Conditions: Hepatitis B, Chronic
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 130
Healthy volunteers: no

Brief summary:
The purpose of this study is to evaluate the efficacy of 48-week study intervention with JNJ-73763989+JNJ-56136379+nucleos(t)ide analog (NA) regimen compared to NA alone assessed by HBsAg levels. This study is part of HepB Wings Platform Trial (PLATFORMPAHPB2001).

Detailed description:
Hepatitis B virus (HBV) is a small deoxyribonucleic acid (DNA) virus that infects the liver and can cause either acute or chronic infection. It consists of a so-called nucleocapsid in which viral DNA is packed with hepatitis B core protein (HBc) and membranous envelope containing hepatitis B surface antigen (HBsAg). Chronic HBV infection may lead to serious illnesses like cirrhosis and hepatocellular carcinoma (HCC). Oral treatment with NAs is effective at suppressing viral DNA formation and lowering virus concentration in blood to levels below lower limit of quantification (LLOQ). JNJ-73763989 is a liver-targeted antiviral therapeutic for subcutaneous injection designed to treat chronic HBV infection via ribonucleic acid interference mechanism but rarely lead to functional cure defined as sustained loss of HBs Ag and HBV DNA in serum. JNJ-56136379 is an orally administered capsid assembly modulator that is being developed for treatment of chronic HBV infection. The aim of study is to evaluate efficacy of 48-week study intervention with JNJ-3989+JNJ-6379+NA regimen compared to NA alone, assessed by HBsAg seroclearance at Week 72 (i.e., 24 weeks after completion of all study interventions at Week 48) without restarting NA treatment in HBeAg negative virologically suppressed chronic hepatitis B (CHB) infected participants who received NA treatment for at least 2 years prior to screening. The study will be 2.3 years and will be conducted in 3 phases: a screening phase (4 weeks), a study intervention phase (48 weeks), and a follow-up phase (48 weeks). Safety will be evaluated by AEs including AEs of special interest to any of the study interventions, clinical laboratory tests, ECGs, vital signs, and physical examinations.

Arms:
arm 1: Participants will receive fixed dose of JNJ-73763989 subcutaneous injection once every 4 weeks along with fixed dose of JNJ-56136379 tablet once daily and nucleos(t)ide analog (NA) treatment (either entecavir \[ETV\], tenofovir disoproxil fumarate \[TDF\], or tenofovir alafenamide \[TAF\]) once daily up to 48 weeks. arm 2: Participants will receive matching placebo for JNJ-73763989 subcutaneous injection once every 4 weeks with matching placebo for JNJ-56136379 once daily and NA treatment (either ETV, TDF or TAF) once daily up to 48 weeks.

Interventions: intervention 1: JNJ-73763989 intervention 2: JNJ-56136379 intervention 3: Placebo for JNJ-73763989 intervention 4: Placebo for JNJ-56136379 intervention 5: Entecavir (ETV) monohydrate intervention 6: Tenofovir disoproxil fumarate (TDF) intervention 7: Tenofovir alafenamide (TAF)
Intervention descriptions: intervention 1: JNJ-73763989 injection will be administered subcutaneously once every 4 weeks up to 48 weeks. intervention 2: JNJ-56136379 tablets will be administered orally once daily up to 48 weeks. intervention 3: Matching placebo for JNJ-73763989 will be administered as subcutaneous injection up to 48 weeks. intervention 4: Matching placebo for JNJ-56136379 tablets will be administered orally up to 48 weeks. intervention 5: ETV tablet will be administered orally once daily up to 48 weeks as NA treatment. intervention 6: TDF will be administered orally once daily up to 48 weeks as NA treatment. intervention 7: TAF will be administered orally once daily up to 48 weeks as NA treatment.

Protocol document:
Prot_000.pdf: 
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
1
Status: Approved,  Date: 26 November 2021
Janssen Research & Development *
Clinical Protocol
Intervention-specific Appendix 2 to Master Protocol PLATFORMPAHPB2001
AMENDMENT 3
A Randomized, Double-blind, Placebo-controlled Phase 2b Study to Evaluate Efficacy,
Pharmacokinetics, and Safety of 48-week Study Intervention With
JNJ-73763989+JNJ-56136379+Nucleos(t)ide Analog (NA) Regimen Compared to NA Alone
in e Antigen-negative Virologically Suppressed Participants With Chronic Hepatitis B
Virus Infection
REEF-2 Study
Protocol 73763989PAHPB2002; Phase 2b
AMENDMENT 4
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 Unlimited Company; 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. 
EudraCT NUMBER: 2019-002674-31
Status: 
Approved 
Date: 
26 November 2021
Prepared by: Janssen Research & Development, a division of Janssen Pharmaceutica NV
EDMS number: 
EDMS-ERI-188471315, 8.0
GCP Compliance: This study will be conducted in compliance with Good Clinical Practice, and applicable regulatory
requirements.
Confidentiality Statement
The information in this document contains trade secrets and commercial information that are privileged or confidential and
may not be disclosed unless such disclosure is required by applicable law or regulations. In any event, persons to whom the
information is disclosed must be informed that the information is privileged or confidential and may not be further disclosed
by them. These restrictions on disclosure will apply equally to all future information supplied to you that is indicated as
privileged or confidential.
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JNJ-73763989 and JNJ-56136379
Clinical Protocol 73763989PAHPB2002
AMENDMENT 4
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
2
Status: Approved,  Date: 26 November 2021
PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE
DOCUMENT HISTORY
Document 
Date
Amendment 4 
This document
Amendment 3 
30-September-2021
Amendment 2 
27-January-2020
Amendment 1 
26-Sept-2019
Original Protocol 
31-Jul-2019
Amendment 4 (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 3, 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
6.7 NA Re-treatment Criteria and Monitoring
After Stopping of NA
10.13 Appendix 13: NA Re-treatment and
Monitoring After Stopping of NA
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JNJ-73763989 and JNJ-56136379
Clinical Protocol 73763989PAHPB2002
AMENDMENT 4
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
3
Status: Approved,  Date: 26 November 2021
Description of Change 
Brief Rationale 
Section Number and Name
Minor grammatical, formatting, 
or spelling changes were made.
Minor errors were noted 
Throughout the protocol
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JNJ-73763989 and JNJ-56136379
Clinical Protocol 73763989PAHPB2002
AMENDMENT 4
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
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Status: Approved,  Date: 26 November 2021
TABLE OF CONTENTS
PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE ............................................................... 2
TABLE OF CONTENTS ............................................................................................................................... 4
LIST OF IN-TEXT TABLES AND FIGURES................................................................................................ 6
1. 
PROTOCOL SUMMARY..................................................................................................................... 7
1.1. 
Synopsis........................................................................................................................................... 7
1.2. 
Schema.......................................................................................................................................... 19
1.3. 
Schedule of Activities..................................................................................................................... 20
1.3.1. 
Schedule of Activities –Screening and Study Intervention Phase............................................. 20
1.3.2. 
Schedule of Activities –Follow-up Phase................................................................................... 25
2. 
INTRODUCTION................................................................................................................................ 29
2.1. 
Study Rationale.............................................................................................................................. 30
2.2. 
Background .................................................................................................................................... 31
2.2.1. 
JNJ-3989 and JNJ-6379............................................................................................................. 31
2.2.2. 
Combination of JNJ-3989 and JNJ-6379 with Entecavir, Tenofovir Disoproxil Fumarate,
or Tenofovir Alafenamide............................................................................................................ 41
2.3. 
Benefit-Risk Assessment............................................................................................................... 43
2.3.1. 
Benefits for Study Participation .................................................................................................. 43
2.3.1.1. 
Known Benefits........................................................................................................................ 43
2.3.1.2. 
Potential Benefits..................................................................................................................... 44
2.3.2. 
Risks for Study Participation....................................................................................................... 44
2.3.2.1. 
Known Risks............................................................................................................................ 44
2.3.2.2. 
Potential Risks......................................................................................................................... 44
2.3.2.2.1. 
Potential Risks for JNJ-3989................................................................................................ 44
2.3.2.2.2. 
Potential Risks for JNJ-6379................................................................................................ 45
2.3.3. 
Benefit-risk Assessment for Study Participation......................................................................... 46
3. 
OBJECTIVES AND ENDPOINTS ..................................................................................................... 47
4. 
STUDY DESIGN ................................................................................................................................ 50
4.1. 
Overall Design................................................................................................................................ 50
4.2. 
Scientific Rationale for Study Design............................................................................................. 53
4.2.1. 
Study-specific Ethical Design Considerations ............................................................................ 55
4.3. 
Justification for Dose...................................................................................................................... 55
4.3.1. 
JNJ-3989.................................................................................................................................... 55
4.3.2. 
JNJ-6379.................................................................................................................................... 55
4.4. 
End of Study Definition................................................................................................................... 56
4.4.1. 
Participant Completion................................................................................................................ 56
4.4.2. 
Study Completion (End of Study Definition)............................................................................... 56
5. 
STUDY POPULATION ...................................................................................................................... 56
5.1. 
Inclusion Criteria............................................................................................................................ 57
5.2. 
Exclusion Criteria........................................................................................................................... 59
5.3. 
Lifestyle Considerations................................................................................................................. 63
5.4. 
Screen Failures.............................................................................................................................. 64
6. 
STUDY INTERVENTION................................................................................................................... 65
6.1. 
Study Intervention(s) Administered................................................................................................ 65
6.2. 
Preparation/Handling/Storage/Accountability ................................................................................ 67
6.3. 
Measures to Minimize Bias: Randomization and Blinding............................................................. 68
6.4. 
Study Intervention Compliance...................................................................................................... 69
6.5. 
Concomitant Therapy..................................................................................................................... 69
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JNJ-73763989 and JNJ-56136379
Clinical Protocol 73763989PAHPB2002
AMENDMENT 4
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
5
Status: Approved,  Date: 26 November 2021
6.6. 
Study Intervention Completion at Week 48.................................................................................... 71
6.7. 
NA Re-treatment Criteria and Monitoring After Stopping of NA..................................................... 71
6.8. 
Intervention After the End of the Study.......................................................................................... 73
7. 
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT
DISCONTINUATION/WITHDRAWAL............................................................................................... 73
7.1. 
Discontinuation of Study Intervention ............................................................................................ 73
7.2. 
Participant Discontinuation/Withdrawal From the Study................................................................ 74
7.2.1. 
Withdrawal From the Use of Research Samples ....................................................................... 74
7.3. 
Lost to Follow-up............................................................................................................................ 74
8. 
STUDY ASSESSMENTS AND PROCEDURES ............................................................................... 74
8.1. 
Efficacy Assessments .................................................................................................................... 75
8.1.1. 
Sequencing................................................................................................................................. 76
8.1.2. 
Patient-reported Outcomes ........................................................................................................ 76
8.2. 
Safety Assessments....................................................................................................................... 77
8.2.1. 
Physical Examinations................................................................................................................ 78
8.2.2. 
Vital Signs................................................................................................................................... 78
8.2.3. 
Electrocardiograms..................................................................................................................... 78
8.2.4. 
Clinical Safety Laboratory Assessments .................................................................................... 78
8.3. 
Adverse Events and Serious Adverse Events ............................................................................... 78
8.3.1. 
Time Period and Frequency for Collecting Adverse Event and Serious Adverse Event
Information.................................................................................................................................. 78
8.3.2. 
Method of Detecting Adverse Events and Serious Adverse Events .......................................... 78
8.3.3. 
Follow-up of Adverse Events and Serious Adverse Events ....................................................... 78
8.3.4. 
Regulatory Reporting Requirements for Serious Adverse Events ............................................. 79
8.3.5. 
Pregnancy................................................................................................................................... 79
8.3.6. 
Adverse Events of Special Interest............................................................................................. 79
8.3.6.1. 
Rash ........................................................................................................................................ 79
8.3.6.1.1. 
Injection Site Reactions........................................................................................................ 80
8.3.6.2. 
Acute Systemic Allergic Reactions.......................................................................................... 80
8.3.6.3. 
Intervention-emergent ALT/AST Elevations............................................................................ 81
8.3.6.4. 
Renal Complications................................................................................................................ 82
8.3.6.5. 
Hematologic Abnormalities...................................................................................................... 82
8.4. 
Treatment of Overdose .................................................................................................................. 83
8.5. 
Pharmacokinetics........................................................................................................................... 83
8.6. 
Pharmacokinetic/Pharmacodynamic Evaluations.......................................................................... 84
8.7. 
Immune Assessments.................................................................................................................... 84
8.8. 
Host Genetics................................................................................................................................. 84
8.9. 
Exploratory Host Biomarkers ......................................................................................................... 85
9. 
STATISTICAL CONSIDERATIONS.................................................................................................. 85
9.1. 
Statistical Hypothesis..................................................................................................................... 85
9.2. 
Sample Size Determination ........................................................................................................... 86
9.3. 
Populations for Analyses................................................................................................................ 86
9.4. 
Statistical Analyses ........................................................................................................................ 86
9.4.1. 
Efficacy Analyses........................................................................................................................ 86
9.4.1.1. 
Primary Efficacy Endpoint (HBsAg Seroclearance 24 Weeks After Completion of All
Study Interventions at Week 48)............................................................................................. 87
9.4.1.2. 
Secondary and Exploratory Efficacy Endpoints ...................................................................... 87
9.4.1.3. 
Resistance Analyses ............................................................................................................... 89
9.4.1.4. 
Patient-reported Outcomes ..................................................................................................... 89
9.4.2. 
Safety Analyses.......................................................................................................................... 89
9.4.3. 
Other Analyses ........................................................................................................................... 89
9.5. 
Interim Analyses............................................................................................................................. 91
9.6. 
Independent Data Monitoring Committee ...................................................................................... 91
9.7. 
Independent Flare Expert Panel .................................................................................................... 92
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JNJ-73763989 and JNJ-56136379
Clinical Protocol 73763989PAHPB2002
AMENDMENT 4
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
6
Status: Approved,  Date: 26 November 2021
10. SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS ............................ 93
10.1. 
Appendix 1: Abbreviations and Definitions of Terms..................................................................... 93
10.2. 
Appendix 2: Clinical Laboratory Tests ........................................................................................... 96
10.3. 
Appendix 3: Regulatory, Ethical, and Study Oversight Considerations......................................... 97
REGULATORY AND ETHICAL CONSIDERATIONS................................................................................. 97
FINANCIAL DISCLOSURE......................................................................................................................... 97
INFORMED CONSENT PROCESS............................................................................................................ 97
DATA PROTECTION.................................................................................................................................. 97
LONG-TERM RETENTION OF SAMPLES FOR ADDITIONAL FUTURE RESEARCH ............................ 97
COMMITTEES STRUCTURE..................................................................................................................... 97
PUBLICATION POLICY/DISSEMINATION OF CLINICAL STUDY DATA................................................. 98
DATA QUALITY ASSURANCE................................................................................................................... 98
CASE REPORT FORM COMPLETION...................................................................................................... 98
SOURCE DOCUMENTS............................................................................................................................. 98
MONITORING............................................................................................................................................. 98
ON-SITE AUDITS ....................................................................................................................................... 98
RECORD RETENTION............................................................................................................................... 98
STUDY AND SITE START AND CLOSURE .............................................................................................. 98
10.4. 
Appendix 4: Adverse Events: Definitions and Procedures for Recording, Evaluating,
Follow-up, and Reporting............................................................................................................... 99
ADVERSE EVENT DEFINITIONS AND CLASSIFICATIONS .................................................................... 99
ATTRIBUTION DEFINITIONS .................................................................................................................... 99
SEVERITY CRITERIA................................................................................................................................. 99
SPECIAL REPORTING SITUATIONS........................................................................................................ 99
PROCEDURES........................................................................................................................................... 99
CONTACTING SPONSOR REGARDING SAFETY ................................................................................... 99
PRODUCT QUALITY COMPLAINT HANDLING ........................................................................................ 99
10.5. 
Appendix 5: Rash Management................................................................................................... 100
10.6. 
Appendix 6: Intervention-emergent ALT/AST Elevations ............................................................ 104
10.7. 
Appendix 7: Cardiovascular Safety –Abnormalities.................................................................... 105
10.8. 
Appendix 8: Contraceptive and Barrier Guidance and Collection of Pregnancy Information...... 106
10.9. 
Appendix 9: DAIDS Table ............................................................................................................ 108
10.10. Appendix 10: HBV-specific Self-stigma Scale ............................................................................. 131
10.11. Appendix 11: 5-Level EuroQol 5-Dimension Questionnaire (EQ-5D-5L).................................... 133
10.12. Appendix 12: Protocol Amendment History................................................................................. 136
10.13. Appendix 13: NA Re-treatment and Monitoring After Stopping of NA......................................... 144
11. REFERENCES................................................................................................................................. 145
INVESTIGATOR AGREEMENT............................................................................................................... 148
LIST OF IN-TEXT TABLES AND FIGURES
TABLES
Table 1: 
Animal/Human Exposure Ratios at NOAEL for JNJ-3989........................................................ 33
Table 2: 
Animal/Human Ratios at the NOAEL in Rat and Dog (Human Exposure at 250mg
JNJ-6379 Once Daily for 28 Days [Study 56136379HPB1001]).............................................. 34
Table 3: 
Disallowed Medication .............................................................................................................. 70
Table 4: 
Concomitant Medications to be Used With Caution ................................................................. 71
Table 5: 
Management of Rash Events by Severity Grade ................................................................... 100
FIGURES
Figure 1: Schematic Overview of the Study............................................................................................. 19
NCT04129554


JNJ-73763989 and JNJ-56136379
Clinical Protocol 73763989PAHPB2002
AMENDMENT 4
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
7
Status: Approved,  Date: 26 November 2021
1. 
PROTOCOL SUMMARY
1.1. 
Synopsis
Clinical Protocol 73763989PAHPB2002: A Randomized, Double-blind, Placebo-controlled Phase 2b
Study to Evaluate Efficacy, Pharmacokinetics, and Safety of 48-week Study Intervention With
JNJ-73763989+JNJ-56136379+Nucleos(t)ide Analog (NA) Regimen Compared to NA Alone in
e Antigen-negative Virologically Suppressed Participants With Chronic Hepatitis B Virus Infection.
Protocol 73763989PAHPB2002 is an intervention-specific appendix (ISA) to Master Protocol
PLATFORMPAHPB2001.
JNJ-73763989 (JNJ-3989) is a liver-targeted antiviral therapeutic for subcutaneous 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 ribonucleic acid
(pgRNA), the precursor of viral relaxed circular deoxyribonucleic acid (DNA). The RNAi triggers
(JNJ-73763976 [JNJ-3976] and JNJ-73763924 [JNJ-3924]) in JNJ-3989 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.
JNJ-56136379 (JNJ-6379) is an orally administered capsid assembly modulator that is being developed
for the treatment of chronic HBV infection. JNJ-6379 binds to hepatitis B core protein 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.
Study intervention refers to JNJ-3989 or placebo for JNJ-3989, JNJ-6379 or placebo for JNJ-6379, and
NA.
OBJECTIVES AND ENDPOINTS
Below is the list of objectives and endpoints that will be evaluated in this study, delineating the details in
alignment with the general objectives listed in the Master Protocol PLATFORMPAHPB2001. The details
specific for this ISA are highlighted (colored fill).
Objectives 
Endpoints
Primary
 
To evaluate the efficacy of 48-week study 
intervention 
with 
JNJ-3989+JNJ-6379+NA 
regimen compared to NA alone. 
 
Proportion of participants with HBsAg
seroclearance at Week 72 (ie, 24 weeks
after completion of all study interventions
at Week 48) without restarting NA
treatment.
Secondary
 
To evaluate the safety and tolerability of the 
study intervention throughout the study. 
 
Safety and tolerability including but not
limited to the proportion of participants
with (serious) adverse events ([S]AEs)
and abnormalities in clinical laboratory
tests 
(including 
hematology, 
blood
biochemistry, 
blood 
coagulation,
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NCT04129554


JNJ-73763989 and JNJ-56136379
Clinical Protocol 73763989PAHPB2002
AMENDMENT 4
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
10
Status: Approved,  Date: 26 November 2021
Hypothesis
The primary hypothesis of this study is that the combination regimen of JNJ-3989+JNJ-6379+NA is more
efficacious than NA treatment alone, as measured by the primary efficacy endpoint, the proportion of
participants with HBsAg seroclearance at Week 72 (ie, 24 weeks after completion of all study
interventions at Week 48) without restarting NA treatment.
OVERALL DESIGN
This ISA describes a Phase 2b study of JNJ-3989 and JNJ-6379. It is a companion document to the
Master Protocol PLATFORMPAHPB2001, which describes the common design elements of the Platform
study  in participants with chronic hepatitis B (CHB). This ISA describes specific and/or additional
protocol elements applicable to this intervention cohort, in which participants will be treated with the
study intervention, JNJ-3989 and JNJ-6379 or placebos, in combination with NA.
The study described in this ISA is a Phase 2b, multicenter, randomized, double-blind, placebo-controlled,
2 parallel-group study to evaluate the efficacy of 48-week study intervention with
a JNJ-3989+JNJ-6379+NA regimen compared to NA treatment alone, assessed by HBsAg seroclearance
at Week 72 (ie, 24 weeks after completion of all study interventions at Week 48) without restarting NA
treatment in HBeAg-negative virologically  suppressed CHB-infected participants who received NA
treatment for at least 2 years prior to screening. All participants will stop all study interventions including
NAs at Week 48 and will be followed up until Week 96. After completing this study, participants may
have the option to enroll into a long-term follow-up study.
The study will be conducted in 3 phases: a screening phase (4 weeks), a 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.
A target of 120 participants will be randomized in a 2:1 ratio to one of the following intervention arms
and will receive study intervention for 48 weeks:
 
Intervention Arm 1 (N=80): 200 mg JNJ-3989 (injection once monthly) +
250 mg JNJ-6379 (tablets once daily [qd]) +
NA* qd;
 
Intervention Arm 2 (N=40): placebo for JNJ-3989 (injection once monthly) +
placebo for JNJ-6379 (tablets qd) +
NA* qd.
* NA: entecavir (ETV), tenofovir disoproxil fumarate (TDF) or tenofovir alafenamide (TAF)
All participants who complete 48-week study intervention should stop all study interventions including
NAs at Week 48. Any relevant change in participant baseline status with regards to ALT, HBV DNA
levels and/or HBeAg status or any other event that in the opinion of the investigator could prevent
stopping NA should be discussed with the sponsor. 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 ‘NA Re-treatment Criteria and Monitoring
After Stopping of NA’ for more details).
The investigator should consider to re-start NA treatment per local standard of care at the EOS visit
(Follow-up Week 48) for participants who discontinued NA treatment at Week 48, 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.
NCT04129554


