide, idelalisib, lumacaftor, nitotane
a
Proton pump inhibitors can be taken up to 7 days before study drug dosing (Day 1). H2 receptor antagonists can be taken up 
to 3 days before study drug dosing (Day 1). Antacids that directly neutralize stomach pH (e.g., Tums, Maalox) are permitted 
but may not be taken within 4 hours (before or after) study drug administration.
b
GI motility agents are prohibited starting 2 days prior to GS-9688/PTM dosing and for the 24 hours postdose
During treatment with TAF (alone or with GS-9688/PTM), use of the following medications 
listed below and on Table 5-2 are prohibited for a minimum of 21 days prior to the 
Baseline/Day 1 visit through Week 48/ED:

Investigational agents or devices for any indication

Agents that reduce renal function or compete for active tubular secretion with tenofovir 
(e.g., cidofovir, acyclovir, valacyclovir, ganciclovir, famciclovir, valganciclovir, high dose or 
multiple NSAIDS, probenecid).

Nephrotoxic agents (e.g., aminoglycosides, amphoterecin B, vancomycin, cidofovir, 
foscarnet, cisplatin, pentamidine, cyclosporine, tacrolimus)

Systemic chemotherapeutic agents, systemic corticosteroids (except short-term use of 
prednisone as a steroid burst [ ≤ 1 week of use], immunosuppressant, or immunomodulating 
agents
Concomitant use of certain medications or herbal/natural supplements (inducers of drug 
transporters i.e., P-gp) with study drug(s) may result in PK interactions. Any medications not on 
the list above should be reviewed with the Sponsor prior to randomization and during the study 
treatment.


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Table 5-2.
Disallowed Concomitant Medications while on TAF
Medication Class
Prohibited Medications
Anticonvulsants
Carbamazepine, Oxcarbazepine, Phenobarbital, Phenytoin: 
may lower concentration of TAF and/or TFV
Antimycobacterials
Rifapentine, Rifabutin, Rifampin
Herbal/Natural Supplements
St. John’s Wort, Echinacea, Milk thistle (i.e., silymarin), 
Chinese herb sho-saiko-to (or Xiao-Shai-Hu-Tang)
Subjects who are currently taking other prescription or non-prescription medications may still be
randomized into the study if, in the judgment of the Sponsor and the Investigator, the medication 
will not interfere with the study procedures or compromise subject safety, efficacy, and/or 
pharmacokinetic assessments. In instances where an excluded medication is initiated prior to 
discussion with the Sponsor, the Investigator must notify Gilead as soon as he/she is aware of the 
use of the excluded medication. For subjects requiring treatment with a concomitant medication 
(including treatment of an adverse event) after starting study drug, the subject’s continued 
participation in the study should be re-evaluated by the investigator, in consultation with the 
Gilead Medical Monitor (or designee) on an ongoing, case-by-case basis. 
Vitamins, acetaminophen, ibuprofen and hormonal contraceptive medications are allowed during 
the study period. The investigator is authorized to administer acetaminophen or ibuprofen for the 
treatment of minor ailments occurring on study without prior consultation with the Gilead 
Medical Monitor. Acetaminophen is the preferred agent, followed by ibuprofen. The Gilead 
Medical Monitor should be consulted before administering acetaminophen at doses > 2 g/day 
and ibuprofen as a single dose of >200 mg or >400 mg/day. 
5.6.
Other Protocol Restrictions
Upon every clinic visit, each subject will be questioned as to their compliance with the below
protocol restrictions. If a subject is unable to comply with any of the restrictions described 
above, the subject’s continued participation in the study will be reevaluated by the investigator in 
consultation with the sponsor.

Subjects will be required to refrain from consumption of grapefruit juice, grapefruits, Seville 
oranges and Seville orange juice 72 hours prior to the first dose of study drug and during the 
course of the study through the follow-up visit.

Subjects will be encouraged to avoid strenuous or prolonged exercise, as well as saunas, 
steam baths, and sunbathing or other prolonged ultraviolet exposure, e.g., in a tanning salon, 
from the screening evaluation until completion of the follow up visit, as these activities are 
known to affect certain clinical laboratory test parameters, (e.g., CK) and will provide false 
indicators of a potentially treatment related toxicity. 


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5.7.
Accountability for GS-9688/PTM and TAF
The investigator is responsible for ensuring adequate accountability of all used and unused 
IMP tablets. This includes acknowledgement of receipt of each shipment of IMP (quantity and 
condition). All used and unused IMP tablets dispensed to subjects must be returned to the site.
GS-9688/PTM and TAF accountability records will be provided to each study site to:

Record the date received and quantity of IMP tablets.

Record the date, subject number and the IMP blister pack/bottle number dispensed.

Record the date, quantity of used and unused IMP tablets returned, along with the initials of 
the person recording the information.
5.8.
Investigational Medicinal Product Return or Disposal
At the beginning of the study, the study monitor will evaluate the study centers 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 sites
SOP will be obtained for central files. Where possible, study drug will be destroyed at the site.
Upon study completion, a copy of the Investigational Drug Accountability records must be filed
at the site. Another copy will be returned to Gilead Sciences. If drug is destroyed on site, the
investigator must maintain accurate records for all study drug bottles and blister packs 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 
Final 
Amendment 1 
The study procedures to be conducted for each subject enrolled in the study are presented in 
tabular fonn in Appendix 2 and described in the text that follows. 
The investigator must doclllllent 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 ti·ial-wide at any time. 
6.2. 
Pretreatment Assessments 
Prior to the conduct of any screening procedures, each candidate must sign an Info1med Consent 
Fonn. Consent is to be obtained in accordance with regulato1y and local Ethics Committee 
requirements. 
6.2.1. 
Screening Visit (Window of -30 Days) 
Subjects will be screened within 30 before randomization to dete1mine eligibility for 
paiiicipation in the study. The following will be perfonned and doclllllented at screening: 
• 
Review of inclusion/exclusion criteria 
• 
Obtain medical histo1y (including HBV disease and ti·eatinent histo1y) 
• 
Review concomitant medications 
• 
Complete Physical examination (including weight, height, and BMI) 
• 
Vital Signs (blood pressure, heaii rate, respiration rate and body temperature) 
• 
Safety laborato1y tests (senun chemistry, hematology, and coagulation) 
• 
12-lead ECG (Subjects must rest quietly in the supine position for a minimlllll of 5 minutes 
prior to the recording) 
• 
Ophthalmologic exam (Days -10 to -1) 
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
Qualitative HBV serology (HBeAg [reflex Hepatitis B e-Antigen (HBeAb) if HBeAg is 
negative] and HBsAg [reflex Hepatitis B surface Antigen (HBsAb) if HBsAg is negative])

HBV DNA levels and resistance surveillance sample

HBV Genotyping by history (if known) and laboratory testing 

Quantitative HBsAg

HCV, HDV and HIV Ab testing (with reflex testing performed if positive)

FibroTest 

AFP (Imaging test required to rule out HCC for subjects with AFP  ≥ 50 ng/mL)

Urinalysis and urine drug screen

For all female subjects of child-bearing potential, serum beta human chorionic gonadotropin 
(β-hCG) 

For female subjects post-menopausal for less than two years, serum follicle-stimulating 
hormone (FSH) testing (if FSH < 40 mIU/mL a serum pregnancy test will be required)

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 30 days after screening for randomization into the study.
From the time of obtaining informed consent through the first administration of investigational 
medicinal product, record all serious adverse events (SAEs), as well as any adverse events 
related to protocol-mandated procedures on the adverse events case report form (CRF/eCRF). 
All other untoward medical occurrences observed during the screening period, including 
exacerbation or changes in medical history are to be captured on the medical history CRF/eCRF. 
See Section 7 Adverse Events and Toxicity Management for additional details.
6.2.2.
Randomization/ Baseline Assessments
All Day 1 (Baseline) tests and procedures must be completed in a fasted state prior to the receipt 
of the first dose of study drug. 

Review of inclusion/exclusion criteria and confirm medical history 

Complete pre-dose physical examination (includes weight, height, BMI)

Review concomitant medications and adverse events (AEs)


GS-9688 
Protocol GS-US-389-2025 
Gilead Sciences, Inc. 
• 
Vital Signs (blood pressure, heait rate, respiration rate and body temperature) 
• 
Safety laborato1y tests (senun chemistry, hematology, and coagulation) 
• 
Urinalysis 
• 
FibroTest 
• 
Sernm ~-hCG, for all female subjects of child-bearing potential 
• 
Urine Pregnancy Test, for all female subjects of child-bearing potential 
• 
HBV DNA and resistance smveillance 
• 
Quantitative HBsAg 
Final 
Amendment 1 
• 
Qualitative HBV serology (HBeAg [reflex HBeAb if HBeAg is negative] and HBsAg 
[ reflex HBsAb if HBsAg is negative]) 
I 
I 
I 
I 
• 
Whole blood gene expression (Paxgene RNA) samples on Day 1 Pre-dose, 1 + 4 hours 
• 
PBMC samples will be collected on Day 1 Pre-dose, 1 + 4 hours 
• 
Sparse (pre-identified) PK plasma sampling 
• 
Holter Monitoring: 
Day 1: Pre-dose (~ 5 minutes of dose) through 4 hours, and 24 hours 
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• 
Randomization 
Final 
Amendment 1 
• 
In clinic GS-9688/PTM study drng dosing. Study drng will be taken orally at approximately 
the same time on the same day once a week ( eve1y 7 days) for 24 doses. 
• 
T AF is to be dosed at approximately the same time daily with food or, in jurisdictions in 
which T AF has been approved, consult the local prescribing infonnation for T AF dose 
recommendations with concomitant medications. Baseline dosing will be no earlier than 
2 hours post GS-9688/PTM weekly dose 
• 
Dmg Administration of GS-9688/PTM 
• 
Dispense study mugs as directed by IWRS 
• 
Instmct the subject on the packaging, storage, and adininistration of both study diug 
GS-9688/PTM and T AF 
• 
Observe the subject taking the first dose of study dmg 
6.3. 
Treatment Assessments (All Visits Have Window of :I: 1 Days) 
All On-Treatment Assessments (Day 2 through Week 23 +24 hours) must be obtained in a fasted 
state prior to taking study diug unless othe1wise indicated: 
• 
Complete pre-dose physical examination (includes weight, height, BMI, vital signs, 
concomitant medications and adverse events [AEs]) on Weeks 2, 4, 8, and 12. 
• 
Symptom directed physical exam (includes weight) on Day 2, Weeks 11, 16, 20, 23 and 
23 + 24 hours. 
• 
Ophthalmologic exam on Week 12 (Days -4 to +10) 
• 
Review concomitant medications and AEs 
• 
Vital Signs (blood pressure, heart rate, respiration rate and body temperature) 
• 
Safety laborato1y tests (senun chemistry, hematology, and coagulation) on Weeks 2, 4, 8, 11, 
12, 16, 20, and 23 
• 
Urinalysis on Weeks 2, 4, 8, 11, 12, 16, 20, and 23 
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Gilead Sciences, Inc. 
Final 
Amendment 1 
• 
Sernm ~-hCG, for all female subjects of child-bearing potential on Weeks 4, 8, 12, 16, 
and20 
• 
Urine Pregnancy Test, for all female subjects of child-bearing potential on Weeks 2 and 11 
• 
HBV DNA and resistance surveillance on Weeks 2, 4, 8, 11, 12, 16, 20, and 23 
• 
Quantitative HBsAg on Weeks 2, 4, 8, 11, 12, 16, 20, and 23 
• 
Qualitative HBV serology (HBeAg [reflex HBeAb if HBeAg is negative] and HBsAg 
[ reflex HBsAb if HBsAg is negative]) on Week 12 
I 
I 
I 
• 
Whole blood gene expression (Paxgene RNA) samples on Days 1 + 24 hours (Day 2) and 
Weeks 11 Pre-dose, 11 +4 hours, 12, 23, 23 +4 hours, and 23 + 24 hours 
• 
PBMC samples will be collected on Days 1 + 24 hours (Day 2) and Weeks 11 Pre-dose, 
11 + 4 hours, 12, 23, 23 + 4 hours, and 23 + 24 hours 
I 
• 
Sparse (pre-identified) PK plasma sampling will occur on Week 23 at pre-dose, 1, 4, and 
24 hours post-dose and Week 11 at pre-dose, 1, and 4 hours post-dose. 
• 
Sparse (timed) plasma PK samples will be obtained on any two of the following visits: 
Weeks 2, 4, 8, 12, 16, and/or 20 at pre-dose and any time between 30 minutes to 4 hours 
post-dose. 
• 
Holter Monitoring: 
Week 11: Pre-dose (~ 5 minutes of dose) through 4 hours 
Week 23: Pre-dose(~ 5 minutes of dose) through 4 hours, and 24 hours 
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Gilead Sciences, Inc. 
Amendment 1
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
In clinic GS-9688 study drug dosing on Weeks 2, 4, 8, 11, 12, 16, 20, and 23. Self/Home 
GS-9688 study drug dosing on Weeks 1, 3, 5, 6, 7, 9, 10, 13, 14, 15, 17, 18, 19, 21, and 22. 
Study drug will be taken orally at approximately the same time on the same day once a week 
(every 7 days) for 24 doses.

TAF is to be dosed at approximately the same time daily with food or, in jurisdictions in 
which TAF has been approved, consult the local prescribing information for TAF dose 
recommendations with concomitant medications. Day 2 through Week 23, TAF dosing will 
be no earlier than 2 hours post GS-9688/PTM weekly dose.

Dispense GS-9688 and TAF on Weeks 4, 8, 12, 16, 20

Perform study drug accountability on both GS-9688/PTM and TAF
6.4.
Post GS-9688/PTM Treatment Assessments (All Visits Have Window of 
± 3 Days except Week 24 ± 1 Day)
Post GS-9688/PTM treatment assessments include the following, performed in a fasted state at 
all visits from Week 24 through Week 48, or in event of ED, unless specifically noted:

Complete physical examination (includes weight, height, BMI)

Ophthalmologic exam on Week 24 (-4days to +10 days)

Review concomitant medications and AEs

Vital Signs (blood pressure, heart rate, respiration rate and body temperature)

Safety laboratory tests (serum chemistry, hematology, and coagulation)

Urinalysis

FibroTest on Weeks 24 and 48/ED

Serum β-hCG, for all female subjects of child-bearing potential

HBV DNA levels and resistance surveillance samples

Qualitative HBV serology (HBeAg [reflex HBeAb if HBeAg is negative] and HBsAg 
[reflex HBsAb if HBsAg is negative]) on Weeks 24, 36, and 48/ED

Quantitative HBsAg
 
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
Whole blood gene expression (PAXgene RNA) samples on Weeks 24 and 48/ED

PBMC samples will be collected on Weeks 24 and 48/ED

Dispense TAF on Weeks 24, 28, and 36.

Perform TAF study drug accountability
If a subject chooses to terminate the study anytime during the post GS-9688/PTM period, all 
subjects should complete all of the above assessments at the ED visit.
6.5.
Treatment Free Follow-Up (TFFU) after ED
Subjects who ED will be followed every 4 weeks for 24 weeks or until initiation of alternative 
CHB therapy, whichever comes first. 
6.5.1.
TFFU after ED Visit Assessments (± 7 Days)
The following evaluations will be performed at follow up visits for subjects when they 
discontinue TAF unless otherwise specified. For more details, refer to Appendix 2.

Review of AEs and concomitant medications

Symptom-directed physical examination

Vital Signs (blood pressure, heart rate, respiration rate and body temperature)

Serum pregnancy test (for all female subjects of child-bearing potential)

Urinalysis

Safety laboratory tests (serum chemistry, hematology, and coagulation) 

HBV DNA levels and resistance surveillance

Quantitative HBsAg
  

Qualitative HBV serology (HBeAg [reflex HBeAb if HBeAg is negative] and HBsAg 
[reflex HBsAb if HBsAg is negative])
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GS-9688 
Protocol GS-US-389-2025 
Gilead Sciences, Inc. 
6.6. 
TFFU Post Study Completion (Week 48) 
Final 
Amendment 1 
Following completion of the 48-week study period the Investigators will be responsible for 
assessing the need to continue study subjects on ti·eatment for CHB. At Week 48, at 
PI discretion, subjects will be managed in one of two ways: 
1) Continue in the study for 48 weeks following the discontinuation ofTAF (Treatment Free 
Follow-Up, TFFU, window of± 7 days) or until an alternative commercially approved CHB 
ti·eatment is sta1ted, whichever occurs first. These subjects will be followed eve1y 4 weeks 
for the first 24 weeks and thereafter at Week 36 and 48 or until initiation of alternative CHB 
therapy, whichever comes first. 
2) Initiate other standard of care CHB therapy immediately at end of study. 
6.6.1. 
TFFU Post Study Completion Visit Assessments (± 7 Days) 
The following evaluations will be perfo1med at follow up visits for subjects when they 
discontinue TAF unless othe1w ise specified. For more details, refer to Appendix 2. 
• 
Review of AEs and concomitant medications 
• 
Symptom-directed physical examination 
• 
Vital Signs (blood pressure, heait rate, respiration rate and body temperature) 
• 
Sernm pregnancy test (for all female subjects of child-bearing potential) 
• 
Urinalysis 
• 
Safety laborato1y tests (senun chemistry, hematology, and coagulation) 
• 
HBV DNA levels and resistance surveillance 
• 
Quantitative HBsAg 
I 
• 
Qualitative HBV serology (HBeAg [reflex HBeAb if HBeAg is negative] and HBsAg 
[ reflex HBsAb if HBsAg is negative]) 
I 
I 
• 
Whole blood gene expression (P AXgene RNA) samples 
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Gilead Sciences, Inc. 
• 
PBMC samples 
I 
Final 
Amendment 1 
At the PI's discretion, subject(s) in the TFFU phase may initiate other standard of care CHB 
therapy at any time per local treatment guidelines. If a subject initiates other standard of care 
CHB therapy for their CHB, TFFU visits will continue for 2 more TFFU visits or until the end of 
the TFFU phase (Week 96), whichever comes first. 
6.7. 
Unscheduled Visits 
The assessments at the unscheduled visits are at the investigator's discretion. 
6.8. 
Pharmacokinetic Assessments 
• 
Sparse (pre-identified) plasma PK Collection: 
Day 1 : Pre-dose, 1, 4 and 24 hours post-dose 
Week 11 : Pre-dose , 1, and 4 hours post-dose 
Week 23: Pre-dose , 1, 4 and 24 hours post-dose 
• 
Sparse (timed) plasma PK Collection (Any 2 of the 2 collections below): 
-
I 
Week 2: Pre-dose and any time between 30 minutes to 4 hours post-dose 
Week 4: Pre-dose and any time between 30 minutes to 4 hours post-dose 
Week 8: Pre-dose and any time between 30 minutes to 4 hours post-dose 
Week 12: Pre-dose and any time between 30 minutes to 4 hours post-dose 
Week 16: Pre-dose and any time between 30 minutes to 4 hours post-dose 
Week 20: Pre-dose and any time between 30 minutes to 4 hours post-dose 
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Gilead Sciences, Inc. 
6.9. 
I 
I 
Pharmacodynamic Assessments 
• 
Whole blood gene expression (Paxgene RNA) samples: 
Days 1: Pre-dose, 4 hours and 24 hours post-dose 
Weeks 11: Pre-dose and 4 hours post-dose 
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Amendment 1 
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Final
Gilead Sciences, Inc. 
Amendment 1
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Week 12: Pre-dose
Week 23: Pre-dose, 4 hours and 24 hours post-dose
Week 24
Week 48/ED
TFFU: Weeks 4, 8, 12, 16, 20, 24, 36, and 48

PBMC: 
Days 1: Pre-dose, 4 hours, and 24 hours post-dose 
Week 11: Pre-dose and 4 hours post-dose
Week 12 Pre-dose
Week 23: Pre-dose, 4 hours, and 24 hours post-dose
Week 24
Week 48/ED
TFFU: Weeks 4, 8, 12, 16, 20, 24, 36, and 48
 
 
 
 
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6.10. 
Safety Assessments 
Final 
Amendment 1 
Assessment of AEs and concomitant medications will continue throughout the duration of the 
study, including TFFU. Laborato1y analyses, physical examinations including vital signs, and 
ECGs/ Holter monitoring will be perfo1med at defined intervals throughout the study. 
Safety Assessments will be perfonned through the study as outlined in Appendix 2. 
6.10.1. 
Electrocardiogram Assessment 
Subjects should rest quietly in the supine position for a minimum of 10 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 prior to any blood draw using the site's standard ECG 
equipment. All ECGs will be obtained using instilllllents that analyze data using the same 
algorithms and produce the same data. for inte1pretation. Electi·ode placement will be perfo1med 
according to the method of Wilson, Goldberger, and Einthoven with a check to confom that the 
a VR lead is not inverted. The investigator or other qualified individuals at the study center will 
review ECGs to assess for changes in ECG intervals and m01phology 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. 
6.10.2. 
Holter Monitoring 
For the pmposes of this study, time-matched digital 12-lead ECGs will be collected as 
continuous recordings. ECGs may be exti·acted from recorded data. at a later time. 
Holter recording will be obtained via continuous 12-lead digital recorder. Baseline and 
on-ti·eatinent ECGs for all ti·eatinents will be measured from the same lead for each subject 
(lead II, when possible). Triplicate ECGs will be exti·acted at various time points for each 
pre-detennined time point as indicated below: 
• 
Holter Monitoring 
Day 1: Pre-dose (~ 5 minutes of dose) through 4 hours, and 24 hours 
Week 11: Pre-dose (~ 5 minutes of dose) through 4 hours 
Week 23: Pre-dose(~ 5 minutes of dose) through 4 hours, and 24 hours 
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Final
Gilead Sciences, Inc. 
Amendment 1
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During ECG sampling, subjects will rest in a supine position for 10 minutes before and during 
the 5-minute window for each pre-determined ECG acquisition time point. ECGs should be 
collected in a calm, relaxed environment. Environmental distractions (including TV, radio, 
video games, and conversation) and the use of electronic devices (including cell phones, tablets, 
and laptops) during both the pre-ECG rest and the ECG recording period must be avoided.
All ECG acquisitions will be carried out before blood sample collections at that time point. 
6.10.3.
Physical Examination
Physical examinations conducted throughout the study will be either a complete physical 
examination or symptom directed physical examination, as outlined in Appendix 2. 
The complete physical examination conducted at screening will also include the following 
assessments:
Review medical history, including history of allergies, prior and current use of ,cigarettes, 
tobacco, or any smoking products, alcohol and illegal drug use, and prior (within 30 days) and 
current medication use.
6.10.4.
Vital Signs 
Assessment of vital signs will include measurement of resting blood pressure, pulse, respiratory 
rate, and oral temperature. Subject body weight will also be assessed at all visits with a complete 
PE. Refer to Appendix 2 for more information.
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
6.10.5.
Clinical Laboratory Tests/Assessments for Safety Evaluations
Blood and urine samples for safety evaluations will be collected throughout the study as outlined 
in Appendix 2.


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6.10.5.1.
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 INR)

Chemistry (fasting): 
Alkaline phosphatase, AST, ALT, total bilirubin, direct and indirect bilirubin, total 
cholesterol, high-density lipoprotein (HDL), LDL, triglycerides (TG), total protein, 
albumin, lactic acid dehydrogenase (LDH), 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 × ULN)

Serum pregnancy test (females of childbearing potential only)

FSH testing (For female subjects post-menopausal for less than two years, if FSH 
< 40 mIU/mL a serum pregnancy test will be required)

HIV, HDV, and HCV testing (screening only)

HBV Viral Parameters:
Qualitative HBV Serology, HBV DNA levels, HBV Resistance Surveillance, 
Quantitative HBsAg, 
6.10.5.2.
Urine Samples
Urine samples will be collected for urinalysis, alcohol and drug screen assessments and urine 
pregnancy as applicable.
6.10.6.
Creatinine Clearance
Weight will be collected at screening and upon admission calculate creatinine clearance (CrCl) 
for inclusion criteria.
Estimated CrCl < 60 mL/min (using the Cockcroft-Gault method) based on serum creatinine and 
actual body weight as measured at the screening evaluation, i.e.
Male: 
(140 – Age [years]) (Weight [kg])
CrCl (mL/min)
72 (Serum Creatinine [mg/dL])
Female: 
(140 – Age [years]) (Weight [kg]) 0.85 
CrCl (mL/min)
72 (Serum Creatinine [mg/dL])
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GS-9688 
Protocol GS-US-389-2025 
Gilead Sciences, Inc. 
6.10.7. 
Ophthalmic Examination 
Final 
Amendment 1 
Ophthalmic Examinations will be perfo1med to assess ophthalmologic findings, including slit 
lamp and fundoscopic examination with retinal photographs (both eyes). An examination of the 
full retinal field should be conducted noting changes or abnonnalities. Photographs of the retina 
must be taken at each exam and filed in the subject's source medical records. A central vendor 
will be used to assess the retinal photographs. Refer to Appendix 2 for ophthalmic examination 
collection time points. 
A procedural window will be given to accommodate ophthalmic assessments. Refer to Section 6 
and Appendix 2 for details. 
6.10.8. 
Adverse Events/Concomitant Medications/Protocol Restrictions 
Evaluation for AEs, review of concomitant medications, and review of protocol restrictions will 
occur at the times shown in Appendix 2. See Section 7 .1 for more info1mation regarding AEs 
and Section 5 and Table 5-1 for more info1mation about concomitant medications. 
6.12. 
Assessments for Premature Discontinuation from Study 
If a subject discontinues study treatment 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 procedures until stabilization per the investigator. 
If this is not possible or acceptable to the subject or investigator, the subject may be withdrawn 
from the study. Evaluations indicating abno1mal results believed to be possibly or probably 
related to study treatment at the ED visit should be repeated weekly or as often as deemed 
appropriate by the investigator until the abno1mality resolves, returns to baseline visit levels, or 
is othe1wise explained. 
6.13. 
Criteria for Discontinuation of Study Treatment 
Discontinuation of dosing for individual subjects will be governed by pre-specified stopping 
rnles for safety and tolerability. 
Study medication may be discontinued in the following instances: 
• 
Intercunent illness that would, in the judgment of the investigator, affect assessments of 
clinical status to a significant degree 
• 
Unacceptable toxicity, as defined in the toxicity management Section 7.6 of the protocol, or 
toxicity that, in the judgment of the investigator, compromises the ability to continue 
study-specific procedures or is considered not to be in the subject's best interest 
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Gilead Sciences, Inc. 
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
Subject request to discontinue for any reason

Subject noncompliance

Pregnancy during the study; refer to Appendix 3

Investigator discretion

Discontinuation of the study at the request of Gilead, a regulatory agency or an institutional 
review board or independent ethics committee (IRB/IEC)

Continuation of dosing will be suspended if three or more Grade 3 or two or more Grade 4 
treatment-emergent, drug related AEs or laboratory abnormalities occur. Decisions to 
reinitiate continuation of dosing will be made by the Sponsor 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 study drugs will be followed for 24 weeks or until the initiation of 
alternative CHB therapy, whichever comes first.
6.14.
Resistance Surveillance
Sequence analysis of the HBV genome will be attempted for all viremic subjects (HBV DNA 
>69 IU/mL) at Week 48 or at early discontinuation (with at least 24 weeks of TAF treatment). 
Additionally, any patient that experiences virologic breakthrough (confirmed HBV DNA 
≥69 IU/mL after having been <69 IU/mL or confirmed HBV DNA ≥1 log10 IU/mL increase from 
nadir) will be evaluated by sequence analysis of the HBV pol/RT.
As it may not be known at the time of the visit whether a patient is viremic or if it will be their 
last study visit, a separate serum sample for potential resistance surveillance will be collected at 
each study visit.
6.15.
End of Study
The end of this study will be the last subject’s last completed study visit observed at Week 48. If 
the subject enrolls in the TFFU phase, the subject will be observed for up to an additional 
48 weeks (Week 96).
6.16.
Post Study Care
Once a subject has completed their study participation, the long-term care of the participant will 
remain 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 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 7.10.1)

Any medical condition or clinically significant laboratory abnormality with an onset date 
before the consent form is signed and not related to a protocol-associated procedure is not an 
AE. It is considered to be pre-existing and should be documented on the medical history 
CRF.
7.1.2.
Serious Adverse Events
A serious adverse event (SAE) is defined as an event that, at any dose, results in the following:

Death

Life-threatening (Note: The term “life-threatening” in the definition of “serious” refers to an 
event in which the subject was at risk of death at the time of the event; it does not refer to an 
event that hypothetically might have caused death if it were more severe.)

In-patient hospitalization or prolongation of existing hospitalization


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
Persistent or significant disability/incapacity

A congenital anomaly/birth defect

A medically important event or reaction: such events may not be immediately 
life-threatening or result in death or hospitalization but may jeopardize the subject or may 
require intervention to prevent one of the other outcomes constituting SAEs. Medical and 
scientific judgment must be exercised to determine whether such an event is a reportable 
under expedited reporting rules. Examples of medically important events include intensive 
treatment in an emergency room or at home for allergic bronchospasm; blood dyscrasias or 
convulsions that do not result in hospitalization; and development of drug dependency or 
drug abuse. For the avoidance of doubt, infections resulting from contaminated medicinal 
product will be considered a medically important event and subject to expedited reporting 
requirements.
7.2.
Assessment of Adverse Events and Serious Adverse Events
The investigator or qualified subinvestigator is responsible for assessing AEs and SAEs for 
causality and severity, and for final review and confirmation of accuracy of event information 
and assessments.
7.2.1.
Assessment of Causality for Study Drugs and Procedures
The investigator or qualified subinvestigator is responsible for assessing the relationship to IMP
therapy using clinical judgment and the following considerations:

No: Evidence exists that the adverse event has an etiology other than the IMP. For SAEs, an 
alternative causality must be provided (e.g., pre-existing condition, underlying disease, 
intercurrent illness, or concomitant medication).

Yes: There is reasonable possibility that the event may have been caused by the 
investigational medicinal product.
It should be emphasized that ineffective treatment should not be considered as causally related in 
the context of adverse event reporting. 
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
AE severity should be recorded and graded according to the modified GSI Grading Scale for 
Severity of AEs and Laboratory Abnormalities (Appendix 4). 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.
The distinction between the seriousness and the severity of an adverse event should be noted.
Severity is a measure of intensity; thus, a severe reaction is not necessarily a serious reaction. For 
example, a headache may be severe in intensity, but would not be classified as serious unless it 
met one of the criteria for serious events.
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.
7.3.
Investigator Requirements and Instructions for Reporting Adverse Events 
and Serious Adverse Events to Gilead 
Requirements for collection prior to study drug initiation:
After informed consent, but prior to initiation of study medication, the following types of events 
should be reported on the case report form (CRF/eCRF): all SAEs and adverse events related to 
protocol-mandated procedures.
7.3.1.
Adverse Events
Following initiation of study treatment, collect all AEs, regardless of cause or relationship, until 
30 days after last administration of study drug(s) and report to the eCRF database as instructed.
Further, any AEs occurring during TFFU should also be reported, regardless of cause or 
relationship.
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.
7.3.2.
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 
CRF/eCRF database and Gilead Pharmacovigilance and Epidemiology (PVE) as instructed. This 
also includes any SAEs resulting from protocol-associated procedures performed after informed 
consent is signed.


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Final 
Amendment 1 
Any SAEs and deaths that occur after the post treatment follow-up visit but within 30-days of the 
last dose of study dmg(s), regardless of causality, should also be reported. 
Investigators are not obligated to actively seek SAEs after the protocol defined follow up period; 
however, if the investigator learns of any SAEs that occur after study pa1ticipation has concluded 
and the event is deemed relevant to the use of IMP, he/she should promptly document and repo1t 
the event to Gilead PVE. 
• 
All AEs and SAEs will be recorded in the CRF/eCRF database within the timelines outlined 
in the CRF/eCRF completion guideline. 
Electronic Serious Adverse Event (eSAE) Repo1ting Process 
• 
Site personnel record all SAE data in the eCRF database and from there tr·ansmit 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 stait), record the 
SAE on the paper serious adverse event repo1t fo1m and submit by e-mail or fax within 
24 hours of the investigator's knowledge of the event to: 
Gilead PVE (previously Gilead 
DSPH): 
Fax: 
E-mail: 
PPD 
PPU 
• 
As soon as it is possible to do so, any SAE repo1ted via paper must be transcribed into the 
eCRF Database according to instructions in the eCRF completion guidelines. 
• If an SAE has been repo1ted via a paper fonn because the eCRF database has been locked, no 
fmther action is necessaiy. 
• 
For fatal or life-threatening events, copies of hospital case repo1ts, autopsy repo1ts, and other 
documents are also to be submitted by e-mail or fax when requested and applicable. 
Transmission of such documents should occur without personal subject identification, 
maintaining the tr·aceability of a document to the subject identifiers. 
• 
Additional infonnation may be requested to ensure the timely completion of accurate safety 
repo1ts. 
• 
Any medications necessaiy for tr·eatinent of the SAE must be recorded onto the concomitant 
medication section of the subject's CRF/eCRF and the event description section of the SAE 
fo1m. 
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7.4.
Gilead Reporting Requirements
Depending on relevant local legislation or regulations, Gilead may be required to expedite to 
worldwide regulatory agencies reports of SAEs, serious adverse drug reactions (SADRs), or 
suspected unexpected serious adverse reactions (SUSARs). In accordance with the EU Clinical 
Trials Directive (2001/20/EC), Gilead or a specified designee will notify worldwide regulatory 
agencies and the relevant IEC in concerned Member States of applicable SUSARs as outlined in 
current regulations as applicable.
Assessment of expectedness for SAEs will be determined by Gilead using reference safety 
information specified in the investigator’s brochure or relevant local label as applicable. 
All investigators will receive a safety letter notifying them of relevant SUSAR reports associated 
with any study IMP. The investigator should notify the IRB or IEC of SUSAR reports as soon as 
is practical, where this is required by local regulatory agencies, and in accordance with the local 
institutional policy. 
7.5.
Clinical Laboratory Abnormalities and Other Abnormal Assessments as 
Adverse Events or Serious Adverse Events
Laboratory abnormalities without clinical significance 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, modification or discontinuation must be 
recorded as an AE, as well as an SAE, if applicable. In addition, laboratory or other abnormal 
assessments (e.g., electrocardiogram, X-rays, vital signs) that are associated with signs and/or 
symptoms must be recorded as an AE or SAE if they meet the definition of an AE (or SAE) as 
described in Sections 7.1.1 and 7.1.2. If the laboratory abnormality is part of a syndrome, record 
the syndrome or diagnosis (i.e., anemia) not the laboratory result (i.e., decreased hemoglobin).
Severity should be recorded and graded according to the modified GSI Grading Scale for 
Severity of Adverse Events and Laboratory Abnormalities as described in Appendix 4. The GSI 
Grading Scale for Severity of Adverse Events and Laboratory Abnormalities has been modified 
to be more appropriate for healthy volunteers and patients with inflammatory diseases 
(e.g. rheumatoid arthritis, asthma, psoriasis). 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.


