Clinical trial NCT04439539
Conditions: Hepatitis B, Chronic
Sponsor: Janssen Research & Development, LLC
Start date: 2020-09-14; Completion date: 2024-02-13
Enrollment: 54 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study is to evaluate the efficacy of a treatment regimen of JNJ-73763989 + pegylated interferon alpha-2a (PegIFN-alpha-2a) + nucleos(t)ide analog (NA).

Detailed description:
Hepatitis B virus (HBV) is a small deoxyribonucleic acid virus that specifically infects the human liver. The acute phase of infection is either followed by an immune controlled state or progresses to chronic hepatitis B. The worldwide estimated prevalence of chronic HBV infection is about 292 million people affected. Hepatitis B surface antigen (HBsAg) seroclearance is currently considered to be associated with the most thorough suppression of HBV replication (termed functional cure). With current available NA treatment strategies, rate of HBsAg seroclearance remains very low (around 3 percent \[%\]) even under long-term treatment. Also, with the persistently high global prevalence of HBV-associated mortality, there is a medical need for more effective finite treatment options that lead to sustained HBsAg seroclearance. JNJ-73763989 is a liver-targeted antiviral therapeutic for subcutaneous injection designed to treat chronic HBV infection via a ribonucleic acid interference (RNAi) mechanism. JNJ-56136379 is an orally administered capsid assembly modulator (CAM) that is being developed for the treatment of chronic HBV infection. The aim of the study is to evaluate the efficacy of a treatment regimen of JNJ-73763989 + PegIFN-alpha-2a + NA with or without JNJ-56136379 in participants with hepatitis B e antigen (HBeAg) positive chronic infection. The study will be conducted in 4 phases: a screening phase, an induction phase with flexible duration, a consolidation phase with or without PegIFN-α2a and a follow-up phase. Safety assessments will include Adverse Events (AEs), serious AEs of the study interventions, clinical laboratory tests, Electrocardiograms (ECGs), vital signs, and physical examinations. The study title reflects the original study design and JNJ-56136379 (JNJ-6379) was initially part of the study intervention but was discontinued as per amendment 6 of the study.

Arms: arm 1: During the Induction phase, participants will receive JNJ-73763989 subcutaneously along with JNJ-56136379 tablet orally with NA (either tenofovir disoproxil or tenofovir alafenamide tablets orally) treatment. At the start of consolidation phase, participants will be randomized to receive PegIFN-alpha-2a subcutaneously in addition to JNJ-73763989 and JNJ-56136379 with NA in arm 1 and arm 2 (without PegIFN-alpha-2a). According to predefined criteria NA treatment may be continued during the follow up (FU) phase. arm 2: Following implementation of protocol amendment- 5 and 6, all participants will receive JNJ-73763989 subcutaneously along with NA (tenofovir disoproxil tablets orally) for 36 weeks (induction phase). In the consolidation phase, participants will receive PegIFN-alpha-2a subcutaneously in addition to JNJ-73763989 and NA for 12 weeks. According to predefined criteria NA treatment may be continued during the follow up (FU) phase. JNJ-56136379 (JNJ-6379) was discontinued as per amendment 6 of the study.
Interventions: intervention 1: JNJ-73763989 intervention 2: PegIFN-alpha-2a intervention 3: Tenofovir disoproxil intervention 4: Tenofovir alafenamide intervention 5: JNJ-56136379
Intervention descriptions: intervention 1: JNJ-73763989 injection will be administered subcutaneously. intervention 2: PegIFN-alpha-2a injection will be administered subcutaneously. intervention 3: Tenofovir disoproxil film-coated tablet will be administered orally. intervention 4: Tenofovir alafenamide film-coated tablet will be administered orally. intervention 5: JNJ-56136379 will be administered orally.

Protocol documents:
Prot_000.pdf: 
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
1
Status: Approved,Date: 25 November 2021
Janssen Research & Development *
Clinical Protocol
Intervention-specific Appendix 3 to Master Protocol PLATFORMPAHPB2001
A Phase 2, randomized, open-label, multicenter study to evaluate efficacy,
pharmacokinetics, safety, and tolerability of treatment with JNJ-73763989, pegylated
interferon alpha-2a, nucleos(t)ide analog with or without JNJ-56136379 in treatment-naïve
patients with HBeAg positive chronic hepatitis B virus infection
The REEF-IT Study
Protocol 73763989PAHPB2005; Phase 2
Amendment 7
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:2019-004978-26
Status: 
Approved
Date: 
25 November 2021
Prepared by: Janssen Research & Development, a division of Janssen Pharmaceutica NV
EDMS number: 
EDMS-ERI-204178715,12.0
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, commercial information, 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 statuses, regulations, rules, protective orders or
otherwise.
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JNJ-73763989 and JNJ-56136379 
Clinical Protocol 73763989PAHPB2005
Amendment 7
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
2
Status: Approved,  Date: 25 November 2021
PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE
DOCUMENT HISTORY
Document 
Date
Amendment 7 
This document
Amendment 6 
30 September 2021
Amendment 5 
30 July 2021
Amendment 4 
30 April 2021
Amendment 3 
26 January 2021
Amendment 2 
08 July 2020
Amendment 1 
24 April 2020
Original Protocol 
19 February 2020
Amendment 7 (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 during follow-up.
With Amendment 6, 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 –Consolidation
Phase and Follow-up Phase
2.3.3 Benefit-Risk Assessment for Study
Participation
4.2 Scientific Rationale for Study Design
6.6.2 NA Re-treatment Criteria and Monitoring
After Stopping of NA
10.16 Appendix 16: NA Re-treatment and
Monitoring After Stopping of NA
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JNJ-73763989 and JNJ-56136379 
Clinical Protocol 73763989PAHPB2005
Amendment 7
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
3
Status: Approved,  Date: 25 November 2021
Description of Change 
Brief Rationale 
Section Number and Name
Minor errors were corrected in 
the Schedule of Activities. 
Correction. 
1.3.1 Schedule of Activities –Screening Phase
and Induction Phase
1.3.2 Schedule of Activities –Consolidation
Phase and Follow-up Phase
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JNJ-73763989 and JNJ-56136379 
Clinical Protocol 73763989PAHPB2005
Amendment 7
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
4
Status: Approved,  Date: 25 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.......................................................................................................................................... 21
1.3. 
Schedule of Activities..................................................................................................................... 24
1.3.1. 
Schedule of Activities –Screening Phase and Induction Phase................................................ 24
1.3.2. 
Schedule of Activities –Consolidation Phase and Follow-up Phase ......................................... 30
2. 
INTRODUCTION................................................................................................................................ 35
2.1. 
Study Rationale.............................................................................................................................. 36
2.2. 
Background .................................................................................................................................... 37
2.2.1. 
Nonclinical Studies ..................................................................................................................... 37
2.2.1.1. 
JNJ-3989 and JNJ-6379.......................................................................................................... 37
2.2.1.2. 
Combination of JNJ-3989 or JNJ-6379 with Tenofovir Disoproxil........................................... 42
2.2.1.3. 
Combination of JNJ-3989 or JNJ-6379 with PegIFN-α2a....................................................... 43
2.2.1.3.1. 
Combination of JNJ-6379 with PegIFN-α2a........................................................................ 43
2.2.1.3.2. 
Combination of JNJ-3989 with PegIFN-α2a........................................................................ 44
2.2.2. 
Clinical Studies ........................................................................................................................... 45
2.2.2.1. 
JNJ-3989 and JNJ-6379.......................................................................................................... 45
2.2.2.2. 
Combination of JNJ-3989 and JNJ-6379 with Tenofovir Disoproxil........................................ 51
2.2.2.3. 
Combination of JNJ-3989 and JNJ-6379 with PegIFN-α2a.................................................... 52
2.3. 
Benefit-Risk Assessment............................................................................................................... 52
2.3.1. 
Benefits for Study Participation .................................................................................................. 53
2.3.1.1. 
Known Benefits........................................................................................................................ 53
2.3.1.2. 
Potential Benefits..................................................................................................................... 53
2.3.2. 
Risks for Study Participation....................................................................................................... 54
2.3.2.1. 
Known Risks............................................................................................................................ 54
2.3.2.2. 
Potential Risks......................................................................................................................... 54
2.3.2.2.1. 
Potential Risks for JNJ-3989................................................................................................ 55
2.3.2.2.2. 
Potential Risks for JNJ-6379................................................................................................ 55
2.3.2.2.3. 
Potential Risks for Tenofovir Disoproxil and PegIFN-α2a.................................................... 57
2.3.3. 
Benefit-Risk Assessment for Study Participation ....................................................................... 57
3. 
OBJECTIVES AND ENDPOINTS ..................................................................................................... 59
4. 
STUDY DESIGN ................................................................................................................................ 62
4.1. 
Overall Design................................................................................................................................ 62
4.2. 
Scientific Rationale for Study Design............................................................................................. 66
4.2.1. 
Study-Specific Ethical Design Considerations ........................................................................... 69
4.3. 
Justification for Dose...................................................................................................................... 70
4.3.1. 
JNJ-3989 .................................................................................................................................... 70
4.3.2. 
JNJ-6379 .................................................................................................................................... 71
4.4. 
End-of-Study Definition .................................................................................................................. 71
5. 
STUDY POPULATION ...................................................................................................................... 72
5.1. 
Inclusion Criteria............................................................................................................................ 72
5.2. 
Exclusion Criteria........................................................................................................................... 75
5.3. 
Lifestyle Considerations................................................................................................................. 80
5.4. 
Screen Failures.............................................................................................................................. 81
6. 
STUDY INTERVENTION................................................................................................................... 82
6.1. 
Study Intervention(s) Administered................................................................................................ 82
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JNJ-73763989 and JNJ-56136379 
Clinical Protocol 73763989PAHPB2005
Amendment 7
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
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Status: Approved,  Date: 25 November 2021
6.2. 
Preparation/Handling/Storage/Accountability ................................................................................ 84
6.3. 
Measures to Minimize Bias: Randomization and Blinding............................................................. 85
6.4. 
Study Intervention Compliance...................................................................................................... 85
6.5. 
Concomitant Therapy..................................................................................................................... 86
6.6. 
Dose Modification........................................................................................................................... 88
6.6.1. 
Study Intervention Completion at Consolidation Week 12 ......................................................... 88
6.6.2. 
NA Re-treatment Criteria and Monitoring After Stopping of NA................................................. 89
6.7. 
Study Intervention After the End of the Study................................................................................ 90
7. 
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT
DISCONTINUATION/WITHDRAWAL............................................................................................... 90
7.1. 
Discontinuation of Study Intervention ............................................................................................ 90
7.2. 
Participant Discontinuation/Withdrawal From the Study................................................................ 93
7.2.1. 
Withdrawal From the Use of Research Samples ....................................................................... 93
7.3. 
Lost to Follow-up............................................................................................................................ 93
8. 
STUDY ASSESSMENTS AND PROCEDURES ............................................................................... 93
8.1. 
Efficacy Assessments .................................................................................................................... 94
8.1.1. 
Sequencing................................................................................................................................. 95
8.1.2. 
Patient-reported Outcomes ........................................................................................................ 95
8.2. 
Safety Assessments....................................................................................................................... 97
8.2.1. 
Physical Examinations................................................................................................................ 97
8.2.2. 
Vital Signs................................................................................................................................... 97
8.2.3. 
Electrocardiograms..................................................................................................................... 97
8.2.4. 
Clinical Safety Laboratory Assessments .................................................................................... 97
8.3. 
Adverse Events, Serious Adverse Events, and Other Safety Reporting ....................................... 98
8.3.1. 
Time Period and Frequency for Collecting Adverse Event and Serious Adverse Event
Information.................................................................................................................................. 98
8.3.2. 
Method of Detecting Adverse Events and Serious Adverse Events .......................................... 98
8.3.3. 
Follow-up of Adverse Events and Serious Adverse Events ....................................................... 98
8.3.4. 
Regulatory Reporting Requirements for Serious Adverse Events ............................................. 98
8.3.5. 
Pregnancy................................................................................................................................... 98
8.3.6. 
Adverse Events of Special Interest............................................................................................. 98
8.3.6.1. 
Injection Site Reactions........................................................................................................... 99
8.3.6.2. 
Intervention-emergent ALT/AST Elevations............................................................................ 99
8.3.6.3. 
Renal Complications.............................................................................................................. 100
8.3.6.4. 
Hematologic Abnormalities.................................................................................................... 101
8.3.7. 
Other Toxicities......................................................................................................................... 101
8.3.7.1. 
Rash ...................................................................................................................................... 102
8.3.7.2. 
Acute Systemic Allergic Reactions........................................................................................ 102
8.4. 
Treatment of Overdose ................................................................................................................ 103
8.5. 
Pharmacokinetics......................................................................................................................... 103
8.5.1. 
Evaluations ............................................................................................................................... 103
8.5.2. 
Analytical Procedures............................................................................................................... 104
8.5.3. 
Pharmacokinetic Parameters and Evaluations......................................................................... 104
8.6. 
Pharmacokinetic/Pharmacodynamic Evaluations........................................................................ 104
8.7. 
Immune Assessments.................................................................................................................. 104
8.8. 
Host Genetics............................................................................................................................... 105
8.9. 
Exploratory Host Biomarkers ....................................................................................................... 105
8.10. 
Medical Encounters...................................................................................................................... 106
9. 
STATISTICAL CONSIDERATIONS................................................................................................ 106
9.1. 
Statistical Hypotheses.................................................................................................................. 106
9.2. 
Sample Size Determination ......................................................................................................... 106
9.3. 
Populations for Analyses.............................................................................................................. 107
9.4. 
Statistical Analyses ...................................................................................................................... 107
9.4.1. 
Efficacy Analyses...................................................................................................................... 107
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JNJ-73763989 and JNJ-56136379 
Clinical Protocol 73763989PAHPB2005
Amendment 7
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
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Status: Approved,  Date: 25 November 2021
9.4.1.1. 
Primary Efficacy Endpoint (HBsAg Seroclearance 24 Weeks After Completion of
Consolidation Phase Treatment)........................................................................................... 108
9.4.1.2. 
Secondary and Exploratory Efficacy Endpoints .................................................................... 108
9.4.1.3. 
Resistance Analyses ............................................................................................................. 109
9.4.1.4. 
Patient-reported Outcomes ................................................................................................... 109
9.4.2. 
Safety Analyses........................................................................................................................ 110
9.4.3. 
Other Analyses ......................................................................................................................... 110
9.5. 
Interim Analyses........................................................................................................................... 111
9.6. 
Data Review Committee .............................................................................................................. 112
9.7. 
Independent Flare Expert Panel .................................................................................................. 112
10. SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS .......................... 113
10.1. 
Appendix 1: Abbreviations and Definitions of Terms................................................................... 113
10.2. 
Appendix 2: Clinical Laboratory Tests ......................................................................................... 116
10.3. 
Appendix 3: Regulatory, Ethical, and Study Oversight Considerations....................................... 117
10.4. 
Appendix 4: Adverse Events: Definitions and Procedures for Recording, Evaluating,
Follow-up, and Reporting............................................................................................................. 119
10.5. 
Appendix 5: Rash Management................................................................................................... 120
10.6. 
Appendix 6: Intervention-emergent ALT/AST Elevations ............................................................ 123
10.7. 
Appendix 7: Cardiovascular Safety –Abnormalities.................................................................... 124
10.8. 
Appendix 8: Contraceptive and Barrier Guidance and Collection of Pregnancy Information...... 125
10.9. 
Appendix 9: DAIDS Table ............................................................................................................ 127
10.10. Appendix 10: Short Form 36 version 2 (SF-36v2) 2010 Questionnaire....................................... 149
10.11. Appendix 11: Hepatitis B Quality of Life Instrument .................................................................... 160
10.12. Appendix 12: 5-Level EuroQol 5-Dimension Questionnaire (EQ-5D-5L) .................................... 166
10.13. Appendix 13: Patient Global Impression of Change Scale.......................................................... 169
10.14. Appendix 14: Protocol Amendment History................................................................................. 170
10.15. Appendix 15: COVID-19 APPENDIX........................................................................................... 182
10.16. Appendix 16: NA Re-treatment and Monitoring After Stopping of NA......................................... 186
11. REFERENCES................................................................................................................................. 187
INVESTIGATOR AGREEMENT............................................................................................................... 189
LIST OF IN-TEXT TABLES AND FIGURES
TABLES
Table 1: 
Animal/Human Exposure Ratios at NOAEL for JNJ-3989........................................................ 39
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]) .............................................. 40
Table 3: 
Disallowed Medication .............................................................................................................. 87
Table 4: 
PegIFN-α2a Hematological Dose Modification Guidelines....................................................... 88
Table 5: 
Sample Size Determination .................................................................................................... 107
Table 6: 
Management of Rash Events by Severity Grade ................................................................... 120
FIGURES
Figure 1: Schematic Overview of Cohort 1 of the Study –Prior to Protocol Amendment 5.................... 21
Figure 2: Schematic Overview of the Study –Per Protocol Amendment 5............................................. 21
Figure 3: Schematic Overview of Cohort 2 of the Study –As of Protocol Amendment 6........................ 22
NCT04439539


JNJ-73763989 and JNJ-56136379 
Clinical Protocol 73763989PAHPB2005
Amendment 7
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
7
Status: Approved,  Date: 25 November 2021
1. 
PROTOCOL SUMMARY
1.1. 
Synopsis
Clinical Protocol 73763989PAHPB2005: A Phase 2, randomized, open-label, multicenter study to evaluate
efficacy, pharmacokinetics, safety, and tolerability of treatment with JNJ-73763989, pegylated interferon
alpha-2a, nucleos(t)ide analog with or without JNJ-56136379 in treatment-naïve patients with HBeAg
positive chronic hepatitis B virus infection. Protocol 73763989PAHPB2005 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 (rcDNA). The RNAi triggers in
JNJ-3989, JNJ-73763976 (JNJ-3976) and JNJ-73763924 (JNJ-3924),are designed to target all HBV RNA
transcripts derived from covalently closed circular deoxyribonucleic acid (cccDNA), as well as transcripts
derived from integrated viral deoxyribonucleic acid (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 analogues (NAs), the current standard of care.29
JNJ-56136379 (JNJ-6379) is an orally administered capsid assembly modulator (CAM) that is being
developed for the treatment of chronic HBV infection. JNJ-6379 binds to hepatitis B core protein (HBc)
and interferes with the viral capsid assembly process, thereby preventing the polymerase-bound pgRNA
encapsidation. This results in the formation of viral HBV capsids, devoid of HBV DNA or RNA
(non-functional capsids), and ultimately in the inhibition of HBV replication. In addition, JNJ-6379 also
acts at an early stage of the viral life cycle by inhibiting the de novo formation of cccDNA potentially by
interfering with the capsid disassembly process. JNJ-6379 was initially part of the study intervention but
has been removed as study intervention with the implementation of an urgent safety measure, as described
in Protocol Amendment 6.
Study interventions:
 
Prior to Protocol Amendment 6: The term “study intervention” throughout the protocol, refers to JNJ-
3989, JNJ-6379, NA and pegylated interferon alpha-2a (PegIFN-α2a).
 
As of Protocol Amendment 6: The term “study intervention” throughout the protocol, refers to JNJ-
3989, NA and PegIFN-α2a.
Study phases:
 
Prior to Protocol Amendment 5: The term “induction phase” corresponds to the first treatment phase
of the study which starts with enrollment and has a flexible duration of 36-60 weeks (inclusive) based
on response-guided treatment (RGT). The term “consolidation phase” corresponds to the second
treatment phase of the study which starts with the randomization to one of the 2 study intervention
arms and has a fixed duration of 12 weeks.
 
With Protocol Amendment 5: The term “induction phase” corresponds to the first treatment phase of
the study which starts with the randomization to one of the 2 study intervention arms and has a fixed
duration of 36 weeks for all participants. The term “consolidation phase” corresponds to the second
treatment phase of the study which has a fixed duration of 12 weeks and includes the addition of
PegIFN-α2a to the study intervention regimens.
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NCT04439539


NCT04439539


JNJ-73763989 and JNJ-56136379 
Clinical Protocol 73763989PAHPB2005
Amendment 7
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
11
Status: Approved,  Date: 25 November 2021
- 
Single-arm: JNJ-3989 + NA + PegIFN-α2a
To distinguish between participants enrolled prior to or after Protocol Amendment 5 is in effect, the terms
Cohort 1 and Cohort 2 will be used. All participants enrolled prior to the Protocol Amendment 5 will
comprise Cohort 1. The participants enrolled after approval of Amendment 5 will comprise Cohort 2.
The study described in this ISA, as of Protocol Amendment 6, is a Phase 2a, single-arm, open-label,
multicenter, interventional study to evaluate the efficacy, pharmacokinetics, safety, and tolerability of
treatment with JNJ-3989+PegIFN-α2a+NA in patients with HBeAg positive chronic HBV infection and
ALT ≤2x ULN who are not currently being treated for their HBV infection (ie, who had <9 months of prior
treatment which ended at least 12 months before screening, including treatment-naïve patients). After
completing this study, participants may have the option to enroll into a long-term follow-up study.
The study will be conducted in 4 phases:
 
A screening phase (4 weeks [if necessary, can be extended to a maximum of 6 weeks decided on a
case-by-case basis and in agreement with the sponsor]).
 
An induction phase:
o Prior to Protocol Amendment 5: RGT of 36-60 weeks (inclusive)
Note: Participants who already passed the Week 36 visit before Protocol Amendment 5 is
in effect, will enter the consolidation phase at the next scheduled visit.
o As of Protocol Amendment 5: fixed duration of 36 weeks for all participants.
 
A consolidation phase (12 weeks).
 
A follow-up (FU) phase (48 weeks).
In total, approximately 60 participants will be enrolled in this study (including approximately 33 after
implementation of Protocol Amendment 6).
The total duration of individual participation will be 100 to 102 weeks. Of note, participants enrolled before
Protocol Amendment 5 is in effect may have a longer induction phase and a total study duration up to 126
weeks.
The induction and consolidation phase have been updated with Protocol Amendment 5 and Protocol
Amendment 6:
 
Before Protocol Amendment 5, enrolled participants will enter an induction phase with triple treatment
(JNJ-3989+JNJ-6379+NA) for a response-guided treatment duration of  ≥36 weeks to ≤60 weeks. End
of the induction phase is defined by either meeting the study defined RGT criterion (HBsAg <10
IU/mL) or reaching study Week 60, whichever comes first. The RGT criterion will be assessed from
Week 36 onwards at each study visit, and the assessment will always be based on lab results from the
previous study visit. If the RGT criterion is met, the participant will complete the induction phase at
that visit and will be randomized in a 1:1 ratio to one of the following intervention arms in the 12-
week consolidation phase: JNJ-3989+JNJ-6379+NA+PegIFN-α2a (Cohort 1, Arm 1) or JNJ-
3989+JNJ-6379+NA (Cohort 1, Arm 2). At the time of writing Protocol Amendment 5, 22 participants
were already enrolled in the study.
Note: Participants enrolled before Protocol Amendment 5 is in effect will switch to the new study
design as soon as Protocol Amendment 5 is in effect. Participants who did not yet reach the Week 36
visit at that time will have PegIFN-α2a added to their treatment regimen at Week 36 for 12 weeks.
Participants who already passed the Week 36 visit and/or were randomized to the group without
NCT04439539


JNJ-73763989 and JNJ-56136379 
Clinical Protocol 73763989PAHPB2005
Amendment 7
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
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Status: Approved,  Date: 25 November 2021
PegIFN-α2a, will have PegIFN-α2a added to their treatment regimen at the next scheduled visit. After
12 weeks, treatment with PegIFN-α2a, JNJ-3989 and JNJ-6379 (if applicable) will be stopped.
 
Per Protocol Amendment 5, based on the number of participants currently enrolled, it is estimated that
approximately 50 participants will be randomized at baseline in a 1:1 ratio to one of the following
intervention arms: JNJ-3989+JNJ-6379+NA (Cohort 2, Arm 3) or JNJ-3989+NA (Cohort 2, Arm 4).
Upon completion of the 36-week induction phase, all participants will enter the 12-week consolidation
phase during which they will have PegIFN-α2a added to their treatment regimen.
Note: With the implementation of an urgent safety measure, as described in Protocol Amendment 6,
participants previously enrolled had to immediately switch to the new study design. Participants had
to stop JNJ-6379 treatment immediately and continue with JNJ-3989+NA treatment up to the end of
the induction phase and will then enter the 12-week consolidation phase during which they will have
PegIFN-α2a added to their treatment regimen.
 
As of Protocol Amendment 6, the study will continue as a single-arm study (JNJ-3989+NA+PegIFN-
α2a). All newly enrolled participants will receive JNJ-3989+NA for 36 weeks (induction phase) and
will then enter the 12-week consolidation phase during which they will have PegIFN-α2a added to
their treatment regimen.
At the end of the consolidation phase, all participants will enter the FU phase and stop treatment with JNJ-
3989+PegIFN-α2a. If NA treatment completion criteria (HBsAg <10 IU/mL, and HBeAg-negative, and
HBV DNA <LLOQ, and ALT <3x upper limit of normal [ULN]) have been met at consolidation Week 12,
NA will also be stopped at the next scheduled visit (ie, FU Week 2), otherwise NA treatment will continue
during the complete FU phase. Participants will be monitored closely during the 48-week FU phase and
should restart NA treatment in accordance with the NA re-treatment criteria.
As of Protocol Amendment 6, study intervention consists of:
 
200 mg JNJ-3989 (SC injection Q4W)
 
245 mg tenofovir disoproxil (tablets qd) –Note: tenofovir disoproxil may be supplied as fumarate
or maleate
 
180 µg PegIFN-α2a (SC injection, QW)
Note: Most participants enrolled before Protocol Amendment 6 was in effect, also received 250 mg JNJ-
6379 (tablets qd) as part of their study intervention.
All participants who consent to participate in the intensive PK substudy (optional) will undergo intensive
PK sampling.
Participants will be considered to have completed the study if they have completed the assessments of the
end-of-study (EOS) visit (ie, FU Week 48).
A data review committee (DRC) 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
Participants who meet the NA treatment completion criteria 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 ofactivities.
NCT04439539


JNJ-73763989 and JNJ-56136379 
Clinical Protocol 73763989PAHPB2005
Amendment 7
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
13
Status: Approved,  Date: 25 November 2021
 
A post-treatment HBV DNA value of >20,000 IU/mL should trigger re-testing of ALT/aspartate
aminotransferase (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, International Normalized Ratio (INR), albumin, and
HBV DNA on a weekly basis until ALT and AST levels have returned to <5x ULN.
After stopping NA treatment, participants should re-start NA treatment:
 
Immediately with signs of decreasing liver function based on laboratory findings (eg, INR, direct
bilirubin) or clinical assessment (eg, ascites, hepatic encephalopathy).
 
Immediately with an HBV DNA value of >100,000 IU/mL (irrespective of confirmation and/or ALT
increase).
 
With confirmed post-treatment HBeAg seroreversion (HBeAg positive after it was negative at NA
completion).
 
With confirmed* post-treatment increases in HBV DNA >2,000 IU/mL and ALT >5x ULN.
 
With confirmed* post-treatment increases in HBV DNA >20,000 IU/mL.
* At least 4 weeks apart –frequency of visits as described above.
Note: Additional re-testing and/or earlier restarting of NA treatment is at the investigator’s discretion, even
if the above cut-offs are not yet met.
To avoid delays in decision making, sites are encouraged to run local re-testing in parallel with central
re-testing in the situations described above that require more frequent re-testing. Local test results are to be
recorded in the CRF and/or source documents, including information on the HBV DNA assay used. In
addition, to avoid delays in NA re-treatment, it should be considered to dispense NA to participants who
potentially met the NA re-treatment criteria (eg, pending confirmation) and who will not be available to
come to the study site immediately at the time the confirmatory test results will become available. This
should ensure that the participant can immediately re-start NA treatment if indicated, upon direct
confirmation by the investigator.
NUMBER OF PARTICIPANTS
In total, a target of approximately 60 adult participants, 18-55 years (inclusive) of age (with a maximum of
approximately 10 participants >45 to ≤55 years of age), with CHB who are HBeAg positive, who are not
currently being treated for their HBV infection (ie, who had <9 months of prior treatment which ended at
least 12 months before screening, including treatment-naïve patients), have HBV DNA ≥20,000 IU/mL and
have ALT ≤2x ULN at screening will be enrolled in this study (including approximately 33 participants
after implementation of Protocol Amendment 6). It is targeted to enroll at least 30% participants with HBV
DNA ≥107 IU/mL and normal ALT at screening in the study.
NCT04439539


JNJ-73763989 and JNJ-56136379 
Clinical Protocol 73763989PAHPB2005
Amendment 7
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
14
Status: Approved,  Date: 25 November 2021
Description of Interventions
Intervention Name 
JNJ-3989 
JNJ-6379*** 
PegIFN-α2a  
Tenofovir disoproxil 
Tenofovir alafenamide*
Type 
Drug 
Drug 
Drug 
Drug 
Drug
Dose Formulation 
Solution for injection  
Tablets 
Solution for injection  
Film coated tablets 
Film coated tablets
Unit Dose Strength(s) 
200 mg/mL 
25 and 100 mg 
180 µg/0.5 mL 
245 mg 
25 mg
Dosage Level(s) 
200 mg once every 4 
weeks (Q4W) 
250 mg once daily (qd) 
180 µg once weekly 
(QW)**
245 mg qd 
25 mg qd
Route of Administration 
Subcutaneous injection 
(preferably in the 
abdomen) 
Oral 
Subcutaneous injection 
(in the thigh or
abdomen)
Oral 
Oral
Use 
Investigational 
intervention  
Investigational 
intervention  
Investigational 
intervention
Background intervention  
Background intervention
Investigational Medicinal 
Product (IMP) and Non-
Investigational Medicinal
Product (NIMP)
IMP  
IMP  
IMP  
IMP  
IMP
Sourcing 
Provided centrally by the 
Sponsor 
Provided centrally by the 
Sponsor 
Provided centrally by the 
Sponsor 
Provided centrally by the 
Sponsor 
Provided centrally by the
sponsor
Packaging and Labeling 
Each unit will be labeled 
with unique medication 
ID number 
Each unit will be labeled 
with unique medication 
ID number 
Commercial supplies 
will be sourced. Each 
unit will be labeled with 
unique medication ID 
number. 
Commercial supplies 
will be sourced. Each 
unit will be labeled with 
unique medication ID 
number. 
Commercial supplies
will be sourced. Each
unit will be labeled with
unique medication ID
number.
In child resistant 
packaging 
In child resistant 
packaging 
In child resistant 
packaging 
In child resistant
packaging
Labels will contain information to meet the applicable regulatory requirements.
Food/Fasting Instructions 
Regardless of food 
intake 
Regardless of food 
intake 
Per the prescribing 
information  
Per the prescribing 
information  
Per the prescribing
information
Q4W: once every 4 weeks; qd: once daily; QW: once weekly.
*In countries where tenofovir alafenamide is available, it may be used for participants who need to switch NA (refer to Section 8.3.6.3).
**For PegIFN-α2a, dose adjustment may be applicable for participants who develop laboratory abnormalities during PegIFN-α2a treatment (refer to Section 6.6).
*** Most participants enrolled before Protocol Amendment 6 was in effect, also received JNJ-6379 as part of their study intervention. As of Protocol Amendment 6:
study intervention includes JNJ-3989, NA and PegIFN-α2a.
NCT04439539


JNJ-73763989 and JNJ-56136379 
Clinical Protocol 73763989PAHPB2005
Amendment 7
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
15
Status: Approved,  Date: 25 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-HBs and
anti-hepatitis B e (anti-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 (see
Schedule of Activities). The following 4 PRO instruments will be used: SF-36v2, HBQOL, EQ-5D-5L, and
PGIC.
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 or serum (as applicable) samples will be used to evaluate the PK ofthe study intervention. Samples
collected for analyses of the study intervention’s concentrations may additionally be used to evaluate safety
or efficacy aspects.
Venous blood samples will be collected for measurement of plasma or serum concentrations, as applicable,
of JNJ-3989 (ie, JNJ-3976 and JNJ-3924), NA and PegIFN-α2a, at time points specified in the Schedule of
Activities. Bioanalysis of NA and PegIFN-α2a is optional at the discretion of the sponsor. Bioanalysis of
JNJ-6379 may also be done on samples collected from participants who received JNJ-6379 up to Protocol
Amendment 5.
NCT04439539


JNJ-73763989 and JNJ-56136379 
Clinical Protocol 73763989PAHPB2005
Amendment 7
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
16
Status: Approved,  Date: 25 November 2021
All participants will have sparse PK sampling. Participants who consent to participate in the intensive PK
substudy (optional) will also undergo intensive PK sampling at time points specified in the Schedule of
Activities.
Data from this study may be combined with other studies via population PK modeling 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 for JNJ-3989 (ie, JNJ-3976 and JNJ-3924), and, optionally, JNJ-
6379, NA and/or PegIFN-α2a, with selected efficacy and/or with selected safety endpoints will be
evaluated, if applicable.
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.
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 mandatory sample for human leukocyte antigen (HLA) haplotyping will be collected from all
participants.
An optional pharmacogenomic (host DNA) blood sample may be collected (preferably at baseline)to allow
for host pharmacogenomic research, where local regulations permit. In addition, host DNA blood samples
to allow for epigenetic analyses may 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.
NCT04439539


JNJ-73763989 and JNJ-56136379 
Clinical Protocol 73763989PAHPB2005
Amendment 7
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
17
Status: Approved,  Date: 25 November 2021
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.
STATISTICAL METHODS
Sample Size Determination
According to the initial study design, the plan was to enroll 80 participants in the study to achieve at least
70 participants to be randomized at the end of the induction phase. At the time of writing Protocol
Amendment 6, 28 participants were already enrolled in the study. Participants who already passed the Week
36 visit and/or were randomized to the group without PegIFN-α2a by the time Protocol Amendment 6 is in
effect, will have PegIFN-α2a added to their treatment regimen at the next scheduled visit and will enter the
12-week consolidation phase. For the purpose of the statistical analyses, all participants enrolled prior to
Protocol Amendment 5 will comprise “Cohort 1”. All participants enrolled after approval of Protocol
Amendment 6 will comprise “Cohort 2”.
With the introduction of the new study design in Protocol Amendment 6 (single-arm), no formal sample
size re-calculation was performed. The targeted total sample size (Cohort 1 and Cohort 2 combined) was
set to approximately 60 participants. With a sample size of 33 participants in Cohort 2 and assuming a 10%
dropout rate, 30 participants in Cohort 2 would be expected to have data for the primary efficacy endpoint
at 24 weeks after stopping all study interventions of the consolidation phase and without restarting NA
treatment. If at least 15 (50%) participants are responders, this sample size will allow to conclude with 90%
confidence that the true response rate is at least 0.34, with a confidence interval (CI) width of 0.322 (90%
CI: 0.339 - 0.661).
Efficacy Analyses
The primary efficacy analysis will be performed when all participants have completed FU Week 24 or
discontinued earlier. The final analysis will be performed when all participants have completed the last
study visit (FU Week 48) or discontinued earlier.
To evaluate the efficacy, the primary analysis set will be the intent-to-treat (ITT) population of Cohort 2:
all participants who were randomized or enrolled and who received at least 1 dose of consolidation phase
study intervention within this ISA will be included in the ITT population. The efficacy for Cohort 1 will be
evaluated on the treated population set. A secondary analysis of efficacy will be performed combining the
data pre- and post-Amendment 6, i.e. combining the data from participants who received PegIFN-α2a but
not JNJ-6379 in Cohort 1 with data of Cohort 2. The approach to combine data from the 2 cohorts will be
described in detail in the Statistical Analysis Plan.
The baseline measurements are defined as the measurements taken closest to but before the first
administration of study intervention on Day 1, unless otherwise specified.
Primary Efficacy Endpoint (HBsAg Seroclearance 24 Weeks After Completion of Consolidation Phase
Treatment)
The primary efficacy endpoint, the proportion of participants with HBsAg seroclearance 24 weeks after
stopping all study interventions of the consolidation phase and without restarting NA treatment, will be
summarized with the point estimate and its 90% CI using the Clopper-Pearson exact method.
Secondary and Exploratory Efficacy Endpoints
Descriptive statistics will be used for all efficacy endpoints which will be summarized by cohort and study
phase. Specific key selected endpoints may be analyzed using suitable categorical data approaches (eg,
Clopper-Pearson interval 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
NCT04439539


JNJ-73763989 and JNJ-56136379 
Clinical Protocol 73763989PAHPB2005
Amendment 7
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
18
Status: Approved,  Date: 25 November 2021
on the Kaplan-Meier estimates (for time-to-event variables), as appropriate. All efficacy analyses will be
repeated combining the data from participants who received PegIFN-α2a but not JNJ-6379 in Cohort 1 with
data from Cohort 2. The approach to combine data from the 2 cohorts will be described in detail in the
Statistical Analysis Plan.
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 (Week 24, end of consolidation phase, end of
induction phase, FU Week 24, and FU Week 48 [EOS]), and between end of the consolidation phase and
FU Week 48 (EOS) for different subgroups: participants with HBsAg seroclearance 24 weeks and 48 weeks
after completion of consolidation phase treatment, in patients stopping NA (at FU Week 2) without
restarting NA treatment, versus those without HBsAg seroclearance at those time points.
Safety Analyses
The 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 descriptive summaries of AEs including AEs of special interest and other
toxicities to any of the study interventions, clinical laboratory tests, ECGs, vital signs, physical
examinations, and eGFR based on serum creatinine (eGFRcr) and cystatin C (eGFRcys). The safety analysis
will be done by study phase and cohort. Results will be presented in tabular format and/or graphically 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 or serum concentrations of JNJ-3989
(ie, JNJ-3976 and JNJ-3924) and, optionally, JNJ-6379, NA and/or PegIFN-α2a, as applicable, and for the
derived PK parameters for noncompartmental PK analysis.
For each participant with intensive PK sampling, concentration-time data of JNJ-3976, JNJ-3924, , and
optionally JNJ-6379, NA and/or PegIFN-α2a will be graphically presented as applicable. Similarly, graphs
of the mean concentration-time profiles and overlay graphs with combined individual concentration-time
profiles will be produced. PK parameters in participants undergoing intensive PK sampling will be
calculated via noncompartmental methods for JNJ-3976 and JNJ-3924, and, optionally, of JNJ-6379, NA
and/orPegIFN-α2a, as applicable. The PK parameters will be maximum concentration(Cmax),concentration
24 hours after administration (C24h),and area under the concentration-time curve from administration to 24
NCT04439539


JNJ-73763989 and JNJ-56136379 
Clinical Protocol 73763989PAHPB2005
Amendment 7
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
19
Status: Approved,  Date: 25 November 2021
hours (AUC24h). The PK parameters will be subjected to an exploratory graphical analysis, including
various transformations, to get a general overview.
To assess the effect of PegIFN-α2a on JNJ-3989, the PK parameters of JNJ-3976 and JNJ-3924
coadministered with PegIFN-α2a in the consolidation phase will be compared to those of JNJ-3976 and
JNJ-3924 in the induction phase as reference (timepoints as specified in the Schedule of Activities). The
primary PK parameters are Cmax  and AUC24h on the logarithmic scale. A mixed effects model will be fitted
to log-transformed PK parameters with phase (induction or consolidation) as a fixed effect and subject as a
random effect.
Special attention will be paid to the plasma or serum 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 concentration-time data of JNJ-3976 and JNJ-3924, and, optionally, of JNJ-6379,
NA and/or PegIFN-α2a may be performed using non-linear mixed effects modeling. Data may be combined
with selected Phase 1 and/or 2 studies to support a relevant structural model. Available participant
characteristics (eg, demographics, laboratory variables, genotypes) will be included in the model as
necessary. Details will be given in a population PK analysis plan and results of the population PK analysis,
if applied, will be presented in a separate report.
Pharmacokinetic/Pharmacodynamic Analyses
Relationships of PK parameters for JNJ-3976 and JNJ-3924, and, optionally, of JNJ-6379, NA and/or
PegIFN-α2a with selected efficacy and with selected safety endpoints will be evaluated and graphically
displayed, if applicable.
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 may be
investigated. Other biomarkers may be explored at the sponsor’s discretion.
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 (eg, efficacy, safety, and/or 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.
NCT04439539


JNJ-73763989 and JNJ-56136379 
Clinical Protocol 73763989PAHPB2005
Amendment 7
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
20
Status: Approved,  Date: 25 November 2021
Interim Analyses
Two interim analyses (IAs) will be conducted to assess safety and evaluate the time course of different
safety and efficacy 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 combination regimens.
The first IA is planned when approximately 50% of the total number of participants enrolledhave completed
Week 24 of the induction phase or discontinued earlier.
The second IA is planned when all participants have completed Week 48 or discontinued earlier.
The study is open-label, and the Sponsor will conduct the pre-planned IA(s). Hence, the study team and the
DRC will have access to the interim analysis results, while the investigators and patients will not.
Additional IAs may be performed by the sponsor before the final analysis, 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.
Data Review Committee
A DRC will be established for continuous monitoring of SAEs, AEs leading to discontinuation, and ALT
flares. This committee will consist of at least one medical expert in the relevant therapeutic area
(hepatology) and at least one statistician; committee membership responsibilities, authorities, and
procedures will be documented in its charter. The committee will meet periodically to review data of the
efficacy parameters measured by different HBV disease blood markers (eg, HBV DNA, HBeAg, HBsAg,
etc).
The DRC members will be appointed before the start of the study to review the interim data for both safety
and efficacy and formulate recommendation(s) to the Sponsor Committee, who will make the final
decision(s). The Sponsor Committee includes representatives from the sponsor’s Clinical, Biostatistics,
Global Medical Safety, and Virology departments. DRC and Sponsor Committee members will not be
involved in the study conduct.
Details on the roles and responsibilities of the DRC and Sponsor Committee, as well as the flows of
communication, will be documented in the DRC charter.
Independent Flare Expert Panel
An IFLEP will be appointed. The IFLEP is composed of 3 independent medical experts with experience
and expertise in hepatitis B and its treatment. The responsibilities of the IFLEP include: conduct regular
review of all relevant and available individual participant study data related to ALT flares; determine and
adjudicate each ALT flare; and provide documentation of the final decision to DRC. Adjudication review
cycles will match DRC schedule and will be set up ideally 2 weeks before DRC.
In order to allow for an unbiased assessment, members of the committee will not serve as studyinvestigators
or as members of the DRC.
Further details on the IFLEP process will be included in the IFLEP charter.
NCT04439539