JNJ-73763989 and JNJ-56136379
Clinical Protocol 73763989PAHPB2002
AMENDMENT 4
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
11
Status: Approved,  Date: 26 November 2021
The investigators and participants will remain blinded to intervention allocation until all participants have
reached Week 72 (or discontinued earlier), while the sponsor’s central study team will be unblinded at the
time of the Week 48 interim analysis (IA). Details on the central study team will be provided in the
Independent Data Monitoring Committee (IDMC) charter.
All participants who consent to participate in the intensive PK subgroup (optional) will undergo intensive
PK sampling (minimally 18 participants).
Participants will be considered to have completed the study if they have completed the assessments of the
end-of-study visit Follow-up Week 48 (Week 96).
An IDMC will be commissioned for this study. In addition, an Independent Flare Expert Panel (IFLEP)
will be appointed.
NA Re-treatment Criteria and Monitoring After Stopping of NA
After completing treatment with JNJ-3989, JNJ-6379 (or their matching placebos) and NA at Week 48 (or
after premature discontinuation), participants 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, alkaline
phosphatase (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 restart 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.
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Clinical Protocol 73763989PAHPB2002
AMENDMENT 4
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
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Status: Approved,  Date: 26 November 2021
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 collected 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.
NUMBER OF PARTICIPANTS
A target of 120 HBeAg-negative virologically suppressed CHB-infected male and female participants,
18-65 years (inclusive) of age will be randomized in a 2:1 ratio to receive either JNJ-3989 and JNJ-6379
in combination with NA  (N=80) or their respective placebos in combination with NA  (N=40).
Randomization will be stratified by screening HBsAg level (<1,000 IU/mL or >1,000 IU/mL), race
(Asian versus non-Asian) and type of NA (TDF/TAF versus ETV).
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AMENDMENT 4
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Status: Approved,  Date: 26 November 2021
Description of Interventions
Intervention name 
JNJ-3989 
Placebo for 
JNJ-3989 
JNJ-6379 
Placebo for 
JNJ-6379 
Entecavir (ETV) 
monohydrate 
Tenofovir 
disoproxil 
fumarate (TDF) 
Tenofovir
alafenamide
(TAF)***
Dosage formulation 
Solution for 
injection  
Solution for 
injection 
Tablets 
Tablets 
Film-coated tablets 
Film-coated 
tablets 
Film-coated
tablets
Unit dose strength(s) 
200 mg/vial 
0.9% saline 
25 and 100 mg 
- 
0.5 mg 
300 mg** 
25 mg
Dosage regimen 
200 mg once 
every 4 weeks 
1 mL once every 
4 weeks 
250 mg qd 
qd 
Lamivudine-refractory 
patients:
1 mg* qd (but should
preferably be treated
with TDF or TAF
instead)
Other indications:
1 mg* qd (must be
agreed upon by the
sponsor)
300 mg qd 
25 mg qd
Route of 
administration 
Subcutaneous 
injection (in the 
abdomen) 
Subcutaneous 
injection (in the
abdomen)
Oral 
Oral 
Oral 
Oral 
Oral
Dosing instructions 
Regardless of 
food intake 
Regardless of 
food intake 
Regardless of 
food intake 
Regardless of 
food intake
On an empty stomach  
With food 
With food
qd: once daily
* 2 tablets of 0.5 mg
** 300 mg TDF is equivalent to tenofovir disoproxil 245 mg
*** In countries where TAF is available, it will be one of the NA treatment options.
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AMENDMENT 4
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Status: Approved,  Date: 26 November 2021
EFFICACY EVALUATIONS
All efficacy assessments will be performed at predefined time points as specified in the Schedule of
Activities.
Qualitative and quantitative HBsAg and HBeAg, and quantitative HBcrAg as well as anti-hepatitis B
surface (HBs) and anti-hepatitis B e (HBe) antibodies 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 request.
HBV 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 request.
In participants enrolled at a site with an on-site Fibroscan device, Fibroscan assessments will be
performed at different time points 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.
Sequencing
Viral genome sequence analysis will be performed to evaluate mutations associated with  the study
intervention.
Patient-reported Outcomes
The impact of HBV treatment on participants will be assessed using PROs at predefined time points. The
following PRO instruments will be used: HBV-specific self-stigma scale and EQ-5D-5L questionnaire.
The content validity of the HBV-specific self-stigma scale is currently being evaluated and the data
collected in this study will be used to assess the psychometric properties of this scale.
SAFETY ASSESSMENTS
Safety and tolerability  (AEs, clinical safety laboratory assessments, ECGs, vital signs and physical
examinations) will be evaluated as described in Section 8.2 of the Master Protocol
PLATFORMPAHPB2001 and at predefined time points as specified in the Schedule of Activities. In
addition, urine samples for urine chemistry and renal biomarkers will be collected.
Specific toxicity management plans are in place for follow-up of rash, injection site reactions, acute
systemic allergic reactions, ALT/aspartate aminotransferase elevations, and renal complications.
PHARMACOKINETICS
Plasma samples will be used to evaluate the PK of the study intervention. Samples collected for analyses
of the study intervention’s plasma concentrations may additionally be used to evaluate safety or efficacy
aspects.
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 subgroup (optional) will
undergo intensive PK sampling at Week 4 (minimally 18  participants). If necessary (eg, for operational
reasons), this visit may be scheduled at Week 8, 12, or 16.
Plasma concentration-time data for JNJ-3989 (ie, JNJ-3976 and JNJ-3924), JNJ-6379 and, optionally, NA
will be analyzed via population PK for all participants. Area under the plasma concentration-time curve
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Status: Approved,  Date: 26 November 2021
over 24 hours (AUC24h) and plasma trough concentrations (C0h) will be estimated using empiric Bayes
estimation.
Plasma concentration-time data for JNJ-3989 (ie, JNJ-3976 and JNJ-3924), JNJ-6379 and, optionally, NA
will be analyzed via noncompartmental methods for all participants who underwent intensive PK
sampling. The main PK parameters will be AUC24h, maximum plasma concentration (Cmax), time to Cmax
(tmax), 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 other studies via population PK modelling to enable the
calculation of the above PK parameters also in participants who only underwent sparse PK sampling.
PHARMACOKINETIC/PHARMACODYNAMIC EVALUATIONS
Relationships of individual PK parameters (intensive PK and population PK, as applicable) for JNJ-3989
(ie, JNJ-3976 and JNJ-3924), JNJ-6379, and NA, as applicable, with selected efficacy and safety
endpoints will be evaluated.
IMMUNE EVALUATIONS
At selected sites, PBMC samples for immune analyses will be collected during study intervention and
follow-up 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.
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 PBMC 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.
HOST GENETICS
A pharmacogenomic (host DNA) blood sample should be collected at baseline to allow for host
pharmacogenomic research, where local regulations permit. In addition, host DNA blood samples to
allow for epigenetic analyses will be collected. These samples could for example be used to assess
changes in frequencies of immune cells such as myeloid derived suppressor cells. These samples will only
be collected from participants who consent separately to this component of the study.
In addition, other samples may be used for exploratory genetic or epigenetic research in participants
consenting separately to this part of the study. No genetic research will be performed on any sample in
participants who have not provided the additional separate consent for host genetic research. These
samples can only be used to investigate the potential association of genetic or epigenetic factors with
efficacy, safety, or PK of the study intervention, or HBV infection, or may be used to develop tests/assays
related to the study intervention or HBV infection.
EXPLORATORY 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.
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AMENDMENT 4
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
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Status: Approved,  Date: 26 November 2021
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 when all participants have completed Week 72 or discontinued
earlier. The final analysis will be performed when all participants have completed the last study visit
(Week 96) or discontinued earlier.
Sample Size Determination
The total study sample size is 120 participants who will be randomly assigned to one of the two
intervention arms in a 2:1 ratio (JNJ-3989+JNJ-6379+NA: placebo+placebo+NA). Statistical power to
test the primary hypothesis was assessed using the Mantel-Haenszel test with a 1-sided Type 1 error rate
of 0.05, assuming the observed percentage of participants with HBsAg seroclearance at Week 72 in the
placebo+placebo+NA arm to be 5%. The sample size of 80 participants in the investigational arm and 40
participants in the control arm provides >91% statistical power to detect a ≥20% difference in the primary
endpoint.
Efficacy Analyses
To evaluate the efficacy, the primary analysis set will be the Intent-to-treat (ITT) population. All
participants who were randomly assigned to an intervention arm and who received at least 1 dose of study
intervention within this ISA will be included in the ITT population. Participants will be analyzed
according to the study intervention they were randomly assigned to.
The baseline measurements are defined as the measurements taken closest to but before the first
administration of study intervention on Day 1.
Primary Efficacy Endpoint (HBsAg Seroclearance 24 Weeks After Completion of All Study
Interventions at Week 48)
The proportion of participants who achieved HBsAg seroclearance at Week 72 (24 weeks after
completion of 48 weeks of treatment with study intervention) without restarting NA treatment will be
compared between intervention arms at a 1-sided 0.05 alpha. The primary endpoint will be compared
between intervention arms using the stratum-adjusted Mantel-Haenszel difference in proportions, where
the stratification factors screening HBsAg level (<1,000 IU/mL or >1,000 IU/mL), race (Asian versus
non-Asian) and type of NA (TDF/TAF versus ETV) determine the strata. The associated 90% confidence
interval for the difference in proportions will also be calculated.
All participants who do not achieve HBsAg seroclearance at Week 72 and/or require NA re-treatment
between Week 48 and Week 72 are considered treatment non-responders for the purpose of the primary
endpoint analysis.
Secondary and Exploratory Efficacy Endpoints
Descriptive statistics will be used for all efficacy endpoints which will be summarized by intervention
arm and study phase. Comparisons between  intervention arms will be done with no adjustment for
multiplicity. Specific key selected endpoints may be analyzed using suitable categorical data approaches
(eg, Cochran-Mantel-Haenszel or logistic regression for proportions or other categorical type of
endpoint), longitudinal repeated measures models (eg, for continuous types of variables), or survival
analysis based on the Kaplan-Meier estimates (for time-to-event variables), as appropriate.
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Status: Approved,  Date: 26 November 2021
Resistance Analyses
The results of HBV viral sequencing will be evaluated by the sponsor virologist. Relevant changes of
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.
Patient-reported Outcomes
The PRO scores will be analyzed descriptively as mean scores over time, and (if applicable) evaluated
based on the proportion of participants experiencing a clinically important improvement or worsening in
PRO scores from baseline during study intervention and follow-up. Analyses will also be performed on
PRO score changes from baseline at specific time points (Weeks 48, 72, 96) and between Week 48 and
later time points for different subgroups: participants with HBsAg seroclearance 24 weeks and 48 weeks
after completion of all study interventions at Week 48 without restarting NA treatment versus those
without HBsAg seroclearance at those time points.
The data collected in this study will be used to assess the psychometric properties of the HBV-specific
self-stigma scale. The psychometric analyses will be described in a separate document and results will be
presented in a separate report.
Safety Analyses
Safety analyses will be based on the safety population and are specified in Section 9.4.3 of the Master
Protocol PLATFORMPAHPB2001. All participants who received at least 1 dose of study intervention
within this ISA will be included in the safety population. Participants will be analyzed according to the
study intervention they actually received.
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
by intervention arm and over time, as appropriate.
Other Analyses
Pharmacokinetic Analyses
Descriptive statistics (n, mean, standard deviation [SD], coefficient of variation [CV], geometric mean,
median, minimum, and maximum) will be calculated for the plasma concentrations of JNJ-6379,
JNJ-3976, JNJ-3924, and NA (ETV, tenofovir, and/or TAF), as applicable, and for the derived plasma PK
parameters for both noncompartmental and population PK analyses.
For each participant with intensive PK sampling, plasma concentration-time data of JNJ-6379, JNJ-3976,
JNJ-3924, and, optionally, NA 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. Plasma PK parameters in participants undergoing intensive PK sampling will
be calculated via noncompartmental methods for JNJ-6379, JNJ-3976, JNJ-3924, and, optionally, NA, as
applicable. The PK parameters will be Cmax, Cτ, and AUC24h. The PK parameters will be subjected to an
exploratory graphical analysis, including various transformations, to get a general overview.
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.
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Status: Approved,  Date: 26 November 2021
Population PK analysis of plasma concentration-time data of JNJ-6379, JNJ-3976, JNJ-3924 and,
optionally, NA will be performed using nonlinear mixed-effects modeling. Data may be combined with
previous Phase 1 and/or 2 studies to support a relevant structural model. Available baseline characteristics
(eg, demographics, laboratory variables, genotypes) will be included in the model as necessary. For
operational reasons, a snapshot date for PK samples to be analyzed will be defined, if required. Samples
collected before this date will be analyzed for JNJ-6379, JNJ-3976, JNJ-3924, and/or NA (as applicable)
and will be included in the population PK analysis. Samples collected after the snapshot date will be
analyzed at a later date, and may be included in a population PK re-analysis when they become available
after database lock. Details will be given in a population PK analysis plan and results of the population
PK analysis will be presented in a separate report.
Pharmacokinetic/Pharmacodynamic Analyses
Relationships of PK parameters for JNJ-6379, JNJ-3976, JNJ-3924 and, optionally, NA (ETV, tenofovir,
and/or TAF) with selected efficacy and safety endpoints will be evaluated and graphically displayed.
Details will be described in the Statistically Analysis Plan.
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 will be investigated. Other biomarkers may be explored at the sponsor’s discretion.
Details of the PK/PD analyses will be described in a population PK/PD analysis plan and results will be
presented in a separate report.
Immune Analyses
Descriptive statistics (n, mean, SD, CV, geometric mean, median, minimum, and maximum) will be used
to describe the magnitude of the gamma interferon (IFN-γ) T-cell response or the CD4+ and CD8+ T-cell
responses (expressing at least 1 cytokine such as interleukin [IL]-2, tumor necrosis factor [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 patients 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 IL-2, TNF-α or
IFN-γ for 1 of the HBV antigens as defined by ELISpot and/or ICS, respectively, will be determined.
Pharmacogenomic Analyses
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 Biomarker Analyses
Statistical approaches to explore correlations between clinical outcome and blood biomarkers vary and
depend on the different data types of the applied technology platforms, as well as on the extent of
observed interindividual variability. 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 Analyses
An IA will be conducted to assess safety and evaluate the time course of different disease markers to
support the sponsor’s interactions with health authorities, as well as to inform internal decisions about
additional studies and/or investigation of other treatment combinations. The IA is planned when  all
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AMENDMENT 4
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
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Status: Approved,  Date: 26 November 2021
e. 
Both the Platform Master ICF and the ISA ICF must be signed before the first study-related activity.
f. 
Minimum criteria for the availability of documentation supporting the eligibility criteria are described in the Source Documents section in Attachment 3 of the
Master Protocol PLATFORMPAHPB2001. Clinical status will be checked at screening and again before first dose of study intervention. If a participant’s clinical
status changes (including any available laboratory results or receipt of additional medical records) after screening but 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.
g. 
Medical history also includes mode of HBV transmission, stage of liver fibrosis, and alcohol consumption. Historical HBV DNA, HBsAg, HBeAg, and ALT data,
if available, will be recorded in the CRF and/or the source document. Available historical data on a previous HBV genotype assessment will also be collected in
the CRF.
h. 
Liver disease staging assessments will be performed based on Fibroscan or liver biopsy results, obtained within 6 months (in case of Fibroscan) or within 2 years
(in case of liver biopsy) prior to screening or at the time of screening.
i. 
Participants must have absence of signs of cirrhosis or portal hypertension (absence of nodules, smooth liver contour, normal portal vein, spleen size <12 cm) and
absence of signs of HCC on an abdominal ultrasound performed within 6 months prior to screening or at the time of screening or clinically relevant renal
abnormalities. 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).
j. 
In between study visits, participants will take oral study intervention at home and they will bring their study intervention with them to each study visit. At study
visits, the study intervention should be taken on site.
k. 
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.
l. 
Complete physical examination, including height (only at screening), body weight, skin examination, and other body systems.
m. Vital signs include supine SBP, DBP, pulse rate, and body temperature.
n. 
All ECGs will be read centrally. Only on Day 1, an ECG will be collected and assessed locally prior to dosing.
o. 
A liver ultrasound is recommended every 6 months for HCC screening in high-risk populations (ie, participants with a family history of HCC, Asian males
>40 years, Asian females >50 years; Africans and African Americans). The liver ultrasound does not need to be repeated at baseline if it was done within 6 months
prior to screening or at the time of screening.
p. 
Biochemistry samples must be taken after fasting for at least 10 hours for measurement of phosphate, calcium, creatinine, and lipids. If applicable, participants
should bring their study intervention with them to each visit and have that day’s intake at the site with breakfast.
q. 
Creatinine clearance (eGFR calculated by the CKD-EPI formula) will be assessed.
r. 
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. Additional tests should be considered based on clinical judgement. For more details and further management guidance, refer to Section 8.3.6.3,
Intervention-emergent ALT/AST Elevations and Section 10.6, Appendix 6, Intervention-emergent ALT/AST Elevations.
s. 
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).
t. 
Urine chemistry sample (quantitative measurement): creatinine, sodium, phosphate, glucose, protein, and albumin.
u. 
Urine sample for selected renal biomarkers including retinol binding protein and beta-2-microglobulin.
v. 
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 (see Section 10.8 Appendix 8: Contraceptive and Barrier Guidance and Collection of Pregnancy Information).
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AMENDMENT 4
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Status: Approved,  Date: 26 November 2021
w. Only applicable to participants who are enrolled at a site with an on-site Fibroscan device. A Fibroscan assessment will only be done at baseline if it was not done
at screening.
x. 
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.
y. 
Samples may be sequenced based on the sponsor virologist’s request, considering the HBV DNA levels.
z. 
Quantitative HBeAg assessment will only be performed in participants who become HBeAg-positive post baseline based on a qualitative HBeAg assay.
aa. Exploratory serology samples may be analyzed at the sponsor’s discretion. Samples may be used to assess virologic or serologic markers of HBV.
bb. All participants will have sparse PK sampling. For all samples, the date and time of the preceding 2 intakes of oral study intervention (JNJ-6379/placebo and NA),
the date and time of the previous JNJ-3989/placebo administration, and the date and time of PK sampling should be recorded. For participants in the intensive PK
subgroup, the sparse PK sample does not need to be collected at the time of an intensive PK visit.
cc. One sample at any time between 2 and 8 hours after JNJ-3989/placebo dosing. Before leaving the study site, the participant’s wellbeing should be confirmed.
dd. Only in case of early withdrawal.
ee. All participants who consent to participate in the intensive PK subgroup (optional) will undergo intensive PK sampling at Week 4 (minimally 18 participants). 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 data collection record (eg, CRF).
ff. 
PBMC samples will be collected at selected sites only. Additional PBMC samples may be taken in case of ALT flares, upon discussion with the sponsor, and may
require an unscheduled visit.
gg. These samples are optional and will only be collected from participants who consent separately to this component of the study.
hh. Adverse events and concomitant medications will be monitored from the time a signed and dated ISA ICF is obtained until completion of the participant’s last
ISA-related procedure.
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Status: Approved,  Date: 26 November 2021
2. 
INTRODUCTION
This intervention-specific appendix (ISA) describes a Phase 2b study of JNJ-73763989
(JNJ-3989) and JNJ-56136379 (JNJ-6379) in combination with a nucleos(t)ide analog (NA). It is
a companion document to the Master Protocol PLATFORMPAHPB2001, which describes the
common design elements of the Platform study in participants with chronic hepatitis B (CHB).
This ISA describes specific and/or additional protocol elements applicable to this intervention
cohort, in which participants will be treated with the study intervention, JNJ-3989 and JNJ-6379
or placebos, in combination with a NA (see Section 2.2.2).
JNJ-3989 is a liver-targeted antiviral therapeutic for subcutaneous 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 ribonucleic acid (pgRNA), the precursor of viral relaxed circular deoxyribonucleic
acid (DNA). The RNAi triggers (JNJ-73763976 [JNJ-3976] and JNJ-73763924 [JNJ-3924]) in
JNJ-3989 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 NAs, the current
standard of care.37
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.
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)14,15 and Addendum.16
An introduction on HBV and the current treatment options is provided in Section 2 of the Master
Protocol PLATFORMPAHPB2001.
The term “study intervention” throughout the protocol, refers to JNJ-3989 or placebo for
JNJ-3989, JNJ-6379 or placebo for JNJ-6379, and NA.
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”.
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2.1. 
Study Rationale
There is a medical need for effective finite treatment with long-term clinical benefits (ie, reduced
mortality and morbidity from cirrhosis and hepatocellular carcinoma [HCC]) in chronically
infected HBV patients under long-term NA therapy.
HBsAg 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”.24
With currently available NA treatment strategies the rate of HBsAg seroclearance remains very
low (around 3%), even under long-term treatment.5 To maintain suppression of HBV replication
and reduce liver injury, life-long treatment with HBV NAs is necessary in most patients, but this
approach is associated with potential non-adherence, possibly triggering relapse of symptomatic
hepatitis as well as emergence of drug resistance with limited re-treatment options.6,9,21,22,30,31,36
The development of new HBV regimens such as JNJ-3989 and JNJ-6379 with different
mechanisms of action seems a promising approach in increasing HBV functional cure, but
development of these agents requires appropriate comparison with current standard of care and
would need to be assessed prospectively in the setting of patients discontinuing NA therapy.
Recent studies explored the concept of stopping NAs in long-term suppressed patients. In some
of these studies, increased incidence of HBsAg seroclearance has been observed in HBeAg-
negative HBV patients off NA therapy (Reveal cohort).19 The landmark study ofHadziyannis in
33 HBeAg-negative patients showed that 39% of the patients who stopped 4-5 years of adefovir
therapy, had HBsAg loss during the follow-up period of 5.5 years.10 Other European studies have
reported that cessation of NA therapy can lead to HBsAg loss over time. In the FINITE study,
the percentage of patients with HBsAg loss increased from 11% (2 of 18) after 48 weeks to 31%
(4 of 13) after 144 weeks after stopping therapy.1 Similar results were reported after stopping 4
years or more of entecavir (ETV) or tenofovir disoproxil fumarate (TDF), with cumulative rates
of HBsAg loss reported to be 5% after 6 months, 16% after 12 months, and 25% after 18
months.28 A recent prespecified analysis of 2 TDF randomized controlled studies evaluated the
outcome after withdrawal of TDF and reported HBsAg loss in 5 (5%) of the 106 HBeAg-
negative patients who entered the 24-week treatment follow-up period.3
In a recent systematic review that included 25 studies mainly from Asia, identification of
predictors of virologic relapse and HBsAg loss after stopping NA led to conflicting results,
partly due to the heterogeneity of the studies and low rate of HBsAg loss (2%).29 Lower baseline
HBsAg level was the only statistical baseline factor for off-therapy HBsAg seroclearance in a
large cohort of 1075 HBeAg-negative patients in Taiwan.18 Studies conducted in Asia have
reported a lower estimated annual incidence of 1.78% of HBsAg loss highlighting potential
differences among Asians and Caucasians.18 A recent European retrospective, observational
cohort study that included 198 NA-treated CHB patients who stopped NA treatment after
HBeAg seroconversion showed 7-fold higher annual HBsAg seroclearance rates in Caucasian
patients compared to non-Caucasians.34
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Status: Approved,  Date: 26 November 2021
After stopping NA treatment, it is expected that most of the patients will have rebound of HBV
DNA. This was reported in the Hadziyannis study where all patients had an initial rebound of
HBV DNA and 76% showed an alanine aminotransferase (ALT) flare suggesting that virologic
relapse might be an important trigger for immune response that could lead to subsequent HBsAg
loss. This was also reported in a recent prospective study showing that level of HBV DNA after
stopping NA was the most important factor for subsequent HBsAg decline.13 Therefore factors
that may influence virologic relapse should be taken into consideration. Some recent studies have
reported that patients treated with TDF experience virologic relapse significantly earlier than
those receiving ETV. In a randomized study of 220 HBeAg-negative Asian patients who stopped
treatment, 71% (47 of 66) treated with TDF had virologic relapse by Week 12, whereas 4.5% of
patients (7 of 154) treated with ETV had virologic relapse in the same period (p <0.0001), while
the overall virologic relapse rate was similar.12 Similarly, in a retrospective study that included
234 HBeAg-negative Asian patients who stopped treatment, median time to virologic relapse
was 18 weeks (TDF) versus 33 weeks (ETV).20
Given the reported influence of race (Asian versus non-Asian), type of NAs (TDF/tenofovir
alafenamide [TAF] versus ETV) and baseline HBsAg level on virologic relapse and
subsequently HBsAg seroclearance, those 3 elements will be included as stratification factors in
the current study.
The main goal of this Phase 2b study is to evaluate the efficacy of 48-week study intervention
with a JNJ-3989+JNJ-6379+NA regimen compared to NA alone, assessed by HBsAg
seroclearance at Week 72 (ie, 24 weeks after completion of all study interventions at Week 48)
without restarting NA treatment in HBeAg-negative virologically suppressed CHB-infected
participants who received NA treatment for at least 2 years prior to screening.
This study is also aiming at identifying baseline and on-treatment markers associated with
sustained off-treatment response.
2.2. 
Background
2.2.1. 
JNJ-3989 and JNJ-6379
Nonclinical Studies
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-month 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 subcutaneous 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 subcutaneous injection at 30 up to 300 mg/kg. In the 24- or 37-week studies,
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JNJ-3989 was administered once weekly for the first month, followed by once monthly thereafter
at 30 up to 180 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.
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 subcutaneous 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 180 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 180 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
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Status: Approved,  Date: 26 November 2021
(cytokine and complement activation), mitochondrial toxicity/cytotoxicity, or platelet
aggregation associated with JNJ-3989 exposure at concentrations up to 250 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 subcutaneous injection of 200 mg JNJ-3989 in human volunteers (Study AROHBV1001)
(Table 1).
Table 1: 
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
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.
a 
Single dose of 200 mg JNJ 3989 in healthy volunteers via subcutaneous injection (Study AROHBV1001; based on recent
clean dataset with data cutoff 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
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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.
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 2.
Table 2: 
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 
265,384 
- 
-
6M rat 
M 
7,540 
93,100 
0.6 
0.4  
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 
3.5
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 animal 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 not relevant 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%).
JNJ-3989 and JNJ-6379
A combination pharmacokinetic (PK) study with JNJ-6379 and JNJ-3989 has been conducted in
male rats (N 3/group), and a GLP, 1-month combination repeat-dose toxicity study is ongoing in
male and female rats.
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Status: Approved,  Date: 26 November 2021
In the combination PK study (FK13466), JNJ-6379 was administered orally at
100 mg eq./kg/day  for 8 days in combination with JNJ-3989 administered subcutaneously on
Days 0 and 7 at 30 or 180 mg/kg. In addition, 2 groups received JNJ-6379 alone (orally at 100
mg eq./kg/day for 8 days), or JNJ-3989 alone (at 180 mg/kg subcutaneously on Days 0 and 7).
Histopathological examinations were performed on the liver and kidney collected 25 hours
postdose on Day 7. No adverse findings for JNJ-3989, JNJ-6379 or for the combination were
noted. No additive or synergistic effects were noted when both compounds were coadministered.
When JNJ-6379 was administered in combination with JNJ-3989, mean maximum  plasma
concentration (Cmax) values and mean area under the plasma concentration-time curve (AUC)
values of JNJ-6379, JNJ-3976 and JNJ-3924 did not change significantly when compared to
dosing both compounds alone.
In the 1-month rat study, JNJ-3989 was administered weekly via subcutaneous injections at dose
levels of 30 and 180 mg/kg when given in combination with JNJ-6379, and at 180 mg/kg for the
monotherapy group. Control animals received both vehicles via the respective routes. JNJ-6379
was administered daily via oral gavage at a dose level of 100 mg/kg.
No treatment-related mortality occurred during the study. Also, no relevant clinical signs were
noted. Body weights and body weight gain were slightly decreased during the last weeks of
treatment in males at ≥30/100 mg/kg and in females at 180/100 mg/kg, with correlating lower
food intake at the high dose.
JNJ-3989 at 180 mg/kg presented vacuolation and basophilic granules in tubular epithelium of
the kidney. At 30 mg/kg no kidney changes were noted.
There were no differences in kidney morphologic alterations between rats dosed with the single
compound JNJ-3989, compared to the group dosed with the combination of the 2 compounds.
Crystals were observed in the urine of animals dosed with JNJ-6379 at 100 mg/kg, either alone
or in combination, with mainly males being affected, and correlating with significant amounts of
drug-related material in the urine (predominantly M7 but also unchanged drug).
No histopathology kidney findings were seen with JNJ-6379 at 100 mg/kg.
No drug-drug interaction (DDI) was seen in this study as well as in the previous study where the
2 compounds were given for 7 days.
In conclusion, daily oral administration of JNJ-6379 at 100 mg/kg in combination with weekly
subcutaneous injection with JNJ-3989 at 30 or 180 mg/kg for one month was 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
100 mg/kg (per os) alone or with JNJ-3989 at 180 mg/kg (subcutaneous) alone. There were no
additive or synergistic changes noted in the kidneys or in clinical pathology.
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Preliminary results of a 3-month combination toxicity study with JNJ-6379 an JNJ-3989 in the
rat became available. In this study, the potential for toxicity of JNJ-6379 when given by daily
oral gavage, and of JNJ-3989 when given by intermittent SC injection, and of both test items
when given in combination, was assessed (TOX13608).
No test article-related mortalities were noted among animals dosed with JNJ-6379 alone, with
JNJ-3989 alone, or with JNJ-6379 + JNJ-3989 at 100/180 mg/kg.
One male rat dosed at 100/60 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 decrease 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. In addition,
a mild decrease in platelet counts was observed in females in the combination group
100/60 mg/kg and 100/180 mg/kg JNJ-6379/JNJ-3989.
No relevant changes on urinary biomarkers were detected in male and female rats given JNJ-
6379 at 100mg/kg/day (clusterin, albumin, ß2-microglobulin, Kidney Injury Molecule-1 (KIM-
1), Neutrophil Gelatinase Associated Lipocalin (NGAL) and cystatin-C).
For further information, refer to the IB Addenda.41,42
Clinical Studies
To date, no clinical information is available for the combination of JNJ-3989 with JNJ-6379. The
following sections provide an overview of the current clinical background information for the
2 compounds separately.
JNJ-3989
Clinical data of JNJ-3989 are available from the ongoing Phase 1/2a AROHBV1001 study with a
safety snapshot date of 26 March 2019. Twenty adult healthy participants have received single
subcutaneous injections of JNJ-3989 (35, 100, 200, 300, and 400 mg) and 72 adult CHB
participants have received multiple doses of JNJ-3989 (25, 50, 100, 200, 300, and 400 mg),
administered as 3 subcutaneous injections separated by either 7-day, 14-day, or 28-day intervals.
All participants either continued or started ETV or TDF 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 CHB 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
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reported in participants on JNJ-3989 treatment. Most reported laboratory abnormalities were
isolated incidences and resolved while on study treatment.
Efficacy was assessed using snapshot data through 02 May 2019. Antiviral activity data were
available for 56 CHB participants who received 3 subcutaneous injections of 25 to 400 mg
JNJ-3989 every 4 weeks. The antiviral activity data showed that administration of JNJ-3989 at
doses of 25 to 400 mg resulted in pronounced mean HBsAg declines which were generally
sustained at least until Day 168 (ie, 16 weeks after last dose) across all doses. No apparent dose
response was observed at doses between 100 and 400 mg JNJ-3989; a reduced mean decline was
observed at the lower dose of 25 mg. Data on the 50 mg dose is still emerging. Treatment status
(ie, virologically suppressed or not treated) did not seem to affect HBsAg changes. Other
measurable serological and virological markers (HBV DNA, HBV RNA, HBeAg, hepatitis B
core-related antigen [HBcrAg]) also showed responses to JNJ-3989, indicating that JNJ-3989
shows target activity on all detectable viral products.
JNJ-6379
At the time of protocol writing, 98 adult healthy and 41 CHB participants have been dosed with
JNJ-6379 in 4 completed Phase 1 studies (56136379HPB1001, 56136379HPB1002,
56136379HPB1003, and 56136379HPB1004). Another Phase 1 study in healthy adult
participants is also completed and clinical study report writing is currently ongoing
(56136379HPB1005). In addition, data are available from 148 adult CHB  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.
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Status: Approved,  Date: 26 November 2021
In Study 56136379HPB1002, study drug 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.
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 a 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.
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Multiple Dose Studies in CHB Participants
In Sessions 8, 9, 10, 11, and A of Study 56136379HPB1001, treatment-naïve CHB-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 CHB participants. Mean JNJ-6379 exposures in CHB participants could be
predicted from data in healthy participants. The PK data show that exposure of JNJ-6379 in CHB
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.
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 CHB 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 CHB participants of whom 33 received 75 mg qd
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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 CHB 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 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. HBV RNA levels at Week 24 were undetectable for 21 (100.0%) of 21 participants on
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 lower limit of quantification (LLOQ) of the HBV DNA
assay. All 5 participants with virologic breakthrough had an 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. NA 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 4 completed Phase 1 studies (56136379HPB1001, 56136379HPB1002,
56136379HPB1003 and 56136379HPB1004) in healthy and CHB participants (N 98 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  CHB participants was safe and well tolerated. No SAEs
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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. Those observations were
supported by the final safety data obtained for Phase 1 Study 56136379HPB1005, in which
14 healthy adult participants received single doses (300 mg) of JNJ-6379.
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 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
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.
2.2.2. 
Combination of JNJ-3989 and JNJ-6379 with Entecavir, Tenofovir
Disoproxil Fumarate, or Tenofovir Alafenamide
Entecavir monohydrate is an HBV NA reverse transcriptase inhibitor indicated for the treatment
of CHB 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.
Tenofovir disoproxil fumarate is a first-generation oral prodrug of the NA tenofovir that is
indicated for the treatment of CHB  in adult and pediatric patients at least 12 years of age. In
addition, TDF in combination with other antiretrovirals is indicated for the treatment of human
immunodeficiency virus 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.
Tenofovir alafenamide is an ester prodrug of the NA tenofovir that is indicated for the treatment
of CHB in adults and that is characterized by a better safety profile than TDF. The most common
adverse reactions (≥10% of participants) is headache.
For further information regarding ETV, TDF, and TAF, refer to the respective currently
approved prescribing information.
There is no common target organ between JNJ-6379 or JNJ-3989 and ETV.27
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The single common toxicity target organ between JNJ-6379, JNJ-3989, and TDF or 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.11,17 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 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 red blood cells in sediment).4,32 No kidney findings were observed in
dogs.
In clinic, dosing JNJ-6379 with NA for 12 weeks, did not show any clinically relevant changes in
kidney parameters/glomerular function.
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 intra-cellular (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 TDF, renal tubular epithelial karyomegaly was observed in rats, dogs, and monkeys.26 In
dogs, the species most sensitive to TDF-related effects on the kidney, additional microscopic
alterations following chronic administration of TDF (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
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Status: Approved,  Date: 26 November 2021
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.7
Overall Nonclinical Assessment of the Combination Therapy
Based on the points listed below, no clinically relevant DDIs and no specific concerns about
additive or synergistic toxicities are expected in kidney when JNJ-6379 or JNJ-3989 are
combined with ETV, or TDF, or TAF:
 
available toxicology data described above (Sections 2.2.1 and 2.2.2)
 
in vitro drug transporters
 
metabolic interaction data
 
absence of relevant DDIs in the combination toxicity studies with JNJ-6379 and JNJ-3989
 
available clinical data with JNJ-6379 (Jade study [56136379HPB2001]) up to 24 weeks
treatment on the absence of changes in kidney parameters/glomerular function.
In addition, pancytopenia in 1 rat and a mild platelet decrease were observed 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 8.3.6.5). For further
information, refer to the IB Addenda. 41,42
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.14,15,16
For the benefit-risk evaluation of ETV, TDF, and TAF, refer to the respective prescribing
information and Summary of Product Characteristics.
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.
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2.3.1.2. 
Potential Benefits
Results from clinical studies with JNJ-3989, JNJ-6379, and NAs 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” mode of action [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 response.8,23,35 By
acting on both viral replication and by reducing barriers to the host immune-response, higher
functional cure rates 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.
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.
2.3.2.2.1. 
Potential Risks for JNJ-3989
Reproductive Risks and Pregnancy
In the EFD  studies, JNJ-3989 was not teratogenic in rats and rabbits. JNJ-3989 showed no
effects on fertility in rats.
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.
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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.
Viral Resistance
Treatment with JNJ-3989 may also 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, TDF, or TAF is expected to minimize the
risk of emerging resistant viral variants.
2.3.2.2.2. 
Potential Risks for JNJ-6379
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 300 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 300 mg eq./kg/day were lowered, and there was
retarded ossification from 100 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.
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.
CCI
CCI
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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 TDF 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
emerging core amino acid mutation T33N, which is known to confer reduced JNJ-6379 activity
in vitro (see Section 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,
Concomitant Therapy.
Please refer to Section 2.2, Background, for details on the safety results in the studies conducted
to date.
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 Study AROHBV1001 (see Section 2.2.1, JNJ-3989 and JNJ-6379,
Subsection “Clinical Studies”). 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 have previously been raised for JNJ-6379 based on
the safety information from studies in healthy adult participants and adult participants with
chronic HBV infection. Most observed AEs were mild in severity and considered not related
to JNJ-6379 by the investigator (see Section 2.2.1, JNJ-3989 and JNJ-6379, Subsection
“Clinical 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, hematologic abnormalities, and events related to cholesterol
increase (Section 8.3.6, Adverse Events of Special Interest and Section 8.2.4, Clinical Safety
Laboratory Assessments). In addition, the following toxicities will also be carefully
monitored: rash and acute systemic allergic reactions (Section 8.3.6, Adverse Events of
Special Interest).
 
Continued careful assessment of the safety, efficacy, and PK during treatment is included in
this study.
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 
To minimize potential risk and stress to participants, the following measures are in place:
 
Utilization of selection criteria which exclude participants who may potentially be at
higher risk of an AE (see Section 5, Study Population).
 
Utilization of withdrawal criteria (see Section 7, Discontinuation of Study Intervention
and Participant Discontinuation/Withdrawal). If a participant drops out due to
withdrawal of consent, he/she retains the option to participate in the safety follow-up
procedures.
 
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, 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 8.2,
Safety Assessments). Events of Special Interest will be closely monitored
(Section 8.3.6, Adverse Events of Special Interest).
 
An Independent Data Monitoring Committee (IDMC) will be established for continuous
monitoring of SAEs, AEs leading to discontinuation, and ALT flares to ensure the
continuing safety of the participants enrolled in the current study (see Section 9.6,
Independent Data Monitoring Committee). In addition, an Independent Flare Expert
Panel (IFLEP) will be appointed to characterize and adjudicate each ALT flare (see
Section 9.7, Independent Flare Expert Panel).
 
After stopping treatment with NA and JNJ-3989 and JNJ-6379, 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 6.7, NA Re-treatment
Criteria and Monitoring After Stopping of NA).
 
The post-treatment monitoring and NA re-treatment criteria 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 (see Section 6.7).
 
JNJ-3989 will be administered using a proper subcutaneous technique to decrease the
risk of ISRs. ISRs will be managed as outlined in  Section  8.3.6, Adverse Events of
Special Interest.
 
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
Below is the list of objectives and endpoints that will be evaluated in this study, delineating the
details in alignment with the general objectives listed in the Master Protocol
PLATFORMPAHPB2001. The details specific for this ISA are highlighted (colored fill).
Objectives 
Endpoints
Primary
 
To evaluate the efficacy of 48-week study  
Proportion of participants with HBsAg
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The study will be conducted in 3 phases: a screening phase (4 weeks), a 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.
Participants will be randomized in a 2:1 ratio to one of the following intervention arms and will
receive study intervention for 48 weeks:
 
Intervention Arm 1 (N 80): 200 mg JNJ-3989 (injection once monthly) +
250 mg JNJ-6379 (tablets qd) +
NA* qd;
 
Intervention Arm 2 (N 40): placebo for JNJ-3989 (injection once monthly) +
placebo for JNJ-6379 (tablets qd) +
NA* qd.
* NA: ETV, TDF, or TAF
All participants who complete 48-week study intervention should stop all study interventions
including NAs at Week 48 (see Section 6.6, Study Intervention Completion at Week 48). 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 6.7, NA Re-treatment Criteria and Monitoring After Stopping of NA, for more
details).
Randomization will be stratified by screening HBsAg level (<1,000 IU/mL or >1,000 IU/mL),
race (Asian versus non-Asian) and type of NA (TDF/TAF versus ETV).
The investigators and participants will remain blinded to intervention allocation until all
participants have reached Week 72 (or discontinued earlier), while the sponsor’s central study
team will be unblinded at the time of the Week 48 IA. Details on the central study team will be
provided in the IDMC charter.
Both the Platform Master informed consent form (ICF) and the ISA ICF must be signed before
the first study-related activity.
Safety and tolerability, including AEs, laboratory assessments, ECGs, vital signs, and physical
examination, will be assessed throughout the study from the time that the ISA ICF is signed until
the completion of the last study-related activity (see Section 8.2, Safety Assessments, and
Section 8.3, Adverse Events and Serious Adverse Events).
Samples for HBV genome sequencing will be taken at the time points indicated in the Schedule
of Activities (see Section 8.1.1, Sequencing). 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.
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Status: Approved,  Date: 26 November 2021
The study includes collection of blood samples for exploratory analysis of viral markers (see
Section 8.1, Efficacy Assessments) and host blood biomarkers at the host RNA, protein, and cell
level (see Section 8.9, Host Biomarkers).
A population PK analysis will be performed based on the available data for JNJ-6379, JNJ-3976,
JNJ-3924 and, optionally, NA, potentially in combination with data from a selection of Phase 1
and/or 2 studies. PK parameters in participants undergoing intensive PK sampling (minimally
18 participants) will be calculated via noncompartmental methods (see Section 8.5,
Pharmacokinetics).
Peripheral blood mononuclear cell samples for immune analyses will be collected at selected
sites at the time points indicated in the Schedule of Activities (see Section 8.7, Immune
Assessments).
A pharmacogenomic blood sample will be collected from participants who consent separately to
this component of the study (see Section 8.8).
Two PRO instruments (the HBV-specific self-stigma scale and EQ-5D-5L questionnaire) will be
used to explore the impact of HBV treatment on participants (see Section 8.1.2, Patient-reported
Outcomes).
Participants will be considered to have completed the study if they have completed the
assessments of the end-of-study visit Follow-up Week 48 (Week 96).
If a participant discontinues study intervention before the end of the 48-week study intervention
phase, follow-up assessments should be obtained until 48 weeks after EOSI unless the participant
withdraws consent. NA treatment (either ETV, TDF or TAF as per local practice) should be
continued at this time as per local treatment guidelines.
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.
The Schedule of Activities summarizes the frequency and timing of efficacy, safety, and other
assessments applicable to the Master Protocol PLATFORMPAHPB2001 and this ISA.
An  IDMC will be commissioned for this study  (Section 9.6, Independent Data Monitoring
Committee). In addition, an IFLEP will be appointed (Section 9.7, Independent Flare Expert
Panel).
A diagram of the study design is provided in Section 1.2, Schema.
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Status: Approved,  Date: 26 November 2021
4.2. 
Scientific Rationale for Study Design
Study Population
Patients with CHB will be eligible if they are currently on NA treatment and are HBeAg
negative.
Patients with 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 regimen evaluated in this study
will first be established in patients without liver cirrhosis prior to initiating studies in patients
with more advanced liver disease.
Control Arm
The safety and tolerability of the investigational combination arm (Intervention Arm 1) will be
compared to those of standard of care NA (Intervention Arm 2).
The analysis of the primary efficacy endpoint and other secondary endpoints will be based on
comparison of the investigational combination arm with the control arm (see Section 9.4,
Statistical Analyses).
Randomization
Randomization will be 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) are evenly balanced across treatment arms, and to enhance the
validity of statistical comparisons across intervention arms.
Stratification Factors
Randomization will be stratified by screening HBsAg level (<1,000 IU/mL or >1,000 IU/mL),
race (Asian versus non-Asian), and type of NA (TDF/TAF  versus ETV) in order to provide a
reasonably balanced representation of the 3 baseline factors across the 2 intervention arms.
Blinding
The investigators and participants will remain blinded to intervention allocation until all
participants have reached Week 72 (or discontinued earlier), while the sponsor’s central study
team will be unblinded at the time of the Week 48 IA.
Blinded treatment will be used to reduce potential bias during data collection and evaluation of
clinical endpoints.
Follow-up Procedures and Criteria for Re-initiation of NA Treatment
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
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Week 48), and weekly visits for patients with ALT/AST ≥3x upper limit of normal (ULN) and
≥3x nadir (ie, lowest value during study participation) 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. 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 6.7, NA Re-treatment Criteria and Monitoring After Stopping of NA).
Re-initiation of NA treatment is also required in case of confirmed HBeAg seroreversion
(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
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.
NA re-treatment and monitoring after stopping of NA are presented graphically in Section 10.13,
Appendix 13.
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Status: Approved,  Date: 26 November 2021
Host DNA and Exploratory Host Biomarker Collection
Refer to Section 4.2 of the Master Protocol PLATFORMPAHPB2001.
4.2.1. 
Study-specific Ethical Design Considerations
Refer to Section 4.2.1 ofthe Master Protocol PLATFORMPAHPB2001.
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.38
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.
4.3.1. 
JNJ-3989
Clinical data of JNJ-3989 are available from the ongoing Phase 1/2a AROHBV1001 study with a
safety snapshot date of 26 March 2019. Twenty adult healthy participants have received single
subcutaneous injections of JNJ-3989 (35, 100, 200, 300, and 400 mg) and 72 adult CHB
participants have received multiple doses of JNJ-3989 (25, 50, 100, 200, 300, and 400 mg),
administered as 3 subcutaneous injections. The injections were separated by either 7-day
intervals (100, 200, and 300 mg doses), 14-day intervals (100 mg dose), or 28-day intervals (all
doses tested). All participants were started on ETV or TDF on Day 1. JNJ-3989 was generally
safe and well tolerated at all doses.
Efficacy was assessed using snapshot data through 02 May 2019. Antiviral activity data were
available for 56 CHB participants who received 3 subcutaneous injections of 25 to 400 mg
JNJ-3989 every 4 weeks. The antiviral activity data showed that administration of JNJ-3989 at
doses of 25 to 400 mg resulted in pronounced mean HBsAg declines which were generally
sustained at least until Day 168 (ie, 16 weeks after last dose) across all doses. No apparent dose
response was observed at doses between 100 and 400 mg JNJ-3989, suggesting that maximal
HBsAg reduction in this short-term study is reached with these doses. A reduced mean decline
was observed at the lower dose of 25 mg. Data on the 50 mg dose is still emerging.
A dose of 200 mg JNJ-3989 once monthly is chosen for the combination treatment regimen of
JNJ-3989+JNJ-6379+NA based on the observed decline in HBsAg in AROHBV1001 at this
dose over 3 injections, and the lack of dose response observed at higher doses.
4.3.2. 
JNJ-6379
A dose of 250 mg JNJ-6379 qd is chosen for this study.
A dose of 250 mg of JNJ-6379 is being considered to ensure maximal viral inhibition via
“primary” MoA (ie, interfering with the capsid assembly process). In addition, it ensures
sufficient high exposures to engage the “secondary” MoA (ie, inhibition of de novo cccDNA
formation). This dose selection is supported by translational PK/PD analyses and viral kinetic
modeling. Analyses of the HBV DNA data from the 4-week 56136379HPB1001 study showed a
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Status: Approved,  Date: 26 November 2021
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 is approached starting from a dose of 75 mg onwards. Since it is 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 will be treated with JNJ-6379 for 48 weeks. Based on the MoA of JNJ-6379, it is
expected that continued complete suppression of virus production and de novo cccDNA
formation over many months is required to achieve reduction of the transcriptional active
cccDNA pool, which is considered a prerequisite for HBsAg reduction and/or seroclearance.
Interim analysis data are available from the ongoing Phase 2a Jade study in which the 250-mg
dose is being tested for 48 weeks. Blinded Week 12 data from 40 virologically suppressed CHB
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.
4.4. 
End of Study Definition
4.4.1. 
Participant Completion
A participant will be considered to have completed the study if he or she has completed
assessments at the final follow-up visit.
4.4.2. 
Study Completion (End of Study Definition)
The study is considered completed with the last visit for the last participant in the study. 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.
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. Refer to Section 5.4, Screen Failures of the Master Protocol PLATFORMPAHPB2001
for conditions under which the repeat of any screening procedures is allowed.
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.
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Status: Approved,  Date: 26 November 2021
Each potential participant must satisfy all inclusion and exclusion criteria from the Master
Protocol PLATFORMPAHPB2001 (numbering prefixed by “M” in the list below) and all
additional intervention-specific inclusion and exclusion criteria (numbering prefixed by “A”).
The latter inclusion and exclusion criteria are highlighted (colored fill). For the few criteria from
the Master Protocol that are specified or more restricted in this ISA, the additional text is also
highlighted (colored fill).
5.1. 
Inclusion Criteria
Each potential participant must satisfy all of the following criteria to be enrolled in the study:
M01/ 
A01. 
Male or female 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.
M02. 
Participant must be medically stable based on physical examination, medical history,
vital signs, and 12-lead ECG performed at screening. If there are abnormalities, they
must be consistent with the underlying illness in the study population. This
determination must be recorded in the participant’s source documents and initialed by
the investigator.
M03/ 
A02. 
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 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, or should
be documented by absence of marker for acute infection such as positive
immunoglobulin M (IgM) anti-hepatitis B surface (HBs) and anti-HBc antibodies,
which can be tested at screening.
The participants should be virologically suppressed. They should:
o Be HBeAg-negative,
o Be on stable HBV treatment, defined as currently receiving NA treatment (ETV,
TDF, or TAF) for at least 24 months prior to screening and having been on the same
NA treatment regimen (at the same dose) as used in this study (see Section 6.1) for
at least 3 months at the time of screening, AND
o Have serum HBV DNA <60 IU/mL on 2 sequential measurements at least 6 months
apart (one of which is at screening), AND
o Have documented ALT  values <2.0x ULN on 2 sequential measurements at least
6 months apart (one of which is at screening).
M04. 
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.
M05/ Participant must sign a Master ICF (specific for the Master Protocol
PLATFORMPAHPB2001) and an ICF specific for this ISA indicating that he or she
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Status: Approved,  Date: 26 November 2021
A03. 
understands the purpose of, and procedures required for, the study and is willing to
participate in the study.
M06. 
Participant must sign a separate ICF  if he or she agrees to provide an optional DNA
sample for research (where local regulations permit). Refusal to give consent for the
optional DNA research sample does not exclude a participant from participation in the
study.
M07/ 
A04.
Criterion modified per Amendment 2.
M07/A04.1. Female participants must be (as defined in  Section 10.8 Appendix 8:
Contraceptive and Barrier Guidance and Collection of Pregnancy Information):
a. 
Not of childbearing potential, OR
b. 
Of childbearing potential and practicing a highly effective, preferably
user-independent method of contraception  at least 30 days prior to
screening (failure rate of <1% per year when used consistently and
correctly) and must agree 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
provided 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: 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.
M08. 
Female participants of childbearing potential must have a negative highly sensitive
serum pregnancy test (-human chorionic gonadotropin) at screening and a negative
urine pregnancy test on Day 1 before the first dose of study intervention.
M09. 
In the investigator’s opinion, the participant is able to understand and comply with
protocol requirements, instructions, and study restrictions (Section 5.3, Lifestyle
Considerations) and is likely to complete the study as planned in this ISA (including the
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negative HCV RNA at screening and documented negative HCV RNA at
least 6 months prior to screening.
 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.
 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.
M02. 
Criterion modified per Amendment 2.
M02.1. 
Participants with evidence of hepatic decompensation at any time
point prior to or at the time of screening:
a. Total bilirubin >1.5xULN,
b. Direct bilirubin >1.2xULN, OR
c. Prothrombin time >1.3xULN (unless caused by anticoagulation
therapy or vitamin K deficiency), OR
d. Serum albumin <3.2 g/dL, OR
e. History of clinical symptoms of hepatic decompensation (eg,
ascites, jaundice, hepatic encephalopathy or coagulopathy,
especially if resulting in a Child-Pugh classification B or C at the
time clinical symptoms present or at screening).
M03. 
History or evidence of clinical signs or symptoms of hepatic decompensation,
including but not limited to: portal hypertension, ascites, hepatic encephalopathy,
esophageal varices.
M04. 
Participants with evidence of liver disease of non-HBV etiology. This includes but is
not limited to hepatitis infections mentioned in exclusion criterion M01/A01, 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
M02a) or any other non-HBV liver disease considered clinically significant by the
investigator.
M05/ 
A02.
Criterion modified per Amendment 2.
M05.1/A02.1. Participants with history or signs of cirrhosis or portal hypertension
(nodules, no smooth liver contour, no normal portal vein, spleen size
≥12 cm) or signs of HCC on an abdominal ultrasound performed
within 6 months prior to screening or at the time of screening or
clinically relevant renal abnormalities. 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
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Status: Approved,  Date: 26 November 2021
specific imaging procedure (contrast enhanced ultrasound, CT  or
MRI).
M06/ 
A03.
Criterion modified per Amendment 2.
M06.1/A03.1. 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 (see Section 10.9,
Appendix 9, DAIDS Table):
a. Estimated creatinine clearance ≥grade 3 (<60 mL/min) at
screening, 
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);
e. Platelet count ≤lower limit of normal (LLN);
f. Alpha-fetoprotein >100 ng/mL;
Note: Participants with alpha-fetoprotein >ULN but ≤100 ng/mL
may be eligible if HCC can be ruled out based on a sensitive
imaging study (eg, CT with contrast or MRI) during screening.
g. Any other laboratory abnormality considered to be clinically
significant by the investigator (also see inclusion criterion
M03/A02).
Note: Retesting of abnormal laboratory values that may lead to
exclusion will be allowed once without prior approval from the
sponsor. Retesting will take place at an unscheduled visit during
the screening phase. Participants with a normal value at retest may
be included.
M07. 
Participants with hemoglobin A1c >8% at screening.
M08. 
Participants with a history of malignancy within 5 years before 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).
M09. 
Criterion modified per Amendment 2.
M09.1 
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-
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Status: Approved,  Date: 26 November 2021
lead ECG at screening.
Note: Retesting of an abnormal ECG that may lead to exclusion will be
allowed once without prior asking approval from the sponsor.
Retesting will take place during an unscheduled visit in the screening
phase. Participants not meeting the above exclusion criterion at retest
may be included.
M10. 
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.
M11. 
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.
M12. 
Participants who have received an organ transplant (except for skin, hair, or cornea
transplants).
M13. 
Participants with any history of or current clinically significant skin disease requiring
regular or periodic treatment.
M14. 
Participants with clinically  relevant alcohol or drug abuse within 12 months of
screening.
M15. 
Participants with history of clinically relevant drug rash.
M16/ 
A04. 
Participants who have taken any disallowed therapies as noted in Section  6.5,
Concomitant Therapy before the planned first dose of study intervention.
M17. 
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
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Status: Approved,  Date: 26 November 2021
2. 
Agree to follow all requirements that must be met during the study  as noted in the
inclusion and exclusion Criteria of the Master Protocol PLATFORMPAHPB2001 and
of this ISA  (Section 5.1, Inclusion Criteria and 5.2, Exclusion Criteria in both
documents) (eg, contraceptive requirements).
5.4. 
Screen Failures
Refer to Section 5.4 of the Master Protocol PLATFORMPAHPB2001 for handling of screen
failures.
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6. 
STUDY INTERVENTION
6.1. 
Study Intervention(s) Administered
Description of Interventions
Intervention name 
JNJ-3989 
Placebo for
JNJ-3989 
JNJ-6379 
Placebo for 
JNJ-6379 
Entecavir (ETV) 
monohydrate 
Tenofovir 
disoproxil 
fumarate (TDF) 
Tenofovir
alafenamide
(TAF)***
Dosage formulation 
Solution for 
injection  
Solution for 
injection 
Tablets 
Tablets 
Film-coated tablets 
Film-coated 
tablets 
Film-coated
tablets
Unit dose strength(s) 
200 mg/vial 
0.9% saline 
25 and 100 mg 
- 
0.5 mg 
300 mg** 
25 mg
Dosage regimen 
200 mg once 
every 4 weeks 
1 mL once every 
4 weeks 
250 mg qd 
qd 
Lamivudine-refractory 
patients:
1 mg* qd (but should
preferably be treated
with TDF or TAF
instead)
Other indications:
1 mg* qd (must be
agreed upon by the
sponsor)
300 mg qd 
25 mg qd
Route of 
administration 
Subcutaneous 
injection (in the 
abdomen) 
Subcutaneous 
injection (in the
abdomen)
Oral 
Oral 
Oral 
Oral 
Oral
Dosing instructions 
Regardless of 
food intake 
Regardless of 
food intake 
Regardless of 
food intake 
Regardless of 
food intake
On an empty stomach  
With food 
With food
qd: once daily
* 2 tablets of 0.5 mg
** 300 mg TDF is equivalent to tenofovir disoproxil 245 mg
*** In countries where TAF is available, it will be one of the NA treatment options.
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Status: Approved,  Date: 26 November 2021
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 for subcutaneous injection
.
The JNJ-6379 supplied for this study is formulated as oral tablets containing 
mg (
) and
mg (
) JNJ-56136379-AAA. The JNJ-6379 tablets should be swallowed as a whole.
JNJ-3989 and JNJ-6379 will be provided under the responsibility of the sponsor. Refer to the iBs
for a list of excipients.14,15,16
The placebo for JNJ-3989 will be a solution for subcutaneous injection 
. The matching placebo for JNJ-6379 consists of the oral tablets without active drug
substance (
 [placebo for 
mg] and 
 [placebo for 
mg]).
The NAs ETV, TDF, and TAF are formulated as oral film-coated tablets of 0.5-mg, 300-mg, and
25-mg strength, respectively.
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, the corresponding placebo, and the NAs will be
done in an open-label way.
Commercial supplies of NAs and sodium chloride 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 and matching placebo will be dispensed in child-resistant packaging. NA 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/placebo injections will be administered subcutaneously (preferably in the abdomen) at
the study site.
In between study visits, participants will take their oral study intervention (JNJ-6379/placebo/NA
treatment) at home and they will bring their oral study intervention with them to each study visit.
At study visits, the oral study intervention should be taken on site to allow biochemistry and
renal biomarker samples to be taken in fasted conditions.
CCI
CCI
CCI
CCI
CCI
CC
CCI
CC
CCI
CCI
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JNJ-73763989 and JNJ-56136379
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Status: Approved,  Date: 26 November 2021
NA treatment will be provided by the sponsor. Investigators should follow guidance detailed in
the respective prescribing information, including special warnings and precaution for use.
During the study, 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, TDF, or TAF prior to screening, they should be treated with one of the other two
NAs during this study.
If clinically indicated, switching from one NA treatment (ETV, TDF, or TAF) to another NA
treatment (ETV, TDF, or TAF) during the study is allowed for all participants after consultation
with the sponsor.
For a definition of study intervention overdose, refer to Section 8.4, Treatment of Overdose.
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 JNJ-6379/placebo/NA treatment
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/placebo and
NA to the participant, and the return of JNJ-6379/placebo and NA from the participant, must be
documented on the intervention accountability form. Participants must be instructed to return all
original containers, whether empty or containing study intervention. The JNJ-3989/placebo
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. 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. Study-site personnel must not
combine contents of the study intervention containers.
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 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.
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Status: Approved,  Date: 26 November 2021
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 of this study. Returned study intervention must not be dispensed
again, not even to the same participant. An intermediate study intervention compliance check is
not considered to be a re-dispensing. Study intervention may not be relabeled or reassigned for
use by other participants in the study.
6.3. 
Measures to Minimize Bias: Randomization and Blinding
Intervention Allocation
Procedures for Randomization and Stratification
Central randomization will be implemented in this study. Participants will be randomly assigned
in a 2:1 ratio to 1 of 2 intervention arms (JNJ-3989+JNJ-6379+NA:placebo+placebo+NA).
Randomization will be based on a computer-generated randomization schedule prepared before
the study by or under the supervision of the sponsor. The randomization will be balanced by
using randomly permuted blocks and will be stratified by screening HBsAg level (<1,000 IU/mL
or >1,000 IU/mL), race (Asian versus non-Asian) and type of NA (TDF/TAF versus ETV).
For more information on the interactive web response system (IWRS), refer to Section 6.3 of the
Master Protocol PLATFORMPAHPB2001.
Blinding
The investigators and participants will remain blinded to intervention allocation until all
participants have reached Week 72 (or discontinued earlier), while the sponsor’s central study
team will be unblinded at the time of the Week 48 IA.
Under normal circumstances, the blind should not be broken until all participants have completed
Week 72 or discontinued earlier. The investigator may in an emergency determine the identity of
the study intervention by contacting the IWRS. While the responsibility to break the study
intervention code in emergency situations resides solely with the investigator, it is recommended
that the investigator contacts the sponsor or its designee to discuss the particular situation, before
breaking the blind, only if this does not delay action with respect to treatment in an emergency
situation. Telephone contact with the sponsor or its designee will be available 24 hours per day, 7
days per week. In the event the blind is broken, the sponsor must be informed as soon as
possible. The date, time, and reason for the unblinding must be documented by the IWRS, in the
appropriate section of the CRF, and in the source document. The documentation received from
the IWRS indicating the code break must be retained with the participant’s source documents in
a secure manner.
Sponsor personnel involved in the pharmacokinetic and pharmacodynamic modeling will have
access to the pharmacokinetic and pharmacodynamic data before formal unblinding. Sponsor
personnel involved in trial conduct, data management, and statistics will not have access to these
data.
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Status: Approved,  Date: 26 November 2021
Participants who have had their study intervention assignment unblinded should continue study
intervention intake (unless instructed otherwise) and should return for scheduled evaluations.
In order to preserve the blinding during the study treatment phase, HBsAg, HBeAg, anti-HBs,
and anti-HBe antibody tests cannot be done locally.
For more information on blinding, refer to Section 6.3 of the Master Protocol
PLATFORMPAHPB2001.
6.4. 
Study Intervention Compliance
JNJ-3989/placebo will be administered at the study site as a subcutaneous injection by qualified
study-site personnel to assure compliance with study requirements.
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.
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 oral study interventions as indicated
in the Schedule of Activities. In case a dose of JNJ-6379/placebo was missed, the dose should be
given as soon as possible but within 12 hours after the scheduled time. Otherwise, the dose
should be skipped and the next dose should be given at the next scheduled time point per the
initial dosing schedule. If more than 3 consecutive doses are missed, the investigator should be
contacted and the case should be discussed with the sponsor. If a dose of NA is missed, the
participant should follow the guidelines in the package insert.
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
Overviews of ISA-specific disallowed medication and concomitant medications that should be
used with caution are provided in Table 3 and Table 4, respectively. For general concomitant
therapy considerations, refer to Section 6.5 ofthe Master Protocol PLATFORMPAHPB2001.
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JNJ-73763989 and JNJ-56136379
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Status: Approved,  Date: 26 November 2021
Table 3: 
Disallowed Medication
Disallowed at any time prior to screening until end of follow-up:
 