GS-9688 
Protocol GS-US-389-2025 
Gilead Sciences, Inc. 
7.6. 
Toxicity Management 
Final 
Amendment 1 
All clinical and clinically significant laborato1y toxicities will be managed according to unifo1m 
guidelines detailed in Appendix 4. 
• 
All Grade 3 or greater AEs and laborato1y abno1m alities will be reviewed by the Sponsor to 
dete1mine if the event is at least possibly treatment-related to dete1mine if the study diug 
should be held or discontinued 
• 
Grade 3 and 4 clinically significant laborato1y abno1m alities should be confin ned by repeat 
testing within 3 calendar days of receipt of results and before investigational medicinal 
product discontinuation, unless such a delay is not consistent with good medical practice. 
• 
Clinical events and clinically significant laborato1y abnonnalities will be graded according to 
the Table for GSI Grading Scale for Severity of Adverse Events and Laborato1y 
Abnonnalities (Appendix 4). 
• 
When restaiiing investigational medicinal product following resolution of the adverse event, 
the investigational medicinal product should be restaiied at full dose that is dependent upon 
discussion with the Gilead Sciences Medical Monitor. 
• 
Administration of study dmg may be discontinued due to a clinical or laborato1y event. The 
Gilead Medical Monitor should be consulted prior to dose discontinuation of study di11g 
unless the investigator believes that immediate action is waiTanted to ensure the continued 
safety of subject. 
• 
Any questions regai·ding toxicity management should be directed to the Gilead Sciences 
Medical Monitor. 
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7.6.2.
Management of GS-9688/PTM Dose Limiting Toxicities
In the event of any DLT, the investigator should discuss with the Gilead Medical Monitor the 
subject’s status until the DLT has resolved.
GS-9688/PTM dosing for a subject will be held if the subject experiences at least one of the 
following DLT:

A confirmed, clinically significant lab abnormality (other than ALT) ≥ Grade 3 considered 
drug-related by the investigator or Sponsor

Dose-limiting ALT flare defined as confirmed ALT ≥ 10x ULN (to be confirmed within 
3 days from receipt of initial laboratory results)
If a subject experiences any of the above DLT, then GS-9688/PTM will be held until repeat labs 
demonstrate that the lab abnormality returns to ≤ Grade 2 levels. Once the lab abnormality 
returns to ≤ Grade 2, GS-9688/PTM can be restarted with medical monitor approval. Subjects 
who experience a dose interruption DLT will continue to be monitored at least once a week, or 
more frequently as clinically needed, until resolution.
GS-9688/PTM dosing for a subject will be permanently discontinued if the subject experiences 
at least one of the following DLTs:

A confirmed ALT increase (i.e. grade shift or 2x previous value) with evidence of worsened 
hepatic function (e.g. Total Bilirubin > 2mg/dL above BL, elevated INR ≥ 1.7 or > 0.5 over 
BL, abnormal serum albumin > 1g/dL decrease from BL)

Prolonged (2 sequential), confirmed, clinically significant lab abnormality (other than ALT) 
≥ Grade 3 considered drug-related by the investigator

Any confirmed recurrence of study drug-related Grade 3 or 4 clinically significant laboratory 
adverse event following dose interruption mandates permanent discontinuation of study drug.

A confirmed ≥ Grade 3 AE (excluding ALT) considered drug-related by the investigator
Subjects who experience a permanent discontinuation DLT will be monitored at least once a 
week, or more frequently as clinically needed, until resolution.
7.6.3.
TAF Dose Modification and Monitoring
Post GS-9688/PTM treatment plus 7 days, based on the results of the confirmatory tests listed in 
Section 7.6.1, the following treatment modifications for TAF are recommended:


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Table 7-1.
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.
The Gilead Medical Monitor should be consulted prior to study drug modification or 
discontinuation when medically feasible.
7.6.4.
Management of Neutropenia
If a subject experiences Grade 2 or higher neutropenia while participating in the study, they 
should return to the study site the following week (within 7 days) for retest and result 
confirmation from the central lab. If Grade 2 or higher neutropenia is confirmed, GS-9688/PTM
dosing should be held until the retest results are available and subject followed weekly until 
neutrophils improves to < Grade 2. At that time, with Gilead medical monitor approval, 
GS-9688/PTM may be rechallenged.
If study drug is re-challenged following a return to < Grade 2, GS-9688/placebo dosing should 
continue as per the original treatment schedule. If any scheduled dosing of GS-9688/placebo is 
missed due to a Grade 2 neutropenia event, it should be captured in the source documentation 
and appropriate CRF.
7.6.5.
Grades 1 and 2 Laboratory Abnormality or Clinical Event
Continue study drug at the discretion of the investigator.


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7.6.6.
Grades 3 and 4 Laboratory Abnormality or Clinical Event
For a Grade 3 and 4 clinical event or clinically significant Grade 3 and 4 laboratory abnormality 
(with the exception of asymptomatic Grade 3 or 4 cholesterol and triglyceride increases or CK 
elevations unrelated to study drug, or hematuria due to menses) confirmed by repeat testing 
(preferably within 3 calendar days after receipt of the original test results), study drug 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 3 and 4 laboratory 
abnormality that is not confirmed by repeat testing should be managed according to the 
algorithm for the new toxicity grade.
7.7.
Other Criteria for Discontinuation of Study Drug

Discontinuation of dosing for individual subjects will be governed by pre-specified stopping 
rules for safety and tolerability.
Study medication may be discontinued in the following instances:

Intercurrent illness that would, in the judgment of the investigator, affect assessments of 
clinical status to a significant degree

Unacceptable toxicity, as defined in the toxicity management Section 7.6 of the protocol, or 
toxicity that, in the judgment of the investigator, compromises the ability to continue 
study-specific procedures or is considered not to be in the subject’s best interest

Subject requests to discontinue for any reason

Subject noncompliance

Pregnancy during the study; refer to Appendix 3

Investigator discretion

Discontinuation of the study at the request of Gilead, a regulatory agency or an IRB or IEC

Continuation of dosing will be suspended if three or more Grade 3 or two or more Grade 4 
treatment-emergent, drug related AEs or laboratory abnormalities occur. Decisions to 
reinitiate continuation of dosing will be made by the Sponsor 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 
disease will be managed according to local standard of care if subjects are discontinued from the 
study. Subjects that discontinue all study drugs will be followed for 24 weeks or until the 
initiation of alternative CHB therapy, whichever comes first.


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An independent, external Data Monitoring Committee (DMC) will review the progress of the 
study and perform safety data review after 20 subjects have completed randomization.
Subsequent meetings may be held approximately every 3 months until the last subject enrolled 
has completed the study drug dosing period. The DMC will provide recommendations as needed 
regarding study conduct and the need for additional meetings or an alternative meeting schedule.
The DMC will be immediately notified in the event of any dose limiting toxicities (DLT) or 
virologic study stopping criteria. 
7.8.
Subject Withdrawal Criteria
Discontinuation of dosing for individual subjects will be governed by pre specified stopping 
rules for safety and tolerability. A subject will be withdrawn from study if they experience one of 
the following:

A confirmed, clinically significant treatment-emergent ≥ Grade 3 adverse event or laboratory 
abnormality (with the exception of asymptomatic Grade 3 or 4 cholesterol and TG increases 
or CK elevations unrelated to study drug, or hematuria due to menses), considered treatment-
related, defined by the GSI Grading Scale (Appendix 4). Subjects should be followed as 
clinically indicated until the laboratory abnormality returns to baseline or is otherwise 
explained, whichever occurs first. Grade 3 and 4 laboratory abnormalities that are not 
confirmed by repeat testing should be managed according to the algorithm for the new 
toxicity grade.

A clinically significant ECG measurement (e.g., a change from baseline QTcF value of 
> 60 msec, 2nd or 3rd degree heart block, or pronounced QRS widening) by confirmed 
measurement as described in Section 6.10.1.
7.9.
Study Specific Stopping Criteria
7.9.1.
Laboratory Abnormalities and Treatment-Emergent Adverse Events
If 3 or more subjects in any cohort experience the same or similar Grade 3 or Grade 4 
treatment-emergent adverse event or confirmed laboratory abnormality (with the exception of 
asymptomatic Grade 3 or 4 cholesterol and TG increases), unless there is a clear and obvious 
physiologic explanation for the events (e.g., blood in urine occurring in a menstruating female, 
CK elevation after strenuous exercise, or TG elevation that is non fasting, etc.), then a review of 
all safety data generated in subjects dosed to date will be initiated. For individuals already on 
study drug, the decision whether or not to complete the full course of study medication will be 
made by the sponsor with disclosure of new information to the study subject(s).
7.9.2.
Virologic Criteria
If 2 or more subjects in a treatment arm experience an increase in HBV DNA of ≥ 69 IU/mL on 
two consecutive visits, unless there is a clear and obvious explanation for the events 
(e.g. nonadherence to OAV), then a review of all safety data generated in subjects dosed to date 
will be initiated. During this time, further enrollment into that treatment arm will be held and not 


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reopened for enrollment until the decision to reinitiate dosing is made by the Sponsor with input 
from the DMC upon review of all safety data generated by subjects dosed to date. For 
individuals already on study drug, the decision whether or not to complete the full course of 
study medication will be made by the Sponsor. Disclosure of this new information will be 
provided to the study subject(s). 
7.10.
Special Situations Reports
7.10.1.
Definitions of Special Situations
Special situation reports include all reports of medication error, abuse, misuse, overdose, reports 
of AEs associated with product complaints, occupational exposure with an AE, pregnancy 
reports regardless of an associated AE and AE in an infant following exposure from 
breastfeeding.  
Medication error is any unintentional error in the prescribing, dispensing, or administration of a 
medicinal product while in the control of the health care provider, subject, or consumer.
Abuse is defined as persistent or sporadic intentional excessive use of a medicinal product by a 
subject.
Misuse is defined as any intentional and inappropriate use of a medicinal product that is not in 
accordance with the protocol instructions or the local prescribing information.
An overdose is defined as an accidental or intentional administration of a quantity of a medicinal 
product given per administration or cumulatively which is above the maximum recommended 
dose as per protocol or in the product labelling (as it applies to the daily dose of the subject in 
question). In cases of a discrepancy in drug accountability, overdose will be established only 
when it is clear that the subject has taken the excess dose(s). Overdose cannot be established 
when the subject cannot account for the discrepancy except in cases in which the investigator has 
reason to suspect that the subject has taken the additional dose(s).
Product complaint is defined as complaints arising from potential deviations in the manufacture, 
packaging, or distribution of the medicinal product.  
Occupational exposure is defined as exposure to a medicinal product as a result of one’s
professional or non-professional occupation. 
Infant exposure from breastfeeding that is associated with an AE. 


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7.10.2.
Instructions for Reporting Special Situations
7.10.2.1.
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 CRF/eCRF completion guidelines for full instructions on the 
mechanism of pregnancy reporting.
The pregnancy itself is not considered an AE nor is an induced elective abortion to terminate a 
pregnancy without medical reasons.
Any premature termination of pregnancy (e.g., a spontaneous abortion, an induced therapeutic 
abortion due to complications or other medical reasons) must be reported within 24 hours as an 
SAE. The underlying medical reason for this procedure should be recorded as the AE term.
A spontaneous abortion is always considered to be an SAE and will be reported as described in 
Section 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: 
 
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 3 for Pregnancy Precautions, Definition for Female of Childbearing Potential, 
and Contraceptive Requirements.
7.10.2.2.
Reporting Other Special Situations
All other special situation reports must be reported on the special situations report form and
forwarded to Gilead PVE within 24 hours of the investigator becoming aware of the situation. 
These reports must consist of situations that involve study IMP and/or Gilead concomitant 
medications, but do not apply to non-Gilead concomitant medications. 
PPD
PPD
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Special situations involving non-Gilead concomitant medications does not need to be reported on 
the special situations report form; however, for special situations that result in AEs due to a 
non-Gilead concomitant medication, the AE should be reported on the AE form. 
Any inappropriate use of concomitant medications prohibited by this protocol should not be 
reported as “misuse,” but may be more appropriately documented as a protocol deviation.
Refer to Section 7.3 and the CRF/eCRF completion guidelines for full instructions on the 
mechanism of special situations reporting.
All clinical sequelae in relation to these special situation reports will be reported as AEs or SAEs 
at the same time using the AE CRF/eCRF and/or the SAE report form. Details of the symptoms 
and signs, clinical management, and outcome will be reported, when available.


GS-9688 
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8. 
STATISTICAL CONSIDERATIONS 
8.1. 
Analysis Objectives and Endpoints 
8.1.1. 
Analysis Objectives 
The primary objectives of this study are as follows: 
Final 
Amendment 1 
• 
To evaluate the safety and tolerability of multiple oral doses of GS-9688 at Week 24 in CHB 
adult subjects who are viremic and not cmTently not being treated 
• 
To evaluate the antiviral activity of GS-9688 as measmed by the propo1iion of subjects with 
~l log10 ID/mL decline from baseline in senun qHBsAg at Week 24 
The secondary objectives of this study are as follows: 
• 
To evaluate the antiviral activity of GS-9688 at Weeks 4, 8, 12 and 48 as measmed by the 
propo1iion of subjects with ~1 log10 IU/mL decline from baseline in sernm qHBsAg 
• 
To evaluate the change in senun qHBsAg (log10 IU/mL) from baseline to Weeks 4, 8, 12, 
24 and 48 
• 
To evaluate the propo1iion of subjects with HBV DNA <LLOQ at Weeks 12, 24, and 48 
• 
To evaluate the propo1iion of subjects with HBsAg loss at Weeks 12, 24 and 48 
• 
To evaluate the propo1iion of subjects with HBeAg loss and seroconversion at Weeks 12, 
24 and48 
• 
To characterize the PK of GS-9688 
• 
To evaluate the propo1iion of subjects experiencing HBV virologic breakthrough 
(2 consecutive visits of HBV DNA ~ 69 IU/mL) 
• 
To evaluate the incidence of drng resistance mutations 
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8.1.2. 
Primary Efficacy Endpoint 
The primary efficacy endpoint is: 
Final 
Amendment 1 
• 
Proportion of subjects with 
1 log10 IU/mL decline in sernm qHBsAg from baseline at 
Week24 
8.1.3. 
Secondary Efficacy Endpoints 
The secondary efficacy endpoints are: 
• 
Proportion of subjects with 
1 log10 IU/mL decline in sernm qHBsAg from baseline at 
Weeks 4, 8, 12 and 48 
• 
Change in sernm qHBsAg (log10 IU/mL) from baseline at Weeks 4, 8, 12, 24 and 48 
• 
Proportion of subjects with HBV DNA <LLOQ at Weeks 12, 24, and 48 
• 
Proportion of subjects with HBsAg loss at Weeks 12, 24 and 48 
• 
Propo1t ion of subjects with HBeAg loss and seroconversion at Weeks 12, 24 and 48 
• 
Propo1t ion of subjects with virologic breakthrough (2 consecutive visits of HBV DNA 
69 IU/mL) 
• 
Propo1t ion of subjects with drng resistance mutations 
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8.2. 
8.2.1. 
8.2.1.1. 
Analysis Conventions 
Analysis Sets 
Efficacy 
Final 
Amendment 1 
The prima1y analysis set for efficacy analysis is the full analysis set (FAS), defined as all 
randomized subjects who took at least 1 dose of the study diug. Subjects will be analyzed 
according to the randomized treatment assignment. In this study, the study di11gs are 
GS-9688/PTM and TAF. 
8.2.1.2. 
Safety 
The prima1y analysis set for safety analysis is the safety analysis set (SAS), defined as all 
subjects who took at least 1 dose of the study diug. Subjects will be analyzed according to the 
treatment actually received. 
8.2.1.3. 
Phaimacokinetics 
The PK analysis set will include all randomized subjects who took at least 1 dose of the study 
diug and have at least 1 nonmissing concentration value repo1ted by the PK laborato1y. 
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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. For 
summary statistics, PK concentration values below the limit of quantitation (BLQ) will be treated 
as zero at pre-dose and one-half of the LLOQ for post dose time points. 
8.4. 
Demographic Data and Baseline Characteristics 
Demographic and baseline measurements will be sUilllnai·ized by treatment group and overall for 
each coho1t using standai·d descriptive methods. 
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Demographic summaries will include age, sex, race and ethnicity.
Baseline data will include a summary of body weight, height, body mass index, HBsAg 
(log10 IU/mL), HBV DNA (log10 IU/mL), HBV genotype, ALT and additional endpoints as 
necessary. 
8.5.
Efficacy Analysis
8.5.1.
Primary Analysis
The primary efficacy analysis will be performed in FAS after the last subject has completed 
Week 24 assessments or discontinued GS-9688 or placebo prematurely.
The proportion of subjects with ≥ 1 log10 IU/mL decline in qHBsAg from baseline at Week 24 
will be evaluated. To compare the GS-9688 1.5 mg dose group and the GS-9688 3 mg dose 
group to the placebo group for HBeAg positive and negative subjects separately, the 
95% confidence intervals (CI) on the proportion difference (1.5 mg – PTM, 3 mg – PTM) will be 
constructed, by baseline HBeAg status (positive, negative), based on the standardized statistic 
and inverting 2 1-sided tests.
In addition, by combining the HBeAg positive and negative subjects, the 2-sided 95% CI of the 
proportion difference (1.5 mg – placebo, 3 mg – placebo) will be constructed by using 
stratum-adjusted Mantel-Haenszel proportions, stratified by 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 for 
each cohort. 
Categorical secondary endpoints will be summarized by number and percentage of subjects that 
meet the endpoint by treatment group for each cohort.
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 for each 
cohort. 
Categorical endpoints will be summarized by number and percentage of subjects who meet the 
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8.6.
Safety Analysis
All safety data collected on or after the first dose of study drug administration up to 30 days after 
the last dose of GS-9688/PTM will be summarized by treatment group according to the study 
drug received for primary analysis at Week 24. Safety data will continue to be collected for TAF 
up to 48 weeks plus 3 days and will be summarized by treatment group according to the 
GS-9688/PTM study drug received. All safety data collected during the study will be included in 
data listings.
8.6.1.
Extent of Exposure
A subject’s extent of exposure to study drug data will be generated from the study drug 
administration page in eCRF. Exposure data will be summarized by treatment group.
8.6.2.
Adverse Events
Clinical and laboratory 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.
Events will be summarized on the basis of the date of onset for the event. A treatment-emergent 
+AE at primary analysis (Week 24) will be defined as any AE with an onset date on or after the 
study drug start date and no later than 30 days after permanent discontinuation of the 
GS-9688/PTM; or any AE leading to premature discontinuation of study drugs. A 
treatment-emergent AE at Week 48 analysis will be defined as any AE with an onset date on or 
after study drugs start date and no later than 3 days after permanent discontinuation of TAF or 30 
days after GS-9688/PTM, whichever comes later; or any AE leading to premature 
discontinuation of study drugs.
Summaries (number and percentage of subjects) of treatment-emergent AEs (by SOC and PT) 
will be provided by treatment group:

All AEs

AEs of Grade 3 or above

AEs of Grade 2 or above

All treatment-related AEs

Treatment-related AEs of Grade 3 or above

Treatment-related AEs of Grade 2 or above

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All treatment-related SAEs 
• 
All AEs leading to temponuy intenuption of the study drng 
• 
All AEs leading to premature discontinuation of the study chug 
• 
All AEs collected during the study will be presented in the data listings. 
8.6.3. 
Laboratory Evaluations 
Final 
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Selected laborato1y data (using conventional units) will be summarized using only observed data. 
Data and the conesponding change from baseline will be summarized by treatment group at each 
measured study visit. 
Graded laborato1y abnonnalities will be defined using the grading scheme in Appendix 4 
(GSI Grading Scale for Severity of Adverse Events and Laborato1y Abno1malities) for analysis 
pmpose. 
Treatment emergent lab abno1malities will be defined as values that increase by at least 
one toxicity grade from baseline at any time post baseline up to the date of the last dose of 
GS-9688/PTM plus 30 days at primaiy analysis (Week 24), and up to the date of the last dose of 
T AF plus 3 days or up to the last dose of GS-9688/PTM plus 30 days, whichever comes later at 
Week 48 analysis. Incidence of treatment-emergent laborato1y abnonnalities will be summai·ized 
by treatment group. 
Values for missing safety laborato1y data will not be imputed; however, a missing baseline result 
will be replaced with a screening result, if available. If no pretreatment laborato1y value is 
available, the baseline value will be assumed to be n01mal (i.e., no grade [Grade 0]) for the 
summary of graded laborato1y abno1malities. 
All laborato1y abno1malities will be included in the listings of laborato1y data. 
8.6.4. 
Other Safety Evaluations 
Individual data for ECG and vital sign measurements will be listed by subject and summai·ized 
for each treatment group by incidence of events/abno1malities or descriptive statistical 
summaries (n, mean, SD, median, QI, Q3, minimum, and maximum), as appropriate. 
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Sample Size 
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Due to the explorato1y nature of this study, the sample size was not detennined by any fo1mal 
power calculation. The number of subjects in each treatment group was decided based on clinical 
expenence. 
8.10. 
Data Monitoring Committee 
An independent, external DMC will review the progress of the study and perfonn safety data 
review after 20 subjects have completed randomization. Subsequent meetings may be held 
approximately eve1y 3 months until the last subject enrolled has completed the GS-9688/PTM 
study drng dosing period. The DMC will provide recommendations as needed regarding study 
conduct and the need for additional meetings or an alternative meeting schedule. The DMC will 
be immediately notified in the event of any DL T or virologic study stopping criteria. 
While the DMC will be asked to advise Gilead regarding future conduct of the study, including 
possible early study te1mination, Gilead retains final decision-making authority on all aspects of 
the study. 
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8.11.
Internal Data Review Team
The study will be unblinded to appropriate GSI study team personnel at the time of primary 
analysis (Week 24 assessment). An Internal Data Review, external to the study team, may be 
unblinded at Week 12 assessment visit to review the unblinded safety and efficacy data in order 
to guide strategic decisions regarding the future of the program. Investigators and subjects will 
remain blinded through Week 48 except in instances of emergency treatment unblinding 
(See Section 5.1.1). 


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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), ICH guidelines, or with the laws and regulations of the country in which the 
research is conducted, whichever affords the greater protection to the study subject. These 
standards are consistent with the European Union Clinical Trials Directive 2001/20/EC and 
Good Clinical Practice Directive 2005/28/EC.
The investigator will ensure adherence to the basic principles of Good Clinical Practice, as 
outlined in 21 CFR 312, subpart D, “Responsibilities of Sponsors and Investigators,” 21 CFR, 
part 50, 1998, and 21 CFR, part 56, 1998.
The investigator and all applicable subinvestigators will comply with 21 CFR, Part 54, 1998, 
providing documentation of their financial interest or arrangements with Gilead, or proprietary 
interests in the investigational drug under study. This documentation must be provided prior to 
the investigator’s (and any subinvestigator’s) participation in the study. The investigator and 
subinvestigator agree to notify Gilead of any change in reportable interests during the study and 
for 1 year following completion of the study. Study completion is defined as the date when the 
last subject completes the protocol-defined activities.
9.1.2.
Institutional Review Board (IRB)/Independent Ethics Committee (IEC) 
Review and Approval
The investigator (or sponsor as appropriate according to local regulations) will submit this 
protocol, Informed Consent Form (ICF), and any accompanying material to be provided to the 
subject (such as advertisements, subject information sheets, or descriptions of the study used to 
obtain informed consent) to an IRB/IEC. The investigator will not begin any study subject 
activities until approval letter from the IRB has been documented and sponsor has also provided 
a letter to the investigator.
Before implementation, the investigator will submit to and receive documented approval from 
the IRB/IEC any modifications made to the protocol or any accompanying material to be 
provided to the subject after initial IRB/IEC approval.
9.1.3.
Informed Consent
The investigator is responsible for obtaining written informed consent from each individual 
participating in this study after adequate explanation of the aims, methods, objectives, and 
potential hazards of the study and before undertaking any study-related procedures. The 
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consent. Each ICF will be appropriately signed and dated by the subject or the subject’s legally 
authorized representative and the person conducting the consent discussion, and also by an 
impartial witness if required by IRB/IEC local requirements. The consent form will inform 
subjects about PG testing and sample retention, and whether they will receive clinically relevant 
PG analysis results.
9.1.4.
Confidentiality
The investigator must assure that subjects’ anonymity will be strictly maintained and that their 
identities are protected from unauthorized parties. Only date of birth, another unique identifier 
(as allowed by local law), and an identification code will be recorded on any form or biological 
sample submitted to the sponsor, IRB/IEC/EC or laboratory. Laboratory specimens must be 
labeled in such a way as to protect subject identity while allowing the results to be recorded to 
the proper subject. Refer to specific laboratory instructions or in accordance with local 
regulations. NOTE: The investigator must keep a screening log showing codes, names, and 
addresses for all subjects screened and for all subjects enrolled in the study. Subject data will be 
processed in accordance with all applicable regulations.
The investigator agrees that all information received from Gilead, including but not limited to the 
IB, this protocol, eCRF, the study drug, and any other study information, remain the sole and 
exclusive property of Gilead during the conduct of the study and thereafter. This information is 
not to be disclosed to any third party (except employees or agents directly involved in the 
conduct of the study or as required by law) without prior written consent from Gilead. The 
investigator further agrees to take all reasonable precautions to prevent the disclosure by any 
employee or agent of the study site to any third party or otherwise into the public domain.
9.1.5.
Study Files and Retention of Records
The investigator must maintain adequate and accurate records to enable the conduct of the study 
to be fully documented and the study data to be subsequently verified. These documents should 
be classified into at least the following two categories: (1) investigator’s study file, and 
(2) subject clinical source documents.
The investigator’s study file will contain the protocol/amendments, CRF and query forms, 
IRB/IEC and governmental approval with correspondence, informed consent, drug records, staff 
curriculum vitae and authorization forms, and other appropriate documents and correspondence.
The required source data should include sequential notes containing at least the following 
information for each subject:

Subject identification (name, date of birth, gender);

Documentation that subject meets eligibility criteria, 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


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
Participation in study (including study number);

Study discussed and date of informed consent;

Dates of all visits;

Documentation that protocol specific procedures were performed;

Results of efficacy parameters, as required by the protocol;

Start and end date (including dose regimen) of IMP, including dates of dispensing and return;

Record of all AEs 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 ED, if it occurs.
All clinical study documents must be retained by the investigator until at least 2 years or 
according to local laws, whichever is longer, after the last approval of a marketing application in 
an ICH region 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 GSI. The investigator must notify GSI before 
destroying any clinical study records.
Should the investigator wish to assign the study records to another party or move them to another 
location, GSI 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 GSI to store 
these records securely away from the site so that they can be returned sealed to the investigator 
in case of an inspection. When source documents are required for the continued care of the 
subject, appropriate copies should be made for storage away from the site.
9.1.6.
Case Report Forms
For each subject consented, an eCRF will be completed by an authorized study staff member 
whose training for this function is completed in EDC. eCRF should be completed on the day of 
the subject visit to enable the sponsor to perform central monitoring of safety data. The 
Eligibility Criteria eCRF should be completed only after all data related to eligibility have been 
received. Subsequent to data entry, a study monitor will perform source data verification within 
the EDC system. Original entries as well as any changes to data fields will be stored in the audit 
trail of the system. Prior to database lock (or any interim time points as described in the clinical 


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data management plan), the investigator will use his/her log in credentials to confirm that the 
forms have been reviewed, and that the entries accurately reflect the information in the source 
documents. The eCRF capture the data required per the protocol schedule of events and 
procedures. System-generated or manual queries will be issued to the investigative site staff as 
data discrepancies are identified by the monitor or internal Gilead staff, who routinely review the 
data for completeness, correctness, and consistency. The site coordinator is responsible for 
responding to the queries in a timely manner, within the system, either by confirming the data as 
correct or updating the original entry, and providing the reason for the update (e.g., data entry 
error). At the conclusion of the trial, Gilead will provide the site with a read-only archive copy of 
the data entered by that site. This archive must be stored in accordance with the records retention 
requirements outlined in Section 9.1.5.
9.1.7.
Study Drug 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. 
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 IRB/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.


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9.2.
Sponsor Responsibilities
9.2.1.
Protocol Modifications
Protocol modifications, except those intended to reduce immediate risk to study subjects, may be 
made only by Gilead. The investigator must submit all protocol modifications to IRB/IEC and 
regulatory authorities in accordance with local requirements and receive documented IRB/IEC 
and regulatory authority approvals before modifications may be implemented.
9.2.2.
Study Report and Publications
A clinical study report (CSR) will be prepared and provided to the regulatory agency. GSI 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. 
9.3.
Joint Investigator/Sponsor Responsibilities
9.3.1.
Payment Reporting
Investigators and their study staff may be asked to provide services performed under this 
protocol, e.g. attendance at Investigator's Meetings.  If required under the applicable statutory 
and regulatory requirements, Gilead will capture and disclose to Federal and State agencies any 
expenses paid or reimbursed for such services, including any clinical trial payments, meal, travel 
expenses or reimbursements, consulting fees, and any other transfer of value.
9.3.2.
Access to Information for Monitoring
In accordance with regulations and guidelines, the study monitor must have direct access to the 
investigator’s source documentation in order to verify the accuracy of the data recorded in the 
CRF/eCRF.
The monitor is responsible for routine review of the CRF/eCRF at regular intervals throughout 
the study to verify adherence to the protocol and the completeness, consistency, and accuracy of 
the data being entered on them. The monitor should have access to any subject records needed to 
verify the entries on the CRF/eCRF. The investigator agrees to cooperate with the monitor to 
ensure that any problems detected through any type of monitoring (central, on site) are resolved.
9.3.3.
Access to Information for Auditing or Inspections
Representatives of regulatory authorities or of GSI 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 GSI medical monitor immediately. The investigator agrees to 
provide to representatives of a regulatory agency or GSI access to records, facilities, and 
personnel for the effective conduct of any inspection or audit.


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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, 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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27 August 2019
Terrault NA, Bzowej NH, Chang KM, Hwang JP, Jonas MM, Murad MH. AASLD guidelines 
for treatment of chronic hepatitis B. Hepatology 2016;63 (1):261-83.
Thum T, Erpenbeck VJ, Moeller J, Hohlfeld JM, Krug N, Borlak J. Expression of Xenobiotic 
Metabolizing Enzymes in Different Lung Compartments of Smokers and 
Nonsmokers. Environ Health Perspect 2006;114 (11):1655-61.
Whelton SP, Narla V, Blaha MJ, Nasir K, Blumenthal RS, Jenny NS, et al. Association between 
resting heart rate and inflammatory biomarkers (high-sensitivity C-reactive 
protein, interleukin-6, and fibrinogen) (from the Multi-Ethnic Study of 
Atherosclerosis). The American journal of cardiology 2014;113 (4):644-9.
Wille-Reece U, Flynn BJ, Lore K, Koup RA, Miles AP, Saul A, et al. Toll-like receptor agonists 
influence the magnitude and quality of memory T cell responses after prime-boost 
immunization in nonhuman primates. J Exp Med 2006;203 (5):1249-58.
World Health Organization (WHO). Hepatitis B. Introduction. Available at: 
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.
Yi YH, Kim YJ, Lee SY, Cho BM, Cho YH, Lee JG. Health Behaviors of Korean Adults with 
Hepatitis B: Findings of the 2016 Korean National Health and Nutrition 
Examination Survey. World J Gastroenterol 2018;24 (28):3163-70.
Zuckerman AJ. Progress towards the comprehensive control of hepatitis B. Gut 1996;38 (2):S1.