JNJ-73763989 and JNJ-56136379 
Clinical Protocol 73763989PAHPB2005
Amendment 7
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
21
Status: Approved,  Date: 25 November 2021
1.2. 
Schema
Figure 1: 
Schematic Overview of Cohort 1of the Study –Prior to Protocol Amendment 5
a 
End of the induction phase is defined by either meeting the study defined RGT criterion (HBsAg <10 IU/mL) or
reaching study Week 60, whichever comes first. The RGT criterion will be assessed from Week 36 onwards, and
the assessment will always be based on lab results from the previous study visit (4 weeks earlier).
b 
If NA treatment completion criteria (HBsAg <10 IU/mL, and HBeAg-negative, and HBV DNA <LLOQ, and
ALT <3x ULN) have been met at consolidation Week 12, NA will be stopped at the next scheduled visit (ie,
FU Week 2), otherwise NA treatment will continue during the complete follow-up phase.
Figure 2: 
Schematic Overview of the Study –Per Protocol Amendment 5
Cohort 1: Participants enrolled before Protocol Amendment 5 is in effect
Per Amendment 5, participants who did not yet reach the Week 36 visit will have PegIFN-α2a added to
their treatment regimen at Week 36 for 12 weeks.
Participants who already passed the Week 36 visit and/or were randomized to the group without PegIFN-
α2a, will have PegIFN-α2a added to their treatment regimen at the next scheduled visit. After 12 weeks,
treatment with PegIFN-α2a, JNJ-3989 and JNJ-6379 will be stopped.
a 
If NA treatment completion criteria (HBsAg <10 IU/mL, and HBeAg-negative, and HBV DNA <LLOQ, and
ALT <3x ULN) have been met at consolidation Week 12, NA will be stopped at the next scheduled visit (ie,
FU Week 2), otherwise NA treatment will continue during the complete follow-up phase.
b 
Depending on the approval date of Amendment 5, the induction phase can be longer than 36 weeks for some of
these participants.
NCT04439539


JNJ-73763989 and JNJ-56136379 
Clinical Protocol 73763989PAHPB2005
Amendment 7
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
22
Status: Approved,  Date: 25 November 2021
Cohort 2: Participants enrolled under Protocol Amendment 5 is in effect
Per Amendment 5, participants will be randomized in a 1:1 ratio at the start of the induction phase to
either receive JNJ-3989 + JNJ-6379 + NA or JNJ-3989 + NA for 36 weeks. At Week 36 all participants
will have PegIFN-α2a added to their treatment regimen for 12 weeks.
a 
If NA treatment completion criteria (HBsAg <10 IU/mL, and HBeAg-negative, and HBV DNA <LLOQ,
and ALT <3x ULN) have been met at consolidation Week 12, NA will be stopped at the next scheduled
visit (ie, FU Week 2), otherwise NA treatment will continue during the complete follow-up phase.
With the implementation of an urgent safety measure, as described in Protocol Amendment 6, participants
previously enrolled had to immediately stop JNJ-6379 treatment, because of the removal of JNJ-6379 as
studyintervention. They were to continue with JNJ-3989+NA treatment up to the end of the induction phase
and then enter the 12-week consolidation phase during which PegIFN-α2a was added to their treatment
regimen.
Because of the urgent removal of JNJ-6379 as study intervention, none of the participants enrolled under
Protocol Amendment 5 did receive JNJ-6379.
Figure 3: 
Schematic Overview ofCohort 2 ofthe Study –As of Protocol Amendment 6
a 
If NA treatment completion criteria (HBsAg <10 IU/mL, and HBeAg-negative, and HBV DNA <LLOQ,
and ALT <3x ULN) have been met at consolidation Week 12, NA will be stopped at the next scheduled
visit (ie, FU Week 2), otherwise NA treatment will continue during the complete follow-up phase.
As of Protocol Amendment 6, the study will continue as a single-arm study (JNJ-3989+NA+PegIFN-α2a).
All newly enrolled participants will receive JNJ-3989+NA for 36 weeks (induction phase) and will then
enter the 12-week consolidation phase during which they will have PegIFN-α2a added to their treatment
regimen.
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Key: ALT: alanine aminotransferase; C: consolidation; DNA: deoxyribonucleic acid; FU: follow-up; HBeAg:
hepatitis B e antigen; HBsAg: hepatitis B surface antigen; HBV: hepatitis B virus; JNJ-3989: JNJ-73763989;
JNJ-6379: JNJ-56136379; n: number of participants; LLOQ: lower limit of quantification; NA: nucleos(t)ide analog;
PegIFN-α2a: pegylated interferon alpha-2a; R: randomization; RGT: response-guided treatment; ULN: upper limit of
normal; Q4W: once every 4 weeks; qd: once daily; QW: once weekly; W: week; WX: last visit of the induction phase
(≥W36 and ≤W60) equivalent to Day 1 of the consolidation phase.
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pp. As of Protocol Amendment 6, new participants will enroll without randomization to receive JNJ 3989+NA for 36 weeks (induction phase) and will then enter the 12 week
consolidation phase during which they will have PegIFN α2a added to their treatment regimen.
qq. Includes close monitoring for neuropsychiatric adverse events during the PegIFN α2a treatment period. Participants who develop a neuropsychiatric adverse event during PegIFN
α2a treatment, will be monitored closely until the neuropsychiatric adverse event resolves, with frequent (at least weekly) follow up phone calls.
rr. 
Most participants enrolled before Protocol Amendment 6 was in effect, have received JNJ 6379 as part of their study intervention. Dispensation of JNJ 6379 stopped immediately
with the removal of JNJ 6379 as study intervention through an urgent safety measure. Participants have to return JNJ 6379 tablets to the site at the next scheduled visit.
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2. 
INTRODUCTION
This intervention-specific appendix (ISA) describes a Phase 2a study of JNJ-73763989
(JNJ-3989). Prior to Protocol Amendment 6, the study intervention also included JNJ-56136379
(JNJ-6379). This ISA 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, pegylated interferon alpha-2a (PegIFN-α2a), and NA (tenofovir disoproxil will be used in
this study) (see Section 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 (rcDNA). The RNAi triggers in JNJ-3989, JNJ-73763976 (JNJ-3976) and JNJ-73763924
(JNJ-3924), are designed to target all HBV RNA transcripts derived from covalently closed
circular deoxyribonucleic acid (cccDNA), as well as transcripts derived from integrated viral
deoxyribonucleic acid (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.29
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 viral HBV capsids, devoid of HBV DNA
or RNA (non-functional capsids), and ultimately in the inhibition of HBV replication. In addition,
JNJ-6379 also acts at an early stage of the viral life cycle by inhibiting the de novo formation of
cccDNA potentially by interfering with the capsid disassembly process. JNJ-6379 was initially
part of the study intervention but has been removed as study intervention with the implementation
of an urgent safety measure, as described in Protocol Amendment 6.
For the most comprehensive nonclinical and clinical information regarding JNJ-3989 and
JNJ-6379, refer to the latest version of the Investigator's Brochures (IBs) and their
Addenda.10,11,13,12
Study interventions:
 
Prior to Protocol Amendment 6: The term “study intervention” throughout the protocol, refers
to JNJ-3989, JNJ-6379, NA and PegIFN-α2a.
 
As of Protocol Amendment 6: The term “study intervention” throughout the protocol, refers
to JNJ-3989, NA and PegIFN α2a.
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The term "sponsor" used throughout this document refers to the entities listed in the Contact
Information page(s), which will be provided as a separate document.
The term "participant" throughout the protocol refers to the common term "subject".
2.1. 
Study Rationale
This study will be conducted in immune tolerant (IT) participants (IT  corresponds to HBeAg
positive chronic infection as per European Association for the Study of the Liver [EASL] 2017
guidelines).4
Recent studies have challenged the notion that the IT phase of chronic HBV infection lacks disease
progression and that an immune response has not been initiated. Antigen-specific immune
tolerance is believed to play a central role in chronification of an acute HBV infection as it prevents
the clearance of infection. Studies have shown that early stages of fibrosis, reflecting hepatocyte
damage, are often present along with clonal hepatocyte expansion, high levels of HBV DNA
integration, and presence of HBV-specific T-cells in the so-called IT phase.17,20 High HBV DNA
levels and persistence of HBeAg are associated with an increased risk of disease progression and
hepatocellular carcinoma (HCC).
Current EASL treatment guidelines proposed a new nomenclature for different disease stages of
chronic hepatitis B virus infection.4 Patients with chronic HBeAg positive HBV infection are
characterized by high HBV DNA and normal alanine aminotransferase (ALT) levels and were
referred to as IT in the past. Following this new nomenclature, the protocol is including patients
that are truly IT (HBV DNA levels ≥107 IU/mL), but also patients with lower HBV DNA levels
(≥20,000 IU/mL) and ALT ≤2x  ULN as long as they are HBeAg positive, treatment-naïve or
having received NA for a short period of time (eg, <9 months to prevent mother-to-child
transmission during pregnancies).
Effectively treating patients with HBeAg positive infection would be desirable, but currently
available treatment options have limited efficacy in this population. Although combination
treatment of 2 NAs led to significantly more patients reaching viral suppression after 192 weeks
than 1 NA alone, very few patients showed HBeAg seroconversion or HBsAg loss.2 Treatment of
IT patients with PegIFN-α2a in combination with an NA showed good efficacy in children, but
limited efficacy in adult IT patients.6,25 Consequently, according to current clinical practice
guidelines (EASL4 and American Association for the Study of Liver Diseases [AASLD]28), there
is no general recommendation for NA treatment in this population.
Combination treatment with JNJ-3989 and NA (with or without JNJ-6379) has the potential to
specifically decrease viral antigen levels and to intensify inhibition of viral replication. Since an
immune suppressive effect is described for HBsAg, the direct reduction of HBsAg levels by JNJ-
3989 is anticipated to contribute to the reversal of the immune tolerance and to the control of the
infection. The addition of short-term PegIFN-α2a to the regimen at a time when HBsAg is already
significantly reduced or eliminated is expected to lead to reactivation of NK-cells. In addition, the
reactivation of the innate immune system by PegIFN-α2a might lead to further activation of
endogenous HBV-specific T-cells.
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2.2. 
Background
For the most comprehensive nonclinical and clinical information regarding JNJ-3989 and
JNJ-6379, refer to the latest version of the Investigator's Brochures (IB)s and their Addenda.
10,11,13,12
JNJ-6379 was initially part of the study intervention but has been removed as study intervention
with the implementation of an urgent safety measure, as described in Protocol Amendment 6. For
completeness, background information on JNJ-6379 is still included in this section.
2.2.1. 
Nonclinical Studies
2.2.1.1. 
JNJ-3989 and JNJ-6379
Nonclinical assessments to support clinical development have been performed for the single agents
JNJ-3989 and JNJ-6379, and also for their combination (up to 3-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, 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.15 The no observed
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Status: Approved,  Date: 25 November 2021
adverse effect level (NOAEL) was therefore considered to be the highest dose tested, ie,
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.15 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,
 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 (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).
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Table 1: 
Animal/Human Exposure Ratios at NOAEL for JNJ-3989
Sex 
NOAEL  
(mg/kg) 
C max 
(ng/mL) 
AUCb 
(ng.h/mL) 
Ratio Total Concentration
Cmax 
A/H Ratio 
AUCb
A/H Ratio
JNJ-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
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
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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  
(
) 
Cmax 
(ng/mL) 
AUC0-24h 
(ng.h/mL) 
Ratio Total
Concentration
Ratio
Concentration
Corrected for
Plasma Protein
Bindingb
Cmax 
A/H 
Ratio 
AUC0-24h 
A/H 
Ratio 
Cmax 
A/H 
Ratio 
AUC0-24h
A/H
Ratio
Human exposurea 
13,798 
267,180 
- 
-
6M rat 
M 
 
7,540 
93,100 
0.6 
0.3 
0.9 
0.6
M 
 
13,600d 
180,000d 
1.0 
0.7 
1.7 
1.1
F 
 
19,900 
233,000 
1.4 
0.9 
2.4 
1.5
9M dog 
M 
 
30,000 
606,000 
2.2 
2.3 
3.3 
3.4
F 
 
22,500 
383,000 
1.6 
1.4 
2.5 
2.2
AUC: area under the plasma concentration time curve; AUC0-24h: area under the plasma concentration time curve from
administration to 24 h; A/H: animal/human ratio; Cmax: maximum plasma concentration; F: female; M: male; NOAEL: no
observed adverse effect level; qd: once daily.
a 
250 mg JNJ 6379 qd for 28 days (Study 56136379HPB1001).
b 
Ratio of the total Cmax or AUC corrected for species difference in plasma unbound fraction. Calculation: [animal Cmax or
AUC0-24h x animal free fraction] / [human Cmax or AUC0-24h x human free fraction].
c 
A dose of 
 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%).
Combination ofJNJ-3989 and JNJ-6379
A 1-month repeat-dose combination toxicity study of JNJ-6379 and JNJ-3989 was conducted in
male and female Sprague-Dawley rats. JNJ-6379 (in PEG400 + 10% PVP-VA) was administered
daily via oral gavage at 100 mg/kg, alone or in combination with JNJ-3989 (in phosphate-buffered
saline) which was administered weekly via subcutaneous injections at 30 and 180 mg/kg. In
addition, 180 mg/kg JNJ-3989 (subcutaneous, weekly) was dosed as well in a monotherapy group.
Control animals received both vehicles via the respective routes.
The data showed that weekly subcutaneous injections with JNJ-3989 at 30 or 180 mg/kg in
combination with daily administration of JNJ-6379 at 100 mg/kg (oral) for one month were well
tolerated with no clinical signs or treatment-related mortality. Changes in clinical pathology and
histopathology were mostly similar to the findings for the monotherapy groups dosed with
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JNJ-6379 at 100 mg/kg (oral) alone or with JNJ-3989 at 180 mg/kg (subcutaneous) alone. The
only synergistic changes included a slight decrease in body weight (gain) at ≥100/30 mg/kg, in
food consumption at 100/180 mg/kg, and a further decrease in lymphoid cellularity in the thymus
of females at 100/180 mg/kg. These alterations were minor and non-adverse in nature. Based on
these results, the NOAEL was considered to be
 Cmax and AUC0 24h values for JNJ-
6379 in males were 13,200 ng/mL and 181,000 ng∙h/mL, and for females 15,500 ng/mL and
206,000 ng∙h/mL, respectively, after 1 month of treatment. The mean Cmax  and AUC0 24h  values
for analyte JNJ-3924 in  males were 20,900 ng/mL and 160,000 ng∙h/mL, and for females
21,300 ng/mL and 125,000 ng∙h/mL, respectively. For analyte JNJ-3976, the mean Cmax  and
AUC0 24h values in males were 35,200 ng/mL and 258,000 ng∙h/mL, and for females 35,300 ng/mL
and 201,000 ng∙h/mL, respectively.
A 3-month combination toxicity study of JNJ-3989 and JNJ-6379 is ongoing, preliminary data is
available. In this study, JNJ-3989 was initially administered weekly (ie, a total of 6 doses) and
monthly thereafter, via subcutaneous injections at dose levels of 60 and 180 mg/kg when given in
combination with JNJ-6379, and at 180 mg/kg for the monotherapy group. JNJ-6379 was
administered daily via oral gavage at a dose level of 100 mg/kg in the monotherapy and
combination groups. Control animals received both vehicles via the respective routes.
No test article-related mortalities were noted among animals dosed with JNJ-6379 alone, JNJ-3989
alone, or with JNJ-6379 + JNJ-3989 at 100/180 mg/kg. One male receiving JNJ-3989 alone at 180
mg/kg died on Day 45, after a rapid change in its clinical condition. The death of this animal was
considered to reflect an acute stress response without a relationship to the test article. One
accidental death due to a possible gavage error was noted among the toxicokinetic (TK) animals
in the 100/60 mg/kg combination group. No bone marrow abnormalities were seen in these 2
animals.
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 decreased hematopoietic cellularity of the bone marrow with pancytopenia including
markedly reduced platelet counts and consequent hemorrhages and blood loss. A relation to the
treatment with JNJ-6379 and/or JNJ-3989 cannot be excluded.
Clinical pathology analysis in this rat revealed a marked decrease in WBCs (neutrophil,
lymphocyte, and monocyte counts), marked decreases in RBC  mass parameters (hemoglobin,
hematocrit, and RBC count) including reticulocyte count, and platelet count. There was a mildly
increased fibrinogen concentration and mildly prolonged prothrombin time. Other clinical
pathology findings were observed for this animal, but they are not related to the bad condition and
euthanasia.
At necropsy, the rat showed dark red discoloration/dark red foci in a wide variety of organs and
tissues, and dark red material in the abdominal cavity adhered to the spleen (freshly clotted blood).
This correlated to minimal to marked hemorrhages in multiple tissues, including brain.
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At microscopic examination, the bone marrow of this animal showed markedly decreased
cellularity of hematopoietic tissue. Based on the morphology of the remaining hematopoietic tissue
and the absence of necrosis, this bone marrow finding was considered not acute but rather subacute
or subchronic in nature. In absence of pre-values or earlier timepoints for hematology, it was not
possible to define the onset of the initiating event. Minimal to marked acute hemorrhages were
noted in a wide range of tissues. Some other microscopic findings unrelated to the event were
identified.
Altogether, the decreased cellularity of hematopoietic tissue in the bone marrow and the
hematology/coagulation data indicate that reduced hematopoiesis resulted in decreases in WBC,
reticulocyte and platelet counts. The hemorrhages were interpreted to be the result of a deficit in
primary hemostasis, consistent with the markedly reduced platelet counts. None of the remaining
animals of this study showed decreased cellularity of the bone marrow.
In addition to the changes described above, decreased platelet counts were seen in females at
100/60 and 100/180 mg/kg JNJ-6379/JNJ-3989. However, the decrease in platelet counts for these
groups was mild, similar across animals within the groups and to those seen in a previous 1-month
combination toxicity study with JNJ-6379/JNJ-3989, and not accompanied by other cytopenia nor
bone marrow abnormalities. The decrease in platelet counts for these groups are likely caused by
a different mechanism than for the male rat that was euthanized on Day 24, as described above.
No relevant changes on urinary biomarkers were detected in male and female rats given JNJ-6379
at 100 mg/kg/day (clusterin, albumin, ß2-microglobulin, Kidney Injury Molecule-1 [KIM-1],
Neutrophil Gelatinase Associated Lipocalin [NGAL] and cystatin-C).
Based on the observation ofpancytopenia in 1 rat and a mild platelet decrease in the combination
groups in the 3-month combination toxicity study, the sponsor is implementing additional
monitoring of significant on-treatment hematologic changes in clinical studies with dosing longer
than 4 weeks (see Section 8.3.6.4). However, no significant abnormalities of hematologic
parameters have been observed in clinical studies to date.
For further information, refer to the IB Addenda for JNJ-3989 and JNJ-6379.10,11,13,12
2.2.1.2. 
Combination of JNJ-3989 or JNJ-6379with Tenofovir Disoproxil
The single common toxicity target organ between JNJ-6379, JNJ-3989, and tenofovir disoproxil
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.8,15 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.
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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).3,27 No kidney findings were observed in dogs.
Although both compounds (JNJ-3989 and JNJ-6379) showed histological kidney findings in the
rat, the primary anatomical location, mechanism and severity are different. For JNJ-3989 the renal
findings are without anticipated clinical or clinicopathological consequences and located in the
proximal part of the nephron (outer cortex) and intracellular (not in the tubular lumen). For
JNJ-6379, the main findings are restricted to male rats and initiate in distal parts of the kidney
(renal pelvis/ papilla) and/or in the lumen of the lower urinary tract with secondary more proximal
changes due to reflux.
For tenofovir disoproxil, renal tubular epithelial karyomegaly was observed in rats, dogs, and
monkeys.21 In dogs, the species most sensitive to tenofovir disoproxil-related effects on the kidney,
additional microscopic alterations following chronic administration of tenofovir disoproxil (10
mg/kg/day for 42 weeks) included individual tubular cell necrosis, tubular dilatation, tubular
degeneration/regeneration, pigment accumulation, and interstitial nephritis. This was associated
with biochemical changes such as slight elevation in serum creatinine, glucosuria, proteinuria, and
increased urine volume. The incidence and severity of nephrotoxicity was dose-related. Effects
were reversible following cessation of treatment. In Rhesus monkeys, biochemical and/or
histopathologic evidence of nephrotoxicity was observed at high doses. In rats, slight elevations in
serum creatinine were observed without any histopathology correlation.
Based on the available toxicology data, there are no specific concerns about additive or synergistic
toxicities in the kidney when JNJ-6379 and JNJ-3989 are combined with tenofovir disoproxil.
2.2.1.3. 
Combination of JNJ-3989 or JNJ-6379with PegIFN-α2a
2.2.1.3.1. 
Combination of JNJ-6379with PegIFN-α2a
As there is no appropriate species for studying the combination of JNJ-6379 with PegIFN-α2a, an
in vitro study on human bone marrow derived erythroid and myeloid progenitors using colony
forming assays was done. JNJ-6379 (5-100 μM) and PegIFN-α2a (Pegasys®, 0.00005-0.1 μM)
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were tested in combination in order to evaluate their potential additive or synergistic effects (study
TOX14629).
The IC50 values of the combination treatment were markedly lower compared to JNJ-6379 alone
for all tested concentrations but similar to the values with PegIFN-α2a alone. When the higher
concentrations of PegIFN-α2a were tested in combination with JNJ-6379, the reduction in colonies
was mainly due to the strong toxicity of PegIFN-α2a at these concentrations.
Comparing the predicted (adding the percent of reduction of JNJ-6379 and PegIFN-α2a alone) and
the actual percent reduction in colonies relative to the solvent control, it became clear that there
were only minimal differences, pointing more to an additive effect and not a synergistic effect
when JNJ-6379 and PegIFN-α2a were combined.
2.2.1.3.2. 
Combination of JNJ-3989 with PegIFN-α2a
The objective of study TOX14273 was to determine the potential additive or synergistic effects
when combining JNJ-3989 (60 or 180 mg/kg, once monthly) with PegIFN-α2a (Pegasys®
0.015 mg/kg twice weekly)given subcutaneouslyfor 3 months to the Cynomolgus monkey (study
TOX14273, preliminary data).
There were no JNJ-3989 related mortalities. JNJ-3989 (alone or combined with PegIFN-α2a) was
well tolerated and did not induce relevant effects on clinical signs, body weight, food consumption,
ophthalmoscopic examination, electrocardiology evaluation, coagulation, clinical chemistry or
urinalysis parameters, cytokines IP-10 and IFNα, as well as organ weight and macroscopic
examination.
Transient local reactions (edema and erythema) were observed at the administration site at
60 and/or 180 mg/kg for JNJ-3989. These reactions were also observed with PegIFN-α2a and
incidentally in control females (erythema only). These reactions were not correlated with
microscopic findings.
JNJ-3989 induced minimal to mild hematological changes starting at 60 mg/kg. These clinical
pathology changes were limited to transient, non-dose-related increases in neutrophils and total
white blood cells in males and females administered 180 mg/kg JNJ-3989 alone or in combination
≥60/0.015 mg/kg JNJ-3989/PegIFN-α2a on Day 30 only. In addition, comparable transient
increases in neutrophils and total white blood cells were also observed in both males and females
administered 0.015 mg/kg PegIFN-α2a alone.
PegIFN-α2ainduced increases in IFNα and IP-10 after the first injection. Levels were at baseline
values prior to dosing on Day 30 and no increases were observed after dosing as well as after
dosing on Day 90. Combination of JNJ-3989 at 60 or 180 mg/kg with PegIFN-α2a did not induce
any further effects than the increases observed with PegIFN-α2a given alone.
JNJ-3989 induced microscopic findings in the lymph nodes and liver. In the mesenteric, axillary,
popliteal and/or other lymph nodes, minimal to mild vacuolation of macrophages were observed
in both sexes administered ≥60 mg/kg/0.015 mg/kg JNJ-3989/PegIFN-α2aor 180 mg/kgJNJ-3989
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alone. In the liver, minimal hypertrophy of Kupffer cells was observed in 1 female administered
180 mg/kg/0.015 mg/kg JNJ-3989/PegIFN-α2a and 2 females administered 180 mg/kg JNJ-3989
alone. The microscopic changes were comparable between the animals administered with JNJ-
3989 alone or in combination with PegIFN-α2a indicating an absence of additive or synergistic
effect.
Systemic exposure to JNJ-3924 and JNJ-3976 in plasma was similar after single and repeated
dosing following administration of JNJ-73763989 alone or combined with reference item PegIFN-
α2a.
In conclusion, the intermittent subcutaneous administration of JNJ-3989 given alone or combined
with PegIFN-α2a for 3 months was well tolerated in Cynomolgus monkeys at levels of 60 and
180 mg/kg. Treatment only induced transient local reactions at the injection site, transient
hematological changes and microscopic findings in liver and lymph nodes, all considered as non-
adverse. The administration of JNJ-3989 in combination with PegIFN-α2a did not amplify any
toxicological effect. Based on these results, there were no additive or synergistic effects on the
toxicity profile and no drug-drug interactions when JNJ-3989 is combined with PegIFN-α2a.
2.2.2. 
Clinical Studies
2.2.2.1. 
JNJ-3989 and JNJ-6379
Combination of JNJ-3989 and JNJ-6379
Clinical data of triple combination treatment of JNJ-3989, JNJ-6379, and NA are available from
the ongoing Phase 1/2a AROHBV1001 study  (Cohort 12). Twelve adult chronic HBV
mono-infected participants have received 3 subcutaneous injections of JNJ-3989 (200 mg Q4W)
in combination with oral JNJ-6379 (250 mg qd) and oral NA treatment (ETV or TDF).
Up to interim analysis cut-off date of 4 October 2019, no deaths, SAEs, or TEAEs leading to study
drug discontinuation were reported. Two (16.7%) participants reported at least 1 TEAE during the
treatment phase. The TEAEs (upper respiratory tract infection and hypertension) were of mild
severity and considered not related to the study drug by the investigator.
The triple combination treatment of JNJ-3989, JNJ-6379, and NA is currently being investigated
in chronic HBV mono-infected participants in the ongoing Phase 2 clinical studies
73763989HPB2001 (REEF-1, 90 participants in triple combination Arm 1) and
73763989PAHPB2002 (REEF-2, 80 participants in triple combination Arm 1).
Since the initial protocol writing, interim results of the REEF-1 and REEF-2 studies had become
available. In the primary REEF-1 analysis (Week 48, end of treatment) the mean reduction of
HBsAg in the triple arm (JNJ-6379+JNJ-3989 100mg+NA) appeared to be less than in the dual
arm (JNJ-3989 100mg+NA). More recent interim results of the REEF-2 study (Week 48, end of
treatment) confirmed this observation when the effect of JNJ-6379+JNJ-3989 200mg+NA on
mean HBsAg level reduction in REEF-2 study is compared to JNJ-3989 200mg+NA in the REEF-
1 study. To match with the REEF-2 population, this cross-study comparison focused on the REEF-
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1 subpopulation of HBeAg negative, virologically suppressed participants with chronic hepatitis
B. PK-PD modelling analyses accounting for variability in baseline characteristics further support
this observation. Therefore, a negative effect of JNJ-6379 on the HBsAg lowering effect of JNJ-
3989+NA is suspected.
The following sections provide an overview of the current clinical background information for the
2 compounds separately.
JNJ-3989 
Clinical data on PK, efficacy, and safety of JNJ-3989 are available from the ongoing Phase 1/2a
AROHBV1001 study with a data cut-off date of 29 October 2019. All dosing with JNJ-3989 has
been completed and ongoing participants are in the follow-up. Twenty adult healthy participants
have received single subcutaneous injections of JNJ-3989 (35, 100, 200, 300, and 400 mg) and
84 adult chronic HBV-infectedparticipants 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 entacavir (ETV) or tenofovir
disoproxil on Day 1.
JNJ-3989 was generally safe and well tolerated with no deaths, serious adverse events (SAEs)
considered at least possibly related to the study intervention, or adverse events (AEs) leading to
study intervention discontinuation. All AEs were mild to moderate, with exception of 1 severe
blood creatine phosphokinase increased in 1 chronic HBV-infected participant. All reported
injection site reactions (ISRs) were mild. Adverse events and laboratory abnormalities were
distributed across all dose levels and also occurred on placebo treatment, except for mild ISRs,
which were only reported in participants on JNJ-3989 treatment. Most reported laboratory
abnormalities were isolated incidences and resolved while on study treatment.
Up to 48-week hematology data from the ongoing Phase 2 clinical study REEF-1
(73763989HPB2001) are available and overall around 5% of the participants experienced AEs or
laboratory abnormalities related to hematology, the majority of mild to moderate severity. The
hematologic abnormalities resolved on continued JNJ-3989+NA treatment.12
Antiviral activity data were available for 56 chronic HBV-infected participants who received
3 subcutaneous injections of 25 to 400 mg JNJ-3989 every 4 weeks (Q4W).7,31 In general, mean
HBsAg declines reached nadir at Day 113 (ie, 8 weeks after last JNJ-3989). Mean HBsAg levels
remained suppressed (below baseline levels) at least until Day 392 (ie, 9 months after last dose)in
a substantial proportion of patients.
JNJ-6379
At the time of protocol writing, 126 adult healthy and 41 chronic HBV-infected participants have
been dosed with JNJ-6379 in 5 completed Phase 1 studies (56136379HPB1001,
56136379HPB1002, 56136379HPB1003, 56136379HPB1004, and 56136379HPB1005). In
addition, data are available from 148 adult chronic HBV-infected participants in the ongoing Phase
2a study, 56136379HPB2001, also referred to as Jade.
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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
AUC0 24h  increased proportionally with dose after single-dose administration of JNJ-6379 doses
of 25 mg to 300 mg and less than dose proportionally at the dose of 600 mg. The AUC from
administration to last quantifiable sampling point (AUC0 last) and the AUC to last sampling point
from time zero extrapolated to infinity (AUC∞) increased proportionally between the JNJ-6379
25-mg and 600-mg dose levels. Mean values for terminal half-life (t1/2term) were comparable for
the 25-mg to 300-mg dose levels, and averaged between 93.3 hours and 110.5 hours. For the 600-
mg dose group, the average t1/2term  was 141.3 hours. Mean values for the total apparent oral
clearance (CL/F) were comparable for the 25-mg, 50-mg and 150-mg dose level, and appeared to
decrease at higher dose levels. Mean values of the apparent volume of distribution were generally
comparable for the different dose groups.
In Study 56136379HPB1002, study 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.
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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.
Multiple Dose Studies in chronic HBV-infected Participants
In Sessions 8, 9, 10, 11, and A of Study 56136379HPB1001, treatment-naïve chronic HBV-
infected-infected participants were administered multiple-dose regimens (25, 75, 150, and 250 mg)
of JNJ-6379 for 28 days. Pharmacokinetics of JNJ-6379 were not markedly different between
healthy participants and chronic HBV-infected participants. Mean JNJ-6379 exposures in chronic
HBV-infected participants could be predicted from data in healthy participants. The PK data show
that exposure of JNJ-6379 in chronic HBV-infected participants is dose proportional and CL/F is
constant over time.
Food Interaction
Although Study 56136379HPB1001 suggested slightly higher exposure of JNJ-6379 in fed
conditions, data from Study 56136379HBP1002 with a higher number of participants showed that
there is no food effect on JNJ-6379 exposure, and a preliminary PK analysis from
Study 56136379HBP1005 suggests the same.
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Drug-drug Interaction
Oral contraceptives: When administered simultaneously with 3 mg drospirenone/0.02 mg
ethinylestradiol in Study 56136379HPB1004, JNJ-6379 increases the extent of exposure and
decreases the CL/F of ethinylestradiol while the peak plasma concentration decreased. In contrast,
JNJ-6379 has no clear effect on the extent of exposure and CL/F of drospirenone, a cytochrome
P450 (CYP)3A4 sensitive progestin: peak plasma concentration decreased while no change in
exposure and apparent clearance was observed. Consequently, oral contraceptives are still
considered to be effective when administered simultaneously with JNJ-6379. However, as a
precaution to avoid high exposure to ethinylestradiol, ethinylestradiol-containing contraceptives
are only allowed if the ethinylestradiol content is ≤20 µg.
Midazolam: In Study 56136379HPB1004, coadministration of 170 mg JNJ-6379 qd with oral
midazolam as a CYP3A4 probe substrate showed a reduction of 41.7% in Cmax and 53.9% in AUC
of midazolam, implying that JNJ-6379 may induce the metabolism of CYP3A4 sensitive
substrates.
Efficacy Studies
Antiviral activity data are available from Part II of Study 56136379HPB1001 (final analysis,
57 treatment-naïve participants treated with multiple-dose regimens of25 to 250 mg JNJ-6379 qd
for 28 days, unblinded). Available antiviral activity data for 4 weeks of treatment with JNJ-6379
in this study showed potent HBV DNA and RNA reductions but no changes in HBsAg, indicating
that longer treatments are needed.
Interim efficacy data are available from the Phase 2a Jade study. Interim analysis (IA) 2 (cut-off
date: 8 February 2019) includes Week 12 data from 64 chronic HBV-infected participants not
treated at screening of whom 26 received 75 mg qd JNJ-6379 monotherapy (open-label) and 38
received 75 mg qd JNJ-6379 or placebo in addition to an NA (blinded). Interim analysis 2 also
includes unblinded Week 24 data from 44 virologically suppressed chronic HBV-infected
participants of whom 33 received 75 mg qd JNJ-6379 and 11 received placebo in addition to an
NA. Interim analysis 3 (cut-off date: 7 March 2019) includes blinded Week 12 data from 40
virologically suppressed chronic HBV-infected participants who received 250 mg qd JNJ-6379 or
placebo in addition to an NA.
The 12-week interim efficacy data in currently not treated participants on 75 mg JNJ-6379
monotherapy showed a mean reduction from baseline of HBV DNA of >3.5 log10 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
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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 IA2 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 IA2 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 was added
for all remaining participants in the JNJ-6379 250 mg monotherapy arm in accordance with the
futility rule mentioned above.
Safety Studies
Data from 5 completed Phase 1 studies (56136379HPB1001, 56136379HPB1002,
56136379HPB1003, 56136379HPB1004, and 56136379HPB1005) in healthy and chronic
HBV-infected participants (N 126 and 41, respectively), indicate that orally administered
JNJ-6379 as single doses up to 600 mg or as multiple doses (250 mg twice daily for 2 days followed
by 170 mg qd for 18 days or 150 mg twice daily for 2 days followed by 100 mg qd for 10 days) in
healthy participants and as multiple doses up to 250 mg for 28 days in chronic HBV-infected
participants was safe and well tolerated. No SAEs considered at least possibly related to the
study intervention were reported. Most AEs were mild and not considered treatment-related, with
no dose-related trends.
Safety data are also available from IAs 2 and 3 conducted for the Phase 2a Jade study, which were
mentioned above. There were no deaths, SAEs considered at least possibly related to the study
intervention, or AEs leading to discontinuation. Most AEs were grade 1 or 2 in severity. The
majority of reported AEs were considered unrelated to JNJ-6379 by the investigator. Grade 2 to 4
AEs considered at least possibly related to JNJ-6379 by the investigator were grade 2 asthenia
(3 participants), grade 4 ALT increased, grade 2 headache, grade 2 vertigo, grade 3 anemia
(corrected to grade 2 by the investigator after the IA cut-off date), grade 2 hypertension, and
grade 2 fatigue (all observed in 1 participant each).
Increased cholesterol is considered a laboratory abnormality of interest for JNJ-6379, based on
safety review from nonclinical and clinical trials. Cholesterol increased was reported as an AE in
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4 (4.1%)participants on JNJ-6379 for the pooled Phase 1 studies, in 1 (2.4%) participant on
JNJ-6379 for the Phase 1 study 56136379HPB1005, and in none of the participants in the Phase 2a
Jade study.
2.2.2.2. 
Combination of JNJ-3989 and JNJ-6379 with Tenofovir Disoproxil
Tenofovir disoproxil (available in several salt forms including tenofovir disoproxil fumarate and
tenofovir disoproxil maleate)is a first-generation oral prodrug of the NA tenofovir that is indicated
for the treatment of chronic HBV infection in adult and pediatric patients at least 12 years of age.
In addition, tenofovir disoproxil in combination with other antiretrovirals is indicated for the
treatment of 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 patients) are
abdominal pain, nausea, insomnia, pruritus, vomiting, dizziness, and pyrexia.
For further information regarding tenofovir disoproxil, refer to the respective currently approved
prescribing information.
Clinical data on dual combination treatment of JNJ-6379 and NA are available from the ongoing
Phase 2a 56136379HPB2001 study (refer to the IB for JNJ-637910,11). In participants treated with
TDF, Ctrough  concentrations of tenofovir at Week 12 were higher in participants receiving TDF in
combination with JNJ-6379 than in participants receiving TDF as monotherapy (94.2 [30.0] and
115 [66.0] ng/mL for 75- and 250-mg JNJ-6379, respectively, vs 66.8 [37.0] ng/mL as TDF
monotherapy).
Clinical data of triple combination treatment of JNJ-3989, JNJ-6379, and NA are available from
the ongoing Phase 1/2a AROHBV1001 study (see Section 2.2.2.1, JNJ-3989 and JNJ-6379).
The single common toxicity target organ between JNJ-6379, JNJ-3989, and tenofovir disoproxil
is the kidney (see Section 2.2.1.2). In clinic, dosing JNJ-6379 or JNJ-3989 with NA for 12 weeks,
did not show any clinically relevant changes in kidney parameters/glomerular function.
Overall Assessment of the Combination Therapy
Based on the points listed below, no clinically relevant DDIs and no specific concerns about
additive or synergistic toxicities in the kidney are expected when JNJ-6379 and JNJ-3989 are
combined with tenofovir disoproxil:
 
Available toxicology data described in Section 2.2.1.2.
 
In vitro drug transporters.
 
Metabolic interaction data.
 
Absence of relevant DDIs in the combination toxicity studies up to 3-month with JNJ-6379
and JNJ-3989.
 
Absence of synergistic or additive histology findings in the kidney observed in the
combination toxicity studies up to 3-month with JNJ-6379 and JNJ-3989.
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 
Available clinical data with JNJ-6379 (Jade study [56136379HPB2001]) up to 48 weeks
treatment on the absence of changes in kidney parameters/glomerular function.
 
