Clinical trial NCT03491553
Conditions: Chronic Hepatitis B
Sponsor: Gilead Sciences
Start date: 2018-04-06; Completion date: 2020-08-10
Enrollment: 48 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The primary objectives of this study are to evaluate the safety, tolerability and antiviral activity of selgantolimod (formerly GS-9688) in virally suppressed chronic hepatitis B (CHB) adults on oral antiviral (OAV) agents.

Detailed description:

Arms: arm 1: Participants with Hepatitis B e Antigen (HBeAg)-positive CHB will remain on their current OAV and receive selgantolimod 3 mg (2 x 1.5 mg tablet) orally on the same day once a week (every 7 days) for 24 doses. After the 24th dose, participants will continue their current OAV therapy 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-negative CHB will remain on their current OAV and receive selgantolimod 3 mg (2 x 1.5 mg tablet) orally on the same day once a week (every 7 days) for 24 doses. After the 24th dose, participants will continue their current OAV therapy 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 will remain on their current OAV and receive selgantolimod 1.5 mg (1 x 1.5 mg tablet) plus 1 tablet of placebo orally on the same day once a week (every 7 days) for 24 doses. After the 24th dose, participants will continue their current OAV therapy 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 4: Participants with HBeAg-negative CHB will remain on their current OAV and receive selgantolimod 1.5 mg (1 x 1.5 mg tablet) plus 1 tablet of placebo orally on the same day once a week (every 7 days) for 24 doses. After the 24th dose, participants will continue their current OAV therapy 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 5: Participants with HBeAg-positive CHB will remain on their current OAV and receive 2 tablets of placebo orally on the same day once a week (every 7 days) for 24 doses. After the 24th dose, participants will continue their current OAV therapy 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 6: Participants with HBeAg-negative CHB will remain on their current OAV and receive 2 tablets of placebo orally on the same day once a week (every 7 days) for 24 doses. After the 24th dose, participants will continue their current OAV therapy 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: Selgantolimod intervention 2: Placebo intervention 3: Hepatitis B virus (HBV) OAV Therapy
Intervention descriptions: intervention 1: Tablet(s) administered orally once weekly intervention 2: Placebo to match (PTM) selgantolimod tablet(s) administered orally once weekly intervention 3: Commercially available HBV OAV therapy could include one of the following:

Tenofovir disoproxil fumarate (TDF; Viread®) Entecavir (Baraclude®) Adefovir (Hepsera®) Lamivudine (Epivir® ) Telbivudine (Tyzeka®) Tenofovir alafenamide (TAF; Vemlidy®)

Protocol documents:
SAP_002.pdf: 
a
STATISTICAL ANALYSIS PLAN ADDENDUM FOR TFFU ANALYSIS
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 Virally-Suppressed Adult 
Subjects with Chronic Hepatitis B
Name of Test Drug:
Selgantolimod
Study Number:
GS-US-389-2024
Protocol Version (Date):
Original:
15 January 2018
Amendment 1:
13 March 2018
Amendment 2:
15 February 2019
Amendment 2.1:
27 August 2019
Analysis Type:
TFFU (Treatment-Free Follow-Up) Analysis
Analysis Plan Version:
1.0
Analysis Plan Date:
11 September 2020
Analysis Plan Author:
CONFIDENTIAL AND PROPRIETARY INFORMATION
PPD
(rJ GILEAU 


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TABLE OF CONTENTS
TABLE OF CONTENTS ..............................................................................................................................................2
1.
INTRODUCTION ................................................................................................................................................3
2.
TYPE OF PLANNED ANALYSIS ......................................................................................................................4
2.1.
TFFU Analysis.........................................................................................................................................4
3.
GENERAL CONSIDERATIONS FOR TFFU ANALYSES ...............................................................................5
3.1.
TFFU Analysis Set...................................................................................................................................5
4.
SUBJECT DISPOSITION ....................................................................................................................................6
4.1.
Subject Disposition ..................................................................................................................................6
5.
EFFICACY ANALYSES .....................................................................................................................................7
6.
SAFETY ANALYSES..........................................................................................................................................8
6.1.
Adverse Events and Deaths......................................................................................................................8
6.1.1.
Adverse Event Dictionary ......................................................................................................8
6.1.2.
Adverse Event Severity..........................................................................................................8
6.1.3.
Serious Adverse Events..........................................................................................................8
6.1.4.
Summaries of Adverse Events and Deaths.............................................................................8
6.2.
Laboratory Evaluations ............................................................................................................................9
6.2.1.
Laboratory Abnormalities during TFFU Period.....................................................................9
6.3.
Vital Signs................................................................................................................................................9
6.4.
Prior and Concomitant Medications.........................................................................................................9
6.4.1.
Prior Medications ...................................................................................................................9
6.4.2.
Concomitant Medications.......................................................................................................9
7.
SOFTWARE.......................................................................................................................................................10
8.
SAP REVISION..................................................................................................................................................11
9.
APPENDICES ....................................................................................................................................................12
Appendix 1.
Table of Contents for Statistical Tables, Figures, and Listings ..............................................13
Appendix 2.
Study Procedure Table (Treatment Free Follow-up)..............................................................15


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1.
INTRODUCTION
This statistical analysis plan (SAP) addendum provides the list of additional tables, figures, and 
listings (TFLs) to be used in final clinical study report (CSR) for Study GS-US-389-2024 during 
the treatment-free follow-up (TFFU) phase. The detailed statistical methods and data 
presentations for the Week 24 and Week 48 analysis were defined in the SAP for Study 
GS-US-384-2024, and the Week 24 and Week 48 analyses were previously completed and will 
not be repeated. This SAP addendum is based on the study protocol Amendment 2.1 dated 
27 August 2019. The SAP addendum will be finalized before data finalization. Any changes 
made after the finalization of the SAP addendum will be documented in the final CSR. 


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2.
TYPE OF PLANNED ANALYSIS
2.1.
TFFU Analysis 
The TFFU analysis will be conducted for subjects who entered the 48-week TFFU period. After 
all subjects have completed the study, outstanding data queries have been resolved or adjudicated 
as unresolvable, and the data have been cleaned and finalized, the TFFU analysis of the data will 
be performed.


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3.
GENERAL CONSIDERATIONS FOR TFFU ANALYSES
Subject disposition will be summarized in All Screened Subjects, adverse events (AE) and
laboratory abnormalities will be summarized using TFFU Analysis Set. By-subject listings will 
be presented for subjects in the TFFU Analysis Set and sorted by subject identification (ID) 
number, visit date, and time (if applicable). Data collected on log forms, such as adverse events 
(AEs), will be presented in chronological order for each subject. The treatment group to which 
subjects were randomized will be used in the listings. Age, sex at birth, race, and ethnicity will 
be included in the listings, if space permits.
Data will be listed according to the nominal visit as recorded in the database during TFFU 
period.
The list of TFLs for TFFU analysis is displayed in Appendix 1.
3.1.
TFFU Analysis Set
The TFFU Analysis Set includes all subjects who continued in the study following the 
discontinuation of oral antiviral (OAV) during the TFFU Phase.


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4.
SUBJECT DISPOSITION
4.1.
Subject Disposition
The key study date last subject last visit for the clinical study report will be provided. The last 
subject last visit for the clinical study report in this study is the last visit of the last subject who 
completed TFFU period.
A summary of subject disposition will be provided by HBeAg status (positive, negative) and 
overall for each treatment group and the study overall. This summary will present the number of 
subjects screened, the number of screen failure subjects who were not randomized, the number of 
subjects who met all eligibility criteria but were not randomized with reasons for subjects not 
randomized, the number of subjects randomized, and the number of subjects in each of the 
categories listed below:

Safety Analysis Set 

Full Analysis Set (FAS)

TFFU Analysis Set

Completed study drug

Did not complete study drug with reasons for premature discontinuation of study drug

Study completion status at Week 48
Completed Week 48
Prematurely discontinued before Week 48

Reason for premature discontinuation of Study at Week 48

TFFU completion status
Completed TFFU
Prematurely discontinued from TFFU

Reason for premature discontinuation of TFFU

Completed study

Did not complete the study with reasons for premature discontinuation of study
For the status of study drug and study completion and the reasons for premature discontinuation, 
the number and percentage of subjects in each category will be provided. The denominator for 
the percentage calculation will be the total number of subjects in the Safety Analysis Set 
corresponding to that column.


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5.
EFFICACY ANALYSES
Plots of the mean (standard deviation,SD) of absolute values and changes from baseline in 
qHBsAg (log10 IU/mL) and HBV DNA (log10 IU/mL) till the end of study will be presented.
Qualitative HBsAg, HBsAb, HBeAg and HBeAb; quantitative HBV Viral Parameters (HBV 
DNA, HBV RNA, HBcrAg, HBeAg and HBsAg, log10 Scale) will be listed using TFFU 
Analysis Set.
Health-related quality of life (HRQoL) surveys will be listed using TFFU Analysis Set. A 
by-subject listing for SF-36 scores, Chronic Liver Disease Questionnaire (CLDQ , overall score) 
and Work Productivity and Activity Impairment Questionnaire: Hepatitis B (WPAI: Hep B; 
including percent overall work impairment, percent activity impairment) after obtaining properly 
transformed scores will be provided by subject ID number and visit in chronological order.


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6.
SAFETY ANALYSES
6.1.
Adverse Events and Deaths
6.1.1.
Adverse Event Dictionary
Clinical and laboratory adverse events (AEs) will be coded using the current version of
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 provided in the AE dataset.
6.1.2.
Adverse Event Severity
Adverse events are graded by the investigator as Grade 1, 2, 3, or 4 according to the toxicity 
criteria specified in the protocol. The severity grade of events for which the investigator did not 
record severity will be categorized as “missing” for tabular summaries and data listings. The 
missing category will be listed last in the summary presentation.
The severity of adverse events will be determined by the investigator as mild, moderate, or 
severe. 
6.1.3.
Serious Adverse Events
Serious adverse events (SAEs) will be identified and captured as SAEs if AEs met the definitions 
of SAEs that were specified in the study protocol. SAEs captured and stored in the clinical 
database will be reconciled with the Gilead Global Product Safety (GLPS) SAE database before 
database finalization.
6.1.4.
Summaries of Adverse Events and Deaths
AEs will be summarized based on the TFFU Analysis Set.
A brief high-level summary of AEs will be for the number and percentage of subjects who
experienced the following: any AE, any AE of Grade 3 or above, any AE of Grade 2 or above, 
any SAE. All deaths observed in the study will also be included in this summary. 
The following data listings will be provided for the subjects in the TFFU Analysis Set:

All AEs

SAEs

Deaths
The listings will indicate whether an event is treatment-emergent, and whether the event
occurred during TFFU.


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6.2.
Laboratory Evaluations
A by-subject listing for laboratory test results will be provided by subject ID number and visit in 
chronological order for hematology, serum chemistry, and urinalysis separately. Values falling 
outside of the relevant reference range and/or having a severity grade of 1 or higher on the 
Gilead Grading Scale for Severity of Adverse Events and Laboratory Abnormalities will be 
flagged in the data listings, as appropriate.
The observed values for ALT will be plotted using a line plot by visit till the end of the study 
using TFFU Analysis Set. 
6.2.1.
Laboratory Abnormalities during TFFU Period
Laboratory abnormalities during TFFU Period are defined as values that increase at least 
1 toxicity grade from last on-treatment visit at any time point during TFFU period, up to the end 
of the study.
6.3.
Vital Signs
A by-subject listing of vital signs will be provided by subject ID number and time point in 
chronological order.
6.4.
Prior and Concomitant Medications
Medications collected at screening and during the study will be coded using the current version 
of the World Health Organization (WHO) Drug Dictionary. 
6.4.1.
Prior Medications
Prior medications are defined as any medications taken before a subject took the first dose of 
study drug.
6.4.2.
Concomitant Medications
Concomitant medications are defined as medications taken while a subject took study drug.
All prior and concomitant medications (other than per-protocol study drugs) will be provided in a 
by-subject listing sorted by subject ID number and administration date in chronological order.


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7.
SOFTWARE
SAS® Software Version 9.4. SAS Institute Inc., Cary, NC, USA.


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8.
SAP REVISION
Revision Date
(DD MMM YYYY)
Section
Summary of Revision
Reason for Revision


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9.
APPENDICES
Appendix 1.
Table of Contents for Statistical Tables, Figures, and Listings
Appendix 2.
Study Procedure Table (Treatment Free Follow-up)


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Appendix 1.
Table of Contents for Statistical Tables, Figures, and Listings
Table 
Number
Title
Analysis Set
15.8.1.1
Key Study Dates
All Screened Subjects
15.8.1.3
Subject Disposition
All Screened Subjects
15.11.2.1.1.3
Adverse Events: Overall Summary During TFFU Period
TFFU Analysis Set
15.11.6.4.6
Laboratory Abnormalities During TFFU Period
TFFU Analysis Set
Figure Number
Title
Analysis Set
15.9.2.5.1
HBsAg (log10 IU/mL) by Visit
TFFU Analysis Set
15.9.2.5.3.2
Change from Baseline in HBsAg (log10 IU/mL) by Visit 
TFFU Analysis Set
15.9.2.5.4
HBV DNA (log10IU/mL) by Visit 
TFFU Analysis Set
15.9.2.5.5
Change from Baseline in HBV DNA (log10IU/mL) by Visit 
TFFU Analysis Set
15.11.1
ALT (U/L) by Visit
TFFU Analysis Set


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Listing Number
Title
Analysis Set
16.2.1.3
Subject Disposition
TFFU Analysis Set
16.2.4.4.1
Prior and Concomitant Medications
TFFU Analysis Set
16.2.6.3
HBV Serology: HBsAg and HBsAb 
TFFU Analysis Set
16.2.6.4
HBV Serology: HBeAg and HBeAb 
TFFU Analysis Set
16.2.6.7
Quantitative HBV Viral Parameters (HBV DNA, HBV RNA, 
HBcrAg, HBeAg and HBsAg, log10 Scale)
TFFU Analysis Set
16.2.7.1.2
All Adverse Events
TFFU Analysis Set
16.2.7.3
Deaths
TFFU Analysis Set
16.2.7.4.2
Serious Adverse Events
TFFU Analysis Set
16.2.8.1.1.1
Hematology Results (Part I): Hematocrit, Hemoglobin, and Platelets
TFFU Analysis Set
16.2.8.1.1.2
Hematology Results (Part II): WBC, Neutrophils, and Lymphocytes
TFFU Analysis Set
16.2.8.1.2.1
Chemistry Results (Part I): ALT, AST, Direct Bilirubin, Indirect 
Bilirubin and Total Bilirubin
TFFU Analysis Set
16.2.8.1.2.2
Chemistry (Part II): Albumin, Calcium, Creatine Kinase, Creatinine, 
and Cockcroft-Gault Creatinine Clearance
TFFU Analysis Set
16.2.8.1.2.3
Chemistry (Part III): Alkaline Phosphatase, LDH, Glucose , Total 
Protein, and Uric Acid
TFFU Analysis Set
16.2.8.1.3.1
Coagulation: International Normalized Ratio (INR) and APTT
TFFU Analysis Set
16.2.8.1.3.2
Urinalysis (Part I): Urine Blood, Bilirubin,, Glucose, Ketones, and 
Leukocyte Esterase
TFFU Analysis Set
16.2.8.1.3.3
Urinalysis (Part II): Nitrite, pH, Protein, Urobilinogen, and Specific 
Gravity
TFFU Analysis Set
16.2.8.1.4
Graded Laboratory Abnormalities
TFFU Analysis Set
16.2.8.1.5
Grade 3 or 4 Laboratory Abnormalities
TFFU Analysis Set
16.2.8.2.1
Vital Signs
TFFU Analysis Set
16.2.8.4
Pregnancy Report
TFFU Analysis Set
16.2.8.5
Comments
TFFU Analysis Set
16.2.9.1
SF-36 Quality of Life Questionnaire
TFFU Analysis Set
16.2.9.2
CLDQ Quality of Life Questionnaire
TFFU Analysis Set
16.2.9.3
WPAI: Hep B Quality of Life Questionnaire
TFFU Analysis Set


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Appendix 2.
Study Procedure Table (Treatment Free Follow-up)
Windows
TFFU Week
(Study Week)
(±7 Days)
Study Procedures
4
(52)
8
(56)
12
(60)
16
(64)
20
(68)
24
(72)
36
(84)
48
(96)
Health Related Quality of Life Surveys
X
X
X
Symptom Directed Physical Exam
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
Safety Labs (Hematology, Serum Chemistry, and
Coagulation)
X
X
X
X
X
X
X
X
Urinalysis
X
X
X
X
X
X
X
X
Serum Pregnancy Test
X
X
X
X
X
X
X
X
Qualitative HBV Serologyc
X
X
X
X
X
X
X
X
HBV DNA levels, HBV Resistance
Surveillance, Quantitative HBsAg
X
X
X
X
X
X
X
X
Quantitative HBCrAg, Quantitative HBeAg, HBV
RNA
X
X
X
X
X
X
X
X
PBMC Collectionl
X
X
X
X
X
X
X
X
Whole Blood gene expression biomarkersm
X
X
X
X
X
X
X
X
Review AEs & Concomitant Medications
X
X
X
X
X
X
X
X
a 
Ophthalmologic Exam window at Screening will be (Days 10 to 1) ,Weeks 12 and 24 (Days 4 to +10)
b 
In the event of a positive result and/or antigen testing for HIV, HDV, or HCV serology, reflex tests will automatically be performed
CCI
CCI
CCI


Selgantol imod 
GS-US-389-2024 Statistical Analysis Plan Addendum 
Final 
C r 
consists of 1-lBeAg and 1-lBsA and reflex 1-lBeAb and reflex 1-lBsAb 
I 
f 
Holter 
omtonng to e co ecte pnor to 
oo co ectton on 
ay an 
_ 
ose) through 4 hours, and 24 hours; Week 11 at pre dose (::S 5 min 
of dose) through 4 hours 
g 
In addition to the clinic GS 9688 study dmg dosing, self/home GS 9688 study dmg dosing will be on Weeks I, 3, 5, 6, 7, 9, I 0, 13, 14, 15, 17, 18, 19, 2 1, and 22 
h 
Sparse (pre identified) PK plasma sampling will occur on Day I and Week 23 at pre dose, I, 4, and 24 hours post dose and at Week 11 at pre dose, I, 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 ost dose. 
r 
k 
Semn plasma PD b1omarkers will be collected on Day I and Week 23 at pre dose, 4 and 24 hours post dose; Weeks 2, 8, 12, 16, 20, 24 and 28 pre dose; and Week 11 pre 
dose and 4 hours pose dose. 
PBMC samples collected on Days I and I +4 hours, I + 24 hours, and on Weeks 11, 11 +4 hours, 12, 23, 23 + 4 hours, 23 + 24 hours, 24, 48/ED, and during TFFU. See also 
footnoted for collection of Leukapheresis samples in lieu of PBMC samples 
m 
Whole blood gene expression (Paxgene RNA) samples collected on Days I and I +4 hours, I + 24 hours, and on Weeks 11, 11 +4 hours, 12, 23, 23 + 24 hours, 24, 48/ED, and 
during TFFU 
n 
The ED visit should be perfom1ed within I week if ED occurs before Week 24; after week 24 ED should be perfom1ed within 2 weeks from notification of study 
discontinuation 
o 
At Week 48, at PI discretion, if a subject discontinues OA V treatment, the subject will be followed every 4 weeks for the first 24 weeks and thereafter at Week 36 and 
Week 48 (TFFU phase). At the PJ's discretion, subject(s) in the TFFU phase may restart commercially available CHB OA V treatment at any time per local treatment 
guidelines. If a subject restarts OA V 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 
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GS-US-389-2024 SAP Addendum for TFFU Analysis v 1.0
ELECTRONIC SIGNATURES
Signed by
Meaning of Signature
Server Date
(dd-MMM-
yyyy hh:mm:ss)
Biostatistics eSigned
09-Sep-2020
15:59:40
Project Team
Leader eSigned
12-Sep-2020
02:35:47
PPD
PPD-

Prot_000.pdf: 
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 Virally-Suppressed Adult Subjects with 
Chronic Hepatitis B
Sponsor:
Gilead Sciences, Inc.
333 Lakeside Drive
Foster City, CA 94404
IND Number:
ClinicalTrials.gov 
Identifier:
129387
NCT03491553
Indication:
Chronic Hepatitis B 
Protocol ID:
GS-US-389-2024
Gilead Medical 
Monitor:
Name:
Telephone:
Mobile:
Fax:
Protocol Version/Date:
Original:
15 January 2018
Amendment 1
13 March 2018
Amendment 2
15 February 2019
Amendment 2.1
27 August 2019
CONFIDENTIALITY STATEMENT
The information contained in this document, particularly unpublished data, is the property or 
under control of Gilead Sciences, Inc., and is provided to you in confidence as an investigator, 
potential investigator, or consultant, for review by you, your staff, and an applicable Institutional 
Review Board or Independent Ethics Committee. The information is only to be used by you in 
connection with authorized clinical studies of the investigational drug described in the protocol. 
You will not disclose any of the information to others without written authorization from 
Gilead Sciences, Inc., except to the extent necessary to obtain informed consent from those 
persons to whom the drug may be administered.
PPD
PPD
PPD
PPD
(rJ GILEAiJ 


