Clinical trial NCT04585789
Conditions: Hepatitis B
Sponsor: Janssen Research & Development, LLC
Start date: 2021-03-11; Completion date: 2024-01-09
Enrollment: 24 participants; Allocation: NON_RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study is to assess changes in intrahepatic hepatitis B surface antigen (HBsAg) between baseline and on-treatment liver biopsy in response to JNJ-3989-based combination treatment.

Detailed description:
The title of protocol reflects the original study design. The study design section is reflecting that the design as of protocol amendment 5 is non-randomized.

Arms: arm 1: Ongoing and new participants will receive JNJ-73763989 subcutaneous (SC) injection once every 4 weeks (last injection at Week 44) and nucleos(t)ide analog (NA) treatment (either entecavir \[ETV\], tenofovir disoproxil or tenofovir alafenamide \[TAF\] tablets) once daily up to 48 weeks. Participants may receive optional treatment with pegylated interferon alpha-2a (PegIFN-alpha-2a) after the Week 40 for a duration of either 12 or 24 weeks at the investigator's discretion. As per amendment-5, JNJ-56136379 is no longer included as part of the study intervention and all participants are counted as single arm in each panel. arm 2: Ongoing and new participants will receive JNJ-73763989 SC injection once every 4 weeks (last injection at Week 44) and NA treatment (ETV, tenofovir disoproxil or TAF tablets) once daily up to 48 weeks. Participants may receive optional treatment with PegIFN-alpha-2a after the Week 40 for a duration of either 12 or 24 weeks at the investigator's discretion. As per amendment-5, JNJ-56136379 is no longer included as part of the study intervention and all participants are counted as single arm in each panel.
Interventions: intervention 1: JNJ-73763989 intervention 2: JNJ-56136379 intervention 3: Entecavir (ETV) intervention 4: Tenofovir disoproxil intervention 5: Tenofovir alafenamide (TAF) intervention 6: PegIFN-alpha-2a (Optional)
Intervention descriptions: intervention 1: JNJ-73763989 will be administered subcutaneously once every 4 weeks up to Week 44. intervention 2: JNJ-56136379 tablets will be administered orally once daily up to 48 weeks. intervention 3: ETV tablet will be administered orally once daily up to 48 weeks as NA treatment. intervention 4: Tenofovir disoproxil will be administered orally once daily up to 48 weeks as NA treatment. intervention 5: TAF will be administered orally once daily up to 48 weeks as NA treatment. intervention 6: PegIFN-alpha-2a injection will be administered subcutaneously once weekly after Week 40 for either 12 or 24 weeks.

Protocol documents:
Prot_002.pdf: 
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
1
Status: Approved,  Date: 25 November 2021
Janssen Research & Development *
Clinical Protocol
A Phase 2 Randomized, Open-label, Parallel-group, Multicenter Study to Assess
Intrahepatic and Peripheral Changes of Immunologic and Virologic Markers in Response
to Combination Regimens Containing JNJ-73763989 and Nucleos(t)ide Analog With or
Without JNJ-56136379 in Patients With Chronic Hepatitis B Virus Infection
The INSIGHT Study
Protocol 73763989HPB2003; Phase 2
AMENDMENT 6
JNJ-73763989 and JNJ-56136379
*Janssen Research & Development is a global organization that operates through different legal entities in
various countries. Therefore, the legal entity acting as the sponsor for Janssen Research & Development
studies may vary, such as, but not limited to Janssen Biotech, Inc.; Janssen Products, LP; Janssen
Biologics, BV; Janssen-Cilag International NV; Janssen, Inc; Janssen Pharmaceutica NV; Janssen
Sciences Ireland UC; Janssen Biopharma Inc.; or Janssen Research & Development, LLC. The term
“sponsor” is used throughout the protocol to represent these various legal entities; the sponsor is
identified on the Contact Information page that accompanies the protocol.
United States (US)sites of this study will be conducted under US Food & Drug Administration
Investigational New Drug (IND) regulations (21 CFR Part 312).
EudraCT NUMBER:2019-004475-39
Status: 
Approved
Date: 
25 November 2021
Prepared by: Janssen Research & Development, a division of Janssen Pharmaceutica NV
EDMS number: 
EDMS-ERI-200320376, 16.0
GCP Compliance: This study will be conducted in compliance with Good Clinical Practice, and applicable regulatory
requirements.
Confidentiality Statement
The information provided herein contains Company trade secrets, commercial or financial information that the Company
customarily holds close and treats as confidential.  The information is being provided under the assurance that the recipient
will maintain the confidentiality of the information under applicable statutes, regulations, rules, protective orders or
otherwise.
NCT04585789


JNJ-73763989 and JNJ-56136379 
Clinical Protocol 73763989HPB2003
AMENDMENT 6
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
2
Status: Approved,  Date: 25 November 2021
PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE
DOCUMENT HISTORY
Document 
Date
Amendment 6 
This document
Amendment 5 
01 October 2021
Amendment 4 
30 July 2021
Amendment 3 
14 August 2020
Amendment 2 
07 May 2020
Amendment 1 
10 April 2020
Original Protocol 
12 February 2020
Amendment 6 (This document)
Overall Rationale for the Amendment: The primary reason for this amendment is to update the criteria
for post-treatment monitoring and for nucleos(t)ide analog (NA) re-treatment for participants who
discontinued NA treatment at Week 48.
With Amendment 5, changes were introduced to the criteria for post-treatment monitoring and NA re-
treatment for patients who discontinued NA treatment. These changes were triggered by a case of
hepatitis B reactivation with subacute hepatic failure (initially  reported as severe clinical ALT flare)
following NA treatment cessation as per protocol in the REEF-2 (73763989PAHPB2002) study which led
to listing of the patient for high urgency liver transplantation. The patient received a donor liver at Week
14 post-stopping NA and has since then showed an uneventful post-operative recovery.
To further protect the safety of study participants, the current amendment includes additional changes to
the criteria for post-treatment monitoring and for NA re-treatment for participants who discontinued NA
treatment.
These changes are based on additional follow-up information from participants in the REEF-2 study who
stopped all treatment including NA per protocol and is incorporating recommendations from Health
Authorities and the independent data monitoring committee.
Description of Change 
Brief Rationale 
Section Number and Name
Update of criteria for post- 
treatment monitoring and for 
NA re-treatment 
In further off-treatment analysis of 
REEF-2 with all participants 
having reached at least 12 weeks of 
follow-up post stopping NA, some 
participants show a pattern of fast 
increase of HBV DNA followed by 
significant elevations of ALT that 
improved after re-starting of NA 
treatment. Based on these 
observations it was decided to
implement more conservative rules
for post-treatment monitoring and
re-treatment criteria for all
participants who met NA treatment
completion criteria and stopped NA
treatment.
1.1 Synopsis
1.3.2 Schedule of Activities - Follow-up
Phase
2.3.3 Benefit-risk Assessment for Study
Participation
4.2 Scientific Rationale for Study Design
6.6.2 NA Re-treatment Criteria
10.12 Appendix 12: NA Re-treatment and
Monitoring After Stopping of NA
Minor errors were corrected
and minor clarifications
were made.
Correction and clarification. 
Throughout the protocol 


JNJ-73763989 and JNJ-56136379 
Clinical Protocol 73763989HPB2003
AMENDMENT 6
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
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Status: Approved,  Date: 25 November 2021
TABLE OF CONTENTS
PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE ............................................................... 2
TABLE OF CONTENTS ............................................................................................................................... 3
LIST OF IN-TEXT TABLES AND FIGURES................................................................................................ 6
1. 
PROTOCOL SUMMARY..................................................................................................................... 7
1.1. 
Synopsis........................................................................................................................................... 7
1.2. 
Schema.......................................................................................................................................... 23
1.3. 
Schedule of Activities..................................................................................................................... 25
1.3.1. 
Schedule of Activities - Screening and Study Intervention Phase ............................................. 25
1.3.2. 
Schedule of Activities - Follow-up Phase ................................................................................... 31
1.3.3. 
Schedule of Activities –Optional PegIFN-α2a Treatment.......................................................... 36
2. 
INTRODUCTION................................................................................................................................ 38
2.1. 
Study Rationale.............................................................................................................................. 40
2.2. 
Background .................................................................................................................................... 41
2.2.1. 
Nonclinical Studies ..................................................................................................................... 41
2.2.1.1. 
JNJ-3989 and JNJ-6379.......................................................................................................... 41
2.2.1.2. 
Combination of JNJ-3989 or JNJ-6379 with Entecavir, Tenofovir Disoproxil, or
Tenofovir Alafenamide............................................................................................................. 46
2.2.1.3. 
Combination of JNJ-3989 with PegIFN-α2a............................................................................ 48
2.2.1.4. 
Combination of JNJ-6379 with PegIFN-α2a............................................................................ 49
2.2.2. 
Clinical Studies ........................................................................................................................... 49
2.2.2.1. 
JNJ-3989 and JNJ-6379.......................................................................................................... 49
2.2.2.2. 
Combination of JNJ-3989 and JNJ-6379 with Entecavir, Tenofovir Disoproxil, or
Tenofovir Alafenamide............................................................................................................. 54
2.2.2.3. 
Combination of JNJ-3989 and JNJ-6379 with PegIFN-α2a.................................................... 56
2.3. 
Benefit-Risk Assessment............................................................................................................... 57
2.3.1. 
Benefits for Study Participation .................................................................................................. 57
2.3.1.1. 
Known Benefits........................................................................................................................ 57
2.3.1.2. 
Potential Benefits..................................................................................................................... 57
2.3.2. 
Risks for Study Participation....................................................................................................... 58
2.3.2.1. 
Known Risks............................................................................................................................ 58
2.3.2.2. 
Potential Risks......................................................................................................................... 58
2.3.2.2.1. 
Potential Risks for JNJ-3989................................................................................................ 58
2.3.2.2.2. 
Potential Risks for JNJ-6379................................................................................................ 59
2.3.2.2.3. 
Potential Risks for Tenofovir Disoproxil and PegIFN-α2a.................................................... 61
2.3.2.3. 
Risks Due to Study Procedures............................................................................................... 61
2.3.2.3.1. 
Potential Risks and Inconvenience Associated with the Liver Biopsy Procedures.............. 61
2.3.2.3.2. 
Potential Risks and Inconvenience Associated with the Optional Leukapheresis
Procedure............................................................................................................................. 62
2.3.3. 
Benefit-risk Assessment for Study Participation......................................................................... 62
3. 
OBJECTIVES AND ENDPOINTS ..................................................................................................... 64
4. 
STUDY DESIGN ................................................................................................................................ 66
4.1. 
Overall Design................................................................................................................................ 66
4.2. 
Scientific Rationale for Study Design............................................................................................. 69
4.2.1. 
Study-Specific Ethical Design Considerations ........................................................................... 73
4.3. 
Justification for Dose...................................................................................................................... 74
4.3.1. 
JNJ-3989 .................................................................................................................................... 74
4.3.2. 
JNJ-6379 .................................................................................................................................... 75
4.4. 
End of Study Definition................................................................................................................... 76
5. 
STUDY POPULATION ...................................................................................................................... 76


JNJ-73763989 and JNJ-56136379 
Clinical Protocol 73763989HPB2003
AMENDMENT 6
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
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Status: Approved,  Date: 25 November 2021
5.1. 
Inclusion Criteria............................................................................................................................ 76
5.2. 
Exclusion Criteria........................................................................................................................... 79
5.3. 
Lifestyle Considerations................................................................................................................. 84
5.4. 
Screen Failures.............................................................................................................................. 84
6. 
STUDY INTERVENTION................................................................................................................... 85
6.1. 
Study Intervention(s) Administered................................................................................................ 85
6.2. 
Preparation/Handling/Storage/Accountability ................................................................................ 89
6.3. 
Measures to Minimize Bias: Randomization and Blinding............................................................. 90
6.4. 
Study Intervention Compliance...................................................................................................... 90
6.5. 
Concomitant Therapy..................................................................................................................... 91
6.6. 
Dose Modification........................................................................................................................... 93
6.6.1. 
Study Intervention Completion at Week 48 ................................................................................ 93
6.6.2. 
NA Re-treatment Criteria and Monitoring after Stopping of NA.................................................. 94
6.7. 
Study Intervention After the End of the Study................................................................................ 96
7. 
DISCONTINUATION OF INVESTIGATIONAL INTERVENTION AND PARTICIPANT
DISCONTINUATION/WITHDRAWAL............................................................................................... 96
7.1. 
Discontinuation of Study Intervention ............................................................................................ 96
7.2. 
Participant Discontinuation/Withdrawal From the Study................................................................ 98
7.2.1. 
Withdrawal From the Use of Research Samples ....................................................................... 98
7.3. 
Lost to Follow-up............................................................................................................................ 99
8. 
STUDY ASSESSMENTS AND PROCEDURES ............................................................................... 99
8.1. 
Liver Biopsy and Fine Needle Aspiration Biopsy......................................................................... 101
8.2. 
Blood Efficacy Assessments........................................................................................................ 102
8.2.1. 
Sequencing............................................................................................................................... 103
8.3. 
Blood Immune Assessments ....................................................................................................... 103
8.3.1. 
Peripheral Blood Mononuclear Cell Immune Analyses ............................................................ 103
8.3.2. 
Leukapheresis (Optional With Separate Consent)................................................................... 104
8.4. 
Safety Assessments..................................................................................................................... 104
8.4.1. 
Physical Examinations.............................................................................................................. 105
8.4.2. 
Vital Signs................................................................................................................................. 105
8.4.3. 
Electrocardiograms................................................................................................................... 105
8.4.4. 
Clinical Safety Laboratory Assessments .................................................................................. 106
8.5. 
Adverse Events and Serious Adverse Events ............................................................................. 106
8.5.1. 
Time Period and Frequency for Collecting Adverse Event and Serious Adverse Event
Information................................................................................................................................ 107
8.5.2. 
Method of Detecting Adverse Events and Serious Adverse Events ........................................ 107
8.5.3. 
Follow-up of Adverse Events and Serious Adverse Events ..................................................... 108
8.5.4. 
Regulatory Reporting Requirements for Serious Adverse Events ........................................... 108
8.5.5. 
Pregnancy................................................................................................................................. 108
8.5.6. 
Adverse Events of Special Interest........................................................................................... 108
8.5.6.1. 
Injection Site Reactions......................................................................................................... 109
8.5.6.2. 
Intervention-emergent ALT/AST Elevations.......................................................................... 109
8.5.6.3. 
Complications From Liver Biopsy.......................................................................................... 110
8.5.6.4. 
Renal Complications.............................................................................................................. 110
8.5.6.5. 
Hematologic Abnormalities.................................................................................................... 111
8.5.7. 
Other Toxicities......................................................................................................................... 111
8.5.7.1. 
Rash ...................................................................................................................................... 111
8.5.7.2. 
Acute Systemic Allergic Reactions........................................................................................ 112
8.6. 
Treatment of Overdose ................................................................................................................ 113
8.7. 
Pharmacokinetics......................................................................................................................... 113
8.7.1. 
Evaluations ............................................................................................................................... 113
8.7.2. 
Analytical Procedures............................................................................................................... 114
8.7.3. 
Pharmacokinetic Parameters and Evaluations......................................................................... 114
8.8. 
Pharmacokinetics/Pharmacodynamics........................................................................................ 114
8.9. 
Host Genetics............................................................................................................................... 114


JNJ-73763989 and JNJ-56136379 
Clinical Protocol 73763989HPB2003
AMENDMENT 6
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
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Status: Approved,  Date: 25 November 2021
8.10. 
Host Biomarkers........................................................................................................................... 115
8.11. 
Medical Encounters...................................................................................................................... 115
9. 
STATISTICAL CONSIDERATIONS................................................................................................ 115
9.1. 
Statistical Hypotheses.................................................................................................................. 115
9.2. 
Sample Size Determination ......................................................................................................... 115
9.3. 
Populations for Analyses.............................................................................................................. 116
9.4. 
Statistical Analyses ...................................................................................................................... 116
9.4.1. 
Analysis of Efficacy and Antiviral Activity ................................................................................. 116
9.4.1.1. 
Analysis of the Primary Endpoint........................................................................................... 117
9.4.1.2. 
Analysis of Secondary Endpoints.......................................................................................... 117
9.4.1.3. 
Analysis of Exploratory Endpoints......................................................................................... 118
9.4.2. 
Safety Analyses........................................................................................................................ 118
9.4.3. 
Other Analyses ......................................................................................................................... 120
9.5. 
Interim Analysis............................................................................................................................ 121
9.6. 
Independent Flare Expert Panel .................................................................................................. 122
10. SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS .......................... 123
10.1. 
Appendix 1: Abbreviations and Definitions of Terms................................................................... 123
10.2. 
Appendix 2: Clinical Laboratory Tests ......................................................................................... 126
10.3. 
Appendix 3: Regulatory, Ethical, and Study Oversight Considerations....................................... 128
REGULATORY AND ETHICAL CONSIDERATIONS............................................................................... 128
FINANCIAL DISCLOSURE....................................................................................................................... 131
INFORMED CONSENT PROCESS.......................................................................................................... 131
DATA PROTECTION................................................................................................................................ 132
LONG-TERM RETENTION OF SAMPLES FOR ADDITIONAL FUTURE RESEARCH .......................... 133
COMMITTEES STRUCTURE................................................................................................................... 133
PUBLICATION POLICY/DISSEMINATION OF CLINICAL STUDY DATA............................................... 133
DATA QUALITY ASSURANCE................................................................................................................. 135
CASE REPORT FORM COMPLETION.................................................................................................... 135
SOURCE DOCUMENTS........................................................................................................................... 136
MONITORING........................................................................................................................................... 137
ON-SITE AUDITS ..................................................................................................................................... 137
RECORD RETENTION............................................................................................................................. 138
STUDY AND SITE START AND CLOSURE ............................................................................................ 138
10.4. 
Appendix 4: Adverse Events: Definitions and Procedures for Recording, Evaluating,
Follow-up, and Reporting............................................................................................................. 140
ADVERSE EVENT DEFINITIONS AND CLASSIFICATIONS .................................................................. 140
ATTRIBUTION DEFINITIONS .................................................................................................................. 141
SEVERITY CRITERIA............................................................................................................................... 141
SPECIAL REPORTING SITUATIONS...................................................................................................... 141
PROCEDURES......................................................................................................................................... 142
CONTACTING SPONSOR REGARDING SAFETY ................................................................................. 143
PRODUCT QUALITY COMPLAINT HANDLING ...................................................................................... 143
10.5. 
Appendix 5: Rash Management................................................................................................... 144
10.6. 
Appendix 6: Intervention-emergent ALT/AST Elevations ............................................................ 147
10.7. 
Appendix 7: Cardiovascular Safety Abnormalities....................................................................... 148
10.8. 
Appendix 8: Contraceptive and Barrier Guidance and Collection of Pregnancy Information...... 149
10.9. 
Appendix 9: DAIDS Table ............................................................................................................ 151
10.10. Appendix 10: Protocol Amendment History................................................................................. 174
10.11. Appendix 11: Covid Appendix...................................................................................................... 183
10.12. Appendix 12: NA Re-treatment and Monitoring After Stopping of NA......................................... 187
11. REFERENCES................................................................................................................................. 188
INVESTIGATOR AGREEMENT............................................................................................................... 191


JNJ-73763989 and JNJ-56136379 
Clinical Protocol 73763989HPB2003
AMENDMENT 6
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
6
Status: Approved,  Date: 25 November 2021
LIST OF IN-TEXT TABLES AND FIGURES
TABLES
Table 1: 
Various Stages of HBV Infection –Terminology and Characteristics (EASL 2017)5 ............... 38
Table 2: 
Animal/Human Exposure Ratios at NOAEL for JNJ-3989........................................................ 42
Table 3: 
Animal/Human Ratios at the NOAEL in Rat and Dog (Human Exposure at 250mg
JNJ-6379 Once Daily for 28 Days [Study 56136379HPB1001]) .............................................. 44
Table 4: 
Disallowed Medication .............................................................................................................. 92
Table 5: 
PegIFN-α2a Hematological Dose Modification Guidelines....................................................... 93
Table 6: 
Management of Rash Events by Severity Grade ................................................................... 144
FIGURES
Figure 1: Schematic Overview of the Study –Prior to Protocol Amendment 5....................................... 23
Figure 2: Schematic Overview of the Study –As of Protocol Amendment 5........................................... 24


JNJ-73763989 and JNJ-56136379 
Clinical Protocol 73763989HPB2003
AMENDMENT 6
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
7
Status: Approved,  Date: 25 November 2021
1. 
PROTOCOL SUMMARY
1.1. 
Synopsis
A Phase 2 Randomized, Open-label, Parallel-group, Multicenter Study to Assess Intrahepatic and
Peripheral Changes of Immunologic and Virologic Markers in Response to Combination Regimens
Containing JNJ-73763989 and Nucleos(t)ide Analog With or Without JNJ-56136379 in Patients With
Chronic Hepatitis B Virus Infection.
JNJ-73763989 (JNJ-3989) is a liver-targeted antiviral therapeutic for subcutaneous (SC)injection designed
to treat chronic hepatitis B virus (HBV) infection via a ribonucleic acid interference (RNAi) mechanism.
Engagement of the cellular RNAi machinery by JNJ-3989 results in specific cleavage of HBV ribonucleic
acid (RNA) transcripts, thereby reducing the levels of HBV proteins and the pre-genomic RNA (pgRNA),
the precursor of viral relaxed circular deoxyribonucleic acid (DNA). The RNAi triggers in JNJ-3989, JNJ-
73763976 (JNJ-3976) and JNJ-73763924 (JNJ-3924), are designed to target all HBV RNA transcripts
derived from covalently closed circular DNA (cccDNA), as well as transcripts derived from integrated viral
DNA. The latter has been suggested to be a significant source of hepatitis B surface antigen (HBsAg) in
hepatitis B e antigen  (HBeAg) negative patients or patients on long term treatment with nucleos(t)ide
analogs (NAs), the current standard of care.35
JNJ-56136379 (JNJ-6379) is an orally administered capsid assembly modulator (CAM) that is being
developed for the treatment of chronic HBV infection. JNJ-6379 binds to hepatitis B core protein (HBc)
and interferes with the viral capsid assembly process, thereby preventing the polymerase-bound pgRNA
encapsidation. This results in the formation of HBV capsids, devoid of HBV DNA or RNA (non-functional
capsids), and ultimately in the inhibition of HBV replication. In addition, JNJ-6379 also acts at an early
stage of the viral life cycle by inhibiting the de-novo formation of cccDNA potentially by interfering with
the capsid disassembly process. JNJ-6379 was initially part of the study intervention for participants but
has been removed as study intervention with the implementation of an urgent safety measure, as described
in Protocol Amendment 5.
Prior to Protocol Amendment 5: The term “study intervention” throughout the protocol, refers to JNJ-3989,
JNJ-6379, NA, and optional PegIFN-α2aa.
As of Protocol Amendment 5: The term “study intervention” throughout the protocol, refers to JNJ-3989,
NA, and optional PegIFN α2a.
OBJECTIVES AND ENDPOINTS
The study will be conducted in 3 phases for all participants: a screening phase (4 weeks), an open-label
study intervention phase (48 weeks), and a follow-up phase (48 weeks). Note that the follow-up period will
be extended for participants who are receiving optional treatment with PegIFN-α2a and who meet NA
treatment completion criteria at the end of treatment with NA and PegIFN-α2a to ensure all participants
have at least one year of follow-up after NA treatment cessation.
The following objectives and endpoints will be assessed overall and by study panel:
Objectives 
Endpoints
Primary
 
To assess changes in intrahepatic HBsAg 
between baseline and on-treatment liver 
 
Changes in the proportion of HBsAg positive
hepatocytes between baseline and on-treatment
Week 40
a 
Note: Optional PegIFN α2a was introduced as ‘study intervention’ as of Protocol Amendment 4.


JNJ-73763989 and JNJ-56136379 
Clinical Protocol 73763989HPB2003
AMENDMENT 6
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
8
Status: Approved,  Date: 25 November 2021
Objectives 
Endpoints
biopsy in response to JNJ-3989-based
combination treatment
Secondary
 
To assess changes in intrahepatic immune 
response 
between 
baseline 
and 
on-treatment liver biopsy  
 
Changes between baseline and on-treatment liver
biopsy in intrahepatic immune response (eg,
CD45+ T-cells, CD4+ T-cells, CD8+ T-cells,
Natural Killer cells, and dendritic cells) in terms
of proportion of cells, cell types, and spatial
redistribution
 
To assess changes in intrahepatic viral 
nucleic acids and proteins between 
baseline and on-treatment liver biopsy  
 
Changes from baseline in intrahepatic viral
parameters 
(such 
as 
cccDNA, 
pgRNA,
intrahepatic RNA, or HBsAg in terms of copy
number, or number of positive cells)
 
Changes from baseline in intrahepatic cccDNA
levels 
and 
transcriptional 
activity
(pgRNA/cccDNA ratio)
 
To evaluate the efficacy of the study 
intervention as measured in blood 
 
The proportion of participants during the study
intervention and follow-up phases with:
 
HBsAg seroclearance at Week 72 (ie, 24
weeks after completion of all study
interventions at Week 48) without restarting
NA treatment.
 
(Sustained) Reduction, suppression, and/or
seroclearance 
considering 
single 
and
multiple markers (such as HBsAg, HBeAg,
HBV DNA and ALT)
 
HBsAg and HBeAg seroconversion
 
Flares (virologic, biochemical, and clinical)
 
Time to first HBsAg seroclearance
 
To evaluate the frequency of virologic 
breakthrough during study intervention  
 
Proportion of participants with virologic
breakthrough
 
To assess HBV-specific T-cell responses 
 
Changes from baseline in HBV-specific
peripheral blood T-cell responses during the
study intervention and follow-up phases
 
To evaluate the safety and tolerability of 
the study intervention 
 
Proportion of participants with (S)AEs and
abnormalities in clinical laboratory tests
(including hematology, blood biochemistry,
blood coagulation, urinalysis, urine chemistry,
and renal biomarkers), 12-lead ECGs, vital signs,
and physical examinations throughout the study
 
To evaluate the plasma PK of JNJ-3989 
(ie, 
JNJ-3976 
and 
JNJ-3924) and 
 
Plasma PK parameters of JNJ-3976, JNJ-3924,
and 
optionally 
of 
JNJ-6379, 
NA  and
PegIFN-α2a, as applicable


JNJ-73763989 and JNJ-56136379 
Clinical Protocol 73763989HPB2003
AMENDMENT 6
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
9
Status: Approved,  Date: 25 November 2021
Objectives 
Endpoints
optionally of JNJ-6379, NA and PegIFN-
α2a, as applicable
Exploratory
 
To explore the relationship of intrahepatic 
markers with blood markers (immune and 
viral)
 
Association between levels and changes in
intrahepatic and blood markers
 
To explore the association of baseline 
characteristics and intrahepatic and/or 
blood (immune and viral) biomarkers at 
baseline and on/off-treatment with selected 
on/off-treatment efficacy variables 
 
Association of baseline characteristics and
baseline and on/off-treatment viral blood markers
(such as baseline NA treatment duration, age, and
baseline and on/off-treatment HBsAg levels)
with selected off-treatment efficacy variables
 
Association of intrahepatic and blood biomarkers
(such as cccDNA levels, T-cell frequency) with
selected on/off-treatment efficacy variables
 
To explore intrahepatic immune and viral 
changes at Week 72 and/or during off- 
treatment flares (only for participants with 
Week 72 biopsy available) 
 
Changes from baseline and on-treatment liver
biopsy in intrahepatic immune and viral markers
at Week 72 and/or during off-treatment flares
(only for participants with Week 72 biopsy
available)
 
To explore changes in the severity of liver 
disease 
 
Changes in fibrosis (according to Fibroscan liver
stiffness measurements) at the end of study
intervention (EOSI) and end of follow-up versus
screening/baseline*
 
To explore the efficacy in terms of changes 
in HBV RNA and hepatitis B core-related 
antigen (HBcrAg) levels. 
 
Changes from baseline in HBV RNA and
HBcrAg levels during study intervention and
follow-up phases. 
 
To explore the relationship between 
plasma PK parameters (JNJ-3989 [ie, 
JNJ-3976 and JNJ-3924] and/or JNJ-6379 
and/or NA  and/or PegIFN-α2a) and 
selected 
pharmacodynamic 
(PD) 
parameters of efficacy and/or safety, as
applicable
 
Relationship between various plasma PK
parameters (JNJ-3976 and JNJ-3924, and/or
JNJ-6379, and/or NA, and/or PegIFN-α2a) and
selected efficacy and/or safety endpoints, as
applicable
 
To explore the HBV genome sequence 
 
The 
emergence 
of 
intervention-associated
mutations during the study intervention and
follow-up phases
 
To assess the impact of baseline HBV genome
polymorphisms on selected on/off-treatment
efficacy variables
* Only applicable to participants who are enrolled at a site with an on-site Fibroscan device.
Hypothesis
As this is an exploratory study, no hypothesis will be tested.


JNJ-73763989 and JNJ-56136379 
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AMENDMENT 6
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Status: Approved,  Date: 25 November 2021
OVERALL DESIGN
As of Protocol Amendment 5, this study is a Phase 2 single-arm, open-label, multicenter, study to assess
intrahepatic and peripheral changes of immunologic and virologic markers in response to a combination
regimen containing JNJ-3989 and NA in chronic HBV-infected participants.
With the implementation of an urgent safety measure, as described in Protocol Amendment 5, JNJ-6379
has been removed as study intervention and the study will continue as a single-arm study. Participants
randomized to Arm 1 had to stop JNJ‑6379 treatment immediately but continue JNJ-3989 + NA treatment.
In addition, participants who provide separate consent may receive optional treatment with PegIFN-α2a
starting after the Week 40 biopsy (or after the optional leukapheresis if applicable) but before the Week 48
visit. The duration (either 12 or 24 weeks) will be at the investigator’s discretion.
A target of 24 chronic HBV-infected male and female participants, 18-65 years (inclusive) of age will be
enrolled in 2 panels, approximately 12 participants in each panel. Panel 1 will consist of participants who
are HBeAg positive and not currently treated and Panel 2 will consist of participants who are HBeAg
negative and virologically suppressed by entecavir (ETV), tenofovir disoproxil, or tenofovir alafenamide
(TAF) treatment.
The study will be conducted in 3 phases for all participants: a screening phase (4 weeks), an open-label
study intervention phase (48 weeks), and a follow-up phase (48 weeks). If necessary, eg, for operational
reasons, the screening phase may be extended up to a maximum of 6 weeks on a case-by-case basis and in
agreement with the sponsor. The duration of individual participation will be up to 102 weeks. Note that the
follow-up period will be extended for participants who are receiving optional treatment with PegIFN-α2a
and who meet NA treatment completion criteria at the end of treatment with NA and PegIFN-α2a to ensure
all participants have at least one year of follow-up after NA treatment cessation. For those participants, the
duration of individual participation may be extended up to 126 weeks.
Prior to Protocol Amendment 5, participants were randomized in a 1:1 ratio within each panel to receive
one of the following interventions (ie, treatments)for 48 weeks:
 
Intervention arm 1, combination regimen JNJ-3989+JNJ-6379+NA (target of12 participants):
 
200 mg JNJ-3989 (SC injection once every 4 weeks [Q4W], with the last injection at Week 44),
AND
 
250 mg JNJ-6379 (tablets once daily [qd]), AND
 
NA: ETV, tenofovir disoproxil, or TAF (tablets qd)
 
Intervention arm 2, combination regimen JNJ-3989+NA (target of 12 participants):
 
200 mg JNJ-3989 (SC injection Q4W, with the last injection at Week 44), AND
 
NA: ETV, tenofovir disoproxil, or TAF (tablets qd)
As of Protocol Amendment 5:
 
Participants who were randomized to study intervention with JNJ-6379 prior to Protocol Amendment
5, had to stop JNJ-6379 treatment immediately but will still receive the following interventions (ie,
treatments) for 48 weeks:
 
200 mg JNJ-3989 (SC injection Q4W, with the last injection at Week 44), AND
 
NA: ETV, tenofovir disoproxil, or TAF (tablets qd)
 
New participants will enroll without randomization within each panel to receive the combination
regimen JNJ-3989 + NA as study intervention for 48 weeks:


JNJ-73763989 and JNJ-56136379 
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Status: Approved,  Date: 25 November 2021
 
200 mg JNJ-3989 (SC injection Q4W, with the last injection at Week 44), AND
 
NA: ETV, tenofovir disoproxil, or TAF (tablets qd)
For participants who consented to receive optional PegIFN-α2a, the PegIFN-α2a treatment will be
completed after 12 or 24 weeks at the investigator’s discretion.
All participants will complete treatment with JNJ-3989 after a fixed duration of 48 weeks. If the NA
treatment completion criteria (see “Study Intervention Completion at Week 48”) are met based on clinical
laboratory tests performed at Week 44, treatment with NA will also be completed at Week 48. In
participants not meeting these criteria, NA treatment will continue during the follow-up phase. Participants
who are receiving optional treatment with PegIFN-α2a and who have not met NA treatment completion
criteria at Week 48 may have NA treatment completion criteria assessed at the end of treatment with
PegIFN-α2a and stop NA if criteria are met.
All participants will have sparse PK sampling on Day 1 and at Weeks 4, 12, and 24 (and at early
withdrawal). All participants who consent to participate in the intensive PK substudy (optional) will
undergo intensive PK sampling at Week 4.
All participants will be monitored closely during the follow-up phase and, if applicable, should restart NA
treatment in accordance with the NA re-treatment criteria mentioned below.
Prior to Protocol Amendment 5, randomization within each panel was stratified by Fibroscan score (<7 kPa
vs ≥7 kPa). Randomization and stratification are not applicable anymore per Protocol Amendment 5.
A participant will be considered to have completed the study if he or she has completed the assessments at
Follow-up Week 48. The follow-up phase will be extended by 24 weeks (ie, up to Follow-up Week 72) for
participants who are receiving optional treatment with PegIFN-α2a and who meet NA treatment completion
criteria at the end of treatment with NA + PegIFN-α2a.
An Independent Flare Expert Panel (IFLEP) will be appointed for this study.
Study Intervention Completion at Week 48
Participants will complete treatment with JNJ-3989 after a fixed duration of 48 weeks. If all of the below
criteria are met based on clinical laboratory tests performed at Week 44, treatment with NA will also be
completed at the next scheduled visit (ie, Week 48):
 
The participant has ALT <3x upper limit of normal (ULN), AND
 
The participant has HBV DNA < lower limit of quantification (LLOQ), AND
 
The participant is HBeAg negative, AND
 
The participant has HBsAg <10 International Units Per Milliliter (IU/mL).
Note: In case of ALT elevation ≥3x ULN at Week 44 the investigator must consider different potential
causes of increased ALT to ensure appropriate work up and management as needed. If the ALT elevation
is unrelated to HBV activity and/or <3x ULN by Week 48, NA completion may be considered at the
discretion of the investigator and in consultation with the sponsor.
Participants who do not meet the above criteria at Week 48 should continue NA treatment during the
48-week follow-up phase. Participants who are receiving optional treatment with PegIFN-α2a and who
have not met NA treatment completion criteria at Week 48 may have NA treatment completion criteria
assessed at the end of treatment with PegIFN-α2a and stop NA if criteria are met. The follow-up phase will
be extended up by 24 weeks (ie, up to Follow-up Week 72) for participants who are receiving optional


JNJ-73763989 and JNJ-56136379 
Clinical Protocol 73763989HPB2003
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Status: Approved,  Date: 25 November 2021
treatment with PegIFN-α2a and who meet NA treatment completion criteria at the end of treatment with
NA + PegIFN-α2a.
NA Re-treatment Criteria and Monitoring After Stopping of NA
Participants who meet the NA treatment completion criteria (as described above) will be monitored closely
during the follow-up phase.
After stopping NA treatment, participants should be monitored as follows:
 
Regular monitoring visits will be every 4 weeks during the follow-up phase in accordance with the
schedule of activities.
 
A post-treatment HBV DNA value of >20,000 IU/mL should trigger re-testing of ALT/AST, HBV
DNA, and total and direct bilirubin within a maximum of 7 days from receipt of the data and further
repeats as necessary (ie, weekly until HBV DNA returns to <20,000 IU/mL).
 
A post-treatment HBV DNA value of >2,000 IU/mL (but <20,000 IU/mL) should trigger a re-test
within 14 days from receipt of the data and further repeats as necessary (ie, every other week until
HBV DNA returns to <2,000 IU/mL).
 
A post-treatment ALT value of >5x ULN should trigger re-testing of ALT, AST, ALP, total and direct
bilirubin, international normalized ratio (INR), albumin, and HBV DNA on a weekly basis until ALT
and AST levels have returned to <5x ULN.
After stopping NA treatment, participants should re-start NA treatment:
 
Immediately with signs of decreasing liver function based on laboratory findings (eg, INR, direct
bilirubin) or clinical assessment (eg, ascites, hepatic encephalopathy).
 
Immediately with an HBV DNA value of >100,000 IU/mL (irrespective of confirmation and/or ALT
increase).
 
With confirmed post-treatment HBeAg seroreversion (HBeAg positive after it was negative at NA
completion)
 
With confirmed* post-treatment increases in HBV DNA >2,000 IU/mL and ALT >5x ULN
 
With confirmed* post-treatment increases in HBV DNA >20,000 IU/mL.
* At least 4 weeks apart –frequency of visits as described above
Note:Additional re-testing and/or earlier restarting of NA treatment is at the investigator’s discretion, even
if the above cut-offs are not yet met.
To avoid delays in decision making, sites are encouraged to run local re-testing in parallel with central re-
testing in the situations described above that require more frequent re-testing. Local test results are to be
recorded in the CRF and/or source documents, including information on the HBV DNA assay used. In
addition, to avoid delays in NA re-treatment, it should be considered to dispense NA to participants who
potentially met the NA re-treatment criteria (eg, pending confirmation) and who will not be available to
come to the study site immediately at the time the confirmatory test results will become available. This
should ensure that the participant can immediately restart NA treatment if indicated, upon direct
confirmation by the investigator.
In case NA treatment is re-started, participants will be followed until the end of the study or until clinical
stabilization, whichever comes later.
NA re-treatment criteria during follow-up are presented graphically in Section 10.12, Appendix 12: NA
Re-treatment During Follow-up.


JNJ-73763989 and JNJ-56136379 
Clinical Protocol 73763989HPB2003
AMENDMENT 6
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Status: Approved,  Date: 25 November 2021
NUMBER OF PARTICIPANTS
A target of 24 chronic HBV-infected adult male and female participants will be randomized or enrolled.


JNJ-73763989 and JNJ-56136379 
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Status: Approved,  Date: 25 November 2021
Description of Interventions
Intervention 
name
JNJ-3989 
JNJ-6379****
PegIFN-α2a  
Entecavir (ETV) 
monohydrate 
Tenofovir 
disoproxil 
Tenofovir
alafenamide (TAF)*
Type 
Drug 
Drug 
Drug 
Drug 
Drug 
Drug
Dosage 
formulation 
Solution for 
injection  
Tablets 
Solution for 
injection
Film-coated tablets 
Film-coated tablets 
Film-coated tablets
Unit dose 
strength(s)
200 mg/vial 
25 and 100 mg 
180 µg/0.5 mL 
0.5 mg 
245 mg 
25 mg
Dosage level 
200 mg once every 
4 weeks (Q4W) 
250 mg once daily 
(qd) 
180 µg once weekly 
(QW)**
Nucleoside-naïve patients: 
0.5 mg qd
Lamivudine-refractory
patients:
1 mg* qd (but should
preferably be treated with
tenofovir disoproxil or
TAF instead)
Other indications:
1 mg* qd (must be agreed
upon by the sponsor)
245 mg qd 
25 mg qd
Route of 
administration 
Subcutaneous 
injection preferably 
in the abdomen  
Oral 
Subcutaneous 
injection (in the
thigh or abdomen)
Oral 
Oral 
Oral
Use 
Investigational 
intervention  
Investigational 
intervention  
Investigational 
intervention  
Background intervention  
Background 
intervention  
Background
intervention
Sourcing 
Provided centrally 
by the sponsor 
Provided centrally 
by the sponsor 
Provided centrally 
by the sponsor*** 
Provided centrally by the 
sponsor 
Provided centrally 
by the sponsor 
Provided centrally
by the sponsor
Packaging and 
Labeling 
Each unit will be 
labeled with unique 
medication ID 
number 
Each unit will be 
labeled with unique 
medication ID 
number 
Commercial 
supplies will be 
sourced. Each unit 
will be labeled with 
unique medication 
ID number*** 
Commercial supplies will 
be sourced. Each unit will 
be labeled with unique 
medication ID number 
Commercial supplies 
will be sourced. 
Each unit will be 
labeled with unique 
medication ID 
number 
Commercial supplies
will be sourced.
Each unit will be
labeled with unique
medication ID
number
In child-resistant 
packaging 
In child-resistant 
packaging*** 
In child-resistant 
packaging 
In child-resistant 
packaging 
In child-resistant
packaging
Labels will contain information to meet the applicable regulatory requirements.


JNJ-73763989 and JNJ-56136379 
Clinical Protocol 73763989HPB2003
AMENDMENT 6
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Status: Approved,  Date: 25 November 2021
Intervention
name
JNJ-3989 
JNJ-6379****
PegIFN-α2a  
Entecavir (ETV)
monohydrate
Tenofovir
disoproxil
Tenofovir
alafenamide (TAF)*
Food/Fasting
instructions
Regardless of food
intake
Regardless of food
intake
Per the prescribing 
information  
Per prescribing
information
Per prescribing
information
Per prescribing
information
Q4W: once every 4 weeks; qd: once daily; QW: once weekly
* 
In countries where TAF is available, it will be one of the NA treatment options.
** 
For PegIFN α2a, dose adjustment may be applicable for participants who develop laboratory abnormalities during PegIFN α2a treatment.
*** May vary based on local regulations.
**** Participants enrolled before Protocol Amendment 5 was in effect, may have received JNJ 6379 as part of their study intervention. As of Protocol Amendment 5: study
intervention includes JNJ 3989, NA and optionally PegIFN α2a.


JNJ-73763989 and JNJ-56136379 
Clinical Protocol 73763989HPB2003
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Status: Approved,  Date: 25 November 2021
LIVER BIOPSYAND FINE NEEDLE ASPIRATION BIOPSY
Percutaneous core liver biopsies and fine needle aspiration biopsies (FNABs)will be performed at Week -1
and Week 40. If participants agree to undergo an additional optional liver biopsy, FNAB and/or core liver
biopsy samples may be taken at the selected location at Follow-up Week 24 or at the time points clinically
indicated.
Following local standard practice the biopsy location will be identified with ultrasound (which will also be
used to rule out contraindicating conditions for a biopsy) and after application of local anesthesia the FNAB
samples and core liver biopsy samples will be collected.
The liver biopsy procedure should be preceded and followed by standard medical monitoring according to
local medical practice. This may include an overnight stay at the investigator’s discretion. The use of low-
dose aspirin is allowed with exception of 7 days prior to biopsies (see Section 6.5).
The liver tissue will be used to assess HBsAg. Changes from baseline in the proportion of HBsAg positive
hepatocytes under therapy will be assessed.
In addition, the liver tissue may also be used to assess other HBV markers in the liver such as, but not
limited to, total intracellular HBV RNA and DNA, HBeAg, and HBc. Changes in the quantity and
potentially changes in the spatial distribution of these markers (including HBsAg) under therapy may be
assessed. Viral genome (RNA or DNA) or transcript sequencing/analyses as well as assessment of HBV
integrants in the host genome may be performed.
Intrahepatic immune status at baseline and response to treatment will be assessed. Both innate and adaptive
immune compartment will be characterized, by measuring the relative number of specific cells and the
expression of functional markers in each cell population using various single cell approaches, such as single
cells transcriptomics in  FNABs and Immunofluorescence staining, and transcriptomics and proteomics
profiling in core needle biopsies. Depending on the latest platform developments (spatial transcriptomics,
in situ sequencing approaches, etc.), methods for immune cells characterization might be adjusted.
Hepatitis B virus-specific T-cells, although very rare in FNABs, may be characterized and counted by
multimers binding assays, staining and sorting for positive cells. Downstream profiling of collected
HBV-specific T-cells may be performed by T-cell receptor sequencing and RNA sequencing.
Infiltrating immune cells will be used for the evaluation of innate and adaptive immune responses, which
can be compared to responses in peripheral blood mononuclear cell (PBMCs).
Hepatitis B virus cccDNA levels may be assessed using quantitative polymerase chain reaction (qPCR)
methods on a single cell level using laser capture microdissection or bulk analyses. The exact protocol of
cccDNA measurement will be determined based on the latest method available considering the performance
characteristics and the validation status of the assay. Southern Blot-based methods or novel methods for
cccDNA detection (eg, fluorescent in situ hybridization [FiSH]) might be used depending on the availability
of sample and established methodology. Quantification of intracellular pre-genomic HBV RNA can be used
to determine transcriptional activity of HBV cccDNA by assessing the ratio of pgRNA levels over cccDNA
levels.
Immune and virologic markers in the liver and/or changes thereof on-treatment will be used to assess
association with blood markers and/or treatment response and outcome.
Remaining samples may be used for determination of liver JNJ-3989 (ie, JNJ-3976 and JNJ-3924) and/or
JNJ-6379 concentrations and/or research on viral and host biomarkers and immune markers at the viral
and/or host RNA/DNA, protein, and cell level.


JNJ-73763989 and JNJ-56136379 
Clinical Protocol 73763989HPB2003
AMENDMENT 6
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Status: Approved,  Date: 25 November 2021
BLOOD EFFICACY ASSESSMENTS
Qualitative and quantitative HBsAg and HBeAg, and quantitative HBcrAg as well as antibodies against
HBsAg and HBeAg will be determined using validated serologic assays in a central laboratory. Samples
for the determination of HBsAg and HBeAg will be processed in real-time. Samples for the determination
of HBcrAg can be analyzed in batch and at the sponsor’s discretion.
Hepatitis B virus DNA and HBV RNA will be quantified at central laboratories using validated assays for
the quantification of HBV DNA and HBV RNA. Samples for the determination of HBV DNA will be
processed in real-time. Samples for the determination of HBV RNA can be analyzed in batch and at the
sponsor’s discretion.
Hepatitis B virus DNA, HBsAg, HBeAg, anti-HBs, and anti-HBe antibody testing results will be provided
to the investigator and the sponsor from screening until the end of follow-up.
In participants enrolled at a site with an on-site Fibroscan device, Fibroscan assessments will be performed
to determine changes in fibrosis levels.
Samples may be used by the sponsor for additional exploratory assessments analyzing the serologic and
virologic characteristics of HBV infection and efficacy or safety of the study intervention.
Viral genome sequence analysis will be performed to identify pre-existing baseline polymorphisms and to
evaluate emergence of mutations associated with JNJ-3989, and/or JNJ-6379, and/or NA treatment.
BLOOD IMMUNE ASSESSMENTS
Peripheral Blood Mononuclear Cell Immune Analyses
Samples for PBMC immune analyses will be collected during the study intervention and follow-up phases
and will be analyzed centrally for HBV-specific responses by enzyme-linked immunospot (ELISpot) and/or
intracellular cytokine staining (ICS) after stimulation with HBV-specific antigens. ELISpot detects T-cells
that secrete gamma interferon (IFN-γ) in response to a specific antigenic stimulation, whereas ICS
determines the frequency of CD4+ and CD8+ T-cells secreting cytokines such as IFN-γ, interleukin (IL)-2
and tumor necrosis factor (TNF)-α in response to a specific antigenic stimulation. Hepatitis B virus-specific
T-cells may be characterized in PBMCs by binding assays (multimer staining) combined with downstream
TCR and transcriptome profiling.
Additional experiments may be performed to further phenotypically and functionally characterize PBMCs
using proliferation or cytotoxic assays or other methods such as cytometry by time of flight to evaluate
innate and adaptive immune responses. Leftover samples may  be used at the sponsor’s discretion for
additional exploratory research related to HBV infection or study intervention (safety/efficacy).
Additional PBMC samples may be taken in case of ALT flares, upon discussion with the sponsor, which
may require an unscheduled visit.
Leukapheresis (Optional With Separate Consent)
Leukapheresis allows to selectively collect higher quantities of PBMCs from participants without
withdrawing large volumes of blood.
Leukapheresis will only be performed for participants who consent separately to this component of the
study. Participants may withdraw such consent at any time without affecting their participation in other
aspects of the study.
Leukapheresis may be done at least 1 week (and up to 3 weeks) after the liver biopsies (see Schedule of
Activities). Prior to the procedure, the participant’s wellbeing will be checked and leukapheresis will only


JNJ-73763989 and JNJ-56136379 
Clinical Protocol 73763989HPB2003
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Status: Approved,  Date: 25 November 2021
be offered if there is no clinical reason against it. If a participant has had a recent febrile illness, the
leukapheresis should be postponed until body temperature is normal for at least 72 hours.
The leukapheresis procedure should mainly follow local standard procedures. Additional guidelines will be
provided via a separate manual in order to standardize this process across sites.
One leukapheresis session is expected to last between 1.5 - 5 hours.
During the procedure, the participant will receive intravenous saline infusions and citrate-based
anticoagulant. Use of heparin for anticoagulation is not allowed. A specialized leukapheresis trained
research nurse or physician will be in attendance and in charge of the participant’s immediate medical care
to monitor the leukapheresis.
After completion of the leukapheresis procedure, participants will stay at the site for at least 30 minutes to
monitor for any relevant safety events. Additional safety procedures may be performed at the discretion of
the site staff. Participants are advised to refrain from exercise and strenuous activities for 3 day after the
leukapheresis visit.
SAFETYEVALUATIONS
Safety and tolerability will be assessed throughout the study from the time that the informed consent form
is signed until completion of the last study-related activity, which may include contact for follow-up of
safety. The evaluations of safety and tolerability will include monitoring of (S)AEs, physical examinations
(including body weight), vital signs measurements, triplicate 12-lead ECGs, and clinical laboratory tests
(including hematology, blood biochemistry, blood coagulation, urinalysis, urine chemistry, and renal
biomarkers). Any clinically relevant changes occurring during the study must be recorded in the AE section
of the case report form.
Specific toxicity management plans in line with the known pharmacological profile of the study
intervention (and the drug classes) evaluated in this study are implemented.
PHARMACOKINETIC EVALUATIONS
Venous blood samples will be collected for measurement of plasma concentrations of JNJ-3989 (ie,
JNJ-3976 and JNJ-3924), NA (ETV, TAF, or tenofovir) and PegIFN-α2a, as applicable, at time points
specified in the Schedule of Activities. Bioanalysis of NA and PegIFN-α2a is optional at the discretion of
the sponsor. Bioanalysis of JNJ-6379 may also be done on samples collected from participants who received
JNJ-6379 up to Protocol Amendment 4.
All participants will have sparse PK sampling on Day 1 and at Weeks 4, 12, and 24 (and at early
withdrawal). All participants who consent to participate in the intensive PK substudy (optional) will
undergo intensive PK sampling at Week 4. If necessary (eg, for operational reasons), this visit may be
scheduled at Week 8, 12, or 16.
Plasma concentration-time data for JNJ-3976, JNJ-3924, and optionally, JNJ-6379, NA and/or PegIFN-α2a
will be analyzed via noncompartmental methods for all participants who underwent intensive PK sampling.
The main PK parameter will be area under the plasma concentration-time curve over 24 hours (AUC24h),
Cmax, tmax, plasma trough concentration (C0h), plasma concentration at the end of the dosing interval (τ) (Cτ),
and minimum plasma concentration (Cmin). Additional exposure parameters may be calculated if applicable.
Data from this study may be combined with data from a selection of Phase 1 and 2 studies via population
PK modelling. Individual estimates of PK parameters may be generated from the population PK analysis
for potential use in exposure-response analysis.


JNJ-73763989 and JNJ-56136379 
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Status: Approved,  Date: 25 November 2021
PHARMACOKINETIC/PHARMACODYNAMIC EVALUATIONS
Relationships of individual PK parameters for JNJ-3976, JNJ-3924, and optionally, JNJ-6379, NA and/or
PegIFN-α2a, with selected liver and blood biomarkers, and/or with selected safety endpoints may be
evaluated.
HOST GENETICS
A pharmacogenomic blood sample will be collected (preferably at baseline) to allow for the identification
of genetic factors that may influence the efficacy, safety, or PK of the study intervention, to identify genetic
factors associated with HBV infection, or to develop assays for the study intervention or HBV infection.
A blood sample will be taken for human leukocyte antigen (HLA) typing. In addition, host DNA blood
samples to allow for epigenetic analyses will be collected.
HOST BIOMARKERS
The study includes collection of blood samples for exploratory analysis of host blood biomarkers at the
host RNA, protein, and cell level.
Samples can only be used for research related to study intervention or HBV infection or may be used to
develop tests/assays related to study intervention or HBV infection.
Blood samples will be taken that can be used to explore immunogenicity of JNJ-3989. The emergence of
antibodies to JNJ-3989 (antidrug antibodies) might be analyzed using assays such as an enzyme-linked
immunosorbent assay.
STATISTICAL METHODS
The primary analysis will be performed at the time when all participants have completed Week 48 or
discontinued earlier. The final analysis will be performed when all participants have completed the last
study visit (Follow-up Week 48) or discontinued earlier.
Given the exploratory nature of the study and the limited sample size per intervention arm per panel, no
statistical testing will be performed. All data will be summarized descriptively including 90% confidence
intervals as appropriate.
Statistical Hypotheses
As this is an exploratory study, no hypothesis will be tested.
Sample Size Determination
This study aims to enroll 18 to 24 participants in total across Panels 1 and 2, ie, 8 to 12 participants per
study panel. Due to the exploratory nature of the study, the sample size was determined based on clinical
and feasibility considerations related to the liver biopsy procedures performed multiple times during the
study, rather than a formal statistical calculation.
Analyses of Efficacy and Antiviral Activity
To evaluate the efficacy and antiviral activity in blood and liver, the primary analysis set will be the intent-
to-treat (ITT)population.
All efficacy summaries will be presented with descriptive statistics, overall and by study panel.
If the endpoint is continuous, the descriptive statistics will include the number of participants, mean,
standard deviation (SD), median, range, and interquartile range. If the endpoint is binary or categorical, the
frequency distribution with the number and percentage of participants in each category will be calculated.


JNJ-73763989 and JNJ-56136379 
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Status: Approved,  Date: 25 November 2021
Graphic displays will also be used to summarize the data and to visualize trends by study panel.
Where applicable, additional specifics for analyses of primary, secondary, and exploratory endpoints are
detailed below.
Analysis of the Primary Endpoint
The primary endpoint is the change between baseline and on-treatment liver biopsy (Week 40) in terms of
the proportion of HBsAg-positive hepatocytes. The primary endpoint will be summarized descriptively and
modelled with an appropriate statistical model accounting for the number of hepatocytes sampled in each
liver biopsy. The change from baseline will be summarized for the overall study population and within each
panel, together with the between-panel difference in the change.
Analysis of Secondary Endpoints
Changes in Intrahepatic Immune Response
Variation in proportion of major cell populations, such as but not limited to CD4+ T-cells, CD8+ T-cells,
CD45+ T-cells, Natural Killer cells, and dendritic cells, defined by single cell transcriptomics (in FNABs)
and immunofluorescence staining (in core needle biopsies), will be assessed at Week 40 and compared to
baseline, overall and by study panel.
The functional characterization of major cell populations will be assessed by transcriptomics and/or
proteomics for major cell populations of interest at Week 40 and compared to baseline similarly.
Changes in Intrahepatic Viral Nucleic Acids and Proteins
Changes from baseline in cccDNA level and/or transcriptional activity will be assessed using the general
considerations outlined above.
Furthermore, the difference in the level of infected hepatocytes at baseline will be assessed by comparing
cccDNA level and/or transcriptional activity.
Analyses of other viral markers will be performed descriptively. Statistical analyses will depend on the
assay technology applied and the scope of the analyses.
Analysis of Exploratory Endpoints
The association between intrahepatic markers and blood (immune and viral) markers will be explored both
at baseline and on-treatment by study panel using graphical displays and relevant correlation coefficients.
Impact of baseline characteristics on selected efficacy variables and their association with intrahepatic and
blood markers will also be evaluated using similar methods.
Identification of markers (either intrahepatic or blood) that could potentially be associated with selected
efficacy variables (such  as decrease in blood HBsAg levels, intrahepatic cccDNA levels or any other
relevant variables) will be conducted. Impact of treatment on different blood and hepatic markers will also
be evaluated.
Safety Analyses
The Safety Population will be used for all safety analyses and includes all participants who received at least
one dose of study intervention.
Safety will be evaluated by means of descriptive summaries of AEs including AEs of special interest to any
of the study interventions, clinical laboratory tests, ECGs, vital signs, and physical examinations. The safety


JNJ-73763989 and JNJ-56136379 
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Status: Approved,  Date: 25 November 2021
analysis will be done by study phase. Results will be presented in tabular format and/or graphically over
time, as appropriate.
Other Analyses
Pharmacokinetic Analyses
Descriptive statistics (number of participants, mean, SD, coefficient of variation, geometric mean, median,
minimum, and maximum) will be calculated for the plasma concentrations of JNJ-3976, JNJ-3924, and
optionally, JNJ-6379, NA and/or PegIFN-α2a, as applicable, and for the derived plasma PK parameters
(noncompartmental analysis).
Special attention will be paid to the plasma concentrations and PK parameters of those participants who
discontinued the study for an AE, or who experienced an AE ≥grade 3 or an SAE.
For each participant with intensive PK sampling, plasma concentration-time data of JNJ-3976, JNJ-3924,
and/or JNJ-6379, and/or NA and/or PegIFN-α2a will be graphically presented. Similarly, graphs of the
mean plasma concentration-time profiles and overlay graphs with combined individual plasma
concentration time profiles will be produced. Pharmacokinetic parameters will be subjected to an
exploratory graphical analysis, including various transformations, to get a general overview.
Population PK analysis of plasma concentration-time data JNJ-3976, JNJ-3924, and optionally, JNJ-6379,
NA and/or PegIFN-α2a may be performed using nonlinear mixed-effects modeling. Data may be combined
with those from Phase 1 and/or 2 studies to support a relevant structural model. Available baseline
characteristics (eg, demographics, laboratory variables, genotypes) may  be included in the model as
necessary. Details will be given in a population PK analysis plan and results of the population PK analysis,
if applied, will be presented in a separate report.
Individual estimates of PK parameters may be generated from the population PK analysis for potential use
in exposure-response analysis.
Pharmacokinetic/Pharmacodynamic Analyses
Relationships of PK parameters for JNJ-3976, JNJ-3924, and optionally, JNJ-6379, NA and/or PegIFN-α2a
with selected efficacy and with selected safety endpoints may be evaluated and graphically displayed.
Modeling of key PD parameters (eg, HBsAg, HBV DNA) may be performed using population PK/PD. If
PK/PD modeling of key efficacy endpoints is performed, treatment effect and possible covariates such as
disease progression may be investigated. Other biomarkers may be explored at the sponsor’s discretion.
Resistance Analysis
The results of HBV viral sequencing will be evaluated by the sponsor virologist. Relevant changes in amino
acid and/or nucleic acid variations (eg, substitutions) in the HBV genome will be tabulated and described.
Additional exploratory characterization of the HBV viral sequence and phenotype may be performed and
reported separately.
Pharmacogenomic Analyses
The statistical approach for analyzing the exploratory host DNA research may depend on the objective of
the analyses (efficacy, safety, and PK) and possibly relevant genes at the time of analysis. Analyses will be
conducted at the sponsor’s discretion, will always be under the sponsor’s supervision, and results will be
presented either in the clinical study report or a separate report.


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Host Exploratory Biomarker Analyses
Statistical approaches to explore associations between treatment response/clinical outcome and blood and
liver biomarkers vary and depend on the different data types of the applied technology platforms, as well
as on the extent of observed differences between participants. Analyses will be conducted at the sponsor’s
discretion, will always be under the sponsor’s supervision, and results will be presented either in the clinical
study report or a separate report.
Interim Analysis
Two interim analyses (IAs) may be performed: when all participants have completed Week 20 in the
intervention phase (or discontinued earlier)and when they have completed Week 72 in the follow-up phase
(ie, Follow-up Week 24) (or discontinued earlier). These IAs will be performed by the sponsor to support
interactions with health authorities, as well as to support internal decisions about additional studies and/or
investigation of other combination regimens.
Both primary and interim analyses will be based on all data available at the predefined cut-off time points
and may include data at later time points for those participants who have reached subsequent visits.
Independent Flare Expert Panel
An IFLEP will be appointed for this study. The IFLEP is composed of 3 independent medical experts with
experience and expertise in hepatitis B and its treatment. The IFLEP will monitor ALT flares and will make
recommendations regarding flare management based on an analysis of aggregate data.
In order to allow for an unbiased assessment, members of the IFLEP will not serve as study investigators.
Further details on the IFLEP process will be included in the IFLEP charter.


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1.2. 
Schema
Figure 1: 
Schematic Overview of the Study –Prior to Protocol Amendment 5
ETV: entecavir; N: number of participants; LB: (planned) liver biopsy; NA=nucleos(t)ide analog; Q4W: once every
4 weeks; qd: once daily; TAF: tenofovir alafenamide; TD: tenofovir disoproxil; QW: once weekly
* Participants who provide separate consent may receive optional treatment with PegIFN-α2a starting after the
Week 40 biopsy (or after the optional leukapheresis visit if applicable) for a duration of either 12 or 24 weeks at the
investigator’s discretion.
** Treatment with JNJ-3989 (and JNJ-6379 if applicable) will be stopped at Week 48. Optional treatment with
PegIFN-α2a will be stopped after 12 or 24 weeks (at the investigator’s discretion). NA treatment may be stopped at
Week 48 (or later for participants on PegIFN-α2a treatment) if NA treatment completion criteria are met.


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Status: Approved,  Date: 25 November 2021
Figure 2: 
Schematic Overview of the Study –As of Protocol Amendment 5
ETV: entecavir; N: number of participants; LB: (planned) liver biopsy; NA=nucleos(t)ide analog; Q4W: once every
4 weeks; qd: once daily; TAF: tenofovir alafenamide; TD: tenofovir disoproxil; QW: once weekly
* Participants who provide separate consent may receive optional treatment with PegIFN-α2a starting after the
Week 40 biopsy (or after the optional leukapheresis visit if applicable) for a duration of either 12 or 24 weeks at the
investigator’s discretion.
** Treatment with JNJ-3989 will be stopped at Week 48. Optional treatment with PegIFN-α2a will be stopped after
12 or 24 weeks (at the investigator’s discretion). NA treatment may be stopped at Week 48 (or later for participants
on PegIFN-α2a treatment) if NA treatment completion criteria are met.
*** The follow-up phase will be extended for participants who are receiving optional treatment with PegIFN-α2a
and who meet NA treatment completion criteria at the end of treatment with NA and PegIFN-α2a to ensure all
participants have at least one year of follow-up after NA treatment cessation.
Note:Former Arm 1 participants will now be joining Arm 2, both in terms of treatment assignment as well as how
they will be statistically analyzed.