Available clinical data of triple combination treatment of JNJ-3989, JNJ-6379, and NA
described in Section 2.2.2.1.
A mild platelet decrease was seen after 3-month dosing of rats given JNJ-6379 and JNJ-3989.
2.2.2.3. 
Combination of JNJ-3989 and JNJ-6379 with PegIFN-α2a
PegIFN-α2a is a covalent conjugate of recombinant alfa-2a interferon that is indicated for the
treatment of chronic hepatitis B in adult and pediatric patients at least 3 years of age. In addition,
PegIFN-α2a in combination with other medicinal products is indicated for the treatment of chronic
hepatitis C virus (HCV)-infection in adult and pediatric patients at least 5 years of age and not
treated before. The most common adverse reactions (≥10% of participants) are anorexia, anxiety,
headache, concentration impairment, dyspnea, cough, alopecia, dermatitis, pruritis, dry skin,
myalgia, arthralgia, asthenia, pyrexia, and fatigue. For further information regarding PegIFN-α2a,
refer to the currently approved prescribing information.
Treatment with PegIFN-α2ahas been associated with decreases in platelet count (common adverse
reaction). In the ongoing Phase 1/2a AROHBV1001 study (see Section 2.2.2.1), no effect on
platelet count has been observed in the triple combination treatment cohort 12 (JNJ-3989, JNJ-
6379, and NA). Of the 84 adult chronic HBV-infected participants that received 3 subcutaneous
injections of JNJ-3989, 6 participants developed grade 1 platelet reduction with no general trend
towards a continuous decline. For JNJ-6379, no effect on platelet count has been observed in
ongoing Phase 2a HPB2001 study (Jade) for the 189 adult chronic HBV-infected participants that
were dosed with JNJ-6379.
Based on preclinical data, a potential common toxicity target organ between JNJ-6379, JNJ-3989,
and PegIFN-α2a is the bone marrow (see Section 2.2.1, Nonclinical Studies). Bone marrow
suppression is a known side effect of PegIFN-α2a (rare).
No pharmacokinetic (PK)interaction is expected between JNJ-3989 and PegIFN-α2a based on the
known pharmacologic profiles of JNJ-3989 and PegIFN-α2a.13,29
At the time of protocol amendment 5 writing, no clinical data on the combination of JNJ-3989 and
JNJ-6379 with PegIFN-α2a are available. Nonclinical studies to investigate the effect on platelet
count decreases and on bone marrow in non-human primates (JNJ-3989) and bone marrow stem
cells (JNJ-6379)were completed, and results are summarized in Section 2.2.1.3..
2.3. 
Benefit-Risk Assessment
More detailed information about the known and expected benefits and risks of JNJ-3989 and JNJ-
6379 may be found in the respective IBs and their Addenda.10,11,13,12
For the benefit-risk evaluation of tenofovir disoproxil and PegIFN-α2a refer to the respective
prescribing information and Summary of Product Characteristics.
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JNJ-6379 was initially part of the study intervention but has been removed as study intervention
with the implementation of an urgent safety measure, as described in Protocol Amendment 6.
Emerging data from the REEF-1 and REEF-2 studies resulted in an unfavorable benefit-risk
balance of JNJ-6379 in combination with JNJ-3989+NA, compared to JNJ-3989+NA alone.
Therefore, the Sponsor decided to discontinue treatment with JNJ-6379 in all ongoing clinical
studies effective immediately. Participants who were on treatment with JNJ-6379 were contacted
and requested to stop taking JNJ-6379, while continuing treatment with NA, JNJ-3989 and
PegIFN-α2a (as applicable). For newly enrolled participants, JNJ-6379 was taken out of the
treatment regimen. For completeness, the benefit-risk assessment for JNJ-6379 is still included in
this section.
2.3.1. 
Benefits for Study Participation
2.3.1.1. 
Known Benefits
The clinical benefit of JNJ-3989 and JNJ-6379 remains to be established.
2.3.1.2. 
Potential Benefits
Results from clinical studies with JNJ-3989, JNJ-6379, NAs, and PegIFN-α2a may be useful for
the development of a novel therapeutic approach for chronic HBV infection.
The combination of JNJ-6379 and JNJ-3989 on a background of an NA 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.5,18,19 By acting on both viral replication
and by reducing barriers to the host immune response, higher functional cure rates may be
achieved.
The addition of short-term PegIFN-α2a (12-week consolidation phase) to the regimen at a time
when HBsAg is already significantly reduced or eliminated, which is assumed to be associated
with potential restoration of the immune response,may lead to further improvement of the immune
response (such as reactivation of NK-cells and further activation of endogenous HBV-specific T-
cells) and ultimately could lead to immune control of HBV (ie, functional cure). In addition,
PegIFN-α2a has shown to have direct antiviral effects on HBV which could also contribute to the
efficacy of the regimen. By adding short-term PegIFN-α2a to the regimen, higher functional cure
rates may be achieved.
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Investigating the treatment regimen JNJ-3989 + PegIFN-α2a + NAs with and without JNJ-6379 in
this immune tolerant study population might be useful for the development ofa treatment for this
population that currently has no recommended treatment options.
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.
Side effect profile of PegIFN-α2a is well established and includes, but is not limited to,
neuropsychiatric, autoimmune, ischemic, ophthalmologic, hematological, and infectious
disorders. Exacerbations of hepatitis during hepatitis B therapy are common and characterized by
transient and potentially severe increases in serum ALT. Marked increases in ALT were sometimes
accompanied by bilirubin elevation and other liver test abnormalities. In many, but not all cases,
these disorders resolve after stopping PegIFN-α2a therapy. For a full list of known risks for
PegIFN-α2a refer to the respective prescribing information and Summary of Product
Characteristics.
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/HBeAg. Whether this occurs at higher frequency
during or after treatment with JNJ-6379 and JNJ-3989 is not known. In this context it is also
possible that the interventional treatment lead to a transition of participants to a more
“immune-active” disease stage. In this case long-term NA treatment after end of study
participation may be needed.
This study will be conducted in a study population that according to current treatment guidelines
(EASL)4 does not have a general treatment indication. As discussed in Section 2.1, Study
Rationale, this is mainly driven by the limited efficacy of NA treatment in patients with HBeAg
positive infection and by the fact that NA treatment, once initiated, usually has to be continued
lifelong. The assumption to achieve functional cure with the investigated treatment regimen would
change this benefit assessment,but clinical evidence is not yet available.
Please refer to Section 2.2, Background, for details on the safety results in the studies conducted
to date.
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2.3.2.2.1. 
Potential Risks for JNJ-3989
ALT Elevations
ALT elevations are considered an important potential risk for JNJ-3989. Two distinct patterns of
ALT elevations have been observed in participants receiving JNJ-3989: a rapidly rising and
resolving ALT elevation or a more sustained pattern of ALT elevation. The latter has been
observed in HBV/HDV co-infected participants in study 73763989HPB2004 during double-blind
treatment phase. A causal association of ALT elevations with JNJ-3989 has not been confirmed
and the underlying mechanism for ALT elevations being more frequent in the context of
HBV/HDV co-infection is not yet understood.12
Reproductive Risks and Pregnancy
In the EFD studies, JNJ-3989 was not teratogenic in rats and rabbits. The fertility in male and
female rats is not impacted with JNJ-3989 up to a dose of 180 mg/kg/week.
Based on the difference in metabolic pathways and in vitro data indicating absence of impact of
JNJ-3989 on CYP enzymes and transporters, no clinically relevant interactions are anticipated
between JNJ-3989 and oral contraceptives.
Potential Genotoxicity
JNJ-3989 is considered to be devoid of genotoxic activity. Nonclinical carcinogenicity studies
have not been conducted.
Other Potential Toxicity/Events of Special Interest
Hematologic abnormalities are an event of special interest for JNJ-3989 and JNJ-6379 based on
animal studies (refer to 2.3.2.2.2 for further information).
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 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 NAs, is expected to minimize the risk of emerging
resistant viral variants.
2.3.2.2.2. 
Potential Risks for JNJ-6379
Since the initial protocol writing, interim results of the REEF-1 and REEF-2 studies had become
available. The data suggested that JNJ-6379 has a negative impact on the HBsAg lowering effect
of JNJ-3989+NA (see Section 2.2.2.1). In addition, there were new insights in the adverse renal
profile of JNJ-6379 (see below). Taken together, it was concluded that JNJ-6379 had an
unfavorable benefit-risk balance in combination with JNJ-3989+NA, compared to JNJ-3989+NA
alone. Therefore, the Sponsor decided to discontinue treatment with JNJ-6379 in all ongoing
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clinical studies effective immediately. For completeness, the potential risks for JNJ-6379 are still
described in this section.
Reproductive Risks and Pregnancy
In the fertility study in females, early embryonic development was affected: an increase in pre- and
post-implantation loss, reduction in implantation and live fetuses at 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 
. 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,
 At this dose, the AUC0 24h was 99,200 ng.h/mL and the Cmax was 6,880 ng/mL.
Potential Genotoxicity
JNJ-6379 was not genotoxic in the in vitro and in vivo tests.
JNJ-6379 did not affect male or female fertility. Carcinogenicity studies are not yet conducted.
Other Potential Toxicity/Events of Special Interest
Based on nonclinical findings in rats and dogs and based on clinical findings, increased cholesterol
was identified as a laboratory abnormality of interest.
Renal complications are considered an event of special interest for JNJ-6379. Immediate
treatment-emergent decrease in mean eGFRcr, which was initially observed in the JADE study,
has also been observed in both JNJ-6379 treatment arms in the ongoing REEF-1 study. The
eGFRcr values remained reduced during treatment, with a fast rebound after end of treatment. The
eGFRcr decrease (calculated from serum creatinine) may be an anomaly due to JNJ-6379 possibly
interfering with tubular excretion of creatinine via inhibition of MATE-1 transporter.11 This
hypothesis was supported by the absence of a pattern of increased biomarkers of proximal tubulo-
toxicity (the beta-2-microglobulin/creatinine and the retinol binding protein/creatinine ratios),
suggesting that the eGFRcr reduction was due to transporter inhibition at the level of creatinine
excretion from the proximal tubule rather than renal toxicity.
Emerging data from the REEF-2 study confirmed the transient pattern of eGFRcr declines but, in
addition, showed an increase of the beta-2-microglobulin/creatinine and the retinol binding
protein/creatinine ratios in some participants when TDF was continued and combined with JNJ-
6379+JNJ-3989. These new data are suggesting that JNJ-6379 in combination with TDF may
contribute to renal tubulo-toxicity.
CCI
CCI
CCI
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Hematologic abnormalities are considered an event of special interest for JNJ-3989 and JNJ-6369.
Mild thrombocytopenia was observed in recently conducted non-clinical toxicology studies with
the combination of JNJ-3989 and JNJ-6379. In addition, in a 3-month combination study with
80 rats, 1 rat developed pancytopenia related to bone marrow depletion after 23 days of dosing.
Previously, in a 9-month dog study in 24 dogs treated with JNJ-6379 alone, pancytopenia which
correlated with a marked increase in plasma cell-like cells in the bone marrow was observed in
1 dog after 60 days of dosing. Refer to Section 8.3.6.4. A minor additive effect was observed in
vitro in human bone marrow derived erythroid and myeloid progenitors when combining JNJ-6379
and Peg-IFN-α2a.10
Viral Resistance
Treatment with JNJ-6379 may lead to emergence of viral variants with reduced susceptibility or
resistance to JNJ-6379. Based on nonclinical data, these variants remain susceptible to tenofovir
disoproxil 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.
2.3.2.2.3. 
Potential Risks for Tenofovir Disoproxil and PegIFN-α2a
For the general potential risks of tenofovir disoproxil and PegIFN-α2a refer to the respective
prescribing information and Summary of Product Characteristics.
Risks specific for this study design are listed below:
 PegIFN-α2a might increase the immunogenicity of JNJ-3989.
 Combination of PegIFN-α2a with JNJ-3989 and JNJ-6379 might increase the risk of
hematologic abnormalities and/or of bone marrow suppression.
 JNJ-6379 might increase tenofovir plasma concentrations.
2.3.3. 
Benefit-Risk Assessment for Study Participation
Based on the available data and taking into account the measures taken to minimize risk to
participants ofthis study, the potential risks identified in association with the study treatment are
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justified by the anticipated benefits that may be afforded to participants with  HBeAg positive
chronic hepatitis B virus infection and normal ALT 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 2.2.2, 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 had been raised for JNJ-6379 at the time of initial
protocol writing, based on the safety information from studies in healthy adult participants
and adult participants with chronic HBV infection. Most observed AEs at that time were mild
in severity and considered not related to JNJ-6379 by the investigator (see Section 2.2.2,
Clinical Studies). At the time of Protocol Amendment 6 writing, it was concluded that JNJ-
6379 has an unfavorable benefit-risk balance in combination with JNJ-3989+NA, compared
to JNJ-3989+NA alone (see Section 2.3.2.2.2). Therefore, the Sponsor decided to discontinue
treatment with JNJ-6379 in all ongoing clinical studies effective immediately, as a measure to
minimize risk to participants of this and other studies.
 
Events of Special Interest are significant AEs that are judged to be of special interest because
of clinical importance, known class effects or based on nonclinical signals. Events of Special
Interest that will be carefully monitored during the study, include ISRs, ALT/aspartate
aminotransferase (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 8.3.7,
Other Toxicities).
 
Continued careful assessment of the safety, efficacy, and PK during treatment is included in
this study.
 
To minimize potential risk and stress to participants, the following measures are in place:
 
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 and other toxicities will be closely monitored
(Section 8.3.6, Adverse Events of Special Interest and Section 8.3.7, Other Toxicities).
 
Based on pre-clinical and clinical data available today, the combination of JNJ-3989,
tenofovir disoproxil, and short-term PegIFN-α2a is considered safe. Data from
nonclinical combination toxicity studies (Section 2.2.1.3) showed a minimal additive
effect on myeloid and erythroid cells in vitro when combining JNJ-6379 and PegIFN-α2a
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and confirmed that combination of PegIFN-α2a with JNJ-3989 did not induce any
synergistic or additive effect in monkeys up to 3 months of treatment. Review of 48-week
hematology data from the ongoing Phase 2 clinical study REEF-1 (Section 2.2.2.1) did
not identify any safety concerns.
 
The impact of PegIFN-α2a addition to JNJ-3989 on ALT elevations is not known. Strict
rules for management of ALT elevation are in place (refer to Section 8.3.6.2,
Intervention-emergent ALT/AST Elevations).
 
A Data ReviewCommittee (DRC) 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, Data Review 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 JNJ-3989, JNJ-6379 (if applicable), PegIFN-α2a, and NA
(if NA completion criteria are met at consolidation Week 12), participants will be
monitored closely during the follow-up phase, with frequent follow-up visits and
pre-defined NA re-treatment criteria in case of flares (Section 6.6.2, 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 (Section 6.6.2).
 
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 followedup 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 a treatment 
regimen of JNJ-3989 + PegIFN-α2a + NA. 
 
Proportion of participants with HBsAg
seroclearance 24 weeks after stopping all
study interventions of the consolidation phase
and without restarting NA treatment.
Secondary
 
To evaluate the safety and tolerability of the 
study intervention. 
 
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),
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HYPOTHESIS
As this is an exploratory proof of concept (PoC) study, no formal statistical hypothesis has been
formulated.
4. 
STUDY DESIGN
4.1. 
Overall Design
This ISA describes a Phase 2a study of JNJ-3989. Prior to Protocol Amendment 6, the study
intervention also included JNJ-6379. This ISA is a companion document to the Master Protocol
PLATFORMPAHPB2001, which describes the common design elements of the Platform study in
participants with CHB. This ISA describes specific and/or additional protocol elements applicable
to this intervention cohort, in which participants will be allocated to the following study
intervention:
- Prior to Protocol Amendment 5 (Cohort 1):
o Arm 1: JNJ-3989 + JNJ-6379 + NA + PegIFN-α2a
o Arm 2: JNJ-3989 + JNJ-6379 + NA
Note: Participants who were randomized to the group without PegIFN-α2a prior to
Protocol Amendment 5, will have PegIFN-α2a added to their treatment regimen, for 12
weeks,at the next scheduled visit (see details below).
- Per Protocol Amendment 5 (Cohort 2):
o Arm 3: JNJ-3989 + JNJ-6379 + NA + PegIFN-α2a
o Arm 4: JNJ-3989 + NA + PegIFN-α2a
Note: Participants enrolled under Protocol Amendment 5 did not receive JNJ-6379
because of the immediate removal of JNJ-6379 as study intervention through an urgent
safety measure (see details below).
- As of Protocol Amendment 6 (Cohort 2):
o Single-arm: JNJ-3989 + NA + PegIFN-α2a
To distinguish between participants enrolled prior to or after Protocol Amendment 5 is in effect,
the terms Cohort 1 and Cohort 2 will be used. All participants enrolled prior to the Protocol
Amendment 5 will comprise Cohort 1. The participants enrolled after approval of Amendment 5
will comprise Cohort 2.
The study described in this ISA, as of Protocol Amendment 6, is a Phase 2a, single-arm, open-
label, multicenter, interventional study  to evaluate the efficacy, pharmacokinetics, safety, and
tolerability of treatment with JNJ-3989+PegIFN-α2a+NA in patients with HBeAg positive chronic
HBV infection and ALT ≤2x ULN who are not currently being treated for their HBV infection (ie,
who had <9 months of prior treatment which ended at least 12 months before screening, including
treatment-naïve patients). After completing this study, participants may have the option to enroll
into a long-term follow-up study.
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In total, a target of approximately 60 adult participants, 18-55 years (inclusive) of age (with a
maximum of approximately 10 participants >45 to ≤55 years of age), with CHB who are HBeAg
positive, who are not currently being treated for their HBV infection (ie, who had <9 months of
prior treatment which ended at least 12 months before screening, including treatment-naïve
patients), have HBV DNA ≥20,000 IU/mL and have ALT ≤2x ULN at screening will be enrolled
in this study  (including approximately 33 participants after implementation of Protocol
Amendment 6). It is targeted to enroll at least 30% participants with HBV DNA ≥107 IU/mL and
normal ALT at screening in the study.
The study will be conducted in 4 phases:
 
A screening phase (4 weeks [if necessary, can be extended to a maximum of 6 weeks
decided on a case-by-case basis and in agreement with the sponsor]).
 
An induction phase:
o Prior to Protocol Amendment 5: RGT of36-60 weeks (inclusive)
Note: Participants who already passed the Week 36 visit before Protocol
Amendment 5 is in effect, will enter the consolidation phase at the next scheduled
visit.
o As of Protocol Amendment 5: fixed duration of 36 weeks
 
A consolidation phase (12 weeks).
 
A follow-up (FU) phase (48 weeks).
The total duration of individual participation will be 100 to 102 weeks. Of note, participants
enrolled before Protocol Amendment 5 is in effect may have a longer induction phase and a total
study duration up to 126 weeks.
The induction and consolidation phase have been updated with Protocol Amendment 5 and
Protocol Amendment 6:
 
Prior to Protocol Amendment 5, enrolled participants will enter an induction phase with triple
treatment (JNJ-3989]+JNJ-6379+NA) for a response-guided treatment duration of  ≥36 weeks
to ≤60 weeks. End of the induction phase is defined by either meeting the study defined RGT
criterion (HBsAg <10 IU/mL) or reaching study Week 60, whichever comes first. The RGT
criterion will be assessed from Week 36 onwards at each study visit, and the assessment will
always be based on lab results from the previous study visit. If the RGT criterion is met, the
participant will complete the induction phase at that visit and will be randomized in a 1:1 ratio
to one of the following intervention arms in the 12-week consolidation phase: JNJ-3989+JNJ-
6379+NA+PegIFN-α2a (Cohort 1, Arm 1) or JNJ-3989+JNJ-6379+NA (Cohort 1, Arm 2). At
the time of writing Protocol Amendment 5, 22 participants were already enrolled in the study.
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Note: Participants enrolled before Protocol Amendment 5 is in effect will switch to the new
study design as soon as Protocol Amendment 5 is in effect. Participants who did not yet reach
the Week 36 visit at that time will have PegIFN-α2a added to their treatment regimen at Week
36 for 12 weeks. Participants who already passed the Week 36 visit and/or were randomized
to the group without PegIFN-α2a, will have PegIFN-α2a added to their treatment regimen at
the next scheduled visit. After 12 weeks, treatment with PegIFN-α2a, JNJ-3989 and JNJ-6379
(if applicable) will be stopped.
 
Per Protocol Amendment 5, based on the number of participants currently enrolled, it is
estimated that approximately 50 participants will be randomized at baseline in a 1:1 ratio to
one of the following intervention arms: JNJ-3989+JNJ-6379+NA (Cohort 2, Arm 3) or JNJ-
3989+NA (Cohort 2, Arm 4). Upon completion of the 36-week induction phase, all
participants will enter the 12-week consolidation phase during which they will have PegIFN-
α2a added to their treatment regimen.
Note: With the implementation of an urgent safety measure, as described in Protocol
Amendment 6, participants previously enrolled had to immediately switch to the new study
design. Participants had to stop JNJ-6379 treatment immediately and continue with JNJ-
3989+NA treatment up to the end of the induction phase and will then enter the 12-week
consolidation phase during which they will have PegIFN-α2a added to their treatment
regimen.
 
As of Protocol Amendment 6, the study will continue as a single-arm study (JNJ-
3989+NA+PegIFN-α2a). All newly enrolled participants will receive JNJ-3989+NA for 36
weeks (induction phase) and will then enter the 12-week consolidation phase during which
they will have PegIFN-α2a added to their treatment regimen.
At the end of the consolidation phase, all participants will enter the FU phase and stop treatment
with JNJ-3989+PegIFN-α2a. If NA treatment completion criteria (HBsAg <10 IU/mL, and
HBeAg-negative, and HBV DNA <LLOQ, and ALT <3x upper limit of normal [ULN]) have been
met at consolidation Week 12, NA will also be stopped at the next scheduled visit (ie, FU Week
2), otherwise NA treatment will continue during the complete FU phase. Participants will be
monitored closely during the 48-week FU phase and should restart NA treatment in accordance
with the NA re-treatment criteria (see Section 6.6.2, NA Re-treatment Criteria and Monitoring
After Stopping of NA, for more details).
As of Protocol Amendment 6, study intervention consists of:
 
200 mg JNJ-3989 (SC injection Q4W)
 
245 mg tenofovir disoproxil (tablets qd) Note: tenofovir disoproxil may be supplied as
fumarate or maleate
 
180 µg PegIFN-α2a (SC injection, QW)
Note: Most participants enrolled before Protocol Amendment 6 was in effect, also received 250
mg JNJ-6379 (tablets qd) as part of their study intervention.
Both the Platform Master informed consent form (ICF) and the ISA ICF must be signed before the
first study-related activity.
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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).
Efficacy will be evaluated using different parameters including HBsAg and HBeAg (see
Section 8.1).
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.
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, Exploratory Host Biomarkers).
A population PK analysis may be performed based on the available data for JNJ-3989 (ie,
JNJ-3976 and JNJ-3924), and optionally JNJ-6379, NA  and/or PegIFN-α2a, potentially in
combination with data from a selection of Phase 1 and/or 2 studies. PK parameters in participants
undergoing intensive PK sampling will be calculated via noncompartmental methods (see
Section 8.5, Pharmacokinetics). To assess the effect of PegIFN-α2a on JNJ-3989, the PK
parameters of JNJ-3989 coadministered with PegIFN-α2a at Week 8 (or 4) of the consolidation
phase will be compared to those of JNJ-3989 at Week 24 (or 28 or 32) of the induction phase as
reference. A similar analysis may be done for JNJ-6379.
PBMC 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 and samples for epigenetic testing will be collected from
participants who consent separately to this component of the study (see Section 8.8, Host
Genetics).
Four PRO instruments (SF-36v2, HBQOL, EQ-5D-5L, PGIC) 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 (EOS) visit (ie, FU Week 48).
If a participant prematurely (before the end of the consolidation phase) discontinues JNJ-3989),
the participant will enter the 48-week follow-up phase and complete the follow-up schedule as per
the Schedule of Activities, unless the participant withdraws consent. In this case, NA treatment
may be continued or, in consultation with the sponsor, discontinued based on investigator
judgement or completed based on the NA treatment completion criteria (see Section 6.6).
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If a participant prematurely discontinues PegIFN-α2a (before the end of the consolidation phase),
treatment with JNJ-3989 and NA should be continued as planned.
If a participant withdraws prematurely, 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 (this visit should be performed within 2 month of
withdrawal).
The Schedule of Activities summarizes the frequency and timing of efficacy, safety, and other
assessments applicable to the Master Protocol PLATFORMPAHPB2001 and this ISA.
A DRC will be established for this study (Section 9.6, Data Review 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.
4.2. 
Scientific Rationale for Study Design
Study Population
This study was initiallydesigned to assess the combination treatment with JNJ-3989 and JNJ-6379
on top of NA and with or without PegIFN-α2a in patients with HBeAg positive chronic infection.
In Protocol Amendment 6, the study was redesigned to assess the combination treatment with JNJ-
3989 and PegIFN-α2a on top of NA in patients with HBeAg positive chronic infection. It includes
patients that are believed to be truly “immune tolerant” (chronic HBV infection as per EASL 2017
guidelines)4 with very high HBV DNA levels and normal ALT, but also patients with lower HBV
DNA and/or minimally elevated ALT (ALT ≤2x ULN at screening). To ensure the group of “true
immune tolerant” participants is well represented, it is targeted to enroll at least 30% participants
with HBV DNA ≥107 IU/mL and normal ALT in the study.
Effective treatment options for the study population would have the potential to initiate treatment
at an earlier disease stage to prevent disease progression and development of cancer at later ages.
In addition, patients with HBeAg positive infection are believed to have the lowest level of T cell
exhaustion and therefore might show a better capacity to mount an effective immune control
following the study intervention.
Addition of PegIFN-α2a to Treatment Regimen
The addition of short-term PegIFN-α2a to the regimen at a time when HBsAg is already
significantly reduced or eliminated is expected to lead to reactivation of NK-cells. In addition, the
reactivation of the innate immune system by PegIFN-α2a might lead to further activation of
endogenous HBV-specific T-cells.
Study Design Change –Protocol Amendment 5
Based on preliminary 48-week treatment data from the REEF-1 study and insights from ILC
(EASL) 2021, PegIFN-α2a will be added to the treatment regimen for all participants, to increase
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the potential of achieving functional cure. By adding JNJ-6379 to the treatment regimen, its
potential benefit in currently not treated HBeAg positive participants can be properly evaluated.
The presence of JNJ-6379 is expected to enhance the reduction of HBV DNA levels in currently
not treated HBeAg positive participants. However, the benefit of adding JNJ-6379 to JNJ-
3989+NA in terms of 1) on-treatment effect on other viral markers (eg, HBsAg and HBeAg) and
2) off-treatment responses is less clear.
The study design was updated such that participants will be randomized at baseline, in a 1:1 ratio
to receive either JNJ-3989+JNJ-6379+NA or JNJ-3989 + NA for a fixed duration of 36 weeks
(induction phase) instead of a response-guided treatment duration. The induction phase will be
followed by a 12-week consolidation phase during which PegIFN-α2a will be added to the
treatment regimen for all participants.
Study Design Change –Protocol Amendment 6
Based on 
emerging data from the REEF-1 (73763989HPB2001) 
and REEF-2
(73763989PAHPB2002) studies, the study design has been adapted through an urgent safety
measure, as described in Protocol Amendment 6.
In summary, the data from the REEF-1 and REEF-2 studies suggested that JNJ-6379 has a negative
impact on the HBsAg lowering effect of JNJ-3989+NA (see details in Section 2.2.2.1) and that
JNJ-6379 in combination with TDF may further contribute to renal tubulo-toxicity (see details in
Section 2.3.2.2.2). Together, this led to a conclusion of an unfavorable benefit-risk balance of JNJ-
6379 in combination with JNJ-3989+NA, compared to JNJ-3989+NA alone. Therefore, the
Sponsor decided to discontinue treatment with JNJ-6379 in all ongoing clinical studies effective
immediately. Participants currently on treatment with JNJ-6379 were contacted and requested to
stop taking JNJ-6379, while continuing treatment with NA, JNJ-3989, and PegIFN-α2a (as
applicable). For newly enrolled participants, JNJ-6379 was taken out of the treatment regimen. 
Furthermore, the sponsor decided to make additional changes to the study design because of a
severe clinical ALT flare that was reported following discontinuation of NA treatment in a
participant who was randomized to the control arm (placebo + placebo + NA) in the REEF-2 study.
Discontinuation of NA treatment was following the protocol-defined criteria and was in line with
recent EASL treatment guidelines.4 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 the safety of participants, the protocol was amended: more frequent
monitoring and a new NA re-treatment criterion were added for all participants who discontinued
NA treatment during follow-up.
Randomization and Stratification
As of Protocol Amendment 6, randomization will no longer be used in this study. Prior to Protocol
Amendment 6, randomization and stratification were performed as described below.
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Randomization
Randomization occurred at the start of the induction phase. Randomization was used to minimize
bias in the assignment of participants to intervention arms, to increase the likelihood that known
and unknown participant attributes (eg,demographic and baseline characteristics) are evenly
balanced across intervention arms, and to enhance the validity of statistical comparisons across
intervention arms.
Stratification Factors
Randomization was stratified by HBV DNA level at screening (≥107 IU/mL OR <107 IU/mL)and
race (Asian versus non-Asian; for participants in Cohort 2), in order to provide a reasonably
balanced representation of these factors across the 2 intervention arms.
Criteria for Completion of NA Treatment
At the end of the consolidation phase, all participants will enter the FU phase and stop treatment
with JNJ-3989+PegIFN-α2a. If NA treatment completion criteria (described in Section 6.6) have
been met at consolidation Week 12, NA will also be stopped at the next scheduled visit (ie,at FU
Week 2), otherwise NA treatment will continue during the complete FU duration. The treatment
completion criteria which take ALT, HBV DNA, HBeAg, and HBsAg levels into consideration,
have been selected to ensure that only participants with a chance of sustained off-treatment
response are allowed to complete all study intervention. Across a range of studies, HBsAg levels
below 100 IU/mL are consistently associated with favorable off-treatment response.16,22 The
stringent HBsAg cut-offof 10 IU/mL for NA treatment completion was chosen to account for the
direct effect of JNJ-3989 on HBsAg levels.
After stopping all study interventions, participants will be monitored closely during the 48-week
follow-up phase and should restart NA treatment in accordance with the NA re-treatment criteria
(see Section 6.6.2, NA Re-treatment Criteria and Monitoring After Stopping of NA, for more
details).
Follow-up Procedures and Criteria for Re-initiation of NA Treatment
To ensure safety of patients during the FU phase, an ALT flare management plan is in place,
including an additional visit after completion of NA treatment (at FU Week 2), and weekly visits
for patients with ALT/AST ≥3xULN 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 may be reflecting an activation of the host cellular immune
response,which may contribute to achieving 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
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ALT increase),will trigger immediate re-initiation of NA treatment based on protocol-defined NA
re-treatment criteria (see Section 6.6.2, 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 criteria and monitoring after stopping of NA  are presented graphically in
Section 10.16, Appendix 16.
Host DNA and Exploratory Host Biomarker Collection
Refer to Section 4.2 ofthe Master Protocol PLATFORMPAHPB2001.
4.2.1. 
Study-Specific Ethical Design Considerations
Refer to Section 4.2.1 of the 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.
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4.3. 
Justification for Dose
The proposed dose and treatment duration are selected to maximize suppression of the virus
including its antigen production to increase the chance for patients to achieve HBsAg
seroclearance assessed 24 weeks after stop of all treatment (ie, functional cure) with a finite
therapy. The selection is supported by scientific understanding of available data. For both agents,
the highest doses are selected that are currently being tested in ongoing Phase 2b studies REEF-1
(73763989HPB2001) and REEF-2 (73763989PAHPB2002) (ie, 200 mg for JNJ-3989 and 250 mg
for JNJ-6379).
Note: JNJ-6379 was initially part of the study intervention but has been removed as study
intervention with the implementation of an urgent safety measure, as described in Protocol
Amendment 6.
4.3.1. 
JNJ-3989
Clinical data on PK, efficacy, and safety of JNJ-3989 are available from the ongoing Phase 1/2a
AROHBV1001 study with a data cut-off date of 29 October 2019. All dosing with JNJ-3989 has
been completed and ongoing participants are in the follow-up phase. Twenty  adult healthy
participants have received single subcutaneous injections of JNJ-3989 (35, 100, 200, 300, and 400
mg) and 84 adult chronic HBV-infected participants have received multiple doses of JNJ-3989 (25,
50, 100, 200, 300, and 400 mg), administered as 3 subcutaneous injections separated by either 7-
day, 14-day, or 28-day intervals. All participants either continued or started on ETV or tenofovir
disoproxil on Day 1.
JNJ-3989 was generally safe and well tolerated at all doses. No clinically relevant safety signal
was identified.
Antiviral activity data were available for 56 chronic HBV-infected participants who received
3 subcutaneous injections of 25 to 400 mg JNJ-3989 Q4W  .7,31 In general, mean HBsAg declines
reached nadir at Day 113 (ie, 8 weeks after last JNJ-3989). Mean HBsAg levels remained
suppressed (below baseline levels) at least until Day 392 (ie, 9 months after last dose) in a
substantial proportion of patients. The HBsAg levels at Day 392 were variable with some patients
having HBsAg levels close to baseline levels while a substantial proportion of patients still had
HBsAg levels >1 log10 IU/mL lower than the baseline levels. JNJ-3989 showed activity on other
serological markers (HBV DNA, HBV RNA, HBeAg and HBcrAg), frequently with sustained
reduction at least until day 362. No apparent dose response was observed at doses between 100 mg
and 400 mg JNJ-3989, a numerically smaller mean decline was observed at the lower doses of 25
mg and 50 mg, mainly apparent after end of JNJ-3989 dosing.
A dose of 200 mg JNJ-3989 Q4W is chosen based on the observed decline in HBsAg in
Study AROHBV1001 at this dose over 3 injections, and the lack of a substantial incremental
efficacy response at higher doses.
The Phase 2b study REEF-1 is designed to establish the optimal dose of JNJ-3989. Based on data
from the Phase 1/2a study AROHBV1001 with limited treatment duration, 200 mg was selected
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as the highest dose of JNJ-3989 tested in REEF-1. Until lower doses are proven equivalently
effective in REEF-1, additional combination studies with JNJ-3989 and JNJ-6379 are conducted
with 200 mg of JNJ-3989.
4.3.2. 
JNJ-6379
Note: JNJ-6379 was initially part of the study intervention but has been removed as study
intervention with the implementation of an urgent safety measure, as described in Protocol
Amendment 6.
At the time of initial protocol writing, a dose of 250 mg JNJ-6379 qd was chosen for this study.
A dose of 250 mg of JNJ-6379 was considered to ensure maximal viral inhibition via “primary”
MoA (ie, interfering with the capsid assembly process). In addition, it ensured sufficient high
exposures to engage the “secondary” MoA (ie, inhibition of de novo cccDNA formation). This
dose selection was supported by translational PK/PD analyses and viral kinetic modeling. Analyses
of the HBV DNA data from the 4-week 56136379HPB1001 study showed a profound but slightly
less substantial reduction of plasma HBV DNA, as a measure of the “primary” MoA, in the 25 mg
dose group compared to the 75 mg and higher dose groups, suggesting that for JNJ-6379 maximum
effect (Emax) in terms of HBV DNA inhibition via primary MoA was approached starting from a
dose of 75 mg onwards. Since it was not possible to derive the engagement of the “secondary”
MoA from the available short-term data, the in vitro primary human hepatocyte 90% effective
concentration values in the presence of serum proteins obtained for both MoAs were used to
translate from the “primary” to the “secondary” MoA.
Participants were to be treated with JNJ-6379 for a minimum of 48 weeks to a maximum of
72 weeks. Based on the dual MoA of JNJ-6379, complete suppression of virus production and de
novo cccDNA formation over many months could reduce the transcriptional activity of the
cccDNA, both potentially contributing to HBsAg reduction and/or seroclearance.
Interim analysis data were at that time available from the ongoing Phase 2a Jade study in which
the 250-mg dose was being tested for 48 weeks. Blinded Week 12 data from 40 virologically
suppressed chronic HBV-infected participants who received 250 mg qd JNJ-6379 or placebo in
addition to an NA showed that there were no deaths, grade 4 AEs, or AEs leading to
discontinuation. Most AEs were mild or moderate in severity.
4.4. 
End-of-Study Definition
End-of-Study Definition
The EOS  is considered as the last visit (FU Week 48 or early discontinuation) 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.
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Study Completion Definition
A participant will be considered to have completed the study if he or she has completed
assessments at the last visit (ie, FU Week 48).
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.
Note: Retesting to assess eligibility will be allowed once, using an unscheduled visit during the
screening period.
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.
For a discussion of the statistical considerations of participant selection, refer to Section 9.2,
Sample Size Determination.
Each potential participant must satisfy all inclusion and exclusion criteria from the Master Protocol
PLATFORMPAHPB2001 (numbering prefixed by “M” in the list below if unchanged and by “A”
if specified or more restricted in this ISA) and all additional intervention-specific inclusion and
exclusion criteria (numbering prefixed by “A”). The latter inclusion and exclusion criteria as well
as the additional text to criteria from the Master Protocol are highlighted (colored fill).
5.1. 
Inclusion Criteria
Each potential participant must satisfy all of the following criteria to be enrolled in the study:
A01 
(M01)
Criterion modified per Amendment 3
A01.1 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 ≤55 years of age with a maximum of
approximately 10 participants >45 to ≤55 years of age.
M02 
Participants 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.
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A03 
(M03d)
Criterion modified per Amendment 3
A03.1 Criterion modified per Amendment 5
A03.2 Participants must have chronic HBeAg positive HBV infection documented by
serum HBsAg positivity at screening. In addition, chronicity must be documented by
any of the following at least 6 months prior to screening: serum HBsAg positivity,
HBeAg positivity or HBV DNA positivity, documented transmission event. If none of
the above are available, the following ways of documenting chronicity are acceptable at
time of screening: liver biopsy with changes consistent with chronic HBV, or absence
of marker for acute infection such as positive immunoglobulin M (IgM) anti-hepatitis B
surface (HBs) and anti-HBc antibodies.
In addition, participants must:
a. be not currently treated (defined as having received <9 months of NA treatment
≥12 months prior to screening) including treatment-naïve participants (defined as
never having received treatment with HBV antiviral medicines, including NAs and
IFN products), AND
b. be HBeAg positive, AND
c. have serum HBV DNA at screening ≥20,000 IU/mL, AND
d. have ALT ≤2x ULN at screening and at least once >6 months prior to screening.
M04 
Participants must have a body mass index (BMI; weight in kg divided by the square of
height in meters) between 18.0 and 35.0 kg/m2, extremes included.
A05 
(M05) 
Participants (or their legally acceptable representative)must sign a Master ICF (specific
for the Master Protocol PLATFORMPAHPB2001) and must sign an ICF specific for
this intervention cohort, indicating that he or she understands the purpose of, and
procedures required for, the study and is willing to participate in the study.
M06 
Participants 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.
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- 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.a
- Participants with a positive HIV-1 or HIV-2 antibody/antigen test at screening
should have a confirmatory HIV RNA test, to rule out false positive results. They
can be enrolled if they have a negative HIV RNA test at screening. Participants
with evidence of HIV-1 or HIV-2 infection who are on antiretroviral treatment are
excluded.
M02.1 Participants with evidence of hepatic decompensation at any time point prior to or at
the time of screening:
a. Total bilirubin >1.5xULNb, OR
b. Direct bilirubin >1.2xULNb, OR
c. Prothrombin time >1.3xULN (unless caused by anticoagulation therapy or vitamin
K deficiency)b, OR
d. Serum albumin <3.2 g/dLb, 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 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 M02.1)
or any other non-HBV liver disease considered clinically significant by the investigator.
M05 
Participants with signs of HCC or clinically relevant renal abnormalities on an
abdominal ultrasound performed within 6 months prior to screening or at the time of
screening. In case of suspicious findings on conventional ultrasound the participant
a Negative HEV RNA may also be acceptable to rule out active HEV infection depending on local standard practices.
b Unless explained by a clinical setting that is not hepatic decompensation
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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).
A06 
(M06)
Criterion modified per Amendment 5
A06.1 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:
a. Estimated glomerular filtration rate based on serum creatinine (eGFRcr) <80
mL/min/1.73 m2 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,contrast enhanced
ultrasound, CT or MRI) during screening.
g. Any other laboratory abnormality considered to be clinically significant by the
investigator (also see inclusion criterion A03).
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).
M09.1 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-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
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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.
A16 
(M16) 
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
intervention, or is currently enrolled in an interventional clinical study with an
investigational product.
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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 
JNJ-6379*** 
PegIFN-α2a  
Tenofovir disoproxil 
Tenofovir alafenamide*
Type 
Drug 
Drug 
Drug 
Drug 
Drug
Dose Formulation 
Solution for injection  
Tablets 
Solution for injection  
Film coated tablets 
Film coated tablets
Unit Dose Strength(s) 
200 mg/mL 
25 and 100 mg 
180 µg/0.5 mL 
245 mg 
25 mg
Dosage Level(s) 
200 mg once every 4 
weeks (Q4W) 
250 mg once daily (qd) 
180 µg once weekly 
(QW)**
245 mg qd 
25 mg qd
Route of Administration 
Subcutaneous injection 
(preferably in the 
abdomen) 
Oral 
Subcutaneous injection 
(in the thigh or
abdomen)
Oral 
Oral
Use 
Investigational 
intervention  
Investigational 
intervention  
Investigational 
intervention
Background intervention  
Background intervention
Investigational Medicinal 
Product (IMP) and Non-
Investigational Medicinal
Product (NIMP)
IMP  
IMP  
IMP  
IMP  
IMP
Sourcing 
Provided centrally by the 
Sponsor 
Provided centrally by the 
Sponsor 
Provided centrally by the 
Sponsor 
Provided centrally by the 
Sponsor 
Provided centrally by the
sponsor
Packaging and Labeling 
Each unit will be labeled 
with unique medication 
ID number 
Each unit will be labeled 
with unique medication 
ID number 
Commercial supplies 
will be sourced. Each 
unit will be labeled with 
unique medication ID 
number. 
Commercial supplies 
will be sourced. Each 
unit will be labeled with 
unique medication ID 
number. 
Commercial supplies
will be sourced. Each
unit will be labeled with
unique medication ID
number.
In child resistant 
packaging 
In child resistant 
packaging 
In child resistant 
packaging 
In child resistant
packaging
Labels will contain information to meet the applicable regulatory requirements.
Food/Fasting Instructions 
Regardless of food 
intake 
Regardless of food 
intake 
Per the prescribing 
information  
Per the prescribing 
information  
Per the prescribing
information
Q4W: once every 4 weeks; qd: once daily; QW: once weekly.
*In countries where tenofovir alafenamide is available, it may be used for participants who need to switch NA (refer to Section 8.3.6.3).
**For PegIFN-α2a, dose adjustment may be applicable for participants who develop laboratory abnormalities during PegIFN-α2a treatment (refer to Section 6.6).
*** Most participants enrolled before Protocol Amendment 6 was in effect, also received JNJ-6379 as part of their study intervention. As of Protocol Amendment 6:
study intervention includes JNJ-3989, NA and PegIFN α2a.
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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, 
JNJ-3989 will be manufactured and provided under the responsibility of the sponsor. Refer to the
IB for a list of excipients.13,12
NA (tenofovir disoproxil) and PegIFN-α2a treatment will be provided by the sponsor. Refer to the
prescribing information for a list of excipients.
Tenofovir disoproxil is formulated as oral film-coated tablet of 245 mg strength.
PegIFN-α2a formulated as solution for subcutaneous injection in a prefilled syringe with
180 µg/0.5 mL of PegIFN-α2a, will be provided by the sponsor. Refer to the prescribing
information for a list of excipients.
Packaging and Labeling
All study interventions will be packaged with each unit labeled with a unique medication ID
number. Commercial supplies of tenofovir disoproxil and PegIFN-α2a will be sourced and a
clinical study label will be applied. Study intervention labels will contain information to meet the
applicable regulatory requirements.
NA (tenofovir disoproxil) and PegIFN-α2a treatment may also be repackaged into child-resistant
packaging if this is not already the case.
No study interventions can be repacked or relabeled without prior approval from the sponsor.
Study Intervention Administration
Study intervention administration must be captured in the source documents and the CRF.
JNJ-3989 injections will be administered subcutaneously (preferably in the abdomen)at the study
site.
NA and PegIFN-α2a treatment will be provided by the sponsor. Investigators should follow
guidance detailed in the respective prescribing information, including special warnings and
precaution for use.
In between study visits, participants will take their NA orally at home and they will bring their NA
with them to each study visit. Study-site personnel will instruct participants on how to take their
NA orally at home. At study visits, NA should be taken on site to allow biochemistry and renal
biomarker samples to be taken in fasted conditions.
CCI
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For PegIFN-α2a, administration should be done SC in the thigh or abdomen, preferably in the
evening by self-injection. Used PegIFN-α2a syringes should be separated from the needle via the
sharps container and then placed into their original box and returned to the site, if allowed per local
guidelines and regulations. The used needles in the sharps container will be returned to the study
site after completion of the consolidation phase or disposed of following local standard procedures.
If desired, participants can also choose to have the weekly administration of PegIFN-α2a
performed at the study site irrespective of the time of day.
JNJ-3989 and PegIFN-α2a should be injected subcutaneously into different areas of the abdomen
and approximate location should be recorded.
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 study intervention for at home use
as indicated for this protocol.
Refer to the pharmacy manual/study site investigational product and procedures manual for
additional guidance on study intervention preparation, handling, and storage.
Accountability
The investigator is responsible for ensuring that all study intervention received at the site is
inventoried and accounted for throughout the study. The dispensing of NA (tenofovir disoproxil)
and PegIFN-α2a (if applicable) to the participant, and the return of JNJ-6379, NA (tenofovir
disoproxil), and PegIFN-α2a from the participant (if applicable), 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 and PegIFN-α2a injections
administered to the participant must be documented on the intervention accountability form. All
study intervention will be stored and disposed of according to the sponsor's instructions. Study-
site personnel must not combine contents of the study intervention containers.
Participants who stopped JNJ-6379 per Protocol Amendment 6, must return their JNJ-6379 supply
at the next scheduled visit. The return of JNJ-6379 from the participant must be documented on
the intervention accountability form.
Study intervention must be handled in strict accordance with the protocol and the container label,
and must be stored at the study site in a limited-access area or in a locked cabinet under appropriate
environmental conditions. Unused study intervention, and 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
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site is an authorized destruction unit and study intervention supplies are destroyed on-site, this
must also be documented on the intervention return form.
Potentially hazardous materials containing hazardous liquids, such as used ampules, needles, and
vials, should be disposed of immediately in a safe manner and therefore will not be retained for
intervention accountability purposes. Details on handling of used PegIFN-α2a syringes are
described in Section 6.1, Study Intervention(s) Administered.
Study intervention should be dispensed under the supervision of the investigator or a qualified
member of the study-site personnel, or by a hospital/clinic pharmacist. Study intervention will be
supplied only to participants participating in the study. Returned study intervention must not be
dispensed again, even to the same participant. Whenever a participant brings his or her oral study
intervention to the study site for pill count, this is not seen as a return of supplies. Study
intervention may not be relabeled or reassigned for use by other participants. The investigator
agrees neither to dispense the study intervention from, nor store it at, any site other than the study
sites agreed upon with the sponsor. Further guidance and information for the final disposition of
unused study interventions are provided in the Study Reference Manual.
6.3. 
Measures to Minimize Bias: Randomization and Blinding
Intervention Allocation
Procedures for Randomization and Stratification
As of Protocol Amendment 6, randomization will not be used in this study. All participants will
be assigned to receive JNJ-3989 + NA + PegIFN-α2a by the interactive web response system
(IWRS).
Prior to Protocol Amendment 6, randomization and stratification were performed as described
below.
Central randomization was implemented in this study. Participants were randomly assigned in a
1:1 ratio to 1 of 2 intervention  arms based on a computer-generated randomization schedule
prepared before the study by or under the supervision of the sponsor. The randomization was
balanced by using randomly permuted blocks and was stratified by screening HBV DNA level
(≥107 IU/mL OR <107 IU/mL) and race (Asian versus non-Asian; for participants in Cohort 2).
For more information on the interactive web response system (IWRS), refer to Section 6.3 of the
Master Protocol PLATFORMPAHPB2001.
Blinding
As this is an open-label study, blinding procedures are not applicable.
6.4. 
Study Intervention Compliance
JNJ-3989 will be administered at the study site as a subcutaneous injection by qualified study-site
personnel to assure compliance with study requirements.
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The participants will be requested to bring unused study interventions and empty packaging to the
study site at each visit.
Every effort should be made to have the participant take the study interventions as indicated in the
Schedule of Activities.
 If an injection of JNJ-3989 was missed, the injection should be given as soon as possible
but within 3 weeks after the scheduled time. Otherwise, the injection should be skipped
and the next injection should be given at the next scheduled time point per the initial
injection schedule.
 If a dose of NA is missed, the participant should follow the guidelines in the prescribing
information.
 If an injection of PegIFN-α2a is missed, the participant should follow the guidelines in the
prescribing information.
If a participant’s study intervention intake is not according to the protocol, the investigator will
take the necessary measures to ensure future adherence to the protocol.
An optional medication diary to document study intervention intake can be made available for
participants with an observed or known risk for study intervention non-compliance. The completed
diaries are reviewed by the site staff and discussed with the participants for compliance monitoring
and counseling. Completed diaries will be returned to the site staff to add to the source documents.
6.5. 
Concomitant Therapy
Note: With the removal of JNJ-6379 as study intervention in Protocol Amendment 6, JNJ-6379-
specific disallowed medications and concomitant medications to be used with caution are no longer
applicable and have been removed.
An overview of ISA-specific disallowed medication is provided in Table 3.
Local guidelines on the use of live vaccines in participants receiving PegIFN-α2a should be
followed, including for the second dose of Sputnik V (which contains rAd5, with a theoretical risk
of replication competence). Sputnik Light, which is the first dose of Sputnik V (with rAd26) is not
considered a live vaccine. See below for further guidance on the use of COVID-19 vaccines.
Note that locally approved COVID-19 vaccines (including those that received emergency use
authorization or conditional marketing authorization) are allowed throughout the study. The
following recommendations should be applied to accommodate COVID-19 vaccination during the
consolidation phase:
 COVID-19 vaccine and PegIFN-α2a should not be administered on the same day.
 If required, PegIFN-α2a injection can be delayed with 2 days. The next PegIFN-α2a
injection should be performed at the scheduled time.
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 If required, skipping a PegIFN-α2a injection may be considered after consultation with the
Sponsor.
 Vaccination with Sputnik V should take above-mentioned consideration about live
vaccines into account.
All COVID-19 vaccination-related data (eg, COVID-19 vaccination, AEs, AE management)
should be appropriately captured in the CRF and source documents. Refer to the COVID-19
vaccine and/or PegIFN-α2a prescribing information for more details.
For general concomitant therapy considerations, refer to Section 6.5 of the Master Protocol
PLATFORMPAHPB2001.
Table 3: 
Disallowed Medication
Disallowed at any time prior to screening until end of follow-up:
 