Any CAM and oligonucleotide-based HBV treatment (eg, siRNA and antisense oligonucleotides), 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).
Disallowed from 6 months prior to baseline until end of follow-up:
 
Any systemically (eg, intravenously, intramuscularly, orally, subcutaneously) administered medication that
directly or indirectly interferes with immune responses (eg, cyclosporine, interleukins, IFN, programmed
death-[ligand] 1 inhibitors, systemic corticosteroids exceeding 5 mg of prednisolone equivalent/day).
Disallowed from 1 month prior to screening until end of follow-up:
 
Moderate and potent inhibitors of CYP3A4 (eg, azole anti-fungals, macrolide antibiotics, diltiazem,
verapamil).
 
Moderate and potent inducers of CYP3A4 (anti-epileptics: eg, carbamazepine, oxcarbazepine,
[fos]phenytoin, and phenobarbital; anti-tuberculosis drugs: rifabutin, rifampin, and rifapentine; other:
bosentan, modafinil).
 
Inhibitors of breast cancer resistance protein (BCRP) transporter (eg, curcumin, cyclosporine A,
eltrombopag) or P-glycoprotein transporter (eg, amiodarone, azithromycin clarithromycin, diltiazem,
dronedarone, erythromycin, felodipine, itraconazole, ketoconazole, quinidine, ritonavir, verapamil).
 
Any medication that reduces renal function or competes for active tubular secretion (eg cimetidine,
probenecid, quinidine).
Disallowed from screening until end of follow-up:
 
Products containing Hypericum perforatum (St. John’s wort).
 
Any anti-HBV drug (including vaccines) other than the study intervention taken in the context of this study.
Note:  NA standard ofcare treatment is allowed.
 
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.
Disallowed from 1 week prior to baseline until 12 weeks after EOSI:
 
Ethinylestradiol-containing contraceptives with an ethinylestradiol content >20 µg.
Note: Starting treatment with ethinylestradiol-containing contraceptives during the study is not allowed.
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Status: Approved,  Date: 26 November 2021
Table 4: 
Concomitant Medications to be Used With Caution
The following concomitant medications are allowed but should be used with caution with monitoring of AEs
and desired efficacy. Alternative medications or adjusted doses should be considered.
 
Analgesics: ergoloid mesylates, ergotamine tartrate, dihydroergotamine and methylergonovine.
 
Calcium channel blockers: eg, amlodipine, bepridil, nicardipine, nifedipine, and nisoldipine.
 
Lipid-lowering drugs: eg, atorvastatin, lovastatin, pitavastatin, pravastatin, rosuvastatin, simvastatin.
 
Phosphodiesterase 5 inhibitors: sildenafil, vardenafil, tadalafil.
 
Sedatives/anxiolytics: midazolam, triazolam.
 
Acid-reducing agents: antacids (eg, aluminium and magnesium hydroxide) (recommended to separate
antacid and oral study intervention administration by 4 hours).
 
Ethinylestradiol-containing contraceptives:
o 
Only allowed if on a stable treatment regimen for ≥3 months prior to screening and the
ethinylestradiol content is ≤20 µg.
o 
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.
 
Hormone replacement therapy in postmenopausal women: allowed if on a stable treatment regimen (ie,
same dose and not starting or stopping for 2 weeks prior to baseline until 12 weeks after EOS
intervention). Applicable procedures and treatment guidance based on package inserts should be respected.
 
Anticoagulants.
Note: aspirin and other antiplatelet agents are allowed.
Note: The list of disallowed concomitant medication and medication to be used with caution 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 prescribing information for ETV, TDF, and TAF should be consulted for any additional
prohibited medication.
Medications requiring subcutaneous injection (other than JNJ-3989/placebo; eg, insulin) should
be administered away from the JNJ-3989 injection site.
6.6. 
Study Intervention Completion at Week 48
All participants should stop all study interventions (JNJ-3989, JNJ-6379, and NA  or both
placebos and NA) at Week 48.
Any relevant change in participant baseline status with regards to ALT, HBV DNA levels and/or
HBeAg status or any other event that in the opinion of the investigator could prevent stopping
NA should be discussed with the sponsor.
For participants who cannot stop NA treatment, follow-up assessments will be obtained until
Week 96.
6.7. 
NA Re-treatment Criteria and Monitoring After Stopping of NA
After completing treatment with JNJ-3989, JNJ-6379 (or their matching placebos) and NA at
Week 48 (or after premature discontinuation), participants will be monitored closely during the
follow-up phase.
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Status: Approved,  Date: 26 November 2021
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, alkaline
phosphatase (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 restart 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 collected 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.
Management of intervention-emergent ALT/AST elevations is discussed in Section 8.3.6.3,
Intervention-emergent ALT/AST Elevations.
NA re-treatment criteria and monitoring after stopping of NA  are presented graphically in
Section 10.13, Appendix 13.
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Status: Approved,  Date: 26 November 2021
6.8. 
Intervention After the End of the Study
Refer to Section 6.7 of the Master Protocol PLATFORMPAHPB2001.
The investigator should consider to re-start NA treatment per local standard of care at the EOS
visit (Follow-up Week 48) for participants who discontinued NA treatment at Week 48, 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 STUDY INTERVENTION AND PARTICIPANT
DISCONTINUATION/WITHDRAWAL
If a participant discontinues study intervention for any reason before Week 48, the participant
will have an early withdrawal visit and will enter follow-up unless he/she withdraws consent. If
the reason for withdrawal from the study is withdrawal of consent, then the participant will be
offered an optional safety follow-up visit. Study intervention assigned to the participant who
discontinued study intervention may not be assigned to another participant.
7.1. 
Discontinuation of Study Intervention
JNJ-3989 and JNJ-6379 (or matching placebos) must be discontinued before Week 48 for all
reasons listed in Section 7.1 of the Master Protocol PLATFORMPAHPB2001 and for all
additional intervention-specific reasons. All the discontinuation criteria are listed below and the
intervention-specific criteria are highlighted (colored fill). For the few criteria from the Master
Protocol that are specified or more restricted in this ISA, the changes compared to the Master
Protocol are also highlighted (colored fill). When JNJ-3989 or JNJ-6379 (or the matching
placebos) are discontinued, NA treatment may be continued or, in consultation with the sponsor,
discontinued based on investigator judgement.
The discontinuation criteria are:
 
The investigator believes that for safety or tolerability reasons (eg, AE) it is in the best
interest of the participant to discontinue JNJ-3989 and JNJ-6379 (or matching placebos).
 
The participant becomes pregnant.
 
The participant has a ≥grade 3 rash or allergic reaction.
 
The participant has signs of hepatic decompensation (ie, clinical evidence of ascites,
bleeding varices, or hepatic encephalopathy).
 
The participant has a confirmed ≥grade 3 estimated glomerular filtration rate (eGFR)
abnormality and a drop from baseline of >10 mL/min/1.73 m2, considered at least possibly
related to JNJ-3989 or JNJ-6379. Change of NA treatment should be considered according
to the prescribing information.
 
The participant has a 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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Status: Approved,  Date: 26 November 2021
 
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 investigator in consultation with the sponsor
should consider changing the NA (to an NA that is not cross-resistant to the current NA,
after evaluation of all data available). 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 8.3.6.3 and Schedule of Activities).
 
The participant has ALT/AST elevations, as described in  Section 8.3.6.3,
Intervention-emergent ALT/AST Elevations.
Note: The grades are based on the DAIDS Toxicity Grading Scale (see Section 10.9,
Appendix 9, DAIDS Table).
7.2. 
Participant Discontinuation/Withdrawal From the Study
In case a participant is withdrawn from the study intervention cohort for any of the reasons listed
in Section 7.2 of the Master Protocol PLATFORMPAHPB2001, additional participants will not
be entered.
7.2.1. 
Withdrawal From the Use of Research Samples
Refer to Section 7.2.1 of the Master Protocol PLATFORMPAHPB2001.
7.3. 
Lost to Follow-up
Refer to Section 7.3 of the Master Protocol PLATFORMPAHPB2001.
8. 
STUDY ASSESSMENTS AND PROCEDURES
Overview
Refer to Section 8 of the Master Protocol PLATFORMPAHPB2001.
The PRO assessments and ECGs should be completed before any tests, procedures or other
consultations for that visit.
The total blood volume to be collected from each participant during planned assessments for the
entire study will be approximately 1200 mL. In addition, PBMC samples (at selected sites only;
approximately 300 mL), optional exploratory host genotyping and epigenetic research samples
(approximately 60 mL) and optional intensive PK samples (approximately 66 mL) may be
collected.
Note: The total blood volume to be collected from each participant may vary, depending on
several factors (eg, unscheduled re-tests, re-sampling, individual variations).
Sample Collection and Handling
Refer to Section 8 of the Master Protocol PLATFORMPAHPB2001.
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Status: Approved,  Date: 26 November 2021
Study-specific Materials
In addition to the items described in Section 8 of the Master Protocol PLATFORMPAHPB2001,
the investigator will be provided with the following supplies:
 
A binder with the PRO instruments,
 
Prescribing Information for ETV, TDF, and TAF,
 
Contact information page(s).
8.1. 
Efficacy Assessments
All efficacy assessments will be performed at predefined time points as specified in the Schedule
of Activities.
Qualitative and quantitative HBsAg and HBeAg, and quantitative HBcrAg as well as anti-HBs
and anti-hepatitis B e (HBe) antibodies 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 request.
HBV 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 request.
HBeAg and anti-HBe antibody testing results from the Week 44 visit onwards will be provided
for each participant to the investigator and the sponsor at the next visit (ie, from the Week 48
visit onwards). HBsAg and anti-HBs testing results from the Week 44 visit onwards will be
provided for each participant to the investigator from FU Week 2 onwards. The blinded post-
baseline results collected prior to the Week 44 visit will be provided to the investigator at the end
of the study to complete the participant’s medical records. Note that screening and Day 1 predose
results are not blinded. HBV DNA results will be provided to the investigator and the sponsor
from screening until the end of follow-up. In order to preserve the blinding during the study
treatment phase, HBsAg, HBeAg, anti-HBs, and anti-HBe antibody tests cannot be done locally.
It is the responsibility of the investigator:
 
To monitor HBV DNA results and ensure that JNJ-3989 and JNJ-6379 (or the matching
placebos) are discontinued in participants with confirmed virologic breakthrough  (see
Section 7.1, Discontinuation of Study Intervention),
 
To assess if NA treatment cannot be stopped at Week 48 due to any relevant change in
participant baseline status with regards to ALT, HBV DNA levels and/or HBeAg status or
any other event (see Section 6.6, Study Intervention Completion at Week 48),
 
To assess whether restart of NA treatment during follow-up is needed (see Section 6.7, NA
Re-treatment Criteria and Monitoring After Stopping of NA).
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JNJ-73763989 and JNJ-56136379
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In participants enrolled at a site with an on-site Fibroscan device, Fibroscan assessments will be
performed at different time points 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.
8.1.1. 
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.
8.1.2. 
Patient-reported Outcomes
The impact of HBV treatment on participants will be assessed using PROs at predefined time
points (see Schedule of Activities). The following PRO instruments will be used: HBV-specific
self-stigma scale and EQ-5D-5L questionnaire.
The PRO assessments will be performed by all participants. Participants should complete these
assessments in their native language or if there is no version available in their native language, a
version in a language in which the participant is fluent and literate. It is preferable that
participants are able to read and write to complete the assessments by themselves. If a participant
is unable to read or has visual or other physical limitations that make it difficult to read or
complete the assessments, trained study-site personnel may read the questions and responses
aloud exactly as they appear on the assessment and record the participant’s responses.
Study-site personnel will record in the CRF whether the PRO  assessments were performed
during the study visit.
The participant should be provided a quiet place to complete the PRO assessments, and
instructed how to complete the PRO assessments. When deciding which answer to report,
participants should not receive any help from anyone accompanying them (such as family
members and friends) or study-site personnel; the responses should reflect the participant’s
interpretation and response.
Participants’ responses to the PRO questionnaires will not be reported as AEs or SAEs.
HBV-specific Self-stigma Scale, Version 1.0
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The HBV-specific self-stigma scale is an HBV-specific PRO instrument designed to assess the
experience and impact of self-stigma. The current version consists of 37 items. The items cover
aspects of self-stigma such as a) devaluation, inferiority, and worthlessness, b) marginalization
and alienation, c) secrecy and concealment, d) shame and guilt, and e) withdrawal and social
isolation. Each of the 37 items is graded on a 5-point Likert scale (1 “Never”, 2 “Rarely”,
3 “Sometimes”, 4 “Often”, and 5 “Always”). It takes less than 15 minutes to complete the
scale. The content validity of the scale is currently being evaluated and the data collected in this
study will be used to assess the psychometric properties of the scale.33,39
The HBV-specific self-stigma scale version 1.0 is provided in Section 10.10, Appendix 10,
HBV-specific Self-stigma Scale.
5-Level EuroQol 5-Dimension Questionnaire
The EQ-5D-5L questionnaire is a brief, 2-page, generic health-related quality-of-life assessment
that evaluates a subject’s self-rated health state on 5 dimensions (mobility, self-care, usual
activities, pain/discomfort, anxiety/depression). Additionally, a VAS records the subject’s
self-rated health on a vertical VAS where the endpoints are labelled ‘best imaginable health
state’ (100) and ‘worst imaginable health state’ (0). This information can be used as a
quantitative measure of health outcome as judged by the subject. EQ-5D scores include the
following:
 
EQ-5D Valuation Index score (a weighted scoring ofthe 5 dimension scores with a possible
range from 0 to 1);
 
EQ-5D VAS score (with a possible range from 0 [worst imaginable health] to 100 [best
imaginable health]);
 
EQ-5D descriptive system scores (5 scores reflecting each of the 5 dimensions ranging from
0 [no limitation] to 4 [incapacity]).
It takes about 2 minutes to complete the EQ-5D-5L questionnaire.
A representative example of the EQ-5D-5L questionnaire is provided in Section 10.11,
Appendix 11, 5-Level EuroQol 5-Dimension Questionnaire (EQ-5D-5L).
8.2. 
Safety Assessments
Safety and tolerability (AEs, clinical safety laboratory assessments, ECGs, vital signs and
physical examinations) will be evaluated as described in Section 8.2 of the Master Protocol
PLATFORMPAHPB2001 and at predefined time points as specified in the Schedule of
Activities.
Additional clinical safety laboratory assessments specific for this protocol are described in
Section 10.2, Appendix 2, Clinical Laboratory Tests.
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8.2.1. 
Physical Examinations
Refer to Section 8.2.1 ofthe Master Protocol PLATFORMPAHPB2001.
8.2.2. 
Vital Signs
Refer to Section 8.2.2 of the Master Protocol PLATFORMPAHPB2001.
Clinically relevant abnormalities in vital signs are defined in Section 10.7, Appendix 7,
Cardiovascular Safety Abnormalities.
8.2.3. 
Electrocardiograms
Refer to Section 8.2.3 of the Master Protocol PLATFORMPAHPB2001.
Clinically relevant abnormalities in ECG  are defined in Section 10.7, Appendix 7,
Cardiovascular Safety Abnormalities.
8.2.4. 
Clinical Safety Laboratory Assessments
Refer to Section 8.2.4 ofthe Master Protocol PLATFORMPAHPB2001.
In addition, urine samples for urine chemistry and renal biomarkers will be collected as noted in
Section 10.2, Appendix 2, Clinical Laboratory Tests.
For this study, the laboratory abnormality of cholesterol increase is identified as laboratory
abnormality of interest.
8.3. 
Adverse Events and Serious Adverse Events
Adverse events and SAEs will be evaluated as described in Section 8.3 of the Master Protocol
PLATFORMPAHPB2001, including handling of pregnancy described in Section 8.3.5.
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 Attachment 4 of the Master Protocol PLATFORMPAHPB2001.
8.3.1. 
Time Period and Frequency for Collecting Adverse Event and Serious
Adverse Event Information
Refer to Section 8.3.1 of the Master Protocol PLATFORMPAHPB2001.
8.3.2. 
Method of Detecting Adverse Events and Serious Adverse Events
Refer to Section 8.3.2 of the Master Protocol PLATFORMPAHPB2001.
8.3.3. 
Follow-up of Adverse Events and Serious Adverse Events
Refer to Section 8.3.3 ofthe Master Protocol PLATFORMPAHPB2001.
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8.3.4. 
Regulatory Reporting Requirements for Serious Adverse Events
Refer to Section 8.3.4 ofthe Master Protocol PLATFORMPAHPB2001.
8.3.5. 
Pregnancy
Refer to Section 8.3.5 of the Master Protocol PLATFORMPAHPB2001.
8.3.6. 
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, and events related to cholesterol increase (Section 8.2.4, Clinical Safety
Laboratory Assessments). In addition, the following toxicities will also be carefully monitored:
rash and acute systemic allergic reactions.
For participants reporting rash, ISRs, acute systemic allergic reactions, ALT/AST elevations, and
renal complications as specified in the DAIDS Toxicity Grading Scale (see Section 10.9,
Appendix 9, DAIDS Table), the following should be done.
8.3.6.1. 
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.
All rash events should be captured in the AE section of the CRF. A separate Rash page will be
completed in case of a rash event.
Monitoring of the evolution of rash events will be performed as described in Table 5 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, red blood cell
[RBC] count, white blood cell [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 JNJ-6379
(or placebos) need to be permanently discontinued. NAs can be continued. If the rash is
considered to be most likely due to concomitant illness or non-study drugs, standard
management, including discontinuation of the likely causative agent, should be undertaken.
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8.3.6.1.1. 
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. Evaluation 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) will need to 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.
8.3.6.2. 
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 JNJ-6379 (or placebos). Rechallenge is not allowed. The participant’s
NA treatment may be discontinued based on investigator judgement in consultation with the
sponsor.
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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 JNJ-6379 (or placebos).
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.
8.3.6.3. 
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 AFP, ALT, AST, ALP, bilirubin (total and direct), INR,
albumin, and HBV DNA. Additional tests should be considered based on clinical judgement
(Refer to 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/L and ≥3x baseline value, JNJ-3989
and JNJ-6379 (or their matching placebos) should be discontinued. In both cases, NA treatment
should be continued. The participant will be monitored (laboratory testing of ALT, AST, ALP,
bilirubin [total and direct], INR, albumin, and HBV DNA) on a weekly basis until ALT and/or
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
 
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
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the participant should discontinue JNJ-3989 and JNJ-6379 (or their matching placebos) and
should be monitored on a weekly basis or as per good clinical practice until ALT and/or 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 can be considered
based on clinical judgement.
The NA re-treatment criteria and monitoring after stopping of NA are presented in Section 6.7.
8.3.6.4. 
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 eGFR abnormalities with reduction from
baseline by at least 10 mL/min/1.73 m2 will permanently discontinue the intake of JNJ-3989 and
JNJ-6379 (or placebos) if considered at least possibly  related to JNJ-3989 or JNJ-6379 and
should be followed appropriately until resolution of the AE or toxicity. Rechallenge is not
allowed. Change of NA treatment should be considered according to the prescribing information.
8.3.6.5. 
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 treatment. In the Phase 1/2a
AROHBV1001 study with JNJ-3989, mild transient thrombocytopenia (Grade 1) 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 NAs. The transient thrombocytopenia was not considered clinically
significant. No thrombocytopenia or pancytopenia was observed in 12 patients 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 or <100 GI/L or reduction from baseline by at least 50%
 
Hemoglobin: Decrease of at least 2 g/dL from baseline or at least Grade 2 (DAIDS)
 