GS-9688
Protocol GS-US-389-2025
Final
Gilead Sciences, Inc. 
Amendment 1
CONFIDENTIAL
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11.
APPENDICES
Appendix 1.
Investigator Signature Page
Appendix 2.
Study Procedures Tables
Appendix 3.
Pregnancy Precautions, Definition for Female of Childbearing Potential, and 
Contraceptive Requirements
Appendix 4.
GSI Grading Scale for Severity of Adverse Events and Laboratory Abnormalities


GS-9688 
Protocol GS-US-389-2025 
Final 
Gilead Sciences, Inc. 
Amendment 1 
Appendix 1. 
Investigator Signature Page 
GILEAD SCIENCES, INC. 
333 LAKESIDE DRIVE 
FOSTER CITY, CA 94404 
STUDY ACKNOWLEDGEMENT 
A Phase 2, Randomized, Double-Blind, Placebo-Controlled, Multi-center Study to Evaluate the 
Safety, Tolerability and Antiviral Activity of GS-9688 in Viremic Adult Subjects with Chronic 
Hepatitis B who are not currently on Treatment 
GS-US-389-2025, Amendment 1, 27 August 2019 
This protocol has been approved by Gilead Sciences, lnc. The following signature documents 
this approval. 
PPD 
[P[PD 
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 
Page 120 
27 August 2019 


GS-9688
Protocol GS-US-389-2025
Final
Gilead Sciences, Inc. 
Amendment 1
CONFIDENTIAL
Page 121
27 August 2019
Appendix 2.
Study Procedures Tables
Part A.
Study Procedures Required at Screening Visit
Screening Study Procedures – Window (-30 days)
Obtain written Informed Consent
Review of Inclusion/Exclusion Criteria
Medical History (including HBV disease and treatment history)
Review AEs & concomitant medications
Complete Physical Exam (Including Height, Weight and BMI)
Vital Signs (blood pressure, heart rate, respiration rate and body temperature)
Safety Labs (hematology, serum chemistry, and coagulation)
12-Lead ECG
Ophthalmologic exam (Window Days -10 to -1)
Qualitative HBV Serology Qualitative (HBV serology consists of HBeAg and HBsAg and reflex HBeAb and reflex HBsAb at Screening and all visits indicated in Part B)
HBV DNA levels
HBV Resistance Surveillance
HBV Genotyping (By history if known and laboratory testing )
Quantitative HBsAg
HCV, HDV and HIV Ab testing (In the event of a positive result and/or antigen testing for HIV, HDV, or HCV serology, reflex tests will automatically be performed )
FibroTest
Alpha Fetoprotein
Urinalysis for urine drug screen, alcohol , and urine pregnancy testing
Serum Pregnancy Test (for all female subjects of child-bearing potential)
Follicle-stimulating Hormone (FSH, for female subjects post-menopausal for less than two years)


GS-9688
Protocol GS-US-389-2025
Final
Gilead Sciences, Inc. 
Amendment 1
CONFIDENTIAL
Page 122
27 August 2019
Part B.
Study Procedure Table (On and Post GS-9688/PTM Treatment Assessments)
On Treatment
Post GS-9688/PTM 
Treatment
Days
Weeks
Days
Windows
(±1 Day)
(±3 Days)
(±7 Days)
Study Procedures
Baseline
(Day 1)
Day 2
(Day 1 +24hrs)
2
4
8
11
12
16
20
23
23+24 
hrs
24
28
36
48
EDa
TFFU
after ED
Review of 
inclusion/exclusion 
criteria and confirm 
medical history
X
Complete Physical Exam 
(including weight, 
height, BMI)
X
X
X
X
X
X
X
X
X
X
Symptom Directed 
Physical Exam
X
X
X
X
X
X
X
Ophthalmologic examc
X
X
Review AEs & 
Concomitant 
Medications
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Vital Signs (blood 
pressure, heart rate, 
respiration rate and body 
temperature)
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Safety Labs 
(Hematology, Serum 
Chemistry, and 
Coagulation)
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Urinalysis
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X


GS-9688 
Protocol GS-US-389-2025 
Final 
Gilead Sciences, Inc. 
Amendment 1 
Post GS-9688/PTM 
On Treatment 
Treatment 
Days 
Weeks 
Days 
Windows 
(±1 Day) 
(±3 Days) 
(±7 Days) 
Baseline 
Day2 
23+24 
TFFU 
Study Procedures 
(Day 1) 
(Day 1 +24hrs) 
2 
4 
8 
11 
12 
16 
20 
23 
hrs 
24 
28 
36 
48 
ED• 
after ED 
FibroTest 
X 
X 
X 
X 
Serum Pregnancy Test' 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Urine Pregnancy Testd 
X 
X 
X 
HBV DNA levels, HBV 
Resistance Surveillance, 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Quantitative HBsAg 
Qualitative HBV 
X 
X 
X 
X 
X 
X 
X 
Serology 
Whole Blood gene 
X 
X 
X 
X 
X 
X 
X 
X 
X 
expression biomarkersg 
PBMC Collectionh 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Sparse (timed) plasma 
X 
X 
X 
X 
X 
X 
PK sample Collection; 
CONFIDENTIAL 
Page 123 
27 August 2019 


GS-9688
Protocol GS-US-389-2025
Final
Gilead Sciences, Inc. 
Amendment 1
CONFIDENTIAL
Page 124
27 August 2019
On Treatment
Post GS-9688/PTM 
Treatment
Days
Weeks
Days
Windows
(±1 Day)
(±3 Days)
(±7 Days)
Study Procedures
Baseline
(Day 1)
Day 2
(Day 1 +24hrs)
2
4
8
11
12
16
20
23
23+24 
hrs
24
28
36
48
EDa
TFFU
after ED
Sparse (pre-identified)
plasma PK sample 
Collectionj
X
X
X
Holter Monitoringk
X
X
X
Randomization
X
In Clinic GS-9688 
Dosing & 
Accountabilitym
X
X
X
X
X
X
X
X
X
X
TAF Dispensation and 
Accountability
X
X
X
X
X
X
X
X
X
X
CCI
CCI
CCI
CCI
-----------------------------------------------------------------


GS-9688 
Protocol GS-US-389-2025 
Gilead Sciences, Inc. 
Final 
Amendment 1 
Part C. 
Study Procedure Table (Treatment Free Follow-up Post Study Completion)0 
Windows 
Symptom Directed Physical Exam 
Vital Signs 
(blood pressme, hea1t rate, respiration rate and body 
temperature) 
Safety Labs (Hematology, Senun Chemistiy, and 
Coagulation) 
Urinalysis 
Sel11Ill Pregnancy Test 
Qualitative HBV Serology 
HBV DNA levels, HBV Resistance Surveillance, 
Quantitative HBsAg 
PBMC Collectionh 
Whole Blood gene expression biomarkersg 
CONFIDENTIAL 
X 
X 
X 
X 
X 
X 
X 
TFFU Weekb 
(Study Week) 
(±7 Days) 
----.. Ill
•: 
t I 
t 
t : 
: • 
I 
I 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
--------------------------------
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Page 125 
27 August 2019 


GS-9688 
Protocol GS-US-389-2025 
Gilead Sciences, Inc. 
Final 
Amendment 1 
a 
b 
C 
d 
r 
r 
g 
h 
J 
k 
r 
The ED visit should be performed within I week if ED occurs before Week 24; after week 24 ED should be performed within 2 weeks from notification of study 
discontinuation. 
Subjects will be followed every 4 weeks for the first 24 weeks and thereafter at Week 36 and 48 or until the initiation of altemative CHB therapy, whichever comes first. 
Ophthahnologic exam windows per visit: Screening (Days -10 to -1), Week 12 and Week 24 (-4 days to +IO days) 
For female subjects of childbearing potential, the pregnancy test will be pe1fo1med at all study visits as indicated. Positive urine test will be confumed with serum test. 
Pregnanc testino should include revention counselino. 
10 e 
oo gene expression 
axgene RNA samp es co ected on Days I pre-dose and I +4 hom·s, I + 24 hotu-s post-dose, and on Weeks 11 pre-dose, 11 +4 hom·s post-dose, 
12 pre-dose, 23 pre-dose, 23 + 4 hotu-s , 23 + 24 hom·s post-dose, PT Week 24, 48/ED, and TFFU Week 4, 8, 12, 16, 20, 24, 36, and 48. 
PBMC samples collected on Days I predose and I +4 hom·s, I + 24 hotu-s post-dose, and on Weeks 11 pre-dose, 11 +4 hotu-s post-dose, 12 pre-dose, 23 pre-dose, 23 + 4 hotu-s, 
23 + 24 hom·s post-dose, PT Week 24, 48/ED, and TFFU Week 4, 8, 12, 16, 20, 24, 36, and 48. 
Sparse (timed) plasma PK samples will be obtained on any two of the following visits: Weeks 2, 4, 8, 12, 16, and/or 20 at pre-dose and any time between 30 minutes to 
4 hotu-s post-dose. 
Sparse (pre-identified) PK plasma sampling will occur on Day I and Week 23 at pre-dose, I, 4, and 24 hotu·s post-dose and at Week 11 at pre-dose, I, and 4 hours post-dose. 
Holter Monitoring to be collected prior to blood collection on Day I and Week 23 at pre-dose (:S: 5 min of dose) through 4 hours, and 24 hours; Week 11 at pre-dose (:S: 5 min 
of dose through 4 hom·s 
m 
a 1hon tot e c m1c 
stu y ·ug osmg, se 
1ome 
stu 
1g osmg w1 
eon 
ee s , , , , , , IO, 13, 14, 15, 17, 18, 19, 21, and 22 
n 
At Week 48, at PI discretion, following the discontinuation ofTAF (window of± 7 days), the subject will be followed eve1y 4 weeks for the fu-st 24 weeks and thereafter at 
Week 36 and Week 48 (TFFU phase). At the PI's discretion, subject(s) in the TFFU phase may initiate other standard of care CHB therapy at any time per local treahnent 
guidelines. If a subject initiates other standard of care CHB therapy for their CHB, TFFU visits will continue for 2 more TFFU visits or until the end of the TFFU phase 
(Week 96), whichever comes first. 
CONFIDENTIAL 
Page 126 
27 August 2019 


GS-9688
Protocol GS-US-389-2025
Final
Gilead Sciences, Inc. 
Amendment 1
CONFIDENTIAL
Page 127
27 August 2019
Appendix 3.
Pregnancy Precautions, Definition for Female of Childbearing 
Potential, and Contraceptive Requirements
1) Definitions
a) Definition of Childbearing Potential
For the purposes of this study, a female born subject is considered of childbearing potential 
following the initiation of puberty (Tanner stage 2) until becoming post-menopausal, unless 
permanently sterile or with medically documented ovarian failure.  
Women are considered to be in a postmenopausal state when they are > 54 years of age with 
cessation of previously occurring menses for > 12 months without an alternative cause.  In 
addition, women of any age with amenorrhea of > 12 months may also be considered 
postmenopausal if their follicle stimulating hormone (FSH) level is in the postmenopausal range 
and they are not using hormonal contraception or hormonal replacement therapy.
Permanent sterilization includes hysterectomy, bilateral oophorectomy, or bilateral 
salpingectomy in a female subject of any age.
b) Definition of Male Fertility
For the purposes of this study, a male born subject is considered fertile after the initiation of 
puberty unless the subject is permanently sterile by bilateral orchiectomy or medical 
documentation.
2) Contraception Requirements for Female Subjects
a) Study Drug Effects on Pregnancy and Hormonal Contraception with GS-9688/PTM
The risks of treatment with GS-9688 during pregnancy have not been evaluated. The 
reproductive and developmental toxicity studies with GS-9688 have not been conducted to date. 
Drug-drug interaction (DDI) with hormones used for contraception is not available. Therefore, 
the use of hormonal contraception with GS-9688 is not recommended. Pregnancy must be 
excluded before the start of treatment with study drug and prevented thereafter by reliable, 
highly effective contraceptive methods. Pregnancy tests will be performed regularly throughout 
this study. Please refer to the latest version of the IB for additional information.
b) Study Drug Effects on Pregnancy and Hormonal Contraception with 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 orembryo-fetal 
development. However, there are no clinical studies of TAF in pregnant women. Please refer to 
the latest version of the investigator’s brochure for additional information.


GS-9688
Protocol GS-US-389-2025
Final
Gilead Sciences, Inc. 
Amendment 1
CONFIDENTIAL
Page 128
27 August 2019
c) Contraception Requirements for Female Subjects of Childbearing Potential
The inclusion of female subjects of childbearing potential requires the use of highly effective 
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 at the baseline/Day-1 visit prior to randomization/enrollment. 
Female subjects must agree to 1 of the following from screening until 30 days following the end 
of relevant systemic exposure:

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 with a failure rate of < 1% per year
Tubal sterilization
Vasectomy in the male partner (provided that the partner is the sole sexual partner and 
had confirmation of surgical success 3 months after procedure)
Female subjects must also refrain from egg donation and in vitro fertilization during treatment 
and until at least 30 days after the end of relevant systemic exposure to GS-9688/PTM or 7 days 
after the last dose of TAF, whichever comes later.
3) Contraception Requirements for Male Subjects
It is theoretically possible that a relevant systemic concentration may be achieved in a female 
partner from exposure of the male subject’s seminal fluid.  Therefore, male subjects with female 
partners of childbearing potential must use condoms during treatment and until 90 days after the 
end of relevant systemic exposure. Additional contraception recommendations should also be 
considered if the female partner is not pregnant.
Male subjects must also refrain from sperm donation during treatment and until at least 90 days 
after the end of relevant systemic exposure. 
4) Unacceptable Birth Control Methods
Birth control methods that are unacceptable include periodic abstinence (e.g., calendar, 
ovulation, symptothermal, postovulation methods), withdrawal (coitus interruptus), spermicides 
only, and lactational amenorrhea method. A female condom and a male condom should not be 
used together.


GS-9688
Protocol GS-US-389-2025
Final
Gilead Sciences, Inc. 
Amendment 1
CONFIDENTIAL
Page 129
27 August 2019
5) Procedures to be Followed in the Event of Pregnancy
Subjects will be instructed to notify the investigator if they become pregnant at any time during 
the study, or if they become pregnant within 30 days (90 days for female partners of male 
subjects) of last study drug dose. Subjects who become pregnant or who suspect that they are 
pregnant during the study, including TFFU, 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 7.10.2.1.


GS-9688
Protocol GS-US-389-2025
Final
Gilead Sciences, Inc. 
Amendment 1
CONFIDENTIAL
Page 130
27 August 2019
Appendix 4.
GSI Grading Scale for Severity of Adverse Events and Laboratory Abnormalities
Antiviral Toxicity Grading Scale Version: 01 April 2015
HEMATOLOGY
Grade 1
Grade 2
Grade 3
Grade 4
Hemoglobin
HIV POSITIVE
Adult and Pediatric 57 
Days
8.5 to 10.0 g/dL 
85 to 100 g/L
7.5 to 8.5 g/dL 
75 to 85 g/L
6.5 to 7.5 g/dL 
65 to 75 g/L
6.5 g/dL
65 g/L
HIV NEGATIVE
Adult and Pediatric 57 
Days 
10.0 to 10.9 g/dL
100 to 109 g/L
OR
Any decrease from Baseline
2.5 to 3.5 g/dL
25 to 35 g/L
9.0 to 10.0 g/dL
90 to 100 g/L
OR
Any decrease from Baseline
3.5 to 4.5 g/dL
35 to 45 g/L
7.0 to 9.0 g/dL
70 to 90 g/L
OR
Any decrease from Baseline
4.5 g/dL
45 g/L
7.0 g/dL
70 g/L
Infant, 36–56 Days
(HIV POSITIVE OR
NEGATIVE)
8.5 to 9.4 g/dL
85 to 94 g/L
7.0 to 8.5 g/dL
70 to 85 g/L
6.0 to 7.0 g/dL
60 to < 70 g/L
6.0 g/dL
< 60 g/L
Infant, 22–35 Days
(HIV POSITIVE OR
NEGATIVE)
9.5 to 10.5 g/dL
95 to 105 g/L
8.0 to 9.5 g/dL
80 to 95 g/L
7.0 to 8.0 g/dL
70 to 80 g/L
7.0 g/dL
70 g/L
Infant, 1–21 Days
(HIV POSITIVE OR
NEGATIVE)
12.0 to 13.0 g/dL
120 to 130 g/L
10.0 to 12.0 g/dL
100 to 120 g/L
9.0 to 10.0 g/dL
90 to 100 g/L
9.0 g/dL
90 g/L
Absolute Neutrophil Count  
(ANC)
Adult and Pediatric, 
≥ 7 Months#
1000 to 1300/mm3
750 to 1000/mm3
500 to 750/mm3
500/mm3
1.00 to 1.30 GI/L
0.75 to 1.00 GI/L
0.50 to 0.75 GI/L
0.50 GI/L
Absolute CD4+ Count
HIV NEGATIVE ONLY
Adult and Pediatric > 13 Years
300 to 400/mm3
300 to 400/μL
200 to 300/mm3
200 to 300/μL
100 to 200/mm3
100 to 200/μL
100/mm3
100/μL


GS-9688
Protocol GS-US-389-2025
Final
Gilead Sciences, Inc. 
Amendment 1
CONFIDENTIAL
Page 131
27 August 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-9688
Protocol GS-US-389-2025
Final
Gilead Sciences, Inc. 
Amendment 1
CONFIDENTIAL
Page 132
27 August 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-9688
Protocol GS-US-389-2025
Final
Gilead Sciences, Inc. 
Amendment 1
CONFIDENTIAL
Page 133
27 August 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 mmolL
6.1 to  <7.0 mg/dL
1.51 to < 1.74 mmolL
< 6.1 mg/dL
< 1.51 mmol/L
Infant, 7 Days
6.5 to 7.5 mg/dL
1.61 to 1.88  mmol/L
6.0 to 6.5 mg/dL
1.49 to < 1.61 mmol/L
5.5 to 6.0 mg/dL
1.36 to < 1.49 mmol/L 
5.5 mg/dL
< 1.36 mmol/L
Hypercalcemia (corrected 
for albumin if appropriate*)
Adult and Pediatric 
7 Days
>ULN to 11.5 mg/dL
11.5 to 12.5 mg/dL
12.5 to 13.5 mg/dL
13.5 mg/dL
>ULN to 2.88 mmol/L
2.88 to 3.13 mmol/L
3.13 to 3.38 mmol/L
3.38 mmol/L
Infant, 7 Days
11.5 to 12.4 mg/dL
2.86 to 3.10  mmol/L
12.4 to 12.9 mg/dL
> 3.10 to 3.23  mmol/L
12.9 to 13.5 mg/dL
> 3.23 to 3.38  mmol/L
13.5 mg/dL
> 3.38 mmol/L
Hypocalcemia (ionized)
3.0 mg/dL to LLN
2.5 to < 3.0 mg/dL
2.0 to 2.5 mg/dL
2.0 mg/dL
0.74 mmol/L to LLN
0.62 to 0.74 mmol/L
0.49 to 0.62 mmol/L
0.49 mmol/L
Hypercalcemia (ionized)
ULN to 6.0 mg/dL
6.0 to 6.5 mg/dL
6.5 to 7.0 mg/dL
7.0 mg/dL
ULN to 1.50 mmol/L
1.50 to 1.63 mmol/L
1.63 to 1.75 mmol/L
1.75 mmol/L
Hypomagnesemia
1.40 to  <LLN mg/dL
1.2 to <LLN mEq/L
1.04 to 1.40 mg/dL
0.9 to   1.2 mEq/L
0.67 to 1.04 mg/dL
0.6 to 0.9 mEq/L
0.67 mg/dL
0.6 mEq/L
0.58 to <LLN mmol/L
0.43 to 0.58 mmol/L
0.28 to 0.43 mmol/L
0.28 mmol/L


GS-9688
Protocol GS-US-389-2025
Final
Gilead Sciences, Inc. 
Amendment 1
CONFIDENTIAL
Page 134
27 August 2019
CHEMISTRY
Grade 1
Grade 2
Grade 3
Grade 4
Hypophosphatemia
Adult and Pediatric
14 Years
2.0 to < LLN mg/dL
0.63  to LLN mmol/L
1.5 to 2.0 mg/dL
0.47 to 0.63 mmol/L
1.0 to 1.5 mg/dL
0.31 to 0.47 mmol/L
1.0 mg/dL
0.31 mmol/L
Pediatric 1 Year–14 Years
3.0 to <LLN mg/dL
0.96 to <LLN mmol/L
2.5 to 3.0 mg/dL
0.80 to < 0.96 mmol/L
1.5 to 2.5 mg/dL
0.47 to < 0.80 mmol/L
1.5 mg/dL
< 0.47 mmol/L
Pediatric 1 Year
3.5 to <LLN mg/dL
1.12 to <LLN mmol/L
2.5 to 3.5 mg/dL
0.80 to < 1.12 mmol/L
1.5 to 2.5 mg/dL
0.47 to < 0.80 mmol/L
1.5 mg/dL
< 0.47 mmol/L
Hyperbilirubinemia 
Adult and Pediatric 
> 14 Days
1.0 to 1.5 ULN 
1.5 to 2.5 ULN
2.5 to 5.0 ULN 
5.0 ULN 
Infant, 14 Days
(non-hemolytic)
NA
20.0 to 25.0 mg/dL
342 to 428 μmol/L
25.0 to 30.0 mg/dL
> 428 to 513 μmol/L
30.0 mg/dL
> 513 μmol/L
Infant, 14 Days
(hemolytic)
NA
NA
20.0 to 25.0 mg/dL
342 to 428 μmol/L
25.0 mg/dL
> 428 μmol/L
Blood Urea Nitrogen
1.25 to 2.50 ULN 
2.50 to 5.00 ULN 
5.00 to 10.00 ULN 
10.00 ULN
Hyperuricemia
>ULN to 10.0 mg/dL 
10.0 to 12.0 mg/dL 
12.0 to 15.0 mg/dL 
15.0 mg/dL
>ULN to 597 μmol/L
597 to 716 μmol/L
716 to 895 μmol/L
895 μmol/L
Hypouricemia 
Adult and Pediatric
≥ 1 year   
Infant  < 1 Year
1.5 mg/dL to LLN
87 μmol/L to LLN
1.0 to 1.5 mg/dL
57 to 87 μmol/L
0.5 to 1.0 mg/dL
27 to 57 μmol/L
0.5 mg/dL
27 μmol/L
N/A
1.0 mg/dl to <LLN-
57 μmol to <LLN
0.5 to 1.0 mg/dL
27 to 57 μmol/L
0.5 mg/dL
27 μmol/L
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


GS-9688
Protocol GS-US-389-2025
Final
Gilead Sciences, Inc. 
Amendment 1
CONFIDENTIAL
Page 135
27 August 2019
CHEMISTRY
Grade 1
Grade 2
Grade 3
Grade 4
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/L to <LLN
8.0 to 11.0 mEq/L
8.0 mEq/L
11.0 mmol/L to <LLN
8.0 to 11.0 mmol/L
8.0 mmol/L
Triglycerides
(Fasting)
NA
500 to 750 mg/dL
5.64–8.47 mmol/L
750 to 1200 mg/dL
8.47–13.55 mmol/L
1200 mg/dL
13.55 mmol/L
LDL (Fasting)
Adult
130 to 160 mg/dL
>160 to 190 mg/dL
> 190 mg/dL
NA
3.35 to 4.15 mmol/L
>4.15 to 4.92 mmol/L
>4.92 mmol/L
LDL (Fasting)
Pediatric >2 to <18 years
110 to 130 mg/dL
>130 to 190 mg/dL
> 190 mg/dL
NA
2.84 to 3.37 mmol/L
>3.37 to  4.92 mmol/L
>4.92 mmol/L
Hypercholesterolemia
(Fasting)
200 to 239 mg/dL
239 to 300 mg/dL
300 mg/dL
NA
5.16 to 6.19 mmol/L
6.19 to 7.77 mmol/L
7.77 mmol/L
Pediatric 18 Years
170 to 199 mg/dL
4.39 to 5.15 mmol/L
199 to 300 mg/dL
5.15 to 7.77 mmol/L
300 mg/dL
7.77 mmol/L
NA
Creatine Kinase
3.0 to 6.0 ULN
6.0 to 10.0 ULN
10.0 to 20.0 ULN
20.0 ULN
*
Calcium should be corrected for albumin if albumin is < 4.0 g/dL
**
An overlap between the Grade 1 scale and the Lab’s normal range for creatinine may result for Male subjects >70 yrs.  Please follow the Gilead convention of grading any 
result within the LLN and ULN a 0.  


GS-9688
Protocol GS-US-389-2025
Final
Gilead Sciences, Inc. 
Amendment 1
CONFIDENTIAL
Page 136
27 August 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


GS-9688
Protocol GS-US-389-2025
Final
Gilead Sciences, Inc. 
Amendment 1
CONFIDENTIAL
Page 137
27 August 2019
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.


GS-9688
Protocol GS-US-389-2025
Final
Gilead Sciences, Inc. 
Amendment 1
CONFIDENTIAL
Page 138
27 August 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 
(eg, malignant hypertension) 
OR Hospitalization (other than 
ER visit) indicated
Pediatric 17 Years (with 
repeat testing at same visit)
NA
91st–94th percentile adjusted 
for age, height, and gender 
(systolic and/or diastolic)
≥95th percentile adjusted 
for age, height, and gender 
(systolic and/or diastolic)
Life-threatening consequences 
(eg, malignant hypertension) 
OR Hospitalization indicated 
(other than emergency room 
visit)
Hypotension
NA
Symptomatic, corrected with 
oral fluid replacement
Symptomatic, IV fluids 
indicated
Shock requiring use of 
vasopressors or mechanical 
assistance to maintain blood 
pressure
Pericardial Effusion
Asymptomatic, small 
effusion requiring no 
intervention
Asymptomatic, moderate or 
larger effusion requiring no 
intervention
Effusion with 
non-life-threatening 
physiologic consequences 
OR Effusion with nonurgent 
intervention indicated
Life-threatening consequences 
(eg, tamponade) OR Urgent 
intervention indicated


GS-9688
Protocol GS-US-389-2025
Final
Gilead Sciences, Inc. 
Amendment 1
CONFIDENTIAL
Page 139
27 August 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, eg, Torsade de 
pointes or other associated 
serious ventricular 
dysrhythmia
Pediatric 16 Years
Asymptomatic, QTc interval 
0.450 to 0.464 sec 
Asymptomatic, QTc interval 
0.465 to 0.479 sec 
Asymptomatic, QTc interval 
0.480 sec 
Life-threatening 
consequences, eg, Torsade de 
pointes or other associated 
serious ventricular 
dysrhythmia
Thrombosis/Embolism
NA
Deep vein thrombosis AND 
No intervention indicated 
(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-9688
Protocol GS-US-389-2025
Final
Gilead Sciences, Inc. 
Amendment 1
CONFIDENTIAL
Page 140
27 August 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)


GS-9688
Protocol GS-US-389-2025
Final
Gilead Sciences, Inc. 
Amendment 1
CONFIDENTIAL
Page 141
27 August 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-9688
Protocol GS-US-389-2025
Final
Gilead Sciences, Inc. 
Amendment 1
CONFIDENTIAL
Page 142
27 August 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 [eg, tube feeding or 
total parenteral nutrition]
Ascites
Asymptomatic
Symptomatic AND Intervention 
indicated (eg, diuretics or 
therapeutic paracentesis)
Symptomatic despite 
intervention
Life-threatening consequences
Cholecystitis
NA
Symptomatic AND Medical 
intervention indicated
Radiologic, endoscopic, or 
operative intervention 
indicated
Life-threatening consequences 
(eg, sepsis or perforation) 
Constipation 
NA
Persistent constipation requiring 
regular use of dietary 
modifications, laxatives, or 
enemas 
Obstipation with manual 
evacuation indicated
Life-threatening consequences 
(eg, obstruction)
Diarrhea 
Adult and Pediatric 
1 Year
Transient or intermittent 
episodes of unformed stools 
OR Increase of 3 stools 
over baseline/24 hour
Persistent episodes of unformed 
to watery stools OR Increase of 
4–6 stools over baseline per 
24 hours. 
Bloody diarrhea OR Increase 
of 7 stools per 24-hour 
period OR IV fluid 
replacement indicated
Life-threatening consequences 
(eg, hypotensive shock)
Pediatric 1 Year
Liquid stools (more 
unformed than usual) but 
usual number of stools
Liquid stools with increased 
number of stools OR Mild 
dehydration
Liquid stools with moderate 
dehydration
Liquid stools resulting in 
severe dehydration with 
aggressive rehydration 
indicated OR Hypotensive 
shock
Dysphagia-Odynophagia 
Symptomatic but able to eat 
usual diet
Symptoms causing altered 
dietary intake without medical 
intervention indicated
Symptoms causing severely 
altered dietary intake with 
medical intervention indicated
Life-threatening reduction in 
oral intake


GS-9688
Protocol GS-US-389-2025
Final
Gilead Sciences, Inc. 
Amendment 1
CONFIDENTIAL
Page 143
27 August 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 (eg, aspiration, 
choking)
Nausea 
Transient (24 hours) or 
intermittent nausea with no 
or minimal interference with 
oral intake
Persistent nausea resulting in 
decreased oral intake for 
24-48 hours
Persistent nausea resulting in 
minimal oral intake for 
48 hours OR Aggressive 
rehydration indicated 
(eg, IV fluids)
Life-threatening consequences 
(eg, hypotensive shock)
Pancreatitis
NA
Symptomatic AND 
Hospitalization not indicated 
(other than ER visit)
Symptomatic AND 
Hospitalization indicated 
(other than ER visit)
Life-threatening consequences 
(eg, sepsis, circulatory failure, 
hemorrhage)
Proctitis (functional-
symptomatic)
Also see Mucositis/ 
Stomatitis for Clinical 
Exam
Rectal discomfort AND No 
intervention indicated
Symptoms causing greater than 
minimal interference with usual 
social & functional activities OR 
Medical intervention indicated 
Symptoms causing inability to 
perform usual social/ 
functional activities OR 
Operative intervention 
indicated 
Life-threatening consequences 
(eg, perforation)
Vomiting
Transient or intermittent 
vomiting with no or 
minimal interference with 
oral intake
Frequent episodes of vomiting 
with no or mild dehydration
Persistent vomiting resulting 
in orthostatic hypotension OR 
Aggressive rehydration 
indicated
Life-threatening consequences 
(eg, hypotensive shock)


GS-9688
Protocol GS-US-389-2025
Final
Gilead Sciences, Inc. 
Amendment 1
CONFIDENTIAL
Page 144
27 August 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 
(eg, suicidal/homicidal 
ideation or attempt, acute 
psychosis) OR Causing 
inability to perform basic 
self-care functions
Altered Mental Status 
For Dementia, see Cognitive 
and Behavioral/Attentional 
Disturbance (including 
dementia and ADD)
Changes causing no or 
minimal interference with 
usual social & functional 
activities
Mild lethargy or somnolence 
causing greater than minimal 
interference with usual social 
& functional activities
Confusion, memory 
impairment, lethargy, or 
somnolence causing inability 
to perform usual social & 
functional activities
Delirium OR obtundation, OR 
coma
Ataxia 
Asymptomatic ataxia 
detectable on exam OR 
Minimal ataxia causing no 
or minimal interference with 
usual social & functional 
activities
Symptomatic ataxia causing 
greater than minimal 
interference with usual social 
& functional activities
Symptomatic ataxia causing 
inability to perform usual 
social & functional activities 
Disabling ataxia causing 
inability to perform basic 
self-care functions
Cognitive and 
Behavioral/Attentional 
Disturbance (including 
dementia and Attention 
Deficit Disorder) 
Disability causing no or 
minimal interference with 
usual social & functional 
activities OR Specialized 
resources not indicated
Disability causing greater than 
minimal interference with 
usual social & functional 
activities OR Specialized 
resources on part-time basis 
indicated
Disability causing inability to 
perform usual social & 
functional activities OR 
Specialized resources on a 
full-time basis indicated
Disability causing inability to 
perform basic self-care 
functions OR 
Institutionalization indicated
CNS Ischemia
(acute)
NA
NA
Transient ischemic attack
Cerebral vascular accident 
(CVA, stroke) with 
neurological deficit 


GS-9688
Protocol GS-US-389-2025
Final
Gilead Sciences, Inc. 
Amendment 1
CONFIDENTIAL
Page 145
27 August 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-9688
Protocol GS-US-389-2025
Final
Gilead Sciences, Inc. 
Amendment 1
CONFIDENTIAL
Page 146
27 August 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 
(eg, status epilepticus), or 
difficult to control 
(eg, 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 
(eg, severity or focality) 
Seizures of any kind that are 
prolonged, repetitive 
(eg, status epilepticus), or 
difficult to control 
(eg, refractory epilepsy)
Seizure 
– Pediatric 18 Years
Seizure, generalized onset 
with or without secondary 
generalization, lasting 
< 5 minutes with < 24 hours 
post ictal state
Seizure, generalized onset 
with or without secondary 
generalization, lasting 
5-20 minutes with 
< 24 hours post ictal state
Seizure, generalized onset 
with or without secondary 
generalization, lasting 
> 20 minutes 
Seizure, generalized onset 
with or without secondary 
generalization, requiring 
intubation and sedation
Syncope (not associated 
with a procedure)
NA
Present
NA
NA
Vertigo
Vertigo causing no or 
minimal interference with 
usual social & functional 
activities
Vertigo causing greater than 
minimal interference with 
usual social & functional 
activities 
Vertigo causing inability to 
perform usual social & 
functional activities
Disabling vertigo causing 
inability to perform basic 
self-care functions


GS-9688
Protocol GS-US-389-2025
Final
Gilead Sciences, Inc. 
Amendment 1
CONFIDENTIAL
Page 147
27 August 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-9688
Protocol GS-US-389-2025
Final
Gilead Sciences, Inc. 
Amendment 1
CONFIDENTIAL
Page 148
27 August 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 
[eg, tube feeding or total 
parenteral nutrition]


GS-9688
Protocol GS-US-389-2025
Final
Gilead Sciences, Inc. 
Amendment 1
CONFIDENTIAL
Page 149
27 August 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 (eg, upper 
arm/thigh)
Erythema OR Induration 
OR Edema involving 
50% surface area of the 
extremity segment 
(eg, upper arm/thigh) OR 
Ulceration OR Secondary 
infection OR Phlebitis OR 
Sterile abscess OR Drainage
Necrosis (involving dermis and 
deeper tissue)
Pruritis Associated with 
Injection 
See also Skin: Pruritis 
(itching—no skin lesions)
Itching localized to injection 
site AND Relieved 
spontaneously or with 
48 h treatment 
Itching beyond the injection 
site but not generalized OR 
Itching localized to injection 
site requiring 48 h treatment 
Generalized itching causing 
inability to perform usual 
social & functional 
activities
NA


GS-9688
Protocol GS-US-389-2025
Final
Gilead Sciences, Inc. 
Amendment 1
CONFIDENTIAL
Page 150
27 August 2019
ENDOCRINE/METABOLIC
Grade 1
Grade 2
Grade 3
Grade 4
Lipodystrophy (eg, back 
of neck, breasts, 
abdomen)
Detectable by study 
participant or caregiver 
(for young children and 
disabled adults)
Detectable on physical exam by 
health care provider
Disfiguring OR Obvious 
changes on casual visual 
inspection
NA
Diabetes Mellitus
NA
New onset without need to initiate 
medication OR Modification of 
current meds to regain glucose 
control
New onset with initiation of 
indicated med OR Diabetes 
uncontrolled despite treatment 
modification
Life-threatening consequences 
(eg, ketoacidosis, 
hyperosmolar non-ketotic 
coma) 
Gynecomastia
Detectable by study 
participant or caregiver 
(for young children and 
disabled adults)
Detectable on physical exam by 
health care provider
Disfiguring OR Obvious on 
casual visual inspection
NA
Hyperthyroidism 
Asymptomatic
Symptomatic causing greater than 
minimal interference with usual 
social & functional activities OR 
Thyroid suppression therapy 
indicated
Symptoms causing inability to 
perform usual social & 
functional activities OR 
Uncontrolled despite treatment 
modification 
Life-threatening consequences 
(eg, thyroid storm)
Hypothyroidism
Asymptomatic
Symptomatic causing greater than 
minimal interference with usual 
social & functional activities OR 
Thyroid replacement therapy 
indicated
Symptoms causing inability to 
perform usual social & 
functional activities OR 
Uncontrolled despite treatment 
modification 
Life-threatening consequences 
(eg, myxedema coma)
Lipoatrophy (eg, fat loss 
from the face, extremities, 
buttocks)
Detectable by study 
participant or caregiver 
(for young children and 
disabled adults)
Detectable on physical exam by 
health care provider
Disfiguring OR Obvious on 
casual visual inspection
NA


GS-9688
Protocol GS-US-389-2025
Final
Gilead Sciences, Inc. 
Amendment 1
CONFIDENTIAL
Page 151
27 August 2019
GENITOURINARY
Grade 1
Grade 2
Grade 3
Grade 4
Intermenstrual Bleeding 
(IMB)
Spotting observed by participant 
OR Minimal blood observed 
during clinical or colposcopic 
exam
Intermenstrual bleeding not 
greater in duration or amount 
than usual menstrual cycle
Intermenstrual bleeding greater 
in duration or amount than usual 
menstrual cycle
Hemorrhage with 
life-threatening hypotension 
OR Operative intervention 
indicated
Urinary Tract 
obstruction (eg, stone)
NA
Signs or symptoms of urinary 
tract obstruction without 
hydronephrosis or renal 
dysfunction
Signs or symptoms of urinary 
tract obstruction with 
hydronephrosis or renal 
dysfunction
Obstruction causing 
life-threatening 
consequences
INFECTION
Grade 1
Grade 2
Grade 3
Grade 4
Infection (any other 
than HIV infection)
Localized, no systemic antiμbial 
treatment indicated AND 
Symptoms causing no or 
minimal interference with usual 
social & functional activities
Systemic antiμbial treatment 
indicated OR Symptoms 
causing greater than minimal 
interference with usual social 
& functional activities
Systemic antiμbial treatment 
indicated AND Symptoms 
causing inability to perform 
usual social & functional 
activities OR Operative 
intervention (other than simple 
incision and drainage) indicated
Life-threatening 
consequences 
(eg, septic shock)
Basic Self-care Functions: Activities such as bathing, dressing, toileting, transfer/movement, continence, and feeding.
Usual Social & Functional Activities: Adaptive tasks and desirable activities, such as going to work, shopping, cooking, use of transportation, pursuing a hobby, etc.