GS-9688
Protocol GS-US-389-2024
Final
Gilead Sciences, Inc. 
Amendment 2.1
CONFIDENTIAL
Page 2
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TABLE OF CONTENTS
TABLE OF CONTENTS ..............................................................................................................................................2
LIST OF IN-TEXT TABLES........................................................................................................................................5
LIST OF IN-TEXT FIGURES ......................................................................................................................................5
PROTOCOL SYNOPSIS ..............................................................................................................................................6
GLOSSARY OF ABBREVIATIONS AND DEFINITION OF TERMS....................................................................23
1.
INTRODUCTION ..............................................................................................................................................27
1.1.
Background ............................................................................................................................................27
1.2.
GS-9688 .................................................................................................................................................28
1.2.1.
General Information .............................................................................................................28
1.2.2.
Preclinical Pharmacology and Toxicology...........................................................................28
1.2.3.
Genotoxicity.........................................................................................................................30
1.2.4.
Safety Pharmacology............................................................................................................30
1.2.5.
Nonclinical Pharmacology ...................................................................................................31
1.2.6.
Clinical Trials of GS-9688 ...................................................................................................32
1.3.
Rationale for This Study ........................................................................................................................40
1.3.1.
GS-9688 for Treatment of Virally-Suppressed Subjects with Chronic 
Hepatitis B............................................................................................................................40
1.3.2.
Rationale for the Dose Selection..........................................................................................40
1.3.3.
Rationale for Treatment Duration ........................................................................................41
1.4.
Risk/Benefit Assessment for the Study..................................................................................................42
1.4.1.
..............................................43
1.5.
Compliance ............................................................................................................................................43
2.
OBJECTIVES.....................................................................................................................................................44
3.
STUDY DESIGN................................................................................................................................................46
3.1.
Study Design..........................................................................................................................................46
3.2.
Study Treatments ...................................................................................................................................46
3.3.
Duration of Treatment............................................................................................................................48
3.4.
Pharmacokinetic Assessment .................................................................................................................48
3.5.
Pharmacodynamic Assessments.............................................................................................................48
3.6.
Biomarker Testing..................................................................................................................................48
3.6.1.
Biomarker Samples to Address the Study Objectives:.........................................................48
3.6.2.
Samples for Optional Future Research.................................................................................49
3.6.3.
Sample for Optional Genomic Research ..............................................................................49
3.7.
End of Study...........................................................................................................................................49
4.
SUBJECT POPULATION..................................................................................................................................50
4.1.
Number of Subjects and Subject Selection ............................................................................................50
4.2.
Inclusion Criteria....................................................................................................................................50
4.3.
Exclusion Criteria...................................................................................................................................51
5.
INVESTIGATIONAL MEDICINAL PRODUCTS ...........................................................................................53
5.1.
Randomization, Blinding and Treatment Codes ....................................................................................53
5.1.1.
Procedures for Breaking Treatment Codes...........................................................................53
5.2.
Description and Handling of GS-9688 and Placebo to Match ...............................................................54
5.2.1.
Formulation..........................................................................................................................54
5.2.2.
Packaging and Labeling .......................................................................................................54
5.2.3.
Storage and Handling...........................................................................................................54
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5.3.
Dosage and Administration of GS-9688 ................................................................................................55
5.4.
Fasting State Dosing ..............................................................................................................................55
5.5.
Concomitant Medications ......................................................................................................................55
5.6.
Accountability for GS-9688...................................................................................................................57
5.7.
Investigation Medicinal Product Return or Disposal .............................................................................58
6.
STUDY PROCEDURES ....................................................................................................................................59
6.1.
Subject Enrollment and Treatment Assignment.....................................................................................59
6.2.
Pretreatment Assessments......................................................................................................................59
6.2.1.
Screening Visit (Window of -30 Days)................................................................................59
6.3.
On-Treatment Assessments (All Visits Have Window of ± 1 Days) .....................................................60
6.3.1.
..............................................62
6.4.
Post-Treatment Assessments (All Visits Have Window of ± 3 Days except Week 24 ± 1 Day)...........63
6.5.
Treatment Free Follow-up (TFFU) Visit Assessments (± 7 Days) ........................................................64
6.5.1.
............................................65
6.6.
Unscheduled Visits.................................................................................................................................65
6.7.
Pharmacokinetic Assessments................................................................................................................65
6.7.1.
...............................................65
6.8.
Pharmacodynamic Assessments.............................................................................................................66
6.8.1.
............................................67
6.8.2.
TruCulture Samples..............................................................................................................68
6.9.
Safety Assessments ................................................................................................................................69
6.9.1.
Electrocardiogram Assessment ............................................................................................69
6.9.2.
Holter Monitoring ................................................................................................................69
6.9.3.
Physical Examination...........................................................................................................70
6.9.4.
Vital Signs............................................................................................................................70
6.9.5.
Clinical Laboratory Tests/Assessments for Safety Evaluations ...........................................70
6.9.6.
Creatinine Clearance ............................................................................................................71
6.9.7.
Ophthalmic Examination......................................................................................................71
6.9.8.
Adverse Events/Concomitant Medications/Protocol Restrictions........................................72
6.10.
Sample Storage.......................................................................................................................................72
6.11.
Assessments for Premature Discontinuation from Study.......................................................................72
6.12.
Criteria for Discontinuation of Study Treatment....................................................................................72
6.13.
Resistance Surveillance..........................................................................................................................73
6.14.
End of Study...........................................................................................................................................73
6.15.
Post Study Care......................................................................................................................................73
7.
ADVERSE EVENTS AND TOXICITY MANAGEMENT...............................................................................74
7.1.
Definitions of Adverse Events, Adverse Reactions, and Serious Adverse Events.................................74
7.1.1.
Adverse Events.....................................................................................................................74
7.1.2.
Serious Adverse Events........................................................................................................74
7.2.
Assessment of Adverse Events and Serious Adverse Events.................................................................75
7.2.1.
Assessment of Causality for Study Drugs and Procedures...................................................75
7.2.2.
Assessment of Severity ........................................................................................................76
7.3.
Investigator Requirements and Instructions for Reporting Adverse Events and Serious 
Adverse Events to Gilead.......................................................................................................................76
7.3.1.
Adverse Events.....................................................................................................................76
7.3.2.
Serious Adverse Events........................................................................................................76
7.4.
Gilead Reporting Requirements.............................................................................................................78
7.5.
Clinical Laboratory Abnormalities and Other Abnormal Assessments as Adverse Events or 
Serious Adverse Events..........................................................................................................................78
7.6.
Toxicity Management ............................................................................................................................79
7.6.1.
ALT Elevation or Flare Management...................................................................................79
7.6.2.
Management of Dose Limiting Toxicities............................................................................80
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7.6.3.
Management of Neutropenia................................................................................................80
7.6.4.
Grades 1 and 2 Laboratory Abnormality or Clinical Event..................................................81
7.6.5.
Grades 3 and 4 Laboratory Abnormality or Clinical Event..................................................81
7.7.
Other Criteria for Discontinuation of Study Drug..................................................................................81
7.8.
Subject Withdrawal Criteria...................................................................................................................82
7.9.
Study Specific Stopping Criteria............................................................................................................82
7.9.1.
Laboratory Abnormalities and Treatment-Emergent Adverse Events..................................82
7.9.2.
Virologic Criteria .................................................................................................................83
7.10.
Special Situations Reports......................................................................................................................83
7.10.1.
Definitions of Special Situations..........................................................................................83
7.10.2.
Instructions for Reporting Special Situations.......................................................................84
8.
STATISTICAL CONSIDERATIONS................................................................................................................86
8.1.
Analysis Objectives and Endpoints........................................................................................................86
8.1.1.
Analysis Objectives..............................................................................................................86
8.1.2.
Primary Efficacy Endpoint...................................................................................................87
8.1.3.
Secondary Efficacy Endpoints .............................................................................................87
8.2.
Analysis Conventions.............................................................................................................................87
8.2.1.
Analysis Sets ........................................................................................................................87
8.3.
Data Handling Conventions ...................................................................................................................88
8.4.
Demographic Data and Baseline Characteristics ...................................................................................88
8.5.
Efficacy Analysis ...................................................................................................................................88
8.5.1.
Primary Analysis..................................................................................................................88
8.5.2.
Secondary Analyses .............................................................................................................89
8.5.3.
Analysis of Other Endpoints of Interest ...............................................................................89
8.6.
Safety Analysis.......................................................................................................................................89
8.6.1.
Extent of Exposure...............................................................................................................89
8.6.2.
Adverse Events.....................................................................................................................89
8.6.3.
Laboratory Evaluations ........................................................................................................90
8.6.4.
Other Safety Evaluations......................................................................................................91
8.7.
Pharmacokinetic Analysis......................................................................................................................91
8.8.
Exploratory Analysis..............................................................................................................................91
8.9.
Sample Size............................................................................................................................................92
8.10.
Data Monitoring Committee ..................................................................................................................92
8.11.
Internal Data Review Team....................................................................................................................92
9.
RESPONSIBILITES...........................................................................................................................................93
9.1.
Investigator Responsibilities ..................................................................................................................93
9.1.1.
Good Clinical Practice..........................................................................................................93
9.1.2.
Institutional Review Board (IRB)/Independent Ethics Committee (IEC) 
Review and Approval...........................................................................................................93
9.1.3.
Informed Consent.................................................................................................................93
9.1.4.
Confidentiality......................................................................................................................94
9.1.5.
Study Files and Retention of Records ..................................................................................94
9.1.6.
Case Report Forms...............................................................................................................95
9.1.7.
Study Drug Accountability and Return ................................................................................96
9.1.8.
Inspections............................................................................................................................96
9.1.9.
Protocol Compliance............................................................................................................96
9.2.
Sponsor Responsibilities ........................................................................................................................96
9.2.1.
Protocol Modifications.........................................................................................................96
9.2.2.
Study Report and Publications .............................................................................................97
9.3.
Joint Investigator/Sponsor Responsibilities ...........................................................................................97
9.3.1.
Payment Reporting...............................................................................................................97
9.3.2.
Access to Information for Monitoring..................................................................................97


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9.3.3.
Access to Information for Auditing or Inspections ..............................................................97
9.3.4.
Study Discontinuation..........................................................................................................97
10.
REFERENCES ...................................................................................................................................................98
11.
APPENDICES ..................................................................................................................................................102
Appendix 1.
Investigator Signature Page..................................................................................................103
Appendix 2.
Study Procedure Table(s) .....................................................................................................104
Appendix 3.
Pregnancy Precautions, Definition for Female of Childbearing Potential, and 
Contraceptive Requirements.................................................................................................110
Appendix 4.
GSI Grading Scale for Severity of Adverse Events and Laboratory Abnormalities.............112
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)................................................................................................33
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) ..................................................................................34
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 WereVirally Suppressed or Viremic 
(PK Analysis Set). ..................................................................................................................36
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)................................................................................................39
Table 5-1.
List of Agents Disallowed......................................................................................................56
LIST OF IN-TEXT FIGURES
Figure 3-1.
Study Schema.........................................................................................................................46


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Gilead Sciences, Inc. 
Amendment 2.1
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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 Virally-Suppressed Adult Subjects with 
Chronic Hepatitis B
IND Number:
ClinicalTrials.gov 
Identifier:
129387
NCT03491553
Study Centers 
Planned:
Approximately 6 centers in New Zealand and the United States
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 virally suppressed chronic hepatitis B 
(CHB) adult subjects on oral antivirals (OAV)

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 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 pharmacokinetics (PK) of GS-9688 

To evaluate the proportion of subjects experiencing Hepatitis B 
virus (HBV) virologic breakthrough (2 consecutive visits of HBV 
DNA ≥69 IU/mL)

To evaluate the incidence of drug resistance mutations


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The exploratory objectives of this study are as follows: 
Study Design:
This is a multicenter, randomized, double-blind, placebo-controlled 
Phase 2 study of GS-9688 in virally suppressed CHB subjects on 
OAV.
Approximately 50 virally suppressed subjects currently being treated 
with a commercially available OAV for CHB will be enrolled into 
two cohorts within this study (1:1) that will run in parallel. 

Cohort 1: HBeAg-positive CHB subjects

Cohort 2: HBeAg-negative CHB subjects
Within each cohort, approximately 25 subjects will be randomized in 
a 1:2:2 in ratio to one of the three treatment arms (A: B: C). All 
subjects will remain on their current commercially available OAV 
therapy for 48 weeks, in addition to the following treatments:
Treatment Arm A: Approximately 5 subjects 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 10 subjects will be administered 
GS-9688 1.5 mg orally on the same day once a week (every 7 days) 
for 24 doses
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Gilead Sciences, Inc. 
Amendment 2.1
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Treatment Arm C: Approximately 10 subjects 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.
Subjects should take their OAV treatment 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. 
After the 24th dose (Week 23 visit), GS-9688/PTM will be 
discontinued. Subjects will continue being treated with their original 
commercially available OAV 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.
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 OAV (ie, TFFU phase) 
2) Continue current standard of care CHB therapy with Week 48 
representing the last study visit. 
At the PI’s discretion, subject(s) in the TFFU phase may restart 
commercially available CHB OAV treatment at any time per local 
treatment guidelines. If a subject restarts OAV therapy for their CHB, 
TFFU visits will continue for 2 more TFFU visits or until the end of 
the TFFU phase (Study 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.
The study will be unblinded to appropriate Gilead Sciences Inc. (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. 


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Gilead Sciences, Inc. 
Amendment 2.1
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Sample for Optional Genomic Research
 
 
Samples for Optional Future Research
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
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Gilead Sciences, Inc. 
Amendment 2.1
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Pharmacokinetic (PK) Assessments
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.
 
 
 
All available PK data may be used for population PK.
Number of Subjects 
Planned:
Approximately 50 subjects
Each Cohort will enroll approximately 25 subjects (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 virally suppressed on treatment 
with a commercially available nucleos(t)ide HBV polymerase 
inhibitor (tenofovir alafenamide, tenofovir disoproxil fumurate, 
entecavir, adefovir, lamivudine, telbivudine, either as single agents or 
in combination) for at least 6 months.
Duration of 
Treatment:
GS-9688 or PTM will be administered once a week (every 7 days) for 
24 treatment doses. Subjects will remain on their current 
commercially available HBV OAV for the entire 48 week duration of 
study.
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
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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) Have been on commercially available HBV OAV treatment(s) 
(tenofovir alafenamide, tenofovir disoproxil fumurate, entecavir, 
adefovir, lamivudine, telbivudine, either as single agents or in 
combination) for at least 6 months with no change in regimen for 
3 months prior to screening.
7) HBV Deoxyribonucleic acid (DNA) ≤ 20 IU/mL (lower limit of 
quantitation [LLOQ];  measured at least once by local laboratory 
assessment) for 6 or more months prior to Screening
8) HBV DNA < 20 IU/mL at Screening
9) 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.
10) Must be willing and able to comply with all study requirements
Exclusion Criteria
Subjects who meet any of the following exclusion criteria are not to 
be enrolled in this study:
1) 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


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2) 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) >3x Upper Limit of Normal 
(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])
3) 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
4) 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
5) 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
6) Significant cardiovascular, pulmonary, or neurological disease in 
the opinion of the investigator


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7) 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
8) 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
9) Received solid organ or bone marrow transplant 
10) Received prolonged systemic therapy with immunomodulators 
(e.g. corticosteroids) or biologics (e.g. monoclonal antibody, 
interferon) within 3 months of screening
11) Use of another investigational agent within 90 days of screening, 
unless allowed by the Sponsor
12) Current alcohol or substance abuse judged by the investigator to 
potentially interfere with subject compliance
13) Known hypersensitivity to study drug or formulation excipients
14) Women who are breastfeeding, pregnant or who wish to become 
pregnant during the course of the study
15) 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
16) Male subjects unwilling to refrain from sperm donation during 
and until at least 90 days after the last study drug dose
17) Use of any prohibited concomitant medications as described in 
Section 5.5 and Table 5-1
18) Believed by the Study Investigator to be inappropriate for study 
participation for any reason not otherwise listed
Study Procedures/
Frequency:
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 hour assessments), Day 1 + 24 hours (Day 2), Weeks 2, 4, 8, 
11 (includes post-dose 1 and 4 hour assessments), 12, 16, 20, 
23 (includes post-dose 1 and 4 hour assessments), and 
23 + 24 hours

Post-Study Treatment Period: Weeks 24, 28, 36, and 48


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Gilead Sciences, Inc. 
Amendment 2.1
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Screening assessments include:

Review of inclusion/exclusion criteria

Obtain medical history (including HBV disease and treatment 
history) 

Obtain Informed Consent, 
 
 

Review concomitant medications 

Complete Physical examination (including weight, height, BMI, 
vital signs)

Safety laboratory tests (serum chemistry, hematology, and 
coagulation)

12-lead ECG

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)

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)
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Amendment 2.1
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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 Treatment Phase 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. 

Ophthalmologic exam on Week 12  (Days -4 to +10)

In clinic GS-9688 study drug dosing on Day 1 and 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.

Safety laboratory tests (serum chemistry, 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

Serum β-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, and 23

Qualitative HBV serology (HBeAg [reflex HBeAb if HBeAg is 
negative] and HBsAg [reflex HBsAb if HBsAg is negative]) on 
Day 1 and Week 12

Quantitative HBsAg on Day 1 and Weeks 2, 4, 8, 11, 12, 16, 20, 
and 23

Quantitative HBeAg, HBV RNA and HBV core-related antigen 
(HBcrAg) on Day 1 and Weeks 4, 8, 12, 16, and 20


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
 

Serum and plasma PD biomarkers on Days 1 Pre-dose, 
1 + 4 hours, 1 + 24 hours and Weeks 2, 8, 11, 11 + 4 hours, 12, 
16, 20, 23, 23 + 4 hours and 23 + 24 hours

TruCulture sample on Day 1 pre-dose

Whole blood gene expression (Paxgene RNA) samples on Days 1
Pre-dose, 1+4 hour, 1 + 24 hours 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, 
1 + 24 hours and Weeks 11, 11 + 4 hours, 12, 23, 23 + 4 hours, 
and 23 + 24 hours

Toll-like receptor (TLR8) SNP genotyping on Day 1 but may be 
collected at any time during the study or at any unscheduled visit

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: 
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 

 

HRQoL Surveys (SF-36, CLDQ, and WPAI) on Day 1 and 
Week 12

Randomization on Day 1
If a subject chooses to terminate 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.
CCI
CCI


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Final
Gilead Sciences, Inc. 
Amendment 2.1
CONFIDENTIAL
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Post-study treatment assessments include the following, performed 
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 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

Quantitative HBeAg, HBV RNA and HBcrAg 

 

Serum and plasma PD biomarkers on Weeks 24 and 28

Whole blood gene expression (PAXgene RNA) samples on 
Weeks 24 and 48/ED

PBMC samples will be collected on Weeks 24 and 48/ED

HRQoL Surveys (SF-36, CLDQ, and WPAI) on Weeks 24 
and 48/ED
If a subject chooses to terminate the study anytime during the 
post -treatment period, all subjects should complete all of the above 
assessments at the ED visit.
CCI
CCI


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Protocol GS-US-389-2024
Final
Gilead Sciences, Inc. 
Amendment 2.1
CONFIDENTIAL
Page 18
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 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.
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 
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. 


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Final
Gilead Sciences, Inc. 
Amendment 2.1
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Grade 3 and 4 clinically significant laboratory abnormalities, ALT 
elevations meeting definition of ALT flare or dose-limiting flare, and 
Grade 2 neutropenia should be confirmed by repeat testing within 
7 calendar days of receipt of results. 
ALT Elevation or Flare Management
Subjects with on-treatment ALT flare defined as serum ALT 
> 2 BL and ≥5 ULN (with or without associated symptoms) 
should be managed according to the guidance below. 
All on-treatment ALT flares should be confirmed within 3 days of
receipt of results. During the visit, a clinical assessment of the subject 
should be performed. The assessment should include a complete 
physical examination, evaluation of the subject’s mental status and 
the following laboratory tests: 

Laboratory parameters: serum ALT and aspartate 
aminotransferase (AST), alkaline phosphatase, total and 
fractionated bilirubin, gamma-glutamyl transferase (GGT), INR 
and serum albumin

If the ALT elevation/flare is confirmed, the central clinical 
laboratory will conduct reflex testing for HBV DNA, qualitative 
HBV serology (HBeAg [reflex HBeAb if HBeAg is negative] and 
HBsAg [reflex HBsAb if HBsAg is negative]), Hepatitis A Virus 
(HAV) immunoglobulin M (IgM), HCV RNA, HDV RNA, and 
Hepatitis E Virus (HEV) IgM
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 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
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.


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Gilead Sciences, Inc. 
Amendment 2.1
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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.
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 or toxicity that, in the judgment of the 
investigator, compromises the ability to continue study-specific 
procedures or is considered to not be in the subject’s best interest 

Subject requests to discontinue for any reason

Subject noncompliance

Pregnancy during the study 

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 4treatment-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.


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Final
Gilead Sciences, Inc. 
Amendment 2.1
CONFIDENTIAL
Page 21
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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

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:
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 
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 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.


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Gilead Sciences, Inc. 
Amendment 2.1
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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.
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 the archival of essential documents.


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Final
Gilead Sciences, Inc. 
Amendment 2.1
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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
AE
adverse event
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
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
CPN
chronic progressive nephropathy
CRF
case report form
CRO
clinical research organization
CSR
clinical study report
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


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Amendment 2.1
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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
HCC
hepatocellular carcinoma
HCV
hepatitis C virus
HDV
hepatitis D virus
HED
human equivalent doses
HEV
hepatitis E virus
HDL
high-density lipoprotein
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


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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
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
PEG
pegylated interferon-α
PG
Pharmacogenomics
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


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Amendment 2.1
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PTM
placebo-to-match
PTT
partial thromboplastin time
PVC
Polyvinyl chloride
PVE
Pharmacovigilance and Epidemiology
QD
One a day
QRS
electrocardiographic deflection between the beginning of the Q wave and termination of the 
S wave, representing time for ventricular depolarization
QT
electrocardiographic interval between the beginning of the Q wave and termination of the 
T wave, representing the time for both ventricular depolarization and repolarization to occur
QTcF
QT interval corrected for heart rate using the Fridericia formulation
RBC
red blood cell
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
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 
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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Amendment 2.1
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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 (ie, 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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Amendment 2.1
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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.


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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.
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.


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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 
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.


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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. 
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 WereVirally 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 


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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. 
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. 
 
 
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 
CCI
-


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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 doe 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.
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.  


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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).
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 


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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.
1.3.
Rationale for This Study
1.3.1.
GS-9688 for Treatment of Virally-Suppressed Subjects with Chronic 
Hepatitis B 
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 a finite 
treatment duration.  The primary objective is to evaluate the safety, tolerability and efficacy of 
GS-9688 in addition to oral nucleos(t)ide HBV polymerase inhibitors 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 virally-suppressed CHB subjects to minimize safety 
risks and maximize efficacy benefits associated with GS-9688. Because they have stable viral 
suppression on treatment with an oral antiviral medication, these subjects have lower levels of 
HBV virions and proteins, including HBsAg, within the serum as well as lower expression of 
HBV antigens within infected hepatocytes. This lower antigen burden enhances the safety profile 
of immune stimulating approaches to CHB treatment, including GS-9688. In addition, a virally 
suppressed population may have a higher chance of response to GS-9688, as suggested by the 
observation that  immune responsiveness of chronic HBV patients is improved in patients who 
are on chronic suppressive antiviral therapy. 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.


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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 data from this study 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 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 virally suppressed (currently on OAV) 
CHB patients.
1.3.3.
Rationale for Treatment Duration
As no reductions in HBsAg levels were anticipated or observed with 2 once-weekly doses, a
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 
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1.4.
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. 
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
Sections 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-389-2024 will
investigate the efficacy of 24 doses of GS-9688 at two dose levels (1.5 and 3 mg) administered 
weekly to virally suppressed CHB patients currently being treated with an OAV. 