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ALP: alkaline phosphatase; ALT: alanine aminotransferase; AST: aspartate aminotransferase; CKD-EPI: Chronic Kidney Disease Epidemiology Collaboration; CRF:
case report form; CT: computed tomography; D/d: day; DBP: diastolic blood pressure; DNA: deoxyribonucleic acid; ECG: electrocardiogram; eGFR: estimatedglomerular
filtration rate; FSH: follicle-stimulating hormone; HBc: hepatitis B core protein; HBe(Ag): hepatitis B e (antigen); HBcrAg: hepatitis B core-related antigen; HBs(Ag):
hepatitis B surface (antigen); HBV: hepatitis B virus; HCC hepatocellular carcinoma; HIV-1 (-2): human immunodeficiency virus type 1 (type 2); HLA: human leukocyte
antigen; ICF: informed consent form; IgM: immunoglobulin M; MRI: magnetic resonance imaging; NA: nucleos(t)ide analog; PBMC: peripheral blood mononuclear cell;
PK: pharmacokinetic; RNA: ribonucleic acid; SBP: systolic blood pressure; ULN: upper limit of normal; W/w: week; WD: withdrawal.
a. 
All study visits are to be scheduled relative to the baseline (Day 1) visit date.
b. 
If necessary (eg, for operational reasons), the screening phase may be extended up to a maximum of 6 weeks in agreement with the sponsor.
c. 
Day 1 samples are to be collected before the first dose of study intervention.
d. 
End of study intervention. If NA treatment completion criteria are not met at Week 48 (see Section 6.6.1), participants will continue NA treatment during the
follow-up phase. Participants who discontinue study intervention early will have an early WD visit and will enter follow-up (see the Schedule of
Activities - Follow-up Phase) unless they withdraw consent. Participants who withdraw consent will be offered an optional safety follow-up visit to occur on the
day of consent withdrawal. For the optional safety follow-up visit, assessments are at the investigator’s discretion and could be similar to the early WD visit.
e. 
The ICF must be signed before the first study-related activity.
f. 
If participants agree to undergo an optional liver biopsy, they must sign a separate ICF at screening or at any time prior to the optional liver biopsy (which may
take place at Follow-up Week 24, or at any time during the study when clinically indicated). Refusal to give consent for these optional liver biopsy samples does
not exclude a participant from participation in the study.
g. 
Minimum criteria for the availability of documentation supporting the eligibility criteria will be described in Section 10.3, Appendix 3, Regulatory, Ethical and
Study Oversight Considerations. Clinical status will be checked at screening and again before the first liver biopsies at Week -1 and before the first dose of study
intervention. If a participant’s clinical status changes (including any available laboratory results or receipt of additional medical records) after the start of screening
but before the first liver biopsies at Week -1 or before the first dose of study intervention is given such that he or she no longer meets all eligibility criteria, then the
participant should be excluded from participation in the study. Retesting to assess eligibility will be allowed once, using an unscheduled visit during the screening
period.
h. 
Medical history also includes mode of HBV transmission, stage of liver fibrosis, and alcohol consumption. Historical HBV DNA data and available data on
previous HBV genotype assessments will be recorded in the CRF. Historical HBsAg, HBeAg, and ALT data, if available, will be recorded in the source document.
i. 
Liver disease staging assessments will be performed based on Fibroscan obtained within 6 months prior to screening or at the time of screening.
j. 
Only applicable to participants who are enrolled at a site with an on-site Fibroscan device.
k. 
Participants must have absence of signs of cirrhosis or portal hypertension (absence of nodules, smooth liver contour, normal portal vein, spleen size <12 cm),
absence of signs of HCC or clinically relevant renal abnormalities on an abdominal ultrasound performed within 6 months prior to screening or at the time of
screening. In case of suspicious findings on conventional ultrasound the participant may still be eligible if HCC or clinically relevant renal abnormalities have been
ruled out by a more specific imaging procedure (contrast enhanced ultrasound, CT or MRI). Additional ultrasound assessments may be performed when clinically
indicated.
l. 
A liver ultrasound is recommended approximately every 24 weeks for HCC screening.
m. Following local standard practice the biopsy location will be identified with ultrasound (which will also be used to rule out contraindicating conditions for a
biopsy) and after application oflocal anesthesia the FNAB samples and core liver biopsy samples will be collected. Prior to any on-treatment biopsy, a recent
(≤1 week) coagulation and hematology panel, and a platelet aggregation test are required (pre-biopsy visit). Prior to the off-treatment biopsies, blood coagulation
and platelets will be assessed at a local laboratory according to local practice. On-treatment (pre)biopsy can either occur during a regularly scheduled visit or an
unscheduled visit.
n. 
In between study visits, participants will take oral study intervention at home. Participants will be requested to bring their study intervention with them to each
study visit. At study visits, the study intervention should be taken on site.


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o. 
Participants enrolled before Protocol Amendment 5 was in effect, may have received JNJ-6379 as part of their study intervention. Dispensation of JNJ-6379
stopped immediately with the removal of JNJ-6379 as study intervention through an urgent safety measure. Participants have to return JNJ-6379 tablets to the site
at the next scheduled visit.
p. 
NA will be dispensed at Week 48 for intake during the follow-up phase in case the participant cannot stop NA treatment at Week 48.
q. 
Complete physical examination, including height (only at screening), body weight, skin examination, and other body systems (see Section 8.4.1).
r. 
Vital signs include supine SBP, DBP, pulse rate, and body temperature.
s. 
All ECGs will be read centrally; ECGs should be completed before any tests, procedures or other consultation for that visit. 
t. 
Biochemistry samples must be taken after fasting for at least 10 hours for measurement of phosphate, calcium, creatinine, and lipids. Participants should bring their
oral study intervention with them to each visit and have that day’s intake at the site with breakfast.
u. 
Creatinine clearance (eGFR calculated by the CKD-EPI formula) will be assessed.
v. 
Intervention-emergent ALT/AST elevations (ie, ALT and/or AST ≥3x ULN and ≥3x nadir [ie, lowest value during study participation]), should trigger an
assessment of confounding factors (alcohol intake, change in concomitant medication, and comorbidities)and a confirmatory visit, to be scheduled preferably
within 7 days of the receipt of the initial ALT/AST results, to repeat laboratory testing of AFP, ALT, AST, ALP, bilirubin (total and direct), INR, albumin, and
HBV DNA until ALT and AST levels have returned to <5x ULN and HBV DNA is <20,000 IU/mL. Additional tests should be considered based on clinical
judgement. For more details and further management guidance refer to Section 8.5.6.2 and Section 10.6.
w. Urinalysis by dipstick: specific gravity, pH, glucose, protein, blood, ketones, bilirubin, urobilinogen, nitrite, leukocyte esterase, and microscopic analysis if needed.
The dipstick reading should be done as soon as possible and in accordance with the manufacturer’s recommendation. In case of a positive dipstick result, a urine
sample will be set aside for additional examination of the positive parameter (eg, quantification as applicable).
x. 
Urine chemistry sample (quantitative measurement): creatinine, sodium, phosphate, glucose, protein, and albumin.
y. 
Urine sample for selected renal biomarkers including retinol binding protein and beta-2-microglobulin.
z. 
For postmenopausal women only: an FSH level in the postmenopausal range may be used to confirm a postmenopausal state in women not using hormonal
contraception or hormonal replacement therapy. However, in the absence of 12 months of amenorrhea, a single FSH measurement is insufficient to confirm a
woman is not of childbearing potential.
aa. HBV genotype will be determined at baseline using standard genotyping assay if HBV DNA levels are sufficiently high. For participants with low HBV DNA
levels, available historical data on previous HBV genotype assessment will be collected in the CRF. Exploratory genotyping assays might be performed.
bb. HBcrAg and HBV RNA samples may be batched and only selected samples may be tested at the sponsor’s request. Samples can be used for assessment of other
serologic/virologic markers of HBV.
cc. Samples may be sequenced based on the sponsor virologist’s request, considering the HBV DNA levels.
dd. Participants must first complete HBeAg testing and have results reviewed by the investigator to confirm if they qualify for study participation.
ee. Quantitative HBeAg assessment will only be performed in participants who are defined HBeAg positive at screening or who become HBeAg positive post-baseline
based on a qualitative HBeAg assay.
ff. 
Exploratory serology samples may be analyzed at the sponsor’s discretion. Samples may be used to assess virologic or serologic markers of HBV.
gg. All participants will have sparse PK sampling for JNJ-3976, JNJ-3924, and NA (ETV, TAF, or tenofovir). Bioanalysis of NA and/or PegIFN-α2a is optional at the
discretion of the sponsor. Bioanalysis of JNJ-6379 may also be done on samples collected from participants who received JNJ-6379 up to Protocol Amendment 4
For all samples, the date and time of the preceding intake of oral study intervention (NA), the date and time of the previous JNJ-3989 administration, and the date
and time of PK sampling should be recorded. Sparse PK sampling is not required if the participant is part of the intensive PK subgroup and has an extensive PK
sampling at the same visit.
hh. One sample at any time between 2 and 8 hours after JNJ-3989 dosing. Before leaving the study site, the participant’s wellbeing should be confirmed.
ii. 
Only in case of early withdrawal.


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jj. 
All participants who consent to participate in the intensive PK subgroup (optional) will undergo intensive PK sampling at Week 4. If necessary (eg, for operational
reasons), this visit may be scheduled at Week 8, 12, or 16. The study intervention should be taken on site and time of dosing should be recorded. Pharmacokinetic
samples will be taken predose and 15 minutes, 30 minutes, 1, 2, 3, 4, 6, 8,* 10,* and 24 hours postdose (*the 8 and 10 hours postdose samples are optional). All
efforts will be made to obtain the PK samples at the exact nominal time relative to dosing. However, samples obtained within 20% of the nominal time from dosing
(eg, +/- 12 minutes of a 60-minute time point) will not be captured as a protocol deviation if the exact time of the sample collection is noted on the source
document and CRF.
kk. Leukapheresis is optional and will only be performed for participants who provided separate consent for this procedure. Refusal to give consent for leukapheresis
does not exclude a participant from participation in the study. The leukapheresis procedure will be performed at least 1 week (and up to 3 weeks)after the liver
biopsies; this can either occur during a regularly scheduled visit or an unscheduled visit. Prior to the procedure, the participant’s wellbeing will be checked and
leukapheresis will only be offered if there is no clinical reason against it. If a participant has had a recent febrile illness, the leukapheresis should be postponed until
body temperature is normal for at least 72 hours. One leukapheresis session is expected to last between 1.5 - 5 hours. During the procedure, the participant will
receive intravenous saline infusions and citrate-based anticoagulant. Use of heparin for anticoagulation is not allowed. After completion of the leukapheresis
procedure, participants will stay at the site for at least 30 minutes to monitor for any relevant safety events. Participants are advised to refrain from exercise and
strenuous activities for 3 days after the leukapheresis visit.
ll. 
Additional PBMC samples may be taken in case of ALT flares, upon discussion with the sponsor, and may require an unscheduled visit.
mm. The pharmacogenomic (DNA) sample should preferably be collected at baseline.
nn. Adverse events and concomitant medications will be monitored from the time a signed and dated ICF is obtained until completion of the participant’s last
study-related procedure.
oo. Includes close monitoring for neuropsychiatric adverse events during the optional PegIFN-α2a treatment period. Participants who develop a neuropsychiatric
adverse event during optional PegIFN-α2a treatment, will be monitored closely until the neuropsychiatric adverse event resolves, with frequent (at least weekly)
follow-up phone calls.
pp. As of Protocol Amendment 5, new participants will enroll without randomization within each panel to receive the combination regimen JNJ-3989 + NA as study
intervention for 48 weeks.








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j. 
Biochemistry samples must be taken after fasting for at least 10 hours for measurement of phosphate, calcium, creatinine, and lipids.
k. 
Creatinine clearance (eGFR calculated by the CKD-EPI formula) will be assessed.
l. 
ALT/AST elevations (ie, ALT and/or AST ≥3x ULN and ≥3x nadir [ie, lowest value during study participation]), should trigger an assessment of confounding
factors (alcohol intake, change in concomitant medication, and comorbidities) and a confirmatory visit, to be scheduled preferably within 7 days of the receipt of
the initial ALT/AST results, to repeat laboratory testing of AFP, ALT, AST, ALP, bilirubin (total and direct), INR, albumin, and HBV DNA until ALT and AST
levels have returned to <5x ULN and HBV DNA is <20,000 IU/mL. Additional tests should be considered based on clinical judgement. For more details and
further management guidance refer to Section 8.5.6.2 and Section 10.6.
m. Liver function tests only.
n. 
Urinalysis by dipstick: specific gravity, pH, glucose, protein, blood, ketones, bilirubin, urobilinogen, nitrite, leukocyte esterase, and microscopic analysis if needed.
The dipstick reading should be done as soon as possible and in accordance with the manufacturer’s recommendation. In case of a positive dipstick result, a urine
sample will be set aside for additional examination of the positive parameter at the central laboratory (eg, quantification as applicable).
o. 
Urine chemistry sample (quantitative measurement): creatinine, sodium, phosphate, glucose, protein, and albumin.
p. 
A urinalysis and urine chemistry sample will be taken at Follow-up Week 4. In case of abnormalities, the tests should be repeated at the following visits.
q. 
Urine pregnancy tests for at-home use will be provided to the participants as necessary to ensure urine pregnancy tests are performed at least every 4 weeks.
Results will be reported at the next visit. If positive, the participant should contact the site immediately.
r. 
Only applicable to participants who are enrolled at a site with an on-site Fibroscan device.
s. 
HBcrAg and HBV RNA samples may be batched and only selected samples may be tested at the sponsor’s request. Samples can be used for assessment of other
serologic/virologic markers of HBV.
t. 
Samples may be sequenced based on the sponsor virologist’s request, considering the HBV DNA levels. A sample for viral genome sequencing will be taken at an
unscheduled visit for confirmation of virologic relapse.
u. 
Exploratory serology samples may be analyzed at the sponsor’s discretion. Samples may be used to assess virologic or serologic markers of HBV.
v. 
Leukapheresis is optional and will only be performed for participants who provided separate consent for this procedure. Refusal to give consent for these optional
procedures does not exclude a participant from participation in the study. The leukapheresis procedure will be performed at least 1 week (and up to 3 weeks) after
the liver biopsy; this can either occur during a regularly scheduled visit or an unscheduled visit. If no liver biopsy is being performed during follow-up,
leukapheresis should take place around the FU W24 time point. Prior to the procedure, the participant’s wellbeing will be checked and leukapheresis will only be
offered if there is no clinical reason against it. If a participant has had a recent febrile illness, the leukapheresis should be postponed until body temperature is
normal for at least 72 hours. One leukapheresis session is expected to last between 1.5 - 5 hours. During the procedure, the participant will receive intravenous
saline infusions and citrate-based anticoagulant. Use of heparin for anticoagulation is not allowed. After completion of the leukapheresis procedure, participants
will stay at the site for at least 30 minutes to monitor for any relevant safety events. Participants are advised to refrain from exercise and strenuous activities for 3
days after the leukapheresis visit.
w. Additional PBMC samples may be taken in case of ALT flare, upon discussion with the sponsor, and may require an unscheduled visit.
x. 
Adverse events and concomitant medications will be monitored from the time a signed and dated ICF is obtained until completion of the participant’s last study-
related procedure.
y. 
With implementation of Protocol Amendment 5, the follow-up phase of 48 weeks will be extended for participants who are receiving optional treatment with
PegIFN-α2a and who meet NA treatment completion criteria at the end of treatment with NA and PegIFN-α2a to ensure all study participants will be followed for
at least one year after NA treatment cessation. Visits will be scheduled at least every 4 weeks and assessments will be similar to assessments performed at the FU
W28 visit. At the respective EOS visit for these participants, assessments as described in the FU W48 EOS visit will be performed.
z. 
NA treatment should be re-started in accordance with the NA re-treatment criteria (refer to Section 6.6.2 and Section 10.12 Appendix 12 for guidance after
stopping NA treatment.)


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aa. The investigator should consider to re start NA treatment per local standard of care at the EOS visit (Follow up Week 48 up to maximum Follow up Week 72) for participants who
met the NA treatment completion criteria at Week 48 or for participants who met NA treatment completion criteria at the end of treatment with PegIFN α2a during the follow up
phase, who did not re start NA treatment during the follow up phase, and who did not achieve and maintain HBsAg seroclearance. NA will not be provided by the sponsor after the
final study visit.






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2. 
INTRODUCTION
Chronic Hepatitis B Infection
Hepatitis B virus (HBV) is a small deoxyribonucleic acid (DNA) virus that specifically infects the
human liver. It consists of a nucleocapsid in which the viral DNA is packed with hepatitis B core
protein (HBc) and a membraneous envelope containing hepatitis B surface antigen (HBsAg). The
acute phase of the infection (less than 6 months) is either followed by an immune controlled state
(spontaneous cure from the infection) or progresses to chronic hepatitis B (more than 6 months).
Chronic HBV infection may lead to serious illnesses such as liver cirrhosis and decompensation,
and hepatocellular carcinoma (HCC), often with fatal outcome.33
The worldwide estimated prevalence of chronic HBV infection is 4.9% with about 292 million
people affected.28 Despite the availability of an efficacious prophylactic vaccine, yearly rates of
new infections remain high. Approximately 680,000 people per year worldwide die from cirrhosis
and HCC due to chronic HBV infection.31
The natural course of chronic HBV infection is the consequence of a complex interaction between
the virus and the host which in the chronic setting might evolve over a duration of decades. This
is associated with different disease phases or stages. The European Association for the Study of
the Liver (EASL) guidelines differentiate between chronic infection and chronic hepatitis
(Table 1).
Table 1: 
Various Stages of HBV Infection –Terminology and Characteristics (EASL 2017)5
HBeAg positive 
HBeAg negative
Chronic 
infection
Chronic hepatitis 
Chronic infection  Chronic hepatitis
HBsAg 
High  
High/intermediate 
Low  
Intermediate
HBeAg 
Positive 
Positive 
Negative 
Negative
HBV DNA  
>107 IU/mL 
104-107 IU/mL 
<2,000 IU/mL°° 
>2,000 IU/mL
ALT  
Normal 
Elevated 
Normal 
Elevated*
Liver disease 
None/minimal 
Moderate/severe 
None 
Moderate/severe
Old 
terminology  
Immune tolerant 
Immune reactive HBeAg 
positive 
Inactive carrier 
HBeAg negative chronic
hepatitis
ALT: alanine aminotransferase; DNA: deoxyribonucleic acid; EASL: European Association for the Study of the Liver;
HBeAg: hepatitis B e antigen; HBsAg: hepatitis B surface antigen; HBV: hepatitis B virus; IU/mL: International Units Per
Milliliter
* Persistently or intermittently. °°HBV deoxyribonucleic acid (DNA) levels can be between 2,000 and 20,000 IU/mL in
some patients without signs of chronic hepatitis.
Note that different definitions and naming of HBV disease phases may be used across different countries/regions.
According to the EASL treatment guidelines, the primary treatment goal for patients with chronic
HBV infection is to improve survival and quality of life by preventing progression of liver disease,
particularly to cirrhosis, liver failure, and HCC.
Irrespective of the hepatitis B e antigen (HBeAg) status, antiviral therapy is recommended for all
patients with signs of active chronic hepatitis.2,5,30,33 Approved therapies for chronic HBVinfection
are pegylated interferon alpha (PEG-IFN-α) and nucleos(t)ide analog (NA) inhibitors (ie, NA


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treatment) of the HBV polymerase/reverse transcriptase, the enzyme synthesizing HBV DNA from
pre-genomic ribonucleic acid (pgRNA).
Oral treatment with NAs is effective at suppressing viral DNA formation and lowering virus
concentration in the blood to levels below the lower limit of quantification (LLOQ) of the HBV
DNA assays commonly used. This is associated with normalization of liver enzymes and reduced
or halted progression of liver disease to cirrhosis and/or decompensation and even with regression
of cirrhotic transformation.4,18,22,25,36 While the risk of HCC development is reduced as well, it is
not eliminated.18,22,25
Hepatitis B surface antigen seroclearance 24 weeks after end of treatment is currently considered
to be associated with the most thorough suppression of HBV replication and has been termed
“functional cure”.21 Unfortunately, with currently available NA treatment strategies the rate of
HBsAg seroclearance remains very low (around 3%) even under long-term treatment.
Pegylated IFN is associated with a slightly higher rate of HBsAg seroclearance compared to NAs
and is recommended for a fixed treatment duration of 48 weeks, but is administered
subcutaneously (SC)and is associated with higher toxicity than NAs.27
With the low rate of functional cure with current treatments, and persistently high global
prevalence of HBV-associated mortality,5,33 there is a medical need for more effective finite
treatment options that lead to sustained seroclearance of HBsAg and HBV DNA off treatment
("functional cure"). In order to achieve an effective finite treatment, combination of therapies with
different mechanisms of action, as is standard of care for other chronic viral infections like hepatitis
C virus (HCV)and human immunodeficiency virus (HIV), is deemed required.
A challenge for the clinical development of novel HBV agents is that while blood markers are used
to assess their efficacy and immune response induced by these agents, their target organ is the
liver. Although some of the efficacy blood markers are very well established from a clinical
perspective, questions remain on how good these markers correlate with intrahepatic events, such
as HBV covalently closed circular DNA (cccDNA) level and transcriptional activity. In addition,
the immune response measured in the periphery is known to insufficiently reflect the situation in
the liver. For example, the frequency of HBV-specific T-cells as well as liver resident immune
cells cannot be adequately assessed by measuring immune response in the periphery. Multiple
studies have shown the value of full needle core biopsies as well as fine needle aspirates to assess
intrahepatic virologic and immunologic events of HBV. A wide range of methods are currently
available, such as polymerase chain reaction (PCR) based methods, single cell analyses and high
multiplex fluorescence-based methods.
JNJ-73763989 (JNJ-3989) is a liver-targeted antiviral therapeutic for SC injection designed to treat
chronic HBV infection via a ribonucleic acid interference (RNAi) mechanism. JNJ-3989 consists
of two RNAi triggers, one targeting the HBsAg open reading frame (JNJ-73763976 [JNJ-3976]),
and one targeting the HBV X protein open reading frame (JNJ-73763924 [JNJ-3924]). Hence,
engagement of the cellular RNAi machinery by JNJ-3989 results in specific cleavage of HBV
ribonucleic acid (RNA) transcripts, thereby reducing the levels of HBV proteins and the pgRNA,


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the precursor of viral relaxed circular DNA. The RNAi triggers in JNJ-3989 injection are designed
to target all HBV RNA transcripts derived from cccDNA, as well as transcripts derived from
integrated viral DNA. The latter has been suggested to be a significant source of HBsAg in HBeAg
negative patients or patients on long term treatment with NAs, the current standard of care.35
JNJ-56136379 (JNJ-6379) is an orally administered capsid assembly modulator (CAM) that is
being developed for the treatment of chronic HBV infection. JNJ-6379 binds to HBc and interferes
with the viral capsid assembly process, thereby preventing the polymerase-bound pgRNA
encapsidation. This results in the formation of HBV capsids, devoid of HBV DNA or RNA (non-
functional capsids), and ultimately in the inhibition of HBV replication. In addition, JNJ-6379 also
acts at an early stage of the viral life cycle by inhibiting the de-novo formation of cccDNA
potentially by interfering with the capsid disassembly process. JNJ-6379 was initially part of the
study intervention but has been removed as study intervention with the implementation of an
urgent safety measure, as described in Protocol Amendment 5.
Prior to Protocol Amendment 5, the term “study intervention” throughout the protocol, refers to
JNJ-3989, JNJ-6379, NA, and optional PegIFN-α2aa.
As of Protocol Amendment 5, the term “study intervention” throughout the protocol, refers to
JNJ-3989, NA, and optional PegIFN-α2a.
The term "sponsor" used throughout this document refers to the entities listed in the Contact
Information page(s), which will be provided as a separate document.
The term "participant" throughout the protocol refers to the common term "subject".
2.1. 
Study Rationale
This liver biopsy study is primarily performed to assess changes in intrahepatic viral and host
immune markers in response to JNJ-3989-based combination treatment. This analysis can be used
to characterize mode of action (MoA) of the treatment. Furthermore, this study aims to explore
association of hepatic and peripheral viral and/or host markers with selected efficacy variables,
identify subpopulations that show a defined response, and identify cellular and molecular
determinants of response. Hepatic and peripheral viral and immune markers and their correlations
will be assessed. In addition, changes in liver histology may be assessed. The totality of results
may be used to inform on the optimal use of therapeutics in current or future combinations. This
study aims to assess intrahepatic events in the context of a full (48-week) treatment regimen as
used in 2 ongoing Phase 2b studies in a similar HBV population to facilitate comparison of the
results across studies.
The efficacy and safety of finite treatment duration will be assessed with a fixed 48-week treatment
duration for JNJ-3989, in combination with NA treatment. Participants meeting pre-defined
response criteria (outlined in Section 6.6.1) will also complete NA treatment after 48 weeks. The
a 
Note: Optional PegIFN α2a was introduced as ‘study intervention’ as of Protocol Amendment 4.


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participants may also receive optional treatment with PegIFN-α2a for either 12 or 24 weeks at the
investigator’s discretion, to investigate whether addition of PegIFN-α2a towards the end of the
existing treatment regimen further decreases HBsAg.
2.2. 
Background
For the most comprehensive nonclinical and clinical information regarding JNJ-3989 and
JNJ-6379, refer to the latest version of the Investigator's Brochure (IB) and addenda.14 16,39
Note: JNJ-6379 was initially part of the study intervention but has been removed as study
intervention with the implementation of an urgent safety measure, as described in Protocol
Amendment 5. For completeness, background information on JNJ-6379 is still included in this
section.
2.2.1. 
Nonclinical Studies
2.2.1.1. 
JNJ-3989 and JNJ-6379
Nonclinical assessments to support clinical development have been performed for the single agents
JNJ-3989 and JNJ-6379, and also for their combination (up to 3 months studies).
JNJ-3989
Little potential for off-target inhibition of human gene expression in participants is expected, based
on in silico human genome database screening.
The nonclinical safety profile of JNJ-3989 has been evaluated through a series of in vitro and in
vivo studies. Repeat-dose SC toxicity studies of 2 weeks up to 24 or 37 weeks were conducted in
rat and monkey, respectively. In the 2-week studies, JNJ-3989 was administered once weekly via
SC injection at
up to 
mg/kg. In the 24- or 37-week studies, JNJ-3989 was administered
once weekly for the first month, followed by once monthly thereafter at
up to
 mg/kg. JNJ-
3989 was well tolerated in these studies.
In the 2-week and the 24-week studies in rat, JNJ-3989-related target organs were the liver, the
kidney, and the injection site. The mandibular and mesenteric lymph nodes were identified as
target organ in the 24-week study only. In the liver, hepatocyte alteration and hepatocyte mitosis,
accompanied by an increase in hepatocellular vacuoles, oval cell hyperplasia, Kupffer cell
vacuolation and/or increased liver weights were observed. The hepatocyte findings correlated to
increased alkaline phosphatase (ALP) activity levels seen in the 24-week study. Kidney findings
were characterized by cytoplasmic alteration of the cortical tubule epithelium. At the injection site,
mononuclear cell or vacuolated macrophage infiltrates, epidermal exudate, hemorrhages and/or
interstitial granules were observed. Macrophage vacuolation was observed in the sinus spaces of
the mandibular and mesenteric lymph nodes.
Liver findings persisted throughout the recovery period. Partial recovery was observed in the
kidney. No findings were present anymore at the injection sites and the lymph nodes at the end of
the recovery period.
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All these changes likely represented the distribution, accumulation, and clearance of JNJ-3989 and
were considered not to be adverse due to the nature of the findings and the low severity. These are
commonly described findings for N-acetylgalactosamine-conjugated RNAi.17 The no observed
adverse effect level (NOAEL) was therefore considered to be the highest dose tested, ie,
mg/kg
in the 24-week study.
In the 2-week study in monkey, apart from a minimally increased ALP activity which was
considered not adverse, no JNJ-3989-related effects were observed. In the 37-week study,
JNJ-3989-related target organs were the liver, mandibular and/or mesenteric lymph nodes, and the
SC injection site. Findings included Kupffer cell basophilia/hypertrophy in the liver, vacuolated
macrophages in the lymph nodes, and macrophage infiltrates in the injection site. Partial
reversibility was observed for these findings. This likely represented the distribution,
accumulation, and clearance of JNJ-3989 and was considered not to be adverse due to the low
severity and/or nature of the findings. These are commonly described findings for
N-acetylgalactosamine-conjugated RNAi.17 A non-adverse minimally increased ALP activity was
observed at 
mg/kg without a microscopic correlate. The NOAEL in the monkey was
considered to be the highest dose tested, ie,
mg/kg in the 37-week study.
In the embryofetal development (EFD) studies, JNJ-3989 was not teratogenic in rats and rabbits.
The fertility study showed no effects on parental and reproductive parameters in male and female
rats given JNJ-3989 up to a dose of 
mg/kg/week.
JNJ-3989 was shown to be non-genotoxic when tested in the bacterial reverse mutation assay, and
in vitro and in vivo micronucleus test.
Results of the non-Good Laboratory Practice (GLP) in vitro studies demonstrated there is no
potential for induction of the innate immune system (cytokine and complement activation),
mitochondrial toxicity/cytotoxicity, or platelet aggregation associated with JNJ-3989 exposure at
concentrations up to
µg/mL.
The animal-to-human exposure ratios were calculated using rat and monkey exposures at NOAEL
from the 24-week and 37-week studies, respectively, and human exposures after a single SC
injection of 200 mg JNJ-3989 in human volunteers (Study AROHBV1001) (Table 2).
Table 2: 
Animal/Human Exposure Ratios at NOAEL for JNJ-3989
Sex 
NOAEL  
(mg/kg) 
C max 
(ng/mL) 
AUC  
b
(ng.h/mL) 
Ratio Total Concentration
Cmax 
A/H Ratio 
AUCb
A/H Ratio
JNJ-3976
Human exposurea 
1,315 
20,136 
- 
-
24-week 
ratc 
M 
41,100 
437,000 
31.3 
21.7
F 
43,100 
270,000 
32.8 
13.4
37-week 
monkeyd 
M 
73,200 
1,230,000 
55.7 
61.1
F 
65,800 
988,000 
50.0 
49.1
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Table 2: 
Animal/Human Exposure Ratios at NOAEL for JNJ-3989
Sex 
NOAEL  
(mg/kg) 
C max 
(ng/mL) 
AUCb 
(ng.h/mL) 
Ratio Total Concentration
Cmax 
A/H Ratio 
AUCb
A/H Ratio
JNJ-3924
Human exposurea 
363 
4,605
24-week 
ratc 
M 
25,200 
271,000 
69.4 
58.8
F 
26,200 
163,000 
72.2 
35.4
37-week 
monkeyd 
M 
21,600 
383,000 
59.5 
83.2
F 
23,000 
392,000 
63.4 
85.1
AUC: area under the plasma concentration time curve; AUC0-24h: area under the plasma concentration time curve from
administration to 24 h; AUC0-last: area under the plasma concentration time curve from administration to last quantifiable sampling
point; A/H: animal/human ratio; Cmax: maximum plasma concentration; F: female; M: male; NOAEL: no observed adverse effect
level; PK: pharmacokinetics; SC: subcutaneous
a 
Single dose of 200 mg JNJ 3989 in healthy volunteers via SC injection (Study AROHBV1001; based on recent clean dataset
with data cut off 29 October 2019. Clinical PK update will be included in next revision of the IB).
b
AUC0-last for human exposure; AUC0-24h for animal exposures
c
Once weekly dosing for 4 weeks, followed by once monthly dosing, up to a total of 24 weeks
d
Once weekly dosing for 5 weeks followed by once monthly dosing, up to a total of 37 weeks
JNJ-6379
Following 6 months of treatment in rats, the kidney and female reproductive tract (irregular estrous
cycle) were identified as target organs. However, after further assessment of the kidney findings
and their clinical relevance, it is deemed unlikely that the retrograde nephropathy seen in 1 out of
20 male rats following 6 months of dosing with JNJ-6379 at 100 mg eq./kg/day are relevant for
the clinical studies. The retrograde nephropathy was partially recovered after a 9-week recovery
period. In the 6-month rat study, female rats (at 200 mg eq./kg/day) showed an irregular estrous
cycle, from which they recovered at the end of the 9-week treatment-free period. These irregular
estrous cycles were also apparent in the female fertility studies (main and mechanistic). These
changes were related to lowered hormone levels (luteinizing hormone, progesterone, estradiol).
JNJ-6379, however, did not affect female fertility. The fetal loss seen during the early stages of
pregnancy was considered to result from low hormone levels. In the dog study, no changes were
observed in the reproductive tract at higher exposures in dogs.
In the 9-month dog study, the target organs identified were the adrenal glands and bone marrow.
The adrenal glands did not show degenerative changes or loss of function and were therefore
considered as non-adverse target organs. One female dog out of 4 dosed at 25 mg eq./kg/day (the
highest dose) was sacrificed on Day 61, after showing poor health condition. A JNJ-6379 plasma
level of 42,000 ng/mL was observed for this animal on Day 61, at approximately 24 hours after
last dosing. Pronounced clinical pathologic changes, including pancytopenia, were noted. Marked
increase in plasma cell-like cells was seen in the bone marrow during histopathologic examination,
resulting in a marked reduction of hematopoietic tissue and extramedullary hematopoiesis in liver
and spleen. The cause of the deteriorating condition was likely related to changes in the bone
marrow. A second dog in the same dose group with pancytopenia recovered after a drug holiday
and was re-exposed uneventfully.
In the EFD studies, JNJ-6379 was not teratogenic in rats and rabbits.
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JNJ-6379 was not genotoxic in the in vitro micronucleus and Ames tests, and in the in vivo
micronucleus tests in rats.
Animal/human ratios at the NOAEL in rat and dog for human exposure at 250 mg JNJ-6379 once
daily (qd) for 28 days are displayed in Table 3.
Table 3: 
Animal/Human Ratios at the NOAEL in Rat and Dog (Human Exposure at 250 mg JNJ-6379
Once Daily for 28 Days [Study 56136379HPB1001])
Sex 
NOAEL  
(mg eq./kg/day) 
Cmax 
(ng/mL) 
AUC0-24h 
(ng.h/mL) 
Ratio Total
Concentration
Ratio
Concentration
Corrected for
Plasma Protein
Bindingb
Cmax 
A/H 
Ratio 
AUC0-24h 
A/H 
Ratio 
Cmax 
A/H 
Ratio 
AUC0-24h
A/H
Ratio
Human exposurea 
13,798 
267,180 
- 
-
6M rat 
M 
7,540 
93,100 
0.6 
0.3 
0.9 
0.6
M 
13,600d 
180,000d 
1.0 
0.7 
1.7 
1.1
F 
19,900 
233,000 
1.4 
0.9 
2.4 
1.5
9M dog 
M 
30,000 
606,000 
2.2 
2.3 
3.3 
3.4
F 
22,500 
383,000 
1.6 
1.4 
2.5 
2.2
AUC: area under the plasma concentration time curve; AUC0-24h: area under the plasma concentration time curve from
administration to 24 h; A/H: animal/human ratio; Cmax: maximum plasma concentration; F: female; M: male; NOAEL: no
observed adverse effect level; qd: once daily.
a 
250 mg JNJ 6379 qd for 28 days (Study 56136379HPB1001).
b 
Ratio of the total Cmax or AUC corrected for species difference in plasma unbound fraction. Calculation: [animal Cmax or
AUC0-24h x
mal free fraction] / [human Cmax or AUC0-24h x human free fraction].
c 
A dose of
mg eq./kg/day in male rats is considered to be above the NOAEL due to kidney findings in male rats, which
are likely 
elevant for human.
d 
The plasma Cmax of 13,600 ng/mL and AUC0-24h of 180,000 ng.h/mL in male rats at 100 mg eq./kg/day corresponds to an
unbound Cmax of 1,754 ng/mL and AUC0-24h of 23,220 ng.h/mL (fraction unbound rat plasma 12.9%). This unbound plasma
exposure will be achieved in humans at a total plasma Cmax of 22,784 ng/ml and AUC0-24h of 301,558 ng.h/mL (fraction
unbound in human plasma 7.7%).
Combination of JNJ-3989 and JNJ-6379
A 1-month repeat-dose combination toxicity study of JNJ-6379 and JNJ-3989 was conducted in
male and female Sprague-Dawley rats. JNJ-6379 (in PEG400 + 10% PVP-VA) was administered
daily via oral gavage at
mg/kg, alone or in combination with JNJ-3989 (in phosphate-buffered
saline) which was administered weekly via SC injections a
and
mg/kg. In addition,
mg/kg JNJ-3989 (SC, weekly) was dosed as well in a monotherapy group. Control animals
received both vehicles via the respective routes.
The data showed that weekly SC injections with JNJ-3989 a
o
mg/kg in combination with
daily administration of JNJ-6379 at 
mg/kg (oral) for one month were well tolerated with no
clinical signs or treatment-related mortality. Changes in clinical pathology and histopathology
were mostly similar to the findings for the monotherapy groups dosed with JNJ-6379 at
mg/kg
(oral) alone or with JNJ-3989 at 
mg/kg (SC) alone. The only synergistic changes included a
slight decrease in body weight (gain) at ≥
mg/kg, in food consumption at 
 mg/kg,
and a further decrease in lymphoid cellularity in the thymus of females at 
 mg/kg. These
alterations were minor and non-adverse in nature. Based on these results, the NOAEL was
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considered to be 
 mg/kg. Maximum plasma concentration (Cmax) and AUC0 24h  values for
JNJ-6379 in males were 13,200 ng/mL and 181,000 ng∙h/mL, and for females 15,500 ng/mL and
206,000 ng∙h/mL, respectively, after 1 month of treatment. The mean Cmax  and AUC0 24h  values
for analyte JNJ-3924 in males were 20,900 ng/mL and 160,000 ng∙h/mL, and for females
21,300 ng/mL and 125,000 ng∙h/mL, respectively. For analyte JNJ-3976, the mean Cmax  and
AUC0 24h values in males were 35,200 ng/mL and 258,000 ng∙h/mL, and for females 35,300 ng/mL
and 201,000 ng∙h/mL, respectively.
A 3-month combination toxicity study of JNJ-3989 and JNJ-6379 is ongoing, preliminary data is
available. In this study, JNJ-3989 was initially administered weekly (ie, a total of 6 doses) and
monthly thereafter, via SC injections at dose levels o
and 
mg/kg when given  in
combination with JNJ-6379, and at 180 mg/kg for the monotherapy group. JNJ-6379 was
administered daily via oral gavage at a dose level of 
mg/kg in the monotherapy and
combination groups. Control animals received both vehicles via the respective routes.
No test article-related mortalities were noted among animals dosed with JNJ-6379 alone, JNJ-3989
alone, or with JNJ-6379 + JNJ-3989 at
mg/kg. One male receiving JNJ-3989 alone at
mg/kg died on Day 45, after a rapid change in its clinical condition. The death ofthis animal was
considered to reflect an acute stress response without a relationship to the test article. One
accidental death due to a possible gavage error was noted among the toxicokinetic animals in the
mg/kg combination group. No bone marrow abnormalities were seen in these 2 animals.
One male rat dosed at
mg/kg JNJ-6379/JNJ-3989 was euthanized on Day 24 after showing
severe clinical signs in the morning (decreased activity, erected fur, pallor, and cold to touch). No
clinical signs were noted for this animal until Day 23, and body weight and weight gain were
unaffected during the first 3 weeks of the study. The cause of moribundity was considered to be a
markedly decreased hematopoietic cellularity of the bone marrow with pancytopenia, including
markedly reduced platelet counts and consequent hemorrhages and blood loss. A relation to the
treatment with JNJ-6379 and/or JNJ-3989 cannot be excluded.
Clinical pathology analysis in this rat revealed a marked decrease in white blood cells (WBCs)
(neutrophil, lymphocyte, and monocyte counts), marked decreases in red blood cell (RBC) mass
parameters (hemoglobin, hematocrit, and RBC count) including reticulocyte count, and platelet
count. There was a mildly increased fibrinogen concentration and mildly prolonged prothrombin
time. Other clinical pathology findings were observed for this animal, but they are not related to
the bad condition and euthanasia.
At necropsy, the rat showed dark red discoloration/dark red foci in a wide variety of organs and
tissues, and dark red material in the abdominal cavity adhered to the spleen (freshly clotted blood).
This correlated to minimal to marked hemorrhages in multiple tissues, including brain.
At microscopic examination, the bone marrow of this animal showed markedly decreased
cellularity of hematopoietic tissue. Based on the morphology of the remaining hematopoietic tissue
and the absence of necrosis, this bone marrow finding was considered not acute but rathersubacute
or subchronic in nature. In absence of pre-values or earlier time points for hematology, it was not
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possible to define the onset of the initiating event. Minimal to marked acute hemorrhages were
noted in a wide range of tissues. Some other microscopic findings unrelated to the event were
identified.
Altogether, the decreased cellularity of hematopoietic tissue in the bone marrow and the
hematology/coagulation data indicate that reduced hematopoiesis resulted in decreases in WBC,
reticulocyte, and platelet counts. The hemorrhages were interpreted to be the result of a deficit in
primary hemostasis, consistent with the markedly reduced platelet counts. None of the remaining
animals of this study showed decreased cellularity of the bone marrow.
In addition to the changes described above, decreased platelet counts were seen in females at
and
mg/kg JNJ-6379/JNJ-3989. However, the decrease in platelet counts for these
groups was mild, similar across animals within the groups and to those seen in a previous 1-month
combination toxicity study with JNJ-6379/JNJ-3989, and not accompanied by other cytopenia nor
bone marrow abnormalities. The decrease in platelet counts for these groups are likely caused by
a different mechanism than for the male rat that was euthanized on Day 24, as described above.
No relevant changes on urinary biomarkers were detected in male and female rats given JN-6379
at 
mg/kg/day (clusterin, albumin, ß2-microglobulin, Kidney Injury Molecule-1 [KIM-1],
Neutrophil Gelatinase Associated Lipocalin [NGAL] and cystatin-C).
Based on the observation of pancytopenia in 1 rat and a mild platelet decrease in the combination
groups in the 3-month combination toxicity study, the sponsor is implementing additional
monitoring of significant on-treatment hematologic changes in clinical studies with dosing longer
than 4 weeks (see Section 8.5.6.5). However, no significant abnormalities of hematologic
parameters have been observed in clinical studies to date.
For further information, refer to the IBs and addenda.14 16,39
2.2.1.2. 
Combination of JNJ-3989 or JNJ-6379 with Entecavir, Tenofovir
Disoproxil, or Tenofovir Alafenamide
There is no common target organ between JNJ-6379 or JNJ-3989 and entecavir (ETV).23 The
single common toxicity target organ between JNJ-6379, JNJ-3989, and tenofovir disoproxil or
tenofovir alafenamide (TAF)is the kidney.
In the chronic rat studies with JNJ-3989, slight alteration of the renal tubular epithelium was
characterized by basophilic stippling and/or microvacuolation of the cytoplasm of renal tubules in
the outer cortex in rats. These findings were not considered toxicologically meaningful since they
were related to compound accumulation, there was no evidence of cellular damage
(degeneration/necrosis) and there were no correlated clinical pathology indicators of changes in
renal function.12,17 These kidney findings have been observed in both the 2-week and 6-month
studies and did not worsen over time. No kidney findings were observed in monkeys.
In the chronic rat study (6 months) with JNJ-6379, retrograde nephropathy, secondary to papillary
or pelvic calculi/precipitates, was noted in male rats but not in dogs or female rats. This finding is
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mainly due to precipitation or calculi formation in distal parts of the kidney/lower urinary tract and
is of limited relevance to man, due to differences in urinary composition and functional anatomy
between (male) rats and humans. In general, compounds or metabolites of low solubility and high
renal clearance may cause concretions in the kidneys/ urinary tract, especially at high doses, as the
urine concentrates in the distal nephron and supersaturation of the compound can occur. Urinary
pH, proteins and osmolality can also influence the formation of urinary concretions. Male rat urine
normally has a high concentration of protein and high osmolality. In addition, rats may be
predisposed to retrograde nephropathy because they are known to experience spontaneous urine
reflux during micturition or urinary bladder contraction, and this reflux phenomenon can be
increased or exacerbated by treatment induced obstructions. The retrograde nephropathy in male
rats correlated with increased urea and creatinine in plasma and with urinary changes (red/brown
discolored urine, increased volume, decreased pH, presence of blood and white and RBCs in
sediment).3,32 No kidney findings were observed in dogs.
Although both compounds (JNJ-3989 and JNJ-6379) showed histological kidney findings in the
rat, the primary anatomical location, mechanism and severity are different. For JNJ-3989 the renal
findings are without anticipated clinical or clinicopathological consequences and located in the
proximal part of the nephron (outer cortex) and intracellular (not in the tubular lumen). For JNJ-
6379, the main findings are restricted to male rats and initiate in distal parts of the kidney (renal
pelvis/ papilla) and/or in the lumen of the lower urinary tract with secondary more proximal
changes due to reflux.
For tenofovir disoproxil, renal tubular epithelial karyomegaly was observed in rats, dogs, and
monkeys.24 In dogs, the species most sensitive to tenofovir disoproxil-related effects on the kidney,
additional microscopic alterations following chronic administration of tenofovir disoproxil
(10 mg/kg/day for 42 weeks) included individual tubular cell necrosis, tubular dilatation, tubular
degeneration/regeneration, pigment accumulation, and interstitial nephritis. This was associated
with biochemical changes such as slight elevation in serum creatinine, glucosuria, proteinuria, and
increased urine volume. The incidence and severity of nephrotoxicity was dose-related. Effects
were reversible following cessation of treatment. In Rhesus monkeys, biochemical and/or
histopathologic evidence of nephrotoxicity was observed at high doses. In rats, slight elevations in
serum creatinine were observed without any histopathology correlation.
For TAF, minimal renal cortical tubular karyomegaly and/or basophilia was seen in rats and dogs.
In addition, minimal renal cortical tubular degeneration/regeneration were reported in dogs. No
renal findings were reported in monkeys.6
Based on the available toxicology data, there are no specific concerns about additive or synergistic
toxicities in the kidney when JNJ-6379 or JNJ-3989 are combined with ETV, tenofovir disoproxil
or TAF.


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2.2.1.3. 
Combination of JNJ-3989 with PegIFN-α2a
A 3-month combination toxicity study of JNJ-3989 and PegIFN-α2a (Pegasys®) was conducted
in male and female Cynomolgus monkeys (Study TOX14273). JNJ-3989 was administered at
or 
mg/kg (SC, monthly) in combination with PegIFN-α2a at 0.015 mg/kg (SC, twice weekly).
In addition,
mg/kg JNJ-3989 (SC, monthly) or PegIFN-α2a (0.015 mg/kg; SC, twice weekly)
were dosed in monotherapy groups. The study was conducted in monkeys as the toxicity profile
of both PegIFN-α2a and JNJ-3989 were known in monkeys (rat studies were not performed with
PegIFN-α2a).
There were no test item-related mortalities. JNJ-3989 (alone or combined with PegIFN-α2a) was
well tolerated and did not induce effects on clinical signs, body weight, food consumption,
ophthalmoscopic examination, electrocardiology evaluation, coagulation, clinical chemistry or
urinalysis parameters, as well as organ weight and macroscopic examination.
Transient local reactions (edema and erythema) were observed at the administration site a
and/or 
mg/kg JNJ-3989. These reactions were also observed with PegIFN-α2a alone and
incidentally in control females (erythema only). They were not correlated with microscopic
findings.
Administration of JNJ-3989 alone or combined with PegIFN-α2a elicited minimal to mild,
transient (on Day 30 only), non-dose-related increases in neutrophils and total WBCs. Similar
findings were observed in the group administered 0.015 mg/kg PegIFN-α2a alone.
The combination of JNJ-3989 with PegIFN-α2a did not induce any further effects on biomarkers
(interferon gamma inducible protein 10 and interferon alpha) than the increases observed with
PegIFN-α2a treatment alone on Day 1.
JNJ-3989-related microscopic findings were observed in the lymph nodes (minimal to mild
vacuolation of macrophages) at ≥60 mg/kg and in the liver (minimal hypertrophy of Kupffer cells)
at
mg/kg in single agent and combination groups. The microscopic changes were comparable
between the animals administered with JNJ-3989 alone or combined with PegIFN-α2a indicating
an absence of synergistic effect.
Systemic exposure to JNJ-3924 and JNJ-3976 in plasma was similar after single and repeated
dosing following administration of JNJ-73763989 alone or combined with reference item PegIFN-
α2a.
In conclusion, the intermittent SC administration of JNJ-3989 up to 
mg/kg given alone or
combined with PegIFN-α2a for 3 months was well tolerated in Cynomolgus monkeys at up to
mg/kg. Treatment only induced transient local reactions at the injection site, transient
hematological changes and microscopic findings in liver and lymph nodes, all considered as non-
adverse. In addition, the administration of PegIFN-α2a in combination with test item did not
amplify any toxicological effect. Based on these results, there were no additive or synergistic
effects on the toxicity profile and no drug-drug interactions when JNJ-3989 is combined with
PegIFN-α2a.
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI


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For further information, refer to the latest version of the IB and IB addendum for JNJ-398915,16.
2.2.1.4. 
Combination of JNJ-6379 with PegIFN-α2a
As there is no appropriate species for studying the combination of JNJ-6379 with PegIFN-α2a, an
in vitro study on human bone marrow derived erythroid and myeloid progenitors using colony
forming assays was done. JNJ-6379 (5-100 μM) and PegIFN-α2a (Pegasys®, 0.00005-0.1 μM)
were tested in combination in order to evaluate their potential additive or synergistic effects (study
TOX14629).
The IC50 values of the combination treatment were markedly lower compared to JNJ-6379 alone
for all tested concentrations but similar to the values with PegIFN-α2a alone. When the higher
concentrations of PegIFN-α2a were tested in combination with JNJ-6379, the reduction in colonies
was mainly due to the strong toxicity of PegIFN-α2a at these concentrations.
Comparing the predicted (adding the percent of reduction of JNJ-6379 and PegIFN-α2a alone) and
the actual percent reduction in colonies relative to the solvent control, it became clear that there
were only minimal differences, pointing more to an additive effect and not a synergistic effect
when JNJ-6379 and PegIFN-α2a were combined.
2.2.2. 
Clinical Studies
2.2.2.1. 
JNJ-3989 and JNJ-6379
JNJ-3989
Clinical data on pharmacokinetics (PK), efficacy, and safety of JNJ-3989 are available from the
ongoing Phase 1/2a AROHBV1001 study with a data cut-off date of 29 October 2019. All dosing
with JNJ-3989 has been completed and ongoing participants are in the follow-up. Twenty adult
healthy participants have received single SC injections of JNJ-3989 (35, 100, 200, 300, and 400
mg) and 84 adult chronic HBV-infected participants have received multiple doses of JNJ-3989
(25, 50, 100, 200, 300, and 400 mg), administered as 3 SC injections separated by either 7-day,
14-day, or 28-day intervals. All participants either continued or started ETV or tenofovir disoproxil
on Day 1.
JNJ-3989 was generally safe and well tolerated with no deaths, serious adverse events (SAEs)
considered at least possibly related to the study intervention, or adverse events (AEs) leading to
study intervention discontinuation. All AEs were mild to moderate, with exception of 1 severe
blood creatine phosphokinase increased in 1 chronic HBV-infected participant. All reported
injection site reactions (ISRs) were mild. Adverse events and laboratory abnormalities were
distributed across all dose levels and also occurred on placebo treatment, except for mild ISRs,
which were only reported in participants on JNJ-3989 treatment. Most reported laboratory
abnormalities were isolated incidents and resolved while on study intervention.
Antiviral-activity data were available for 56 chronic HBV-infected participants who received 3 SC
injections of 25 to 400 mg JNJ-3989 every 4 weeks (Q4W).8,37 In general, mean HBsAg declines
reached nadir at Day 113 (ie, 8 weeks after last JNJ-3989). Mean HBsAg levels remained


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suppressed (below baseline levels) at least until Day 392 (ie, 9 months after last dose) in a
substantial proportion of patients.
JNJ-6379
At the time of protocol writing, 126 adult healthy and 41 chronic HBV-infected participants have
been dosed with JNJ-6379 in 5 completed Phase 1 studies (56136379HPB1001,
56136379HPB1002, 56136379HPB1003, 56136379HPB1004, and 56136379HPB1005). In
addition, data are available from 148 adult chronic HBV-infected participants in the ongoing Phase
2a study, 56136379HPB2001, also referred to as JADE.
Human Pharmacokinetics and Product Metabolism
Single Dose Studies in Healthy Participants
In Study 56136379HPB1001, single ascending doses (25, 50, 150, 300 and 600 mg) of JNJ-6379
(or placebo) were administered under fasting conditions to healthy participants. No major
differences were observed in the shape of the mean JNJ-6379 plasma concentration-time curves
for the different dose levels. Mean and individual PK profiles showed minimal lag-time. A single
rather flat concentration peak was observed in the PK profiles of most participants. Plasma
concentrations in the terminal phase declined generally in parallel for all dose levels. The Cmax and
AUC from administration to 24 hours (AUC0 24h) increased proportionally with dose after
single-dose administration of JNJ-6379 doses of 25 mg to 300 mg and less than dose
proportionally at the dose of 600 mg. The AUC from administration to last quantifiable sampling
point (AUC0 last) and the AUC to last sampling point from time zero extrapolated to infinity
(AUC∞) increased proportionally between the JNJ-6379 25-mg and 600-mg dose levels. Mean
values for terminal half-life (t1/2term) were comparable for the 25-mg to 300-mg dose levels, and
averaged between 93.3 hours and 110.5 hours. For the 600-mg dose group, the average t1/2term was
141.3 hours. Mean values for the total apparent oral clearance (CL/F) were comparable for the
25-mg, 50-mg and 150-mg dose level, and appeared to decrease at higher dose levels. Mean values
of the apparent volume of distribution were generally comparable for the different dose groups.
In Study 56136379HPB1002, study intervention exposure levels using a novel tablet formulation,
containing hydroxypropylmethylcellulose E5 based spray-dried powder, were similar to exposure
levels observed in study 56136379HPB1001 using the original formulation, both in fed conditions.
The relative bioavailability of new 25-mg oral tablets of JNJ-6379 administered as a 150-mg dose
under fasting and fed conditions, and of new 100-mg oral tablets of JNJ-6379 administered as a
300-mg dose under fasting conditions, was assessed in healthy adult participants. Assuming
proportionality, based on the geometric mean ratios between the 3x 100-mg dose, fasting (test)
and the 6x 25-mg dose, fasting (reference) of the dose-normalized PK parameters, Cmax  was
21.56% lower for the 100-mg tablet strength compared to the 25-mg tablet strength, and AUC0 last
and AUC∞were similar. The median time to reach Cmax (tmax) was around 1.75 hours when 150 mg
JNJ-6379 was dosed as 6x 25-mg oral tablets, and around 3.00 hours when 300 mg JNJ-6379 was
dosed as 3x 100-mg oral tablets.


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In Study 56136379HPB1005, the oral bioavailability of a single 300-mg dose of JNJ-6379
administered as a 100-mg tablet containing hydroxypropylmethylcellulose-acetate succinate based
spray-dried powder (test tablet) was assessed. All 14 healthy adult participants received a
300-mg dose of JNJ-6379 under fasted conditions. Preliminary PK analysis was performed and
mean Cmax  was 3,105 ng/mL, mean AUC0 72h  was 111,286 ng.h/mL and mean AUC∞ was
280,926 ng.h/mL. The median tmax was around 3.00 hours. These preliminary PK parameter values
are comparable to the PK parameters obtained after administration of JNJ-6379 formulated as
hydroxypropylmethylcellulose E5 based spray-dried powder tablet.
Multiple Dose Studies in Healthy Participants
In Session 7 of Study 56136379HPB1001, participants received 150 mg JNJ-6379 twice daily
under fed conditions for the first 2 days of treatment, followed by 100 mg JNJ-6379 qd until
Day 12. JNJ-6379 plasma concentrations accumulated during the study (accumulation ratio of
approximately 6). The CL/F at steady-state and the t1/2term were similar to values observed after
single-dose administration, suggesting time-linear PK.
In Study 56136379HPB1004, participants received 250 mg of JNJ-6379 twice daily on Days 6 and
7 (fed conditions), followed by 170 mg qd on Day 8 to 25 in fed conditions (with exception of
Day 21). On Day 21, a single dose of JNJ-6379 170 mg and a single dose of
drospirenone/ethinylestradiol 3 mg/0.02 mg and a single dose of midazolam 2 mg were
administered under fasted conditions. Mean JNJ-6379 Cmax  and area under the plasma analyte
concentration-time curve over the dose interval (AUCτ) increased between Day 6 (first dose of
JNJ-6379) and Day 20 as JNJ-6379 plasma concentrations accumulated due to the multiple-dose
regimen administered in this study. Steady-state was reached before Day 20. Plasma
concentration-time 
profiles 
of 
JNJ-6379 
were 
similar 
to 
those 
observed 
in
Study 56136379HPB1001.
Multiple Dose Studies in chronic HBV-infected Participants
In Sessions 8, 9, 10, 11, and A of Study 56136379HPB1001, treatment-naïve chronic
HBV-infected-infected participants were administered multiple-dose regimens (25, 75, 150, and
250 mg) of JNJ-6379 for 28 days. Pharmacokinetics of JNJ-6379 were not markedly different
between healthy participants and chronic HBV-infected participants. Mean JNJ-6379 exposures in
chronic HBV-infected participants could be predicted from data in healthy participants. The PK
data show that exposure of JNJ-6379 in chronic HBV-infected participants is dose proportional
and CL/F is constant over time.
Food Interaction
Although Study 56136379HPB1001 suggested slightly higher exposure of JNJ-6379 in fed
conditions, data from Study 56136379HBP1002 with a higher number of participants showed that
there is no food effect on JNJ-6379 exposure, and a preliminary PK analysis from
Study 56136379HBP1005 suggests the same.


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Drug-drug Interaction
Oral contraceptives: When administered simultaneously with 3 mg drospirenone/0.02 mg
ethinylestradiol in Study 56136379HPB1004, JNJ-6379 increases the extent of exposure and
decreases the CL/F of ethinylestradiol while the peak plasma concentration decreased. In contrast,
JNJ-6379 has no clear effect on the extent of exposure and CL/F of drospirenone, a cytochrome
P450 (CYP)3A4 sensitive progestin: peak plasma concentration decreased while no change in
exposure and apparent clearance was observed. Consequently, oral contraceptives are still
considered to be effective when administered simultaneously with JNJ-6379. However, as a
precaution to avoid high exposure to ethinylestradiol, ethinylestradiol-containing contraceptives
are only allowed if the ethinylestradiol content is ≤20 µg.
Midazolam: In Study 56136379HPB1004, coadministration of 170 mg JNJ-6379 qd with oral
midazolam as a CYP3A4 probe substrate showed a reduction of 41.7% in Cmax and 53.9% in AUC
of midazolam, implying that JNJ-6379 may induce the metabolism of CYP3A4 sensitive
substrates.
Efficacy Studies
Antiviral activity data are available from Part II of Study 56136379HPB1001 (final analysis,
57 treatment-naïve participants treated with multiple-dose regimens of 25 to 250 mg JNJ-6379 qd
for 28 days, unblinded). Available antiviral activity data for 4 weeks of treatment with JNJ-6379
in this study showed potent HBV DNA and RNA reductions but no changes in HBsAg, indicating
that longer treatments are needed.
Interim efficacy data are available from the Phase 2a JADE study. Interim analysis (IA)2 (cut-off
date: 8 February 2019) includes Week 12 data from 64 chronic HBV-infected participants not
treated at screening of whom 26 received 75 mg qd JNJ-6379 monotherapy (open-label) and 38
received 75 mg qd JNJ-6379 or placebo in addition to an NA (blinded). Interim analysis 2 also
includes unblinded Week 24 data from 44 virologically suppressed chronic HBV-infected
participants of whom 33 received 75 mg qd JNJ-6379 and 11 received placebo in addition to an
NA. Interim analysis 3 (cut-off date: 7 March 2019) includes blinded Week 12 data from 40
virologically suppressed chronic HBV-infected participants who received 250 mg qd JNJ-6379 or
placebo in addition to an NA.
The 12-week interim efficacy data in currently not treated participants on 75 mg JNJ-6379
monotherapy showed a mean reduction from baseline of HBV DNA of >3.5 log10 International
Units Per Milliliter (IU/mL) at Week 12. This decline was similar to the mean decline in
participants treated with JNJ-6379 or placebo in combination with an NA (data still blinded).
The 24-week interim efficacy data in virologically suppressed participants on 75 mg JNJ-6379
showed that most participants had HBV DNA levels below the limit of quantification at baseline.
At 24 weeks of treatment, 5 (23.8%) of 21 participants on JNJ-6379 experienced a mean reduction
from baseline in HBV RNA of >2 log10 IU/mL versus 1 (14.3%) of 7 participants on placebo.
Hepatitis B virus RNA levels at Week 24 were undetectable for 21 (100.0%) of 21 participants on


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JNJ-6379 and 4 (57.1%) of 7 participants on placebo. No relevant mean changes from baseline in
HBsAg and HBeAg were noted so far.
In the monotherapy arm with 75 mg JNJ-6379, 5 of 28 participants (status after IA cut-off date)
experienced a virologic breakthrough defined as confirmed on-treatment HBV DNA increase by
>1 log10 from nadir level or confirmed on-treatment HBV DNA level >200 IU/mL in participants
who had HBV DNA level below the LLOQ of the HBV DNA assay. All 5 participants with
virologic breakthrough hadan emerging core amino acid mutation T33N, which is known to confer
reduced JNJ-6379 activity in vitro. All 5 participants discontinued JNJ-6379 and started NA
treatment. An urgent safety measure was implemented to discontinue JNJ-6379 treatment in all
participants in this arm and offer NA treatment. No cases of virologic breakthrough were observed
in any of the arms combining JNJ-6379/placebo with NA treatment. A futility rule was
implemented in the 250 mg JNJ-6379 monotherapy arm (if ≥1 participant in the 250 mg
monotherapy arm experiences virologic breakthrough during the first 24 weeks of treatment, NA
treatment will be added to JNJ-6379 treatment as soon as possible for all remaining participants).
In the monotherapy arm with 250 mg JNJ-6379, 1 participant experienced virologic breakthrough
(status after IA cut-off date). The participant discontinued JNJ-6379 treatment and started NA
treatment at the withdrawal visit, due to meeting non-response criteria. Nucleos(t)ide analog
treatment will be added for all remaining participants in the JNJ-6379 250 mg monotherapy arm
in accordance with the futility rule mentioned above.
Safety Studies
Data from 5 completed Phase 1 studies (56136379HPB1001, 56136379HPB1002,
56136379HPB1003, 56136379HPB1004, and 56136379HPB1005) in healthy and chronic
HBV-infected participants (N 126 and 41, respectively), indicate that orally administered
JNJ-6379 as single doses up to 600 mg or as multiple doses (250 mg twice daily for 2 days followed
by 170 mg qd for 18 days or 150 mg twice daily for 2 days followed by 100 mg qd for 10 days) in
healthy participants and as multiple doses up to 250 mg for 28 days in chronic HBV-infected
participants was safe and well tolerated. No SAEs considered at least possibly related to the
study intervention were reported. Most AEs were mild and not considered treatment-related, with
no dose-related trends.
Safety data are also available from IAs 2 and 3 conducted for the Phase 2a JADE study, which
were mentioned above. There were no deaths, SAEs considered at least possibly related to the
study intervention, or AEs leading to discontinuation. Most AEs were grade 1 or 2 in severity. The
majority of reported AEs were considered unrelated to JNJ-6379 by the investigator. Grade 2 to 4
AEs considered at least possibly related to JNJ-6379 by the investigator were grade 2 asthenia
(3 participants), grade 4 alanine aminotransferase (ALT) increased, grade 2 headache, grade 2
vertigo, grade 3 anemia (corrected to grade 2 by the investigator after the IA cut-off date), grade 2
hypertension, and grade 2 fatigue (all observed in 1 participant each).
Increased cholesterol is considered a laboratory abnormality of interest for JNJ-6379, based on
safety review from nonclinical and clinical trials. Cholesterol increased was reported as an AE in


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4 (4.1%)participants on JNJ-6379 for the pooled Phase 1 studies, in 1 (2.4%) participant on
JNJ-6379 for the Phase 1 study 56136379HPB1005, and in none of the participants in the Phase 2a
JADE study.
Combination of JNJ-3989 and JNJ-6379
Clinical data of triple combination treatment of JNJ-3989, JNJ-6379, and NA are available from
the ongoing Phase 1/2a AROHBV1001 study (Cohort 12). Twelve adult chronic HBV
mono-infected participants have received 3 SC injections of JNJ-3989 (200 mg Q4W) in
combination with oral JNJ-6379 (250 mg qd) and oral NA treatment (ETV or tenofovir disoproxil).
Up to the interim analysis (IA) cut-off date of 29 October 2019, no deaths, SAEs, or
treatment-emergent adverse events (TEAEs) leading to study intervention discontinuation were
reported. Two (16.7%) participants reported at least 1 TEAE during the treatment phase. The
TEAEs (upper respiratory tract infection and hypertension) were of mild severity and considered
not related to the study intervention by the investigator.
The triple combination treatment of JNJ-3989, JNJ-6379, and NA is currently being investigated
in chronic HBV mono-infected participants in the ongoing Phase 2 clinical studies
73763989HPB2001 (REEF-1, 90 participants in triple combination Arm 1) and
73763989PAHPB2002 (REEF-2, 80 participants in triple combination Arm 1). Up to 48-week
hematology data from the ongoing Phase 2 clinical study REEF-1 are available and overall around
5% of the participants experienced AEs or laboratory abnormalities related to hematology, the
majority of mild to moderate severity. The hematologic abnormalities resolved on continued JNJ-
3989+JNJ-6379+NA treatment.16
Since the initial protocol writing, interim results of the REEF-1 and REEF-2 studies had become
available. In the primary REEF-1 analysis (Week 48, end of treatment) the mean reduction of
HBsAg levels in the triple arm (JNJ-6379+JNJ-3989 100mg+NA) appeared to be less than in the
dual arm (JNJ-3989 100mg+NA). More recent interim results of the REEF-2 study (Week 48, end
of treatment) confirmed this observation when the effect of JNJ-6379+JNJ-3989 200mg+NA on
mean HBsAg level reduction in REEF-2 study is compared to JNJ-3989 200mg+NA in the
REEF-1 study. To match with the REEF-2 population, this cross-study comparison focused on the
REEF-1 subpopulation of HBeAg negative, virologically suppressed participants with chronic
hepatitis B. PK-PD modelling analyses accounting for variability in baseline characteristics further
support this observation. Therefore, a negative effect of JNJ-6379 on the HBsAg lowering effect
of JNJ-3989+NA is suspected.
2.2.2.2. 
Combination of JNJ-3989 and JNJ-6379 with Entecavir, Tenofovir
Disoproxil, or Tenofovir Alafenamide
Entecavir monohydrate is an HBV NA reverse transcriptase inhibitor indicated for the treatment
of chronic HBV infection in adults and children at least 2 years of age with evidence of active viral
replication and either evidence of persistent elevations in serum aminotransferases (ALT or
aspartate aminotransferase [AST]) or histologically active disease. The most common adverse
reactions (≥3% of participants) are headache, fatigue, dizziness, and nausea.