Any HBV antiviral medicines (including vaccines, NAs, and IFN products) other than the study
intervention taken in the context of this study.
Note: Prior hepatic treatment with herbal or nutritional products is allowed but should be stopped at
screening.
Note: <9 months of prior NA treatment is allowed but should have ended at least 12 months before
screening.
Disallowed from 6 months prior to screening until end of follow-up:
 
Any investigational agent, investigational vaccine, invasive investigational medical device, or
investigational biological product (other than the study intervention taken in the context of this study).
Note: For investigational COVID-19 vaccines administered within 6 months prior to screening, an
exception will be made as long as the vaccine has been approved (or received emergency use authorization
or conditional marketing authorization) at the time of screening.
Disallowed from 6 months prior to baseline until end of follow-up:
 
Any systemically (eg, intravenously, intramuscularly, orally, subcutaneously) administered medication
that directly or indirectly interferes with immune responses (eg, cyclosporine, interleukins, programmed
death-[ligand] 1 inhibitors,systemic corticosteroids exceeding 5 mg of prednisolone equivalent/day).
Disallowed from screening until end of follow-up:
 
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.
Note: The list of disallowed concomitant medication is not exhaustive; for products falling in one
of the categories and not mentioned by name, the sponsor should be contacted to determine
whether the product can be allowed.
The prescribing information for tenofovir disoproxil and PegIFN-α2a should be consulted for any
additional prohibited medication. In case of flu-like symptoms after administration of PegIFN-α2a,
paracetamol up to a maximum of 2 g per 24 hours and a maximum of 6 g per week is allowed.
Medications requiring subcutaneous injection (other than JNJ-3989 and PegIFN-α2a; eg, insulin)
should be administered away from the JNJ-3989 and PegIFN-α2a injection sites.
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6.6. 
Dose Modification
Dose modifications of JNJ-3989 and NA (increase or decrease of dose level) are not permitted
during the study.
For PegIFN-α2a, dose adjustment guidelines are applicable for participants who develop
laboratory abnormalities during PegIFN-α2a treatment, as recommended in the locally approved
prescribing information for PegIFN-α2a and upon investigator’s assessment. The guidance from
the Pegasys USPI has been provided as an example (see Table 4).
Table 4: 
PegIFN-α2a Hematological Dose Modification Guidelines
Laboratory Values 
Recommended Dose
ANC <750 cells/mm³ 
Reduce to 135µg
ANC <500 cells/mm³ 
Discontinue treatment until ANC values return to more than 1,000 cells/mm³.
Reinstitute at 90µg and monitor ANC.
Platelet <50,000 cells/mm³ 
Reduce to 90µg
Platelet <25,000 cells/mm³ 
Discontinue treatment
ANC: absolute neutrophil count
Source: Pegasys USPI
For participants who prematurely discontinue PegIFN-α2a, treatment with PegIFN-α2a may be
restarted according to the recommendations from the locally approved prescribing information for
PegIFN-α2a.
6.6.1. 
Study Intervention Completion at Consolidation Week 12
With the implementation of Protocol Amendment 6, all participants had to stop JNJ-6379
treatment immediately.
Participants will complete treatment with JNJ-3989 and PegIFN-α2aat the end of the consolidation
phase (Consolidation Week 12). If all of the following NA treatment completion criteria are met
at consolidation Week 12, NA will also be stopped at the next scheduled visit (ie,at FU Week 2):
 
The participant has ALT <3x ULN, AND
 
The participant has HBV DNA <LLOQ, AND
 
The participant is HBeAg-negative, AND
 
The participant has HBsAg <10 IU/mL.
Note:In case of ALT elevation ≥3x ULN at consolidation Week 12, the investigator must consider
different potential causes of increased ALT to ensure appropriate work up and management as
needed. If the ALT elevation is unrelated to HBV activity and/or <3x ULN by FU Week 2, NA
completion may be considered at the discretion of the investigator and in consultation with the
sponsor.
Participants who do not meet the above criteria at consolidation Week 12 should continue NA
treatment during the 48-week follow-up.
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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 met the NA treatment completion criteria at
Consolidation Week 12, 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.
If a participant prematurely (before the end of the consolidation phase) discontinues JNJ-3989,
follow-up assessments should be obtained as per the Schedule of Activities until 48 weeks after
the end of investigational intervention unless the participant withdraws consent. If a participant
prematurely discontinues PegIFN-α2a (before the end of the consolidation phase), treatment with
JNJ-3989 and NA should be continued as planned. In case the participant withdraws consent, NA
treatment may be continued or, in consultation with the sponsor, discontinued, based on the above
mentioned NA treatment completion criteria.
6.6.2. 
NA Re-treatment Criteria and Monitoring After Stopping of NA
Participants who meet the NA treatment completion criteria outlined in Section 6.6.1, Study
Intervention Completion at Consolidation Week 12, will be monitored closely during the follow-up
phase.
After stopping NA treatment, participants should be monitored as follows:
 
Regular monitoring visits will be every 4 weeks during the follow-up phase in accordance
with the Schedule of Activities.
 
A post-treatment HBV DNA value of >20,000 IU/mL should trigger re-testing of ALT/AST,
HBV DNA, and total and direct bilirubin within a maximum of 7 days from receipt of the data
and further repeats as necessary (ie, weekly until HBV DNA returns to <20,000 IU/mL).
 
A post-treatment HBV DNA value of >2,000 IU/mL (but <20,000 IU/mL) should trigger a
re-test within 14 days from receipt of the data and further repeats as necessary (ie, every other
week until HBV DNA returns to <2,000 IU/mL).
 
A post-treatment ALT value of >5x ULN should trigger re-testing of ALT, AST, ALP, total
and direct bilirubin, INR, albumin, and HBV DNA on a weekly basis until ALT and AST
levels have returned to <5x ULN.
After stopping NA treatment, participants should re-start NA treatment:
 
Immediately with signs of decreasing liver function based on laboratory findings (eg,
International Normalized Ratio [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.
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Clinical Protocol 73763989PAHPB2005
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Status: Approved,  Date: 25 November 2021
 
With confirmed* post-treatment increases in HBV DNA >20,000 IU/mL.
* At least 4 weeks apart frequency of visits as described above
Note: Additional re-testing and/or earlier restarting of NA treatment is at the investigator’s
discretion, even if the above cut-offs are not yet met.
To avoid delays in decision making, sites are encouraged to run local re-testing in parallel with
central re-testing in the situations described above that require more frequent re-testing. Local test
results are to be recorded in the CRF and/or source documents,including information on the HBV
DNA assay used. In addition, to avoid delays in NA re-treatment, it should be considered to
dispense NA to participants who potentially met the NA re-treatment criteria (eg, pending
confirmation) and who will not be available to come to the study site immediately at the time the
confirmatory test results will become available. This should ensure that the participant can
immediately re-start NA treatment if indicated, upon direct confirmation by the investigator.
In case NA treatment is re-started, participants will be followed until the end of the study or until
clinical stabilization, whichever comes later.
Refer to Appendix 16 in Section 10.16 for a graphical representation.
6.7. 
Study 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 met the NA treatment completion criteria at
Consolidation Week 12, 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 consolidation Week 12, 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
With the implementation of Protocol Amendment 6, all participants had to stop JNJ-6379
treatment immediately.
Treatment with JNJ-3989 and PegIFN-α2a must be discontinued before consolidation Week 12
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
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Clinical Protocol 73763989PAHPB2005
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Status: Approved,  Date: 25 November 2021
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.
Withdrawal of Consent
A participant declining to return for scheduled visits does not necessarily constitute withdrawal of
consent. Alternate follow-up mechanisms that the participant agreed to when signing the consent
form apply as local regulations permit.
7.2.1. 
Withdrawal From the Use of Research Samples
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.
If applicable, all PRO assessments and ECGs should be completed before any tests, procedures,
or other consultations for that visit.
For participants enrolled prior to Protocol Amendment 5: The maximum amount of blood drawn
from each participant in this study will not exceed 2100 mL. Note: The maximum amount will
only be reached if patients are treated within the study for the maximal duration of 72 weeks plus
48 weeks of follow-up.
For participants enrolled as of Protocol Amendment 6: The maximum amount of blood drawn
from each participant during planned assessments in this study will be approximately 1,885 mL.
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, follow-up visits that are not
mandatory for participants who continue NA treatment or have restarted NA treatment during the
follow-up period).
Repeat or unscheduled samples may be taken for safety reasons or for technical issues with the
samples.
Sample Collection and Handling
Refer to Section 8 of the Master Protocol PLATFORMPAHPB2001.
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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 tenofovir disoproxil and PegIFN-α2a,
 
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 (anti-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.
Hepatitis B virus DNA, HBsAg, HBeAg, anti-HBs, and anti-HBe antibody testing results will be
provided to the investigator and the sponsor from screening until the end of follow-up.
It is the responsibility of the investigator:
 
To monitor HBV DNA results and ensure that JNJ-3989 and PegIFN-α2a are discontinued
in participants with confirmed virologic breakthrough (see Section 7.1, Discontinuation of
Study Intervention),
 
To assess if NA treatment completion criteria are met (see Section 6.6, Study Intervention
Completion at Consolidation Week 12),
 
To assess whether restart of NA treatment during follow-up is needed (see Section 6.6.2,
NA Re-treatment Criteria and Monitoring After Stopping of NA).
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.
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Clinical Protocol 73763989PAHPB2005
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Status: Approved,  Date: 25 November 2021
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 4 PRO instruments will be used: SF-36v2,
HBQOL, EQ-5D-5L, and PGIC.
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.
Short Form 36 version 2
SF-36v2 is a generic 36-item instrument designed to measure health status that can be interpreted
using 2 summary scores Physical Component Summary(PCS) and Mental Component Summary
(MCS) 
as well as domain subscales. The SF-36v2 consists of 8 subscales. Although SF-36v2
PCS and MCS scores include information from all 8 SF-36 domain subscales, the PCS score gives
more weight to physical aspects of HRQoL as represented in the Physical functioning, Physical
role limitations, Pain, and General health perception domain scores. The MCS score gives more
weight to the emotional and social aspects of HRQoL as assessed by the Vitality, Social function,
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Clinical Protocol 73763989PAHPB2005
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Status: Approved,  Date: 25 November 2021
Social role limitations, and Mental health domain scores. Participants self-report on items that have
between 2-6 response options per item using Likert-type responses (eg,none of the time, some of
the time, etc.). Summations of item scores of the same subscale give the subscale scores, which
are transformed into a range from 0 to 100; 0 worst HRQoL, 100 best HRQoL. PCS and MCS
scores are constructed as a T-score with a mean of 50 and SD of 10; higher scores indicate better
health status. The 4-week recall version will be used.
It takes about 10 minutes to complete the SF-36v2 questionnaire. See Section 10.10, Appendix 10,
Short Form 36 version 2 (SF-36v2) 2010 Questionnaire for a representative example of the
SF-36v2.
Hepatitis B Quality of Life Instrument, Version 1.0
The HBQOL26 version 1 is a 31-item disease-specific instrument designed to measure HRQoL for
participants with CHB. The instrument includes 7 subscales/domains, including psychological
well-being, anticipation anxiety, vitality, stigma, vulnerability, transmission, and viral
response. Each of the 31 items is scored on a 5-level response scale. Each subscale score is simply
calculated as the average score among the items included in that subscale. In addition to the 7
subscales, there is a single global score that reflects the results on all 31 items. The global score is
the average score among all the items in the HBQOL. Responses are transformed along a 0 to 100-
point scale, where lower scores denote less HRQoL impact, and higher scores denote more HRQoL
impact (ie, 0 best score; 100 worst score).
It takes about 10 minutes to complete the HBQOL version 1.
See Section 10.11, Appendix 11, Hepatitis B Quality of Life Instrument for a representative
example of the HBQOL version 1.
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 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). This information can be used as a quantitative
measure of health outcome as judged by the participant. EQ-5D scores include the following:
 
EQ-5D Valuation Index score (a weighted scoring of the 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]).
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Clinical Protocol 73763989PAHPB2005
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Status: Approved,  Date: 25 November 2021
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  10.12,
Appendix 12, 5-Level EuroQol 5-Dimension Questionnaire (EQ-5D-5L).
Patient Global Impression of Change Scale, Version 1.0
The PGIC scale9,14 is a single-item PRO scale aimed at assessing the participant’s perceptions of
change (improvement or worsening) in how they feel overall compared to the beginning of the
study. Response options include: “Much better”, “Better”, “A little better”, “No change”, “A little
worse”, “Worse”, “Much worse”. It takes less than a minute to complete the scale. The PGIC
responses will be used as anchors to perform responder analyses and to evaluate the ability to
detect change for the HBQOL and the HBV-specific self-stigma PRO scale.
The PGIC scale version 1 is provided in Section 10.13, Appendix 13, Patient Global Impression
of Change Scale.
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.
8.2.1. 
Physical Examinations
Refer to Section 8.2.1 of the Master Protocol PLATFORMPAHPB2001.
In addition, a complete physical examination also includes examination of the head, neck, and
thyroid.
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 of the Master Protocol PLATFORMPAHPB2001.
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Status: Approved,  Date: 25 November 2021
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.
Note: cholesterol increase is a laboratory abnormality of interest specific for JNJ-6379, which was
part of the study intervention up to Protocol Amendment 5. Because most participants who were
enrolled before Protocol Amendment 6 was in effect, also received JNJ-6379 as part of their study
intervention, monitoring of cholesterol increases will be continued.
8.3. 
Adverse Events, Serious Adverse Events, and Other Safety Reporting
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.
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, hematologic abnormalities, and events related to cholesterol increase (Section
8.2.4, Clinical Safety Laboratory Assessments).
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Clinical Protocol 73763989PAHPB2005
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Status: Approved,  Date: 25 November 2021
For participants reporting ISRs, ALT/AST elevations, renal complications, and hematologic
abnormalities as specified in the DAIDS Toxicity Grading Scale (see Section 10.9, Appendix 9,
DAIDS Table), the following should be done.
Note: renal complications and cholesterol increase are AESIs specific for JNJ-6379, which was
part of the study intervention up to Protocol Amendment 5. Because most participants who were
enrolled before Protocol Amendment 6 was in effect, also received JNJ-6379 as part of their study
intervention, the AESIs have not been revised with the removal of JNJ-6379.
8.3.6.1. 
Injection Site Reactions
At the time points specified in the Schedule of Activities or at an unscheduled visit if needed, an
evaluation of the injection site will be performed based on participant’s description and/or physical
examination. 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. 
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 Section 10.6, Appendix 6, Intervention-emergent ALT/AST Elevations). The confirmatory visit
should be scheduled as soon as possible, preferably within 7 days of the receipt of the initial
ALT/AST results. In case the repeat laboratory testing shows an isolated ALT/AST elevation (ie,
with stable albumin, bilirubin [total and direct], and INR) the participant may continue study
intervention. In case of confirmed ALT elevation >1,000 U/Land ≥3x the baseline value, JNJ-3989
and PegIFN-α2a should be discontinued unless dynamics of the ALT elevation are indicating
improvement towards resolution of the flare. In both cases, NA treatment should be continued.
The participant will be monitored (laboratory testing of ALT, AST, ALP, bilirubin [total and
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direct], INR, albumin, and HBV DNA)on a weekly basis until ALT and AST levels have returned
to <5x ULN and HBV DNA is <20,000 IU/mL.
If the ALT and/or AST level is ≥3x ULN and ≥3x nadir and is associated with any of the following
laboratory results or clinical symptoms:
 
INR ≥1.5, OR
 
direct bilirubin >1.5x ULN, OR
 
serum albumin <3.0 g/dL, OR
 
ascites, hepatic encephalopathy, or liver-related symptoms (eg, severe fatigue, nausea,
vomiting, right upper quadrant pain in the absence of an alternative medical explanation), OR
 
other indication of reduced liver function
the participant should discontinue JNJ-3989 andPegIFN-α2aand should be monitored on a weekly
basis or as per good clinical practice until ALT and AST levels have returned to <5x ULN, 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 (Refer to
Section 10.6, Appendix 6, Intervention-emergent ALT/AST Elevations).
In case of prolonged ALT elevation >3x ULN AND >2x nadir, which lasts at least 12 weeks, the
decision to continue JNJ-3989 and PegIFN-α2a should be based upon virologic parameters (eg,
HBsAg, HBV DNA) and should be made in consultation with the sponsor.
PegIFN-α2a may need to be discontinued in clinically significant cases of ALT increase or in
combined increase of ALT and direct bilirubin. Refer to the prescribing information for PegIFN-
α2a.23,24
The NA re-treatment criteria and monitoring after stopping of NA are presented in Section 6.6.2.
8.3.6.3. 
Renal Complications
If renal complications develop, participants should be closely monitored for disturbances in
creatinine clearance. Additional investigations can be performed at the investigator’s discretion.
Participants must be treated as clinically appropriate.
Participants who develop confirmed grade 3 or 4 eGFRcr abnormalities that was confirmed by
eGFRcys will change their NA from tenofovir disoproxil to TAF (if the patient was receiving
tenofovir disoproxil), according to the prescribing information. If the abnormality persists despite
change of NA or if the patient is not receiving tenofovir disoproxil, he or she will permanently
discontinue the intake of JNJ-3989 and PegIFN-α2a if considered at least possibly related to JNJ-
3989 or PegIFN-α2a, and should be followed appropriately until resolution of the AE or toxicity.
Rechallenge is not allowed.
For all participants having received at least one dose of JNJ-6379, renal safety monitoring will be
continued.
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8.3.6.4. 
Hematologic Abnormalities
Mild thrombocytopenia was observed in recently conducted non-clinical toxicology studies with
the combination of JNJ-3989 and JNJ-6379. In addition, in a 3-month combination study with
80 rats, 1 rat developed pancytopenia related to bone marrow depletion after 23 days of dosing.
Previously, in a 9-month dog study in 24 dogs treated with JNJ-6379 alone, pancytopenia which
correlated with a marked increase in plasma cell-like cells in the bone marrow was observed in
1 dog after 60 days of dosing.
No thrombocytopenia or pancytopenia has been observed in the ongoing Jade study
(56136379HPB2001) investigating JNJ-6379/Placebo with or without NA treatment. All
232 participants have completed at least 24 weeks of study intervention. In 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 participants when JNJ-3989
and JNJ-6379 were given in combination over a 12-week period.
Based on the non-clinical findings, any relevant abnormalities in hematologic parameters will be
carefully monitored as described below:
 
Platelet counts: <100,000 cells/mm3 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)
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 treatment
with JNJ-3989 and PegIFN-α2a should be considered. In case of discontinuation, NA treatment
should be continued.
8.3.7. 
Other Toxicities
The following toxicities will be carefully monitored: rash and acute systemic allergic reactions.
For participants reporting rash or acute systemic allergic reactions as specified in the DAIDS
Toxicity Grading Scale (see Section 10.9, Appendix 9, DAIDS Table), the following should be
done.
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8.3.7.1. 
Rash
Participants should be informed that they should contact their doctor immediately when they
notice any generalized skin reaction. This skin reaction should be evaluated in the clinic the
same day (if possible) or the next possible day.
All rash events should be captured in the AE section of the CRF. Separate Rash pages will be
completed in case of a rash event.
Monitoring of the evolution of rash events will be performed as described in Table 6 in
Section 10.5, Appendix 5, Rash Management.
When safety blood samples are drawn as per the rash management guidelines, these should be
processed by the local laboratory. The following parameters will need to be tested: AST, ALT,
sedimentation rate, complete blood cell count (including hemoglobin, hematocrit, RBC count,
WBC count, differential count [neutrophils, lymphocytes, monocytes, eosinophils, and basophils],
and platelet count), and creatinine. The values of the local laboratory assessments need to be
transcribed in the CRF by the study site personnel.
The participant may be treated symptomatically until the rash resolves. Oral antihistamines
(eg,cetirizine, levocetirizine) and/or topical corticosteroids may provide symptomatic relief but
effectiveness of these measures has not been established. If systemic corticosteroids exceeding
5 mg of prednisolone equivalent/day are required for treatment of rash, JNJ-3989 and PegIFN-α2a
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.
8.3.7.2. 
Acute Systemic Allergic Reactions
Grade 1 (Localized Urticaria [Wheals] With no Medical Intervention Indicated)
Participants may continue the intake of study interventions.
Cetirizine, levocetirizine, topical corticosteroids or antipruritic agents may be prescribed.
Participants should be advised to contact the investigator immediately if there is any worsening of
the acute systemic allergic reaction.
Grade 2 (Localized Urticaria With Intervention Indicated, or Mild Angioedema With no
Intervention Indicated)
Participants may continue the intake of study interventions.
Cetirizine, levocetirizine, topical corticosteroids or antipruritic agents may be prescribed.
Participants should be advised to contact the investigator immediately if there is any worsening of
the acute systemic allergic reaction, in which case the participant will permanently discontinue the
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intake of JNJ-3989 and PegIFN-α2a. Rechallenge is not allowed. The participant’s NA treatment
may be discontinued based on investigator judgement in consultation with the sponsor.
Grade 3 (Generalized Urticaria, Angioedema With Intervention Indicated, or Symptoms of
Mild Bronchospasm) and Grade 4 (Acute Anaphylaxis, Life-threatening Bronchospasm, or
Laryngeal Edema)
Participants will permanently discontinue the intake of JNJ-3989 and PegIFN-α2a. 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.
8.4. 
Treatment of Overdose
For this study, any dose ofJNJ-3989 greater than the protocol-specified dose (refer to Section 6.1)
will be considered an overdose; any dose of NA (tenofovir disoproxil) and PegIFN-α2a greater
than the prescribed dose will be considered an overdose. The sponsor does not recommend specific
therapeutic intervention for an overdose.
In the event of an overdose, the investigator or treating physician should:
 
Contact the Medical Monitor immediately.
 
Closely monitor the participant for AE/SAE and laboratory abnormalities.
 
Obtain a 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 or serum samples, as applicable,will be used to evaluate the PK ofthe study intervention.
Samples collected for analyses of the study intervention’s concentrations may additionally be used
to evaluate safety or efficacy aspects.
8.5.1. 
Evaluations
Venous blood samples will be collected for measurement of plasma or serum (as applicable)
concentrations of JNJ-3989 (ie, JNJ-3976 and JNJ-3924), NA and PegIFN-α2a, at time points
specified in the Schedule of Activities. Bioanalysis of NA and PegIFN-α2a is optional at the
discretion of the sponsor. Bioanalysis of JNJ-6379 may also be done on samples collected from
participants who received JNJ-6379 up to Protocol Amendment 5.
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All participants will have sparse PK sampling. Participants who consent to participate in the
intensive PK substudy (optional) will also undergo intensive PK sampling at time points specified
in the Schedule of Activities.
8.5.2. 
Analytical Procedures
Pharmacokinetics
At the sponsor’s discretion, a selection of samples may be analyzed to determine concentrations
of JNJ-3989 (ie, JNJ-3976 and JNJ-3924)and, optionally,JNJ-6379, NA and/or PegIFN-α2a using
a validated, specific, and sensitive liquid chromatography-mass spectrometry method or liquid
chromatography fluorescence method, as applicable by or under the supervision of the sponsor.
PK samples may be stored for future exploratory analysis of protein binding or the metabolite
profile. Genetic analyses will not be performed on these samples. Participant confidentiality will
be maintained.
8.5.3. 
Pharmacokinetic Parameters and Evaluations
Concentration-time data for JNJ-3976 and JNJ-3924, and optionally JNJ-6379, NA and/or
PegIFN-α2a will be analyzed via noncompartmental methods for all participants who underwent
intensive PK sampling. The PK parameters will be Cmax, C24h, and AUC24h. Additional exposure
parameters may be calculated if applicable. To assess the effect of PegIFN-α2a on JNJ-3989, the
PK parameters of JNJ-3976 and JNJ-3924 coadministered with PegIFN-α2a in the consolidation
phase will be compared to those of JNJ-3976 and JNJ-3924 in the induction phase as reference
(timepoints as specified in the Schedule of Activities).
Data from this study may be combined with other studies via population PK modeling 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 for JNJ-3976 and JNJ-3924, and optionally JNJ-6379,
NA and/or PegIFN-α2a, with selected efficacy  and/or with selected safety endpoints will be
evaluated, if applicable.
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.
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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 mandatory sample for human leukocyte antigen (HLA) haplotyping will be collected from all
participants.
An optional pharmacogenomic (host DNA) blood sample maybe collected (preferably at baseline)
to allow for host pharmacogenomic research, where local regulations permit. In addition, host
DNA blood samples to allow for epigenetic analyses may be collected. These samples could for
example be used to assess changes in frequencies of immune cells such as myeloid derived
suppressor cells. 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. These samples will only be collected from participants who consent separately to this
component of the study. Further, a participant may withdraw such consent at 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
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(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 of the Master Protocol PLATFORMPAHPB2001.
8.10. Medical Encounters
Eventual medical encounters will be collected in the CRF by the investigator and study site
personnel for all participants throughout the study.
9. 
STATISTICAL CONSIDERATIONS
Statistical analysis will be done by the sponsor or under the authority of the sponsor. A general
description of the statistical methods to be used to analyze the efficacy and safety data is outlined
below. Specific details will be provided in the Statistical Analysis Plan (SAP).
9.1. 
Statistical Hypotheses
As this is an exploratory PoC study, no formal statistical hypothesis has been formulated.
9.2. 
Sample Size Determination
According to the initial study design, the plan was to enroll 80 participants in the study to achieve
at least 70 participants to be randomized at the end of the induction phase. At the time of writing
Protocol Amendment 6, 28 participants were already enrolled in the study. Participants who
already passed the Week 36 visit and/or were randomized to the group without PegIFN-α2a by the
time Protocol Amendment 6 is in effect, will have PegIFN-α2a added to their treatment regimen
at the next scheduled visit and will enter the 12-week consolidation phase. For the purpose of the
statistical analyses, all participants enrolled prior to the Protocol Amendment 5 will comprise
“Cohort 1”. All participants enrolled after approval of Amendment 6 will comprise “Cohort 2”.
With the introduction of the new study design in Protocol Amendment 6 (single-arm), no formal
sample size re-calculation was performed. The targeted total sample size (Cohort 1 and Cohort 2
combined) was set to approximately 60 participants. With a sample size of 33 participants in
Cohort 2 and assuming a 10% dropout rate, 30 participants in Cohort 2 would be expected to have
data for the primary efficacy endpoint at 24 weeks after stopping all study interventions of the
consolidation phase and without restarting NA treatment. If at least 15 (50%) participants are
responders, this sample size will allow to conclude with 90% confidence that the true response rate
is at least 0.34, with a confidence interval (CI) width of 0.322 (90% CI: 0.339 - 0.661). Table 5
shows the 90 % CI and the corresponding width for proportion of responders of 0.30, 0.50, 0.70,
and 0.90.
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Table 5: 
Sample Size Determination
N=30
Proportion of 
responders
90% CI* 
Width of CI
0.30 
0.166-0.465 
0.299
0.50 
0.339-0.661 
0.322
0.70 
0.535-0.834 
0.299
0.90 
0.761-0.972 
0.211
CI: confidence interval.
* Clopper-Pearson exact method is used.
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 an ICF specific for this ISA.
Treated 
All participants who received at least 1 dose of study intervention within this ISA.
Intent-to-treat 
(ITT) 
All participants who were randomized or enrolled and who received at least 1 dose of
consolidation phase study intervention within this ISA.
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 FU
Week 24 or discontinued earlier. The final analysis will be performed when all participants have
completed the last study visit (FU Week 48)or discontinued earlier.
To evaluate the efficacy, the primary analysis set will be the ITT population (ie, for Cohort 2,
defined in Section 9.3). The efficacy for Cohort 1 will be evaluated on the treated population set.
A secondary analysis of efficacy will be performed combining the data pre- and post-Amendment
6, i.e. combining the data from participants who received PegIFN-α2a but not JNJ-6379 in Cohort
1 with data of Cohort 2. The approach to combine data from the 2 cohorts will be described in
detail in the Statistical Analysis Plan.
All efficacy summaries will be presented with descriptive statistics by cohort. If the endpoint is
continuous, the descriptive statistics will include the number of participants, mean, standard
deviation (SD), median, and 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 cohort. Graphic displays will also be used to summarize the data.
The baseline measurements are defined as the measurements taken closest to but before the first
administration of study intervention on Day 1, unless otherwise specified.
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9.4.1.1. 
Primary Efficacy Endpoint (HBsAg Seroclearance 24 Weeks After
Completion of Consolidation Phase Treatment)
The primary efficacy endpoint, the proportion of participants with HBsAg seroclearance 24 weeks
after stopping all study interventions of the consolidation phase and without restarting NA
treatment, will be summarized with the point estimate and its 90% CI using the Clopper-Pearson
exact method.
All participants who do not achieve HBsAg seroclearance 24 weeks off-treatment post
consolidation and/or require NA re-treatment within any time prior to FU Weeks 24 are considered
treatment non-responders for the purpose of the primary endpoint analysis. If the HBsAg value at
24 weeks post consolidation  is missing, the non-missing value closest to 24 weeks post
consolidation within the window of 12 weeks prior/after will be used. In addition, participants who
do not have data within the analysis window of ±12 weeks around the Week 24 assessment will
be defined as non-responder.
9.4.1.2. 
Secondary and Exploratory Efficacy Endpoints
Descriptive statistics will be used for all efficacy endpoints which will be summarized by cohort
and study phase. Specific key selected endpoints may be analyzed using suitable categorical data
approaches (eg, Clopper-Pearson interval 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. All efficacy analyses will be repeated combining the data from participants who
received PegIFN-α2a but not JNJ-6379 in Cohort 1 with data from Cohort 2. 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 the end of
consolidation treatment, respectively, will be tabulated by cohort.
The proportion of participants meeting the NA treatment completion criteria at the end of the
consolidation phase will be analyzed and summarized.
The efficacy of the study intervention during the follow-up phase will also be evaluated. The
proportion of participants with HBsAg seroclearance at 48 weeks after stopping all study
interventions of the consolidation phase and without restarting NA treatment, the proportion of
participants with HBV DNA <LLOQ at 48 weeks after completing all study interventions, the
proportion of participants meeting the NA treatment completion criteria during follow-up, the
proportion of participants achieving partial response (HBV DNA suppression  without HBsAg
seroclearance 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 cohort . For the
estimation of binary endpoints and their CI, the Clopper-Pearson method will be used for a single
sample proportion.
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The proportion of participants who reach HBV DNA <LLOQ after restart of NA treatment during
follow-up will also be tabulated by cohort with the point estimate with corresponding 90% CIs
using the Clopper-Pearson exact method.
The blood markers (such as HBsAg, HBeAg, HBV DNA, and ALT) during study intervention and
follow-up will also be summarized by cohort 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, HBeAg, HBV DNA, and ALT) and various thresholds for the viral
biomarker levels and/or changes from baseline will be summarized by cohort. The proportion of
participants with HBsAg and HBeAg seroconversion will be tabulated by cohort. Descriptive
statistics on values and changes from baseline over time in HBsAg, HBeAg and HBV DNA will
be summarized by cohort.
The time to achieve first HBsAg and HBeAg seroclearance post randomization will be
summarized, respectively,based on Kaplan-Meier estimates in tables and graphs.
The proportion of participants with HBsAg, HBeAg, and HBV DNA levels and/or changes from
baseline below/above different cut-offs, will be analyzed as appropriate by cohort and over time.
The proportion of participants who reach HBV DNA undetectability after re-start of NA treatment
will be summarized by cohort.
Graphic data displays will also be used to summarize the efficacy data by cohort and over time.
Missing data for secondary and exploratory endpoints may be handled with a similar approach as
the primary endpoint, adjusting the analysis window (e.g., ±12 weeks) for the specific time point
as appropriate. If no data is available in the appropriate window for the given time point of interest
then the imputation to non-response will be used in case of binary variables, and only observed
cases for continuous variables.
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 (Week 24, end of
consolidation phase, end of induction phase, FU Week 24, and FU Week 48 [EOS]), and between
end of the consolidation phase and FU Week 48 (EOS) for different subgroups: participants with
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HBsAg seroclearance 24 weeks and 48 weeks after completion of consolidation phase treatment,
in patients stopping NA (at FU Week 2) without restarting NA treatment, versus those without
HBsAg seroclearance at those time points.
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 descriptive summaries of AEs including AEs of special interest and
other toxicities to any of the study interventions, clinical laboratory tests, ECGs, vital signs,
physical examinations, eGFRcr and eGFRcys. The safety analysis will be done by study phase and
cohort. Results will be presented in tabular format and/or graphically 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 or serum concentrations of JNJ-3989
(ie, JNJ-3976 and JNJ-3924) and, optionally, JNJ-6379, NA and/or PegIFN-α2a, as applicable,
and for the derived PK parameters for noncompartmental PK analysis.
For each participant with intensive PK sampling, concentration-time data of JNJ-3976 and JNJ-
3924, and optionally JNJ-6379, NA and/or PegIFN-α2a will be graphically presented. Similarly,
graphs of the mean concentration-time profiles and overlay graphs with combined individual
concentration-time profiles will be produced. PK parameters in participants undergoing intensive
PK sampling will be calculated via noncompartmental methods for JNJ-3976 and JNJ-3924, and
optionally of JNJ-6379, NA and/or PegIFN-α2a, as applicable. The PK parameters will be Cmax,
C24h, and AUC24h. The PK parameters will be subjected to an exploratory graphical analysis,
including various transformations, to get a general overview.
To assess the effect of PegIFN-α2a on JNJ-3989, the PK parameters of JNJ-3976 and JNJ-3924
coadministered with PegIFN-α2a at Week 8 (or 4) of the consolidation phase will be compared to
those of JNJ-3976 and JNJ-3924 at Week 24 (or 28 or 32) of the induction phase as reference. The
primary PK parameters are Cmax and AUC24h on the logarithmic scale. A mixed effects model will
be fitted to log-transformed PK parameters with phase (induction or consolidation) as a fixed effect
and subject as a random effect.
Special attention will be paid to the 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 concentration-time data of JNJ-3976 and JNJ-3924, and, optionally, of
JNJ-6379, NA and/or PegIFN-α2a may be performed using non-linear mixed effects modeling.
Data may be combined with selected Phase 1 and/or 2 studies to support a relevant structural
model. Available participant characteristics (eg, demographics, laboratory variables, genotypes)
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will be included in the model as necessary. Details will be given in a population PK analysis plan
and results of the population PK analysis, if applied,will be presented in a separate report.
Pharmacokinetic/Pharmacodynamic Analyses
Relationships of PK parameters for JNJ-3976 and JNJ-3924, and, optionally, of JNJ-6379, NA
and/or PegIFN-α2a with selected efficacy and with selected safety endpoints will be evaluated and
graphically displayed, if applicable.
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 may be investigated. Other biomarkers may be explored at the sponsor’s discretion.
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 (eg, efficacy, safety, and/or 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
Two IAs will be conducted to assess safety and evaluate the time course of different safety and
efficacy 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 combination
regimens.
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The first IA is planned when approximately 50% of the total number of participants enrolled have
completed Week 24 of the induction phase or discontinued earlier. The second IA is planned when
all participants have completed Week 48 or discontinued earlier.
The study is open-label, and the Sponsor will conduct the pre-planned IA(s). Hence, the study
team and the DRC will have access to the interim analysis results, while the investigators and
patients will not.
Additional IAs may be performed by the sponsor before the final analysis, 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. 
Data Review Committee
A DRC will be established as noted in Committees Structure in Appendix 10.3, Regulatory,
Ethical, and Study Oversight Considerations.
The Sponsor Committee includes representatives from the sponsor’s Clinical, Biostatistics, Global
Medical Safety, and Virology departments. DRC and Sponsor Committee members will not be
involved in the study conduct. The Sponsor Committee will review the time course of the different
HBV disease blood markers to make internal decisions and prepare for interactions with Health
Authorities. Details on the roles and responsibilities of the DRC and the Sponsor Committee will
be described in the charter.
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 hepatitis B and its treatment. The IFLEP will monitor ALT flares and
will make recommendations regarding flare management based on an analysis of aggregate data.
In order to allow for an unbiased assessment, members of the committee will not serve as study
investigators or as members of the DRC. 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
AASLD  
American Association for the Study of Liver Diseases
AE 
adverse event
A/H  
animal/human ratio
AFP  
alpha-fetoprotein
ALP  
alkaline phosphatase
ALT  
alanine aminotransferase
APASL 
Asian Pacific Association for the Study of the Liver
AST  
aspartate aminotransferase
AUC  
area under the concentration-time curve
AUC0-xh  
area under the concentration-time curve from administration to x hours
AUC0-last 
area under the concentration-time curve from administration to last quantifiable sampling point
AUC∞ 
area under the concentration-time curve to last sampling point from time zero extrapolated to
infinity
AUCτ 
area under the concentration-time curve over the dosing interval (τ)
BCRP  
breast cancer resistance protein
BMI 
body mass index
bpm  
beats per minute
C24h  
concentration 24 hours after administration
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
CLint 
intrinsic clearance
Cmax  
maximum concentration
CRF  
case report form
CT  
computed tomography
Cτ 
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
DRC  
Data review committee
EASL 
European Association for the Study of the Liver
ECG  
electrocardiogram
EFD  
embryofetal development
eGFRcr 
estimated glomerular filtration rate based on serum creatinine
eGFRcys 
estimated glomerular filtration rate based on cystatin C
ELISpot 
enzyme-linked immunospot
Emax  
maximum effect
EOS  
end-of-study
EOSI 
end-of-study intervention
EQ-5D-5L 
5-Level EuroQol 5-Dimension
ETV  
entecavir
FU 
follow-up
FSH  
follicle-stimulating hormone
GCP  
Good Clinical Practice
GESA  
Gastroenterological Society of Australia
GLP  
Good Laboratory Practice
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HBc 
hepatitis B core protein
HBQOL 
Hepatitis B Quality of Life
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
HIV(-1/2) 
human immunodeficiency virus (type 1/2)
HLA  
human leukocyte antigen
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
IFLEP  
Independent Flare Expert Panel
IFN  
interferon
IFN-γ 
gamma interferon
IgG  
immunoglobulin G
IgM  
immunoglobulin M
IL 
Interleukin
IND  
Investigational New Drug
INR  
International Normalized Ratio
ISA  
intervention-specific appendix
ISR  
injection site reaction
IT  
immune tolerant
ITT  
intent-to-treat
IWRS  
interactive web response system
KIM-1 
Kidney Injury Molecule-1
LLN  
lower limit of normal
LLOQ  
lower limit of quantification
MAV  
minimum acceptable value
MCS  
mental component summary
MoA  
mode of action
MRI 
magnetic resonance imaging
NA  
nucleos(t)ide analog
NGAL 
Neutrophil Gelatinase Associated Lipocalin
NK cells 
natural killer cells
NOAEL 
no observed adverse effect level
PBMC  
peripheral blood mononuclear cell
PCS  
physical component summary
PD 
pharmacodynamic(s)
PegIFN-α2a 
pegylated interferon alpha-2a
PGIC  
Patient Global Impression of Change
pgRNA  
pre-genomic ribonucleic acid
PK 
pharmacokinetic(s)
PoC  
proof of concept
PRO  
patient-reported outcome(s)
Q4W  
once every 4 weeks
qd 
once daily
QTcF  
QT interval corrected for heart rate according to Fridericia’s formula
QW 
once weekly
RBC  
red blood cell
rcDNA  
relaxed circular deoxyribonucleic acid
RGT  
response-guided treatment
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Status: Approved,  Date: 25 November 2021
RNA  
ribonucleic acid
RNAi 
ribonucleic acid interference
SAE 
serious adverse event
SAP  
Statistical Analysis Plan
SBP 
systolic blood pressure
SD 
standard deviation
SF-36v2 
Short Form 36 version 2
siRNA  
small interfering ribonucleic acid
t1/2term  
terminal half-life
T4 
thyroxine
TAF  
tenofovir alafenamide
TDF  
tenofovir disoproxil fumarate
TK 
toxicokinetic
tmax  
time to reach Cmax
TNF  
tumor necrosis factor
TSH  
thyroid-stimulating hormone
TV 
target value
ULN  
upper limit of normal
US  
United States
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
specific study intervention within this Platform study, and in whom the efficacy and
safety of that intervention is evaluated
Study intervention  
Prior to Protocol Amendment 6: JNJ-73763989, JNJ-56136379,NA (tenofovir
disoproxil) and PegIFN-α2a
As ofProtocol Amendment 6: JNJ-73763989, NA (tenofovir disoproxil) and
PegIFN-α2a
Study intervention phase 
36-week induction phase plus 12-week consolidation phase
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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Clinical Protocol 73763989PAHPB2005
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Status: Approved,  Date: 25 November 2021
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
Data Review Committee
A DRC will be established for continuous monitoring of SAEs, AEs leading to discontinuation,
and ALT flares. This committee will consist of at least one medical expert in the relevant
therapeutic area (hepatology) and at least one statistician; committee membership responsibilities,
authorities, and procedures will be documented in its charter. The committee will meet periodically
to review data of the efficacy parameters measured by different HBV disease blood markers (eg,
HBV DNA, HBeAg, HBsAg, etc).
The DRC members will be appointed before the start of the study to review the interim data for
both safety and efficacy and formulate recommendation(s) to the Sponsor Committee, who will
make the final decision(s). The Sponsor Committee includes representatives from the sponsor’s
Clinical, Biostatistics, Global Medical Safety and Virology departments. DRC and Sponsor
Committee members will not be involved in the study conduct.
Details on the roles and responsibilities of the DRC and Sponsor Committee, as well as the flows
of communication, will be documented in the DRC charter.
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 study data related to
ALT flares; determine and adjudicate each ALT flare; and provide documentation of the final
decision to DRC. Adjudication review cycles will match DRC schedule and will be set up ideally
2 weeks before DRC.
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Status: Approved,  Date: 25 November 2021
In order to allow for an unbiased assessment, members of the committee will not serve as study
investigators or as members of the DRC.
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 6: 
Management of Rash Events by Severity Grade
Definition 
Study
Intervention
Action
Activities by Daya
Referral to
Dermatologist and
Dermatology
Activities
Grade 1 rash
(with or
without
pruritus)b
Erythema 
Study
intervention
intake may be
continued at the
investigator’s
discretion
Day 0: optional on-site visit for initial rash evaluation may be performed
at the investigator’s discretion.
Safety laboratory assessments may be performed at the investigator’s
discretion (recommended if visit occurs).
Digital 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 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
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 6: 
Management of Rash Events by Severity Grade
Definition 
Study
Intervention
Action
Activities by Daya 
Referral to
Dermatologist and
Dermatology
Activities
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
PegIFN α2a; 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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Status: Approved,  Date: 25 November 2021
Table 6: 
Management of Rash Events by Severity Grade
Definition 
Study
Intervention
Action
Activities by Daya 
Referral to
Dermatologist and
Dermatology
Activities
Grade 4 rash 
Exfoliative dermatitis 
OR  
Mucous membrane
involvement in at least
2 distinct sites OR
Erythema multiforme
major OR
Stevens-Johnson 
syndrome OR  
Toxic epidermal
necrolysis OR
Necrosis requiring 
surgery  
Must permanently 
discontinue
JNJ-3989 and
PegIFN α2a; 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.
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.
 