SAP_001.pdf: 
S T A TI S TI C A L A N A L Y SI S P L A N
St u d y Title:
A P hase 2, Ra n d o mize d, D o u ble- Bli n d, Place b o -C o ntr olle d, 
M ulti -ce nter St u d y t o E val uate t he Safet y, T olera bilit y a n d 
A nti viral Acti vit y  of G S-9 6 8 8 i n Vire mic A d ult S u bjects wit h 
C hr o nic He patitis B w h o are n ot c urre ntl y o n Treat me nt
N a me of Test Dr u g:
G S - 96 8 8
St u d y N u m ber:
G S -U S -3 8 9- 2 0 2 5
Pr ot oc ol Versi o n ( D ate ):
Ori gi nal:
2 3 Marc h
2 0 1 8
A me n d me nt 1 : 
2 7 A u g ust 2 0 1 9
A n al ysis T y pe:
Wee k 2 4
A nal ys is, Wee k 4 8 A nal ysis, a n d Fi nal A nal y sis
A n al ysis Pl a n Versi o n:
Versi o n 1. 1
A n al ysis Pl a n D ate:
3 1 Oct o ber , 2 0 1 9
A n al ysis Pl a n A ut h or:
C O N FI D E N TI A L A N D P R O P RI E T A R Y I N F O R M A TI O N
P P D
(rJ GI L E Ai: > 


G S -9 6 8 8
G S -U S -3 8 9 -2 0 2 5
Statistical A nal ysis Pla n
Versi o n 1. 1
C O N FI D E N TI A L
Pa ge 2
3 1 Oct o ber 2 0 1 9
T A B L E O F C O N T E N T S
C CI
T A B L E O F C O N T E N T S ..............................................................................................................................................2
LI S T O F I N -T E X T T A B L E S ........................................................................................................................................4
LI S T O F I N - TE X T FI G U R E S ......................................................................................................................................4
LI S T O F A B B R E VI A TI O N S ........................................................................................................................................5
P H A R M A C O KI N E TI C A B B R E VI A TI O N S................................................................................................................ 8
1.
I N T R O D U C TI O N ................................................................................................................................................9
1. 1.
St u d y O bjecti ves ......................................................................................................................................9
1. 2.
St u d y Desi g n ..........................................................................................................................................1 0
1. 3.
Sa m ple Size a n d P o w er ..........................................................................................................................1 2
2.
T Y P E O F P L A N N E D A N A L Y SI S ....................................................................................................................1 3
2. 1.
Data M o nit ori n g C o m mittee A nal ysis ...................................................................................................1 3
2. 2.
I nter nal Data Re vie w Tea m A nal ysis.....................................................................................................1 3
2. 3.
Wee k 2 4 A nal ysis
..................................................................................................................................1 3
2. 4.
Wee k 4 8 A nal ysis
..................................................................................................................................1 3
2. 5.
Fi nal A nal ysis ( T F F U) ...........................................................................................................................1 3
3.
G E N E R A L C O N SI D E R A TI O N S F O R D A T A A N A L Y S E S ............................................................................1 4
3. 1.
A nal ysis Sets ..........................................................................................................................................1 4
3. 1. 1.
All Ra n d o m ize d A nal ysis Set ...............................................................................................1 4
3. 1. 2.
F ull A nal ysis Set ..................................................................................................................1 4
3. 1. 3.
Safet y A nal ysis Set ...............................................................................................................1 4
3. 1. 4.
P har m ac o ki netic A nal ysis Set ..............................................................................................1 5
3. 1. 6.
Bi o mar ker A nal ysis Set ........................................................................................................1 5
3. 1. 7.
T F F U A nal ysis Set ...............................................................................................................1 5
3. 2.
S u b ject Gr o u pi n g ...................................................................................................................................1 5
3. 3.
Strata a n d C o variates ..............................................................................................................................1 5
3. 4.
E xa mi nati o n of S u bject S u bsets .............................................................................................................1 6
3. 5.
M ulti ple C o m paris o ns ............................................................................................................................1 6
3. 6.
Mis si n g Data a n d O utliers ......................................................................................................................1 6
3. 6. 1.
Missi n g Data
........................................................................................................................1 6
3. 6. 2.
O utliers .................................................................................................................................1 6
3. 7.
Data Ha n dli n g C o n ve nti o ns a n d Tra nsf or mati o ns .................................................................................1 6
3. 8.
A nal ysis Visit Wi n d o ws .........................................................................................................................1 8
3. 8. 1.
Defi niti o n of First D ose Da y, Last D ose Da y, a n d St u d y Da y .............................................1 8
3. 8. 2.
A nal ysis Visit Wi n d o ws .......................................................................................................1 8
3. 8. 3.
Selecti o n of Data i n t he E ve nt of M ulti ple Rec or ds i n a n A nal ysis
Wi n d o w ................................................................................................................................2 1
4.
S U BJ E C T DI S P O SI TI O N ..................................................................................................................................2 3
4. 1.
S u bject E nr oll me nt a n d Dis p ositi o n .......................................................................................................2 3
4. 2.
E xte nt of St u d y Dr u g E x p os ure a n d A d here nce .....................................................................................2 4
4. 2. 1.
D urati o n of E x p os ure t o St u d y Dr u g ....................................................................................2 4
4. 2. 2.
A d here nce t o St u d y Dr u g .....................................................................................................2 5
4. 3.
Pr ot oc ol De viati o ns ................................................................................................................................2 7
5.
B A S E LI N E C H A R A C T E RI S TI C S ....................................................................................................................2 8
-


G S -9 6 8 8 
G S -U S -3 8 9 -2 0 2 5 
St atisti c al A n al ysis P la n 
V ersi o n 1. 1 
5. 1. 
D e m o gr a p hi cs ........................................................................................................................................ 2 8 
5. 2. 
Ot h er B as eli n e C h ar a ct eristi cs ............................................................................................................... 2 8 
5. 3. 
M e di c al Hist or y ...................................................................................................................................... 2 9 
6. 
E F FI C A C Y A N A L Y S E S ................................................................................................................................... 3 0 
6. 1. 
Pri m ar y Effi c a c y E n d p o i nt ..................................................................................................................... 3 0 
6. 1. 1. 
D efi niti o n of Pri m ar y Effi c a c y E n d p o i nt ............................................................................. 3 0 
6. 1. 2 . 
St atisti c al H y p ot h esis f or Pri m m y Effi c a c y E n d p oi nt... ....................................................... 3 0 
6. 1. 3.  
A n al ysis of Pri m ar y Effi c a c y E n d p o i nt... ............................................................................. 3 0 
6. 1. 4 .  
Su b gr o u p A n al ysis of Pri m m y Effi c a c y E n d p oi nt ............................................................... 3 1 
6. 2. 
S e c o n d ar y Effi c a c y E n d p oi nts ............................................................................................................... 3 1 
6. 2. 1. 
D efi niti o n of S e c o n d ar y Effi c a c y E n d p o i nts ........................................................................ 3 1 
6. 2. 2.  
A n al sis M et h o ds f or S e c o n d a 
Effi c a c 
E n d oi nts .......................................................... 3 2 
6. 4 . 
7. 
S A F E T Y A N A L Y S E S ........................................................................................................................................ 3 6 
7. 1. 
A d v ers e E v e nts a n d Deat hs .................................................................................................................... 3 6 
7. 1. 1.  
A d v ers e E v e nt Di cti o n ar y .................................................................................................... 3 6 
7. 1. 2. 
A d v ers e E v e nt S e v erit y ........................................................................................................ 3 6 
7. 1. 3. 
R el ati o ns hi p of A d v ers e E v e nts t o S t u dy Dr u g .................................................................... 3 6 
7 . 1. 4 . 
S eri o us A d v ers e E v e nts ........................................................................................................ 3 6 
7. 1. 5. 
Tr e at m e nt -E m er g e nt A d v ers e E v e nts ................................................................................... 3 6 
7. 1. 6.  
S u m m ari es of A d v ers e E ve nts a n d D e at hs ........................................................................... 3 7 
7 . 2. 
L a b or at or y E val u ati o ns .......................................................................................................................... 3 9 
7. 2. 1.  
S u m m ari es of N u m eri c L a b or at or y R es ults ......................................................................... 4 0 
7. 2. 2. 
Gr a d e d L a b or at or y Val u es ................................................................................................... 4 0 
7 . 2. 3. 
Li v er -r el at e d L a b or at or y E val u ati o ns ................................................................................... 4 1 
7. 2. 4 . 
D ose L i miti ng T o xi citi es ...................................................................................................... 4 2 
7. 3. 
B o d y W ei g ht, B o d y Mass I n d e x a n d Yitai Si g ns ................................................................................... 4 3 
7. 4 . 
Pri or a n d C o n c o mit a nt M e di c ati o ns ....................................................................................................... 4 3 
7. 4 . 1. 
Pri or M e di c ati o ns ................................................................................................................. 4 3 
7. 4 . 2. 
C o n c o mit a nt M e di c ati o ns ..................................................................................................... 4 4 
7. 5. 
El e ctr o c ar di o gr a m R es ults ..................................................................................................................... 4 5 
7. 6. 
Ot h er S af et y M e as ur es ........................................................................................................................... 4 5 
7. 7. 
C h a n g es fr o m Pr ot o c ol -S p e cifi e d S af et y A n al ys es ................................................................................ 4 5 
8. 
P H A R M A C O KI N E TI C A N A L Y S E S ................................................................................................................ 4 6 
8. 1. 
P K S a m pl e C oll e cti o n ............................................................................................................................ 4 6 
'1'-
Est 1 mat m n o P K P ar a m et ers ............................................................................................... 4 6 
8. 1. 3. 
P K P ar a m et ers ...................................................................................................................... 4 7 
8. 1. 4 .  
A nal ysis of D os e Pr o p orti o n alit y ......................................................................................... 4 8 
8. 2. 
P K A n al ys es R el at e d t o S p ars e P K S a m pli n g ........................................................................................ 4 9 
9. 
R E F E R E N C E S ................................................................................................................................................... 5 0 
1 0 . S O F T W A R E ....................................................................................................................................................... 5 1 
11 . S A P R E VI SI O N .................................................................................................................................................. 5 2 
1 2 . A P P E N DI C E S .................................................................................................................................................... 5 3 
C O N FI D E N T IA L 
P a g e 3 
3 I O ct o b er 2 0 1 9 


G S -9 6 8 8 
G S -U S -3 8 9 -2 0 2 5 
St atisti c al A n al ysis P la n 
V ersi o n 1. 1 
T a bl e 3- 1. -
T a ble 3- 3. 
T a ble 3- 4 . 
T a ble 3- 5. 
T a ble  8- 1. 
T a ble  8- 2. 
Fig ur e I. 
C O N FI D E N TI A L 
S c h e d ule of A ss essm e nts ........................................................................................................ 5 4 
LI S T O F I N- T E X T T A B L E S 
A n al ys is  Visit Wi n d o ws f or O n -tre a t me nt q H Bs A g, H B V D N A a n d S af et y 
La b or a t or  D ata ...................................................................................................................... 19 
A n al ys is  Visit Wi n d o ws f or O n -tre a t me nt Q u ali t ativ e H B V S e r ol og y .................................. 2 0 
A n al ys is  Visit Wi n d o ws f or O n -tre a t me nt Yi tai Si g ns .......................................................... 2 0 
A n al ys is  Visit Wi n d o ws f or  Pos ttrea t me nt ( Tre a t me nt  Fr ee F o il o w U p Per i o d) ................... 2 1 
S t u dy Tre a t me nts a n d A sso c iat e d A n al yt e ............................................................................. 4 7 
P K P ar a m et ers ........................................................................................................................ 4 7 
LI S T O F I N- T E X T FI G U R E S 
S t ud y S c h e m a• ........................................................................................................................ 1 1 
P a g e 4 
3 I O ct o b er 2 0 1 9 


G S -9 6 8 8
G S -U S -3 8 9 -2 0 2 5
Statistical A nal ysis Pla n
Versi o n 1. 1
C O N FI D E N TI A L
Pa ge 5
3 1 Oct o ber 2 0 1 9
LI S T O F A B B R E VI A TI O N S
A E
a d verse e ve nt
A N O V A
a nal ysis of varia nce
A L P
al kali ne p h os p hatase
A L T
ala ni ne a mi n otra nsferase
A S T
as partate tra nsa mi nase
A T C
a nat o mical t hera pe utic c he mical
A U C
area u n der t he c ur ve
A V
atri o ve ntric ular
B L Q
bel o w  t he li mit of q ua ntitati o n
B MI
b o d y mass i n de x
B P M
beats per mi n ute
C- Q T
c o nce ntrati o n-Q T
C G
C oc kcr oft -Ga ult
C H B
c hr o nic he patitis B
CI
c o nfi de nce i nter val
C K
creati ne ki nase
C L D Q
C hr o nic Li ver Disease Q uesti o n naire
C S R
cli nical st u d y re p ort
C V
c oefficie nt of variati o n
D L T
d ose li miti n g t o xicit y
D M C
data m o nit ori n g c o m mittee
D N A
de o x yri b o n ucleic aci d
E C G
electr ocar di o gra m
e C R F
electr o nic case re p ort f or m
e G F R
esti mate d gl o mer ular filtrati o n rate
E O T
e n d of treat me nt
E T
earl y ter mi nati o n
F A S
f ull a nal ysis set
F U
foll o w -u p
G L S M
ge o metric least -s q uares mea ns
H Bcr A g
he patitis B c ore -relate d a nti ge n
H B V
he patitis B vir us
H Be A b
he patitis B e a nti b o d y
H Be A g
he patitis B e a nti ge n
H Bs A b
he patitis B s urface a nti b o d y
H Bs A g
he patitis B s urface a nti ge n
H L G T
h i g h le vel gr o u p ter m
H L T
hi g h le vel ter m


G S -9 6 8 8
G S -U S -3 8 9 -2 0 2 5
Statistical A nal ysis Pla n
Versi o n 1. 1
C O N FI D E N TI A L
Pa ge 6
3 1 Oct o ber 2 0 1 9
H R
heart rate
H R Q o L
healt h -relate d q ualit y of life
I D
ide ntificati o n
I D R T
inter nal d ata re vie w te a m
I N R
i nter nati o nal n or malize d rati o
I X R S
i nteracti ve v oice or we b res p o nse s yste m
L D H
lactate de h y dr o ge nase
L L T
l o wer le vel ter m
L O Q
li mit of q ua ntitati o n
L L O Q
l o wer li mit of q ua ntitati o n
Me d D R A
Me dical Dicti o nar y f or Re g ulat or y Acti vities
M H
Ma ntel- Hae nszel
O A V
oral a nti viral
P B M C
peri p heral bl o o d m o n o n uclear cell
P D
p har mac o d y na mics
Pe g -I F N
pe g ylate d i nterfer o n
P K
p har mac o ki netics
P T
preferre d ter m
P T M
place b o -t o-matc h
P V E
P har m ac o vi gila nce a n d E pi de mi ol o g y
Q 1
first q uartile
Q 3
t hir d q uartile
q H Bs A g
q ua ntitati ve he patitis B s urface a nti ge n
R B C
re d bl o o d cell
R N A
ri b o n ucleic aci d
S A E
seri o us a d verse e ve nt
S A P
statistical a nal ysis pla n
S D
sta n dar d de viati o n
S E
sta n dar d err or
S N Ps
si n gle n ucle oti de p ol y m or p his ms
S O C
s yste m or ga n class
T A F 
Te n of o vir Alafe na mi de
T E
treat me nt e mer ge nt
T F F U
Treat me nt free f oll o w u p
T F Ls
ta bles, fi g ures, a n d listi n gs
T L R
t oll-li ke rece pt or
T N D
tar get n ot detecte d
U L N
u p per li mit of n or m al
W B C
w hite bl o o d cell
W H O
W orl d Healt h Or ga nizati o n


G S -9 6 8 8
G S -U S -3 8 9 -2 0 2 5
Statistical A nal ysis Pla n
Versi o n 1. 1
C O N FI D E N TI A L
Pa ge 7
3 1 Oct o ber 2 0 1 9
W P AI: He p B
W or k Pr o d ucti vit y a n d Acti vit y I m pair me nt Q uesti o n naire : He patitis B


G S -9 6 8 8
G S -U S -3 8 9 -2 0 2 5
Statistical A nal ysis Pla n
Versi o n 1. 1
C O N FI D E N TI A L
Pa ge 8
3 1 Oct o ber 2 0 1 9
P H A R M A C O KI N E TI C A B B R E VI A TI O N S
A U C 0- 2 4
area u n der t he c o nce ntrati o n d uri n g 2 4 h o urs
% A U C
e x p
perce nta ge of A U C e xtra p olate d bet w ee n A U C last a n d A U C i nf
A U C i nf
area u n der t he c o nce ntrati o n vers us ti me c ur ve e xtra p olate d t o i nfi nite ti me, calc ulate d as 
A U C last + ( Clast/ λz)
A U C last
area u n der t he c o nce ntrati o n vers us ti me c ur ve fr o m ti me zer o t o t he last q ua ntifia ble 
c o nce ntrati o n
A U C ta u
area u n der t he c o nce ntrati o n vers us ti me c ur ve o ver t he d osi n g i nter val
C last
last o bser ve d q ua ntifia ble c o nce ntrati o n of t he dr u g 
C ma x
ma xi m u m o bser ve d c o nce ntrati o n of dr u g 
C ta u
o bser ve d dr u g c o nce ntrati o n at t he e n d of t he d osi n g i nter val
C L/ F
a p pare nt oral cleara nce after a d mi nistrati o n of t he dr u g:
at stea d y state: C L/ F = D ose/ A U C i nf , w here “ D ose” is t he d ose of t he dr u g
τ
T he n o mi nal ti me p oi nt f or a ke y e ve nt or d osi n g i nter val 
t1/ 2
esti mate of t he ter mi nal eli mi nati o n half -life of t he dr u g, calc ulate d b y di vi di n g t he nat ural l o g of 
2 b y t he ter mi nal eli mi nati o n rate c o nsta nt ( z)
T last
ti me ( o bser ve d ti me p oi nt) of Clast
T ma x
ti me ( o bser ve d ti me p oi nt) of Cma x
z
ter mi nal eli mi nati o n rate c o nsta nt, esti mate d b y li near re gressi o n of t he ter mi nal eli mi nati o n 
p hase of t he c o nce ntrati o n of dr u g vers us ti me c ur ve
V z/ F
a p pare nt v ol u me of distri b uti o n of t he dr u g


G S -9 6 8 8
G S -U S -3 8 9 -2 0 2 5
Statistical A nal ysis Pla n
Versi o n 1. 1
C O N FI D E N TI A L
Pa ge 9
3 1 Oct o ber 2 0 1 9
1.
I N T R O D U C TI O N
T his statistical a nal y sis pla n ( S A P) descri bes t he statistical a nal ysis met h o ds a n d data 
prese ntati o ns t o be use d i n ta bles, fi g ures, a n d listi n gs ( T F Ls) i n t he cli nical st u d y re p ort ( C S R) 
f or St u d y  G S-U S -3 8 9- 2 0 2 5. T his S A P is base d o n t he st u d y pr ot oc ol A me n d me nt 1 date d 
2 7 A u g ust 2 0 1 9 a n d t he electr o nic case re p ort f or m (e C R F). T h is S A P will be fi nalize d bef ore 
t he I nter nal Data Re vie w Tea m A nal ys is. A n y c ha n ges ma de after t he fi nalizati o n of t he S A P 
will be d oc u me nte d i n t he C S R.
I n t his S A P, Wee k 2 4 a nal y sis a n d Wee k 4 8 a nalysis will be descri be d i n details. F or fi nal 
a nal ys is (treat me nt free f oll o w u p peri o d), data listi n gs will be s h o w n, a n d su m mar y  ta bles ma y 
be prese nte d as a p pr o priate.
1. 1. 
St u d y O bjecti ves
T he pri mar y  o bjecti ves of t his st u d y are as f oll o ws:

T o e val uate t he safet y a n d t olera bilit y of m ulti ple oral d oses of G S -9 6 8 8 a t Wee k 2 4 i n C H B 
a d ult su bjects w h o are vire mic a n d c urre ntl y n ot bei n g treate d 

T o e val uate t he a nti viral acti vit y  of G S-9 6 8 8 as meas ure d b y t he pr o p orti o n of s u bjects wit h 
≥1 l o g 1 0 I U/ m L decli ne fr o m baseli ne i n ser u m q ua ntitati ve he patitis B s urface a nti ge n 
( q H Bs A g) at Wee k 2 4
T he sec o n dar y  o bjecti ves of t his st u d y are as f oll o ws:

T o e val uate t he a nti viral acti vi t y of G S-9 6 8 8 at Wee ks 4, 8, 1 2 a n d 4 8 as meas ure d b y t he 
pr o p orti o n of s u bjects wit h ≥1 l o g 1 0 I U/ m L decli ne fr o m baseli ne i n ser u m q H Bs A g

T o e val uate t he c ha n ge i n ser u m q H Bs A g (l o g1 0 I U/ m L) fr o m baseli ne t o Wee ks 4, 8, 1 2, 2 4 
a n d 4 8

T o e val uate t he pr o p orti o n of s u bjects wit h H B V D N A < L L O Q at Wee ks 1 2, 2 4, a n d 4 8

T o e val uate t he pr o p orti o n of s u bjects wit h H Bs A g l oss at Wee ks 1 2, 2 4 a n d 4 8

T o e val uate t he pr o p orti o n of s u bjects wit h He patitis B e-A nti ge n ( H Be A g) l oss a n d 
ser oc o n versi o n at Wee ks 1 2, 2 4 a n d 4 8

T o c haracterize t he P K of G S - 9 6 8 8

T o e val uate t he pr o p orti o n of s u bjects e x perie nci n g H B V vir ol o gic b rea kt hr o u g h 
( 2 c o nsec uti ve visits of H B V D N A ≥6 9 I U/ m L)

T o e va l uate t he i nci de nce of dr u g resista nce m utati o ns


G S -9 6 8 8 
G S -U S -3 8 9 -2 0 2 5 
St atisti c al A n al ysis Pl a n 
I 
I 
I 
I 
I 
I 
I 
I 
I 
1. 2 .  
St u dy D esi g n 
V ersi o n 1. 1 
T h is is a m u ltic e nt er, r a n d o miz e d, d o u bl e- b li n de d, pl a c e b o- c o ntr o lle d P h a s e 2 st u d y of G S- 9 6 8 8 
i n vi r e mi c a d u lt C H B s u bje cts n ot c urr e ntl y o n O A V tr e at m e nt. 
C O N FI D E N T IA L 
P a g e 1 0 
3 I O ct o b er 2 0 1 9 


G S -9 6 8 8
G S -U S -3 8 9 -2 0 2 5
Statistical A nal ysis Pla n
Versi o n 1. 1
C O N FI D E N TI A L
Pa ge 1 1
3 1 Oct o ber 2 0 1 9
Fi g ure 1.
St u d y Sc he m a a
a
At Wee k 4 8, per PI ’s discreti o n, s u bjects will be ma na ge d i n o ne of t w o wa ys:
1.
C o nti n ue i n t he st u d y f or 4 8 wee ks f oll o wi n g t he disc o nti n uati o n of T A F (T F F U , wi n d o w of ± 7 da ys ) or u ntil a n 
alter nati ve c o m merciall y a p pr o ve d C H B treat me nt is starte d, w hic he ver occ urs first
2.
I nitiate ot her sta n dar d of care C H B t hera p y wit h Wee k 4 8 re prese nti n g t he last st u d y visit
A p pr o xi matel y  6 5 vire mic s u bjects w h o are n ot c urre ntl y bei n g treate d for C H B will be e nr olle d 
i nt o t w o c o h orts wit hi n t his st u d y t hat will r u n i n parallel. 

C o h ort 1 ( n  4 0): H Be A g-p ositi ve C H B s u bjects

C o h ort 2 ( n  2 5): H Be A g-ne gati ve C H B s u bjects
Wit hi n eac h c o h ort, s u bjects
will be ra n d o mize d i n a 1: 2: 2 i n rati o t o o ne of t he t hree treat me nt 
ar ms ( A: B: C) f or wee kl y d osi n g of G S-9 6 8 8/ P T M f or 2 4 d oses . 
All s u bjects will als o be treate d wit h T A F 2 5 m g oral dail y  f or t he d urati o n of t he st u d y, 
4 8 wee ks, i n a d diti o n t o t he f oll o wi n g treat me nts:
Tre at me nt Ar m A: A p pr o xi mate l y 8 s u bjects i n C o h ort 1 a n d a p pr o xi matel y 5 s u bjects i n 
C o h ort 2 will be a d mi nistere d place b o -t o-matc h ( P T M) orall y o n t h e sa me da y o nce a wee k 
(e ver y 7 d a y s) f or 2 4 d oses 
Tre at me nt Ar m B: A p pr o xi matel y  1 6 s u bjects i n C o h ort 1 a n d a p pr o xi matel y 1 0 s u bjects i n 
C o h ort 2 will be a d mi nistere d G S - 9 6 8 8 1. 5 m g orall y  o n t he sa me da y o nce a wee k 
(e ver y 7 d a y s) f or 2 4 d oses
Tre at me nt Ar m C: A p pr o xi matel y  1 6 s u bjects i n C o h ort 1 a n d a p pr o xi matel y 1 0 s u bjects i n 
C o h ort 2 will be a d mi nistere d G S - 9 6 8 8 3 m g orall y  o n t he sa me da y o nce a wee k (e ver y 7 d a y s) 
f or 2 4 d oses
B a s e lin e 
( D a y 1) 
Ar m A 
N = 8 
Ar m B 
N = 1 6 
Ar m c 
N = 1 6 
H B e A g- p o siti v e C H B s u bj e ct s 
N = 4 0 
C o h o rt 2: 
H B e A g- n e g ati v e C H B s u bj e ct s 
N = 2 5 
' C o h orl 1 a n d C o h ort 2 wi ll r u n I n p ar a llel 
W e e k 2 3 ( L ast G S -9 6 8 8/ P T M D o s e ) 
W e e k 4 8 /r n 
i 
T AF 
Pl a c e b o T o M at c h 
I 
W e e kl y • 2 4 d o s e, 
T AF 
G S -9 6 8 8 1. 5 m g 
I 
W e e k l y • 2 4 d o s e s 
T AF 
G S -9 6 8 8 3 m g 
I 
W e e k l y • 2 4 d o s e, 
B a s e lin e 
( D a y 1) 
Ar m A 
N = S 
Ar m B 
N =l O 
Ar m c 
N =l O 
W e e k 2 3 ( L a st G S -9 6 8 8/ P T M D o s e) 
W e e k 4 8 /f D 
i 
T AF 
P l ac e b o T o M at c h 
I 
W e e kl y• 2 4 d o s e, 
T AF 
G S -9 6 8 8 1 . 5 m g 
I 
W e e k l y• 2 4 d o s e, 
T AF 
G S -9 6 8 8 3 m g 
I 
W e e k l y x 2 4 d o s e, 


G S -9 6 8 8
G S -U S -3 8 9 -2 0 2 5
Statistical A nal ysis Pla n
Versi o n 1. 1
C O N FI D E N TI A L
Pa ge 1 2
3 1 Oct o ber 2 0 1 9
All G S- 9 6 8 8 st u d y  dr u g d oses will be a d mi nistere d i n faste d state.
F oll o wi n g c o m pleti o n of t he 4 8 -wee k st u d y peri o d t he I n vesti gat ors will be res p o nsi ble f or 
assessi n g t he nee d t o c o nti n ue st u d y  s u bjects o n treat me nt f or C H B. At Wee k 4 8, at Pri nci pal 
I n vesti gat or ( PI) discreti o n, s u bjects will be ma na ge d i n o ne of t w o wa ys:
1)
C o nti n ue i n t he st u d y  f or 4 8 wee ks f oll o wi n g t he disc o nti n uati o n of T A F ( Treat me nt Free 
F oll o w -U p, T F F U , wi n d o w of ± 7 da y s) or u ntil a n alter nati ve c o m merciall y a p pr o ve d C H B 
treat me nt is starte d, w hic he ver occ urs first
2)
I nitiate ot her sta n dar d of care C H B t hera py i m me diatel y  at e n d of st u d y.
At t he PI ’s discreti o n, s u bject(s) i n t he T F F U p hase ma y i nitiate ot her sta n dar d of care C H B 
t hera py at a n y ti me per l ocal treat me nt g ui deli nes. If a s u bject i nitiates ot her sta n dar d of care 
C H B t hera p y f or t heir C H B, T F F U visits will c o nti n ue f or 2 m ore T F F U visits or u ntil t he e n d of 
t he T F F U p hase ( Wee k 9 6), w hic he ver c o mes first.
T he t otal st u d y d urati o n f or eac h s u bject will be 4 8 wee ks wit h u p t o a n a d diti o nal 4 8 wee ks if 
c o nti n ue d i nt o t he T F F U p hase . C o h ort 1 a n d 2 c o nsist of 2 4 d oses (W ee k 2 3) of treat me nt of 
G S -9 6 8 8 st u d y  dr u g/ P T M, a n d 4 8 wee ks of T A F treat me nt.
T he sc he d ule of assess me nts i s pr o vi de d as a n a p pe n di x (A p pe n di x 1 ).
1. 3.
S a m ple Size a n d P o wer
D ue t o t he e x pl orat or y  nat ure of t his st u d y, t he sa m ple size was n ot deter mi ne d b y a n y f or mal 
p o wer calc u lati o n. T he n u m ber of s u bjects i n eac h treat me nt gr o u p was deci de d base d o n cli nical 
e x perie nce.


G S -9 6 8 8
G S -U S -3 8 9 -2 0 2 5
Statistical A nal ysis Pla n
Versi o n 1. 1
C O N FI D E N TI A L
Pa ge 1 3
3 1 Oct o ber 2 0 1 9
2.
T Y P E O F  P L A N N E D A N A L Y SI S
2. 1.
D at a M o nit ori n g C o m mittee A n al ysis
A n i n de pe n de nt, e xter nal data m o nit ori n g c o m mittee ( D M C) will re vie w t he pr o gress of t he 
st u d y a n d perf or m i nteri m re vie ws of t he safety data t o pr otect s u bject welfare a n d preser ve 
st u d y i nte grity. T o e ns ure t he best i nterests of t he s u bjects, t he D M C will rec o m me n d t o t he 
s p o ns or if t he nat ure, fre q ue nc y, a n d se verity of a d verse effects ass ociate d wit h t he st u d y 
treat me nt warra nt t he earl y ter mi nati o n of t he st u d y, t he c o nti n uati o n of t he st u d y, or t he 
c o nti n uati o n of t he st u d y wit h m o dificati o ns.
T he i nitial D M C data re vie w meeti n g will be c o n d ucte d afte r 2 0 s u bjects ha ve c o m plete d 
ra n d o mizati o n. S u bse q ue nt meeti n gs ma y be hel d a p pr o xi matel y e ver y 3 m o nt hs u ntil t he last 
s u bject e nr olle d has c o m plete d t he G S-9 6 8 8/ P T M st u d y  dr u g d osi n g peri o d.
T he D M C’s r ole a n d res p o nsi bilities a n d t he sc o pe of a nal ys is t o be pr o vi de d t o t he D M C are 
pr o vi de d i n a m ut uall y  a gree d-u p o n c harter, w hic h defi nes t he D M C me m bers hi p, meeti n g 
l o gistics, a n d meeti n g fre q ue nc y.
2. 2.
I ntern al D at a Re vie w Te a m A n al ysis
A n inter nal d ata re vie w tea m (I D R T), e xter nal t o t he st u d y tea m, ma y be u n bli n de d after all 
s u bjects ha ve c o m pleted Wee k 1 2 or pre mat urel y disc o nti n ue d fr o m t he st u d y treat me nt pri or t o 
Wee k 1 2 . T he I D R T will re vie w t he u n bli n de d safet y , P D a n d efficac y data i n or der t o g ui de 
strate gic decisi o ns re gar di n g t he f ut ure of t he pr o gra m. T he I D R T will f u ncti o n i n de pe n de ntl y  
fr o m all ot her i n di vi d uals ass ociate d wit h t he c o n d uct of t his st u d y , i ncl u di n g i n vesti gat ors, 
Gilea d pers o n nel i n v ol ve d i n t he pr o gra m, t he st u d y  ma na ge me nt tea m, a n d ot her c o m mittees 
(e g, et hics c o m mittees) o verseei n g t he trial.
T he I D R T’s r ole a n d res p o nsi bilities a n d t he sc o pe of a nal ys is t o be pr o vi de d t o t he I D R T are 
pr o vi de d i n a m ut uall y  a gree d-u p o n c harter, w hic h defi ne s t he I D R T me m bers hi p, meeti n g 
l o gistics, a n d meeti n g fre q ue nc y.
2. 3.
Wee k 2 4
A n al ysis
T he Wee k 2 4 a nal ys is will be c o n d ucte d after all s u bjects ha ve c o m plete d Wee k 2 4 or 
pre mat urel y disc o nti n ue d st u d y  treat me nt pri or t o Wee k 2 4 . T he st u d y  will be u n bli n de d at t he 
ti me of t he Wee k 2 4 a nal y sis.
2. 4.
Wee k 4 8 A n al ysis
T he Wee k 4 8 a nal ys is will be perf or me d after all s u bjects ha ve c o m plete d Wee k 4 8 or 
pre mat urel y disc o nti n ue d st u d y  treat me nt pri or t o Wee k 4 8, o utsta n di n g data q ueries ha ve bee n 
res ol ve d or a dj u dicate d as u nres ol va ble, a n d t he data ha ve bee n clea ne d a n d fi nalize d.
2. 5.
Fi n al A n al ysis ( T F F U)
T he fi nal a nal y sis will be c o n d ucte d f or s u bjects w h o e ntere d t he T F F U peri o d s u bse q ue nt t o 
st u d y dr u g disc o nti n uati o n u p t o st u d y Wee k 4 8
or pre mat urel y disc o nti n ue d st u d y  treat me nt 
pri or t o Wee k 4 8 .