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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-gp/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.
1.4.1.
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
1.5.
Compliance
This study will be conducted in compliance with this protocol, 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 
virally suppressed CHB adult subjects on OAV

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 HBsAg loss at Weeks 12, 24 and 48

To evaluate the proportion of subjects with 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
The exploratory objectives of this study are as follows: 
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GS-9688 
Protocol GS-US-389-2024 
Gilead Sciences Inc. 
3. 
STUDY DESIGN 
3.1. 
Study Design 
Final 
Amendment 2 .1 
This is a multicenter, randomized, double-blind, placebo-controlled Phase 2 study of GS-9688 in 
virally suppressed adult CHB subjects on OA V. 
Figure 3-1. 
Study Schema 
~= 
HBeAg-positive CHB subJe<ts 
N- 25 
HBeAg-negative CHB , ubject• 
I 
111= 25 
We•lt 23 (La,t GS-9688/ 
W•ek 23 I Lost GS-9G88/ 
Pl""8boDo«>) 
Week48/ED 
Placebo O<>so) 
Week48/[D 
Arm A 
N=S 
Arm 6 
N=10 
ArmC 
~10 
Placebo 
weekly x 24 doses 
GS-9688 1.5 mg 
weekly, 24 dose, 
GS-961!8 3 mg 
weekly • 24 dose., 
OAVTherapy 
OAVTherapy 
OAVTherapy 
a 
Coho11 1 and Coho1t 2 w-ill nm in parallel 
Arm A 
N=5 
Arm B 
N=10 
Placebo 
weekfy x 24 do!>es 
GS-9688 1.5 !Tl£ 
weekly x 24 do~s 
GS-96883 mg 
weeklv x 24 dose. 
b 
At Week 48, per PI's discretion, subjects will be managed in one of two ways: 
OAVTherapy 
OAVTherapy 
OAVTherapy 
1. 
Continue in the study for 48 weeks follo\oving the discontinuation of OA V (ie, TFFU) 
2. 
Continue current standard of care CHB therapy with Week 48 representing the last study visit 
3.2. 
Study Treatments 
Approximately 50 virally suppressed subjects cmTently being treated with a commercially 
available OA V for CHB will be em·olled into two coholis within this study (1: 1) that will nm in 
parallel. 
• 
Cohort 1: HBeAg-positive CHB subjects 
• 
Cohort 2: HBeAg-negative CHB subjects 
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Within each cohort, approximately 25 subjects will be randomized in a 1:2:2 ratio to one of the 
three treatment arms (A: B: C). All subjects will remain on their current commercially available 
OAV therapy for 48 weeks, in addition to the following treatments:

Treatment Arm A: Approximately 5 subjects will be administered PTM orally on the same 
day once a week (every 7 days) for 24 doses 

Treatment Arm B: Approximately 10 subjects will be administered GS-9688 1.5 mg plus 
PTM tablet orally on the same day once a week (every 7 days) for 24 doses

Treatment Arm C: Approximately 10 subjects 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. Subjects should take their 
OAV treatment 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.
After the 24th dose (Week 23 visit), GS-9688/PTM will be discontinued. Subjects will continue 
being treated with their original commercially available OAV 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 TFFU phase.
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 OAV (ie, TFFU phase) 
2) Continue current standard of care CHB therapy with Week 48 representing the last study 
visit.
At the PI’s discretion, subject(s) in the TFFU phase may restart commercially available CHB 
OAV treatment at any time per local treatment guidelines. If a subject restarts OAV therapy for 
their CHB, TFFU visits will continue for 2 more TFFU visits or until the end of the TFFU phase 
(Study 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.
The study will be unblinded to appropriate Gilead Sciences Inc., (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. 


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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. Cohort 1 and 2 consist of 24 doses (Week 23) of treatment of 
GS-9688 study drug/PTM.
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 6.7.
 
 
3.5.
Pharmacodynamic Assessments
Pharmacodynamic assessments (serum and plasma PD biomarkers and 
) 
will be performed throughout the study as outlined in Section 6.8.
3.6.
Biomarker Testing 
3.6.1.
Biomarker Samples to Address the Study Objectives:
The following biological specimens will be collected from all subjects in this study and will be 
used to evaluate the association of exploratory systemic and/or tissue specific biomarkers with 
study drug response, including efficacy and/or AEs and the targeted pathway and/or the 
validation of a diagnostic.  The specific analyses will include, but will not be limited to, the 
biomarkers and assays as described within the protocol.  Because biomarker science is a rapidly 
evolving area of investigation, it is not possible to specify prospectively all tests that will be done 
on the specimens provided.  The testing outlined below is based upon the current state of 
scientific knowledge. It may be modified during or after the end of the study to remove tests no 
longer indicated and/or to add new tests based upon the growing state of art knowledge. 
Biomarker samples will be collected as described in Appendix 2.
These samples will be destroyed no later than 15 years after the end of study. Blood samples for 
assessing biomarkers related to GS-9688 and its mechanism of action will be collected on the 
assigned study days as outlined in Appendix 2.
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3.6.2.
Samples for Optional Future Research
 
 
 
 
 
 
 
 
.
3.6.3.
Sample for Optional Genomic Research
 
 
 
 
 
 
 
 
 
 
 
 
3.7.
End of Study
The end of this study will be the last subject’s last completed study visit at Week 48. If the 
subject enrolls in the TFFU phase, the subject will be observed for up to an additional 48 weeks 
(Study Week 96).
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4.
SUBJECT POPULATION
4.1.
Number of Subjects and Subject Selection
A total of approximately 50 subjects will be enrolled in the study, aged 18-65 years inclusive, 
with CHB and currently on a commercially available 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) Have been on a commercially available HBV OAV treatment(s) (tenofovir alafenamide, 
tenofovir disoproxil fumurate, entecavir, adefovir, lamivudine, telbivudine, either as single 
agents or in combination) with no change in regimen for 3 months prior to screening.
7) HBV DNA ≤20 IU/mL lower limit of quantitation (LLOQ); (measured at least once by local 
laboratory assessment) for 6 or more months prior to Screening
8) HBV DNA < 20 IU/mL at Screening
9) Screening ECG without clinically significant abnormalities and with QTcF interval 
(QT corrected using Fridericia’s formula) ≤450 msec for males and ≤ 470 msec for females.
10) Must be willing and able to comply with all study requirements


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4.3.
Exclusion Criteria
Subjects who meet any of the following exclusion criteria are not to be enrolled in this study:
1) 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) 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 cell/mm3 (or < 1000 cell/mm3 if considered a physiological 
variant in a subject of African descent)
d) ALT > 3x ULN 
e) 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/uL
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])
3) Co-infection with human immunodeficiency virus (HIV), hepatitis C virus (HCV) or 
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Subjects who are HCV Ab positive, but have a documented negative HCV RNA, are eligible
4) 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
5) 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
6) Significant cardiovascular, pulmonary, or neurological disease in the opinion of the 
investigator
7) 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
8) Chronic liver disease of a non-HBV etiology (e.g. Wilson’s disease, hemochromatosis, 
alpha-1-antitrypsin deficiency, cholangitis), except for non-alcoholic fatty liver disease
9) Received solid organ or bone marrow transplant 
10) Received prolonged systemic therapy with immunomodulators (e.g. corticosteroids) or 
biologics (e.g. monoclonal antibody, interferon) within 3 months of screening
11) Use of another investigational agent within 90 days of screening, unless allowed by the 
Sponsor
12) Current alcohol or substance abuse judged by the investigator to potentially interfere with 
subject compliance
13) Known hypersensitivity to study drug or formulation excipients
14) Women who are breastfeeding, pregnant or who wish to become pregnant during the course 
of the study
15) 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
16) Male subjects unwilling to refrain from sperm donation during and until at least 90 days after 
the last study drug dose
17) Use of any prohibited concomitant medications as described in Section 5.5
18) Believed by the Study Investigator to be inappropriate for study participation for any reason 
not otherwise listed.


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Amendment 2.1
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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 (N=5), blinded GS-9688
1.5 mg (N=10), or GS-9688 3 mg (N=10). 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 Epidemiolgy (PVE) may independently unblind cases 
for expedited reporting of suspected unexpected serious adverse reactions (SUSARs).


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Protocol GS-US-389-2024
Final
Gilead Sciences, Inc. 
Amendment 2.1
CONFIDENTIAL
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27 August 2019
5.2.
Description and Handling of GS-9688 and Placebo to Match 
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. 
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, polyethylene glycol (PEG) 3350, and 
talc. PTM GS-9688 tablets are identical in size, shape, color and appearance to the active 
GS-9688 tablets.
5.2.2.
Packaging and Labeling
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 (ie, 2 strips/8ct) are placed into a paperboard child resistant wallet 
system in accordance with the dosage strategy.
Study drug(s) to be distributed to centers in the US and other participating countries shall be 
labeled to meet applicable requirements of the US FDA, EU Guideline to Good Manufacturing 
Practice - Annex 13 (Investigational Medicinal Products), and/or other local regulations. 
5.2.3.
Storage and Handling
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.
To ensure the stability and proper identification, study drug(s) should not be stored in a container 
other than the container in which they were supplied. 
Consideration should be given to handling, preparation, and disposal through measures that 
minimize drug contact with the body. Appropriate precautions should be followed to avoid direct 
eye contact or exposure when handling.


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Final
Gilead Sciences, Inc. 
Amendment 2.1
CONFIDENTIAL
Page 55
27 August 2019
5.3.
Dosage and Administration of GS-9688
Approximately 50 virally suppressed subjects currently being treated with a commercially 
available OAV for CHB will be enrolled into two cohorts within this study (1:1). 

Cohort 1: HBeAg-positive CHB subjects

Cohort 2: HBeAg-negative CHB subjects
Within each cohort, approximately 25 subjects will be randomized in a 1:2:2 ratio to one of the 
three treatment arms (A: B: C). All subjects will remain on their current commercially available
OAV therapy for 48 weeks, in addition to the following treatments:
Treatment Arm A: Approximately 5 subjects will be administered PTM orally on the same day 
once a week (every 7 days) for 24 doses 
Treatment Arm B: Approximately 10 subjects will be administered GS-9688 1.5 mg plus PTM 
tablet orally on the same day once a week (every 7 days) for 24 doses
Treatment Arm C: Approximately 10 subjects will be administered GS-9688 3 mg orally on the 
same day once a week (every 7 days) for 24 doses
For the purpose of the study all doses will be administered in fasted state. Subjects should take 
their OAV treatment 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.
After the 24th dose (Week 23 visit), GS-9688/PTM will be discontinued. Subjects will continue 
being treated with their original commercially available OAV 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 TFFU phase.
5.4.
Fasting State Dosing 
Study drug will be administered at approximately the same time each day 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.
5.5.
Concomitant Medications
Concomitant medications taken within 30 days prior to Screening, up to and including 30 days 
after the last administration of study drug or at Week 48, whichever occurs last, 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.  


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Amendment 2.1
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The following medications on the list (Table 5-1) and those listed here 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): Hematologic stimulating agents 
(eg, erythropoiesis-stimulating agents; granulocyte colony stimulating factor [GCSF]; and 
thrombopoietin [TPO] mimetics).
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). This is not an exhaustive 
list of agents. Systemic immunosuppressant (except short term use of prednisone as a steroid 
burst [≤1 week of use]) and cytotoxic medications are also prohibited as they could interfere 
with the immunomodulatory effects of GS-9688.
Any medications not on the list (Table 5-1) should be reviewed with the Sponsor prior to 
randomization and during the study treatment period with GS-9688/PTM.
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. Vitamins, acetaminophen, ibuprofen and hormonal contraceptive 
medications are allowed during the study period.
Table 5-1.
List of Agents Disallowed
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
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


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Final
Gilead Sciences, Inc. 
Amendment 2.1
CONFIDENTIAL
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27 August 2019
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. 
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. Other Protocol Restrictions:

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, eg, 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, (eg, CK) and will provide false 
indicators of a potentially treatment related toxicity. 
Upon every admission to the clinic, each subject will be questioned as to their compliance with 
the above 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.
5.6.
Accountability for GS-9688
The investigator is responsible for ensuring adequate accountability of all used and unused IMP. 
This includes acknowledgement of receipt of each shipment of IMP (quantity and condition). All 
used and unused IMP dispensed to subjects must be returned to the site.
GS-9688 accountability records will be provided to each study site to:

Record the date received and quantity of IMP kits

Record the date, subject number, subject initials, the IMP kit number dispensed

Record the date, quantity of used and unused IMP returned, along with the initials of the 
person recording the information.


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Final
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Amendment 2.1
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5.7.
Investigation 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 kits and/or 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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Protocol GS-US-389-2024
Final
Gilead Sciences, Inc. 
Amendment 2.1
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6.
STUDY PROCEDURES
The study procedures to be conducted for each subject enrolled in the study are presented in 
tabular form in Appendix 2 and described in the text that follows. 
The investigator must document any deviation from protocol procedures and notify the sponsor 
or contract research organization (CRO).
6.1.
Subject Enrollment and Treatment Assignment
Entry into screening does not guarantee enrollment into the study. In order to manage the total
trial enrollment, Gilead, at its sole discretion, may suspend screening and/or enrollment at any
site or trial-wide at any time.
6.2.
Pretreatment Assessments
Prior to the conduct of any screening procedures, each candidate must sign an Informed Consent 
Form. Consent is to be obtained in accordance with regulatory and local Ethics Committee 
requirements.
6.2.1.
Screening Visit (Window of -30 Days)
Subjects will be screened within 30 days of the baseline visit to determine eligibility for 
participation in the study.

Review of inclusion/exclusion criteria

Obtain medical history (including HBV disease and treatment history) 

Obtain Informed Consent, 

Review concomitant medications 

Complete physical examination (including weight, height, BMI, vital signs)

12-lead ECG – (ECG must be taken before blood drawn and subjects must rest quietly in the 
supine position for a minimum of 10 minutes prior to the recording)

Ophthalmologic exam (Days -10 to -1)

Sample Collection for:
Safety laboratory tests (serum chemistry, hematology, and coagulation)
HCV, HDV and HIV Ab testing (with reflex testing performed if positive)
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Qualitative HBV serology (HBeAg [reflex HBeAb if HBeAg is negative] and HBsAg 
[reflex HBsAb if HBsAg is negative])
HBV DNA levels and resistance surveillance
HBV genotyping by history (if known)
Quantitative HBsAg
FibroTest
AFP [An imaging test will be required for subjects with AFP  ≥ 50 ng/mL]
Urinalysis, urine drug screen, serum β-hCG (for all female subjects of child-bearing 
potential), and FSH testing (for female subjects post-menopausal for less than two years, 
if FSH < 40 mIU/ mL a serum pregnancy test will be required)
 
 
 
 
 
 
 
 
 
.
6.3.
On-Treatment Assessments (All Visits Have Window of ± 1 Days)
All Day 1 (baseline) tests and procedures must be completed prior to the receipt of the first dose 
of study drug. 
All Treatment Phase 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 on Day 1 and Weeks 2, 4, 8, and 12. 
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
Symptom directed physical exam on Day 2, Weeks 11, 16, 20, 23 and 23 +24 hours. 
Complete physical examination should include weight, BMI, height, vital signs, 
concomitant medications and AEs
Symptom directed physical examination should include weight, vital signs, 
concomitant medications and AEs

Ophthalmologic exam on Week 12 (Days -4 to +10)

In clinic GS-9688 study drug dosing on Day 1 and 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 on the same day approximately at the same time
once a week (every 7 days) for 24 doses.

Safety laboratory tests (serum chemistry, 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

Serum β-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 and11

HBV DNA and resistance surveillance on Day 1 and 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 Day 1 and Week 12

Quantitative HBsAg on Day 1 and Weeks 2, 4, 8, 11, 12, 16, 20, and 23

Quantitative HBeAg, HBV RNA and HBV core-related antigen (HBcrAg) on Day 1 and 
Weeks 4, 8, 12, 16, and 20


Serum and plasma PD biomarkers on Days 1 Pre-dose, 1 + 4 hours, 1 + 24 hours and 
Weeks 2, 8, 11, 11 + 4 hours,12, 16, 20, 23, 23 + 4 hours, and 23 + 24 hours

TruCulture sample on Day 1 pre-dose
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
Whole blood gene expression (Paxgene RNA) samples on Days 1 Pre-dose, 1+4 hour,
1 + 24 hours 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, 1 + 24 hours and Weeks 11, 
11 + 4 hours, 12, 23, 23 + 4 hours, and 23 + 24 hours

TLR8 SNP genotyping on Day 1 but may be collected at any time during the study or at any 
unscheduled visit

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.

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

 

Health Related Quality of Life (HRQoL) Surveys (SF-36, CLDQ, and WPAI) on Day 1 and 
Week 12

Randomization  on Day 1
If a subject chooses to terminate the study anytime during the treatment period, all subjects 
should complete all of the above assessments at the ED visit except for the sparse (timed) plasma 
PK sample.
6.3.1.
 
 
 
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Amendment 2.1
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. 
6.4.
Post-Treatment Assessments (All Visits Have Window of ± 3 Days except 
Week 24 ± 1 Day)

Complete physical examination (includes weight, height, BMI, vital signs, concomitant 
medications and AEs)

Ophthalmologic exam on Week 24 (Days -4 to +10)

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 and resistance surveillance

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

Quantitative HBeAg, HBV RNA and HBcrAg 


Pharmacodynamic assessments: 
Serum and plasma PD biomarkers on Weeks 24 and 28
Whole blood gene expression (PAXgene RNA) samples on Weeks 24 and 48/ED
PBMC samples will be collected on Weeks 24 and 48/ED

HRQoL Surveys (SF-36, CLDQ, and WPAI) on Weeks 24 and 48/ED
If a subject chooses to terminate the study anytime during the post-treatment period, all subjects 
should complete all of the above assessments at the ED visit.
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Amendment 2.1
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6.5.
Treatment Free Follow-up (TFFU) Visit Assessments (± 7 Days)
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, per PI 
discretion, if a subject discontinues OAV treatment, the subject will be followed every 4 weeks 
for the first 24 weeks and thereafter at Week 36 and Week 48 in the TFFU phase. 
The following evaluations will be performed at TFFU visits 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

Quantitative HBeAg, HBV RNA, Quantitative HBcrAg

Qualitative HBV serology (HBeAg [reflex HBeAb if HBeAg is negative] and HBsAg
[reflex HBsAb if HBsAg is negative])

PBMC


 

Whole blood gene expression (PAXgene RNA) samples 

HRQoL Surveys (SF-36, CLDQ, and WPAI) on TFFU Week 12 (Study Week 60),TFFU 
Week 24 (Study Week 72) and TFFU Week 48 (Study Week 96)
At the PIs discretion, subject(s) in the TFFU phase may restart commercially available CHB 
OAV treatment at any time per local treatment guidelines. If a subject restarts OAV therapy for 
their CHB, TFFU visits will continue for 2 more TFFU visits or until the end of the TFFU phase 
(Study Week 96), whichever comes first.
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Amendment 2.1
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6.5.1.
 
 
 
 
 
 
 
 
 
6.6.
Unscheduled Visits
The assessments at the unscheduled visits are at the investigator’s discretion.
6.7.
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):
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
6.7.1.
 
 
 
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Amendment 2.1
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6.8.
Pharmacodynamic Assessments

Serum and plasma PD biomarkers:
Day 1: Pre-dose, 4 and 24 hours post-dose
Week 2: Pre-dose 
Week 8: Pre-dose 
Week 11: Pre-dose and 4 hours post-dose
Week 12: Pre-dose 
Week 16: Pre-dose 
Week 20: Pre-dose 
Week 23: Pre-dose, 4 and 24 hours post-dose
Week 24: Pre-dose 
Week 28: Pre-dose 

TruCulture sample:
Day 1: Pre-dose

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
Week 12
Week 23: Pre-dose, 4 hours and 24 hours post-dose
Week 24
Week 48/ED
All TFFU visits: Weeks 4, 8, 12, 16, 20, 24, 36 and 48


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
PBMC: 
Days 1: Pre-dose, 4 hours, and 24 hours post-dose
Week 11: Pre-dose and 4 hours post-dose
Week 12
Week 23: Pre-dose, 4 hours, and 24 hours post-dose
Week 24
Week 48/ED
All TFFU visits: Weeks 4, 8, 12, 16, 20, 24, 36 and 48

TLR8 SNP genotyping: 
Day 1 but may be collected at any time during the study or at any unscheduled visit


Optional genomic research: 
6.8.1.
 
 
 
 
 
CCI
CCI
CCI


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6.8.2.
TruCulture Samples
TruCulture tubes are customized blood collection tubes manufactured to contain GS-9688 and 
will be used to assess the ex vivo activation of peripheral blood of subjects in the study.
CCI
I 
I 


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6.9.
Safety Assessments
Assessment of AEs and concomitant medications will continue throughout the duration of the 
study, including TFFU. Laboratory analyses, physical examinations including vital signs, and 
ECGs/ Holter monitoring will be performed at defined intervals throughout the study.
Safety Assessments will be performed through the study as outlined in Appendix 2.
6.9.1.
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 instruments that analyze data using the same 
algorithms and produce the same data for interpretation. Electrode placement will be performed 
according to the method of Wilson, Goldberger, and Einthoven with a check to confirm that the 
aVR 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 morphology as compared with 
pretreatment ECGs. ECG interval measurements output by the machine will be used for bedside 
safety monitoring.
Collection of additional ECGs for routine safety monitoring at additional time points or days is at 
the discretion of the investigator based on GCP.
6.9.2.
Holter Monitoring
For the purposes of this study, time-matched digital 12-lead ECGs will be collected as 
continuous recordings. ECGs may be extracted from recorded data at a later time.
Holter recording will be obtained via continuous 12-lead digital recorder. Baseline and 
on-treatment ECGs for all treatments will be measured from the same lead for each subject 
(lead II, when possible). Triplicate ECGs will be extracted at various time points for each 
pre-determined time points 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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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 tpoint. 
6.9.3.
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.
6.9.4.
Vital Signs 
Vital sign measurements include blood pressure, heart rate, respiration rate, and temperature and 
should be taken once subjects have been seated or in the supine position. Subject position for 
measurement should be kept consistent throughout the study. Refer to Appendix 2 for vital signs 
collection time points.
6.9.5.
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.
6.9.5.1.
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)


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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, Quantitative HBCrAg, Quantitative HBeAg, and HBV RNA
6.9.5.2.
Urine Samples
Urine samples will be collected for urinalysis, alcohol and drug screen assessments and urine 
pregnancy as applicable.
6.9.6.
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])
6.9.7.
Ophthalmic Examination
Ophthalmic Examinations will be performed 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 abnormalities. Photographs of the retina 
must be taken at each exam and filed in the subject’s source medical records. A central vendor 
will be used to assess the retinal photographs. Refer to Appendix 2 for ophthalmic examination 
collection time points.
A procedural window will be given to accommodate ophthalmic assessments. Refer to 
Appendix 2 for details.


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6.9.8.
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 information regarding AEs 
and Section 5 and Table 5-1 for more information about concomitant medications.
6.10.
Sample Storage
The stored blood samples may be used by Gilead or its research partner for future clinical 
laboratory testing to provide additional data to answer questions that relate to the main study. At 
the conclusion of this study, the backup PK samples may be retained in storage by Gilead at its 
research partner facility for a period up to 2 years. 
6.11.
Assessments for Premature Discontinuation from Study
If a subject discontinues study treatment dosing for example as a result of an AE, every attempt 
should be made to keep the subject in the study and continue to perform the required 
study-related 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 abnormal 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 abnormality resolves, returns to baseline visit levels, or 
is otherwise explained.
6.12.
Criteria for Discontinuation of Study Treatment

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 request to discontinue for any reason

Subject noncompliance

Pregnancy during the study; refer to Appendix 3

Investigator discretion


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
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 up to 48 weeks if continued into the
Treatment Free Follow-up (TFFU) phase.
6.13.
Resistance Surveillance
Sequence analysis of the HBV genome may be attempted for any subject who is currently being 
treated with OAV and experiences viremia (HBV DNA > 69 IU/mL) at any time point. 
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.
6.14.
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 (Study Week 96).
6.15.
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 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 (eg, pre-existing condition, underlying disease, 
intercurrent illness, or concomitant medication).

Yes: There is reasonable possibility that the event may have been caused by the 
investigational medicinal product.
It should be emphasized that ineffective treatment should not be considered as causally related in 
the context of adverse event reporting. 
The relationship to study procedures (eg, invasive procedures such as venipuncture or biopsy) 
should be assessed using the following considerations:

No: Evidence exists that the adverse event has an etiology other than the study procedure.