Reticulocytes: Reduction to <0.5% of the RBC count
 
Neutrophil count: Treatment emergent reduction to at least Grade 2 (DAIDS)
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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
investigational study treatment (JNJ-3989 and/or JNJ-6379/placebo) should be considered. In
case of discontinuation, NA treatment should be continued.
8.4. 
Treatment of Overdose
For this study, any dose of JNJ-3989 and JNJ-6379 greater than  the protocol-specified dose
(refer to Section 6.1) will be considered an overdose; any dose of NA (ETV, TDF or TAF)
greater than the prescribed dose will be considered an overdose. The sponsor does not
recommend specific 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 will be made by the investigator in consultation with the
Medical Monitor based on the clinical evaluation of the participant.
8.5. 
Pharmacokinetics
Plasma samples will be used to evaluate the PK of the study intervention. Samples collected for
analyses of the study intervention’s plasma concentrations may additionally be used to evaluate
safety or efficacy aspects.
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 subgroup (optional)
will undergo intensive PK sampling at Week 4 (minimally 18 participants). If necessary (eg, for
operational reasons), this visit may be scheduled at Week 8, 12, or 16.
Plasma concentration-time data for JNJ-3989 (ie, JNJ-3976 and JNJ-3924), JNJ-6379 and,
optionally, NA will be analyzed via population PK for all participants. Area under the plasma
concentration-time curve over 24 hours (AUC24h) and plasma trough concentrations (C0h) will be
estimated using empiric Bayes estimation.
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Plasma concentration-time data for JNJ-3989 (ie, JNJ-3976 and JNJ-3924), JNJ-6379 and,
optionally, NA will be analyzed via noncompartmental methods for all participants who
underwent intensive PK sampling. The main PK parameters will be AUC24h, Cmax, tmax, 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 other studies via population PK modelling to enable
the calculation of the above PK parameters also in participants who only underwent sparse PK
sampling.
8.6. 
Pharmacokinetic/Pharmacodynamic Evaluations
Relationships of individual PK parameters (intensive PK and population PK, as applicable) for
JNJ-3989 (ie, JNJ-3976 and JNJ-3924), JNJ-6379, and NA, as applicable, with selected efficacy
and safety endpoints will be evaluated.
8.7. 
Immune Assessments
At selected sites, PBMC samples for immune analyses will be collected during study
intervention and follow-up 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.
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 PBMC 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.
8.8. 
Host Genetics
A pharmacogenomic (host DNA) blood sample should be collected at baseline to allow for host
pharmacogenomic research, where local regulations permit. In addition, host DNA blood
samples to allow for epigenetic analyses will be collected. These samples could for example be
used to assess changes in frequencies of immune cells such as myeloid derived suppressor cells.
These samples will only be collected from participants who consent separately to this component
of the study. Complete host genomic testing may be done to search for links of specific genes to
(HBV-related) liver disease or to the PK, PD, efficacy, safety, or tolerability of the study
intervention. Only host DNA research related to the study interventions under this protocol or to
chronic HBV infection will be performed. Further, a participant may withdraw such consent at
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any time without affecting their participation in other aspects of the study, or their future
participation in the Platform study (see Section 7.2.1 of the Master Protocol
PLATFORMPAHPB2001).
In addition, other samples may be used for exploratory genetic or epigenetic research in
participants consenting separately to this part of the study. No genetic research will be performed
on any sample in participants who have not provided the additional separate consent for host
genetic research. These samples can only be used to investigate the potential association of
genetic or epigenetic factors with efficacy, safety, or PK of the study intervention, or HBV
infection, or may be used to develop tests/assays related to the study intervention or HBV
infection.
These analyses will be performed at the sponsor’s discretion, will always be under the sponsor’s
supervision, and may be reported separately.
8.9. 
Exploratory 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 at the time points indicated
in the Schedule of Activities. Leftovers of other samples might also be used for exploratory
research of host and viral markers.
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.
These analyses will be performed at the sponsor’s discretion, will always be under the sponsor’s
supervision, and may be reported separately from the main study report.
More information is provided in Section 8.8 ofthe Master Protocol PLATFORMPAHPB2001.
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 (SAP).
9.1. 
Statistical Hypothesis
The primary hypothesis of this study is that the combination regimen of JNJ-3989+JNJ-
6379+NA is more efficacious than NA treatment alone, as measured by the primary efficacy
endpoint, the proportion of participants with HBsAg seroclearance at Week 72 (ie, 24 weeks
after completion of all study interventions at Week 48) without restarting NA treatment.
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9.2. 
Sample Size Determination
The total study sample size is 120 participants who will be randomly assigned to one of the two
intervention  arms in a 2:1 ratio (JNJ-3989+JNJ-6379+NA: placebo+placebo+NA). Statistical
power to test the primary hypothesis was assessed using the Mantel-Haenszel test with a 1-sided
Type 1 error rate of 0.05, assuming the observed percentage of participants with HBsAg
seroclearance at Week 72 in the placebo+placebo+NA arm to be 5%. The sample size of
80 participants in the investigational arm and 40 participants in the control arm provides >91%
statistical power to detect a ≥20% difference in the primary endpoint.
The 2:1 randomization ratio (N 80:40, JNJ-3989+JNJ-6379+NA:placebo+placebo+NA) was
chosen to balance statistical and clinical considerations as it provides adequate evidence of
efficacy and safety, with the benefit of offering study participants a higher chance to receive
investigational treatment. Safety will be compared between arms descriptively only, and no
inferential testing is planned.
9.3. 
Populations for Analyses
For purposes of analysis, the following populations are defined:
Population 
Description
Screened 
All participants who signed the ICF for the Master Protocol and this ISA
Enrolled 
All participants who were randomly assigned to an intervention arm in this ISA
Intent-to-treat 
(ITT) 
All participants who were randomly assigned to an intervention arm and who received at
least 1 dose of study intervention within this ISA. Participants will be analyzed according to
the study intervention they were randomly assigned to.
Safety  
All participants who received at least 1 dose of study intervention within this ISA.
Participants will be analyzed according to the study intervention they actually received.
9.4. 
Statistical Analyses
9.4.1. 
Efficacy Analyses
The primary efficacy analysis will be performed when all participants have completed Week 72
or discontinued earlier. The final analysis will be performed when all participants have
completed the last study visit (Week 96) or discontinued earlier.
To evaluate the efficacy, the primary analysis set will be the Intent-to-treat (ITT) population
(defined in Section 9.3).
All efficacy summaries will be presented with descriptive statistics by intervention arm. 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. 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 by intervention arm. Graphic displays will also be used
to summarize the data. Summaries will also be presented by randomization stratification factors,
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screening HBsAg level (<1,000 IU/mL or >1,000 IU/mL), race (Asian versus non-Asian) and
type of NA (TDF/TAF versus ETV).
The baseline measurements are defined as the measurements taken closest to but before the first
administration of study intervention on Day 1.
9.4.1.1. 
Primary Efficacy Endpoint (HBsAg Seroclearance 24 Weeks After
Completion of All Study Interventions at Week 48)
The proportion of participants who achieved HBsAg seroclearance at Week 72 (24 weeks after
completion of 48 weeks of treatment with study interventions) without restarting NA treatment
will be compared between intervention arms at a 1-sided 0.05 alpha. The primary endpoint will
be compared between intervention arms using the stratum-adjusted Mantel-Haenszel difference
in proportions,25 where the stratification factors screening HBsAg level (<1,000 IU/mL or
>1,000 IU/mL), race (Asian versus non-Asian) and type of NA (TDF/TAF  versus ETV)
determine the strata. The associated 90% confidence interval (CI) for the difference in
proportions will also be calculated.
All participants who do not achieve HBsAg seroclearance at Week 72 and/or require NA
re-treatment between Week 48 and Week 72 are considered treatment non-responders for the
purpose of the primary endpoint analysis. In addition, participants who withdraw from treatment
prior to Week 48 or from the study prior to Week 72 will be defined as non-responder. If the
HBsAg value at Week 72 is missing, the non-missing value closest to Week 72 within the
window of Weeks 60-84 (12 weeks prior/after Week 72) will be used.
Additional analyses may be performed on the primary efficacy endpoint using the Bayesian
methodology to leverage the Platform framework. Posterior probabilities will be calculated for
the treatment difference in the primary efficacy endpoint. This Bayesian analysis may
incorporate historical data and/or data from other ISAs that may enter the Platform study in the
future. Details on the Bayesian approach will be provided in the Modelling and Simulation
Report.
9.4.1.2. 
Secondary and Exploratory Efficacy Endpoints
Descriptive statistics will be used for all efficacy endpoints which will be summarized by
intervention arm and study phase. Comparisons between intervention arms will be done with no
adjustment for multiplicity. Specific key selected endpoints may be analyzed using suitable
categorical data approaches (eg, Cochran-Mantel-Haenszel or logistic regression for proportions
or other categorical type of endpoint), longitudinal repeated measures models (eg, for continuous
types of variables), or survival analysis based on the Kaplan-Meier estimates (for time-to-event
variables), as appropriate. Details will be described in the SAP.
To evaluate the efficacy at the end of treatment, the proportion of participants with HBsAg
seroclearance and the proportion of participants with HBV DNA <LLOQ  at Week 48,
respectively, will be tabulated by study intervention arm. Between arm comparisons for both
endpoints will be evaluated using the stratum-adjusted Mantel-Haenszel difference in
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proportions, where the stratification factors screening HBsAg level (<1,000 IU/mL or
≥1,000 IU/mL), race (Asian versus non-Asian) and type of NA (TDF/TAF  versus ETV)
determine the strata and corresponding 90% cIs.
The efficacy of the study intervention during the follow-up phase will also be evaluated. The
proportion of participants with HBsAg seroclearance at Week 96 without restarting NA
treatment, the proportion of participants with HBV DNA <LLOQ at Weeks 72 and 96,
respectively, the proportion of participants achieving partial response (HBV suppression without
restarting NA treatment) at different time points during follow-up, the proportion of participants
with flares (virologic, biochemical, and clinical), and the proportion of participants requiring NA
re-treatment during follow-up will be tabulated by intervention arm. The comparison between
the intervention arms will be done using the stratum-adjusted Mantel-Haenszel difference in
proportions, as described above. A similar analysis will be conducted for the proportion of
participants with HBsAg seroclearance 24 and 48 weeks, respectively, after stopping all study
interventions without restarting NA treatment.
The proportion of participants who reach HBV DNA <LLOQ and/or ALT normalization after
restart of NA treatment during follow-up will also be tabulated by intervention arm and the
comparison  between  the intervention arms will be done using the Mantel-Haenszel test for
difference in proportions as described above.
The blood markers (such as HBsAg, HBV DNA, and ALT) during study intervention and
follow-up will also be summarized by intervention arm over time and plotted. The proportion of
participants with virologic breakthrough (on treatment) and the proportion of participants with
(sustained) reduction, suppression, and/or seroclearance during follow-up considering single and
multiple markers (such as HBsAg, HBV DNA, and ALT) will be summarized by intervention
arm. The proportion of participants with HBsAg seroconversion will be tabulated by intervention
arm. Descriptive statistics on values and changes from baseline over time in HBsAg and HBV
DNA will be summarized by intervention arm. Additional summaries will be provided by the
randomization stratification factors (screening HBsAg level [<1,000 IU/mL or >1,000 IU/mL],
race [Asian versus non-Asian] and type of NA [TDF/TAF versus ETV]).
The time to achieve first HBsAg seroclearance will be summarized based on Kaplan-Meier
estimates in tables and graphs and compared between study interventions using the log rank test.
The proportion of participants with HBsAg levels and/or changes from baseline below/above
different cut-offs, and the proportion of participants with HBV DNA levels and/or changes from
baseline below/above different cut-offs will be analyzed as appropriate by intervention arm and
over time. The proportion of participants with ALT decrease and normalization will be tabulated
by intervention arm.
Graphic data displays will also be used to summarize the efficacy data by intervention arm and
over time.
In addition, the potential association between treatment outcome and baseline factors (including
but not limited to screening HBsAg level [<1,000 IU/mL or ≥1,000 IU/mL], race [Asian versus
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non-Asian] and type of NA [TDF/TAF versus ETV], and other HBV and host characteristics)
will be explored by multivariate analyses and exploration of interaction terms.2 Exploratory
subgroup summaries will be displayed graphically in forest plots.
9.4.1.3. 
Resistance Analyses
The results of HBV viral sequencing will be evaluated by the sponsor virologist. Relevant
changes of 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.
9.4.1.4. 
Patient-reported Outcomes
The PRO  scores will be analyzed descriptively as mean scores over time, and (if applicable)
evaluated based on the proportion of participants experiencing a clinically important
improvement or worsening in PRO scores from baseline during study intervention and
follow-up. Analyses will also be performed on PRO score changes from baseline at specific time
points (Weeks 48, 72, 96) and between Week 48 and later time points for different subgroups:
participants with HBsAg seroclearance 24 weeks and 48 weeks after completion of all study
interventions at Week 48 without restarting NA treatment versus those without HBsAg
seroclearance at those time points. Further details will be provided in the SAP.
The data collected in this study will be used to assess the psychometric properties of the
HBV-specific self-stigma scale. The psychometric analyses will be described in a separate
document and results will be presented in a separate report.
9.4.2. 
Safety Analyses
The safety analyses will be based on the safety population  (defined in Section 9.3) and are
specified in Section 9.4.3 of the Master Protocol PLATFORMPAHPB2001.
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 by intervention arm and over time, as appropriate.
9.4.3. 
Other Analyses
Pharmacokinetic Analyses
Descriptive statistics (n, mean, SD, coefficient of variation [CV], geometric mean, median,
minimum, and maximum) will be calculated for the plasma concentrations of JNJ-6379,
JNJ-3976, JNJ-3924, and NA (ETV, tenofovir, and/or TAF), as applicable, and for the derived
plasma PK parameters for both noncompartmental and population PK analyses.
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For each participant with intensive PK sampling, plasma concentration-time data of JNJ-6379,
JNJ-3976, JNJ-3924, and, optionally, NA 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. Plasma PK parameters in participants undergoing
intensive PK sampling will be calculated via noncompartmental methods for JNJ-6379,
JNJ-3976, JNJ-3924, and, optionally, NA, as applicable. The PK parameters will be Cmax, Cτ, and
AUC24h. The PK parameters will be subjected to an exploratory graphical analysis, including
various transformations, to get a general overview.
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.
Population PK analysis of plasma concentration-time data of JNJ-6379, JNJ-3976, JNJ-3924 and,
optionally, NA will be performed using nonlinear mixed-effects modeling. Data may be
combined with previous Phase 1 and/or 2 studies to support a relevant structural model.
Available baseline characteristics (eg, demographics, laboratory variables, genotypes) will be
included in the model as necessary. For operational reasons, a snapshot date for PK samples to
be analyzed will be defined, if required. Samples collected before this date will be analyzed for
JNJ-6379, JNJ-3976, JNJ-3924, and/or NA (as applicable) and will be included in the population
PK analysis. Samples collected after the snapshot date will be analyzed at a later date, and may
be included in a population PK re-analysis when they become available after database lock.
Details will be given in a population PK analysis plan and the results of the population PK
analysis will be presented in a separate report.
Pharmacokinetic/Pharmacodynamic Analyses
Relationships of PK parameters for JNJ-6379, JNJ-3976, JNJ-3924 and, optionally, NA (ETV,
tenofovir, and/or TAF) with selected efficacy and safety endpoints will be evaluated and
graphically displayed. Details will be described in the SAP.
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 will be investigated. Other biomarkers may be explored at
the sponsor’s discretion. Details of the PK/PD analyses will be described in a population PK/PD
analysis plan and results will be presented in a separate report.
Immune Analyses
Descriptive statistics (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 patients with positive responses based on the magnitude of the IFN-γ T-cell response or the
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CD4+ or CD8+ T-cells expressing at least 1 of the cytokines amongst IL-2, TNF-α or IFN-γ for
1 of the HBV antigens as defined by ELISpot and/or ICS, respectively, will be determined.
Pharmacogenomic Analyses
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 Biomarker Analyses
Statistical approaches to explore correlations between clinical outcome and blood biomarkers
vary and depend on the different data types of the applied technology platforms, as well as on the
extent of observed interindividual variability. 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 Analyses
An IA  will be conducted to assess safety and evaluate the time course of different disease
markers to support the sponsor’s interactions with health authorities, as well as to inform internal
decisions about additional studies and/or investigation of other treatment combinations. The IA
is planned when all participants have completed Week 48 or discontinued earlier. The sponsor’s
central study team will be unblinded at this IA. Details on this team will be provided in the
IDMC charter.
Up to two additional IAs may be performed by the sponsor between Week 48 and the primary
analysis at Week 72, to support interactions with health authorities.
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.
More details are provided in Section 9.5 of the Master Protocol PLATFORMPAHPB2001.
9.6. 
Independent Data Monitoring Committee
At the analysis time points specified above and at regular intervals, an IDMC will meet and
review unblinded data to ensure the continuing safety of the participants enrolled in the study. In
addition, at the analysis time points specified above, the IDMC will also review the unblinded
results of selected efficacy parameters measured by different HBV disease blood markers (eg,
HBV DNA, HBsAg, etc).
The IDMC members will be appointed before the start of the study to review unblinded interim
data for both safety and efficacy and formulate recommendation(s) to the Sponsor Committee,
who will make the final decision(s). Possible recommendations of the IDMC include, but are not
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limited to, stopping the study for safety concerns, or study amendments. The Sponsor Committee
includes representatives from the sponsor’s Clinical, Biostatistics, Global Medical Safety and
Virology departments who are not involved in the study conduct.
Details on the roles and responsibilities of the IDMC and Sponsor Committee, as well as the
flows of communication, will be documented in the IDMC charter.
More details are provided in Section 9.6 of the Master Protocol PLATFORMPAHPB2001.
9.7. 
Independent Flare Expert Panel
An IFLEP will be appointed. The IFLEP  is composed of 3 independent medical experts with
experience and expertise in HBV and its treatment. The responsibilities of the IFLEP include:
conduct regular review of all relevant and available individual participant blinded study data
related to ALT flares; determine and adjudicate each ALT flare; and provide documentation of
the final decision to IDMC. Adjudication review cycles will match IDMC schedule and will be
set up ideally 2 weeks before IDMC.
In order to allow for an unbiased assessment, members of the committee will not serve as study
investigators or as members of the IDMC and will be blinded to the treatment assigned to each
participant.
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
Abbreviations
AE 
adverse event
A/H  
animal/human ratio
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 hours
AUC0-last 
area under the plasma concentration-time curve from administration to last quantifiable sampling
point
AUC∞ 
area under the plasma concentration-time curve to last sampling point from time zero extrapolated
to infinity
AUCτ 
area under the plasma concentration-time curve over the dosing interval (τ)
bpm  
beats per minute
C0h  
plasma trough concentration
CAM  
capsid assembly modulator
cccDNA  
covalently closed circular deoxyribonucleic acid
CHB  
chronic hepatitis B
CI 
confidence interval
CKD-EPI 
Chronic Kidney Disease Epidemiology Collaboration
CL/F  
total apparent oral clearance
Cmax  
maximum plasma concentration
Cmin  
minimum plasma concentration
CRF  
case report form
CT  
computed tomography
Cτ 
plasma concentration at the end of the dosing interval (τ)
CV  
coefficient of variation
CYP  
cytochrome P450
DAIDS  
Division of Acquired Immunodeficiency Syndrome
DBP  
diastolic blood pressure
DDI 
drug-drug interaction
DNA  
deoxyribonucleic acid
ECG  
electrocardiogram
EFD  
embryofetal development
eGFR  
estimated glomerular filtration rate
ELISpot 
enzyme-linked immunospot
Emax  
maximum effect
EOSI 
end-of-study intervention
EQ-5D-5L 
5-Level EuroQol 5-Dimension
ETV  
entecavir
GCP  
Good Clinical Practice
GLP  
Good Laboratory Practice
HBc 
hepatitis B core protein
HBcrAg 
hepatitis B core-related antigen
HBe(Ag) 
hepatitis B e (antigen)
HBs(Ag) 
hepatitis B surface (antigen)
HBV  
hepatitis B virus
HCC  
hepatocellular carcinoma
HCV  
hepatitis C virus
HDV  
hepatitis D virus
HEV  
hepatitis E virus
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HIV(-1/2) 
human immunodeficiency virus (type 1/2)
IA  
interim analysis
IB  
Investigator’s Brochure
ICF  
informed consent form
ICH  
International Council for Harmonisation of Technical Requirements for Pharmaceuticals for
Human Use
ICS  
intracellular cytokine staining
IDMC  
Independent Data Monitoring Committee
IFLEP  
Independent Flare Expert Panel
IFN-γ 
gamma interferon
IgG  
immunoglobulin G
IgM  
immunoglobulin M
IL 
Interleukin
INR  
International Normalized Ratio
ISA  
intervention-specific appendix
ISR  
injection site reaction
ITT  
Intent-to-treat
IWRS  
interactive web response system
LLN  
lower limit ofnormal
LLOQ  
lower limit of quantification
MoA  
mode of action
MRI 
magnetic resonance imaging
NA  
nucleos(t)ide analog
NOAEL 
no observed adverse effect level
PBMC  
peripheral blood mononuclear cell
PD 
pharmacodynamic(s)
pgRNA  
pre-genomic ribonucleic acid
PK 
pharmacokinetic(s)
PRO  
patient-reported outcome(s)
qd 
once daily
QTcF  
QT interval corrected for heart rate according to Fridericia’s formula
RBC  
red blood cell
RNA  
ribonucleic acid
RNAi 
ribonucleic acid interference
SAE 
serious adverse event
SAP  
Statistical Analysis Plan
SBP 
systolic blood pressure
SD 
standard deviation
siRNA  
small interfering ribonucleic acid
t1/2term  
terminal half-life
TAF  
tenofovir alafenamide
tmax  
time to reach Cmax
TDF  
tenofovir disoproxil fumarate
TNF  
tumor necrosis factor
ULN  
upper limit of normal
VAS  
Visual Analog Scale
WBC  
white blood cell
Definitions of Terms
ALT/AST nadir 
Lowest ALT/AST value during study participation
End-of-study intervention 
(EOSI)
Time of the last administration of study intervention
HBsAg seroclearance 
HBsAg negativity based on the assay used
HBsAg seroconversion 
HBsAg negativity and anti-HBs antibody positivity
Intervention cohort 
Cohorts of adult participants with chronic hepatitis B virus infection who receive a
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specific study intervention within this Platform study, and in whom the efficacy and
safety of that intervention is evaluated
Study intervention  
JNJ-73763989 or placebo, JNJ-56136379 or placebo, and NA (either ETV, TDF, or
TAF)
Study intervention phase 
48-week phase from randomization to last administration of study intervention
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
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10.3. Appendix 3: Regulatory, Ethical, and Study Oversight Considerations
REGULATORY AND ETHICAL CONSIDERATIONS
Refer to Attachment 3 of the Master Protocol PLATFORMPAHPB2001.
FINANCIAL DISCLOSURE
Refer to Attachment 3 of the Master Protocol PLATFORMPAHPB2001.
INFORMED CONSENT PROCESS
Refer to Attachment 3 of the Master Protocol PLATFORMPAHPB2001.
DATA PROTECTION
Refer to Attachment 3 of the Master Protocol PLATFORMPAHPB2001.
LONG-TERM RETENTION OF SAMPLES FOR ADDITIONAL FUTURE RESEARCH
Refer to Attachment 3 of the Master Protocol PLATFORMPAHPB2001.
COMMITTEES STRUCTURE
Independent Data Monitoring Committee
At the analysis time points specified above and at regular intervals, an IDMC  will meet and
review unblinded data to ensure the continuing safety of the participants enrolled in the study. In
addition, at the analysis time points specified above, the IDMC will also review the unblinded
results of selected efficacy parameters measured by different HBV disease blood markers (eg,
HBV DNA, HBsAg, etc).
The IDMC members will be appointed before the start of the study to review unblinded interim
data for both safety and efficacy and formulate recommendation(s) to the Sponsor Committee,
who will make the final decision(s). Possible recommendations of the IDMC include, but are not
limited to, stopping the study for safety concerns, or study amendments. The Sponsor Committee
includes representatives from the sponsor’s Clinical, Biostatistics, Global Medical Safety and
Virology departments who are not involved in the study conduct.
Details on the roles and responsibilities of the IDMC and Sponsor Committee, as well as the
flows of communication, will be documented in the IDMC charter.
More details are provided in Attachment 3 of the Master Protocol PLATFORMPAHPB2001.
Independent Flare Expert Panel
An IFLEP will be appointed. The IFLEP is composed of 3 independent medical experts with
experience and expertise in HBV and its treatment. The responsibilities of the IFLEP include:
conduct regular review of all relevant and available individual participant blinded study data
related to ALT flares; determine and adjudicate each ALT flare; and provide documentation of
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the final decision to IDMC. Adjudication review cycles will match IDMC schedule and will be
set up ideally 2 weeks before IDMC.
In order to allow for an unbiased assessment, members of the committee will not serve as study
investigators or as members of the IDMC and will be blinded to the treatment assigned to each
participant.
Further details on the IFLEP process will be included in the IFLEP charter.
PUBLICATION POLICY/DISSEMINATION OF CLINICAL STUDY DATA
Refer to Attachment 3 of the Master Protocol PLATFORMPAHPB2001.
DATA QUALITY ASSURANCE
Refer to Attachment 3 of the Master Protocol PLATFORMPAHPB2001.
CASE REPORT FORM COMPLETION
Refer to Attachment 3 of the Master Protocol PLATFORMPAHPB2001.
SOURCE DOCUMENTS
Refer to Attachment 3 of the Master Protocol PLATFORMPAHPB2001.
MONITORING
Refer to Attachment 3 of the Master Protocol PLATFORMPAHPB2001.
ON-SITE AUDITS
Refer to Attachment 3 of the Master Protocol PLATFORMPAHPB2001.
RECORD RETENTION
Refer to Attachment 3 of the Master Protocol PLATFORMPAHPB2001.
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
Refer to Attachment 3 of the Master Protocol PLATFORMPAHPB2001.
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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
Refer to Attachment 4 of the Master Protocol PLATFORMPAHPB2001.
ATTRIBUTION DEFINITIONS
Refer to Attachment 4 of the Master Protocol PLATFORMPAHPB2001.
SEVERITY CRITERIA
Refer to Attachment 4 of the Master Protocol PLATFORMPAHPB2001.
SPECIAL REPORTING SITUATIONS
Refer to Attachment 4 of the Master Protocol PLATFORMPAHPB2001.
PROCEDURES
Refer to Attachment 4 of the Master Protocol PLATFORMPAHPB2001.
CONTACTING SPONSOR REGARDING SAFETY
Refer to Attachment 4 of the Master Protocol PLATFORMPAHPB2001.
PRODUCT QUALITY COMPLAINT HANDLING
Refer to Attachment 4 of the Master Protocol PLATFORMPAHPB2001.
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10.5. Appendix 5: Rash Management
Table 5: 
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 picturesc 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
picturesc of skin lesions) may be performed at the
investigator’s discretion.
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 picturesc of skin lesions may be taken at the
investigator’s discretion. Digital picturesc 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
Referral to
dermatologist at the
discretion of the
investigatord
Biopsy not required,
but may be performed
at the dermatologist’s
discretion
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Table 5: 
Management of Rash Events by Severity Grade
Definition 
Study Intervention
Action
Activities by Daya 
Referral to
Dermatologist and
Dermatology
Activities
clinical stability is reached.
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 picturesc of skin lesions may be taken at the
investigator’s discretion.
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 and
JNJ-6379 (or
placebos); 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 picturesc 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 picturesc 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
picturesc of skin lesions) are recommended to be
performed until the rash severity resolves to grade 2 or
grade 1.
Requiredd
Biopsy not required,
but may be performed
at the dermatologist’s
discretion.
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Table 5: 
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 and
JNJ-6379 (or
placebos); 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 picturesc 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 picturesc 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
picturesc of skin lesions) are recommended to be
performed until the rash severity resolves to grade 2 or
grade 1.
Requiredd
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 
Digital pictures to be taken at the clinical site upon consent of the participant.
d 
If applicable, dermatologist visit should occur preferably within 24 hours after onset of rash.
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Notes:
 
Local laboratory assessments are to be used for rash management. The values of the local laboratory assessments need to be transcribed in the CRF by the study
site personnel.
 
If a copy of the dermatologist's report, biopsy, and/or digital pictures are required, they should be deidentified and will be provided to 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, Delta, C, E: IgM anti-HAV; delta IgM, IgG and PCR, HCV RNA, IgM and IgG anti-HEV, HEV RNA
 
CMV, HSV, EBV infection: IgM and IgG anti-CMV, IgM and IgG anti-HSV; IgM and IgG anti-EBV, PCR
 
HIV
 
Ig-Electrophoresis
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Status: Approved,  Date: 26 November 2021
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 International Council for Harmonisation of
Technical Requirements for Pharmaceuticals for Human Use (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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Status: Approved,  Date: 26 November 2021
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 8.3.5.
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 follicle-stimulating hormone (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 to confirm a
woman is not of childbearing potential. 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.
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 ovulation
 Intrauterine device (IUD)
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 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 ovulation
oral
intravaginal
transdermal
injectable
 Progestogen-only hormone contraception associated with inhibition of ovulation
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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Status: Approved,  Date: 26 November 2021
25. Hepatitis B has had a damaging effect on my education
                               
26. My family life has been disrupted because I have hepatitis B
                               
27. I have stopped socialising with some people because of their reactions to
me having hepatitis B
                               
28. Some people have treated me differently because I have hepatitis B
                               
29. People discriminated against me because I have hepatitis B
                               
30. I felt like people were avoiding touching me because of my hepatitis B
                               
31. I worried that people would reject me when they found out I have
hepatitis B
                               
32. I have been hurt by how people reacted because I have hepatitis B
                               
33. I felt frustrated by other people’s lack of understanding of hepatitis B
                               
34. I was not afraid to tell people I had hepatitis B
                               
35. I was comfortable with others knowing I have hepatitis B
                               
36. I was ashamed to seek medical care because of my hepatitis B
                               
37. I was afraid to seek medical care because of my hepatitis B
                               
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Status: Approved,  Date: 26 November 2021
10.11. Appendix 11: 5-Level EuroQol 5-Dimension Questionnaire (EQ-5D-5L)
Note: This appendix provides a representative example of the questionnaire that will be used in
this study. The site should always use the most recently provided version of the questionnaire.
Health Questionnaire
English version for the UK
UK(English) © 2009 EuroQol Group. EQ 5D™ is a trade mark of the EuroQol Group
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Status: Approved,  Date: 26 November 2021
Under each heading, please check the ONE box that best describes your health TODAY.
MOBILITY
I have no problems in walking about 

I have slight problems in walking about 

I have moderate problems in walkingabout 

I have severe problems in walking about 

I am unable to walk about 

SELF-CARE
I have no problems washing or dressing myself 

I have slight problems washing or dressing myself 

I have moderate problems washing or dressing myself 

I have severe problems washing or dressing myself 

I am unable to wash or dress myself 

USUAL ACTIVITIES (e.g. work, study, housework,
family or leisure activities)
I have no problems doing my usual activities 

I have slight problems doing my usual activities 

I have moderate problems doing my usual activities 

I have severe problems doing my usual activities 

I am unable to do my usual activities 

PAIN / DISCOMFORT
I have no pain or discomfort 

I have slight pain or discomfort 

I have moderate pain or discomfort 

I have severe pain or discomfort 

I have extreme pain or discomfort 

ANXIETY / DEPRESSION
I am not anxious or depressed 

I am slightly anxious or depressed 

I am moderately anxious or depressed 

I am severely anxious or depressed 

I am extremely anxious or depressed 

UK(English) © 2009 EuroQol Group. EQ 5D™ is a trade mark of the EuroQol Group
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Status: Approved,  Date: 26 November 2021
 We would like to know how good or bad your health is TODAY.
 This scale is numbered from 0 to 100.
 100 means the best health you can imagine.
0 means the worst health you can imagine.
 Mark an X on the scale to indicate how your health is TODAY.
 Now, please write the number you marked on the scale in the box
below.
YOUR HEALTH TODAY 
UK(English) © 2009 EuroQol Group. EQ 5D™ is a trade mark of the EuroQol Group
10
0
20
30
40
50
60
80
70
90
100
5
15
25
35
45
55
75
65
85
95
The best health 
you can imagine
The worst health
you can imagine
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Status: Approved,  Date: 26 November 2021
10.12. Appendix 12: Protocol Amendment History
The Protocol Amendment Summary of Changes Table for the current amendment is located
directly before the Table of Contents (TOC).
Amendment 3(30 September 2021)
Overall Rationale for the Amendment:
The primary reason for this amendment is to add a new NA re-treatment criterion   and to include more
frequent monitoring for participants who discontinued NA treatment at Week 48 or during follow-up.
A severe clinical alanine aminotransferase (ALT) flare following discontinuation of NA treatment was
reported in a virologically suppressed HBeAg negative participant on long-term tenofovir disoproxil
fumarate (TDF) treatment, who was randomized to the control arm (placebo + placebo + NA) in the
REEF-2 (73763989PAHPB2002) study. The participant presented with 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 guidelines5. 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.
Other clarifications and corrections were also made as detailed below.
Description of Change 
Brief Rationale 
Section Number and Name
A new NA re-treatment 
criterion was added for 
participants who discontinued 
NA treatment at Week 48. 
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
2.3.2.2 Potential Risks
4.2 Scientific Rationale for Study Design
6.7 NA Re-treatment Criteria During Follow-up
8.3.6.3 Intervention-emergent ALT/AST
Elevations
6.8 Intervention After the End of the Study
10.13 Appendix 13: NA Re-treatment During
Follow-up
Participants who discontinued 
NA treatment at Week 48 , 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
unchanged. 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. 
1.1 Synopsis
1.3.2 Schedule of Activities –Follow-up Phase
8 STUDY ASSESSMENTS AND
PROCEDURES
Clarifications were made to the 
urine pregnancy testing during
follow-up.
Clarification. 
1.3.2 Schedule of Activities –Follow-up Phase
Clarifications were made 
Clarification. 
1.3.2 Schedule of Activities –Follow-up Phase
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Status: Approved,  Date: 26 November 2021
Description of Change 
Brief Rationale 
Section Number and Name
concerning the optional safety
follow-up visit for participants
who withdraw consent during
follow-up.
The contraceptive guidance 
from the Master Protocol was 
replaced by ISA-specific 
contraceptive guidance, which 
includes the following updates 
versus the Master Protocol 
version: 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. 
1.3.1 Schedule of Activities –Screening and
Study Intervention Phase
5.1 Inclusion Criteria
10.8 Appendix 8: Contraceptive and Barrier
Guidance and Collection of Pregnancy
Information
The formulations numbers for 
JNJ-6379 were corrected and
formulation numbers for
placebo were added.
Correction. 
6.1 Study Intervention(s) Administered
Minor grammatical, formatting, 
or spelling changes were made.
Minor errors were noted 
Throughout the protocol
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Status: Approved,  Date: 26 November 2021
Amendment 2 (27 January 2020)
Overall Rationale for the Amendment: Based on a nonclinical finding from the preliminary
results of the 3-Month Combination toxicity study with JNJ-6379 and JNJ-3989 in the rat, the
protocol was amended to include hematologic abnormalities as an event of special interest, to
trigger a mandatory higher visit frequency with unscheduled visits in case of significant on-
treatment reduction in hematologic parameters, and to include treatment discontinuation criteria
in relation to hematological abnormalities as precautionary measures. No significant
abnormalities of hematologic parameters have been observed in clinical trials to date.
Furthermore, clarifications, additions and corrections were made throughout the protocol.
Main Changes
Section Number
and Name
Description of Change 
Brief Rationale 
2.3.3 Benefit-risk
Assessment for
Study Participation
8.3.6.5 Hematologic
Abnormalities
Addition of management of
hematologic abnormalities
In response to a serious and unexpected adverse
nonclinical finding, any relevant abnormalities in
hematologic parameters will be carefully monitored
to trigger a mandatory higher visit frequency in case
of significant on-treatment reduction in hematologic
parameters to ensure closer follow-up.
2.2.1 JNJ-3989 and
JNJ-6379
Preclinical update: Addition of
preliminary results from 3-month
combination toxicity study with
JNJ-3989 and JNJ-6379
Preliminary results of the 3-month combination
toxicity study with JNJ-6379 and JNJ-3989 in the
rat include an update on the sacrifice of one male rat
receiving JNJ-6379 orally at 100 mg/kg/day and
JNJ-3989 SC at 60 mg/kg related to bone marrow
depletion with pancytopenia including marked
thrombocytopenia.
Clarifications, Additions and Corrections
1.3.1 Schedule of
Activities –
Screening and Study
Intervention Phase
Addition of HBeAg (qualitative) 
assessment at Week 44 
Negative HBeAg status needs to be confirmed at
Week 48 before stopping NA treatment based on the
Week 44 result using the qualitative HBeAg assay
8.1 Efficacy
Assessments
Blinding of post-baseline (Day1)
HBsAg results to investigators and
participants until follow-up
Week 2
All participants who complete the Week 48 visit,
should stop all study interventions including NAs at
Week 48. HBsAg level is part of the primary
endpoint. In order to avoid any bias, HBsAg results
will be made available after stopping NA and from
FU Week 2 visit onwards.
1.3.1 Schedule of
Activities –
Screening and Study
Intervention Phase
1.3.2 Schedule of
Activities –Follow-
up Phase
10.6 Appendix 6:
Intervention-
emergent ALT/AST
Elevations
Addition of Alpha-fetoprotein
measurement every 24 weeks and
in case of ALT flares
Alpha-fetoprotein is of interest to link to liver
ultrasound assessment for the screening of HCC
every 6 months. In addition, alpha-fetoprotein has
been reported to be associated with HBsAg decline.
Thus, it is relevant to assess this marker.
1.3.1 Schedule of
Activities –
Language was added for
participants in the intensive PK
To avoid unnecessary duplication of PK sampling
for participants in the intensive PK subgroup.
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Screening and Study
Intervention Phase
subgroup, such that the sparse PK
sample does not need to be
collected at the time of an
intensive PK visit.
1.3.1 Schedule of
Activities –
Screening and Study
Intervention Phase
1.3.2 Schedule of
Activities –Follow-
up Phase
8 STUDY
ASSESSMENTS
AND
PROCEDURES
The recommendation regarding
the order of assessments in case of
multiple assessments at the same
time point was removed (refer to
Master protocol
PLATFORMPAHPB2001
amendment 2).
For more flexibility in timing of the assessments.
The PRO assessment and ECGs should be
prioritized, but the order of the other assessments is
of less importance.
1.3.1 Schedule of
Activities –
Screening and Study
Intervention Phase,
5.2 Exclusion
Criteria
Updated language, explaining that
the abdominal ultrasound 6
months prior to screening or at
screening will also be used to rule
out any clinically relevant renal
abnormalities.
Additional safety measure.
1.3.1 Schedule of
Activities –
Screening and Study
Intervention Phase
Updated footnote for liver
ultrasound assessment at baseline
Liver ultrasound is performed every 6 months to
monitor for development of HCC in participants
with increased risk for HCC. No need to repeat liver
ultrasound assessment at baseline if done within 6
months
1.3.2 Schedule of
Activities –Follow-
up Phase
Visit windows for follow-up
Week 2 and Week 4 were updated
Visit windows for follow-up Week 2 and Week 4
were increased from +/-2 days to +/-4 days to allow
sufficient time for laboratory results to come in,
especially HBeAg results, in order to assess re-
treatment criteria.
5.1 Inclusion
Criteria
A timeframe was added for female
participants of childbearing
potential to use a highly effective
method of contraception for at
least 30 days prior to screening.
The minimum time period for contraceptive use
prior to screening ensures adequate protection of
females of childbearing potential.
5.2 Exclusion
Criteria
The note in exclusion criterion
M01/A01 was modified to allow
participants with positive HCV,
HDV or HEV antibody test to
enroll if an active infection can be
ruled out (refer to Master protocol
PLATFORMPAHPB2001
amendment 2).
To only exclude patients with active infection. Some
patients may carry antibodies after an acute
infection, which never developed into a chronic
infection.
5.2 Exclusion
Criteria
Exclusion criterion M02 was
modified to include ‘total bilirubin
>1.5x ULN’. In addition, the
reference to benign cause such as
Gilbert’s disease was removed for
‘direct bilirubin’ (refer to Master
protocol
PLATFORMPAHPB2001
amendment 2).
For clarification as no threshold for total bilirubin
was included.
For correction as Gilbert’s syndrome is often
associated with increased indirect bilirubin, not
direct bilirubin.
5.2 Exclusion
Criteria
Pancreatic amylase elevation
≥grade 3 was added in exclusion
criterion M06/A03 (refer to
Master protocol
Additional safety measure.
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PLATFORMPAHPB2001
amendment 2).
5.2 Exclusion
Criteria
Exclusion criterion M09 was
updated to exclude participants
with PR interval >220 ms instead
of >200 ms
To align with ongoing HBV protocols with
JNJ-3989 where a less restrictive cutoff was
selected.
1.1 Synopsis/
Description of
Interventions
6.1 Study
Intervention(s)
Administered
Specification on which NA
treatments are available for the
study was adapted.
To account for import restrictions with regards to
tenofovir alafenamide (TAF) in some participating
countries as well as indications other than
lamivudine-resistant for ETV 1 mg.
6.4 Study
Intervention
Compliance
Instructions for handling of missed
or delayed injections with
JNJ-3989 were added.
For completeness, to ensure adequate treatment in
case of missed or delayed injections with JNJ-3989.
6.5 Concomitant
Therapy
Over-the-counter products, herbal
medications and dietary
supplements were removed from
the disallowed concomitant
medication list.
For clarification. Only products containing
Hypericum perforatum are disallowed.
7.1 Discontinuation
of Study
Intervention
This section was updated to
describe that only participants who
have taken the disallowed
concomitant medication for ≥7
days and have no intention to
discontinue the concomitant
medication will be discontinued
from the study intervention.
To avoid accidental intake of disallowed
concomitant medication triggering the
discontinuation of study intervention.
8.3.6.3 Intervention-
emergent ALT/AST
Elevations
10.2 Appendix 2:
Clinical Laboratory
Tests
10.6 Appendix 6:
Intervention-
emergent ALT/AST
Elevations
Added wording for ALT/AST
elevations management, added
baseline value as reference for
stopping criteria, and ensure that
all relevant liver tests are
performed
For closer patient safety monitoring and
management
8.3.6.1.1 Injection
Site Reactions
10.5 Appendix 5:
Rash Management
It was specified that digital
pictures can only be taken if the
participant has specifically
consented to this.
Language on the collection of
digital pictures was updated to
describe that if digital pictures are
required, they should be de-
identified and will be provided to
the sponsor.
To protect the participant’s privacy.
To clarify that the pictures are optional and explain
the proper steps to follow.
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6.3 Measures to
Minimize Bias:
Randomization and
Blinding
Added language explaining that
persons involved in PK and viral
load modeling will have access to
the PK and viral load data before
formal unblinding, while persons
involved in trial conduct, data
management and statistics will not
have access to these data.
To allow the sponsor to make informed portfolio
decisions for further development of the compound
while protecting the blind prior to the primary
analysis.
6.3 Measures to
Minimize Bias:
Randomization and
Blinding
8.1 Efficacy
Assessments
Addition of “In order to preserve
the blinding during the study
treatment phase, HbsAg, HbeAg,
anti-HBs, and anti-Hbe antibody
tests cannot be done locally.”
Clarification to avoid local unblinding via
assessment of these parameters
6.5 Concomitant
Therapy –Table 3
NA standard of care treatment is
not part of “any anti HBV drug
that are disallowed from screening
until end of follow-up”
Clarification
1.3.1 Schedule of
Activities –
Screening and Study
Intervention Phase
ECG at baseline needs to be
performed and assessed locally
prior to dosing but are not part of
eligibility criteria assessed after
screening.
Clarification
1.1 Synopsis/
Description of
Interventions
6.1 Study
Intervention(s)
Administered
Subcutaneous injection of
JNJ-3989 is now unambiguously
described to be administered in the
abdomen, instead of by
preference.
For clarification and consistency in approach.
1.1 Synopsis/
Description of
Interventions
1.2 Schema
6.1 Study
Intervention(s)
Administered
“Once monthly” in the dosage
regimen of JNJ-3989 was replaced
by “once every 4 weeks”.
For clarification
7.1 Discontinuation
of Study
Intervention
8.3.6.4 Renal
Complications
The relationship for
discontinuation criterion for a
confirmed ≥grade 3 eGFR
abnormality and a drop from
baseline of >10 mL/min/1.73 m²
was clarified to refer specifically
to JNJ-3989 and JNJ-6379 instead
of investigational intervention.
For clarification
8.3.6.1.1 Injection
Site Reactions
Wording was modified such that
all ISRs will need to be reported in
the CRF, but not by default as an
AE.
For clarification
5.1 Inclusion
Criteria
Update alphanumeric code IC
A07/M09 to A07/M10 as male
contraception requirement is IC 10
in Master Platform Protocol
Correction
2.2.1 JNJ-3989 and
JNJ-6379
Limited updates were made to the
nonclinical sections where
relevant
Correction
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2.3.2.2.1 Potential
Risks for JNJ-3989
2.3.2.2.2 Potential
Risks for JNJ-6379
Potential risk on viral resistance to
JNJ-3989 was moved to Section
2.3.2.2.1 as appropriate.
Correction
8 STUDY
ASSESSMENTS
AND
PROCEDURES
Approximations of total blood
volumes were modified.
A note was added with regards to
total blood volume.
Correction
To clarify that the total blood volume to be collected
from each participant may vary.
1.3.1 Schedule of
Activities –
Screening and Study
Intervention Phase
A time window was added for
intensive PK sampling.
For completeness
2.2.1 JNJ-3989 and
JNJ-6379
Clarification of fertility study  
For completeness
5.2 Exclusion
Criteria
Individuals under a legal 
protection measure were added to
criterion #M22 as an additional
example of vulnerable participants
(refer to Master protocol
PLATFORMPAHPB2001
amendment 2).
For completeness
1.1 Synopsis/
Description of
Interventions
6.1 Study
Intervention(s)
Administered
The volume of the placebo for 
JNJ-3989 was added to the dosage
regimen.
For completeness
1.3.1 Schedule of
Activities –
Screening and Study
Intervention Phase
2.3.2.2.1 Potential
Risks for JNJ-3989
6.1 Study
Intervention(s)
Administered
6.5 Concomitant
Therapy
7.1 Discontinuation
of Study
Intervention
10.1 Appendix 1:
Abbreviations and
Definitions of Terms
10.9 Appendix 9:
DAIDS Table
Minor grammatical, formatting, or
spelling changes were made.
Minor errors corrected.
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Amendment 1 (26 September 2019)
Overall Rationale for the Amendment: Following Health Authority (HA) feedback under the Voluntary
Harmonisation Procedure, the protocol was amended as specified below.
Section Number 
and Name
Description of Change 
Brief Rationale
1.1 Synopsis,
9.4.1.1 Primary
Efficacy Endpoint
(HBsAg
Seroclearance 24
Weeks After
Completion of All
Study Interventions
at Week 48)
Methods for handling missing data were added to
the protocol.
Per HA request, instead of referring
to the SAP, the approach to handle
missing data in the primary analysis
of the primary efficacy endpoint
was added.
5.1 Inclusion
Criteria
Numbering of the inclusion criteria was updated
due to addition of an inclusion criterion to the
master protocol.
Formatting
5.2 Exclusion
Criteria, 11
REFERENCES
Exclusion criterion #7 was amended to also include
known allergies, hypersensitivity, or intolerance to
placebo content.
Per HA feedback, exclusion
criterion #7 was corrected to also
include placebo content.
6.1 Study
Intervention(s)
Administered
It was clarified that during treatment with ETV,
TDF or TAF, guidance per the respective
prescribing information should be followed, in
particular with reference to special warnings and
precautions for use.
For consistency and completeness
and per HA feedback, reference to
the prescribing information of
ETV, TDF, and TAF was added for
guidance during NA treatment.
6.3 Measures to
Minimize Bias:
Randomization and
Blinding
Wording on unblinding was updated to clarify that
the investigator will contact the sponsor before
unblinding but only if this does not delay action
with respect to treatment in case of emergency.
The protocol currently recommends
the investigator contact the sponsor
before breaking the blind if
possible. The text was updated to
emphasize participant safety per
HA feedback.
6.5 Concomitant
Therapy
More general recommendation to consider
alternative medications or adjusted doses was
provided in Table 4 (Concomitant Medications to
be Used With Caution).
As JNJ-6379 is a mild inducer of
CYP3A, CYP3A substrates are
included in the table of concomitant
medications to be used with caution
(Table 4). More general
recommendation to consider
alternative medications or adjusted
doses was provided in this table per
HA request.
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10.13. Appendix 13: NA Re-treatment and Monitoring After Stopping of NA
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11. 
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disoproxil fumarate in non-cirrhotic HBeAg-negative patients—FINITE study. J Hepatol. 2017;67:918-924.
2. Brooks ST, Whitely E, Egger M, Smith GD, Mulheran PA, Peters TJ. Subgroup analyses in randomized trials:
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3. Buti M, Wong DK, Gane E, et al. Safety and efficacy of stopping tenofovir disoproxil fumarate in patients with
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4. Cohen SM, Johansson SL, Arnold LL, Lawson TA. Urinary tract calculi and thresholds in carcinogenesis. Food
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5. European Association for the Study of the Liver. EASL Clinical Practice Guidelines on the management of
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8. Fang Z, Li J, Yu X, et al. Polarization of monocytic myeloid-derived suppressor cells by hepatitis B surface
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9. Ford N, Scourse R, Lemoine M, et al. Adherence to Nucleos(t)ide Analogue Therapies for Chronic Hepatitis B
Infection: A systematic review and meta-analysis. Hepatol Commun. 2018;2(10):1160-1116.
10. Hadziyannis SJ, Sevastianos,V, Rapti I, Vassilopoulos D, Hadziyannis E. Sustained responses and loss of
HBsAg in HBeAg-negative patients with chronic hepatitis B who stop longterm treatment with adefovir.
Gastroenterology. 2012;143:629-636.
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12. Höner Zu Siederdissen C, Hui AJ, Sukeepaisarnjaroen W, et al. Contrasting timing of virological relapse after
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14. Investigator’s Brochure: JNJ-73763989 Edition 3. Janssen Research & Development (May 2019).
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16. Investigator’s Brochure: JNJ-56136379 Edition 4, Addendum 1. Janssen Research & Development (May 2019).
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therapeutics in subacute studies. Toxicologic Pathology. 2018;46(7):735-745.
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19. Jeng W-J, Yang H-I, Chen Y-C, et al. Increased incidence of HBsAg seroclearance in HBeAg negative chronic
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20. Kuo MT, Hu TH, Hung CH, et al. Hepatitis B virus relapse rates in chronic hepatitis B patients who discontinue
either entecavir or tenofovir. Aliment Pharmacol Ther. 2019;49(2):218-228.
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21. Lee M, Keeffe EB. Study of adherence comes to the treatment of chronic hepatitis B. J Hepatol. 2011;54:6–8.
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23. Li H, Zhai N, Wang Z, et al. Regulatory NK cells mediated between immunosuppressive monocytes and
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24. Lok AS, Zoulim F, Dusheiko G, Ghany MG. Hepatitis B cure: from discovery to regulatory approval.
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25. Mantel N and Haenszel W. Statistical aspects of the analysis of data from retrospective studies of disease. J Natl
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27. Memorandum to Advisory Committee Members and Guests from Entecavir Review Team. Briefing document
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28. 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.
29. Papatheodoridis G, Vlachogiannakos I, Cholongitas E, et al. Discontinuation of oral antivirals in chronic
hepatitis B: a systematic review. Hepatology. 2016;63(5):1481-1492.
30. Scaglione SJ, Lok AS. Effectiveness of hepatitis B treatment in clinical practice. Gastroenterology.
2012;142:1360-1368.
31. Sorrell MF, Belongia EA, Costa J, et al. National Institutes of Health Consensus Development Conference
Statement: Management of hepatitis B. Ann Intern Med. 2009;150:104–110.
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. US Food and Drug Administration. Guidance for Industry. Patient-Reported Outcome Measures: Use in
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measure-use-medical-product-development-support-labeling-claims. Accessed on 4 June 2019.
34. Van Hees S, Chi H, Hansen B, et al. Sustained off-treatment viral control is associated with high hepatitis B
surface antigen seroclearance rates in Caucasian patients with nucleos(t)ide analogue–induced HBeAg
seroconversion. J Viral Hepat. 2019;26(6):766–769.
35. 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.
36. Woo G, Tomlinson G, Nishikawa Y, et al. TDF and ETV are the most effective antiviral agents for chronic
hepatitis B: A systematic review and Bayesian meta-analyses. Gastroenterology. 2010;139:1218–1229.
37. 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).
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39. Zumbo BD, Chan EKH. Validity and Validation in Social, Behavioral, and Health Sciences. Springer Press;
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41. Investigator’s Brochure: JNJ-73763989 Edition 3, Addendum 1. Janssen Research & Development
(January 2020).
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2020).
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INVESTIGATOR AGREEMENT
I have read this protocol and agree that it, in conjunction with the accompanying Master Protocol,
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 course of the study, written
notification will be provided by the investigator to the sponsor, and a protocol amendment will not be required.
PPD
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Signature
User 
Date 
Reason
26-Nov-2021
15:32:04
(GMT)
Document Approval
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Status: Approved,  Date: 25 May 2020
Janssen Research & Development *
Clinical Protocol
COVID-19 Appendix
Intervention-specific Appendix 2 to Master Protocol PLATFORMPAHPB2001
A Randomized, Double blind, Placebo-controlled Phase 2b Study to Evaluate Efficacy, 
Pharmacokinetics, and Safety of 48-week Study Intervention With 
JNJ-73763989+JNJ-56136379+Nucleos(t)ide Analog (NA) Regimen Compared to NA Alone 
in e Antigen-negative Virologically Suppressed Participants With Chronic Hepatitis B 
Virus Infection
REEF-2 study
Protocol 73763989PAHPB2002; Phase 2b
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: 2019-002674-31
Status:
Approved  
Date:
25 May 2020
Prepared by:
Janssen Research & Development, a division of Janssen Pharmaceutica NV  
EDMS number:
EDMS-RIM-66038, 2.0
THIS APPENDIX APPLIES TO ALL CURRENT APPROVED VERSIONS OF PROTOCOL
73763989PAHPB2002 (EDMS-ERI-188471315)
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.
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Status: Approved,  Date: 25 May 2020
COVID-19 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 case report form (CRF). 
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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Status: Approved,  Date: 25 May 2020
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.
Screening and Randomization:

Enrollment of new participants may continue based on the investigator’s assessment of risks 
versus benefits, depending on the situation at a particular site, and the ability to monitor 
participant safety. 

Baseline visits for participants recently screened for this study should be postponed if the 
current situation does not allow for an orderly conduct of the study.
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 investigator. Where DTP shipments or handover to 
delegates are deemed necessary, the process must be coordinated between the site and sponsor
staff following DTP procedures for arranging shipment and adhering to associated approvals 
and documentation requirements.

JNJ-3989/placebo should always be administered by an unblinded nurse at the study site or, if 
site visits are not possible, at the participant’s home. Per protocol amendment 1, if a scheduled 
injection of JNJ-3989/placebo 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 
NCT04129554


COVID-19 Appendix
JNJ-73763989
Clinical Protocol 73763989PAHPB2002
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
4
Status: Approved,  Date: 25 May 2020
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 used for the treatment of COVID-19. 

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.
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 maintain 
treatment blinding, HBsAg, HBeAg, anti-HBs and anti-HBe antibody tests during the study 
intervention phase cannot be done locally (unless instructed otherwise by the sponsor).

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

Collecting patient-reported outcomes (where appropriate translations and licensing are 
available)

If JNJ-3989/placebo is administered at the patient’s home, it will need to be done by an 
unblinded nurse (who received study-specific training)

Delivering oral study interventions

Any data related to adverse events, concomitant medication, vital signs, and ECGs will be 
reviewed and assessed by the investigator.

In addition, participants may have tele-health visits conducted by blinded qualified site 
personnel via phone or video conversation as per local regulation. Assessments may include 
review of adverse events (including injection site reactions), concomitant medications, study 
intervention accountability. Participants will also be questioned regarding general health status 
to fulfill any physical examination requirement. Patient-reported outcomes may be collected 
(where appropriate translations and licensing are available) following the Site Assisted 
Administration Process Guidance.
NCT04129554


COVID-19 Appendix
JNJ-73763989
Clinical Protocol 73763989PAHPB2002
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
5
Status: Approved,  Date: 25 May 2020

Procedures and timings should follow the Schedule of Activities as closely as possible. 
Standard Adverse Event/Serious Adverse Event reporting requirements apply.
Informed consent:

Consenting and re-consenting of participants for the measures taken (including also remote 
consenting by phone or video consultation) will be performed as applicable 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 visits and 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.
NCT04129554


COVID-19 Appendix
JNJ-73763989
Clinical Protocol 73763989PAHPB2002
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
6
Status: Approved,  Date: 25 May 2020
INVESTIGATOR AGREEMENT
I have read this document 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 course of the study, written 
notification will be provided by the investigator to the sponsor, and a protocol amendment will not be required.
PPD
NCT04129554


Signature
User
Date
Reason
26-May-2020
06:49:59
(GMT)
Document Approval
PPD
NCT04129554

SAP_001.pdf: 
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
1
Status: Approved, Date: 08 July 2022
Janssen Research & Development
Statistical Analysis Plan
Intervention-specific Appendix 2 to Master Protocol PLATFORMPAHPB2001
A Randomized, Double blind, Placebo-controlled Phase 2b Study to Evaluate Efficacy, 
Pharmacokinetics, and Safety of 48-week Study Intervention With JNJ 73763989+JNJ 
56136379+Nucleos(t)ide Analog (NA) Regimen Compared to NA Alone in HBe Antigen 
negative Virologically Suppressed Participants With Chronic Hepatitis B Virus Infection
The REEF-2 Study
Protocol 73763989PAHPB2002; Phase 2b
JNJ-73763989 and JNJ-56136379
Status:
Approved
Date:
08 July 2022
Prepared by:
Janssen Research & Development, a division of Janssen Pharmaceutica NV
Document No.: EDMS-ERI-200976680, 2.0
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.
NCT04129554


JNJ-73763989 and JNJ-56136379  
Statistical Analysis Plan 73763989PAHPB2002
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
2
Status: Approved, Date: 08 July 2022
TABLE OF CONTENTS
TABLE OF CONTENTS ............................................................................................................................... 2
AMENDMENT HISTORY.............................................................................................................................. 6
ABBREVIATIONS ........................................................................................................................................ 8
1.
INTRODUCTION................................................................................................................................ 10
1.1.
Trial Objectives and Endpoints ...................................................................................................... 10
1.2.
Trial Design .................................................................................................................................... 12
1.3.
Statistical Hypotheses for Trial Objectives..................................................................................... 13
1.4.
Sample Size Justification ............................................................................................................... 13
1.5.
Randomization and Blinding .......................................................................................................... 14
2.
GENERAL ANALYSIS DEFINITIONS .............................................................................................. 14
2.1.
Analysis Phases and Visit Windows .............................................................................................. 14
2.1.1.
Analysis Phase ........................................................................................................................... 14
2.1.2.
Relative Day by Study Phase ..................................................................................................... 15
2.1.2.1.
Double Blind Relative Day....................................................................................................... 15
2.1.2.2.
Follow Up Relative Day ........................................................................................................... 15
2.1.3.
Analysis Visits and Time Points.................................................................................................. 15
2.2.
Baseline ......................................................................................................................................... 17
2.3.
Analysis Sets.................................................................................................................................. 17
2.4.
Definition of Subgroups.................................................................................................................. 18
2.4.1.
Subgroups for Efficacy Analyses................................................................................................ 18
2.4.2.
Subgroups for Safety Analyses .................................................................................................. 19
2.5.
Missing and Partial Dates Imputation Rules .................................................................................. 20
2.5.1.
Adverse Event Dates.................................................................................................................. 20
2.5.2.
HBV Diagnosis and Infection Dates ........................................................................................... 21
2.5.3.
Prior and Concomitant Medication Dates................................................................................... 21
2.5.4.
Alcohol Dates.............................................................................................................................. 21
3.
INTERIM ANALYSIS AND DATA MONITORING COMMITTEE REVIEW....................................... 22
3.1.
Interim Analysis.............................................................................................................................. 22
3.2.
Independent Flares Monitoring ...................................................................................................... 22
4.
SUBJECT INFORMATION................................................................................................................ 22
4.1.
Disposition Information................................................................................................................... 23
4.2.
Demographics and Baseline Characteristics ................................................................................. 23
4.2.1.
Demographic Characteristics ..................................................................................................... 24
4.2.2.
Baseline Characteristics ............................................................................................................. 24
4.3.
Medical History............................................................................................................................... 26
4.4.
Prior and Concomitant Medications ............................................................................................... 26
4.5.
Protocol Deviations ........................................................................................................................ 27
4.6.
Extent of Exposure......................................................................................................................... 27
4.7.
Treatment Compliance................................................................................................................... 28
5.
EFFICACY ......................................................................................................................................... 28
5.1.
Analysis Specifications................................................................................................................... 29
5.1.1.
Level of Significance................................................................................................................... 29
5.1.2.
Data Handling Rules................................................................................................................... 29
5.2.
Primary Efficacy Endpoint.............................................................................................................. 30
5.2.1.
Definition..................................................................................................................................... 30
5.2.2.
Main Estimand for the Primary Endpoint.................................................................................... 30
5.2.2.1.
Main Estimator......................................................................................................................... 31
5.2.2.1.1.
Analysis Methods ................................................................................................................. 31
NCT04129554


JNJ-73763989 and JNJ-56136379  
Statistical Analysis Plan 73763989PAHPB2002
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
3
Status: Approved, Date: 08 July 2022
5.2.2.1.2.
Data Included ....................................................................................................................... 31
5.2.2.1.3.
Assumptions......................................................................................................................... 31
5.2.2.1.4.
Missing Data Handling Rule................................................................................................. 31
5.2.2.2.
Sensitivity Estimators of the Main Estimand ........................................................................... 32
5.2.2.2.1.
Sensitivity Estimator 1 For the Main Estimand (Homogeneity Assumption)........................ 32
5.2.2.2.1.1.
Assumptions...................................................................................................................... 33
5.2.2.2.1.2.
Analysis Methods.............................................................................................................. 33
5.2.2.2.2.
Sensitivity Estimator 2 For the Main Estimand (LOCF) ....................................................... 33
5.2.2.2.2.1.
Assumptions...................................................................................................................... 33
5.2.2.2.2.2.
Missing Data Handling Rule.............................................................................................. 33
5.2.2.2.3.
Sensitivity Estimator 3 For the Main Estimand (Missing as Non-response) ........................ 34
5.2.2.2.3.1.
Assumptions...................................................................................................................... 34
5.2.2.2.3.2.
Missing Data Handling Rule.............................................................................................. 34
5.2.2.2.4.
Sensitivity Estimator 4 For the Main Estimand (Tipping Point)............................................ 34
5.2.2.2.4.1.
Assumptions...................................................................................................................... 34
5.2.2.2.4.2.
Missing Data Handling Rule.............................................................................................. 34
5.2.2.3.
Supplementary Estimators of the Main Estimand ................................................................... 35
5.2.2.3.1.
Supplementary Estimator 1 (ITT Analysis Set + MI)............................................................ 35
5.2.2.3.2.
Supplementary Estimator 2 (ITT Analysis Set + LOCF) ...................................................... 35
5.2.2.3.3.
Supplementary Estimator 3 (ITT Analysis Set + Missing as Non-Response)...................... 35
5.2.2.3.4.
Supplementary Estimator 4 (ITT Analysis Set + Tipping Point)........................................... 36
5.2.3.
Supplementary Estimand for the Primary Endpoint (Per-Protocol Analysis Set)....................... 36
5.2.3.1.
Main Estimator......................................................................................................................... 36
5.2.3.1.1.
Analysis Methods ................................................................................................................. 36
5.2.3.1.2.
Data Included ....................................................................................................................... 37
5.2.3.1.3.
Assumptions......................................................................................................................... 37
5.2.3.1.4.
Missing Data Handling Rule................................................................................................. 37
5.2.4.
Subgroup Analyses of the Primary Endpoint.............................................................................. 37
5.3.
Major Secondary Endpoints........................................................................................................... 38
5.3.1.
Definitions ................................................................................................................................... 38
5.3.1.1.
Binary Endpoints ..................................................................................................................... 38
5.3.1.1.1.
HBsAg Seroclearance.......................................................................................................... 38
5.3.1.1.2.
Suppressed HBV DNA ......................................................................................................... 39
5.3.1.1.3.
Thresholds Based on HBsAg and HBV DNA....................................................................... 39
5.3.1.1.4.
HBsAg Seroconversion........................................................................................................ 39
5.3.1.1.5.
HBsAg and HBV DNA cut-offs ............................................................................................. 40
5.3.1.1.6.
Flares ................................................................................................................................... 40
5.3.1.1.7.
Virologic Breakthrough......................................................................................................... 42
5.3.1.1.8.
NA Re-Treatment Criteria During Follow-Up ....................................................................... 42
5.3.1.1.9.
ALT Normalization................................................................................................................ 43
5.3.1.2.
Continuous Endpoints ............................................................................................................. 43
5.3.1.3.
Time to Event Endpoints ......................................................................................................... 43
5.3.1.3.1.
First HBsAg Seroclearance.................................................................................................. 43
5.3.1.3.2.
Time to Flare ........................................................................................................................ 44
5.3.1.3.3.
Time to Virologic Breakthrough............................................................................................ 44
5.3.1.4.
Endpoints for Correlation......................................................................................................... 44
5.3.2.
Analysis Methods........................................................................................................................ 46
5.3.2.1.
Binary Endpoints ..................................................................................................................... 46
5.3.2.1.1.
Suppressed HBV DNA ......................................................................................................... 46
5.3.2.1.2.
HBsAg Seroconversion........................................................................................................ 46
5.3.2.1.3.
Flares ................................................................................................................................... 47
5.3.2.1.4.
NA Re-Treatment Criteria During Follow-Up ....................................................................... 47
5.3.2.2.
Continuous Endpoints ............................................................................................................. 47
5.3.2.2.1.
HBsAg and HBV DNA .......................................................................................................... 47
5.3.2.3.
Time to Event Endpoints ......................................................................................................... 48
5.3.2.4.
Endpoints for Correlation......................................................................................................... 49
5.4.
Exploratory Endpoints.................................................................................................................... 49
5.4.1.
Definitions ................................................................................................................................... 49
NCT04129554


JNJ-73763989 and JNJ-56136379  
Statistical Analysis Plan 73763989PAHPB2002
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
4
Status: Approved, Date: 08 July 2022
5.4.1.1.
Binary Endpoints ..................................................................................................................... 49
5.4.1.1.1.
Partial Cure .......................................................................................................................... 49
5.4.1.1.2.
HBV RNA and HBcrAg......................................................................................................... 49
5.4.1.1.3.
Anti-HBe Antibodies ............................................................................................................. 50
5.4.1.1.4.
Impact of Finite Treatment Duration on Functional Cure..................................................... 50
5.4.1.1.5.
Treatment Failure................................................................................................................. 51
5.4.1.2.
Continuous Endpoints ............................................................................................................. 51
5.4.1.2.1.
Decline in HBsAg and HBV DNA Levels.............................................................................. 51
5.4.1.3.
Time to Event Endpoints ......................................................................................................... 51
5.4.1.3.1.
HBV RNA <LOD................................................................................................................... 51
5.4.1.3.2.
HBcrAg Undetectability ........................................................................................................ 52
5.4.1.3.3.
Time to Appearance of Anti-HBs Antibodies........................................................................ 52
5.4.1.3.4.
Time to Appearance of Anti-HBe Antibodies ....................................................................... 52
5.4.2.
Analysis Methods........................................................................................................................ 53
5.4.2.1.
Binary Endpoints ..................................................................................................................... 53
5.4.2.2.
Continuous Endpoints ............................................................................................................. 53
5.4.2.2.1.
Fibrosis................................................................................................................................. 53
5.4.2.2.2.
HBV RNA and HBcrAg......................................................................................................... 53
5.4.2.2.3.
Anti-HBs ............................................................................................................................... 54
5.4.2.3.
Time to Event Endpoints ......................................................................................................... 54
6.
SAFETY............................................................................................................................................. 54
6.1.
Adverse Events .............................................................................................................................. 54
6.1.1.
Definitions ................................................................................................................................... 54
6.1.2.
Analysis Methods........................................................................................................................ 55
6.1.3.
Adverse Events of Special Interest............................................................................................. 55
6.2.
Clinical Laboratory Tests................................................................................................................ 56
6.2.1.
Definitions ................................................................................................................................... 56
6.2.2.
Analysis Methods........................................................................................................................ 58
6.2.3.
Creatinine and Glomerular Filtration........................................................................................... 58
6.2.3.1.
eGFR ....................................................................................................................................... 58
6.2.3.2.
Proximal Renal Tubular Function ............................................................................................ 59
6.3.
Electrocardiogram.......................................................................................................................... 61
6.3.1.
Definitions ................................................................................................................................... 61
6.3.2.
Analysis Methods........................................................................................................................ 61
6.4.
Vital Signs and Body Temperature ................................................................................................ 62
6.4.1.
Definitions ................................................................................................................................... 62
6.4.2.
Analysis Methods........................................................................................................................ 63
6.5.
Physical Examination..................................................................................................................... 63
7.
VIRAL GENOME SEQUENCE ANALYSIS....................................................................................... 64
7.1.
Time Points and Samples .............................................................................................................. 64
7.2.
Definitions ...................................................................................................................................... 64
7.3.
Parameters to Analyze................................................................................................................... 65
7.4.
Positions & Genetic Variations of Interest...................................................................................... 66
7.5.
Analysis Methods ........................................................................................................................... 68
7.5.1.
Post-Baseline.............................................................................................................................. 68
7.5.2.
Over the Study Period ................................................................................................................ 69
7.6.
HBV genotype ................................................................................................................................ 69
8.
PHARMACOKINETICS/PHARMACODYNAMICS ........................................................................... 70
8.1.
Pharmacokinetics........................................................................................................................... 70
8.2.
Pharmacokinetic/Pharmacodynamic Relationships....................................................................... 70
8.3.
Immune Response......................................................................................................................... 70
9.
PATIENT-REPORTED OUTCOMES................................................................................................. 70
9.1.
HBV-specific Self-stigma PRO Scale............................................................................................. 71
9.1.1.
Definition..................................................................................................................................... 71
NCT04129554


JNJ-73763989 and JNJ-56136379  
Statistical Analysis Plan 73763989PAHPB2002
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
5
Status: Approved, Date: 08 July 2022
9.1.2.
Analysis Methods........................................................................................................................ 71
9.2.
5-Level EuroQol 5-Dimension Questionnaire ................................................................................ 71
9.2.1.
Definition..................................................................................................................................... 71
9.2.2.
Analysis Methods........................................................................................................................ 72
REFERENCES............................................................................................................................................ 74
ATTACHMENTS......................................................................................................................................... 75
Attachment 1.
Selected Major Protocol Deviations For Analysis Purposes.......................................... 75
Attachment 2.
Adverse Events of Special Interest List of Preferred Terms.......................................... 77
Attachment 3.
EQ-5D-5L Crosswalk Value Sets................................................................................... 83
NCT04129554


JNJ-73763989 and JNJ-56136379  
Statistical Analysis Plan 73763989PAHPB2002
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
6
Status: Approved, Date: 08 July 2022
AMENDMENT HISTORY
Document History
Document
Date
Amendment 1
This document
Original SAP
05 February 2021
Overall rationale for Amendment 1: This administrative amendment incorporates additional 
clarifications on endpoints, data handling rules, and analysis timepoints and intervals that have 
previously been documented in the Data Presentation Specification for past interim analyses.
Clarifications, Additions, Corrections
Section Number and Name
Description of Change
Rationale
2.1.1 Analysis Phase
Revised logic for deriving the end 
date of the Double-blind phase.
Previous logic did not account for 
subjects potentially continuing NA 
treatment after end of Double-blind 
phase.
2.1.3 Analysis Visits and 
Time Points
Revised Table 2 to incorporate new 
visits at Follow-up Weeks 28, 32, 40, 
and 44.
Protocol Amendment 3 (finalized 30 
September 2021) added new visits to 
allow more frequent monitoring of NA 
re-treatment criteria.
5.1.2 Data Handling Rules
Revised ULOQ and Imputed Values 
data cutpoints for HBsAg and 
HBeAg.
Update from Central Laboratory.
5.3.1.1.5 HBsAg and HBV 
DNA cut-offs
Added new HBV DNA cut-off: 
100,000 IU/mL.
Cut-off added to align with revised NA 
re-treatment criteria in Protocol 
Amendment 4 (finalized 26 November 
2021).
5.3.1.1.6 Flares
5.3.2.1.3 Flares
Revised definitions for virologic,
biochemical, and clinical flares.
The definition of flares was updated 
after approval of the original SAP (dated
05 February 2021). Updates included to 
clearly define the stop time of the flare. 
Biochemical flares was also updated to 
account for summarizing flares after NA 
re-treatment. A new HBV DNA 
threshold was added for virologic and 
clinical flares (Derivation 1): 100,000 
IU/mL.
5.3.1.1.7 Virologic 
Breakthrough
Updated definition for virologic 
breakthrough.
Additional clarification needed in 
definition.
5.3.1.1.9 ALT 
Normalization
Updated definition for ALT elevation.
Definition updated to account for 
subjects who may have ALT=ULN.
NCT04129554


JNJ-73763989 and JNJ-56136379  
Statistical Analysis Plan 73763989PAHPB2002
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
7
Status: Approved, Date: 08 July 2022
Clarifications, Additions, Corrections
Section Number and Name
Description of Change
Rationale
5.3.1.2 Continuous 
Endpoints
Specified analysis of changes in 
HBsAg from both EOT and Week 48 
in follow-up.
Additional analysis for HBsAg was 
decided to be performed after approval 
of the original SAP (dated 05 February 
2021)
5.3.1.3.1 First HBsAg 
Seroclearance
5.4.1.3 Time to Event 
Endpoints
Some time-to-event endpoints will 
also be analyzed by censoring at NA
re-treatment.
Sensitivity analysis.
5.4.1.1.5 Treatment Failure
Defined treatment failure at Week 96.
The original SAP defined treatment 
failure only at Week 72, yet described 
analyses of treatment failure at Weeks 
72 and 96.
7.4 Positions & Genetic 
Variations of Interest
Added lists of genetic variations for 
JNJ-3976 and JNJ-3924.
Updated list requested by Virology.
Attachment 1. Selected 
Major Protocol Deviations 
For Analysis Purposes
Specified how to determine if a 
subject has the major protocol 
deviation “Efficacy evaluation not 
done at Week 72” as listed in 
Attachment 1 Sequence No. 25.
Algorithm updated to not only check 
DV.DVCRIT records, but also the 
central lab data.
NCT04129554


JNJ-73763989 and JNJ-56136379  
Statistical Analysis Plan 73763989PAHPB2002
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
8
Status: Approved, Date: 08 July 2022
ABBREVIATIONS
AE
adverse event
ALT
alanine aminotransferase
AST
aspartate aminotransferase
ATC
anatomic and therapeutic class
BMI
body mass index
CHB
chronic hepatitis B
CI
confidence interval
CRF
case report form
CV
coefficient of variation
DAIDS
division of acquired immunodeficiency syndrome
DB
double blind
ECG
electrocardiogram
EOS
end of study
EOT
end of treatment
eCRF
electronic case report form
ETV
entecavir
HBcrAg
hepatitis B core-related antigen 
HBe
hepatitis B envelope
HBs
hepatitis B surface
HBeAg
hepatitis B envelope antigen
HBsAg
hepatitis B surface antigen
HBV
hepatitis B virus
HBV DNA
hepatitis B virus deoxyribonucleic acid
HBV RNA
hepatitis B virus ribonucleic acid
HIV-1(-2)
human immunodeficiency virus type 1 (type 2)
ICE
intercurrent event
ICS
intracellular cytokine staining
IDMC
independent data monitoring committee
iFLEP
independent flares expert panel
IQR
interquartile range
ISA
intervention-specific appendix
ISR
injection site reaction
ITT
Intent-to-treat
IU/mL
international units per milliliter
IWRS
interactive website response system
LLOQ
lower limit of quantification
LOCF
last observation carried forward
MedDRA
medical dictionary for regulatory activities
MH
Mantel-Haenszel
mITT
modified intent-to-treat
NA
nucleos(t)ide analog
NGS
next generation sequencing
PBMC
peripheral blood mononuclear cell
PC
precore
PD
pharmacodynamic(s)
PK
pharmacokinetic(s)
PP
per protocol
PRO
patient-reported outcomes
QTcF
QT interval corrected for heart rate according to Fridericia
RR
Interval between R wave of one heartbeat and R wave of preceding heartbeat
SAE
serious adverse event
SAP
statistical analysis plan
SD
standard deviation
TEAE
treatment-emergent adverse event
TAF
tenofovir alafenamide
TD
target detected
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TDF
tenofovir disoproxil fumarate
TND
target not detected
TNF
tumor necrosis factor
ULN 
upper limit of normal
WBC
white blood cell
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JNJ-73763989 and JNJ-56136379  
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Status: Approved, Date: 08 July 2022
1.
INTRODUCTION
This statistical analysis plan (SAP) for the 73763989PAHPB2002 phase 2b trial describes the 
statistical analyses and definitions to assess the efficacy and safety of study interventions including 
JNJ-73763989 (200 mg), JNJ-56136379 (250 mg), and Nucleos(t)ide analogs (NA) in hepatitis B 
e antigen (HBeAg) negative virologically suppressed participants with chronic hepatitis B (CHB). 
In the rest of the document the abbreviations JNJ-3989 and JNJ-6379 are used to refer to the 
treatments JNJ-73763989 and JNJ-56136379, respectively.
This study is part of the platform trial PLATFORMPAHPB2001in participants with CHB. The 
protocol amendment for 73763989PAHPB2002 constitutes the Intervention-specific Appendix
(ISA) that describes all the specific and/or additional features of this study complementing the 
common design elements of the platform trial described in the Master Protocol. 
This SAP is to be interpreted in conjunction with the ISA Amendment-2 finalized on 27 January 
2020, and with the Master Protocol Amendment-2 for PLATFORMPAHPB2001 finalized on 27 
January 2020.
Due to the global impact of the pandemic Coronavirus Disease 2019 (COVID-19), the study team 
has decided to define the primary analysis set for efficacy as the modified Intention-to-Treat 
(mITT) analysis set, which excludes from the ITT set all participants impacted by the pandemic 
defined as those participants who, because of COVID-19 or similar pandemics related reasons, 
withdrew prematurely from the study prior to Week 72, or had no efficacy assessment for the 
primary endpoint.
Details of the pharmacokinetic (PK) and pharmacokinetic/pharmacodynamics (PK/PD) analyses 
will be described in a separate analysis and modeling plan.
1.1.
Trial Objectives and Endpoints
Objectives
Endpoints
Primary

To evaluate the efficacy of 48-week study 
intervention 
with 
JNJ-3989+JNJ-6379+NA 
regimen compared to NA alone.

Proportion of participants with HBsAg 
seroclearance at Week 72 (ie, 24 weeks 
after completion of all study interventions 
at Week 48) without restarting NA 
treatment.
Secondary

To evaluate the safety and tolerability of the 
study intervention throughout the study.

Safety and tolerability including but not 
limited to the 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.
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Objectives
Endpoints

To evaluate the efficacy of the study intervention 
at the end of treatment.

Proportion of participants with HBsAg 
seroclearance at Week 48.

Proportion of participants with HBV DNA 
<LLOQ at Week 48.

To evaluate the efficacy as measured by blood 
markers (such as HBsAg, HBV DNA, and ALT) 
during study intervention and follow-up.

Proportion of participants with HBsAg 
seroclearance at Week 96 (ie, 48 weeks 
after completion of all study interventions 
at Week 48) without restarting NA 
treatment.

Proportion of participants with HBsAg 
seroclearance 24 weeks after stopping all 
study interventions without restarting NA 
treatment.

Proportion of participants with HBsAg 
seroclearance 48 weeks after stopping all 
study interventions without restarting NA 
treatment.

Proportion of participants with (sustained) 
reduction, 
suppression, 
and/or 
seroclearance considering single and 
multiple markers (such as HBsAg, HBV 
DNA and ALT).

Proportion of participants with HBsAg 
seroconversion.

Change from baseline over time in HBsAg 
and HBV DNA.

Time 
to 
achieve 
first 
HBsAg 
seroclearance.

Proportion of participants with HBsAg 
levels and/or changes from baseline 
below/above different cut-offs (eg, HBsAg 
<100 IU/mL or >1 log10 IU/mL reduction 
in HBsAg from baseline).

Proportion of participants with HBV DNA 
levels and/or changes from baseline 
below/above 
different 
cut-offs 
(eg, 
<LLOQ of the assay). 

Proportion of participants with flares 
(virologic, biochemical, and clinical).

To 
evaluate 
the 
frequency 
of 
virologic 
breakthrough during study intervention.