G S -9 6 8 8
G S -U S -3 8 9 -2 0 2 5
Statistical A nal ysis Pla n
Versi o n 1. 1
C O N FI D E N TI A L
Pa ge 1 4
3 1 Oct o ber 2 0 1 9
3.
G E N E R A L  C O N SI D E R ATI O N S F O R D A T A  AN A L Y S E S
A nal y sis res ults will be prese nte d usi n g descri pti ve statistics. F or cate g orical varia bles, t he 
n u m ber a n d perce nta ge of s u bjects i n eac h cate g or y  will be prese nte d; f or c o nti n u o us varia bles, 
t he n u m ber of s u bjects (n ), mea n, sta n dar d de viati o n (S D ) or stan dar d err or ( S E ), me dia n, 
first q uartile ( Q 1 ), t hir d q uartile (Q 3 ), mi ni m u m, a n d ma xi m u m will be prese nte d.
B y -s u bject listi n gs will be prese nte d f or s u bjects i n t he All Ra n d o mize d A nal ysis Set a n d s orte d 
b y  s u bject i de ntificati o n (I D) n u m ber, visit date, a n d ti me (if a p plica ble). Data c ollecte d o n l o g 
f or ms, s uc h as a d verse e ve nts ( A Es), will be prese nte d i n c hr o n ol o gical or der f or eac h s u bject. 
T he treat me nt gr o u p t o w hic h s u bjects were ra n d o mize d will be use d i n t he listi n gs. A ge, se x at 
birt h, race, a n d et h nicit y will be i ncl u de d i n t he listi n gs, if s pace per mits.
3. 1.
A n al ysis Sets
A nal y sis sets defi ne t he s u bjects t o be i ncl u de d i n a n a nalys is. A nalys is sets a n d t heir defi niti o ns 
are pr o vi de d i n t his secti o n. T he a nal ys is set will be i de ntifie d a n d i ncl u de d as a s u btitle of eac h 
ta ble, fi g ure, a n d listi n g.
F or eac h a nal ys is set, the n u m ber a n d perce nta ge of s u bjects eli gi ble f or i ncl usi o n, as well as t he 
n u m ber a n d perce nta ge of s u bjects w h o were e xcl u de d a n d t he reas o ns f or t heir e xcl usi o n, will 
be s u m marize d b y treat me nt gr o u p.
A listi n g of reas o ns f or e xcl usi o n fr o m a nal y sis sets will be pr o vi de d b y  s u bject.
3. 1. 1.
All R a n d o mize d A n al ysis Set
T he All Ra n d o mize d A nal y sis Set i ncl u des all s u bjects w h o were ra n d o mize d i n t he st u d y.
S u bjects are gr o u pe d wit hi n t he All Ra n d o mize d A nal ysis Set b y t he treat me nt gr o u p t o w hic h
t he y were ra n d o mized. 
3. 1. 2.
F ull A n al ysis Set
T he F ull A nal ys is S et ( F A S) i ncl u des all ra n d o mize d s u bjects w h o t o o k at least 1 d ose of t he 
st u d y dr u g. T he st u d y dr u g i n t his st u d y is G S -9 6 8 8 or P T M . S u bjects are gr o u pe d wit hi n t he 
F A S b y t he treat me nt gr o u p t o w hic h t he y were ra n d o mize d. T his is t he pri mar y a nal ys is set f or 
efficac y a nalys es.
3. 1. 3. 
S afet y A n al ysis Set
T he S afet y A nal y sis S et i ncl u des all s u bjects w h o t o o k at least 1 d ose of t he st u d y dr u g. S u bjects 
are gr o u pe d wit hi n t he Safet y A nal ys is Set acc or di n g t o t he tr eat me nt t he y act ually recei ve d. 
T his is t he pri mar y  a nalysis set f or safet y a nal ys es.


G S -9 6 8 8 
G S -U S -3 8 9 -2 0 2 5 
St atisti c al A n al ysis Pl a n 
3. 1. 4. 
P h a r m a c o ki n eti c A n al ysis S et 
V ersi o n 1. 1 
T h e P h a n n a c o ki n et ic (P K ) A n a lys is S et in cl u d es a ll r a n d o miz e d s u bje cts w h o t o o k at le ast 
1 d os e of t he st u d y dr u g a n d h a v e at le ast 1 n o m n issi ng c o n c e ntr ati o n v a lu e r e p ort e d b y t h e P K 
la b or at or y. T hi s is t h e pr i mar y a n alys is s et f or a ll P K a n alys es . Wit hi n t h e P K A n a lys is Set, 
t h os e s u bj e cts wi t h e v a lu a b le P K w ill b e in cl u d e d f or p ar a m et er esti m ati o n. 
-
-
3. 1. 7. 
T F F U A n al ysis S et 
T h e T F F U A n al y sis S et w ill in cl u d e a ll s u bj e cts w h o w er e r a n d o miz e d i nt o t h e st u d y, recei ve d at 
least 1 d ose of st u d y dr u g a n d e nt er e d t h e T F F U p eri o d . 
3. 2. 
S u bj e ct G r o u pi n g 
F or a n alys es b as e d o n t he All R a n d o mi z e d A n al ys is S et, F A S, or Bi o m ar k er A n al y sis Set, 
s u bje cts w ill b e gr o u p e d a c c or di n g t o t h e tr e at m e nt t o w hi c h t h e w er e r a n d o mi z e d. F or a n a lyses 
b as e d o n S af et y A n al ys is Set, P K A n a lys is S et 
s u bje cts w ill b e 
gr o u p e d a c c or d i ng t o t h e tr e at m e nt t h e y a ct u a lly r e c eiv e d . T h e a ct u a l tr e at m e nt r e c eiv e d w ill 
di ffer fr o m t he r a n d o miz e d tr e at m e nt o n l y w h e n t h e a ct u al tr e at m e nt di ffers fr o m r a n d o mi z e d 
tr e at m e nt f or t h e e nt ire tr e at m e nt d ur ati o n. 
3. 3. 
St r at a a n d C o v a ri at es 
S u bj e cts w ill b e r a n d o ml y ass i g ne d t o tr e at m e nt gr o u ps via t he i nter a ct iv e v o ice or w e b r es p o ns e 
s yst em (I X R S) wi t h a  1 : 2: 2 i n r ati o usi n g a str atifie d r a n d o miz atio n s ch e d u le. Str at ific ati o n w ill 
b e b as e d o n t h e f ollo w in g v ar ia b les: 
• 
H B e A g ( p ositiv e, n e g at ive) 
If t h er e are di s cr e p a n cies i n str atific atio n f a ct or of H B e A g v a lu es b et w e e n t h e I X R S a n d t h e 
cli ni c al d at a b as e, t h e v a lu es r e c or d e d i n t h e cli ni c al d at a b as e w ill b e us e d f or a n a lys es . 
S af et y a n d effi c a cy e n d p oi nt s will b e e v alu at e d b y b as e lin e H B e A g st at us a n d o v er a ll f or e a c h 
tr e at m e nt gr o u p . 
C O N FI D E N T IA L 
P a g e 1 5 
3 I O ct o b er 2 0 1 9 


G S -9 6 8 8
G S -U S -3 8 9 -2 0 2 5
Statistical A nal ysis Pla n
Versi o n 1. 1
C O N FI D E N TI A L
Pa ge 1 6
3 1 Oct o ber 2 0 1 9
3. 4.
E x a mi n ati o n of S u bject S u bsets
D ue t o t he e x pl orat or y  nat ure a n d t he s mall sa m ple size of t his st u d y, s u b gr o u p a nalys es base d 
o n pres u me d pr o g n ostic baseli ne c haract eristics will n ot be perf or me d f or efficac y e n d p oi nts .
3. 5.
M ulti ple C o m p aris o ns
A dj ust me nts f or m ulti plicit y  will n ot be ma de beca use n o f or mal statistical h y p ot hesis testi n g
will be perf or me d i n t his st u d y .
3. 6.
Missi n g D at a a n d O utliers
3. 6. 1.  
Missi n g D at a
I n ge neral, missi n g data will n ot be i m p ute d u nless met h o ds f or ha n dli n g missi n g data are 
s pecifie d. E xce pti o ns are prese nte d i n t his d oc u me nt.
A missi n g baseli ne la b orat or y res ult will be treate d as n or mal ( i.e., n o t o xicit y gra de) f or t he 
la b orat or y a b n or malit y s u m mar y.
B ot h baseli ne a n d p ost baseli ne b or derli ne res ults f or H Be A g, he patitis B e a nti b o d y  (H Be A b ), 
H Bs A g, a n d he patitis B s urface a nti b o d y  (H Bs A b ) will be i m p ute d as f oll o ws:

H Bs A b/ H Be A b b or derli ne 
H Bs A b/ H Be A b ne gati ve

H Bs A g/ H Be A g b or derli ne 
H Bs A g/ H Be A g p ositi ve
F or missi n g last d ose date of st u d y  dr u g, i m p utati o n r ules are descri be d i n Secti o n 3. 8. 1 . T he 
ha n dli n g of missi n g or i nc o m pl ete dates f or A E o nset is descri be d i n Secti o n 7. 1. 5. 2 , a n d f or 
pri or a n d c o nc o mita nt me dicati o ns i n Secti o n 7. 4 .
3. 6. 2.
O utliers
O utliers will be i de ntifie d d uri n g t he data ma na ge me nt a n d data a nal ys is pr ocess, b ut n o 
se nsiti vit y a nalys es will be c o n d ucte d. All data will be i ncl u de d i n t he data a nal ys is. 
3. 7.  
D at a H a n dli n g C o n ve nti o ns a n d Tr a nsf or m ati o ns
T he f oll o wi n g c o n ve nti o ns will be use d f or t he i m p utati o n of date of birt h w he n it is partiall y  
missi n g or n ot c ollecte d:

If o nl y m o nt h a n d year of birt h is c ollecte d, t he n “ 1 5” will be i m p ute d as t he da y  of birt h

If o nl y year of birt h is c ollecte d, t he n “ 0 1 J ul y” will be i m p ute d as t he da y a n d m o nt h of birt h

If year of birt h is missi n g, t he n date of birt h will n ot be i m p ute d


G S -9 6 8 8
G S -U S -3 8 9 -2 0 2 5
Statistical A nal ysis Pla n
Versi o n 1. 1
C O N FI D E N TI A L
Pa ge 1 7
3 1 Oct o ber 2 0 1 9
I n ge neral, a ge c ollecte d at Da y 1 (i n ye ars) will be use d f or a nal ys es a n d prese nte d i n listi n gs. If 
a ge at Da y 1 is n ot a vaila ble f or a s u bject, t he n a ge deri ve d base d o n date of birt h a n d t he Da y 1 
visit date will be use d i nstea d. If a n e nr olle d s u bject was n ot d ose d wit h a n y st u dy dr u g, t he 
ra n d o mizati o n date will be use d i nstea d of t he Da y 1 visit date. F or scree n fail ures, t he date t he 
first i nf or me d c o nse nt was si g ne d will be use d f or t he a ge deri vati o n. A ge re q uire d f or 
l o n git u di nal a n d te m p oral calc ulati o ns a n d a nal yses (e. g., esti mates of creati ni ne cleara nce, a ge 
at date of A E) will be base d o n a ge deri ve d fr o m date of birt h a n d t he date of t he meas ure me nt or 
e ve nt, u nless ot her wise s pecifie d.
N o n - P K data t hat are c o nti n u o us i n nat ure b ut are less t ha n t he l o wer li mit of q ua ntitati o n (L O Q) 
or a b o ve t he u p per L O Q will be i m p ute d as f oll o ws:

A val ue t hat is 1 u nit less t ha n t he L O Q will be use d t o calc ulate descri pti ve statistics if t he 
dat u m is re p orte d i n t he f or m of “ x” ( w here x is c o nsi dere d t he L O Q). F or e xa m ple, if t he 
val ues are re p orte d as < 5 0 a n d < 5. 0, val ues of 4 9 a n d 4. 9, res pecti vely, will be use d t o 
calc ulate s u m mar y statistics. A n e xce pti o n t o t his r ule is a n y val ue re p orte d as < 1 or < 0. 1, 
etc. F or val ues re p orte d as < 1 or < 0. 1, a val ue of 0. 9 or 0. 0 9, res pecti vel y , will be use d t o 
calc ulate s u m mar y statistics.

A val ue t hat is 1 u nit a b o ve t he L O Q will be use d t o calc ulate descri pti ve statistics if t he 
dat u m is re p orte d i n t he f or m of “ > x” ( w here x is c o nsi dere d t he L O Q). Val ues wit h deci mal 
p oi nts will f oll o w t he sa m e l o gic as a b o ve.

T he L O Q will be use d t o calc ulate descri pti ve statistics if t he dat u m is re p orte d i n t he f or m of 
“≤ x” or “ ≥ x” ( w here x is c o nsi dere d t he L O Q).
F or H B V D N A, if t he val ue i n I U/ m L  is a b o ve t he u p per L O Q, t he c orres p o n di n g dil ute d H B V 
D N A val ue, if a vaila ble, will be use d.
If met h o ds base d o n t he ass u m pti o n t hat t he data are n or mall y distri b ute d are n ot a de q uate, 
a nal ys es ma y be perf or me d o n tra nsf or me d data, e g, l o g-tra nsf or me d data, or n o n para metric 
a nal ys is met h o ds ma y be use d, as a p pr o priate.
Nat ural l o garit h m tra nsf or mati o n will be use d f or plas ma/ bl o o d c o nce ntrati o ns a n d a nal ys is of 
P K para meters. Plas ma c o nce ntrati o n val ues t hat are bel o w t he li mit of q ua ntitati o n ( B L Q) will 
be prese nte d as “ B L Q” i n t he c o nce ntrati o n data listi n g. Val ues t hat are B L Q will be treate d as 
0 at pre d ose ti me p oi nts, a n d o ne -half t he val ue of t he L O Q at p ost baseli ne ti me p oi nts.
T he f oll o wi n g c o n ve nti o ns will be use d f or t he prese ntati o n of s u m mar y  a n d or der statistics: 

If at least 1 s u bject has a c o nce ntrati o n val ue of B L Q f or t he ti me p oi nt, t he mi ni m u m val ue 
will be dis pla y e d as “ B L Q”.

If m ore t ha n 2 5 % of t he s u bjects ha ve a c o nce ntrati o n data val ue of B L Q f or a gi ve n ti me 
p oi nt, t he mi ni m u m a n d Q 1 val ues will be dis pla ye d as “ B L Q”.


G S -9 6 8 8
G S -U S -3 8 9 -2 0 2 5
Statistical A nal ysis Pla n
Versi o n 1. 1
C O N FI D E N TI A L
Pa ge 1 8
3 1 Oct o ber 2 0 1 9

If m ore t ha n 5 0 % of t he s u bjects ha ve a c o nce ntrati o n data val ue of B L Q f or a gi ve n ti me 
p oi nt, t he mi ni m u m, Q 1, a n d me dia n val ues will be dis pla y e d as “ B L Q”.

If m ore t ha n 7 5 % of t he s u bjects ha ve a c o nce ntrati o n data val ue of B L Q f or a gi ve n ti me 
p oi nt, t he mi ni m u m, Q 1, me dia n, a n d Q 3 val ues will be dis pla y e d as “ B L Q”.

If all s u bjects ha ve c o nce ntrati o n data val ues of B L Q f or a gi ve n ti me p oi nt, all or der 
statistics ( mi ni m u m, Q 1, me dia n, Q 3, a n d ma xi m u m) will be dis pla ye d as “ B L Q”.
P K para mete rs t hat are B L Q will be i m p ute d as o ne- half L O Q bef ore l o g tra nsf or mati o n or 
statistical m o del fitti n g.
3. 8.
A n al ysis Visit Wi n d o ws
3. 8. 1.
Defi niti o n of First D ose D a y, L ast D ose D a y, a n d St u d y D a y
First D ose  Date is defi ne d as t he mi ni m u m of t he first d ose date of G S- 9 6 8 8 a n d TA F.
Last D ose Date is defi ne d as t he ma xi m u m of t he last d ose date of G S- 9 6 8 8 a n d T A F. If T A F is 
o n g oi n g, t he last d ose of T A F is t he ma xi m u m of t he latest T A F d ose date, visit date, vital si g n 
assess me nt date, a n d la b date a vaila ble .
Baseli ne is defi ne d as t he last a vaila ble o bser vati o n o n or pri or t o t he first d ose date. 
St u d y  d a y will be calc ulate d fr o m t he first d ose date a n d deri ve d as f oll o ws:

F or p ost d ose st u d y da ys : Assess me nt Date First D os e Date of St u d y  Dr u g + 1

F or da y s pri or t o t he first d ose: Assess me nt Date 
First D os e Date of St u d y Dr u g
T heref ore , st u d y D a y  1 is t he da y of first d ose of eit her st u d y dr u g a d mi nistrati o n .
3. 8. 2.
A n al ysis Visit Wi n d o ws
S u bject visits mi g ht n ot occ ur o n pr ot oc ol -s pecifie d da ys. T heref ore, f or t he p ur p ose of a nal ys is, 
o bser vati o ns will be assi g ne d t o a nal ys is wi n d o ws.
D ata c ollecte d u p t o t he ma xi m u m of t he last d ose date of G S - 9 6 8 8 + 8 da y s a n d T A F + 3 d a y s
will be c o nsi dere d as o n- treat me nt data w hereas data c ollecte d aft erwar ds will be c o n si dere d as 
p osttreat me nt (treat me nt free f oll o w u p peri o d) data . Data fr o m o p ht hal m ol o g y  assess me nt,  
 
 will be s u m marize d acc or di n g t o t he 
n o mi nal visit as rec or de d i n t he data base.
O n -treat me nt data will be ma p pe d t o t he a nal ys is wi n d o ws defi ne d i n Ta ble 3- 1 , Ta ble 3- 2 , 
Ta ble 3 - 3, a n d Ta ble 3 - 4. Ta ble 3 - 5
C CI
s h o we d a nal ys is visit wi n d o ws f or p ost treat me nt peri o d .


G S -9 6 8 8
G S -U S -3 8 9 -2 0 2 5
Statistical A nal ysis Pla n
Versi o n 1. 1
C O N FI D E N TI A L
Pa ge 1 9
3 1 Oct o ber 2 0 1 9
T a ble 3- 1.
A n al ysis Visit Wi n d o ws f or O n -tre at me nt q H Bs A g, H B V D N A a n d 
S afet y L a b or at or y D at a
A n al ysis Visit
N o m i n al St u d y D a y
L o wer Li mit
U p per Li mit
Baseli ne
1
( n o ne)
1
Wee k 2
1 5
2
2 2
Wee k 4
2 9
2 3
4 3
Wee k 8
5 7
4 4
6 7
Wee k 1 1
7 8
6 8
8 1
Wee k 1 2
8 5
8 2
9 9
Wee k 1 6
1 1 3
1 0 0
1 2 7
Wee k 2 0
1 4 1
1 2 8
1 5 1
Wee k 2 3
1 6 2
1 5 2
1 6 5
Wee k 2 4
1 6 9
1 6 6
1 8 3
Wee k 2 8
1 9 7
1 8 4
2 2 5
Wee k 3 6
2 5 3
2 2 6
2 9 5
Wee k 4 8
3 3 7
2 9 6
≥ 3 3 7
C CI


G S -9 6 8 8
G S -U S -3 8 9 -2 0 2 5
Statistical A nal ysis Pla n
Versi o n 1. 1
C O N FI D E N TI A L
Pa ge 2 0
3 1 Oct o ber 2 0 1 9
T a ble 3- 3.
A n al ysis Visit Wi n d o ws f or O n -tre at me nt Q u alit ati ve H B V Ser ol o g y
A n al ysis Visit
N o m i n al St u d y D a y
L o wer Li mit
U p per Li mit
Baseli ne
1
( n o ne)
1
Wee k 1 2
8 5
2
1 2 7
Wee k 2 4
1 6 9
1 2 8
2 1 1
Wee k 3 6
2 5 3
2 1 2
2 9 5
Wee k 4 8
3 3 7
2 9 6
≥ 3 3 7
T a ble 3 - 4.
A n al ysis Visit Wi n d o ws f or O n -tre at me nt Vit al Si g ns
A n al ysis Visit
N o m i n al St u d y D a y
L o wer Li mit
U p per Li mit
Baseli ne
1
( n o ne)
1
D a y  1 + 2 4 hrs
2
2
2
Wee k 2
1 5
3
2 2
Wee k 4
2 9
2 3
4 3
Wee k 8
5 7
4 4
6 7
Wee k 1 1
7 8
6 8
8 1
Wee k 1 2
8 5
8 2
9 9
Wee k 1 6
1 1 3
1 0 0
1 2 7
Wee k 2 0
1 4 1
1 2 8
1 5 1
Wee k 2 3
1 6 2
1 5 2
1 6 5
Wee k 2 4
1 6 9
1 6 6
1 8 3
Wee k 2 8
1 9 7
1 8 4
2 2 5
Wee k 3 6
2 5 3
2 2 6
2 9 5
Wee k 4 8
3 3 7
2 9 6
≥ 3 3 7
P osttreat me nt data will be ma p pe d as f oll o ws:
T F F U Da y   Assess me nt D ate 
Last D ose Date of G S -9 6 8 8 or T A F ( w hic he ver c o mes last)


G S -9 6 8 8
G S -U S -3 8 9 -2 0 2 5
Statistical A nal ysis Pla n
Versi o n 1. 1
C O N FI D E N TI A L
Pa ge 2 1
3 1 Oct o ber 2 0 1 9
T a ble 3- 5.  
A n al ysis Visit Wi n d o ws f or P osttre at me nt ( Tre at me nt Free F oll o w U p
Peri o d)
A n al ysis Visit
T F F U D a y
L o wer Li mit
U p per Li mit
T F F U Wee k 4
2 9
4
4 3
T F F U Wee k 8
5 7
4 4
7 1
T F F U Wee k 1 2
8 5
7 2
9 9
T F F U Wee k 1 6
1 1 3
1 0 0
1 2 7
T F F U Wee k 2 0
1 4 1
1 2 8
1 5 5
T F F U Wee k 2 4
1 6 9
1 5 6
2 1 1
T F F U Wee k 3 6
2 5 3
2 1 2
2 9 5
T F F U Wee k 4 8
3 3 7
2 9 6
> = 3 3 7
3. 8. 3.
Selecti o n of D at a i n t he E ve nt of M ulti ple Rec or ds i n a n A n al ysis
Wi n d o w
De pe n di n g o n t he statistical a nal ys is met h o d, si n gle val ues ma y be re q uire d f or eac h a nal ysis 
wi n d o w. F or e xa m ple, c ha n ge fr o m baseli ne b y visit us uall y  re q uires a si n gle val ue, w hereas a 
ti me-t o-e ve nt a nal ys is w o ul d n ot re q uire 1 val ue per a nalys is wi n d o w.
If m ulti ple vali d, n o n missi n g , c o nti n u o us meas ure me nt s e xist i n a n a nal ysis wi n d o w, rec or ds 
will be c h ose n base d o n t he f oll o wi n g r ules if a si n gle val ue is nee de d:

I n ge neral, t he baseli ne val ue will be t he last n o n missi n g val ue o n or pri or t o t he first d ose 
date of st u d y dr u g , u nless s pecifie d differe ntly. If m ulti ple meas ure me nts occ ur o n t he sa me 
da y , t he last n on missi n g val ue pri or t o t he ti me of first d osi n g of st u d y  dr u g will be 
c o nsi dere d as t he baseli ne val ue. If t hese m ulti ple meas ure me nts occ ur at t he sa me ti me or 
t he ti me is n ot a vaila ble, t he a vera ge of t hese meas ure me nts will be c o nsi dere d t he baseli ne 
v al ue.

C CI
F or p ost baseli ne val ues (e xce pt f or ala ni ne a mi n otra nsferase [ A L T] ): 
T he rec or d cl osest t o t he n o mi nal da y  f or t hat visit will be selecte d.
If t here are 2 rec or ds t hat are e q ui dista nt fr o m t he n o mi nal da y, t he later rec or d will be 
selecte d.
If t here is m ore t ha n 1 rec or d o n t he selecte d da y, t he a vera ge will be ta ke n e xce pt f or 
q H Bs A g (I U/ m L) , H B V D N A (I U/ m L) , 
f or w hic h t he ge o metric mea n will be ta ke n.


G S -9 6 8 8
G S -U S -3 8 9 -2 0 2 5
Statistical A nal ysis Pla n
Versi o n 1. 1
C O N FI D E N TI A L
Pa ge 2 2
3 1 Oct o ber 2 0 1 9

F or p ost baseli ne A L T val ues : 
T he rec or d wit h t he lar gest val ue wit hi n t he sa me a nalys is wi n d o w will be selecte d
If t here is m ore t ha n 1 rec or d wit h t he lar gest val ue, t he latest rec or d will be selecte d.
If t here are m ulti ple lar gest rec or ds wit h t he sa me ti me or n o ti me rec or de d o n t he sa me 
da y , a n y o ne of t hese meas ure me nts ca n be selecte d as t he a nal ysis val ue. 
If m ulti ple vali d, n o n missi n g , cate g orical meas ure me nts e xist i n an a nal y sis wi n d o w, a n d a 
si n gle val ue is nee de d, rec or ds will be c h ose n base d o n t he f oll o wi n g r ules:

F or baseli ne, t he last a vaila ble rec or d o n or pri or t o t he date of t he first d ose of st u d y dr u g 
will be selecte d. If t here are m ulti ple rec or ds wit h t he sa me ti me or n o ti me rec or de d o n t he 
sa me da y, t he val ue wit h t he l o west se verit y will be selecte d f or safety data (e g, n or mal will 
be selecte d o ver a b n or mal f or safety electr ocar di o gra m [ E C G ] fi n di n gs), a n d t he m ost 
c o nser vati ve val ue will be selecte d f or efficac y  data (e g, ne gati ve will be selecte d o ver 
p ositi ve f or H Be A g a n d H Bs A g , w hereas p ositi ve will be selecte d o ver ne gati ve f or H Be A b 
a n d H Bs A b).

F or p ost baseli ne val ues :
T he m ost c o nser vati ve val ue (e g, a b n or mal will be selecte d o ver n or mal f or safet y E C G)
wit hi n t he a nal ysis wi n d o w will be selecte d , e xce pt f or H B V ser ol o g y ( H Bs A g, H Bs A b, 
H Be A g, a n d H Be A b), f or w hic h t he m ost fa v ora ble val ue (ie, ne gati ve will be selecte d 
o ver p ositi ve f or H Bs A g a n d H Be A g, w hereas p ositi ve will be selecte d o ver ne gati ve f or 
H Bs A b a n d H Be A b) will be selecte d . 
I n t he e ve nt t hat m ore t ha n 1 val ue wit hi n a n a nal y sis wi n d o w is e q ual, t he val ue 
c ollecte d cl osest t o t he n o mi nal da y  will be selecte d.
If t here are 2 rec or ds t hat are e q ui dista nt fr o m t he n o mi nal da y, t he later rec or d will be 
selecte d.
If t here is m ore t ha n 1 rec or d o n t he selecte d da y, t he latest rec or d will be selecte d; if 
t hese meas ure me nts were rec or de d at t he sa me ti me or n o ti me rec or de d , a n y o ne of t hese 
meas ure me nts ca n be selecte d as t he a nal ys is val ue. 


G S -9 6 8 8
G S -U S -3 8 9 -2 0 2 5
Statistical A nal ysis Pla n
Versi o n 1. 1
C O N FI D E N TI A L
Pa ge 2 3
3 1 Oct o ber 2 0 1 9
4.
S U B J E C T DI S P O SI TI O N
4. 1.
S u bject E nr oll me nt a n d Dis p osi ti o n
A s u m mar y  of s u bject e nr oll me nt will be pr o vi de d b y  eac h treat me nt gr o u p a n d G S -9 6 8 8 o verall
(i n t he or der of 3 m g, 1. 5 m g, o verall G S - 9 6 8 8, a n d place b o) f or eac h c o u ntr y a n d i n vesti gat or
wit hi n a c o u ntr y . T he s u m mar y will prese nt t he n u m ber a n d perce nta ge of s u bjects e nr olle d. F or 
eac h c ol u m n, t he de n o mi nat or f or t he perce nta ge calc ulati o n will be t he t otal n u m ber of s u bjects 
a nal yz e d f or t hat c ol u m n. If t here are discre pa ncies i n t he val ue use d f or stratificati o n
(ie, H Be A g stat u s) assi g n me nt bet wee n t he I X R S a n d t he cli nical data base, t he val ue c ollecte d i n 
t he cli nical data base will be use d f or t he s u m mar y. A listi n g of s u bjects wit h discre pa ncies i n t he 
H Be A g val ue use d f or stratificati o n assi g n me nt bet wee n t he I X R S a n d t he cli nical data base at 
t he ti me of data fi nalizati o n will be pr o vi de d.
T he ra n d o mizati o n sc he d ule use d f or t he st u d y will be pr o vi de d as a n a p pe n di x t o t he C S R.
A s u m mar y of s u bject dis p ositi o n will be pr o vi de d b y  eac h treat me nt gr o u p a n d G S -9 6 8 8 o verall
(i n t he or der of 3 m g, 1. 5 m g, o verall G S - 9 6 8 8, a n d place b o). T his s u m mar y will prese nt t he 
n u m ber of s u bjects scree ne d, t he n u m ber of scree n fail ure s u bjects w h o were n ot ra n d o mize d, t he 
n u m ber of s u bjects w h o met all eli gi bilit y  criteria b ut were n ot ra n do mize d wit h reas o ns f or 
s u bjects n ot ra n d o mize d , t he n u m ber of s u bjects ra n d o mize d, a n d t he n u m ber of s u bjects i n eac h 
of t he cate g ories liste d bel o w :

S afet y Anal ys is S et 

F A S

P K A nal y sis Set

Treat me nt Free F oll o w U p A nal y sis Set

G S -9 6 8 8/ P T M c o m pleti o n stat us
C o m plete d s t u d y dr u g
Pre mat urel y disc o nti n ue d st u d y  dr u g

C CI
Reas o n f or pre mat ure disc o nti n uati o n of G S -9 6 8 8/ P T M
C CII 
I 


G S -9 6 8 8
G S -U S -3 8 9 -2 0 2 5
Statistical A nal ysis Pla n
Versi o n 1. 1
C O N FI D E N TI A L
Pa ge 2 4
3 1 Oct o ber 2 0 1 9

T A F c o m pleti o n stat us
C o m plete d s t u d y dr u g
Pre m at urel y disc o nti n ue d st u d y  dr u g

Reas o n f or pre mat ure disc o nti n uati o n of T A F

T F F U c o m pleti o n stat us
C o m plete d T F F U
Pre mat urel y disc o nti n ue d fr o m T F F U

Reas o n f or pre mat ure disc o nti n uati o n of T F F U

S t u d y c o m pleti o n stat us
C o m plete d st u d y
Pre mat urel y disc o nti n u e d st u d y

Reas o ns f or pre mat ure disc o nti n uati o n of st u d y
F or t he stat us of st u d y dr u g a n d st u d y c o m pleti o n a n d t he reas o ns f or pre mat ure disc o nti n uati o n, 
t he n u m ber a n d perce nta ge of s u bjects i n eac h cate g or y will be pr o vi de d. T he de n o mi nat or f or 
t he perce nta ge calc ulati o n will be t he t otal n u m ber of s u bjects i n t he Safety A nal ysis Set 
c orres p o n di n g t o t hat c ol u m n . In a d diti o n, a fl o wc hart will be pr o vi de d t o de pict t he dis p ositi o n.
T he f oll o wi n g b y- s u bject listi n gs will be pr o vi de d b y s u bject I D n u m ber i n asce n di n g or der t o 
s u p p ort t he a b o ve s u m mar y ta bles:

Reas o ns f or pre mat ure st u d y  dr u g or st u d y disc o nti n uati o n

Reas o ns f or pre mat ure disc o nti n uati o n fr o m T F F U
4. 2.
E xte nt of St u d y Dr u g E x p os ure a n d A d here nce
E xte nt of e x p os ure t o st u d y  dr u g will be e xa mi ne d b y assessi n g t he t otal d urati o n of e x p os ure t o 
st u d y dr u g a n d t he le vel of a d here nce relati ve t o t he st u d y dr u g re gi me n s pecifie d i n t he pr ot oc ol. 
4. 2. 1.
D ur ati o n of E x p os ure t o St u d y Dr u g
T otal d urati o n of e x p os ure t o st u d y  dr u g will be defi ne d as last d ose d ate mi n us first d ose date 
pl us 1 f or T A F a n d pl us 7 f or G S- 9 6 8 8, re gar dless of a n y te m p orar y i nterr u pti o ns i n st u d y dr u g 
a d mi nistrati o n , a n d will be e x presse d i n wee ks usi n g u p t o 1 deci mal place ( e g, 4. 5 wee ks). If t he 
last st u d y dr u g d ose date is missi n g, t he latest date a m o n g t he st u d y dr u g e n d date, cli nical visit 
date, la b orat or y  sa m ple c ollecti o n date, a n d vital si g ns assess me nt date t hat occ urre d d uri n g t he 
o n- treat me nt peri o d will be use d.