A copy of the dermatologist’s report, biopsy, and/or digital pictures if performed, should be made anonymous and provided to the sponsor.
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Clinical Protocol 73763989PAHPB2005
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Status: Approved,  Date: 25 November 2021
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: 25 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 Guidancea
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: 25 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)
 Intrauterine hormone-releasing system (IUS)
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Status: Approved,  Date: 25 November 2021
 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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10.11. Appendix 11: Hepatitis B Quality of Life Instrument
CCI
CCI
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Scaling and Scoring Instructions
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10.12. Appendix 12: 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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UK(English) © 2009 EuroQol Group. EQ 5D™ is a trade mark of the EuroQol Group
CCI
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10.13. Appendix 13: Patient Global Impression of Change Scale
Please select how you feel about yourself now in comparison to how you felt about
yourself at the beginning of this study.  (Select one response)
 Much better
 Better
 A little better
 No change
 A little worse
 Worse
 Much worse
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10.14. Appendix 14: Protocol Amendment History
The Protocol Amendment Summary of Changes Table for the current amendment is located
directly before the Table of Contents (TOC).
Amendment 6 (30 September 2021)
Overall Rationale for the Amendment:The primary reasons for this amendment are to remove JNJ-6379
as study intervention, to add a new nucleos(t)ide analog (NA) re-treatment criterion for participants who
discontinued NA treatment during follow-up, and to include more frequent monitoring for participants who
discontinued NA treatment during follow-up.
Based on emerging data from recent interim analyses of the REEF-1 (73763989HPB2001) and REEF-2
(73763989PAHPB2002) studies, the benefit-risk profile of JNJ-6379 in combination with JNJ-3989+NA
is unfavorable compared to JNJ-3989+NA.
In the primary REEF-1 analysis (Week 48, end of treatment) the mean reduction of hepatitis B surface
antigen (HBsAg) in the triple arm (JNJ-6379+JNJ-3989 100mg+NA) appeared to be less than in the dual
arm (JNJ-3989 100mg+NA). More recent interim results of the REEF-2 study (Week 48, end of treatment)
confirmed this observation when the effect of JNJ-6379+JNJ-3989 200mg+NA on mean HBsAg level
reduction in the REEF-2 study is compared to JNJ-3989 200mg+NA in the REEF-1 study. To match with
the REEF-2 population, this cross-study comparison focused on the REEF-1 subpopulation of hepatitis B
e antigen (HBeAg) negative, virologically suppressed participants with chronic hepatitis B.
Pharmacokinetic-pharmacodynamic modelling analyses accounting for variability in baseline
characteristics further support this observation. Therefore, a negative impact of JNJ-6379 on the HBsAg
lowering effect of JNJ-3989+NA is suspected.
From a safety perspective, transient reductions of estimated glomerular filtration rate based on creatinine
(eGFRcr) in  JNJ-6379 containing treatment arms with fast recovery after end of treatment had been
described in the Jade study (56136379HPB2001) and was confirmed in the REEF-1 study. In absence of a
pattern of increased biomarkers of proximal tubulo-toxicity (the beta-2-microglobulin/creatinine and the
retinol binding protein/creatinine ratios), the eGFRcr reduction during treatment was interpreted as
transporter inhibition at the level of creatinine excretion from the proximal tubule rather than renal toxicity.
Recent data from REEF-2 confirm the transient pattern of eGFRcr declines but, in addition, show an
increase of the beta-2-microglobulin/creatinine and the retinol binding protein/creatinine ratios in some
participants when tenofovir disoproxil fumarate (TDF) treatment was continued and combined with JNJ-
6379+JNJ-3989. These new data are suggesting that JNJ-6379 in combination with TDF may contribute to
renal tubulo-toxicity. There was no apparent increase in the beta-2-microglobulin/creatinine or retinol
binding protein/creatinine ratios in participants receiving entecavir (ETV; active or control arm), nor in
participants receiving TDF+placebo.
The negative impact of JNJ-6379, when combined with JNJ-3989+NA, on HBsAg reduction, taken together
with the adverse renal profile, leads to conclusion of an unfavorable benefit-risk balance of JNJ-6379 in
combination with JNJ-3989+NA, compared to JNJ-3989+NA alone. Therefore, the Sponsor has decided to
discontinue treatment with JNJ-6379 in all ongoing clinical studies effective immediately. Participants
currently on treatment with JNJ-6379 will be contacted and requested to stop taking JNJ-6379, while
continuing treatment with NA, JNJ-3989 and pegylated interferon alpha-2a (PegIFN-α2a; as applicable).
For newly enrolled participants, JNJ-6379 will no longer be included in the treatment regimen. 
In addition, a new NA re-treatment criterion and more frequent monitoring for participants who
discontinued NA treatment during follow-up were included. The reason for these changes is a severe
clinical alanine aminotransferase (ALT) flare that was reported following discontinuation of NA treatment
in a virologically suppressed HBeAg negative participant on long-term TDF treatment who was randomized
to the control arm (placebo + placebo + NA) in the REEF-2 study. The participant presented with hepatitis
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B virus (HBV) DNA levels that increased rapidly, before any relevant changes in liver markers were noted.
Discontinuation of NA treatment followed the protocol-defined criteria and was in line with recent
European Association for the Study of the Liver (EASL) treatment guidelines.4 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.
Furthermore, the PegIFN-α2a eligibility criteria, the PegIFN-α2a discontinuation criteria, and the
monitoring of neuropsychiatric adverse events during PegIFN-α2a treatment were amended to be consistent
with the PegIFN-α2a prescribing information.
Other changes, clarifications and corrections were also made as detailed below.
Description of Change 
Brief Rationale 
Section Number and Name
JNJ-6379 has been removed
as study intervention.
Participants enrolled before
Protocol Amendment 6 had
to stop JNJ-6379 treatment
immediately. They will
continue with JNJ-
3989+NA treatment up to
the end of the induction
phase and will then enter the
consolidation phase during
which they will have
PegIFN-α2a added to their
treatment regimen. 
Throughout the protocol,
elements specific for JNJ-
6379 have been modified.
Based on emerging data from
recent interim analyses of the
REEF-1 and REEF-2 studies,
showing that the benefit-risk
profile of JNJ-6379 in
combination with JNJ-3989+NA
is unfavorable compared to JNJ-
3989+NA.
1.1 Synopsis
1.2 Schema
1.3.1 Schedule of Activities –Screening
Phase and Induction Phase
1.3.2 Schedule of Activities –Consolidation
Phase and Follow-up Phase
2 INTRODUCTION
2.2 Background
2.2.2.1 JNJ-3989 and JNJ-6379
2.3 Benefit-Risk Assessment
2.3.2.2.2 Potential Risks for JNJ-6379
2.3.3 Benefit-Risk Assessment for Study
Participation
3 OBJECTIVES AND ENDPOINTS
4.1 Overall Design
4.2 Scientific Rationale for Study Design
4.3 Justification for Dose
4.3.2 JNJ-6379
5.1 Inclusion Criteria
5.2 Exclusion Criteria
6.1 Study Intervention(s) Administered
6.2
Preparation/Handling/Storage/Accountability
6.3 Measures to Minimize Bias:
Randomization and Blinding
6.4 Study Intervention Compliance
6.5 Concomitant Therapy
6.6 Dose Modification
6.6.1 Study Intervention Completion at
Consolidation Week 12
7.1 Discontinuation of Study Intervention
8.1 Efficacy Assessments
8.2.4 Clinical Safety Laboratory
Assessments
8.3.6 Adverse Events of Special Interest
8.3.7 Other Toxicities
8.4 Treatment of Overdose
8.5.2 Analytical Procedures
8.5.3 Pharmacokinetic Parameters and
Evaluations
8.6 Pharmacokinetic/Pharmacodynamic
Evaluations
9.2 Sample Size Determination
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Description of Change 
Brief Rationale 
Section Number and Name
9.3 Populations for Analyses
9.4.1 Efficacy Analyses
9.4.2 Safety Analyses
9.4.3 Other Analyses
10.1 Appendix 1: Abbreviations and
Definitions of Terms
10.5 Appendix 5: Rash Management
10.6 Appendix 6: Intervention-emergent
ALT/AST Elevations
A new NA re-treatment 
criterion was added for 
participants who 
discontinued NA treatment 
during follow-up. 
To ensure that participants with 
significant HBV DNA increases 
during treatment free follow-up 
are monitored at least weekly 
and/or immediately re-start NA 
treatment irrespective of ALT 
levels. 
1.1 Synopsis
1.3.2 Schedule of Activities –Consolidation
Phase and Follow-up Phase
2.3.2.2 Potential Risks
4.2 Scientific Rationale for Study Design
6.6.1 Study Intervention Completion at
Consolidation Week 12
6.6.2 NA Re-treatment Criteria During
Follow-up
6.7 Study Intervention After the End of the
Study
8.3.6.2 Intervention-emergent ALT/AST
Elevations
10.6 Appendix 6: Intervention-emergent
ALT/AST Elevations
10.16 Appendix 16: NA Re-treatment
During Follow-up
Participants who 
discontinue NA treatment 
during follow-up, will be 
monitored more frequently, 
with a study visit at least 
once every 4 weeks. 
The visit frequency for 
participants who continue 
NA treatment or have
restarted NA treatment
during the follow-up period
and for whom the HBV
DNA and ALT values are
stable remains at least once
every 12 weeks.
For participants with
increased follow-up, the
total blood volume to be
collected during the study
will increase.
To further protect the safety of 
participants. 
1.1 Synopsis
1.3.2 Schedule of Activities –Consolidation
Phase and Follow-up Phase
4.2 Scientific Rationale for Study Design
6.6.2 NA Re-treatment Criteria During
Follow-up
8 STUDY ASSESSMENTS AND
PROCEDURES
The PegIFN-α2a 
discontinuation criteria were 
updated to clarify that 
participants with moderate 
or severe depression or 
other psychiatric symptoms 
should immediately
discontinue PegIFN-α2a
treatment.
In addition, participants will
be closely monitored for
Upon Health Authority request 
and to be consistent with the 
PegIFN-α2a prescribing 
information  
1.3.1 Schedule of Activities –Screening
Phase and Induction Phase
1.3.2 Schedule of Activities –Consolidation
Phase and Follow-up Phase
5.2 Exclusion Criteria
7.1 Discontinuation of Study Intervention
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Description of Change 
Brief Rationale 
Section Number and Name
neuropsychiatric adverse
events during the PegIFN-
α2a treatment period.
Participants who develop a
neuropsychiatric adverse
event during PegIFN-α2a
treatment will be monitored
closely until the
neuropsychiatric adverse
event resolves, by frequent
(at least weekly) follow-up
phone calls.
Furthermore, exclusion
criterion A25 was amended
to exclude participants with
a history of a severe
psychiatric disorder.
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
Phase and Induction Phase
5.1 Inclusion Criteria
10.8 Appendix 8: Contraceptive and Barrier
Guidance and Collection of Pregnancy
Information
It was clarified that a 
participant who prematurely 
discontinues PegIFN-α2a 
(before the end of the 
consolidation phase) should
continue treatment with
JNJ-3989 and NA as
planned.
Clarification 
4.1 Overall Design
6.6.1 Study Intervention Completion at
Consolidation Week 12
7.1 Discontinuation of Study Intervention
Recommendations 
regarding the use of live 
vaccines during the study
were added.
Clarification regarding the use of 
live vaccines during the study  
6.5 Concomitant Therapy
10.15 Appendix 15: COVID-19 APPENDIX
It was clarified that venous 
blood samples will be 
collected for measurement 
of JNJ-3989, NA, and 
PegIFN-α2a. Bioanalysis of 
NA and PegIFN-α2a is 
optional at the discretion of 
the sponsor. Bioanalysis of 
JNJ-6379 may also be done
on samples collected from
Clarification 
1.1 Synopsis
1.3.1 Schedule of Activities –Screening
Phase and Induction Phase
1.3.2 Schedule of Activities –Consolidation
Phase and Follow-up Phase
3 OBJECTIVES AND ENDPOINTS
4.1 Overall Design
8.5.1 Evaluations
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Description of Change 
Brief Rationale 
Section Number and Name
participants who received
JNJ-6379 up to Protocol
Amendment 5.
Exclusion criterion A01 was 
adapted to clarify that 
participants with a positive
HIV-1 or HIV-2
antibody/antigen test at
screening should have a
confirmatory HIV RNA
test, to rule out false
positive results. They can be
enrolled if they have a
negative HIV RNA test at
screening.
It was also clarified that
participants with evidence
of HIV-1 or HIV-2 infection
who are on antiretroviral
treatment are excluded. 
Clarification upon Health 
Authority request
5.2 Exclusion Criteria
It was clarified that a copy 
of the dermatologist’s
report, biopsy, and/or digital
pictures if performed for
rash management, should be
made anonymous and
provided to the sponsor.
Clarification 
10.5 Appendix 5: Rash Management
Minor errors were corrected 
and minor clarifications
were made.
Correction and clarification. 
Throughout the protocol
Amendment 5 (30 July 2021)
Overall Rationale for the Amendment: The primary reason for this amendment is a change in
study treatment regimens, based on the availability of preliminary 48-week treatment data from
the Phase 2b study REEF-1 (73763989HPB2001), and new data presented during the European
Association for the Study of the Liver (EASL) conference of 2021 showing that HBsAg declines
with siRNA treatment can be increased when combined with PegIFN.30
The REEF-1 study is evaluating the efficacy of 3 doses of JNJ-3989 (40, 100, or 200 mg Q4W) +
NA, of JNJ-3989 100 mg Q4W + JNJ-6379 + NA, of JNJ-6379 + NA, and of NA alone. It was
shown that all combination regimens were safe and well-tolerated through the end of treatment at
Week 48. The JNJ-3989 200 mg dose achieved the highest response rate of 19.1% for the primary
endpoint of meeting the NA treatment completion criteria at Week 48 (ie, ALT <3x ULN, and
HBV DNA <LLOQ, and HBeAg-negative, and HBsAg <10 IU/mL). No participant in the JNJ-
6379+NA arm and 1 participant in the NA alone arm achieved the primary endpoint. The largest
mean (SD) decline at Week 48, of 3.56 (1.328) log10 IU/mL, was observed in the JNJ-3989 200
mg + NA arm in currently not treated HBeAg positive participants. The mean HBsAg decline
followed a biphasic pattern, with the steeper decline during the first 24 weeks followed by a more
shallow decline between Week 24 and Week 48. At Week 48, a limited number of participants
reached HBsAg seroclearance. The addition of JNJ-6379 to JNJ-3989+NA did not increase HBsAg
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reduction, while mean change from baseline in HBV DNA at the end of treatment (Week 48) was
largest for the currently not treated HBeAg positive participants in the treatment arms containing
JNJ-6379. To assess the effect of JNJ-6379 in treatment-naïve patients with HBeAg positive
chronic hepatitis B virus infection in this study, participants will be randomized to JNJ-
3989+PegIFN-α2a+NA, with or without JNJ-6379.
The updated study design takes into consideration the above-described elements for participants
who are already enrolled and for all new participants who will be randomized under this
amendment.
Additional changes were made as specified in the table below.
Description of Change 
Brief Rationale 
Section Number and Name
The study design was updated
such that participants (Cohort
2) will be randomized at
baseline in a 1:1 ratio to
receive either JNJ-3989+JNJ-
6379+NA or JNJ-3989+NA for
a fixed duration of 36 weeks
(induction phase) instead of a
response-guided treatment
duration. The induction phase
will be followed by a 12-week
consolidation phase during
which PegIFN-α2a will be
added to the treatment regimen
for all participants.
Guidance to the investigator is
provided for participants who
were enrolled before Protocol
Amendment 5 is in effect
(Cohort 1).
The statistical analyses were
updated as well, to align with
the new design. The sample
size was adjusted for Cohort 2
to be randomized in a 1:1 ratio
to 2 regimens, and the
response-guided treatment
criterion was removed from the
stratification factors.
Based on preliminary 48-week
treatment data from the REEF-
1 study and insights from
EASL 2021, PegIFN-α2a will
be added to the treatment
regimen for all participants, to
increase the potential of
achieving functional cure. In
addition, the updated study
design allows a better
evaluation of the potential
benefit of JNJ-6379 in
currently not treated HBeAg
positive participants.
1.1 Synopsis
1.2 Schema
1.3 Schedule of Activities
2 INTRODUCTION
2.1 Study Rationale
2.2.2 Clinical Studies
2.3.1.2 Potential Benefits
2.3.3 Benefit-Risk Assessment for Study
Participation
3 OBJECTIVES AND ENDPOINTS
4.1 Overall Design
4.2 Scientific Rationale for Study Design
5.2 Exclusion Criteria6.1 Study
Intervention(s) Administered
6.2
Preparation/Handling/Storage/Accountability
6.3 Measures to Minimize Bias:
Randomization and Blinding
6.6.1 Study Intervention Completion at
Consolidation Week 12
7.1 Discontinuation of Study Intervention
8 STUDY ASSESSMENTS AND
PROCEDURES
8.1 Efficacy Assessments
8.3.6 Adverse Events of Special Interest
8.5 Pharmacokinetics
8.6 Pharmacokinetic/Pharmacodynamic
Evaluations
9.2 Sample Size Determination
9.4.1 Efficacy Analyses
9.4.1.1 Primary Efficacy Endpoint (HBsAg
Seroclearance 24 Weeks After Completion
of Consolidation Phase Treatment)
9.4.1.2 Secondary and Exploratory Efficacy
Endpoints
9.4.3 Other Analyses
9.5 Interim Analyses
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Description of Change 
Brief Rationale 
Section Number and Name
10.1 Appendix 1: Abbreviations and
Definitions of Terms
10.5 Appendix 5: Rash Management
10.6 Appendix 6: Intervention-emergent
ALT/AST Elevations
10.15 Appendix 15: COVID-19 APPENDIX
Race (Asian versus non-Asian) 
was included as a new 
stratification factor for 
participants in Cohort 2. 
To provide a reasonably 
balanced representation of race 
and HBV genotypes across the 
2 intervention arms of Cohort 
2. 
1.1 Synopsis
4.1 Overall Design
4.2 Scientific Rationale for Study Design
6.3 Measures to Minimize Bias:
Randomization and Blinding
9.4.1 Efficacy Analyses
9.4.1.1 Primary Efficacy Endpoint (HBsAg
Seroclearance 24 Weeks After Completion
of Consolidation Phase Treatment)
9.4.1.2 Secondary and Exploratory Efficacy
Endpoints
The ALT cut off for inclusion 
(criterion A03) was updated 
from normal ALT to ALT ≤2x 
ULN. 
As for some patients the reason 
for screen failure was a slight 
and transient elevation of ALT, 
experts in the field have 
recommended to include 
patients with ALT up to ≤2x
ULN.
1.1 Synopsis
2.1 Study Rationale
4.1 Overall Design
4.2 Scientific Rationale for Study Design
5.1 Inclusion Criteria
ALT elevations were added as 
a potential risk and the section 
on management of ALT 
elevations was updated. 
To provide additional guidance 
on measures to further protect 
the safety of participants 
during treatment with JNJ- 
3989, based on emerging data 
from studies REEF-1 and 
REEF-D. 
2.3.2.1 Known Risks
2.3.2.2.1 Potential Risks for JNJ-3989
2.3.3 Benefit-Risk Assessment for Study
Participation
8.3.6.2 Intervention-emergent ALT/AST
Elevations
10.6 Appendix 6: Intervention-emergent
ALT/AST Elevations
The nonclinical background 
was updated. 
For completeness 
2.2.1.3.2 Combination of JNJ-3989 with
PegIFN-α2a
2.3.3 Benefit-Risk Assessment for Study
Participation
Text was added on dose 
modifications for PegIFN-α2a. 
For completeness 
1.1 Synopsis
6.1 Study Intervention(s) Administered
6.6 Dose Modification
7.1 Discontinuation of Study Intervention
Update of follow-up 
procedures and criteria for re- 
initiation of NA treatment. 
For clarification 
4.2 Scientific Rationale for Study Design
6.6.2 NA Re-treatment Criteria During
Follow-up
10.16 Appendix 16: NA Re-treatment
During Follow-up
A study intervention 
discontinuation criterion was
added for participants who
withdraw consent.
For completeness 
7.1 Discontinuation of Study Intervention
Study intervention 
discontinuation criteria on 
For clarification 
7.1 Discontinuation of Study Intervention
8.3.6.3 Renal Complications
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Description of Change 
Brief Rationale 
Section Number and Name
hepatic decompensation and
eGFRcr abnormality were
updated.
Guidance was included for 
participants with confirmed
HBV virologic breakthrough,
on continuation of study
treatment and on additional
sample collection for viral
sequencing.
For completeness 
7.1 Discontinuation of Study Intervention
Language was added on data 
collection for medical
encounters.
For completeness 
8.10 Medical Encounters
Language on urine pregnancy 
testing for at-home use during 
the COVID-19 pandemic was 
updated.
To provide additional guidance 
on urine pregnancy testing at
home.
10.15 Appendix 15: COVID-19 APPENDIX
Guidance on source data 
verification/monitoring and site 
audits during the COVID-19 
pandemic was added. 
To provide additional guidance 
on source data
verification/monitoring and
site audits.
10.15 Appendix 15: COVID-19 APPENDIX
Exclusion criterion A01 (M01) 
concerning evidence of HIV-1
or HIV 2 infection at screening
and exclusion criterion A06
(M06) concerning laboratory
abnormalities at screening was
updated.
For clarification 
5.2 Exclusion Criteria
It was clarified that JNJ-3989 
should preferably be 
administered via subcutaneous
injection in the abdomen
For clarification 
1.1 Synopsis
6.1 Study Intervention(s) Administered
Head, neck, and thyroid were 
added to complete physical
examination.
For completeness. 
8.2.1 Physical Examinations
Management of rash and acute 
systemic allergic reactions 
were moved under a separate 
subheader. 
For correction and clarification 
as rash and acute systemic 
allergic reactions are not
considered AESIs for JNJ-
3989 or JNJ-6379.
8.3.6 Adverse Events of Special Interest
8.3.7 Other Toxicities
Minor errors were corrected 
and minor clarifications were
made.
Correction and clarification. 
Throughout the protocol
Amendment 4 (30 April 2021)
Overall Rationale for the Amendment: The primary  reason for this amendment is to add
guidance on the concomitant use of COVID-19 vaccines and PegIFN-α2a.
Description of Change 
Brief Rationale 
Section Number and Name
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Status: Approved,  Date: 25 November 2021
Guidance was added on the 
concomitant use of COVID-19 
vaccines and PegIFN-α2a 
Due to overlapping safety 
profiles of PegIFN-α2a and 
COVID-19 vaccines
6.5 Concomitant Therapy
10.15 Appendix 15: COVID-19 APPENDIX
A liver ultrasound will be done 
yearly for all participants and 
remains recommended every 6 
months for high-risk 
populations
The demographics of the 
African/African American 
population considered at high-
risk for developing HCC and
who fall under 6-monthly liver
ultrasound screening are
further specified
As per standard practice for the 
monitoring of patients with 
chronic HBV infection  
To better align with the
AASLD guidelines
1.3.1 Schedule of Activities –Screening
Phase and Induction Phase
1.3.2 Schedule of Activities –Consolidation
Phase and Follow-up Phase
Language on urine pregnancy 
testing for at-home use was 
updated 
To provide additional guidance 
on urine pregnancy testing at 
home
1.3.2 Schedule of Activities –Consolidation
Phase and Follow-up Phase
Minor corrections were made 
Correction 
1.3.2 Schedule of Activities –Consolidation
Phase and Follow-up Phase
Amendment 3 (26 January 2021)
Overall Rationale for the Amendment:The primary reason for this amendment is to increase the upper
age limit for participant inclusion from 45 years to 55 years and to allow participants who received
<9 months of NA treatment if not within 12 months prior to screening. In addition, other changes and minor
clarifications and corrections were made as detailed below.
Description of Change 
Brief Rationale 
Section Number and Name
Upper age limit for inclusion
was changed from 45 years to
55 years with a maximum of
approximately 10 participants
>45 to ≤55 years of age.
Typically, CHB patients with
high HBV DNA and normal
ALT are relatively young.
However, in practice older
patients up to 55 years of age
are still seen in this stage of
CHB.
1.1 Synopsis
4.1 Overall Design
5.1 Inclusion Criteria
In addition to NA treatment
naïve participants, participants
who have received <9 months
of NA treatment ≥12 months
prior to screening (eg, during
pregnancy to prevent mother-
to-child-transmission) are also
allowed.
If the requirements for HBV
DNA and ALT are met at study
entry, no relevant impact of
prior short-term NA treatment is
expected.
1.1 Synopsis
2.1 Study Rationale
4.1 Overall Design
5.1 Inclusion Criteria
Exclusion criterion A25 e was
updated to include a separate,
lower ANC cut off for black or
African American participants.
The black or African American
population generally has lower
ANC values compared with
other populations.
5.2 Exclusion Criteria
The exclusion criterion on
CD4+ cell count was removed.
This criterion only applies to
HBV/HIV coinfected patients
who are excluded from
participation in this study.
5.2 Exclusion Criteria
If JNJ-6379 is discontinued,
participants may continue JNJ-
3989 (and PegIFN-α2a if
Discontinuation of JNJ-6379
does not necessarily lead to
7.1 Discontinuation of Study Intervention
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Description of Change 
Brief Rationale 
Section Number and Name
applicable) after discussion 
with the sponsor. 
discontinuation of JNJ-3989
(and PegIFN-α2a if applicable).
Anticoagulants were moved 
from the list of disallowed 
medications to the list of 
concomitant medications to be
used with caution.
Preclinical and clinical data for 
JNJ-3989 and JNJ-6379 do not
show evidence of coagulopathy.
6.5 Concomitant Therapy
Nonclinical data on the 
combination of JNJ-3989 or 
JNJ-6379 with PegIFN-α2a 
were added. 
These data confirm that JNJ- 
3989 or JNJ-6379 in 
combination with PegIFN-α2a 
is well tolerated. 
2.2.1.3.1 Combination of JNJ-6379 with
PegIFN-α2a
2.2.1.3.2 Combination of JNJ-3989 with
PegIFN-α2a
2.2.2.3 Combination of JNJ-3989 and JNJ-6379
with PegIFN-α2a
2.3.3 Benefit-Risk Assessment for Study
Participation
Cystatin C was added to the 
blood chemistry panel. 
PK information on the
combination of TDF with JNJ-
6379 was added.
Clinical study data suggest 
increased tenofovir plasma 
concentrations when given in 
combination with JNJ-6379.
Therefore, additional renal
monitoring by means of cystatin
C testing was added to the
protocol.
2.2.2.2 Combination of JNJ-3989 and JNJ-6379
with Tenofovir Disoproxil
10.2 Appendix 2: Clinical Laboratory Tests
The potential for JNJ-6379 to 
increase tenofovir plasma 
concentrations was added to the 
potential risks. 
Clinical study data suggest 
increased tenofovir plasma 
concentrations when given in
combination with JNJ-6379.
2.3.2.2.3 Potential Risks for Tenofovir
Disoproxil and PegIFN-α2a
A footnote was added to 
exclusion criteria 2 a, b, c and d
to clarify that bilirubin,
prothrombin time and serum
albumin above or below the cut
off are exclusionary unless they
can be explained by anything
other than hepatic
decompensation.
Clarification  
5.2 Exclusion Criteria
Minor errors were corrected. 
Correction  
1.3.1 Schedule of Activities –Screening Phase
and Induction Phase
1.3.2 Schedule of Activities –Consolidation
Phase and Follow-up Phase
6.1 Study Intervention(s) Administered
6.2 Preparation/Handling/Storage/Accountability
6.6.1 Study Intervention Completion at
Consolidation Week 12
8.3 Adverse Events, Serious Adverse Events,
and Other Safety Reporting
8.3.6.5 Hematologic Abnormalities
10.4 Appendix 4: Adverse Events: Definitions
and Procedures for Recording, Evaluating,
Follow-up, and Reporting
10.11 Appendix 11: Hepatitis B Quality of Life
Instrument
Amendment 2 (08 July 2020)
Overall Rationale for the Amendment:The protocol was amended as specified below
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Description of Change 
Brief Rationale 
Section Number and Name
The COVID-19 appendix was 
updated to include details on home 
health visits performed by a nurse 
To allow visits to be performed by a 
nurse at the participant's home 
(following the schedule of activities
as closely as possible) in case of
restrictions due to the COVID-19
pandemic
10.15 Appendix 15: COVID-19
APPENDIX
All references to blinding/unblinding 
in the COVID-19 appendix were 
removed
Minor corrections 
10.15 Appendix 15: COVID-19
APPENDIX
Other clarifications and additions 
made to the COVID-19 appendix  
10.15 Appendix 15: COVID-19
APPENDIX
Correct position of footnote 'h' 
1.3.1 Schedule of Activities –
Screening Phase and Induction
Phase
Footnote 'r' was corrected to ensure 
the Day-1 ECG will be collected and 
assessed locally  
1.3.1 Schedule of Activities –
Screening Phase and Induction
Phase
Exclusion criterion M04 should 
reference criterion M02.1 instead of
A02a
5.2 Exclusion Criteria
Amendment 1 (24-April-2020)
Overall Rationale for the Amendment: Following Health Authority (HA) feedback the protocol was
amended as specified below
Description of Change 
Brief Rationale 
Section Number and Name
TSH and T4 testing were added at 
screening, end of induction phase, 
and end of consolidation phase 
To ensure participants meet 
eligibility criteria related to thyroid 
function and to ensure thyroid 
function is monitored as per the 
PegIFN-α2a prescribing information 
1.3.1 Schedule of Activities –
Screening Phase and Induction
Phase
1.3.2 Schedule of Activities –
Consolidation Phase and Follow-up
Phase
10.2 Appendix 2: Clinical
Laboratory Tests
It was added that participants with a 
decrease or loss of vision will have a 
prompt and complete ophthalmic 
examination during induction and 
consolidation phase 
Given the known ophthalmologic 
toxicities of PegIFN-α2a, 
ophthalmic examinations will be 
continued through the consolidation 
phase as indicated 
1.3.1 Schedule of Activities –
Screening Phase and Induction
Phase
1.3.2 Schedule of Activities –
Consolidation Phase and Follow-up
Phase
Exclusion criterion A25 was 
amended to exclude participants 
with depression or psychiatric
disorders that are not adequately
controlled on a stable medication
regimen
To be consistent with the PegIFN- 
α2a prescribing information
5.2 Exclusion Criteria
Criteria were added for 
discontinuation of treatment with 
PegIFN-α2a
In line with the PegIFN-α2a 
prescribing information  
7.1 Discontinuation of Study
Intervention
The discontinuation criterion related 
to disallowed medication was 
updated
In line with the list of disallowed 
medications in Table 3 
7.1 Discontinuation of Study
Intervention
Contraindications for PegIFN-α2a 
treatment assessed at screening will 
need to be re-assessed at the end of 
For completeness 
1.3.1 Schedule of Activities –
Screening Phase and Induction
Phase
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Description of Change 
Brief Rationale 
Section Number and Name
the induction phase prior to 
randomization (i.e., prior to start of
PegIFN-α2a treatment)
5.2 Exclusion Criteria
Additional details on handling 
missing data were added to the 
protocol 
For completeness 
9.4.1.1 Primary Efficacy Endpoint
(HBsAg Seroclearance 24 Weeks
After Completion of Consolidation
Phase Treatment)
9.4.1.2 Secondary and Exploratory
Efficacy Endpoints
Information on the confidence level 
used for sample size calculation was 
added
For completeness 
1.1 Synopsis
9.2 Sample Size Determination
Additional details on the analysis of 
the primary endpoint were added 
For completeness 
9.4.1.1 Primary Efficacy Endpoint
(HBsAg Seroclearance 24 Weeks
After Completion of Consolidation
Phase Treatment)
Additional details were added on 
who will have access to the interim 
analysis results
For completeness 
1.1 Synopsis
9.5 Interim Analyses
Liver biopsy result within 1 year 
prior to screening (instead of 2 years 
prior to screening) or at the time of 
screening is allowed for eligibility
For consistency with the inclusion 
criteria 
1.3.1 Schedule of Activities –
Screening Phase and Induction
Phase
Guidance on study conduct during 
the COVID-19 pandemic was added 
Options for study-related participant 
management are being provided in 
the event of disruption to the study 
conduct due to the COVID-19
pandemic.
1.3 Schedule of Activities
10.15 Appendix 15: COVID-19
APPENDIX
Minor errors were corrected 
Correction 
Title Page and footer
2.2.2.1 JNJ-3989 and JNJ-6379
2.2.2.2 Combination of JNJ-3989
and JNJ-6379 with Tenofovir
Disoproxil
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10.15. Appendix 15: COVID-19 APPENDIX
GUIDANCE ON STUDY CONDUCT DURING THE COVID-19 PANDEMIC
This appendix applies to all current approved versions of protocol 73763989PAHPB2005.
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 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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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 ofrisks 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 unable to visit the study site, direct-to-patient (DTP) shipment or handover to
a caregiver or delegate of oral study intervention may be implemented, where allowed per
local regulations and if requested by the treating study physician. Where DTP shipments or
handover to delegates are deemed necessary, the process must be coordinated between the site
and sponsor staff following standard DTP procedures for arranging shipment and adhering to
associated approvals and documentation requirements.
 