Proportion of participants with virologic 
breakthrough.

To evaluate the proportion of participants 
requiring NA re-treatment during follow-up.

Proportion of participants who meet the 
NA re-treatment criteria.
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Status: Approved, Date: 08 July 2022
Objectives
Endpoints

To identify baseline and on-treatment markers 
associated with sustained off-treatment response.

Correlation of baseline characteristics and 
baseline/on-treatment viral blood markers 
(such as baseline NA treatment duration, 
age, and baseline/on-treatment HBsAg 
levels) with selected off-treatment efficacy 
variables.

To evaluate the PK of JNJ-3989 (JNJ-3976 and 
JNJ-3924), JNJ-6379, and NA, as applicable.

Population PK parameters of JNJ-3989 
(JNJ-3976 and JNJ-3924), JNJ-6379, and 
NA, as applicable.
Exploratory

To evaluate the efficacy of NA re-treatment 
during follow-up.

Proportion of participants with decline in 
HBV DNA, ALT and/or HBsAg levels 
after restart of NA treatment during 
follow-up.

To explore changes in the severity of liver 
disease.

Changes 
in 
fibrosis 
(according 
to 
Fibroscan liver stiffness measurements) at 
end-of-study intervention (EOSI) and end 
of follow-up versus baseline.

To explore the efficacy in terms of changes in 
HBV RNA and HBcrAg levels.

Changes from baseline in HBV RNA and 
HBcrAg levels during study intervention 
and follow-up.

To explore the impact of study intervention on 
participants’ 
self-stigma 
and 
health-related 
quality of life using patient-reported outcomes 
(PROs) during study intervention and follow-up 
and to assess the psychometric properties of the 
HBV-specific self-stigma scale.

Changes over time in score on the 
HBV-specific self-stigma scale.

Psychometric 
properties 
of 
the 
HBV-specific self-stigma scale.

Changes over time in the 5-Level EuroQol 
5-Dimension (EQ-5D-5L) Visual Analog 
Scale (VAS) score and Index score.

To explore the relationship of PK with selected 
pharmacodynamic (PD) parameters of efficacy 
and safety.

Relationship of various PK parameters 
with 
selected 
efficacy 
and 
safety 
endpoints.

To explore the HBV genome sequence during 
study intervention and follow-up.

Assessment 
of 
intervention-associated 
mutations.

To explore HBV-specific T-cell responses during 
study intervention and follow-up.*

Changes from baseline in HBV-specific 
peripheral blood T-cell responses.
* Peripheral blood mononuclear cell (PBMC) samples for immune analyses will be collected at selected sites only.
1.2.
Trial Design
This is a Phase 2b, multicenter, randomized, double-blind, placebo-controlled, 2-arm parallel-
group 
study 
to 
evaluate 
the 
efficacy 
of 
48-week 
study 
intervention 
with 
a JNJ-3989+JNJ-6379+NA regimen compared to NA treatment alone, assessed by HBsAg 
seroclearance at Week 72 (ie, 24 weeks after completion of all study interventions at Week 48) 
without restarting NA treatment in HBeAg-negative virologically suppressed CHB-infected 
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participants who received NA treatment for at least 2 years prior to screening. All participants will 
stop all study interventions including NAs at Week 48 and will be followed up until Week 96. 
After completing this study, participants may have the option to enroll into a long-term follow-up 
study.
A target of 120 HBeAg-negative virologically suppressed CHB-infected male and female 
participants, 18-65 years (inclusive) of age, who received NA treatment for at least 2 years prior 
to screening will be randomized in a 2:1 ratio to one of the following intervention arms:

Arm 1 (N=80): 200 mg JNJ-3989 + 250 mg JNJ-6379 + NA 

Arm 2 (N=40): Placebo + Placebo + NA 
NA treatment refers to entecavir (ETV), or tenofovir disoproxil fumarate (TDF), or tenofovir 
alafenamide (TAF).
The study will be conducted in the following phases: 

Screening phase: 4 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.

Double-blind study intervention phase: from Day 1 (ie, baseline) up to Week 48. All 
participants who complete 48-week study intervention should stop all study interventions 
including NAs at Week 48.

Follow-up phase: for 48 weeks after the end of investigational intervention.
An Independent Data Monitoring Committee (IDMC) was commissioned for this study to monitor 
and review data in an unblinded manner on a regular basis to ensure the continuing safety of the 
study participants. The committee will meet periodically to review unblinded data, as well as the 
efficacy and safety results from the interim analyses (IAs) at prespecified time points (see Section 
3). A separate IDMC SAP describes details of the safety and efficacy analyses included in the 
IDMC periodical data reviews.
In addition, an independent Flare Expert Panel (iFLEP) was appointed for flares monitoring and 
adjudication. Details on the IDMC and iFLEP activities are described in their respective charter. 
1.3.
Statistical Hypotheses for Trial Objectives
The primary hypothesis of this study is that the combination regimen of JNJ-3989+JNJ-6379+NA 
is more efficacious than NA treatment alone, as measured by the primary efficacy endpoint, the 
proportion of participants with HBsAg seroclearance at Week 72 (ie, 24 weeks after completion 
of all study interventions at Week 48) without restarting NA treatment (ie, from Week 48 through 
Week 72).
1.4.
Sample Size Justification
The total study sample size is 120 participants who will be randomly assigned to one of the two 
intervention arms in a 2:1 ratio (JNJ-3989+JNJ-6379+NA: placebo+placebo+NA). Statistical 
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power to test the primary hypothesis was assessed using the Mantel-Haenszel test with a 1-sided 
Type 1 error rate of 0.05, assuming the observed percentage of participants with HBsAg 
seroclearance at Week 72 in the placebo+placebo+NA arm to be 5%. The sample size of 
80 participants in the investigational arm and 40 participants in the control arm provides >91% 
statistical power to detect a ≥20% difference in the primary endpoint.
1.5.
Randomization and Blinding
Randomization
Central randomization is implemented in this study. Participants will be randomly assigned in a 
2:1 ratio to 1 of 2 intervention arms (JNJ-3989+JNJ-6379+NA:placebo+placebo+NA). The 
randomization is stratified by screening HBsAg level (<1,000 IU/mL or >1,000 IU/mL), race 
(Asian versus non-Asian) and type of NA (TDF/TAF versus ETV).
Blinding
The investigators and participants will remain blinded to intervention allocation until all 
participants have reached Week 72 (or discontinued earlier), while the sponsor’s central study team 
will be unblinded at the time of the Week 48 IA.
Sponsor personnel involved in the pharmacokinetic and pharmacodynamic modelling will have 
access to the pharmacokinetic and pharmacodynamic data before formal unblinding for the 
primary analysis.
2.
GENERAL ANALYSIS DEFINITIONS
The SAP will use throughout the document the following definitions:

Study treatment refers to: JNJ-3989, JNJ-6379, placebo and NA (ETV, TDF, or TAF)

Study agent refers to: JNJ-3989, JNJ-6379, or placebo

Study intervention arm refers to: 

Arm 1: JNJ-3989 (200 mg) + JNJ-6379 (250mg qd) + NA

Arm 2: Placebo + Placebo + NA
2.1.
Analysis Phases and Visit Windows
2.1.1.
Analysis Phase
The analysis phases are defined in Table 1 below.
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 
Double-blind Study 
intervention 
Date of first study agent
intake
Maximum [Date of last study treatment (JNJ-3989/placebo or JNJ-
6379/placebo) intake, Week 48] + 5 daysa or cut-off dateb, 
whichever comes first
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Table 1: Analysis Phases Start and End Dates
Analysis phase
Start date
End date
Follow-up
End of the double-blind 
study intervention phase + 1 
day
The end date will be derived as trial termination date (date of last 
contact) or cut-off dateb, whichever comes first
a +5 days is only attributed to adverse events and concomitant medications.
b Cut-off dates will be defined to match the prespecified timepoints for IDMC safety monitoring, interim analyses, the 
primary analysis and the final analysis, respectively.
2.1.2.
Relative Day by Study Phase
An analysis relative day (ADY) will be calculated for all assessments at all visits for each 
participant.
2.1.2.1.
Double Blind Relative Day
Double Blind (DB) start date (DB Day 1) is defined as the date of first study intervention intake. 
If the date of the first study treatment administration differs among the treatments (e.g. JNJ-3989, 
JNJ-6379, or NA), the earliest administration date is used. All efficacy and safety assessments 
during the double-blind phase will be assigned a day relative to this date.
The DB study day in the double-blind treatment phase (ADY) is defined as:
DB ADY=visit date – DB start date+1
for visits on or after DB Day 1, and 
DB ADY=visit date – DB start date
for visits before DB Day 1 (Screening phase).
There is no ‘DB Day 0’.
2.1.2.2.
Follow Up Relative Day
Follow Up (FU) start date (FU Day 1) is defined in Table 1. All efficacy and safety assessments 
during the FU phase will be assigned a day relative to this date.
The FU study day in the FU treatment phase (ADY) is defined as:
FU ADY=visit date – FU start date+1
2.1.3.
Analysis Visits and Time Points
All visits for all assessments (safety, efficacy or PK) will be uniquely allocated within each phase 
to an analysis time point based on the analysis relative day (ADY) compared with the target day 
based on Table 2. All assignments will be made in chronological order. Once a visit is assigned to 
a visit window (Time interval in Table 2), it will no longer be used for a later time point except for 
the end of treatment (EOT) and the end of study (EOS) visits. If two or more visits fall within the 
same interval in the same phase, only one measurement will be selected for the analysis time point 
per phase in order to have only one evaluation per participant. The following rules will be applied: 
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1.
The measurement closest to the target day in that phase will be used. 
2.
If the measurements fall equidistant from the target day, the last measurement in chronological 
order within the interval will be used per phase.
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.
The listings will include all measurements, also those multiple assessments within the same visit 
window/phase. 
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.
Note: For the selection of the patient-reported outcome (PRO) measurements the above algorithm 
needs to be performed on the entire questionnaire (filled in at a specific date and time) and not on 
the individual questions /items (i.e., not mixing answers from different questionnaires)
Table 2 provides the analysis time points, time intervals for each visit per analysis phase.
Table 2:
Analysis Time Point and Time Intervals by Analysis Phase
Analysis phase
DB Target 
day
Analysis time 
point (Week)
Analysis time point
(label)
Time interval (DB days)
Screening
-∞
-1
Screening
<0
Double-blind 
Study 
intervention
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, 350]
last visit in 
double-blind 
phase
49*
EOT
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Table 2:
Analysis Time Point and Time Intervals by Analysis Phase
Follow-up
FU Target 
day
Analysis time 
point (Week)
Analysis time point
(label)
Time interval (FU days)
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, 190]
197
76
Follow-up Week 28**
[191, 204]
211
78
Follow-up Week 30
[205, 218]
225
80
Follow-up Week 32**
[219, 232]
253
84
Follow-up Week 36
[233, 274]
281
88
Follow-up Week 40**
[275, 288]
295
90
Follow-up Week 42
[289, 302]
309
92
Follow-up Week 44**
[303, 316]
337
96
Follow-up Week 48
[317, +∞]
last visit in 
the study
999*
EOS
*End of treatment (EOT) visit will be the last post-baseline visit in double-blind phase, and End of study (EOS) visit (last available data during the 
follow-up) will be the last visit in the study.
** Visits at Follow-up Weeks 28, 32, 40, and 44 were added to the study with Protocol Amendment 3 (finalized on 30 September 2021) to allow more 
frequent monitoring of NA re-treatment criteria. Consequently, the time intervals for Follow-up Weeks 30 and 42 have been shortened to create space 
for the new visits.
2.2.
Baseline
In general, the baseline assessment is defined as the last observed non-missing measurement before 
the date and time of the first administration of any of study treatments. 
In case the first administration time is missing, the first observed measurement on DB Day 1 will 
be used as the baseline measurement. If no observed measurement on DB Day 1, the last observed 
measurement before DB Day 1 will be used as the baseline assessment.
2.3.
Analysis Sets
All randomized analysis set: All participants who were randomized in the study. Participants will 
be analyzed according to the study intervention they were randomly assigned to.
Intent-to-Treat analysis set (ITT): All participants who were randomized in the study and received 
at least one dose of study treatment within this ISA. Participants will be analyzed according to the 
study intervention they were randomly assigned to.
Modified Intent-to-Treat analysis set (mITT): All participants who were randomized in the study 
and received at least one dose of study treatment excluding those participants impacted by the 
pandemic defined as those participants who, because of COVID-19 or similar pandemics related 
reasons, withdrew prematurely from the study prior to Week 72, or had no efficacy assessment for 
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the primary endpoint. COVID-19 or similar pandemics related reasons may include for example 
missed visits due to travel restriction, shortage of lab kits at the planned visit, missed collection of 
blood sample at key time points for the primary efficacy endpoint, etc. Participants will be 
analyzed according to the study intervention they were randomly assigned to.
Safety analysis set: All participants who received at least one dose of study treatment within this 
ISA. Participants will be analyzed according to the study intervention they actually received.
Per protocol analysis set (PP): All participants in the ITT analysis set who do not have any of the 
selected major protocol deviations that may affect the assessment of efficacy in terms of the 
primary endpoint at Week 72. 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 
Section 4.5 and Attachment 1. Participants will be analyzed according to the study intervention 
they were randomly assigned to.
The PK analysis set: All participants who have received at least one dose of study treatment and 
have at least one valid blood sample drawn for PK analysis.
2.4.
Definition of Subgroups
The following demographic and screening/baseline characteristics will be used to define subgroups 
of interest for efficacy analyses (primary endpoint) and selected safety analyses (see Sections 6.1.2
and 6.2.2).
Due to the small sample size of the study, only subgroups with approximately 10% of the 
population (i.e., 12 subjects total) within the level of the subgroup across intervention arms will 
be reported in summary tables. Nevertheless, interpretation should be done with caution in the 
event of small sample sizes within a subgroup.
2.4.1.
Subgroups for Efficacy Analyses

Sex: Male, Female

Age categories: ≤45 years, > 45 years

Type of NA at study entry – stratification levels: 

TDF/TAF

Entecavir (ETV) 

Type of NA at study entry – categorization levels

TDF

TAF

ETV 

Duration of NA (see Section 4.2.2): > 2 years to ≤4 years, > 4 years to ≤8 years, > 8 years

Race: Asian, non-Asian
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
HBsAg level at baseline – stratification levels: 

<1,000 IU/mL

≥1,000 IU/mL

HBsAg level at baseline – categorization levels: 

<1,000 IU/mL

≥1,000 IU/mL-<10,000 IU/mL

≥10,000 IU/mL

HBV DNA level at baseline: 

<LLOQ TND

< LLOQ TD

<LLOQ

≥LLOQ

HBV RNA level at baseline: 

Negative

< 1,000 copies /mL

≥1,000 copies /mL

HBcrAg level at baseline:

<3 log U/mL

≥3 log U/mL-<4 log U/mL

≥4 log U/mL

HBsAg Antibody (Anti-HBs) level at baseline:

<LLOQ

≥LLOQ

<10 mIU/mL

≥10 mIU/mL

Alanine Transferase (ALT) at baseline: ≤ 1.0 ULN, > 1.0 ULN - <2.5 ULN, ≥ 2.5 ULN

Anti-HBe antibody at baseline: Positive, Negative
2.4.2.
Subgroups for Safety Analyses

Age categories: ≤45 years, > 45 years

Sex: Male, Female

Type of NA at study entry: 

TDF
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
TAF

ETV

Duration of NA (see Section 4.2.2): > 2 years to ≤4 years, > 4 years to ≤8 years, > 8 years
2.5.
Missing and Partial Dates Imputation Rules
For analysis and reporting purposes, missing or partial dates in adverse event (AE onset date; AE 
end date), 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.
2.5.1.
Adverse Event Dates
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.
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JNJ-73763989 and JNJ-56136379  
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Status: Approved, Date: 08 July 2022
2.5.2.
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.
2.5.3.
Prior and 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 date 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 (DB Day 1) 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 treatment date.
If the medication was taken after study start (DB Day 1) 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 indicates 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 indicates as not ongoing. 
Generally, participants should only be taking one NA medication at a time. Therefore, the imputed 
dates will need further adjustment as to not overlap with the next adjacent NA taken.
2.5.4.
Alcohol Dates 
In case of partially missing 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 end date, further adjustment of the imputed start date is 
required. It will be imputed as the end date
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Status: Approved, Date: 08 July 2022

if end date is completely missing and marked as Ongoing then impute with randomization 
date. Otherwise, no imputation if completely missing.
3.
INTERIM ANALYSIS AND DATA MONITORING COMMITTEE REVIEW
The IDMC will conduct unblinded periodic data reviews to ensure the continuing safety of the 
study participants during the entire course of the study. Details on the roles and responsibilities of 
the IDMC, as well as data reviews and the flows of communication, are documented in the IDMC 
charter. The IDMC will also review the results of the interim analysis (IA) comprising cumulative 
safety and selected efficacy endpoints for providing the sponsor with further insight and 
interpretation of the data and the primary analysis. The timepoints of the safety reviews, and further 
details on the safety data and selected efficacy (HBV disease blood markers) are specified in a 
separate document, the IDMC SAP. 
3.1.
Interim Analysis
The one interim analysis will be conducted to monitor safety and evaluate the time course of 
different disease markers to support the sponsor’s interactions with health authorities, as well as 
inform decisions about additional studies and/or investigation of other treatment combinations. 
This IA is planned when all participants have completed Week 48 or discontinued earlier.
Up to two additional IAs may be performed at the sponsor’s discretion between Week 48 and 
Week 72 to support interactions with health authorities. Both primary and interim analysis will be 
based on all data available at the predefined cut-off time, including data at later time points for 
those participants who have reached subsequent visits.
The primary analysis will be conducted at the time when all participants have completed Week 72 
or discontinued earlier. 
The final analysis will be performed when all participants have completed the last study visit
(Week 96) or discontinued earlier.
This SAP covers the definitions of analysis sets, derived variables and statistical methods for the 
primary, and final analyses of this study.
3.2.
Independent Flares Monitoring
Flares in this study will be adjudicated by the independent Flares Expert Panel (iFLEP). The iFLEP 
flare adjudication results are sent to the IDMC Chairperson, and the information will include 
conclusions and review history for each flare. Additional details are provided in the iFLEP Charter 
document. Flares are defined in Section 5.3.1.1.6.
4.
SUBJECT INFORMATION
All the summaries will be done on the ITT analysis set unless specified otherwise for a specific 
display.
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Status: Approved, Date: 08 July 2022
4.1.
Disposition Information
The number and percentage of participants who are screened, screened failure and reason for that 
screening failure will be tabulated. Only an all participants group (total N) will be provided.
A summary of the number of participants randomized, randomized and not treated, in the safety, 
ITT, mITT and PP sets, respectively, will be summarized by intervention arm. 
Completion/withdrawal information, study disposition and treatment disposition will be 
summarized for both the ITT and safety sets (only for ITT set if the safety set is identical to ITT).
An overview of the study disposition will be provided by intervention arm 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. The number and percentage of participants under each phase (i.e. double-blind 
study intervention phase, and follow-up phase) will also be tabulated. 
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 IA 
or primary analysis cut-off (except the final analysis) will be presented by treatment and 
intervention arm. The incidences of treatment discontinuation reasons will also be summarized by 
study intervention arm for each treatment and overall. 
A listing including information (i.e. the date of last study visit, the last study phase and time point 
[phase and week], the date of discontinuation and the reason) on participants which prematurely 
discontinue from the study and/or study treatment will be included. Information on the NA re-
treatment will also be included.
4.2.
Demographics and Baseline Characteristics
Tabulations of demographic and baseline characteristics will be presented by intervention arm and 
overall for the ITT and PP analysis sets. Continuous variables will be summarized by descriptive 
statistics including the number of participants, mean, standard deviation, standard error, median, 
range and interquartile range. Categorical/binary variables will be summarized by counts and 
percentages.
Additional summaries will be presented by the 3 randomization stratification factors (HBsAg level, 
race and type of NA). The randomization stratification factors are reported by IWRS and also 
entered in the Electronic Case Report Form (eCRF). A cross–tabulation of the stratification factors
collected by the IWRS vs. eCRF will also be provided by intervention arm to identify any 
mismatch. In case of discrepancies between the 2 sources, the randomization factors as entered in 
the eCRF will be used in the analyses/summaries. If the eCRF data is missing, then the IWRS data 
will be used.
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JNJ-73763989 and JNJ-56136379  
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Status: Approved, Date: 08 July 2022
4.2.1.
Demographic Characteristics
The following demographic characteristics will be summarized by study intervention arm and 
overall. 

Sex: Male, Female, Unknown, Undifferentiated

Age (years)

Age categories: ≤30 years, >30-≤ 45years, > 45 years-≤60 years, >60 years

Race: American Indian or Alaska Native, Asian, Black or African American, Native Hawaiian 
or other Pacific Islander, White, Not reported, Unknown

In case the participant is Asian provide subgroup: Asian Indian, Chinese, Filipino, 
Japanese, Korean, Vietnamese, Other Asian

Ethnicity: Hispanic or Latino, Not Hispanic or Latino, Not Reported, Unknown

Country

Height at baseline (cm)

Weight at baseline (kg)

Body mass index (BMI) at baseline (kg/m2) = weight at baseline (kg) / (height at baseline
(m))2 (rounded to 1 decimal)

Body mass index group: Underweight <18.5, Normal ≥18.5-<25, Overweight ≥25-<30 and 
Obese ≥30           

History of Tobacco use: Yes/No 

Type of Substance (Beer, Wine, Distilled Spirits): Current/Former/Never

Type of Substance (Beer, Wine, Distilled Spirits) Duration (Months) = (stop date – start date 
+1)/30.4375; rounded to 1 decimal

Standard drinks containing alcohol (weekly period)
4.2.2.
Baseline Characteristics
For the viral activity parameters (e.g. HBsAg, HBV DNA), baseline values are used unless 
specified differently.

Duration of HBV infection (Years) = (date of randomization – date of HBV infection 
+1)/365.25; rounded to 1 decimal

Time since HBV diagnosis (Years) = (date of randomization
–
date of HBV 
diagnosis+1)/365.25; rounded to 1 decimal

Mode of HBV infection: Sexual transmission, intravenously injectable drug use, blood
transfusion, Hemophilia-associated injection, occupational exposure, mother to child 
transmission, unknown, and other

For HBeAg negative participants only: Time since HBeAg seroconversion (Years) = (date of 
randomization – date of HBeAg seroconversion+1)/365.25; rounded to 1 decimal. 
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Status: Approved, Date: 08 July 2022

Prior treatment for HBV infection: Lamivudine, Telbivudine, Adefovir, Tenofovir Disoproxil 
Fumarate (TDF), Tenofovir Alafenamide Fumarate (TAF), Entecavir, IFN, Other

Duration of NA (Years) = (Sum of all NA treatment duration [prior and current])/365.25; 
rounded to 1 decimal; calculated as: end date – start date +1. If the end date is missing for 
latest NA treatment, then the randomization date is used.

Type of NA at study entry: TDF, TAF, ETV

HBsAg at baseline (quantitative: IU/mL and log10 IU/mL)  

HBsAg level at baseline (quantitative: IU/mL):

Participants with HBsAg <100 IU/mL

Participants with HBsAg <500 IU/mL

Participants with HBsAg <1,000 IU/mL

Participants with HBsAg ≥1,000 IU/mL

Participants with HBsAg <10,000 IU/mL

Participants with HBsAg ≥10,000 IU/mL

HBV DNA at baseline (quantitative: IU/mL and log10 IU/mL)

HBV DNA category at baseline (quantitative: IU/mL):

Participants with HBV DNA < LLOQ (20 IU/mL) target detected (TD) and target not 
detected (TND)

Participants with HBV DNA < LLOQ (20 IU/mL) TD

Participants with HBV DNA < LLOQ (20 IU/mL) TND

Participants with HBV DNA ≥LLOQ - < 60 IU/mL

Participants with HBV DNA ≥ 60 IU/mL

HBV RNA (quantitative: copies/mL and log10 copies/mL)

HBV RNA category at baseline (quantitative: copies/mL):

Participants with HBV RNA TND

Participants with HBV RNA < limit of detection (LOD)

Participants with HBV RNA < 1000 copies /mL

Participants with HBV RNA < LLOQ

Participants with HBV RNA ≥LLOQ

Hepatitis B core related antigen (HBcrAg) at baseline (quantitative: log U/mL)

HBcrAg category at baseline (quantitative: log U/mL):

Participants with HBcrAg <3 log U/mL

Participants with HBcrAg ≥3 log U/mL-<4 log U/mL
NCT04129554


JNJ-73763989 and JNJ-56136379  
Statistical Analysis Plan 73763989PAHPB2002
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Status: Approved, Date: 08 July 2022

Participants with HBcrAg ≥4 log U/mL

HBsAg (Anti-HBs) status at baseline (qualitative): Positive/Negative

HBsAg Antibody (Anti-HBs) at baseline (quantitative: mIU/mL and log10 mIU/mL) 

HBsAg Antibody (Anti-HBs) category at baseline (quantitative: mIU/mL):

Participants with Anti-HBs <10 mIU/mL

Participants with Anti-HBs ≥10 mIU/mL

Alanine Transferase (ALT) at baseline:

Baseline ALT values (U/L))

Baseline ALT toxicity grade according to DAIDS

Baseline ALT categorization (≤ 1.0 ULN, > 1.0 ULN to <2.5 ULN, ≥ 2.5 ULN)

Fibroscan score at baseline (quantitative: kPa)

Fibrosis Stage: F0, F1, and F2

HBV genotype (using historical information or sequence based HBV genotyping data): 
Genotype A, B, C, D, E, F, G, H, I, J, and Unknown; 

Hemoglobin at baseline (quantitative: g/L)

Platelets at baseline (quantitative: 109//L)

GFR from Creatinine Adjusted for BSA at baseline (quantitative: mL/sec/m2)
4.3.
Medical History
A tabulation of the general medical history coded terms will be provided by body system class and 
by intervention arm.
4.4.
Prior and Concomitant Medications
All medications will be coded using the World Health Organization-Drug Dictionary. Tabulations 
will include prior and concomitant medications which are defined as follows:
(i)
Prior medications are defined as medications with a start date occurring before the date 
of DB Day 1 regardless of when dosing of the medication ended. 
(ii)
Concomitant medications are defined as medications received on or after DB Day 1, 
medication that was received before initial dosing and continued after initial dosing of 
the study interventions, or medication with missing stop date. 
Medication that started before the DB Day 1 and continued afterwards will be summarized both 
as prior and, separately, as concomitant medication. All concomitant medications will be allocated 
to one or multiple analysis phases depending on their start date and end date and also taking into 
account the eCRF flag to indicate if it is taken before/after study start or still ongoing.
(iii)
Concomitant medications of interest include the following categories:
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Status: Approved, Date: 08 July 2022

Oral contraceptives (hormonal contraceptive of systemic use)

Medications that impact immune system (e.g. corticosteroids, cyclosporin, interferon)

Medications that can be subject to CYP3A4 induction or CYP3A4 inhibition
A frequency tabulation of prior medications, and concomitant medications will be shown by 
Anatomical Therapeutic Chemical (ATC) class level 2, level 4 and preferred terms by intervention 
arm. In addition, the concomitant medications and cconcomitant medications of interest will be 
summarized by analysis phase. A listing of prior medications, concomitant medications, and 
concomitant medications of interest, respectively, will be also provided.
4.5.
Protocol Deviations
Only major protocol deviations will be summarized. 
Major protocol deviations and violations will be based on clinical review, but not limited to, the 
following criteria: (1) entered but did not satisfy criteria, (2) received wrong treatment or incorrect 
dose, (3) received a disallowed concomitant treatment, (4) developed withdrawal criteria but not 
withdrawn, (5) other. Protocol deviations will be closely monitored during the execution of the 
study and the final set of protocol deviation criteria will be finalized before the primary analysis 
database lock.
All major protocol deviations will be tabulated by coded term by intervention arm for the ITT 
analysis set. 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 1) will be identified and finalized prior to the primary database lock to define the Per-
Protocol population (Section 2.3). The number and percentage of ITT participants who are 
included in the PP analysis set will be summarized by intervention arm, accompanied by number 
and percentage of ITT participants who are excluded from the PP analysis set with the incidence 
of the major protocol deviations.
4.6.
Extent of Exposure
Extent of exposure to study treatments will be summarized and presented based on the safety 
analysis set. The total duration of exposure during the DB phase will be calculated by each study 
treatment (JNJ-3989/corresponding placebo, JNJ-6379/corresponding placebo, and NA) 
separately and summarized descriptively by intervention arm. The duration of treatment with NA 
will be summarized also for the follow up phase by intervention arm.
Because of the different route and frequency of treatment administration across the 3 agents (for 
JNJ-3989 one subcutaneous injection once every 4 weeks, and for JNJ-6379 and for NA once daily 
oral dosing) the total duration of exposure (weeks) will be calculated for each agent as follows: 

JNJ-3989/placebo: [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-73763989 and JNJ-56136379  
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Status: Approved, Date: 08 July 2022

JNJ-6379/placebo: (Min (Date of the last JNJ-6379/placebo administration, Date of treatment 
disposition for JNJ-6379/placebo, Date of trial disposition, Date of 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 cut-off) - first drug administration date in the given 
phase + 1)/ 7
Cut-off dates will be defined to match the prespecified timepoints for IDMC periodical data 
reviews, interim analysis and the primary analysis, respectively (see Section 3).
The number and percentage of participants who skipped any dose of JNJ-3989/placebo or 
JNJ-6379/placebo or NA will be summarized separately for each study treatment by intervention 
arm during the DB phase. Additionally, the number and percentage of participants who missed 2 
or more JNJ-3989/placebo injections, or who missed more than 5 JNJ-6379/placebo doses within 
a four week period, or who missed more than 5 doses of NA within a four week period.
For NA treatment, the total duration of exposure will be calculated separately for the DB and FU 
phase. For FU, the total duration will add up the weeks from the start of FU for those participants 
who met the requirement to re-start NA treatment. Those participants who stopped NA treatment 
at Week 48 and never restarted NA treatment thereafter will be counted as having zero weeks of 
NA exposure during the FU phase.
4.7.
Treatment Compliance 
Treatment compliance will be summarized for the safety analysis set by intervention arm for each 
study treatment except NA.
Treatment compliance (%) is defined as follows:
For JNJ-3989/placebo: (Total number of injections received/ 12) * 100%
For JNJ-6379/placebo: (Total medication intake / 4 *7 *48) * 100%
As the 250 mg daily dose of JNJ-6379/placebo consists of 4 tablets (2 tablets of 100 mg strength 
and 2 tablets of 25 mg strength), the denominator is 1,344 tablets= 4*7*48. The numerator 
representing the total medication intake for JNJ-6379/placebo is calculated as:
Total medication intake = (Total number of tablets dispensed–Total number of tablets 
returned)
5.
EFFICACY
All efficacy data will be analyzed by intervention arm, analysis phase and over time (when 
applicable). The primary analysis set will be the mITT analysis set (see definition in Section 2.3). 
Selected efficacy endpoints will be also analyzed using the ITT and PP analysis sets, respectively 
(see definition in Section 2.3). Efficacy assessments over time will be performed at the analysis 
time points defined in Section 2.1.
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Status: Approved, Date: 08 July 2022
5.1.
Analysis Specifications
All efficacy endpoints will be summarized descriptively by study intervention arm. In general, 
continuous variables will be summarized using descriptive statistics (for example, may include the 
number of participants, mean, standard deviation (SD), two-sided 90% 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. Descriptive summaries will be provided by 
stratification factors (i.e. screening HBsAg level [<1,000 IU/mL or >1,000 IU/mL], race [Asian 
versus non-Asian] and type of NA [TDF/TAF versus ETV]) for secondary efficacy endpoints.
Graphic displays will also be used to summarize the data. 
5.1.1.
Level of Significance
All statistical hypothesis tests will be based on one-sided alpha level of 0.05, and 90% confidence 
interval (CI) will be presented, unless otherwise specified. 
5.1.2.
Data Handling Rules
Those measurements collected from screening visit to the end of study will be handled according 
to the following rules in Table 3.
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
124,925.00 IU/mL
w/o dilution 
249,750.00 IU/mL
with dilution
0.025 IU/mL (a)
137,417.50 IU/mL w/o 
dilution (b)
274,725.00 IU/mL (b) with 
dilution
HBeAg
0.11 IU/mL
1,400.00 IU/mL w/o 
dilution
7,000.00 IU/mL with 
dilution
0.055 IU/mL (a)
1,540.00IU/mL(b) w/o 
dilution
7,700.00 IU/mL(b) with 
dilution
HBcrAg*
3.0 log10
U/mL
7.0 log10 U/mLw/o 
dilution
9.0 log10 U/mL with 
dilution
2.7 log10 U/mL
7.7 log10 U/mL(b)(c)
w/o dilution
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) w/o 
dilution
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Status: Approved, Date: 08 July 2022
Table 3: Data Handling Rules for HBV Virology and Serology Assessments
HBV 
parameter
LLOQ
ULOQ
Imputed Values
   If value< LLOQ
             If value> ULOQ
HBV RNA*
LLOQ = 4.04 
log10 cp/mL
LOD = 2.49 
log10 cp/mL
NAP
If <LOD or target not 
detected then 2.19
log10 cp/mL
NAP
Anti-HBs
5mIU/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
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 indicated in this table
All other viral activity data with values <LLOQ which are not included in the data handling rules 
above will be imputed by the absolute value divided by 2.
5.2.
Primary Efficacy Endpoint
5.2.1.
Definition
The primary endpoint, also known as “functional cure”, is the proportion of participants who 
achieved HBsAg seroclearance at Week 72 (24 weeks after completion of 48 weeks of treatment 
with all study interventions) without restarting NA treatment.
5.2.2.
Main Estimand for the Primary Endpoint
Study Objective: To evaluate the efficacy of the study intervention 24 weeks off-treatment.
Scientific Question: in HBeAg negative, virologically suppressed adult population with chronic 
HBV infection, what is the benefit of JNJ-3989 200 mg+JNJ-6379+NA (Arm 1) for 48 weeks in 
terms of functional cure 24 weeks after stopping all study interventions compared with NA alone 
(Arm 2)?
A) Study Intervention:

Arm 1: JNJ-3989 (200 mg) + JNJ-6379 (250 mg qd) + NA

Arm 2: Placebo + Placebo + NA 
B) Study Population: HBeAg-negative chronic HBV-infected patients who are virologically 
suppressed by being treated with NA.
C) Variable: Response status defined as participants who meet the criteria defining functional 
cure at Week 72 (responders) as in Section 5.2.1
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D) Intercurrent events: 

Treatment discontinuation prior to Week 48: if the participant discontinued treatment 
prior to Week 48 then s/he will be considered non-responder (composite strategy).

Major protocol deviations affecting efficacy: Attachment 1 identifies the deviations 
considered intercurrent event. Participants with such deviations and who have missing 
data for the endpoint will be considered as non-responders (composite strategy). For 
all other deviations not considered intercurrent events, the data are used regardless of 
the occurrence of major protocol deviations (treatment policy strategy).

Deaths prior to Week 72 are handled in a composite strategy as participants who die 
prior to Week 72 will be considered as non-responders.