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There is no common target organ between JNJ-6379 or JNJ-3989 and ETV.23
Tenofovir disoproxil (available in several salt forms including tenofovir disoproxil fumarate and
tenofovir disoproxil maleate) is a first-generation oral prodrug of the NA tenofovir that is indicated
for the treatment of chronic HBV infection in adult and pediatric patients at least 12 years of age.
In addition, tenofovir disoproxil in combination with other antiretrovirals is indicated for the
treatment of HIV type 1 (HIV-1) infection in adult and pediatric patients at least 2 years of age.
The most common adverse reactions (≥10% of participants) are abdominal pain, nausea, insomnia,
pruritus, vomiting, dizziness, and pyrexia.
TAF is an ester prodrug of the NA tenofovir that is indicated for the treatment of chronic HBV-
infected in adults and that is characterized by a better safety profile than tenofovir disoproxil. The
most common adverse reaction (≥10% of participants) is headache.
The single common toxicity target organ between JNJ-6379, JNJ-3989, and tenofovir disoproxil
or TAF is the kidney (see Section 2.2.1.2).
Clinical data on dual combination treatment of JNJ-6379 and NA are available from the ongoing
Phase 2a 56136379HPB2001 study (JADE).14 In participants treated with tenofovir disoproxil,
Ctrough  concentrations of tenofovir at Week 12 were higher in participants receiving tenofovir
disoproxil in combination with JNJ-6379 than in participants receiving tenofovir disoproxil as
monotherapy (94.2 [30.0] and 115 [66.0] ng/mL for 75- and 250-mg JNJ-6379, respectively in
combination with tenofovir disoproxil, vs 66.8 [37.0] ng/mL as tenofovir disoproxil monotherapy).
Clinical data of triple combination treatment of JNJ-3989, JNJ-6379, and NA are available from
the ongoing Phase 1/2a AROHBV1001 study (see Section 2.2.2.1). Dosing JNJ-6379 or JNJ-3989
with NA for 12 weeks, did not show any clinically relevant changes in kidney
parameters/glomerular function.
For further information regarding ETV, tenofovir disoproxil, and TAF, refer to the respective
currently approved prescribing information.
Overall Assessment of the Combination Therapy
Based on the points listed below, no clinically relevant drug-drug interactions (DDIs) and no
specific concerns about additive or synergistic toxicities in the kidney are expectedwhen JNJ-6379
or JNJ-3989 are combined with ETV, or tenofovir disoproxil, or TAF:
 
Available toxicology data, described in Section 2.2.2.1
 
In vitro drug transporters
 
Metabolic interaction data
 
Absence of relevant DDIs in the combination toxicity studies up to 3 months with JNJ-6379
and JNJ-3989
 
Absence of synergistic or additive histology findings in the kidney observed in the
combination toxicity studies up to 3 months with JNJ-6379 and JNJ-3989


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 
Available clinical data with JNJ-6379 (JADE study [56136379HPB2001]) up to 48 weeks
treatment on the absence of changes in kidney parameters/glomerular function
 
Available clinical data of triple combination treatment of JNJ-3989, JNJ-6379, and NA
described in Section 2.2.2.1.
In addition, pancytopenia in 1 rat and a mild platelet decrease were seen in the combination groups
in the 3-month combination toxicity study (preliminary data, Section 2.2.1). No significant
abnormalities of hematologic parameters have been observed in clinical studies to date. The
sponsor is implementing additional monitoring of significant on-treatment hematologic changes
in clinical studies with dosing longer than 4 weeks (see Section 8.5.6.5). For further information,
refer to the IBs and addenda.14 16,39
2.2.2.3. 
Combination of JNJ-3989 and JNJ-6379 with PegIFN-α2a
PegIFN-α2a is a covalent conjugate of recombinant alfa-2a interferon that is indicated for the
treatment of chronic hepatitis B in adult and pediatric patients at least 3 years of age. In addition,
PegIFN-α2a in combination with other medicinal products is indicated for the treatment of chronic
hepatitis C virus (HCV)-infection in adult and pediatric patients at least 5 years of age and not
treated before. The most common adverse reactions (≥10% of participants) are anorexia, anxiety,
headache, concentration impairment, dyspnea, cough, alopecia, dermatitis, pruritis, dry skin,
myalgia, arthralgia, asthenia, pyrexia, and fatigue. For further information regarding PegIFN-α2a,
refer to the currently approved prescribing information.
Treatment with PegIFN-α2ahas been associated with decreases in platelet count (common adverse
reaction). In the ongoing Phase 1/2a AROHBV1001 study (see Section 2.2.2.1), no effect on
platelet count has been observed in the triple combination treatment cohort 12 (JNJ-3989,
JNJ-6379, and NA). Of the 84 adult chronic HBV-infected participants that received
3 subcutaneous injections of JNJ-3989, 6 participants developed grade 1 platelet reduction with no
general trend towards a continuous decline. For JNJ-6379, no effect on platelet count has been
observed in the ongoing Phase 2a study 56136379HPB2001 (JADE) for the 189 adult chronic
HBV-infected participants that were dosed with JNJ-6379.
Based on preclinical data, a potential common toxicity target organ between JNJ-6379, JNJ-3989,
and PegIFN-α2a is the bone marrow (see Section 2.2.1.1). Bone marrow suppression is a known
side effect of PegIFN-α2a (rare).
No pharmacokinetic (PK)interaction is expected between JNJ-3989 and PegIFN-α2a based on the
known pharmacologic profile of JNJ-398915,16,41.
At the time of protocol amendment 4 writing, no clinical data on the combination of JNJ-3989 and
JNJ-6379 with PegIFN-α2a are available. Nonclinical studies to investigate the effect on platelet
count decreases and on bone marrow in non-human primates (JNJ-3989) and bone marrow stem
cells (JNJ-6379) were completed, and results are summarized in Section 2.2.1.1.


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2.3. 
Benefit-Risk Assessment
More detailed information about the known and expected benefits and risks of JNJ-3989 and JNJ-
6379 may be found in the respective IBs and addenda.14 16,39
For the benefit-risk evaluation of ETV, tenofovir disoproxil, TAF, and PegIFN-α2a refer to the
respective prescribing information.
JNJ-6379 was initially part of the study intervention but has been removed as study intervention
with the implementation of an urgent safety measure, as described in Protocol Amendment 5.
Emerging data from the REEF-1 and REEF-2 studies resulted in an unfavorable benefit-risk
balance of JNJ-6379 in combination with JNJ-3989+NA, compared to JNJ-3989+NA alone.
Therefore, the Sponsor decided to discontinue treatment with JNJ-6379 in all ongoing clinical
studies effective immediately. Participants who were on treatment with JNJ-6379 were contacted
and requested to stop taking JNJ-6379, while continuing treatment with NA, JNJ-3989 and
PegIFN-α2a. For newly enrolled participants, JNJ-6379 was taken out of the treatment regimen.
For completeness, the benefit-risk assessment for JNJ-6379 is still included in this section.
2.3.1. 
Benefits for Study Participation
2.3.1.1. 
Known Benefits
The clinical benefit of JNJ-3989 and JNJ-6379 remains to be established.
2.3.1.2. 
Potential Benefits
Results from clinical studies with JNJ-3989, JNJ-6379, NAs, and optional PegIFN-α2a may be
useful for the development of a novel therapeutic approach for chronic HBV infection.
The combination of JNJ-6379 and JNJ-3989 on a background of NAs would target different stages
of the viral life cycle. While NA treatment reduces HBV DNA to levels close to or below the
LLOQ of the HBV DNA assay, HBV replication is not completely inhibited, resulting in
replenishment of the cccDNA pool. The addition of JNJ-6379, which targets the HBV capsid
assembly (“primary” MoA) and the de novo cccDNA formation (“secondary” MoA), is expected
to block HBV replication more profoundly by inhibiting formation of HBV RNA and DNA
containing particles, and to inhibit de novo cccDNA formation, ultimately leading to reduction in
cccDNA levels/transcriptional activity and HBsAg seroclearance (“intensified viral suppression”).
The addition of JNJ-3989 to an NA, or to JNJ-6379 in combination with an NA, is expected to
intensify viral suppression (further) by downregulating levels of the HBV DNA precursor pgRNA.
In addition, JNJ-3989 reduces levels of all viral proteins including HBsAg, which is known to
interfere with the host immune responses.7,20,34 By acting on both viral replication and by reducing
barriers to the host immune-responses, higher functional cure rates may be achieved.
The addition of short-term PegIFN-α2a (for 12 or 24 weeks) to the regimen at a time when HBsAg
is already significantly reduced or eliminated, may lead to further improvement of the immune
response (such as reactivation of NK-cells and further activation of endogenous HBV-specific T-
cells) and ultimately could lead to immune control of HBV (ie, functional cure). In addition,


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PegIFN-α2a has shown to have direct antiviral effects on HBV which could also contribute to the
efficacy of the regimen. By adding short-term PegIFN-α2a to the regimen, higher efficacy may be
achieved.
2.3.2. 
Risks for Study Participation
2.3.2.1. 
Known Risks
No known risks associated with JNJ-3989 or JNJ-6379 have been identified from clinical
observations so far in the Phase 1 and 2 studies. Injection site reactions were identified as adverse
drug reactions for JNJ-3989.
The side effect profile of PegIFN-α2a is well established and includes, but is not limited to,
neuropsychiatric, autoimmune, ischemic, ophthalmologic, hematological, and infectious
disorders. Exacerbations of hepatitis during hepatitis B therapy are common and characterized by
transient and potentially severe increases in serum ALT. Marked increases in ALT were sometimes
accompanied by bilirubin elevation and other liver test abnormalities. In many, but not all cases,
these disorders resolve after stopping PegIFN-α2a therapy. For a full list of known risks for
PegIFN-α2a, refer to the respective prescribing information.
2.3.2.2. 
Potential Risks
All therapies have the potential to cause adverse experiences. In addition, the discontinuation of
NA treatment bares a risk of hepatitis B flares.
Patients with positive HBV DNA and positive HBsAg can always experience increases in liver
transaminases which may indicate immune activation and may result in the reduction of viral
parameters such as HBV DNA and/or HBsAg. Whether this occurs at higher frequency during or
after treatment with JNJ-6379 and JNJ-3989 is not known.
Please refer to Section 2.2 for details on the safety results in the studies conducted to date.
2.3.2.2.1. 
Potential Risks for JNJ-3989
ALT Elevations
ALT elevations are considered an important potential risk for JNJ-3989. Two distinct patterns of
ALT elevations have been observed in participants receiving JNJ-3989: a rapidly rising and
resolving ALT elevation or a more sustained pattern of ALT elevation. The latter has been
observed in HBV/HDV co-infected participants in study 73763989HPB2004 during double-blind
treatment phase. A causal association of ALT elevations with JNJ-3989 has not been confirmed
and the underlying mechanism for ALT elevations being more frequent in the context of
HBV/HDV co-infection is not yet understood.16
Reproductive Risks and Pregnancy
In the EFD studies, JNJ-3989 was not teratogenic in rats and rabbits. The fertility in male and
female rats is not impacted with JNJ-3989 up to a dose of 
mg/kg/week.
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Based on the difference in metabolic pathways and in vitro data indicating absence of impact of
JNJ-3989 on CYP enzymes and transporters, no clinically relevant interactions are anticipated
between JNJ-3989 and oral contraceptives.
Potential Genotoxicity
JNJ-3989 is considered to be devoid of genotoxic activity. Nonclinical carcinogenicity studies
have not been conducted.
Other Potential Toxicity/Events of Special Interest
JNJ-3989 is considered non-cytotoxic, did not activate human platelet aggregation, did not activate
the innate immune system to a significant degree in vitro, and did not activate complement in vitro.
Hematologic abnormalities are an event of special interest for JNJ-3989 and JNJ-6379 based on
animal studies (refer to Section 2.3.2.2.2 for further information).
Viral Resistance
Treatment with JNJ-3989 may lead to viral resistance, but resistance to JNJ-3989 is not anticipated
to impact treatment with other small interfering RNAs (siRNAs). Using these agents in
combination, especially in combination with ETV or tenofovir is expected to minimize the risk of
emerging resistant viral variants.
2.3.2.2.2. 
Potential Risks for JNJ-6379
Since the initial protocol writing, interim results of the REEF-1 and REEF-2 studies had become
available. The data suggested that JNJ-6379 has a negative impact on the HBsAg lowering effect
of JNJ-3989+NA (see Section 2.2.2.1). In addition, there were new insights in the adverse renal
profile of JNJ-6379 (see below). Taken together, it was concluded that JNJ-6379 had an
unfavorable benefit-risk balance in combination with JNJ-3989+NA, compared to JNJ-3989+NA
alone. Therefore, the Sponsor decided to discontinue treatment with JNJ-6379 in all ongoing
clinical studies effective immediately. For completeness, the potential risks for JNJ-6379 are still
described in this section.
Reproductive Risks and Pregnancy
In the fertility study in females, early embryonic development was affected: an increase in pre- and
post-implantation loss, reduction in implantation and live fetuses at 
mg eq./kg/day. The fetal
loss seen during the early stages of pregnancy was considered the result of low hormone levels
(decreased luteinizing hormone, progesterone, estradiol) induced by treatment with JNJ-6379.
In the EFD studies, JNJ-6379 was not teratogenic in rats and rabbits.
In the EFD study in rats, fetal weights at
mg eq./kg/day were lowered, and there was retarded
ossification from 
mg eq./kg/day onwards. The NOAEL for EFD was considered to be
mg
eq./kg/day. At this dose, the AUC0 24h was 84,000 ng.h/mL and the Cmax was 5,190 ng/mL.
CCI
CCI
CCI
CCI


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In the EFD study in rabbits, the NOAEL for EFD was considered to be the highest dose tested, ie,
mg eq./kg/day. At this dose, the AUC0 24h was 99,200 ng.h/mL and the Cmax was 6,880 ng/mL.
Potential Genotoxicity
JNJ-6379 was not genotoxic in the in vitro and in vivo tests.
JNJ-6379 did not affect male or female fertility. Carcinogenicity studies are not yet conducted.
Other Potential Toxicity/Events of Special Interest
Based on nonclinical findings in rats and dogs and based on clinical findings, increased cholesterol
was identified as a laboratory abnormality of interest.
Renal complications are considered an event of special interest for JNJ-6379. Immediate
treatment-emergent decrease in mean eGFR, which was initially observed in the JADE study, has
also been observed in both JNJ-6379 treatment arms in the ongoing REEF-1 study. The eGFRcr
values remained reduced during treatment, with a fast rebound after end of treatment. The eGFR
decrease (calculated from serum creatinine) may be an anomaly due to JNJ-6379 possibly
interfering with tubular excretion of creatinine via inhibition of MATE-1 transporter.39 This
hypothesis was supported by the absence of a pattern of increased biomarkers of proximal tubulo-
toxicity (the beta-2microglobulin/creatinine and the retinol binding protein/creatinine ratios),
suggesting that the eGFRcr reduction was due to transporter inhibition at the level of creatinine
excretion from the proximal tubule rather than renal toxicity.
Emerging data from the REEF-2 study became available, confirming the transient pattern of
eGFRcr declines but, in addition, showing an increase of the beta-2microglobulin/creatinine and
the retinol binding protein/creatinine ratios in some participants when TDF was continued and
combined with JNJ-6379+JNJ-3989. These new data are suggesting that JNJ-6379 in combination
with TDF may contribute to renal tubulo-toxicity.
Hematologic abnormalities are considered an event of special interest for JNJ-3989 and JNJ-6369.
Mild thrombocytopenia was observed in recently conducted non-clinical toxicology studies with
the combination of JNJ-3989 and JNJ-6379. In addition, in a 3-month combination study with
80 rats, 1 rat developed pancytopenia related to bone marrow depletion after 23 days of dosing.
Previously, in a 9-month dog study in 24 dogs treated with JNJ-6379 alone, pancytopenia which
correlated with a marked increase in plasma cell-like cells in the bone marrow was observed in
1 dog after 60 days of dosing. Refer to Section 8.5.6.5. A minor additive effect was observed in
vitro in human bone marrow derived erythroid and myeloid progenitors when combining JNJ-6379
and Peg-IFN-α2a.14
Viral Resistance
Treatment with JNJ-6379 may lead to emergence of viral variants with reduced susceptibility or
resistance to JNJ-6379. Based on nonclinical data, these variants remain susceptible to tenofovir
and ETV but might affect treatment options with CAMs in the future. All 5 participants with
virologic breakthrough in the JADE study who received 75 mg JNJ-6379 monotherapy, had an
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emerging core amino acid mutation T33N, which is known to confer reduced JNJ-6379 activity in
vitro (see Section 2.2.2.1 for the results of the IAs).
Drug-drug Interactions
Based on results from DDI study 56136379HPB1004 investigating the potential effect of
coadministration of JNJ-6379 with oral contraceptives, it is not anticipated that the efficacy of oral
contraceptives will be impacted during coadministration with JNJ-6379 since the exposure of a
progestin sensitive to CYP3A4 induction was not significantly affected by coadministration of
JNJ-6379. In contrast, it is anticipated that coadministration with ethinylestradiol-containing
contraceptives will result in an increased exposure to ethinylestradiol. Therefore, specific
requirements on the use of ethinylestradiol-containing contraceptives are included in Section 6.5.
2.3.2.2.3. 
Potential Risks for Tenofovir Disoproxil and PegIFN-α2a
For the general potential risks of tenofovir disoproxil and PegIFN-α2a refer to the respective
prescribing information.
Risks specific for this study design are listed below:
 
PegIFN-α2a might increase the immunogenicity of JNJ-3989.
 
Combination of PegIFN-α2a with JNJ-3989 and JNJ-6379 might increase the risk of
hematologic abnormalities and/or of bone marrow suppression.
 
JNJ-6379 might increase tenofovir plasma concentrations.
2.3.2.3. 
Risks Due to Study Procedures
2.3.2.3.1. 
Potential Risks and Inconvenience Associated with the Liver Biopsy
Procedures
Percutaneous core liver biopsies and fine needle aspiration biopsies (FNAB) will be performed
during this study for research purposes.
The risks and complications related to these procedures will be described in the informed consent
form (ICF)and may include:
 
Pain and discomfort located at or near the puncture site and radiating upwards toward the right
shoulder region, which may last for up to a few hours or rarely days after the procedure.
 
Bleeding at the biopsy site.
 
Infection and internal bleeding and/or puncture of other internal organs (gall bladder, lung,
intestine or kidney) which can lead to serious complications (uncommon
1 in 1000 to 1 in
100) including the need for emergency surgery, blood transfusion, or removal of organs.
Deaths directly related to liver biopsy occur rarely (approximately 1 in every 10,000 biopsies).


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2.3.2.3.2. 
Potential Risks and Inconvenience Associated with the Optional
Leukapheresis Procedure
Participants who provide separate consent may undergo leukapheresis. The risks and
complications related to this procedure will be described in the ICF and may include:
 
Frequent side effects (~5% of participants): chills, reactions to the citratebased anticoagulant
(eg, prolonged bleeding for up to 20 minutes after the procedure), numbness or tingling of the
lips, face, or on the fingertips, muscle cramps, abnormal heart rhythm, or metallic taste in the
mouth
 
Occasional side effects (<5% of participants): bruising or discomfort at the injection sites,
pain/numbness in the arm (usually of short duration), tiredness the day following the
procedure, weakness, nausea/vomiting, fainting due to decreased blood pressure, pink or red
coloration of urine, hemolysis
 
Rare side effects (≤1% of participants): superficial inflammation of the vein in the arm that is
being used for the procedure which may result in pain, heat, and redness, pulmonary
embolism, rapid breathing, chest pain, or cough
2.3.3. 
Benefit-risk Assessment for Study Participation
Based on the available data and proposed safety measures, the overall risk/benefit assessment for
JNJ-3989 and JNJ-6379 clinical studies is deemed acceptable for the following reasons:
 
At the time of protocol writing, JNJ-3989 was generally safe and well tolerated during the
ongoing Phase 1/2a Study AROHBV1001 (see Section 2.2.2). All but one AE were mild or
moderate in severity. All ISRs, identified as adverse drug reactions for JNJ-3989, were mild
in intensity.
 
No clinically significant safety concerns had been raised for JNJ-6379 at the time of initial
protocol writing, based on the safety information from studies in healthy adult participants
and adult participants with chronic HBV infection. Most observed AEs at that time were mild
in severity and considered not related to JNJ-6379 by the investigator (see Section 2.2.2). At
the time of Protocol Amendment 5 writing, it was concluded that JNJ-6379 has an unfavorable
benefit-risk balance in combination with JNJ-3989+NA, compared to JNJ-3989+NA alone
(see Section 2.3.2.2.2). Therefore, the Sponsor decided to discontinue treatment with JNJ-
6379 in all ongoing clinical studies effective immediately, as a measure to minimize risk to
participants of this and other studies.
 
Events of Special Interest are significant AEs that are judged to be of special interest because
of clinical importance, known class effects or based on nonclinical signals. Events of Special
Interest that will be carefully monitored during the study include ISRs, ALT/AST elevations,
renal complications, hematological abnormalities, and events related to cholesterol increase
(Section 8.5.6 and Section 8.4.4). In addition, the following toxicities will also be carefully
monitored: rash and acute systemic allergic reactions (Section 8.5.7).
 
Continued careful assessment of the safety, efficacy, and PK during treatment is included in
this study.
 
To minimize potential risk and stress to participants, the following measures are in place:


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Utilization of selection criteria which exclude participants who may potentially be at
higher risk of an AE (see Section 5).
 
Utilization of withdrawal criteria (see Section 7). If a participant drops out due to
withdrawal of consent, he/she retains the option to participate in the safety follow-up
procedures.
 
Following local standard practice the biopsy location will be identified with ultrasound
(which will also be used to rule out contraindicating conditions for a biopsy). At the
off-treatment biopsy, blood coagulation and platelets will be assessed according to local
practice. Prior to the on-treatment biopsy, a recent (≤ 1 week) coagulation and
hematology panel and a platelet aggregation test are required, to ensure normal count and
function of platelets and normal coagulation parameters. Site selection will be based on
their experience in the performance of core liver biopsies and FNABs.
 
Participants will be monitored closely during the optional leukapheresis. In case of
serious complications, the leukapheresis procedure will be stopped immediately.
Participants will stay on site for at least 30 minutes after leukapheresis to monitor for
potential side effects. Additional safety-related assessments may be performed at the
discretion of the investigator and may include additional laboratory tests after the
procedure to measure hematologic parameters.
 
At regular time points throughout the study (see Schedule of Activities), blood samples
for biochemistry, blood coagulation, and hematology and urine samples for urinalysis,
urine chemistry, and renal biomarkers will be collected. Vital signs (systolic and diastolic
blood pressure [SBP and DBP]), pulse rate, and body temperature), height (only at
screening), body weight, and electrocardiograms (ECGs) will be recorded throughout the
study. Physical examinations will be performed and AEs will be assessed (see
Section 8.3, Safety Assessments). Events of Special Interest will be closely monitored
(Section 8.5.6, Adverse Events of Special Interest).
 
Based on pre-clinical and clinical data available today, the combination of JNJ-3989, JNJ-
6379, tenofovir disoproxil, and short-term PegIFN-α2a is considered safe. Data from
nonclinical combination toxicity studies showed a minimal additive effect on myeloid
and erythroid cells in vitro when combining JNJ-6379 and PegIFN-α2a (Section 2.2.1.4)
and confirmed that combination of PegIFN-α2a with JNJ-3989 did not induce any
synergistic or additive effect in monkeys up to 3 months of treatment (Section 2.2.1.3).
Review of 48-week hematology data from the ongoing Phase 2 clinical study REEF-1
(Section 2.2.2.1) did not identify any safety concerns.
 
The impact of PegIFN-α2a addition to JNJ-3989 on ALT elevations is not known in the
context of HBV monoinfection. Strict rules for management of ALT elevation are in place
(refer to Section 8.5.6.2, Intervention-emergent ALT/AST Elevations).
 
An Independent Flare Expert Panel (IFLEP) will be appointed to characterize and
adjudicate each ALT flare (see Section 9.6).
 
After stopping treatment with NA, JNJ-3989, JNJ-6379 (if applicable), and PegIFN-α2a
(if applicable), participants will be monitored closely during the follow-up phase, with
frequent follow-up visits and pre-defined NA re-treatment criteria in case of flares
(Section 6.6.2).


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The post-treatment monitoring and NA re-treatment criteria (Section 6.6.2) were further
updated based on findings from a case of post-treatment HBV reactivation with subacute
hepatic failure and assessment of additional REEF-2 study data.
 
JNJ-3989 will be administered using a proper SC technique to decrease the risk of ISRs.
Injection site reactions will be managed as outlined in Section 8.5.6.1.
 
Any clinically significant abnormalities persisting at the end of the study/early
discontinuation will be followed up by the investigator until resolution (return to baseline)
or until stabilization (to be agreed upon with the sponsor).
3. 
OBJECTIVES AND ENDPOINTS
The following objectives and endpoints will be assessed overall and by study panel:
Objectives 
Endpoints
Primary
 
To assess changes in intrahepatic HBsAg
between baseline and on-treatment liver
biopsy  in response to JNJ-3989-based
combination treatment
 
Changes in the proportion of HBsAg positive
hepatocytes between baseline and on-treatment
Week 40
Secondary
 
To assess changes in intrahepatic immune
response 
between 
baseline 
and
on-treatment liver biopsy
 
Changes between baseline and on-treatment liver
biopsy in intrahepatic immune response (eg,
CD45+ T-cells, CD4+  T-cells, CD8+  T-cells,
Natural Killer cells, and dendritic cells) in terms
of proportion  of cells, cell types, and spatial
redistribution
 
To assess changes in intrahepatic viral
nucleic acids and proteins between
baseline and on-treatment liver biopsy
 
Changes from baseline in  intrahepatic viral
parameters 
(such 
as cccDNA, 
pgRNA,
intrahepatic RNA, or HBsAg in terms of copy
number, or number of positive cells)
 
Changes from baseline in intrahepatic cccDNA
levels 
and 
transcriptional 
activity
(pgRNA/cccDNA ratio)
 
To evaluate the efficacy of the study
intervention as measured in blood
 
The proportion of participants during the study
intervention and follow-up phases with:
 
HBsAg seroclearance at Week 72 (ie, 24
weeks after completion of all study
interventions at Week 48) without restarting
NA treatment.
 
(Sustained) Reduction, suppression, and/or
seroclearance 
considering 
single 
and
multiple markers (such as HBsAg, HBeAg,
HBV DNA and ALT)
 
HBsAg and HBeAg seroconversion
 
Flares (virologic, biochemical, and clinical)


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Objectives 
Endpoints
 
Time to first HBsAg seroclearance
 
To evaluate the frequency of virologic 
breakthrough during study intervention  
 
Proportion of participants with virologic
breakthrough
 
To assess HBV-specific T-cell responses 
 
Changes from baseline in HBV-specific
peripheral blood T-cell responses during the
study intervention and follow-up phases
 
To evaluate the safety and tolerability of 
the study intervention 
 
Proportion of participants with (S)AEs and
abnormalities in clinical laboratory tests
(including hematology, blood biochemistry,
blood coagulation, urinalysis, urine chemistry,
and renal biomarkers), 12-lead ECGs, vital signs,
and physical examinations throughout the study
 
To evaluate the plasma PK of JNJ-3989 
(ie, 
JNJ-3976 
and 
JNJ-3924) and 
optionally of JNJ-6379, NA  and/or 
PegIFN-α2a, as applicable
 
Plasma PK parameters of JNJ-3976, JNJ-3924,
and optionally of JNJ-6379, NA  and/or
PegIFN-α2a, as applicable
Exploratory
 
To explore the relationship of intrahepatic 
markers with blood markers (immune and 
viral)
 
Association between levels and changes in
intrahepatic and blood markers
 
To explore the association of baseline 
characteristics and intrahepatic and/or 
blood (immune and viral) biomarkers at 
baseline and on/off-treatment with selected 
on/off-treatment efficacy variables 
 
Association of baseline characteristics and
baseline and on/off-treatment viral blood markers
(such as baseline NA treatment duration, age, and
baseline and on/off-treatment HBsAg levels)
with selected off-treatment efficacy variables
 
Association of intrahepatic and blood biomarkers
(such as cccDNA levels, T-cell frequency) with
selected on/off-treatment efficacy variables
 
To explore intrahepatic immune and viral 
changes at Week 72 and/or during off- 
treatment flares (only for participants with 
Week 72 biopsy available) 
 
Changes from  baseline and on-treatment liver
biopsy in intrahepatic immune and viral markers
at Week 72 and/or during off-treatment flares
(only for participants with Week 72 biopsy
available)
 
To explore changes in the severity of liver 
disease 
 
Changes in fibrosis (according to Fibroscan liver
stiffness measurements) at the end of study
intervention (EOSI) and end of follow-up versus
screening/baseline*
 
To explore the efficacy in terms of changes 
in HBV RNA and hepatitis B core-related 
antigen (HBcrAg) levels. 
 
Changes from baseline in HBV RNA and
HBcrAg levels during study intervention and
follow-up phases. 
 
To explore the relationship between  
plasma PK parameters (JNJ-3989 [ie, 
JNJ-3976 and JNJ-3924] and/or JNJ-6379 
and/or NA  and/or PegIFN-α2a) and
selected 
pharmacodynamic 
(PD)
 
Relationship between various plasma PK
parameters (JNJ-3976 and JNJ-3924, and/or
JNJ-6379, and/or NA, and/or PegIFN-α2a) and


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Objectives 
Endpoints
parameters of efficacy and/or safety, as 
applicable 
selected efficacy and/or safety endpoints, as
applicable
 
To explore the HBV genome sequence 
 
The 
emergence 
of 
intervention-associated
mutations during the study intervention and
follow-up phases
 
To assess the impact of baseline HBV genome
polymorphisms on selected on/off-treatment
efficacy variables
* Only applicable to participants who are enrolled at a site with an on-site Fibroscan device.
Refer to Section 8 for evaluations related to endpoints.
HYPOTHESIS
As this is an exploratory study, no hypothesis will be tested.
4. 
STUDY DESIGN
4.1. 
Overall Design
As of Protocol Amendment 5, the study is a Phase 2 single-arm, open-label, multicenter, study to
assess intrahepatic and peripheral changes of immunologic and virologic markers in response to a
combination regimen containing JNJ-3989 and NA in chronic HBV-infected participants.
With the implementation of an urgent safety measure, as described in Protocol Amendment 5,
JNJ-6379 has been removed as study intervention and the study will continue as a single-arm study.
Participants randomized to Arm 1 had to stop JNJ‑6379 treatment immediately but continue JNJ-
3989 + NA treatment.
In addition, participants who provide separate consent may receive optional treatment with
PegIFN-α2a starting after the Week 40 biopsy (or after the optional leukapheresis if applicable)
but before the Week 48 visit. The duration (either 12 or 24 weeks) will be at the investigator’s
discretion.
A target of 24 chronic HBV-infected male and female participants, 18-65 years (inclusive) of age
will be enrolled in 2 panels, approximately 12 participants in each panel. Panel 1 will consist of
participants who are HBeAg positive and not currently treated and Panel 2 will consist of
participants who are HBeAg negative and virologically suppressed by ETV, tenofovir disoproxil,
or TAF treatment.
The study will be conducted in 3 phases for all participants: a screening phase (4 weeks), an open-
label study intervention phase (48 weeks), and a follow-up phase (48 weeks). If necessary, eg, for
operational reasons, the screening phase may be extended up to a maximum of 6 weeks on a case-
by-case basis and in agreement with the sponsor. The duration of individual participation will be
up to 102 weeks. Note that the follow-up period will be extended for participants who are receiving
optional treatment with PegIFN-α2a and who meet NA treatment completion criteria at the end of


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treatment with NA and PegIFN-α2a to ensure all participants have at least one year of follow-up
after NA treatment cessation. For those participants, the duration of individual participation may
be extended up to 126 weeks.
Prior to Protocol Amendment 5, participants were randomized in a 1:1 ratio within each panel to
receive one of the following interventions (ie, treatments)for 48 weeks:
 
Interventionarm 1, combination regimen JNJ-3989+JNJ-6379+NA (target of 12 participants):
 
200 mg JNJ-3989 (SC injection Q4W, with the last injection at Week 44), AND
 
250 mg JNJ-6379 (tablets qd), AND
 
NA: ETV, tenofovir disoproxil, or TAF (tablets qd)
 
Intervention arm 2, combination regimen JNJ-3989+NA (target of 12 participants):
 
200 mg JNJ-3989 (SC injection Q4W, with the last injection at Week 44), AND
 
NA: ETV, tenofovir disoproxil, or TAF (tablets qd)
As of Protocol Amendment 5:
 
Participants who were randomized to study intervention with JNJ-6379 prior to Protocol
Amendment 5, had to stop JNJ-6379 treatment immediately but will still receive the following
interventions (ie, treatments) for 48 weeks:
 
200 mg JNJ-3989 (SC injection Q4W, with the last injection at Week 44), AND
 
NA: ETV, tenofovir disoproxil, or TAF (tablets qd)
 
New participants will enroll without randomization within each panel to receive the
combination regimen JNJ-3989 + NA as study intervention for 48 weeks:
 
200 mg JNJ-3989 (SC injection Q4W, with the last injection at Week 44), AND
 
NA: ETV, tenofovir disoproxil, or TAF (tablets qd)
In addition, participants who provide separate consent may receive optional treatment with
PegIFN-α2a starting after the Week 40 biopsy (or after the optional leukapheresis if applicable).
The duration (either 12 or 24 weeks) will be at the investigator’s discretion. This will allow to
investigate whether addition of PegIFN-α2a for 12 or 24 weeks may increase the participant’s
chance to achieve HBsAg loss.
All participants will complete treatment with JNJ-3989 after a fixed duration of 48 weeks. If the
NA treatment completion criteria (outlined in Section 6.6.1) are met based on clinical laboratory
tests performed at Week 44, treatment with NA will also be completed at Week 48. In participants
not meeting these criteria, NA treatment will continue during the follow-up phase. Participants
who are receiving optional treatment with PegIFN-α2a and who have not met NA treatment
completion criteria at Week 48 may have NA treatment completion criteria assessed at the end of
treatment with PegIFN-α2a and stop NA if criteria are met.


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All participants will be monitored closely during the follow-up phase and, if applicable, should
restart NA treatment in accordance with the NA re-treatment criteria (see Section 6.6.2 for more
details).
Prior to Protocol Amendment 5, randomization within each panel was stratified by Fibroscan score
(<7 kPa vs ≥7 kPa). Randomization and stratification are not applicable anymore per Protocol
Amendment 5.Safety and tolerability, including (S)AEs, laboratory assessments, ECGs, vital
signs, and physical examination, will be assessed throughout the study from the time of signing
the ICF until completion of the last study-related activity (see Section 8.4 and Section 8.5).
At Week-1 and Week 40, FNAB samples and core liver biopsy samples will be taken. Additional
optional FNAB and/or core liver biopsy samples may be taken (eg, at follow-up Week 24) from
participants who provide separate consent (see Section 8.1).
Efficacy will be evaluated using different parameters including HBsAg and HBeAg (see
Section 8.2).
Samples for HBV genome sequencing will be taken at the time points indicated in the Schedule of
Activities (see Section 8.2.1). Sequencing of samples obtained may be triggered by the sponsor’s
virologist based on changes in HBV DNA levels observed in each individual participant and the
limits of the sequencing assay.
Peripheral blood mononuclear cell (PBMC) samples for immune analyses will be collected at the
time points indicated in the Schedule of Activities (see Section 8.3).
The study includes collection of blood samples for exploratory analysis of viral markers (see
Section 8.1) and host blood biomarkers at the host RNA, protein, and cell level (see Section 8.10).
All participants will have sparse PK sampling on Day 1 and at Weeks 4, 12, and 24 (and at early
withdrawal). All participants who consent to participate in the intensive PK substudy (optional)
will undergo intensive PK sampling at Week 4.
A population PK analysis may be performed based on the available data for JNJ-6379, JNJ-3989,
and optionally, NA and/or PegIFN-α2a, potentially in combination with data from a selection of
Phase 1 and/or 2 studies. PK parameters in participants undergoing intensive PK sampling will be
calculated via noncompartmental methods.
Pharmacokinetic/pharmacodynamic relations may be explored (see Section 8.8).
Host DNA samples will be collected to allow for the identification of genetic factors (see
Section 8.9). In addition, host DNA blood samples to allow for epigenetic analyses will be
collected.
Human leukocyte antigen (HLA) typing will be performed as indicated in the Schedule of
Activities.


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In case of premature discontinuation of investigational intervention (before Week 48), follow-up
assessments should be obtained until 48 weeks after EOSI unless the participant withdraws
consent.
If a participant withdraws before completing the study intervention, the reason for withdrawal (if
known) is to be documented in the case report form (CRF) and in the source document. Participants
who withdraw consent will be offered an optional safety follow-up visit.
An IFLEP will be appointed for this study (see Section 9.6).
A diagram of the study design is provided in Section 1.2.
4.2. 
Scientific Rationale for Study Design
Study Population
Patients with chronic HBV infection  will be eligible if (1) they are HBeAg positive and not
currently being treated or (2) if they are HBeAg negative and virologically suppressed by NA
treatment.
Patients with advanced liver fibrosis or liver cirrhosis are excluded, as the goal of the study is to
assess the potential of a finite treatment to achieve functional cure, and discontinuation of
treatment in patients with cirrhosis is not current practice due to concerns about poor tolerability
of liver flares associated with increased viral replication. The safety of the combination regimens
evaluated in this study will first be established in patients without liver cirrhosis prior to initiating
studies in patients with more advanced liver disease.
Study Design Change –Protocol Amendment 5
Based on 
emerging data from the REEF-1 (73763989HPB2001) 
and REEF-2
(73763989PAHPB2002) studies, the study design has been adapted in Protocol Amendment 5.
In summary, the data from the REEF-1 and REEF-2 studies suggested that JNJ-6379 has a negative
impact on the HBsAg lowering effect of JNJ-3989+NA (see details in Section 2.2.2.1) and that
JNJ-6379 in combination with TDF may further contribute to renal tubulo-toxicity (see details in
Section 2.3.2.2.2). Together, this led to a conclusion of an unfavorable benefit-risk balance of JNJ-
6379 in combination with JNJ-3989+NA, compared to JNJ-3989+NA alone. Therefore, the
Sponsor decided to discontinue treatment with JNJ-6379 in all ongoing clinical studies effective
immediately. Participants currently on treatment with JNJ-6379 were contacted and requested to
stop taking JNJ-6379, while continuing treatment with NA, JNJ-3989, and PegIFN-α2a. For newly
enrolled participants, JNJ-6379 was taken out of the treatment regimen. 
Furthermore, the sponsor decided to make additional changes to the study design because of a
severe clinical ALT flare that was reported following discontinuation of NA treatment in a
participant who was randomized to the control arm (placebo + placebo + NA) in the REEF-2 study.
Discontinuation of NA treatment was following the protocol-defined criteria and in line with recent
EASL treatment guidelines5. Flares following NA discontinuation are not unexpected, but the


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rapid evolution and clinical deterioration seen in this participant who had no history or evidence
of liver cirrhosis was unforeseeable. Therefore, to protect the safety of participants, the protocol
was amended: more frequent monitoring of participants who discontinued NA treatment during
follow-up was included and the NA re-treatment criteria for all participants who discontinued NA
treatment were revised.
In addition, the follow-up phase in this study has been extended to ensure that all participants have
at least one year of follow-up after NA treatment cessation.
Randomization, Stratification Factors and Blinding
Note that randomization and stratification are not applicable anymore per Protocol Amendment 5.
Prior to Protocol Amendment 5, randomization and stratification were performed as described
below.
Within each of the two study panels (ie, HBeAg positive patients who are not currently being
treated and HBeAg negative patients being virologically suppressed by NA treatment),
randomization was used to minimize bias in the assignment of participants to intervention arms,
to increase the likelihood that known and unknown participant attributes (eg, demographic and
baseline characteristics) were evenly balanced across intervention  groups, and to enhance the
validity of statistical comparisons across intervention arms.
Randomization within each panel was stratified by Fibroscan score (<7 kPa vs ≥7 kPa).
As this is an exploratory study, participants will be treated in an open-label fashion. In addition,
most relevant assessments will be based on objective markers (biopsy and peripheral immunology)
and are not subject to bias from the participants or observers.
Criteria for Completion of NA Treatment
To explore the possibility of finite treatment, all participants who completed the 48-week study
intervention will stop all study interventions including NAs at Week 48 if they meet NA treatment
completion criteria (described in Section 6.6.1). The treatment completion criteria which take
ALT, HBV DNA, HBeAg and HBsAg levels into consideration, have been selected to ensure that
only participants with a chance of sustained off-treatment response are allowed to complete all
study intervention. Across a range of studies, HBsAg levels below 100 IU/mL are consistently
associated with favorable off treatment response.19,26 The stringent HBsAg cutoff of 10 IU/mL for
NA treatment completion was chosen to account for the direct effect of JNJ-3989 on HBsAg levels.
Participants who are receiving optional treatment with PegIFN-α2a and who have not met NA
treatment completion criteria at Week 48 may have NA treatment completion criteria assessed at
the end of treatment with PegIFN-α2a and stop NA if criteria are met.
After stopping all study interventions, participants will be monitored closely during the 48-week
follow-up phase and should restart NA treatment in accordance with the NA re treatment criteria
(see Section 6.6.2, for more details).


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Follow-up Procedures and Criteria for Re-initiation of NA Treatment
The follow-up period will be extended for participants who are receiving optional treatment with
PegIFN-α2a and who meet NA treatment completion criteria at the end of treatment with NA and
PegIFN-α2a to ensure all participants have at least one year of follow-up after NA treatment
cessation.
To ensure safety of patients during the follow-up phase, an ALT flare management plan is in place,
including a high visit frequency for patients after completion of NA treatment (at Week 48), and
weekly visits for patients with ALT/AST ≥3x upper limit of normal (ULN) and ≥3x nadir until
stabilization.
Increases in ALT and HBV DNA are frequently seen in patients after discontinuation of NA
treatment. These ALT elevations can be reflecting an activation of the host cellular immune
response and can as such lead to functional cure. Cases of fulminant HBV reactivation with fatal
outcome were described after cessation of NA treatment, but the vast majority of such cases were
described in patients with decompensated liver disease at the time of NA discontinuation. These
patients are not eligible to participate in the study. Still, a vigilant follow-up of patients during this
phase of the study is critical to ensure patient safety. Increases in ALT that are accompanied by
signs of decreased liver function, or an HBV DNA value of >100,000 IU/mL (irrespective of
confirmation and/or ALT increase), will trigger immediate re-initiation of NA treatment based on
protocol-defined NA re-treatment criteria (see Section 6.6.2).
Re-initiation of NA treatment is also required in case of confirmed HBeAg seroconversion
(HBeAg positive after it was negative at NA completion), in case of confirmed* ALT increase
(>5x ULN) in combination with increased HBV DNA replication (>2,000 IU/mL), and in case of
confirmed* increased HBV DNA replication at higher levels (>20,000 IU/mL).
* At least 4 weeks apart
A post-treatment HBV DNA value of >20,000 IU/mL should trigger re-testing of ALT/AST, HBV
DNA, and total and direct bilirubin within a maximum of 7 days from receipt of the data and
further repeats as necessary (ie, weekly until HBV DNA returns to <20,000 IU/mL). A post-
treatment HBV DNA value of >2,000 IU/mL (but <20,000 IU/mL) should trigger a re-test within
14 days from receipt of the data and further repeats as necessary (ie, every other week until HBV
DNA returns to <2,000 IU/mL). A post-treatment ALT value of >5x ULN should trigger re-testing
of ALT, AST, ALP, total and direct bilirubin, INR, albumin, and HBV DNA on a weekly basis
until ALT and AST levels have returned to <5x ULN. Additional re-testing and/or earlier restarting
of NA treatment is at the investigator’s discretion, even if the above cut-offs are not yet met.
To avoid delays in decision making, sites are encouraged to run local re-testing in parallel with
central re-testing in the situations described above that require more frequent re-testing. Local test
results are to be recorded in the CRF and/or source documents, including information on the HBV
DNA assay used. In addition, to avoid delays in NA re-treatment, it should be considered to
dispense NA to participants who potentially met the NA re-treatment criteria (eg, pending
confirmation) and who will not be available to come to the study site immediately at the time the


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confirmatory test results will become available. This should ensure that the participant can
immediately restart NA treatment if indicated, upon direct confirmation by the investigator.
The decision to re-start NA treatment should take into consideration the dynamics of HBV DNA
and/or ALT values and should be discussed with the sponsor. Refer to Section 6.6.2.
NA re-treatment criteria during follow-up are presented graphically in Section 10.12, Appendix
12: NA Re-treatment During Follow-up.
Liver Biopsy
HBV is a hepatropic virus, with the liver being the site of its replication which requires a
modulation of intrahepatic immune response to allow the establishment of a chronic persistent
infection. Although some of the viral blood markers are well established from a clinical
perspective, questions remain on the relationship of these markers with intrahepatic events, such
as expression of viral proteins (eg, HBsAg), HBV pgRNA, DNA and cccDNA level and
transcriptional activity in the liver, ie, the target organ of HBV infection. Similarly, while
assessment of peripheral immune response can provide insights into the HBV related immune
response, it is well accepted that a large proportion of the relevant immune responses are enriched
and/or restricted to the liver environment.10,11,29 For example, many HBV specific CD8+ T-cells
have a tissue-resident phenotype and innate-like populations such as mucosal associated invariant
T (MAIT) cells and Natural Killer cells are enriched with the latter having also a specialized liver-
resident component.11,29
Collecting liver biopsy samples will allow to perform critical assessments of intrahepatic virologic
and immune events occurring in response to treatment with JNJ-3989, JNJ-6379 and NA, and to
correlate the findings in the liver with treatment response and to viral and immune blood markers.
In addition, these analyses are expected to improve the understanding of the molecular
mechanisms of the treatment interventions and to provide important insight into the HBV
pathology.
Both core liver biopsies and fine needle aspirates will be collected for high dimensional profiling
of the liver tissue. The cryopreserved core biopsies will allow characterization of the infected
hepatocytes compartment and phenotyping of the major immune cell populations (proportion of
cells and spatial distribution). The liver tissue will be used to assess changes from baseline in the
proportion of HBsAg positive hepatocytes under therapy. In addition, the liver tissue will also be
used to assess other HBV markers in the liver such as, but not limited to, pgRNA, total intracellular
HBV RNA and DNA, and HBc. Changes in the quantity and potentially changes in the spatial
distribution of these markers (including HBsAg) under JNJ-3989 and JNJ-6379 (if applicable)
containing therapy or NA treatment will be assessed. Viral genome (RNA or DNA) sequencing of
the samples as well as assessment of HBV viral transcripts and HBV DNA integrants in the host
genome may be performed. This will also allow to compare viral parameters assessed in the liver
with viral parameters in the blood compartment.


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From an immune perspective, both, the innate and adaptive intrahepatic immune compartment will
be characterized. These analyses will include cells such as CD4+ T-cells, CD8+ T-cells, CD45+
cells, dendritic cells, and Natural Killer cells. Characterization of infiltrating immune cells will be
used for the evaluation of innate and adaptive immune responses, which can be compared to
responses in the PBMCs collected during the study.
Fine needle aspirates biopsies will be profiled by single cell transcriptomics approaches to better
understand the innate and adaptive immune cells composition and functional status9 (very few
hepatocytes are expected to be collected with fine needle aspirates). Hepatitis B virus-specific
T-cells will be one of the main targeted cell populations, detected and sorted by multimers binding
assays. Downstream transcriptomic profiling of collected HBV specific T-cells may be performed
by T-cell receptor sequencing and RNA sequencing. Similar multimer binding assays approaches
might be applied to leukapheresis collected PBMCs, as HBV specific T-cells are present in very
low frequency in patients with chronic HBV infection.9
Remaining samples may be used for determination of liver JNJ-3989 (ie, JNJ-3976 and JNJ-3924)
and/or JNJ-6379 concentrations and/or research on viral and host biomarkers and immune markers
at the viral and/or host RNA/DNA, protein, and cell level.
Host DNA and Biomarker Collection
It is recognized that genetic variation can be an important contributory factor to interindividual
differences in intervention distribution and response and can also serve as a marker for disease
susceptibility and prognosis. Pharmacogenomic research may help to explain interindividual
variability in clinical outcomes and may help to identify population subgroups that respond
differently to an intervention. The goal of the pharmacogenomic component is to collect DNA to
allow the identification of genetic factors that may influence the efficacy, safety, or PK of
JNJ-3989 and JNJ-6379, to identify genetic and epigenetic factors associated with HBV infection,
or to develop assays for the study intervention or HBV infection.
Biomarker samples will be collected to evaluate the MoA  of JNJ-3989 and JNJ-6379 (if
applicable) in combination with NA, help to explain interindividual variability in clinical
outcomes, or may help to identify population subgroups that respond differently to an intervention.
The biomarker research can be used to address questions related to the safety, PK, and efficacy of
the study intervention and HBV infection or to develop assays for the study intervention or HBV
infection.
Host DNA (pharmacogenomic) and biomarker samples may be used to help address emerging
issues and to enable the development of safer, more effective, and ultimately individualized
therapies.
4.2.1. 
Study-Specific Ethical Design Considerations
Potential participants will be fully informed of the risks and requirements of the study and, during
the study, participants will be given any new information that may affect their decision to continue
participation. They will be told that their consent to participate in the study is voluntary and may be


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withdrawn at any time with no reason given and without penalty or loss of benefits to which they
would otherwise be entitled. Only participants who are fully able to understand the risks, benefits,
and potential AEs of the study, and provide their consent voluntarily will be enrolled.
Percutaneous core liver biopsies and FNABs will be performed during this study for research
purposes. The risks and complications related to these procedures are described in Section 2.3.2.3.
These risks and complications will be described in the ICF and will be clearly explained to
potential participants prior to enrollment.
While all participants will receive the study intervention in combination with an approved therapy
for HBV infection, some ethical consideration should be given to the fact that participants will not
have access to potentially alternative or new effective therapies for the duration of the study
(intervention and follow-up phase) since they may not begin any other approved or investigational
therapies for treatment of HBV infection during this time. Participants with worsening HBV
infection can discontinue the investigational intervention at any time, and the investigational
intervention should be discontinued if a participant requires additional therapy for HBV infection.
The total blood volume to be collected is considered to be an acceptable amount of blood to be
collected over this time period from the population in this study based upon the standard of the
American Red Cross standard blood donation.1
4.3. 
Justification for Dose
The proposed dose and treatment duration are selected to maximize the chance for patients to
achieve functional cure and are supported by scientific understanding of available data. For both
compounds, doses are selected that are currently being tested in ongoing Phase 2b studies
REEF-1(73763989HPB2001) and REEF-2 (73763989PAHPB2002) (ie, 200 mg for JNJ-3989 and
250 mg for JNJ-6379).
Note: JNJ-6379 was initially part of the study intervention but has been removed as study
intervention with the implementation of an urgent safety measure, as described in Protocol
Amendment 5.
4.3.1. 
JNJ-3989
Clinical data on PK, efficacy, and safety of JNJ-3989 are available from the ongoing Phase 1/2a
AROHBV1001 study with a data cut-off date of 29 October 2019. All dosing with JNJ-3989 has
been completed and ongoing participants are in the follow-up phase. Twenty adult healthy
participants have received single SC injections of JNJ-3989 (35, 100, 200, 300, and 400 mg) and
84 adult chronic HBV-infected participants have received multiple doses of JNJ-3989 (25, 50, 100,
200, 300, and 400 mg), administered as 3 SC injections separated by either 7 day, 14-day, or 28-
day intervals. All participants either continued or started on ETV or tenofovir disoproxil on Day 1.
JNJ-3989 was generally safe and well tolerated at all doses. No clinically relevant safety signal
was identified.


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Antiviral activity data were available for 56 chronic HBV-infected participants who received 3 SC
injections of 25 to 400 mg JNJ-3989 Q4W. In general, mean HBsAg declines reached nadir at Day
113 (ie, 8 weeks after last JNJ-3989). Mean HBsAg levels remained suppressed (below baseline
levels) at least until Day 392 (ie, 9 months after last dose) in a substantial proportion of patients.8,37
A dose of 200 mg JNJ-3989 Q4W is chosen based on the observed decline in HBsAg in study
AROHBV1001 at this dose over 3 injections, and the lack of a substantial incremental efficacy
response at higher doses.
The Phase 2b study REEF-1 is designed to establish the optimal dose of JNJ-3989. Based on data
from the Phase 1/2a study AROHBV1001 with limited treatment duration, 200 mg was selected
as the highest dose of JNJ-3989 tested in REEF-1. Until lower doses are proven equivalently
effective in REEF-1, additional combination studies with JNJ-3989 and JNJ-6379 are conducted
with 200 mg of JNJ-3989.
4.3.2. 
JNJ-6379
Note: JNJ-6379 was initially part of the study  intervention but has been removed as study
intervention with the implementation of an urgent safety measure, as described in Protocol
Amendment 5.
At the time of initial protocol writing, a dose of 250 mg JNJ-6379 qd was chosen for this study.
A dose of 250 mg of JNJ-6379 was being considered to ensure maximal viral inhibition via
“primary” MoA (ie, interfering with the capsid assembly process). In addition, it ensured sufficient
high exposures to engage the “secondary” MoA (ie, inhibition of de novo cccDNA formation).
This dose selection was supported by translational PK/PD analyses and viral kinetic modeling.
Analyses of the HBV DNA data from the 4-week 56136379HPB1001 study showed a profound
but slightly less substantial reduction of plasma HBV DNA, as a measure of the “primary” MoA,
in the 25 mg dose group compared to the 75 mg and higher dose groups, suggesting that for JNJ-
6379 maximum effect (Emax) in terms of HBV DNA inhibition via primary MoA was approached
starting from a dose of 75 mg onwards. Since it was not possible to derive the engagement of the
“secondary” MoA from the available short term data, the in vitro primary human hepatocyte 90%
effective concentration values in the presence of serum proteins obtained for both MoAs were used
to translate from the “primary” to the “secondary” MoA.
Participants were to be treated with JNJ-6379 for 48 weeks. Based on the MoA of JNJ-6379, it
was expected that continued complete suppression of virus production and de novo cccDNA
formation over many months was required to achieve reduction of the transcriptional active
cccDNA pool, which was considered a prerequisite for HBsAg reduction and/or seroclearance.
Interim analysis data were at that time available from the ongoing Phase 2a JADE study in which
the 250-mg dose was being tested for 48 weeks. Blinded Week 12 data from 40 virologically
suppressed chronic HBV-infected participants who received 250 mg qd JNJ-6379 or placebo in
addition to an NA showed that there were no deaths, grade 4 AEs, or AEs leading to
discontinuation. Most AEs were mild or moderate in severity.


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4.4. 
End of Study Definition
End of Study Definition
The end of study (EOS)is considered as the last visit (Follow-up Week 48 or early discontinuation)
for the last participant in the study. With implementation of Protocol Amendment 5, the last visit
for the last participant in the study may be up to Follow-up Week 72 (see Study Completion
Definition below for rationale). The final data from the study site will be sent to the sponsor (or
designee) after completion of the final participant visit at that study site, in the time frame specified
in the Clinical Trial Agreement.
Study Completion Definition
A participant will be considered to have completed the study if he or she has completed the
assessments at Follow-up Week 48. With implementation of Protocol Amendment 5, the follow-
up phase of 48 weeks will be extended with a maximum of 24 weeks (ie, Follow-up Week 72) for
participants who are receiving optional treatment with PegIFN-α2a and who meet NA treatment
completion criteria at the end of treatment with NA and PegIFN-α2a to ensure all participants have
at least one year of follow-up after NA treatment cessation.
5. 
STUDY POPULATION
Screening for eligible participants will be performed within 4 weeks before administration of the
study intervention. If necessary, eg, for operational reasons, the screening phase may be extended
up to a maximum of 6 weeks on a case-by-case basis and in agreement with the sponsor.
The inclusion and exclusion criteria for enrolling participants in this study are described below. If
there is a question about these criteria, the investigator must consult with the appropriate sponsor
representative and resolve any issues before enrolling a participant in the study. Waivers are not
allowed.
Retesting to assess eligibility will be allowed once, using an unscheduled visit during the screening
period.
For a discussion of the statistical considerations of participant selection, refer to Section 9.2.
5.1. 
Inclusion Criteria
Each potential participant must satisfy all of the following criteria to be enrolled in the study:
1. 
Adult participants ≥18 years of age (or the legal age of consent in the jurisdiction in which
the study is taking place) to ≤65 years of age.
2. 
Participants must be medically stable on the basis of physical examination, medical
history, vital signs, and triplicate 12-lead ECG performed at screening. Anyabnormalities
must be consistent with the underlying illness in the study population  and this


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determination must be recorded in the participant's source documents and initialed by the
investigator.
3. 
Participants must have HBV infection documented by serum HBsAg positivity at
screening. In addition, chronicity must be documented by any of the following at least
6 months prior to screening: serum HBsAg positivity, HBeAg positivity or HBV DNA
positivity, ALT elevation  above ULN without another cause than HBV infection,
documented transmission event, liver biopsy with changes consistent with chronic HBV.
If none of the above are available, the following ways of documenting chronicity are
acceptable at the time of screening: absence of marker for acute infection such as
immunoglobulin M (IgM) anti-HBs and anti-HBc antibodies, which  can be tested at
screening.
4. 
Participants who are not currently treated (defined as not having been on HBV treatment,
including NAs and IFN products within 6 months prior to screening), including treatment-
naïve participants (defined as never having received HBV treatment, including NAs and
IFN products) should:
a. be HBeAg positive, AND
b. have serum HBV DNA at screening ≥20,000 IU /mL, AND
c. have ALT levels at screening <10x ULN, AND
d. have indication for NA treatment according to local standard practice.
5. 
Virologically suppressed participants should:
a. be HBeAg negative, AND
b. be on stable HBV treatment, defined as currently receiving NA treatment (ETV,
tenofovir disoproxil, or TAF) for at least 6 months prior to screening and have been
on the same NA treatment regimen (at the same dose) for at least 3 months at the
time of screening, AND
c. have serum HBV DNA <60 IU/mL on 2 measurements at least 3 months apart (one
of which is at screening), AND
d. have documented ALT values <2.0x ULN on 2 measurements at least 3 months apart
(one of which is at screening).
6. 
Participants must have HBsAg >100 IU/mL at screening.
7. 
Participants must have a body mass index (weight in kg divided by the square of height
in meters) between 18.0 and 35.0 kg/m2, extremes included.
8. 
Participants must have fibroscan liver stiffness measurement ≤9.0 kPa within 6 months
prior to screening or at the time of screening.
Note: Other radiologic liver staging modalities (eg, acoustic radiation force impulse)
might be used if standard practice at the site or if otherwise validated and agreed with the


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sponsor. Results should be equivalent to Metavir F0-F2 with absence of signs of portal
hypertension.
Note: Conventional imaging procedures (eg, conventional liver ultrasound, computed
tomography [CT] or magnetic resonance imaging [MRI]) and serum marker panels are
not allowed to rule out severe fibrosis or cirrhosis.
9. 
Female participants of childbearing potential must have a negative highly sensitive serum
pregnancy test (-human chorionic gonadotropin [-hCG]) at screening and a negative
urine pregnancy test on Day 1 before the first dose of study intervention.
10. 
Criterion modified per Amendment 5
10.1 A woman must be (as defined in Section 10.8, Appendix 8, Contraceptive and Barrier
Guidance and Collection of Pregnancy Information):
a. not of childbearing potential
b. of childbearing potential and practicing a highly effective, preferably user-
independent method of contraception (failure rate of <1% per year when used
consistently and correctly) for at least 30 days prior to screening and agrees to remain
on a highly effective method while receiving study intervention and until 90 days
after last dose of study intervention.
Examples of highly effective methods of contraception are located in Section 10.8,
Appendix 8, Contraceptive and Barrier Guidance and Collection of Pregnancy
Information.
Note: Typical use failure rates may differ from those when used consistently and
correctly. Use should be consistent with local regulations regarding the use of
contraceptive methods for participants in clinical studies.
Note (no longer applicable as of Protocol Amendment 5, because of the removal of
JNJ-6379 as study intervention): Female participants of childbearing potential who
are on a stable treatment regimen with hormonal contraceptives (ie, same dose and
not starting or stopping hormonal contraceptive use for at least 30 days prior to
screening) should continue the same dose regimen until 90 days after the last dose of
study intervention. Ethinylestradiol-containing contraceptives are only allowed if the
ethinylestradiol content is ≤20 µg. Female participants stable on an ethinylestradiol-
containing regimen with a dose >20 µg who switch to an ethinylestradiol-containing
regimen with a dose ≤20 µg, should be on that new regimen for at least 1 week before
the first dose of study intervention. For female participants of childbearing potential
who will start a hormonal contraceptive treatment during the study, ethinylestradiol-
containing contraceptives are not allowed.
11. 
Male participants must agree to wear a condom when engaging in any activity that allows
for passage of ejaculate to another person during the study intervention period and until
90 days after last dose of study intervention.