Yes: The adverse event occurred as a result of protocol procedures, (eg., venipuncture)


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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 CRF/eCRF: all SAEs and AEs 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 or at Week 48, whichever occurs last, 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 AE is stable, if possible. Gilead 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 (ie, signing the informed consent) and throughout the duration of the 
study, including the protocol-required post treatment follow-up period and TFFU, must be 
reported to the CRF/eCRF database and Gilead PVE as instructed. This also includes any SAEs 
resulting from protocol-associated procedures performed after informed consent is signed.
Any SAEs and deaths that occur after the post treatment follow-up visit but within 30-days of the 
last dose of study drug, regardless of causality, should also be reported. 


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Investigators are not obligated to actively seek SAEs after the protocol defined follow-up period,
however, if the investigator learns of any SAEs that occur after study participation has concluded 
and the event is deemed relevant to the use of IMP, he/she should promptly document and report 
the event to Gilead PVE.

All AEs and SAEs will be recorded in the CRF/eCRF database within the timelines outlined 
in the eCRF completion guideline. 
Electronic Serious Adverse Event (eSAE) Reporting Process

Site personnel record all SAE data in the eCRF database and from there transmit the SAE 
information to Gilead 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 information electronically, because the 
eCRF database cannot be accessed or is not available (including at study start), record the 
SAE on the paper serious adverse event report form and submit by e-mail or fax within 
24 hours of the investigator’s knowledge of the event to:
PVE previously known as Gilead DSPH:
Fax:
E-mail:

As soon as it is possible to do so, any SAE reported via paper must be transcribed into the 
eCRF Database according to instructions in the eCRF completion guidelines.

If an SAE has been reported via a paper form because the eCRF database has been locked, no 
further action is necessary. 

For fatal or life-threatening events, copies of hospital case reports, autopsy reports, and other 
documents are also to be submitted by e-mail or fax when requested and applicable. 
Transmission of such documents should occur without personal subject identification, 
maintaining the traceability of a document to the subject identifiers.

Additional information may be requested to ensure the timely completion of accurate safety 
reports.

Any medications necessary for treatment of the SAE must be recorded onto the concomitant 
medication section of the subject’s CRF/eCRF and the event description section of the SAE 
form.
PPD
PPD


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7.4.
Gilead Reporting Requirements
Depending on relevant local legislation or regulations, including the applicable US FDA Code of 
Federal Regulations, the EU Clinical Trials Directive (2001/20/EC) and relevant updates, and 
other country-specific legislation or regulations, Gilead may be required to expedite to 
worldwide regulatory agencies reports of SAEs, serious adverse drug reactions (SADRs), or 
suspected unexpected serious adverse reactions (SUSARs). In accordance with the EU Clinical 
Trials Directive (2001/20/EC), Gilead or a specified designee will notify worldwide regulatory 
agencies and the relevant IEC in concerned Member States of applicable SUSARs as outlined in 
current regulations.
Assessment of expectedness for SAEs will be determined by Gilead using reference safety 
information specified in the investigator’s brochure or relevant local label as applicable. 
All investigators will receive a safety letter notifying them of relevant SUSAR reports associated 
with any study IMP. The investigator should notify the IRB or IEC of SUSAR reports as soon as 
is practical, where this is required by local regulatory agencies, and in accordance with the local 
institutional policy. 
7.5.
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.


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7.6.
Toxicity Management
All clinical and clinically significant laboratory toxicities will be managed according to uniform 
guidelines detailed in Appendix 3.

All Grade 3 or greater AEs and laboratory abnormalities will be reviewed by the Sponsor to 
determine if the event is at least possibly treatment-related to determine if the study drug 
should be held or discontinued

Grade 3 and 4 clinically significant laboratory abnormalities should be confirmed by repeat 
testing within 3 calendar days of receipt of results and before investigational medicinal 
product discontinuation, unless such a delay is not consistent with good medical practice.

Clinical events and clinically significant laboratory abnormalities will be graded according to 
the Table for GSI Grading Scale for Severity of Adverse Events and Laboratory 
Abnormalities (Appendix 4).

When restarting investigational medicinal product following resolution of the adverse event,
the investigational medicinal product should be restarted at full dose that is dependent upon 
discussion with the Gilead Sciences Medical Monitor.

Administration of study drug may be discontinued due to a clinical or laboratory event. The
Gilead Medical Monitor should be consulted prior to dose discontinuation of study drug
unless the investigator believes that immediate action is warranted to ensure the continued
safety of subject.

Any questions regarding toxicity management should be directed to the Gilead Sciences
Medical Monitor.
7.6.1.
ALT Elevation or Flare Management
Subjects with on-treatment ALT flare defined as serum ALT > 2 BL and ≥5 ULN (with or 
without associated symptoms) should be managed according to the guidance below. 
All on-treatment ALT flare should be confirmed within 3 days of receipt of results. During the 
visit, a clinical assessment of the subject should be performed. The assessment should include a 
complete physical examination, evaluation of the subject’s mental status and the following 
laboratory tests: 

Laboratory parameters: serum ALT, AST, alkaline phosphatase, total and fractionated
bilirubin, gamma-glutamyl transferase (GGT), INR and serum albumin.

If the ALT elevation/flare is confirmed, the central clinical laboratory will conduct reflex 
testing for plasma HBV DNA, qualitative HBV serology (HBeAg [reflex HBeAb if HBeAg 
is negative] and HBsAg [reflex HBsAb if HBsAg is negative]), HAV IgM, HCV RNA, HDV 
RNA, and HEV IgM.


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7.6.2.
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 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.
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.


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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.
7.6.4.
Grades 1 and 2 Laboratory Abnormality or Clinical Event
Continue study drug at the discretion of the investigator.
7.6.5.
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 or continuation of dosing will be made by the Sponsor upon review of all safety 
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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 up to 24 weeks if continued 
into the Treatment Free Follow-up (TFFU) phase.
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 6.9.1.
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).


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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 
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 poststudy drug follow-up 
period, to Gilead PVE using the pregnancy report form within 24 hours of becoming aware of 
the pregnancy.
Refer to the eCRF completion guidelines for full instructions on the mechanism of pregnancy 
reporting.
The pregnancy itself is not considered an AE nor is an induced elective abortion to terminate a 
pregnancy without medical reasons.
Any premature termination of pregnancy (eg, a spontaneous abortion, an induced therapeutic 
abortion due to complications or other medical reasons) must be reported within 24 hours as an 
SAE. The underlying medical reason for this procedure should be recorded as the AE term.
A spontaneous abortion is always considered to be an SAE and will be reported as described in 
Section 7.3.2. 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
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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.


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8.
STATISTICAL CONSIDERATIONS
8.1.
Analysis Objectives and Endpoints
8.1.1.
Analysis Objectives
The primary objectives of this study are as follows:

To evaluate the safety and tolerability of multiple oral doses of GS-9688 at Week 24 in 
virally suppressed CHB adult subjects on OAV

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 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 HBsAg loss at Weeks 12, 24 and 48

To evaluate the proportion of subjects with 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
The exploratory objectives of this study are as follows: 
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8.1.2.
Primary Efficacy Endpoint
The primary efficacy endpoint of this study is the proportion of subjects with ≥1 log10 IU/mL 
decline in serum qHBsAg from baseline at Week 24
8.1.3.
Secondary Efficacy Endpoints
The secondary endpoints of this study include:

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

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
8.2.
Analysis Conventions
8.2.1.
Analysis Sets
8.2.1.1.
Efficacy 
The primary analysis set for efficacy analysis is the full analysis set (FAS), defined as all 
randomized subjects who took at least 1 dose of the study drug. Subjects will be analyzed 
according to the randomized treatment assignment. In this study, the study drugs are GS-9688 
and placebo.
8.2.1.2.
Safety
The primary analysis set for safety analysis is the safety analysis set (SAS), defined as all 
subjects who took at least 1 dose of the study drug. Subjects will be analyzed according to the 
treatment actually received. 
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8.2.1.3.
Pharmacokinetics
The PK analysis set will include all randomized subjects who took at least 1 dose of the study 
drug and have at least 1 nonmissing concentration value reported by the PK laboratory.
 
 
8.2.1.4.
Pharmacodynamic Biomarkers
The primary analysis set for PD biomarker analysis is the biomarker analysis set, defined as all 
randomized subjects who took at least 1 dose of the study drug and have at least 1 nonmissing 
biomarker value for each respective biomarker.
8.3.
Data Handling Conventions
For the primary efficacy endpoint and the categorical secondary efficacy endpoints, missing data 
will be handled using a missing = failure approach.
For the drug resistant mutations endpoint, a missing = excluded approach will be employed. 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 postdose time points.
8.4.
Demographic Data and Baseline Characteristics
Demographic and baseline measurements will be summarized by treatment group and overall for 
each cohort using standard descriptive methods.
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, concomitant HBV OAV, 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.
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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 
endpoint by treatment group for each cohort.
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 study drug will be summarized by treatment group according to the 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 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 study drug; or any AE leading to premature 
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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

All SAEs

All treatment-related SAEs

All AEs leading to temporary interruption of the study drug

All AEs leading to premature discontinuation of the study drug
All AEs collected during the study will be presented in the data listings. 
8.6.3.
Laboratory Evaluations
Selected laboratory data (using conventional units) will be summarized using only observed data. 
Data and the corresponding change from baseline will be summarized by treatment group at each 
measured study visit. 
Graded laboratory abnormalities will be defined using the grading scheme in Appendix 4
(GSI Grading Scale for Severity of Adverse Events and Laboratory Abnormalities) for analysis 
purpose. 
Incidence of treatment-emergent laboratory abnormalities, defined as values that increase by at 
least one toxicity grade from baseline at any time post baseline, up to and including the date of 
last dose of study drug plus 30 days, will be summarized by treatment group. 
Values for missing safety laboratory data will not be imputed; however, a missing baseline result 
will be replaced with a screening result, if available. If no pretreatment laboratory value is 
available, the baseline value will be assumed to be normal (i.e., no grade [Grade 0]) for the 
summary of graded laboratory abnormalities.
All laboratory abnormalities will be included in the listings of laboratory data.


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8.6.4.
Other Safety Evaluations
Individual data for ECG and vital sign measurements will be listed by subject and summarized 
for each treatment group by incidence of events/abnormalities or descriptive statistical 
summaries (n, mean, SD, median, Q1, Q3, minimum, and maximum), as appropriate.
8.7.
Pharmacokinetic Analysis
 
 
 
 
 
 
. 
8.8.
Exploratory Analysis
 
 
 
 
 
 
 
 
.
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8.9.
Sample Size
Due to the exploratory nature of this study, the sample size was not determined by any formal 
power calculation. The number of subjects in each treatment group was decided based on clinical 
experience.
8.10.
Data Monitoring Committee
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 DLT or virologic study stopping 
criteria.
While the DMC will be asked to advise Gilead regarding future conduct of the study, including 
possible early study termination, Gilead retains final decision-making authority on all aspects of 
the study.
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.
RESPONSIBILITES
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 GCP 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, ie, history, physical examination, and 
confirmation of diagnosis (to support inclusion and exclusion criteria);

Documentation of the reason(s) a consented subject is not enrolled;


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
Participation in study (including study number);

Study discussed and date of informed consent;

Dates of all visits;

Documentation that protocol specific procedures were performed;

Results of efficacy parameters, as required by the protocol;

Start and end date (including dose regimen) of IMP, including dates of dispensing and return;

Record of all 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 documented according to study procedures. eCRF should be 
completed on the day of the subject visit to enable the sponsor to perform central monitoring of 
safety data.  The Eligibility Criteria eCRF should be completed only after all data related to 
eligibility have been received.  Subsequent to data entry, a study monitor will perform source 
data verification within the EDC system. Original entries as well as any changes to data fields 
will be stored in the audit trail of the system.  Prior to database lock (or any interim time points 
as described in the clinical data management plan), the investigator will use his/her log in 


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


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9.2.2.
Study Report and Publications
A clinical study report (CSR) will be prepared and provided to the regulatory agency. 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.
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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10.
REFERENCES
Benias P, Min A. Goals of Antiviral Therapy for Hepatitis B: HBeAg Seroconversion, HBsAg 
Seroconversion, Histologic Improvement, and Possible Impact on Risk of 
Hepatocellular Carcinoma. Curr Hepatitis Rep 2011;10.
Chuang TH, Ulevitch RJ. Cloning and characterization of a sub-family of human toll-like 
receptors: hTLR7, hTLR8 and hTLR9. Eur Cytokine Netw 2000;11 (3):372-8.
Dienstag JL, Goldin RD, Heathcote EJ, Hann HWL, Woessner M, Stephenson SL, et al.
Histological outcome during long-term lamivudine therapy. Gastroenterology 
2003;124 (1):105-17.
Ding X, Kaminsky LS. Human Extrahepatic Cytochromes P450: Function in Xenobiotic 
Metabolism and Tissue-Selective Chemical Toxicity in the Respiratory and 
Gastrointestinal Tracts. Annu Rev Pharmacol Toxicol 2003;43:149-73.
Du J, Wu Z, Ren S, Wei Y, Gao M, Randolph GJ, et al. TLR8 agonists stimulate newly recruited 
monocyte-derived cells into potent APCs that enhance HBsAg immunogenicity. 
Vaccine 2010;28 (38):6273-81.
European Association for the Study of the Liver. EASL 2017 Clinical Practice Guidelines on the 
Management of Hepatitis B Virus Infection. J Hepatol 2017;67 (2):370-98.
European Association for the Study of the Liver (EASL). EASL Clinical Practice Guidelines: 
Management of chronic hepatitis B virus infection [published version]. J 
Hepatology 2012;57:167-85.
Fattovich G, Giustina G, Sanchez-Tapias J, Quero C, Mas A, Olivotto PG, et al. Delayed 
clearance of serum HBsAg in compensated cirrhosis B: relation to interferon 
alpha therapy and disease prognosis. Am J Gastroenterol 1998;93 (6):896-900.
G. B. D. Mortality Causes of Death Collaborators. Global, Regional, and National Life 
Expectancy, All-Cause Mortality, and Cause-Specific Mortality for 249 Causes of 
Death, 1980-2015: A Systematic Analysis for the Global Burden of Disease Study 
2015. Lancet 2016;388:1459-544.
Global Burden of Disease Cancer Collaboration, Fitzmaurice C, Dicker D, Pain A, Hamavid H, 
Moradi-Lakeh M, et al. The Global Burden of Cancer 2013. JAMA oncology 
2015;1 (4):505-27.
Gorski KS, Waller EL, Bjornton-Severson J, Hanten JA, Riter CL, Kieper WC, et al. Distinct 
indirect pathways govern human NK-cell activation by TLR-7 and TLR-8 
agonists. International immunology 2006;18 (7):1115-26.


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Amendment 2.1
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Hemmi H, Kaisho T, Takeuchi O, Sato S, Sanjo H, Hoshino K, et al. Small anti-viral compounds 
activate immune cells via the TLR7 MyD88-dependent signaling pathway. Nature 
immunology 2002;3 (2):196-200.
Idilman R, Cinar K, Seven G, Bozkus Y, Elhan A, Bozdayi M, et al. Hepatitis B surface antigen 
seroconversion is associated with favourable long-term clinical outcomes during 
lamivudine treatment in HBeAg-negative chronic hepatitis B patients. J Viral 
Hepat 2012;19 (3):220-6.
Jo J, Tan AT, Ussher JE, Sandalova E, Tang XZ, Tan-Garcia A, et al. Toll-like receptor 8 agonist 
and bacteria trigger potent activation of innate immune cells in human liver. PLoS 
pathogens 2014;10 (6):e1004210.
Kim GA, Lim YS, An J, Lee D, Shim JH, Kim KM, et al. HBsAg seroclearance after nucleoside 
analogue therapy in patients with chronic hepatitis B: clinical outcomes and 
durability. Gut 2013;63:1325-32.
Kim JH, Sherman ME, Curriero FC, Guengerich FP, Strickland PT, Sutter TR. Expression of 
Cytochromes P450 1A1 and 1B1 in Human Lung from Smokers, Non-Smokers, 
and Ex-Smokers. Toxicol Appl Pharmacol 2004;199 (3):210-9.
Kwon H, Lok AS. Hepatitis B therapy. Nature reviews. Gastroenterology & hepatology 2011;8 
(5):275-84.
Liaw Y-F, Kao J-H, Piratvisuth T, Chan HLY, Chien R-N, Liu C-J, et al. Asian-Pacific 
consensus statement on the management of chronic hepatitis B: a 2012 update. 
Hepatol International 2012;6:531-61.
Liaw YF. Impact of hepatitis B therapy on the long-term outcome of liver disease. Liver Int 
2011;31 Suppl 1:117-21.
Liu J, Xu C, Hsu LC, Luo Y, Xiang R, Chuang TH. A five-amino-acid motif in the undefined 
region of the TLR8 ectodomain is required for species-specific ligand recognition. 
Mol Immunol 2010;47 (5):1083-90.
Lok AS. Evolution of nucleoside/tide analogues for hepatitis B: is the ideal drug here yet? J 
Hepatol 2009;51 (2):416-8.
Lok AS. Hepatitis: Long-term therapy of chronic hepatitis B reverses cirrhosis. Nature reviews. 
Gastroenterology & hepatology 2013;10 (4):199-200.
Lu H, Dietsch GN, Matthews MAH, Yang Y, Ghanekar S, Inokuma M, et al. VTX-2337 is a 
novel TLR8 agonist that activates NK cells and augments ADCC. Clin Cancer 
Res 2012;18:499-509.


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Moucari R, Korevaar A, Lada O, Martinot-Peignoux M, Boyer N, Mackiewicz V, et al. High 
rates of HBsAg seroconversion in HBeAg-positive chronic hepatitis B patients 
responding to interferon: a long-term follow-up study. J Hepatol 2009;50 
(6):1084-92.
Northfelt DW, Ramanathan RK, Cohen PA, Von Hoff DD, Weiss GJ, Dietsch GN, et al. A phase 
I dose-finding study of the novel Toll-like receptor 8 agonist VTX-2337 in adult 
subjects with advanced solid tumors or lymphoma. Clin Cancer Res 2014;20 
(14):3683-91.
O'Neill LA, Golenbock D, Bowie AG. The history of Toll-like receptors - redefining innate 
immunity. Nature reviews 2013;13 (6):453-60.
Peng G, Guo Z, Kiniwa Y, Voo KS, Peng W, Fu T, et al. Toll-Like Receptor 8–Mediated 
Reversal of CD4+ Regulatory T Cell Function. Science 2005;309 (5739):1380-4.
Peppa D, Micco L, Javaid A, Kennedy PT, Schurich A, Dunn C, et al. Blockade of 
immunosuppressive cytokines restores NK cell antiviral function in chronic 
hepatitis B virus infection. PLoS pathogens 2010;6 (12):e1001227.
Rehermann B, Nascimbeni M. Immunology of hepatitis B virus and hepatitis C virus infection. 
Nature reviews 2005;5 (3):215-29.
Sarin SK, Kumar M, Lau GK, Abbas Z, Chan HL, Chen CJ, et al. Asian-Pacific clinical practice 
guidelines on the management of hepatitis B: a 2015 update. Hepatol Int 2015.
Schweitzer A, Horn J, Mikolajczyk RT, Krause G, Ott JJ. Estimations of worldwide prevalence 
of chronic hepatitis B virus infection: a systematic review of data published 
between 1965 and 2013. Lancet 2015;386:1546-55.
Simonetti J, Bulkow L, McMahon BJ, Homan C, Snowball M, Negus S, et al. Clearance of 
hepatitis B surface antigen and risk of hepatocellular carcinoma in a cohort 
chronically infected with hepatitis B virus. Hepatology 2010;51 (5):1531-7.
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.


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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.