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.
 
JNJ-3989 should be administered by a nurse at the study site or, if this is not possible, at the
participant’s home. Of note, if a scheduled injection of JNJ-3989 is not possible, the injection
should be given as soon as possible within 3 weeks after the scheduled time.
Continuation of study intervention:
 
Any issue with continuation of study intervention should be discussed with the sponsor and
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 a participant’s safety is considered at risk due to
study intervention, study intervention will be temporarily or permanently discontinued, while
every effort should be made to maintain follow-up on study. The benefit of continuing study
intervention should be assessed by the investigator for each individual participant, considering
the potential impact of reduced direct clinical supervision on participant safety.
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 
If a participant develops a COVID-19 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. Study intervention must be discontinued if prohibited
medication is used.
 
When a participant, for whom study intervention has been interrupted, recovers from
suspected or confirmed SARS-CoV-2 infection or related disease and all AEs related to
SARS-CoV-2 infection improve to Grade ≤1, the investigator should discuss with the sponsor
about resuming study intervention.
COVID-19 vaccination during the study:
Local guidelines on the use of live vaccines in participants receiving PegIFN-α2a should be
followed, including for the second dose of Sputnik V (which contains rAd5, with a theoretical risk
of replication competence). Sputnik Light, which is the first dose of Sputnik V (with rAd26) is not
considered a live vaccine. See below for further guidance on the use of COVID-19 vaccines.
Locally approved COVID-19 vaccines (including those that received emergency use authorization
or conditional marketing authorization) are allowed throughout the study. The following
recommendations should be applied to accommodate COVID-19 vaccination during the
consolidation phase:
 COVID-19 vaccine and PegIFN-α2a should not be administered on the same day.
 If required, PegIFN-α2a injection can be delayed with 2 days. The next PegIFN-α2a
injection should be performed at the scheduled time.
 If required, skipping a PegIFN-α2a injection may be considered after consultation with the
Sponsor.
 Vaccination with Sputnik V should take above-mentioned consideration about live
vaccines into account.
All COVID-19 vaccination-related data (eg, COVID-19 vaccination, AEs, AE management)
should be appropriately captured in  the CRF and source documents. Refer to the COVID-19
vaccine and/or PegIFN-α2a prescribing information for more details.
Study visits and assessments:
 
If possible, central laboratory testing as outlined in the Schedule of Activities is to be
continued. If central laboratory tests cannot be performed, the use of a local laboratory is
allowed for study evaluations. A copy of the local laboratory report should be reviewed by the
investigator and filed with the source documents, along with reference ranges.
 To safely maintain participants on study intervention while site capabilities are compromised
by COVID-19-related restrictions, study visits may be performed by a nurse (who received
study-specific training) at the participant’s home (home health visits) 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:
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Status: Approved,  Date: 25 November 2021
 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 participant-reported outcomes (where appropriate translations and licensing are
available)
 If JNJ-3989 is administered at the participant’s home, it will need to be done by a nurse
(who received study-specific training)
 Delivering oral study interventions and urine pregnancy tests for at-home use
 
Any data related to adverse events, concomitant medication, vital signs, and ECGs will be
reviewed and assessed by the investigator.
 
In addition, participants may have tele-health visits conducted by qualified site personnel via
phone or video conversation as per local regulation. Assessments may include review of
adverse events (including injection site reactions), concomitant medications, and 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.
 
Procedures and timings should follow the Schedule of Activities as closely as possible.
Standard Adverse Event/Serious Adverse Event reporting requirements apply.
 Ultrasound (and fibroscan where applicable) should be done as close as possible to the time
points specified in the Schedule of Activities. However, if this is not possible due to COVID-
19 related restrictions, the imaging test should be performed as soon as possible.
 Consenting and re-consenting of participants will be performed as applicable for the measures
taken (including also remote consenting by phone or video consultation) and according to local
guidance for informed consent applicable during the COVID-19 pandemic.
Source Data Verification/Monitoring:
 In case on-site monitoring visits are not possible, the site monitor may contact the investigator
to arrange monitoring activities remotely (in accordance with site and local requirements).
Additional on-site monitoring visits may be needed in the future to catch up on source data
verification.
Site Audits:
 During the COVID-19 pandemic and at the impacted sites, study site Good Clinical Practice
(GCP) audits with direct impact/engagement from the investigator and study site personnel
would not be conducted in order to comply with national, local, and/or organizational social
distancing restrictions. Additional quality assurance activities such as remote audits or focused
review of study-related documents may take place with limited impact/engagement if possible.
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10.16. Appendix 16: NA Re-treatment and Monitoring After Stopping of NA
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11. 
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Clinical Protocol 73763989PAHPB2005
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Meeting, Boston November 2019,Poster LP4. Available at: http://ir.arrowheadpharma.com/static-
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INVESTIGATOR AGREEMENT
I have read this protocol and agree that it contains all necessary details for carrying out this study. I will
conduct the study as outlined herein and will complete the study within the time designated.
I will provide copies of the protocol and all pertinent information to all individuals responsible to me who
assist in the conduct of this study. I will discuss this material with them to ensure that they are fully informed
regarding the study intervention, the conduct of the study, and the obligations of confidentiality.
Coordinating Investigator (where required):
Name (typed or printed):
Institution and Address:
Signature: 
Date:
(Day Month Year)
Principal (Site) Investigator:
Name (typed or printed):
Institution and Address:
Telephone Number:
Signature: 
Date:
(Day Month Year)
Sponsor's Responsible Medical Officer:
Name (typed or printed): 
Institution: 
Janssen Research & Development
Signature: 
[electronic signature appended at the end of the protocol] 
Date:
(Day Month Year)
Note: If the address or telephone number of the investigator changes during the study, written notification will be
provided by the investigator to the sponsor, and a protocol amendment will not be required.
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NCT04439539


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Date 
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17:23:18
(GMT)
Document Approval
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NCT04439539

SAP_001.pdf: 
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
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Status: Approved,  Date: 27 March 2024
Janssen Research & Development
Statistical Analysis Plan
Intervention-specific Appendix 3 to Master Protocol PLATFORMPAHPB2001
A Phase 2, randomized, open-label, multicenter study to evaluate efficacy, 
pharmacokinetics, safety, and tolerability of treatment with JNJ-73763989, pegylated 
interferon alpha-2a, nucleos(t)ide analog with or without JNJ-56136379 in treatment-naïve 
patients with HBeAg positive chronic hepatitis B virus infection
The REEF-IT Study
Protocol 73763989PAHPB2005; Phase 2
JNJ-73763989 and JNJ-56136379
Status:
Approved
Date:
27 March 2024
Prepared by:
Janssen Research & Development, a division of Janssen Pharmaceutica NV
Document No.: EDMS-RIM-152699, 5.0
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.
NCT04439539


JNJ-73763989 and JNJ-56136379)
Statistical Analysis Plan      
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
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Status: Approved,  Date: 27 March 2024
TABLE OF CONTENTS
TABLE OF CONTENTS ............................................................................................................................... 2
LIST OF TABLES ......................................................................................................................................... 5
LIST OF FIGURES ....................................................................................................................................... 5
AMENDMENT HISTORY.............................................................................................................................. 6
ABBREVIATIONS ...................................................................................................................................... 13
1.
INTRODUCTION................................................................................................................................ 15
1.1.
Trial Objectives and Endpoints ...................................................................................................... 15
1.2.
Trial Design .................................................................................................................................... 17
1.3.
Statistical Hypotheses for Trial Objectives..................................................................................... 22
1.4.
Sample Size Determination ........................................................................................................... 22
1.5.
Randomization and Blinding .......................................................................................................... 23
2.
GENERAL ANALYSIS DEFINITIONS .............................................................................................. 23
2.1.
Analysis Phases and Visit Windows .............................................................................................. 24
2.1.1.
Analysis Phase ........................................................................................................................... 24
2.1.2.
Relative Day by Study Phase ..................................................................................................... 25
2.1.2.1.
Induction Phase Relative Day ................................................................................................. 25
2.1.2.2.
Consolidation Relative Day ..................................................................................................... 26
2.1.2.3.
Follow Up Relative Day ........................................................................................................... 26
2.1.3.
Analysis Visits and Time Points.................................................................................................. 26
2.2.
Baseline ......................................................................................................................................... 29
2.2.1.
Study Baseline............................................................................................................................ 29
2.2.2.
Consolidation Baseline Timepoint .............................................................................................. 29
2.3.
Analysis Sets.................................................................................................................................. 29
2.4.
On-treatment and off-treatment periods......................................................................................... 30
2.5.
Definition of Subgroups.................................................................................................................. 31
2.5.1.
Subgroups for Efficacy Analyses................................................................................................ 31
2.5.2.
Subgroups for Safety Analyses .................................................................................................. 31
2.6.
Missing and Partial Dates Imputation Rules .................................................................................. 32
2.6.1.
Adverse Event Onset Date and Resolution Date ....................................................................... 32
2.6.2.
HBV Diagnosis and Infection Dates ........................................................................................... 33
2.6.3.
Concomitant Medication Dates................................................................................................... 33
2.6.4.
Dates of Alcohol Consumptions ................................................................................................. 33
3.
DATA REVIEW COMMITTEE AND INTERIM ANALYSES.............................................................. 34
3.1.
Data Review Committee ................................................................................................................ 34
3.2.
Independent Flares Monitoring ...................................................................................................... 34
3.3.
Data Reviews and Interim Analyses .............................................................................................. 34
3.3.1.
Data Reviews.............................................................................................................................. 34
3.3.2.
Interim Analyses ......................................................................................................................... 35
3.3.3.
Analysis Overview of Data Reviews, Interim Analysis, Primary and Final Analyses ................. 35
4.
SUBJECT INFORMATION................................................................................................................ 37
4.1.
Disposition Information................................................................................................................... 37
4.2.
Demographic and Baseline Characteristics................................................................................... 37
4.2.1.
Demographic Characteristics ..................................................................................................... 38
4.2.2.
Baseline Characteristics ............................................................................................................. 38
4.3.
Medical History............................................................................................................................... 40
4.4.
Prior and Concomitant Medications ............................................................................................... 40
4.5.
Protocol Deviations ........................................................................................................................ 41
4.6.
Extent of Exposure......................................................................................................................... 41
NCT04439539


JNJ-73763989 and JNJ-56136379)
Statistical Analysis Plan      
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Status: Approved,  Date: 27 March 2024
4.7.
Treatment Compliance................................................................................................................... 42
5.
EFFICACY ......................................................................................................................................... 43
5.1.
Analysis Specifications................................................................................................................... 43
5.1.1.
Level of Significance................................................................................................................... 44
5.1.2.
Data Handling Rules................................................................................................................... 44
5.2.
Primary Efficacy Endpoint.............................................................................................................. 45
5.2.1.
Definition..................................................................................................................................... 45
5.2.2.
Analysis Methods........................................................................................................................ 45
5.2.2.1.
Missing Data Handling............................................................................................................. 45
5.2.2.1.1.
Observed Case Data............................................................................................................ 45
5.2.2.1.2.
Missing as Non-Responder.................................................................................................. 45
5.2.2.1.3.
Last Observation Carried Forward (LOCF).......................................................................... 46
5.2.3.
Subgroup Analyses of Primary Efficacy Endpoint ...................................................................... 46
5.2.4.
Per-Protocol Analysis ................................................................................................................. 46
5.3.
Secondary Endpoints..................................................................................................................... 46
5.3.1.
Definitions ................................................................................................................................... 46
5.3.1.1.
Binary Endpoints ..................................................................................................................... 46
5.3.1.1.1.
Reaching HBsAg <10 IU/mL During the Induction Phase ................................................... 46
5.3.1.1.2.
NA Treatment Completion Criteria....................................................................................... 46
5.3.1.1.2.1.
NA Treatment Completion Criteria During the Study........................................................ 46
5.3.1.1.2.2.
NA Re-Treatment Criteria and Monitoring After Stopping of NA ...................................... 47
5.3.1.1.3.
HBsAg Seroclearance.......................................................................................................... 48
5.3.1.1.4.
HBeAg Seroclearance.......................................................................................................... 48
5.3.1.1.5.
HBsAg and HBeAg Seroconversion .................................................................................... 48
5.3.1.1.6.
Suppressed HBV DNA ......................................................................................................... 49
5.3.1.1.7.
Thresholds Based on HBsAg, HBeAg, HBV DNA and Multiple Markers............................. 49
5.3.1.1.8.
Virologic Breakthrough......................................................................................................... 51
5.3.1.1.9.
Flares ................................................................................................................................... 51
5.3.1.2.
Values and Changes Over Time Endpoints ............................................................................ 53
5.3.1.2.1.
HBsAg, HBeAg, HBV DNA and ALT.................................................................................... 53
5.3.1.3.
Time to Event Endpoints ......................................................................................................... 53
5.3.1.3.1.
Time to First HBsAg Seroclearance..................................................................................... 53
5.3.1.3.2.
Time to First HBV DNA < LLOQ .......................................................................................... 53
5.3.2.
Analysis Methods........................................................................................................................ 53
5.3.2.1.
Binary Outcomes ..................................................................................................................... 54
5.3.2.1.1.
NA Treatment Completion Criteria....................................................................................... 54
5.3.2.1.1.1.
NA Treatment Completion Criteria During the Study........................................................ 54
5.3.2.1.1.2.
NA Re-Treatment Criteria and Monitoring After Stopping of NA ...................................... 54
5.3.2.1.2.
HBsAg Seroclearance.......................................................................................................... 55
5.3.2.1.3.
HBsAg and HBeAg Seroconversion .................................................................................... 55
5.3.2.1.4.
Suppressed HBV DNA ......................................................................................................... 55
5.3.2.1.5.
Thresholds based on HBsAg, HBeAg, HBV DNA and Multiple Markers ............................. 56
5.3.2.1.6.
Virologic Breakthrough......................................................................................................... 56
5.3.2.1.7.
Flares ................................................................................................................................... 56
5.3.2.2.
Values and Change Over Time Endpoints .............................................................................. 57
5.3.2.2.1.
HBsAg, HBeAg, HBV DNA and ALT.................................................................................... 57
5.3.2.3.
Time to Event Endpoints ......................................................................................................... 57
5.3.2.3.1.
Time to First HBsAg Seroclearance..................................................................................... 58
5.3.2.3.2.
Time to First HBV DNA < LLOQ .......................................................................................... 58
5.4.
Exploratory Endpoints.................................................................................................................... 58
5.4.1.
Definitions ................................................................................................................................... 58
5.4.1.1.
Binary and Categorical Endpoints ........................................................................................... 58
5.4.1.1.1.
End of Follow-up Phase HBsAg response........................................................................... 58
5.4.1.1.2.
Treatment Failure................................................................................................................. 59
5.4.1.1.3.
Thresholds of HBV RNA and HBcrAg Levels ...................................................................... 59
5.4.1.1.4.
Thresholds Based Multiple Markers for participants who completed NA Treatment........... 60
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Statistical Analysis Plan      
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Status: Approved,  Date: 27 March 2024
5.4.1.1.5.
Anti-HBe Antibodies ............................................................................................................. 61
5.4.1.2.
Values and Change Over Time Endpoints .............................................................................. 61
5.4.1.2.1.
HBV RNA and HBcrAg......................................................................................................... 61
5.4.1.2.2.
Anti-HBs Antibodies ............................................................................................................. 61
5.4.1.2.3.
Liver Stiffness Measurements.............................................................................................. 61
5.4.1.3.
Endpoints for Correlation......................................................................................................... 61
5.4.1.3.1.
Association between several endpoints after the beginning of the consolidation 
phase.................................................................................................................................... 61
5.4.2.
Analysis Methods........................................................................................................................ 62
5.4.2.1.
Binary Endpoints ..................................................................................................................... 62
5.4.2.1.1.
Treatment Failure................................................................................................................. 62
5.4.2.1.2.
Thresholds based on HBV RNA and HBcrAg Levels .......................................................... 62
5.4.2.1.3.
Anti-HBe Antibodies ............................................................................................................. 62
5.4.2.1.4.
Thresholds Based Multiple Markers for participants who completed NA Treatment........... 63
5.4.2.2.
Values and Change Over Time Endpoints .............................................................................. 63
5.4.2.2.1.
HBV RNA and HBcrAg......................................................................................................... 63
5.4.2.2.2.
Anti-HBs Antibodies ............................................................................................................. 63
5.4.2.2.3.
Liver Stiffness Measurements.............................................................................................. 64
5.4.2.3.
Endpoints for Correlation......................................................................................................... 64
5.4.2.3.1.
Association Between Baseline Characteristics/Viral Blood Markers and Selected 
Efficacy Variables................................................................................................................. 64
6.
SAFETY............................................................................................................................................. 64
6.1.
Adverse Events .............................................................................................................................. 64
6.1.1.
Definitions ................................................................................................................................... 64
6.1.2.
Analysis Methods........................................................................................................................ 65
6.1.3.
Adverse Events of Special Interest (AESI)................................................................................. 66
6.2.
Clinical Laboratory Tests................................................................................................................ 66
6.2.1.
Definitions ................................................................................................................................... 66
6.2.2.
Analysis Methods........................................................................................................................ 68
6.2.3.
Renal Safety ............................................................................................................................... 69
6.2.3.1.
eGFR ....................................................................................................................................... 69
6.2.3.1.1.
Proximal Renal Tubular Function Proteinuria by Quantitative Assessment ........................ 69
6.2.3.1.2.
Proteinuria by Urinalysis (Dipstick) ...................................................................................... 70
6.2.3.1.3.
Other Renal Biomarkers....................................................................................................... 70
6.2.3.1.4.
Phosphate Excretion ............................................................................................................ 70
6.2.3.1.5.
Subclinical Renal Proximal Tubulopathy.............................................................................. 70
6.2.4.
Electrocardiogram....................................................................................................................... 71
6.2.4.1.
Definitions................................................................................................................................ 71
6.2.4.2.
Analysis Methods .................................................................................................................... 72
6.2.5.
Vital Signs and Body Temperature............................................................................................. 73
6.2.5.1.
Definitions................................................................................................................................ 73
6.2.5.2.
Analysis Methods .................................................................................................................... 74
6.2.6.
Physical Examination.................................................................................................................. 74
7.
VIRAL GENOME SEQUENCE ANALYSIS....................................................................................... 74
7.1.
Time Points and Samples .............................................................................................................. 74
7.2.
Definitions ...................................................................................................................................... 75
7.3.
Parameters to Analyze................................................................................................................... 76
7.4.
Positions & Genetic Variations of Interest...................................................................................... 77
7.5.
Analysis Methods ........................................................................................................................... 79
7.5.1.
Baseline ...................................................................................................................................... 79
7.5.2.
Post-Baseline.............................................................................................................................. 79
7.5.3.
Over the Study Period ................................................................................................................ 80
7.6.
HBV genotype ................................................................................................................................ 81
8.
OTHER ANALYSIS ........................................................................................................................... 81
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JNJ-73763989 and JNJ-56136379)
Statistical Analysis Plan      
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Status: Approved,  Date: 27 March 2024
8.1.
Pharmacokinetics........................................................................................................................... 81
8.2.
Pharmacokinetic/Pharmacodynamic Relationships....................................................................... 82
8.3.
Immune Analyses........................................................................................................................... 82
9.
PATIENT-REPORTED OUTCOMES................................................................................................. 82
9.1.
Hepatitis B Quality of Life Instrument (HBQOL)............................................................................. 83
9.1.1.
Definition..................................................................................................................................... 83
9.1.2.
Analysis Methods........................................................................................................................ 84
9.2.
Short Form 36 version 2................................................................................................................. 84
9.2.1.
Definition..................................................................................................................................... 84
9.2.2.
Analysis Methods........................................................................................................................ 85
9.3.
5-Level EuroQol 5-Dimension Questionnaire ................................................................................ 85
9.3.1.
Definition..................................................................................................................................... 85
9.3.2.
Analysis Methods........................................................................................................................ 86
9.4.
Patient Global Impression of Change Scale (PGIC)...................................................................... 87
9.4.1.
Definition..................................................................................................................................... 87
9.4.2.
Analysis Methods........................................................................................................................ 87
10.
REFERENCES................................................................................................................................... 88
ATTACHMENT 1: SELECTED MAJOR PROTOCOL DEVIATIONS FOR ANALYSIS 
PURPOSES ....................................................................................................................................... 89
ATTACHMENT 2: ADVERSE EVENTS OF SPECIAL INTEREST LIST OF PREFERRED 
TERMS............................................................................................................................................... 95
LIST OF TABLES
Table 1:
Analysis Phases Start and End Dates...................................................................................... 24
Table 2:
Analysis Time Points and Time Intervals by Analysis Phase ................................................... 27
Table 3:
Overview of Data Summaries and Different Analyses: Data Reviews, Planned 
Interims, Primary and Final Analyses ....................................................................................... 35
Table 4:
Data Handling Rules for HBV Virology and Serology Assessments ........................................ 44
Table 5:
Laboratory Parameters ............................................................................................................. 66
LIST OF FIGURES
Figure 1:
Schematic Overview of Cohort 1 of the Study – Prior to Protocol Amendment #5 .................. 19
Figure 2:
Schematic Overview of the Study – Per Protocol Amendment 5 ............................................. 19
Figure 3:
Schematic Overview of Cohort 2 of the Study – As of Protocol Amendment 6........................ 20
NCT04439539


JNJ-73763989 and JNJ-56136379)
Statistical Analysis Plan      
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
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Status: Approved,  Date: 27 March 2024
AMENDMENT HISTORY
Document History
Document
Date
Amendment 4
01 April 2024
Amendment 3
06 April 2023
Amendment 2
29 March 2023
Amendment 1
3 December 2021
Original SAP
26 February 2021
Amendment 4:
Overall rationale of this Amendment:
This administrative amendment incorporates additional clarifications on subgroups and analyses
which have been documented in the Data Presentation Specification.
Clarifications, Additions, Corrections
Section Number and Name
Description of Change
Rationale
2.5.1 Subgroup for Efficacy 
Analyses
Addition of the following subgroups:
-
Immune tolerant
-
Peg-responder definition #1
-
Peg-responder definition #2
Removal of the following subgroups: 
-
NA treatment history
-
Fibrosis stage 
-
Sex
-
Geographical region
-
Duration of exposure to antigens
Regrouping of the age categories: >30 
years - ≤45 years, >45 years - ≤55 
years in one category: >30 years
To allow for a more focused assessment of 
factors impacting efficacy outcomes and 
reduce the overall number of outputs
5.4.1.3.1.
Association 
Between Baseline 
Characteristics/Viral Blood 
Markers and Selected Efficacy 
Variables
Removal of the correlation analyses 
between off-treatment HBV markers and 
other endpoints
Insufficient data for correlation analysis 
since there is only one patient who has met 
the NA treatment completion criteria and 
stopped NA (i.e. off-treatment) at CW12.
5.4.1.3.1.
Association 
between several endpoints 
The title has been changed to reflect the 
analyses detailed in this subsection.
To characterize association between 
changes in viral and safety markers during 
PegIFN administration.
NCT04439539


JNJ-73763989 and JNJ-56136379)
Statistical Analysis Plan      
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Status: Approved,  Date: 27 March 2024
Clarifications, Additions, Corrections
Section Number and Name
Description of Change
Rationale
after the beginning of the 
consolidation phase
Addition of the correlations between the 
following endpoints will be evaluated: 
-
Maximum ALT increase (U/L) 
vs Maximum HBV DNA increase (log10 
IU/mL) between Consolidation Baseline 
and FU Week 4
-
Maximum ALT increase (U/L) 
vs 
Maximum 
Neutrophils 
(10^9/L) 
decrease between Consolidation Baseline 
and FU Week 4
-
Maximum ALT increase (U/L) 
vs Maximum HBsAg decrease (log10 
IU/mL) between Consolidation Baseline 
and FU Week 4
-
Additional 
HBsAg 
decline 
(log10 IU/mL) at CW12 vs Maximum 
Neutrophils 
decrease 
between 
Consolidation Baseline and FU Week 4
-
Additional 
HBsAg 
decline 
(log10 IU/mL) at CW12 vs Maximum 
ALT 
increase 
(U/L) 
between 
Consolidation Baseline and FU Week 4
Amendment 3:
Two hyperlinks were not working correctly. Updates have been made to have the SAP 
submission ready.
Amendment 2:
Overall rationale of this Amendment:
This administrative amendment incorporates additional clarifications on endpoints, on analysis 
population, on sample size, which have been documented in the Data Presentation Specification.
NCT04439539


JNJ-73763989 and JNJ-56136379)
Statistical Analysis Plan      
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Status: Approved,  Date: 27 March 2024
Clarifications, Additions, Corrections
Section Number and Name
Description of Change
Rationale
2.3 Analysis set
The PegIFN α2a ITT and mPegIFN α2a 
ITT analysis sets have been removed
These two analysis sets are not part of the 
protocol and not so different from the ITT 
population. They are no longer of interest.
2.4. On-treatment and off-
treatment periods
A section to define the on-treatment and 
off-treatment periods has been added
Clarification
2.5.1 Subgroup for Efficacy 
Analyses
Removal of the following subgroups: 
-
NA treatment history
-
Fibrosis stage 
Subcategories 
have 
been 
regrouped/removed
for the following 
factors:
-
For HBsAg level at baseline: 
the subcategories <1,000 IU/mL 
and ≥1,000 IU/mL-<10,000 
IU/mL are replaced by <10,000 
IU/mL
-
For HBcrAg level at baseline: all 
patients are in the category >4 
log10 IU/mL and ≤9 log10 
IU/mL, this subgroup has been 
removed
-
For HBeAg level at baseline: 
the subcategories >ULOQ and 
>5 log10 IU/mL have no patient 
so new subcategories have been 
set: ≥3 log10 IU/mL and <3 
log10 IU/mL
Subcategories have been 
regrouped/removed to have enough patients 
(at least 6 patients, which corresponds to 
10% of the targeted sample size) or because 
they are no longer of interest.
Section 5.3.1.1.2.2 NA Re-
Treatment criteria
The proportion of participants who met 
each sub-criterion will not be calculated
This information is not available in the 
CRF
Section 5.3.1.1.7. Thresholds 
Based on HBsAg, HBeAg, 
HBV DNA and Multiple 
Markers
Subcategories have been added based on 
multiple markers threshold (HBsAg and 
HBV DNA)
New subcategories of interest have been 
added to be consistent with REEF-1
Section 5.3.1.3 Time to Event
Endpoints
The following time to event endpoints
have been removed:
-
Time to first HBsAg <10 IU/mL
-
Time to first HBsAg <100 
IU/mL
The only time to event of interest are the 
following: 
-
Time to first HBsAg seroclearance
-
Time to first HBV DNA<LLOQ
NCT04439539


JNJ-73763989 and JNJ-56136379)
Statistical Analysis Plan      
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
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Status: Approved,  Date: 27 March 2024
Clarifications, Additions, Corrections
Section Number and Name
Description of Change
Rationale
-
Time to first HBsAg decline >1 
log10 IU/mL
-
Time to first HBsAg decline >2 
log10 IU/mL
-
Time to first HBsAg decline >3 
log10 IU/mL
-
Time to first flare
-
Time 
to 
first 
HBeAg 
seroclearance
-
Time 
to 
first 
virologic 
breakthrough
The remaining time to event endpoints are 
no longer of interest.
Section 5.4.1.1.1 Partial cure
The section has been removed
The Partial cure is no longer of interest
Section 5.4.1.3, Time to event 
endpoints
This section has been removed
The following time to event endpoints are 
no longer of interest:
-
Time to first HBV RNA<LOD
-
Time 
to 
first 
HBcrAg 
undetectability
-
Time to Appearance of Anti-HBs 
antibodies
-
Time to Appearance of Anti-HBe 
antibodies
Section 5.4.2.1.1 Partial cure
The section has been removed
The definition for partial cure is outdated 
and thus no need to perform the analyses.
Section 5.4.2.3,Time to event 
endpoints
This section has been removed
The following time to event endpoints are 
no longer of interest:
-
Time to first HBV RNA<LOD
-
Time 
to 
first 
HBcrAg 
undetectability
-
Time to Appearance of Anti-HBs 
antibodies
-
Time to Appearance of Anti-HBe 
antibodies
Section 7.4 Positions & 
Genetic Variations of Interest
Added lists of genetic variations for JNJ-
3976 and JNJ-3924
List of positions and variants has been 
updated to reduce analyses, to focus on the 
essential lists and to capture that other lists 
have been removed.
Section 8.3 Immune analyses
Analyses may be done instead of will be 
done.
Clarification 
NCT04439539


JNJ-73763989 and JNJ-56136379)
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Clarifications, Additions, Corrections
Section Number and Name
Description of Change
Rationale
Attachment 1: Selected major 
protocol deviations for 
analyses purposes
Remove the inclusion/exclusion criteria 
with no impact in the efficacy and safety 
analyses from the list of major protocol 
deviations
Select the necessary conditions for a 
participant to be part of the per protocol 
population.
Attachment 2: Adverse events 
of Special Interest
Update the PT
Meddra version has changed: from version 
23.1 to version 25.1
Amendment 1 
Overall rationale for the SAP Amendment: This amendment aims to align the Statistical 
Analysis Plan (SAP) to the ISA Protocol Amendment #5 issued on July 30, 2021 and the ISA 
Protocol Amendment #6 issued on September 30, 2021 and the ISA Protocol Amendment #7
issued on November 26, 2021where the main changes in the study design include to remove JNJ-
6379 as study intervention, to add a new nucleos(t)ide analog (NA) re-treatment criterion for 
participants who discontinued NA treatment during follow-up, and to include more frequent 
monitoring for participants who discontinued NA treatment during follow-up, to update the criteria 
for post-treatment monitoring and for NA re-treatment for participants who discontinued NA 
treatment during follow-up and to a fixed 36-week duration of the induction phase.
The primary reason for removing JNJ-6379 was based on new data from recent interim analyses 
of the REEF-1 (73763989HPB2001) and REEF-2 (73763989PAHPB2002) studies, have shown 
an unfavorable benefit-risk profile of JNJ-6379 in combination with JNJ-3989+NA compared to 
JNJ-3989+NA alone (Negative impact of JNJ-6379, when combined with JNJ-3989+NA, on 
HBsAg reduction and adverse renal profile). Therefore, the Sponsor has decided to discontinue 
treatment with JNJ-6379 in all ongoing clinical studies effective immediately. Participants 
currently on treatment with JNJ-6379 will be contacted and requested to stop taking JNJ-6379, 
while continuing treatment with NA and JNJ-3989. For newly enrolled participants after urgent 
safety measurement (USM), JNJ-6379 will no longer be included in the treatment regimen. 
The main reason for additional NA re-treatment criterion is a severe clinical alanine 
aminotransferase (ALT) flare that was reported following discontinuation of NA treatment in a 
virologically suppressed HBeAg negative participant on long-term TDF treatment who was 
randomized to the control arm (placebo + placebo + NA) in the REEF-2 study. The participant 
presented with hepatitis B virus (HBV) DNA levels that increased rapidly, before any relevant 
changes in liver markers were noted. Discontinuation of NA treatment followed the protocol-
defined criteria and was in line with recent European Association for the Study of the Liver (EASL) 
treatment guidelines.1 Flares following NA discontinuation are not unexpected, but the rapid 
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Status: Approved,  Date: 27 March 2024
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. 
The main reason for updating the criteria for post-treatment monitoring and NA re-treatment for 
patients who discontinued NA treatment is 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.
Two cohorts have been introduced to distinguish between participants enrolled prior to or after 
ISA Protocol Amendment #5. All participants enrolled prior to ISA Protocol Amendment #5 will 
comprise Cohort 1, of which some may be randomized to either study intervention Arm 1 or Arm 
2. Protocol Amendment #5 was not implemented due to the USM and no participants will be 
receiving Protocol Amendment #5 treatment, the participants enrolled after approval of ISA 
Protocol Amendment #6 will comprise Cohort 2.
Main changes and their rationale are clarified in the table below.
Section Number and Name
Description of Change
Rationale
Section 1.2 Trial Design
The study design was updated such that 
participants (Cohort 2) will receive JNJ-
3989+NA for a fixed duration of 36 
weeks (induction phase) instead of a 
response-guided treatment duration. The 
induction phase will be followed by a 
12-week consolidation phase during 
which PegIFN-α2a will be added to the 
treatment regimen for all participants.
JNJ-6379 was discontinued in all 
ongoing clinical studies effective 
immediately. 
Based on preliminary 48-week 
treatment data from the REEF-1 
study and insights from EASL 
2021, PegIFN-α2a will be added to 
the treatment regimen for all 
participants, to increase the 
potential of achieving functional 
cure. 
New data from recent interim 
analyses of the REEF-1 
(73763989HPB2001) and REEF-2 
(73763989PAHPB2002) studies, 
have shown an unfavorable benefit-
risk profile of JNJ-6379 in 
combination with JNJ-3989+NA 
compared to JNJ-3989+NA alone.
Section 1.4 Sample Size 
Determination
With the introduction of the new study 
design in Protocol Amendment 6 (single-
arm), no formal sample size re-
calculation was performed.
Alignment of the sample size 
justification for Cohort 2 to the new 
design elements.
Section 2.1.1 Analysis Phase
Analysis Phase start date and end date 
have been updated.
Alignment to the new fixed-
duration induction phase; separation 
of definition of start/stop dates for 
participants in Cohort 1 (pre- or 
post-amendment) and in Cohort 2.
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Section Number and Name
Description of Change
Rationale
Section 3.3.2 Interim Analyses
The second IA is planned when all 
participants have completed Week 48 or 
discontinued earlier.
To align IA to the new design Week 
48 (End of Treatment) in the ISA 
Protocol Amendment #6.
Section 5 Efficacy
The efficacy for Cohort 1 will be 
evaluated on the treated population set. 
A secondary analysis of efficacy will be 
performed combining the data from 
participants who received PegIFN-α2a
but not JNJ-6379 in Cohort 1 with data 
of Cohort 2. 
To align with trial design changes
in the ISA Protocol Amendment #6.
Section 5.3.1.1.2 NA Re-
Treatment Criteria and 
Monitoring After Stopping of 
NA
Update of follow-up procedures and 
criteria for re-initiation of NA treatment
and criteria for post-treatment 
monitoring and NA re-treatment for 
patients who discontinued NA treatment
For clarification as per ISA
Protocol Amendment #6 and #7.
Section 6.2.4 Physical 
Examination
Head, neck, and thyroid were added to 
complete physical examination
For completeness
Attachment 1: Selected Major 
protocol Deviations for 
Analysis Purposes
List was updated to incorporate the 
updated inclusion/exclusion criteria as 
per ISA protocol amendment #6. 
For completeness
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ABBREVIATIONS
ADY
analysis relative day
AE
adverse event
AESI
adverse event of special interest
ALT
alanine aminotransferase
AST
aspartate aminotransferase
ATC
anatomic and therapeutic class
ATEOC
analysis time point (Week) for EOC
ATEOI
analysis time point (Week) for EOI
AUC24h
area under the concentration-time curve at 24 hours
BMI
body mass index
CHB
chronic hepatitis B
C24h
concentration 24 hours after administration
CI
confidence interval
Cmax
maximum concentration
CRF
case report form
CV
coefficient of variation
DAIDS
division of acquired immunodeficiency syndrome 
DNA
deoxyribonucleic acid
DR
data review
DRC
data review committee
EASL
european association for the study of the liver
ECG
electrocardiogram
EOC
end of consolidation phase
EOI
end of induction phase
EOS
end of study
EOT
end of treatment
eCRF
electronic case report form
eGFR
estimated glomerular filtration rate
EQ-5D-5L
5-Level EuroQol 5-Dimension
FEPO4
urine fractional excretion of phosphate
FU
follow-up
GGT
Gamma-glutamyltransferase
HBQOL
hepatitis B Quality of Life
HBcrAg
hepatitis B core-related antigen
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 
ICS
intracellular cytokine staining
iFLEP
independent flares expert panel
IA
interim analysis
IFN
interferon
IQR
interquartile range
IRT
item response theory
ISR
injection site reaction
ITT
intent-to-treat
IU/mL
international units per milliliter
IWRS
interactive website response system
LiPA
line probe assay
LLOQ
lower limit of quantification
LOCF
last observation carried forward
MAR
missing at random
MAV
minimum acceptable value
MCS
mental component summary
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MedDRA
medical dictionary for regulatory activities 
MH
Mantel-Haenszel
MI
multiple imputation
mITT
modified intent-to-treat
mTreated
modified treated
MSE
missing score estimation
NA
nucleos(t)ide analog
NGS
next generation sequencing
PBMC
peripheral blood mononuclear cell
PCS
physical component summary
PD
pharmacodynamic(s)
PegIFN-α2a
pegylated interferon alpha-2a 
PGIC
Patient Global Impression of Change
PK
pharmacokinetic(s)
PoC
proof of concept
PP
per protocol
PRO
patient-reported outcomes
Q4W
every 4 weeks
qd
once daily
QTc
corrected QC interval
QTcF
QT interval corrected for heart rate according to Fridericia
QW
once weekly
RBP
rentinol binding protein
RGT
response-guided treatment
RR
Interval between R wave of one heartbeat and R wave of preceding heartbeat 
RT
reference timepoint
SAE
serious adverse event
SAP
statistical analysis plan
SCr
serum creatinine
SD
standard deviation
SF-36v2
Short Form 36 version 2
SPO4
serum phosphate
T4
thyroxine
TAF
tenofovir alafenamide
TD
target detected
TEAE
treatment-emergent adverse event
TeD
tenofovir disoproxil
TND
target not detected
TNF
tumor necrosis factor
TSH
thyroid stimulating hormone
TV
target value
ULN
upper limit of normal
UACR
urine albumin to creatinine ratio
UPCR
urine protein to creatinine ratio
USM
urgent safety measurement
VAS
Visual Analog Scale
WBC
white blood cell
       
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1.
INTRODUCTION
This statistical analysis plan (SAP) for the 73763989PAHPB2005 phase 2 trial describes the 
statistical analyses and definitions to assess the efficacy and safety of study interventions including 
JNJ-73763989, pegylated interferon alpha-2a (PegIFN-α2a), Nucleos(t)ide analogs (NA) regimen 
with or without JNJ-56136379 in patients with HBeAg positive chronic hepatitis B (CHB) virus 
infection and ALT ≤2x ULN who are not currently being treated for their HBV infection (i.e., who 
had <9 months of prior treatment which ended at least 12 months before screening, including 
treatment-naïve patients). 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. JNJ-6379 was 
initially part of the study intervention but has been removed as study intervention with the 
implementation of an urgent safety measure, as described in Protocol Amendment 6.
This study is part of the platform trial PLATFORMPAHPB2001 in participants with CHB.  The 
protocol amendment for 73763989PAHPB2005 constitutes the Intervention Specific Appendix 
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 clinical protocol Amendment-6 finalized on 
30 September 2021, and with the Master Protocol Amendment-3 for PLATFORMPAHPB2001 
finalized on 21 January 2021.
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 a treatment 
regimen of JNJ-3989 + PegIFN-α2a + NA.

Proportion of participants with HBsAg 
seroclearance 24 weeks after stopping all 
study interventions of the consolidation phase 
and without restarting NA treatment.
Secondary

To evaluate the safety and tolerability of the 
study intervention.

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, 
urinalysis, 
urine 
chemistry, and renal biomarkers), 12-lead 
electrocardiograms (ECGs), vital signs, and 
physical examinations throughout the study.

To evaluate the efficacy of the study 
intervention during the treatment period.

Proportion of participants reaching HBsAg 
<10 IU/mL at the end induction phase (Week 
36).
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Objectives
Endpoints

Proportion of participants meeting the NA 
treatment completion criteria at the end of the 
consolidation phase.

To evaluate the efficacy of the study 
intervention during the follow-up (FU) phase.

Proportion of participants with HBsAg 
seroclearance 48 weeks after stopping all 
study interventions of the consolidation phase 
and without restarting NA treatment.