G S -9 6 8 8
G S -U S -3 8 9 -2 0 2 5
Statistical A nal ysis Pla n
Versi o n 1. 1
C O N FI D E N TI A L
Pa ge 2 5
3 1 Oct o ber 2 0 1 9
T he t otal d urati o n of e x p os ure t o st u d y dr u g will be s u m marize d usi n g descri pti ve statistics 
( n, mea n, S D , me dia n, Q 1, Q 3, mi ni m u m, a n d ma xi m u m) a n d usi n g t he n u m ber (ie, c u m ulati ve
c o u nts) a n d perce nta ge of s u bjects e x p ose d t hr o u g h t he f oll o wi n g ti me peri o ds: baseli ne
( ≥1 d a y ), Wee k 2 ( ≥ 1 5 da y s), Wee k 4
(≥ 2 9 da y s), Wee k 8 ( ≥ 5 7 da y s), Wee k 1 1 ( ≥ 7 8 da y s), 
Wee k 1 2
(≥ 8 5 da y s), Wee k 1 6 (≥ 1 1 3 da y s), Wee k 2 0 (≥ 1 4 1 da y s), Wee k 23 ( ≥ 1 6 2 da y s) f or 
G S - 9 6 8 8 a n d baseli ne ( ≥1 da y ), Wee k 4 (≥ 2 9 da ys), Wee k 8 ( ≥ 5 7 d a y s), Wee k 1 2 (≥ 8 5 da y s), 
Wee k 1 6 ( ≥ 1 1 3 da y s), Wee k 2 0 ( ≥ 1 4 1 da ys), Wee k 2 4 ( ≥ 16 9 d a y s), Wee k 2 8 (≥ 1 9 7 d a y s), 
Wee k 3 6 ( ≥ 2 5 3 d a y s), a n d Wee k 4 8 (≥ 3 3 7 da y s) f or T A F.
S u m maries will be pr o vi de d b y  eac h treat me nt gr o u p a n d G S - 9 6 8 8 o verall (i n t he or der of 3 m g, 
1. 5 m g, o verall G S - 9 6 8 8, a n d place b o) f or t he S afet y A nal ys is S et.
N o f or mal statistical testi n g is pla n ne d.
4. 2. 2.
A d here nce t o St u d y Dr u g
T he t otal n u m ber of d oses a d mi nistere d will be s u m marize d usi n g descri pti ve statistics ( n, mea n, 
S D, me dia n, Q 1, Q 3, mi ni m u m, a n d ma xi m u m).
T he pres u me d t otal n u m ber of ta blets ta ke n b y a s u bject will be deter mi ne d b y  t he data c ollecte d 
o n t he dr u g acc o u nta bilit y e C R F usi n g t he f oll o wi n g f or m ula:
T ot al N u m b er of T a bl ets T a k e n =
 N o. of T a bl ets Dis p e ns e d  − N o. of T a bl ets R et ur n e d 4. 2. 2. 1.
Prescri be d G S - 9 6 8 8 A d here nce
T he le vel of prescri be d a d here nce t o t he st u d y dr u g will be deter mi ne d b y t he t otal a m o u nt of 
st u d y dr u g ta ke n relati ve t o t he t otal a m o u nt of st u d y dr u g s pecifie d b y t he pr ot oc ol f or a s u bject 
w h o c o m pletes treat me nt i n t he st u d y. 
T he le vel of prescri be d a d here nce of G S - 9 6 8 8 will be e x presse d as a perce nta ge usi n g t he 
f oll o wi n g f or m ula:
T he n u m ber of ta blets ta ke n f or G S -9 6 8 8 will be calc ulate d as t he rec or de d s u m of ta blets ta ke n 
b y  a s u bject. If a s u bject di d n ot rec or d ha vi n g ta ke n a ta blet d uri n g t he prescri be d treat me nt 
peri o d, t he n t he ta blet will be treate d as n ot ta ke n.
P 
. b d A d h 
d o/t) 
( 
T ot al Ar n o u nt of St u d y Dr u g T a k e n 
) l 0 0¾ 
r es c n e 
erenc....._ o = -----------------
x 
o 
T ot al Ar n o u nt of St u d y Dr u g S p e cifi e d b y Pr ot o c o l 


G S -9 6 8 8
G S -U S -3 8 9 -2 0 2 5
Statistical A nal ysis Pla n
Versi o n 1. 1
C O N FI D E N TI A L
Pa ge 2 6
3 1 Oct o ber 2 0 1 9
4. 2. 2. 2.
A d here nce t o T A F
A d here nce ( %) of T A F will be calc ulate d as f oll o ws:
N u m ber of t a blets t a ke n at a disti nct dis pe nsi n g peri o d is calc ulate d as t he mi ni m u m 
of (a) t he dail y  n u m ber of ta blets prescri be d f or T A F m ulti plie d b y t he d ur ati o n of 
tre at me nt at t he dis pe nsi n g peri o d of t he sa me dis pe nsi n g date, a n d ( b) t he n u m ber of 
ta blets ta ke n ( n u m ber of ta blets dis pe nse d mi n us t he n u m ber of ta blets ret ur ne d). T otal 
n u m ber of ta blets ta ke n is deter mi ne d b y s u m mi n g t he n u m ber of ta blets ta ke n fr o m all 
e val ua ble dis pe nsi n g peri o ds.
N u m ber of t a blets prescri be d at a disti nct dis pe nsi n g peri o d is calc ulate d as t he dail y 
n u m ber of ta blets prescri be d f or T A F m ulti plie d b y t he d urati o n of treat me nt at t he 
dis pe nsi n g peri o d of t he sa me dis pe nsi n g date. T otal n u m ber of ta blets prescri be d is 
deter mi ne d b y s u m mi n g t he n u m ber of ta blets prescri be d fr o m all e val ua ble dis pe nsi n g 
peri o ds.
T he d ur ati o n of tre at me nt at a dis pe nsi n g peri o d f or a st u d y dr u g is calc ulate d as t he 
mi ni m u m of (a) t he last ret ur ne d date of t he sa me dis pe nsi n g peri o d f or t he st u d y  dr u g, 
( b) date of pre mat ure disc o nti n uati o n of t he st u d y dr u g, a n d (c) ne xt dis pe ns i n g d ate of 
t he st u d y dr u g, mi n us dis pe nsi n g date of t he st u dy dr u g.
T he ne xt dis pe nsi n g d ate is t he f oll o wi n g dis pe nsi n g date of t he st u dy dr u g re gar dless of 
t he b ottle ret ur n date.
N ote: If calc ulate d a d here nce is greater t ha n 1 0 0 %, t he res ult will be set t o 1 0 0 %.
F or T A F, a rec or d w here t he n u m ber of ta blets ret ur ne d was missi n g ( wit h “ Yes” a ns were d f or 
t he q uesti o n “ Was t he B ottle Ret ur ne d?”), it is ass u me d t he n u m ber of ta blets ret ur ne d was 0. If 
t he n u m ber of ta blets dis pe nse d was missi n g wit h t he missi n g or u n k n o w n b ottle stat us, all 
rec or ds f or t he sa me dis pe nsi n g date f or t hat st u dy dr u g will be e xcl u de d fr o m t he calc ulati o ns 
f or b ot h de n o mi nat or a n d n u merat or. 
Descri pti ve statistics f or t he le vel of prescri be d a d here nce t o st u d y dr u g ( n, mea n, SD, me dia n, 
Q 1, Q 3, mi ni m u m, a n d ma xi m u m) a n d t he n u m ber a n d perce nta ge of s u bjects bel o n gi n g t o 
a d here nce cate g ories ( < 9 5 %, ≥ 9 5 % f or G S-9 6 8 8 a n d < 8 0 %, ≥8 0 % t o < 9 0 %, ≥9 0 % f or T A F ) 
will be pr o vi de d b y  H Be A g stat us ( p ositi ve, ne gati ve) a n d o verall wit hi n ea c h treat me nt gr o u p 
f or t he Safety A nal ys is Set. 
N o f or mal statistical testi n g is pla n ne d.
A b y -s u bject listi n g of st u d y dr u g a d mi nistrati o n a n d dr u g acc o u nta bilit y will be pr o vi de d 
se paratel y b y s u bject I D n u m ber (i n asce n di n g or der) a n d visit (i n c hr o n olo gical or der).
( I N o. of T a bl ets T a k e n at Eac h Dis p e nsi n g P eri o d 
) 
A d h er e n c e t o T A F ( %) = -------------------
x 1 0 0 % 
I N o. of T a bl ets Pr es cri b e d at Eac h Dis p e nsi n g P eri o d 


G S -9 6 8 8
G S -U S -3 8 9 -2 0 2 5
Statistical A nal ysis Pla n
Versi o n 1. 1
C O N FI D E N TI A L
Pa ge 2 7
3 1 Oct o ber 2 0 1 9
4. 3. 
Pr ot oc ol De vi ati o ns
S u bjects w h o di d n ot meet t he eli gi bilit y  criteria f or st u d y e ntr y, b ut e nr olle d i n t he st u d y will be 
s u m marize d re gar dless of w het her or n ot t he y were e xe m pte d b y t he s p o ns or. T he s u m mar y will 
prese nt t he n u m ber a n d perc e nta ge of s u bjects w h o di d n ot meet at least 1 eli gi bilit y (i ncl usi o n or 
e xcl usi o n) criteri o n a n d t he n u m ber of s u bjects w h o di d n ot meet s pecific criteria b y eac h 
treat me nt gr o u p a n d G S -9 6 8 8 o verall (i n t he or der of 3 m g, 1. 5 m g, o verall G S- 9 6 8 8, a n d 
place b o) base d o n t he All Ra n d o mize d A nal y sis Set. A b y-s u bject listi n g will be pr o vi de d f or 
s u bjects w h o di d n ot meet at least 1 eli gi bilit y criteri o n. T he listi n g will prese nt t he eli gi bilit y 
criteri o n ( or criteria if m ore t ha n 1 de viati o n) t hat a s u bject di d n ot meet a n d relate d c o m me nts, if 
c ollecte d.
Pr ot oc ol de viati o ns occ urri n g after s u bjects e ntere d t he st u d y  are d oc u me nte d d uri n g r o uti ne 
m o nit ori n g. T he n u m ber a n d perce nta ge of s u bjects wit h i m p orta nt pr ot oc ol de viati o ns b y  
de viati o n reas o n (e g, n o na d here nce t o st u d y  dr u g, vi olati o n of select i ncl usi o n/e xcl usi o n criteria) 
will be s u m marize d b y  eac h treat me nt gr o u p a n d G S -9 6 8 8 o verall (i n t he or der of 3 m g, 1. 5 m g, 
o verall G S - 9 6 8 8, a n d place b o) f or t he All Ra n d o mize d A nal y sis Set. A b y -s u bject listi n g will be 
pr o vi de d f or t h ose s u bjects wit h i m p orta nt pr ot oc ol de viati o n.
S u bjects w h o recei ve d st u d y dr u g ot her t ha n t heir treat me nt assi g n me nt at ra n d o mizati o n will be 
liste d wit h t he start a n d st o p dates t hat t he y recei ve d i nc orrect st u d y treat me nt.


G S -9 6 8 8
G S -U S -3 8 9 -2 0 2 5
Statistical A nal ysis Pla n
Versi o n 1. 1
C O N FI D E N TI A L
Pa ge 2 8
3 1 Oct o ber 2 0 1 9
5.
B A S E L I N E C H A R A C T E RI S TI C S
5. 1.
De m o gr a p hics
S u bject de m o gra p hi c varia bles (ie, a ge, se x, race, et h nicit y a n d re gi o n [ U S, n o n-U S] ) will be 
s u m marize d b y  H Be A g stat us ( p ositi ve, ne gati ve) a n d o verall f or eac h treat me nt gr o u p a n d st u d y 
o verall usi n g descri pti ve statistics ( n, mea n, S D, me dia n, Q 1, Q 3, mi ni m u m, a n d ma xi m u m) f or 
a ge, a n d usi n g t he n u m ber a n d perce nta ge of s u bjects f or a ge cate g ories ( < 5 0 ye ars, ≥5 0 ye ars), 
se x, race, et h nicity, a n d re gi o n . T he s u m mar y  of de m o gra p hic data will be pr o vi de d f or t he 
Safet y  A nalys is Set.
A b y -s u bject de m o gra p hic listi n g, i ncl u di n g t he i nf or me d c o nse nt date, will be pr o vi de d b y 
s u bject I D n u m ber i n asce n di n g or der.
5. 2.
Ot her B aseli ne C h ar acteristics
Ot her baseli ne c haracteristics i ncl u de

B o d y  wei g ht ( k g)

Hei g ht (c m)

B o d y mass i n de x ( B MI; k g/ m 2) as a c o nti n u o us varia ble a n d as cate g ories ( < 1 8. 5 k g/ m 2, 
≥1 8. 5 k g/ m 2
2 5 k g/ m 2, ≥ 2 5 k g/ m 2
3 0 k g/ m 2, ≥ 3 0 k g/ m 2)

H ist or y of cirr h osis, cirr h osis deter mi nati o n met h o d , a n d A P RI  ( < 1, > 1)

Fi br o Test sc ore as a c o nti n u o us varia ble a n d fi br osis sta ge b y  Fi br oT est sc ore as a 
cate g orical varia ble ( 0. 0 0  0. 4 8, 0. 4 9  0. 7 4, 0. 7 5  1. 0 0)

H Bs A g (l o g 1 0 I U/ m L) as a c o nti n u o us varia ble a n d as cate g ories ( < 2 l o g1 0 I U/ m L, 
≥2 l o g1 0 I U/ m L   3 l o g1 0 I U/ m L, ≥3 l o g1 0 I U/ m L   4 l o g 1 0 I U/ m L, ≥ 4 l o g 1 0 I U/ m L)

H B V D N A (l o g 1 0 I U/ m L) as a c o nti n u o us varia ble a n d as cate g ories (< 7 l o g 1 0 I U/ m L, 
≥7 l o g1 0 I U/ m L 
8 l o g 1 0 I U/ m L, ≥ 8 l o g 1 0 I U/ m L)

H Be A b ( p ositi ve, ne gati ve)

H B V ge n ot y p e

A L T ( U/ L) as a c o nti n u o us va ria ble a n d as cate g ories base d o n ce ntral la b orat or y  n or mal 
ra n ge (≤ u p per li mit of n or mal [ U L N] , > U L N; ≤5 × U L N, > 5 × U L N; ≤1 0 × U L N, 
> 1 0 U L N )


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
A L T le vel as cate g ories base d o n A merica n Ass ociati o n f or t he St u d y of Li ver Diseases 
( A A S L D) n or mal ra n ge wit h t he U L N as 2 5 U/ L f or fe male a n d 3 5 U/ L f or male ( ≤ U L N, 
> U L N; ≤5 × U L N, > 5 × U L N; ≤1 0 × U L N, > 1 0 U L N )

Pri or oral n ucle osi de/ n ucle oti de treat me nt ( yes, n o)

Pre vi o us i nterfer o n e x perie nce t o treat H B V ( yes, n o)

D urati o n of bei n g H B V p ositi ve ( years) as a c o nti n u o us varia ble

M o de of H B V i nfecti o n

E sti mate d gl o mer ular filtrati o n rate (e G F R) usi n g t he C oc kcr oft -Ga ult e q uati o n ( m L/ mi n)
e G F R will be calc ulate d b y  t he C oc kcr oft- Ga ult met h o d: e G F RC G ( m L/ mi n) 
[( 1 4 0 a ge ( yea rs)) × wei g ht ( k g) × ( 0. 8 5 if fe male)] / (ser u m creati ni ne ( m g/ d L) × 7 2), 
w here wei g ht is t otal b o d y  mass i n kil o gra ms.
T hese baseli ne c haracteristics will be s u m marize d b y  H Be A g stat us ( p ositi ve, ne gati ve) a n d 
o verall f or eac h treat me nt gr o u p a n d st u d y o v erall usi n g descri pti ve statistics ( n, mea n, S D, 
me dia n, Q 1, Q 3, mi ni m u m, a n d ma xi m u m) f or c o nti n u o us varia bles a n d usi n g n u m ber a n d 
perce nta ge of s u bjects f or c ate g orical varia bles . T he s u m mar y of baseli ne c haracteristics will be 
pr o vi de d f or t he S afet y A nal y sis S et.
A b y -s u bject listi n g of baseli ne c haracteristics will be pr o vi de d b y s u bject I D n u m ber i n 
asce n di n g or der.
A se parate by- s u bject data listi n g f or cirr h osis deter mi nati o n will be pr o vi de d f or all s u bjects at 
scree ni n g.
A se parate b y- s u bject data listi n g f or HB V treat me nt hist or y will be pr o vi de d f or t he Safety 
A nal y sis Set. T he listi n g will dis pla y t he pr e vi o us H B V treat me nt e x perie nce, pre vi o us H B V 
re gi me n a n d treat me nt , t he treat me nt d urati o n, a n d t he reas o n f or treat me nt disc o nti n uati o n for 
treat me nt e x perie nce d s u bjects .
5. 3.
Me dic al Hist or y
Me dical hist or y  was c ollecte d at scree ni n g .
D ata will be c o de d usi n g t he c urre nt versi o n of Me dical Dicti o nar y  f or Re g ulat or y Acti vities
( Me d D R A). M e dical hist or y will be s u m marize d b y s yste m or ga n class (S O C) a n d preferre d 
ter m ( P T) b y  eac h treat me nt gr o u p a n d G S -9 6 8 8 o verall (i n t he or der of 3 m g, 1. 5 m g, o verall 
G S - 9 6 8 8, a n d place b o). S u bjects w h o re p orte d 2 or m ore me dical hist or y  ite ms t hat are c o de d t o 
t he sa me S O C a n d/ or P T will be c o u nte d o nl y o nce b y t he u ni q ue c o de d ter m i n t he s u m mar y. 
T he s u m mar y  will be pr o vi de d f or t he Safet y A nal ysis Set. N o f or mal statistical testi n g is 
pla n ne d. 
A b y -s u bject listi n g will als o be pr o vi de d. 


G S -9 6 8 8
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6.
E F FI C A C Y  AN A L Y S E S
6. 1.
Pri m ar y Effic ac y E n d p oi nt
6. 1. 1.
Defi niti o n of Pri m ar y Effic ac y E n d p oi nt
T he pri mar y  efficac y e n d p oi nt is t he pr o p orti o n of s u bjects wit h ≥ 1 l o g1 0 I U/ m L decli ne i n 
q H Bs A g fr o m baseli ne at Wee k 2 4 .
6. 1. 2.
St atistic al H y p ot hesis f or Pri m ar y Effic ac y E n d p oi nt
N o statistical h y p ot hesis testi n g will be perf or me d. 
6. 1. 3.
A n al ysis of Pri m ar y Effic ac y E n d p oi nt
T he pri mar y efficac y a nal ysis will be perf or me d f or t he F A S after t he last s u bj ect has c o m plete d 
Wee k 2 4 assess me nts or pre mat urel y disc o nti n ue d st u d y  dr u g.
T o c o m pare t he G S -9 6 8 8 1. 5 m g d ose gr o u p a n d t he G S -9 6 8 8 3 m g d ose gr o u p t o t he place b o 
gr o u p f or H Be A g p ositi ve a n d ne gati ve s u bjects se paratel y , poi nt esti mates a n d t he 2 -si de d
9 5 % e xact c o nfi de nce i nter val s (CI s) of t he pri mar y  efficac y e n d p oi nt will be pr o vi de d base d o n
t he Cl o p per -Pears o n met h o d { Cl o p per 1 9 3 4 } b y  H Be A g stat us ( p ositi ve, ne gati ve) a n d o verall 
f or eac h treat me nt gr o u p. I n a d diti o n, p oi nt esti mates a n d t he 2-si de d 9 5 % e xact CIs of t he 
pr o p orti o n differe nce ( 1. 5 m g 
P T M, 3 m g 
P T M), will be dis pla y e d se parately b y H Be A g 
stat us ( p ositi ve, ne gati ve) f or eac h treat me nt gr o u p. C Is f or t he pr o p orti o n differe nces will be 
c o nstr ucte d base d o n t he sta n dar dize d statistic a n d i n verti n g t w o 1- si de d tests { C ha n 1 9 9 9 }.
T o c o m pare t he G S -9 6 8 8 1. 5 m g d ose gr o u p a n d t he G S -9 6 8 8 3 m g d ose gr o u p wit h t he place b o 
gr o u p f or p o ole d H Be A g p ositi ve a n d ne gati ve s u bjects, t he pr o p orti o n differe nce s
( 1. 5 m g - P T M, 3 m g 
P T M) a n d t he c orres p o n di n g 9 5 % CI s will be calc ulate d usi n g t he 
strat u m-a dj uste d Ma ntel -Hae nszel ( M H) met h o d { K oc h 1 9 8 9 } , stratifie d by H Be A g stat us 
( p ositi ve, ne gati ve), as f oll o ws: 
w here

( P1
P 2)  
∑   ∑  , is t he strat u m-a dj uste d M H pr o p orti o n differe nce, w here     −
   is t he pr o p orti o n differe nce of Gr o u p s 1 a n d 2 i n strat u m h ( h
1 a n d 2).

             , is t he wei g ht base d o n t he har m o nic mea n of sa m ple sizes f or strat u m h, w here 
   a n d 
are the sa m ple sizes of Gr o u ps 1 a n d 2 i n strat u m h.
h
n 2
P 1 - P 2 ± Z (l -a/ 2 ) X S E( P 1 - P 2) , 


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Statistical A nal ysis Pla n
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Pa ge 3 1
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
S E( P 1
P 2)   ∑    ∗
(   ∗
)
    ∗
(   ∗
)
  (∑  ), w here   ∗
=
    .     a n d   ∗
=
    .      , w here
   a n d    are t he n u m bers of s u bjects wit h ≥ 1 l o g1 0 I U/ m L decli ne i n q H Bs A g fr o m 
baseli ne at Wee k 2 4 i n Gr o u ps 1 a n d 2 i n strat u m h.

α  0. 0 5 f or t his st u d y.

Z ( 1 α/ 2)
 Z0. 9 7 5
 1. 9 6 is t he 9 7. 5t h perce ntile of t he n or mal distri b uti o n.
If t he c o m p ute d l o wer c o nfi de nce b o u n d is less t ha n 1, t he l o wer b o u n d is defi ne d as 1. If t he 
c o m p ute d u p per c o nfi de nce b o u n d is greater t ha n 1, t he n t he u p per b o u n d is defi ne d as 1.
T he p oi nt esti mate s a n d t he 2- si de d 9 5 % e xact CIs base d o n t he Cl o p per -Pears o n met h o d will 
als o be pr o vi de d f or t he pr o p orti o n s i n eac h treat me nt gr o u p.
A F orest pl ot will gra p hicall y  prese nt t he p oi nt esti mates a n d t he CI s o n t he pr o p orti o n 
differe nce ( 1. 5 m g 
P T M, 3 m g 
P T M ) b y  H Be A g stat us ( p ositi ve, ne gati ve) a n d o verall f or 
eac h treat me nt gr o u p.
6. 1. 4. 
S u b gr o u p A n al ysis of Pri m ar y Effic ac y E n d p oi nt
N o s u b g r o u p a nal ys es will be perf or me d.
6. 2.
Sec o n d ar y Effic ac y E n d p oi nts
6. 2. 1.
Defi niti o n of Sec o n d ar y Effic ac y E n d p oi nts
T he s ec o n dar y efficac y e n d p oi nts i ncl u de t he f oll o wi n g:

Pr o p orti o n of s u bjects wit h ≥ 1 l o g 1 0 I U/ m L decli ne i n q H Bs A g fr o m b aseli ne at Wee ks 4, 8, 
1 2, a n d 4 8

C ha n ge fr o m baseli ne i n q H Bs A g (l o g 1 0 I U/ m L) at Wee k s 4, 8, 1 2, 2 4, a n d 4 8

Pr o p orti o n of s u bjects wit h H B V D N A < L L O Q at Wee ks 1 2, 2 4, a n d 4 8

Pr o p orti o n of s u bjects w h o ac hie ve H Bs A g l oss at Wee k s 1 2, 2 4, a n d 4 8

Pr o p orti o n of H Be A g -p ositi ve s u bjects w h o ac hie ve H Be A g l oss a n d ser oc o n versi o n at 
Wee k s 1 2, 2 4, a n d 4 8

P r o p ortio n of s u bjects e x perie nci n g H B V vir ol o gic brea kt hr o u g h ( 2 c o nsec uti ve visits of 
H B V D N A ≥ 6 9 I U/ m L)

I nci de nce of dr u g resista nce m utati o ns


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Statistical A nal ysis Pla n
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H B V Ser ol o g y defi niti o ns:

H Bs A g l oss : H Bs A g c ha n gi n g fr o m p ositi ve at baseli ne t o ne gati ve at a n y p ost baseli ne visit.

C o nfir me d H Bs A g l oss : H Bs A g l oss c o nfir me d b y a n y 2 c o nsec uti ve res ults.

H Bs A g l oss re versi o n : A n y p ost baseli ne H Bs A g p ositi ve res ult f oll o wi n g H Bs A g l oss.

H Bs A b s er oc o n versi o n : H Bs A b c ha n gi n g fr o m ne gati ve or missi n g at baseli ne t o p ositi ve at 
a n y p ost baseli ne visit.  

C o nfir me d H Bs A b ser oc o n versi o n: H Bs A b c ha n gi n g fr o m ne gati ve or missi n g at baseli ne 
t o p ositi ve at a n y p ost baseli ne visit c o nfir me d b y a n y 2 c o nsec uti ve res ults.

H Bs A b s er ore versi o n : A n y p ost baseli ne H Bs A b ne gati ve res ult f oll o wi n g H Bs A b 
ser oc o n versi o n.
H Be A g -relate d ter mi n ol o g y is defi ne d si milarl y.
T he L L O Q f or H B V D N A is defi ne d as 2 0 I U/ m L. T he L L O Q f or q H Bs A g is defi ne d as 
0. 0 5 I U/ m L.
Missi n g data will be treate d as a n o ne ve nt u nless ot her wise s pecifie d (e g, n o H Bs A g l oss, n o 
ser oc o n versi o n, etc.)
6. 2. 2.
A n al ysis Met h o ds f or Sec o n d ar y Effic ac y E n d p oi nts
T he pr o p orti o n of s u bjects wit h ≥ 1 l o g 1 0 I U/ m L decli ne i n q H Bs A g fr o m b aseli ne at Wee k s 4, 8, 
1 2, a n d 4 8 will be a nal yz e d usi n g t he F A S si milarl y t o t he pri mar y efficac y e n d p oi nt. P oi nt 
esti mates a n d 2-si de d 9 5 % e xact CI s of t he pr o p orti o ns will be pr o vi de d base d o n t he
Cl o p per -Pears o n met h o d b y  H Be A g stat us ( p ositi ve, ne gati ve) a n d o verall f or eac h treat me n t 
gr o u p . I n a d diti o n, p oi nt esti mates a n d 2-si de d 9 5 % e xact CIs of t he pr o p orti o n differe nce 
( 1. 5 m g 
P T M, 3 m g 
P T M ), will be dis pla ye d se paratel y b y H Be A g stat us ( p ositi ve, ne gati ve)
a n d o verall f or eac h treat me nt gr o u p .
T he pr o p orti o n of s u bjects wit h H B V D N A < L L O Q at Wee ks 1 2, 2 4, a n d 4 8 will be e val uate d 
b y  H Be A g stat us ( p ositi ve, ne gati ve) a n d o verall. Pr o p orti o n p oi nt esti mates a n d t he 2 -si de d 
9 5 % e xact CI s will be calc ulate d base d o n t he Cl o p per -Pears o n met h o d.
A s u m mar y  ta ble will be pr o vi de d f or H Bs A g-relate d ser ol o g y res ults. T he pr o p orti o n of 
s u bjects w h o ha ve e ver ha d H Bs A g l oss, c o nfir me d H Bs A g l oss, o n- treat me nt H Bs A g l oss, 
p osttreat me nt H Bs A g l oss (f or s u bjects wit h p ositi ve H Bs A g at t he e n d of t he o n-treat me nt 
peri o d) , H Bs A g l oss wit h H Bs A b ser oc o n versi o n, H Bs A g l oss wit h H Bs A b ser ore versi o n, a n d 
H Bs A g l oss re versi o n wit h or wit h o ut H Bs A b ser oc o n versi o n will be s u m marize d b y H Be A g 
stat us ( p ositi ve, ne gati ve) a n d o verall f or eac h treat me nt gr o u p. 


G S -9 6 8 8 
G S -U S -3 8 9 -2 0 2 5 
S tatistic al A nal ys is Pl a n 
A d d itio n a l sm m n ar y t a bles m a y b e pr o vi d e d f or t he f ollo w in g: 
If ~ 3 s u b j ects a c h ie v ed H B s A g  l oss, 
Vers io n  1. 1 
•  
Th e pr o p orti o n of s u bj e cts wi t h H B s A g  l oss w ill b e s m m n ar i ze d b y vis it t hr o ug h W e e k 4 8; 
If ~ 3 s u b j ects a c h ie v ed H B s A g  l oss wi t h H B sA b s er o c o nv e rsio n , 
• 
T h e pr o p orti o n of s u bj e cts wi t h H B sA b s er o c o nv e rs io n w ill b e s m m n ar i ze d b y vis it t hr o ug h 
W e e k 4 8 
• 
T h e pr o p orti o n of s u bj e cts w h o h a v e e v e r h a d H B s A g  l oss w i t h H B s A b s er o c o nv e rs i o n, 
c o nfi n ne d H B s A b s er o c o nv e rs i o n, o n-tr e at m e nt H B s A b s er o c o nv e rs i o n, p o s ttre at m e nt 
H B sA b s er o c o nv e rsio n (f or su b j ects wit h n e gat iv e or m i ssi n g H B s A b at t he e n d of t he 
o n-tr e at m e nt p eri o d ) w ill b e s m m n ar iz e d. 
F or su bj e cts i n t he F A S w i t h b a s e li ne H B e A g s t at us p o sitiv e, si m ilar sm m n ar y t a bles w ill b e 
pr o v i de d. 
T h e pr o p orti o n of su bj e cts e x p eri e n c i n g H B V vi r ol o gic br e a kt hr o u g h b y W e e k 4 8 w ill b e 
e va lu at e d b y H B e A g s t at us (p o s itiv e, n e gativ e) a n d o v e r all f or e a c h tre at me nt gr o u p f or a ll 
su bj ects i n t h e F A S . 
S m m n ar y st atisti cs w ill b e p r es ent e d  b y H B e A g s t at us (p o sitiv e, n e gat i v e) a n d o v e r all f or e a c h 
tre at m e nt gr o u p f or a b s olut e v a l u es a n d c h a ng e fr o m b a s e lin e i n H B V D N A (l og, o I U/m L ) a n d 
q H B s A g (l og , o I U/m L ) b y visit t hr o ug h W e ek 4 8 . C at e gori c a l d ecli n e t a bles f or q H B s A g 
(l og , o I U/m L ) a n d H B V D N A (l og , o I U/m L ) will a ls o b e pr es ent e d. 
I m p ut atio n r ules d escri b e d  i n S ecti o n 3. 6. 1 w ill b e u s ed t o as si g n H B e A g a n d H B s A g st at us f or 
b or d e rlin e results. A M issi n g  
E xcl u d e d a p pr o a c h w ill b e p e rf o n ne d. 
Pl ot s of t he m e a n ± S D a n d m e di a n ( Q 1, Q 3 ) of a b s olut e v al u es a n d c h a ng es fr o m b as e lin e i n 
H B V D N A a n d q H B s A g t hr o ug h W e ek 4 8 w ill b e pr es e nt e d b y H B e A g s t at us (p o s itiv e, 
n e gat iv e) a n d o v e r all f or e a c h tre at me nt gr o u p . 
Dr u g r es ist a n ce m ut at io n s w ill b e a n a l y z e d s ep ar at el y fr o m t h e S A P a n d w ill b e r e p ort e d  i n t he 
C S R. 
--
C O N FI D E N TI A L 
P a g e 3 3 
3 I O ct o b er 2 0 19 


G S -9 6 8 8 
G S -U S -3 8 9 -2 0 2 5 
St atisti c al A n al ysis P la n 
I 
I -
I 
I 
-
C O N FI D E N T IA L 
Versi o n 1. 1 
P a g e 3 4 
3 I O ct o b er 2 0 1 9 


G S -9 6 8 8 
G S -U S -3 8 9 -2 0 2 5 
St atisti c al A n al ysis P la n 
6. 4. 
C h a n g es F r o m P r ot o c ol- S p e cifi e d Effi c a c y A n al ys es 
T h er e are n o pl a n n e d c h a n g es fr om pr ot o c o l-s p e cifie d effic a c y a n alys es . 
C O N FI D E N T IA L 
P a g e 3 5 
Versi o n 1. 1 
3 I O ct o b er 2 0 1 9 


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Statistical A nal ysis Pla n
Versi o n 1. 1
C O N FI D E N TI A L
Pa ge 3 6
3 1 Oct o ber 2 0 1 9
7.
S A F E T Y  AN A L Y S E S
Treat me nt - e mer ge nt a d verse e ve nts ( T E A Es) a n d seri o us T E A Es will be s u m marize d f or t he 
s u bjects i n t he Safet y A nal y sis Set. F or s u bjects i n t he T F F U A nalys is Set, b y-s u bject listi n gs
will be pr o vi de d, a n d s u m mar y  ta bles ma y be prese nte d as a p pr o priate.
7. 1.
A d verse E ve nts a n d De at hs
7. 1. 1.
A d verse E ve nt Dicti o n ar y
Cli nical a n d la b orat or y  a d verse e ve nts ( A Es ) will be c o de d usi n g t he c urre nt versi o n of
Me d D R A . S O C, hi g h le vel gr o u p ter m ( H L G T), hi g h le vel ter m ( H L T), preferre d ter m ( P T), a n d 
l o wer le vel ter m ( L L T) will be pr o vi de d i n t he A E data set.
7. 1. 2.
A d verse E ve nt Se verit y
A d verse e ve nts are gra de d b y  t he i n vesti gat or as Gra de 1, 2, 3, or 4 acc or di n g t o t o xicit y criteria
s pecifie d i n t he pr ot oc ol. T he se verity gra de of e ve nts f or w hic h t he i n vesti gat or di d n ot rec or d 
se verity will be cate g orize d as “ missi n g” f or ta b ular s u m maries a n d data listi n gs . T he missi n g 
cate g or y will be liste d last i n t he s u m mar y prese ntati o n .
T he se verit y of a d verse e ve nts will be deter mi ne d b y t he i n vesti gat or as mil d, m o derate, or 
se vere. 
7. 1. 3.  
Rel ati o ns hi p of A d verse E ve nts t o St u d y Dr u g
Relate d A Es are t h ose f or w hic h t he i n vesti gat or selecte d “ Relate d” o n t he A E e C R F t o t he 
q uesti o n of “ Relate d t o St u d y  Treat me nt.” Relate d ness will al wa y s defa ult t o t he i n vesti gat or’s 
c h oice, n ot t hat of t he me dical m o nit or. E ve nts f or w hic h t he i n vesti gat or di d n ot rec or d
relati o ns hi p t o st u d y dr u g will be c o nsi dere d relate d t o st u d y dr u g f or s u m mar y p ur p oses. 
H o we ver, b y -s u bject listi n gs will s h o w t he relati o ns hi p as missi n g.
7. 1. 4.
Seri o us A d verse E ve nts
Seri o us a d verse e ve nts ( S A Es) will be i de ntifie d a n d ca pt ure d as S A Es if A Es met t he defi niti o ns 
of S A E s t hat were s pecifie d i n t he st u d y pr ot oc ol. S A Es ca pt ure d a n d st o re d i n t he cli nical 
data base will be rec o ncile d wit h t he S A E data base fr o m t he Gilea d P har mac o vi gila nce a n d 
E pi de mi ol o g y  (P V E ) bef ore data base fi nalizati o n.
7. 1. 5.
Tre at me nt -E m er ge nt A d verse E ve nts
7. 1. 5. 1.
Defi niti o n of Treat me nt -E mer ge nt A d verse E ve nts
A treat me nt -e mer ge nt A E at Wee k 2 4 will be defi ne d as a n y A E wit h a n o nset date o n or after 
t he st u d y dr u g start date a n d n o later t ha n 3 0 da ys after per ma ne nt disc o nti n uati o n of t he 
G S -9 6 8 8/ P T M; or a n y  A E lea di n g t o pre mat ure disc o nti n uati o n of st u d y dr u gs. 