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11.
APPENDICES
Appendix 1.
Investigator Signature Page
Appendix 2.
Study Procedure Table(s)
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


PPD
PPD
GS-9688 
Protocol GS-US-389-2024 
Final 
Gilead Sciences, lnc. 
Amendment 2.1 
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 Virally-Suppressed Subjects with 
Chronic Hepatitis B 
GS-US-389-2024 Protocol Amendment 2.1, 27 August 2019 
This protocol has been approved by Gilead Sciences, Inc. The following signature documents 
this approval. 
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 a11 
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 umber 
CONFIDENTIAL 
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Appendix 2.
Study Procedure Table(s)
Part A. Study Procedures Required at Screening Visit
Screening Study Procedures – Window (-30 days)
Written Informed Consent
Review of Inclusion/Exclusion Criteria
Medical History (including HBV disease and treatment history)
Ophthalmologic Exama
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)
HIV, HDV, and HCV Testingb
12-Lead ECG
Fibrotest
Alpha Fetoprotein
Urinalysis 
Urine Drug Screen
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)
Qualitative HBV Serologyc
HBV DNA levels
HBV Resistance Surveillance
HBV Genotyping (By history if known)
Quantitative HBsAg
Review AEs & Concomitant Medications
CCI


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Part B. Study Procedure Table (On and Post GS-9688/PTM Treatment Assessments)
On Treatment
Post GS-9688/PTM Treatment
Days
Weeks
Windows
(±1 Days)
(±3 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
EDn
Ophthalmologic 
Exama
X
X
Health Related 
Quality of Life 
Surveys
X
X
X
X
X
Complete Physical 
Exam
X
X
X
X
X
X
X
X
X
X
Symptom Directed 
Physical Exam
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
Safety Labs 
(Hematology, Serum 
Chemistry, and 
Coagulation) 
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Holter Monitoringf
X
X
X
X
X
Fibrotest
X
X
X
X
Urinalysis 
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Serum Pregnancy Test
X
X
X
X
X
X
X
X
X
X
X


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On Treatment
Post GS-9688/PTM Treatment
Days
Weeks
Windows
(±1 Days)
(±3 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
EDn
Urine Pregnancy Test
X
X
X
Qualitative HBV 
Serologyc
X
X
X
X
X
X
HBV DNA levels, 
HBV Resistance 
Surveillance,  
Quantitative HBsAg
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Quantitative HBCrAg,  
Quantitative HBeAg,  
HBV RNA 
X
X
X
X
X
X
X
X
X
X
X
Randomization
X
In Clinic 
GS-9688 Dosing & 
Accountabilityg
X
X
X
X
X
X
X
X
X
Sparse (pre-identified) 
plasma PKh
X
X
X
X
X
Sparse (timed) plasma 
PK sample Collectioni
X
X
X
X
X
X
Serum and Plasma PD 
Biomarkersk
X
X
X
X
X
X
X
X
X
X
X
X
TruCulture
X
CCI
I 
I 
I 111 I I I 
I I 
I 
I 
I 
I 
I 


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On Treatment
Post GS-9688/PTM Treatment
Days
Weeks
Windows
(±1 Days)
(±3 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
EDn
PBMC Collectionl
X
X
X
X
X
X
X
X
X
TLR8 SNP
Collect TLR8 SNP genotyping sample on Day 1 but may be collected at any time during the study or at any unscheduled visit.
Whole Blood gene 
expression 
biomarkersm
X
X
X
X
X
X
X
X
X
Review AEs & 
Concomitant 
Medications
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
CCI
CCI
CCI


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Amendment 2.1
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Part C. Study Procedure Table (Treatment Free Follow-up)o
TFFU Week
(Study Week)
Windows
(±7 Days)
Study Procedures
4
(52)
8
(56)
12
(60)
16
(64)
20
(68)
24
(72)
36
(84)
48
(96)
Health Related Quality of Life Surveys
X
X
X
Symptom Directed Physical Exam
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
Safety Labs (Hematology, Serum Chemistry, and 
Coagulation) 
X
X
X
X
X
X
X
X
Urinalysis 
X
X
X
X
X
X
X
X
Serum Pregnancy Test
X
X
X
X
X
X
X
X
Qualitative HBV Serologyc
X
X
X
X
X
X
X
X
HBV DNA levels,  HBV Resistance Surveillance,  
Quantitative HBsAg
X
X
X
X
X
X
X
X
Quantitative HBCrAg,  Quantitative HBeAg,  HBV RNA 
X
X
X
X
X
X
X
X
PBMC Collectionl
X
X
X
X
X
X
X
X
Whole Blood gene expression biomarkersm
X
X
X
X
X
X
X
X
Review AEs & Concomitant Medications
X
X
X
X
X
X
X
X
CCI
CCI
CCI


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Amendment 2.1
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a
Ophthalmologic Exam window at Screening will be (Days -10 to -1) ,Weeks 12 and 24 (Days -4 to +10) 
b
In the event of a positive result and/or antigen testing for HIV, HDV, or HCV serology, reflex tests will automatically be performed
c
Qualitative HBV serology consists of HBeAg and HBsAg and reflex HBeAb and reflex HBsAb
d
 
 
e
 
 
 
 
f
Holter Monitoring to be collected prior to blood collection on Day 1 and Week 23 at  pre-dose (≤ 5 min of dose) through 4 hours, and 24 hours; Week 11 at pre-dose 
(≤5 min of dose) through 4 hours 
g
In addition to the clinic GS-9688 study drug dosing, self/home GS-9688 study drug dosing will be on Weeks 1, 3, 5, 6, 7, 9, 10, 13, 14, 15, 17, 18, 19, 21, and 22  
h
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.
i
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.
j
 
k
Serum/plasma PD biomarkers will be collected on Day 1 and Week 23 at pre-dose, 4 and 24 hours post-dose; Weeks 2, 8, 12, 16, 20, 24 and 28 pre-dose; and Week 11 
pre-dose and 4 hours pose-dose.
l
PBMC samples collected on Days 1 and 1+4 hours, 1 + 24 hours, and on Weeks 11, 11+4 hours, 12, 23, 23 + 4 hours, 23 + 24 hours, 24, 48/ED, and during TFFU.  See also 
footnote d for collection of Leukapheresis samples in lieu of PBMC samples
m
Whole blood gene expression (Paxgene RNA) samples collected on Days 1 and 1+4 hours, 1 + 24 hours, and on Weeks 11, 11+4 hours, 12, 23, 23 + 24 hours, 24, 48/ED, and 
during TFFU
n
The ED visit should be performed within 1 week if ED occurs before Week 24; after week 24 ED should be performed within 2 weeks from notification of study 
discontinuation 
o
At Week 48, at PI discretion, if a subject discontinues OAV treatment, the subject will be followed every 4 weeks for the first 24 weeks and thereafter at Week 36 and Week 
48 (TFFU phase). At the PI’s discretion, subject(s) in the TFFU phase may restart commercially available CHB OAV treatment at any time per local treatment guidelines. If 
a subject restarts OAV 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.
CCI
CCI
CCI


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Amendment 2
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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
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) 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.


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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
Essure® microinsert system (provided confirmation of success 3 months after procedure)
Vasectomy in the male partner (provided that the partner is the sole sexual partner and 
had confirmation of surgical success 3 months after procedure)
Female subjects must also refrain from egg donation and in vitro fertilization during treatment 
and until at least 30 days after the end of relevant systemic exposure.
3) Contraception Requirements for Male Subjects
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 (eg, 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.
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-389-2024
Final
Gilead Sciences, Inc. 
Amendment 2.1
CONFIDENTIAL
Page 112
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-389-2024
Final
Gilead Sciences, Inc. 
Amendment 2.1
CONFIDENTIAL
Page 113
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-389-2024
Final
Gilead Sciences, Inc. 
Amendment 2.1
CONFIDENTIAL
Page 114
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-389-2024
Final
Gilead Sciences, Inc. 
Amendment 2.1
CONFIDENTIAL
Page 115
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 mmol/L
6.1 to  <7.0 mg/dL
1.51 to < 1.74 mmol/L
< 6.1 mg/dL
< 1.51 mmol/L
Infant, 7 Days
6.5 to 7.5 mg/dL
1.61 to 1.88  mmol/L
6.0 to 6.5 mg/dL
1.49 to < 1.61 mmol/L
5.5 to 6.0 mg/dL
1.36 to < 1.49 mmol/L 
5.5 mg/dL
< 1.36 mmol/L
Hypercalcemia (corrected 
for albumin if appropriate*)
Adult and Pediatric 
7 Days
>ULN to 11.5 mg/dL
11.5 to 12.5 mg/dL
12.5 to 13.5 mg/dL
13.5 mg/dL
>ULN to 2.88 mmol/L
2.88 to 3.13 mmol/L
3.13 to 3.38 mmol/L
3.38 mmol/L
Infant, 7 Days
11.5 to 12.4 mg/dL
2.86 to 3.10  mmol/L
12.4 to 12.9 mg/dL
> 3.10 to 3.23  mmol/L
12.9 to 13.5 mg/dL
> 3.23 to 3.38  mmol/L
13.5 mg/dL
> 3.38 mmol/L
Hypocalcemia (ionized)
3.0 mg/dL to LLN
2.5 to < 3.0 mg/dL
2.0 to 2.5 mg/dL
2.0 mg/dL
0.74 mmol/L to LLN
0.62 to 0.74 mmol/L
0.49 to 0.62 mmol/L
0.49 mmol/L
Hypercalcemia (ionized)
ULN to 6.0 mg/dL
6.0 to 6.5 mg/dL
6.5 to 7.0 mg/dL
7.0 mg/dL
ULN to 1.50 mmol/L
1.50 to 1.63 mmol/L
1.63 to 1.75 mmol/L
1.75 mmol/L
Hypomagnesemia
1.40 to  <LLN mg/dL
1.2 to <LLN mEq/L
1.04 to 1.40 mg/dL
0.9 to   1.2 mEq/L
0.67 to 1.04 mg/dL
0.6 to 0.9 mEq/L
0.67 mg/dL
0.6 mEq/L
0.58 to <LLN mmol/L
0.43 to 0.58 mmol/L
0.28 to 0.43 mmol/L
0.28 mmol/L
Hypophosphatemia
Adult and Pediatric
14 Years
2.0 to < LLN mg/dL
0.63  to LLN mmol/L
1.5 to 2.0 mg/dL
0.47 to 0.63 mmol/L
1.0 to 1.5 mg/dL
0.31 to 0.47 mmol/L
1.0 mg/dL
0.31 mmol/L
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


GS-9688
Protocol GS-US-389-2024
Final
Gilead Sciences, Inc. 
Amendment 2.1
CONFIDENTIAL
Page 116
27 August 2019
CHEMISTRY
Grade 1
Grade 2
Grade 3
Grade 4
Pediatric 1 Year
3.5 to <LLN mg/dL
1.12 to <LLN mmol/L
2.5 to 3.5 mg/dL
0.80 to < 1.12 mmol/L
1.5 to 2.5 mg/dL
0.47 to < 0.80 mmol/L
1.5 mg/dL
< 0.47 mmol/L
Hyperbilirubinemia 
Adult and Pediatric 
> 14 Days
1.0 to 1.5 ULN 
1.5 to 2.5 ULN
2.5 to 5.0 ULN 
5.0 ULN 
Infant, 14 Days
(non-hemolytic)
NA
20.0 to 25.0 mg/dL
342 to 428 μmol/L
25.0 to 30.0 mg/dL
> 428 to 513 μmol/L
30.0 mg/dL
> 513 μmol/L
Infant, 14 Days
(hemolytic)
NA
NA
20.0 to 25.0 mg/dL
342 to 428 μmol/L
25.0 mg/dL
> 428 μmol/L
Blood Urea Nitrogen
1.25 to 2.50 ULN 
2.50 to 5.00 ULN 
5.00 to 10.00 ULN 
10.00 ULN
Hyperuricemia
>ULN to 10.0 mg/dL 
10.0 to 12.0 mg/dL 
12.0 to 15.0 mg/dL 
15.0 mg/dL
>ULN to 597 μmol/L
597 to 716 μmol/L
716 to 895 μmol/L
895 μmol/L
Hypouricemia
Adult and Pediatric
≥ 1 year
Infant  < 1 Year
1.5 mg/dL to LLN
87 μmol/L to LLN
1.0 to 1.5 mg/dL
57 to 87 μmol/L
0.5 to 1.0 mg/dL
27 to 57 μmol/L
0.5 mg/dL
27 μmol/L
N/A
1.0 mg/dl to <LLN-
57 μmol to <LLN
0.5 to 1.0 mg/dL
27 to 57 μmol/L
0.5 mg/dL
27 μmol/L
Creatinine** 
1.50 to 2.00 mg/dL
133 to 177 μmol/L
2.00 to 3.00 mg/dL
177 to 265 μmol/L
3.00 to 6.00 mg/dL 
265 to 530 μmol/L
6.00 mg/dL
530 μmol/L
Bicarbonate
Adult and Pediatric 
≥ 4 Years
16.0 mEq/L to LLN 
11.0 to 16.0 mEq/L
8.0 to 11.0 mEq/L
8.0 mEq/L
16.0 mmol/L to LLN
11.0 to 16.0 mmol/L
8.0 to 11.0 mmol/L
8.0 mmol/L
Pediatric < 4 Years
NA
11.0 mEq/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


GS-9688
Protocol GS-US-389-2024
Final
Gilead Sciences, Inc. 
Amendment 2.1
CONFIDENTIAL
Page 117
27 August 2019
CHEMISTRY
Grade 1
Grade 2
Grade 3
Grade 4
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-389-2024
Final
Gilead Sciences, Inc. 
Amendment 2.1
CONFIDENTIAL
Page 118
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-389-2024
Final
Gilead Sciences, Inc. 
Amendment 2.1
CONFIDENTIAL
Page 119
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-389-2024
Final
Gilead Sciences, Inc. 
Amendment 2.1
CONFIDENTIAL
Page 120
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-389-2024
Final
Gilead Sciences, Inc. 
Amendment 2.1
CONFIDENTIAL
Page 121
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 
(eg, anticoagulation, lysis 
filter, invasive procedure) 
Deep vein thrombosis AND 
Intervention indicated (eg, 
anticoagulation, lysis filter, 
invasive procedure) 
Embolic event (eg, pulmonary 
embolism, life-threatening 
thrombus) 
Vasovagal Episode (associated 
with a procedure of any kind)
Present without loss of 
consciousness 
Present with transient loss of 
consciousness
NA 
NA
Ventricular Dysfunction 
(congestive heart failure, 
CHF)
NA
Asymptomatic diagnostic 
finding AND intervention 
indicated
New onset with symptoms 
OR Worsening symptomatic 
CHF
Life-threatening CHF


GS-9688
Protocol GS-US-389-2024
Final
Gilead Sciences, Inc. 
Amendment 2.1
CONFIDENTIAL
Page 122
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-389-2024
Final
Gilead Sciences, Inc. 
Amendment 2.1
CONFIDENTIAL
Page 123
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-389-2024
Final
Gilead Sciences, Inc. 
Amendment 2.1
CONFIDENTIAL
Page 124
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-389-2024
Final
Gilead Sciences, Inc. 
Amendment 2.1
CONFIDENTIAL
Page 125
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-389-2024
Final
Gilead Sciences, Inc. 
Amendment 2.1
CONFIDENTIAL
Page 126
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-389-2024
Final
Gilead Sciences, Inc. 
Amendment 2.1
CONFIDENTIAL
Page 127
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-389-2024
Final
Gilead Sciences, Inc. 
Amendment 2.1
CONFIDENTIAL
Page 128
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-389-2024
Final
Gilead Sciences, Inc. 
Amendment 2.1
CONFIDENTIAL
Page 129
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-389-2024
Final
Gilead Sciences, Inc. 
Amendment 2.1
CONFIDENTIAL
Page 130
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-389-2024
Final
Gilead Sciences, Inc. 
Amendment 2.1
CONFIDENTIAL
Page 131
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-389-2024
Final
Gilead Sciences, Inc. 
Amendment 2.1
CONFIDENTIAL
Page 132
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-389-2024
Final
Gilead Sciences, Inc. 
Amendment 2.1
CONFIDENTIAL
Page 133
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


GS-9688
Protocol GS-US-389-2024
Final
Gilead Sciences, Inc. 
Amendment 2.1
CONFIDENTIAL
Page 134
27 August 2019

SAP_001.pdf: 
STATISTICAL ANALYSIS PLAN
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 Virally-Suppressed Adult 
Subjects with Chronic Hepatitis B
Name of Test Drug:
GS-9688
Study Number:
GS-US-389-2024
Protocol Version (Date):
Original:
15 January 2018
Amendment 1:
13 March 2018
Analysis Type:
Week 24 Analysis and Final Analysis
Analysis Plan Version:
1.0
Analysis Plan Date:
18 January 2019
Analysis Plan Author:
CONFIDENTIAL AND PROPRIETARY INFORMATION
PPD
PPD
(r} GILEAU 


GS-9688
GS-US-389-2024 Statistical Analysis Plan
Final
CONFIDENTIAL
Page 2
18 January 2019
TABLE OF CONTENTS
TABLE OF CONTENTS ..............................................................................................................................................2
LIST OF IN-TEXT TABLES........................................................................................................................................4
LIST OF IN-TEXT FIGURES ......................................................................................................................................4
LIST OF ABBREVIATIONS........................................................................................................................................5
PHARMACOKINETIC ABBREVIATIONS................................................................................................................7
1.
INTRODUCTION ................................................................................................................................................8
1.1.
Study Objectives ......................................................................................................................................8
1.2.
Study Design............................................................................................................................................9
1.3.
Sample Size and Power..........................................................................................................................10
2.
TYPE OF PLANNED ANALYSIS ....................................................................................................................11
2.1.
Data Monitoring Committee Analysis ...................................................................................................11
2.2.
Internal Data Review Team Analysis.....................................................................................................11
2.3.
Week 24 Analysis ..................................................................................................................................11
2.4.
Final Analysis ........................................................................................................................................11
3.
GENERAL CONSIDERATIONS FOR DATA ANALYSES............................................................................12
3.1.
Analysis Sets..........................................................................................................................................12
3.1.1.
All Randomized Analysis Set...............................................................................................12
3.1.2.
Full Analysis Set ..................................................................................................................12
3.1.3.
Safety Analysis Set...............................................................................................................12
3.1.4.
Pharmacokinetic Analysis Set..............................................................................................13
3.1.5.
Pharmacokinetic Substudy Analysis Set ..............................................................................13
3.1.6.
Biomarker Analysis Set........................................................................................................13
3.2.
Subject Grouping ...................................................................................................................................13
3.3.
Strata and Covariates..............................................................................................................................13
3.4.
Examination of Subject Subsets.............................................................................................................13
3.5.
Multiple Comparisons............................................................................................................................13
3.6.
Missing Data and Outliers......................................................................................................................14
3.6.1.
Missing Data ........................................................................................................................14
3.6.2.
Outliers.................................................................................................................................14
3.7.
Data Handling Conventions and Transformations .................................................................................14
3.8.
Analysis Visit Windows.........................................................................................................................16
3.8.1.
Definition of Study Day .......................................................................................................16
3.8.2.
Analysis Visit Windows.......................................................................................................16
3.8.3.
Selection of Data in the Event of Multiple Records in an Analysis
Window................................................................................................................................18
4.
SUBJECT DISPOSITION ..................................................................................................................................20
4.1.
Subject Enrollment and Disposition.......................................................................................................20
4.2.
Extent of Study Drug Exposure and Adherence.....................................................................................21
4.2.1.
Duration of Exposure to Study Drug....................................................................................21
4.2.2.
Adherence to Study Drug.....................................................................................................21
4.3.
Protocol Deviations................................................................................................................................22
5.
BASELINE CHARACTERISTICS....................................................................................................................24
5.1.
Demographics ........................................................................................................................................24
5.2.
Other Baseline Characteristics ...............................................................................................................24
5.3.
Medical History......................................................................................................................................25


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6.
EFFICACY ANALYSES ...................................................................................................................................26
6.1.
Primary Efficacy Endpoint.....................................................................................................................26
6.1.1.
Definition of Primary Efficacy Endpoint .............................................................................26
6.1.2.
Statistical Hypothesis for Primary Efficacy Endpoint..........................................................26
6.1.3.
Analysis of Primary Efficacy Endpoint................................................................................26
6.1.4.
Subgroup Analysis of Primary Efficacy Endpoint ...............................................................27
6.2.
Secondary Efficacy Endpoints ...............................................................................................................27
6.2.1.
Definition of Secondary Efficacy Endpoints........................................................................27
6.2.2.
Analysis Methods for Secondary Efficacy Endpoints..........................................................28
6.3.
Exploratory Efficacy Endpoints.............................................................................................................29
6.3.1.
Definition of Exploratory Efficacy Endpoints......................................................................29
6.3.2.
Analysis Methods for Exploratory Efficacy Endpoints........................................................30
6.4.
Changes From Protocol-Specified Efficacy Analyses............................................................................30
7.
SAFETY ANALYSES........................................................................................................................................31
7.1.
Adverse Events and Deaths....................................................................................................................31
7.1.1.
Adverse Event Dictionary ....................................................................................................31
7.1.2.
Adverse Event Severity........................................................................................................31
7.1.3.
Relationship of Adverse Events to Study Drug....................................................................31
7.1.4.
Serious Adverse Events........................................................................................................31
7.1.5.
Treatment-Emergent Adverse Events...................................................................................31
7.1.6.
Summaries of Adverse Events and Deaths...........................................................................32
7.2.
Laboratory Evaluations ..........................................................................................................................33
7.2.1.
Summaries of Numeric Laboratory Results .........................................................................34
7.2.2.
Graded Laboratory Values ...................................................................................................34
7.2.3.
Liver-related Laboratory Evaluations...................................................................................35
7.2.4.
Dose Limiting Toxicities......................................................................................................36
7.2.5.
Study Specific Stopping Criteria..........................................................................................37
7.3.
Body Weight, Body Mass Index and Vital Signs...................................................................................37
7.4.
Prior and Concomitant Medications.......................................................................................................38
7.4.1.
Prior Medications .................................................................................................................38
7.4.2.
Concomitant Medications.....................................................................................................38
7.5.
Electrocardiogram Results .....................................................................................................................39
7.6.
Other Safety Measures ...........................................................................................................................39
7.7.
Changes From Protocol-Specified Safety Analyses...............................................................................40
8.
PHARMACOKINETIC ANALYSES ................................................................................................................41
8.1.
PK Sample Collection............................................................................................................................41
8.1.1.
PK Analyses Related to Intensive PK Sampling..................................................................41
8.1.2.
Estimation of PK Parameters ...............................................................................................41
8.1.3.
Pharmacokinetic Parameters ................................................................................................42
8.1.4.
Analysis of Dose Proportionality .........................................................................................43
8.2.
PK Analyses Related to Sparse PK Sampling........................................................................................44
9.
REFERENCES ...................................................................................................................................................45
10.
SOFTWARE.......................................................................................................................................................46
11.
SAP REVISION..................................................................................................................................................47
12.
APPENDICES ....................................................................................................................................................48
Appendix 1.
Schedule of Assessments........................................................................................................49
Appendix 2.
HRQoL Score Calculation Algorithms...................................................................................53


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LIST OF IN-TEXT TABLES
Table 3-1.
Analysis Visit Windows for On-treatment qHBsAg, HBV DNA and Safety 
Laboratory Data......................................................................................................................16
Table 3-2.
Analysis Visit Windows for On-treatment Quantitative HBeAg, Quantitative 
HBCrAg and HBV RNA........................................................................................................17
Table 3-3.
Analysis Visit Windows for On-treatment Qualitative HBV Serology..................................17
Table 3-4.
Analysis Visit Windows for On-treatment Vital Signs ..........................................................17
Table 3-5.
Analysis Visit Windows for Posttreatment qHBsAg, HBV DNA, Quantitative 
HBeAg, HBCrAg, HBV RNA, Vital Signs and Safety Laboratory Data...............................18
Table 3-6.
Analysis Visit Windows for Posttreatment Qualitative HBV Serology .................................18
Table 8-1.
Study Treatments and Associated Analytes ...........................................................................42
Table 8-2.
PK Parameters for Each Analyte............................................................................................42
LIST OF IN-TEXT FIGURES
Figure 1.
Study Schemaa..........................................................................................................................9


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LIST OF ABBREVIATIONS
AE
adverse event
ANOVA
analysis of variance
ALP
alkaline phosphatase
ALT
alanine aminotransferase
AST
aspartate transaminase
ATC
anatomical therapeutic chemical
AUC
area under the curve
AV
atrioventricular
BLQ
below the limit of quantitation
BMI
body mass index
BPM
beats per minute
C-QT
concentration-QT
CG
Cockcroft-Gault
CHB
chronic hepatitis B
CI
confidence interval
CK
creatine kinase
CLDQ
Chronic Liver Disease Questionnaire
CSR
clinical study report
CV
coefficient of variation
DLT
dose limiting toxicity
DMC
data monitoring committee
DNA
deoxyribonucleic acid
ECG
electrocardiogram
eCRF
electronic case report form
eGFR
estimated glomerular filtration rate
EOT
end of treatment
ET
early termination
FAS
full analysis set
FU
follow-up
GLSM
geometric least-squares means
HBcrAg
hepatitis B core-related antigen
HBV
hepatitis B virus
HBeAb
hepatitis B e antibody
HBeAg
hepatitis B e antigen
HBsAb
hepatitis B surface antibody
HBsAg
hepatitis B surface antigen
HLGT
high level group term
HLT
high level term
HR
heart rate


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HRQoL
health-related quality of life
ID
identification
IDRT
internal data review team
INR
international normalized ratio
IXRS
interactive voice or web response system
LDH
lactate dehydrogenase
LLT
lower level term
LOQ
limit of quantitation
LLOQ
lower limit of quantitation
MedDRA
Medical Dictionary for Regulatory Activities
MH
Mantel-Haenszel
OAV
oral antiviral
PBMC
peripheral blood mononuclear cell
PD
pharmacodynamics
Peg-IFN
pegylated interferon
PK
pharmacokinetics
PT
preferred term
PTM
placebo-to-match
PVE
Pharmacovigilance and Epidemiology
Q1
first quartile
Q3
third quartile
qHBsAg
quantitative hepatitis B surface antigen
RBC
red blood cell
RNA
ribonucleic acid
SAE
serious adverse event
SAP
statistical analysis plan
SD
standard deviation
SE
standard error
SNPs
single nucleotide polymorphisms
SOC
system organ class
TE
treatment emergent
TFLs
tables, figures, and listings
TLR
toll-like receptor
TND
target not detected
ULN
upper limit of normal
WBC
white blood cell
WHO
World Health Organization
WPAI: Hep B
Work Productivity and Activity Impairment Questionnaire: Hepatitis B