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12. 
Female participants must agree not to donate eggs (ova, oocytes) for the purposes of
assisted reproduction during the study intervention period and until 90 days after last dose
of study intervention.
13. 
Male participants must agree not to donate sperm for the purpose of reproduction during
the study intervention phase and until 90 days after last dose of study intervention.
14. 
Participants must sign an ICF indicating that he or she understands the purpose of, and
procedures required for, the study and is willing to participate in the study.
15. 
Participants must separately consent if he or she agrees to undergo optional study
procedures (ie, leukapheresis, intensive PK, and/or optional biopsy). Refusal to give
consent to one or all of these optional study procedures does not exclude from
participation in the study.
16. 
In the investigator’s opinion, the participant is able to understand and comply with
protocol requirements, instructions, and study restrictions and is likely to complete the
procedures as planned for this this study.
5.2. 
Exclusion Criteria
Any potential participant who meets any of the following criteria will be excluded from
participating in the study:
1. 
Criterion modified per Amendment 4
1.1 Criterion modified per Amendment 5
1.2 Participants with evidence of hepatitis A virus infection (hepatitis A antibody IgM),
HCV infection (HCV antibody), hepatitis D virus (HDV)infection (HDV antibody), or
hepatitis E virus (HEV) infection (HEV antibody IgM), or HIV-1 or HIV-2 infection
(laboratory confirmed) at screening.
Note: Participants with a positive HCV antibody test can be enrolled if they have
negative HCV RNA at screening and documented negative HCV RNA at least 6 months
prior to screening.
Note: Participants with a positive HDV antibody test may be enrolled after discussion
with the sponsor if an active HDV co-infection can be ruled out by documentation of
negative HDV RNA.
Note: Participants with a positive IgM antibody test for HEV infection may be enrolled
after discussion with the sponsor if an active HEV infection can be ruled out by
documentation of negative anti-HEV IgG.a
a 
Negative HEV RNA may also be acceptable to rule out active HEV infection depending on local standard
practices.


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Note: Participants with a positive HIV-1 or HIV-2 antibody/antigen test at screening
should have a confirmatory HIV RNA test, to rule out false positive results. They can
be enrolled if they have a negative HIV RNA test at screening. Participants with
evidence of HIV-1 or HIV-2 infection who are on antiretroviral treatment are excluded.
2. 
Participants with any of the following laboratory abnormalities within 12 months prior
to screening or at the time of screening:
a. Total bilirubin >1.5x ULNa, OR
b. Direct bilirubin >1.2x ULNa, OR
c. Serum albumin <3.2 g/dLa,
3. 
History or evidence of clinical signs/symptoms of hepatic decompensation including
but not limited to: portal hypertension, ascites, hepatic encephalopathy, esophageal
varices.
4. 
Participants with evidence of liver disease of non-HBV etiology. This includes but is
not limited to hepatitis virus infections mentioned in exclusion criterion 1, drug- or
alcohol related liver disease, autoimmune hepatitis, hemochromatosis, Wilson’s
disease, α-1 antitrypsin deficiency, primary biliary cholangitis, primary sclerosing
cholangitis, Gilbert’s syndrome (mild cases are allowed, see exclusion criterion 2a), or
any other non-HBV liver disease considered clinically significant by the investigator.
5. 
Participants with history or signs of cirrhosis or portal hypertension (nodules, no smooth
liver contour, no normal portal vein, spleen size ≥12 cm), signs of HCC or clinically
relevant renal abnormalities on an abdominal ultrasound performed within 6 months
prior to screening or at the time of screening.
Note:In case of suspicious findings on conventional ultrasound the participant may still
be eligible if HCC or clinically relevant renal abnormalities have been ruled out by a
more specific imaging procedure (contrast enhanced ultrasound, CT or MRI).
6. 
Participants with one or more of the following laboratory abnormalities at screening as
defined by the Division of Acquired Immunodeficiency Syndrome (DAIDS) Toxicity
Grading Scale:
a. Estimated glomerular filtration rate (eGFRcr) ≥grade 3 (<60 mL/min/1.73m²),
calculated by the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI)
formula;
b. Pancreatic lipase elevation ≥grade 3;
c. Pancreatic amylase elevation ≥grade 3
d. Hemoglobin ≤10.9 g/dL (males), ≤10.4 g/dL (females);
a 
Unless explained by a clinical setting that is not hepatic decompensation.


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e. Platelet count ≤lower limit of normal (LLN);
f. Alpha-fetoprotein (AFP) >100 ng/mL;
Note: Participants with AFP >ULN but ≤100 ng/mL may be eligible if HCC can
be ruled out based on a sensitive imaging study (eg, contrast enhanced ultrasound,
CT, or MRI) during screening.
g. Any other laboratory abnormality considered to be clinically significant by the
investigator.
7. 
Participants with presence of coagulopathy or bleeding disorder as indicated by:
a. International normalized ratio (INR) ≥1.1 x ULN;
b. Partial thromboplastin time > 1.1 x ULN;
c. Any signs of prolonged bleeding (>10 minutes).
8. 
Participants with presence of hemoglobinopathy (including sickle cell disease,
thalassemia).
9. 
Participants who had a liver biopsy performed prior to screening that led to
complications and that in the opinion of the investigator would prohibit another liver
biopsy.
10. 
Participants with history of amyloidosis.
11. 
Participant refusal to accept blood transfusions.
12. 
Participants with hemoglobin A1c >8% at screening.
13. 
Participants with a history of malignancy within 5 years prior to screening (exceptions
are squamous and basal cell carcinomas of the skin and carcinoma in situ of the cervix,
or malignancy, which are considered cured with minimal risk of recurrence).
14. 
Participants with abnormal sinus rhythm (heart rate <45 or >100 beats per minute
[bpm]); QT interval corrected for heart rate according to Fridericia’s formula (QTcF)
>450 ms for males and >470 ms for females; QRS interval ≥120 ms; PR interval
>220 ms ; abnormal conduction; or any other clinically significant abnormalities on a
12-lead ECG at screening.
15. 
Participants with a history of or current cardiac arrhythmias (eg, extrasystole,
tachycardia at rest), history of risk factors for Torsade de Pointes syndrome (eg,
hypokalemia, family history of long QT Syndrome) or history or other clinical evidence
of significant or unstable cardiac disease (eg, angina, congestive heart failure,
myocardial infarction, diastolic dysfunction, significant arrhythmia and/or coronary
heart disease), moderate to severe valvular disease, or uncontrolled hypertension at
screening.


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16. 
Participants with any current or previous illness for which, in the opinion of the
investigator and/or sponsor, participation would not be in the best interest of the
participant (eg, compromise the well-being) or that could prevent, limit, or confound
the protocol specified assessments. This may include but is not limited to significant
vascular, pulmonary (eg, chronic obstructive pulmonary disease), gastrointestinal (eg,
significant diarrhea, gastric stasis, or constipation that in the investigator’s opinion
could influence drug absorption or bioavailability), endocrine (eg, thyroid disease),
neurologic, hematologic, rheumatologic, psychiatric, neoplastic, or metabolic
disturbances. Any condition possibly affecting drug absorption (eg, gastrectomy or
other significant gastrointestinal tract surgery, such as gastroenterostomy, small bowel
resection, or active enterostomy) will also lead to exclusion.
17. 
Participants who have received an organ transplant (except for skin, hair, or cornea
transplants).
18. 
Participants with any history of or current clinically significant skin disease requiring
regular or periodic treatment.
19. 
Participants with  clinically relevant drug or alcohol abuse within 12 months before
screening.
20. 
Participants with history of clinically relevant drug rash.
21. 
Participants who have taken any disallowed therapies as noted in Section 6.5 before the
planned first dose of study intervention.
22. 
Participants having used any invasive investigational medical device within 3 months,
or having received an investigational intervention or a biological product,
immunoglobulin or other blood product not intended for the treatment of HBV within
6 months or 5 half-lives (whichever is longer), before the planned first dose of study
intervention, or is currently enrolled in an interventional clinical study with an
investigational product.
23. 
Female participants who are pregnant, or breast-feeding, or planning to become
pregnant while enrolled in this study or within 90 days after the last dose of study
intervention.
24. 
Male participants who plan to father a child while enrolled in this study or within
90 days after the last dose of study intervention.
25. 
Participants who had major surgery (eg, requiring general anesthesia), excluding
diagnostic surgery, within 12 weeks before screening; or who have not fully recovered
from surgery; or have surgery planned during the time of expected participation in the
study.


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Note: Participants with planned surgical procedures to be conducted under local
anesthesia may participate.
26. 
Participant is an employee of the investigator or study site, with direct involvement in
the proposed study or other studies under the direction of that investigator or study site,
as well as family members of the employees or the investigator.
27. 
Vulnerable participants (eg, incarcerated individuals, individuals under a legal
protection measure).
28. 
Criterion modified per Amendment 5
28.1 Participants with known allergies, hypersensitivity, or intolerance to JNJ-3989 or
its excipients (refer to the IBs and addendum).14 16
29. 
Participants with contraindications to the use of ETV, tenofovir disoproxil, or TAF per
local prescribing information.
30. 
For participants undergoing optional leukapheresis: contraindications to the use of
citrate-based anticoagulation per local prescribing information.
Additional exclusion criteria for optional PegIFN-α2a treatment:
31. 
Criterion added per Amendment 4
Criterion modified per Amendment 5
31.1 The following needs to be checked after the participant has signed the separate
consent to receive the optional PegIFN-α2a treatment.
a. Patients with signs or symptoms compatible with autoimmune disorders.
b. Participants with bone marrow suppression.
c. Patients with hypoglycemia, hyperglycemia, and/or diabetes mellitus, who cannot
be effectively controlled by medication.
d. Participants with pre-existing ophthalmologic disorders.
e. Participants with one or more of the following laboratory abnormalities:
 
ANC <1,500 cells/mm3 (<1,000 cells/mm³ for black or African American
participants).
 
Serum creatinine >1.5xULN.
 
Inadequately controlled thyroid function (TSH and T4).
f. Participants with a history of a severe psychiatric disorder, including severe
depression, suicidal ideation and attempted suicide, or a current depression or other


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psychiatric disorders that is not adequately controlled on a stable medication
regimen.
NOTE: Investigators should ensure that all study enrollment criteria have been met at screening.
If a participant's clinical status changes (including any available laboratory results or receipt of
additional medical records) after screening but before the Week -1 liver biopsy or before the first
dose of study intervention is given such that he or she no longer meets all eligibility criteria, then
the participant should be excluded from participation in the study. The required source
documentation to support meeting the enrollment criteria are noted in Section 10.3, Appendix 3,
Regulatory, Ethical, and Study Oversight Considerations.
5.3. 
Lifestyle Considerations
Potential participants must be willing and able to adhere to the following lifestyle restrictions
during the course of the study to be eligible for participation:
1. 
Agree to follow all requirements as outlined in Section 6.5 (details regarding prohibited
and restricted therapy during the study).
2. 
Agree to follow all requirements that must be met during the study as noted in the
Inclusion and Exclusion Criteria (eg, contraceptive requirements).
5.4. 
Screen Failures
NOTE: Retesting of abnormal laboratory values that may lead to exclusion will be allowed once.
Retesting will take place during an unscheduled visit in the screening phase.
Participant Identification, Enrollment, and Screening Logs
The investigator agrees to complete a participant identification and enrollment log to permit easy
identification of each participant during and after the study. This document will be reviewed by
the sponsor study-site contact for completeness.
The participant identification and enrollment log will be treated as confidential and will be filed
by the investigator in the study file. To ensure participant confidentiality, no copy will be made.
All reports and communications relating to the study will identify participants by participant
identification and age at initial informed consent. In cases where the participant is not randomized
into the study, the date seen and age at initial informed consent will be used.
Individuals who do not meet the criteria for participation in this study (screen failure) may not be
rescreened without the sponsor’s agreement.


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6. 
STUDY INTERVENTION
6.1. 
Study Intervention(s) Administered
Physical Description of Study Interventions
The JNJ-3989 supplied for this study will be provided as an aqueous clear, colorless to light yellow
solution with 200 mg/mL of JNJ-3989 (containing the two RNAi triggers, JNJ-3976 and JNJ-3924)
for SC injection, containing
(
).
Note that as of Protocol Amendment 5, JNJ-6379 is no longer included as part of the study
intervention in this study.
Prior to implementation of Protocol Amendment 5, the JNJ-6379 supplied for this study was
formulated as oral tablets containin
mg (
) and 
mg (
)JNJ-56136379-AAA. The
JNJ-6379 tablets had to be swallowed as a whole.
JNJ-3989 and JNJ-6379 will be/was to be provided under the responsibility of the sponsor. Refer
to the IBs and addenda for a list of excipients.14 16,39
The NAs ETV, tenofovir disoproxil, and TAF formulated as oral film-coated tablets of 0.5-mg,
245-mg, and 25-mg strength, respectively, will be provided by the sponsor.
PegIFN-α2a formulated as solution for subcutaneous injection in a prefilled syringe with
180 µg/0.5 mL of PegIFN-α2a, will be provided by the sponsor. Refer to the prescribing
information for a list of excipients.
Packaging and Labeling
All study interventions will be packaged with each unit labeled with a unique medication ID
number. Packaging and labeling of JNJ-3989, JNJ-6379, PegIFN-α2a, and the NAs will be/was to
be done in an open label way. Commercial supplies of NAs and PegIFN-α2a will be sourced and
a clinical study label will be applied. Study intervention labels will contain information to meet
the applicable regulatory requirements.
JNJ-6379 was to be dispensed in child-resistant packaging. Nucleos(t)ide analog and PegIFN-α2a
treatment may also be repackaged into child-resistant packaging if this is not already the case.
No study interventions can be repacked or relabeled without prior approval from the sponsor.
Study Intervention Administration
Study intervention administration must be captured in the source documents and the CRF.
JNJ-3989 injections will be administered SC (preferably in the abdomen)at the study site.
In between study visits, participants will take their oral study intervention (NA treatment) at home
and they will bring their oral study intervention with them to each study visit. At study visits, the
CCI
CCI
CCI
CCI
CCI
CCI


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oral study intervention should be taken on site to allow biochemistry and renal biomarker samples
to be taken in fasted conditions.
During the study, virologically suppressed participants will continue the same NA treatment they
were receiving at time of screening (and during at least 3 months prior to screening). In case
participants experienced toxicity to ETV, tenofovir disoproxil, or TAF prior to screening, they
should be treated with one of the other two NAs during this study.
Participants who are not receiving any HBV treatment at screening will receive tenofovir
disoproxil at start of intervention.
If clinically indicated, switching from one NA treatment (ETV, tenofovir disoproxil, or TAF) to
another NA treatment (ETV, tenofovir disoproxil, or TAF) during the study is allowed for all
participants after consultation with the sponsor.
For PegIFN-α2a, administration should be done SC in the thigh or abdomen, preferably in the
evening by self-injection. Used PegIFN-a2a syringes should be separated from the needle via the
sharps container and then placed into their original box and returned to the site, if allowed per local
guidelines and regulations. The used needles in the sharps container will be returned to the study
site after completion of treatment with PegIFN- α2a or disposed of following local standard
procedures. If desired, participants can also choose to have the weekly administration of
PegIFN-α2a performed at the study site irrespective of the time of day.
If JNJ-3989 and PegIFN-α2a are both injected in the abdomen, they should be injected into
different areas of the abdomen and approximate location should be recorded.
For a definition of study intervention overdose, refer to Section 8.5.7.


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Description of Interventions
Intervention name 
JNJ-3989 
JNJ-6379**** 
PegIFN-α2a 
Entecavir (ETV) 
monohydrate 
Tenofovir 
disoproxil 
Tenofovir
alafenamide (TAF)*
Type 
Drug 
Drug 
Drug 
Drug 
Drug 
Drug
Dosage formulation 
Solution for injection  
Tablets 
Solution for 
injection
Film coated tablets 
Film coated tablets 
Film coated tablets
Unit dose strength(s) 
200 mg/vial 
25 and 100 mg 
180 µg/0.5 mL 
0.5 mg 
245 mg 
25 mg
Dosage level 
200 mg once every 
4 weeks (Q4W) 
250 mg once daily 
(qd) 
180 µg once weekly 
(QW)** 
Nucleoside naïve 
patients:
0.5 mg qd
Lamivudine refractory
patients:
1 mg* qd (but should
preferably be treated
with tenofovir
disoproxil or TAF
instead)
Other indications:
1 mg* qd (must be
agreed upon by the
sponsor)
245 mg qd 
25 mg qd
Route of 
administration 
Subcutaneous 
injection preferably in 
the abdomen  
Oral 
Subcutaneous 
injection (in the
thigh or abdomen)
Oral 
Oral 
Oral
Use 
Investigational 
intervention  
Investigational 
intervention  
Investigational 
intervention  
Background 
intervention  
Background 
intervention  
Background
intervention
Sourcing 
Provided centrally by 
the sponsor 
Provided centrally by 
the sponsor 
Provided centrally 
by the Sponsor*** 
Provided centrally by 
the sponsor 
Provided centrally 
by the sponsor 
Provided centrally by
the sponsor
Packaging and 
Labeling 
Each unit will be 
labeled with unique 
medication ID number 
Each unit will be 
labeled with unique 
medication ID number 
Commercial 
supplies will be 
sourced. Each unit 
will be labeled with 
unique medication 
ID number*** 
Commercial supplies 
will be sourced. Each 
unit will be labeled with 
unique medication ID 
number 
Commercial 
supplies will be 
sourced. Each unit 
will be labeled with 
unique medication 
ID number 
Commercial supplies
will be sourced. Each
unit will be labeled
with unique
medication ID
number


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Intervention name 
JNJ-3989 
JNJ-6379**** 
PegIFN-α2a 
Entecavir (ETV) 
monohydrate 
Tenofovir 
disoproxil 
Tenofovir
alafenamide (TAF)*
In child resistant 
packaging 
In child resistant 
packaging*** 
In child resistant 
packaging 
In child resistant 
packaging 
In child resistant
packaging
Labels will contain information to meet the applicable regulatory requirements.
Food/Fasting 
instructions 
Regardless of food 
intake 
Regardless of food 
intake 
Per the prescribing 
information  
Per prescribing 
information  
Per prescribing 
information  
Per prescribing
information
Q4W: once every 4 weeks; qd: once daily; QW: once weekly
* 
In countries where TAF is available, it will be one of the NA treatment options.
** 
For PegIFN-α2a, dose adjustment may be applicable for participants who develop laboratory abnormalities during PegIFN-α2a treatment (refer to Section 6.6).
*** May vary based on local regulations.
**** Participants enrolled before Protocol Amendment 5 was in effect, may have received JNJ-6379 as part oftheir study intervention. As of Protocol Amendment 5:
study intervention includes JNJ-3989, NA and optionally PegIFN α2a


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6.2. 
Preparation/Handling/Storage/Accountability
Preparation/Handling/Storage
All study interventions must be stored as specified on the product specific labeling.
Study-site personnel will instruct participants on how to store study intervention for at-home use
as indicated for this protocol.
Refer to the pharmacy manual/study site investigational product and procedures manual for
additional guidance on study intervention preparation, handling, and storage.
Accountability
The investigator is responsible for ensuring that all study intervention received at the site is
inventoried and accounted for throughout the study. The dispensing of JNJ-6379 (prior to Protocol
Amendment 5), NA, and PegIFN-α2a (if applicable) to the participant, and the return of JNJ-6379,
NA, and PegIFN-α2a (if applicable) from the participant, must be documented on the intervention
accountability form. Participants must be instructed to return all original containers, whether
empty or containing oral study intervention. The JNJ-3989 and, if applicable, PegIFN-α2a
injections administered to the participant must be documented on the intervention accountability
form. All study intervention will be stored and disposed of according to the sponsor's instructions.
Study-site personnel must not combine contents of the study intervention containers.
Participants who stopped JNJ-6379 per Protocol Amendment 5, must return their JNJ-6379 supply
at the next scheduled visit. The return of JNJ-6379 from the participant must be documented on
the intervention accountability form.
Study intervention must be handled in strict accordance with the protocol and the container label,
and must be stored at the study site in a limited-access area or in a locked cabinet under appropriate
environmental conditions. Unused study intervention, and oral study intervention returned by the
participant, must be available for verification by the sponsor's study site monitor during on-site
monitoring visits. The return to the sponsor of unused study intervention, or used returned study
intervention for destruction, will be documented on the intervention return form. When the study
site is an authorized destruction unit and study intervention supplies are destroyed on-site, this
must also be documented on the intervention return form.
Potentially hazardous materials containing hazardous liquids, such as used ampules, needles,
syringes and vials, should be disposed of immediately in a safe manner and therefore will not be
retained for intervention accountability purposes. Details on handling of used PegIFN-α2asyringes
are described in Section 6.1, Study Intervention(s) Administered.
Study intervention should be dispensed under the supervision of the investigator or a qualified
member of the study-site personnel, or by a hospital/clinic pharmacist. Study intervention will be
supplied only to participants participating in the study. Returned study intervention must not be
dispensed again, even to the same participant. Whenever a participant brings his or her oral study


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intervention to the study site for pill count, this is not seen as a return of supplies. Study
intervention may not be relabeled or reassigned for use by other participants. The investigator
agrees neither to dispense the study intervention from, nor store it at, any site other than the study
sites agreed upon with the sponsor. Further guidance and information for the final disposition of
unused study interventions are provided in the Study Reference Manual.
6.3. 
Measures to Minimize Bias: Randomization and Blinding
Intervention Allocation
Procedures for Randomization and Stratification
Prior to Protocol Amendment 5, central randomization was implemented in this study. Participants
were randomly assigned within each panel to 1 of 2 intervention  arms in a 1:1 ratio (Arm 1
[JNJ-3989+JNJ-6379+NA]:Arm 
2 [JNJ-3989+NA]) based on a computer-generated
randomization schedule prepared before the study by or under the supervision of the sponsor. The
randomization was balanced by using randomly permuted blocks and was stratified within each
panel by Fibroscan score (<7 kPa vs ≥7 kPa). The interactive web response system (IWRS)
assigned a unique intervention code, which dictated the intervention assignment and matching
study intervention kit for the participant. The requestor had to use his or her own user identification
and personal identification number when contacting the IWRS and had to give the relevant
participant details to uniquely identify the participant.
As of Protocol Amendment 5, all participants will enroll without randomization within a study
panel. The interactive web response system (IWRS) will assign a unique intervention code with
matching study intervention kit for the participant. The requestor must use his or her own user
identification and personal identification number when contacting the IWRS and will then give the
relevant participant details to uniquely identify the participant.
Blinding
As this is an open label study, blinding procedures are not applicable.
6.4. 
Study Intervention Compliance
JNJ-3989 will be administered at the study site as a SC injection by qualified study-site personnel
to assure compliance with study requirements.
The participants will be requested to bring unused oral study interventions and empty packaging
to the study site at each visit.
Every effort should be made to have the participant take the study interventions as indicated in the
Schedule of Activities.
 
If an injection of JNJ-3989 was missed, the injection should be given as soon as possible but
within 3 weeks after the scheduled time. Otherwise, the injection should be skipped and the
next injection should be given at the next scheduled time point per the initial injection
schedule.


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 
If a dose of NA is missed, the participant should follow the guidelines in the package insert.
 
If an injection of PegIFN-α2a is missed, the participant should follow the guidelines in the
prescribing information.
If a participant’s study intervention intake is not according to the protocol, the investigator will
take the necessary measures to ensure future adherence to the protocol.
An optional medication diary to document oral study intervention intake can be made available for
participants with an observed or known risk for study intervention non-compliance. The completed
diaries are reviewed by the site staff and discussed with the participants for compliance monitoring
and counseling. Completed diaries will be returned to the site staff to add to the source documents.
6.5. 
Concomitant Therapy
Note: With the removal of JNJ-6379 as study intervention in Protocol Amendment 5, JNJ-
6379-specific disallowed medications and concomitant medications to be used with caution are no
longer applicable and have been removed.
Prestudy therapies administered up to 30 days before the start of screening must be recorded at
screening. If applicable, the participant’s last anti-HBV treatment prior to screening must also be
recorded.
Concomitant therapies must be recorded throughout the study, from signing of the ICF until
completion of the participant’s last study-related procedure. Concomitant therapies should also be
recorded beyond the last study-related procedure only in conjunction with new or worsening
S(AE)s.
All therapies (prescription or over-the-counter medications, including vaccines, vitamins, herbal
supplements; non-pharmacologic therapies such as electrical stimulation, acupuncture, special
diets, exercise regimens, or other specific categories of interest) different from the study
intervention must be recorded in the CRF. Recorded information will include a description of the
type of therapy, duration of use, dosing regimen, route of administration, and indication.
Modification of an effective preexisting therapy should not be made for the explicit purpose of
entering a participant into the study.
Local guidelines on the use of live vaccines in participants receiving PegIFN-α2a should be
followed, including for the second dose of Sputnik V (which contains rAd5, with a theoretical risk
of replication competence). Sputnik Light, which is the first dose of Sputnik V (with rAd26) is not
considered a live vaccine. See below for further guidance on the use of COVID-19 vaccines.
Note that locally approved COVID-19 vaccines (including those that received emergency use
authorization or conditional marketing authorization) are allowed throughout the study. For
participants receiving PegIFN-α2a, the following recommendations should be applied to
accommodate COVID-19 vaccination during PegIFN-α2a treatment:


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 
COVID-19 vaccine and PegIFN-α2a should not be administered on the same day.
 
If required, PegIFN-α2a injection can be delayed with 2 days. The next PegIFN-α2a injection
should be performed at the scheduled time.
 
If required, skipping a PegIFN-α2a injection may be considered after consultation with the
Sponsor.
 
Vaccination with Sputnik V should take above-mentioned consideration about live vaccines
into account.
All COVID-19 vaccination-related data (eg, COVID-19 vaccination, AEs, AE management)
should be appropriately captured in the CRF and source documents. Refer to the COVID-19
vaccine and/or PegIFN-α2a prescribing information for more details.
An overview of disallowed medication is provided in Table 4.
Table 4: 
Disallowed Medication
Disallowed at any time prior to screening until end of follow-up:
 
Any CAM and oligonucleotide-based treatment (eg, siRNA and antisense oligonucleotides, nucleic acid
polymers, etc.), other than the study intervention taken in the context of this study.
Disallowed from 6 months prior to screening until end of follow-up:
 
Any investigational agent, investigational vaccine, invasive investigational medical device, or
investigational biological product (other than the study intervention taken in the context of this study).
Note: For investigational COVID-19 vaccines administered within 6 months prior to screening, an
exception will be made as long as the vaccine has been approved (or received emergency use authorization
or conditional marketing authorization) at the time of screening.
Disallowed from 6 months prior to baseline until end of follow-up:
 
For participants currently not being treated: Any anti-HBV drug (including vaccines) other than the study
intervention taken in the context of this study.
Note: Prior hepatic treatment with herbal or nutritional products is allowed but should be stopped at
screening.
 
Any systemically (eg, intravenously, intramuscularly, orally, subcutaneously) administered medication
that directly or indirectly interferes with immune responses (eg, cyclosporine, interleukins, IFN, systemic
corticosteroids exceeding 5 mg of prednisolone equivalent/day).
Disallowed from 1 month prior to screening until end of follow-up:
 
Anticoagulants and antiplatelet agents.
Note: The use of citrate-based anticoagulant is allowed for participants during the leukapheresis
procedure. Use of heparin for anticoagulation is not allowed.
Note: The use of ibuprofen or paracetamol is allowed. Use of low-dose aspirin is allowed with exception
of 7 days prior to biopsies.
Disallowed from screening until end of follow-up:
 
Any anti-HBV drug (including vaccines) other than the study intervention taken in the context of this
study.
Note: NA standard of care treatment is allowed for virologically suppressed participants.
 
Biotin (>1 mg daily dose), either taken alone or as part of a multivitamin formulation.
Note: The use of other vitamins is allowed.
 
Topical steroids (>7 days) under occlusive dressing.


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Note: The list of disallowed medication is not exhaustive; for products falling in one of the
categories and not mentioned by name, the sponsor should be contacted to determine whether the
product can be allowed.
The sponsor must be notified in advance (or as soon as possible thereafter) of any instances in
which prohibited therapies are administered.
The prescribing information for ETV, tenofovir disoproxil, TAF, and PegIFN-α2a should be
consulted for any additional prohibited medication. In case of flu-like symptoms after
administration of PegIFN-α2a, paracetamol up to a maximum of 2 g per 24 hours and a maximum
of 6 g per week is allowed.
Medications requiring SC injection (other than JNJ-3989 and PegIFN-α2a; eg, insulin) should be
administered away from the JNJ-3989 and PegIFN-α2a injection sites.
6.6. 
Dose Modification
Dose modifications of JNJ-3989 and NA (increase or decrease of dose level) are not permitted
during the study.
For PegIFN-α2a, dose adjustment guidelines are applicable for participants who develop
laboratory abnormalities during PegIFN-α2a treatment, as recommended in the locally approved
prescribing information for PegINF-α2a and upon investigator’s assessment.
Refer to the example from the Pegasys USPI and SmPC (see Table 5).
Table 5: 
PegIFN-α2a Hematological Dose Modification Guidelines
Laboratory Values 
Recommended Dose
ANC <750 cells/mm³ 
Reduce to 135µg
ANC <500 cells/mm³ 
Discontinue treatment until ANC values return to more than 1,000 cells/mm³.
Reinstitute at 90µg and monitor ANC.
Platelet <50,000 cells/mm³ 
Reduce to 90µg
Platelet <25,000 cells/mm³ 
Discontinue treatment
ANC: absolute neutrophil count
Source: Pegasys USPI and SmPC
For participants who prematurely discontinue PegIFN-α2a, treatment with PegIFN-α2a may be
restarted according to the recommendations from the locally approved prescribing information for
PegIFN-α2a.
6.6.1. 
Study Intervention Completion at Week 48
With the implementation of Protocol Amendment 5, all participants had to stop JNJ-6379
treatment immediately.
Participants will complete treatment with JNJ-3989 after a fixed duration of 48 weeks. If all of the
below criteria are met based on clinical laboratory tests performed at Week 44, treatment with NA
will also be completed at the next scheduled visit (ie, Week 48):


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 
The participant has ALT <3x ULN, AND
 
The participant has HBV DNA <LLOQ, AND
 
The participant is HBeAg negative, AND
 
The participant has HBsAg <10 IU/mL.
Note: In case of ALT elevation ≥3x ULN at Week 44 the investigator must consider different
potential causes of increased ALT to ensure appropriate work up and management as needed. If
the ALT elevation is unrelated to HBV activity and/or <3x ULN by Week 48, NA completion may
be considered at the discretion of the investigator and in consultation with the sponsor.
Participants who do not meet the above criteria at Week 48 should continue NA treatment during
the 48-week follow-up phase. Participants who are receiving optional treatment with PegIFN-α2a
and who have not met NA treatment completion criteria at Week 48 may have NA treatment
completion criteria assessed at the end of treatment with PegIFN-α2a and stop NA if criteria are
met.
If a participant prematurely discontinues investigational intervention before Week 48, follow-up
assessments should be obtained as per the Schedule of Activities until 48 weeks after the end of
investigational intervention unless the participant withdraws consent. In this case, NA treatment
may be continued or, in consultation with the sponsor, discontinued, based on the above-mentioned
NA treatment completion criteria.
With the implementation of Protocol Amendment 5, the follow-up period will be extended for
participants who are receiving optional treatment with PegIFN-α2a and who meet NA treatment
completion criteria at the end of treatment with NA and PegIFN-α2a to ensure all participants have
at least one year of follow-up after NA treatment cessation.
The investigator should consider to re-start NA treatment per local standard of care at the EOS
visit (Follow-up Week 48 up to maximum Follow-up Week 72) for participants who met the NA
treatment completion criteria at Week 48 or for participants who met NA treatment completion
criteria at the end of treatment with PegIFN-α2a during the follow-up phase, who did not re-start
NA treatment during the follow-up phase, and who did not achieve and maintain HBsAg
seroclearance. NA will not be provided by the sponsor after the final study visit.
6.6.2. 
NA Re-treatment Criteria and Monitoring after Stopping of NA
Participants who meet the NA treatment completion criteria outlined in Section 6.6.1 will be
monitored closely during the follow-up phase.
After stopping NA treatment, participants should be monitored as follows:
 
Regular monitoring visits will be every 4 weeks during the follow-up phase in accordance
with the Schedule of Activities.


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 
A post-treatment HBV DNA value of >20,000 IU/mL should trigger re-testing of ALT/AST,
HBV DNA, and total and direct bilirubin within a maximum of 7 days from receipt of the data
and further repeats as necessary (ie, weekly until HBV DNA returns to <20,000 IU/mL).
 
A post-treatment HBV DNA value of >2,000 IU/mL (but <20,000 IU/mL) should trigger a re-
test within 14 days from receipt of the data and further repeats as necessary (ie, every other
week until HBV DNA returns to <2,000 IU/mL).
 
A post-treatment ALT value of >5x ULN should trigger re-testing of ALT, AST, ALP, total
and direct bilirubin, INR, albumin, and HBV DNA on a weekly basis until ALT and AST
levels have returned to <5x ULN.
After stopping NA treatment, participants should re-start NA treatment:
 
Immediately with signs of decreasing liver function based on laboratory findings (eg, INR,
direct bilirubin) or clinical assessment (eg, ascites, hepatic encephalopathy),
 
Immediately with an HBV DNA value of >100,000 IU/mL (irrespective of confirmation
and/or ALT increase).
 
With confirmed post-treatment HBeAg seroreversion (HBeAg positive after it was negative
at NA completion)
 
With confirmed* post-treatment increases in HBV DNA >2,000 IU/mL and ALT >5x ULN
 
With confirmed* post-treatment increases in HBV DNA >20,000 IU/mL.
* At least 4 weeks apart frequency of visits as described above
Note:
Additional re-testing and/or earlier restarting of NA treatment is at the investigator’s discretion,
even if the above cut-offs are not yet met.
To avoid delays in decision making, sites are encouraged to run local re-testing in parallel with
central re-testing in the situations described above that require more frequent re-testing. Local test
results are to be recorded in the CRF and/or source documents, including information on the HBV
DNA assay used. In addition, to avoid delays in NA re-treatment, it should be considered to
dispense NA to participants who potentially met the NA re-treatment criteria (eg, pending
confirmation) and who will not be available to come to the study site immediately at the time the
confirmatory test results will become available. This should ensure that the participant can
immediately re-start NA treatment if indicated, upon direct confirmation by the investigator.
In case NA treatment is re-started, participants will be followed until the end of the study or until
clinical stabilization, whichever comes later.
Refer to Appendix 12 in Section 10.12 for a graphical representation.


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6.7. 
Study Intervention After the End of the Study
Participants will be instructed that study intervention will not be made available to them after they
have completed/discontinued study intervention  and that they should return to their primary
physician to determine standard of care.
The investigator should consider to re-start NA treatment per local standard of care at the EOS
visit (Follow-up Week 48 up to maximum Follow-up Week 72) for participants who met the NA
treatment completion criteria at Week 48 or for participants who met NA treatment completion
criteria at the end of treatment with PegIFN-α2a during the follow-up phase, who did not re-start
NA treatment during the follow-up phase, and who did not achieve and maintain HBsAg
seroclearance. NA will not be provided by the sponsor after the final study visit.
7. 
DISCONTINUATION OF INVESTIGATIONAL INTERVENTION AND
PARTICIPANT DISCONTINUATION/WITHDRAWAL
7.1. 
Discontinuation of Study Intervention
With the implementation of Protocol Amendment 5, all participants had to stop JNJ-6379
treatment immediately.
Treatment with JNJ-3989 and/or PegIFN-α2a must be discontinued if any of the criteria listed
below apply. If JNJ-3989 is discontinued, PegIFN-α2a should also be discontinued. If PegIFN-
α2a is discontinued, JNJ-3989 should be continued. NA treatment may be continued or, in
consultation with the sponsor or discontinued based on investigator judgement.
 
The participant withdraws consent to receive study intervention.
 
The investigator believes that for safety reasons or tolerability reasons (eg, AE) it is in the
best interest of the participant to discontinue JNJ-3989 (and, if applicable, PegIFN-α2a).
 
The participant becomes pregnant.
 
The participant has a ≥grade 3 rash (see Section 10.5, Appendix 5, Rash Management) or
allergic reaction (see Section 8.5.7.2).
 
The participant has signs of hepatic decompensation (ie, clinical evidence of ascites, bleeding
varices, or hepatic encephalopathy) or an increase in direct bilirubin >1.5x ULN in
combination with INR ≥1.5x ULN or albumin <3.0 g/dL.
 
The participant has a confirmed ≥grade 3 eGFRcr abnormality and a drop from baseline of
>10 mL/min/1.73 m2, considered at least possibly related to JNJ-3989 (or PegIFN-α2a) that
persists despite changing tenofovir disoproxil to ETV or TAF (if the patient was receiving
tenofovir disoproxil)(see Section 8.5.6.4).
 
The participant has a confirmed QTcF prolongation (defined as a QTcF value of >500 ms, or
an increase from baseline of >60 ms) at any given time point.
 
The participant requires ≥7 days of treatment with any of the disallowed medications listed in
Section 6.5 and does not intend to discontinue treatment with the disallowed medication.


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 
The participant has confirmed HBV virologic breakthrough (ie, confirmed on-treatment HBV
DNA increase by >1 log10 IU/mL from nadir or confirmed on-treatment HBV DNA level >200
IU/mL in participants who had HBV DNA level <LLOQ of the HBV DNA assay). In case of
virologic breakthrough, the same assessments will be done at an unscheduled visit as will be
done in case of an ALT flare, but no PBMC sample will be taken (see Section 8.5.6.1 and
Schedule of Activities), changing the NA should be considered in consultation with the
sponsor.
If virologic breakthrough occurs during JNJ-3989 and PegIFN-α2a administration, this does
not automatically lead to stop of JNJ-3989 and/or PegIFN-α2a but should be
assessed/discussed with the Sponsor.
In case of virologic breakthrough, a viral sequencing sample will be collected at the next visit.
 
The participant has ALT/AST elevations, as described in Section 8.5.6.2.
 
The participant has confirmed ≥grade 3 hematologic abnormalities as described in
Section 8.5.6.5.
NOTE: The grades are based on the DAIDS Toxicity Grading Scale (see Section  10.9,
Appendix 9, DAIDS Table).
In addition, PegIFN-α2a (if applicable) must immediately be discontinued for any of the following
reasons:
 
Participant has platelet count <25,000 cells/mm3
 
Participant has ANC <500 cells/mm3
Note: PegIFN-α2a treatment can be restarted when ANC values return to more than 1,000
cells/mm3 (see details in Section 6.6, Dose Modification)
 
Participant develops evidence of hepatic decompensation during treatment, or ALT increase
clinically significant or accompanied by direct bilirubin increase
 
Participant develops thyroid disorders or diabetes during treatment and cannot be controlled
with medication
 
Participant develops new or worsening ophthalmologic disorders
 
Participant develops any deterioration of cardiovascular status
 
Participant develops serious, acute hypersensitivity reaction (eg, urticaria, angioedema,
bronchoconstriction, anaphylaxis)
 
Participant develops serious infection (bacterial, viral, fungal) and/or sepsis
 
Participant develops persistent or unexplained pulmonary infiltrates or pulmonary function
impairment
 
Participant with onset or worsening of psoriatic lesion
 
Participant develops moderate or severe depression, or other psychiatric symptoms (for mild
depression, treatment discontinuation may be considered)


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Note: Participants who develop a neuropsychiatric AE during optional PegIFN-α2a
treatment, will be monitored closely until the neuropsychiatric AE resolves, with frequent
(at least weekly) follow-up phone calls.
 
Participant develops colitis symptoms (such as but not limited to abdominal pain, bloody
diarrhea, and fever)
 
Participant develops symptoms or signs suggestive of pancreatitis
If a participant discontinues investigational intervention for any reason before Week 48, then the
early withdrawal assessments should be obtained. The participant will enter the follow-up phase
and complete the follow-up schedule unless the participant withdraws consent. Participants who
withdraw consent will be offered an optional safety follow-up visit to occur on the day of consent
withdrawal. Study intervention assigned to the participant who discontinued study intervention
may not be assigned to another participant.
In case a participant withdraws consent for the second biopsy, the study participant may continue
the study intervention and visit schedule as outlined in the Schedule of Activities.
7.2. 
Participant Discontinuation/Withdrawal From the Study
A participant will NOT be automatically withdrawn from the study if he or she has to discontinue
study intervention before Week 48.
A participant will be withdrawn from the study for any of the following reasons:
 
Lost to follow-up,
 
Withdrawal of consent,
 
Death.
When a participant withdraws before study  completion, the reason for withdrawal is to be
documented in the CRF and in the source document. If the reason for withdrawal from the study
is withdrawal of consent then no additional assessments are allowed. No additional participants
will be enrolled in case a participant withdraws from the study.
Withdrawal of Consent
A participant declining to return for scheduled visits does not necessarily constitute withdrawal of
consent. Alternate follow-up mechanisms that the participant agreed to when signing the consent
form apply as local regulations permit.
7.2.1. 
Withdrawal From the Use of Research Samples
Withdrawal From the Use of Samples in Future Research
The participant may withdraw consent for use of samples for research (refer to Long-Term
Retention of Samples for Additional Future Research in Section 10.3, Appendix 3, Regulatory,
Ethical, and Study Oversight Considerations). In such a case, samples will be destroyed after they


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are no longer needed for the clinical study. Details of the sample retention  for research are
presented in the main ICF and in the separate ICF for optional research samples.
7.3. 
Lost to Follow-up
To reduce the chances of a participant being deemed lost to follow-up, prior to randomization
attempts should be made to obtain contact information from each participant, eg, home, work, and
mobile telephone numbers and email addresses for both the participant as well as appropriate
family members.
A participant will be considered lost to follow-up if he or she repeatedly fails to return for
scheduled visits and is unable to be contacted by the study site. A participant cannot be deemed
lost to follow-up until all reasonable efforts made by the study-site personnel to contact the
participant are deemed futile. The following actions must be taken if a participant fails to return to
the study site for a required study visit:
 
The study-site personnel must attempt to contact the participant to reschedule the missed visit
as soon as possible, to counsel the participant on the importance of maintaining the assigned
visit schedule, to ascertain whether the participant wishes to or should continue in the study.
 
Before a participant is deemed lost to follow-up, the investigator or designee must make every
reasonable effort to regain contact with the participant (where possible, 3 telephone calls, e-
mails, fax, and, if necessary, a certified letter to the participant’s last known mailing address,
or local equivalent methods). These contact attempts should be documented in the
participant’s medical records.
 
Should the participant continue to be unreachable, he or she will be considered to have
withdrawn from the study.
Should a study site close, eg, for operational, financial, or other reasons, and the investigator cannot
reach the participants to inform them, their contact information will be transferred to another study
site.
8. 
STUDY ASSESSMENTS AND PROCEDURES
Overview
The Schedule of Activities summarizes the frequency and timing of efficacy, PK, PD, immune,
biomarker, pharmacogenomic and safety measurements applicable to this study.
If applicable, ECGs should be completed before any tests, procedures, or other consultations for
that visit. Blood collections for PK and PD assessments should be kept as close to the specified
time as possible. Samples obtained within 20% of the nominal time from dosing (eg, ±12 minutes
of a 60-minute time point) will not be captured as a protocol deviation if the exact time of the
sample collection is noted on the source document and CRF. Other measurements may be done
earlier than specified time points if needed. Actual dates and times of assessments will be recorded
in the source documentation and CRF.


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Additional serum or urine pregnancy tests may be performed, as determined necessary by the
investigator or required by local regulation, to establish the absence of pregnancy at any time
during the participation in the study.
The amount of blood drawn from each participant over the entire course of this study will be
approximately 1200 mL.
During the leukapheresis procedure, WBCs will be separated from the blood, while the rest of the
blood is returned to circulation. This process typically yields approximately 200 ml of cells. For
participants undergoing all 3 optional leukapheresis procedures, approximately 600 ml will be
collected.
For participants receiving optional PegIFN-α2a treatment, an additional amount of maximum
50 mL of blood will be drawn. In case participants continue NA treatment during the optional
PegIFN-α2a treatment, an additional amount of maximum 200 mL of blood will be drawn during
additional visits every 4 weeks to ensure at least one year of follow-up after NA treatment cessation
(extended follow-up phase up to 72 weeks).
Repeat or unscheduled samples may be taken for safety reasons or for technical issues with the
samples.
Sample Collection and Handling
The actual dates and times of sample collection, as well as the actual start and stop times of the
leukapheresis procedure, must be recorded in the CRF or laboratory requisition form.
Refer to the Schedule of Activities for the timing and frequency of all sample collections.
Instructions for the collection, handling, storage, and shipment of samples are found in the
laboratory manual that will be provided. Collection, handling, storage, and shipment of samples
must be under the specified, and where applicable, controlled temperature conditions as indicated
in the laboratory manual.
Study-specific Materials
The investigator will be provided with the following supplies:
 
IB and any addenda for JNJ-3989,
 
Prescribing Information for ETV, tenofovir disoproxil, TAF, and PegIFN-α2a,
 
Pharmacy manual/study site investigational product and procedures manual,
 
Laboratory manuals,
 
IWRS Manual,
 
CRF Completion Guidelines,
 
Sample ICF,


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 
Contact information page(s).
8.1. 
Liver Biopsy and Fine Needle Aspiration Biopsy
Percutaneous core liver biopsies and FNABs will be performed at the time points indicated in the
Schedule of Activities. If participants agree to undergo an optional liver biopsy, additional FNAB
and/or core liver biopsy samples may be taken at the selected location at Follow-up Week 24 or at
the time points clinically indicated.
Following local standard practice the biopsy location will be identified with ultrasound (which will
also be used to rule out contraindicating conditions for a biopsy) and after application of local
anesthesia the FNAB samples and core liver biopsy samples will be collected.
The liver biopsy procedure should be preceded and followed by standard medical monitoring
according to local medical practice. This may include an overnight stay at the investigator’s
discretion. The use of low-dose aspirin is allowed with exception of 7 days prior to biopsies (see
Section 6.5).
The liver tissue will be used to assess HBsAg. Changes from baseline in the proportion of HBsAg
positive hepatocytes under therapy will be assessed.
In addition, the liver tissue may also be used to assess other HBV markers in the liver such as, but
not limited to, total intracellular HBV RNA and DNA, HBeAg, and HBc. Changes in the quantity
and potentially changes in the spatial distribution of these markers (including HBsAg) under
therapy may be assessed. Viral genome (RNA or DNA) or transcript sequencing/analyses as well
as assessment of HBV integrants in the host genome may be performed.
Intrahepatic immune status at baseline and response to treatment will be assessed. Both innate and
adaptive immune compartment will be characterized, by measuring the relative number of specific
cells and the expression of functional markers in each cell population using various single cell
approaches, such as single cell transcriptomics in FNABs and Immunofluorescence staining, and
transcriptomics and proteomics profiling in core needle biopsies. Depending on the latest platform
developments (spatial transcriptomics, in situ sequencing approaches, etc.), methods for immune
cells characterization might be adjusted.
Hepatitis B virus-specific T-cells, although very rare in FNABs, may be characterized and counted
by multimers binding assays, staining and sorting for positive cells. Downstream profiling of
collected HBV-specific T-cells may be performed by T-cell receptor sequencing and RNA
sequencing.
Infiltrating immune cells will be used for the evaluation of innate and adaptive immune responses,
which can be compared to responses in PBMCs.
Intrahepatic virologic status at baseline and response to treatment will be assessed with a range of
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Hepatitis B virus cccDNA levels may be assessed using quantitative polymerase chain reaction
(qPCR) methods on a single cell level using laser capture microdissection or bulk analyses. The
exact protocol of cccDNA measurement will be determined based on the latest method available
considering the performance characteristics and the validation status of the assay. Southern
Blot-based methods or novel methods for cccDNA detection (eg, fluorescent in situ hybridization
[FiSH]) might be used depending on the availability of sample and established methodology.
Quantification of intracellular pre-genomic HBV RNA can be used to determine transcriptional
activity of HBV cccDNA by assessing the ratio of pgRNA levels over cccDNA levels.
Immune and virologic markers in the liver and/or changes thereof under therapy will be used to
assess association with blood markers and/or treatment response and outcome.
Remaining samples may be used for determination of liver JNJ-3989 (ie, JNJ-3976 and JNJ-3924)
and/or JNJ-6379 concentrations and/or research on viral and host biomarkers and immune markers
at the viral and/or host RNA/DNA, protein, and cell level.
Samples can only be used for research related to JNJ-3989, JNJ-6379, NA, chronic HBV infection,
or chronic HBV infection related disease or may be used to develop tests/assays related to JNJ-
3989, JNJ-6379, NA, or chronic HBV infection.
These latter exploratory analyses will be performed at the sponsor’s discretion and will always be
under the sponsor's supervision.
8.2. 
Blood Efficacy Assessments
Efficacy assessments will be performed at the time points indicated in the Schedule of Activities.
Qualitative and quantitative HBsAg and HBeAg, and quantitative HBcrAg as well as antibodies
against HBsAg and HBeAg will be determined using validated serologic assays in a central
laboratory. Samples for the determination of HBsAg and HBeAg will be processed in real-time.
Samples for the determination of HBcrAg can be analyzed in batch and at the sponsor’s discretion.
Hepatitis B virus DNA and HBV RNA will be quantified at central laboratories using validated
assays for the quantification of HBV DNA and HBV RNA. Samples for the determination of HBV
DNA will be processed in real-time. Samples for the determination of HBV RNA can be analyzed
in batch and at the sponsor’s discretion.
Hepatitis B virus DNA, HBsAg, HBeAg, anti-HBs, and anti-HBe antibody testing results will be
provided to the investigator and the sponsor from screening until the end of follow-up.
It is the responsibility of the investigator:
 
To monitor HBV DNA results and ensure that investigational intervention is discontinued in
participants with virologic breakthrough (see Section 7.1),
 
To assess if NA treatment completion criteria are met (see Section 6.6.1),
 
To assess whether re-start of NA treatment during follow-up is needed (see Section 6.6.2).


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In participants enrolled at a site with an on-site Fibroscan device, Fibroscan assessments will be
performed to determine changes in fibrosis levels.
Samples may be used by the sponsor for additional exploratory assessments analyzing the
serologic and virologic characteristics of HBV infection and efficacy or safety of the study
intervention.
8.2.1. 
Sequencing
Viral genome sequence analysis will be performed to evaluate mutations associated with the study
intervention.
Sequencing of the HBV genome will be performed to monitor HBV variants present at the time
points indicated in the Schedule of Activities. The sequencing of samples may be triggered by the
sponsor virologist based on changes in HBV DNA levels observed in each individual participant
and the limits of the sequencing assay.
Samples may be used by the sponsor for additional assessments analyzing the serologic and
virologic characteristics of the HBV infection and efficacy of the study intervention, including
viral genotypic and phenotypic assessments.
8.3. 
Blood Immune Assessments
8.3.1. 
Peripheral Blood Mononuclear Cell Immune Analyses
Samples for PBMC immune analyses will be collected during the study intervention and follow-up
phases and will be analyzed centrally for HBV-specific responses by enzyme-linked immunospot
(ELISpot) and/or intracellular cytokine staining (ICS) after stimulation with HBV-specific
antigens. ELISpot detects T-cells that secrete gamma interferon (IFN-γ) in response to a specific
antigenic stimulation, whereas ICS determines the frequency of CD4+ and CD8+ T-cells secreting
cytokines such as IFN-γ, interleukin (IL)-2 and tumor necrosis factor (TNF)-α in response to a
specific antigenic stimulation. Hepatitis B virus-specific T-cells may be characterized in PBMCs
by binding assays (multimer staining) combined with downstream TCR and transcriptome
profiling.
Additional experiments may be performed to further phenotypically and functionally characterize
PBMCs using proliferation or cytotoxic assays or other methods such as cytometry by time of
flight to evaluate innate and adaptive immune responses. Leftover samples may be used at the
sponsor’s discretion for additional exploratory research related to HBV infection or study
intervention (safety/efficacy).
Additional PBMC samples may be taken in case of ALT flare, upon discussion with the sponsor,
which may require an unscheduled visit.


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8.3.2. 
Leukapheresis (Optional With Separate Consent)
Leukapheresis allows to selectively collect higher quantities of PBMCs from participants without
withdrawing large volumes of blood.
Leukapheresis will only be performed for participants who consent separately to this component
of the study. Participants may withdraw such consent at any time without affecting their
participation in other aspects of the study.
Leukapheresis may be done at least 1 week (and up to 3 weeks) after the liver biopsies (see
Schedule of Activities). Prior to the procedure, the participant’s wellbeing will be checked and
leukapheresis will only be offered if there is no clinical reason against it. If a participant has had a
recent febrile illness, the leukapheresis should be postponed until body temperature is normal for
at least 72 hours.
The leukapheresis procedure should mainly  follow local standard procedures. Additional
guidelines will be provided via a separate manual in order to standardize this process across sites.
One leukapheresis session is expected to last between 1.5 - 5 hours.
During the procedure, the participant will receive intravenous saline infusions and citrate-based
anticoagulant. Use of heparin for anticoagulation  is not allowed. A specialized leukapheresis
trained research nurse or physician  will be in attendance and in charge of the participant’s
immediate medical care to monitor the leukapheresis.
After completion of the leukapheresis procedure, participants will stay at the site for at least
30 minutes to monitor for any relevant safety events. Additional safety procedures may be
performed at the discretion of the site staff. Participants are advised to refrain from exercise and
strenuous activities for 3 day after the leukapheresis visit.
8.4. 
Safety Assessments
Safety and tolerability will be assessed throughout the study from the time that the ICF is signed
until completion of the last study-related activity, which may include contact for follow-up of
safety. The evaluations of safety and tolerability will include monitoring of (S)AEs, physical
examinations (including body weight), vital signs measurements, triplicate 12-lead ECGs, and
clinical laboratory tests (including hematology, blood biochemistry, blood coagulation, urinalysis,
urine chemistry, and renal biomarkers) at predefined time points as specified in the Schedule of
Activities. Any clinically relevant changes occurring during the study must be recorded on the
Adverse Event section of the CRF.
Adverse events will be reported and followed by the investigator as specified in Section 8.5 and
Section 10.4, Appendix 4, Adverse Events: Definitions and Procedures for Recording, Evaluating,
Follow-Up, and Reporting.


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Specific toxicity management plans in line with the known pharmacological profile of the study
intervention (and the drug classes) evaluated in this study are implemented (Sections 8.5.6 and
8.5.7).
Any clinically significant abnormalities persisting at the end of the study/early withdrawal will be
followed by the investigator until resolution or until a clinically stable condition is reached.
Details regarding the IFLEP are provided in Section 9.6 and in the Committees Structure in
Section 10.3, Appendix 3, Regulatory, Ethical, and Study Oversight Considerations.
8.4.1. 
Physical Examinations
A complete physical examination (including height [at screening only], body weight, skin
examination, and other body systems) will be performed at screening, Week 24, and Week 48. A
symptom-directed physical examination (including body weight) will be performed at the time
points indicated in the Schedule of Activities.
A complete physical examination includes the following: general appearance, eyes, ears, nose,
throat, cardiovascular system, respiratory system, gastro-intestinal system, head, neck, thyroid,
and skin and mucous membranes. A neurological and musculoskeletal examination will be
performed, as well as an examination of the lymph nodes. Body weight and temperature will be
measured. Height will be measured at the screening visit only.
8.4.2. 
Vital Signs
Body temperature, pulse rate, and supine SBP and DBP will be assessedat the time points indicated
in the Schedule of Activities.
Blood pressure and pulse rate measurements will be assessed with a completely automated device.
Manual techniques will be used only if an automated device is not available.
Blood pressure and pulse/heart rate measurements should be preceded by at least 5 minutes of rest
in a quiet setting without distractions (eg, television, cell phones).
Clinically relevant abnormalities in vital signs are defined in Section 10.7, Appendix 7,
Cardiovascular Safety Abnormalities.
8.4.3. 
Electrocardiograms
Twelve-lead triplicate ECGs will be collected at the time points indicated in the Schedule of
Activities and when clinically indicated.
During the collection of ECGs, participants should be in a quiet setting without distractions (eg,
television, cell phones). Participants should rest in a supine position for at least 5 minutes before
ECG collection and should refrain from talking or moving arms or legs.


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At each time point at which triplicate ECGs are required, 3 individual ECG tracings should be
obtained as closely as possible in succession, but no more than 2 minutes apart. The full set of
triplicates should be completed in less than 10 minutes.
Evaluation of the triplicate 12-lead ECGs will be based on the mean value of the triplicate
parameters.
All ECGs will be read centrally. Only on Day 1, pre-dose ECG assessment will also be done locally
on-site. Preferably, all ECGs will be read and interpreted under supervision of one and the same
qualified person.
Clinically relevant abnormalities in ECG are defined in Section 10.7, Appendix 7, Cardiovascular
Safety Abnormalities.
8.4.4. 
Clinical Safety Laboratory Assessments
Blood samples for serum chemistry and hematology and a urine sample for urinalysis will be
collected as noted in Section 10.2, Appendix 2, Clinical Laboratory Tests. The investigator must
review the laboratory results, document this review, and record any clinically relevant changes
occurring during the study in the adverse event section of the CRF. The laboratory reports must be
filed with the source documents.
Participants need to have fasted for at least 10 hours before biochemistry samples are taken for
measurement of phosphate, calcium, creatinine, and lipids. Participants are to bring their oral study
intervention with them to each study visit and have that day’s intake at the site.
In case a grade 3 or grade 4 laboratory abnormality occurs, that is considered to be clinically
significant by the investigator, a confirmatory test must be performed preferably within 48 hours
but no later than 72 hours after the results have become available.
For this study, the laboratory abnormality of cholesterol increase is identified as laboratory
abnormality of interest.
Note: cholesterol increase is a laboratory abnormality of interest specific for JNJ-6379, which was
part of the study intervention up to Protocol Amendment 4. Because participants who were
enrolled before Protocol Amendment 5 was in effect, also received JNJ-6379 as part of their study
intervention, monitoring of cholesterol increases will be continued.
8.5. 
Adverse Events and Serious Adverse Events
Special attention will be paid to those participants who discontinue the study for an AE, or who
experience an AE of at least grade 3, or an SAE. The grades are based on the DAIDS Toxicity
Grading Scale (Section 10.9, Appendix 9, DAIDS Table).
Timely, accurate, and complete reporting and analysis of safety information from clinical studies
are crucial for the protection of participants, investigators, and the sponsor, and are mandated by
regulatory agencies worldwide. The sponsor has established Standard Operating Procedures in


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conformity with regulatory requirements worldwide to ensure appropriate reporting of safety
information; all clinical studies conducted by the sponsor or its affiliates will be conducted in
accordance with those procedures.
Adverse events will be reported by the participant (or, when appropriate, by a caregiver, surrogate,
or the participant's legally acceptable representative) for the duration of the study.
For further details on AEs and SAEs (Definitions and Classifications; Attribution Definitions;
Severity Criteria; Special Reporting Situations; Procedures) as well as product quality complaints,
refer to Section 10.4, Appendix 4, Adverse Events: Definitions and Procedures for Recording,
Evaluating, Follow-Up, and Reporting.
8.5.1. 
Time Period and Frequency for Collecting Adverse Event and Serious
Adverse Event Information
All Adverse Events
All adverse events and special reporting situations, whether serious or non-serious, will be reported
from the time a signed and dated ICF is obtained until completion of the participant's last study-
related procedure, which may include contact for follow-up of safety. SAEs, including those
spontaneously reported to the investigator within 30 days after the last dose of study intervention,
must be reported using the SAE Form. The sponsor will evaluate any safety information that is
spontaneously reported by an investigator beyond the time frame specified in the protocol.
Serious Adverse Events
All SAEs occurring during the study must be reported to the appropriate sponsor contact person
by study-site personnel immediately and within 24 hours of their knowledge of the event.
Information regarding SAEs will be transmitted to the sponsor using the SAE Form, which must
be completed and signed by a physician from the study site, and transmitted to the sponsor within
24 hours. The initial and follow-up reports of a SAE should be made by facsimile (fax).
8.5.2. 
Method of Detecting Adverse Events and Serious Adverse Events
Care will be taken not to introduce bias when detecting AEs or SAEs. Open-ended and nonleading
verbal questioning of the participant is the preferred method to inquire about adverse event
occurrence.
Solicited Adverse Events
Solicited AEs are predefined local (at the injection site) for which the participant is specifically
questioned. Information on ISRs (Section 8.5.6.1) will be solicited.
Unsolicited Adverse Events
Unsolicited adverse events are all adverse events for which the participant is not specifically
questioned.


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8.5.3. 
Follow-up of Adverse Events and Serious Adverse Events
Adverse events, including pregnancy, will be followed by the investigator as specified in
Section 10.4, Appendix 4, Adverse Events: Definitions and Procedures for Recording, Evaluating,
Follow-up, and Reporting.
8.5.4. 
Regulatory Reporting Requirements for Serious Adverse Events
The sponsor assumes responsibility for appropriate reporting of adverse events to the regulatory
authorities. The sponsor will also report to the investigator (and the head of the investigational
institute where required) all suspected unexpected serious adverse reactions (SUSARs). The
investigator (or sponsor where required) must report SUSARs to the appropriate Independent
Ethics Committee/Institutional Review Board (IEC/IRB) that approved the protocol unless
otherwise required and documented by the IEC/IRB.
8.5.5. 
Pregnancy
All initial reports of pregnancy in female participants or partners of male participants must be
reported to the sponsor by the study-site personnel within 24 hours of their knowledge of the event
using the appropriate pregnancy notification form. Abnormal pregnancy outcomes (eg,
spontaneous abortion, fetal death, stillbirth, congenital anomalies, ectopic pregnancy) are
considered SAEs and must be reported using the SAE Form. Any participant who becomes
pregnant during the study must discontinue further investigational intervention (JNJ-3989).
Follow-up information regarding the outcome of the pregnancy and any postnatal sequelae in the
infant will be required.
8.5.6. 
Adverse Events of Special Interest
Events of Special Interest are significant AEs that are judged to be of special interest because of
clinical importance, known class effects or based on nonclinical signals. Events of Special Interest
that will be carefully monitored during the study include ISRs, ALT/AST elevations, renal
complications, hematological abnormalities, and events related to cholesterol increase
(Section 8.4.4, Clinical Safety Laboratory Assessments). In addition, the following toxicities will
also be carefully monitored: rash and acute systemic allergic reactions.
For participants reporting ALT/AST elevations, rash, ISRs, acute systemic allergic reactions, renal
complications, and hematological abnormalities as specified in the DAIDS Toxicity Grading Scale
(see Section 10.9, Appendix 9, DAIDS Table), the following should be done.
Note: renal complications and cholesterol increase are AESIs specific for JNJ-6379, which was
part of the study intervention up to Protocol Amendment 4 and has been removed with the
implementation of Protocol Amendment 5. Because participants who were enrolled before
Protocol Amendment 5 was in effect, also received JNJ-6379 as part of their study intervention,
the AESIs have not been revised with the removal of JNJ-6379. For all participants having received
at least one dose of JNJ-6379, renal safety monitoring will be continued.