Proportion of participants with HBV DNA 
<LLOQ 48 weeks after stopping all study 
interventions of the consolidation phase and 
without restarting NA treatment.

Frequency of viral and/or biochemical flares 
and/or clinical flares.

Proportion of participants requiring NA 
re-treatment.

To evaluate efficacy of the study intervention 
as measured by blood markers (such as 
HBsAg, HBeAg, HBV DNA, and alanine 
aminotransferase 
[ALT]) 
during 
study 
intervention and follow-up.

Proportion of participants with (sustained) 
reduction, suppression, and/or seroclearance 
considering single and multiple markers (such 
as HBsAg, HBeAg, HBV DNA, and ALT).

Proportion of participants with HBsAg and 
HBeAg seroconversion.

Change from baseline over time in HBsAg, 
HBeAg, and HBV DNA.

Time to achieve HBsAg seroclearance, and/or
HBV DNA <LLOQ.

Proportion of participants with HBeAg, 
HBsAg, and HBV DNA levels and/or changes 
from baseline below/above different cut-offs.

To evaluate the frequency of virologic 
breakthrough.

Proportion of participants with virologic 
breakthrough.

To evaluate the efficacy of NA re-treatment in 
participants who meet the criteria for NA 
re-treatment.

Proportion 
of 
participants 
who 
reach 
HBV DNA undetectability after re-start of 
NA treatment during follow-up.

To evaluate the pharmacokinetics (PK) of 
JNJ-3989 (ie, JNJ-3976 and JNJ-3924) and 
optionally 
of 
JNJ 
6379, 
NA 
and/or
PegIFN-α2a.

PK parameters of JNJ-3976 and JNJ-3924.

Optionally, PK parameters of JNJ 6379, NA 
and/or PegIFN-α2a compared to historical 
data.
Exploratory

To identify baseline and on-treatment markers 
associated with efficacy.

Association of baseline characteristics and 
baseline/on-treatment viral blood markers 
(such as age, and baseline/on-treatment 
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Objectives
Endpoints
HBsAg 
levels) 
with 
selected 
efficacy 
variables.

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 efficacy of the study intervention 
in terms of changes in HBV RNA and 
HBcrAg levels.

Changes from baseline in HBV RNA and 
HBcrAg levels during the study intervention 
and follow-up.

To explore the impact of study intervention on 
participants’ 
physical 
and 
emotional 
functioning, and health-related quality of life 
using patient-reported outcomes (PROs) 
during study intervention and follow-up.

Changes over time in score on the Short Form 
36 version 2 (SF-36v2).

Changes over time in score on the Hepatitis B 
Quality of Life (HBQOL) Instrument.

Changes over time in the 5-Level EuroQol 
5-Dimension (EQ-5D-5L) Visual Analog 
Scale (VAS) score and Index score.

Changes over time on the Patient Global 
Impression of Change (PGIC).

To explore the relationship between plasma 
PK
parameters 
(JNJ-3976, 
JNJ-3924, 
optionally JNJ 6379, NA, and/or PegIFN-α2a) 
and 
selected 
pharmacodynamic 
(PD) 
parameters of efficacy and/or safety, as 
applicable.

Relationship between various plasma PK
parameters 
(JNJ-3976, 
JNJ-3924, 
and 
optionally JNJ 6379, NA, and/or PegIFN-α2a) 
and selected efficacy and/or safety endpoints, 
as applicable.

To explore the effect of PegIFN-α2a 
coadministration on the PK of JNJ-3989 
(optional PK substudy).

Effect of PegIFN-α2a coadministration on the 
PK of JNJ-3976 and JNJ-3924.

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 2a, randomized, open-label, multicenter, parallel-group, interventional study to 
evaluate the efficacy, pharmacokinetics, safety, and tolerability of treatment with JNJ-3989+
PegIFN-α2a +NA regimen with or without JNJ-6379 in patients with HBeAg positive chronic 
HBV infection and ALT ≤2x ULN who are not currently being treated for their HBV infection 
(i.e., who had <9 months of prior treatment which ended at least 12 months before screening, 
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including treatment-naïve patients). After completing this study, participants may have the option 
to enroll into a long-term follow-up study.
A target of approximately 60 adult participants (including approximately 33 after implementation 
of Protocol Amendment #6), 18-55 years (inclusive) of age (with a maximum of approximately 10 
participants >45 to ≤55 years of age), with CHB who are HBeAg positive, who are not currently 
treated for their HBV infection (including treatment-naïve patients), have HBV DNA ≥20,000 
IU/mL and have ALT ≤2x ULN at screening will be enrolled in this study. It is targeted to enroll 
at least 30% participants with HBV DNA ≥107 IU/mL and normal ALT at screening in the study.
The study will be conducted in 4 phases: 

A screening phase (4 weeks [if necessary, can be extended to a maximum of 6 weeks decided 
on a case-by-case basis and in agreement with the sponsor]).

An induction phase:
o
Prior to Protocol Amendment #5: response-guided treatment (RGT) of 36-60 weeks 
(inclusive). 
Note: Participants who already passed the Week 36 visit before Protocol Amendment 
#5 is in effect, will enter the consolidation phase at the next scheduled visit.
o
As of Protocol Amendment #5: fixed duration of 36 weeks for all participants.

A consolidation phase (12 weeks). 

A follow-up (FU) phase (48 weeks).
The total duration of individual participation will be between 100 and 126 weeks. Of note, 
participants enrolled after Protocol Amendment #5 will be between 100 and 102 weeks; and the 
participants enrolled before Protocol Amendment #5 may have a longer induction phase and a total 
study duration up to 126 weeks.
To distinguish between participants enrolled prior to or after Protocol Amendment #5 is in effect, 
the terms Cohort 1 and Cohort 2 will be used. All participants enrolled prior to the Protocol
Amendment #5 will comprise Cohort 1. RGT criterion is defined as having HBsAg <10 IU/mL.
Protocol Amendment #5 was not implemented due to the USM and no participants will be 
receiving Protocol Amendment #5 treatment, the participants enrolled after approval of 
Amendment #6 will comprise Cohort 2.
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The schematics of the trial changes per Protocol Amendment #5 are presented in Figure 1 and 
Figure 2 to show the history of protocol amendment.
Figure 1:
Schematic Overview of Cohort 1 of the Study – Prior to Protocol Amendment #5
a
End of the induction phase is defined by either meeting the study defined RGT criterion (HBsAg <10 IU/mL) or 
reaching study Week 60, whichever comes first. The RGT criterion will be assessed from Week 36 onwards, and 
the assessment will always be based on lab results from the previous study visit (4 weeks earlier).
b
If NA treatment completion criteria (HBsAg <10 IU/mL, and HBeAg-negative, and HBV DNA <LLOQ, and 
ALT <3x ULN) have been met at consolidation Week 12, NA will be stopped at the next scheduled visit (ie, 
FU Week 2), otherwise NA treatment will continue during the complete follow-up phase.
Figure 2:
Schematic Overview of the Study – Per Protocol Amendment 5
Cohort 1: Participants enrolled before Protocol Amendment #5 is in effect
Per Amendment #5, participants who did not yet reach the Week 36 visit will have PegIFN-α2a added to 
their treatment regimen at Week 36 for 12 weeks.
Participants who already passed the Week 36 visit and/or were randomized to the group without PegIFN-
α2a, will have PegIFN-α2a added to their treatment regimen at the next scheduled visit. After 12 weeks, 
treatment with NA, PegIFN-α2a, JNJ-3989 and JNJ-6379 (if applicable) will be stopped.
a
If NA treatment completion criteria (HBsAg <10 IU/mL, and HBeAg-negative, and HBV DNA <LLOQ, and
ALT <3x ULN) have been met at consolidation Week 12, NA will be stopped at the next scheduled visit (ie, 
FU Week 2), otherwise NA treatment will continue during the complete follow-up phase.
b
Depending on the approval date of Amendment #5, the induction phase can be longer than 36 weeks for some 
of these participants.
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Cohort 2: Participants enrolled under Protocol Amendment #5 is in effect
Per Amendment #5, participants will be randomized in a 1:1 ratio at the start of the induction phase to 
either receive JNJ-3989 + JNJ-6379 + NA or JNJ-3989 + NA for 36 weeks. At Week 36 all participants 
will have PegIFN-α2a added to their treatment regimen for 12 weeks.
a
If NA treatment completion criteria (HBsAg <10 IU/mL, and HBeAg-negative, and HBV DNA <LLOQ, 
and ALT <3x ULN) have been met at consolidation Week 12, NA will be stopped at the next scheduled 
visit (ie, FU Week 2), otherwise NA treatment will continue during the complete follow-up phase.
With the implementation of an urgent safety measure, as described in Protocol Amendment 6, participants 
previously enrolled had to immediately stop JNJ-6379 treatment, because of the removal of JNJ-6379 as 
study intervention. They were to continue with JNJ-3989+NA treatment up to the end of the induction phase 
and then enter the 12-week consolidation phase during which PegIFN-α2a was added to their treatment 
regimen.
Because of the urgent removal of JNJ-6379 as study intervention, none of the participants enrolled under 
Protocol Amendment #5 did receive JNJ-6379.
Figure 3:
Schematic Overview of Cohort 2 of the Study – As of Protocol Amendment 6
a
If NA treatment completion criteria (HBsAg <10 IU/mL, and HBeAg-negative, and HBV DNA <LLOQ, 
and ALT <3x ULN) have been met at consolidation Week 12, NA will be stopped at the next scheduled 
visit (ie, FU Week 2), otherwise NA treatment will continue during the complete follow-up phase.
As of Protocol Amendment 6, the study will continue as a single-arm study (JNJ-3989+NA+PegIFN-α2a), 
as schematized in Figure 3. All newly enrolled participants will receive JNJ-3989+NA for 36 weeks 
(induction phase) and will then enter the 12-week consolidation phase during which they will have PegIFN-
α2a added to their treatment regimen.
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Key: ALT: alanine aminotransferase; C: consolidation; DNA: deoxyribonucleic acid; FU: follow-up; HBeAg: 
hepatitis B e antigen; HBsAg: hepatitis B surface antigen; HBV: hepatitis B virus; JNJ-3989: JNJ-73763989; 
JNJ-6379: JNJ-56136379; n: number of participants; LLOQ: lower limit of quantification; NA: nucleos(t)ide analog; 
PegIFN-α2a: pegylated interferon alpha-2a; R: randomization; RGT: response-guided treatment; ULN: upper limit of 
normal; Q4W: once every 4 weeks; qd: once daily; QW: once weekly; W: week; WX: last visit of the induction phase 
(≥W36 and ≤W60) equivalent to Day 1 of the consolidation phase.
The induction and consolidation phase have been updated as below:

Before Protocol Amendment #5, enrolled participants will enter an induction phase with 
triple combination treatment (JNJ-3989 + JNJ-6379 + NA) for a response-guided treatment 
duration of ≥36 weeks to ≤60 weeks. End of the induction phase is defined by either 
meeting the study defined RGT criterion (HBsAg <10 IU/mL) or reaching study Week 60, 
whichever comes first. The RGT criterion will be assessed from Week 36 onwards at each 
study visit, and the assessment will always be based on lab results from the previous study 
visit. Participants will be randomized in a 1:1 ratio to one of the following intervention 
arms in the 12-week consolidation phase: JNJ-3989+JNJ-6379+NA+PegIFN-α2a (Cohort 
1, Arm 1) or JNJ-3989+JNJ-6379+NA (Cohort 1, Arm 2).
Note: Participants enrolled before Protocol Amendment #5 is in effect will switch to the 
new study design as soon as Protocol Amendment #5 is in effect. The details are in the 
Figure 2 Cohort 1. 

Per Protocol Amendment #5, participants will be randomized at baseline in a 1:1 ratio to 
one of the following intervention arms: JNJ-3989+JNJ-6379+NA (Cohort 2, Arm 3) or 
JNJ-3989+NA (Cohort 2, Arm 4). Upon completion of the 36-week induction phase, all 
participants will enter the 12-week consolidation phase during which they will have 
PegIFN-α2a added to their treatment regimen.
Note: With the implementation of an urgent safety measure, as described in Protocol 
Amendment 6, participants previously enrolled had to immediately switch to the new study 
design. Participants had to stop JNJ-6379 treatment immediately and continue with JNJ-
3989+NA treatment up to the end of the induction phase and will then enter the 12-week 
consolidation phase during which they will have PegIFN-α2a added to their treatment 
regimen.

As of Protocol Amendment 6, the study will continue as a single-arm study (JNJ-
3989+NA+PegIFN-α2a). All newly enrolled participants will receive JNJ-3989+NA for 36 
weeks (induction phase) and will then enter the 12-week consolidation phase during which 
they will have PegIFN-α2a added to their treatment regimen. 
At the end of the consolidation phase, all participants will enter the FU phase and stop treatment 
with JNJ-3989+PegIFN-α2a. If NA treatment completion criteria (HBsAg <10 IU/mL, and 
HBeAg-negative, and HBV DNA <LLOQ, and ALT <3x upper limit of normal [ULN]) have been 
met at consolidation Week 12, NA will also be stopped at the next scheduled visit (ie, FU Week 
2), otherwise NA treatment will continue during the complete FU phase. Participants will be 
monitored closely during the 48-week FU phase and should restart NA treatment in accordance 
with the NA re-treatment criteria.
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As of protocol Amendment #6, study intervention consists of:

200 mg JNJ-3989 (SC injection Q4W) 

245 mg tenofovir disoproxil (tablets qd) – Note: tenofovir disoproxil may be supplied as 
fumarate or maleate

180 µg PegIFN-α2a (SC injection, QW)
Note: Most participants enrolled before Protocol Amendment #6 was in effect, also received 250 
mg JNJ-6379 (tablets qd) as part of their study intervention.
All participants will be considered to have completed the study if they have completed the 
assessments of the end-of-study (EOS) visit (ie, FU Week 48).
A data review committee (DRC) will be commissioned for this study. In addition, an Independent 
Flare Expert Panel (IFLEP) will be appointed.
1.3.
Statistical Hypotheses for Trial Objectives
As this is an exploratory proof of concept (PoC) study, no formal statistical hypothesis has been 
formulated.
1.4.
Sample Size Determination
According to the initial study design, the plan was to enroll 80 participants in the study to achieve 
at least 70 participants to be randomized in a 1:1 ratio to one of the 2 intervention arms after 
completion of the induction phase. Based on the number of participants currently enrolled, 
participants who already passed the Week 36 visit and/or were randomized to the group without 
PegIFN-α2a by the time Protocol Amendment 6 is in effect, will have PegIFN-α2a added to their 
treatment regimen at the next scheduled visit and will enter the 12-week consolidation phase. For 
the purpose of the statistical analyses, all participants enrolled prior to Protocol Amendment #5 
will comprise “Cohort 1”. Protocol Amendment #5 was not implemented due to the USM and no 
participants will be receiving Protocol Amendment #5 treatment. All participants enrolled after 
approval of Protocol Amendment 6 will comprise “Cohort 2”.
With the introduction of the new study design in Protocol Amendment 6 (single-arm), no formal 
sample size re-calculation was performed. The targeted total sample size (Cohort 1 and Cohort 2 
combined) was set to approximately 60 participants. With a sample size of 33 participants in 
Cohort 2 and assuming a 10% dropout rate, 30 participants in Cohort 2 would be expected to have 
data for the primary efficacy endpoint at 24 weeks after stopping all study interventions of the 
consolidation phase and without restarting NA treatment.
If at least 15 (50%) participants are responders, this sample size will allow to conclude with 90% 
confidence that the true response rate is at least 0.34, with a confidence interval (CI) width of 0.322 
(90% CI: 0.339 - 0.661). 
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1.5.
Randomization and Blinding
Randomization
For participants in Cohort 1, a distinction will be made depending on the timing when the ISA 
protocol Amendment #6 will be in effect. Protocol Amendment #5 was not implemented due to 
the USM and no participants will be receiving Protocol Amendment #5 treatment.

If a participant of Cohort 1 is in between Week 36 and 60 and met the RGT criteria prior 
to Amendment #5 approval, then he/she will be randomly assigned in a 1:1 ratio to 1 of 2 
intervention arms (Arm 1 = JNJ-3989+JNJ-6379+NA+PegIFN-α2a; or Arm 2 = JNJ-
3989+JNJ-6379+NA). The randomization is stratified by screening HBV DNA level (≥
107 IU/mL OR <107 IU/mL) and timing of meeting the study defined RGT criterion (at 
Week 36 OR after Week 36 up to Week 48 OR after Week 48 up to Week 60 OR not met 
before or at Week 60) for participants in Cohort 1.

If a participant of Cohort 1 has not yet reached Week 36, or did not meet RGT criteria up 
to Week 60 prior to Amendment #5 approval, then he/she will not be randomized, but will 
have PegIFN-α2a added to his/her treatment regimen at the next scheduled visit. After 12 
weeks, treatment with NA, PegIFN-α2a, JNJ-3989 and JNJ-6379 will be stopped, 
regardless of the actual duration of induction (which may exceed 36 weeks).
For participants in Cohort 2 as of Protocol Amendment #6, the study will continue as a single-arm 
study (JNJ-3989+NA+PegIFN-α2a). All newly enrolled participants will receive JNJ-3989+NA 
for 36 weeks (induction phase) and will then enter the 12-week consolidation phase during which 
they will have PegIFN-α2a added to their treatment regimen.
Blinding
As this is an open-label study, blinding procedures are not applicable.
2.
GENERAL ANALYSIS DEFINITIONS
The SAP will use throughout the document the following definitions:
The term “induction phase” corresponds to the first treatment phase of the study starting with 
enrollment into induction phase of flexible duration of 36-60 weeks (inclusive) for Cohort 1 and 
starting with randomization or enrollment into the induction phase of a fixed duration of 36 weeks 
for Cohort 2.
The term “consolidation phase” corresponds to the second treatment phase of the study starting 
with the first PegIFN-α2a intake with a fixed duration of 12 weeks for both cohorts.  

Study treatment/intervention refers to: JNJ-3989, JNJ-6379, NA (TeD, or TAF) and PegIFN-
α2a prior to Protocol Amendment #6; JNJ-3989, NA (TeD, or TAF) and PegIFN-α2a as of 
Protocol Amendment #6.

Study agent refers to: JNJ-3989, JNJ-6379, and PegIFN-α2a prior to Protocol Amendment #6; 
JNJ-3989 and PegIFN-α2a as of Protocol Amendment #6.
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
Study intervention arm will be specified with Cohort 1 and Cohort 2 which are distinguished
between participants enrolled prior to or after Protocol Amendment #6 as the Protocol 
Amendment #5 was not implemented due to the USM and no participants will be receiving 
Protocol Amendment #5 treatment. All participants enrolled prior to the Protocol Amendment 
#5 will comprise Cohort 1. The participants enrolled after approval of Amendment #6 who will 
comprise Cohort 2. The Study intervention arm in the SAP will be

Cohort 1:
o
JNJ-3989 + JNJ-6379 + NA + PegIFN-α2a
o
JNJ-3989 + NA + PegIFN-α2a

Cohort 2:
o
JNJ-3989 + NA + PegIFN-α2a
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 (excluding 
PegIFN-α2a)
Induction phase 
Cohort1: 
Date of first study agent 
intake (excluding PegIFN-
α2a)
Cohort1:
Participants who are randomized: 
Min{Max[Date of first PegIFN-α2a intake, Date of 
randomization] -1 day,  cut-off dateb}
Participants who are not randomized but receive 
PegIFN-α2a: 
Min[Date of first PegIFN-α2a intake-1 day, cut-off dateb]
Participants who are not randomized and did not 
receive PegIFN-α2a: 
Min{Min[JNJ-3989 discontinuation datea, early study 
withdrawal visit date, max(Week 36 to 60 visit date from 
induction phase)] + 5 daysa, cut-off dateb} 
Cohort 2: Date of first 
study agent intake 
(excluding PegIFN-α2a)
Cohort 2: 
Participants who receive PegIFN-α2a: 
Min[Date of first PegIFN-α2a intake – 1 day, cut-off 
dateb]
Participants who did not receive PegIFN-α2a: 
Min{Min[JNJ-3989 discontinuation datea, early study 
withdrawal visit date, Week 36 visit date from induction 
phase] + 5 daysa, cut-off dateb} 
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Analysis phase
Start date
End date
Consolidation phase
Cohort 1:
Participants who receive 
PegIFN- α2a:
Date of first PegIFN-α2a 
intake
Participants who did not 
receive PegIFN- α2a:
date of any study agent 
intake after Max[Week 36 to 
60 visit date]
Otherwise: Missing
Cohort1:
Participants who did not withdraw from the study 
prior to the Consolidation Week (CW) 12 visit date:
Min{Max[last intake date of any study agent (excluding 
NA), CWc12], JNJ-3989 discontinuation datea} + 5 daysa
or cut-off dateb, whichever occurs first 
Participants who withdrew from the study prior to the 
Consolidation Week 12 visit date:
Min[JNJ-3989 discontinuation datea, early study 
withdrawal visit date] + 5 daysa or cut-off dateb, 
whichever occurs first 
Otherwise: Missing
Cohort 2:
Participants receive 
PegIFN- α2a:
Date of first PegIFN-α2a 
intake
Participants who did not 
receive PegIFN- α2a:
Date of any study agent 
intake after Week 36 visit 
date
Otherwise: Missing
Cohort 2;
Participants who did not withdraw from the study 
prior to the Consolidation Week 12 visit date:
Min{Max[last intake date of any study agent (excluding 
NA), CW12], JNJ-3989 discontinuation datea} + 5 daysa
or cut-off dateb, whichever occurs first 
Participants who withdrew from the study prior to the 
Consolidation Week 12 visit date:
Min[JNJ-3989 discontinuation datea, early study 
withdrawal visit date] + 5 daysa or cut-off dateb, 
whichever occurs first 
Otherwise: Missing
Follow-up 
Participants who did not 
withdraw informed 
consent during induction 
or consolidation phase:
Max[End date of induction 
phase, End date of 
consolidation phase] +1
Otherwise: Missing
Max[study discontinuation date, study completion date] or 
cut-off dateb, whichever occurs first
Otherwise: Missing
a Addition of 5 days is only applicable for JNJ-3989 discontinuation due to Adverse Events and Concomitant 
Medications.
b Cut-off dates will be defined to match the prespecified timepoints for DRC safety monitoring, interim analyses and the primary
and final analyses, respectively. 
c CW = Consolidation Week
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 by study phase.
2.1.2.1.
Induction Phase Relative Day
Induction start date (Induction Day 1) is defined in the Table 1 Induction phase. All efficacy and 
safety assessments during the induction phase will be assigned an analysis study day relative to 
this date.  
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The study day in the induction treatment phase (ADY) is defined as:
Induction ADY=visit date – Induction start date+1
for visits on or after induction Day 1, and 
Induction ADY=visit date – Induction start date
for visits before induction Day 1 (Screening phase).
There is no ‘induction Day 0’.
2.1.2.2.
Consolidation Relative Day
Consolidation start date (Consolidation Day 1) is defined in the Table 1 Consolidation phase. 
All efficacy and safety assessments during the consolidation phase will be assigned an analysis 
study day relative to this date.  
The consolidation study day in the consolidation treatment phase (ADY) is defined as:
Consolidation ADY=visit date – Consolidation start date+1
for visits on or after consolidation Day 1. There is no ‘consolidation Day 0’.
2.1.2.3.
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
for visits on or after FU Day 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 target day according to 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 induction (EOI), which is the 
same visit as the consolidation baseline, the end of consolidation (EOC) and the end of study (EOS) 
visits, if applicable. 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, except for the production of the spaghetti plots for which all measures 
will be displayed. The following rules will be applied: 
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.
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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 induction (i.e., EOI), end of consolidation (i.e., EOC) and end of study (i.e., EOS) time 
points will be included in all analysis over time unless stated otherwise.
Because of the different scenarios for Cohort 1 vs Cohort 2 participants, a flag called Analysis 
Timepoint EOI (ATEOI) is created for each participant to identify the potentially different time 
point of end of induction phase. Similarly, an additional variable will be generated to identify the 
analysis timepoint for End of Consolidation (ATEOC).
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 Points and Time Intervals by Analysis Phase
a) Screening and Induction Phases (Cohort 1 and 2)
Analysis 
phase
Target day
Analysis time point (Week)
Analysis time 
point
(label)
Time interval 
(Induction 
days)
Cohort 1aa
Cohort 1b b
Cohort 2 c
Screening
-∞
-1
-1
-1
Screening
<0
Induction 
1
0
0
0
Baseline
Pre-dose: 1
15
2
2
2
Week 2
[2,22]
29
4
4
4
Week 4
[23,36]
43
6
6
6
Week 6
[37,50]
57
8
8
8
Week 8
[51, 71]
85
12
12
12
Week 12
[72, 99]
113
16
16
16
Week 16
[100, 127]
141
20
20
20
Week 20
[128, 155]
169
24
24
24
Week 24
[156, 183]
197
28
28
28
Week 28
[184, 211]
225
32
32
32
Week 32
[212, 239]
253
36 a
36 b
36 c
Week 36
[240, 267]
281
40 a
N/A
N/A
Week 40
[268, 295]
309
44 a
N/A
N/A
Week 44
[296, 323]
337
48 a
N/A
N/A
Week 48
[324,351]
365
52 a
N/A
N/A
Week 52
[352, 379]
393
56 a
N/A
N/A
Week 56
[380, 407]
421
60 a
N/A
N/A
Week 60
[408, 435]
last visit in 
induction phase
61a, d
37 b, d
37 c, d
EOI d
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a If the participant was enrolled prior to the Protocol Amendment #5 was in effect (Cohort 1) and has already passed the Week 36 
visit and/or has been randomized to the group without PegIFN-α2a, then he/she will have PegIFN-α2a added to their treatment 
regimen at the next scheduled visit. The EOI visit could occur between Week 36 and Week 60 (inclusive).
b If the participant was enrolled prior to the Protocol Amendment #5 was in effect (Cohort 1) and did not pass the Week 36 visit, 
he/she will have PegIFN-α2a added to their treatment regimen at Week 36. 
c If the participants was enrolled after the Protocol Amendment #6 (Cohort 2), he/she will have PegIFN-α2a added to their 
treatment regimen at Week 36. 
d End of induction phase (EOI) visit will be the last visit in Induction phase. 
N/A=not applicable
b) Consolidation Phases (Cohort 1 & 2)
Analysis
phase
Target day
Analysis time point (Week)
Consolidation 
Analysis time 
points
(label)
Time interval 
(Consolidation 
days) h
Cohort 1ae
Cohort 1bf
Cohort 2g
Consolidation 
1
ATEOIi+1
36
36
C Baseline
1
15
ATEOIi+1
38
38
C Week 2
[1,22]
29
ATEOIi+3
40
40
C Week 4
[23,36]
43
ATEOIi+5  
42  
42  
C Week 6
[37,50]
57
ATEOIi+7
44 
44 
C Week 8
[51, 71]
85
ATEOIi+11 
48 
48 
C Week 12
[72, 99]
last visit in 
consolidation phase
ATEOIi+12e, j
49f, j
49g, j
EOCj
e Analysis time point for Cohort 1 will be based on end date of the induction phase in the Table 2 a) above.
f Analysis time point for Cohort 1 will be based on end date of the induction phase in the Table 2 a) above.
g Analysis time point for Cohort 2 will be based on end date of the induction phase in the Table 2 a) above.
h Relative to Consolidation start date (see the Table 1).
i ATEOI = Analysis time point (Week) for EOI.
j End of consolidation (EOC) visit will be the last post baseline visit in the Consolidation phase.
c) Follow-Up Phase (Cohort 1 & 2)
Analysis
phase
(FU)
Target day
Analysis time point (Week)
Analysis time 
point
(label)
Time 
interval 
(FU days) n
Cohort 1ak
Cohort 1bl
Cohort 2m
Follow-
up
15
ATEOCo+1
50
50
FU Week 2
[1, 22]
29
ATEOCo+3 
52
52
FU Week 4
[23, 43]
57
ATEOCo+7 
56
56
FU Week 8
[44, 71]
85
ATEOCo+11 
60
60
FU Week 12
[72, 99]
113
ATEOCo+15 
64
64
FU Week 16
[100, 127]
141
ATEOCo+19 
68
68
FU Week 20
[128, 155]
169
ATEOCo+23 
72
72
FU Week 24
[156, 183]
197
ATEOCo+27
76
76
FU Week 28
[184, 211]
225
ATEOCo+31
80
80
FU Week 32
[212, 239]
253
ATEOCo+35 
84
84
FU Week 36
[240, 267]
281
ATEOCo+39
88
88
FU Week 40
[268, 295]
309
ATEOCo+43
92
92
FU Week 44
[296, 323]
337
ATEOCo+47 
96
96
FU Week 48
[324, +∞]
last visit in the 
study
999k, p
999l, p
999m, p
EOSp
k, Analysis time point for Cohort 1 will be based on end date of the induction and consolidation phase.
l Analysis time point for Cohort 1 will be based on end date of the induction and consolidation phase.
m Analysis time point for Cohort 2 will be based on end date of the induction and consolidation phase.
n Relative to follow-up start date.
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o ATEOC = Analysis time point (Week) for EOC.
p   End of study (EOS) visit (last available data during the follow-up) will be the last visit in the study.
2.2.
Baseline
2.2.1.
Study 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 the induction phase. 
In case the first administration time is missing, the first observed measurement on Induction Day 
1 will be used as the baseline measurement. If no observed measurement on Induction Day 1, the 
last observed measurement before Induction Day 1 will be used as the baseline assessment.
The baseline defined above is the study baseline and will be used for all analysis throughout the 
induction, consolidation and follow up phases.
2.2.2.
Consolidation Baseline Timepoint
For the participants who receive PegIFN- α2a, the consolidation baseline assessment is defined as 
the date of first PegIFN- α2a intake. For the participants who did not receive PegIFN- α2a, the 
consolidation baseline will be defined as the date of any study agent intake after Max[Week 36 to 
60 visit date] for Cohort 1 and the date of any study agent intake after Week 36 visit date for Cohort 
2.
2.3.
Analysis Sets
Due to a potential impact of future Coronavirus Disease 2019 (COVID-19) pandemics on the study 
data collection, study treatment adherence and study conduct, the modified treated (mTreated) 
analysis set and the modified intent-to-treat analysis (mITT) set are defined to target the estimation 
of the treatment effect without the pandemic-related influences.
If there is a relevant difference (5% of total population or more participants in total) from the ITT 
analysis vs the mITT analysis set, then, the mTreated, and mITT will be used. However, if there 
is less than 5% difference, then the Treated and ITT, will be used.
Treated analysis set: All participants who received at least 1 dose of study treatment within this 
ISA.
Modified Treated analysis set (mTreated): All participants who received at least one dose of study
treatment, excluding participants who have no efficacy assessment for the primary endpoint (24
weeks after stopping all study treatment of the consolidation phase) because of COVID-19 or 
similar pandemics related reasons (e.g., 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 analysis 
endpoint, etc.). 
Intent-to-Treat analysis set (ITT): All participants who were randomized or enrolled and who 
received at least 1 dose of consolidation phase study intervention within this ISA. 
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Modified Intent-to-Treat analysis set (mITT): All participants who were randomized or enrolled
and received at least one dose of the consolidation phase study intervention 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 FU Week 24
or had no efficacy assessment for the primary endpoint (24 weeks after stopping all study 
interventions of the consolidation phase). 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 analysis endpoint, etc.
Safety analysis set: All participants who received at least one dose of study intervention.
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 24 weeks after stopping all study interventions of the consolidation phase. 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: Selected Major 
Protocol Deviations for Analysis Purposes. Participants will be analyzed according to the study 
intervention they were randomly assigned to.
Pharmacokinetics analysis set (PK): The PK analysis set is defined as subjects who have received 
at least 1 dose of any of the study interventions and have at least 1 valid blood sample drawn for 
PK analysis.
2.4.
On-treatment and off-treatment periods 
The on-treatment period begins with the first drug intake date and finishes with the maximum 
between:

Last dose of NA + 2 days,

Last dose of PegIFN α2a+ 10 days,

Last dose of JnJ-3989 + 28 days.
The off-treatment period stops if the NA re-treatment starts.
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2.5.
Definition of Subgroups
The following demographic and screening/baseline characteristics will be used to define subgroups 
of interest for efficacy analyses (primary endpoint and key secondary endpoint) and selected safety 
analyses (see Section 6). 
2.5.1.
Subgroups for Efficacy Analyses

Age categories: 18 years -≤30 years, >30 years 

Race: Asian, non-Asian

ALT level at baseline: normal, >ULN

HBsAg level at baseline:

<10,000 IU/mL

≥10,000 IU/mL-<100,000 IU/mL

≥100,000 IU/mL

HBV DNA level at screening:

<107 IU/mL

≥107 IU/mL

Immune tolerant at baseline 

Yes: HBV DNA level > 7 log10 IU/mL and ALT ≤ULN

No: HBV DNA level ≤7 log10 IU/mL or ALT >ULN

Pegylated Interferon responder definition #1

First, compare the ALT maximum value between Consolidation Baseline and FU Week 
4 with the last value of ALT before or at the first Pegylated Interferon intake date. If the 
increase in ALT is >=100%, then the patient is considered as a “responder” to Pegylated 
Interferon. If the increase in ALT is <100%, then the patient is considered as a “non-
responder” to Pegylated Interferon. Only patients who have received at least one dose of 
Pegylated interferon are considered.

Pegylated Interferon responder definition #2
A linear regression model using the four last HBsAg measures before Consolidation Baseline is 
performed to estimate predicted value of HBsAg at CW12. If a decline higher that 0.5 log10 
HBsAg is observed compared to the predicted value, then the patient is considered as a “responder” 
to Pegylated Interferon. Only patients who have received at least one dose of Pegylated interferon 
are considered.
2.5.2.
Subgroups for Safety Analyses

Sex: Male, Female

Race: Asian, non-Asian
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
Body mass index (BMI) group: Underweight <18.5, Normal ≥18.5 - <25, Overweight ≥25 -
<30, and Obese ≥30

Age categories: 18 years - ≤30 years, >30 years 
2.6.
Missing and Partial Dates Imputation Rules
For analysis and reporting purposes, missing or partial dates in adverse event (AE onset date; AE 
end date), HBV diagnosis and infection dates, concomitant therapies (start date; end date) will be 
imputed according to the rules in the following subsections. The original, non-imputed, dates will 
be used only in listings.
2.6.1.
Adverse Event Onset Date and Resolution Date
Partial AE onset dates will be imputed as follows:

If the AE onset date is missing the day only, it will be set to:

The first day of the month when the AE occurred, if month/year of the AE onset date is 
different than the month/year of the first administration of study treatment date in 
induction phase.

The day of the first study treatment administration in induction phase, if the month/year 
of the AE onset date is the same as the month/year of the first study treatment 
administration in induction phase but the month/year of the AE resolution date is 
different.

The earliest between the day of the first study treatment administration date in induction 
phase 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 in induction phase 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 treatment 
administration in induction phase.

Month and day of the first study treatment administration in induction phase, 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 treatment 
administration in induction phase.

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.
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
Completely missing resolution dates will not be imputed.
2.6.2.
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.
2.6.3.
Concomitant Medication Dates
In case of partially missing concomitant medication start/end dates, the following imputation rules 
will be applied:

the 15th of the month, if only the day is missing.

the 30th of June, if only the year is available.

if the imputed start date is after the concomitant medication end date, further adjustment of the 
imputed start 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 (Induction 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 (Induction 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.
2.6.4.
Dates of Alcohol Consumptions
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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
if end date is completely missing and marked as Ongoing then impute with Date of first study 
agent intake (excluding PegIFN-α2a) for Cohort 1 and randomization date or date of first study 
agent intake (excluding PegIFN-α2a) for Cohort 2. Otherwise, no imputation if completely 
missing
3.
DATA REVIEW COMMITTEE AND INTERIM ANALYSES
3.1.
Data Review Committee
The DRC will conduct periodic data reviews to ensure the continuing safety of the study 
participants during the entire course of the study. The DRC will also review the results of the 
primary and interim analyses (IAs) comprising cumulative safety and selected efficacy endpoints
for providing the sponsor with further insight and interpretation of the data. Details on the roles 
and responsibilities of the DRC, as well as data reviews and the flows of communication, are
documented in the DRC charter.
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 DRC 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 5.3.1.1.9.
3.3.
Data Reviews and Interim Analyses
3.3.1.
Data Reviews
Data review meetings will take place as follows:

The first data review will be performed after approximately 20 participants completed 4 weeks 
of treatment.

The second data review will be performed after approximately 40 participants completed 12 
weeks of treatment.

Thereafter, data reviews will occur quarterly.

An additional data review will occur once 10 participants have completed 4 weeks of 
consolidation phase treatment with PegIFN-α2a. This data review may be part of a quarterly 
data review/the second data review if the timing of the 10 participants target coincides with a 
scheduled quarterly review/the second data review, otherwise, this data review will occur as a 
separate review.
Safety data comprising AEs, SAEs, AEs of special interest, laboratory data, electrocardiogram 
(ECG) data and any other data applicable for the study, will be summarized, plotted and provided 
as appropriate.  
Besides the safety variables listed above, selected efficacy parameters for review may include 
values and changes from baseline over time in HBV disease blood markers (e.g., HBV DNA, 
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HBeAg, and HBsAg), proportion of participants with virologic breakthrough, flares, and 
proportion of participants with HBsAg seroclearance.
3.3.2.
Interim Analyses
Two interim analyses (IAs) are planned to assess safety and evaluate the time course of different 
safety and efficacy 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 
combination regimens.  
The first IA is planned when 50% of the participants have completed Week 24 of the induction 
phase or discontinued earlier. The second IA is planned when all participants have completed 
Week 48, which corresponds to Consolidation Week 12, or discontinued earlier.
The primary analysis will be conducted at the time when all participants have completed FU 
Week 24 or discontinued earlier.
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.
The final analysis will be performed when all participants have completed the last study visit (FU 
Week 48) or discontinued earlier.
3.3.3.
Analysis Overview of Data Reviews, Interim Analysis, Primary and 
Final Analyses
The overview of data domains and specific endpoints that will be provided to the DRC for review 
is provided in Table 3. Details on the type of summaries and analyses of both efficacy and safety 
variables are described in the following sections.
Table 3:
Overview of Data Summaries and Different Analyses: Data Reviews, Planned Interims, Primary 
and Final Analyses
DR1
(N=20 w/
Induction 
Week 4 
data)
DR2
(N=40 w/ 
Induction 
Week 12 
data)
DR
quarterlya
IA1
Week 24 data
(50% of the 
total 
participants)
IA2b
Week 48 data
(100% of the 
total 
participants)
Primary 
analysis/ FU 
Week 24 
(100% of the 
total 
participants)
Final 
analysis/ FU 
Week 48 
(100% of the 
total 
participants)
Subject Information 
Baseline & Demographic 
characteristics
X
X
X
X
X
X
X
Disposition and Study 
Populations 
X
X
X
X
X
X
X
Extent of Exposure 
X
X
X
X
X
X
X
Safety
TEAEs, SAEs, AE of 
interest, fatal AEs, AEs 
causing treatment 
discontinuation
X
X
X
X
X
X
X
Laboratory Tests
X
X
X
X
X
X
X
ECG
X
X
X
X
X
X
Vital signs
X
X
X
X
X
X
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DR1
(N=20 w/
Induction 
Week 4 
data)
DR2
(N=40 w/ 
Induction 
Week 12 
data)
DR
quarterlya
IA1
Week 24 data
(50% of the 
total 
participants)
IA2b
Week 48 data
(100% of the 
total 
participants)
Primary 
analysis/ FU 
Week 24 
(100% of the 
total 
participants)
Final 
analysis/ FU 
Week 48 
(100% of the 
total 
participants)
Efficacy   
Proportion of participant 
with HBsAg seroclearance 
over time during FU phase
X
X
X
X
Proportion of participants 
with HBsAg seroclearance 
over time during induction 
phase
X
X
X
X
X
X
Proportion of participants 
with HBsAg seroclearance 
over time during 
consolidation phase
X
X
X
X
X
Proportion of participants 
with HBV DNA <LLOQ 
X
X
X
X
X
X
Proportion of participants 
with HBsAg seroconversion
X
X
X
X
X
Proportion of participants 
with HBeAg seroconversion
X
X
X
X
X
HBsAg, HBeAg, HBV 
DNA: 
     Values and 
changes over 
time
      Proportions of 
participants reaching given 
cut-offs
X
X
X
X
X
X
Virologic breakthrough
X
X
X
X
X
X
X
Flaresc: Viral, Biochemical, 
Clinical 
X
X
X
X
X
X
X
Correlation baseline 
characteristics with 
baseline/on-treatment viral 
blood markers
X
X
X
X
HBV RNA and HBcrAg
     Values and 
changes over 
time
      Proportions of 
participants reaching given 
cut-offs
X
X
X
X
X
Change in T-cell responsed
X
X
X
Time to event analyses
X
Viral Genome Sequence Analysis e
Viral genome sequence
X
X
HBV genotype
X
X
Hepatitis B Quality of Life
HRQoL:
       Values and change over 
time
       Proportion of 
participants experiencing a 
clinically important 
improvement or worsening 
from baseline
X
a Applies to the additional DR of 10 participants having completed 4 WKs of consolidation phase treatment
b Applicable to potential additional IAs before the final analysis
c Viral and Clinical flares will be summarized for the DR quarterly and IAs
d If there are available data, it will be analyzed
e A separate virology report may be prepared
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4.
SUBJECT INFORMATION
All the summaries will be done by cohort on the Treated, ITT, and safety analysis set unless 
specified otherwise for a specific display. The PegIFN-α2a ITT, mTreated, mITT and 
mPegIFN-α2a ITT analysis sets may be used as indicated in Section 2.3.
4.1.
Disposition Information
The number and percentage of participants who are screened, screened failure and reason for that 
screening failure will be tabulated by cohort and combined cohort (JNJ-3989+NA+PegIFN-α2a). 
Only an all participants group (total N) will be provided.
For Cohort 1, a summary of the number of participants enrolled in the induction phase, enrolled 
and not treated in the induction phase, randomized/enrolled and treated in the consolidation phase, 
randomized/enrolled but not treated in the consolidation phase, entered in the FU phase, entered 
and not met the NA treatment completion criteria, entered and not retreated with NA in the FU 
phase, will be summarized. 
For Cohort 2, a summary of the number of participants, randomized/enrolled in the induction 
phase, randomized/enrolled and not treated in the induction and/or consolidation phase, entered in 
the FU phase, entered and not met the NA treatment completion criteria, entered and not retreated 
with NA in the FU phase, will be summarized. 
Completion/withdrawal information, study disposition and treatment disposition will be 
summarized by cohort. 
An overview of the study disposition will be provided by analysis phase, cohort 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 analysis phase 
(i.e., induction phase, consolidation phase and follow-up phase) by cohort 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 IAs
or primary analysis cut-off (except the final analysis) will be presented by analysis phase, cohort
and overall. The incidences of treatment discontinuation reasons will also be summarized by
analysis phase, cohort and overall. 
A listing including information (i.e., cohort, the date of last study visit, the last analysis phase and 
time point [phase and week], the date of discontinuation and the reason) on participants which 
prematurely discontinue from the study and/or study treatment will be included. Information on 
NA discontinuation and/or re-treatment will also be included.
4.2.
Demographic and Baseline Characteristics
Tabulations of demographic and baseline characteristics will be presented by cohort, combined 
cohort and overall. Continuous variables will be summarized by descriptive statistics including the 
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number of participants, mean, standard deviation, standard error, median, range and interquartile 
range. Categorical/binary variables will be summarized by counts and percentages.
4.2.1.
Demographic Characteristics
The following demographic characteristics will be summarized by cohort, combined cohort and 
overall. 