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PHARMACOKINETIC ABBREVIATIONS
AUC0-24
area under the concentration during 24 hours
%AUCexp
percentage of AUC extrapolated between AUClast and AUCinf
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
Clast
last observed quantifiable concentration of the drug 
Cmax
maximum observed concentration of drug 
Ctau
observed drug concentration at the end of the dosing interval
CL/F
apparent oral clearance after administration of the drug:
at steady state: CL/F = Dose/AUCinf , where “Dose” is the dose of the drug
τ
The nominal time point for a key event or dosing interval 
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 (z)
Tlast
time (observed time point) of Clast
Tmax
time (observed time point) of Cmax
z
terminal elimination rate constant, estimated by linear regression of the terminal elimination phase 
of the concentration of drug versus time curve
Vz/F
apparent volume of distribution of the drug


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1.
INTRODUCTION
This statistical analysis plan (SAP) describes the statistical analysis methods and data 
presentations to be used in tables, figures, and listings (TFLs) in the clinical study report (CSR) 
for Study GS-US-389-2024. This SAP is based on the study protocol Amendment 1 dated 
13 March 2018 and the electronic case report form (eCRF). This SAP will be finalized before the 
Week 24 analysis. Any changes made after the finalization of the SAP will be documented in the 
CSR.
1.1.
Study Objectives
The primary objectives of this study are as follows:

To evaluate the safety and tolerability of multiple oral doses of GS-9688 at Week 24 in 
virally suppressed chronic hepatitis B (CHB) adult subjects on oral antivirals (OAVs)

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 hepatitis B surface antigen (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 pharmacokinetics (PK) of GS-9688 

To evaluate the proportion of subjects experiencing hepatitis B virus (HBV) virologic 
breakthrough (2 consecutive visits of HBV deoxyribonucleic acid (DNA) ≥ 69 IU/mL)

To evaluate the incidence of drug resistance mutations


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The exploratory objectives of this study are as follows:
1.2.
Study Design
This is a multicenter, randomized, double-blind, placebo-controlled Phase 2 study of GS-9688 in 
virally suppressed adult CHB subjects on OAVs.
Figure 1.
Study Schemaa
CCI
Cohort 1: 
Cohort 2: 
HBeAg-positive CHB subjects 
HBeAg-n egative CHB subjects 
N= 25 
N:25 
Bd,:!,~lin1:t 
W=l 23 (Last GS-9688/ 
lld:!.eli, m 
Week.23 (Last GS-9688/ 
(Day 1) 
Placebo uose) 
Wook48/ED 
(Day- 1) 
Placebo uose) 
Wook48/ED 
Arm A 
OAVTherapy 
Arm A 
OAVTherapy 
N=5 
fll=5 
Placl:!bo 
Placebo 
weekly x 24 doses 
weekly x 24 doses 
Arm B 
OAVTherapy 
ArmB 
OAVTherapy 
N::::10 
N=10 
GS-968815 Mg 
GS-9688 L5 mg 
weekly x 24 closes 
weekly x 24 closes 
Arm C 
OAVTherapy 
Arm ( 
OAVTherapy 
N=lO 
N=l O 
Gs-9688 3 mg 
Gs-9688 3 mg 
weekly x 24 doses 
weekly x 24 doses 
a 
Coho11 1 and Coho11 2 will nm in parallel 


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Approximately 50 virally suppressed subjects currently being treated with a commercially 
available OAV for CHB will be enrolled into 2 cohorts in this study.

Cohort 1 (N = 25): HBeAg-positive CHB subjects

Cohort 2 (N = 25): HBeAg-negative CHB subjects
Within each cohort, approximately 25 subjects will be randomized in a 1:2:2 ratio to one of the 
3 treatment arms (A: B: C). For the 48-week duration of the study, all subjects will remain on 
their current commercially available OAV therapy in addition to the following treatments:

Treatment Arm A: Approximately 5 subjects 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 10 subjects 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 10 subjects 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 the fasted state.
After the 24th dose (Week 23 visit), GS-9688/PTM will be discontinued. Subjects will continue 
being treated with their original approved OAV and will be followed until the end of study 
(Week 48/early termination [ET]). The total study duration for each subject will be 48 weeks 
inclusive of the treatment period. Subjects will be instructed to take their OAV treatment and 
other commercially available medications no earlier than 2 hours after GS-9688/PTM dosing.
The total time to complete all study visits is approximately 52 weeks, including the following 
periods:

Up to 30 day screening period

A 48-week period including 24 doses of weekly treatment of GS-9688/PTM and 48 weeks of 
OAV
The schedule of assessments is provided as an appendix (Appendix 1).
1.3.
Sample Size and Power
Due to the exploratory nature of this study, the sample size was not determined by any formal 
power calculation. The number of subjects in each treatment group was decided based on clinical 
experience.


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2.
TYPE OF PLANNED ANALYSIS
2.1.
Data Monitoring Committee Analysis
An independent, external data monitoring committee (DMC) will review the progress of the 
study and perform interim reviews of the safety data to protect subject welfare and preserve 
study integrity. To ensure the best interests of the subjects, the DMC will recommend to the 
sponsor if the nature, frequency, and severity of adverse effects associated with the study 
treatment warrant the early termination of the study, the continuation of the study, or the 
continuation of the study with modifications.
The initial DMC data review meeting will be conducted after 20 subjects have completed 
randomization. Subsequent meetings may be held approximately every 3 months, with the final 
meeting held after the last subject enrolled has completed the study drug dosing period.
The DMC’s role and responsibilities and the scope of analysis to be provided to the DMC are 
provided in a mutually agreed-upon charter, which defines the DMC membership, meeting 
logistics, and meeting frequency.
2.2.
Internal Data Review Team Analysis
An internal data review team (IDRT), external to the study team, may be unblinded after all 
subjects have completed Week 12 or prematurely discontinued from the study treatment prior to 
Week 12. The IDRT will review the unblinded safety, PD and efficacy data in order to guide 
strategic decisions regarding the future of the program. The IDRT will function independently 
from all other individuals associated with the conduct of this study, including investigators, 
Gilead personnel involved in the program, the study management team, and other committees 
(eg, ethics committees) overseeing the trial.
The IDRT’s role and responsibilities and the scope of analysis to be provided to the IDRT are 
provided in a mutually agreed-upon charter, which defines the IDRT membership, meeting 
logistics, and meeting frequency.
2.3.
Week 24 Analysis
The Week 24 analysis will be conducted after all subjects have completed Week 24 or 
prematurely discontinued study treatment prior to Week 24. The study will be unblinded at the 
time of the Week 24 analysis.
2.4.
Final Analysis
After all subjects have completed the study, outstanding data queries have been resolved or 
adjudicated as unresolvable, and the data have been cleaned and finalized, the final analysis of 
the data will be performed.


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3.
GENERAL CONSIDERATIONS FOR DATA ANALYSES
Analysis results will be presented using descriptive statistics. For categorical variables, the 
number and percentage of subjects in each category will be presented; for continuous variables, 
the number of subjects (n), mean, standard deviation (SD) or standard error (SE), median, 
first quartile (Q1), third quartile (Q3), minimum, and maximum will be presented.
By-subject listings will be presented for subjects in the All Randomized Analysis Set and sorted 
by subject identification (ID) number, visit date, and time (if applicable). Data collected on log 
forms, such as adverse events (AEs), will be presented in chronological order for each subject. 
The treatment group to which subjects were randomized will be used in the listings. Age, sex at 
birth, race, and ethnicity will be included in the listings, if space permits.
3.1.
Analysis Sets
Analysis sets define the subjects to be included in an analysis. Analysis sets and their definitions 
are provided in this section. The analysis set will be identified and included as a subtitle of each 
table, figure, and listing.
For each analysis set, the number and percentage of subjects eligible for inclusion, as well as the 
number and percentage of subjects who were excluded and the reasons for their exclusion, will 
be summarized by treatment group.
A listing of reasons for exclusion from analysis sets will be provided by subject.
3.1.1.
All Randomized Analysis Set
The All Randomized Analysis Set includes all subjects who were randomized in the study.
Subjects are grouped within the All Randomized Analysis Set by the treatment group to which
they were randomized. 
3.1.2.
Full Analysis Set
The Full Analysis Set (FAS) includes all randomized subjects who took at least 1 dose of the 
study drug. The study drug in this study is GS-9688 or PTM. Subjects are grouped within the 
FAS by the treatment group to which they were randomized. This is the primary analysis set for 
efficacy analyses.
3.1.3.
Safety Analysis Set
The Safety Analysis Set includes all subjects who took at least 1 dose of the study drug. Subjects 
are grouped within the Safety Analysis Set according to the treatment they actually received. 
This is the primary analysis set for safety analyses.


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3.1.4.
Pharmacokinetic Analysis Set
The PK Analysis Set includes all randomized subjects who took at least 1 dose of the study drug 
and have at least 1 nonmissing concentration value reported by the PK laboratory. This is the 
primary analysis set for all PK analyses.
3.1.5.
Pharmacokinetic Substudy Analysis Set
 
 
 
3.1.6.
Biomarker Analysis Set
The Biomarker Analysis Set includes all randomized subjects who took at least 1 dose of the
study drug and have at least 1 nonmissing biomarker value for each respective biomarker. The 
biomarkers to be analyzed under this SAP include IL-1RA and IL-12p40 only.
3.2.
Subject Grouping
For analyses based on the All Randomized Analysis Set, FAS, or Biomarker Analysis Set,
subjects will be grouped according to the treatment to which they were randomized.
 
3.3.
Strata and Covariates
Approximately 25 HBeAg-positive subjects (Cohort 1) and approximately 25 HBeAg negative 
subjects (Cohort 2) will be randomly assigned to treatment arms (A, B, or C) in a 1:2:2 ratio
using an interactive voice or web response system (IXRS). Stratification will be based on the 
following variable: 

HBeAg (positive, negative)
If there are discrepancies in stratification factor values between the IXRS and the clinical
database, the values recorded in the clinical database will be used for analyses.
Analysis endpoints will be evaluated by baseline HBeAg status and overall for each treatment 
group.
3.4.
Examination of Subject Subsets
Due to the exploratory nature and the small sample size of this study, subgroup analyses based 
on presumed prognostic baseline characteristics will not be performed for efficacy endpoints.
3.5.
Multiple Comparisons
Adjustments for multiplicity will not be made because no formal statistical hypothesis testing
will be performed in this study.
CCI
CCI


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3.6.
Missing Data and Outliers
3.6.1.
Missing Data
In general, missing data will not be imputed unless methods for handling missing data are 
specified. Exceptions are presented in this document.
A missing baseline laboratory result will be treated as normal (ie, no toxicity grade) for the 
laboratory abnormality summary.
Both baseline and postbaseline borderline results for HBeAg, hepatitis B e antibody (HBeAb), 
HBsAg, and hepatitis B surface antibody (HBsAb) will be imputed as follows:

HBsAb/HBeAb borderline HBsAb/HBeAb negative

HBsAg/HBeAg borderline HBsAg/HBeAg positive
For missing last dose date of study drug, imputation rules are described in Section 3.8.1. The 
handling of missing or incomplete dates for AE onset is described in Section 7.1.5.2, and for 
prior and concomitant medications in Section 7.4.
3.6.2.
Outliers
Outliers will be identified during the data management and data analysis process, but no 
sensitivity analyses will be conducted. All data will be included in the data analysis. 
3.7.
Data Handling Conventions and Transformations
The following conventions will be used for the imputation of date of birth when it is partially 
missing or not collected:

If only month and year of birth is collected, then “15” will be imputed as the day of birth

If only year of birth is collected, then “01 July” will be imputed as the day and month of birth

If year of birth is missing, then date of birth will not be imputed
In general, age collected at Day 1 (in years) will be used for analyses and presented in listings. If 
age at Day 1 is not available for a subject, then age derived based on date of birth and the Day 1 
visit date will be used instead. If an enrolled subject was not dosed with any study drug, the 
randomization date will be used instead of the Day 1 visit date. For screen failures, the date the 
first informed consent was signed will be used for the age derivation. Age required for 
longitudinal and temporal calculations and analyses (eg, estimates of creatinine clearance, age at 
date of AE) will be based on age derived from date of birth and the date of the measurement or 
event, unless otherwise specified.


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Non-PK data that are continuous in nature but are less than the lower limit of quantitation (LOQ) 
or above the upper LOQ will be imputed as follows:

A value that is 1 unit less than the LOQ will be used to calculate descriptive statistics if the 
datum is reported in the form of “x” (where x is considered the LOQ). For example, if the 
values are reported as < 50 and < 5.0, values of 49 and 4.9, respectively, will be used to 
calculate summary statistics. An exception to this rule is any value reported as < 1 or < 0.1, 
etc. For values reported as < 1 or < 0.1, a value of 0.9 or 0.09, respectively, will be used to 
calculate summary statistics.

A value that is 1 unit above the LOQ will be used to calculate descriptive statistics if the 
datum is reported in the form of “> x” (where x is considered the LOQ). Values with decimal 
points will follow the same logic as above.

The LOQ will be used to calculate descriptive statistics if the datum is reported in the form of 
“≤ x” or “≥ x” (where x is considered the LOQ).
For HBV DNA, if the value in IU/mL is above the upper LOQ, the corresponding diluted HBV 
DNA value, if available, will be used.
If methods based on the assumption that the data are normally distributed are not adequate, 
analyses may be performed on transformed data, eg, log-transformed data, or nonparametric 
analysis methods may be used, as appropriate.
Natural logarithm transformation will be used for plasma/blood concentrations and analysis of 
PK parameters. Plasma concentration values that are below the limit of quantitation (BLQ) will 
be presented as “BLQ” in the concentration data listing. Values that are BLQ will be treated as 
0 at predose time points, and one-half the value of the LOQ at postbaseline time points.
The following conventions will be used for the presentation of summary and order statistics: 

If at least 1 subject has a concentration value of BLQ for the time point, the minimum value 
will be displayed as “BLQ”.

If more than 25% of the subjects have a concentration data value of BLQ for a given time 
point, the minimum and Q1 values will be displayed as “BLQ”.

If more than 50% of the subjects have a concentration data value of BLQ for a given time 
point, the minimum, Q1, and median values will be displayed as “BLQ”.

If more than 75% of the subjects have a concentration data value of BLQ for a given time 
point, the minimum, Q1, median, and Q3 values will be displayed as “BLQ”.

If all subjects have concentration data values of BLQ for a given time point, all order 
statistics (minimum, Q1, median, Q3, and maximum) will be displayed as “BLQ”.
PK parameters that are BLQ will be imputed as one-half LOQ before log transformation or 
statistical model fitting.


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3.8.
Analysis Visit Windows
3.8.1.
Definition of Study Day
Study day will be calculated from the first dose date of study drug and derived as follows:

For postdose study days: Assessment Date – First Dose Date of Study Drug + 1

For days prior to the first dose: Assessment Date – First Dose Date of Study Drug
Therefore, study Day 1 is the day of first dose of study drug.
The last dose date of the study drug will be the stop date on the study drug administration eCRF 
for the record where the “study drug was permanently withdrawn” flag is “Yes”.
If the last study drug dose date is missing, the latest date among the study drug end date, clinical 
visit date, laboratory sample collection date, and vital signs assessment date that occurred during 
the on-treatment period will be used.
3.8.2.
Analysis Visit Windows
Subject visits might not occur on protocol-specified days. Therefore, for the purpose of analysis, 
observations will be assigned to analysis windows.
Data collected up to the last dose date + 8 days will be considered as on-treatment data whereas 
data collected afterwards will be considered as posttreatment data. 
On-treatment data will be mapped to the analysis windows defined in Table 3-1, Table 3-3, and 
Table 3-4.
Table 3-1.
Analysis Visit Windows for On-treatment qHBsAg, HBV DNA and 
Safety Laboratory Data
Analysis Visit
Nominal Study Day
Lower Limit
Upper Limit
Baseline
1
(none)
1
Week 2
15
2
22
Week 4
29
23
43
Week 8
57
44
67
Week 11
78
68
81
Week 12
85
82
99
Week 16
113
100
127
Week 20
141
128
151
Week 23
162
152
165
Week 24
169
166
≥ 169


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Table 3-2.
Analysis Visit Windows for On-treatment Quantitative HBeAg, 
Quantitative HBCrAg and HBV RNA
Analysis Visit
Nominal Study Day
Lower Limit
Upper Limit
Baseline
1
(none)
1
Week 4
29
2
43
Week 8
57
44
71
Week 12
85
72
99
Week 16
113
100
127
Week 20
141
128
155
Week 24
169
156
≥ 169
Table 3-3.
Analysis Visit Windows for On-treatment Qualitative HBV Serology
Analysis Visit
Nominal Study Day
Lower Limit
Upper Limit
Baseline
1
(none)
1
Week 12
85
2
127
Week 24
169
128
≥ 169
Table 3-4.
Analysis Visit Windows for On-treatment Vital Signs
Analysis Visit
Nominal Study Day
Lower Limit
Upper Limit
Baseline
1
(none)
1
Day 1 + 24 hrs
2
2
2
Week 2
15
3
22
Week 4
29
23
43
Week 8
57
44
67
Week 11
78
68
81
Week 12
85
82
99
Week 16
113
100
127
Week 20
141
128
151
Week 23
162
152
165
Week 24
169
166
≥ 169
Posttreatment data will be mapped to the posttreatment analysis windows, which will be defined 
by follow-up (FU) Day (ie, FU Day = Assessment Date – Last Dose Date of Study Drug) as 
described in Table 3-5 and Table 3-6.


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Table 3-5.
Analysis Visit Windows for Posttreatment qHBsAg, HBV DNA, 
Quantitative HBeAg, HBCrAg, HBV RNA, Vital Signs and Safety
Laboratory Data
Analysis Visit
Nominal FU Day
Lower Limit
Upper Limit
Week 28
35
9
63
Week 36
91
64
133
Week 48
175
134
≥175
Table 3-6.
Analysis Visit Windows for Posttreatment Qualitative HBV Serology
Analysis Visit
Nominal FU Day
Lower Limit
Upper Limit
Week 36
91
9
133
Week 48
175
134
≥ 175
Data from ophthalmology assessment, PD biomarkers, and HRQoL surveys will be summarized 
according to the nominal visit as recorded in the database.
3.8.3.
Selection of Data in the Event of Multiple Records in an Analysis Window
Depending on the statistical analysis method, single values may be required for each analysis 
window. For example, change from baseline by visit usually requires a single value, whereas a 
time-to-event analysis would not require 1 value per analysis window.
If multiple valid, nonmissing, continuous measurements exist in an analysis window, records 
will be chosen based on the following rules if a single value is needed:

In general, the baseline value will be the last nonmissing value on or prior to the first dose 
date of study drug, unless specified differently. If multiple measurements occur on the same 
day, the last nonmissing value prior to the time of first dosing of study drug will be 
considered as the baseline value. If these multiple measurements occur at the same time or 
the time is not available, the average of these measurements will be considered the baseline 
value.

For postbaseline values (except for alanine aminotransferase [ALT]): 
The record closest to the nominal day for that visit will be selected.
If there are 2 records that are equidistant from the nominal day, the later record will be 
selected.
If there is more than 1 record on the selected day, the average will be taken except for 
qHBsAg (IU/mL), HBV DNA (IU/mL), and quantitative HBeAg (IU/mL), for which the 
geometric mean will be taken.


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


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4.
SUBJECT DISPOSITION
4.1.
Subject Enrollment and Disposition
A summary of subject enrollment will be provided by HBeAg status (positive, negative) and 
overall for each treatment group and study overall for each country and investigator within a 
country. The summary will present the number and percentage of subjects enrolled. For each 
column, the denominator for the percentage calculation will be the total number of subjects 
analyzed for that column. If there are discrepancies in the value used for stratification
(ie, HBeAg status) assignment between the IXRS and the clinical database, the value collected in 
the clinical database will be used for the summary. A listing of subjects with discrepancies in the 
HBeAg value used for stratification assignment between the IXRS and the clinical database at 
the time of data finalization will be provided.
The randomization schedule used for the study will be provided as an appendix to the CSR.
A summary of subject disposition will be provided by HBeAg status (positive, negative) and 
overall for each treatment group and the study overall. This summary will present the number of 
subjects screened, the number of screen failure subjects who were not randomized, the number of 
subjects who met all eligibility criteria but were not randomized with reasons for subjects not 
randomized, the number of subjects randomized, and the number of subjects in each of the 
categories listed below:

Safety Analysis Set 

FAS

PK Analysis Set


Biomarker Analysis Set (for IL-1RA and IL-12p40 only)

Continuing study drug

Completed study drug

Did not complete study drug with reasons for premature discontinuation of study drug

Continuing study

Completed study

Did not complete the study with reasons for premature discontinuation of study
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For the status of study drug and study completion and the reasons for premature discontinuation, 
the number and percentage of subjects in each category will be provided. The denominator for 
the percentage calculation will be the total number of subjects in the Safety Analysis Set 
corresponding to that column. In addition, a flowchart will be provided to depict the disposition.
The following by-subject listings will be provided by subject ID number in ascending order to 
support the above summary tables:

Reasons for premature study drug or study discontinuation
4.2.
Extent of Study Drug Exposure and Adherence
Extent of exposure to study drug will be examined by assessing the total duration of exposure to 
study drug and the level of adherence relative to the study drug regimen specified in the protocol.
4.2.1.
Duration of Exposure to Study Drug
Total duration of exposure to study drug will be defined as last dose date minus first dose date 
plus 7, regardless of any temporary interruptions in study drug administration, and will be 
expressed in weeks using up to 1 decimal place (eg, 4.5 weeks). If the last study drug dose date is 
missing, the latest date among the study drug end date, clinical visit date, laboratory sample 
collection date, and vital signs assessment date that occurred during the on-treatment period will 
be used.
The total duration of exposure to study drug will be summarized using descriptive statistics 
(n, mean, SD, median, Q1, Q3, minimum, and maximum) and using the number (ie, cumulative
counts) and percentage of subjects exposed through the following time periods: baseline
(≥1 day), Week 2 (≥ 15 days), Week 4 (≥ 29 days), Week 8 (≥ 57 days), Week 11 (≥ 78 days), 
Week 12 (≥ 85 days), Week 16 (≥ 113 days), Week 20 (≥ 141 days), Week 23 (≥ 162 days).
Summaries will be provided by HBeAg status (positive, negative) and overall for each treatment
group for the Safety Analysis Set.
No formal statistical testing is planned.
4.2.2.
Adherence to Study Drug
The total number of doses administered will be summarized using descriptive statistics (n, mean, 
SD, median, Q1, Q3, minimum, and maximum).
The presumed total number of tablets taken by a subject will be determined by the data collected 
on the drug accountability eCRF using the following formula:







Returned
Tablets
of
No.
Dispensed
Tablets
of
No.
Taken
Tablets
of
Number 
Total


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4.2.2.1.
Prescribed Adherence
The level of prescribed adherence to the study drug regimen will be determined by the total 
amount of study drug taken relative to the total amount of study drug specified by the protocol 
for a subject who completes treatment in the study. 
The level of prescribed adherence will be expressed as a percentage using the following formula:
%
100
  
Protocol
by 
Specified
Drug
Study 
of
Amount 
Total
Taken  
Drug
Study 
of
Amount 
Total
(%)
Adherence
Prescribed








Note: If calculated adherence is greater than 100%, the result will be set to 100%.
For a record where the number of tablets returned was missing (with “Yes” answered for the
question “Was the Blister Pack Returned?”), it is assumed the number of tablets returned was 0. 
If the number of tablets dispensed was missing or any study drug blister was not returned or the
blister return status was unknown for the same dispensing date, all records for the same 
dispensing date for that study drug will be excluded from the calculations for both denominator 
and numerator.
Descriptive statistics for the level of prescribed adherence to study drug (n, mean, SD, median, 
Q1, Q3, minimum, and maximum) and the number and percentage of subjects belonging to 
adherence categories (< 95%, ≥ 95%) will be provided by HBeAg status (positive, negative) and 
overall within each treatment group for the Safety Analysis Set. 
No formal statistical testing is planned.
A by-subject listing of study drug administration and drug accountability will be provided 
separately by subject ID number (in ascending order) and visit (in chronological order).
4.3.
Protocol Deviations
Subjects who did not meet the eligibility criteria for study entry, but enrolled in the study will be 
summarized regardless of whether or not they were exempted by the sponsor. The summary will 
present the number and percentage of subjects who did not meet at least 1 eligibility (inclusion or 
exclusion) criterion and the number of subjects who did not meet specific criteria by HBeAg 
status (positive, negative) and overall for each treatment group based on the All Randomized 
Analysis Set. A by-subject listing will be provided for subjects who did not meet at least 
1 eligibility criterion. The listing will present the eligibility criterion (or criteria if more than 
1 deviation) that a subject did not meet and related comments, if collected.