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8.5.6.1. 
Injection Site Reactions
At the time points specified in the Schedule of Activities or at an unscheduled visit if needed, an
evaluation of the injection site will be performed based on participant’s description and/or physical
examination. Evaluations will be recorded in the source documents and will include at a minimum
the time of occurrence, time of resolution and a description of the abnormality including its
maximal diameter. For each ISR, information on pain, erythema, induration and pruritus should
be obtained as specified in the DAIDS scale (see Section 10.9, Appendix 9, DAIDS Table).
All ISRs (including ISRs below grade 1) should be recorded in the special events section of the
CRF.
Digital pictures will be taken when considered appropriate; all efforts should be made to collect
images in case of grade 3 and 4 ISRs. Digital pictures will only be taken and collected from
participants who consent separately to this component of the study. If digital pictures are required,
they should be de-identified and provided to the sponsor.
8.5.6.2. 
Intervention-emergent ALT/AST Elevations
Elevated liver enzyme activity can be triggered by the underlying HBV disease as well as by the
study intervention.
Management of intervention-emergent ALT/AST elevations is presented graphically  in
Section 10.6, Appendix 6, Intervention-emergent ALT/AST Elevations, and is described below.
Any intervention-emergent elevation of ALT and/or AST ≥3x ULN and ≥3x nadir (ie, lowest value
during study participation) should trigger an assessment of confounding factors (alcohol intake,
change in concomitant medication, and comorbidities) and should trigger a confirmatory study
visit to repeat laboratory testing of ALT, AST, ALP, AFP, bilirubin (total and direct), INR,
albumin, and HBV DNA. Additional tests should be considered based on clinical judgement (refer
to Section 10.6, Appendix 6, Intervention-emergent ALT/AST Elevations). The confirmatory visit
should be scheduled as soon as possible, preferably within 7 days of the receipt of the initial
ALT/AST results. In case the repeat laboratory testing shows an isolated ALT/AST elevation (ie,
with stable albumin, bilirubin [total and direct], and INR) the participant may continue study
intervention. In case of confirmed ALT elevation >1,000 U/Land ≥3x the baseline value, JNJ-3989
(and PegIFN-α2a, if applicable) should be discontinued. In both cases, NA treatment should be
continued. The participant will be monitored on a weekly basis (laboratory testing of ALT, AST,
ALP, AFP, bilirubin [total and direct], INR, albumin, and HBV DNA) until ALT and AST levels
have returned to <5x ULN and HBV DNA is <20,000 IU/mL.
If the ALT and/or AST level is ≥3x ULN and ≥3x nadir and is associated with any of the following
laboratory results or clinical symptoms:
 
INR ≥1.5, OR
 
direct bilirubin >1.5x ULN, OR
 
serum albumin <3.0 g/dL, OR


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 
ascites, hepatic encephalopathy, or liver-related symptoms (eg, severe fatigue, nausea,
vomiting, right upper quadrant pain in the absence of an alternative medical explanation), OR
 
other indication of reduced liver function
the participant should discontinue JNJ-3989 (and PegIFN-α2a, if applicable) and should be
monitored on a weekly basis or as per good clinical practice until ALT and AST levels have
returned to <5x ULN and HBV DNA is <20,000 IU/mL and, if present, liver-related symptoms
have improved. NA treatment should be continued. Additional tests should be considered based
on clinical judgement (refer to Section 10.6, Appendix 6, Intervention-emergent ALT/AST
Elevations).
In case of prolonged ALT elevation >3x ULN AND >2x nadir, which lasts at least 12 weeks, the
decision to continue JNJ-3989 and/or PegIFN-α2a should be based upon virologic parameters (eg,
HBsAg, HBV DNA) and should be made in consultation with the sponsor.
PegIFN-α2a may need to be discontinued in clinically significant cases of ALT increase or in
combined increase of ALT and direct bilirubin. Refer to the prescribing information for PegIFN-
α2a.41,42
The NA re-treatment criteria during follow-up are presented in Section 6.6.2.
8.5.6.3. 
Complications From Liver Biopsy
Participants should be closely monitored for liver biopsy complications. Infection and internal
bleeding and/or puncture of other internal organs (gall bladder, lung, intestine or kidney) can lead
to serious complications (uncommon 1 in 1000 to 1 in 100) including the need for emergency
surgery, blood transfusion or removal of organs. Deaths directly related to liver biopsyoccur rarely
(approximately 1 in every 10,000 biopsies). Criteria for participant selection and laboratory
assessments are in place to minimize these risks. Additional investigations can be performed at the
investigator’s discretion. Participants must be treated as clinically appropriate.
8.5.6.4. 
Renal Complications
If renal complications develop, participants should be closely monitored for disturbances in
creatinine clearance. Additional investigations can be performed at the investigator’s discretion.
Participants must be treated as clinically appropriate.
Participants who develop confirmed grade 3 or 4 eGFRcr abnormalities with reduction  from
baseline by at least 10 mL/min/1.73 m2 will change their NA from tenofovir disoproxil to ETV or
TAF (if the patient was receiving tenofovir disoproxil), according to the prescribing information.
If the abnormality persists despite change of NA or if the patient is not receiving tenofovir
disoproxil, he or she will permanently discontinue the intake of JNJ-3989 (and PegIFN-α2a, if
applicable) if the abnormality is considered at least possibly related to JNJ-3989, and should be
followed appropriately until resolution of AE or toxicity. Rechallenge is not allowed.
For all participants having received at least one dose of JNJ-6379, renal safety monitoring will be
continued.


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8.5.6.5. 
Hematologic Abnormalities
Mild thrombocytopenia was observed in recently conducted non-clinical toxicology studies with
the combination of JNJ-3989 and JNJ-6379. In addition, in a 3-month combination study with
80 rats, 1 rat developed pancytopenia related to bone marrow depletion after 23 days of dosing.
Previously, in a 9-month dog study in 24 dogs treated with JNJ-6379 alone, pancytopenia which
correlated with a marked increase in plasma cell-like cells in the bone marrow was observed in
1 dog after 60 days of dosing.
No thrombocytopenia or pancytopenia has been observed in the ongoing JADE study
(56136379HPB2001) investigating JNJ-6379/Placebo with or without NA treatment. All 232
participants have completed at least 24 weeks of study intervention. In a Phase 1 study with JNJ-
3989, mild (Grade 1) transient thrombocytopenia was observed in 6 out of 84 participants
receiving 3 SC injections of JNJ-3989 alone over a period of up to 12 weeks with background of
NA. The transient thrombocytopenia was not considered clinically significant. No
thrombocytopenia or pancytopenia was observed in 12 participants when JNJ-3989 and JNJ-6379
were given in combination over a 12-week period.
Based on the non-clinical findings, any relevant abnormalities in hematologic parameters will be
carefully monitored as described below:
 
Platelet counts: <100, 000 cells/mm3 (at least Grade 2 [DAIDS]) or <100 GI/L or reduction
from baseline by at least 50% baseline
 
Hemoglobin: Decrease from baseline of at least 2 g/dL from baseline or at least Grade 2
(DAIDS)
 
Reticulocyte count: Reduction to <0.5% of the RBC count
 
Neutrophil count: Treatment-emergent reduction to at least Grade 2 (DAIDS)
In case any one of the above criteria are met, a confirmatory visit should be scheduled as soon as
possible, preferably within 7 days of the receipt of the initial results. Confirmation of the results
will trigger weekly or biweekly  (every other week) unscheduled visits until improvement or
stabilization of the respective parameter(s). Stabilization is defined as no further significant
reduction over two consecutive visits.
In case of confirmed Grade 3 or Grade 4 hematologic abnormalities, discontinuation of JNJ-3989
(and PegIFN-α2a, if applicable]) should be considered. In case of discontinuation, NA treatment
should be continued.
8.5.7. 
Other Toxicities
8.5.7.1. 
Rash
Participants should be informed that they should contact their doctor immediately when they notice
any generalized skin reaction. This skin reaction should be evaluated in the clinic the same day (if
possible) or the next day.


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All rash events should be captured in the special events section of the CRF. A set of separate Rash
pages will be completed in case of a rash event.
Monitoring of the evolution of rash events will be performed as described in Table 6 in
Section 10.5, Appendix 5, Rash Management.
When safety blood samples are drawn as per the rash management guidelines, these should be
processed by the local laboratory. The following parameters will need to be tested: AST, ALT,
sedimentation rate, complete blood cell count (including hemoglobin, hematocrit, RBC count,
WBC count, differential count [neutrophils, lymphocytes, monocytes, eosinophils, and basophils],
and platelet count), and creatinine. The values of the local laboratory assessments need to be
transcribed in the CRF by the study site personnel.
The participant may be treated symptomatically until the rash resolves. Oral antihistamines (eg,
cetirizine, levocetirizine) and/or topical corticosteroids may provide symptomatic relief but
effectiveness of these measures has not been established. If systemic corticosteroids exceeding
5 mg of prednisolone equivalent/day are required for treatment of rash, JNJ-3989 (and
PegIFN-α2a, if applicable) needs to be permanently discontinued. NA treatment can be continued.
If the rash is considered to be most likely due to concomitant illness or non-study interventions,
standard management, including discontinuation of the likely causative agent, should be
undertaken.
8.5.7.2. 
Acute Systemic Allergic Reactions
Grade 1 (Localized Urticaria [Wheals] With no Medical Intervention Indicated)
Participants may continue the intake of study interventions.
Cetirizine, levocetirizine, topical corticosteroids or antipruritic agents may be prescribed.
Participants should be advised to contact the investigator immediately if there is any worsening of
the acute systemic allergic reaction.
Grade 2 (Localized Urticaria With Intervention Indicated, or Mild Angioedema With no
Intervention Indicated)
Participants may continue the intake of study interventions.
Cetirizine, levocetirizine, topical corticosteroids or antipruritic agents may be prescribed.
Participants should be advised to contact the investigator immediately if there is any worsening of
the acute systemic allergic reaction, in which case the participant will permanently discontinue the
intake of JNJ-3989 (and PegIFN-α2a, if applicable). Rechallenge is not allowed. The participant’s
NA treatment may be discontinued based on investigator judgement in consultation with the
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Grade 3 (Generalized Urticaria, Angioedema With Intervention Indicated, or Symptoms of
Mild Bronchospasm) and Grade 4 (Acute Anaphylaxis, Life-Threatening Bronchospasm, or
Laryngeal Edema)
Participants will permanently discontinue the intake of JNJ-3989 (and PegIFN-α2a, if applicable).
Rechallenge is not allowed. The participant’s NA treatment may be discontinued based on
investigator judgement in consultation with the sponsor.
Participants will be treated as clinically appropriate. Participants should be followed until
resolution of the AE and standard management should be undertaken.
8.6. 
Treatment of Overdose
For this study, any dose of JNJ-3989 greater than the protocol-specified dose (refer to Section 6.1)
will be considered an overdose; any dose of NA (ETV, tenofovir disoproxil, or TAF) and PegIFN-
α2a greater than the prescribed dose will be considered an overdose. The sponsor does not
recommend specific therapeutic intervention for an overdose.
In the event of an overdose, the investigator or treating physician should:
 
Contact the Medical Monitor immediately.
 
Closely monitor the participant for AE/SAE and laboratory abnormalities.
 
Obtain a plasma sample for PK analysis as soon as possible from the date of the last dose of
study intervention if requested by the Medical Monitor (determined on a case-by-case basis).
 
Document the quantity of the excess dose as well as the duration of the overdosing in the CRF.
Decisions regarding dose interruptions or modifications will be made by the investigator in
consultation with the Medical Monitor based on the clinical evaluation of the participant.
8.7. 
Pharmacokinetics
Plasma samples will be used to evaluate the PK of JNJ-3989 (ie, JNJ-3976 and JNJ-3924), and,
optionally, JNJ-6379, NA  and/or PegIFN-α2a, as applicable. Serum collected for PK may
additionally be used to evaluate safety or efficacy aspects that address concerns arising during or
after the study period. Genetic analyses will not be performed on these samples. Participant
confidentiality will be maintained.
8.7.1. 
Evaluations
Venous blood samples will be collected for measurement of plasma concentrations of JNJ-3976,
JNJ-3924, NA (ETV, TAF, or tenofovir) and PegIFN-α2a, as applicable, at time points specified
in the Schedule of Activities. Bioanalysis of NA and PegIFN-α2a is optional at the discretion of
the sponsor. Bioanalysis of JNJ-6379 may also be done on samples collected from participants
who received JNJ-6379 up to Protocol Amendment 4.
All participants will have sparse PK sampling on Day 1 and at Weeks 4, 12, and 24 (and at early
withdrawal). All participants who consent to participate in the intensive PK substudy (optional)


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will undergo intensive PK sampling at Week 4. If necessary (eg, for operational reasons), this visit
may be scheduled at Week 8, 12, or 16.
8.7.2. 
Analytical Procedures
Pharmacokinetics
Plasma samples will be analyzed to determine concentrations of JNJ-3976 and JNJ-3924 using a
validated, specific, and sensitive liquid chromatography-fluorescence hybridization method under
the supervision of the sponsor.
At the sponsor’s discretion, plasma samples may be analyzed to determine concentrations of
JNJ-6379 and/or NA and/or PegIFN-α2a using a validated, specific, and sensitive liquid
chromatography-mass spectrometry method under the supervision of the sponsor.
Plasma PK samples may be stored for future exploratory analysis of protein binding or the
metabolite profile. Genetic analyses will not be performed on these plasma samples. Participant
confidentiality will be maintained.
8.7.3. 
Pharmacokinetic Parameters and Evaluations
Parameters
Plasma concentration-time data for JNJ-3989 (ie, JNJ-3976 and JNJ-3924) and, optionally,
JNJ-6379, NA and/or PegIFN-α2a will be analyzed via noncompartmental methods for all
participants who underwent intensive PK sampling. The main PK parameter will be area under the
plasma concentration-time curve over 24 hours (AUC24h), Cmax, tmax, plasma trough concentration
(C0h), plasma concentration at the end of the dosing interval (τ) (Cτ), and minimum plasma
concentration (Cmin). Additional exposure parameters may be calculated if applicable.
Data from this study may be combined with data from a selection of Phase 1 and 2 studies via
population PK modelling. Individual estimates of PK parameters may be generated from the
population PK analysis for potential use in exposure-response analysis.
8.8. 
Pharmacokinetics/Pharmacodynamics
Relationships of individual PK parameters for JNJ-3976, JNJ-3924, and, optionally, JNJ-6379,
NA and/or PegIFN-α2a, with selected liver and blood biomarkers, and/or with selected safety
endpoints may be evaluated.
8.9. 
Host Genetics
A pharmacogenomic blood sample will be collected (preferably at baseline) to allow for the
identification of genetic factors that may influence the efficacy, safety, or PK of the study
intervention, to identify genetic factors associated with HBV infection, or to develop assays for
the study intervention or HBV infection.
A blood sample will be taken for HLA typing as indicated in the Schedule of Activities. In addition,
host DNA blood samples to allow for epigenetic analyses will be collected.


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8.10. Host Biomarkers
The study includes collection of blood samples for exploratory analysis of host blood biomarkers
at the host RNA, protein, and cell level. Sampling will be performed in all participants at the time
points indicated in the Schedule of Activities.
Samples can only be used for research related to study intervention or HBV infection or may be
used to develop tests/assays related to study intervention or HBV infection.
Blood samples will be taken at the time points indicated in the Schedule of Activities which can
be used to explore immunogenicity of JNJ-3989. The emergence of antibodies to JNJ-3989
(antidrug antibodies) might be analyzed using assays such as an enzyme-linked immunosorbent
assay.
8.11. Medical Encounters
Eventual medical encounters will be collected in the CRF by the investigator and study site
personnel for all participants throughout the study.
9. 
STATISTICAL CONSIDERATIONS
Statistical analysis will be done by the sponsor or under the authority of the sponsor. A general
description of the statistical methods to be used to analyze the efficacy and safety data is outlined
below. Specific details will be provided in the Statistical Analysis Plan.
The primary analysis will be performed at the time when all participants have completed Week 48
or discontinued earlier. The final analysis will be performed when all participants have completed
the last study visit (Follow-up Week 48) or discontinued earlier. For the IAs, please refer to
Section 9.5.
9.1. 
Statistical Hypotheses
As this is an exploratory study, no hypothesis will be tested.
9.2. 
Sample Size Determination
This study aims to enroll 18 to 24 participants in total across Panels 1 and 2, ie, 8 to 12 participants
per study panel.
Due to the exploratory nature of the study, the sample size was determined based on clinical and
feasibility considerations related to the liver biopsy procedures performed multiple times during
the study, rather than a formal statistical calculation. Nevertheless, a sample size of 8 to 12
participants each in Panel 1 and 2 is considered sufficient to provide adequate precision of the
estimate of the primary endpoint (change from baseline to Week 40 in the proportion of HBsAg-
positive hepatocytes) as estimated by the 80% confidence interval (CI).
For the estimation of the absolute change in the proportion of HBsAg-positive hepatocytes from
baseline to Week 40 for the overall study population (Panels 1 and 2 combined), the following
assumptions were made. Assuming an absolute reduction of 70% in Panel 1 (75% at baseline


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versus 5% at Week 40) and 29% in Panel 2 (30% at baseline versus to 1% at Week 40), and
assuming an inter-subject variability of the change equal to 0.5 on the logit scale in both panels, a
binomial model40 including visit as covariate with normal random effects provides an expected
width of the 80% CI of 16.7% for N 24, a width of 17.9% for N 20, and a width of 20.3% for
N 16. The point estimates (two-sided 80% CI) are 50.8% (42.5%; 59.1%) with N 24, 50.7%
(41.8%; 59.7%) with N 20, and 50.6% (40.5%; 60.8%) with N 16.
For the between-panel difference in the absolute reduction in the proportion of HBsAg-positive
hepatocytes from baseline to Week 40 using the binomial model described above augmented with
panel as an additional covariate and the same inter-subject variability, the estimated width of the
two-sided 80% CI around the difference (Panel 1 
Panel 2) is 17.6% for N 24 (12 per panel),
19.3% for N 20 (10 per panel), and 21.2% for N 16 (8 per panel). The point estimates (80% CI)
are 40.4% (31.5%; 49.2%) for N 24, 39.2% (29.6%; 48.9%) for N 20, and 39.4% (28.8%; 50.0%)
for N 16.
In addition, N 20 would also be sufficient to provide adequate precision for a between-panel
difference in the relative change from baseline of at least 26% in case of large inter-subject
variability.
Assuming a drop rate of 20%, the sample size will be therefore set to 12 participants per panel for
Panels 1 and 2.
9.3. 
Populations for Analyses
For purposes of analysis, the following populations are defined:
Population 
Description
Randomized 
All participants who were randomized in the study
Enrolled 
All participants who were enrolled in the study
Intent-to-treat 
(ITT) 
All participants who were either randomly assigned or enrolled to an intervention arm and
received at least 1 dose of study intervention. Participants will be analyzed according to the
study intervention they were randomly assigned or enrolled to.
Safety  
All participants who received at least 1 dose of study intervention. Participants will be
analyzed according to the study intervention they actually received.
9.4. 
Statistical Analyses
The Statistical Analysis Plan will include a more technical and detailed description of the statistical
analyses described in this section. This section is a summary of the planned statistical analyses of
the most important endpoints including primary and key secondary endpoints.
Given the exploratory nature of the study and the limited sample size per panel, no statistical
testing will be performed. All data will be summarized descriptively including 80% confidence
intervals as appropriate.
9.4.1. 
Analysis of Efficacy and Antiviral Activity
To evaluate the efficacy and antiviral activity in blood and liver, the primary analysis set will be
the ITT population. Efficacy and antiviral activity will be assessed for participants in Panels 1


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and 2. For all efficacy and antiviral activity endpoints, unless specified otherwise, the following
comparisons will be addressed:
1. Overall population, pooling all participants regardless of panels.
Between Panels 1 and 2: HBeAg-positive patients who are not currently being treated
versus HBeAg-negative patients being virologically suppressed by NA treatment.
All efficacy summaries will be presented with descriptive statistics, overall and by study panel.
If the endpoint is continuous, the descriptive statistics will include the number of participants,
mean, standard deviation (SD), median, range, and interquartile range. If the endpoint is binary or
categorical, the frequency distribution with the number and percentage of participants in each
category will be calculated.
Graphic displays will also be used to summarize the data and to visualize trends by study panel.
Where applicable, additional specifics for analyses of primary, secondary, and exploratory
endpoints are detailed below.
9.4.1.1. 
Analysis of the Primary Endpoint
The primary endpoint is the change between baseline and on-treatment liver biopsy (Week 40) in
terms of the proportion of HBsAg positive hepatocytes. The primary endpoint will be summarized
descriptively and modelled with an appropriate statistical model accounting for the number of
hepatocytes sampled in each liver biopsy. The change from baseline will be summarized for the
overall study population and within each panel, together with the between-panel difference in the
change..
No imputation rule will be applied for the analysis on the ITT population since only complete
cases will be considered. In addition, the treatment policy strategy will be followed to account for
the occurrence of intercurrent events, such as treatment discontinuation prior to Week 40, ie, all
biopsies collected at Week 40 will be used, regardless of occurrence of treatment discontinuation
prior to Week 40. This strategy is supported by the small sample size, the exploratory nature of
the study and ethical considerations.
In addition, a sensitivity analysis on the ITT population will be combining a treatment policy
strategy with the Baseline Observation Carried Forward (BOCF) approach.
9.4.1.2. 
Analysis of Secondary Endpoints
Secondary endpoints will be analyzed on the ITT population.
Changes in Intrahepatic Immune Response
Variation in proportion of major cell populations, such as but not limited to CD45+ T-cells, CD4+
T-cells, CD8+  T-cells, Natural Killer cells, and dendritic cells, defined by single cell


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transcriptomics (in FNABs) and immunofluorescence staining (in core needle biopsies), will be
assessed at Week 40 and compared to baseline, overall and by study panel.
The functional characterization of major cell populations will be assessed by transcriptomics
and/or proteomics for major cell populations of interest at Week 40 and compared to baseline
similarly.
Changes in Intrahepatic Viral Nucleic Acids and Proteins
Changes from baseline in cccDNA level and/or transcriptional activity will be assessed using the
general considerations outlined above.
Furthermore, the difference in the level of infected hepatocytes at baseline will be assessed by
comparing cccDNA level and/or transcriptional activity.
Analyses of other viral markers will be performed descriptively. Statistical analyses will depend
on the assay technology applied and the scope of the analyses.
9.4.1.3. 
Analysis of Exploratory Endpoints
Exploratory endpoints will be analyzed on the ITT population.
The association between intrahepatic markers and blood (immune and viral) markers will be
explored both at baseline and on-treatment by study panel using graphical displays and relevant
correlation coefficients.
Impact of baseline characteristics on selected efficacy variables and their association with
intrahepatic and blood markers will also be evaluated using similar methods.
Identification of markers (either intrahepatic or blood) that could potentially be associated with
selected efficacy variables (such as decrease in blood HBsAg levels, intrahepatic cccDNA levels
or any other relevant variables) will be conducted. Impact of treatment on different blood and
hepatic markers will also be evaluated.
9.4.2. 
Safety Analyses
All safety analyses will be made on the Safety Population (Section 9.3).
Safety will be evaluated by means of descriptive summaries of AEs including AEs of special
interest to any of the study interventions, clinical laboratory tests, ECGs, vital signs, and physical
examinations. The safety analysis will be done by study phase. Results will be presented in tabular
format and/or graphically over time, as appropriate.
Adverse Events
The verbatim terms used in the CRF by investigators to identify AEs will be coded using the
Medical Dictionary for Regulatory Activities (MedDRA). Intervention-emergent AEs are AEs
with onset during the intervention phase or that are a consequence of a pre-existing condition that
has worsened since baseline. All reported intervention-emergent AEs will be included in the


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analysis. For each AE, the percentage of participants who experience at least 1 occurrence of the
given event will be summarized.
Summaries, listings, datasets, or participant narratives may be provided, as appropriate, for those
participants who die, who discontinue intervention due to an AE, or who experience a severe or a
serious AE.
Adverse Events Related to the Applied Study Procedures
Summaries, listings, datasets, or participant narratives will be provided, as appropriate, for those
enrolled participants who die, or who experience an AE or a severe or a serious AE related to the
applied study procedures.
All AE’s linked to the study procedure will be evaluated in conjunction with other systemic
symptoms and laboratory abnormalities: information on time of onset, duration of events, time to
resolution, concomitant therapies, and relationship to study procedures (eg, liver biopsies, blood
collection and leukapheresis) will be summarized and described in the report.
Clinical Laboratory Tests
Laboratory data will be summarized by type of laboratory test. Descriptive statistics will be
calculated for each  laboratory analyte at baseline and for observed values and changes from
baseline at each scheduled time point by study phase. A graphical presentation of changes from
baseline over time in selected laboratory tests will be also used.
The laboratory abnormalities will be determined according to the criteria specified in the DAIDS
Toxicity Grading Scale (see Section 10.9, Appendix 9, DAIDS Table) or in accordance with the
normal ranges of the clinical laboratory if no gradings are available. The number and percentage
of the participants who experience (worst) laboratory abnormalities will be tabulated by
intervention arm and study phase. Shifts in toxicity grades will be tabulated by study phase.
Electrocardiogram
Electrocardiogram data will be summarized by ECG  parameter. Descriptive statistics will be
calculated at baseline and for observed values and changes from baseline at each scheduled time
point. Frequency tabulations of the abnormalities will be made.
The ECG variables that will be analyzed are heart rate, PR interval, QRS interval, QT interval, and
QTcF.13
Descriptive statistics of QTc intervals and changes from baseline will be summarized at each
scheduled time point. The percentage of participants with QTc interval >450 milliseconds,
>480 milliseconds, or >500 milliseconds will be summarized, as will the percentage of participants
with QTc interval increases from baseline >30 milliseconds or >60 milliseconds. Shifts in QTc
interval categories will be tabulated by study phase.


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All clinically relevant abnormalities in ECG waveform that are changes from the baseline readings
will be reported (eg, changes in T-wave morphology or the occurrence of U-waves.
Vital Signs
Vital signs including temperature, pulse rate, and supine blood pressure (SBP and DBP) will be
summarized over time, using descriptive statistics and/or graphically. The percentage of
participants with values beyond clinically important limits will be summarized.
Physical Examinations
Physical examination findings will be summarized at each scheduled time point. Descriptive
statistics will be calculated at baseline and for observed values and changes from baseline at each
scheduled time point. Frequency tabulations of the abnormalities will be made.
9.4.3. 
Other Analyses
Pharmacokinetic Analyses
Descriptive statistics (number of participants, mean, SD, coefficient of variation, geometric mean,
median, minimum, and maximum) will be calculated for the plasma concentrations of JNJ-3976,
JNJ-3924, and optionally, JNJ-6379, NA and/or PegIFN-α2a, as applicable, and for the derived
plasma PK parameters (noncompartmental analysis).
Special attention will be paid to the plasma concentrations and PK parameters of those participants
who discontinued the study for an AE, or who experienced an AE ≥Grade 3 or an SAE.
For each participant with intensive PK sampling, plasma concentration-time data of JNJ-3976,
JNJ-3924, and/or JNJ-6379, and/or NA and/or PegIFN-α2a will be graphically presented.
Similarly, graphs of the mean plasma concentration-time profiles and overlay graphs with
combined individual plasma concentration time profiles will be produced. Pharmacokinetic
parameters will be subjected to an exploratory graphical analysis, including various
transformations, to get a general overview.
Population PK analysis of plasma concentration-time data of JNJ-3976, JNJ-3924, and optionally,
JNJ-6379, NA and/or PegIFN-α2a may be performed using nonlinear mixed-effects modeling.
Data may be combined with those from Phase 1 and/or 2 studies to support a relevant structural
model. Available baseline characteristics (eg, demographics, laboratory variables, genotypes) may
be included in the model as necessary. Details will be given in a population PK analysis plan and
results of the population PK analysis, if applied, will be presented in a separate report.
Individual estimates of PK parameters may be generated from the population PK analysis for
potential use in exposure-response analysis.


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Pharmacokinetic/Pharmacodynamic Analyses
Relationships of PK parameters for JNJ-3976, JNJ-3924, and optionally, JNJ-6379, NA and/or
PegIFN-α2a with selected efficacy and with selected safety endpoints may  be evaluated and
graphically displayed.
Modeling of key PD parameters (eg, HBsAg, HBV DNA) may be performed using population
PK/PD. If PK/PD modeling of key efficacy endpoints is performed, treatment effect and possible
covariates such as disease progression may be investigated. Other biomarkers may be explored at
the sponsor’s discretion.
Resistance Analysis
The results of HBV viral sequencing will be evaluated by the sponsor virologist. Relevant changes
in  amino acid and/or nucleic acid variations (eg, substitutions) in the HBV genome will be
tabulated and described.
Additional exploratory characterization of the HBV viral sequence and phenotype may be
performed and reported separately.
Pharmacogenomic Analysis
The statistical approach for analyzing the exploratory host DNA research, including epigenetic
analyses, may depend on the objective of the analyses (efficacy, safety, and PK) and possibly
relevant genes at the time of analysis. Analyses will be conducted at the sponsor’s discretion, will
always be under the sponsor’s supervision, and results will be presented either in the clinical study
report or a separate report.
Host Exploratory Biomarker Analysis
Statistical approaches to explore correlations between treatment response/clinical outcome and
blood and liver biomarkers vary and depend on the different data types of the applied technology
platforms, as well as on the extent of observed differences between participants. Analyses will be
conducted at the sponsor’s discretion, will always be under the sponsor’s supervision, and results
will be presented either in the clinical study report or a separate report.
9.5. 
Interim Analysis
Two IAs may be performed: when all participants have completed Week 20 in the intervention
phase (or discontinued earlier) and when they have completed Week 72 in the follow-up phase (ie,
Follow-up Week 24) (or discontinued earlier). These IAs will be performed by the sponsor to
support interactions with health authorities, as well as to supportinternal decisions about additional
studies and/or investigation of other combination regimens.
Both primary and interim analyses will be based on all data available at the predefined cut-off time
points and may include data at later time points for those participants who have reached subsequent
visits.


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9.6. 
Independent Flare Expert Panel
An IFLEP will be appointed for this study. The IFLEP is composed of 3 independent medical
experts with experience and expertise in hepatitis B and its treatment. The IFLEP will monitor
ALT flares and will make recommendations regarding flare management based on an analysis of
aggregate data.
In order to allow for an unbiased assessment, members of the committee will not serve as study
investigators.
Further details on the IFLEP process will be included in the IFLEP charter.


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10. 
SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS
10.1. Appendix 1: Abbreviations and Definitions of Terms
AE 
adverse event
AFP  
alpha-fetoprotein
ALP  
alkaline phosphatase
ALT  
alanine aminotransferase
AST  
aspartate aminotransferase
AUC  
area under the plasma concentration-time curve
AUC0-xh  
area under the plasma concentration-time curve from administration to x h
AUC0-last 
area under the plasma concentration-time curve from administration to last quantifiable sampling
point
AUCτ 
area under the plasma concentration-time curve over the dose interval (tau) at steady-state
AUC∞ 
area under the plasma concentration-time curve to last sampling point from time zero extrapolated
to infinity
bpm  
beats per minute
CAM  
capsid assembly modulator
cccDNA  
covalently closed circular deoxyribonucleic acid
CKD-EPI 
Chronic Kidney Disease Epidemiology Collaboration
CL/F  
total apparent oral clearance
Cmax  
maximum plasma concentration
CRF  
case report form
CT  
computed tomography
CYP  
cytochrome P450
DAIDS  
Division of Acquired Immunodeficiency Syndrome
DBP  
diastolic blood pressure
DDI 
drug-drug interaction
DNA  
deoxyribonucleic acid
EASL 
European Association for the Study of the Liver
ECG  
electrocardiogram
eDC  
electronic data capture
EFD  
embryofetal development
eGFR  
estimated glomerular filtration rate
eGFRcr 
estimated glomerular filtration rate based on serum creatinine
ELISpot 
enzyme-linked immunospot
EOS  
end of study
EOSI 
end of study intervention
ETV  
entecavir
FNAB  
fine needle aspiration biopsy
FSH  
Follicle-stimulating hormone
FU Wx  
Follow-up Week x
GCP  
Good Clinical Practice
GLP  
Good Laboratory Practice
HBc 
hepatitis B core protein
HBcrAg 
hepatitis B core-related antigen
HBe 
hepatitis B e
HBeAg 
hepatitis B e antigen
HBs 
hepatitis B surface
HBsAg 
hepatitis B surface antigen
HBV  
hepatitis B virus
HCC  
hepatocellular carcinoma
HCV  
hepatitis C virus
HDV  
hepatitis D virus
HEV  
hepatitis E virus
HIV-1(-2) 
human immunodeficiency virus type 1 (type 2)
HLA  
human leukocyte antigen
HRT  
hormonal replacement therapy


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IA  
interim analysis
IB  
Investigator’s Brochure
ICF  
informed consent form
ICH  
International Council for Harmonisation of Technical Requirements for Pharmaceuticals for
Human Use
ICMJE 
International Committee of Medical Journal Editors
ICS  
intracellular cytokine staining
IEC  
Independent Ethics Committee
IFLEP  
Independent Flare Expert Panel
IFN  
interferon
IFN-γ 
gamma interferon
IgM  
immunoglobulin M
IL 
interleukin
INR  
International Normalized Ratio
IRB  
Institutional Review Board
ISR  
injection site reaction
ITT  
Intent-to-treat
IU/mL 
International Units Per Milliliter
IWRS  
interactive web response system
LLN  
lower limit of normal
LLOQ  
lower limit of quantification
MoA  
mode of action
MRI 
magnetic resonance imaging
NA  
nucleos(t)ide analog
NOAEL 
no observed adverse effect level
(q)PCR  
(quantitative) polymerase chain reaction
PD 
pharmacodynamic(s)
PegIFN-α2a 
pegylated interferon alpha-2a
PK 
pharmacokinetic(s)
PBMC  
peripheral blood mononuclear cell
pgRNA  
pre-genomic ribonucleic acid
PQC  
Product Quality Complaint
Q4W  
once every 4 weeks
qd 
once daily
QTcF  
QT interval corrected for heart rate according to Fridericia
RBC  
red blood cell
RNA  
ribonucleic acid
RNAi 
ribonucleic acid interference
SAE 
serious adverse event
SBP 
systolic blood pressure
SC 
subcutaneous
SD 
standard deviation
siRNA  
small interfering RNA
SUSAR  
suspected unexpected serious adverse reaction
t1/2term  
terminal half-life
T4 
thyroxine
tmax  
time to reach the maximum plasma concentration
TAF  
tenofovir alafenamide
TEAE 
treatment-emergent adverse event
TNF  
tumor necrosis factor
TSH  
thyroid-stimulating hormone
ULN 
upper limit of normal
WBC  
white blood cell


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Definitions of Terms
Study intervention  
Prior to Protocol Amendment 5: JNJ-73763989 (JNJ-3989), JNJ-56136379 (JNJ-6379) and
NA (either ETV, tenofovir disoproxil, or TAF)
As of Protocol Amendment 5: JNJ-73763989 (JNJ-3989)and NA (either ETV, tenofovir
disoproxil, or TAF)
Functional cure 
HBsAg seroclearance 24 weeks after end of treatment
HBsAg or HBeAg 
seroclearance
HBsAg or HBeAg negativity, respectively, based on the assay used
HBsAg or HBeAg 
seroconversion
HBsAg or HBeAg negativity and anti-HBs or anti-HBe antibody positivity, respectively
Virologic 
breakthrough  
Confirmed on-treatment HBV DNA increase by >1 log10 IU/mL from nadir or confirmed
on-treatment HBV DNA level >200 IU/mL in participants who had HBV DNA level
<LLOQ of the HBV DNA assay
ALT/AST nadir 
Lowest ALT/AST value during study participation




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In case of a positive dipstick result, a urine sample will be set aside for additional
examination of the positive parameter at the central laboratory (eg, quantification as
applicable).
Urine 
Chemistry 
(quantitative 
measurement)
Creatinine 
Sodium  
Phosphate 
Glucose
Protein
Albumin
Renal 
Biomarkers 
Retinol binding protein
Beta-2-microglobulin
Note: These renal biomarkers are to assess proximal renal tubular function.
Other Tests 
 
Serum pregnancy testing for women of childbearing potential at screening.
 
Urine pregnancy testing for women of childbearing potential at the time points
indicated in the Schedule of Activities.
 
Follicle-stimulating hormone (FSH) testing for postmenopausal women at
screening.
 
Testing for hepatitis A, B, C, D, and E virus and HIV-1 and -2 at screening.
 
Testing for HBsAg, HBeAg, HBcrAg, and anti-HBs and anti-HBe antibodies at
the time points indicated in the Schedule of Activities.
 
Determination of coagulation parameters will be performed at the time points
indicated in the Schedule of Activities. International Normalized Ratio (INR)will
be calculated by the central laboratory.
 
Alpha-fetoprotein at screening.
Other optional 
tests in
response to
ALT flare 
(refer to
Section 10.6,
Appendix 6,
Intervention-
emergent
ALT/AST
Elevations)
 
Testing for HIV-1 and -2, and hepatitis A, C, D, and E.
 
Testing for CMV, HSV, EBV infection.
 
Ig-electrophoresis
Thyroid 
function tests 
TSH
T4


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10.3. Appendix 3: Regulatory, Ethical, and Study Oversight Considerations
REGULATORY AND ETHICAL CONSIDERATIONS
Investigator Responsibilities
The investigator is responsible for ensuring that the study is performed in accordance with the
protocol, current International Council for Harmonisation of Technical Requirements for
Pharmaceuticals for Human Use (ICH)guidelines on Good Clinical Practice (GCP), and applicable
regulatory and country-specific requirements.
Good Clinical Practice is an international ethical and scientific quality standard for designing,
conducting, recording, and reporting studies that involve the participation of human participants.
Compliance with this standard provides public assurance that the rights, safety, and well-being of
study participants are protected, consistent with the principles that originated in the Declaration of
Helsinki, and that the study data are credible.
Protocol Amendments
Neither the investigator nor the sponsor will modify this protocol without a formal amendment by
the sponsor. All protocol amendments must be issued by the sponsor, and signed and dated by the
investigator. Protocol amendments must not be implemented without prior IEC/IRB approval, or
when the relevant competent authority has raised any grounds for non-acceptance, except when
necessary to eliminate immediate hazards to the participants, in which case the amendment must
be promptly submitted to the IEC/IRB and relevant competent authority. Documentation of
amendment approval by the investigator and IEC/IRB must be provided to the sponsor. When the
change(s) involve only logistic or administrative aspects of the study, the IEC/IRB (where
required) only needs to be notified.
During the course of the study, in situations where a departure from the protocol is unavoidable,
the investigator or other physician in attendance will contact the appropriate sponsor representative
listed in the Contact Information page(s), which will be provided as a separate document. Except
in emergency situations, this contact should be made before implementing any departure from the
protocol. In all cases, contact with the sponsor must be made as soon as possible to discuss the
situation and agree on an appropriate course of action. The data recorded in the CRF and source
documents will reflect any departure from the protocol, and the source documents will describe
this departure and the circumstances requiring it.
Regulatory Approval/Notification
This protocol and any amendment(s) must be submitted to the appropriate regulatory authorities
in each respective country, if applicable. A study may not be initiated until all local regulatory
requirements are met.


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Required Prestudy Documentation
The following documents must be provided to the sponsor before shipment of study intervention
to the study site:
 
Protocol and amendment(s), if any, signed and dated by the principal investigator
 
A copy of the dated and signed (or sealed, where appropriate per local regulations), written
IEC/IRB approval of the protocol, amendments, ICF, any recruiting materials, and if
applicable, participant compensation programs. This approval must clearly identify the
specific protocol by title and number and must be signed (or sealed, where appropriate per
local regulations) by the chairman or authorized designee.
 
Name and address of the IEC/IRB, including a current list of the IEC/IRB members and their
function, with a statement that it is organized and operates according to GCP and the
applicable laws and regulations. If accompanied by a letter of explanation, or equivalent, from
the IEC/IRB, a general statement may be substituted for this list. If an investigator or a
member of the study-site personnel is a member of the IEC/IRB, documentation must be
obtained to state that this person did not participate in the deliberations or in the vote/opinion
of the study.
 
Regulatory authority approval or notification, if applicable
 
Signed and dated statement of investigator (eg, Form FDA 1572), if applicable
 
Documentation of investigator qualifications (eg, curriculum vitae)
 
Completed investigator financial disclosure form from the principal investigator, where
required
 
Signed and dated clinical trial agreement, which includes the financial agreement
 
Any other documentation required by local regulations
The following documents must be provided to the sponsor before enrollment of the first
participant:
 
Completed investigator financial disclosure forms from all subinvestigators
 
Documentation of subinvestigator qualifications (eg, curriculum vitae)
 
Name and address of any local laboratory conducting tests for the study, and a dated copy of
current laboratory normal ranges for these tests, if applicable
 
Local laboratory documentation demonstrating competence and test reliability
(eg, accreditation/license), if applicable
Independent Ethics Committee or Institutional Review Board
Before the start of the study, the investigator (or sponsor where required) will provide the IEC/IRB
with current and complete copies of the following documents (as required by local regulations):
 
Final protocol and, if applicable, amendments
 
Sponsor-approved ICF (and any other written materials to be provided to the participants)


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 
IB (or equivalent information) and amendments/addenda
 
Sponsor-approved participant recruiting materials
 
Information on compensation for study-related injuries or payment to participants for
participation in the study, if applicable
 
Investigator's curriculum vitae or equivalent information (unless not required, as documented
by the IEC/IRB)
 
Information regarding funding, name of the sponsor, institutional affiliations, other potential
conflicts of interest, and incentives for participants
 
Any other documents that the IEC/IRB requests to fulfill its obligation
This study will be undertaken only after the IEC/IRB has given full approval of the final protocol,
amendments (if any, excluding the ones that are purely administrative, with no consequences for
participants, data or study conduct, unless required locally), the ICF, applicable recruiting
materials, and participant compensation programs, and the sponsor has received a copy of this
approval. This approval letter must be dated and must clearly identify the IEC/IRB and the
documents being approved.
Approval for the collection of optional samples for research and for the corresponding ICF must
be obtained from the IEC/IRB. Approval for the protocol can be obtained independent of this
optional research component.
During the study the investigator (or sponsor where required) will send the following documents
and updates to the IEC/IRB for their review and approval, where appropriate:
 
Protocol amendments (excluding the ones that are purely administrative, with no
consequences for participants, data or study conduct)
 
Revision(s) to ICF and any other written materials to be provided to participants
 
If applicable, new or revised participant recruiting materials approved by the sponsor
 
Revisions to compensation for study-related injuries or payment to participants for
participation in the study, if applicable
 
New edition(s) of the IB and amendments/addenda
 
Summaries of the status of the study at intervals stipulated in guidelines of the IEC/IRB (at
least annually)
 
Reports of adverse events that are serious, unlisted/unexpected, and associated with the study
intervention
 
New information that may adversely affect the safety of the participants or the conduct of the
study
 
Deviations from or changes to the protocol to eliminate immediate hazards to the participants
 
Report of deaths of participants under the investigator's care
 
Notification if a new investigator is responsible for the study at the site


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 
Development Safety Update Report and Line Listings, where applicable
 
Any other requirements of the IEC/IRB
For all protocol amendments (excluding the ones that are purely administrative, with no
consequences for participants, data or study conduct), the amendment and applicable ICF revisions
must be submitted promptly to the IEC/IRB for review and approval before implementation of the
change(s).
At least once a year, the IEC/IRB will be asked to review and reapprove this study, where required.
At the end of the study, the investigator (or sponsor where required) will notify the IEC/IRB about
the study completion.
Country Selection
This study will only be conducted in those countries where the intent is to launch or otherwise help
ensure access to the developed product if the need for the product persists, unless explicitly
addressed as a specific ethical consideration in Section 4.2.1.
Other Ethical Considerations
For study-specific ethical design considerations, refer to Section 4.2.1.
FINANCIAL DISCLOSURE
Investigators and subinvestigators will provide the sponsor with sufficient, accurate financial
information in accordance with local regulations to allow the sponsor to submit complete and
accurate financial certification or disclosure statements to the appropriate regulatory authorities.
Investigators are responsible for providing information on financial interests during the course of
the study and for 1 year after completion of the study.
Refer to Required Prestudy Documentation (above) for details on financial disclosure.
INFORMED CONSENT PROCESS
Each participant must give written consent according to local requirements after the nature of the
study has been fully explained. The ICF(s) must be signed before performance of any study-related
activity. The ICF(s) that is/are used must be approved by both the sponsor and by the reviewing
IEC/IRB and be in a language that the participant can read and understand. The informed consent
should be in accordance with principles that originated in the Declaration of Helsinki, current ICH
and GCP guidelines, applicable regulatory requirements, and sponsor policy.
Before enrollment in the study, the investigator or an authorized member of the study-site
personnel must explain to potential participants the aims, methods, reasonably anticipated benefits,
and potential hazards of the study, and any discomfort participation in the study may entail.
Participants will be informed that their participation is voluntary and that they may withdraw
consent to participate at any time. They will be informed that choosing not to participate will not
affect the care the participant will receive for the treatment of his or her disease. Participants will


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be told that alternative treatments are available if they refuse to take part and that such refusal will
not prejudice future treatment. Finally, they will be told that the investigator will maintain a
participant identification register for the purposes of long-term follow-up if needed and that their
records may be accessed by health authorities and authorized sponsor personnel without violating
the confidentiality of the participant, to the extent permitted by the applicable law(s) or regulations.
By signing the ICF the participant is authorizing such access. It also denotes that the participant
agrees to allow his or her study physician to recontact the participant for the purpose of obtaining
consent for additional safety evaluations, and subsequent disease-related treatments, if needed.
The participant will be given sufficient time to read the ICF and the opportunity to ask questions.
After this explanation and before entry into the study, consent should be appropriately recorded
by means of the participant's personally dated signature. After having obtained the consent, a copy
of the ICF must be given to the participant.
Where local regulations require, a separate ICF may be used for the required DNA component of
the study.
If the participant is unable to read or write, an impartial witness should be present for the entire
informed consent process (which includes reading and explaining all written information) and
should personally date and sign the ICF after the oral consent of the participant is obtained.
DATA PROTECTION
Privacy of Personal Data
The collection and processing of personal data from participants enrolled in this study will be
limited to those data that are necessary to fulfill the objectives of the study.
These data must be collected and processed with adequate precautions to ensure confidentiality
and compliance with applicable data privacy protection laws and regulations. Appropriate
technical and organizational measures to protect the personal data against unauthorized disclosures
or access, accidental or unlawful destruction, or accidental loss or alteration must be put in place.
Sponsor personnel whose responsibilities require access to personal data agree to keep the identity
of participants confidential.
The informed consent obtained from the participant includes explicit consent for the processing of
personal data and for the investigator/institution to allow direct access to his or her original medical
records (source data/documents) for study-related monitoring, audit, IEC/IRB review, and
regulatory inspection. This consent also addresses the transfer of the data to other entities and to
other countries.
The participant has the right to request through the investigator access to his or her personal data
and the right to request rectification of any data that are not correct or complete. Reasonable steps
will be taken to respond to such a request, taking into consideration the nature of the request, the
conditions of the study, and the applicable laws and regulations.


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Exploratory DNA, PK/PD, and biomarker research is not conducted under standards appropriate
for the return of data to participants. In addition, the sponsor cannot make decisions as to the
significance of any findings resulting from exploratory research. Therefore, exploratory research
data will not be returned to participants or investigators, unless required by law or local regulations.
Privacy and confidentiality of data generated in the future on stored samples will be protected by
the same standards applicable to all other clinical data.
LONG-TERM RETENTION OF SAMPLES FOR ADDITIONAL FUTURE RESEARCH
Samples collected in this study may be stored for up to 15 years (or according to local regulations)
for additional research. Samples will only be used to understand JNJ-3989 and JNJ-6379,the NAs
(ETV, tenofovir disoproxil, and TAF), and PegIFN-α2a, to understand chronic HBV infection, to
understand differential intervention responders, and to develop tests/assays related to JNJ-3989
and JNJ-6379 the NAs (ETV, tenofovir disoproxil, and TAF), and chronic HBV infection. The
research may begin at any time during the study or the post-study storage period.
Stored samples will be coded throughout the sample storage and analysis process and will not be
labeled with personal identifiers. Participants may withdraw their consent for their samples to be
stored for research (refer to Section 7.2.1).
COMMITTEES STRUCTURE
Independent Flare Expert Panel
An IFLEP will be appointed for this study. The IFLEP is composed of 3 independent medical
experts with experience and expertise in hepatitis B and its treatment. The IFLEP will monitor
ALT flares and will make recommendations regarding flare management based on an analysis of
aggregate data.
In order to allow for an unbiased assessment, members of the committee will not serve as study
investigators
Further details on the IFLEP process will be included in the IFLEP charter.
PUBLICATION POLICY/DISSEMINATION OF CLINICAL STUDY DATA
All information, including but not limited to information regarding JNJ-3989 and JNJ-6379 or the
sponsor's operations (eg, patent application, formulas, manufacturing processes, basic scientific
data, prior clinical data, formulation information) supplied by the sponsor to the investigator and
not previously published, and any data, including pharmacogenomic or exploratory biomarker
research data, generated as a result of this study, are considered confidential and remain the sole
property of the sponsor. The investigator agrees to maintain this information in confidence and use
this information only to accomplish this study and will not use it for other purposes without the
sponsor's prior written consent.
The investigator understands that the information developed in the study will be used by the
sponsor in connection with the continued development ofJNJ-3989 and JNJ-6379, and thus may


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be disclosed as required to other clinical investigators or regulatory agencies. To permit the
information derived from the clinical studies to be used, the investigator is obligated to provide
the sponsor with all data obtained in the study.
The results of the study will be reported in a Clinical Study Report generated by the sponsor and
will contain data from all study sites that participated in the study as per protocol. Recruitment
performance or specific expertise related to the nature and the key assessment parameters of the
study will be used to determine a coordinating investigator for the study. Results of
pharmacogenomic or exploratory biomarker analyses performed after the Clinical Study Report
has been issued will be reported in a separate report and will not require a revision of the Clinical
Study Report.
Study participant identifiers will not be used in publication of results. Any work created in
connection with performance of the study and contained in the data that can benefit from copyright
protection (except any publication by the investigator as provided for below) shall be the property
of the sponsor as author and owner of copyright in such work.
Consistent with Good Publication Practices and International Committee of Medical Journal
Editors (ICMJE) guidelines, the sponsor shall have the right to publish such primary (multicenter)
data and information without approval from the investigator. The investigator has the right to
publish study site-specific data after the primary data are published. If an investigator wishes to
publish information from the study, a copy of the manuscript must be provided to the sponsor for
review at least 60 days before submission for publication or presentation. Expedited reviews will
be arranged for abstracts, poster presentations, or other materials. If requested by the sponsor in
writing, the investigator will withhold such publication for up to an additional 60 days to allow for
filing of a patent application. In the event that issues arise regarding scientific integrity or
regulatory compliance, the sponsor will review these issues with the investigator. The sponsor will
not mandate modifications to scientific content and does not have the right to suppress information.
For multicenter study designs and sub-study approaches, secondary results generally should not
be published before the primary endpoints of a study have been published. Similarly, investigators
will recognize the integrity of a multicenter study by not submitting for publication data derived
from the individual study site until the combined results from the completed study have been
submitted for publication, within 18 months after the study end date, or the sponsor confirms there
will be no multicenter study publication. Authorship of publications resulting from this study will
be based on the guidelines on authorship, such as those described in the ICMJE Recommendations
for the Conduct, Reporting, Editing and Publication of Scholarly Work in Medical Journals, which
state that the named authors must have made a significant contribution to the conception or design
of the work; or the acquisition, analysis, or interpretation of the data for the work; and drafted the
work or revised it critically for important intellectual content; and given final approval of the
version to be published; and agreed to be accountable for all aspects of the work in ensuring that
questions related to the accuracy or integrity of any part of the work are appropriately investigated
and resolved.


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Registration of Clinical Studies and Disclosure of Results
The sponsor will register and disclose the existence of and the results of clinical studies as required
by law. The disclosure of the final study results will be performed after the end of study in order
to ensure the statistical analyses are relevant.
DATA QUALITY ASSURANCE
Data Quality Assurance/Quality Control
Steps to be taken to ensure the accuracy and reliability of data include the selection of qualified
investigators and appropriate study sites, review of protocol procedures with the investigator and
study-site personnel before the study, periodic monitoring visits by the sponsor, and direct
transmission of clinical laboratory data from a central laboratory to the sponsor's data base. Written
instructions will be provided for collection, handling, storage, and shipment of samples.
Guidelines for CRF completion will be provided and reviewed with study-site personnel before
the start of the study.
The sponsor will review CRF for accuracy and completeness during on-site monitoring visits and
after transmission to the sponsor; any discrepancies will be resolved with the investigator or
designee, as appropriate. After upload of the data into the study database they will be verified for
accuracy and consistency with the data sources.
CASE REPORT FORM COMPLETION
Case report forms are prepared and provided by the sponsor for each participant in electronic
format. All data relating to the study must be recorded in CRF. All CRF entries, corrections, and
alterations must be made by the investigator or authorized study-site personnel. The investigator
must verify that all data entries in the CRF are accurate and correct.
The study data will be transcribed by study-site personnel from the source documents onto an
electronic CRF, if applicable. Study-specific data will be transmitted in a secure manner to the
sponsor.
Worksheets may be used for the capture of some data to facilitate completion of the CRF. Any
such worksheets will become part of the participant's source documents. Data must be entered into
CRF in English. The CRF must be completed as soon as possible after a participant visit and the
forms should be available for review at the next scheduled monitoring visit.
All participative measurements (eg, pain scale information or other questionnaires) will be
completed by the same individual who made the initial baseline determinations whenever possible.
If necessary, queries will be generated in the electronic data capture (eDC) tool. If corrections to
a CRF are needed after the initial entry into the CRF, this can be done in either of the following
ways:


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 
Investigator and study-site personnel can make corrections in the eDC tool at their own
initiative or as a response to an auto query (generated by the eDC tool).
 
Sponsor or sponsor delegate can generate a query for resolution by the investigator and study-
site personnel.
SOURCE DOCUMENTS
At a minimum, source documents consistent in the type and level of detail with that commonly
recorded at the study site as a basis for standard medical care must be available for the following:
participant identification, eligibility, and study identification; study discussion and date of signed
informed consent; dates of visits; dates of blood collection, date and time of start and end of
leukapheresis, results of safety and efficacy parameters as required by the protocol; record of all
adverse events and follow-up of adverse events; concomitant medication; intervention
receipt/dispensing/return records; study intervention administration information; and date of study
completion and reason for early discontinuation of investigational intervention or withdrawal from
the study, if applicable.
The author of an entry in the source documents should be identifiable.
Specific details required as source data for the study and source data collection methods will be
reviewed with the investigator before the study and will be described in the monitoring guidelines
(or other equivalent document).
The following data will be recorded directly into the CRF and will be considered source data:
 
Race
 
Blood pressure and pulse/heart rate
 
Height and weight
 
Details of physical examination
The minimum source documentation requirements for Section 5.1 and Section 5.2 that specify a
need for documented medical history are as follows:
 
Referral letter from treating physician or
 
Complete history of medical notes at the site
 
Discharge summaries
Inclusion and exclusion criteria not requiring documented medical history must be verified at a
minimum by participant interview or other protocol required assessment (eg, physical
examination, laboratory assessment) and documented in the source documents.
An eSource system may be utilized, which contains data traditionally maintained in a hospital or
clinic record to document medical care (eg, electronic source documents) as well as the clinical
study-specific data fields as determined by the protocol. This data is electronically extracted for


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use by the sponsor. If eSource is utilized, references made to the CRF in the protocol include the
eSource system but information collected through eSource may not be limited to that found in the
CRF.
MONITORING
The sponsor will use a combination of monitoring techniques (central, remote, or on-site
monitoring)to monitor this study.
The sponsor will perform on-site monitoring visits as frequently as necessary. The monitor will
record dates of the visits in a study site visit log that will be kept at the study site. The first
post-initiation visit will be made as soon as possible after enrollment has begun. At these visits,
the monitor will compare the data entered into the CRF with the source documents
(eg, hospital/clinic/physician’s office medical records); a sample may be reviewed. The nature and
location of all source documents will be identified to ensure that all sources of original data
required to complete the CRF are known to the sponsor and study-site personnel and are accessible
for verification by the sponsor study-site contact. If electronic records are maintained at the study
site, the method of verification must be discussed with the study-site personnel.
Direct access to source documents (medical records) must be allowed for the purpose of verifying
that the recorded data are consistent with the original source data. Findings from this review will
be discussed with the study-site personnel. The sponsor expects that, during monitoring visits, the
relevant study-site personnel will be available, the source documents will be accessible, and a
suitable environment will be provided for review of study-related documents. The monitor will
meet with the investigator on a regular basis during the study to provide feedback on the study
conduct.
In addition to on-site monitoring visits, remote contacts can occur. It is expected that during these
remote contacts, study-site personnel will be available to provide an update on the progress of the
study at the site.
Central monitoring will take place for data identified by the sponsor as requiring central review.
ON-SITE AUDITS
Representatives of the sponsor's clinical quality assurance department may visit the study site at
any time during or after completion of the study to conduct an audit of the study in compliance
with regulatory guidelines and company policy. These audits will require access to all study
records, including source documents, for inspection. Participant privacy must, however, be
respected. The investigator and study-site personnel are responsible for being present and available
for consultation during routinely scheduled study-site audit visits conducted by the sponsor or its
designees.
Similar auditing procedures may also be conducted by agents of any regulatory body, either as part
of a national GCP compliance program or to review the results of this study in support of a


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regulatory submission. The investigator should immediately notify the sponsor if he or she has
been contacted by a regulatory agency concerning an upcoming inspection.
RECORD RETENTION
In compliance with the ICH/GCP guidelines, the investigator/institution will maintain all CRF and
all source documents that support the data collected from each participant, as well as all study
documents as specified in ICH/GCP Section 8, Essential Documents for the Conduct of a Clinical
Trial, and all study documents as specified by the applicable regulatory requirement(s). The
investigator/institution will take measures to prevent accidental or premature destruction of these
documents.
Essential documents must be retained until at least 2 years after the last approval of a marketing
application in an ICH region and until there are no pending or contemplated marketing applications
in an ICH region or until at least 2 years have elapsed since the formal discontinuation of clinical
development of the investigational product. These documents will be retained for a longer period
if required by the applicable regulatory requirements or by an agreement with the sponsor. It is the
responsibility of the sponsor to inform the investigator/institution as to when these documents no
longer need to be retained.
If the responsible investigator retires, relocates, or for other reasons withdraws from the
responsibility of keeping the study records, custody must be transferred to a person who will accept
the responsibility. The sponsor must be notified in writing of the name and address of the new
custodian. Under no circumstance shall the investigator relocate or dispose of any study documents
before having obtained written approval from the sponsor.
If it becomes necessary for the sponsor or the appropriate regulatory authority to review any
documentation relating to this study, the investigator/institution must permit access to such reports.
STUDY AND SITE START AND CLOSURE
First Act of Recruitment
The first site open is considered the first act of recruitment and it becomes the study start date.
Study Termination
The sponsor reserves the right to close the study site or terminate the study at any time for any
reason at the sole discretion of the sponsor. Study sites will be closed upon study completion. A
study site is considered closed when all required documents and study supplies have been collected
and a study-site closure visit has been performed.
The investigator may initiate study-site closure at any time, provided there is reasonable cause and
sufficient notice is given in advance of the intended termination.


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Reasons for the early closure of a study site by the sponsor or investigator may include but are not
limited to:
 
Failure of the investigator to comply with the protocol, the requirements of the IEC/IRB or
local health authorities, the sponsor's procedures, or GCP guidelines
 
Inadequate recruitment of participants by the investigator
 
Discontinuation of further study intervention development


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10.4. Appendix 4: Adverse Events: Definitions and Procedures for Recording,
Evaluating, Follow-up, and Reporting
ADVERSE EVENT DEFINITIONS AND CLASSIFICATIONS
Adverse Event
An AE is any untoward medical occurrence in a clinical study participant administered a medicinal
(investigational or non-investigational) product. An AE does not necessarily have a causal
relationship with the intervention. An AE can therefore be any unfavorable and unintended sign
(including an abnormal finding), symptom, or disease temporally associated with the use of a
medicinal (investigational or non-investigational) product, whether or not related to that medicinal
(investigational or non-investigational) product. (Definition per ICH)
This includes any occurrence that is new in onset or aggravated in severity or frequency from the
baseline condition, or abnormal results of diagnostic procedures, including laboratory test
abnormalities.
Note: The sponsor collects adverse events starting with the signing of the ICF (refer to All Adverse
Events under Section 8.5.1 for time of last AE recording).
Serious Adverse Event
A SAE based on ICH and EU Guidelines on Pharmacovigilance for Medicinal Products for Human
Use is any untoward medical occurrence that at any dose:
 
Results in death
 
Is life-threatening
(The participant 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.)
 
Requires inpatient hospitalization or prolongation of existing hospitalization
 
Results in persistent or significant disability/incapacity
 
Is a congenital anomaly/birth defect
 
Is a suspected transmission of any infectious agent via a medicinal product
 
Is Medically Important*
*Medical and scientific judgment should be exercised in deciding whether expedited reporting is also appropriate in
other situations, such as important medical events that may not be immediately life threatening or result in death or
hospitalization but may jeopardize the participant or may require intervention to prevent one of the other outcomes
listed in the definition above. These should usually be considered serious.
If a serious and unexpected adverse event occurs for which there is evidence suggesting a causal
relationship between the study intervention and the event (eg, death from anaphylaxis), the event
must be reported as a serious and unexpected suspected adverse reaction even if it is a component
of the study endpoint (eg, all-cause mortality).


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Unlisted (Unexpected) Adverse Event/Reference Safety Information
An adverse event is considered unlisted if the nature or severity is not consistent with the applicable
product reference safety information. For JNJ-3989 and JNJ-6379, the expectedness of an adverse
event will be determined by whether or not it is listed in the IB. For ETV, tenofovir disoproxil,
and TAF with a marketing authorization, the expectedness of an adverse event will be determined
by whether or not it is listed in the package insert.
ATTRIBUTION DEFINITIONS
Assessment of Causality
The causal relationship to study intervention is determined by the Investigator. The following
selection should be used to assess all AEs.
Related
There is a reasonable causal relationship between study intervention administration and the AE.
Not Related
There is not a reasonable causal relationship between study intervention administration and the
AE.
The term "reasonable causal relationship" means there is evidence to support a causal relationship.
SEVERITY CRITERIA
An assessment of severity grade will be made by the investigator using the general categorical
descriptors outlined in the DAIDS Toxicity Grading Scale (see Section 10.9, Appendix 9, DAIDS
Table).
SPECIAL REPORTING SITUATIONS
Safety events of interest on a sponsor study intervention in an interventional studythat may require
expedited reporting or safety evaluation include, but are not limited to:
 
Overdose of a sponsor study intervention
 
Suspected abuse/misuse of a sponsor study intervention
 
Accidental or occupational exposure to a sponsor study intervention
 
Medication error, intercepted medication error, or potential medication error involving a
sponsormedicinal product (with or without patient exposure to the sponsormedicinal product,
eg, product name confusion, product label confusion, intercepted prescribing or dispensing
errors)
 
Exposure to a sponsor study intervention from breastfeeding
Special reporting situations should be recorded in the CRF. Any special reporting situation that
meets the criteria of a SAE should be recorded on the SAE page of the CRF.


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PROCEDURES
All Adverse Events
All adverse events, regardless of seriousness, severity, or presumed relationship to study
intervention, must be recorded using medical terminology in the source document and the CRF.
Whenever possible, diagnoses should be given when signs and symptoms are due to a common
etiology (eg, cough, runny nose, sneezing, sore throat, and head congestion should be reported as
"upper respiratory infection"). Investigators must record in the CRF their opinion concerning the
relationship of the adverse event to study therapy. All measures required for adverse event
management must be recorded in the source document and reported according to sponsor
instructions.
In the context of this study, AEs and SAEs associated with/triggered by the liver biopsies,
leukapheresis, or blood collection procedures are to be reported to the sponsor.
For all studies with an outpatient phase, including open-label studies, the participant must be
provided with a "wallet (study) card" and instructed to carry this card with them for the duration
of the study indicating the following:
 
Study number
 
Statement, in the local language(s), that the participant is participating in a clinical study
 
Investigator's name and 24-hour contact telephone number
 
Local sponsor's name and 24-hour contact telephone number (for medical personnel only)
 
Site number
 
Participant number
 
Any other information that is required to do an emergency breaking of the blind
Serious Adverse Events
All SAEs that have not resolved by the end of the study, or that have not resolved upon
discontinuation of the participant's participation in the study, must be followed until any of the
following occurs:
 
The event resolves
 
The event stabilizes
 
The event returns to baseline, if a baseline value/status is available
 
The event can be attributed to agents other than the study intervention or to factors unrelated
to study conduct
 
It becomes unlikely that any additional information can be obtained (participant or health care
practitioner refusal to provide additional information, lost to follow-up after demonstration of
due diligence with follow-up efforts)


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Suspected transmission of an infectious agent by a medicinal product will be reported as a SAE.
Any event requiring hospitalization (or prolongation of hospitalization) that occurs during the
course of a participant's participation in a study must be reported as a SAE, except hospitalizations
for the following:
 
Hospitalizations not intended to treat an acute illness or adverse event (eg, social reasons such
as pending placement in long-term care facility)
 
Surgery or procedure planned before entry into the study (must be documented in the CRF).
Note: Hospitalizations that were planned before the signing of the ICF, and where the
underlying condition for which the hospitalization was planned has not worsened, will not be
considered SAEs. Any adverse event that results in a prolongation of the originally planned
hospitalization is to be reported as a new SAE.
The cause of death of a participant in a study, whether or not the event is expected or associated
with the study intervention, is considered an SAE.
CONTACTING SPONSOR REGARDING SAFETY
The names (and corresponding telephone numbers) of the individuals who should be contacted
regarding safety issues or questions regarding the study are listed in the Contact Information
page(s), which will be provided as a separate document.
PRODUCT QUALITY COMPLAINT HANDLING
A product quality complaint (PQC) is defined as any suspicion of a product defect related to
manufacturing, labeling, or packaging, ie, any dissatisfaction relative to the identity, quality,
durability, or reliability of a product, including its labeling or package integrity. A PQC may have
an impact on the safety and efficacy of the product. Timely, accurate, and complete reporting and
analysis of PQC information from studies are crucial for the protection of participants,
investigators, and the sponsor, and are mandated by regulatory agencies worldwide. The sponsor
has established procedures in conformity with regulatory requirements worldwide to ensure
appropriate reporting of PQC information; all studies conducted by the sponsor or its affiliates will
be conducted in accordance with those procedures.
Procedures
All initial PQCs must be reported to the sponsor by the study-site personnel within 24 hours after
being made aware of the event.
If the defect is combined with a SAE, the study-site personnel must report the PQC to the sponsor
according to the SAE reporting timelines (refer to Section 8.5.1). A sample of the suspected
product should be maintained for further investigation if requested by the sponsor.
Contacting Sponsor Regarding Product Quality
The names (and corresponding telephone numbers) of the individuals who should be contacted
regarding product quality issues are listed in the Contact Information page(s), which will be
provided as a separate document.