G S -9 6 8 8
G S -U S -3 8 9 -2 0 2 5
Statistical A nal ysis Pla n
Versi o n 1. 1
C O N FI D E N TI A L
Pa ge 3 7
3 1 Oct o ber 2 0 1 9
A treat me nt-e mer ge nt A E at Wee k 4 8 will be defi ne d as a n y A E wit h a n o nset date o n or after 
t he first d ose date a n d n o later t ha n 3 da ys after per ma ne nt disc o nti n uati o n of T A F or 3 0 da ys 
after G S -9 6 8 8/ P T M, w hic he ver c o mes later; or a n y  A E lea di n g t o pre mat ure disc o nti n uati o n of 
st u d y dr u gs.
7. 1. 5. 2.
I nc o m plete Dates
If t he o nset date of t he A E is i nc o m plete a n d t he A E st o p date is n ot pri or t o t he first d osi n g date 
of st u d y  dr u g, t he n t he m o nt h a n d year ( or year al o ne if m o nt h is n ot rec or de d) of o nset 
deter mi ne w het h er a n A E is treat me nt e mer ge nt . T he e ve nt is c o nsi dere d treat me nt e mer ge nt if 
b ot h of t he f oll o wi n g 2 criteria are met :

T he A E o nset is t he sa me as or after t he m o nt h a n d y ear ( or year) of t he first d ose date of
st u d y dr u g, a n d

T he A E o nset date is t he sa me as or bef ore t he m o nt h a n d year ( or year) of t he date 
c orres p o n di n g t o t he c ut off date fr o m T E A E defi niti o n i n Secti o n 7. 1. 5. 1
A n A E wit h c o m ple tely missi n g o nset a n d st o p date s, or wit h t he o nset date missi n g a n d a 
st o p date later t ha n t he first d osi n g date of st u d y  dr u g, will be c o nsi dere d t o be treat me nt
e mer ge nt. I n a d diti o n, a n A E wit h t he o nset date missi n g a n d i nc o m plete st o p date wit h t he sa me 
or later m o nt h a n d ye ar ( or year al o ne if m o nt h is n ot rec or de d) as t he first d osi n g date of st u d y  
dr u g will be c o nsi dere d treat me nt e mer ge nt.
7. 1. 6.
S u m m aries of A d verse E ve nts a n d De at hs
A Es will be s u m marize d base d o n t he Safet y  A nal ysis Set.
F or t he Wee k
2 4 a n al ysis , T E A Es at Wee k 2 4 will be s u m marize d as descri be d bel o w. F or t he 
Wee k 4 8 a n al ysis , 2 sets of s u m maries will be ge nerate d: ( 1) all T E A Es at Wee k 2 4 ( 2) all 
T E A Es at Wee k 4 8 . F or t he Fi n al a n al ysis , data listi n gs will be prese nte d , a n d s u m mar y ta bles 
ma y  be prese nte d f or s u bjects i n t he T F F U A nalys is Set as a p pr o priate.
A brief hi g h -le vel s u m mar y of T E A Es will be pr o vi de d b y  eac h treat me nt gr o u p a n d G S - 9 6 8 8
o verall (i n t he or der of 3 m g, 1. 5 m g, o verall G S - 9 6 8 8, a n d place b o) f or the n u m ber a n d 
perce nta ge of s u bjects w h o e x perie nce d t he f oll o wi n g: T E A E s, Gra de 3 or hi g her 
T E A Es , G S - 9 6 8 8/ P T M or T A F T E treat me nt-relate d A Es, Gra de 3 or hi g her G S -9 6 8 8/ P T M or
T A F T E treat me nt-relate d A Es, T E S A E s, G S -9 6 8 8/ P T M or T A F T E treat me nt-relate d S A E s, 
A E s lea di n g t o pre mat ure disc o nti n uati o n of st u d y dr u g ( G S-9 6 8 8/ P T M or T A F) , A E s lea di n g t o
te m p orar y i nterr u pti o n of st u d y dr u g ( G S-9 6 8 8/ P T M or T A F) . Deat hs (treat me nt e mer ge nt or 
n o n- treat me nt e mer ge nt) o bser ve d i n t he st u d y will als o be i ncl u de d i n t his s u m mar y. 


G S -9 6 8 8
G S -U S -3 8 9 -2 0 2 5
Statistical A nal ysis Pla n
Versi o n 1. 1
C O N FI D E N TI A L
Pa ge 3 8
3 1 Oct o ber 2 0 1 9
A d verse e ve nt su m maries will pr o vi de t he n u m ber a n d perce nta ge of s u bjects wit h T E A Es b y
S O C a n d P T b y treat me nt gr o u p a n d G S -9 6 8 8 o verall (i n t he or der of 3 m g, 1. 5 m g, overall 
G S -9 6 8 8 , a n d Place b o) as f oll o ws:

T E A Es ( wit h se verit y)

T E A Es wit h Gra de 3 or hi g her

T E t reat me nt-relate d A Es 

G S -9 6 8 8/ P T M T E treat me nt-relate d A Es 

T A F T E treat me nt-relate d A Es 

T E t reat me nt-relate d A Es of Gra de 3 or hi g her

G S -9 6 8 8/ P T M T E treat me nt-relate d A Es of Gra de 3 or hi g her

T A F T E treat me nt-relate d A Es of Gra de 3 or hi g her

T E S A Es

T E t reat me nt-relate d S A Es 

G S -9 6 8 8/ P T M T E treat me nt-relate d S A Es 

T A F T E treat me nt-relate d S A Es 

T E A Es lea di n g t o pre mat ure disc o nti n uati o n of G S -9 6 8 8/ P T M 

T E A Es lea di n g t o p re mat ure disc o nti n uati o n of T A F

T E A Es lea di n g t o te m p orar y i nterr u pti o n of G S -9 6 8 8/ P T M 

T E A Es lea di n g t o te m p orar y i nterr u pti o n of T A F
M ulti ple e ve nts will be c o u nte d o nl y  o nce per s u bject i n eac h s u m mar y . A d verse e ve nts will be 
s u m marize d a n d liste d first i n al p habetic or der b y S O C a n d t he n b y  P T i n desce n di n g or der of 
t otal fre q ue nc y wit hi n eac h S O C. F or s u m maries b y  se verity gra de, t he m ost se vere gra de will be 
use d f or t h ose A Es t hat occ urre d m ore t ha n o nce i n a n i n di vi d ual s u bject d uri n g t he st u d y. 
I n a d diti o n t o t he a b o ve s u m mar y ta bles, T E A Es , Gra de 3 or hi g her T E A Es, a n d 
treat me nt-e mer ge nt treat me nt-relate d A Es will be s u m marize d b y  P T o nl y , i n desce n di n g or der 
of t otal fre q ue nc y.


G S -9 6 8 8
G S -U S -3 8 9 -2 0 2 5
Statistical A nal ysis Pla n
Versi o n 1. 1
C O N FI D E N TI A L
Pa ge 3 9
3 1 Oct o ber 2 0 1 9
I n a d diti o n t o t he b y-treat me nt s u m maries descri be d a b o ve, data listi n gs will be pr o vi de d f or t he 
f oll o wi n g A Es :

All A Es , i n dicati n g w het her t he e ve nt is treat me nt e mer ge nt

All A Es of Gra de 3 or hi g her

All S A Es

All d eat hs

A Es lea di n g t o p re mat ure disc o nti n uati o n of st u d y dr u g

A E s lea di n g t o te m p orar y i nterr u pti o n of st u d y dr u g
F or s u bjects i n t he T F F U A nal ysis Set, b y-s u bject listi n gs will be pr o vi de d as f oll o ws:

All A Es

A Es of Gra de 3 or hi g her

All S A Es

All deat hs
T he listi n gs will i n dicate w het her a n e ve nt is treat me nt- e mer ge nt, a n d w het her t he e ve nt
occ urre d d uri n g T F F U .
7. 2.
L a b or at or y E v al u ati o ns
La b orat or y  data c ollecte d d uri n g t he st u d y will be a nalyz e d a n d s u m marize d usi n g b ot h 
q ua ntitati ve a n d q ualitati ve met h o ds. S u m maries of la b orat or y  data will be pr o vi de d f or t he 
S afet y Anal ys is S et a n d will i ncl u de all a vaila ble data . T he a n al y sis will be base d o n val ues 
re p orte d i n c o n ve nti o nal units. W he n val ues are bel o w t he L O Q , t he y will be liste d as s uc h, a n d 
t he cl osest i m p ute d val ue will be use d f or t he p ur p ose of calc ulati n g s u m mar y statistics as 
s pecifie d i n Secti o n 3. 7 . He m ol y ze d test res ults will n ot be i ncl u de d i n t he a nalys is, b ut t he y will 
be liste d i n b y -s u bject la b orat or y listi n gs.
A b y -s u bject listi n g for la b orat or y  test res ults will be pr o vi de d b y s u bject I D n u m ber a n d visit i n 
c hr o n ol o gical or der f or he mat ol o g y , ser u m c he mistr y, a n d uri nalys is se paratel y. Val ues falli n g 
o utsi de of t he rele va nt refere nce ra n ge a n d/ or ha vi n g a se verit y gra de of 1 or hi g h er o n t he 
Gilea d Gra di n g Scale f or Se verit y  of A d verse E ve nts a n d La b orat or y A b n or malities will be 
fla g ge d i n t he data listi n gs, as a p pr o priate.
N o f or mal statistical testi n g is pla n ne d.


G S -9 6 8 8
G S -U S -3 8 9 -2 0 2 5
Statistical A nal ysis Pla n
Versi o n 1. 1
C O N FI D E N TI A L
Pa ge 4 0
3 1 Oct o ber 2 0 1 9
7. 2. 1. 
S u m m aries of N u meric L a b or at or y Res ults
Descri pti ve statistics ( n , mea n, S D, me dia n, Q 1, Q 3, mi ni m u m , a n d ma xi m u m) will be pr o vi de d 
usi n g all a vaila ble data b y  eac h treat me nt gr o u p a n d G S -9 6 8 8 o verall (i n t he or der of 3 m g, 
1. 5 m g, o verall G S -9 6 8 8 , a n d Place b o) f or c he mistr y (i ncl u di n g A L T, as partate a mi n otra nsferase 
[A S T ], t otal bilir u bi n, al kali ne p h os p hatase [ A LP], creati ne ki nase [ C K], fasti n g t otal 
c h olester ol, fasti n g gl uc ose, i nter nati o nal n or malize d rati o [ I NR] , lactate de h ydr o ge nase [L D H ]), 
he mat ol o g y  (i ncl u di n g he mat ocrit, he m o gl o bi n, l ym p h oc y tes, ne utr o p hils , w hite bl o o d cells
[ W B C], platelets ), creati ni ne a n d esti mate d creati ni ne cleara nce calc ulate d b y  t he 
C o ckcr oft -Ga ult met h o d as f oll o ws:

Baseli ne val ues 

Val ues at eac h p ost baseli ne visit

C ha n ge fr o m baseli ne at eac h p ost baseli ne visit
A baseli ne la b orat or y  val ue is defi ne d as t he last meas ure me nt o btai ne d o n or pri or t o t he 
date/ti me of first d ose of st u d y  dr u g. C ha n ge fr o m baseli ne t o a p ost baseli ne visit will be defi ne d 
as t he visit val ue mi n us t he baseli ne val ue. T he mea n, me dia n, Q 1, Q 3, mi ni m u m , a n d ma xi mu m 
will be dis pla y e d t o t he re p orte d n u m ber of di gits; S D val ues will be dis pla ye d t o t he re p orte d 
n u m ber of di gits pl us 1.
Me dia n ( Q 1 , Q 3) of t he o bser ve d val ues f or A L T, t otal bilir u bi n, l y m p h oc ytes, a n d ne utr o p hils 
will be pl otte d usi n g a li ne pl ot b y visit a n d b y . 
I n t he case of m ulti ple val ues i n a n a nalys is wi n d o w, data will be selecte d f or a nalys is as 
descri be d i n Secti o n 3. 8. 3 .
7. 2. 2.
Gr a de d L a b or a t or y V al ues
T he Gilea d Gra di n g Scale f or Se verit y of A d verse E ve nt s a n d La b orat or y A b n or malities will be 
use d t o assi g n t o xicit y gra des ( 0 t o 4) t o la b orat or y res ults f or a nal ysis. Gra de 0 i ncl u des all 
val ues t hat d o n ot meet t he criteria f or a n a b n or malit y  of at least Gra de 1. F or la b orat or y tests 
wit h criteria f or b ot h i ncrease d a n d decrease d le vels, a nal yses f or eac h directi o n (ie, i ncrease d, 
decrease d) will be prese nte d se paratel y.
7. 2. 2. 1.
Trea t me nt-E mer ge nt La b orat or y  A b n or malities
Treat me nt -e mer ge nt la b orat or y a b n or malities are defi ne d as val ues t hat i ncrease at least 
1 t o xicit y gra de fr o m baseli ne at a ny p ost baseli ne ti me p oi nt , u p t o a n d i ncl u di n g t he date of t he 
last d ose of st u d y dr u g pl us 3 0 da y s f or G S-9 6 8 8/ P T M
at Wee k 2 4, a n d 3 da y s f or T A F or 
3 0 da y s f or G S-9 6 8 8/ P T M at Wee k 4 8 , w hic he ver c o mes later f or s u bjects w h o per ma ne ntl y  
disc o nti n ue d st u d y  dr u g, or t he last a vaila ble date i n t he data base s na ps h ot f or s u bjects w h o w e re 
still o n treat me nt at t he ti me of t he a nal ys is. If t he rele va nt baseli ne la b orat or y val ue is missi n g, 
a n y a b n or malit y of at least Gra de 1 o bser ve d wit hi n t he ti me fra me s pecifie d a b o ve will be 
c o nsi dere d treat me nt e mer ge nt.


G S -9 6 8 8
G S -U S -3 8 9 -2 0 2 5
Statistical A nal ysis Pla n
Versi o n 1. 1
C O N FI D E N TI A L
Pa ge 4 1
3 1 Oct o ber 2 0 1 9
7. 2. 2. 2.
S u m maries of La b orat or y  A b n or malities
La b orat or y  data t hat are cate g orical will be s u m marize d usi n g t he n u m ber a n d perce nta ge of 
s u bjects i n t he st u d y wit h t he gi ve n res p o nse at baseli ne a n d eac h sc he d ule d p ost baseli ne visit.
F or t he Wee k 2 4 a n al ysis , treat me nt e mer ge nt ( T E) la b orat or y a b n or malities will be 
s u m marize d f or all T E la b orat or y a b n or malities at Wee k 2 4. F or t he Wee k 4 8 a n al ysis , 2 sets of 
s u m maries will be ge nerate d: ( 1) all T E la b orat or y a b n or malities at Wee k 2 4 ( 2) all T E 
la b orat or y a b n or malities at Wee k 4 8. F or t he Fi n al a n al ysis , data listi n gs will be prese nte d, a n d 
s u m mar y ta bles ma y be prese nte d f or s u bjects i n t he T F F U A nal ysis Set as a p pr o priate.  
T he f oll o wi n g s u m maries ( n u m ber a n d perce nta ge of s u bjects) f or la b orat or y a b n or malities will 
be pr o vi de d b y la borat or y test a n d b y  eac h treat me nt gr o u p a n d G S - 9 6 8 8 overall (i n t he or der of 
3 m g, 1. 5 m g, o verall G S -9 6 8 8 , a n d Place b o); s u bjects will be cate g orize d acc or di n g t o t he m ost 
se vere p ost baseli ne a b n or malit y gra de f or a gi ve n la borat or y test:

G ra de d la b orat ory a b n or malities

G ra de 3 or 4 la b orat or y a b n or malities
F or all s u m maries of la b orat or y  a b n or malities, t he de n o mi nat or is t he n u m ber of s u bjects wit h 
n o n missi n g p ost baseli ne val ues .
B y- s u bject listi n gs of all gra de d la b orat or y a b n or malities a n d Gra de 3 or 4 la b orat or y 
a b n or malities will be pr o vi de d b y  s u bject I D n u m ber a n d visit i n c hr o n ol o gical or der. T h ese
listi n gs will i ncl u de all test res ults t hat were c ollecte d t hr o u g h o ut t he st u d y f or t he la borat or y test
of i nterest , wit h all a p plica ble se verity gra des a n d a b n or mal fla gs dis pla ye d.
7. 2. 3.
Li ver -rel ate d L a b or at or y E v al u ati o ns
Li ver -relate d a b n or malities after i nitial st u d y dr u g d osi n g will be e xa mi ne d a n d s u m marize d b y  
H Be A g stat us ( p ositi ve, ne gati ve) a n d f or eac h treat me nt gr o u p a n d G S -9 6 8 8 o verall (i n t he 
or der of 3 m g, 1. 5 m g, o verall G S - 9 6 8 8, a n d place b o) usi n g t he n u m ber a n d perce nta ge of 
s u bjects w h o were re p orte d t o ha ve t he f oll o wi n g la b orat or y test val ues f or a n y p ost baseli ne 
meas ure me nts ( base d o n ce ntral la b n or mal ra n ge):

A L T > 1. 5 na dir a n d o ne of t he f oll o wi n g: 
A L T ≥ 2 baseli ne 
A L T ≥ 1 0 U L N
A L T ≥ 3 U L N a n d total b ilir u bi n ≥ 2 U L N
A L T ≥ 3 U L N a n d I NR ≥ 1. 7   


G S -9 6 8 8
G S -U S -3 8 9 -2 0 2 5
Statistical A nal ysis Pla n
Versi o n 1. 1
C O N FI D E N TI A L
Pa ge 4 2
3 1 Oct o ber 2 0 1 9
A L T flare , A A S L D He patitis flare, a n d A L T ele vati o n will als o be s u m marize d usi n g t he 
n u m ber a n d perce nta ge of s u bjects f or a n y p ost baseli ne meas ure me nts ( base d o n b ot h ce ntral la b 
a n d A A S L D n or mal ra n ge):

A L T flare: A L T > 2 baseli ne a n d ≥ 5 U L N

A A S L D H e patitis flare: A LT i ncrease ≥ 3 baseli ne a n d > 1 0 0 U/ L

A L T ele vati o n: A L T > 1. 5 na dir a n d o ne of t he f oll o wi n g: 
A L T ≥ 2 baseli ne
A L T ≥ 2. 5 U L N a n d < 5 U L N
A L T ≥ 5 U L N a n d < 1 0 U L N
A L T ≥1 0 U L N
F or t he Wee k 2 4 a n al ysis , all li ver-relate d T E la b orat or y  a b n or malities a n d A LT flare/ele vati o n 
will be s u m marize d. F or t he Wee k 4 8 a n al ysis , 2 sets of s u m maries will be ge nerate d: ( 1) all 
li ver-relate d T E la b orat or y a b n or malities a n d A L T flare/ele vati o n at Wee k 2 4 ( 2) all li ver-relate d 
T E la b orat or y  a b n or malities a n d A L T flare/ele vati o n at Wee k 4 8. F or t he Fi n al a n al ysis , data 
listi n gs will be prese nte d, a n d s u m mar y ta bles ma y be prese nte d usi n g t he T F F U A nal ys is Set as 
a p pr o priate.  
F or i n di vi d ual la b orat or y tests, s u bjects will be c o u nte d o nce base d o n t he m ost se vere 
p ost baseli ne val ues. F or t he c o m p osite criteria of A L T a n d t otal bilir u bi n or I N R , s u bjects will 
be c o u nte d o nce w he n t he criteria are met at t he sa me p ost baseli ne visit date. T he de n o mi nat or is 
t he n u m ber of s u bjects i n t he Safety A nal ys is Set w h o ha ve n o n missi n g p ost baseli ne val ues of all 
rele va nt tests at t he sa me p ost baseli ne visit date. A listi n g of s u bjects w h o met at least 1 of t he 
a b o ve criteria will be pr o vi de d.
7. 2. 4.  
D ose Li miti n g T o xicities
G S - 9 6 8 8/P T M a n d/ or T A F d osi n g f or a s u bject will be hel d or per ma ne ntl y  disc o nti n ue d if t he 
s u bject e x perie nces at least o ne of t he f oll o wi n g d ose li miti n g t o xicities ( D L Ts):

C o nfir me d , cli nicall y si g nifica nt la b orat or y a b n or malit y ( ot her t ha n A L T) ≥ Gra de 3

C o nfir me d A L T ≥ 1 0 U L N 

C o nfir me d A L T i ncrease (ie, at least 1 gra de i ncrease or 2 pre vi o us val ue) wit h e vi de nce of 
w orse ne d he patic f u ncti o n (e g, t otal bilir u bi n > 2 m g/ d L a b o ve baseli ne , ele vate d I N R 
≥1. 7 or > 0. 5 a b o ve baseli ne , a b n or mal ser u m al b u mi n > 1 g/ d L decrease fr o m baseli ne )

Treat me nt -relate d A E ≥ Gra de 3


G S -9 6 8 8
G S -U S -3 8 9 -2 0 2 5
Statistical A nal ysis Pla n
Versi o n 1. 1
C O N FI D E N TI A L
Pa ge 4 3
3 1 Oct o ber 2 0 1 9
“ C o nfir me d” is defi ne d as 2 c o nsec uti ve res ults, i ncl u di n g retests.
A s u m mar y  ta ble will be ge nerate d, i n w hic h eac h s u bject will be c o u nte d o nce f or a n y  
occ urre nce of a D L T. T he de n o mi nat or will be t he n u m ber of s u bjects i n t he Safet y A nal ys is Set. 
G S - 9 6 8 8/P T M a n d/ or T A F d osi n g will als o be hel d if a s u bject e x perie nces a c o nfir me d Gra de 2 
or a b o ve ne utr o pe nia. A s u m mar y  ta ble will be pr o vi de d f or t he n u m ber a n d perce nta ge of 
s u bjects wit h c o nfir me d Gra de 2 or a b o ve T E A Es of ne utr o pe nia or c o nfir me d Gra de 2 or a b o ve 
T E la b orat or y a b n or malit y  of ne utr o phils. 
B y- s u bject listi n gs will als o be pr o vi de d i n dicati n g t he occ urre nce of a n y D L Ts or Gra de 2 or 
a b o ve ne utr o pe nia t o s u p p ort t he s u m mar y  ta bles.
7. 3.
B o d y Wei g ht, B o d y M ass I n de x a n d Vit al Si g ns
Descri pti ve statistics will be pr o vi de d b y eac h treat me nt gr o u p a n d G S -9 6 8 8 o verall (i n t he or der 
of 3 m g, 1. 5 m g, o verall G S - 9 6 8 8, a n d place b o) f or b o d y wei g ht, B MI a n d vital si g ns as f oll o ws:

Baseli ne val ue

Val ues at eac h p ost baseli ne visit

C ha n ge fr o m baseli ne at eac h p ost baseli ne visit
A baseli ne val ue is defi ne d as t he last a vaila ble val ue c ollecte d o n or pri or t o t he date/ti me of 
first d ose of st u d y dr u g. C ha n ge fr o m baseli ne at a p ost baseli ne visit will be defi ne d as t he 
p ost baseli ne val ue mi n us t he baseli ne val ue.
I n t he case of m ulti ple val ues i n a n anal ys is wi n d o w, data will be selecte d f or a nalys is as 
descri be d i n Secti o n 3. 8. 3 . N o f or mal statistical testi n g is pla n ne d.
A b y -s u bject listi n g of vital si g ns will be pr o vi de d b y s u bject I D n u m ber a n d ti me p oi nt i n 
c hr o n ol o gical or der. A listi n g of b o d y  wei g ht a n d B MI will be pr o vi de d se parately.
7. 4.
Pri or a n d C o nc o mit a nt Me dic ati o ns
Me dicati o ns c ollecte d at scree ni n g a n d d uri n g t he st u d y  will be c o de d usi n g t he c urre nt versi o n 
of t he W orl d Healt h Or ga nizati o n ( W H O) Dr u g dicti o nar y . 
7. 4. 1. 
Pri or Me dic ati o ns
P ri or me dicati o ns are defi ne d as a ny me dicati o ns ta ke n bef ore a s u bject t o o k t he first d ose of 
st u d y dr u g. O nl y pri or H B V me dicati o ns will be s u m marize d. A b y- s u bject listi n g of pri or H B V 
me dicati o ns will als o be pr o vi de d.


G S -9 6 8 8
G S -U S -3 8 9 -2 0 2 5
Statistical A nal ysis Pla n
Versi o n 1. 1
C O N FI D E N TI A L
Pa ge 4 4
3 1 Oct o ber 2 0 1 9
Pri or H B V me dicati o ns will be s u m marize d b y preferre d na me usi n g t he n u m ber a n d perce nta ge 
of s u bjects b y  H Be A g stat us ( p ositi ve, ne gati ve) a n d f or eac h treat me nt gr o u p a n d G S - 9 6 8 8 
o verall (i n t he or der of 3 m g, 1. 5 m g, o verall G S - 9 6 8 8, a n d place b o). A s u bject re p orti n g t he 
sa me me dicati o n m ore t ha n o nce will be c o u nte d o nl y o nce w he n calc ulati n g t he n u m ber a n d 
perce nta ge of s u bjects w h o recei ve d t hat me dicati o n. T he s u m mar y  will be or dere d by preferre d 
na me i n or der of desce n di n g o verall fre q ue nc y. F or dr u gs wit h t he sa me fre q ue nc y, s orti n g will 
be d o ne al p ha beticall y.
F or t he p ur p oses of a nal ysis, a n y me dicati o n wit h a start date pri or t o t he first d os e date of st u d y 
dr u g will be i ncl u de d i n t he pri or me dicati o n s u m mar y re gar dless of w he n t he st o p date is. If a 
partial start date is e ntere d t he me dicati o n will be c o nsi dere d pri or u nless t he m o nt h a n d year 
(if d a y  is missi n g) or ye ar (if da y a n d m o nt h are missi n g) of t he start date are after the first 
d osi n g date. Me dicati o ns wit h a c o m pletel y missi n g start date will be i ncl u de d i n t he pri or 
me dicati o n s u m mar y , u nless ot her wise s pecifie d.
S u m maries will be base d o n t he Safet y A nal ys is Set. N o f or mal statistical testi n g is pla n ne d.
7. 4. 2.
C o nc o mit a nt M e dic ati o ns
C o nc o mita nt me dicati o ns are defi ne d as me dicati o ns ta ke n w hile a s u bject t o o k st u d y  dr u g. Use 
of c o nc o mita nt me dicati o ns will be s u m marize d a n d preferre d na me usi n g t he n u m ber a n d 
perce nta ge of s u bjects b y  eac h treat me nt gr o u p a n d G S -9 6 8 8 o veral l (i n t he or der of 3 m g, 
1. 5 m g, o verall G S - 9 6 8 8, a n d place b o). A s u bject re p orti n g t he sa me me dicati o n m ore t ha n o nce 
will be c o u nte d o nl y  o nce w he n calc ulati n g t he n u m ber a n d perce nta ge of s u bjects w h o recei ve d 
t hat me dicati o n. T he s u m mar y will be or dere d b y  preferre d na me i n desce n di n g o verall 
fre q ue nc y. F or dr u gs wit h t he sa me fre q ue nc y, s orti n g will be d o ne al p ha beticall y.
F or t he p ur p oses of a nal ysis, a n y me dicati o ns wit h a start date pri or t o or o n t he first d os e date of 
st u d y dr u g a n d c o nti n ued t o be ta ke n after t he first d osi n g date, or starte d after t he first d osi n g 
date b ut pri or t o or o n t he last d osi n g date of st u d y dr u g will be c o nsi dere d c o nc o mita nt 
me dicati o ns. Me dicati o ns starte d a n d st o p pe d o n t he sa me da y  as t he first d osi n g date or t he last 
d osi n g date of st u d y  dr u g will als o be c o nsi dere d c o nc o mita nt. Me dicati o ns wit h a st o p date pri or 
t o t he date of first d osi n g date of st u dy dr u g or a start date after t he last d osi n g date of st u d y dr u g 
will be e xcl u de d fr o m t he c o nc o mita nt me dicat i o n s u m mar y. If a partial st o p date is e ntere d, a ny 
me dicati o n wit h t he m o nt h a n d y ear (if da y is missi n g) or ye ar (if da y a n d m o nt h are missi n g) 
pri or t o t he date of first st u d y  dr u g a d mi nistrati o n will be e xcl u de d fr o m t he c o nc o mita nt 
me dicati o n s u m mar y . If a partial start date is e ntere d, a ny me dicati o n wit h t he m o nt h a n d year 
(if d a y  is missi n g) or ye ar (if da y a n d m o nt h are missi n g) after t he st u d y dr u g st o p date will be 
e xcl u de d fr o m t he c o nc o mita nt me dicati o n s u m mar y . Me dicati o ns wit h c o m pletel y missi n g start 
a n d st o p dates will be i ncl u de d i n t he c o nc o mita nt me dicati o n s u m mar y , u nless ot her wise 
s pecifie d. 
S u m maries will be base d o n t he Safet y A nal ys is Set. N o f or mal statistical testi n g is pla n ne d.
All pri or a n d c o nc o mita nt me dicati o ns ( ot her t ha n per- pr ot oc ol st u d y  dr u gs) will be pr o vi de d i n a 
b y -s u bject listi n g s orte d b y s u bject I D n u m ber a n d a d mi nistrati o n date i n c hr o n ol o gical or der.


G S -9 6 8 8
G S -U S -3 8 9 -2 0 2 5
Statistical A nal ysis Pla n
Versi o n 1. 1
C O N FI D E N TI A L
Pa ge 4 5
3 1 Oct o ber 2 0 1 9
7. 5. 
Electr oc ar di o gr a m Res ults
E C G a nal ys is res ults are i nte n de d t o i de ntif y mea ni n gf ul a b n or malities. If p ote ntial a b n or malities 
of i nterest are i de ntifie d, f urt her a nal ys es ma y be c o n d ucte d.
Safet y  E C G data will n ot be prese nte d i n t he mai n b o d y of t he C S R si nce safety E C Gs were n ot 
assesse d i n t his st u d y  ot her t ha n as part of t he scree ni n g pr ocess f or p ote ntial ne w s u bjects. 
Ti me -matc he d di gital 1 2 -lea d E C Gs will be c ollecte d as c o nti n u o us rec or di n gs fr o m H olter 
m o nit ors, a n d will be a nal y ze d se paratel y fr o m t his S A P f or t he c o nce ntrati o n -Q T (c -Q T) 
a nal ys is.
A b y -s u bject listi n g f or safety E C G assess me nt res ults will be p r o vi de d b y s u bject I D n u m ber 
a n d ti me p oi nt i n c hr o n ol o gical or der.
7. 6.
Ot her S afet y Me as ures
O p ht hal mic e xa mi nati o ns will be perf or me d, i ncl u di n g slit la m p a n d f u n d osc o pic e xa mi nati o n 
wit h reti nal p h ot o gra p hs ( b ot h e y es). A n e xa mi nati o n of t he f ull reti nal fi el d will be c o n d ucte d 
n oti n g c ha n ges or a b n or malities. P h ot o gra p hs of t he reti na were t o be ta ke n at eac h e xa m , a n d a 
ce ntral ve n d or was use d t o assess t he reti nal p h ot o gra p hs. O p ht hal m ol o g y  data will be c ollecte d 
at scree ni n g, Wee k 1 2, a n d Wee k
2 4. S u m maries of o p ht hal m ol o g y  data will be base d o n 
n o mi nal visits.
A s hift ta ble of t he o verall assess me nt of o p ht hal m ol o g y  res ults at eac h visit c o m pare d wit h 
baseli ne val ues will be prese nte d b y eac h treat me nt gr o u p a n d G S - 9 6 8 8 o verall (i n t he or der of 3 
m g, 1. 5 m g, o verall G S - 9 6 8 8, a n d place b o) usi n g t he f oll o wi n g cate g ories: n or mal; a b n or mal, n ot 
cli nicall y si g nifica nt; a b n or mal, cli nicall y si g nifica nt; or missi n g/ u n k n o w n. T he n u m ber a n d 
perce nta ge of s u bjects i n eac h cr oss -classificati o n gr o u p of t he s hif t ta ble will be prese nte d. 
S u bjects wit h a missi n g val ue at baseli ne or p ost baseli ne will n ot be i ncl u de d i n t he de n o mi nat or 
f or perce nta ge calc ulati o n. N o f or mal statistical testi n g is pla n ne d.
A b y -s u bject listi n g f or o p ht hal m ol o g y assess me nt res ults wil l be pr o vi de d b y s u bject I D n u m ber 
a n d visit i n c hr o n ol o gical or der.
T he s hift ta ble will be ge nerate d f or o p ht hal m ol o g y assess me nt res ults fr o m t he ce ntral rea der.
T he listi n g will i ncl u de res ults fr o m b ot h o n- site i n vesti gat or a n d t he ce ntral rea der.
7. 7.
C h a n ges fr o m Pr ot oc ol -S pecifie d S afet y A n al yses
T here are n o de viati o ns fr o m t he pr ot oc ol-s pecifie d safet y a nal yses.