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Protocol deviations occurring after subjects entered the study are documented during routine 
monitoring. The number and percentage of subjects with important protocol deviations by 
deviation reason (eg, nonadherence to study drug, violation of select inclusion/exclusion criteria) 
will be summarized by HBeAg status (positive, negative) and overall for each treatment group 
for the All Randomized Analysis Set. A by-subject listing will be provided for those subjects 
with important protocol deviation.
Subjects who received study drug other than their treatment assignment at randomization will be 
listed with the start and stop dates that they received incorrect study treatment.


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5.
BASELINE CHARACTERISTICS
5.1.
Demographics
Subject demographic variables (ie, age, sex, race, ethnicity and region [US, non-US]) will be 
summarized by HBeAg status (positive, negative) and overall for each treatment group and study 
overall using descriptive statistics (n, mean, SD, median, Q1, Q3, minimum, and maximum) for 
age, and using the number and percentage of subjects for age categories (< 50 years, ≥50 years), 
sex, race, ethnicity, and region. The summary of demographic data will be provided for the 
Safety Analysis Set.
A by-subject demographic listing, including the informed consent date, will be provided by 
subject ID number in ascending order.
5.2.
Other Baseline Characteristics
Other baseline characteristics include

Body weight (kg)

Height (cm)

Body mass index (BMI; kg/m2) as a continuous variable and as categories (< 18.5 kg/m2, 
≥18.5 kg/m2 – 25 kg/m2, ≥ 25 kg/m2 – 30 kg/m2, ≥ 30 kg/m2)

FibroTest score as a continuous variable and fibrosis stage by FibroTest score as a 
categorical variable (0.00 − 0.48, 0.49 − 0.74, 0.75 − 1.00)

HBsAg (log10 IU/mL) as a continuous variable and as categories (< 2 log10 IU/mL, 
≥2 log10 IU/mL –  3 log10 IU/mL, ≥3 log10 IU/mL –  4 log10 IU/mL, ≥ 4 log10 IU/mL)

HBV DNA (log10 IU/mL) as a continuous variable and as categories (< lower limit of 
quantitation [LLOQ], ≥ LLOQ)

HBeAb (positive, negative)

ALT (U/L) as a continuous variable and as categories based on central laboratory normal 
range (≤ upper limit of normal [ULN], > ULN – 5 × ULN, > 5 × ULN – 10 × ULN, 
> 10 ULN)

ALT level as categories based on American Association for the Study of Liver Diseases 
(AASLD) normal range with the ULN as 25 U/L for female and 35 U/L for male (≤ ULN, 
> ULN – 5 × ULN, > 5 × ULN – 10 × ULN, > 10 ULN

Current oral nucleoside/nucleotide treatment 


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


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6.
EFFICACY ANALYSES
6.1.
Primary Efficacy Endpoint
6.1.1.
Definition of Primary Efficacy Endpoint
The primary efficacy endpoint is the proportion of subjects with ≥ 1 log10 IU/mL decline in 
qHBsAg from baseline at Week 24.
6.1.2.
Statistical Hypothesis for Primary Efficacy Endpoint
No statistical hypothesis testing will be performed. 
6.1.3.
Analysis of Primary Efficacy Endpoint
The primary efficacy analysis will be performed for the FAS after the last subject has completed 
Week 24 assessments or prematurely discontinued study drug.
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, point estimates and the 2-sided 
95% exact confidence intervals (CIs) of the primary efficacy endpoint will be provided based on
the Clopper-Pearson method {Clopper 1934} by HBeAg status (positive, negative) and overall 
for each treatment group. In addition, point estimates and the 2-sided 95% exact CIs of the 
proportion difference (1.5 mg – PTM, 3 mg – PTM), will be displayed separately by HBeAg 
status (positive, negative) for each treatment group. CIs for the proportion differences will be 
constructed based on the standardized statistic and inverting two 1-sided tests {Chan 1999}.
To compare the GS-9688 1.5 mg dose group and the GS-9688 3 mg dose group with the placebo 
group for pooled HBeAg positive and negative subjects, the proportion differences
(1.5 mg - PTM, 3 mg – PTM) and the corresponding 95% CIs will be calculated using the 
stratum-adjusted Mantel-Haenszel (MH) method {Koch 1989}, stratified by HBeAg status 
(positive, negative), as follows: 
where

(P1 – P2) = 

h
h
h
w
d
w
, is the stratum-adjusted MH proportion difference, where 
h
d
=
h
h
p
p
2
1 
is the proportion difference of Groups 1 and 2 in stratum h (h = 1 and 2).

h
w =
h
h
h
h
n
n
n
n
2
1
2
1

, is the weight based on the harmonic mean of sample sizes for stratum h, 
where 
h
n1 and 
h
n2 are the sample sizes of Groups 1 and 2 in stratum h.
P 1 - Pz ± Z(l -a/2 ) x SE(P 1 - Pz), 


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
SE(P1 – P2) = 
2
2
*
2
*
2
1
*
1
*
1
2
)
(
1
)
1(
1
)
1(











h
h
h
h
h
h
h
h
w
n
p
p
n
p
p
w
, where 
1
5.0
1
1
*
1



h
h
h
n
m
p
and 
1
5.0
2
2
*
2



h
h
h
n
m
p
, where
h
m1 and 
h
m2 are the numbers of subjects with ≥ 1 log10 IU/mL 
decline in qHBsAg from baseline at Week 24 in Groups 1 and 2 in stratum h.

α = 0.05 for this study.

Z(1-α/2) = Z0.975 = 1.96 is the 97.5th percentile of the normal distribution.
If the computed lower confidence bound is less than –1, the lower bound is defined as –1. If the 
computed upper confidence bound is greater than 1, then the upper bound is defined as 1.
The point estimates and the 2-sided 95% exact CIs based on the Clopper-Pearson method will 
also be provided for the proportions in each treatment group.
A Forest plot will graphically present the point estimates and the CIs on the proportion 
difference (1.5 mg – PTM, 3 mg – PTM) by HBeAg status (positive, negative) and overall for 
each treatment group.
6.1.4.
Subgroup Analysis of Primary Efficacy Endpoint
No subgroup analyses will be performed.
6.2.
Secondary Efficacy Endpoints
6.2.1.
Definition of Secondary Efficacy Endpoints
The secondary efficacy endpoints include the following:

Proportion of subjects with ≥ 1 log10 IU/mL decline in qHBsAg from baseline at Weeks 4, 8, 
12, and 48

Change from baseline in qHBsAg (log10 IU/mL) at Weeks 4, 8, 12, 24, and 48

Proportion of subjects who achieve HBsAg loss at Weeks 12, 24, and 48

Proportion of HBeAg-positive subjects who achieve HBeAg loss and seroconversion at 
Weeks 12, 24, and 48

Proportion of subjects experiencing HBV virologic breakthrough (2 consecutive visits of 
HBV DNA ≥ 69 IU/mL)

Incidence of drug resistance mutations
J--


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HBV Serology definitions:

HBsAg loss: HBsAg changing from positive at baseline to negative at any postbaseline visit.

Confirmed HBsAg loss: HBsAg loss confirmed by any 2 consecutive results.

HBsAg loss reversion: Any postbaseline HBsAg positive result following HBsAg loss.

HBsAb seroconversion: HBsAb changing from negative or missing at baseline to positive at 
any postbaseline visit.  

Confirmed HBsAb seroconversion: HBsAb changing from negative or missing at baseline 
to positive at any postbaseline visit confirmed by any 2 consecutive results.

HBsAb seroreversion: Any postbaseline HBsAb negative result following HBsAb 
seroconversion.
HBeAg-related terminology is defined similarly.
The LLOQ for HBV DNA is defined as 20 IU/mL. The LLOQ for qHBsAg is defined as 
0.05 IU/mL.
Missing data will be treated as a nonevent unless otherwise specified (eg, no HBsAg loss, no 
seroconversion, etc.)
6.2.2.
Analysis Methods for Secondary Efficacy Endpoints
The proportion of subjects with ≥ 1 log10 IU/mL decline in qHBsAg from baseline at Weeks 4, 8, 
12, and 48 will be analyzed using the FAS similarly to the primary efficacy endpoint. Point 
estimates and 2-sided 95% exact CIs of the proportions will be provided based on the
Clopper-Pearson method by HBeAg status (positive, negative) and overall for each treatment 
group. In addition, point estimates and 2-sided 95% exact CIs of the proportion difference 
(1.5 mg – PTM, 3 mg – PTM), will be displayed separately by HBeAg status (positive, negative)
and overall for each treatment group.
A summary table will be provided for HBsAg-related serology results. The proportion of 
subjects who have ever had HBsAg loss, confirmed HBsAg loss, on-treatment HBsAg loss, 
posttreatment HBsAg loss (for subjects with positive HBsAg at the end of the on-treatment 
period), HBsAg loss with HBsAb seroconversion, HBsAg loss with HBsAb seroreversion, and 
HBsAg loss reversion with or without HBsAb seroconversion will be summarized by HBeAg 
status (positive, negative) and overall for each treatment group. 
Additional summary tables may be provided for the following: 
If ≥ 3 subjects achieved HBsAg loss,

The proportion of subjects with HBsAg loss will be summarized by visit through Week 48;


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If ≥ 3 subjects achieved HBsAg loss with HBsAb seroconversion,

The proportion of subjects with HBsAb seroconversion will be summarized by visit through 
Week 48

The proportion of subjects who have ever had HBsAg loss with HBsAb seroconversion, 
confirmed HBsAb seroconversion, on-treatment HBsAb seroconversion, posttreatment
HBsAb seroconversion (for subjects with negative or missing HBsAb at the end of the 
on-treatment period) will be summarized.
For subjects in the FAS with baseline HBeAg status positive, similar summary tables will be 
provided.
The proportion of subjects experiencing HBV virologic breakthrough by Week 48 will be 
evaluated by HBeAg status (positive, negative) and overall for each treatment group for all 
subjects in the FAS.
Summary statistics will be presented by HBeAg status (positive, negative) and overall for each 
treatment group for absolute values and change from baseline in qHBsAg (log10 IU/mL) by visit 
through Week 48. 
Imputation rules described in Section 3.6.1 will be used to assign HBeAg and HBsAg status for 
borderline results. 
Plots of the mean (SD) of absolute values and changes from baseline in qHBsAg through 
Week 48 will be presented by HBeAg status (positive, negative) and overall for each treatment 
group.
For drug resistance surveillance, sequence analysis of the HBV genome may be attempted for 
any subject who is currently being treated with OAV and experiences viremia (HBV DNA 
> 69 IU/mL) at any time point. Drug resistance mutations will be analyzed separately from this 
SAP and will be reported in the CSR.
6.3.
Exploratory Efficacy Endpoints
6.3.1.
Definition of Exploratory Efficacy Endpoints
 
 
CCI-
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6.3.2.
Analysis Methods for Exploratory Efficacy Endpoints
 
 
 
 
 
 
 
 
 
 
 
 
 
 
6.4.
Changes From Protocol-Specified Efficacy Analyses
There are no planned changes from protocol-specified efficacy analyses.
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7.
SAFETY ANALYSES
7.1.
Adverse Events and Deaths
7.1.1.
Adverse Event Dictionary
Clinical and laboratory adverse events (AEs) will be coded using the current version of
MedDRA. SOC, high level group term (HLGT), high level term (HLT), preferred term (PT), and 
lower level term (LLT) will be provided in the AE dataset.
7.1.2.
Adverse Event Severity
Adverse events are graded by the investigator as Grade 1, 2, 3, or 4 according to toxicity criteria
specified in the protocol. The severity grade of events for which the investigator did not record 
severity will be categorized as “missing” for tabular summaries and data listings. The missing 
category will be listed last in the summary presentation.
The severity of adverse events will be determined by the investigator as mild, moderate, or 
severe. 
7.1.3.
Relationship of Adverse Events to Study Drug
Related AEs are those for which the investigator selected “Related” on the AE eCRF to the 
question of “Related to Study Treatment.” Relatedness will always default to the investigator’s 
choice, not that of the medical monitor. Events for which the investigator did not record
relationship to study drug will be considered related to study drug for summary purposes. 
However, by-subject listings will show the relationship as missing.
7.1.4.
Serious Adverse Events
Serious adverse events (SAEs) will be identified and captured as SAEs if AEs met the definitions 
of SAEs that were specified in the study protocol. SAEs captured and stored in the clinical 
database will be reconciled with the SAE database from the Gilead Pharmacovigilance and 
Epidemiology (PVE) before database finalization.
7.1.5.
Treatment-Emergent Adverse Events
7.1.5.1.
Definition of Treatment-Emergent Adverse Events
Treatment-emergent adverse events (TEAEs) are defined as 1 or both of the following:

Any AEs with an onset date on or after the study drug start date and no later than 30 days 
after permanent discontinuation of study drug

Any AEs leading to premature discontinuation of study drug.


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7.1.5.2.
Incomplete Dates
If the onset date of the AE is incomplete and the AE stop date is not prior to the first dosing date 
of study drug, then the month and year (or year alone if month is not recorded) of onset 
determine whether an AE is treatment emergent. The event is considered treatment emergent if 
both of the following 2 criteria are met:

The AE onset is the same as or after the month and year (or year) of the first dose date of
study drug, and

The AE onset date is the same as or before the month and year (or year) of the date 
corresponding to 30 days after the date of the last dose of study drug 
An AE with completely missing onset and stop dates, or with the onset date missing and a 
stop date later than the first dosing date of study drug, will be considered to be treatment
emergent. In addition, an AE with the onset date missing and incomplete stop date with the same 
or later month and year (or year alone if month is not recorded) as the first dosing date of study 
drug will be considered treatment emergent.
7.1.6.
Summaries of Adverse Events and Deaths
AEs will be summarized based on the Safety Analysis Set.
For the Week 24 Analysis, TEAEs will be summarized as described below. For the Final 
Analysis, 2 sets of summaries will be generated: 1) TEAEs, and 2) all AEs up to Week 48/ET
(including TEAEs and AEs that are not treatment emergent, eg, during OAV treatment after 
Week 24).
A brief high-level summary of AEs will be provided by HBeAg status (positive, negative) and 
overall for each treatment group for the number and percentage of subjects who experienced the 
following: any AE, any AE of Grade 3 or above, any AE of Grade 2 or above, any 
treatment-related AE, any treatment-related AE of Grade 3 or above, any treatment-related AE of 
Grade 2 or above, any SAE, any treatment-related SAE, any AE that led to premature
discontinuation of study drug, any AE that led to temporary interruption of study drug. All 
deaths (treatment emergent or non-treatment emergent) observed in the study will also be 
included in this summary. 
Adverse event summaries will provide the number and percentage of subjects with AEs by SOC,
PT, and severity by HBeAg status (positive, negative) and overall for each treatment group as 
follows:

All AEs

AEs of Grade 3 or above

AEs of Grade 2 or above


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
All treatment-related AEs 

Treatment-related AEs of Grade 3 or above

Treatment-related AEs of Grade 2 or above

All SAEs

All treatment-related SAEs 

AEs leading to premature discontinuation of study drug

AEs leading to temporary interruption of study drug
Multiple events will be counted only once per subject in each summary. Adverse events will be 
summarized and listed first in alphabetic order by SOC and then by PT in descending order of 
total frequency within each SOC. For summaries by severity grade, the most severe grade will be 
used for those AEs that occurred more than once in an individual subject during the study. 
In addition to the above summary tables, all TEAEs and treatment-emergent treatment-related 
AEs will be summarized by PT only, in descending order of total frequency.
In addition to the by-treatment summaries described above, data listings will be provided for the 
following AEs:

All AEs, indicating whether the event is treatment emergent

AEs of Grade 3 or higher

All SAEs

All deaths

AEs leading to premature discontinuation of study drug

AEs leading to temporary interruption of study drug
7.2.
Laboratory Evaluations
Laboratory data collected during the study will be analyzed and summarized using both 
quantitative and qualitative methods. Summaries of laboratory data will be provided for the 
Safety Analysis Set and will include all available data. The analysis will be based on values 
reported in conventional units. When values are below the LOQ, they will be listed as such, and 
the closest imputed value will be used for the purpose of calculating summary statistics as 
specified in Section 3.7. Hemolyzed test results will not be included in the analysis, but they will 
be listed in by-subject laboratory listings.


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A by-subject listing for laboratory test results will be provided by subject ID number and visit in 
chronological order for hematology, serum chemistry, and urinalysis separately. Values falling 
outside of the relevant reference range and/or having a severity grade of 1 or higher on the 
Gilead Grading Scale for Severity of Adverse Events and Laboratory Abnormalities will be 
flagged in the data listings, as appropriate.
No formal statistical testing is planned.
7.2.1.
Summaries of Numeric Laboratory Results
Descriptive statistics (n, mean, SD, median, Q1, Q3, minimum, and maximum) will be provided 
using all available data by HBeAg status (positive, negative) and overall for each treatment
group for chemistry (including ALT, aspartate aminotransferase [AST], total bilirubin, alkaline 
phosphatase [ALP], creatine kinase [CK], fasting total cholesterol, fasting glucose, international 
normalized ratio [INR], lactate dehydrogenase [LDH]), hematology (including hematocrit, 
hemoglobin, lymphocytes, neutrophils, white blood cells [WBC], platelets), creatinine and 
estimated creatinine clearance calculated by the Cockcroft-Gault method as follows:

Baseline values 

Values at each postbaseline visit

Change from baseline at each postbaseline visit
A baseline laboratory value is defined as the last measurement obtained on or prior to the 
date/time of first dose of study drug. Change from baseline to a postbaseline visit will be defined 
as the visit value minus the baseline value. The mean, median, Q1, Q3, minimum, and maximum 
will be displayed to the reported number of digits; SD values will be displayed to the reported 
number of digits plus 1.
Median (Q1, Q3) of the observed values for ALT, total bilirubin, lymphocytes, and neutrophils 
will be plotted using a line plot by visit and by HBeAg status (positive, negative) and overall for 
each treatment group. 
In the case of multiple values in an analysis window, data will be selected for analysis as 
described in Section 3.8.3.
7.2.2.
Graded Laboratory Values
The Gilead Grading Scale for Severity of Adverse Events and Laboratory Abnormalities will be 
used to assign toxicity grades (0 to 4) to laboratory results for analysis. Grade 0 includes all 
values that do not meet the criteria for an abnormality of at least Grade 1. For laboratory tests 
with criteria for both increased and decreased levels, analyses for each direction (ie, increased, 
decreased) will be presented separately.