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10.5. Appendix 5: Rash Management
Table 6: 
Management of Rash Events by Severity Grade
Definition 
Study
Intervention
Action
Activities by Daya
Referral to
Dermatologist and
Dermatology Activities
Grade 1 rash
(with or
without
pruritus)b
Erythema 
Study intervention
intake may be
continued at the
investigator’s
discretion
Day 0: optional on site visit for initial rash evaluation may be
performed at the investigator’s discretion.
Safety laboratory assessments may be performed at the investigator’s
discretion (recommended if visit occurs).
Digital pictures* of skin lesions may be taken at the investigator’s
discretion.
Determine if participant was adhering to the recommended sun-
protective measures. If appropriate, provide sun protection
counseling.
Day 1 and thereafter: appropriate follow-up visits at the investigator’s
discretion until resolution of rash.
Safety laboratory assessments and photography (digital pictures* of
skin lesions) may be performed at the investigator’s discretion.
* Digital pictures to be taken at the clinical site upon consent of the
participant.
Not required
Grade 2 rash
(with or without
pruritus)b
Diffuse,
maculopapular rash,
or dry desquamation
Study intervention
intake may be
continued at the
investigator’s
discretion
Day 0: required on-site visit (if a visit is not possible, telephone
contact with the participant should take place to collect information
and give advice on the necessary measures to be taken).
Safety laboratory assessments may be performed at the investigator’s
discretion (recommended).
Digital pictures* of skin lesions may be taken at the investigator’s
discretion. Digital pictures* of skin lesions are recommended in case
consultation of a dermatologist is required. Determine if participant
was adhering to the recommended sun-protective measures. If
appropriate, provide sun protection counseling.
Day 1 and thereafter: appropriate follow-up visits at the investigator’s
discretion until resolution of rash or until clinical stability is reached.
Referral to dermatologist
at the discretion of the
investigatorc
Biopsy not required, but
may be performed at the
dermatologist’s
discretion


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Table 6: 
Management of Rash Events by Severity Grade
Definition 
Study
Intervention
Action
Activities by Daya 
Referral to
Dermatologist and
Dermatology Activities
Safety laboratory assessments are required on Day 1 and are required
thereafter only if the previous values were abnormal (but may be
performed at the investigator’s discretion). If the rash progresses to a
higher grade, safety laboratory assessments of the higher grade should
be followed.
Digital pictures* of skin lesions may be taken at the investigator’s
discretion.
* Digital pictures to be taken at the clinical site upon consent of the
participant.
Grade 3 rashb 
Vesiculation, moist
desquamation, or
ulceration OR
Any cutaneous event
with 1 of the
following:
- Elevations in
AST/ALT
>2×baseline
value
- Fever >38°C or
100°F
- Eosinophils
>1.00×103/µL
- Serum sickness-
like reaction
Must permanently
discontinue
JNJ-3989; no
rechallenge
allowed
NA treatment may
be discontinued
based on
investigator
judgement in
consultation with
the sponsor
Day 0: required on-site visit.
Safety laboratory assessments required to be performed.
Digital pictures* of skin lesions may be taken at the investigator’s
discretion (recommended).
Determine if participant was adhering to the recommended sun-
protective measures. If appropriate, provide sun protection
counseling.
Day 1: required on-site visit.
Safety laboratory assessments required to be performed.
Digital pictures* of skin lesions may be taken at the investigator’s
discretion (recommended).
Further visit(s): appropriate follow-up required until resolution of rash
or until clinical stability is reached.
Safety laboratory assessments and photography (digital pictures* of
skin lesions) are recommended to be performed until the rash severity
resolves to grade 2 or grade 1.
* Digital pictures to be taken at the clinical site upon consent of the
participant.
Requiredc
Biopsy not required, but
may be performed at the
dermatologist’s
discretion.


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Table 6: 
Management of Rash Events by Severity Grade
Definition 
Study 
Intervention 
Action 
Activities by Daya 
Referral to
Dermatologist and
Dermatology Activities
Grade 4 rash 
Exfoliative 
dermatitis OR  
Mucous membrane
involvement in at
least 2 distinct sites
OR  
Erythema multiforme
major OR
Stevens-Johnson 
syndrome OR  
Toxic epidermal
necrolysis OR  
Necrosis requiring 
surgery  
Must permanently 
discontinue
JNJ-3989; no
rechallenge
allowed
NA treatment may 
be discontinued
based on
investigator
judgement in
consultation with 
the sponsor
Day 0: required on-site visit. 
Safety laboratory assessments required to be performed.
Digital pictures* of skin lesions may be taken at the investigator’s
discretion (recommended).
Determine if participant was adhering to the recommended sun-
protective measures. If appropriate, provide sun protection
counseling.
Day 1: required on-site visit.
Safety laboratory assessments required to be performed.
Digital pictures* of skin lesions may be taken at the investigator’s
discretion (recommended).
Further visit(s): appropriate follow-up required until resolution of rash
or until clinical stability is reached.
Safety laboratory assessments and photography (digital pictures* of
skin lesions) are recommended to be performed until the rash severity
resolves to grade 2 or grade 1.
* Digital pictures to be taken at the clinical site upon consent of the
participant.
Requiredc
Biopsy required and to
be performed as soon as
possible after the onset
of the rash.
AE: adverse event; ALT: alanine aminotransferase; AST: aspartate aminotransferase; NA: nucleos(t)ide analog.
a 
Day 0 of the rash is the first day of investigator assessment and not the first day of rash as reported by the participant. The initial visit should be conducted as soon
as possible after the participant contacts the investigator to report the AE (ie, preferably on Day 0). The initial visit and subsequent visits to manage the rash may
require unscheduled visit(s).
b 
The participant should be advised to contact the investigator immediately if there is any worsening of the rash, if any systemic signs or symptoms appear, or if
mucosal involvement develops. In case the rash evolves to a higher grade than that first observed, management of the rash should follow the guidelines indicated
for the higher grade.
c 
If applicable, dermatologist visit should occur preferably within 24 hours after onset of rash.
Notes:
 Local laboratory assessments are to be used for rash management. The values of the local laboratory assessments need to be transcribed in the eCRF by the study site
personnel.
 Digital pictures that are collected, dermatological consultation reports or biopsy reports that become available, should be de-identified and provided to the sponsor.


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10.6. Appendix 6: Intervention-emergent ALT/AST Elevations
a Additional tests may be considered based on clinical judgement in case of confirmed ALT flares:
 
Hepatitis A, D, C, E: IgM anti-HAV; delta IgM, IgG & PCR, HCV RNA, IgM & IgG anti-HEV, HEV RNA
 
CMV, HSV, EBV infection: IgM & IgG anti-CMV, IgM & IgG anti-HSV; IgM & IgG anti-EBV, PCR
 
HIV
 
Ig-electrophoresis


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10.7. Appendix 7: Cardiovascular Safety Abnormalities
ECG
All important abnormalities from the ECG readings will be listed.
Abnormality Code 
ECG parameter
Heart Rate 
PR  
QRS  
QTcorrected
Abnormalities on actual values
Abnormally low  
<45 bpm  
NAP  
- 
-
Abnormally high  
120 bpm  
>220 ms 
120 ms 
-
Borderline prolonged QT 
- 
- 
- 
450 ms < QTc ≤480 ms
Prolonged QT  
- 
- 
- 
480 ms < QTc <500 ms
Pathologically prolonged QT 
- 
- 
- 
QTc >500 ms
Abnormalities on changes from baseline (∆QTc)
Normal QTc change 
- 
- 
- 
∆QTc <30 ms
Borderline QTc change 
- 
- 
- 
30 ms < ∆QTc <60 ms
Abnormally high QTc change 
- 
- 
- 
∆QTc >60 ms
ECG: electrocardiogram; NAP = not applicable
For absolute QTc parameters the categories are defined based on the ICH E14 GuidanceFa
Vital Signsb
The following abnormalities will be defined for vital signs:
Abnormality Code 
Vital Signs parameter
Pulse 
DBP  
SBP
Abnormalities on actual values
Abnormally low  
45 bpm  
50 mmHg 
90 mmHg
Grade 1 or mild 
- 
>90 mmHg - <100 mmHg 
>140 mmHg - <160 mmHg
Grade 2 or moderate 
- 
100 mmHg - <110 mmHg 
160 mmHg - <180 mmHg
Grade 3 or severe 
- 
110 mmHg 
180 mmHg
Abnormally high  
120 bpm  
- 
-
DBP: diastolic blood pressure; SBP: systolic blood pressure
a The clinical evaluation of QT/QTc interval prolongation and proarrhythmic potential for non-antiarrhythmic drugs
CHMP/ICH/2/04, May 2005.
b The classification of AEs related to hypotension and hypertension will be done according to the DAIDS grading
scale.


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10.8. Appendix 8: Contraceptive and Barrier Guidance and Collection of
Pregnancy Information
Participants must follow contraceptive measures as outlined in Section 5.1. Pregnancy information
will be collected and reported as noted in Section 8.5.5 and Section 10.4, Appendix 4 Adverse
Events: Definitions and Procedures for Recording, Evaluating, Follow-up, and Reporting.
Definitions
Woman of Childbearing Potential (WOCBP)
A woman is considered fertile following menarche and until becoming postmenopausal unless
permanently sterile (see below).
Woman Not of Childbearing Potential
 
premenarchal
A premenarchal state is one in which menarche has not yet occurred.
 
postmenopausal
A postmenopausal state is defined as no menses for 12 months without an alternative medical
cause. A high FSH level (>40 IU/L or mIU/mL) in the postmenopausal range may be used to
confirm a postmenopausal state in women not using hormonal contraception or hormonal
replacement therapy (HRT), however in the absence of 12 months of amenorrhea, a single
FSH measurement is insufficient. If there is a question about menopausal status in women on
HRT, the woman will be required to use one of the non-estrogen-containing hormonal highly
effective contraceptive methods if she wishes to continue HRT during the study.
 
permanently sterile
Permanent sterilization methods include hysterectomy, bilateral salpingectomy, or bilateral
oophorectomy.
Note: If the childbearing potential changes after start of the study (eg, a premenarchal woman
experiences menarche) or the risk of pregnancy changes (eg, a woman who is not heterosexually
active becomes active), a woman must begin a highly effective method of contraception, as
described throughout the inclusion criteria.
If reproductive status is questionable, additional evaluation should be considered.
Contraceptive (birth control) use by men or women should be consistent with local regulations
regarding the acceptable methods of contraception for those participating in clinical studies.
Typical use failure rates may differ from those when used consistently and correctly. Use should
be consistent with local regulations regarding the use of contraceptive methods for participants in
clinical studies.


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Examples of Contraceptives
EXAMPLES OF CONTRACEPTIVESa ALLOWED DURING THE STUDY INCLUDE:
USER INDEPENDENT
Highly Effective Methods That Are User Independent Failure rate of <1% per year when used
consistently and correctly.
 Implantable progestogen-only hormone contraception associated with inhibition of ovulationb
 Intrauterine device (IUD)
 Intrauterine hormone-releasing system (IUS)
 Tubal closure (eg, bilateral tubal occlusion, bilateral tubal ligation)
 Azoospermic partner (vasectomized or due to medical cause)
(Vasectomized partner is a highly effective contraceptive method provided that the partner is the
sole sexual partner of the woman of childbearing potential and the absence of sperm has been
confirmed. If not, additional highly effective method of contraception should be used.
Spermatogenesis cycle is approximately 74 days.)
USER DEPENDENT
Highly Effective Methods That Are User Dependent Failure rate of <1% per year when used
consistently and correctly.
 Combined (estrogen- and progestogen-containing) hormonal contraception associated with
inhibition of ovulationb
 oral
 intravaginal
 transdermal
 injectable
 Progestogen-only hormone contraception associated with inhibition of ovulationb
 oral
 injectable
 Sexual abstinence
(Sexual abstinence is considered a highly effective method only if defined as refraining from
heterosexual intercourse during the entire period of risk associated with the study intervention.
The reliability of sexual abstinence needs to be evaluated in relation to the duration of the study
and the preferred and usual lifestyle of the participant.)
a) Typical use failure rates may differ from those when used consistently and correctly. Use should be
consistent with local regulations regarding the use of contraceptive methods for participants in
clinical studies.


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10.9. Appendix 9: DAIDS Table
DIVISION OF AIDS (DAIDS) TABLE FOR GRADING THE SEVERITY OF ADULT
AND PEDIATRIC ADVERSE EVENTS, VERSION 2.1, PUBLISH DATE: JULY, 2017
The DAIDS grading table is a descriptive terminology to be utilized for AE reporting in this study.
A grading (severity) scale is provided for each AE term.
General Instructions
Grading Adult and Pediatric Adverse Events
When a single parameter is not appropriate for grading an AE in both adult and pediatric
populations, separate parameters with specified age ranges are provided. If there is no distinction
between adult and pediatric populations, the listed parameter should be used for grading an AE in
both populations.
Determining Severity Grade for Parameters Between Grades
If the severity of an AE could fall under either 1 of 2 grades (eg, the severity of an AE could be
either grade 2 or grade 3), sites should select the higher of the 2 grades.
Laboratory normal ranges should be taken into consideration to assign gradings to a laboratory
value.
Definitions
Basic self-care functions 
Adults: activities such as bathing, dressing, toileting,
transfer/movement, continence, and feeding
Young children: activities that are age and culturally appropriate
(eg, feeding self with culturally appropriate eating implements)
Usual social & functional 
activities 
Activities which adults and children perform on a routine basis and
those which are part of regular activities of daily living, for
example:
Adults: adaptive tasks and desirable activities, such as going to
work, shopping, cooking, use of transportation, or pursuing a
hobby
Young Children: activities that are age and culturally appropriate
(eg, social interactions, play activities, learning tasks)
Intervention  
Medical, surgical, or other procedures recommended or provided
by a healthcare professional for the treatment of an AE.
Estimating Severity Grade for Parameters not Identified in the Grading Table
The functional table below should be used to grade the severity of an AE that is not specifically
identified in the grading table. In addition, all deaths related to an AE are to be classified as grade
5.














































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10.10. Appendix 10: Protocol Amendment History
The Protocol Amendment Summary of Changes Table for the current amendment is located
directly before the Table of Contents (TOC).
Amendment 5 (01 October 2021)
Overall Rationale for the Amendment:The primary reasons for this amendment are to remove JNJ-6379
as study intervention, to add a new nucleos(t)ide analog (NA) re-treatment criterion for participants who
discontinued NA treatment during follow-up, and to include more frequent monitoring for participants who
discontinued NA treatment during follow-up.
Based on emerging data from recent interim analyses of the REEF-1 (73763989HPB2001) and REEF-2
(73763989PAHPB2002) studies, the benefit-risk profile of JNJ-6379 in combination with JNJ-3989+NA
is unfavorable compared to JNJ-3989+NA.
In the primary REEF-1 analysis (Week 48, end of treatment) the mean reduction of hepatitis B surface
antigen (HBsAg) in the triple arm (JNJ-6379+JNJ-3989 100mg+NA) appeared to be less than in the dual
arm (JNJ-3989 100mg+NA). More recent interim results of the REEF-2 study (Week 48, end of treatment)
confirmed this observation when the effect of JNJ-6379+JNJ-3989 200mg+NA on mean HBsAg level
reduction in REEF-2 study is compared to JNJ-3989 200mg+NA in the REEF-1 study. To match with the
REEF-2 population, this cross-study comparison focused on the REEF-1 subpopulation of hepatitis B e
antigen (HBeAg) negative, virologically suppressed participants with chronic hepatitis B.
Pharmacokinetic-pharmacodynamic modelling analyses accounting for variability in baseline
characteristics further support this observation. Therefore, a negative impact of JNJ-6379 on the HBsAg
lowering effect of JNJ-3989+NA is suspected.
From a safety perspective, transient reductions of eGFR based on creatinine (eGFRcr) in JNJ-6379
containing treatment arms with fast recovery after end of treatment had been described in the Jade study
(56136379HPB2001) and was confirmed in the REEF-1 study. In absence of a pattern of increased
biomarkers of proximal tubulo-toxicity (the beta-2microglobulin/creatinine and the retinol binding
protein/creatinine ratios), the eGFRcr reduction during treatment was interpreted as transporter inhibition
at the level of creatinine excretion from the proximal tubule rather than renal toxicity.
Recent data from REEF-2 confirm the transient pattern of eGFRcr declines but, in addition, show an
increase of the beta-2microglobulin/creatinine and the retinol binding protein/creatinine ratios in some
participants when tenofovir disoproxil fumarate (TDF) treatment was continued and combined with JNJ-
6379+JNJ-3989. These new data are suggesting that JNJ-6379 in combination with TDF may contribute to
renal tubulo-toxicity. There was no apparent increase in the beta-2-microglobulin/creatinine or retinol
binding protein/creatinine ratios in participants receiving ETV (active or control arm), nor in participants
receiving TDF+placebo.
The negative impact of JNJ-6379, when combined with JNJ-3989 + NA, on HBsAg reduction taken
together with the adverse renal profile leads to conclusion of an unfavorable benefit-risk balance of JNJ-
6379 in combination with JNJ-3989+NA, compared to JNJ-3989+NA alone. Therefore, the Sponsor has
decided to discontinue treatment with JNJ-6379 in all ongoing clinical studies effective immediately.
Participants currently on treatment with JNJ-6379 will be contacted and requested to stop taking JNJ-6379,
while continuing treatment with NA, JNJ-3989 and optional PegIFN-α2a. For newly enrolled participants,
JNJ-6379 will be no longer included in the treatment regimen. 
In addition, a new NA re-treatment criterion and more frequent monitoring for participants who
discontinued NA treatment during follow-up were added. The reason for these changes is a severe clinical
alanine aminotransferase (ALT) flare that was reported following discontinuation of NA treatment in a
virologically suppressed HBeAg negative participant on long-term TDF treatment who was randomized to
the control arm (placebo + placebo + NA) in the REEF-2 study. The participant presented with hepatitis B


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virus (HBV) DNA levels that increased rapidly, before any relevant changes in liver markers were noted.
Discontinuation of NA treatment followed the protocol-defined criteria and was in line with recent
European Association for the Study of the Liver (EASL) treatment guidelines.5 Flares following NA
discontinuation are not unexpected, but the rapid evolution and clinical deterioration seen in this participant
who was anti-HBe antibody positive at screening and had no history or evidence of liver cirrhosis was
unforeseeable. Therefore, to protect safety of participants, the protocol was amended as detailed below.
In addition, based on Health Authority request, it has been clarified that the follow-up phase of 48 weeks
will be extended to ensure that all study participants have at least one year of follow-up after NA treatment
cessation.
Furthermore, the eligibility criteria, the PegIFN-α2a discontinuation criteria, and the monitoring of
neuropsychiatric adverse events during PegIFN-α2a treatment were amended to be consistent with the
PegIFN-α2a prescribing information.
Other changes, clarifications and corrections were also made as detailed below.
Description of Change 
Brief Rationale 
Section Number and Name
Throughout the protocol, JNJ-
6379 has been removed as
study intervention.
Participants enrolled before
Protocol Amendment 5 and
who are being treated with
JNJ-3989+JNJ-6379+NA (Arm
1 in Panel 1 and Panel 2) had to
stop JNJ-6379 treatment
immediately. They will
continue with JNJ-3989+NA
treatment up to the end of the
48-week open-label study
intervention phase and will then
enter the follow-up phase
during which they stop
treatment with JNJ-3989 and
NA if completion criteria are
met. Throughout the protocol,
elements specific for JNJ-6379
have been modified.
Based on emerging data
from recent interim analyses
of the REEF-1 and REEF-2
studies, showing that the
benefit-risk profile of JNJ-
6379 in combination with
JNJ-3989+NA is
unfavorable compared to
JNJ-3989+NA.
1.1 Synopsis
1.2 Schema
1.3.1 Schedule of Activities   Screening and
Study Intervention Phase
2 INTRODUCTION
2.1 Study Rationale
2.2 Background
2.3 Benefit-Risk Assessment
2.3.2.2.2 Potential Risks for JNJ-6379
2.3.3 Benefit-risk Assessment for Study
Participation
3 OBJECTIVES AND ENDPOINTS
4.1 Overall Design
4.2 Scientific Rationale for Study Design
4.3 Justification for Dose
4.3.2 JNJ-6379
5.1 Inclusion Criteria
5.2 Exclusion Criteria
6.1 Study Intervention(s) Administered
6.2
Preparation/Handling/Storage/Accountability
6.3 Measures to Minimize Bias:
Randomization and Blinding
6.4 Study Intervention Compliance
6.5 Concomitant Therapy
6.6 Dose Modification
6.6.1 Study Intervention Completion at Week
48
7.1 Discontinuation of Study Intervention
8 STUDY ASSESSMENTS AND
PROCEDURES
8.4.4 Clinical Safety Laboratory
Assessments8.5.5 Pregnancy8.5.6 Adverse
Events of Special Interest
8.5.7 Other Toxicities
8.6 Treatment of Overdose
8.7 Pharmacokinetics
8.7.1 Evaluations


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8.7.3 Pharmacokinetic Parameters and
Evaluations
8.8 Pharmacokinetics/Pharmacodynamics
9.2 Sample Size Determination
9.3 Populations for Analyses
9.4 Statistical Analyses
9.4.1 Analysis ofEfficacy and Antiviral
Activity
9.4.2 Safety Analyses
9.4.3 Other Analyses
10.1 Appendix 1: Abbreviations and
Definitions of Terms
10.5 Appendix 5: Rash Management
10.6 Appendix 6: Intervention-emergent
ALT/AST Elevations
A new NA re-treatment 
criterion was added for 
participants who discontinued 
NA treatment during follow-up. 
To ensure that participants 
with significant HBV DNA 
increases during treatment- 
free follow-up are monitored 
at least weekly and/or
immediately re-start NA
treatment irrespective of
ALT levels. 
1.1 Synopsis
1.3.2 Schedule of Activities   Follow-up Phase
4.2 Scientific Rationale for Study Design
6.6.2 NA Re-treatment Criteria During Follow-
up
7.1 Discontinuation of Study Intervention
8.5.6.2 Intervention-emergent ALT/AST
Elevations
10.12 Appendix 12: NA Re-treatment During
Follow-up
Participants who discontinue 
NA treatment during follow-up, 
will be monitored more 
frequently, with a study visit at 
least once every 4 weeks. 
The visit frequency for 
participants who continue NA 
treatment or have restarted NA
treatment during the follow-up
period and for whom the HBV
DNA and ALT values are
stable remains at least once
every 12 weeks.
For participants with increased
follow-up, the total blood
volume to be collected during
the study will increase.
To further protect the safety 
of participants. 
1.3.2 Schedule of Activities   Follow-up Phase
2.3.2.2 Potential Risks
6.7 Study Intervention After the End of the
Study
7.1 Discontinuation of Study Intervention
8 STUDY ASSESSMENTS AND
PROCEDURES
A note has been added to 
clarify that the follow-up phase 
of 48 weeks will be extended 
with a maximum of 24 weeks 
(ie, up to Follow-up Week 72) 
to ensure that all study 
participants have at least one 
year of follow-up after NA 
treatment cessation. 
The end of study definition and 
study completion definitions
were updated to include this
possible extension.
For participants with extended
follow-up, the total blood
Upon Health authority 
request. 
1.1 Synopsis
1.2 Schema
1.3.2 Schedule of Activities   Follow-up Phase
4.1 Overall Design
4.2 Scientific Rationale for Study Design
4.4 End of Study Definition
6.6.1 Study Intervention Completion at Week
48
8 STUDY ASSESSMENTS AND
PROCEDURES


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volume to be collected during
the study was updated.
The PegIFN-α2a 
discontinuation criteria were 
updated to clarify that 
participants with moderate or 
severe depression or other 
psychiatric symptoms should 
immediately discontinue
PegIFN-α2a treatment.
In addition, participants will be
closely monitored for
neuropsychiatric adverse events
during the optional PegIFN-α2a
treatment period.
Participants who develop a
neuropsychiatric adverse event
during optional PegIFN-α2a
treatment will be monitored
closely until the
neuropsychiatric adverse event
resolves, with frequent (at least
weekly) follow-up phone calls.
Furthermore, exclusion
criterion 31 was amended to
exclude participants with a
history of a severe psychiatric
disorder.
Upon Health Authority 
request and to be consistent 
with the PegIFN-α2a 
prescribing information 
1.3.1 Schedule of Activities   Screening and
Study Intervention Phase
1.3.3 Schedule of Activities –Optional
PegIFN-α2a Treatment
5.2 Exclusion Criteria
7.1 Discontinuation of Study Intervention
The Contraceptive and Barrier 
Guidance and Collection of 
Pregnancy Information section 
was updated: the list of 
examples which are not
allowed as sole method of
contraception during the study
and the footnote concerning
possible interaction between
hormonal contraception and the
study intervention have been
removed. Additional
clarifications were also made.
Upon Health Authority 
request and to align with the 
latest version of the 
sponsor’s protocol template. 
5.1 Inclusion Criteria
10.8 Appendix 8: Contraceptive and Barrier
Guidance and Collection ofPregnancy
Information
Recommendations regarding 
the use of live vaccines during 
the study were added. 
Clarification considering the 
second dose concerns a life- 
attenuated virus.
6.5 Concomitant Therapy
10.11 Appendix 11: Covid Appendix
It was clarified that venous 
blood samples will be collected 
for measurement of JNJ-3989, 
NA, and PegIFN-α2a. 
However, bioanalysis of NA
and PegIFN-α2a is optional at
the discretion of the sponsor.
Bioanalysis of JNJ-6379 may
also be done on samples
Clarification. 
1.1 Synopsis
1.3.1 Schedule of Activities   Screening and
Study Intervention Phase
3 OBJECTIVES AND ENDPOINTS
8.7 Pharmacokinetics
8.7.1 Evaluations


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collected from participants who
received JNJ-6379 up to
Protocol Amendment 4.
Exclusion criterion 1 was 
adapted to clarify that 
participants with a positive
HIV-1 or HIV-2
antibody/antigen test at
screening should have a
confirmatory HIV RNA test, to
rule out false positive results.
They can be enrolled if they
have a negative HIV RNA test
at screening.
It was also clarified that
participants with evidence of
HIV-1 or HIV-2 infection who
are on antiretroviral treatment
are excluded. 
Clarification upon Health 
Authority request
5.2 Exclusion Criteria
It was clarified that the use of 
low-dose aspirin is allowed 
with exception of 7 days prior 
to biopsies. 
Clarification upon 
investigator’s request. 
1.1 Synopsis
6.5 Concomitant Therapy
8.1 Liver Biopsy and Fine Needle Aspiration
Biopsy
Minor errors were corrected 
and minor clarifications were
made.
Correction and clarification. 
Throughout the protocol
Amendment 4 (30 July 2021)
Overall Rationale for the Amendment: The primary reason for this amendment is to offer participants
optional treatment with PegIFN-α2a for either 12 or 24 weeks starting after the Week 40 biopsy (or after
the optional leukapheresis if applicable), to investigate whether addition of PegIFN-α2a towards the end of
the treatment regimen may enhance response to treatment. This change is based on the availability of
preliminary 48-week treatment data from the Phase 2b study REEF-1 (73763989HPB2001) and new data
presented during the European Association for the Study of the Liver (EASL) conference of 2021 showing
that HBsAg declines with siRNA treatment can be increased when combined with PegIFN. 43
The REEF-1 study is evaluating the efficacy of 3 doses of JNJ-3989 (40, 100, or 200 mg Q4W) + NA, of
JNJ-3989 100 mg Q4W + JNJ-6379 + NA, of JNJ-6379 + NA, and of NA alone. Data showed that all
regimens were safe and well-tolerated through end of treatment at Week 48. The JNJ-3989 200 mg dose
achieved the highest response rate (19.1%) for the primary endpoint of meeting the NA treatment
completion criteria at Week 48 (ie, ALT <3x ULN, HBV DNA <LLOQ, HBeAg-negative [<LLOQ], and
HBsAg <10 IU/mL). No participant in the JNJ-6379 + NA arm and 1 participant in the NA alone arm
achieved the primary endpoint. The largest mean (SD) decline at Week 48 of 3.56 (1.328) log10 IU/mL was
observed in the JNJ-3989 200 mg + NA arm in the HBeAg positive currently not treated participants. The
mean HBsAg decline followed a biphasic pattern, with a steeper decline during the first 24 weeks followed
by a more shallow decline between Week 24 and Week 48. At Week 48, a limited number of participants
reached HBsAg seroclearance.
This amendment will allow to investigate whether addition of PegIFN-α2a for 12 or 24 weeks at or after
the Week 40 biopsy increases the participant’s chances to achieve HBsAg loss.


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Description of Change 
Brief Rationale 
Section Number and Name
In addition to the study 
intervention participants are 
randomized to, they may also 
receive optional treatment with 
PegIFN-α2a after the Week 40 
biopsy (or after the optional 
leukapheresis if applicable) but
before the Week 48 visit. The 
duration (either 12 or 24 
weeks) will be at the 
investigator’s discretion. 
To investigate whether 
addition of PegIFN-α2a 
towards the end of the 
treatment regimen increases 
the participant’s chances to
achieve HBsAg loss.
1.1 Synopsis
1.2 Schema
1.3.3 Schedule of Activities –Optional
PegIFN-α2a Treatment
2 INTRODUCTION
2.1 Study Rationale
2.2.1.3 Combination of JNJ-3989 with
PegIFN-α2a
2.2.1.4 Combination of JNJ-6379 with
PegIFN-α2a
2.2.2.3 Combination of JNJ-3989 and JNJ-
6379 with PegIFN-α2a
2.3 Benefit-Risk Assessment
3 OBJECTIVES AND ENDPOINTS
4.1 Overall Design
5.2 Exclusion Criteria
6.1 Study Intervention(s) Administered
6.2
Preparation/Handling/Storage/Accountability
6.4 Study Intervention Compliance
6.5 Concomitant Therapy
6.6 Dose Modification
7.1 Discontinuation of Study Intervention
8 STUDY ASSESSMENTS AND
PROCEDURES
8.5.6 Adverse Events of Special Interest
8.6 Treatment of Overdose
8.7 Pharmacokinetics
8.8 Pharmacokinetics/Pharmacodynamics
9.4.3 Other Analyses
10.1 Appendix 1: Abbreviations and
Definitions of Terms
10.2 Appendix 2: Clinical Laboratory Tests
10.3 Appendix 3: Regulatory, Ethical, and
Study Oversight Considerations
10.11 Appendix 11: Covid Appendix
11 REFERENCES
ALT elevations were added as 
a potential risk and the section 
on management of ALT 
elevations was updated. 
To ensure the safety of 
participants during treatment 
with JNJ-3989, based on 
emerging data from studies 
REEF-1 and REEF-D.
2.3.2.2.1 Potential Risks for JNJ-3989
8.5.6.1 Injection Site Reactions
10.6 Appendix 6: Intervention-emergent
ALT/AST Elevations
Updates were made to the 
assumed statistical distribution 
and model-based approach that 
will be used in the analysis of 
the primary efficacy endpoint
and also used to justify the
planned sample size.
For increased precision of 
the estimation of the 
primary efficacy endpoint 
and its variability. 
1.1 Synopsis
9.2 Sample Size Determination
9.4.1.1 Analysis of the Primary Endpoint
11 REFERENCES
Removal of the mITT 
population. 
The same approach for 
complete case analysis can 
be implemented using the 
ITT population (including 
1.1 Synopsis
9.3 Populations for Analyses
9.4.1 Analysis of Efficacy and Antiviral
Activity


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all panels) and therefore
mITT can be removed.
Description of efficacy and 
antiviral activity analyses were 
added to clarify the
explorations of interest which
include the statistical analyses
overall for the entire study
population, the comparisons
between panels regardless of
intervention arm, between
intervention arms within panel,
and between intervention arms
across panels.
For clarification and 
completeness. 
9.4.1 Analysis of Efficacy and Antiviral
Activity
Updates were made to the 
clinical background section as 
more data have become 
available. 
For completeness. 
2.2.2.1 JNJ-3989 and JNJ-6379
2.2.2.2 Combination of JNJ-3989 and JNJ-
6379 with Entecavir, Tenofovir Disoproxil, or
Tenofovir Alafenamide
2.3.3 Benefit-risk Assessment for Study
Participation
11 REFERENCES
Update of follow-up procedures 
and criteria for re-initiation of 
NA treatment. 
For clarification. 
4.2 Scientific Rationale for Study Design
6.6.2 NA Re-treatment Criteria During Follow-
up
10.12 Appendix 12: NA Re-treatment During
Follow-up
A study intervention 
discontinuation criterion was
added for participants who
withdraw consent.
For completeness. 
7.1 Discontinuation of Study Intervention
Study intervention 
discontinuation criteria on 
hepatic decompensation and
eGFRcr abnormality were
updated.
For clarification. 
7.1 Discontinuation of Study Intervention
8.5.6.4 Renal Complications
The study intervention 
discontinuation criterion on
virologic breakthrough was
updated.
For completeness. 
7.1 Discontinuation of Study Intervention
Local platelet aggregation 
testing was added to the 
schedule of activities instead of 
only mentioned in a footnote.
Correction. 
1.3.1 Schedule of Activities   Screening and
Study Intervention Phase
1.3.2 Schedule of Activities   Follow-up Phase
The footnotes related to HBeAg 
testing were corrected. 
Correction. 
1.3.1 Schedule of Activities   Screening and
Study Intervention Phase
Language on urine pregnancy 
testing for at-home use was 
updated. 
To provide additional 
guidance on urine pregnancy 
testing at home.
1.3.2 Schedule of Activities   Follow-up Phase
10.11 Appendix 11: Covid Appendix
Exclusion criterion 1 
(concerning evidence of HIV-1
or HIV-2 infection at
screening) and criterion 2 were
updated.
For clarification. 
5.2 Exclusion Criteria


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It was clarified that JNJ-3989 
should preferably be 
administered via subcutaneous
injection in the abdomen.
For clarification. 
1.1 Synopsis
6.1 Study Intervention(s) Administered
Head, neck, and thyroid were 
added to complete physical
examination.
For completeness. 
8.4.1 Physical Examinations
Language was added on 
medical encounters.
For completeness. 
8.11 Medical Encounters
Management ofrash and acute 
systemic allergic reactions were 
moved under a separate 
subheader. 
For correction and 
clarification as rash and
acute systemic allergic
reactions are not considered
AESIs for JNJ-3989 or JNJ-
6379.
8.5.6 Adverse Events of Special Interest
Minor errors were corrected 
and minor clarifications were
made.
Correction and clarification. 
Throughout the protocol
Amendment 3 (14 August 2020)
Overall Rationale for the Amendment:The sample size justification section was updated.
Section Number and Name 
Description of Change 
Brief Rationale
9.2 Sample Size Determination  
11 REFERENCES  
More details were added on the 
justification for sample size
determination
For clarification
1.3.2 Schedule of 
Activities - Follow-up Phase 
Optional biopsy was delinked from 
the leukapheresis procedure 
The leukapheresis procedure was
incorrectly linked with the optional
biopsy
10.11 Appendix 11: Covid 
Appendix  
Guidance on study conduct during 
the COVID-19 pandemic was 
added 
Options for study-related
participant management are being
provided in the event of disruption
to the study conduct due to the
COVID-19 pandemic
Amendment 2 (07 May 2020)
Overall Rationale for the Amendment: Following Health Authority (HA) feedback the protocol was
amended as specified below
Section Number and Name 
Description of Change 
Brief Rationale
1.1 Synopsis, 9.3 Populations for 
Analyses 
An additional population (mITT) 
was added. 
Per HA request, the modified ITT
(mITT) analysis set, restricted to
participants with biopsy data at
both Baseline and Week 40, was
defined as the primary analysis
population for consistency with the
planned observed cases analysis of
the primary efficacy endpoint
described in section 9.4.1.1.


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9.4.1 Analysis of Efficacy and 
Antiviral Activity, 9.4.1.1 Analysis 
of the Primary Endpoint, 9.4.1.2 
Analysis of Secondary Endpoints, 
9.4.1.3 Analysis of Exploratory 
Endpoints
The mITT analysis set was added to 
the ITT set for the purpose of the 
efficacy analyses. 
Per HA request, in order to evaluate
the potential bias in using complete
case analysis, both mITT as
primary analysis set and ITT as
secondary analysis set will be used.
Title page and footer 
Updated confidentiality statement 
In line with the latest protocol
template
Amendment 1 (10 April 2020)
Overall Rationale for the Amendment: Following Health Authority (HA) feedback the protocol was
amended as specified below
Section Number and Name 
Description of Change 
Brief Rationale
9.4.1.1 Analysis of the Primary 
Endpoint 
Methods for handling missing data 
were added to the protocol. 
Per HA request the approach to
handle missing data in the primary
analysis of the primary endpoint
was added.
2.3.2.3.1 Potential Risks and 
Inconvenience Associated with the 
Liver Biopsy Procedures 
8.5.6.3 Complications From Liver
Biopsy
The risk language regarding 
possible serious complications of 
liver biopsies has been updated.  
Per HA request the complications
from a liver biopsy are now
described in the protocol.
1.3.1 Schedule of 
Activities - Screening and Study 
Intervention Phase 
Schedule of Activities - Follow-up
Phase
Additional timepoints were added 
for whole blood single cell
profiling.
Correction


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10.11. Appendix 11: Covid Appendix
GUIDANCE ON STUDY CONDUCT DURING THE COVID-19 PANDEMIC
It is recognized that the Coronavirus Disease 2019 (COVID-19) pandemic may have an impact on
the conduct of this clinical study due to, for example, self-isolation/quarantine by participants and
study-site personnel; travel restrictions/limited access to public places, including hospitals; study-
site personnel being reassigned to critical tasks.
In alignment with recent health authority guidance, the sponsor is providing options for study-
related participant management in the event of disruption to the conduct of the study. This guidance
does not supersede any local or government requirements or the clinical judgement of the
investigator to protect the health and well-being of participants and site staff and maintain
oversight of delegated trial activities. If, at any time, a participant’s safety is considered at risk,
study intervention will be discontinued, and study follow-up will be conducted.
Scheduled visits that cannot be conducted in person at the study site will be performed to the extent
possible remotely/virtually or delayed until such time that on-site visits can be resumed. At each
contact, participants will be interviewed to collect safety data. Key efficacy endpoint assessments
should be performed if required and as feasible. Participants will also be questioned regarding
general health status to fulfill any physical examination requirement.
Every effort should be made to adhere to protocol-specified assessments for participants on study
intervention, including follow-up. Modifications to protocol-required assessments may be
permitted via COVID-19 Appendix after consultation with the participant, investigator, or the
sponsor. Missed assessments/visits will be captured in the clinical trial management system for
protocol deviations. Discontinuations of study interventions and withdrawal from the study should
be documented with the prefix “COVID-19-related” in the CR).
The sponsor will continue to monitor the conduct and progress of the clinical study, and any
changes will be communicated to the sites and to the health authorities according to local guidance.
If a participant has tested positive for COVID-19, the investigator should contact the sponsor’s
responsible medical officer to discuss plans for study intervention and follow-up. Modifications
made to the study conduct as a result of the COVID-19 pandemic should be summarized in the
clinical study report.


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GUIDANCE SPECIFIC TO THIS PROTOCOL
The following emergency provisions are meant to ensure participant safety on study while site
capabilities are compromised by COVID-19 related restrictions. Remote medical consultation and
alternatives to study intervention dispensing, administration, and clinical laboratory assessments
may allow continued study participation for participants in this trial. Before implementing any of
these emergency provisions, the sponsor should be consulted to perform a benefit-risk analysis
and to ensure the measures are executed and documented correctly.
As restrictions are lifted and the acute phase of the COVID-19 pandemic resolves, sites should
revert to original protocol conduct as soon as feasible and in accordance with any country-specific
regulatory requirements.
Dispensing/administration of study intervention:
 For participants able to visit the study site, but who request to reduce visit frequency, or for
whom limited access to the site is expected, an additional supply of oral study intervention can
be provided.
 For participants unable to visit the study site, direct-to-patient (DTP) shipment or handover to
a caregiver or delegate of oral study intervention may be implemented, where allowed per local
regulations and if requested by the treating study physician. Where DTP shipments or handover
to delegates are deemed necessary, the process must be coordinated between the site and
sponsor staff following standard DTP procedures for arranging shipment and adhering to
associated approvals and documentation requirements.
 JNJ-3989 should always be administered by a nurse at the study site or, if site visits are not
possible, at the participant’s home. Per the protocol, if a scheduled injection of JNJ-3989 was
missed, the injection should be given as soon as possible but within 3 weeks after the scheduled
time. Otherwise, the injection should be skipped and the next injection should be given at the
next scheduled time point per the initial injection schedule.
Continuation of study intervention:
 Any issue with continuation and/or provision of study intervention should be discussed with
the sponsor and should be well documented.
 Study intervention should be continued if, in the assessment of the investigator, it does not
result in risk to the participant. If at any time the participant’s safety is considered at risk due
to study intervention, study intervention will be temporarily or permanently discontinued,
while every effort should be made to maintain follow-up on study. The benefit of continuing
study intervention should be assessed by the investigator for each individual participant,
considering the potential impact of reduced direct clinical supervision on participant safety.
 If a participant develops a SARS-CoV-2 infection, the investigator should contact the sponsor
to discuss plans for study intervention and follow-up. A decision to continue study intervention
should be made by the investigator depending on symptoms and concomitant medication(s)
used for the treatment of COVID-19. Study intervention must be discontinued if prohibited
medication is used.


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 When a participant, for whom study intervention has been interrupted, recovers from suspected
or confirmed SARS-CoV-2 infection or related disease and all AEs related to SARS-CoV-2
infection improve to Grade ≤1, the investigator should discuss with the sponsor about resuming
study intervention.
COVID-19 vaccination during the study:
Local guidelines on the use of live vaccines in participants receiving PegIFN-α2a should be
followed, including for the second dose of Sputnik V (which contains rAd5, with a theoretical risk
of replication competence). Sputnik Light, which is the first dose of Sputnik V (with rAd26) is not
considered a live vaccine. See below for further guidance on the use of COVID-19 vaccines.
Locally approved COVID-19 vaccines (including those that received emergency use authorization
or conditional marketing authorization) are allowed throughout the study. For participants
receiving PegIFN-α2a, the following recommendations should be applied to accommodate
COVID-19 vaccination during PegIFN-α2a treatment:
 
COVID-19 vaccine and PegIFN-α2a should not be administered on the same day.
 
If required, PegIFN-α2a injection can be delayed with 2 days. The next PegIFN-α2a injection
should be performed at the scheduled time.
 
If required, skipping a PegIFN-α2a injection may be considered after consultation with the
Sponsor.
 
Vaccination with Sputnik V should take above-mentioned consideration about live vaccines
into account.
All COVID-19 vaccination-related data (eg, COVID-19 vaccination, AEs, AE management)
should be appropriately captured in the CRF and source documents. Refer to the COVID-19
vaccine and/or PegIFN-α2a prescribing information for more details.
Study visits and assessments:
 If possible, central laboratory testing as outlined in the Schedule of Activities is to be
continued. If central laboratory tests cannot be performed, the use of a local laboratory is
allowed for study evaluations. A copy of the local laboratory report should be reviewed by the
investigator and filed with the source documents, along with reference ranges.
 To safely maintain participants on study intervention while site capabilities are compromised
by COVID-19-related restrictions, study visits may be performed by a nurse (who received
study-specific training) at the patient’s home (home health nurse) until such time that on-site
visits can be resumed. The following activities may be completed as required per the Schedule
of Activities and as feasible:
 Sampling, processing and shipping of laboratory samples (as described above)
 Checking study compliance: medication diary (if available), intake of oral study
intervention, storage of oral study intervention
 Performing ECGs


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 If JNJ-3989 is administered at the patient’s home, it will need to be done by a nurse (who
received study-specific training)
 Delivering oral study interventions and urine pregnancy tests for at-home use
 Any data related to adverse events (AEs), concomitant medication, vital signs, and ECGs will
be reviewed and assessed by the investigator.
 In addition, participants may have tele-health visits conducted by qualified site personnel via
phone or video conversation as per local regulation. Assessments may include review of AEs
(including ISRs), concomitant medications, and study intervention accountability. Participants
will also be questioned regarding general health status to fulfill any physical examination
requirement.
 Procedures and timings should follow the Schedule of Activities as closely as possible.
Standard AE/SAE reporting requirements apply.
 Ultrasound (and Fibroscan where applicable) should be done as close as possible to the time
points specified in the Schedule of Activities. However, if this is not possible due to COVID-
19 related restrictions, the imaging test should be performed as soon as possible.
Informed consent:
 Consenting and re-consenting of participants (including also remote consenting by phone or
video consultation) will be performed as applicable for the measures taken and according to
local guidance for informed consent applicable during the COVID-19 pandemic. The process
is to be documented in the source documents.
Source data verification/monitoring:
 In case on-site monitoring visits are not possible, the site monitor may contact the investigator
to arrange monitoring activities remotely (in accordance with site and local requirements).
Additional on-site monitoring visits may be needed in the future to catch up on source data
verification.
Site audits:
 During the COVID-19 pandemic and at the impacted sites, study site GCP audits with direct
impact/engagement from the investigator and study-site personnel would not be conducted in
order to comply with national, local, and/or organizational social distancing restrictions.
Additional quality assurance activities such as remote audits or focused review of study-related
documents may take place with limited impact/engagement if possible.


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10.12. Appendix 12: NA Re-treatment and Monitoring After Stopping of NA


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11. 
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17. Janas MM, Harbison CE, Perry VK, et al. The nonclinical safety profile of GalNac-conjugated RNAi
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20. Li H, Zhai N, Wang Z, et al. Regulatory NK cells mediated between immunosuppressive monocytes and
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Status: Approved,  Date: 25 November 2021
21. Lok AS, Zoulim F, Dusheiko G, Ghany MG. Hepatitis B cure: from discovery to regulatory approval. J
Hepatol. 2017;67(4):847-861.
22. Magalhães-Costa P, Lebre L, Peixe P, Santos S, Chagas C. Hepatocellular carcinoma in chronic hepatitis B
patients on third generation nucleos(t)ides analogs: Risk factors and performance ofa risk score. GE Port J
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February 2005.
24. Memorandum to Advisory Committee Members and Guests from Tenofovir Review Team. Background
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25. Papatheodoridis GV, Chan HLY, Hansen BE, et al. Risk of hepatocellular carcinoma in chronic hepatitis B:
Assessment and modification with current antiviral therapy. J Hepatol. 2015;62:956 967.
26. Papatheodoridis GV, Rigopoulou EI, Papatheodoridi M, et al. DARING-B: discontinuation of effective
entecavir or tenofovir disoproxil fumarate long-term therapy before HBsAg loss in non-cirrhotic HBeAg
negative chronic hepatitis B. Antivir Ther. 2018;23(8):677-685.
27. PEGASYS Summary of Product Characteristics.
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Product Information/human/000395/WC500039195.pdf. Accessed 22 November 2019
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in 2016: a modelling study. Lancet Gastroenterol Hepatol 2018;3:383–403.
29. Rehermann B, Thimme R. Insights From Antiviral Therapy Into Immune Responses to Hepatitis B and C
Virus Infection. Gastroenterology. 2019;156(2):369–383.
30. Sarin KS, Kumar M, Lau GK, et al. Asian-Pacific clinical practice guidelines on the management of hepatitis
B: A 2015 update. Hepatol Int. 2016;10:1-98.
31. Stanaway JD, Flaxman AD, Naghavi M, et al. The global burden of viral hepatitis from 1990 to 2013: findings
from the global burden of disease Study 2013. Lancet. 2016;388(10049):1081-1088.
32. Tannehill-Gregg SH, Dominick MA, Reisinger AJ, et al. Strain-related Differences in Urine Composition of
Male Rats of Potential Relevance to Urolithiasis. Toxicol Pathol. 2009;37:293-305.
33. Terrault NA, Bzowej NH, Chang K, et al. AASLD guidelines for treatment of chronic hepatitis B. Hepatology.
2016;63(1):261 283.
34. Wang S, Chen Z, Hu C, et al. Hepatitis B virus surface antigen selectively inhibits TLR2 ligand-induced IL-12
production in monocytes/macrophages by interfering with JNK activation. J Immunol. 2013;190(10):5142
5151.
35. Wooddell CI, Yuen MF, Chan HL, et al. RNAi-based treatment of chronically infected patients and
chimpanzees reveals that integrated hepatitis B virus DNA is a source of HBsAg. Sci. Transl. Med. 2017; 9:
409.
36. Yuen MF, Chen DS, Dusheiko GM, et al. Hepatitis B virus infection. Nat Rev Dis Prim. 2018; 4: Article
number 18035.
37. Yuen MF, et al. First Clinical Experience with RNA Interference-based Triple Combination Therapy in
Chronic Hepatitis B: JNJ-3989, JNJ-6379 and a Nucleos(t)ide Analogue. The Liver Meeting, Boston 2019, LB
Poster 4.
38. Newcombe RG. Interval estimation for the difference between independent proportions: comparison of eleven
methods. Stat Med. 1998; 17, 873-890.
39. Investigator’s Brochure: JNJ-56136379 Edition 6, Addendum 1. Janssen Research & Development (July
2021).
40. Kassahun W, Neysens T, Molenbergh G, Faes C, Verbeke G. Modeling overdispersed longitudinal binary data
using a combined beta and normal random-effects model. Arch Public Health. 2012;70(1):7


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41. PEGASYS Summary of Product Characteristics. Roche Registration GmbH. Revised July 2020. Available at
https://www.ema.europa.eu/en/documents/product-information/pegasys-epar-product-information en.pdf.
Accessed 4 September 2020.
42. PEGASYS United States Prescribing Information. Hoffmann-La Roche, Inc. Revised October 2017. Available
at https://www.accessdata.fda.gov/drugsatfda docs/label/2017/103964s5270lbl.pdf. Accessed 4 September
2020.
43. Yuen MF, et al. Preliminary on-treatment data from a phase 2 study evaluating VIR-2218 in combination with
pegylated interferon alfa-2a in participants with chronic hepatitis B infection. EASL 2021. PO-824


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INVESTIGATOR AGREEMENT
I have read this protocol and agree that it contains all necessary details for carrying out this study. I will
conduct the study as outlined herein and will complete the study within the time designated.
I will provide copies of the protocol and all pertinent information to all individuals responsible to me who
assist in the conduct of this study. I will discuss this material with them to ensure that they are fully informed
regarding the study intervention, the conduct of the study, and the obligations of confidentiality.
Coordinating Investigator (where required):
Name (typed or printed):
Institution and Address:
Signature: 
Date:
(Day Month Year)
Principal (Site) Investigator:
Name (typed or printed):
Institution and Address:
Telephone Number:
Signature: 
Date:
(Day Month Year)
Sponsor's Responsible Medical Officer:
Name (typed or printed): 
Institution: 
Janssen Research & Development
Signature: 
electronic signature appended at the end of the protocol 
Date:
(Day Month Year)
Note: 
If the address or telephone number of the investigator changes during the study, written notification will be
provided by the investigator to the sponsor, and a protocol amendment will not be required.
PPD


Signature
User 
Date 
Reason
 
 
25-Nov-2021 
10:27:57
(GMT)
Document Approval
PPD

SAP_003.pdf: 
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
1
Status: Approved,  Date: 09 February 2024
Janssen Research & Development
Statistical Analysis Plan
Phase 2 Randomized, Open-label, Parallel-group, Multicenter Study to Assess Intrahepatic 
and Peripheral Changes of Immunologic and Virologic Markers in Response to 
Combination Regimens Containing JNJ-73763989 and Nucleos(t)ide Analog With or 
Without JNJ-56136379 in Patients With Chronic Hepatitis B Virus Infection
The INSIGHT Study
Protocol 73763989HPB2003; Phase 2
JNJ-73763989 and JNJ-56136379
Status:
Approved
Date:
09 February 2024
Prepared by:
Janssen Research & Development, a division of Janssen Pharmaceutica NV
Document No.: EDMS-RIM-270778, 4.0
Compliance: The study described in this report was performed according to the principles of Good Clinical Practice (GCP). 
Confidentiality Statement
The information provided herein contains Company trade secrets, commercial or financial information that the Company 
customarily holds close and treats as confidential.  The information is being provided under the assurance that the recipient
will maintain the confidentiality of the information under applicable statutes, regulations, rules, protective orders or 
otherwise.
NCT05653427


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Status: Approved,  Date: 09 February 2024
TABLE OF CONTENTS
TABLE OF CONTENTS ............................................................................................................................... 2
LIST OF IN-TEXT TABLES.......................................................................................................................... 4
LIST OF IN-TEXT FIGURES ........................................................................................................................ 4
VERSION HISTORY..................................................................................................................................... 5
1.
INTRODUCTION.................................................................................................................................. 8
1.1.
Objectives and Endpoints ................................................................................................................ 8
1.1.1.
For Panels 1 and 2 ....................................................................................................................... 8
1.1.2.
For Panel 3 ................................................................................................................................. 10
1.2.
Study Design.................................................................................................................................. 12
2.
STATISTICAL HYPOTHESES.......................................................................................................... 17
3.
SAMPLE SIZE DETERMINATION.................................................................................................... 17
4.
POPULATIONS (ANALYSIS SETS) FOR ANALYSIS..................................................................... 18
5.
STATISTICAL ANALYSES............................................................................................................... 19
5.1.
General Considerations ................................................................................................................. 19
5.1.1.
Analysis Phase ........................................................................................................................... 19
5.1.2.
Visit Windows ............................................................................................................................. 19
5.1.3.
On-Treatment and Off-Treatment Period ................................................................................... 21
5.1.4.
Missing and Partial Dates Imputation Rules............................................................................... 21
5.1.4.1.
Adverse Event Onset Date and Resolution Date .................................................................... 22
5.1.4.2.
HBV Diagnosis and Infection Dates ........................................................................................ 22
5.1.4.3.
Concomitant Medication Dates................................................................................................ 23
5.1.5.
Data Handling Rules................................................................................................................... 23
5.1.6.
Analysis Specifications ............................................................................................................... 24
5.1.7.
Level of Significance................................................................................................................... 25
5.2.
Participant Dispositions.................................................................................................................. 25
5.3.
Primary Endpoint Analyses............................................................................................................ 25
5.3.1.
For Panels 1 and 2 ..................................................................................................................... 26
5.3.1.1.
Definition of Endpoint .............................................................................................................. 26
5.3.1.2.
Analysis Methods .................................................................................................................... 26
5.3.1.2.1.
Missing Data Handling Rule................................................................................................. 26
5.3.1.2.2.
Primary Analysis of the Primary Endpoint............................................................................ 26
5.3.1.2.2.1.
Overall Analysis ................................................................................................................ 26
5.3.1.2.2.2.
Comparison Between Panels 1 and 2............................................................................... 27
5.3.1.2.3.
Secondary Analysis of the Primary Endpoint....................................................................... 28
5.3.1.2.4.
Sensitivity Analyses ............................................................................................................. 29
5.3.1.2.4.1.
Baseline Observation Carried Forward (BOCF) ............................................................... 29
5.3.1.2.4.2.
Multiple Imputation............................................................................................................ 29
5.3.1.2.4.3.
Per-Protocol Analysis (PP) ............................................................................................... 29
5.3.1.3.
Subgroup Analyses ................................................................................................................. 29
5.3.2.
For Panel 3 ................................................................................................................................. 30
5.3.2.1.
Definition of Endpoints............................................................................................................. 30
5.3.2.2.
Primary Analysis...................................................................................................................... 30
5.4.
Secondary Endpoints Analysis ...................................................................................................... 30
5.4.1.
Intrahepatic Secondary Endpoints.............................................................................................. 30
5.4.1.1.
Intrahepatic Immune Response............................................................................................... 30
5.4.1.1.1.
For Panels 1 and 2............................................................................................................... 30
5.4.1.1.2.
For Panel 3........................................................................................................................... 31
5.4.1.2.
Intrahepatic Viral Parameters.................................................................................................. 31
5.4.1.2.1.
For Panels 1 and 2............................................................................................................... 31


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5.4.1.2.2.
For Panel 3........................................................................................................................... 31
5.4.2.
Blood Peripheral Secondary Endpoints...................................................................................... 31
5.4.2.1.
HBsAg Seroclearance ............................................................................................................. 31
5.4.2.1.1.
Time to HBsAg Seroclearance............................................................................................. 32
5.4.2.2.
HBsAg Seroconversion ........................................................................................................... 32
5.4.2.3.
HBeAg Seroclearance and Seroconversion............................................................................ 32
5.4.2.4.
HBsAg, HBeAg, HBV DNA and ALT ....................................................................................... 33
5.4.2.4.1.
Values and Changes Over Time.......................................................................................... 33
5.4.2.4.1.1.
Change from Baseline Over Time..................................................................................... 33
5.4.2.4.2.
HBsAg Thresholds ............................................................................................................... 34
5.4.2.4.3.
HBeAg Thresholds ............................................................................................................... 34
5.4.2.4.4.
HBV DNA Thresholds .......................................................................................................... 35
5.4.2.4.5.
ALT Decrease and Normalization ........................................................................................ 35
5.4.2.4.6.
Study Intervention Completion at Week 48 and During Follow-up ...................................... 36
5.4.2.4.7.
NA Re-Treatment During Follow-up ........................................................................................ 36
5.4.2.4.8.
ALT Normalization after NA Re-Treatment.......................................................................... 36
5.4.2.4.9.
Thresholds On Multiple Markers .......................................................................................... 36
5.4.2.5.
Functional Cure ....................................................................................................................... 37
5.4.2.6.
Flares....................................................................................................................................... 38
5.4.2.6.1.
Definition .............................................................................................................................. 38
5.4.2.7.
HBV Virologic Breakthrough.................................................................................................... 40
5.4.2.7.1.
Definition .............................................................................................................................. 40
5.4.2.8.
HBV-Specific T-Cells Response.............................................................................................. 40
5.4.3.
Subgroup Analyses..................................................................................................................... 41
5.5.
Exploratory Endpoints Analysis ..................................................................................................... 41
5.5.1.
Relationship Between Intrahepatic and Blood Markers.............................................................. 41
5.5.2.
Association Between Baseline Characteristics or Intrahepatic/Blood Markers with 
Efficacy Variables ....................................................................................................................... 42
5.5.3.
Intrahepatic Immune and Viral Parameters at FU Week 24 (Week 72)..................................... 43
5.5.4.
Liver Stiffness Measurement (LSM) ........................................................................................... 43
5.5.5.
HBV RNA and HBcrAg ............................................................................................................... 44
5.5.6.
Sustained HBsAg Response ...................................................................................................... 44
5.6.
Safety Analyses ............................................................................................................................. 45
5.6.1.
Extent of Exposure ..................................................................................................................... 45
5.6.2.
Adverse Events........................................................................................................................... 46
5.6.3.
Additional Safety Assessments .................................................................................................. 47
5.6.3.1.
Clinical Laboratory Tests......................................................................................................... 47
5.6.3.1.1.
Creatinine and Glomerular Filtration .................................................................................... 49
5.6.3.1.1.1.
eGFR................................................................................................................................. 50
5.6.3.1.1.2.
Proximal Renal Tubular Function...................................................................................... 50
5.6.3.2.
Vital Signs and Physical Examination Findings....................................................................... 52
5.6.3.3.
Electrocardiogram ................................................................................................................... 53
5.7.
Other Analyses............................................................................................................................... 55
5.7.1.
Pharmacokinetics ....................................................................................................................... 55
5.7.2.
Pharmacokinetic/Pharmacodynamic Relationships ................................................................... 55
5.7.3.
Viral Genome Sequence Analysis .............................................................................................. 55
5.7.4.
Definition of Subgroups .............................................................................................................. 55
5.8.
Interim Analyses............................................................................................................................. 56
6.
SUPPORTING DOCUMENTATION .................................................................................................. 58
6.1.
Appendix 1 List of Abbreviations.................................................................................................... 58
6.2.
Appendix 2 Changes to Protocol-Planned Analyses ..................................................................... 60
6.3.
Appendix 3 Demographics and Baseline Characteristics.............................................................. 61
6.3.1.
Demographics............................................................................................................................. 61
6.3.2.
Baseline Characteristics ............................................................................................................. 61
6.4.
Appendix 4 Protocol Deviations ..................................................................................................... 64
6.5.
Appendix 5 Prior and Concomitant Medications............................................................................ 65
6.6.
Appendix 6 Medical History ........................................................................................................... 66


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6.7.
Appendix 7 Intervention Compliance ............................................................................................. 67
6.8.
Appendix 8 Adverse Events of Special Interest............................................................................. 68
6.9.
Appendix 9 Laboratory Toxicity Grading........................................................................................ 73
ATTACHMENT 1.
SIMULATIONS FOR SAMPLE SIZE JUSTIFICATION ............................................ 74
ATTACHMENT 2.
SELECTED MAJOR PROTOCOL DEVIATIONS FOR ANALYSIS 
PURPOSES
79
ATTACHMENT 3.
SAS CODE TO FIT BINOMIAL MIXED MODELS.................................................... 81
7.
REFERENCES................................................................................................................................... 83
LIST OF IN-TEXT TABLES
Table 1:
Analysis Phases Start and End Dates...................................................................................... 19
Table 2:
Visit Windows............................................................................................................................ 20
Table 3:
Data Handling Rules for HBV Virology and Serology Assessments ........................................ 24
Table 4:
List of Intrahepatic and Blood Markers of Interest.................................................................... 41
Table 5:
Laboratory Parameters ............................................................................................................. 47
Table 6:
List of Subgroups of Interest for Efficacy and/or Safety Purpose............................................. 55
Table 7:
Overview of Times of Data Summaries and Analyses at Planned Interim, Primary and 
Final Analyses........................................................................................................................... 56
Table 8:
Demographic Variables............................................................................................................. 61
Table 9:
Baseline Characteristics Variables ........................................................................................... 61
Table 10:
List of scenarios for assumptions on the true proportion of HBsAg+ hepatocytes for 
each panel at each time point................................................................................................... 74
Table 11:
Simulation-based estimates for the overall and between-panel analyses of the 
reduction in proportion of positive hepatocytes ........................................................................ 78
LIST OF IN-TEXT FIGURES
Figure 1:
Schematic Overview of the Study – Prior to Protocol Amendment 5 ....................................... 15
Figure 2:
Schematic Overview of the Study – As of Protocol Amendment 5........................................... 16
Figure 3:
Simulation-based estimated widths of 80% confidence intervals for the (i and ii) overall 
and (iii and iv) between-panel analyses of the reduction in proportion of positive 
hepatocytes............................................................................................................................... 77


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Statistical Analysis Plan 73763989HPB2003
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Status: Approved,  Date: 09 February 2024
VERSION HISTORY
SAP Version History Summary
Document History
Date
Original SAP
14 June 2022
Amendment 1
29 March 2023
Amendment 2
09 February 2024
Amendment 2 (this document)  
Clarifications, Additions, Corrections
Section 
Number 
and 
Name
Description of Change
Rationale
5.4.1.2 Intrahepatic Viral 
Parameters
Some viral parameters have been 
removed.
The data was not collected because of 
various issues with laboratory 
processing.
5.5.1, Table 4 List of 
Intrahepatic and Blood 
Markers of Interest
Removal of some intrahepatic markers 
and endpoints.
The data was not collected because of 
various issues with laboratory 
processing.
5.5.2 Association Between 
Baseline Characteristics or 
Intrahepatic/Blood Markers 
with Efficacy Variables
Added some intrahepatic markers and 
removed others.
Revised list to be consistent with actual 
data that was collected.
6.3.2, Table 9 Baseline 
Characteristics Variables
Removed several intrahepatic markers 
and added description to analysis
Revised list to be consistent with actual 
data that was collected.
5.7.4 Definition of 
Subgroups
Revised definitions of subgroups used 
in analysis of efficacy and safety 
outcomes.
The definitions for the subgroups have 
been revised according to discussions 
with the clinical team. Thresholds for the 
subgroups have also been defined, based 
on interim analysis of subject data.  
5.4.2.4.1.2 Change from 
Baseline to Nadir
Removed analysis
Clinical team decided that this analysis 
was no longer relevant.
Amendment 1 
Overall rational for Amendment 1: This administrative amendment incorporates additional clarification 
on endpoints, data handling rules, on-treatment and off-treatment definition that have previous been 
documented in the Data Presentation Specification for past interim analysis.