NA re-treatment between Week 48 and 72: the participant will be counted as non-
responder (composite strategy).
E) Population-level summary: Difference in proportion of participants with functional cure 
status at Week 72 between study intervention arms.
5.2.2.1.
Main Estimator
5.2.2.1.1.
Analysis Methods
The main estimator is constructed using a Mantel-Haenszel (Mantel N., et al. 1959) test controlling 
for stratification factors, i.e., screening HBsAg level (<1,000 IU/mL or >1,000 IU/mL), race 
(Asian versus non-Asian) and type of NA (TDF/TAF versus ETV) for the difference in proportions
between the intervention arms (Arm 1 minus Arm 2). A 2 sided 90% CI of the difference in 
proportions will be provided.
5.2.2.1.2.
Data Included 
All available data from mITT analysis set, after taking into account all the intercurrent events and 
applying the intercurrent event strategies specified in Section 5.2.2, will be included.
5.2.2.1.3.
Assumptions

Missing Data for HBsAg are Missing at Random (MAR)

The treatment effect is homogeneous across randomization stratification strata 
5.2.2.1.4.
Missing Data Handling Rule
Participants who withdraw from the study prior to Week 72 will be considered as non-responders. 
If a participant remains in the study after experiencing a major protocol deviation (defined for the 
purpose of efficacy analyses and is an intercurrent event) and has missing Week 72 value, then the 
imputation to non-response will be applied. If the value for the endpoint at Week 72 is available, 
then such data will be used to determine their response status.
For the participants still in the study at Week 72 or for participants that have neither discontinued 
treatment early nor experienced any major protocol violations (defined for the purpose of efficacy 
analyses and is an intercurrent event), and HBsAg values missing at Week 72, then the primary 
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Status: Approved, Date: 08 July 2022
method to handle missing data will be the Multiple Imputation (MI) approach (Ratitch B. et al., 
2013) under the assumption of MAR will be applied to a model for continuous HBsAg log values 
over time. 
The MI model will use all available data and be applied to the continuous log-transformed HBsAg 
values (not the binary endpoint). Of note, also the pre-ICE data for those subjects who experienced 
an ICE will be included in the MI model; but for these subjects the response status will be applied
according to the ICE strategies before running the MI model. 
The model will include treatment, the 2 randomization factors (race [Asian versus non-Asian] and 
type of NA [TDF/TAF versus ETV]) and the available non-missing log-transformed HBsAg 
(values < LLOQ, TND or TD will be first substituted following rules described in Table 3) for 
each scheduled time point (Week) and the following demographic and baseline characteristics 
(King G. et al., & Honaker J. et al.): age, gender, and baseline log-transformed value for HBsAg 
level. 
A total of 200 datasets will be generated where both intermittent and monotone missing HBsAg
values will be imputed for each subject relying on non-missing data from all other subjects within 
the same treatment group. Once the 200 completed datasets are generated by filling in the missing 
data with samples from the imputation model, the primary endpoint response status (binary 
variable) will be derived using both imputed and observed HBsAg values at Week 72. 
The MH test will be performed for each dataset to generate individual estimates of the difference 
in proportions and the standard error adjusted on stratification factors. Then the results from these 
multiple imputed datasets are combined (pooled) for obtaining the overall inference and p-value 
in a way that accounts for the variability between imputations (Ratitch B. et al., 2013).
Depending on the amount of missing data, the number of imputed datasets to be generated will be 
increased appropriately from the planned 200 to ensure robustness in the MI results and relative 
efficiency (Graham JW. et al., 2007).
5.2.2.2.
Sensitivity Estimators of the Main Estimand
Sensitivity analyses will be conducted by constructing four sensitivity estimators for the main
estimand as defined in Section 5.2.2. One estimator will test the assumption of homogeneous 
treatment effect across the 3 randomization stratification factors, and the three other ones will use 
different missing data imputation rules. 
5.2.2.2.1.
Sensitivity Estimator 1 For the Main Estimand (Homogeneity 
Assumption)
Homogeneity will be assessed for the comparison vs control arm. For this sensitivity estimator 1, 
the same included data, missing data assumption (MAR), and missing data handling rule (multiple 
imputation) will be applied. The assumption for homogeneity of treatment effect across the 
stratification factors will be tested and, if heterogeneity is found statistically significant, a different 
statistical model is used to define the sensitivity estimator. 
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Status: Approved, Date: 08 July 2022
5.2.2.2.1.1.
Assumptions

Missing Data for HBsAg are Missing at Random 

The treatment effect is non-homogeneous across strata
5.2.2.2.1.2.
Analysis Methods 
Homogeneity of treatment effect for each stratification factor separately will be tested using the 
weighted least squares chi-squared statistic (Lui K. J. et al., 2000) for one-way homogeneity. Tests 
of homogeneity will be assessed at the one-sided 10% level of significance. 
Any heterogeneity found to be statistically significant will be explored using the following 
statistical model for the sensitivity estimator 1.
Statistical model: A logistic regression model on the primary efficacy endpoint using the 3
randomization stratification factors and interaction terms. The model will include intervention arm, 
screening HBsAg level (<1,000 IU/mL or >1,000 IU/mL), race (Asian versus non-Asian) and type 
of NA (TDF/TAF versus ETV) as factors, and the intervention arm-by-factor interaction terms. 
5.2.2.2.2.
Sensitivity Estimator 2 For the Main Estimand (LOCF)
For this sensitivity estimator 2, the same statistical model (stratum-adjusted MH test), and data 
included will be used as for the main estimator (Section 5.2.2.1). The assumption for missing data 
and the rule to handle missing data have changed.
5.2.2.2.2.1.
Assumptions

Missing Data for HBsAg are Missing Completely at Random (Barnes A. et al., 2008)

The treatment effect is homogeneous across strata
5.2.2.2.2.2.
Missing Data Handling Rule
For sensitivity estimator 2, participants who withdraw from the study prior to Week 72 will be 
considered as non-responders. After taking into account all the intercurrent events and applying 
the intercurrent event strategies specified in Section 5.2.2, if a subject who did not experience any 
ICEs has missing response status for the primary endpoint then the LOCF approach will be used 
as follows.
If the HBsAg value is missing at Week 72, the Last Observation Carried Forward (LOCF) in 
conjunction with the next available observation imputation approach will be used. The non-
missing value closest to Week 72 will be selected among the non-missing values which are no 
earlier than 12 weeks prior to Week 72 or no later than 12 weeks after Week 72. If 2 non-missing 
laboratory values are equidistant, the later observation will be preferred. If a subject who did not 
experience any ICE and does not have HBsAg data within ± 12 weeks of Week 72, then the subject 
will be considered as a non-responder.
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JNJ-73763989 and JNJ-56136379  
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Status: Approved, Date: 08 July 2022
5.2.2.2.3.
Sensitivity Estimator 3 For the Main Estimand (Missing as Non-
response) 
For this sensitivity estimator 3, the same statistical model (stratum-adjusted MH test), and data 
included will be used as for the main estimator (Section 5.2.2.1). The assumption for missing data 
and the rule to handle missing data have changed.
5.2.2.2.3.1.
Assumptions

Missing Data for HBsAg are Missing Not at Random 

The treatment effect is homogeneous across strata
5.2.2.2.3.2.
Missing Data Handling Rule
For sensitivity estimator 3, participants who withdraw from the study prior to Week 72 will be 
considered as non-responders. After taking into account all the intercurrent events and applying 
the intercurrent event strategies specified in Section 5.2.2, if a subject who did not experience any 
ICEs has missing response status for the primary endpoint then the primary endpoint status will be 
imputed as non-responders.
5.2.2.2.4.
Sensitivity Estimator 4 For the Main Estimand (Tipping Point)
For this sensitivity estimator 4, the same statistical model (stratum-adjusted MH test), and data 
included will be used as for the main estimator (Section 5.2.2.1). The assumption for missing data 
and the rule to handle missing data have changed.
5.2.2.2.4.1.
Assumptions

Missing Data for HBsAg are Missing Not at Random (MNAR)

The treatment effect is homogeneous across strata
5.2.2.2.4.2.
Missing Data Handling Rule
For sensitivity estimator 4, after taking into account all the intercurrent events and applying the 
intercurrent event strategies specified in Section 5.2.2, the tipping point approach with the 
exhaustive scenario’s analysis will be applied.
For participants with missing response data at Week 72, responder status will be imputed in an 
increasing manner by participant count for each treatment group. Specifically, for each participant 
with missing data at Week 72, a responder/non-responder status will be imputed starting with the 
scenario where all participants are non-responders up to the scenario where all participants are 
responders. This would include all possible scenario combinations of responder/non-responder 
status for all missing data, including scenarios where participants on JNJ-3989+JNJ-6379+NA 
have worse outcomes than participants on placebo+placebo+NA. Within the exhaustive scenarios 
list, the ‘worst case scenario’ will be one of the cases where all participants with missing Week 72
data in the JNJ-3989+JNJ-6379+NA arm will be imputed to ‘non-responders’ and all participants 
with missing data at Week 72 in the placebo+placebo+NA arm will be imputed to “responders”. 
For each scenario, the same statistical model (stratum-adjusted MH test), will be used as for the 
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JNJ-73763989 and JNJ-56136379  
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Status: Approved, Date: 08 July 2022
main estimator of the comparisons vs control (Section 5.2.2.1.1). A graphical display of the p-
value significance will summarize the results across all scenarios for the tipping point analysis.
5.2.2.3.
Supplementary Estimators of the Main Estimand 
Supplementary analyses to better interpret the results will be conducted by constructing additional
estimators for the main estimand of the primary endpoint as defined in Section 5.2.2. This estimator 
will be based on the ITT set (instead of mITT).
To provide a comprehensive interpretation of the study results and the impact of COVID-19 
pandemic on the functional cure at Week 72, the following supplementary estimators will utilize 
the ITT analysis set. 
5.2.2.3.1.
Supplementary Estimator 1 (ITT Analysis Set + MI)
For this supplementary estimator, the same estimand defined in Section 5.2.2, statistical model 
(stratum-adjusted MH test), and assumptions will be used as for the main estimator 
(Section 5.2.2.1).
The missing data approach will follow the MI approach as described in (Section 5.2.2.1.4). 
All available data from ITT analysis set, after taking into account all the intercurrent events and 
applying the intercurrent event strategies specified in Section 5.2.2, will be included.
5.2.2.3.2.
Supplementary Estimator 2 (ITT Analysis Set + LOCF)
For this supplementary estimator, the same estimand defined in Section 5.2.2, statistical model 
(stratum-adjusted MH test), and assumptions will be used as for the main estimator (Section
5.2.2.1). 
The missing data approach will follow the LOCF approach as described in Section 5.2.2.2.2.2.
All available data from ITT analysis set, after taking into account all the intercurrent events and 
applying the intercurrent event strategies specified in Section 5.2.2, will be included.
5.2.2.3.3.
Supplementary Estimator 3 (ITT Analysis Set + Missing as Non-
Response)
For this supplementary estimator, the same estimand defined in Section 5.2.2, statistical model 
(stratum-adjusted MH test), and assumptions will be used as for the main estimator 
(Section 5.2.2.1). 
The missing data approach will follow the missing as non-response approach as described in 
Section 5.2.2.2.3.2.
All available data from ITT analysis set, after taking into account all the intercurrent events and 
applying the intercurrent event strategies specified in Section 5.2.2, will be included.
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Status: Approved, Date: 08 July 2022
5.2.2.3.4.
Supplementary Estimator 4 (ITT Analysis Set + Tipping Point)
For this supplementary estimator, the same estimand defined in Section 5.2.2, statistical model 
(stratum-adjusted MH test), and assumptions will be used as for the main estimator (Section
5.2.2.1). 
This supplementary estimator will use the tipping point approach as described in Section
5.2.2.2.4.2.
All available data from ITT analysis set, after taking into account all the intercurrent events and 
applying the intercurrent event strategies specified in Section 5.2.2, will be included.
5.2.3.
Supplementary Estimand for the Primary Endpoint (Per-Protocol 
Analysis Set)
A) Study Intervention:

Arm 1: JNJ-3989 (200 mg) + JNJ-6379 (250 mg qd) + NA

Arm 2: Placebo + Placebo + NA 
B) Study Population: HBeAg-negative chronic HBV-infected patients who are virologically 
suppressed by being treated with NA and who are able to tolerate the treatment regimen 
and will comply with the treatment schedule as prescribed.
C) Variable: Response status defined as participants who meet the criteria defining functional 
cure at Week 72 (responders) as in Section 5.2.1
D) Intercurrent events: 

Treatment discontinuation prior to Week 48: if the participant discontinued treatment 
prior to Week 48 then s/he will be considered non-responder (composite strategy).

Deaths prior to Week 72 are handled in a composite strategy as participants who die 
prior to Week 72 will be considered as non-responders.

NA re-treatment between Week 48 and 72: the participant will be counted as non-
responder (composite strategy).
E) Population-level summary: Difference in proportion of participants with functional cure 
status at Week 72 between study intervention arms.
5.2.3.1.
Main Estimator
5.2.3.1.1.
Analysis Methods 
Similar stratum-adjusted MH test on the difference of proportions as described for the main 
estimator of the main estimand will be used (see section 5.2.2.1.1).
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JNJ-73763989 and JNJ-56136379  
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Status: Approved, Date: 08 July 2022
5.2.3.1.2.
Data Included
All available data from randomized participants that are included in the PP analysis set will be 
used, after taking into account the intercurrent events and applying the intercurrent event strategies 
specified in Section 5.2.3. 
To complement this analysis because of its inherent bias and allow a better interpretation of the 
results, the proportions of participants excluded from the PP analysis set will be summarized by 
intervention arm and by type of major protocol deviation. 
5.2.3.1.3.
Assumptions

The treatment effect is homogeneous across strata 
5.2.3.1.4.
Missing Data Handling Rule
Participants who withdraw from the study prior to Week 72 will be considered non-responders. 
For the participants still in the study at Week 72 or for participants that have neither discontinued 
treatment early nor experienced any major protocol violations as listed in Attachment 1, but 
HBsAg values missing at Week 72, then the primary method to handle missing data will be the 
imputation to non-responder.
5.2.4.
Subgroup Analyses of the Primary Endpoint
The potential association between the functional cure rate and the randomization stratification 
factors will be explored by a logistic regression model and exploration of the interaction terms
using observed case data. The model will include intervention arm, screening HBsAg level, race 
and type of NA, as factors, and the intervention arm-by-HBsAg level, intervention arm-by-race, 
and intervention arm-by-type of NA interaction terms. The functional cure rate estimates for each 
intervention arm will be derived from this model and presented graphically with their 90% CI in a 
forest plot.
In addition, for assessment of internal consistency and investigation of homogeneity of the 
treatment effect in the primary efficacy endpoint across other subgroups (as defined in 
Section 2.4.1), similarly to what is described above, a logistic regression model (Brooks ST. et al., 
2004) will be estimated for each subgroup variable at a time. The factors in the model will be 
intervention arm, screening HBsAg level, race, type of NA and the subgroup variable as factors, 
and the intervention arm-by-subgroup variable as the interaction-term (Brooks ST. et al., 2004). 
Corresponding 90% CIs will be also calculated without multiplicity adjustment for each 
intervention arm. 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 primary endpoint estimate, its 90% CI resulting from the model across intervention 
arms by the prespecified subgroups.
Tabulations of the primary endpoint by intervention arm and predefined subgroups will be used to 
summarize the data descriptively.
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Status: Approved, Date: 08 July 2022
5.3.
Major Secondary Endpoints
See Section 1.1 for a list of the secondary endpoints. All major secondary endpoints will be 
analyzed using observed case data. Additional analyses with specific imputation methods for 
missing data are added for selected endpoints.
5.3.1.
Definitions
5.3.1.1.
Binary Endpoints
Analyses described below as being with emphasis are for endpoints at selected time points. These 
analyses will utilize imputation methods for handling missing data and will be compared between 
study intervention arms (see Section 5.3.2.1). 
5.3.1.1.1.
HBsAg Seroclearance
Seroclearance of HBsAg is defined as HBsAg level <LLOQ. HBsAg seroclearance may be 
achieved prior to the time point assessed but must be observed at the given week of interest. 
HBsAg seroclearance will be evaluated over all time points when assessed, with emphasis at the 
following time points:

at Week 48

at Week 96 (ie, 48 weeks after completion of all study interventions at Week 48) without 
restarting NA treatment, 

24 weeks after stopping all study interventions (regardless when intervention was stopped) 
without restarting NA treatment, and 

48 weeks after stopping all study interventions (regardless when intervention was stopped) 
without restarting NA treatment 
If the HBsAg value at Week 48 is missing, the LOCF approach will be used with the condition 
that no value earlier than Week 40 may be carried forward.
For the analyses of seroclearance 24 and 48 weeks after stopping all study intervention respectively,
participants with HBsAg seroclearance at the respective time points, and without restarting NA 
treatment will be considered as having achieved this endpoint. If HBsAg values are missing, then 
LOCF in conjunction with the next available observation (if available for 48 weeks after stopping 
all study interventions) imputation approach will be used. The available non-missing HBsAg value 
closest to the time point which is no earlier/later than 12 weeks prior/after to the respective time 
point will be used.
For the analyses of seroclearance at Week 96 participants with HBsAg seroclearance at the 
respective time points, and without restarting NA treatment will be considered as having achieved 
this endpoint. If HBsAg values are missing, then LOCF approach will be used. The available non-
missing HBsAg value closest to the time point which is no earlier than 12 weeks prior to the 
respective time point will be used.
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Status: Approved, Date: 08 July 2022
For all other time points, seroclearance will be analyzed as observed case without imputation.
5.3.1.1.2.
Suppressed HBV DNA 
HBV DNA < LLOQ and HBV DNA TND will be evaluated over time.
5.3.1.1.3.
Thresholds Based on HBsAg and HBV DNA
The following blood marker reduction/seroclearance thresholds over time on treatment, and at 12, 
24, 36 and 48 weeks, respectively, after stopping all study interventions (including NA) and not 
having NA re-treated will be evaluated.

HBsAg <LLOQ and HBV DNA

HBsAg <LLOQ and HBV DNA <LLOQ**

HBsAg <LLOQ and HBV DNA ≥LLOQ

HBsAg ≥LLOQ and HBV DNA <2,000 IU/ml

HBsAg ≥LLOQ and HBV DNA <LLOQ**

HBsAg ≥LLOQ and LLOQ ≤HBV DNA <2,000 IU/ml (See partial cure in 
Section 5.4.1.1.1)

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
** HBV DNA<LLOQ will be summarized by DNA TD, TND and overall.
Due to the exploratory objectives of this Phase 2b study, additional blood marker 
reduction/seroclearance thresholds may also be added at a later point in time according to the 
clinical interest.
5.3.1.1.4.
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.
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JNJ-73763989 and JNJ-56136379  
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Status: Approved, Date: 08 July 2022
5.3.1.1.5.
HBsAg and HBV DNA cut-offs
The cut-offs for HBsAg level are as follows:

<1000 IU/mL

<100 IU/mL

<10 IU/mL

<1 IU/mL

<0.05 IU/mL
The cut-offs for HBsAg change from baseline are as follows:

decrease by ≥0.3 log10 IU/mL

decrease by ≥0.5 log10 IU/mL

decrease by ≥1 log10 IU/mL 

decrease by ≥2 log10 IU/mL 

decrease by ≥3 log10 IU/mL 

decrease by ≥4 log10 IU/mL 
The cut-offs for HBV DNA are as follows:

<LLOQ

<LLOQ TND

<LLOQ TD

<60 IU/mL

<200 IU/mL

<2000 IU/mL

<20000 IU/mL

<100000 IU/mL
HBV DNA change from time of NA re-start

decrease by ≥1 log10 IU/mL

decrease by ≥2 log10 IU/mL

decrease by ≥3 log10 IU/mL

decrease by ≥4 log10 IU/mL

decrease by ≥5 log10 IU/mL
5.3.1.1.6.
Flares
The criteria based on blood markers/lab tests for each of the flare types are defined as below.
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Status: Approved, Date: 08 July 2022
a) 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 all study treatments.
The start date of a virologic flare is defined as the first date of two consecutive visits with HBV 
DNA > 200 IU/mL. The end date of the same virologic flare is defined as the first date when 
HBV DNA value returns to ≤200 IU/mL or the date of 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 four thresholds within the start and end date of that flare as 
follows: 100,000 IU/mL, 20,000 IU/mL, 2,000 IU/mL and 200 IU/mL.
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 all study treatments.
The start date of a virologic flare is defined as the first date of two consecutive visits with HBV 
DNA log10 increase from end of treatment >1 log10. The end date of the same 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 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: 1 log10, 2 log10 and 
3 log10.

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.
b) Biochemical flare is defined as follows:

1 (Yes) = confirmed** ALT and/or AST ≥3x ULN and ≥3x nadir (ie, lowest value 
observed up to the start of the flare)

0 (No) = otherwise
The start date of a biochemical flare is defined as the first date of two consecutive visits with 
ALT and/or AST ≥3x ULN and ≥3x nadir. The end date of the same biochemical flare is 
defined as the first date when there is a 50% reduction from the peak ALT and/or AST level
& <3x ULN.
c)
Clinical flare is defined as follows:
Clinical flare will be assessed with both derivations specified above for virologic flare.
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JNJ-73763989 and JNJ-56136379  
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Status: Approved, Date: 08 July 2022

1 (Yes)= confirmed** HBV DNA > peak threshold and confirmed** ALT and/or AST≥3x 
ULN and ≥3x nadir (ie, lowest value observed up to the start of the flare).

0 (No) = otherwise
A clinical flare occurs when a virologic flare and biochemical flare overlap in time. However, 
if there is no overlap in time, a clinical flare occurs when a virologic flare ends prior to a 
biochemical flare starting, and the end date of the virologic flare is within 4 weeks of the 
biochemical flare start date. The start date of a clinical flare is defined as the minimum start 
date of the virologic flare and the 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 of 
HBV DNA ≤200 IU/mL (or ≤1 log10) and 50% reduction from the peak ALT and/or AST 
level.
** 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 breakthrough in Section 5.3.1.1.7. On-treatment will be defined as the time 
period in which the participant receives any of the study interventions. Off-treatment will be 
defined as the period after stopping all study interventions (including NA). 
5.3.1.1.7.
Virologic Breakthrough
HBV virological 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 didn’t 
have on-treatment HBV DNA level below the lower limit of quantification (LLOQ) or a confirmed 
on-treatment HBV DNA level >200 IU/mL in participants who had on-treatment HBV DNA level 
below the 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 
(including NA).
In addition, participants who experience a virologic breakthrough followed by on-treatment 
biochemical flare will be evaluated.
5.3.1.1.8.
NA Re-Treatment Criteria During Follow-Up
Participants who actually re-started NA treatment during the follow-up phase will be identified
based on the ‘Study Drug Administration for ETV, TDF or TAF’ CRF page.
Participants who meet the NA re-treatment criteria will be identified based on the CRF page of 
‘NA Re-treatment Criteria Assessment’. Each sub-criteria will also be evaluated.
NCT04129554


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Status: Approved, Date: 08 July 2022
5.3.1.1.9.
ALT Normalization 
ALT elevation at baseline is defined as ALT≥ULN. A participant with ALT elevation at baseline 
achieves ALT normalization if his/her ALT value post-baseline is <ULN at any given time point.
Participants who achieve ALT normalization on treatment and off treatment but without restarting
NA treatment will be evaluated over time. 
Participants who were re-treated with NA and who have ALT≥ULN before NA re-treatment and 
reach ALT normalization after NA re-treatment during follow-up will be evaluated.
Additionally, for those participants who restarted NA treatment during the follow-up, the 
participants who reach ALT < ULN and who have ALT less than their nadir value during the study 
will be evaluated.
5.3.1.2.
Continuous Endpoints
Actual values (original unit and log10 transformed values) and changes from baseline (log10
transformed values) over time in HBsAg, HBV DNA and ALT (original unit) will be evaluated.
Change from baseline is defined as follows: value at a given time point minus baseline value.
Changes in HBsAg (log10 transformed values) from both EOT and Week 48 will be evaluated for 
the follow-up period.
The change from baseline value to the nadir (i.e. maximum decrease for each participant) in 
HBsAg and HBV DNA will be evaluated at three intervals: on-treatment nadir, during follow-up 
nadir, and entire study duration nadir. 
5.3.1.3.
Time to Event Endpoints
5.3.1.3.1.
First 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 the following events (i.e. the date of the first occurrence 
of the event – the date of first study intervention intake + 1) will be tabulated:

HBsAg <10 IU/mL

HBsAg <100 IU/mL 

HBsAg decline ≥1.0 log10 IU/mL

HBsAg decline ≥2.0 log10 IU/mL

HBsAg decline ≥3.0 log10 IU/mL
NCT04129554


JNJ-73763989 and JNJ-56136379  
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Status: Approved, Date: 08 July 2022
These endpoints will also be analyzed considering participants who were re-treated with NA before 
achieving the endpoint as censored at the date of NA re-treatment.
5.3.1.3.2.
Time to Flare
Time to biochemical flare (on- and off-treatment), clinical flare off-treatment, and virologic flare
off-treatment will be evaluated.
Time to on-treatment flare will be defined as the number of days between the date of first study 
intervention intake and the date of the first occurrence of on-treatment flare (i.e. the date of the 
first on-treatment flare [the first of the two confirmation visits] of each type- the date of first study 
intervention intake+1). The participants who withdrew early from the study before experiencing
on-treatment flare or who did not experience on-treatment flare will be censored at the last 
available blood markers or liver enzymes assessment at or before EOT.
Time to off-treatment flare will be defined as the number of days between the date of last study 
intervention intake and the date of the first occurrence of off-treatment flare (i.e. the date of 
experiencing the first off-treatment[the first of the two confirmation visits] flare of each type- the 
date of last study intervention intake). The participants who withdrew early from the study before 
experiencing off-treatment flare or who did not experience off-treatment flare will be censored at 
the last available blood markers or liver enzymes assessment.
5.3.1.3.3.
Time to Virologic Breakthrough
Time to HBV virologic breakthrough will be defined as the number of days between the date of 
first study intervention intake and the date of the first occurrence of virologic breakthrough (i.e. 
the date of the first virologic breakthrough [the first of the two confirmation visits] - the date of 
first study intervention intake +1). The participants who withdrew early from the study before 
experiencing virologic breakthrough or who did not experience virologic breakthrough will be 
censored at the last available HBV DNA assessment at or before EOT.
5.3.1.4.
Endpoints for Correlation 
Correlations between baseline characteristics, and on-treatment HBV blood markers and/or their 
change from baseline at Week 24 and 48 with off-treatment endpoints will be evaluated. The list 
of HBV blood markers, including but not limited to, are defined below:
Off treatment HBV marker
Baseline Characteristics/On treatment HBV marker
HBsAg change from baseline at FU Week 12

Age

Baseline NA treatment duration

HBsAg value at baseline

HBsAg change from baseline at Week 24

HBsAg change from baseline at Week 48
HBsAg change from baseline at FU Week 24

Age

Baseline NA treatment duration

HBsAg value at baseline

HBsAg change from baseline at Week 24

HBsAg change from baseline at Week 48
HBsAg change from baseline at FU Week 48

Age
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Status: Approved, Date: 08 July 2022
Off treatment HBV marker
Baseline Characteristics/On treatment HBV marker

Baseline NA treatment duration

HBsAg value at baseline

HBsAg change from baseline at Week 24

HBsAg change from baseline at Week 48
HBsAg seroclearance at FU week 24 (Yes;No)

Age

Baseline NA treatment duration

HBsAg value at baseline

HBsAg change from baseline at Week 48

HBsAg value at Week 48

HBsAg seroclearance at week 24 (Yes;No)

HBsAg seroclearance at week 48 (Yes;No)

Anti-HBe antibodies status at week 48 (Positive:Negative)
HBsAg seroclearance at FU week 48 (Yes;No)

Age

Baseline NA treatment duration

HBsAg value at baseline

HBsAg change from baseline at Week 48

HBsAg value at Week 48

HBsAg seroclearance at week 24 (Yes;No)

HBsAg seroclearance at week 48 (Yes;No)

Anti-HBe antibodies status at week 48 (Positive:Negative)
Partial cure (Yes;No) at FU Week 24 (Yes;No)

Age

Baseline NA treatment duration

HBsAg value at baseline

HBsAg value at Week 48

HBsAg seroclearance at week 24 (Yes;No)

HBsAg seroclearance at week 48 (Yes;No)

Anti-HBe antibodies status at week 48 (Positive:Negative)
Partial cure (Yes;No) at FU Week 48 (Yes;No)

Age

Baseline NA treatment duration

HBsAg value at baseline

HBsAg value at Week 48

HBsAg seroclearance at week 24 (Yes;No)

HBsAg seroclearance at week 48 (Yes;No)

Anti-HBe antibodies status at week 48 (Positive:Negative)
Treatment failure at FU Week 24 (Yes;No)

Age

Baseline NA treatment duration

HBsAg value at baseline

HBsAg value at Week 48

HBsAg seroclearance at week 24 (Yes;No)

HBsAg seroclearance at week 48 (Yes;No)

Anti-HBe antibodies status at week 48 (Positive:Negative)
Treatment failure at FU Week 48 (Yes;No)

Age

Baseline NA treatment duration

HBsAg value at baseline

HBsAg value at Week 48

HBsAg seroclearance at week 24 (Yes;No)

HBsAg seroclearance at week 48 (Yes;No)

Anti-HBe antibodies status at week 48 (Positive:Negative)
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Status: Approved, Date: 08 July 2022
5.3.2.
Analysis Methods
Statistical comparisons of all secondary endpoints between intervention arms will be done with no 
adjustment for multiplicity. 
5.3.2.1.
Binary Endpoints
The number and proportion (%) of participants achieving the endpoints defined in Section 5.3.1.1
will be summarized. The associated 90% CI may also be included.
The following binary endpoints will be compared between treatment arms using a 2-sided 90% CI 
of the difference in proportions between the treatment groups (Arm 1 minus Arm 2) that will be 
constructed using a Mantel-Haenszel test controlling for stratification factors, i.e., HBsAg level 
(<1,000 IU/mL or ≥1,000 IU/mL), race (Asian versus non-Asian) and type of NA (TDF/TAF 
versus ETV):

HBsAg seroclearance:

at Week 48

at Week 96 (ie, 48 weeks after completion of all study interventions at Week 48) without 
restarting NA treatment, 

24 weeks after stopping all study interventions (regardless when intervention was 
stopped) without restarting NA treatment, and 

48 weeks after stopping all study interventions (regardless when intervention was 
stopped) without restarting NA treatment 
Bar charts will be provided for selected endpoints for proportions (%) in each intervention arm.
Cumulative percentage of participants achieving any given decrease from baseline at Week 72 and 
Week 96 in HBsAg and HBV DNA (Section 5.3.1.1.5) will be presented graphically.
Subsections below describe the additional analyses planned for only those specific other secondary 
binary endpoints that require further evaluations.
5.3.2.1.1.
Suppressed HBV DNA 
The number of occurrences each subject has HBV DNA <LLOQ will be determined and 
summarized by intervention arm using frequency distributions and descriptive statistics. 
Additionally, the number of occurrences will be displayed graphically.
5.3.2.1.2.
HBsAg Seroconversion 
For all participants achieving HBsAg seroconversion, descriptive statistics will be calculated for 
the level of anti-HBs antibodies at the timepoint when achieving the HBsAg seroconversion by 
intervention arm. In an additional summary, the level of anti-HBs antibodies at the specific 
timepoint (i.e. Week 48, Week 72, Week 96) will be summarized for the subset of the participants 
achieving HBsAg seroconversion at any time before or at that given timepoint by intervention arm.
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Status: Approved, Date: 08 July 2022
In addition, the number and proportion of participants with appearance of anti-HBs antibodies and 
without seroclearance of HBsAg will also be summarized by intervention arm and analysis phase.
5.3.2.1.3.
Flares
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, by study intervention arm. 
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 intervention arm.
For on-treatment biochemical flares, the incidence of flares causing treatment discontinuation will 
be summarized by intervention arm. 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 and intervention arm. Similarly, the incidence of flares followed by the achievement of 
HBsAg seroclearance (at any time) will be summarized by flare type and intervention arm.
For off-treatment virologic, biochemical and clinical flares, the count and percentage of 
participants who experienced a flare will be summarized by intervention arm and selected 
subgroups (i.e. by NA type at study entry, by HBsAg levels at EOT, by HBcrAg levels at EOT). 
Biochemical flares will also be summarized in the follow-up after NA re-treatment. The cut-offs 
for HBsAg and HBcrAg levels at EOT are provided in Sections 5.3.1.1.5 and 5.4.1.1.2.
Flares that are associated with signs of liver decompensation will be provided in a listing.
5.3.2.1.4.
NA Re-Treatment Criteria During Follow-Up
A cross-tabulation of participants who actually re-started NA treatment (re-started/not restarted) 
versus participants who met the above criteria (met/not met) will be presented over time.
5.3.2.2.
Continuous Endpoints
Descriptive statistics on actual values (original unit and log10 transformed values) and changes 
from baseline (log10 transformed values) over time in HBsAg, HBV DNA, and ALT (original unit) 
will be summarized by intervention arm. Mean (+/- SE) plots of the actual values and the change 
from baseline (log10 transformed) will be presented over time per endpoint by intervention arm.
Subsections below describe the additional analyses planned for only those specific secondary
endpoints that require further evaluations.
5.3.2.2.1.
HBsAg and HBV DNA
The change from baseline value to the nadirs (i.e. maximum decrease for each participant) in 
HBsAg and HBV DNA will be summarized descriptively by intervention arm. Box plots of the 
changes to nadirs in HBsAg and HBV DNA will display the distribution by intervention arm.
NCT04129554


JNJ-73763989 and JNJ-56136379  
Statistical Analysis Plan 73763989PAHPB2002
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Status: Approved, Date: 08 July 2022
Change from baseline based on log10 transform for quantitative HBsAg and HBV DNA will be 
analyzed using mixed effects model for repeated measures [MMRM]) including intervention arm, 
analysis time point (week), their interaction, and 3 randomization stratification factors (screening 
HBsAg level [<1,000 IU/mL or >1,000 IU/mL], race [Asian versus non-Asian] and type of NA 
[TDF/TAF versus ETV]) and baseline blood marker categorical variable as fixed effects. In 
addition, the above model will be augmented with an intervention arm-by-analysis week 
interaction term (i.e. treatment-by-time interaction term) to evaluate the change of treatment effect 
over time and the intervention arm-by-baseline 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 an unstructured (type=UN) covariance 
matrix. In case of convergence problems, simpler variance-covariance structures 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), 90% confidence interval (CI) and p-values will be provided.
Descriptive statistics on actual values (original unit and log10 transformed values) and changes 
from baseline (log10 transformed values) at end of treatment in HBsAg and HBV DNA will be 
summarized by study intervention arm by outcome response (i.e. by functional cure status at Week 
72, and by partial cure status at Week 72).
Spaghetti plots for both absolute values and changes from baseline of HBsAg and HBV DNA will 
be presented over time per blood marker by intervention arm and by selected subgroups (e.g. HBV 
Genotype) and by outcome response (i.e. by functional cure status at Week 72, and by partial cure 
status at Week 72).
Cross-tabulations overtime and overall of quantitative versus qualitative HBsAg values will also 
be presented.
Shift tables in HBV DNA categories from baseline will also be summarized by study intervention 
arm.
Waterfall plots for changes from baseline of HBsAg, and HBV DNA will also be presented.
5.3.2.3.
Time to Event Endpoints
The Kaplan-Meier method will be used to estimate and plot the cumulative incidence by each 
intervention arm. The log-rank test will be performed to compare between the intervention arms. 
The median time with 90% CI will be estimated using Kaplan-Meier method. To explore the 
impact of selected baseline factors in addition of study intervention, the survival probabilities will 
be estimated based on a stratified Cox regression model including study intervention arm, and each 
baseline factor at a time with the intervention arm-by-baseline factor interaction term. The strata
in the stratified Cox model are the 3 randomization stratification factors to allow for a separate 
baseline hazard for each level of those factors. The interaction between study intervention arm and 
baseline/disease characteristic will be explored graphically. 
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JNJ-73763989 and JNJ-56136379  
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Status: Approved, Date: 08 July 2022
5.3.2.4.
Endpoints for Correlation
Correlations will be evaluated graphically with scatter plots and heat maps displaying such 
potential associations by intervention arm and/or selected subgroups (baseline NA treatment 
duration, age, and baseline HBsAg). 
The following correlation coefficients will be calculated by study intervention arm 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. 
5.4.
Exploratory Endpoints
5.4.1.
Definitions
5.4.1.1.
Binary Endpoints
5.4.1.1.1.
Partial Cure
Partial cure will be evaluated at each of the following time points separately: 24 weeks and 48 
weeks after stopping all study interventions. A participant will be defined as having achieved 
partial cure if he/she has:

Stopped all study interventions at any time, and

had HBV DNA level < 2,000 IU/ml quantifiable at the given week of interest, and

had HBsAg ≥LLOQ at the given week of interest, and

not required NA re-treatment after stopping all study interventions.
If the HBV DNA or HBsAg value 24 weeks after stopping all study interventions is missing, the 
LOCF in conjunction with the next available observation imputation approach will be used. The 
available non-missing lab test closest to 24 weeks after stopping all study interventions which is 
no earlier/later than 12 weeks from the actual time point of interest (12 and 36 weeks after stopping 
all study interventions, respectively) will be imputed. If a subject does not have data within 12 and 
36 weeks after stopping all study interventions then the subject will be considered as a non-
responder.
If the HBV DNA or HBsAg value at 48 weeks after stopping all study interventions is missing, 
the LOCF imputation approach will be used. The last available lab test no earlier than 36 weeks 
after stopping all study interventions will be carried forward. If a subject does not have data 36 
weeks after stopping all study interventions then the subject will be considered as a non-responder.
5.4.1.1.2.
HBV RNA and HBcrAg 
The cut-offs for HBV RNA level are as follows:
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
< TND

< LOD

< LLOQ

< 1000 copies/mL
The cut-offs for HBV RNA change from baseline are as follows:

decrease by ≥1 log10 copies/mL

decrease by ≥2 log10 copies/mL

decrease by ≥3 log10 copies/mL
The cut-offs for HBcrAg level are as follows:

<3.0 log U/mL

<4.0 log U/mL
The cut-offs for HBcrAg change from baseline are as follows:

decrease by ≥1 log U/mL

decrease by ≥2 log U/mL

decrease by ≥3 log U/mL

decrease by ≥4 log U/mL
5.4.1.1.3.
Anti-HBe Antibodies 
Participants who have positive and negative Anti-HBe values will be evaluated over time.
5.4.1.1.4.
Impact of Finite Treatment Duration on Functional Cure
The following exploratory analysis will be performed to have a better understanding of the impact 
of finite treatment duration and of the below criteria to stop NA treatment after 48 weeks of 
treatment on the outcome of HBsAg seroclearance 24 weeks off treatment.(functional cure).
For this finite treatment duration analysis, a participant will be defined as having functional cure 
at Week 72 (responder) if he/she has:

completed 48 weeks of treatment, and

met the following criteria at Week 44: 

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.

had HBsAg seroclearance at Week 72 (i.e. 24 weeks after end of study intervention), and
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
not required NA re-treatment between Weeks 48 and 72.
Participants who withdraw from the study prior to Week 72 will be considered as non-responders.
All participants with missing data for the determination of the status will be imputed as non-
responders.
5.4.1.1.5.
Treatment Failure 
Treatment failure and the reasons will be evaluated based on observed case data. A participant will 
be defined as a treatment failure at Week 72 if he/she never achieves functional cure (see Section 
5.2.1) at Week 72.
The reasons for not achieving functional cure are as follows:

HBsAg ≥LLOQ at Week 72

required NA re-treatment between Week 48 and 72
Similarly, a participant will be defined as having treatment failure at Week 96 for either of the 
following reasons:

HBsAg ≥LLOQ at Week 96

required NA re-treatment between Week 48 and 96
5.4.1.2.
Continuous Endpoints
Severity of liver disease at the end of study intervention and follow-up versus baseline will be 
evaluated by the changes in fibrosis according to Fibroscan liver stiffness measurements.
Actual values and changes from baseline (log transformed value) over time in HBV RNA, HBV 
HBcrAg and anti-HBs will be evaluated.
Change will be defined as: value at a given time point minus baseline value.
The change from baseline value to the nadir (i.e. maximum decrease for each participant) in HBV 
RNA and HBcrAg will be evaluated at three intervals: on-treatment nadir, during follow-up nadir, 
and entire study duration nadir. 
5.4.1.2.1.
Decline in HBsAg and HBV DNA Levels 
Participants achieving the maximum decline (change from peak level in follow-up to the lowest 
level achieved during the remainder of follow-up) in the magnitude of the cut-offs as described in 
Section 5.3.1.1.5 will be evaluated by intervention arm and over time in the follow-up phase only 
for those participants who restarted NA treatment during the follow-up.
5.4.1.3.
Time to Event Endpoints
5.4.1.3.1.
HBV RNA <LOD
Time to HBV RNA <LOD is defined as the duration from the date of first study intervention intake
to the date of the first occurrence of HBV RNA <LOD (i.e. the date of the first occurrence of HBV 
RNA <LOD – the date of first study intervention intake + 1). The participant who did not achieve 
NCT04129554


JNJ-73763989 and JNJ-56136379  
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HBV RNA <LOD or who early withdrew from the study before achieving HBV RNA <LOD will 
be censored at the last HBV RNA assessment before the date of withdrawal. Only the participants 
with HBV RNA values ≥LOD+ 0.5 log10 cp/mL (i.e. ≥2.99 log10 cp/mL) at baseline will be 
included in this analysis. Similarly, additional analyses only for participants with HBV RNA 
values ≥LOD+ 1.0 log10 cp/mL and ≥LOD+ 2.0 log10 cp/mL, respectively, will be summarized.
This endpoint will also be analyzed considering participants who were re-treated with NA before 
achieving the endpoint as censored at the date of NA re-treatment.
5.4.1.3.2.
HBcrAg Undetectability
Time to undetectability of HBcrAg is defined as the duration from the date of first study 
intervention intake to the date of the first occurrence of undetectability of HBcrAg (i.e. the date of 
the first occurrence of HBcrAg<LLOQ – the date of first study intervention intake + 1). The 
participant who did not achieve undetectability or who early withdrew from the study before 
achieving undetectability of HBcrAg will be censored at the last HBcrAg assessment before the
date of withdrawal. Only the participants with HBcrAg values ≥LLOQ+ 0.5 log10 U/mL (i.e. ≥3.5 
log10 U/mL) at baseline will be included in this analysis.
This endpoint will also be analyzed considering participants who were re-treated with NA before 
achieving the endpoint as censored at the date of NA re-treatment.
5.4.1.3.3.
Time to Appearance of Anti-HBs Antibodies
Appearance of anti-HBs antibodies is defined as a baseline anti-HBs (quantitative) <LLOQ and a 
post-baseline assessment ≥LLOQ. 
Time to appearance of anti-HBs antibodies is defined as the time (days) from the date of first study 
intervention intake to the date of the first occurrence of anti-HBs antibodies appearance + 1. The 
participant who did not experience emergence of antibodies or who early withdrew from the study 
before showing emergence of anti-HBs antibodies will be censored at the last anti-HBs antibodies
assessment before the date of withdrawal.
This endpoint will also be analyzed considering participants who were re-treated with NA before 
achieving the endpoint as censored at the date of NA re-treatment.
5.4.1.3.4.
Time to 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. 
Time to appearance of anti-HBe antibodies is defined as the time (days) from the date of first study 
intervention intake to the date of the first occurrence of anti-HBe antibodies appearance + 1. The 
participant who did not experience emergence of antibodies or who early withdrew from the study 
before showing emergence of anti-HBe antibodies will be censored at the last anti-HBe antibodies
assessment before the date of withdrawal.
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Status: Approved, Date: 08 July 2022
This endpoint will also be analyzed considering participants who were re-treated with NA before 
achieving the endpoint as censored at the date of NA re-treatment.
5.4.2.
Analysis Methods
Statistical comparisons of all exploratory endpoints between intervention arms will be done with 
no adjustment for multiplicity. 
5.4.2.1.
Binary Endpoints
The number and proportion (%) of participants achieving the endpoints defined in Section 5.4.1.1
will be summarized. The associated 90% CI may also be included.
Participants who achieve partial cure at 24 weeks and 48 weeks after stopping all study 
interventions will be compared between treatment interventions using the Mantel-Haenszel test 
and 90% CIs adjusted for the stratification factors. Similar analysis for the impact of finite 
treatment duration on functional cure will also be done.
Shift tables in Anti-HBe positive/negative values from baseline will also be provided at each time 
point.
5.4.2.2.
Continuous Endpoints 
The values of and changes from baseline in anti-HBs antibodies will be summarized only 
descriptively in a similar manner as described for values and changes from baseline over time in 
other blood disease markers in Section 5.3.2.2.
Waterfall plots for changes from baseline of HBV RNA, HBcrAg and fibrosis will also be 
presented.
Subsections below describe the additional analyses planned for only those specific exploratory
endpoints that require further evaluations.
5.4.2.2.1.
Fibrosis
The changes from baseline at end of study intervention and follow-up will be summarized using 
descriptive statistics (for example, may include n, mean, SD, 90% CI, median, minimum, 
maximum) by intervention arm. The comparison between intervention arms will be done using 
ANCOVA with intervention arm, randomization stratification factors as main effects in the model 
and baseline score as covariate.
At each assessment time point, a frequency distribution of severity scores will be produced by 
intervention arm. A graphical display will also illustrate the findings.
5.4.2.2.2.
HBV RNA and HBcrAg
The changes from baseline value to nadirs (i.e. maximum decrease for each participant) in HBV 
RNA and HBcrAg, respectively, and the various graphical displays will be presented. 
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JNJ-73763989 and JNJ-56136379  
Statistical Analysis Plan 73763989PAHPB2002
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54
Status: Approved, Date: 08 July 2022
5.4.2.2.3.
Anti-HBs
For participants with positive anti-HBs antibodies at baseline who will reach HBsAg seroclearance 
(as defined in Section 5.2.1), descriptive statistics will be calculated for the change of anti-HBs 
antibodies level from baseline at the timepoint when achieving the HBsAg seroclearance by 
intervention arm. In an additional summary, the change of anti-HBs antibodies level from baseline 
at the specific timepoint (i.e. Week 48, Week 72, Week 96) will be summarized descriptively for 
the subset of the participants achieving HBsAg seroclearance at any time before or at that given 
timepoint by intervention arm.
Cross-tabulations overtime of quantitative versus qualitative anti-HBs values, respectively, will 
also be presented.
5.4.2.3.
Time to Event Endpoints
The time-to-event analyses will be analyzed in a similar manner as for the time to event endpoints 
described in the Section 5.3.2.3.
6.
SAFETY
All safety analyses will be performed using the safety analysis set. All assessments will be 
presented by analysis phase, unless other specified. All summaries will be descriptive, and no 
inferential methods will be used to compare intervention arms for safety.
Safety and tolerability will be assessed by evaluating treatment emergent-adverse events (TEAEs), 
physical examinations, vital signs measurements, clinical laboratory tests (including hematology, 
blood biochemistry, blood coagulation, and urinalysis), and ECGs.
Continuous parameters will be summarized using the following statistics: number of observations, 
mean, standard deviation (SD), standard error (SE), minimum, median and maximum, unless 
specified otherwise. Frequencies and percentages will be used for summarizing categorical 
(discrete) data.
As a result of the IDMC ongoing reviews to ensure the continuing safety of study participants, 
additional safety analyses may be generated at the discretion of the Sponsor.
6.1.
Adverse Events
6.1.1.
Definitions
The verbatim terms used in the CRF by investigators to identify adverse events will be coded using 
the Medical Dictionary for Regulatory Activities (MedDRA version 21.1 or higher). Treatment-
emergent AEs (TEAE) are all AEs with a start date on or after the first administration of study 
treatment or any ongoing event that worsens in severity, intensity or frequency after the first 
administration of study treatment. If the event date and/or resolution date is recorded as partial or 
completely missing, then the imputation rules described in Section 2.5.1 will apply.
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6.1.2.
Analysis Methods
The adverse events will be summarized by intervention arm and by analysis phase. Adverse events 
will be allocated to phases based on their start date. If the start date of an event falls between (or 
on) the start and stop date of a study phase, the AE will be attributed to that phase (treatment-
emergent principle). For imputation of partially/fully missing dates please see Section 2.5.1. In 
case of a completely missing start date, the event is allocated to the double-blind study intervention
phase, except if the end date of the AE falls before the first administration of study treatment (DB 
Day 1).
An overview table will summarize the incidence of TEAEs classified in the following categories: 
AEs, serious AEs, related AEs, AEs leading to treatment discontinuation, and fatal AEs by 
presenting by intervention arm the number and percentage of participants who experienced at least 
one of such AE. The overview AEs table will be also presented stratified by the subgroup of 
interests identified in Section 2.4.2.
AE relationship to study treatment is grouped into either related or not related category. A related 
AE is defined as with possible, probable, or very likely relationship with study treatment; not 
related, otherwise.
All adverse events will be presented in a descending order by incidence based on all participants 
(Total column). The following TEAEs tables will be included in the analysis:

All TEAEs

Serious TEAEs

At least grade 3 TEAEs

At least grade 2 TEAEs and related

TEAEs leading to treatment discontinuation 

Related TEAEs
All serious TEAE, related TEAE, TEAE leading to death, TEAE leading to discontinuation, TEAE 
of at least grade 3, or adverse events of special interest (AESIs) will be listed separately. Listings 
will include all information collected on the Adverse Event CRF pages (e.g. information on time 
of onset, duration of events, time of resolution, concomitant therapies and relationship to study 
treatment).
For participants reporting rash, a listing with specific grade will be provided and Rash 
questionnaire will be tabulated by study intervention arm and overall.
6.1.3.
Adverse Events of Special Interest
Incidence of treatment-emergent adverse events of special interest will be summarized by 
intervention arm and analysis phase. The adverse events of special interest include:

ALT/AST elevations
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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
The laboratory abnormalities will be determined according to the criteria specified in the DAIDS 
Toxicity Grading Scale (see Clinical Protocol Section 10.9, Appendix 9, DAIDS Table) or in 
accordance with the normal ranges of the clinical laboratory if no gradings are available.
An assessment is treatment-emergent if the toxicity grade/abnormality worsened as compared to 
the grade/abnormality at baseline; this also includes the shift from abnormally high to abnormally 
low and vice-versa. Post-reference toxicities/abnormalities are always treatment-emergent with
regard to missing toxicities/abnormalities at baseline. The abnormalities ‘Abnormally high’ and 
‘Abnormally low’ are considered equally important.
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. The worst toxicity case is the 
value associated to the highest toxicity grade and is derived per parameter and 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).
Change from baseline will be evaluated for all time points when assessed and is defined as follows: 
value at a given time point minus baseline value.
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). 
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
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.
6.2.2.
Analysis Methods
Descriptive statistics (for example, may include n, mean, SD, minimum, median, and maximum) 
will be calculated for each laboratory analyte for observed values and changes from baseline at 
each scheduled time point by intervention arm and study phase.
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, time point and per 
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 2.4.2.
Plots of mean (+/- SE) values and changes from baseline over time for selected laboratory 
parameters will be presented by intervention arm. 
A listing including all parameters with at least one treatment-emergent toxicity or abnormality per 
participant (exclusion of urinalysis) will be generated. 
Spaghetti-plots for selected laboratory parameters may be presented by intervention arm over time
(with Week shown on x-axis).
6.2.3.
Creatinine and Glomerular Filtration
Unless otherwise specified, time points to be evaluated for these creatinine and glomerular 
filtration analyses will be Baseline, Week 12, Week 24, Week 36 and Week 48.
6.2.3.1.
eGFR
Stages of eGFR at baseline versus the minimum post-baseline eGFR value and the last available 
value will be summarized by count and percent of participants. Kidney disease stages 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-<30%, 30-<50% and 
≥50% decrease from baseline will be tabulated.
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Scatter plots of GFR 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.
6.2.3.2.
Proximal Renal Tubular Function
Proteinuria by Quantitative Assessment
Total urine protein, total urine albumin, UPCR and UACR will be summarized by intervention 
arm 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 intervention arm.
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 
intervention arm. 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 intervention arm 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.
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 intervention arm and visit using 
descriptive statistics.
FEPO4 will be calculated as follows:
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
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 
intervention arm and visit using descriptive statistics. Median (Q1, Q3) change from baseline in 
FEPO4 over time will be plotted by intervention arm. 
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).
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). 
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6.3.
Electrocardiogram
6.3.1.
Definitions
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)
The abnormalities in ECG parameters will be determined according to the criteria specified in the 
Cardiovascular Safety – Abnormalities Table (see Clinical Protocol Appendix 6, 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 treatment-emergent 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 treatment-emergent 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 treatment-emergent.
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).
Change from baseline is defined as follows: value at a given time point minus baseline value.
6.3.2.
Analysis Methods
Only data from the vendor ERT will be analyzed. All other ECG data will be listed.
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.
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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 intervention arm. 
Shift tables will be provided summarizing the shift in ECG 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 (on actual values) versus baseline per parameter by 
study phase will be presented including also the number of participants per abnormality. A 
tabulation of percentage and number of the participants who have treatment-emergent worst 
abnormalities per parameter (i.e. for HR, PR, QRS, and QTcF) and analysis 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 intervention arm 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 intervention arm.
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. 
6.4.
Vital Signs and Body Temperature
6.4.1.
Definitions
The following parameters measurements will be analyzed:

Supine pulse rate (bpm)

Supine systolic blood pressure (mmHg)

Supine diastolic blood pressure (mmHg)

Body temperature (℃)
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The abnormalities in vital signs will be determined according to the criteria specified in the 
Cardiovascular Safety – Abnormalities Table (see Clinical Protocol Section 10.7, Appendix 7).
An assessment is treatment-emergent 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).
Change from baseline is defined as follows: value at a given time point minus baseline value.
6.4.2.
Analysis Methods
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.
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) is provided. Additional vital signs assessments 
corresponding to the rash eCRF pages will be only listed as applicable.
6.5.
Physical Examination
The physical examination findings and abnormalities will be listed.
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7.
VIRAL GENOME SEQUENCE ANALYSIS
The sequencing of samples from participants in this study may be triggered by the sponsor 
virologist based on changes in HBV DNA levels observed in each individual subject and the limits 
of the sequencing assay.
Viral genome sequence analysis will be performed to evaluate the presence of genetic variations 
(including substitutions) associated with JNJ-56136379, JNJ-3989, and/or ETV or TDF/TAF
treatment on both nucleotide and/or amino acid level.
Sequencing of the HBV genome will be performed to monitor HBV variants present at the time 
points indicated in Section 7.1. 
Virology results will be presented by specified timepoints and genetic region and position of 
interest. A separate virology report will be prepared. 
7.1.
Time Points and Samples
When analyzing sequencing data, the focus will be on genetic variants at 

Time Point of Sequence at Virologic Breakthrough: time point with sequence data available 
closest to the time point of virologic breakthrough (FTPT) (see Section 5.3.1.1.7 for virologic 
breakthrough definition)

Time Point of Sequence at Virologic Flare: time point with sequence data available closest to 
the time point of Virologic flare (see Section 5.3.1.1.6 for virologic flare definition)

Time Point of Sequence at Re-treatment during Post-treatment Follow-up: time point with 
sequence data available closest to time point where re-treatment criteria is met (see Section 
5.3.1.1.8)

Aggregated Post-Baseline Study Period (ASSEQ): entire post-baseline study period, 
aggregate of all available time points in the study with sequence data available

Aggregated Post-Baseline Treatment Period (ATSEQ): entire post-baseline treatment period, 
aggregate of all available post-baseline time points during the treatment phase with sequence 
data available
Given only participants who are on stable NA treatment and who have HBV DNA <60 IU/mL at 
screening will be enrolled in this study, no baseline sequencing can be performed. In the 
exceptional case baseline HBV DNA levels are above the sensitivity limit of the sequencing assay 
used, the baseline sample may be sequenced.
7.2.
Definitions

The presence of genetic variations is defined as changes (on the amino acid or nucleotide 
level) in the subject viral sequence compared to a HBV genotype specific reference viral 
sequence and/or the universal HBV reference sequence (NCBI ID X02763). The reference 
sequence to be used is provided in the database. The reference viral sequences to be used are:
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A), which is the master reference sequence of the HBV db, will be used as universal reference 
sequence.
All NGS data will be collected using a nt and aa read frequency cut-off of ≥0.01. For the analysis 
of nt changes and/or aa substitutions in terms of frequency of variant, a read frequency cut-off of 
≥0.15 will be used. The persistence of nt changes and aa substitutions will be evaluated using a 
cut-off of ≥0.15 and ≥0.01. 
The applicability of the sequencing approach described here (eg, the 0.01 sensitivity limit) will be 
assessed during the development program and might be adapted if needed.
7.4.
Positions & Genetic Variations of Interest
On the nucleotide level:
In the basal core promotor region:

1762 and 1764 (ECo numbering will be used)
In the precore region:

1896 (ECo numbering will be used)
In the basal core/precure region

Combination of basal core promotor and/or precore region
In the JNJ-3989 binding pocket positions:

JNJ-3976 (S Trigger)

Long list (N=21): 259, 260, 261, 262, 263, 264, 265, 266, 267, 268, 269, 270, 271, 272, 
273, 274, 275, 276, 277, 278, and 279

Short list (N=17): 262, 263, 264, 265, 266, 267, 268, 269, 270, 271, 272, 273, 274, 275, 
276, 277, and 278

JNJ-3924 (X Trigger)

Long list (N=21): 1779, 1780, 1781, 1782, 1783, 1784, 1785, 1786, 1787, 1788, 1789, 
1790, 1791, 1792, 1793, 1794, 1795, 1796, 1797, 1798, and 1799

Short list (N=17): 1782, 1783, 1784, 1785, 1786, 1787, 1788, 1789, 1790, 1791, 1792, 
1793, 1794, 1795, 1796, 1797, and 1798

In the JNJ-3976/JNJ-3924
Combination of JNJ-3989 binding site positions JNJ-3976 and/or JNJ-3924
Amino acid level:
In the HBV core protein (based on putative binding pocket [Bourne C. et al., 2006 & Katen S.P. 
et al., 2013])
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
Long list (n=48): 18, 19, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 37, 38, 102, 103, 105, 106, 
107, 109, 110, 111, 114, 115, 116, 117, 118, 119, 121, 122, 123, 124, 125, 126, 127, 128, 129, 
131, 132, 133, 134, 136, 137, 138, 139, 140, 141

Due to an insertion of 12 amino acids in the N-terminal part of core, the 48 HBV Core Protein 
positions of interest for HBV genotype G are 30, 31, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 
49, 50, 114, 115, 117, 118, 119, 121, 122, 123, 126, 127, 128, 129, 130, 131, 133, 134, 135, 
136, 137, 138, 139, 140, 141, 143, 144, 145, 146, 148, 149, 150, 151, 152, 153. 
Based on some recent more detailed published structural data (Klumpp K. et al., 2015, Qiu Z. et 
al., 2016, Zhou Z. et al., 2017, & Tu J. et al., 2017), and some in house structural analysis, a more 
shortened list of core positions of interest can be defined:

Short list (n=29): 23, 24, 25, 29, 30, 33, 37, 38, 102, 105, 106, 109, 110, 118, 121, 122, 124, 
125, 127, 128, 129, 132, 133, 134, 137, 138, 139, 140, 141

Due to an insertion of 12 amino acids in the N-terminal part of core, the 29 HBV Core 
Protein positions of interest for HBV genotype G are 35, 36, 37, 41, 42, 45, 49, 50, 114, 
117, 118, 121, 122, 130, 133, 134, 136, 137, 139, 140, 141, 144, 145, 146, 149, 150, 151, 
152, 153

Short list (n=15): 23, 24, 25, 29, 30, 33, 37, 105, 106, 109, 110, 118, 124, 127, 128.

Due to an insertion of 12 amino acids in the N-terminal part of core, the 15 HBV Core 
Protein positions of interest for HBV genotype G are 35, 36, 37, 41, 42, 45, 49, 117, 118, 
121, 122, 130, 136, 139, 140
In the pol/RT protein:

169, 173, 180, 181, 184, 194, 202, 204, 236, 250
See below breakdown of relative amino acid position of the 10 POI in the RT-domain of 
polymerase by HBV genotype. 
HBV GT-A
HBV-GT-B/C/F/H/I
HBV GT-D
HBV-GT-E/G
POL 
number
RT 
number
POL 
number
RT 
number
POL 
number
RT 
number
POL 
number
RT 
number
517
169
515
169
504
169
514
169
521
173
519
173
508
173
518
173
528
180
526
180
515
180
525
180
529
181
527
181
516
181
526
181
532
184
530
184
519
184
529
184
542
194
540
194
529
194
539
194
550
202
548
202
537
202
547
202
552
204
550
204
539
204
549
204
584
236
582
236
571
236
581
236
598
250
596
250
585
250
595
250
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In the major hydrophilic loop of the S-protein region (linked to vaccine escape):

Amino acids 99 to 169

Positions of interest: 116, 118, 120, 126, 129, 130, 131, 133, 134, 141, 142, 143, 144, 145, 
164, 195, and 196.
7.5.
Analysis Methods
Frequencies and percentages will be presented at the time points specified above for the specified 
parameters. The denominator is the number of subjects with sequencing data at the selected time 
point. 
A frequency output and/or figure will only be generated if number of participants with respective 
sequence information available (i.e. baseline sequence info for baseline outputs and paired 
baseline/post-baseline sequence info for post-baseline outputs) for that respective output or figure 
is greater or equal to 5 (N≥5).
For comparison of amino acid or nucleotide levels to universal or genotype specific HBV reference 
sequences descriptive summaries may be performed by subgroups. 
7.5.1.
Post-Baseline

Time of Virologic Breakthrough (if applicable)
For virologically suppressed participants who experience virologic breakthrough but who don't 
have baseline sequence information available, the frequency of genetic variations (with a primary 
focus on substitutions) at time of viral breakthrough will be tabulated in frequency outputs (n, %), 
based on NGS data (1% and 15% cut-off), for participants with viral sequence info available at 
time of viral breakthrough.
The return to wild type for subjects with virologic breakthrough and genetic variations at time of 
virologic breakthrough will be tabulated in frequency outputs based on NGS data, as well as the 
genetic variations in subjects who did not return to wild type.

Time of Virologic /Clinical Flare (if applicable)
For virologically suppressed participants who experience virologic/clinical flare but who don't 
have baseline sequence information available, the frequency of genetic variations (with a primary 
focus on substitutions) at time of virological/clinical flare will be tabulated in frequency outputs 
(n, %), based on NGS data (1% and 15% cut-off), for participants with viral sequence information 
available at time of flare.
The return to wild type for subjects with virologic/clinical flare and genetic variations at time of 
virologic/clinical flare will be tabulated in frequency outputs based on NGS data, as well as the 
genetic variations in subjects who did not return to wild type.

Time of Re-treatment during Post-treatment Follow-up  
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For virologically suppressed participants who meet NA re-treatment criteria but who don't have 
baseline sequence information available, the frequency of genetic variations (with a primary focus 
on substitutions) at time of meeting NA re-treatment criteria will be tabulated in frequency outputs 
(n, %), based on NGS data (1% and 15% cut-off), for participants with viral sequencing 
information available at time of meeting NA re-treatment criteria.
The return to wild type for subjects who meet re-treatment criteria during follow-up and genetic 
variations at time of meeting the re-treatment criteria will be tabulated in frequency outputs based 
on NGS data, as well as the genetic variations in subjects who did not return to wild type.

Other Post-Baseline
The frequency of variant of genetic variations at other time points will be tabulated in frequency 
outputs (n, %), based on NGS data (1% and 15% cut-off), and the genetic variations will be listed 
for all subjects. Time points of specific interest are end-of-treatment, time point of re-treatment, 
and end-of-study. 
7.5.2.
  Over the Study Period
For all subjects, listings with relevant baseline disease and demographic characteristics, session 
info, all genetic variations at baseline (if available), at time of virologic breakthrough (if 
applicable), at end of study treatment, and at end of study will be generated. 
For all subjects, listings with relevant baseline disease and demographic characteristics, session 
info, and aggregate post-baseline sequence data over the whole treatment period, and aggregate 
post-baseline sequence data over the whole study period will be generated.
7.6.
HBV genotype
For all subjects for whom viral sequencing is performed, also an HBV genotype will be reported 
using the HBV full genome sequence and phylogenetic analysis. The number and percentage of 
subjects by HBV genotype for study analysis will be tabulated. 
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Status: Approved, Date: 08 July 2022
8.
PHARMACOKINETICS/PHARMACODYNAMICS
8.1.
Pharmacokinetics 
Two types of PK analyses will be conducted, including noncompartmental analysis in the PK sub-
study participants and population PK analysis in all participants. Details of the PK analyses will 
be described in a separate analysis plan and results will be reported separately.
8.2.
Pharmacokinetic/Pharmacodynamic Relationships 
Relationships of PK parameters for JNJ-3989, JNJ-6379, JNJ-3924 and/or NAs (ETV, TAF and/or 
TDF), as applicable, with selected efficacy and with selected safety endpoints will be evaluated, 
applying graphical tools and, if feasible, statistical models.
Modeling of key pharmacodynamic parameters (e.g. HBsAg, HBV DNA) may be performed using 
population pharmacokinetics/pharmacodynamics (PK/PD). Details of the PK/PD analyses will be 
described in a population PK/PD analysis plan and results will be presented in a separate report.
8.3.
Immune 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 
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 by intervention arm 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.
9.
PATIENT-REPORTED OUTCOMES
The impact of HBV treatment on participants will be assessed using PROs at predefined time 
points. The following PRO instruments will be used: HBV-specific self-stigma scale and 
EQ-5D-5L questionnaire. All PRO analyses will be performed using the ITT analysis set.
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9.1.
HBV-specific Self-stigma PRO Scale
9.1.1.
Definition
The HBV-specific self-stigma scale is a hepatitis B-specific PRO instrument designed to assess 
the experience and impact of self-stigma. The current version consists of 37 items. The items cover 
aspects of self-stigma such as a) devaluation, inferiority, and worthlessness, b) marginalization 
and alienation, c) secrecy and concealment, d) shame and guilt, and e) withdrawal and social 
isolation. Each of the 37 items is graded on a 5-point Likert scale (1=“Never”, 2=“Rarely”, 
3=“Sometimes”, 4=“Often”, and 5=“Always”).
9.1.2.
Analysis Methods
Descriptive statistics of the actual values and change from baseline values at each timepoint 
(including baseline and available analysis time point) for the scores will be displayed for each 
aspect by intervention arm. The proportion of participants experiencing a clinically important 
improvement or worsening from baseline (if applicable) at each timepoint will be calculated by 
intervention arm. Analyses will also be performed on the changes from baseline at specific time 
points as appropriate for different subgroups: participants with versus participants without HBsAg 
seroclearance 24 weeks and 48 weeks after completion of all study intervention at Week 48.
In addition, effect sizes will be calculated to measure the magnitude of difference between means 
in all different intervention arms using an ANCOVA, with intervention arm, and 3 randomization 
stratification factors, as main effect in the model, and the three 2-way intervention arm-
stratification factor interaction terms, and baseline as covariate. The LS means of the change from 
baseline on the analysis time points with estimates, SE, 90% CI, p-values will be presented. A 
graphical representation may be used to display the adjusted mean change from baseline.
9.2.
5-Level EuroQol 5-Dimension Questionnaire
9.2.1.
Definition
The EQ-5D-5L questionnaire is a generic health-related quality-of-life assessment that evaluates 
a participant’s self-rated health state on 5 dimensions (mobility, self-care, usual activities, 
pain/discomfort, anxiety/depression). Additionally, a VAS records the participant’s self-rated 
health on a vertical VAS where the endpoints are labelled ‘best imaginable health state’ (100) and 
‘worst imaginable health state’ (0). 
The EQ-5D-5L questionnaire will be analyzed in 3 ways:

EQ-5D descriptive system scores (5 scores reflecting each of the 5 dimensions see Attachment 
3 for a representative example of the EQ-5D-5L).
An assessment that evaluates a subject’s self-rated health state on 5 dimensions (mobility, 
self-care, usual activities, pain/discomfort, anxiety/depression) with 5 possible levels (no 
problems (level code = 1), slight problems (level code = 2), moderate problems (level code = 
3), severe problems (level code = 4), extreme problems (level code = 5)). 
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
EQ-5D VAS a continuous score ranging from 0 to 100 (with a possible range from 0 [worst 
imaginable health] to 100 [best imaginable health]);
This information can be used as a quantitative measure of health outcome as judged by the 
subject. 

EQ-5D Valuation Index The information of the 5 dimensions of the descriptive system 
summarized intone index. (a weighted scoring of the 5 dimensions scores with a possible 
range from 0 to 1);
EQ-5D Valuation index summarizes the information of the 5 dimensions of the descriptive system
as below.
a. Assign the level code 1, 2, 3, 4 and 5 to each level of the 5 dimensions (see above)
b. Create a health state for each patient-time point combination. A health state is a combination 
of 5 level codes; one level code for each dimension. The dimensions are ordered as described 
in the attachment.
E.g. health state 12543 indicates ‘no problems in walking about, slight problems washing or 
dressing myself, unable to do my usual activities, severe pain or discomfort, moderately 
anxious or depressed’.
c. Assign an index value (valuation index) to each observed health state using the UK
crosswalk value set as defined in Attachment 3. Based on the origin of the subjects, another 
method can be used.
Missing Data:

If – for a questionnaire – one (or more) dimensions of the descriptive system are missing, then

The EQ-5D VAS will be tabulated if not missing

The valuation index will not be tabulated

The non-missing dimensions of EQ-5D descriptive system will be summarized

If – for a questionnaire – the EQ-5D VAS is missing then the EQ-5D descriptive system and 
validation index will be tabulated if complete.
9.2.2.
Analysis Methods
For the EQ-5D descriptive system, descriptive statistics on the actual value and change from 
baseline will be presented. 
For the EQ-5D VAS and for the Valuation index, descriptive statistics for the actual and change 
from baseline values at each time point will be displayed. In addition, mean changes from baseline 
will be explored per subgroup: participants with versus participants without HBsAg seroclearance 
24 weeks and 48 weeks after completion of all study intervention at Week 48. The clinically 
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important thresholds of 7 and 10 will be used to interpret the mean change from baseline in the 
VAS. 
The number (and percentage) of participants with clinically important improvement/ worsening 
will be presented for EQ-5D VAS:

Clinical Important Improvement = change from baseline ≥7, and also for ≥ 10

Clinical Important Worsening = change from baseline ≤-7, and also for ≤-10. 

Other changes from baseline values are categorized as ‘No Clinically Important Change’.
A cumulative distribution function of the EQ-5D VAS will be drawn at different time points 
(baseline and changes from baseline).
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REFERENCES
Barnes A., Mallinckrodt C. et al. The impact of missing data and how it is handled on the rate of false-positive 
results in drug development. Pharmaceut. Statist. 2008; 7: 215–225
Bourne, C. R., Finn, M. G., & Zlotnick, A. (2006). Global structural changes in hepatitis B virus capsids induced by 
the assembly effector HAP1. Journal of virology, 80(22), 11055-11061.
Brooks ST, Whitely E, Egger M, Smith GD, Mulheran PA, Peters TJ. Subgroup analyses in randomized trials: risks 
of subgroup-specific analyses; power and sample size for the interaction test. J Clin Epidemiol. 2004;229-236
Graham JW, Olchowski A E, Gilreath T D, How Many Imputations are Really Needed? Some Practical 
Clarifications of Multiple Imputation Theory, Prev Sci . 2007 Sep;8(3):206-13
Honaker J, King G et al.. Amelia II: A Program for Missing Data. Journal of Statistical Software, 45, 7, Pp. 1-47.
Katen, S. P., Tan, Z., Chirapu, S. R., Finn, M. G., & Zlotnick, A. (2013). Assembly-directed antivirals differentially 
bind quasiequivalent pockets to modify hepatitis B virus capsid tertiary and quaternary structure. Structure, 21(8), 
1406-1416.
King G., Honaker J., Joseph A., et al. Analyzing Incomplete Political Science Data: An Alternative Algorithm for 
Multiple Imputation. American Political Science Review, Vol. 95:49-69.
Klumpp, K., Lam, A. M., Lukacs, C., Vogel, R., Ren, S., Espiritu, C., ... & Efimov, A. (2015). High-resolution 
crystal structure of a hepatitis B virus replication inhibitor bound to the viral core protein. Proceedings of the 
National Academy of Sciences, 112(49), 15196-15201.
Lui K.J., Kelly C. A Revisit on Tests for Homogeneity of the Risk Difference, Biometrics, 2000; 56:309-315.
Mantel N and Haenszel W. Statistical aspects of the analysis of data from retrospective studies of disease. J Natl 
Cancer Inst. 1959;22:719-748.
Qiu, Z., Lin, X., Zhou, M., Liu, Y., Zhu, W., Chen, W., ... & Huang, M. (2016). Design and synthesis of orally 
bioavailable 4-methyl heteroaryldihydropyrimidine based hepatitis B virus (HBV) capsid inhibitors. Journal of 
medicinal chemistry, 59(16), 7651-7666.
Ratitch B., Lipkovitch I., O’Kelly M. (2013), Combining Analysis Results from Multiply Imputed Categorical Data, 
PhasrmaSUG, Paper SP03.
Tu, J., Li, J. J., Shan, Z. J., & Zhai, H. L. (2017). Exploring the binding mechanism of 
Heteroaryldihydropyrimidines and Hepatitis B Virus capsid combined 3D-QSAR and molecular dynamics. Antiviral 
research, 137, 151-164.
Zhou, Z., Hu, T., Zhou, X., Wildum, S., Garcia-Alcalde, F., Xu, Z., ... & Shen, F. (2017). 
Heteroaryldihydropyrimidine (HAP) and sulfamoylbenzamide (SBA) inhibit hepatitis B virus replication by 
different molecular mechanisms. Scientific reports, 7, 42374.
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Attachment 2.
Adverse Events of Special Interest List of Preferred Terms
Adverse 
Event of 
Special 
Interest
Source
Preferred Term
ALT/AST 
elevation
(Modified) Liver related investigations, 
signs and symptoms (SMQ) narrow, 
(MedDRA v23.1)
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
(Modified) Acute renal failure (SMQ) 
broad (MedDRA v23.1)
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
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Adverse 
Event of 
Special 
Interest
Source
Preferred Term
Renal tubular necrosis
Urine output decreased
Nephropathy
Nephropathy toxic
Glomerulonephropathy
Nephrolithiasis
Cholesterol 
increase
Dyslipidaemia (SMQ), (MedDRA 
v23.1)
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
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
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Adverse 
Event of 
Special 
Interest
Source
Preferred Term
Very low density lipoprotein decreased
Very low density lipoprotein increased
Hematologic 
abnormalities
(Modified)  Haematopoietic cytopenias 
affecting more than one type of blood 
cell (SMQ), (MedDRA v23.1)
Aplastic anaemia
Autoimmune aplastic anaemia
Bicytopenia
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 count abnormal
Blood disorder
Bone marrow disorder
Bone marrow infiltration
Bone marrow myelogram abnormal
Bone marrow necrosis
Bone marrow toxicity
Haematotoxicity
Myelodysplastic syndrome
Myelodysplastic syndrome transformation
Myelofibrosis
Myeloid metaplasia
Plasmablast count decreased
Scan bone marrow abnormal
Hematologic 
abnormalities
(Modified) Haematopoietic erythropenia 
(SMQ), (MedDRA v23.1)
Aplasia pure red cell
Aplastic anaemia
Erythroblast count decreased
Erythroid maturation arrest
Erythropenia
Hypoplastic anaemia
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Status: Approved, Date: 08 July 2022
Adverse 
Event of 
Special 
Interest
Source
Preferred Term
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
Reticulocyte percentage decreased
Hematologic 
abnormalities
(Modified)  Haematopoietic leukopenia 
(SMQ), (MedDRA v23.1)
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
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Adverse 
Event of 
Special 
Interest
Source
Preferred Term
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
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
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Adverse 
Event of 
Special 
Interest
Source
Preferred Term
White blood cell count abnormal
White blood cell disorder
Hematologic 
abnormalities
(Modified) Haematopoietic 
thrombocytopenia (SMQ), (MedDRA 
v23.1)
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
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Attachment 3.
EQ-5D-5L Crosswalk Value Sets 
Crosswalk value sets, (obtained from https://euroqol.org/eq-5d-instruments/eq-5d-5l-
about/valuation-standard-value-sets/crosswalk-index-value-calculator/) are located in the DPS.
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