G S -9 6 8 8 
G S -U S -3 8 9 -2 0 2 5 
St atisti c al A n al ysis Pl a n 
8. 
P H A R M A C O KI N E TI C A N A L Y S E S 
8. 1. 
P K S a m pl e C oll e cti o n 
Versi o n 1. 1 
S p ars e ( pr e-i d e ntifi e d) P K pl as m a s a m p lin g w ill o c c ur f or a ll s u bj e cts o n D a y 1 a n d W e e k 2 3 at 
pr e d os e, 1, 4, a n d 2 4 h o urs p ost d os e a n d at W e e k 1 1 at pr e d os e, 1, a n d 4 h o urs p ost d os e . S p ars e 
(ti me d) pl as m a P K s a m p les w ill b e o bt a in e d o n a n y t w o of t h e f ollo w in g visi ts: W e e ks 2, 4, 8, 
1 2,  1 6, a n d/or 2 0 at pr e d os e a n d a n y tim e b et w e e n 3 0 mi n ut es t o 4 h o urs p ost d os e . 
T h e s p ars e P K s a m p le will n ot b e c o lle ct e d o n t h e d a y t he s u bje ct p arti cip at es in t h e P K 
s u bst u d y. -
8. 1. 2 .  
Esti m ati o n of P K P a r a m et e rs 
P K p ar a m et ers w ill b e estim at e d us in g P h o e ni x W i n N o n li n® s oft w ar e us in g st a n d ar d 
n o n c o m p art m e nt a l m et h o ds . Th e lin e ar /l o g tr a p e z oid a l r ule will b e us e d i n c o nju n cti o n w i t h t h e 
a p pr o priat e n o n c o m p art m e nt a l m o d e l, wit h i n p ut v a lu es f or d os e le v e l, d os in g tim e, pl as m a 
c o n c e ntr ati o n, a n d c orr es p o n di n g r e al-tim e v a lu es, b as e d o n dr u g d os in g tim es w h e n e v er 
p oss i ble. 
A ll pr e d os e s a m pl e tim es b ef or e tim e- z er o w ill b e c o n v ert e d t o z er o . 
F or ar e a u n d er t he c ur v e ( A U C), s a m p les B L Q of t h e bi o a n a lytic a l ass a ys o c c urri n g pr ior t o t he 
a c h ie v e m e nt of t he first q u a nt ifia ble c o n c e ntr atio n w ill b e ass ig n e d a c o n c e ntr atio n v a lu e of 0 t o 
pr e v e nt o v er est im ati o n of t h e i nitial A U C . S a m p les t h at ar e B L Q at a ll ot h er tim e p o ints w ill b e 
tr e at e d as mi ssin g d at a i n W i n N o n li n. Th e n o m in a l tim e p o int f or a k e y e v e nt or d os in g int er v a l 
(-r) m a y b e us e d t o p e nni t dir e ct c alc u lati o n of A U C o v er s p e cific tim e int er v a ls. Th e 
a p pr o priat e n ess of t his a p pr o a c h w ill b e ass ess e d b y t h e P K s c ie nt ist o n a pr ofi le- b y- pr ofi le 
b as is. 
P K p ar a m et ers s u c h as A U C nr, Az a n d t112 ar e d e p e n d e nt o n a n a c c ur at e est im at io n of t h e t e nni n a l 
e li1ni n atio n p h as e of dr u g . Th e a p pr o priat e n ess of c a lc u lat in g t h es e p ar a m et ers w ill b e e v a lu at e d 
u p o n i ns p e cti o n of P K d at a o n a pr ofi le- b y- pr ofi le b as is b y t h e P K s cie nt ist. 
C O N FI D E N T IA L 
P a g e 4 6 
3 I O ct o b er 2 0 1 9 


G S -9 6 8 8 
G S -U S -3 8 9 -2 0 2 5 
S tatistic al A nal ys is Pl a n 
8. 1. 3. 
P K P a r a m et e rs 
T a bl e 8- 1. 
St u d y T r e at m e nts a n d Ass o ci at e d A n al yt e 
T r e at m e nt G r o u p 
T r e at m e nt 
B 
G S -9 6 8 8 1. 5 m g o n c e a wee k f or 2 4 wee ks 
C 
G S -9 6 8 8 3 m g o n c e a wee k f or 2 4 wee ks 
Vers io n  1. 1 
A n al y te 
G S -9 6 8 8 
G S -9 6 8 8 
T h e a n a l yte a n d p ar a m et ers pr es e nte d i n T a b le 8- 2 will b e u s ed t o e v alu at e t he P K o bj ect iv es of 
t he st u dy. T h e pr i mar y P K p ar a m et ers are A U Ci ast, A U C o 2 4, A U G nr, a n d C m ax of G S- 9 6 8 8 . T h e 
P K p ar a m et ers t o b e esti mate d i n t his st u dy are list e d a n d d e fi ne d i n t he P K A b br e v iati o ns 
s ect io n . 
T a bl e 8- 2. 
P K P ar a m et ers 
A n al yt e 
P a r a meter s 
G S -9 6 8 8 
A U C 1ast, A U C o . 24, A U C; nr, o/oA U Ce x p, Cnax, T max, C 1ast, T 1ast, A-z, C L/ F, V / F, a n d t112 
I n div i du a l su bj e ct c o n c entr ati o n d at a a n d i n di vid u a l su bj e ct P K p ar a m et ers f or G S- 9 6 8 8 w ill b e 
list e d a n d sm m n ar iz e d usin g d es cript iv e st atistics b y d o s e. S u m m ar y st atistics ( n, m ea n , S D , 
c o e fficient of v ariat io n [ %C V ], m e dia n , mi n , m a x , Q 1, a n d Q 3) w ill b e pr es e nt e d f or b ot h 
i n di vid u a l su bj e ct c o n ce ntr ati o n d at a b y t i me p oi nt a n d in d i vi d ual su bj ect P K p ar a m et ers b y 
d o s e. M or e o v e r, t he g e o m e tri c mea n , 9 5 % CI , a n d t he me a n a n d S D of t he n at ur a l 
l og -tr a ns f o n ne d v alu es w ill b e pr es e nt e d f or in d i vi d u al su bj ect P K p ar a m et er d at a . 
I n div i du a l c o n c entr ati o n d at a listi ngs a n d sm m n ar ies w ill in cl u d e a ll su bj e cts wit h c o n c e ntr ati o n 
d at a . T h e sa m p le size f or e a c h ti me p oi nt w ill b e b a s ed o n t he n u m b er of su bj e cts wi t h 
n o m ni ss i ng c o n c entr ati o n d at a at t h at ti me p oi nt. T h e n m n b er of su bj ects wit h c o n c e ntr ati o n 
B L Q w ill b e pr es ent e d f or e a c h ti me p o i nt. F or sm m n ar y st atistics, B L Q v al u es w ill b e treate d as 
0 at pr e d o s e a n d o n e - h alf of t he L L O Q f or p o st d os e ti me p o i nts. 
I n div i du a l P K p ar a m eter d at a listi ngs a n d sm m n ar ies w ill in cl u d e a ll su bj e cts f or w h o m P K 
p ar a m et ers c a n b e d eri v e d. T h e sa m p le siz e f or ea c h P K p ar a m eter w ill b e b a s ed o n t he n u m b er 
of su bj ects wit h n o m ni ss i ng d at a f or t h at P K p ar a m ete r. 
T h e f ollo wi n g t a bles w ill b e pr o vi d e d b y d o se: 
• 
I n div i du a l su bj e ct c o n c entr atio n d at a a n d sm m n ar y st atistics 
• 
I n divi d u a l su bj e ct plas m a P K p ar a m eters a n d sm m n ar y st atistics 
C O N FI D E N TI A L 
P a g e 4 7 
3 I O ct o b er 2 0 19 


G S -9 6 8 8 
G S -U S -3 8 9 -2 0 2 5 
St atisti c al A n al ysis Pl a n 
T h e f ollo wi n g fig ur es m a y b e pr o vi d e d b y d os e: 
Versi o n 1. 1 
•  
Me a n( ± S D) c o n c e ntr at io n d at a v ers us ti me ( on lin e ar a n d s emil o g ar it h mi c s c ales) 
•  
Me d ia n (Ql , Q 3 ) c o n c e ntr ati o n d at a v ers us ti me ( o n lin e ar a n d s emil o g ar it h mi c s c ales) 
I n a d d iti o n, a fig ur e m a y als o b e pr o vi d e d f or in d ivid u a l s u bje ct c o n c e ntr atio n d at a vs . ti me 
( o n li ne ar a n d s emil o g ar it h mi c s c ales) . St u d y D a y ( D a y 1, W e e k 2 3) w ill b e us e d t o o v e rla y d at a 
i n t h es e pl ots . 
I n divi d u a l, me a n, a n d m e d ia n p ost d os e c o n c e ntr atio n v a lu es t h at ar e : S L L O Q w ill n ot b e 
dis p la y e d i n t h e fig ur es a n d r e m ai nin g p o i nts c 0 1 mecte d . 
8. 1. 4. 
A n al ysis of D os e P r o p o rti o n alit y 
If d at a ar e a v aila b le, d os e pr o p ortio n a lit y w ill b e o bt ai n e d b y c o m p ari n g P K p ar a m et ers a cr oss 
e v a lu at e d d os e le v e ls. 
D a y 1 a n d o n W e e k 2 3 P K p ar a m et ers m a y b e p o o le d t o ass ess d os e pr o p orti o n a lit y a cr oss 
e v a lu at e d d os es . 
A n a l ysis of V ar ia n c e 
A n A N O V A m o d el us in g P R O C MI X E D w ill b e us e d t o esti mat e t h e r ati o of t h e P K p ar a m et er 
at e a c h d os e le v e l t o t h e P K p ar a m et er at t h e r ef er e n c e d os e . T h e p ar a m et ers w ill b e 
d os e- n o n n a liz e d a n d n at ur a l lo g-tr a nsf o n n e d pr ior t o a n a lys is. T h e r ef er e n c e d os e is  1. 5 mg, 
d et e nni n e d b y t h e P K s c ienti st. D o s e n o n n a liz atio n is c alc u lat e d b y divi di n g e a c h P K p ar a m et er 
v a lu e b y t h e r ati o of t h e t est d os e /r ef er e n c e d os e . T h e r ati o of g e o m etri c  le ast-s q u ar es m e a ns 
( GL S M) a n d t h e c orr es p o n di n g 9 0 % CI w ill b e est i mat e d f or e a ch P K p ar a m et er of i nt er est. 
T h e st atistic a l m o d el w ill in cl u d e d os e as a fix e d eff e ct. T h e f ollo w i ng S A S P R O C MI X E D c o d e 
w ill pr o v id e t h e d os e c o m p aris o n a n a lys is a n d t h e 9 0 % CI c a lc u latio ns f or t h e n at ur al 
l og-tr an sf o nn e d n o n n a liz e d P K p ar a m et ers . Si milar c o d e w ill b e us e d f or ot h er n at ur al 
l og-tr a n sf o nn e d n o n n a liz e d p ar a m et ers a n d d os e le v e ls. 
P R O C MI X E D; 
C L A S S d os e; 
M O D E L ln C ma x 
d os e; 
L S M E A N S d os e /cl alp h a 0. 1 O; 
E S TI M A T E " 3 m g vs 1. 5 m g " d os e - 1 1 / cl alp h a 0. 1 O; 
R U N; 
C O N FI D E N T IA L 
P a g e 4 8 
3 I O ct o b er 2 0 1 9 


G S -9 6 8 8
G S -U S -3 8 9 -2 0 2 5
Statistical A nal ysis Pla n
Versi o n 1. 1
C O N FI D E N TI A L
Pa ge 4 9
3 1 Oct o ber 2 0 1 9
T he E S TI M A T E state me nt is use d t o pr o d uce t he p oi nt esti mate a n d c orres p o n di n g 9 0 % CI of
t he differe nce i n P K para meters of i nterest o n a l o garit h mic scale. T he test -t o-refere nce rati o a n d
t he 9 0 % CI will be calc ulate d b y e x p o ne ntiati o n of t he p oi nt esti mate a n d t he c orres p o n di n g
l o wer a n d u p per li mits.
A s u m mar y  ta ble a n d a listi n g of S A S a nalys is o ut p ut will be pr o vi de d.
8. 2.
P K A n al yses Rel ate d t o S p arse P K S a m pli n g
F or P K A nal ys is Set, s parse (pre -i de ntifie d) P K data will be s u m marize d b y ti me p oi nt.
I n di vi d ual s u bject c o nce ntrati o n data will be liste d a n d s u m marize d usi n g descri pti ve statistics 
b y  d ose. S u m mar y statistics ( n, mea n, S D, perce nt c oefficie nt of variati o n [ % C V], me dia n, mi n, 
ma x, Q 1, a n d Q 3) will be prese nte d f or i n di vi d ual s u bject c o nce ntrati o n data b y  ti me p oi nt b y 
d ose.  
I n di vi d ual c o nce ntrati o n data listi n gs a n d s u m maries will i ncl u de all s u bjects wit h c o nce ntrati o n 
data. T he sa m ple size f or eac h ti me p oi nt will be base d o n t he n u m ber of s u bjects wit h 
n o n missi n g c o nce ntrati o n data at t hat ti me p oi nt. T he n u m ber of s u bjects wit h c o nce ntrati o n 
B L Q will be prese nte d f or eac h ti me p oi nt. F or s u m mar y  statistics, B L Q val ues will be treate d as 
0 at pre d ose a n d o ne -half of t he L L O Q f or p ost d ose ti me p oi nts. 
T he f oll o wi n g ta bles will be pr o vi de d f or G S -9 6 8 8 b y  d ose:

C CI
I n di vi d ual s u bject c o nce ntrati o n data a n d s u m mar y statistics
F or all s u bjects i n t he P K A nal ysis Set, P K sa m pli n g details b y s u bject ( usi n g c o nce ntrati o n data 
fr o m all s parse 
plas ma P K sa m pli n g), i ncl u di n g pr oce d ures, differe nces i n 
sc he d ule d a n d act ual dra w ti mes, a n d sa m ple a ge will be pr o vi de d i n a listi n g.


G S -9 6 8 8
G S -U S -3 8 9 -2 0 2 5
Statistical A nal ysis Pla n
Versi o n 1. 1
C O N FI D E N TI A L
Pa ge 5 0
3 1 Oct o ber 2 0 1 9
9.
R E F E R E N C E S
C ha n I S, Z ha n g Z. Test -base d e xact c o nfi de nce i nter vals f or t he differe nce of t w o bi n o mial 
pr o p orti o ns. Bi o metrics 1 9 9 9; 5 5 ( 4): 1 2 0 2- 9.
Cl o p per CJ, Pears o n E S. T he Use of C o nfi de nce or Fi d ucial Li mits I ll ustrate d i n t he Case of t he 
Bi n o mial. Bi o metri ka 1 9 3 4; 2 6 ( 4): 4 0 4- 1 3.
K oc h G G, Carr GJ, A mara I A, St o kes M E, Ur y nia k TJ. Cate g orical Data A nal y sis. C ha pter 1 3 i n 
Berr y , D. A. (e d.).  Statistical Met h o d ol o g y i n t he P har mace utical Scie nces. Ne w 
Y or k: Marcel De k ker, I nc., 1 9 8 9: p p. 4 1 4 - 2 1. 


G S -9 6 8 8
G S -U S -3 8 9 -2 0 2 5
Statistical A nal ysis Pla n
Versi o n 1. 1
C O N FI D E N TI A L
Pa ge 5 1
3 1 Oct o ber 2 0 1 9
1 0.
S O F T WA R E
S A S ® S oft ware Versi o n 9. 4 . S A S Instit ute I nc., Car y , N C, U S A.


G S -9 6 8 8
G S -U S -3 8 9 -2 0 2 5
Statistical A nal ysis Pla n
Versi o n 1. 1
C O N FI D E N TI A L
Pa ge 5 2
3 1 Oct o ber 2 0 1 9
1 1.
S A P  R E VI SI O N
Re visi o n D ate
(D D M M M Y Y Y Y )
Secti o n
S u m m ar y of Re visi o n
Re as o n f or Re visi o n
3 1 O C T 2 0 1 9
4. 1; 4. 2. 1; 
4. 3; 5. 3; 
7. 1. 6; 7. 2. 1; 
7. 2. 2. 2; 
7. 2. 3; 7. 3; 
7. 4. 1; 7. 4. 2; 
7. 6
F or s u m maries usi n g Safet y 
A nal ysis Set (e xce pt li ver-relate d 
a b n or malit y, A L T flare/ele vati o n 
o ut p ut , a n d pri or H B V me ds ), we 
r e mo ve “ b y H Be A g stat us” .
T his is t o be c o nsiste nt wit h 
u p dates fr o m st u d y G S -U S -
3 8 9 -2 0 2 4.
5. 2
A d d hist or y of cirr h osis a n d 
cirr h osis deter mi nati o n met h o d 
f or baseli ne c haracteristics.
7. 1. 6
Re m o ve A Es of Gra de 2 or 
a b o ve, treat me nt -relate d A Es of 
Gra de 2 or a b o ve
7. 1. 6
U p date A E ta bles t o kee p se verit y 
f or t he T E A E ta ble o nl y.
7. 6
S hift ta ble of o p ht hal m ol o g y 
res ult will o nl y be ge nerate d 
base d o n ce ntral rea der, n ot o n -
site i n vesti gat or.
6. 3. 2
Mea n
± S D pl ot w ill be prese nte d 
i nstea d of me dia n pl ot f or 
H Be A g, H Bcr A g a n d H B V R N A.
7. 2. 5
Re m o ve t his secti o n as st u d y 
s pecific st o p pi n g criteria is 
re vie we d b y t he D M C.


G S -9 6 8 8
G S -U S -3 8 9 -2 0 2 5
Statistical A nal ysis Pla n
Versi o n 1. 1
C O N FI D E N TI A L
Pa ge 5 3
3 1 Oct o ber 2 0 1 9
1 2.
A P P E N DI C E S
C CI
A p pe n di x 1.
Sc he d ule of Assess me nts
-


G S -9 6 8 8
G S -U S -3 8 9 -2 0 2 5
Statistical A nal ysis Pla n
Versi o n 1. 1
C O N FI D E N TI A L
Pa ge 5 4
3 1 Oct o ber 2 0 1 9
A p pe n di x 1.
Sc he d ule of Assess me nts
P art A.
St u d y Pr oce d ures Re q uire d at Scree ni n g Visit
Scree ni n g St u d y Pr oce d ures – Wi n d o w ( -3 0 d a ys)
O btai n w ritte n I nf or me d C o nse nt
Re vie w of  I ncl usi o n/ E xcl usi o n Criteria
Me dical Hist or y (i ncl u di n g H B V disease a n d treat me nt hist or y)
Re vie w A Es & c o nc o mita nt me dicati o ns
C o m plete P h ysical E xa m (I ncl u di n g Hei g ht, Wei g ht a n d B MI)
Vital Si g ns ( bl o o d press ure, heart rate, res pirati o n rate a n d b o d y te m perat ure)
Safet y La bs ( he mat ol o g y, ser u m c he mistr y, a n d c oa g ulati o n)
1 2 -Lea d E C G
O p ht hal m ol o gic e xa m ( Wi n d o w Da ys -1 0 t o -1)
Q ualitati ve H B V Ser ol o g y Q ualitati ve ( H B V ser ol o g y c o nsists of H Be A g a n d H Bs A g a n d refle x H Be A b a n d refle x H Bs A b at Scree ni n g a n d all visits i n dicate d i n Part B)
H B V D N A le vels
H B V Resista nce S ur veilla nce
H B V Ge n ot y pi n g ( B y hist or y if k n o w n a n d la b orat or y testi n g )
Q ua ntitati ve H Bs A g
H C V, H D V a n d HI V A b testi n g (I n t he e ve nt of a p ositi ve res ult a n d/ or a nti ge n testi n g f or HI V, H D V, or H C V ser ol o g y, refle x tests will a ut o maticall y be perf or me d )
Fi br o T est
Al p ha Fet o pr otei n
Uri nal ysis f or uri ne dr u g scree n, alc o h ol , a n d uri ne pre g na nc y testi n g
Ser u m Pre g na nc y Test (f or all fe mal e s u bjects of c hil d -beari n g p ote ntial)
F ollicle -sti m ulati n g H or m o ne ( F S H, f or fe male s u bjects p ost-me n o pa usal f or less t ha n t w o years)


G S -9 6 8 8
G S -U S -3 8 9 -2 0 2 5
Statistical A nal ysis Pla n
Versi o n 1. 1
C O N FI D E N TI A L
Pa ge 5 5
3 1 Oct o ber 2 0 1 9
P art B.
St u d y Pr oce d ure T a ble ( O n a n d P ost G S - 9 6 8 8/ P T M Tre at me nt Assess me nts)
O n Tre at m e nt
P ost G S -9 6 8 8/ P T M 
Tre at m e nt
D a ys
Wee ks
D a ys
Wi n d o ws
( ± 1 D a y)
( ± 3 D a ys)
( ± 7 D a ys)
St u d y Pr oce d ures
B aseli ne
( D a y 1)
D a y 2
( D a y 1 
+ 2 4 hrs)
2 
4 
8
1 1 
1 2 
1 6 
2 0 
2 3
2 3 + 2 4 hrs
2 4 
2 8 
3 6 
4 8
E D a
T F F U 
after E D
Re vie w of  
i ncl usi o n/e xcl usi o n 
criteria a n d c o nfir m 
me dical hist or y
X
C o m plete P h ysical E xa m 
(i ncl u di n g wei g ht, 
hei g ht, B MI)
X
X  
X  
X  
X
X  
X  
X  
X  
X
S y m pt o m Directe d 
P h y sical E xa m
X
X  
X  
X  
X  
X
X
O p ht hal m ol o gic e xa m c
X
X
Re vie w A Es & 
C o nc o mita nt 
Me dicati o ns
X
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X
Vital Si g ns ( bl o o d 
press ure, heart rate, 
res pirati o n rate a n d b o d y 
t e mperat ure)
X
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X
Safet y La bs 
( He mat ol o g y, Ser u m 
C he mistr y, a n d 
C oa g ulati o n)
X
X  
X  
X  
X  
X  
X  
X  
X
X  
X  
X  
X  
X  
X
Uri nal ysis
X
X  
X  
X  
X  
X  
X  
X  
X
X  
X  
X  
X  
X  
X


G S -9 6 8 8
G S -U S -3 8 9 -2 0 2 5
Statistical A nal ysis Pla n
Versi o n 1. 1
C O N FI D E N TI A L
Pa ge 5 6
3 1 Oct o ber 2 0 1 9
O n Tre at m e nt
P ost G S -9 6 8 8/ P T M 
Tre at m e nt
D a ys
Wee ks
D a ys
Wi n d o ws
( ± 1 D a y)
( ± 3 D a ys)
( ± 7 D a ys)
St u d y Pr oce d ures
B aseli ne
( D a y 1)
D a y 2
( D a y 1 
+ 2 4 hrs)
2 
4 
8
1 1 
1 2 
1 6 
2 0 
2 3
2 3 + 2 4 hrs
2 4 
2 8 
3 6 
4 8
E D a
T F F U 
after E D
Fi br o Test
X
X
X  
X
Ser u m Pre g na nc y Test d
X
X  
X  
X  
X  
X
X  
X  
X  
X  
X  
X
Uri ne Pre g na nc y Test d
X
X
X
H B V D N A le vels, H B V 
Resista nce S ur veilla nce, 
Q ua ntitati ve H Bs A g
X
X  
X  
X  
X  
X  
X  
X  
X
X  
X  
X  
X  
X  
X
Q ualitati ve H B V 
Ser ol o g y
X
X
X  
X  
X  
X  
X
W h ole Bl o o d ge ne 
e x pressi o n bi o mar kers g
X
X
X  
X
X  
X  
X
X  
X
P B M C C ollecti o n h
X
X
X  
X
X  
X  
X
X  
X
S parse ( ti me d) plas ma 
P K sa m ple C ollecti o ni
X  
X  
X  
X  
X  
X
C CI
C CI
-


G S -9 6 8 8
G S -U S -3 8 9 -2 0 2 5
Statistical A nal ysis Pla n
Versi o n 1. 1
C O N FI D E N TI A L
Pa ge 5 7
3 1 Oct o ber 2 0 1 9
O n Tre at m e nt
P ost G S -9 6 8 8/ P T M 
Tre at m e nt
D a ys
Wee ks
D a ys
Wi n d o ws
( ± 1 D a y)
( ± 3 D a ys)
( ± 7 D a ys)
St u d y Pr oce d ures
B aseli ne
( D a y 1)
D a y 2
( D a y 1 
+ 2 4 hrs)
2 
4 
8
1 1 
1 2 
1 6 
2 0 
2 3
2 3 + 2 4 hrs
2 4 
2 8 
3 6 
4 8
E D a
T F F U 
after E D
S parse ( pre i de ntifie d)
plas ma P K sa m ple 
C ollecti o n j
X
X
X
H olter M o nit ori n g
k
X
X
X
Ra n d o mizati o n
X
I n Cli nic G S-9 6 8 8 
D osi n g & 
Acc o u nta bilit y m
X
X  
X  
X  
X  
X  
X  
X  
X
X
T A F Dis pe nsati o n a n d 
Acc o u nta bilit y
X
X  
X  
X  
X  
X
X  
X  
X  
X
C CI
C CI


G S -9 6 8 8
G S -U S -3 8 9 -2 0 2 5
Statistical A nal ysis Pla n
Versi o n 1. 1
C O N FI D E N TI A L
Pa ge 5 8
3 1 Oct o ber 2 0 1 9
P art C . 
St u d y Pr oce d ure T a ble (Tre at me nt Free F oll o w -u p P ost St u d y C o m pleti o n )n
T F F U Wee k b
( St u d y Wee k)
Wi n d o ws
( ± 7 D a ys)
St u d y Pr oce d ures
4
( 5 2)
8
( 5 6)
1 2
( 6 0)
1 6
( 6 4)
2 0
( 6 8)
2 4
( 7 2)
3 6
( 8 4)
4 8
( 9 6)
S y m pt o m Directe d P h ysical E xa m
X
X  
X  
X  
X  
X  
X  
X
Vital Si g ns
( bl o o d press ure, heart rate, res pirati o n rate a n d b o d y 
t e mperat ure)
X
X  
X  
X  
X  
X  
X  
X
Safet y La bs ( He mat ol o g y, Ser u m C he mistr y, a n d 
C oa g ulati o n) 
X
X  
X  
X  
X  
X  
X  
X
Uri nal ysis 
X
X  
X  
X  
X  
X  
X  
X
Ser u m Pre g na nc y Test
X
X  
X  
X  
X  
X  
X  
X
Q ualitati ve H B V Ser ol o g y
X
X  
X  
X  
X  
X  
X  
X
H B V D N A le vels,  H B V Resista nce S ur veilla nce,  
Q ua ntitati ve H Bs A g
X
X  
X  
X  
X  
X  
X  
X
P B M C C ollecti o n h
X
X  
X  
X  
X  
X  
X  
X
W h ole Bl o o d ge ne e x pressi o n bi o mar kers
g
X
X  
X  
X  
X  
X  
X  
X
Re vie w A Es & C o nc o mita nt Me dicati o ns
X
X  
X  
X  
X  
X  
X  
X
C CI
C CI
C CI
C CI
-----------------------------------------------


G S -9 6 8 8 
G S -U S -3 8 9 -2 0 2 5 
St atisti c al A n al ysis P la n 
a 
T h e E D visit s h o u l d b e perf o m 1e d wi t hi n  I w e e k if E D o c c u rs b ef o r e W e e k 2 4 ; after wee k 2 4 E D s h o u l d b e perf o m 1e d wi t hi n 2 w e e ks fr o m n ot ificatio n of st u d y 
di s c o ntin u at io n. 
V ersi o n 1. 1 
b 
S u b je cts w ill b e f o llo w e d e v er y 4 w e e ks f or t h e first 2 4 w e e ks a n d t h er e aft er at W e e k 3 6 a n d 4 8 or u nt il t h e i nitiat io n of al t er n ativ e C H B t h er a p y, w h ic h e v er c o m es first. 
c 
O p ht h a lm o lo g ic e x a m wi n d o ws p er visi t: S cr e e n in g (D a ys 
I O t o I), W e e k 
12 a n d W e e k 2 4 (  4 d a ys t o + I O d a ys ) 
d 
F o r fe ma le s u bje cts of c h ild b e ar in g p ot e nt ial, t h e pr e g n a n c y t est w ill b e perf o m 1e d at a ll st u d y visi ts as in d ic at e d. P os itiv e ur in e t est w ill b e c o nfi m 1e d wi t h s e m m test. 
r 
r 
Pr e g n a n c t estin g s h o u l d in cl u d e re v e nt io n c o u ns e lin g. 
g 
W h o le blo o d g e n e e x p ress io n ( P a x g e n e R N A ) s a m p les c o lle ct e d o n D a ys I pr e d os e a n d I + 4 h o urs , I + 2 4 h o urs p ost d os e , a n d o n W e e ks 
11 pr e d os e , 11 + 4 h o urs p ost d os e , 
12 pr e d os e , 2 3 pr e d os e , 2 3 + 4 h o urs , 2 3 + 2 4 h o urs p ost d os e , P T W e e k 2 4 , 4 8 /E D , a n d T F F U W e e k 4, 8,  12,  16, 2 0 , 2 4 , 3 6 , a n d 4 8. 
h 
P B M C s a m p les c o lle ct e d o n D a ys I pr e d os e a n d I + 4 h o u rs, I + 2 4 h o u rs p ost d os e , a n d o n Wee ks 
11 pr e d os e , 11 + 4 h o u rs p ost d os e ,  12 pre d os e , 2 3 pre d os e , 2 3 + 4 h o u rs, 
2 3 + 2 4 h o urs p ost d os e , P T W e e k 2 4 , 4 8 /E D , a n d T F F U W e e k 4, 8,  12,  16, 2 0 , 2 4 , 3 6 , a n d 4 8. 
S p ars e (ti me d) pl as m a P K s a m p les w ill b e o bt a in e d o n a n y t w o of t h e f o llo w in g visi ts: W e e ks 2, 4, 8,  12,  16, a n d/ or 2 0 at pr e d os e a n d a n y tim e b et w e e n 3 0 mi n ut es t o 
4 h o u rs p ost d os e . 
j 
S p ars e ( pre i de ntifi e d) P K pl as m a s a m p lin g w ill o c c ur o n D a y I a n d W e e k 2 3 at pr e d os e , I, 4, a n d 2 4 h o urs p ost d os e a n d at W e e k 
11 at pr e d os e , I, a n d 4 h o urs p ost d os e. 
k 
I-l oit er M o n it orin g t o b e c o lle ct e d p rior t o bl o o d c o lle ct io n o n D a y I a n d W e e k 2 3 at pr e d os e (:5 5 mi n of d os e ) t hr o u g h 4 h o u rs, a n d 2 4 h o u rs; W e e k 
11 at pre d os e (:5 5 mi n 
r 
of d os e) t hr o u h 4 h o u rs 
111 
n a 
1t 1 0 nt ot e c 1m c 
st u y m g 
os m g , s e 
o m e 
st u y m g 
os m g w 1 
e o n 
e e s  ,  ,  ,  ,  ,  ,  10,  13,  14,  15,  17,  18,  19, 2 1, a n d 2 2 
n 
At W e e k 4 8 , at PI dis cr etio n , f o llo w in g t h e dis c o ntin u at io n of T A F ( win d o w of ± 7 d a ys ), t h e s u bj e ct w ill b e f o llo w e d e v er y 4 w e e ks f or t h e first 2 4 w e e ks a n d t h er e aft er at 
W e e k 3 6 a n d W e e k 4 8 (T F F U p h as e). At t h e PJ's di s cr etio n , s u bj e ct(s) i n t h e T F F U p h as e m a y i nitiat e ot h er st a n d ar d of c ar e CJ- 1 B t h er a p y at a n y tim e p er lo c a l tr e at m e nt 
g u id e lines. !f a s u bj e ct i nitiat es ot h er st a n d ar d of ca r e CJ- 1 B t h er a p y f or t h eir C H B , T F F U visi ts w ill c o nt in u e f or 2 m o re T F F U visi ts or u nt il t h e e n d of t h e T F F U p h as e 
(W e e k 9 6) , w h ic h e v er c o m es first. 
C O N FI D E N T IA L 
P a g e 5 9 
3 I O ct o b er 2 0 1 9 


G S -9 6 8 8 
G S -U S -3 8 9 -2 0 2 5 
St atisti c al A n al ysis P la n 
I 
I 
I 
I 
I 
I 
I 
I 
C O N FI D E N T IA L 
V ersi o n 1. 1 
P a g e 6 0 
3 I O ct o b er 2 0 1 9 


G S -9 6 8 8
G S -U S -3 8 9 -2 0 2 5
Statistical A nal ysis Pla n
Versi o n 1. 1
C CI
C O N FI D E N TI A L
Pa ge 6 1
3 1 Oct o ber 2 0 1 9