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Clarifications, Additions, Corrections
Section Number and Name
Description of Change
Rationale
5.1.3 On-Treatment and 
Off-Treatment Period
Added definition for the on-treatment 
and off-treatment period.
Previous logic did not account for 
different end of the on-treatment period 
based on the last study agent.
5.1.5 Data Handling Rules
Revised ULOQ and Imputed Values 
data cutpoints for HBsAg, HBeAg
and HBcrAg.
Updated guidelines for the imputation 
of HBV DNA.
Improved language for clarity and 
precision.
5.1.6 Analysis 
Specifications
Added to text to avoid time-to-event 
and subgroup analyses in case that 
there are not enough data.
Improved language for clarity.
5.3.1.2.4.2 Multiple 
Imputation
Reduced the number of imputed 
datasets to 20.
Number of imputed datasets was 
reduced due to limited missing data.
5.4.1.2 Intrahepatic Viral 
Parameters
Added the analysis of Intrahepatic 
HBcAg.
Added endpoint which was not included 
in the previous version.
5.4.2.3 HBeAg 
Seroclearance and 
Seroconversion
5.4.2.4 HBsAg, HBeAg,
HBV DNA and ALT
5.4.2.4.3 HBeAg Thresholds
Updated text for HBeAg analyses 
which will be performed only for 
HBeAg positive participants at study 
entry.
Improved language for clarity and 
precision.
5.4.2.4.9 Thresholds On 
Multiple Markers
Added two thresholds HBsAg and 
HBV DNA thresholds
Additional analyses for HBsAg and 
HBV DNA thresholds were decided to 
be performed after approval of the 
original SAP (dated 14 June 2022).
5.4.2.7.2. Time to Flare
5.4.2.8.2. Time to HBV 
Virologic Breakthrough
These sections were removed due to 
reduced sample size.
Time to event analyses were removed 
due to reduced number of events for this 
type of analysis.
Partial Cure
Removed the partial cure endpoint 
and analysis.
The initial planned analysis of this 
endpoint is covered by other analyses.
5.5.6 Sustained HBsAg 
Response
Added section with definitions of 
HBsAg sustained response and their 
analyses.
Additional analysis for HBsAg was 
included to better characterize off-
treatment HBsAg response.


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Clarifications, Additions, Corrections
Section Number and Name
Description of Change
Rationale
5.7.3 Viral Genome 
Sequence Analysis
Removed subsections.
Subsections were removed to simplify 
the analysis.
5.7.4 Definition of 
Subgroups
Removed some subgroups.
Considering the small sample size, it 
was decided to remove some subgroups.
Medications of Special 
Interest
Removed the medications of special 
interest section.
Removal due to discontinuation of JNJ-
6379.
7 References
Removed references related to Viral 
Genome Sequencing.
References were removed due to 
removal of the subsections from the 
Viral Genome Sequencing section.
Throughout the document
Clarification of text.
Typographical corrections or improved 
language for clarity and precision.


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1.
INTRODUCTION
This statistical analysis plan (SAP) is for study 73763989HPB2003 (INSIGHT): A Phase 2 
randomized, open-label, parallel-group, multicenter study to assess intrahepatic and peripheral 
changes of immunologic and virologic markers in response to combination regimens containing 
JNJ-73763989 (JNJ-3989) and nucleos(t)ide analog (NA) with or without JNJ-56136379 (JNJ-
6379) in patients with chronic hepatitis B virus (HBV) infection. Participants who provide separate 
consent may additionally receive optional treatment with pegylated interferon alpha-2a (PegIFN-
α2a).
This SAP, which is to be interpreted in conjunction with the Clinical Protocol Amendment 6
(finalized on 25 November 2021) and country-specific Amendment 6/FRA-3 (finalized on 25
November 2021), describes the definitions of analysis sets, derived variables, and statistical 
methods to assess efficacy, safety, and pharmacokinetics/pharmacodynamics (PK/PD) of the study 
intervention arms. Details of the plasma PK/PD analyses will be described in a separate analysis
and modeling plan.
INSIGHT will enroll patients in three study panels. Panel 1 will consist of participants who are 
HBeAg positive and not currently treated. Panel 2 will consist of participants who are HBeAg 
negative and virologically suppressed by entecavir (ETV), tenofovir disoproxil (TD), or tenofovir 
alafenamide (TAF) treatment. Panel 3 will consist of participants who are HBeAg positive or
negative and are either not currently treated or virologically suppressed by ETV or TD treatment.
Panels 1 and 2 will have one set of objectives and endpoints, while Panel 3 will have its own set.
Note: The Panel 3 data analysis is for the country-specific Amendment 6/FRA-3 and concerns 
only 4 patients from France.
As of Protocol Amendment 5, participants who were previously randomized to receive JNJ-6379 
treatment had to immediately stop JNJ-6379 and will thereafter receive JNJ-3989 and NA only. 
New participants will enroll without randomization to receive JNJ-3989 and NA.
1.1.
Objectives and Endpoints
1.1.1.
For Panels 1 and 2
In Panels 1 and 2, the following objectives and endpoints will be assessed, overall and by study 
panel:
Objectives (Panels 1 and 2)
Endpoints (Panels 1 and 2)
Primary

To assess changes in intrahepatic HBsAg 
between baseline and on-treatment liver 
biopsy in response to JNJ-3989-based 
combination treatment

Changes in the proportion of HBsAg positive 
hepatocytes between baseline and on-treatment 
Week 40


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Objectives (Panels 1 and 2)
Endpoints (Panels 1 and 2)
Secondary

To assess changes in intrahepatic immune 
response 
between 
baseline 
and 
on-treatment liver biopsy

Changes between baseline and on-treatment liver 
biopsy in intrahepatic immune response (e.g., 
CD45+ T-cells, CD4+ T-cells, CD8+ T-cells, 
Natural Killer cells, and dendritic cells) in terms 
of proportion of cells, cell types, and spatial 
redistribution

To assess changes in intrahepatic viral 
nucleic acids and proteins between 
baseline and on-treatment liver biopsy

Changes from baseline in intrahepatic viral 
parameters 
(such 
as 
cccDNA, 
pgRNA, 
intrahepatic RNA, or HBsAg in terms of copy 
number, or number of positive cells)

Changes from baseline in intrahepatic cccDNA 
levels 
and 
transcriptional 
activity 
(pgRNA/cccDNA ratio)

To evaluate the efficacy of the study 
intervention as measured in the periphery

The proportion of participants during the study 
intervention and follow-up phases with:

HBsAg seroclearance at Week 72 (i.e., 24 
weeks after completion of all study 
interventions at Week 48) without restarting 
NA treatment.

(Sustained) Reduction, suppression, and/or 
seroclearance 
considering 
single 
and 
multiple markers (such as HBsAg, HBeAg, 
HBV DNA and ALT) 

HBsAg and HBeAg seroconversion 

Flares (virologic, biochemical, and clinical)

Time to first HBsAg seroclearance

To evaluate the frequency of virologic 
breakthrough during study intervention

Proportion 
of 
participants 
with 
virologic 
breakthrough

To assess HBV-specific T-cell responses

Changes 
from 
baseline 
in 
HBV-specific 
peripheral blood T-cell responses during the 
study intervention and follow-up phases

To evaluate the safety and tolerability of 
the study intervention 

Proportion of participants with (S)AEs and 
abnormalities 
in 
clinical 
laboratory 
tests 
(including hematology, blood biochemistry, 
blood coagulation, urinalysis, urine chemistry, 
and renal biomarkers), 12-lead ECGs, vital signs, 
and physical examinations throughout the study

To evaluate the plasma PK of JNJ-3989 
(i.e.,
JNJ-3976 and JNJ-3924),
and 
optionally of JNJ-6379, NA, and PegIFN-
α2a, as applicable

Plasma PK parameters of JNJ-3976, JNJ-3924, 
and optionally of JNJ-6379, NA, and PegIFN-
α2a, as applicable


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Objectives (Panels 1 and 2)
Endpoints (Panels 1 and 2)
Exploratory

To explore the relationship of intrahepatic 
markers with blood markers (immune and 
viral)

Association between levels and changes in 
intrahepatic and blood markers

To explore the association of baseline 
characteristics and intrahepatic and/or 
blood (immune and viral) biomarkers at 
baseline and on/off-treatment with selected 
on/off-treatment efficacy variables

Association of baseline characteristics and 
baseline and on/off-treatment viral blood markers 
(such as baseline NA treatment duration, age, and 
baseline and on/off-treatment HBsAg levels) 
with selected off-treatment efficacy variables 

Association of intrahepatic and blood biomarkers 
(such as cccDNA levels, T-cell frequency) with 
selected on/off-treatment efficacy variables

To explore intrahepatic immune and viral 
changes at Week 72 and/or during off-
treatment flares (only for participants with 
Week 72 biopsy available)

Changes from baseline and on-treatment liver 
biopsy in intrahepatic immune and viral markers 
at Week 72 and/or during off-treatment flares 
(only for participants with Week 72 biopsy 
available)

To explore changes in the severity of liver 
disease

Changes in fibrosis (according to Fibroscan liver 
stiffness measurements) at the end of study 
intervention (EOSI) and end of follow-up versus 
screening/baseline*

To explore the efficacy in terms of changes 
in HBV RNA and hepatitis B core-related 
antigen (HBcrAg) levels. 

Changes from baseline in HBV RNA and 
HBcrAg levels during study intervention and 
follow-up phases.

To explore the relationship between 
plasma PK parameters (JNJ-3989 [i.e.,
JNJ-3976 and JNJ-3924] and/or JNJ-6379 
and/or NA
and/or PegIFN-α2a) and 
selected 
pharmacodynamic 
(PD) 
parameters of efficacy and/or safety, as 
applicable

Relationship between various plasma PK 
parameters (JNJ-3976 and JNJ-3924, and/or 
JNJ-6379, and/or NA, and/or PegIFN-α2a) and 
selected efficacy and/or safety endpoints, as 
applicable

To explore the HBV genome sequence

The 
emergence 
of 
intervention-associated 
mutations during the study intervention and 
follow-up phases

To assess the impact of baseline HBV genome 
polymorphisms on selected on/off-treatment 
efficacy variables
* Only applicable to participants who are enrolled at a site with an on-site Fibroscan device.
1.1.2.
For Panel 3
An additional single-arm Panel 3 will be enrolled to assess liver concentrations of JNJ-3989, i.e.,
JNJ-73763976 (JNJ-3976), JNJ-73763924 (JNJ-3924), and JNJ-87719164 (also known as M65, a
deaminated metabolite of JNJ-3976) in HBV-infected participants.


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The following objectives and endpoints will be assessed for Panel 3:
Objectives (Panel 3)
Endpoints (Panel 3)
Primary*

To assess changes in drug concentrations 
over 
time 
during 
JNJ-3989-based 
combination treatment

Liver concentrations of JNJ-3989 (i.e., JNJ-3976 
and JNJ-3924)* measured at treatment Weeks 12 
and 40

Assessment of drug accumulation in the liver 
over time

Correlation of liver and plasma PK levels
Secondary

To evaluate the plasma PK of JNJ-3989 
(i.e.,
JNJ-3976 and JNJ-3924), and 
optionally of NA and PegIFN-α2a, as 
applicable

Plasma PK parameters of JNJ-3989 (i.e.,
JNJ-3976 and JNJ-3924), and optionally of NA
and PegIFN-α2a, as applicable

To evaluate the efficacy of the study 
intervention as measured in the periphery

The number of participants during the study 
intervention and follow-up phases with:

HBsAg seroclearance at Week 72 (i.e., 24 
weeks after completion of all study 
interventions at Week 48) without restarting 
NA treatment.

(Sustained) Reduction, suppression, and/or 
seroclearance 
considering 
single 
and 
multiple markers (such as HBsAg, HBeAg, 
HBV DNA and ALT) 

HBsAg and HBeAg seroconversion 

Flares (virologic, biochemical, and clinical)

Time to first HBsAg seroclearance

To evaluate the frequency of virologic 
breakthrough during study intervention

Number
of 
participants 
with 
virologic 
breakthrough

To assess HBV-specific T-cell responses

Changes 
from 
baseline 
in 
HBV-specific 
peripheral blood T-cell responses during the 
study intervention and follow-up phases

To evaluate the safety and tolerability of 
the study intervention 

Number
of participants with (S)AEs and 
abnormalities 
in 
clinical 
laboratory 
tests 
(including hematology, blood biochemistry,
blood coagulation, urinalysis, urine chemistry, 
and renal biomarkers), 12-lead ECGs, vital signs, 
and physical examinations throughout the study
Exploratory

To assess changes in intrahepatic immune 
response 
between 
early 
and 
later 
on-treatment liver biopsy, if applicable

Values at Weeks 12 and 40 and change at W40
from Week 12 liver biopsy in intrahepatic 
immune response (e.g., CD45+ T-cells, CD4+ 
T-cells, CD8+ T-cells, Natural Killer cells, and 


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Objectives (Panel 3)
Endpoints (Panel 3)
dendritic cells) in terms of proportion of cells and
cell types

To assess changes in intrahepatic viral 
nucleic acids and proteins between early 
and later on-treatment liver biopsy, if 
applicable

Values at Weeks 12 and 40 and change at
Week 40
from Week 12 liver biopsy in
intrahepatic viral parameters (such as cccDNA, 
pgRNA, intrahepatic RNA, or HBsAg in terms of 
copy number, or number of positive cells)

Values at Weeks 12 and 40 and change at
Week 40
from Week 12 liver biopsy in
intrahepatic cccDNA levels and transcriptional 
activity (pgRNA/cccDNA ratio)

To explore the relationship between liver
and plasma PK parameters (JNJ-3989 [i.e.,
JNJ-3976 and JNJ-3924] and/or NA and/or 
PegIFN-α2a) 
and 
selected 
pharmacodynamic (PD) parameters of 
efficacy and/or safety, as applicable

Relationship between various plasma PK 
parameters (JNJ-3989 [i.e.,
JNJ-3976 and 
JNJ-3924], and/or NA, and/or PegIFN-α2a) and 
selected efficacy and/or safety endpoints, as 
applicable

To explore the association of baseline 
characteristics and blood (immune and 
viral) biomarkers at baseline and on/off-
treatment with selected on/off-treatment 
efficacy variables

Association of baseline characteristics and 
baseline and on/off-treatment viral blood 
markers (such as baseline NA treatment duration, 
age, and baseline and on/off-treatment HBsAg 
levels) with selected off-treatment efficacy 
variables 

To explore changes in the severity of liver 
disease

Changes in fibrosis (according to Fibroscan liver 
stiffness measurements) at the end of study 
intervention (EOSI) and end of follow-up versus 
screening/baseline**

To explore the efficacy in terms of changes 
in HBV RNA and hepatitis B core-related 
antigen (HBcrAg) levels. 

Changes from baseline in HBV RNA and 
HBcrAg levels during study intervention and 
follow-up phases.

To explore the HBV genome sequence

The 
emergence 
of 
intervention-associated 
mutations during the study intervention and 
follow-up phases

To assess the impact of baseline HBV genome 
polymorphisms on selected on/off-treatment 
efficacy variables
* The focus of the primary objective for Panel 3 will be the liver concentrations of JNJ-3989 (i.e., JNJ-3976 and 
JNJ-3924). If there is any sample remaining after the drug concentration measurements, the applicable secondary 
and exploratory objectives will be assessed.
** Only applicable to participants who are enrolled at a site with an on-site Fibroscan device
1.2.
Study Design
A target of 24 chronic HBV-infected male and female participants, 18-65 years (inclusive) of age


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will be enrolled in Panels 1 and 2, approximately 12 participants in each panel. In Panel 3, a target 
of 4-6 chronic HBV-infected male and female participants will be enrolled.

Panel 1 will consist of participants who are HBeAg positive and not currently treated.

Panel 2 will consist of participants who are HBeAg negative and virologically suppressed by 
ETV, TD, or TAF treatment.

Panel 3 will consist of participants who are HBeAg positive or negative and are either not 
currently treated or virologically suppressed by ETV or TD treatment.
The study will be conducted in 3 phases for all participants: 

A screening phase (4 to 6 weeks),

An open-label study intervention phase (48 weeks),

A follow-up phase (48 weeks). Note that the follow-up period will be extended up to an 
additional 24 weeks for participants who are receiving optional treatment with PegIFN-α2a 
and who meet NA treatment completion criteria at the end of treatment with NA and PegIFN-
α2a to ensure all participants have at least one year of follow-up after NA treatment cessation.
The duration of individual participation will be up to 102 weeks for participants who stop NA 
treatment at the end of the open-label phase, or up to 126 weeks for participants who stop NA 
treatment during the follow-up phase.
Prior to Protocol Amendment 5, in Panels 1 and 2, participants were randomized in a 1:1 ratio 
within each panel to receive one of the following interventions (i.e., treatments) for 48 weeks:

Arm 1, combination regimen JNJ-3989+JNJ-6379+NA:

200 mg JNJ-3989 (SC injection Q4W, with the last injection at Week 44), and

250 mg JNJ-6379 (tablets qd), and

NA: ETV, TD, or TAF (tablets qd)

Arm 2, combination regimen JNJ-3989+NA:

200 mg JNJ-3989 (SC injection Q4W, with the last injection at Week 44), and

NA: ETV, TD, or TAF (tablets qd).
As of Protocol Amendment 5, in Panels 1 and 2, participants who were previously randomized to 
Arm 1 had to stop JNJ-6379 treatment immediately but will still receive JNJ-3989 and NA –
effectively joining Arm 2. New participants will enroll without randomization to Arm 2.
No participants were enrolled in Panel 3 before Protocol Amendment 5 was in effect. Therefore, 
all Panel 3 participants will enroll without randomization to receive the Arm 2 regimen.
In addition, participants who provide separate consent may receive optional treatment with 
PegIFN-α2a starting after the Week 40 biopsy (or after the optional leukapheresis if applicable) 
but before the Week 48 visit. The duration (either 12 or 24 weeks) will be at the investigator’s 


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discretion. This will allow investigation of whether addition of PegIFN-α2a for 12 or 24 weeks 
may increase the participant’s chance to achieve HBsAg loss.
All participants will complete treatment with JNJ-3989 after a fixed duration of 48 weeks. 
Treatment with NA will also be completed at Week 48 except for participants not meeting the NA 
treatment completion criteria (outlined in Protocol Section 6.6.1). In participants not meeting these 
criteria, NA treatment will continue during the follow-up phase. Participants who are receiving 
optional treatment with PegIFN-α2a and who have not met NA treatment completion criteria at 
Week 48 may have NA treatment completion criteria assessed at the end of treatment with PegIFN-
α2a and stop NA if criteria are met.
In case of premature discontinuation of study agent JNJ-3989 (before Week 48), follow-up
assessments should be obtained until 48 weeks after End Of Study Intervention (EOSI) unless the 
participant withdraws consent. Participants who withdraw consent will be offered an optional 
safety follow-up visit.
The SAP will use throughout the document the following definitions:

Study treatment refers to JNJ-6379, JNJ-3989, NA (either ETV, TD, or TAF), and PegIFN-
α2a.

Study agent refers to JNJ-6379 and JNJ-3989

Arm refers to:
o
Arm 1: JNJ-3989+JNJ-6379+NA

Arm 2: JNJ-3989+NA
A schematic overview of the study is presented in Figure 1 (Prior to Protocol Amendment 5) and 
in Figure 2 (As of Protocol Amendment 5).


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Figure 1:
Schematic Overview of the Study – Prior to Protocol Amendment 5
ETV: entecavir; N: number of participants; LB: (planned) liver biopsy; NA: nucleos(t)ide analog; Q4W: once every 
4 weeks; qd: once daily; TAF: tenofovir alafenamide; TD: tenofovir disoproxil; QW: once weekly
* Participants who provide separate consent may receive optional treatment with PegIFN-α2a starting 
after the Week 40 biopsy (or after the optional leukapheresis visit if applicable) for a duration of either 12 
or 24 weeks at the investigator’s discretion.
** Treatment with JNJ-3989 (and JNJ-6379 if applicable) will be stopped at Week 48. Optional treatment 
with PegIFN-α2a will be stopped after 12 or 24 weeks (at the investigator’s discretion). NA treatment 
may be stopped at Week 48 (or later for participants on PegIFN-α2a treatment) if NA treatment 
completion criteria are met.


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Figure 2:
Schematic Overview of the Study – As of Protocol Amendment 5
ETV: entecavir; N: number of participants; LB: (planned) liver biopsy; NA: nucleos(t)ide analog; Q4W: once every 
4 weeks; qd: once daily; TAF: tenofovir alafenamide; TD: tenofovir disoproxil; QW: once weekly
* Participants who provide separate consent may receive optional treatment with PegIFN-α2a starting after the 
Week 40 biopsy (or after the optional leukapheresis visit if applicable) for a duration of either 12 or 24 weeks at 
the investigator’s discretion.
** Treatment with JNJ-3989 (and JNJ-6379 if applicable) will be stopped at Week 48. Optional treatment with 
PegIFN-α2a will be stopped after 12 or 24 weeks (at the investigator’s discretion). NA treatment may be stopped 
at Week 48 (or later for participants on PegIFN-α2a treatment) if NA treatment completion criteria are met.
*** The follow-up phase will be extended for participants who are receiving optional treatment with PegIFN-α2a 
and who meet NA treatment completion criteria at the end of treatment with NA and PegIFN-α2a to ensure all 
participants have at least one year of follow-up after NA treatment cessation.
Note: Former Arm 1 participants (randomized before Protocol Amendment 5) will now be joining Arm 2, both in 
terms of treatment assignment as well as how they will be statistically analyzed.


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2.
STATISTICAL HYPOTHESES
As this is an exploratory study, no hypothesis has been formulated.
3.
SAMPLE SIZE DETERMINATION
This study aims to enroll 18 to 24 participants in total across Panels 1 and 2, i.e., 8 to 12 participants 
per study panel. In Panel 3, approximately 4-6 participants will be enrolled.
Regarding Panels 1 and 2, due to the exploratory nature of the study, the sample size was 
determined based on clinical and feasibility considerations related to the liver biopsy procedures 
performed multiple times during the study, rather than a formal statistical calculation.
Nevertheless, a sample size of 8 to 12 participants each in Panel 1 and 2 is considered sufficient to 
provide adequate precision of the estimate of the primary endpoint (change from baseline to Week 
40 in the proportion of HBsAg+ hepatocytes) as estimated by the 80% confidence interval (CI). 
For the estimation of the absolute change in the proportion of HBsAg+ hepatocytes from baseline 
to Week 40 for the overall study population (Panels 1 and 2 combined), the following assumptions 
were made. Assuming an absolute reduction of 70% in Panel 1 (75% at baseline versus 5% at 
Week 40) and 29% in Panel 2 (30% at baseline versus to 1% at Week 40), and assuming an inter-
subject variability of the change equal to 0.5 on the logit scale in both panels, a binomial model
(Kassahun et al 2012)including visit as covariate with normal random effects provides an expected 
width of the 80% CI of 16.7% for N=24, a width of 17.9% for N=20, and a width of 20.3% for 
N=16. The point estimates (two-sided 80% CI) are 50.8% (42.5%; 59.1%) with N=24, 50.7%
(41.8%; 59.7%) with N=20, and 50.6% (40.5%; 60.8%) with N=16.
For the between-panel difference in the absolute reduction in the proportion of HBsAg+
hepatocytes from baseline to Week 40 using the binomial model described above augmented with 
panel as an additional covariate and the same inter-subject variability, the estimated width of the 
two-sided 80% CI around the difference (Panel 1 – Panel 2) is 17.6% for N=24 (12 per panel), 
19.3% for N=20 (10 per panel), and 21.2% for N=16 (8 per panel). The point estimates (80% CI) 
are 40.4% (31.5%; 49.2%) for N=24, 39.2% (29.6%; 48.9) for N=20, and 39.4% (28.8%; 50.0%) 
for N=16.
In addition, N=20 would also be sufficient to provide adequate precision for a between-panel 
difference in the relative change from baseline of at least 26% in case of large inter-subject 
variability.
Assuming a drop rate of 20%, the sample size will be therefore set to 12 participants per panel for 
Panels 1 and 2. See Attachment 1 for further details on the justification of the sample size.
For Panel 3, the justification of the sample size is based on clinical and feasibility considerations 
due to the exploratory nature of the primary endpoint (liver drug concentration).


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4.
POPULATIONS (ANALYSIS SETS) FOR ANALYSIS
Analysis Sets
Description
Screened
All participants who signed the ICF for the protocol.
Enrolled
All participants who were enrolled in the study.
Randomized 
All participants who were randomly assigned to an 
intervention arm before protocol amendment 5.
Intent-to-treat (ITT)a
All participants who were randomly assigned or enrolled
to an intervention arm and received at least 1 dose of 
study intervention. Participants will be analyzed 
according to the study intervention they were randomly 
assigned or enrolled to.
Per Protocol (PP)
All participants in the ITT who do not have any of the 
selected major protocol deviations that may affect the 
assessment of efficacy. The selected major protocol 
deviations for efficacy analysis purposes that will be 
used to identify the participants included in the PP set 
are described in Attachment 2. Participants will be 
analyzed according to the study intervention they were 
randomly assigned or enrolled to.
Safety
All participants who received at least 1 dose of study 
intervention. Participants will be analyzed according to 
the study intervention they actually received.
a: defined as Full Analysis Set (FAS) as per the SAP Template v15.0


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5.
STATISTICAL ANALYSES
5.1.
General Considerations
5.1.1.
Analysis Phase
The analysis phases are defined in Table 1 below. Note that the screening, open-label, and follow-
up phases are non-overlapping and cover the entire study period. The optional PegIFN-α2a 
treatment phase, in contrast, may overlap with both the open-label and follow-up phases.
Table 1:
Analysis Phases Start and End Dates
Analysis phase
Start date
End date
Screening
The date of signing the 
informed consent 
1 day before the first study agent intake (JNJ-3989 or JNJ-
6379)
Open-label study 
intervention 
Date of first study agent
intake (JNJ-3989 or JNJ-
6379)
Earliest of the following dates:

Early discontinuation date for JNJ-3989 + 5 daysa

Study termination date

Max{
Date of last JNJ-3989 intake,
Date of Week 48 visit
} + 5 daysa

Cut-off dateb
Follow-up
End date of open-label
phase + 1 day
Min (study termination date, study completion date, cut-off 
dateb)
Optional PegIFN-
α2a treatment
Date of first PegIFN-α2a 
intake
Min (Date of last PegIFN-α2a intake + 5 daysa, cut-off dateb)
a : Addition of 5 days is only applicable for Adverse Events and Concomitant Medications.
b : Cut-off dates will be defined to match the prespecified timepoints for interim analyses, the primary analysis and the final 
analysis, respectively.
5.1.2.
Visit Windows
As participants do not always adhere to the protocol visit schedule, visits will be allocated within 
each phase to an analysis time point based on the time intervals in Table 2.
If a participant has two or more actual visits in a visit window (“time interval” in Table 2), only 
one will be selected as the protocol visit according to the following rules:
1. The measurement closest to the target day will be used.
2. If the measurements fall equidistant from the target day, the last measurement in 
chronological order will be used.
3. If there are two or more measurements on the same day, then the last measurement in 
chronological order will be used. If the time of the assessment is not available, the highest 
record/sequence number will be selected.
Only the protocol visits will be included for calculating summary statistics across participants 
within a time point or for statistical models using longitudinal data. However, listings or figures 


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of individual participant-level data (including spaghetti plots), or analyses that identify a maximum 
or minimum value across time points (e.g., maximum ALT value), may include all measurements.
End of treatment (i.e., EOT) and end of study (i.e., EOS) time points will be included in all analysis 
over time unless stated otherwise.
Special rule for Follow-up Week 48 (FU W48): Note that the time interval for FU W48 is open on 
the right, [324, +∞), while the next time interval is [352, 379]. Any visit in follow-up days [324, 
351] will be assigned to FU W48. If a patient does not have a visit date in that interval but does 
have visits on or after follow-up day 352, then the earliest such visit will be assigned to FU W48. 
Any additional visits on or after follow-up day 352 will be assigned to an “Ext” follow-up visit 
according to Table 2.
Table 2:
Visit Windows
a) Screening and Open-Label Phases
Analysis
phase
Target day
Analysis
time point
(Week)
Analysis
time point
(Label)
Open-label
time interval 
(Days)
Screening
-∞
-1
Screening
<0
Open-Label
1
0
Baseline
Pre-dose: 1
15
2
Week 2
[2, 22]
29
4
Week 4
[23, 43]
57
8
Week 8
[44, 71]
85
12
Week 12
[72, 99]
113
16
Week 16
[100, 127]
141
20
Week 20
[128, 155]
169
24
Week 24
[156, 183]
197
28
Week 28
[184, 211]
225
32
Week 32
[212, 239]
253
36
Week 36
[240, 267]
281
40
Week 40
[268, 295]
309
44
Week 44
[296, 323]
337
48
Week 48
[324, 351]
last visit in 
open-label phase
49 a
EOT a
a End of treatment (EOT) visit will be the last post-baseline visit in open-label phase as defined in Table 1.


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b) Follow-Up Phase
Analysis
phase
Target day
Analysis
time point
(Week)
Analysis
time point
(Label)
Follow-up
time interval
(Days)
Follow-up
15
50
Follow-up Week 2
[1, 22]
29
52
Follow-up Week 4
[23,43]
57
56
Follow-up Week 8
[44, 71]
85
60
Follow-up Week 12
[72, 99]
113
64
Follow-up Week 16
[100, 127]
141
68
Follow-up Week 20
[128, 155]
169
72
Follow-up Week 24
[156, 183]
197
76
Follow-up Week 28
[184, 211]
225
80
Follow-up Week 32
[212, 239]
253
84
Follow-up Week 36
[240, 267]
281
88
Follow-up Week 40
[268, 295]
309
92
Follow-up Week 44
[296, 323]
337
96
Follow-up Week 48
[324, +∞)
365
100
Follow-up Week 52 (Ext)
[352, 379]
393
104
Follow-up Week 56 (Ext)
[380, 407]
421
108
Follow-up Week 60 (Ext)
[408, 435]
449
112
Follow-up Week 64 (Ext)
[436, 463]
477
116
Follow-up Week 68 (Ext)
[464, 491]
505
120
Follow-up Week 72 (Ext)
[492, +∞)
last visit in 
the study
999 a
EOS a
a End of study (EOS) visit (last available data during the follow-up phase) will be the last visit in the study.
Note: The visits labeled with “Ext” are only for participants who completed PegIFN administration and NA treatment during 
the follow-up phase.
5.1.3.
On-Treatment and Off-Treatment Period
The on-treatment period begins with the first drug intake and finishes with the maximum between:

Last dose of NA+ 2 days

Last dose of PegIFN-α2a +10 days

Last dose of JNJ-3989 + 28 days
The off-treatment period starts after the end of on-treatment period and stops if the NA re-treatment 
starts.
5.1.4.
Missing and Partial Dates Imputation Rules
For analysis and reporting purposes, missing or partial dates in adverse event (AE onset date; AE 
end date), HBV diagnosis and infection dates, concomitant therapies (start date; end date) will be 
imputed according to the rules in the following subsections. The original, non-imputed, dates will 
be used only in listings.


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5.1.4.1.
Adverse Event Onset Date and Resolution Date
Partial AE onset dates will be imputed as follows:

If the AE onset date is missing the day only, it will be set to:

The first day of the month when the AE occurred, if month/year of the AE onset date 
is different than the month/year of the first administration of study treatment date.

The day of the first study treatment administration, if the month/year of the AE onset 
date is the same as the month/year of the first study treatment administration but the 
month/year of the AE resolution date is different.

The earliest between the day of the first study treatment administration date and day 
of AE resolution date, if month/year of the AE onset are the same as both the 
month/year of the first study drug administration and the AE resolution date.

If the AE onset date is missing both day and month, it will be set to the earliest of:

January 1 of the year of onset, as long as this date is on or after the first study drug 
administration.

Month and day of the first study treatment administration, if this date is in the same 
year of AE onset date.

December 31 if the AE onset date year is prior to the year of the first study drug 
administration. 

The AE resolution date.

Completely missing onset dates will not be imputed.
Partial AE resolution dates not marked as ongoing will be imputed as follows:

If the resolution date of an AE is missing the day only, it will be set to the earliest of the last 
day of that month or the day of the date of death, if the participant died in that month.

If the resolution date of an AE is missing both day and month, it will be set to the earliest of 
December 31 of that year or the day and month of the date of death, if the participant died in 
that year.

Completely missing resolution dates will not be imputed.
5.1.4.2.
HBV Diagnosis and Infection Dates
If the reported date is partially missing, the following imputation rules will be applied:

the 15th of the month, if only the day is missing.

the 30th of June, if only the year is available.

No imputation if completely missing.


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5.1.4.3.
Concomitant Medication Dates
In case of partially missing concomitant medication start/end dates, the following imputation rules 
will be applied:

the 15th of the month, if only the day is missing.

the 30th of June, if only the year is available.

If the imputed start date is after the concomitant medication end date, further adjustment of 
the imputed start dates is required. It will be imputed as the concomitant medication end date.

No imputation if completely missing.
If the medication was taken prior to study start based on eCRF question, and the imputed start date 
is after first treatment date, further adjustment of the imputed start date is required. It will be 
imputed as the day prior to first dosing date. 
If the medication was taken after study start based on eCRF question, and the imputed start date is 
prior to first dosing date, the imputed start date will be further adjusted to be the first study 
treatment dosing date. The partially missing medication end date will be imputed following the 
rule described at the beginning of this section to ensure it is on or after first dosing date, and after 
its start date.

In case of a completely missing start date, the concomitant therapy will be considered as 
having started before the trial, unless the eCRF indicating that the medication was taken after 
study start.

In case of a completely missing end date, the concomitant therapy will be considered as 
ongoing at the end of the trial, unless the eCRF indicating not ongoing. 
5.1.5.
Data Handling Rules
Those measurements collected from screening visit to the end of study will be handled according 
to the following rules summarized in Table 3.


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Table 3:
Data Handling Rules for HBV Virology and Serology Assessments
HBV 
parameter
LLOQ
ULOQ
Imputed Values
If value < LLOQ
If value > ULOQ
HBsAg
0.05 IU/mL
249,750.00 IU/mL
with dilution
0.025 IU/mL (a)
274,725.00 IU/mL (b)
with dilution
HBeAg
0.11 IU/mL
7,000.00 IU/mL
with dilution
0.055 IU/mL (a)
7,700.00 IU/mL(b)
with dilution
HBcrAg*
3.0 Log10 U/mL
9.0 Log10 U/mL
with dilution
2.7 Log10 U/mL
9.9 Log10 U/mL (b)
with dilution
HBV DNA
20 IU/mL
170,000,000 IU/mL
w/o dilution
If target detected: 
15 IU/mL**
If target not detected: 
5 IU/mL **
187,000,000(b)(c) IU/mL
w/o dilution
HBV RNA*
LLOQ = 2.939 log10
cp/mL (i.e., 869 
cp/mL)
LOD = 1.398 log10
cp/mL (i.e., 25 cp/mL)
NAP
If < LOD or target 
not detected then 
1.114 log10 cp/mL
(13 cp/mL)
NAP
Anti-HBs
5 mIU/mL
10000.0 mIU/mL
2.5 mIU/mL(a)
11000.0 mIU/mL (b)
* As new assays become available different data handling rules may apply
** For HBV DNA <LLOQ: Spaghetti plots showing absolute values, the imputed value will be 15 IU/mL for 
both target detected and target not detected. All other tables, listings and figures, will be produced using 15 
IU/mL as an imputed value if target is detected and 5 IU/mL if target is not detected.
Key: NAP=Not applicable
(a) LLOQ/2
(b) ULOQ+(ULOQ/10)
(c) If the original result > ULOQ, then take the re-test value (i.e., diluted result). If the diluted result is not 
available, use the imputed value of the original result indicated in this table. 
All other non-intrahepatic viral activity data not included in the data handling rules above, as well 
as continuous intrahepatic parameters obtained from liver biopsies (e.g., liver concentration of 
JNJ-3989), with values <LLOQ will be imputed by the LLOQ divided by 2. For parameters 
reported on the log scale, imputed values should be derived on the linear scale, not the log scale, 
and then converted back to the log scale. E.g., if a parameter has LLOQ = 3.0 Log10 U/mL
(equivalent to 1,000 U/mL), the imputed value should be log(10LLOQ 2
⁄ ) = LLOQ – log10(2) = 
2.7 Log10 U/mL (equivalent to 500 U/mL).
5.1.6.
Analysis Specifications
In general, continuous variables will be summarized using descriptive statistics including the 
number of participants, mean, standard deviation (SD), standard error (SE), 2-sided 80%
confidence interval (CI), median, and range. Binary or categorical variables will be summarized 
using the number and percentage of participants in each category. For time-to-event variables, a 
summary table including number of participants included in the analysis, number of participants 
censored, 25th and 75th percentiles and median time-to event will be shown. Graphic displays will 
also be used to summarize the data.
Descriptive statistics on actual values (original unit and log10 transformed values, when 
appropriate) and changes from baseline (log10 transformed values when appropriate) will be 


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summarized over time. Mean (+/- SE) plots of the actual values and the change from baseline 
(log10 transformed when appropriate) will be presented over time.
As applicable, analyses will be carried out separately for each panel, for the combination of Panels 
1 and 2, for the combination of all three panels, and for the pooled cohorts – across all three panels 
– of participants who are (1) HBeAg positive and not currently treated and (2) HBeAg negative 
and virologically suppressed by an NA. Additionally, some analyses will be carried out separately 
for participants who opt out of receiving PegIFN-α2a and those who opt to receive it for 12 or 24 
weeks.
5.1.7.
Level of Significance
Due to the exploratory nature of this study, no formal statistical test will be performed. Two-sided 
80% CI will be provided with the summary statistics. No adjustment for multiple CIs will be made.
5.2.
Participant Dispositions
The number and percentage of participants who are screened, fail screening, and reason for that
screening failure will be tabulated by study panel for the Screened Analysis Set.
The number and percentage of participants enrolled, enrolled and not treated, and reason for not 
being treated will be tabulated by study panel for the Enrolled Analysis Set.
Study disposition and treatment disposition will be summarized for the ITT Analysis Set, as 
described below.
An overview of the study disposition will be provided by analysis phase, study panel, and overall. 
The number and percentage of participants who completed or discontinued (or are ongoing [except 
the final analysis]) and the number and percentage of participants for each study discontinuation 
reason will be summarized.
An overview of the treatment disposition will be provided. The number and percentage of 
participants who completed or discontinued study treatment or were ongoing at the time of the IAs
or primary analysis cut-off (except the final analysis) will be presented by analysis phase, study 
panel, and overall. The incidences of treatment discontinuation reasons will also be summarized 
by analysis phase, study panel, and overall. 
A listing including information (i.e., study panel, the date of last study visit, the last analysis phase
and time point [phase and week], the date of discontinuation and the reason) on participants who
prematurely discontinue from the study and/or study treatment will be included. Information on 
NA discontinuation and/or re-treatment will also be included.
5.3.
Primary Endpoint Analyses
All primary endpoint analyses will be based on the ITT set, unless specified otherwise. Only 
selected analyses of selected endpoints will be repeated on the PP set, as will be indicated.


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5.3.1.
For Panels 1 and 2
5.3.1.1.
Definition of Endpoint
The primary endpoint for Panels 1 and 2 is defined as the change in the proportion of HBsAg+
hepatocytes between baseline and on-treatment Week 40.
5.3.1.2.
Analysis Methods
5.3.1.2.1.
Missing Data Handling Rule
The primary rule to handle missing data is to use complete-case analysis, i.e., participants must 
have both baseline and Week 40 biopsy assessments with non-missing number of evaluated 
hepatocytes and HBsAg+ hepatocytes at both visits.
5.3.1.2.2.
Primary Analysis of the Primary Endpoint
5.3.1.2.2.1.
Overall Analysis
The change from baseline in proportion of HBsAg+ hepatocytes at Week 40 will be estimated 
overall – pooling Panels 1 and 2 – by modelling the proportion of HBsAg+ hepatocytes using a 
binomial mixed model with normal random effects to account for potential overdispersion
(Kassahun et al 2012). The potential for overdispersion is supported by preliminary off-treatment 
results on chronic hepatitis B donors (Sources: Commercial biospecimen sources from Avaden 
Biospecimen and BioIVT as well as from a pilot phase of phase 0 study NOPRODHPB0012; 
hereafter referred to as the “donors data”).
The binomial mixed model will model the number of HBsAg+ hepatocytes for each participant at 
each time point as follows:
 ~ Binomial,  
logit() = (" + $)
%&'&(
intercept
+ (- + .)
%&'&(
slope
0
for subject 5 = 1, … , 7 and
visit 0 = 0 (for baseline) or 1 (for Week 40)
$, … , $= ~
iid (0, SDintercept)
., … , .= ~
iid (0, SDslope)
with:
-
Yij: number of HBsAg+ hepatocytes of subject i at visit j
-
Nij: total number of hepatocytes sampled from subject i at visit j
-
pij: probability of a hepatocyte being HBsAg+ for subject i at visit j
-
α: Fixed intercept (baseline log-odds of a hepatocyte being HBsAg+) for a “typical” 
subject, i.e., a subject whose random intercept and slope both equal 0
-
ξi: Subject-specific random effect for overdispersion of the intercept
-
β: Fixed slope (change in the log-odds from baseline to Week 40) for a “typical” subject


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-
γi: Subject-specific random effect for overdispersion of the slope
-
n: total number of patients
The input data for this model are Yij, Nij, and n. There are four parameters to estimate: α, β, 
SDintercept, and SDslope.
Estimates of the absolute and relative changes from baseline in the proportion of HBsAg+
hepatocytes at Week 40 and associated 80% CIs will be obtained from the model as follows. Let 
p0 and p1 be the proportion of infected hepatocytes at times 0 (baseline) and 1 (Week 40) for a 
“typical” subject. Based on the binomial model, p0 = expit(α) and p1 = expit(α + β), where
expit(x) = exp(x)/[1 + exp(x)] is the inverse of the logit function. The absolute and relative changes
from baseline are therefore
-
Absolute change:  − = expit(" + -) −expit(")
-
Relative change: 
BCDBE
BE
=
BC
BE −1 =
expit(FGH)
expit(F) −1
SAS code to fit the binomial mixed model and estimate the quantities of interest is provided in 
Attachment 3. We may also report estimates and CIs for p0 and p1.
Additional models may be evaluated depending on the distribution of data (such as Poisson, 
Negative-Binomial or Zero-Inflated regression models) and comparison of fit statistics would be 
performed to select the most adequate model. Additional covariates may be added to the model 
based on clinical considerations.
All biopsy data will be used for this analysis, including data collected after treatment 
discontinuation or occurrence of major protocol deviations (Appendix 4) potentially affecting the 
primary endpoint (see Attachment 2).
5.3.1.2.2.2.
Comparison Between Panels 1 and 2
Study panel will be included as an additional covariate in the model described in                       
Section 5.3.1.2.2.1. That is, the model for logit() will become
logit() = [" + JFK(panel = 1) + $]
%&&&&&&&'&&&&&&&(
intercept
+ [- + JHK(panel = 1) + .]
%&&&&&&&&'&&&&&&&&(
slope
0
with:
-
α: Fixed intercept for a “typical” Panel 2 subject
-
δα: Fixed difference in intercepts (Panel 1 minus Panel 2) for “typical” subjects
-
β: Fixed slope for a “typical” Panel 2 subject
-
δβ: Fixed difference in slopes (Panel 1 minus Panel 2) for “typical” subjects
-
paneli: Panel number (1 or 2) for subject i
All other aspects of the model are unchanged from the specification in Section 5.3.1.2.2.1.


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The input data for this model are Yij, Nij, paneli, and n. There are six parameters to estimate: α, δα, 
β, δβ, SDintercept, and SDslope.
Estimates of the absolute and relative changes from baseline in the proportions of HBsAg+
hepatocytes at Week 40 will be provided for both Panels 1 and 2. The between-panel differences 
(Panel 1 minus Panel 2) in absolute and relative changes will also be estimated. Each estimate will 
be accompanied by an 80% CI. The estimates can be obtained from the binomial model as follows. 
Let p0 and p1 be the proportion of infected hepatocytes at times 0 (baseline) and 1 (Week 40) for a 
“typical” Panel 1 subject, and let q0 and q1 be defined analogously for a “typical” Panel 2 subject.
Based on the binomial model, we have the following relations:
M = expit(")
M = expit(" + -)
 = expit(" + JF)
 = expit(" + JF) + (- + JH) 
From this we can obtain within-panel contrasts for the absolute change from baseline ( − and
M −M) and the relative change (NCONE
NE
and PCOPE
PE ). The between-panel contrasts of interest are then
-
Difference (Panel 1 minus 2) in absolute change: ( −) −(M −M)
-
Difference (Panel 1 minus 2) in relative change: Q
BCDBE
BE R −Q
SCDSE
SE R
SAS code to fit the binomial mixed model and estimate the quantities of interest is provided in 
Attachment 3. We may also report estimates and CIs for p0, p1, q0, and q1.
All biopsy data will be used and only complete cases will be considered, similarly to the approach 
chosen for the primary analysis.
5.3.1.2.3.
Secondary Analysis of the Primary Endpoint
A secondary, descriptive analysis of the primary endpoint will be conducted. For each participant 
i at visit j (0 for baseline; 1 for Week 40), the observed proportion of HBsAg+ hepatocytes will be 
calculated as T
UVW = /, where  and  are the number of HBsAg+ hepatocytes and the 
total number of evaluated hepatocytes from the biopsy sample, respectively.
The change from baseline to Week 40 will then be calculated for each participant as 
Δ
UVW = T
UVW −T
UVW. The distributions of the T
UVW, T
UVW, and Δ
UVW across the participants will be 
described, both overall and by panel. Graphical displays may be used, including spaghetti plots 
(connecting T
UVW to T
UVW) and boxplots.
In addition, scatterplots displaying  versus  will be provided.


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5.3.1.2.4.
Sensitivity Analyses
5.3.1.2.4.1.
Baseline Observation Carried Forward (BOCF)
The primary and secondary analyses of the primary endpoint will be repeated by imputing any 
missing count of HBsAg+ hepatocytes at Week 40 (due to premature treatment discontinuation or 
insufficient biopsy material or missing biopsy assessment at Week 40) by the count of HBsAg+ 
hepatocytes at baseline. In case the number of evaluated hepatocytes at Week 40 is available but 
the count of HBsAg+ hepatocytes is missing, both values will be replaced by baseline data. In case 
of missing biopsy assessment at baseline, no imputation will be performed, and those participants 
will not be included in the analysis.
5.3.1.2.4.2.
Multiple Imputation
The secondary analysis of the primary endpoint will be repeated by using multiple imputation (MI)
to impute any missing count of HBsAg+ hepatocytes at baseline and Week 40. Participants with 
missing biopsy assessments at both time points will not be included in the analysis.
The MI model will be applied to the continuous, logit-transformed proportions T
UVW, as defined in 
Section 5.3.1.2.3. The model will be used separately for each panel, and will include the available 
non-missing logit-transformed proportions T
UVW, and may include age, gender, log-transformed 
peripheral HBsAg at baseline and Week 40, and type of NA (TD/TAF versus ETV).
A planned total of 20 datasets will be generated for each panel. Depending on the amount of 
missing data, the number of imputed datasets to be generated may be increased appropriately to 
ensure robustness in the MI results and relative efficiency.
From each imputed dataset we will obtain values for T
UVW, T
UVW, and Δ
UVW. The distributions of 
these three quantities across the participants and imputed datasets will be described, both overall 
and by panel. The means of T
UVW and T
UVW will be obtained for each participant across imputed 
datasets and displayed in a spaghetti plot.
5.3.1.2.4.3.
Per-Protocol Analysis (PP)
The primary and secondary analyses of the primary endpoint will be repeated with the PP set. All 
biopsy data will be used and only complete cases will be considered.
5.3.1.3.
Subgroup Analyses
The potential association between the primary endpoint and baseline characteristics (Appendix 3) 
may be explored graphically using forest and scatter plots. The baseline subgroups of interest for 
efficacy are defined in Section 5.7.4.


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The potential association between the primary endpoint and treatment-related characteristics may 
be explored both by using summary tables and plots. Subgroups in this category include: 

Received at least 1 dose of JNJ-6379 (No / Yes);

Treatment with PegIFN-α2a during study (No / Yes / Yes for 12 weeks / Yes for 24 weeks).
5.3.2.
For Panel 3
5.3.2.1.
Definition of Endpoints
The primary endpoints for Panel 3 are defined as the liver concentrations of JNJ-3989 (i.e., JNJ-
3976, JNJ-3924, and M65), measured at treatment Weeks 12 and 40.
5.3.2.2.
Primary Analysis
Individual listings and descriptive statistics (n, mean, SD, SE, median, minimum and maximum) 
for JNJ-3976 and JNJ-3924 liver and plasma concentrations, and M65 liver concentrations, as well 
as the ratio of liver to plasma concentrations at Weeks 12 and 40 will be provided. In addition, the 
ratio of M65 to JNJ-3976 at Weeks 12 and 40 will be calculated.
Scatterplots of individual JNJ-3976, JNJ-3924, and M65 liver concentrations by time point will be 
provided. Additionally, scatterplots of HBsAg change from baseline at Week 40 by JNJ-3976,  
JNJ-3924, and M65 liver concentrations at Week 40 will be provided.
5.4.
Secondary Endpoints Analysis
All secondary endpoints will be analyzed for the ITT set.
5.4.1.
Intrahepatic Secondary Endpoints
As a general consideration, no imputation rule will be applied in case of missing biopsy assessment 
or insufficient biopsy sample material required to obtain the individual intrahepatic markers at 
baseline and/or Week 12 and/or Week 40. Some imputation rule may be applied for specific 
endpoints and will be described in the relevant section(s).
5.4.1.1.
Intrahepatic Immune Response 
5.4.1.1.1.
For Panels 1 and 2
The following immune cells will be evaluated:

CD45+ T-cells,

CD4+ T-cells,

CD8+ T-cells, 

Natural Killer (NK) cells,

Dendritic cells
Additional immune cells may be explored.


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Estimations on change in proportions using a similar mixed model as described in Section 5.3.1.2.2
with an appropriate distribution for each type of cells will be provided. It may differ from the 
assumption of binomial distribution made for the primary endpoint.
In addition, similar summary statistics and graphical displays on the calculated change in 
proportion will be provided as defined in Section 5.3.1.2.3. Additional immune cells may be 
evaluated depending on data availability and clinical interest. Spatial distribution for each cell type 
at baseline and Week 40 will be graphically evaluated.
5.4.1.1.2.
For Panel 3
The same immune cells as described in Section 5.4.1.1.1 may be analyzed for Panel 3 at Week 12 
and Week 40. Descriptive analyses may be provided as defined in Section 5.3.1.2.3. 
5.4.1.2.
Intrahepatic Viral Parameters
5.4.1.2.1.
For Panels 1 and 2
Descriptive statistics on actual values at baseline and Week 40 and changes from baseline at 
Week 40 will be summarized for the following parameters:

Number and proportion of cccDNA-positive hepatocytes

Number and proportion pgRNA-positive hepatocytes

Number and proportion of silent hepatocytes

cccDNA levels (positive/negative)

pgRNA levels (positive/negative)
Number of cells will be expressed in original unit and proportions or ratios will be provided in 
both original and log10 transformed scales. Change from baseline will be provided in log10 
transformed unit. In addition, same graphical displays as described in Section 5.3.1.2.3 will be 
provided.
5.4.1.2.2.
For Panel 3
The number and proportion of HBsAg+ hepatocytes, as well as the same viral parameters described 
in Section 5.4.1.2.1, may be provided at Week 12 and Week 40, depending on the availability of 
biopsy material.
5.4.2.
Blood Peripheral Secondary Endpoints
5.4.2.1.
HBsAg Seroclearance
HBsAg seroclearance, defined as quantitative HBsAg <LLOQ (see Table 3), will be evaluated at 
all time points.
If the HBsAg value at Weeks 40 or 48 is missing, the LOCF approach will be used with the 
condition that no value more than 8 weeks prior to the respective time point may be carried 
forward. At FU Weeks 12, 24, 36 and 48, and at 24, 36, and 48 weeks after stopping all study 


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interventions, if an HBsAg value is missing, then LOCF approach will be used with the condition 
that no value more than 12 weeks prior to the respective time point will be used. For all other time 
points, seroclearance will be analyzed as observed case without imputation.
The proportion of participants who achieve HBsAg seroclearance over time will be summarized.
5.4.2.1.1.
Time to HBsAg Seroclearance
Time to HBsAg seroclearance is defined as the number of days between the date of first study 
intervention intake and the date of the first occurrence of HBsAg seroclearance (i.e., the date of 
the first HBsAg seroclearance – the date of first study intervention intake + 1). The participants 
who withdrew early from the study before achieving HBsAg seroclearance or who did not achieve 
HBsAg seroclearance will be censored at the last available HBsAg assessment.
In addition, time to the first occurrence of HBsAg <10 IU/mL (i.e., the date of the first occurrence 
of HBsAg <10 IU/mL – the date of first study intervention intake + 1) and HBsAg <100 IU/mL 
(i.e., the date of the first occurrence of HBsAg <100 IU/mL – the date of first study intervention 
intake + 1) will also be evaluated.
The Kaplan-Meier method will be used to estimate and plot the cumulative incidence. The median 
time with 80% CI will be estimated using Kaplan-Meier method, if possible.
5.4.2.2.
HBsAg Seroconversion
Seroconversion of HBsAg is defined as having achieved HBsAg seroclearance and appearance of 
anti-HBs antibodies.
The seroconversion will only be assessed at the time points when the anti-HBs antibodies 
assessment is available. If the HBsAg value is missing at that specific time point, then the non-
missing lab test closest to that specific timepoint will be used. If the non-missing lab test before 
and after the specific timepoint fall equidistant from the target timepoint, the later one will be used 
to impute the missing value.
Appearance of anti-HBs antibodies is defined as a baseline anti-HBs antibodies (quantitative) 
<LLOQ and a post-baseline assessment ≥LLOQ. A sensitivity analysis will be conducted using 
the threshold of 10 mIU/mL, i.e., appearance of anti-HBs antibodies is defined as a baseline anti-
HBs antibodies (quantitative) <10 mIU/mL and a post-baseline assessment ≥10 mIU/mL.
5.4.2.3.
HBeAg Seroclearance and Seroconversion
Seroclearance of HBeAg is defined as (quantitative) HBeAg <LLOQ. The HBeAg seroclearance
will be summarized only for HBeAg positive participants at study entry.
Seroclearance will be analyzed as observed case without imputation and with imputation using 
LOCF approach. For the imputation with LOCF approach, we impute the missing data with the 
following restriction. If the HBeAg value at Weeks 40 or 48 is missing, the LOCF approach will 
be used with the condition that no value more than 8 weeks prior to the respective time point may 
be carried forward. At FU Weeks, if an HBeAg value is missing, then LOCF approach will be used 


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with the condition that no value before the FU phase or more than 12 weeks prior to the respective 
time point will be used. For all other time points, seroclearance will be analyzed as observed case 
without imputation.
The proportion of participants who achieve HBeAg seroclearance over time will be summarized. 
Seroconversion of HBeAg is defined as having achieved HBeAg seroclearance together with 
appearance of anti-HBe antibodies. Appearance of anti-HBe antibodies is defined as a baseline 
anti-HBe antibodies (qualitative) with a "NEGATIVE" result and a post-baseline assessment with 
“POSITIVE” result. The seroconversion of HBeAg will be summarized only for HBeAg positive 
participants at study entry.
The seroconversion will only be assessed at the time points when the anti-HBe antibodies 
assessment is available. If the HBeAg value is missing at that specific time point, then the non-
missing lab test closest to that specific timepoint will be used. If the non-missing lab test before 
and after the specific timepoint fall equidistant from the target timepoint, the later one will be used 
to impute the missing value.
The number and proportion of participants who achieve HBeAg seroconversion will be 
summarized.
5.4.2.4.
HBsAg, HBeAg, HBV DNA and ALT
5.4.2.4.1.
Values and Changes Over Time
5.4.2.4.1.1.
Change from Baseline Over Time
Descriptive statistics on actual values [original unit and log10 transformed values (except for ALT)]
and changes from baseline (in original unit for ALT and log10 transformed values otherwise) over 
time in HBsAg, HBeAg (for HBeAg positive participants at study entry), HBV DNA and ALT 
will be summarized and mean (+/- SE) plots of the values and the change from baseline over time
will be presented.
Change from baseline based on log10 transform for quantitative HBsAg, HBeAg (for HBeAg 
positive participants at study entry) and HBV DNA will be analyzed using mixed effects model 
for repeated measures [MMRM]) including analysis time point (week), and HBV baseline status 
(HBeAg positive and not currently treated or HBeAg negative and virologically suppressed) as 
fixed effects. In addition, the above model will be augmented with a HBV baseline status by time 
point interaction term. The covariance structure will include a random intercept at the level of the 
participant to capture between-participant variability, while within-participant variability will be 
captured with a Compound Symmetry (type=CS) covariance matrix. In case of convergence 
problems, another simpler variance-covariance structure such as Toeplitz or AR (1) will be 
considered. The selection of any of these structures will be determined after exploration of the 
observed correlation structure. The LS mean of change from baseline, standard error (SE), and 
80% CI will be provided.


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Spaghetti plots for both absolute values and changes from baseline of HBsAg, HBeAg, HBV DNA,
and ALT will be presented over time.
Waterfall plots for changes from baseline of HBsAg, HBeAg, HBV DNA, and ALT will also be 
presented.
5.4.2.4.2.
HBsAg Thresholds
The number and proportion of participants who meet the following HBsAg thresholds over time
will be summarized descriptively.
Thresholds for HBsAg absolute values:

<1000 IU/mL

<100 IU/mL

<10 IU/mL

<1 IU/mL

<LLOQ (0.05 IU/mL)
Of note, seroclearance of HBsAg is defined as HBsAg <LLOQ. 
Thresholds for HBsAg reduction from baseline:

≥0.3 log10 IU/mL 

≥0.5 log10 IU/mL 

≥1 log10 IU/mL 

≥2 log10 IU/mL 

≥3 log10 IU/mL 

≥4 log10 IU/mL 
5.4.2.4.3.
HBeAg Thresholds
The number and proportion of participants who meet the following HBeAg thresholds over time
will be summarized descriptively. The HBeAg thresholds will be summarized only for HBeAg 
positive participants at study entry.
Thresholds for HBeAg absolute values:

< 100 IU/mL

< 10 IU/mL

< 1 IU/mL

< LLOQ (0.11 IU/mL) 
Of note, seroclearance of HBeAg is defined as (quantitative) HBeAg <LLOQ. 


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Thresholds for HBeAg reduction from baseline:

≥0.3 log10 IU/mL 

≥0.5 log10 IU/mL 

≥1 log10 IU/mL 

≥2 log10 IU/mL 

≥3 log10 IU/mL 
5.4.2.4.4.
HBV DNA Thresholds
The number and proportion of participants who meet the following HBV DNA thresholds over 
time will be summarized descriptively.
Thresholds for HBV DNA absolute values:

< LLOQ 

< LLOQ TND

< LLOQ TD

<60 IU/mL

<100 IU/mL

<200 IU/mL 

<1000 IU/mL 

<2000 IU/mL

<20000 IU/mL
Thresholds for HBV DNA reduction from baseline:

≥1 log10 IU/mL 

≥2 log10 IU/mL 

≥3 log10 IU/mL 

≥4 log10 IU/mL 

≥5 log10 IU/mL
5.4.2.4.5.
ALT Decrease and Normalization
A participant with ALT elevation (ALT≥ULN) at baseline is defined to achieve ALT 
normalization if his/her ALT value post-baseline is <ULN at any given time point.
The number and proportion of participants who achieve the following ALT normalizations will be 
summarized descriptively over time, only for the subjects who had ALT elevation at baseline:


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
On treatment ALT normalization, i.e., while being treated with JNJ-3989 and/or JNJ-6379 
and/or NA and/or PegIFN-α2a).

Off treatment ALT normalization, i.e., after stopping JNJ-3989, JNJ-6379, NA, and PegIFN-
α2a.
Descriptive statistics of the absolute values and changes from baseline over time in ALT will be 
summarized for those participants who had ALT elevation at baseline. An additional summary of 
descriptive statistics of the ALT absolute values and changes from baseline over time will be 
provided for participants who had ALT values within the normal range at baseline.
5.4.2.4.6.
Study Intervention Completion at Week 48 and During Follow-up
Participants will complete treatment with JNJ-3989 after a fixed duration of 48 weeks. If all of the
below criteria are met based on clinical laboratory tests performed at Week 44, treatment with NA
will also be completed at the next scheduled visit (ie, Week 48):

The participant has ALT <3x ULN, AND

The participant has HBV DNA <LLOQ, AND

The participant is HBeAg negative, AND

The participant has HBsAg <10 IU/mL.
Participants who do not meet the above criteria at Week 48 should continue NA treatment during
the 48-week follow-up phase. Participants who are receiving optional treatment with PegIFN-α2a
and who have not met NA treatment completion criteria at Week 48 may have NA treatment
completion criteria assessed at the end of treatment with PegIFN-α2a and stop NA if criteria are
met.
Proportion of participants who have met NA completion criteria, and reasons for not meeting, will 
be summarized at Week 48 and at the end of treatment with PegIFN-α2a. 
5.4.2.4.7.
NA Re-Treatment During Follow-up
Proportion of participants who have NA re-treatment during follow-up will be summarized.
5.4.2.4.8.
ALT Normalization after NA Re-Treatment
Proportion of participants who have ALT≥ULN before NA re-treatment and reach ALT 
normalization after NA re-treatment during follow-up will be summarized.
5.4.2.4.9.
Thresholds On Multiple Markers
The number and proportion of
participants who meet the following blood marker 
reduction/seroclearance thresholds at 12, 24, 36 and 48 weeks, respectively, after stopping all study 
interventions (including NA and PegIFN-α2a) and not having NA re-treated will be summarized 
descriptively for each marker and each threshold listed below.