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7.2.2.1.
Treatment-Emergent Laboratory Abnormalities
Treatment-emergent laboratory abnormalities are defined as values that increase at least 
1 toxicity grade from baseline at any postbaseline time point, up to and including the date of the 
last dose of study drug plus 30 days for subjects who permanently discontinued study drug, or 
the last available date in the database snapshot for subjects who were still on treatment at the 
time of an interim analysis. If the relevant baseline laboratory value is missing, any abnormality 
of at least Grade 1 observed within the time frame specified above will be considered treatment
emergent.
7.2.2.2.
Summaries of Laboratory Abnormalities
Laboratory data that are categorical will be summarized using the number and percentage of 
subjects in the study with the given response at baseline and each scheduled postbaseline visit.
For the Week 24 Analysis, treatment-emergent laboratory abnormalities will be summarized as 
described below. For the Final Analysis, 2 sets of summaries will be generated:
1) treatment-emergent laboratory abnormalities, and 2) all laboratory abnormalities up to 
Week 48/ET (including both treatment-emergent and non-treatment-emergent laboratory 
abnormalities, eg, during OAV treatment after Week 24). 
The following summaries (number and percentage of subjects) for laboratory abnormalities will 
be provided by laboratory test and by HBeAg status (positive, negative) and overall for each 
treatment group; subjects will be categorized according to the most severe postbaseline 
abnormality grade for a given laboratory test:

Graded laboratory abnormalities

Grade 3 or 4 laboratory abnormalities
For all summaries of laboratory abnormalities, the denominator is the number of subjects with 
nonmissing postbaseline values.
By-subject listings of all graded laboratory abnormalities and Grade 3 or 4 laboratory 
abnormalities will be provided by subject ID number and visit in chronological order. These
listings will include all test results that were collected throughout the study for the laboratory test
of interest, with all applicable severity grades and abnormal flags displayed.
7.2.3.
Liver-related Laboratory Evaluations
Liver-related abnormalities after initial study drug dosing will be examined and summarized 
using the number and percentage of subjects who were reported to have the following laboratory 
test values for any postbaseline measurements (based on central lab normal range):

ALT > 1.5 nadir and one of the following: 
ALT ≥ 2 baseline 


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ALT ≥ 10 ULN
ALT ≥ 3 ULN and total bilirubin ≥ 2 ULN
ALT ≥ 3 ULN and INR ≥ 1.7
ALT flare, AASLD Hepatitis flare and ALT elevation will also be summarized using the number 
and percentage of subjects for any postbaseline measurements as follows (based on both central 
lab and AASLD normal range):

ALT flare: ALT > 2 baseline and ≥ 5 ULN

AASLD Hepatitis flare: ALT ≥ 3 baseline and > 100 U/L

ALT elevation: ALT > 1.5 nadir and one of the following: 
ALT ≥ 2 baseline
ALT ≥ 2.5 ULN and < 5 ULN
ALT ≥ 5 ULN and < 10 ULN
ALT ≥10 ULN
For the Week 24 Analysis, liver-related abnormalities and ALT flare/elevation will be 
summarized using data from all postbaseline visits up to and including the date of last dose of 
study drug plus 30 days. For the Final Analysis, 2 sets of summaries will be generated: 1) using 
data from all postbaseline visits up to and including the date of last dose of study drug plus 
30 days, and 2) using data from all postbaseline visits up to Week 48/ET.
For individual laboratory tests, subjects will be counted once based on the most severe 
postbaseline values. For the composite criteria of ALT and total bilirubin or INR, subjects will 
be counted once when the criteria are met at the same postbaseline visit date. The denominator is 
the number of subjects in the Safety Analysis Set who have nonmissing postbaseline values of all 
relevant tests at the same postbaseline visit date. A listing of subjects who met at least 1 of the 
above criteria will be provided.
7.2.4.
Dose Limiting Toxicities
GS-9688/PTM dosing for a subject will be held or permanently discontinued if the subject 
experiences at least one of the following dose limiting toxicities (DLTs):

Confirmed, clinically significant laboratory abnormality (other than ALT) ≥ Grade 3

Confirmed ALT ≥ 10 ULN


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
Confirmed ALT increase (ie, at least 1 grade increase or 2 previous value) with evidence of 
worsened hepatic function (eg, total bilirubin > 2 mg/dL above baseline, elevated INR 
≥1.7 or > 0.5 above baseline, abnormal serum albumin > 1 g/dL decrease from baseline)

Treatment-related AE ≥ Grade 3
“Confirmed” is defined as 2 consecutive results, including retests.
A summary table will be generated, in which each subject will be counted once for any 
occurrence of a DLT. The denominator will be the number of subjects in the Safety Analysis Set. 
GS-9688/PTM dosing will also be held if a subject experiences a confirmed Grade 2 or above 
neutropenia. A summary table will be provided for the number and percentage of subjects with 
confirmed Grade 2 or above TEAEs of neutropenia or confirmed Grade 2 or above TE laboratory 
abnormality of neutrophils. 
By-subject listings will also be provided indicating the occurrence of any DLTs or Grade 2 or 
above neutropenia to support the summary tables.
7.2.5.
Study Specific Stopping Criteria
7.2.5.1.
Laboratory Abnormalities
Grade 3 or above TEAE experienced by 3 or more subjects will be summarized by SOC, PT, 
severity and by cohort. Grade 3 or above treatment-emergent laboratory abnormalities (except 
for cholesterol and triglyceride increases) experienced by 3 or more subjects will also be 
summarized by cohort.
7.2.5.2.
Virologic Criteria
A summary table will be provided for the number and percentage of subjects who have 
experienced virologic breakthrough (defined as an increase in HBV DNA to ≥ 69 IU/mL 
confirmed by 2 consecutive results, including retests) by HBeAg status (positive, negative) and 
overall for each treatment group. 
7.3.
Body Weight, Body Mass Index and Vital Signs
Descriptive statistics will be provided by HBeAg status (positive, negative) and overall for each 
treatment group for body weight, BMI and vital signs as follows:

Baseline value

Values at each postbaseline visit

Change from baseline at each postbaseline visit


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A baseline value is defined as the last available value collected on or prior to the date/time of 
first dose of study drug. Change from baseline at a postbaseline visit will be defined as the 
postbaseline value minus the baseline value.
In the case of multiple values in an analysis window, data will be selected for analysis as 
described in Section 3.8.3. No formal statistical testing is planned.
A by-subject listing of vital signs will be provided by subject ID number and time point in 
chronological order. A listing of body weight and BMI will be provided separately.
7.4.
Prior and Concomitant Medications
Medications collected at screening and during the study will be coded using the current version 
of the World Health Organization (WHO) Drug dictionary. 
7.4.1.
Prior Medications
Prior medications are defined as any medications taken before a subject took the first dose of 
study drug. Only prior HBV medications will be summarized. A by-subject listing of prior HBV 
medications will also be provided.
Prior HBV medications will be summarized by preferred name using the number and percentage 
of subjects by HBeAg status (positive, negative) and overall for each treatment group. A subject 
reporting the same medication more than once will be counted only once when calculating the 
number and percentage of subjects who received that medication. The summary will be ordered 
by preferred name in order of descending overall frequency. For drugs with the same frequency, 
sorting will be done alphabetically.
For the purposes of analysis, any medication with a start date prior to the first dose date of study 
drug will be included in the prior medication summary regardless of when the stop date is. If a 
partial start date is entered the medication will be considered prior unless the month and year 
(if day is missing) or year (if day and month are missing) of the start date are after the first 
dosing date. Medications with a completely missing start date will be included in the prior 
medication summary, unless otherwise specified.
Summaries will be based on the Safety Analysis Set. No formal statistical testing is planned.
7.4.2.
Concomitant Medications
Concomitant medications are defined as medications taken while a subject took study drug. Use 
of concomitant medications will be summarized by preferred name using the number and 
percentage of subjects by HBeAg status (positive, negative) and overall for each treatment 
group. A subject reporting the same medication more than once will be counted only once when 
calculating the number and percentage of subjects who received that medication. The summary 
will be ordered by preferred name in descending overall frequency. For drugs with the same 
frequency, sorting will be done alphabetically.


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For the purposes of analysis, any medications with a start date prior to or on the first dose date of 
study drug and continued to be taken after the first dosing date, or started after the first dosing 
date but prior to or on the last dosing date of study drug will be considered concomitant 
medications. Medications started and stopped on the same day as the first dosing date or the last 
dosing date of study drug will also be considered concomitant. Medications with a stop date prior 
to the date of first dosing date of study drug or a start date after the last dosing date of study drug 
will be excluded from the concomitant medication summary. If a partial stop date is entered, any 
medication with the month and year (if day is missing) or year (if day and month are missing) 
prior to the date of first study drug administration will be excluded from the concomitant 
medication summary. If a partial start date is entered, any medication with the month and year 
(if day is missing) or year (if day and month are missing) after the study drug stop date will be 
excluded from the concomitant medication summary. Medications with completely missing start 
and stop dates will be included in the concomitant medication summary, unless otherwise 
specified. 
Summaries will be based on the Safety Analysis Set. No formal statistical testing is planned.
All prior and concomitant medications (other than per-protocol study drugs) will be provided in a 
by-subject listing sorted by subject ID number and administration date in chronological order.
7.5.
Electrocardiogram Results
Safety ECG data will not be presented in the main body of the CSR since safety ECGs were not 
assessed in this study other than as part of the screening process for potential new subjects. 
Time-matched digital 12-lead ECGs will be collected as continuous recordings from Holter 
monitors, and will be analyzed separately from this SAP for the concentration-QT (c-QT) 
analysis.
A by-subject listing for safety ECG assessment results will be provided by subject ID number 
and time point in chronological order.
7.6.
Other Safety Measures
Ophthalmic examinations will be performed, including slit lamp and fundoscopic examination 
with retinal photographs (both eyes). An examination of the full retinal field will be conducted 
noting changes or abnormalities. Photographs of the retina were to be taken at each exam, and a 
central vendor was used to assess the retinal photographs. Ophthalmology data will be collected 
at screening, Week 12, and Week 24. Summaries of ophthalmology data will be based on 
nominal visits.
A shift table of the overall assessment of ophthalmology results at each visit compared with 
baseline values will be presented by HBeAg status (positive, negative) and overall for each 
treatment group using the following categories: normal; abnormal, not clinically significant; 
abnormal, clinically significant; or missing/unknown. The number and percentage of subjects in 
each cross-classification group of the shift table will be presented. Subjects with a missing value 
at baseline or postbaseline will not be included in the denominator for percentage calculation. No 
formal statistical testing is planned.


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A by-subject listing for ophthalmology assessment results will be provided by subject ID number 
and visit in chronological order.
The above table and listing will be generated for ophthalmology assessment results from both the 
on-site investigator and the central reader separately.
7.7.
Changes From Protocol-Specified Safety Analyses
There are no deviations from the protocol-specified safety analyses.


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8.
PHARMACOKINETIC ANALYSES
8.1.
PK Sample Collection
Sparse (pre-identified) PK plasma sampling will occur for all subjects on Day 1 and Week 23 at 
predose, 1, 4, and 24 hours postdose and at Week 11 at predose, 1, and 4 hours postdose. 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 predose and any time between 30 minutes to 4 hours postdose.
 
 
 
8.1.1.
PK Analyses Related to Intensive PK Sampling
 
8.1.2.
Estimation of PK Parameters
PK parameters will be estimated using Phoenix WinNonlin® software using standard
noncompartmental methods. The linear/log trapezoidal rule will be used in conjunction with the 
appropriate noncompartmental model, with input values for dose level, dosing time, plasma 
concentration, and corresponding real-time values, based on drug dosing times whenever 
possible.
All predose sample times before time-zero will be converted to zero.
For area under the curve (AUC), samples BLQ of the bioanalytical assays occurring prior to the 
achievement of the first quantifiable concentration will be assigned a concentration value of 0 to 
prevent overestimation of the initial AUC. Samples that are BLQ at all other time points will be 
treated as missing data in WinNonlin. The nominal time point for a key event or dosing 
interval (τ) may be used to permit direct calculation of AUC over specific time intervals. The 
appropriateness of this approach will be assessed by the PK scientist on a profile-by-profile 
basis.
PK parameters such as AUCinf, λz and t1/2 are dependent on an accurate estimation of the terminal 
elimination phase of drug. The appropriateness of calculating these parameters will be evaluated 
upon inspection of PK data on a profile-by-profile basis by the PK scientist.
CCI
CCI
CCI


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8.1.3.
Pharmacokinetic Parameters
 
 
Table 8-1.
Study Treatments and Associated Analytes
Treatment Group
Treatment
Analyte
B
GS-9688 1.5 mg once a week for 24 doses
GS-9688
C
GS-9688 3 mg once a week for 24 doses
GS-9688
The analytes and parameters presented in Table 8-1.and Table 8-2 will be used to evaluate the 
PK objectives of the study. The primary PK parameters are AUClast, AUC0-24, AUCinf, and Cmax
of GS-9688. The PK parameters to be estimated in this study are listed and defined in the PK 
Abbreviations section.
Table 8-2.
PK Parameters for Each Analyte
Analyte
Parameters
GS-9688
AUClast, AUC0-24, AUCinf, %AUCexp, Cmax, Tmax, Clast, Tlast, λz, CL/F, Vz/F, and t1/2
Individual subject concentration data and individual subject PK parameters for GS-9688 will be 
listed and summarized using descriptive statistics by dose. Summary statistics (n, mean, SD, 
coefficient of variation [%CV], median, min, max, Q1, and Q3) will be presented for both 
individual subject concentration data by time point and individual subject PK parameters by
dose. Moreover, the geometric mean, 95% CI, and the mean and SD of the natural log-
transformed values will be presented for individual subject PK parameter data.
Individual concentration data listings and summaries will include all subjects with concentration 
data. The sample size for each time point will be based on the number of subjects with 
nonmissing concentration data at that time point. The number of subjects with concentration 
BLQ will be presented for each time point. For summary statistics, BLQ values will be treated as 
0 at predose and one-half of the LLOQ for postdose time points. 
Individual PK parameter data listings and summaries will include all subjects for whom PK 
parameters can be derived. The sample size for each PK parameter will be based on the number 
of subjects with nonmissing data for that PK parameter.
The following tables will be provided for GS-9688 by dose:

Individual subject concentration data and summary statistics

Individual subject plasma PK parameters and summary statistics
CCI


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The following figures may be provided for GS-9688 by dose:

Mean (± SD) concentration data versus time (on linear and semilogarithmic scales)

Median (Q1, Q3) concentration data versus time (on linear and semilogarithmic scales)
In addition, a figure may also be provided for individual subject concentration data vs. time 
(on linear and semilogarithmic scales). Study Day (Day 1, Week 23) will be used to overlay data 
in these plots.
Individual, mean, and median postdose concentration values that are ≤LLOQ will not be 
displayed in the figures and remaining points connected.
 
  
8.1.4.
Analysis of Dose Proportionality
If data are available, dose proportionality will be obtained by comparing PK parameters across
evaluated dose levels.
Dose proportionality will be evaluated based on AUClast, AUCinf, and Cmax obtained on Day 1
and on Week 23 using an analysis of variance (ANOVA) method.
Analysis of Variance
An ANOVA model using PROC MIXED will be used to estimate the ratio of the PK parameter
at each dose level to the PK parameter at the reference dose. The parameters will be 
dose-normalized and natural log-transformed prior to analysis. The reference dose is 1.5 mg, 
determined by the PK scientist. Dose normalization is calculated by dividing each PK parameter
value by the ratio of the test dose/reference dose. The ratio of geometric least-squares means
(GLSM) and the corresponding 90% CI will be estimated for each PK parameter of interest.
The statistical model will include dose as a fixed effect. The following SAS PROC MIXED code
will provide the dose comparison analysis and the 90% CI calculations for the natural
log-transformed normalized PK parameters. Similar code will be used for other natural
log-transformed normalized parameters and dose levels.
PROC MIXED;
CLASS dose;
MODEL lnCmax = dose;
LSMEANS dose/cl alpha=0.10;
ESTIMATE “3 mg vs 1.5 mg” dose -1 1 / cl alpha=0.10;
RUN;
CCI


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The ESTIMATE statement is used to produce the point estimate and corresponding 90% CI of
the difference in PK parameters of interest on a logarithmic scale. The test-to-reference ratio and
the 90% CI will be calculated by exponentiation of the point estimate and the corresponding
lower and upper limits.
A summary table and a listing of SAS analysis output will be provided.
8.2.
PK Analyses Related to Sparse PK Sampling
For PK Analysis Set, sparse (pre-identified) PK data will be summarized by time point.
Individual subject concentration data will be listed and summarized using descriptive statistics 
by dose. Summary statistics (n, mean, SD, percent coefficient of variation [%CV], median, min, 
max, Q1, and Q3) will be presented for individual subject concentration data by time point by 
dose. 
Individual concentration data listings and summaries will include all subjects with concentration 
data. The sample size for each time point will be based on the number of subjects with 
nonmissing concentration data at that time point. The number of subjects with concentration 
BLQ will be presented for each time point. For summary statistics, BLQ values will be treated as 
0 at predose and one-half of the LLOQ for postdose time points. 
The following tables will be provided for GS-9688 by dose:

Individual subject concentration data and summary statistics
For all subjects in the PK Analysis Set, PK sampling details by subject (using concentration data 
from all sparse and intensive plasma PK sampling), including procedures, differences in 
scheduled and actual draw times, and sample age will be provided in a listing.


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


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


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


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12.
APPENDICES
Appendix 1.
Schedule of Assessments
Appendix 2.
HRQoL Score Calculation Algorithms


GS-9688
GS-US-389-2024 Statistical Analysis Plan
Final
CONFIDENTIAL
Page 49
18 January 2019
Appendix 1.
Schedule of Assessments
Part A. Study Procedures Required at Screening Visit
Screening Study Procedures – Window (-30 days)
Written Informed Consent
Review of Inclusion/Exclusion Criteria
Medical History (including HBV disease and treatment history)
Ophthalmologic Exama
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)
HIV, HDV, and HCV Testingb
12-Lead ECG
Fibrotest
Alpha Fetoprotein
Urinalysis 
Urine Drug Screen
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)
Qualitative HBV Serologyc
HBV DNA levels
HBV Resistance Surveillance
HBV Genotyping (By history if known)
Quantitative HBsAg
Review AEs & Concomitant Medications
CCI


GS-9688
GS-US-389-2024 Statistical Analysis Plan
Final
CONFIDENTIAL
Page 50
18 January 2019
Part B. Study Procedure Table (On and Post Treatment Assessments)
Windows
Days
Weeks
(±1 Days)
(±3 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
EDe
Ophthalmologic 
Exama
X
X
Health Related 
Quality of Life 
Surveys
X
X
X
X
X
Complete Physical 
Exam
X
X
X
X
X
X
X
X
X
X
Symptom Directed 
Physical Exam
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
Safety Labs 
(Hematology, 
Serum Chemistry, 
and Coagulation) 
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Holter Monitoringf
X
X
X
X
X
Fibrotest
X
X
X
X
Urinalysis 
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Serum Pregnancy 
Test
X
X
X
X
X
X
X
X
X
X
X
Urine Pregnancy 
Test
X
X
X
Qualitative HBV 
Serologyc 
X
X
X
X
X
X


GS-9688
GS-US-389-2024 Statistical Analysis Plan
Final
CONFIDENTIAL
Page 51
18 January 2019
Windows
Days
Weeks
(±1 Days)
(±3 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
EDe
HBV DNA levels,  
HBV Resistance 
Surveillance,  
Quantitative 
HBsAg
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Quantitative 
HBCrAg,  
Quantitative 
HBeAg,  HBV 
RNA 
X
X
X
X
X
X
X
X
X
X
X
Randomization
X
In Clinic 
GS-9688 Dosing & 
Accountabilityg
X
X
X
X
X
X
X
X
X
Sparse (pre-
identified) plasma 
PKh
X
X
X
X
X
Sparse (timed) 
plasma PK sample 
Collectioni
X
X
X
X
X
X
Serum and Plasma 
PD Biomarkersk
X
X
X
X
X
X
X
X
X
X
X
X
Truculture
X
PBMC Collectionl
X
X
X
X
X
X
X
X
X
TLR8 SNP
Collect TLR8 SNP genotyping sample on Day 1 but may be collected at any time during the study or at any unscheduled visit.
CCI
CCI


GS-9688
GS-US-389-2024 Statistical Analysis Plan
Final
CONFIDENTIAL
Page 52
18 January 2019
Windows
Days
Weeks
(±1 Days)
(±3 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
EDe
Whole Blood gene 
expression 
biomarkersm
X
X
X
X
X
X
X
X
X
Review AEs & 
Concomitant 
Medications
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
a
Ophthalmologic Exam window at Screening will be (Days -10 to -1) ,Weeks 12 and 24 (Days -4 to +10) 
b
In the event of a positive result and/or antigen testing for HIV, HDV, or HCV serology, reflex tests will automatically be performed
c
Qualitative HBV serology consists of HBeAg and HBsAg and reflex HBeAb and reflex HBsAb
d
 
 
 
 
e
The ED visit should be performed within 1 week if ED occurs before Week 24; after week 24 ED should be performed within 2 weeks from notification of study 
discontinuation
f
Holter Monitoring to be collected prior to blood collection on Day 1 and Week 23 at  pre-dose (≤ 5 min of dose) through 4 hours, and 24 hours; Week 11 at pre-dose 
(≤5 min of dose) through 4 hours 
g
In addition to the clinic GS-9688 study drug dosing, self/home GS-9688 study drug dosing will be on Weeks 1, 3, 5, 6, 7, 9, 10, 13, 14, 15, 17, 18, 19, 21, and 22  
h
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.
i
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.
j
 
. 
k
Serum/plasma PD biomarkers will be collected on Day 1 and Week 23 at pre-dose, 4 and 24 hours post-dose; Weeks 2, 8, 12, 16, 20, 24 and 28 pre-dose; and  Week 11 
pre-dose and 4 hours pose-dose.
l
PBMC samples collected on Days 1 and 1+4 hours, 1 + 24 hours, and on Weeks 11, 11+4 hours, 12, 23, 23 + 4 hours, 23 + 24 hours, 24 and 48/ED
m
Whole blood gene expression (Paxgene RNA) samples collected on Days 1 and 1+4 hours, 1 + 24 hours, and on Weeks 11, 11+4 hours, 12, 23, 23 + 24 hours, 24, and 48/ED
CCI
CCI
CCI
CCI


GS-9688
GS-US-389-2024 Statistical Analysis Plan
Final
CONFIDENTIAL
Page 53
18 January 2019
Appendix 2.
HRQoL Score Calculation Algorithms
Short Form (SF)-36 
SF-36 includes 11 questions with multiple sub-questions that yield at 36 questions in total. The 
response is rated on 3-point, 5-point, or 6-point scale. The response needs to be scored 
(http://www.sf-36.org/demos/SF-36v2.html).
Scoring are performed on 8 domains: Physical function (PF), Role physical (RP), Bodily Pain 
(BP), General health perceptions (GH), Vitality (VT), Social functioning (SF), Role emotional 
(RE), Mental health (MH). 
Two summary scales will be presented: 

Physical component score (PCS): combines PF, RP, BP, and GH

Mental component score (MCS): combines VT, SF, RE, and MH
The summary scores aggregate information from the 8 SF-36 domains in a way that captures 
80% to 85% of the variance in the 8 domains.
Chronic Liver Disease Questionnaire (CLDQ)
CLDQ scores are calculated using subject responses to 29 questions in the questionnaire which 
aim to survey how subjects felt during the last two weeks. The response is rated on a 7-point 
scale. If Ri is the score for the patient’s response to the item i, for i=1, 2, …., 29 then the 
6 domain scores are calculated as follows:

Abdominal symptoms (AB) = Mean of {R1, R5, R17}

Fatigue (FA) = Mean of {R2, R4, R8, R11, R13}

Systemic (SY) = Mean of {R3, R6, R21, R23, R27}

Activity (AC) = Mean of {R7, R9, R14}

Emotion (EM) = Mean of {R10, R12, R15, R16, R19, R20, R24, R26}

Worry (WO) = Mean of {R18, R22, R25, R28, R29}
Here “Mean” is the average of nonmissing items (SAS mean function). 
Overall CLDQ score is calculated by taking the mean of 6 domain scores AB, FA, SY, AC, 
EM, WO.


GS-9688
GS-US-389-2024 Statistical Analysis Plan
Final
CONFIDENTIAL
Page 54
18 January 2019
Work Productivity and Activity Impairment Questionnaire: Hepatitis B (WPAI: Hep B)
WPAI: Hep B includes 6 questions to determine employment status, hours missed from work 
due to hepatitis, hours actually worked, the degree to which hepatitis affected work productivity 
while at work and activities performed outside of work. 
The first question is to determine the employment status.  Questions 2 through 5 are applicable to 
employed patients only. Question 6 is applicable to all subjects. Using patient responses to the 
six questions, four scores are derived: 

Percentage of absenteeism, 

Percentage of presenteeism (reduced productivity while at work), 

An overall work impairment score that combines absenteeism and presenteeism, and

Percentage of impairment in activities performed outside of work. 
Greater scores indicate greater impairment 
(http://www.reillyassociates.net/WPAI_Scoring.html).
Score
Source
Formula
Absenteeism
Question 2: During the past seven days, how many hours 
did you miss from work because of {your health 
problems}?
100 x [Q2/(Q2+Q4)]
Question 4: During the past seven days, how many hours 
did you actually work?
Presenteesism
Question 5: During the past seven days, how much did 
{your health problems} affect your productivity while 
you were working?
100 x [(Q5)/10]
Work 
Productivity 
Loss
Question 2: During the past seven days, how many hours 
did you miss from work because of {your health 
problems}?
100 x [Q2/(Q2+Q4) + 
{1 – Q2/(Q2+Q4)}x(Q5)/10]
Question 4: During the past seven days, how many hours 
did you actually work?
Question 5: During the past seven days, how much did 
{your health problems} affect your productivity while 
you were working?
Activity 
Impairment
Question 6: During the past seven days, how much did 
{your health problems} affect your ability to do your 
regular daily activities, other than work at a job?
100 x [(Q6)/10]