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
HBsAg<LLOQ and HBV DNA

HBsAg<LLOQ and HBV DNA<LLOQ**

HBsAg<LLOQ and HBV DNA≥LLOQ

HBsAG<LLOQ and HBV<2,000 IU/ml

HBsAg≥LLOQ and HBV DNA<2,000 IU/ml

HBsAg≥LLOQ and HBV DNA<LLOQ**

HBsAg≥LLOQ and HBV DNA≥LLOQ

HBsAg≥LLOQ and LLOQ ≤HBV DNA<2,000 IU/ml

HBsAg≥LLOQ and HBV DNA≥2,000 IU/ml

HBsAg<100 IU/mL and HBV DNA≥2,000 IU/ml

HBsAg≥100 IU/mL and HBV DNA≥2,000 IU/ml

HBsAg<100 IU/ml and HBV DNA<2000 IU/ml

HBsAg<100 IU/ml and HBV DNA<LLOQ**
** HBV DNA<LLOQ will be summarized overall. Additional analyses may assess HBV 
DNA<LLOQ TD versus TND.
Due to the exploratory objectives of this study, additional blood marker reduction/seroclearance 
thresholds may be added at a later point in time according to the clinical interest.
5.4.2.5.
Functional Cure
A participant will be defined as having achieved Functional Cure (FC) at a given time point during 
the FU phase if he/she has HBsAg seroclearance (as defined in Section 5.4.2.1) at that time point 
and has stopped all study interventions (including NA and PegIFN-α2a) for at least 24 weeks
without re-treatment. 
Participants who discontinue treatment prior to Week 48 (except for JNJ-6379), or who withdraw 
from the study prior to the given time point, will be considered as non-responders for FC in this 
study. The CRF pages of ‘Treatment Disposition of JNJ-3989’, ‘Treatment Disposition of NA 
Treatment’, ‘Treatment Disposition for NA Re-Treatment’ and ‘Treatment Disposition for 
PegIFN-alpha2a’ will be checked to ensure all treatment actually stopped.
Subjects still in the study at a given time point but with missing HBsAg assessment at that time
after implementation of LOCF (as described in Section 5.4.2.1), will be considered as non-
responders.
Number and proportion of participants achieving FC will be summarized at 24, 36, and 48 weeks 
after stopping all study interventions (including NA and PegIFN-α2a). Subjects who never reach 
such time points will be considered as non-responders.


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5.4.2.6.
Flares
5.4.2.6.1.
Definition
The criteria based on blood markers/lab tests for each of the flare types are defined as below.
1.
Virologic flare is defined as follows:
Derivation 1. This derivation of virologic flare will be assessed only for those participants who 
are off-treatment and had HBV DNA<LLOQ at the last observed point on-treatment.
The start date of a confirmed virologic flare is defined as the first date of two consecutive visits 
with HBV DNA > 200 IU/mL. The end date of the same confirmed virologic flare is defined as 
the first date when HBV DNA value returns to ≤200 IU/mL or the date of NA treatment restart, 
whichever comes first. Each virologic flare will be categorized based on the confirmed (i.e., two 
consecutive values) peak HBV DNA above any of the three thresholds within the start and end 
date of that flare as follows: 20,000 IU/mL, 2,000 IU/mL, and 200 IU/mL.

1 (Yes) = confirmed** HBV DNA > peak threshold.

0 (No) = at least one off-treatment HBV DNA measurement available and not meeting the 
criteria of confirmed HBV DNA > peak threshold.

2 (Not applicable) = no off-treatment HBV DNA quantitative measurements available.
Derivation 2. This derivation of virologic flare will be assessed only for those participants who 
are off-treatment and had HBV DNA ≥LLOQ at the last observed point on-treatment.
The start date of a confirmed virologic flare is defined as the first date of two consecutive visits 
with HBV DNA log10 increase > 1 log10 from EOT. The end date of the same confirmed virologic 
flare is defined as the first date when HBV DNA log10 increase from end of treatment returns to 
≤1 log10 or the date of NA treatment restart, whichever comes first. Each virologic flare will be 
categorized based on the confirmed (i.e., two consecutive values) peak HBV DNA increase above 
any of the three thresholds within the start and end date of that flare as follows: 1 log10, 2 log10, 3 
log10.

1 (Yes) = confirmed** HBV DNA increase from EOT > peak threshold

0 (No) = at least one off-treatment HBV DNA measurement available and not meeting the 
criteria of confirmed HBV DNA increase from EOT > peak threshold.

2 (Not applicable) = no off-treatment HBV DNA quantitative measurements available.
** Confirmed means that the criterion should be fulfilled at 2 or more consecutive time points or at 
the last observed time point.
2. Off-treatment biochemical flare is defined as follows:
The start date of a confirmed off-treatment biochemical flare is defined as the first date of two 
consecutive visits with ALT and/or AST ≥3x ULN and ≥3x nadir (i.e., lowest value observed up 


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to the start of the flare) while the participant does not receive any of the study interventions. The 
end date of the same off-treatment biochemical flare is defined as the first date when there is a 
50% reduction from the peak ALT and/or AST level and <3x ULN.

1 (Yes) = confirmed** ALT and/or AST ≥3x ULN and ≥3x nadir (i.e., lowest value observed
up to the start of the flare)

0 (No) = otherwise
3. On-treatment biochemical flare is defined as follows:
The start date of a confirmed on-treatment biochemical flare is defined as the first date of two
consecutive visits with ALT and/or AST ≥3x ULN and ≥3x nadir (i.e., lowest value observed up 
to the start of the flare) while the participant receives any of the study interventions. The end date 
of the same on-treatment biochemical flare is defined as the first date when there is a 50% 
reduction from the peak ALT and/or AST level and <3x ULN, regardless of stopping study 
interventions.

1 (Yes) = confirmed** ALT and/or AST ≥3x ULN and ≥3x nadir (i.e., lowest value observed
up to the start of the flare)

0 (No) = otherwise
4. Clinical flare is defined as follows:
A clinical flare occurs either when a virologic flare and biochemical flare overlap in time or when 
a biochemical flare starts within 4 weeks following the end of a virologic flare.
The start date of a clinical flare is defined as the minimum start date of the virologic flare and 
biochemical flare. The end date of a clinical flare is defined as the maximum end date of the 
virologic flare and biochemical flare, i.e., the later date between HBV DNA returns to ≤200 IU/mL 
(or ≤1 log10) and 50% reduction from the peak ALT and/or AST level and <3x ULN reached 
during the biochemical flare.

1 (Yes) = confirmed** HBV DNA > peak threshold (for derivation 1 of virologic flare) or 
HBV DNA increase from end of treatment > peak threshold (for derivation 2 of virologic 
flare) and confirmed**ALT and/or AST≥3x ULN and ≥3x nadir (i.e., lowest value observed 
up to the start of the biochemical flare).

0 (No) = otherwise
** Confirmed means that the criterion should be fulfilled at 2 or more consecutive time points or at 
the last observed time point.
The virologic and clinical flares will be assessed only off-treatment, while biochemical flares will 
be identified on-treatment and off-treatment, respectively. On-treatment virologic flares are 
described as virologic HBV breakthrough in Section 5.4.2.7.
On-treatment will be defined as the time periods in which the participant receives any of the study 
interventions (JNJ-3989 or JNJ-6379 or NA or PegIFN-α2a). Off-treatment will be defined as the 


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periods when the participants do not receive any of the study interventions (JNJ-3989, JNJ-6379,
NA, and PegIFN-α2a).
The incidence rate will be calculated and summarized for each type of on-treatment or off-
treatment flares (virologic, biochemical and clinical) separately, as well as the overall incidence 
of participants experiencing at least one flare, regardless of type. Additionally, for each participant 
the total number of flares the participant experienced will be counted by type. Such counts will be 
used to summarize the distribution of the total number of flares by type and by study panel.
For on-treatment biochemical flares, the incidence of flares causing treatment discontinuation will 
be summarized. Further, for off-treatment flares, the count and percentage of participants who 
experienced a flare followed by NA re-treatment will be summarized by flare type. Similarly, the 
incidence of flares followed by the achievement of HBsAg seroclearance (at any time) will be 
summarized by flare type.
Flares that are associated with signs of liver decompensation will be provided in a listing.
5.4.2.7.
HBV Virologic Breakthrough
5.4.2.7.1.
Definition
HBV virologic breakthrough is defined as having a confirmed on-treatment HBV DNA increase 
by >1 log10 from nadir level (lowest level reached during treatment) in participants who did not 
have on-treatment HBV DNA level < LLOQ or a confirmed on-treatment HBV DNA level >200 
IU/mL in participants who had on-treatment HBV DNA level <LLOQ. Confirmed HBV DNA 
increase/level means that the criterion should be fulfilled at 2 or more consecutive time points or 
at the last observed on-treatment time point.
On-treatment will be defined as the time period in which the participant receives any of the study 
interventions (JNJ-3989 and/or JNJ-6379 and/or NA and/or PegIFN-α2a).
The number and proportion of participants who experience a virologic breakthrough will be 
summarized descriptively by analysis phase.
The number and proportion of participants who experience a virologic breakthrough followed by 
on-treatment biochemical flare will be summarized descriptively.
5.4.2.8.
HBV-Specific T-Cells Response
Descriptive statistics (for example, may include n, mean, SD, CV, geometric mean, median, 
minimum, and maximum) will be used to describe the magnitude of the IFN-γ T cell response or 
the CD4+ and CD8+ T-cell responses (expressing at least 1 cytokine such as IL-2, TNF-α or IFN-
γ specific to any HBV antigen) as defined by ELISpot and/or ICS, respectively. Changes from 
baseline (if present) will also be tabulated for PBMCs during study intervention and follow-up. 
The proportion (%) of CHB participants with positive responses based on the magnitude of the 
IFN-γ T cell response or the CD4+ or CD8+ T cells expressing at least 1 of the cytokines amongst 


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IL-2, TNF-α or IFN-γ for 1 of the HBV antigens as defined by ELISpot and/or ICS, respectively, 
will be determined. 
Graphs showing the individual subject values as dots, together with horizontal lines indicating the 
corresponding median and interquartile range (IQR) per time point for each assay will be 
presented. The spaghetti plots will be used to show the patient profiles per time point for each 
assay. A graph showing the median and IQR over time will be presented. A bar chart will be used 
to show the breadth of response (i.e., HBV-specific immune response rate for combinations of 
peptide pools).
For intracellular cytokine staining (ICS), for all cytokine combinations (IFNγ and/or TNFα and/or 
IL-2), pie charts will be presented to reflect the distribution of each of the cytokine combinations 
(i.e., the proportion of a specific cytokine combination of the CD4 or CD8 T-cells secreting at least 
one cytokine), and bar charts will be presented to reflect the mean magnitude of each combination.
5.4.3.
Subgroup Analyses
The same subgroups as described in Section 5.3.1.3 may be used to analyze key secondary 
endpoints.
5.5.
Exploratory Endpoints Analysis
5.5.1.
Relationship Between Intrahepatic and Blood Markers
Relationships between intrahepatic and blood markers (Table 4) and/or their change from baseline 
at Week 40 will be evaluated graphically with scatter plots displaying individual associations. 
Means on pooled individual data by study panel and overall mean will also be plotted on the same 
graph.
The following correlation coefficients will be calculated by study panel and overall for the different 
correlation scenarios:

Pearson’s correlation coefficient for two continuous variables. 

Phi correlation coefficient for two binary variables. 

Point biserial correlation coefficient for one binary variable and one continuous variable. 
Potential relationship on the selected subgroups defined in Section 5.7.4 will also be explored 
using the same graphical approach.
The following markers will be considered, i.e., each intrahepatic marker will be plotted against 
each blood marker:
Table 4:
List of Intrahepatic and Blood Markers of Interest
Intrahepatic Markers/Endpoints
Blood Markers/Endpoints
Proportion of HBsAg+ hepatocytes at Week 40
Change from Baseline at Week 40 in proportion of 
HBsAg+ hepatocytes 
HBV DNA level at Week 40 (log10)
HBV RNA level at Week 40 (log10)
HBsAg level at Week 40 (log10)


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Proportion of cccDNA-positive hepatocytes at Week 
40
Change from Baseline at Week 40 in proportion of 
cccDNA-positive hepatocytes 
Proportion of pgRNA-positive hepatocytes at Week 
40
Change from Baseline at Week 40 in proportion of 
pgRNA-positive hepatocytes
pgRNA levels at Week 40 (log10 copies/ cell)
Change from Baseline at Week 40 in pgRNA levels 
(log10 copies/ cell)

HBeAg level at Week 40 (log10)
HBcrAg level at Week 40 (log10)
Change from Baseline at Week 40 in HBV DNA 
(log10)
Change from Baseline at Week 40 in HBV RNA 
(log10)
Change from Baseline at Week 40 in HBsAg (log10)
Change from Baseline at Week 40 in HBeAg (log10)
Change from Baseline at Week 40 in HBcrAg (log10)
Maximum on-treatment ALT decrease 
HBsAg seroclearance at FU Week 24
Additional markers and endpoints may be evaluated when data will be available.
5.5.2.
Association Between Baseline Characteristics or Intrahepatic/Blood 
Markers with Efficacy Variables
The following list of efficacy endpoints of interest will be evaluated: 

Proportion of participants with HBsAg <10 IU/mL at Week 40 (Yes/No)

Proportion of participants with HBsAg <10 IU/ml at Off-Treatment Week 24 (Yes/No)

Proportion of participants with HBsAg Seroconversion at Off-Treatment Week 24 (Yes/No)

Proportion of participants with Functional Cure at Off-Treatment Week 24 (Yes/No)
For each of the endpoints listed above, the potential association with the following selection of 
characteristics or intrahepatic/blood markers may be assessed:

Duration of NA (years)

Age (years)

Duration of infection (years)

Baseline HBeAg level (quantitative), for panel 1 only

Baseline HBV DNA level (log10)

Baseline ALT Level (quantitative)

Baseline Peripheral HBsAg level (log10)

Baseline Number of HBsAg+ hepatocytes (log10)

Proportion of HBsAg+ hepatocytes at baseline

Proportion of cccDNA-positive hepatocytes at Baseline

Proportion of pgRNA-positive hepatocytes at Baseline

HBeAg level (quantitative) at Week 40


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
HBV DNA level (log10) at Week 40

ALT Level (quantitative) at Week 40

Peripheral HBsAg level (log10) at Week 40

Proportion of HBsAg+ hepatocytes (log10) at Week 40

Proportion of cccDNA-positive hepatocytes at Week 40

Proportion of pgRNA-positive hepatocytes at Week 40
These lists may be modified based on clinical relevance and data availability.
For Panels 1 and 2, logistic regression models will be performed for each efficacy endpoint of 
interest, and will include study panel and characteristics/marker of interest as factor, with and 
without the study panel-by-baseline variable as the interaction-terms. Covariates and/or interaction 
terms may be added or removed to a given model for fitting purpose. 
Odd-Ratios (OR) and corresponding 80% CIs will be also calculated without multiplicity 
adjustment overall. Statistical analysis of treatment heterogeneity between subgroups will be 
conducted by assessing the significance of the interaction term. The forest plot will present 
graphically the on/off treatment efficacy OR estimate and its 80% CI resulting from the model by 
the prespecified subgroups on the overall population and by study panels.
5.5.3.
Intrahepatic Immune and Viral Parameters at FU Week 24 (Week 72)
For all participants with biopsy data available at FU Week 24, the same analyses as described in 
Sections 5.3.1.2.3, 5.4.1.1 and 5.4.1.2 may be performed. Graphs over time will display baseline, 
Week 40 and FU Week 24 data.
5.5.4.
Liver Stiffness Measurement (LSM)
The proportion of participants with the following LSM changes from baseline (both in terms of 
reductions and increases) will be evaluated over time at Week 48, FU Week 24 and FU Week 48 
/EOS:

≥1 kPa

≥2 kPa

≥4 kPa

≥6 kPa
Only participants from sites with available VCTE (Fibroscan) will be included in the analysis. 
Within these participants, missing LSM (in kPa) at a specific timepoint will be considered as non-
responders for that timepoint. No imputation rule will be used in case of missing data.
In addition, the change from baseline in LSM will be compared between study panels at Week 48 
using ANCOVA with study panel as main effect in the model and baseline score as covariate.


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At each assessment time point, a frequency distribution of severity scores will be produced. A 
graphical display will also illustrate the findings. In addition, a waterfall plot will be produced to
display the individual changes from baseline in LSM.
5.5.5.
HBV RNA and HBcrAg
HBcrAg will be summarized by treatment history (not currently treated and virologically 
suppressed) and overall, while HBV RNA will only be summarized by treatment history.
The values of and changes from baseline in HBV RNA and HBcrAg, respectively, will be 
summarized only descriptively over time in a similar manner as for values and changes from 
baseline over time in HBsAg, HBeAg, and HBV DNA as described in Section 5.4.2.4.1, including 
the change from baseline value to nadir (i.e., maximum decrease for each participant) and the 
various graphical displays. 
Waterfall plots for changes from baseline of HBV RNA and HBcrAg will also be presented.
5.5.6.
Sustained HBsAg Response
The definitions of sustained response are as follows:
Definition 1 (yes/no): 

For participants with data at the last scheduled follow-up visit (Follow-up Week 48 for 
participants who did not receive PegIFN-α2a or received PegIFN-α2a and did not meet NA 
completion criteria, and last Follow-up visit for participants who received PegIFN-α2a and 
stopped NA during Follow-up): Participants who have a > 1 log decline in HBsAg at last 
scheduled follow-up visit and have an HBsAg <1000 IU/mL at the last scheduled follow-
up visit.

For participants without data at the last scheduled follow-up visit: HBsAg values have a > 
2 log decline at the second most recent visit or >1.5 log decline at the latest visit (most 
recent value used) compared to baseline and have an HBsAg <1000 IU/mL at the last 
available timepoint.
Definition 2 (yes/no): For participants with a >1 log decline in HBsAg from baseline at last follow-
up visit: Among the most recent three visits, the difference between log HBsAg at 2 of 3 last visit 
and 1 of 3 last visit is <0.2, and the difference between log HBsAg at 3 of 3 last visit and 1 of 3 
last visit is <0.2.
Definition 3 (yes/no): For participants with a >1 log decline in HBsAg from baseline at last follow-
up visit: Among the most recent three visits, the difference between log HBsAg at 2 of 3 last visit 
and 1 of 3 last visit is <0.2, and the difference between log HBsAg at 3 of 3 last visit and 1 of 3 
last visit is <0.2 and have an HBsAg <1000 IU/mL at the last available timepoint.


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Definition 4 (>0.2 log increase, +/-0.2 log, >0.2 log decline): Three categories regarding the 
difference between HBsAg level at the last Follow-up timepoint and EOT:

>0.2 log10 decrease: Decreasing level

≤0.2 log10 increase or ≤0.2 log10 decrease: Stable level

>0.2 log10 increase: Increasing level
Due to the exploratory objectives of this Phase 2 study, additional sustained HBsAg response 
definitions may be explored according to the clinical interest.
For all definitions of the sustained HBsAg response, only participants with at least 24 weeks after 
JNJ-3989 stop will be used for the analysis.
The count and proportion (%) of participants achieving sustained HBsAg response will be 
summarized.
Spaghetti plots for HBsAg actual values and change from baseline will be presented by study panel
over time using color coding by category.
5.6.
Safety Analyses
All safety analyses will be based on the safety analysis set based on actual study intervention
received, unless otherwise specified. Summaries will be provided on the overall population and by 
study panel and analysis phase unless specified otherwise.
For all continuous safety variables, descriptive statistics will include the N, mean, standard 
deviation, median, minimum, and maximum. Categorical variables will be summarized using 
frequency counts and percentages.
5.6.1.
Extent of Exposure
The number and percentage of participants who receive each study treatment within a study panel
will be summarized.
Descriptive statistics for duration (N, mean, SD, median, and range [minimum, maximum]) of 
JNJ-3989, JNJ-6379, and NA during the open-label phase, and of PegIFN-α2a, will be 
summarized. Duration of treatment with NA will also be summarized for the follow up phase.
Because of the different route and frequency of treatment administration across the 3 agents (for 
JNJ-3989 one subcutaneous injection once every 4 weeks, for JNJ-6379 and for NA once daily 
tablet, and for PegIFN-α2a one subcutaneous injection every week) the total duration of exposure 
(weeks) will be calculated for each study treatment as follows: 

JNJ-3989: [Min ((Date of last injection+27 days), Date of trial disposition, cut-off date) – date 
of first injection + 1] / 7


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
JNJ-6379: [Min (Date of the last JNJ-6379, Date of treatment disposition for JNJ-6379, Date 
of trial disposition, Date of clinical cut-off)- first drug administration date + 1] / 7

NA: [Min (Date of the last NA administration in the given phase, Date of discontinuation from 
NA, Date of trial disposition, Date of clinical cut-off) - first drug administration date in the 
given phase + 1] / 7

PegIFN-α2a: [Min (Date of the last PegIFN-α2a administration +6 days, Date of 
discontinuation from PegIFN-α2a, Date of trial disposition, Date of clinical cut-off date) –
Date of the first PegIFN-α2a administration + 1] / 7
For NA treatment, the total duration of exposure will be calculated separately for the open-label
and FU phases. For FU, the total duration will add up the weeks of NA treatment in the FU phase 
for those participants who did not stop NA prior to/at Week 48 and the NA re-treatment weeks, if 
any required. Those participants who stopped NA treatment at or before Week 48 and never 
restarted NA treatment thereafter will be counted as having zero weeks of NA exposure during the 
FU.
Cutoff dates will be defined to match the prespecified timepoints for interim analyses and the 
primary analysis, respectively (see Section 5.8).
The number and percentage of participants who skipped any dose of JNJ-3989 or NA during the 
open-label phase, or any dose of PegIFN-α2a, will be summarized separately by study panel.
Additionally, the number and percentage of participants who missed 2 or more JNJ-3989 
injections, or who missed more than 5 doses of NA within a four week period will be provided as 
well as the distribution of the total number of JNJ-3989 injections received.
Study intervention compliance will be summarized descriptively. See Appendix 7 Intervention 
Compliance for further details.
5.6.2.
Adverse Events
The verbatim terms used in the CRF by investigators to identify adverse events will be coded using 
the Medical Dictionary for Regulatory Activities (MedDRA). Any AE occurring at or after the 
initial administration of study intervention is considered to be treatment emergent. If the event 
occurs on the day of the initial administration of study intervention, and either event time or time 
of administration are missing, then the event will be assumed to be treatment emergent. If the event
date is recorded as partial or completely missing, then the event will be considered to be treatment 
emergent unless it is known to be prior to the first administration of study intervention based on 
partial onset date or resolution date. All reported treatment-emergent adverse events will be 
included in the analysis. For each adverse event, the number and percentage of participants who 
experience at least 1 occurrence of the given event will be summarized.
Summary tables will be provided for treatment-emergent adverse events:

AEs

Serious AEs (SAEs)




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on cystatin C in serum (calculated by the CKD-EPI cystatin C equation, denoted as 
eGFRcys)
Routine 
Urinalysis
Dipstick
Specific gravity
pH
Glucose
Protein
Blood
Ketones
Bilirubin
Urobilinogen
Nitrite
Leukocyte esterase
Sediment (if dipstick result is abnormal)
RBCs
WBCs
Epithelial cells
Crystals
Casts
Bacteria
Urine Chemistry 
(quantitative 
measurement)
Creatinine
Sodium
Phosphate
Glucose
Protein
Albumin
Renal 
Biomarkers
Retinol binding protein
Beta-2-microglobulin
Clinical laboratory tests will be displayed for the participants included in the safety analysis set by 
study panel and study phase.
Descriptive statistics and graphical displays will be presented for all chemistry, hematology, and 
urinalysis laboratory tests at scheduled time points.
Change from baseline over time will be summarized for chemistry, hematology, urinalysis tests 
and renal biomarkers and displayed.
Abnormality criteria ([based on the criteria specified in the DAIDS Toxicity Grading Scale (see 
Clinical Protocol Appendix 8, DAIDS Table]) will be applied to baseline and postbaseline values
or in accordance with the normal ranges of the clinical laboratory if no gradings are available.
Postbaseline abnormalities will be compared with their corresponding baseline result:

For toxicity grades, treatment emergent (TE) will be concluded if the postbaseline grade is 
worse than the baseline grade.

For abnormalities based on normal range and/or criteria: If the postbaseline value is above the 
upper limit and the baseline value is below the upper limit (e.g., Normal or Low), then the 
postbaseline abnormality will be considered TE. The same applies to the postbaseline value 
being below the lower limit with the baseline value being above the lower limit (e.g., Normal 
or High).

If the baseline value is missing, a postbaseline abnormality will always be considered as TE.
For each lab parameter, a worst-case analysis will be performed by using the worst abnormality 
and/or worst toxicity grade lab value and time point per participant (Appendix 9). The worst 
toxicity case is the value associated to the highest toxicity grade and is derived per parameter and 


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toxicity direction (hypo / hyper). Worst-case will be derived within each phase, including 
unscheduled assessments. For abnormalities, in case the same subject has both abnormalities (low 
and high) for the same lab test within the same phase, the participant will be counted in the analysis 
for both toxicity directions (abnormally high and low).
Imputation rules:
In case continuous laboratory results are not numerically expressed, but as a character (e.g., ‘less 
than 2’, ‘>25’), these results will be numerically imputed as follows:

If the analysis result contains '<' then the result will be multiplied by 0.999 (e.g., <6.1 becomes 
6.0939). 

If analysis result contains '>' then the result will be multiplied by 1.001 (e.g., >6.1 becomes 
6.1061).

If analysis result contains '≤' or '≥' then only the numeric portion of the result will be used.
This also applies to normal limits expressed as such.
Shift tables will be provided summarizing the shift in laboratory values from baseline over time 
with respect to abnormality criteria (low, normal, high) for each laboratory parameter by study 
phase.
The cross-tabulations of the worst toxicity grades over time versus baseline grade and the worst 
abnormalities versus baseline grade per parameter and per analysis phase will be presented 
including also the number of participants per worst grade and the number of participants per 
abnormality.
A tabulation of percentage and number of the participants who have treatment-emergent worst 
toxicity grades and treatment-emergent worst abnormalities per parameter and analysis phase will 
be included. The incidence table of worst toxicity grade abnormality in laboratory parameters will 
be also presented stratified by the subgroup of interests identified in Section 5.7.4.
Plots of mean (+/- SE) values and changes from baseline over time for alanine transferase (ALT), 
aspartate aminotransferase (AST), alkaline phosphatase, hemoglobin, neutrophils, platelets, 
bilirubin (direct and indirect), lipase, amylase/pancreatic amylase, activated partial thromboplastin 
time, prothrombin time and phosphate will be presented by study panel. Spaghetti-plots for 
selected laboratory parameters will be presented by study panel over time (with Week shown on 
x-axis).
A listing including all parameters with at least one treatment-emergent toxicity or abnormality per 
participant (exclusion of urinalysis) will be generated.
5.6.3.1.1.
Creatinine and Glomerular Filtration
Creatinine and glomerular filtration analyses will be analysed over time.


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5.6.3.1.1.1.
eGFR
Stages of eGFR (eGFRcr or eGFRcys, as described in Table 5) at baseline versus the minimum 
corresponding post-baseline eGFR value and the last available value will be summarized by count 
and percent of participants. Stage of chronic kidney disease (CKD) are defined as follows: 1 
(Normal): eGFR ≥ 90; 2 (Mild): eGFR 60-89; 3 (Moderate): eGFR 30-59; 4 (Severe): eGFR <30.
In addition to the above, the number and proportion of participants with a <10%, 10-<30%, 30-
<50% and ≥50% decrease from baseline will be tabulated.
Scatter plots of eGFR (eGFRcr or eGFRcys) versus other renal biomarkers (total urine protein, 
total urine albumin, urine protein to creatinine ratio [UPCR], urine albumin to creatinine ratio 
[UACR], retinol binding protein (RBP) and beta-2-microglobulin, RBP to creatinine ratio and 
beta-2-microglobulin to creatinine ratio, and urine fractional excretion of phosphate [FEPO4]) will 
also be presented.
5.6.3.1.1.2.
Proximal Renal Tubular Function
Proteinuria by Quantitative Assessment
Total urine protein, total urine albumin, UPCR and UACR will be summarized by study panel and 
visit using descriptive statistics. 
The number and proportion of participants with UACR and UPCR results in the following 
categories over time will be tabulated:

UACR: < 30, ≥ 30 to 300, >300 mg/g

UPCR: < 200 mg/g versus ≥ 200 mg/g
Median (Q1, Q3) percent change from baseline over time will be plotted by study panel.
The evolution over time of total urine protein and total urine albumin will also be presented.
Proteinuria by Urinalysis (Dipstick)
Treatment-emergent proteinuria by urinalysis (dipstick) over time will be summarized by study 
panel. Cross-tabulation of grades overtime versus baseline will also be presented.
Other Renal Biomarkers
Selected renal biomarkers RBP and beta-2-microglobulin, RBP to creatinine ratio and beta-2-
microglobulin to creatinine ratio will be summarized by study panel and visit using descriptive 
statistics. 
The proportions of participants with beta-2-microglobulin to creatinine ratio ≤343.5 μg/g and 
>343.5 μg /g will be tabulated.


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The number and proportion of participants with RBP to creatinine ratio results in the following 
categories overtime will be tabulated:

< 50 years of age: < 130 mcg/g creatinine, ≥ 130 mcg/g creatinine

≥ 50 years of age: < 172 mcg/g creatinine, ≥ 172 mcg/g creatinine
Phosphate excretion
Other renal biomarkers include FEPO4 that will be summarized by study panel and visit using 
descriptive statistics.
FEPO4 will be calculated as follows:

Based on unadjusted serum creatinine:
FEPO4 (%) = (SCr × UPO4) / (SPO4 × UCr) × 100 (%)
Where SCr is serum creatinine concentration, UPO4 is urine phosphate concentration, SPO4 is 
serum phosphate concentration, and UCr is urine creatinine concentration.
The proportions of participants with FEPO4 ≤10% and >10% will be tabulated.
The baseline, post-baseline, and change from baseline in FEPO4 will be summarized by study 
panel and visit using descriptive statistics. Median (Q1, Q3) change from baseline in FEPO4 over 
time will be plotted by study panel. 
Subclinical renal proximal tubulopathy
Potential Markers of Renal Proximal Tubulopathy are:
1. Confirmed increase in serum creatinine ≥ 0.40 mg/dL from baseline. 
2. Confirmed ≥ 2 grade level increase from baseline in graded proteinuria
3. Confirmed ≥ 1 grade level increase from baseline in graded hypophosphatemia
4. Confirmed ≥ 1 grade level increase from baseline in graded glycosuria concurrent with 
serum glucose ≤100 mg/dL (normoglycemic glycosuria)
A confirmed laboratory abnormality is defined as an abnormality observed at 2 consecutive post-
baseline measurements or an abnormality observed at 1 measurement followed by study drug 
discontinuation
A subclinical renal proximal tubulopathy will be defined as confirmed abnormalities in any 2 out 
of the 4 renal parameters (serum creatinine and one or more of the 3 other markers of tubular 
dysfunction).


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Baseline Subclinical renal proximal tubulopathy
Potential Markers of Renal Proximal Tubulopathy at Baseline
1. Grade ≥ 1 serum creatinine 
2. Grade ≥ 2 proteinuria
3. Grade ≥ 1 hypophosphatemia
4. Grade ≥ 1 glycosuria concurrent with serum glucose <=100 mg/dL (normoglycemic 
glycosuria)
A baseline subclinical renal proximal tubulopathy will be defined as abnormalities in any 2 out 
of the 4 renal parameters (serum creatinine + 1 or more of the 3 other markers of tubular 
dysfunction).
5.6.3.2.
Vital Signs and Physical Examination Findings
The following parameters measurements will be analyzed:

Supine pulse rate (bpm)

Supine systolic blood pressure (mmHg)

Supine diastolic blood pressure (mmHg)

Body temperature (℃)
The abnormalities in vital signs will be determined according to the criteria specified in the 
Cardiovascular Safety – Abnormalities Table (see Clinical Protocol Appendix 7).
An assessment is Treatment Emergent (TE) if abnormality worsened as compared to the 
abnormality at baseline; this also includes the shift from abnormally high to abnormally low and 
vice-versa. Post-baseline abnormalities are always treatment-emergent with regard to missing 
abnormalities at baseline. The abnormally high values (i.e., abnormally high, grade 1 or mild, 
grade 2 or moderate, grade 3 or severe) versus the abnormally low values are considered equally 
important.
For each parameter, a “worst-case” analysis will be performed by using the worst abnormality and 
time point per participant. Worst-case will be derived within each phase, including unscheduled 
assessments. In case the same subject has both abnormalities (low and high) for the same test 
within the same phase, the participant will be counted in the analysis for both abnormality 
directions (abnormally high and low).
Vital signs records with partial dates (any of day/month/year is missing) will not be used in the 
analysis but will be listed.
Descriptive statistics of continuous vital sign parameters and body temperature will be calculated 
for observed values and changes from baseline at each scheduled time point.


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Shift tables will be provided summarizing the shift in vital sign and body temperature values from
baseline over time with respect to abnormality criteria (low, normal, high) for each parameter by 
study phase.
A cross-tabulation of the worst abnormalities versus baseline per parameter and study phase will 
be presented including also the number of participants per abnormality, the number of participants 
with treatment emergent abnormalities per abnormality.
A tabulation of percentage and number of the participants who have treatment-emergent worst 
abnormalities per parameter and study phase will be included.
A listing including all parameters for participants with at least one treatment-emergent abnormality 
(on actual values or change from baseline) will be provided. Additional vital signs assessments 
corresponding to the rash eCRF pages will be only listed as applicable.
The physical examination findings and abnormalities will be listed.
5.6.3.3.
Electrocardiogram
Evaluation of the triplicate 12-lead ECGs will be based on the mean value of the triplicate 
parameters and the abnormalities will be defined on the triplicate means. 
The following ECG parameters measurements will be analyzed:

PR interval (ms)

Heart Rate (bpm)

QT interval (ms)

QRS duration (ms)

QTc Corrected (Fridericia’s formula QTcF)
Fridericia’s formula: QTcF (msec) = QT (msec) / (RR (msec)/1000)1/3; if RR is missing, use QT 
(msec) * (HR(bpm)/60)1/3;The abnormalities in ECG parameters will be determined according to 
the criteria specified in the Cardiovascular Safety – Abnormalities Table (see Clinical Protocol 
Appendix 7, Cardiovascular Safety- Abnormalities Table). Abnormalities on actual values are 
provided for HR, PR, QRS and QTcF. Additional abnormalities on change from baseline will be 
provided for QTcF. No abnormalities will be defined for actual uncorrected QT values. 
Uncorrected QT ≥ 500 ms will be flagged and only shown in listings.
An assessment is TE if abnormality worsened as compared to the abnormality at baseline; this also 
includes the shift from abnormally high to abnormally low and vice-versa. Post-reference 
abnormalities are always TE with regard to missing abnormalities at baseline. The abnormally high 
values (i.e., abnormally high, borderline prolonged, prolonged, pathologically prolonged) versus 
the abnormally low values are considered equally important. Abnormalities defined on changes 
from baseline are always TE.


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For each parameter, a “worst-case” analysis will be performed by using the worst abnormality and 
time point per participant. Worst-case will be derived within each phase, including unscheduled 
assessments. In case the same subject has both abnormalities (low and high) for the same test 
within the same phase, the participant will be counted in the analysis for both abnormality 
directions (abnormally high and low).
For the time points on which triplicate ECGs apply, a rounded mean value to the next integer per 
triplet will be calculated per time point before any further handling. This rounded mean value will 
be used through the entire analysis also in case of 1 or 2 missing values.
ECG records with partial dates (any of day/month/year is missing) will not be used in analysis, 
except in the listings. The following imputation rules will be applied.
If heart rate (HR) is missing, it will be calculated using RR (if available) and rounded to the integer 
value (see formula below) before any further handling if applicable. 
60
)
(
)
(
1000
bpm
HR
ms
RR

HR from the vital signs section (i.e., pulse) will not be used in this ECG analysis section. RR 
values (if available) will only be listed. Recalculated HR values will be flagged.
Descriptive statistics will be calculated for observed values and changes from baseline per 
parameter (all parameters except for RR) at each scheduled time point by study panel and analysis 
phase. 
Shift tables will be provided summarizing the shift in ECG values from baseline over time with 
respect to abnormality category (low, normal, high) for each parameter by study phase.
A cross-tabulation of the worst abnormalities (on actual values) versus baseline per parameter by 
study phase will be presented including also the number of participants per abnormality. A 
tabulation of number and percentage of the participants who have TE worst abnormalities per 
parameter (i.e., for HR, PR, QRS and QTcF) and study phase will also be presented. 
A cross-tabulation of the worst change from baseline abnormalities (i.e., for QTcF) versus the 
baseline category per parameter will be presented by study panel and study phase.
Frequency tabulations of categorized corrected QT/QTc change from baseline (<=30 msec, >30-
<=60 msec, >60 msec) and categorized corrected QT/QTc interval values (<=450 msec, >450-
<=480 msec, >480-<= 500 msec, >500 msec) per timepoint will be presented by study panel.
Listings including all parameters for participants with at least one treatment-emergent abnormality 
(on actual values or change from baseline), including all findings (e.g., interpretation, rhythm, or 
technical findings) for participants with uncorrected QT values ≥ 500 ms will be provided 
separately.


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5.7.
Other Analyses
5.7.1.
Pharmacokinetics
Two types of plasma PK analyses will be conducted, including noncompartmental analysis in the 
PK sub-study participants (Section 5.3.2.2) and population PK analysis in all participants. Details 
of the plasma PK analyses will be described in a separate analysis plan and results will be reported 
separately.
5.7.2.
Pharmacokinetic/Pharmacodynamic Relationships
Relationships of plasma PK parameters for JNJ-73763989 (JNJ-73763976 and JNJ-73763924), 
and optionally of JNJ-56136379, NA, and PegIFN-α2a, with selected efficacy and with selected 
safety endpoints will be evaluated and graphically displayed, if applicable.
Modeling of key pharmacodynamic parameters (e.g., HDV RNA, HBsAg) may be performed 
using population pharmacokinetics/pharmacodynamics (PK/PD). Details will be described in a 
population PK/PD analysis plan and results of the PK/PD analysis will be presented in a separate 
report.
5.7.3.
Viral Genome Sequence Analysis
Viral genome sequence analysis may be performed to identify pre-existing baseline 
polymorphisms and to evaluate emergence of genetic variations (including substitutions) 
associated with JNJ-56136379, JNJ-3989, and/or ETV or TD treatment on both nucleotide and/or 
amino acid level.
The sequencing of samples may be triggered by the sponsor virologist based on changes in HBV 
DNA levels observed in each individual participant and the limits of the sequencing assay.
Virology results will be presented by specified timepoints and genetic region and position of 
interest. A separate virology report may be prepared. 
5.7.4.
Definition of Subgroups
Table 6:
List of Subgroups of Interest for Efficacy and/or Safety Purpose
Subgroup
Purpose
Definition
Sex
Efficacy, Safety
Male, Female
Age Group
Efficacy, Safety
≤ 45 years, > 45 years
Race
Efficacy, Safety
Asian, Non-Asian
Body Mass Index
Safety
≤  25, >=25
HBsAg level at baseline
Efficacy
<1000 vs. >=1000
<10,000 vs. >=10,000
Type of NA at Study Entry
Safety
TD, TAF
Received PegIFN-a2a (Optional)
Efficacy, Safety
Yes/No
HBsAg % Positive Cells
Efficacy
<Median vs. >=Median Value
This list of subgroups may be modified based on interim/final results and clinical interest.


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5.8.
Interim Analyses
Two Interim Analyses (IA) may be performed: when all participants have completed Week 20 in 
the study intervention phase (or discontinued earlier) and when they have completed Week 72 (FU 
Week 24) in the follow-up phase (or discontinued earlier). These IAs will be performed by the 
sponsor to support interactions with health authorities, as well as to support internal decisions 
about additional studies and/or investigation of other combination regimens.
Both primary (when all participants have completed Week 48 or discontinued earlier) and interim 
analyses will be based on all data available at the predefined cut-off time points and may include 
data at later time points for those participants who have reached subsequent visits.
The final analysis will be performed when all participants have completed the last study visit 
(Follow-up Week 48) or discontinued earlier.
The overview of data domains and specific endpoints that will be provided for each analysis is 
presented in Table 7.
Table 7:
Overview of Times of Data Summaries and Analyses at Planned Interim, Primary and Final 
Analyses
IA1 when 
all 
participants 
have 
completed 
Week 20
Primary 
Analysis
when all 
participants 
have 
completed 
Week 48
IA2 when all 
participants 
have 
completed FU 
Week 24
Final 
Analysis
when all 
participants 
have 
completed 
FU Week 48
DATA DOMAINS FOR ANALYSIS
Subject Information 
Baseline & Demographic characteristics
X
X
X
X
Disposition and Study Populations 
X
X
X
X
Extent of Exposure 
X
X
X
X
Safety 
TEAEs, SAEs, AE of interest, fatal AEs, AEs 
causing treatment discontinuation
X
X
X
X
Laboratory Tests
X
X
X
X
ECG
X
X
X
X
Vital signs
X
X
X
X
Efficacy
Primary efficacy endpoints
X
X
X
Secondary efficacy endpoints
X
X
X
X
Exploratory Endpoints
X
X
X
X
PK
X
X*
X*
Virologic breakthrough HBV
X
X
X
X
Flares: Viral, Biochemical, Clinical 
X
X
X
X
Viral Genome Sequence Analysis
X
X
X
* If new data are available.
No DMC or Data Review Committee (DRC) is required for this study.


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An Independent Flare Expert Panel (IFLEP) is appointed for this study to monitor ALT flares and 
make recommendations regarding flare management based on analysis of aggregate data. The 
IFLEP is composed of 3 independent medical experts with experience and expertise in hepatitis B 
and its treatment. 
Further details on the IFLEP process will be provided in the IFLEP charter.


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6.
SUPPORTING DOCUMENTATION
6.1.
Appendix 1 List of Abbreviations
AE
adverse event
ALT
alanine aminotransferase
ANCOVA
analysis of covariance
AST
aspartate aminotransferase
ATC
anatomic and therapeutic class
AUC
area under the curve
BMI
body mass index
BSA
body surface area
CHB
chronic hepatitis B
CI
confidence interval
CL
total systemic clearance
Cmax
maximum concentration
CRF
case report form
CSR
Clinical Study Report
CTCAE
Common Terminology Criteria for Adverse Events
CV
coefficient of variation
DMC
Data Monitoring Committee
DPS
Data Presentation Specifications
ECG
electrocardiogram
eCRF
electronic case report form
ETV
entecavir
F (%)
absolute SC bioavailability
FAS
full analysis set
FDA
Food and Drug Administration
HBcrAg
hepatitis B core-related antigen 
HBeAg
hepatitis B e antigen
HBsAg
hepatitis B surface antigen
HBV
hepatitis B virus
ICH
International Conference on Harmonisation
ITT
intent-to-treat
IQ
interquartile
IVRS
interactive voice response system
IWRS
interactive web response system
LLOQ
lower limit of quantification
LOCF
last observation carried forward
MedDRA
Medical Dictionary for Regulatory Activities
MRD
minimum required dilution
NA
nucleos(t)ide analogs
NAb
neutralizing antibodies
PD
pharmacodynamic(s)
PegIFN-α2a
pegylated interferon alpha-2a
PI
principal investigator
PK
pharmacokinetic(s)
PP
per protocol
SAE
serious adverse event
SAP
Statistical Analysis Plan
SD
standard deviation
SMQs
standardised MedDRA queries
TEAE
treatment-emergent adverse event
Tmax
time to maximum concentration
US NCI
United States National Cancer Institute
V
volume distribution
Vz
volume of distribution based on terminal phase
Vz/F
apparent volume of distribution based on terminal phase after extravascular administration


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WHO
World Health Organization
WHO-DD
World Health Organization Drug Dictionary


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6.2.
Appendix 2 Changes to Protocol-Planned Analyses
No change from protocol-planned analyses.








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6.4.
Appendix 4 Protocol Deviations
In general, the following list of major protocol deviations may have the potential to impact 
participants’ rights, safety or well-being, or the integrity and/or result of the clinical study. 
Participants with major protocol deviations will be identified prior to database lock and the 
participants with major protocol deviations will be summarized by category.

Developed withdrawal criteria but not withdrawn

Entered but did not satisfy criteria

Received a disallowed concomitant treatment (Appendix 5)

Received wrong treatment or incorrect dose

Other
All major protocol deviations will be tabulated by coded term by study panel for the ITT. A listing 
of the major protocol deviations will be also presented.
A subset of major protocol deviations that may affect the assessment of efficacy (see list in 
Attachment 2) will be identified and finalized prior to database lock to define the Per-Protocol 
analysis set (see Section 4). The number and percentage of ITT participants who are included in 
the PP analysis set will be summarized by study panel, accompanied by number and percentage of 
ITT participants who are excluded from the PP analysis set with the incidence of the major protocol 
deviations.


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6.5.
Appendix 5 Prior and Concomitant Medications
Prior and Concomitant medications will be coded using the World Health Organization Drug 
Dictionary Prior medications are defined as any therapy used before the day of first dose (partial 
or complete) of any study intervention. Concomitant medications are defined as any therapy used 
on or after the same day as the first dose of study interventions, including those that started before 
and continue on after the first dose of study interventions.
Summaries of concomitant medications will be presented by ATC class 2, level 4 and preferred 
term, study phase, study panel, and overall. The proportion of participants who receive each 
concomitant medication will be summarized as well as the proportion of participants who receive 
at least 1 concomitant medication. 
Prior medications will be summarized by study panel and overall; as well ATC class 2, level 4 and 
preferred term.


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6.6.
Appendix 6 Medical History
A tabulation of the general medical history coded terms will be provided by body system class and 
by study panel and overall.


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6.7.
Appendix 7 Intervention Compliance
Compliance will be summarized descriptively on the Safety Set for each study treatment except
NA.
Treatment compliance (%) is defined as follows:
For JNJ-3989: Total number of injections received / 12 * 100%
For JNJ-6379: Total medication intake / (4 * 7 * X) * 100%, where:

Total medication intake = Total number of tablets dispensed – Total number of tablets 
returned.

X = Number of weeks on 6379 (end date of JNJ-6379 – start date of JNJ-6379) for each 
participant. Note that the 250 mg daily dose of JNJ-6379 consists of 4 tablets (2 tablets 
of 100 mg strength and 2 tablets of 25 mg strength), so the denominator is 4*7*X.
For PegIFN-α2a: Total number of injections received / Total number of injections supposed 
to receive * 100%


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6.8.
Appendix 8 Adverse Events of Special Interest
Adverse events of special interest are defined as follows:
AE Special Interest Category
Preferred Term
AST/ALT elevations
ALANINE AMINOTRANSFERASE ABNORMAL
ALANINE AMINOTRANSFERASE INCREASED
ASPARTATE AMINOTRANSFERASE ABNORMAL
ASPARTATE AMINOTRANSFERASE INCREASED
HEPATIC ENZYME ABNORMAL
HEPATIC ENZYME INCREASED
HEPATIC FUNCTION ABNORMAL
HYPERTRANSAMINASAEMIA
LIVER FUNCTION TEST ABNORMAL
LIVER FUNCTION TEST INCREASED
TRANSAMINASES ABNORMAL
TRANSAMINASES INCREASED
Renal complications
ACUTE KIDNEY INJURY
ANURIA
NEPHROPATHY TOXIC
OLIGURIA
RENAL FAILURE
RENAL IMPAIRMENT
SUBACUTE KIDNEY INJURY
BLOOD CREATININE ABNORMAL
BLOOD CREATININE INCREASED
CREATININE RENAL CLEARANCE ABNORMAL
CREATININE RENAL CLEARANCE DECREASED
CREATININE URINE ABNORMAL
CREATININE URINE DECREASED
CRYSTAL NEPHROPATHY
GLOMERULAR FILTRATION RATE ABNORMAL
GLOMERULAR FILTRATION RATE DECREASED
NEPHRITIS
PROTEINURIA
RENAL FUNCTION TEST ABNORMAL
RENAL TUBULAR DISORDER
RENAL TUBULAR DYSFUNCTION
RENAL TUBULAR INJURY
RENAL TUBULAR NECROSIS
URINE OUTPUT DECREASED
NEPHROPATHY
NEPHROPATHY TOXIC
GLOMERULONEPHROPATHY
NEPHROLITHIASIS
Hematologic Abnormalities
APLASTIC ANAEMIA
AUTOIMMUNE APLASTIC ANAEMIA
BICYTOPENIA


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AE Special Interest Category
Preferred Term
BONE MARROW FAILURE
CYTOPENIA
FEBRILE BONE MARROW APLASIA
FULL BLOOD COUNT DECREASED
GELATINOUS TRANSFORMATION OF THE BONE MARROW
IMMUNE-MEDIATED PANCYTOPENIA
PANCYTOPENIA
PANMYELOPATHY
ASPIRATION BONE MARROW ABNORMAL
BIOPSY BONE MARROW ABNORMAL
BLOOD DISORDER
BONE MARROW DISORDER
BONE MARROW INFILTRATION
BONE MARROW MYELOGRAM ABNORMAL
BONE MARROW NECROSIS
HAEMATOTOXICITY
MYELODYSPLASTIC SYNDROME
MYELODYSPLASTIC SYNDROME TRANSFORMATION
MYELOFIBROSIS
MYELOID METAPLASIA
PLASMABLAST COUNT DECREASED
SCAN BONE MARROW ABNORMAL
APLASIA PURE RED CELL
APLASTIC ANAEMIA
ERYTHROBLAST COUNT DECREASED
ERYTHROID MATURATION ARREST
ERYTHROPENIA
HYPOPLASTIC ANAEMIA
MICROCYTIC ANAEMIA
PROERYTHROBLAST COUNT DECREASED
RED BLOOD CELL COUNT DECREASED
RETICULOCYTE COUNT DECREASED
RETICULOCYTOPENIA
ANAEMIA
ERYTHROBLAST COUNT ABNORMAL
ERYTHROPOIESIS ABNORMAL
HAEMATOCRIT ABNORMAL
HAEMATOCRIT DECREASED
HAEMOGLOBIN ABNORMAL
HAEMOGLOBIN DECREASED
LEUKOERYTHROBLASTIC ANAEMIA
NORMOCHROMIC ANAEMIA
NORMOCHROMIC NORMOCYTIC ANAEMIA
NORMOCYTIC ANAEMIA
PROERYTHROBLAST COUNT ABNORMAL
RED BLOOD CELL COUNT ABNORMAL
RETICULOCYTE COUNT ABNORMAL


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AE Special Interest Category
Preferred Term
RETICULOCYTE PERCENTAGE DECREASED
AGRANULOCYTOSIS
BAND NEUTROPHIL COUNT DECREASED
BAND NEUTROPHIL PERCENTAGE DECREASED
BASOPHIL COUNT DECREASED
BASOPHILOPENIA
B-LYMPHOCYTE COUNT DECREASED
CYCLIC NEUTROPENIA
EOSINOPENIA
EOSINOPHIL COUNT DECREASED
FEBRILE NEUTROPENIA
GRANULOCYTE COUNT DECREASED
GRANULOCYTES MATURATION ARREST
GRANULOCYTOPENIA
IDIOPATHIC NEUTROPENIA
LEUKOPENIA
LYMPHOCYTE COUNT DECREASED
LYMPHOPENIA
METAMYELOCYTE COUNT DECREASED
MONOBLAST COUNT DECREASED
MONOCYTE COUNT DECREASED
MONOCYTOPENIA
MYELOBLAST COUNT DECREASED
MYELOCYTE COUNT DECREASED
NEUTROPENIA
NEUTROPENIC INFECTION
NEUTROPENIC SEPSIS
NEUTROPHIL COUNT DECREASED
PROMYELOCYTE COUNT DECREASED
PURE WHITE CELL APLASIA
T-LYMPHOCYTE COUNT DECREASED
WHITE BLOOD CELL COUNT DECREASED
BASOPHIL COUNT ABNORMAL
BASOPHIL PERCENTAGE DECREASED
B-LYMPHOCYTE ABNORMALITIES
B-LYMPHOCYTE COUNT ABNORMAL
DIFFERENTIAL WHITE BLOOD CELL COUNT ABNORMAL
EOSINOPHIL COUNT ABNORMAL
EOSINOPHIL PERCENTAGE DECREASED
FULL BLOOD COUNT ABNORMAL
GRANULOCYTES ABNORMAL
LEUKOPENIA NEONATAL
LYMPHOCYTE COUNT ABNORMAL
LYMPHOCYTE PERCENTAGE ABNORMAL
LYMPHOCYTE PERCENTAGE DECREASED
MONOCYTE COUNT ABNORMAL
MONOCYTE PERCENTAGE DECREASED


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AE Special Interest Category
Preferred Term
MONONUCLEAR CELL COUNT DECREASED
MYELOBLAST PERCENTAGE DECREASED
MYELOCYTE PERCENTAGE DECREASED
MYELOID MATURATION ARREST
NEUTROPHIL COUNT ABNORMAL
NEUTROPHIL PERCENTAGE DECREASED
PLASMA CELL DISORDER
PLASMA CELLS ABSENT
WHITE BLOOD CELL ANALYSIS ABNORMAL
WHITE BLOOD CELL COUNT ABNORMAL
WHITE BLOOD CELL DISORDER
ACQUIRED AMEGAKARYOCYTIC THROMBOCYTOPENIA
MEGAKARYOCYTES DECREASED
PLATELET COUNT DECREASED
PLATELET MATURATION ARREST
PLATELET PRODUCTION DECREASED
PLATELET TOXICITY
THROMBOCYTOPENIA
MEGAKARYOCYTES ABNORMAL
PLATELET COUNT ABNORMAL
PLATELET DISORDER
PLATELETCRIT ABNORMAL
PLATELETCRIT DECREASED
Cholesterol Increase
BLOOD CHOLESTEROL ABNORMAL
BLOOD CHOLESTEROL ESTERASE INCREASED
BLOOD CHOLESTEROL INCREASED
DYSLIPIDAEMIA
HIGH DENSITY LIPOPROTEIN ABNORMAL
HIGH DENSITY LIPOPROTEIN DECREASED
HIGH DENSITY LIPOPROTEIN INCREASED
HYPERCHOLESTEROLAEMIA
HYPERLIPIDAEMIA
HYPO HDL CHOLESTEROLAEMIA
INTERMEDIATE DENSITY LIPOPROTEIN DECREASED
INTERMEDIATE DENSITY LIPOPROTEIN INCREASED
LDL/HDL RATIO DECREASED
LDL/HDL RATIO INCREASED
LIPID METABOLISM DISORDER
LIPIDS ABNORMAL
LIPIDS INCREASED
LIPOPROTEIN ABNORMAL
LIPOPROTEIN INCREASED
LOW DENSITY LIPOPROTEIN ABNORMAL
LOW DENSITY LIPOPROTEIN DECREASED
LOW DENSITY LIPOPROTEIN INCREASED
NON-HIGH-DENSITY LIPOPROTEIN CHOLESTEROL DECREASED
NON-HIGH-DENSITY LIPOPROTEIN CHOLESTEROL INCREASED


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AE Special Interest Category
Preferred Term
PRIMARY HYPERCHOLESTEROLAEMIA
REMNANT HYPERLIPIDAEMIA
REMNANT-LIKE LIPOPROTEIN PARTICLES INCREASED
TOTAL CHOLESTEROL/HDL RATIO ABNORMAL
TOTAL CHOLESTEROL/HDL RATIO DECREASED
TOTAL CHOLESTEROL/HDL RATIO INCREASED
VERY LOW DENSITY LIPOPROTEIN ABNORMAL
VERY LOW DENSITY LIPOPROTEIN DECREASED
VERY LOW DENSITY LIPOPROTEIN INCREASED


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6.9.
Appendix 9 Laboratory Toxicity Grading
The laboratory abnormalities will be determined according to the criteria specified in the DAIDS 
Toxicity Grading Scale (see Clinical Protocol Appendix 8, DAIDS Table) or in accordance with 
the normal ranges of the clinical laboratory if no gradings are available.




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In contrast, inter-subject differences in the slopes are unknown, so a range of values of SDslope
were considered.
The number of HBsAg+ hepatocytes for subject i at visit j, denoted , was simulated as 
 ~ Binomial,  , where  is the total number of hepatocytes sampled during a biopsy. 
Based on the donors data, we simulated log() ~ (10, 0.35) for the baseline biopsy, and then 
log() ~ (log() , 0.1) for the Week 40 biopsy; values of  and  were then rounded to 
integers.
Statistical Analysis of the Simulated Data
For each simulated dataset, we fit both the overall model as specified in Section 5.3.1.2.2.1 and 
the between-panel model as specified in Section 5.3.1.2.2.2. From the overall model, we estimated 
the absolute and relative reductions from baseline in the overall proportion of HBsAg+
hepatocytes. From the between-panel model, we estimated the between-panel differences in the 
reductions. For each estimate we obtained an 80% confidence interval (CI). Note that, for ease of 
interpretation, we present the changes from baseline as “reductions” – simply the negative of 
changes – so that most of the reported numbers are positive. I.e., a change from 75% to 5% is 
reported as an absolute reduction of 70% rather than as an absolute change of -70%.
We averaged all the estimates across 1000 simulations. The primary metric of interest is the width 
of the 80% CIs, which tell us how precisely we can estimate the reductions of interest given the 
sample size and the assumptions of the data-generating model.
Simulation Results
The 80% CI widths are presented in Figure 3 and again, together with point estimates and 80% CI 
limits, in Table 11. Generally, we see little bias in the point estimates – the average estimated 
reductions and differences in reductions in Table 11 match well with the scenario assumptions in 
10. This is as expected, as binomial mixed models were used to both simulate the data and carry 
out the estimation.
The precision of the estimates are of course greater – meaning narrower CIs – with 12 patients per 
panel than with either 8 or 10 patients. However, the loss in precision with fewer patients is not 
large in the simulated scenarios, as shown in Figure 3. E.g., in Scenario A with SDslope = 1.0, as 
the sample size per panel increases from 8 to 12 the width of the 80% CI decreases from 20.3% to 
16.7% for the overall absolute reduction from baseline; and from 21.8% to 18.1% for the between-
panel difference in the absolute reduction.
For the overall absolute reduction (OAR) from baseline, varying the value of SDslope has minimal 
impact on the CI widths. Across Scenarios A, B, and C, the CI widths vary from roughly 8% to 
17% with 12 patients per panel and from 10% to 21% with 8 patients per panel. Generally, the CI 
widths appear to be larger when the true OAR is larger.
For the overall relative reduction (ORR) from baseline, both the value of SDslope and the scenario 
assumptions (A, B, or C) have large impacts on the CI widths. In Scenario A the precision was 


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excellent regardless of the value of SDslope, but in Scenario C the precision is both worse and highly 
dependent on the value of SDslope. In contrast with the OAR, the CI widths for the estimated ORR 
appear to be larger when the true ORR is smaller.
The general pattern of CI widths observed for the OAR and ORR hold as well for the between-
panel difference in absolute reduction (DAR) and relative reduction (DRR). That this, the CI 
widths for the DAR do not vary much by SDslope, but are larger when the within-panel absolute 
reductions (which the model must estimate for each panel in order to estimate the between-panel 
DAR) are larger. For the DRR, the CI widths vary both by SDslope and scenario, with larger widths 
when the within-panel relative reductions are smaller. The CI widths for the DAR and DRR are of 
course larger than for the OAR and ORR – the model for between-panel differences has more 
parameters to estimate and, from another perspective, the DAR is essentially the difference 
between two OARs, and so the imprecision of the two OARs combine and propagate to the DAR 
(and analogously for the DRR as the difference of two ORRs).
Conclusions and Recommendations
The gains in precision as the sample size per panel increases from 8 to 12 are not large – the bigger 
factors are the true effect sizes and the between-patient variability, both of which are beyond our 
control. Yet we recommend maintaining the current target of 12 patients per panel (for Panels 1 
and 2) both to gain as much precision as is feasible and to allow for the likelihood of incomplete 
data due to patient dropout. Assuming 20% dropout, we would have only 9-10 patients per panel 
with usable data for the primary analysis. With this sample size, we may still achieve adequate 
precision for the overall reduction from baseline, whether absolute or relative. For the between-
panel differences, however, we have less confidence in achieving adequate precision regardless of 
the sample size we choose.


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Figure 3:
Simulation-based estimated widths of 80% confidence intervals for the (i and ii) overall and (iii 
and iv) between-panel analyses of the reduction in proportion of positive hepatocytes
The widths of the 80% CIs were obtained by averaging the estimates across 1000 simulations. The true proportions 
of HBsAg+ hepatocytes at baseline Week 40 in each scenario were:
Scenario A: 75%    5% for Panel 1 and 30%  1% for Panel 2
Scenario B: 75%    5% for Panel 1 and 30%10% for Panel 2
Scenario C: 60% 20% for Panel 1 and 30%10% for Panel 2








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ATTACHMENT 3.
SAS CODE TO FIT BINOMIAL MIXED MODELS
SAS (version 9.4) PROC NLMIXED may be used to fit the binomial mixed models specified in 
Sections 5.3.1.2.2.1 and 5.3.1.2.2.2. The advantage of NLMIXED over PROC GLIMMIX – which 
can also fit binomial mixed models – lies in the power of NLMIXED’s ESTIMATE statement, 
which can conveniently estimate non-linear functions of model parameters. In particular, this 
allows for convenient estimation of both point estimates and confidence intervals for the absolute 
and relative changes from baseline and the between-panel differences in the changes.
For the overall analysis in Section 5.3.1.2.2.1, code similar to the following may be used, where 
the input dataset insight should have variables named id, time, y, and N.
%macro expit(x);
(exp(&x) / (1 + exp(&x)))
%mend;
ods output AdditionalEstimates=estimates; * save ESTIMATE statement output;
proc nlmixed data=insight alpha=0.2;
parms a b 0 SD_int SD_slope 0.5; * initialize parameters;
* specify binomial model with random effects;
intercept = a + RE_int;
slope = b + RE_slope;
logit_p = intercept + slope*time;
p = %expit(logit_p);
random RE_int RE_slope ~ normal([0,0],[SD_int**2,0,SD_slope**2]) subject=id;
model y ~ binomial(N,p);
* estimate proportions and the change in proportions;
p0 = %expit(a);
p1 = %expit(a+b);
estimate "(1) p0" 100*p0;
estimate "(2) p1" 100*p1;
estimate "(3) Abs. change (p1-p0)" 100*(p1 - p0);
estimate "(4) Rel. change (p1-p0)/p0" 100*(p1/p0 - 1);
run;
For the between-panel analysis in Section 5.3.1.2.2.2, code similar to the following may be used, 
where the input dataset insight should have variables named id, time, panel, y, and N.
ods output AdditionalEstimates=estimates; * save ESTIMATE statement output;
proc nlmixed data=insight alpha=0.2;
parms a delta_a b delta_b 0 SD_int SD_slope 0.5; * initialize parameters;
* specify binomial model with random effects;
intercept = a + delta_a*(panel = 1) + RE_int;
slope = b + delta_b*(panel = 1) + RE_slope;
logit_p = intercept + slope*time;
p = %expit(logit_p);
random RE_int RE_slope ~ normal([0,0],[SD_int**2,0,SD_slope**2]) subject=id;
model y ~ binomial(N,p);
* estimate proportions, changes in proportions, and differences in changes;
q0 = %expit(a);
q1 = %expit(a+b);


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p0 = %expit(a+delta_a);
p1 = %expit(a+delta_a + b+delta_b);
estimate "(A1) Panel 1: p0" 100*p0;
estimate "(A2) Panel 1: p1" 100*p1;
estimate "(A3) Panel 1: Abs. change (p1-p0)" 100*(p1 - p0);
estimate "(A4) Panel 1: Rel. change (p1-p0)/p0" 100*(p1/p0 - 1);
estimate "(B1) Panel 2: q0" 100*q0;
estimate "(B2) Panel 2: q1" 100*q1;
estimate "(B3) Panel 2: Abs. change (q1-q0)" 100*(q1 – q0);
estimate "(B4) Panel 2: Rel. change (q1-q0)/q0" 100*(q1/q0 - 1);
estimate "(C1) Panel 1 minus 2: Diff in abs. change (A3-B3)"
100*(p1 - p0) - 100*(q1 - q0);
estimate "(C2) Panel 1 minus 2: Diff in rel. change (A4-B4)"
100*(p1/p0 - 1) - 100*(q1/q0 - 1);
run;


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7.
REFERENCES
1.
Kassahun W. Neysens T., Molenbergh G., Faes C., Verbeke G. (2012). Modeling overdispersed longitudinal 
binary data using a combined beta and normal random-effects model. Archives of Public Health, 70:7.