Sex: Male, Female, Undifferentiated, Unknown

Age (years)

Age categories: 18 years - ≤30 years, >30 - ≤45years, >45 years - ≤55 years

Race: American Indian or Alaska Native, Asian (Japanese, Other Asian), Black or African 
American, Native Hawaiian or Other Pacific Islander, White, Multiple, Not reported

Ethnicity: Hispanic or Latino, Not Hispanic or Latino, Not Reported

Region: Asia (Japan and Taiwan), Europe (France, Germany, Russia, Spain, Turkey and UK), 
North America (Canada and US)

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)

BMI group: Underweight <18.5, Normal ≥18.5-<25, Overweight ≥25-<30 and Obese ≥30           

History of Tobacco use: Yes/No 

Alcohol consumption:

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., HBeAg, HBsAg, HBV DNA, HBV RNA, HBcrAg, anti-
HBs antibody, anti-HBe antibody), baseline values are used unless specified differently.

Prior exposure to NA versus treatment 

Duration of HBV infection (Years) = (date of first study agent administration – date of HBV 
infection +1)/365.25; rounded to 1 decimal

Time since HBV diagnosis (Years) = (date of first study agent administration – 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
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
HBeAg at baseline (qualitative): positive, negative, borderline

HBeAg at baseline (quantitative): values in IU/mL and log10 IU/mL 

HBeAg category at baseline (quantitative: IU/mL):

Participants with HBeAg > ULOQ

Participants with HBeAg ≤ULOQ

Participants with HBeAg <3 log10 IU/mL

Participants with HBeAg ≥3 log10 IU/mL

Participants with HBeAg <4 log10 IU/mL

Participants with HBeAg ≥4 log10 IU/mL

HBsAg at baseline (qualitative): positive, negative

HBsAg at baseline (quantitative): values in IU/mL and log10 IU/ml  

HBsAg category at baseline (quantitative: IU/mL):

Participants with HBsAg > ULOQ

Participants with HBsAg ≤ULOQ

Participants with HBsAg <1,000 IU/mL

Participants with HBsAg ≥1,000 IU/mL-<10,000 IU/mL

Participants with HBsAg ≥10,000 IU/mL-<100,000 IU/mL

Participants with HBsAg ≥100,000 IU/mL

HBV DNA at baseline (quantitative): values in IU/mL and log10 IU/mL

HBV DNA category at baseline (quantitative: IU/mL):

Participants with HBV DNA < 107 IU/mL

Participants with HBV DNA ≥ 107IU/mL

HBV RNA at baseline (quantitative): values in copies/mL and log10 copies/mL

HBV RNA category at baseline (quantitative: copies/mL):

Participants with HBV RNA target not detected (TND)

Participants with HBV RNA < limit of detection (LOD)

Participants with HBV RNA < 1,000 copies /mL

Participants with HBV RNA ≥1,000-< 10,000 copies /mL

Participants with HBV RNA ≥10,000-<1,000,000 copies /mL

Participants with HBV RNA ≥1,000,000-<10,000,000 copies /mL

Participants with HBV RNA ≥10,000,000 copies /mL

Participants with HBV RNA < LLOQ
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
Participants with HBV RNA ≥LLOQ

Hepatitis B core related antigen (HBcrAg) at baseline (quantitative): values in 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

Participants with HBcrAg≥4 log U/mL-<9 log U/mL

Participants with HBcrAg≥9 log U/mL

Alanine Transferase (ALT) at baseline:

Baseline ALT values (U/L)

Participants with normal ALT

Fibroscan score at baseline (quantitative: kPa)

Fibrosis Stage: F0, F1, or F2

HBV genotype: Genotype A, B, C, D, E, F, G, H, I, J and Unknown 

Anti-HBs antibody (quantitative) at baseline: values in mIU/mL and log10 mIU/mL

Anti-HBs antibody category at baseline (quantitative: mIU/mL):

Participants with Anti-HBs antibody level > LLOQ

Participants with Anti-HBs antibody level ≤LLOQ

Participants with Anti-HBs antibody level >10 mIU/mL

Participants with Anti-HBs antibody level >100 mIU/mL

Anti-HBs antibody (qualitative) at baseline: positive, negative

Anti-HBe antibody (qualitative) at baseline: positive, negative
4.3.
Medical History
A tabulation of the general medical history coded terms will be provided by body system class and 
by cohort.
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 Induction Day 1 regardless of when dosing of the medication ended. 
(ii)
Concomitant medications are defined as medications received on or after Induction
Day 1, medication that was received before initial dosing and continued after initial 
dosing of the study interventions, or medication with missing stop date.  
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Medication that started before the Induction Day 1 and continued afterwards will be summarized 
both as prior and, separately, as concomitant medication. All concomitant medications will be 
displayed by cohort and 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:

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 cohort. The 
proportion of participants who received at least one concomitant medication will also be 
summarized. 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 by cohort, combined cohort and overall. 
Major protocol deviations will be based on clinical review, but not limited to, the following 
criteria: (1) entered but did not satisfy inclusion/exclusion criteria, (2) received wrong treatment 
or incorrect dose, (3) received a disallowed concomitant treatment, (4) efficacy not done at 
schedule visit, (5) developed withdrawal criteria but not withdrawn, (6) 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 cohort for the Treated, and 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: Selected Major Protocol Deviations for Analysis Purposes ) will be identified and 
finalized prior to the primary database lock to define the Per-Protocol analysis set (Section 2.3). 
The number and percentage of ITT participants who are included in the PP analysis set will be 
summarized, 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 induction and consolidation phase will be 
calculated by each study treatment separately and summarized descriptively. Exposure of each 
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study treatment will also be summarized across induction and consolidation phase. The duration 
of treatment with NA will be summarized also for the follow up phase by cohort. 
Because of the different route and frequency of treatment administration across the 4 study 
treatments (for JNJ-3989 one subcutaneous injection once every 4 weeks, and for JNJ-6379 and 
for NA once daily tablet, and for PegIFN-α2a one subcutaneous injection weekly) the total duration 
of exposure (weeks) will be calculated for each study treatment as follows:
Induction and consolidation phase separately:

JNJ-3989: [Min((Date of the last JNJ-3989 injection in the given phase+27 days), Date of trial 
disposition, cut-off date) – Date of the first JNJ-3989 injection in the given phase + 1] / 7

JNJ-6379: [Min (Date of the last JNJ-6379 administration in the given phase, Date of treatment 
disposition for JNJ-6379) – Date of the first JNJ-6379 administration in the given phase + 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 the first NA administration in the given phase + 1] / 7
Consolidation phase only:

PegIFN-α2a: [Min (Date of the last PegIFN-α2a administration in the given phase +6 days, 
Date of discontinuation from PegIFN-α2a, Date of trial disposition, Date of clinical cut-off
date) – Date of the first PegIFN-α2a administration in the given phase + 1] /7
Total exposure to JNJ-3989, JNJ-6379, and NA for the overall treatment period (induction and 
consolidation phase) will be calculated as the sum of total exposure in induction, and consolidation 
phase.
Cut-off dates will be defined to match the prespecified timepoints for DRC periodical data reviews, 
interim analyses and the primary analysis, respectively (see Section 3).
The number and percentage of participants who skipped any dose of JNJ-3989 or JNJ-6379 or NA
or PegIFN-α2a will be summarized separately for each study treatment during the induction and 
consolidation phase. Additionally, the number and percentage of participants who missed 2 or 
more JNJ-3989 injections, or who missed more than 5 doses of NA within a four-week period will 
be presented.
For FU, the total duration will add up the weeks of NA treatment. Those participants who stopped 
NA treatment at or before consolidation Week 12 (end of consolidation phase) 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 for each study treatment
except NA.
Treatment compliance for induction and consolidation phase (%) is defined as follows.
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Induction Phase (Cohort 1)

For JNJ-3989: (Total number of injections received/Total number of injections supposed to be 
received a) * 100%

For JNJ-6379: (Total medication intake / 4 *7 *X) * 100%

As the 250 mg daily dose of JNJ-6379 consists of 4 tablets (2 tablets of 100 mg strength 
and 2 tablets of 25 mg strength). The numerator representing the total medication intake 
for JNJ-6379 is calculated as:

Total medication intake = (Total number of tablets dispensed–Total number of tablets
returned).
a for each participant, the individual RGT length (weeks) determines the number of injections 
supposed to be received.
X: is the number of weeks on 6379 (end date of JNJ-6379 – start date of JNJ-6379) for each 
participant
Treatment compliance during induction phase will also be summarized descriptively by the timing 
of meeting the RGT criterion (categories are defined in Section 5.3.1.1.1). 
Induction Phase (Cohort 2)

For JNJ-3989: (Total number of injections received/ 9) * 100%
Consolidation Phase

For JNJ-3989: (Total number of injections received/ 3) * 100%

For PegIFN-α2a: (Total number of injections received/ 12) * 100%
5.
EFFICACY
All efficacy data will be analyzed by cohort, combined cohort and overall, analysis phase and over 
time (when applicable). The primary analysis set will be the ITT analysis set for the primary 
efficacy endpoint, and the Treated analysis set for the rest efficacy endpoints. A secondary analysis 
set (combined cohort) will be performed combining the data from participants who received 
PegIFN-α2a but not JNJ-6379 in Cohort 1 with data of Cohort 2 by analysis phase, the PegIFN-
α2a ITT analysis set will be used. This combined cohort is for the selected efficacy endpoints. 
The mTreated, mITT, and mPegIFN-α2a ITT will be used if relevant difference between the sets 
exist (see Section 2.3). Selected efficacy endpoints will be also analyzed using the PP analysis set
(see definition in Section 2.3). Efficacy assessments over time will be performed at the analysis 
time points defined in Section 2.1.
5.1.
Analysis Specifications
All efficacy endpoints will be summarized descriptively by analysis phase, cohort, combined 
cohort and overall. In general, continuous variables will be summarized using descriptive statistics 
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including the number of participants, mean, standard deviation (SD), standard error (SE), 
confidence interval (CI), median, and range. The confidence level is detailed in Section 5.1.1.
Binary or categorical variables will be summarized using the number and percentage of 
participants in each category. For time-to-event variables, a summary table including number of 
participants included in the analysis, number of participants censored, 25th and 75th percentiles and 
median time-to event will be shown. Graphic displays will also be used to summarize the data. 
Participants who have taken at least one dose of JNJ-6379 during induction phase could be referred 
as being part of Trt-1 group and the other participants who have never taken JNJ-6379 as being 
part of Trt-2 group.
5.1.1.
Level of Significance
Due to exploratory nature of this study, no formal test will be performed. Only two-sided 90% CIs 
will be provided.  
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 summarized in Table 4.
Table 4:
Data Handling Rules for HBV Virology and Serology Assessments
HBV 
parameter
LLOQ
ULOQ
Imputed Values
   If value< LLOQ
             If value> ULOQ
HBsAg
0.05 IU/mL
249,750.00 IU/mL
with dilution
0.025 IU/mL (a)
274,725.00 IU/mL (b) with 
dilution
HBeAg
0.11 IU/mL
7,000.00 IU/mL with 
dilution
0.055 IU/mL (a)
7,700.00 IU/mL(b) with 
dilution
HBcrAg*
3.0 log10
U/mL
7.0 log10 U/mL w/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) IU/mL w/o 
dilution
HBV RNA*
LLOQ = 2.939 
log10 cp/mL
(i.e., 869 
cp/mL)
LOD = 1.398 
log10 cp/mL 
NAP
If <LOD or target not 
detected then 1.114 
log10 cp/mL (i.e., 13
cp/mL)
NAP
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HBV 
parameter
LLOQ
ULOQ
Imputed Values
   If value< LLOQ
             If value> ULOQ
(i.e., 25
cp/mL)
Anti-HBs
5 mIU/mL
10000.0 mIU/mL
2.5 mIU/mL(a)
11000.0 mIU/mL (b)
* As new assays become available different data handling rules may apply.
** For HBV DNA <LLOQ: Spaghetti plots showing absolute values, the imputed value will be 15 IU/mL for both 
target detected and target not detected. All other tables, listings and figures, will be produced using 15 IU/mL as an 
imputed value if target is detected and 5 IU/mL if target is not detected. 
Key: NAP=Not applicable
(a) LLOQ/2
(b) ULOQ+(ULOQ/10)
(c) If the original result > ULOQ, then take the re-test value (i.e., diluted result). If the diluted result is not 
available, use the imputed value 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 efficacy endpoint, also known as “functional cure”, is the proportion of participants 
with HBsAg seroclearance 24 weeks after stopping all study interventions at the end of the 
consolidation phase and without restarting NA treatment.
5.2.2.
Analysis Methods
All participants who do not achieve HBsAg seroclearance 24 weeks off-treatment during FU
and/or require NA re-treatment within any time prior to FU Week 24 are considered treatment 
non-responders for the purpose of the primary endpoint analysis. The primary endpoint will be 
summarized with the point estimate and its 90% CI by using the Clopper-Pearson exact method
by cohort.
5.2.2.1.
Missing Data Handling
Missing data will be handled with three approaches: observed data analysis, missing as non-
responder, and LOCF.
5.2.2.1.1.
Observed Case Data 
Participants who have missing HBsAg values at FU Week 24 will not be used for the analysis.
5.2.2.1.2.
Missing as Non-Responder
Participants who do not have HBsAg data in analysis window of FU Week 24 will be defined as 
non-responders.
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5.2.2.1.3.
Last Observation Carried Forward (LOCF)
The third approach to handle missing data is based on the LOCF principle (single imputation). If 
the HBsAg value at FU Week 24 is missing and NA treatment has not been restarted, then LOCF 
in conjunction with the next available observation imputation will be applied. The available non-
missing HBsAg value closest to the time point which is no earlier/later than 12 weeks prior/after 
to the FU Week 24 time point will be used. Participants who do not have data within the analysis 
window of ±12 weeks around the FU Week 24 assessment will be defined as non-responders.
5.2.3.
Subgroup Analyses of Primary Efficacy Endpoint
The primary efficacy endpoint will be summarized descriptively using the number and percentage 
of participants by cohort by each subgroup of interest (Section 2.5.1). 
5.2.4.
Per-Protocol Analysis
The analysis of the primary efficacy endpoint will be performed on the PP set, as defined in
Section 2.3, using observed case data.
The proportion of responders will be summarized descriptively using the number and percentage 
of participants by cohort.
5.3.
Secondary Endpoints
See Section 1.1 for a list of the secondary endpoints.
5.3.1.
Definitions
5.3.1.1.
Binary Endpoints
5.3.1.1.1.
Reaching HBsAg <10 IU/mL During the Induction Phase
The participant has reached HBsAg <10 IU/mL at the end the induction phase, and the assessment 
will always be based on lab results.
5.3.1.1.2.
NA Treatment Completion Criteria
5.3.1.1.2.1.
NA Treatment Completion Criteria During the Study
NA treatment completion criteria are defined as follows:

HBsAg <10 IU/mL, and 

HBeAg-negative (<LLOQ), and 

HBV DNA <LLOQ, and 

ALT <3x upper limit of normal [ULN]
The NA completion criteria will be assessed based on clinical laboratory tests and summarized at 
consolidation Week 12 and during FU phase.
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5.3.1.1.2.2.
NA Re-Treatment Criteria and Monitoring After Stopping of NA
Participants who meet the NA treatment completion criteria 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/aspartate aminotransferase (AST), HBV DNA, and total and direct bilirubin within a 
maximum of 7 days from receipt of the data and further repeats as necessary (i.e., 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 (i.e., 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, International Normalized Ratio (INR), albumin, 
and HBV DNA on a weekly basis until ALT and AST levels have returned to <5x ULN.
After stopping NA treatment, participants should re-start NA treatment:

Immediately with signs of decreasing liver function based on laboratory findings (eg, INR, 
direct bilirubin) or clinical assessment (e.g., 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.  
In case NA treatment is re-started, participants will be followed until the end of the study or until 
clinical stabilization, whichever comes later.
Participants who actually re-started NA treatment and monitoring after stopping of NA will be 
identified based on the ‘Study Drug Administration for NA’ CRF page.
Participants who meet the NA re-treatment criteria will be identified based on the CRF page of 
‘NA Re-treatment Criteria Assessment’.
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5.3.1.1.3.
HBsAg Seroclearance  
Seroclearance of HBsAg is defined as a (quantitative) 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.
HBsAg seroclearance will be also evaluated when assessed at all time points after stopping all 
study interventions (regardless when intervention was stopped) and without restarting NA 
treatment.
If the HBsAg value at FU Week 12 is missing, the next available observation will be used. The 
next non-missing lab test no later than FU Week 24 will be imputed.
If the HBsAg value at FU Week 24 is missing, the LOCF in conjunction with the next available 
observation imputation approach will be used. The available non-missing lab test closest to FU 
Week 24 which is no earlier/later than 12 weeks from the actual time point of interest (FU Week 
12 and FU Week 36, respectively) will be imputed.
If the HBsAg value at FU Week 36 is missing, the LOCF in conjunction with the next available 
observation imputation approach will be used. The available non-missing lab test closest to FU 
Week 36 which is no earlier/later than 12 weeks from the actual time point of interest (FU Week 
24 and FU Week 48, respectively) will be imputed.
If the HBsAg value at FU Week 48 is missing, the LOCF will be used with the condition that no 
value earlier than FU Week 36 may be carried forward.
For all other time points, seroclearance will be analyzed as observed case without imputation.
5.3.1.1.4.
HBeAg Seroclearance  
Seroclearance of HBeAg is defined as a (quantitative) HBeAg level <LLOQ and is assessed for 
participants HBeAg positive at baseline only. 
5.3.1.1.5.
HBsAg and HBeAg Seroconversion
Seroconversion of HBsAg is defined as having achieved HBsAg seroclearance (as quantitative 
HBsAg level <LLOQ) and appearance of anti-HBs antibodies, defined as a baseline anti-HBs 
(quantitative) <LLOQ and a post-baseline assessment ≥LLOQ.
Seroconversion of HBeAg is defined as having achieved HBeAg seroclearance (as quantitative
HBeAg level < LLOQ) and appearance of anti-HBe antibodies, defined as a baseline anti-Hbe 
antibodies (qualitative) with a "NEGATIVE" result and a post-baseline assessment with 
“POSITIVE” result. 
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The seroconversion will only be assessed at the time points when the anti-HBs or anti-HBe 
antibodies assessment is available. 
5.3.1.1.6.
Suppressed HBV DNA 
HBV DNA < LLOQ (HBV DNA detectable or HBV DNA TND) will be evaluated all time points 
when assessed after stopping all study interventions at the end of the consolidation phase and 
without restarting NA treatment.
HBV DNA < LLOQ (HBV DNA detectable or HBV DNA TND) will be also evaluated when 
assessed at all time points after stopping all study interventions (regardless when intervention was 
stopped) and without restarting NA treatment.
If the HBV DNA value at FU Week 12 is missing, the next available observation will be used. The 
next non-missing lab test no later than FU Week 24 will be imputed.
If the HBV DNA value at FU Week 24 is missing, the LOCF in conjunction with the next available 
observation imputation approach will be used. The available non-missing lab test closest to FU 
Week 24 which is no earlier/later than 12 weeks from the actual time point of interest (FU Week 
12 and FU Week 36, respectively) will be imputed.
If the HBV DNA value at FU Week 36 is missing, the LOCF in conjunction with the next available 
observation imputation approach will be used. The available non-missing lab test closest to FU 
Week 36 which is no earlier/later than 12 weeks from the actual time point of interest (FU Week 
24 and FU Week 48, respectively) will be imputed.
If the HBV DNA value at FU Week 48 is missing, the LOCF approach will be used with the 
condition that no value earlier than FU Week 36 may be carried forward. 
For all other time points, HBV DNA will be analyzed as observed case without imputation.
5.3.1.1.7.
Thresholds Based on HBsAg, HBeAg, HBV DNA and Multiple Markers
Thresholds for HBsAg values:

<1000 IU/mL

<100 IU/mL

<10 IU/mL

<1 IU/mL

<0.05 IU/mL
Thresholds for HBsAg decreases from baseline:

≥0.3 log10 IU/mL 

≥0.5 log10 IU/mL 

≥1 log10 IU/mL 
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
≥2 log10 IU/mL 

≥3 log10 IU/mL 

≥4 log10 IU/mL 
Thresholds for HBeAg values (assessed for participants HBeAg Positive at baseline only):

< 100 IU/mL

< 10 IU/mL

< 1 IU/mL

< LLOQ (0.11 IU/mL) 
Of note, seroclearance of HBeAg is defined as (quantitative) HBeAg<LLOQ. 
Thresholds for HBeAg decreases from baseline (assessed for participants HBeAg Positive at 
baseline only):

≥0.3 log10 IU/mL 

≥0.5 log10 IU/mL 

≥1 log10 IU/mL 

≥2 log10 IU/mL 

≥3 log10 IU/mL 
Thresholds for HBV DNA values:

< LLOQ for target detected and not detected

< LLOQ for target not detected

< LLOQ for target detected

<60 IU/mL

<100 IU/mL

<200 IU/mL

<1000 IU/mL 

<2000 IU/mL

<20000 IU/mL
Thresholds for HBV DNA decreases from baseline:

≥1 log10 IU/mL 

≥2 log10 IU/mL 

≥3 log10 IU/mL 

≥4 log10 IU/mL 
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
≥5 log10 IU/mL
5.3.1.1.8.
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) 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 
lower limit of quantification (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.
5.3.1.1.9.
Flares
The criteria based on blood markers/lab tests for each of the flare types are defined as below.
a) Virologic flare is defined as follows:
Virologic flare will be assessed only for those participants who are off-treatment and had HBV 
DNA < LLOQ at the last observed time point on all study treatments.
The start of a confirmed virologic flare is defined as the first date of two consecutive visits 
with HBV DNA > 200 IU/mL. The end date of the same confirmed virologic flare is defined 
as the first date when HBV DNA value returns to ≤200 IU/mL or the date of NA treatment 
restart, whichever comes first. Each virologic flare will be categorized based on the confirmed 
(i.e., two consecutive values) peak HBV DNA above any of the three thresholds within the 
start and end date of that flare as follows: 20,000 IU/mL 2,000 IU/mL and 200 IU/mL

1 (Yes) = confirmed** HBV DNA > peak threshold.   

0 (No) = at least one off-treatment HBV DNA measurement available and not meeting 
the criteria of confirmed HBV DNA > peak threshold.

2 (Not applicable) = no off-treatment HBV DNA quantitative measurements available.
b) Off-treatment Biochemical flare is defined as follows:
The start date of a confirmed off-treatment biochemical flare is defined as the first date of two 
consecutive visits with ALT and/or AST ≥3x ULN and ≥3x nadir (i.e., lowest value observed 
up to the time point of meeting the biochemical flare criteria) while the participant does not 
receive any of the study interventions. The end date of the same off-treatment biochemical 
flare is defined as the first date when there is a 50% reduction from the peak ALT and/or AST 
level & < 3x ULN.
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
1 (Yes) = confirmed** ALT and/or AST ≥3x ULN and ≥3x nadir (i.e., lowest value 
observed during off-treatment period up to the time point of meeting the biochemical flare 
criteria)

0 (No) = otherwise
c) On-treatment Biochemical flare is defined as follows:
The start date of a confirmed on-treatment biochemical flare is defined as the first date of two 
consecutive visits with ALT and/or AST ≥3x ULN and ≥3x nadir (i.e., lowest value observed 
up to the time point of meeting the biochemical flare criteria) while the participant receives 
any of the study interventions. The end date of the same on-treatment biochemical flare is 
defined as the first date when there is a 50% reduction from the peak ALT and/or AST level 
& < 3x ULN, regardless of stopping the study interventions.

1 (Yes) = confirmed** ALT and/or AST ≥3x ULN and ≥3x nadir (i.e., lowest value 
observed on-treatment period up to the time point of meeting the biochemical flare criteria)

0 (No) = otherwise
d) Clinical flare is defined as follows:
A clinical flare occurs either when a virologic flare and biochemical flare overlap in time or 
when a biochemical flare starts within 4 weeks following the end of a virologic flare. The start 
date of a clinical flare is defined as the minimum start date of the virologic flare and 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 between HBV DNA returns to ≤200 
IU/mL and 50% reduction from the peak ALT and/or AST level & < 3x ULN .

1 (Yes)= confirmed** HBV DNA > peak threshold and confirmed** ALT and/or AST ≥
3x ULN and confirmed** ≥3x nadir (i.e., lowest value observed during off-treatment 
period up to the time point of meeting the flare criteria).

0 (No) = otherwise
** Confirmed means that the criterion should be fulfilled at 2 or more consecutive time points or at 
the last observed time point.
The virologic and clinical flares will be assessed only off-treatment, while biochemical flares will 
be identified on treatment and off treatment, respectively. On-treatment virologic flares are 
described as virologic breakthrough in Section 5.3.1.1.8. 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). In addition, the 
proportion of subjects with off-treatment virologic flares, ALT and clinical flare for subjects who 
met NA treatment completion criteria and stopped NA will be shown.
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5.3.1.2.
Values and Changes Over Time Endpoints
5.3.1.2.1.
HBsAg, HBeAg, HBV DNA and ALT
Actual values (original unit and log10 transformed values) and changes from baseline (log10
transformed values) over time in HBsAg, HBeAg (for participants HBeAg positive at baseline 
only), HBV DNA and ALT (actual values only) will be evaluated.
Change from baseline is defined as follows: value at a given time point minus baseline value.
The change from baseline value to nadir (i.e., maximum decrease for each participant) in HBsAg, 
HBeAg 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.
Time to First HBsAg Seroclearance
Time to first 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.
Time to the first occurrence of the events above will be also analyzed considering the participants 
who were retreated with NA before achieving the event will be censored at the date of NA 
retreatment.
5.3.1.3.2.
Time to First HBV DNA < LLOQ
Time to first HBV DNA < LLOQ is defined as the number of days between the date of first study 
intervention intake and the date of the first occurrence of HBV DNA < LLOQ (i.e., the date of the 
first HBV DNA < LLOQ – the date of first study intervention intake + 1). The participants who 
withdrew early from the study before achieving HBV DNA < LLOQ or who did not achieve HBV 
DNA < LLOQ will be censored at the last available HBV DNA assessment.
Time to first HBV DNA < LLOQ will be also analyzed considering the participants who were 
retreated with NA before achieving HBV DNA < LLOQ will be censored at the date of NA 
retreatment.
5.3.2.
Analysis Methods
Statistical analyses of all secondary endpoints will be performed by cohort using Treated analysis 
set. The selected secondary endpoints efficacy analyses will use combining the data from 
participants who received PegIFN-α2a but not JNJ-6379 in Cohort 1 with data of Cohort 2, the 
PegIFN-α2a ITT analysis set will be used. If applicable, additional statistical analyses (descriptive 
statistics and spaghetti plots) may be added for each of the following subgroups: participants who 
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received at least one dose of JNJ-6379 and an induction phase duration of ≤36 weeks, participants 
who received at least one dose of JNJ-6379 and an induction phase duration >36 weeks, 
participants who never received JNJ-6379. The mTreated and mPegIFN-α2a ITT will be used if 
relevant difference between the sets exists (see Section 2.3).
5.3.2.1.
Binary Outcomes 
The number and proportion (%) of participants achieving the endpoints will be summarized. The 
associated 90% CI may also be included.
5.3.2.1.1.
NA Treatment Completion Criteria
5.3.2.1.1.1.
NA Treatment Completion Criteria During the Study
The count and proportion of participants who met the NA treatment completion criteria (as defined
Section 5.3.1.1.2.1) and at any time during the study, regardless of the treatment duration, will be 
summarized by cohort.
Starting at consolidation Week 12, the incidence of participants who did not meet the NA treatment 
completion criteria will be summarized by cohort and at each timepoint during the study, 
accompanied by the distribution of each of the 4 criteria that is not met. The NA treatment 
completion criteria are based on a threshold for the laboratory tests of ALT, HBV DNA, HBeAg 
and HBsAg as defined in Section 5.3.1.1.2.1.
The count and proportion of participants who met the NA treatment completion criteria (as defined 
in Section 5.3.1.1.2.1) at any time during the FU phase, regardless of the treatment duration, will 
be summarized by cohort. All of NA treatment completion criteria will be checked based on 
clinical laboratory tests in FU phase.
A listing including the participants who do not meet the NA completion criteria at consolidation 
Week 12, and the NA completion criteria will be generated. A bar chart for including the 
participants who do not meet the NA completion criteria at consolidation Week 12 will be 
generated.
5.3.2.1.1.2.
NA Re-Treatment Criteria and Monitoring After Stopping of NA
The number and proportion of participants who meet the criteria for NA re-treatment at any time 
during FU will be summarized descriptively by cohort. Only the subset of ITT participants who 
meet the NA treatment completion criteria at any time during the study and actually stop NA 
treatment will be included in the analysis (as defined in Section 5.3.1.1.2.2).
The proportion of participants who actually re-started NA treatment and monitoring after stopping 
of NA on the basis of the ‘Study Drug Administration for NA’ CRF page will be summarized 
separately over time by cohort.
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In addition, the proportion of participants who met the above criteria according to the flag on the 
CRF page of ‘NA Re-treatment Criteria Assessment’ during the follow-up phase will be 
summarized over time by cohort. 
A cross-tabulation of participants who actually re-started NA treatment (re-started/not restarted) 
versus participants versus participants who met the above criteria (met/not met) will be presented 
over time.
A listing including all participants who meet the NA re-treatment criteria and monitoring after 
stopping of NA will be generate. This listing will also include information whether they actually 
re-started NA treatment (re-started/not restarted).
5.3.2.1.2.
HBsAg Seroclearance
The proportion of participants achieving HBsAg seroclearance over time will be summarized by
cohort and analysis phase. Separate analyses will be performed for participants who completed 
treatment as planned (at the end of consolidation phase), and regardless when treatment was 
stopped.
The proportion of participants with HBsAg seroclearance at the end of consolidation treatment 
will be tabulated by cohort. 
The proportion of participants with HBsAg seroclearance will be evaluated at all off-treatment 
time points, respectively, after stopping all study interventions and without restarting NA 
treatment. In an additional summary, these proportions will be calculated with the denominator 
including only on those participants who have reached the off-treatment timepoint, and have 
stopped all interventions including NA and have not restarted NA prior to the timepoint of interest.
5.3.2.1.3.
HBsAg and HBeAg Seroconversion 
The number and proportion of participants who achieve HBsAg and HBeAg seroconversion will 
be summarized descriptively by cohort and analysis phase over time. 
For 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 cohort.  
In an additional summary, the level of anti-HBs antibodies at the specific timepoint (i.e., end of 
consolidation, FU Week 24, FU Week 36 and FU Week 48) will be summarized for the subset of 
the participants achieving HBsAg seroconversion at any time before or at that given timepoint by 
cohort.
5.3.2.1.4.
Suppressed HBV DNA
The proportion of participants achieving HBV DNA <LLOQ (overall and separately for HBV 
DNA detectable and HBV DNA TND) will be summarized by cohort and analysis phase over time.
The proportion of participants with HBV DNA<LLOQ (overall and separately for HBV DNA 
detectable and HBV DNA TND) will be evaluated at each of the off-treatment time points, 
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respectively, after stopping all study interventions and without restarting NA treatment. In an 
additional summary, these proportions will be calculated with the denominator including only on 
those participants who have reached
the off-treatment timepoint, and have stopped all 
interventions including NA and have not restarted NA prior to the timepoint of interest.
The proportion of participants who reach HBV DNA <LLOQ (overall and separately for HBV 
DNA detectable and HBV DNA TND) after restart of NA treatment during follow-up will also be 
tabulated by cohort.
The number of occurrences each subject has HBV DNA<LLOQ (overall and separately for HBV 
DNA detectable and HBV DNA TND) will be determined and summarized by cohort using 
frequency distributions and descriptive statistics. Additionally, the number of occurrences will be 
displayed graphically.
5.3.2.1.5.
Thresholds based on HBsAg, HBeAg, HBV DNA and Multiple Markers
The proportion of participants achieving the cut-offs as defined in Section 5.3.1.1.7 will be 
summarized by cohort and analysis phase over time. 
Cumulative percentage of participants achieving any given decrease from baseline in HBsAg, 
HBeAg and HBV DNA respectively at the end of induction, end of consolidation, and all FU time 
points, separately, will be presented graphically.
For the thresholds based on multiple markers, the number and proportion of participants who meet 
the blood marker reduction/seroclearance thresholds at all FU time points, respectively, after 
stopping all study interventions (including NA) and not having NA re-treated will be summarized 
descriptively by cohort for each marker and each threshold listed in Section 5.3.1.1.7.
5.3.2.1.6.
Virologic Breakthrough
The number and proportion of participants who experience a virologic breakthrough will be 
summarized descriptively by cohort and analysis phase.
The number and proportion of participants who experience a virologic breakthrough followed by 
on-treatment biochemical flare will be summarized descriptively by cohort.
5.3.2.1.7.
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 cohort. 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 
cohort.
For on-treatment biochemical flares, the incidence of flares causing treatment discontinuation will 
be summarized by cohort. Further, for off-treatment flares, the count and percentage of participants 
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who experienced a flare followed by NA re-treatment will be summarized by flare type and cohort. 
Similarly, the incidence of flares followed by the achievement of HBsAg seroclearance (at any 
time) will be summarized by flare type and cohort.
Flares that are associated with signs of liver decompensation will be provided in a listing.
5.3.2.2.
Values and Change Over Time Endpoints
5.3.2.2.1.
HBsAg, HBeAg, HBV DNA and ALT
Descriptive statistics on actual values (original unit and log10 transformed values), changes from 
baseline (log10 transformed values), changes from consolidation reference time point (log10
transformed values) over time in HBsAg, HBeAg, HBV DNA and ALT will be summarized by
cohort and analysis phase. Mean (+/- SE) plots of the actual values, change from baseline (log10
transformed) and change from consolidation reference time point (log10 transformed) will be 
presented over time per blood marker by cohort and analysis phase.
In addition, the change from baseline value to the nadirs (i.e., maximum decrease for each 
participant) will be summarized descriptively by cohort. Box plots of the changes to nadir in 
HBsAg, HBeAg and HBV DNA will display the distribution by cohort.
Descriptive statistics on actual values (original unit and log10 transformed values) and changes 
from baseline (log10 transformed values) at end of consolidation in HBsAg, HBeAg, HBV DNA
and ALT (original unit), respectively, will be summarized by cohort, by NA treatment completion 
criteria status at the end of consolidation phase, by functional cure status at FU Week 24 and 48, 
and for participants who achieved functional cure 24 weeks after stopping all study interventions 
regardless of meeting the NA completion criteria) and at the end of FU phase.
Cross-tabulations overtime and overall of quantitative versus qualitative HBsAg and HBeAg 
values, respectively, will also be presented.
Spaghetti plots for both absolute values and changes from baseline of HBsAg, HBeAg, HBV DNA
and ALT will be presented over time (all data collected including unscheduled visit, all data within 
the same time interval, see Section 2.1.3) per blood marker by cohort and by selected subgroups 
(e.g. HBV Genotype), by NA treatment completion criteria status at the end of consolidation phase, 
by functional cure status at FU Week 24 and 48, and for participants who achieved functional cure 
24 weeks after stopping all study interventions regardless of meeting the NA completion criteria)
and at the end of FU, separately, will be presented graphically.
Shift tables in HBV DNA categories from baseline will also be summarized by cohort and analysis 
phase.
5.3.2.3.
Time to Event Endpoints
All time to event variables will be analyzed for all treated participants.
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5.3.2.3.1.
Time to First HBsAg Seroclearance
Time to first HBsAg seroclearance will be summarized. The Kaplan-Meier method will be used to 
estimate and plot the cumulative incidence. The median time with 90% CI will be estimated using 
Kaplan-Meier method.
In addition, the number and percentage of participants who had an event or were censored will be 
reported.
5.3.2.3.2.
Time to First HBV DNA < LLOQ
Time to HBV DNA < LLOQ will be analyzed following the methodology in Section 5.3.2.3.1.
5.4.
Exploratory Endpoints
5.4.1.
Definitions
5.4.1.1.
Binary and Categorical Endpoints
5.4.1.1.1.
End of Follow-up Phase HBsAg response
The number and proportion of participants with sustained response according to the below 
different definitions will be summarized descriptively by cohort, combined cohort, overall and by 
analysis phase.
End of follow-up phase HBsAg Response definition #1:

For participants with Follow-up Week 48 data: participants who had a >1 log10 decline 
from baseline in HBsAg at Follow-up Week 48 and HBsAg < 1000 IU/mL at Follow-up 
Week 48

For participants without Follow-up Week 48 data: participants who had a >2 log10 decline 
from baseline in HBsAg at Follow-up Week 24 or a >1.5 log10 decline from baseline in 
HBsAg at Follow-up Week 36 (most recent value used) and HBsAg < 1000 IU/mL at the 
last available timepoint.
End of follow-up phase HBsAg Response definition #2:

For participants who had a >1 log10 decline from baseline in HBsAg at the last Follow-up 
visit: among the 3 most recent visits, the difference between log10 HBsAg at 2 of the 3 last 
visits and 1 of the 3 last visits is < 0.2, and the difference between log10 HBsAg at 3 of the 
3 last visits and 1 of the 3 last visits is < 0.2.
End of follow-up phase HBsAg Response definition #3:

For participants with a >1 log10 decline from baseline in HBsAg at the last Follow-up 
visit: among the 3 most recent visits, the difference between log10 HBsAg at 2 of the 3 
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last visits and 1 of the 3 last visits is <0.2, and the difference between log10 HBsAg at 3 
of the 3 last visits and 1 of the 3 last visits is <0.2 and had HBsAg <1,000 IU/mL at the 
last available timepoint. 
End of follow-up phase HBsAg Response definition #4:

Three categories regarding the difference between HBsAg level at the last Follow-up 
timepoint from CW12: 
o
>0.2 log10 decrease: Decreasing level
o
≤0.2 log10 increase or ≤0.2 log10 decrease: Stable level
o
>0.2 log10 increase: Increasing level
5.4.1.1.2.
Treatment Failure
A participant will be defined as off-treatment failure if he/she never had HBsAg seroclearance 
24 weeks after stopping all study interventions at the end of the consolidation phase and without 
restarting NA treatment.
5.4.1.1.3.
Thresholds of HBV RNA and HBcrAg Levels
Thresholds for HBV RNA values:

TND

< LOD

< LLOQ

< 1000 IU/mL
Thresholds for HBV RNA decreases from baseline:

≥1 log IU/mL

≥2 log IU/mL

≥3 log IU/mL

≥4 log IU/mL

≥5 log IU/mL
Thresholds for HBcrAg values:

<3.0 log U/mL

<4.0 log U/mL
Thresholds for HBcrAg decreases from baseline:

≥1 log IU/mL

≥2 log IU/mL
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
≥3 log IU/mL

≥4 log IU/mL

≥5 log IU/mL

≥6 log IU/mL
5.4.1.1.4.
Thresholds Based Multiple Markers for participants who completed 
NA Treatment
Thresholds based on multiple markers:

HBsAg<LLOQ and HBV DNA

HBsAg<LLOQ and HBV DNA<LLOQ**

HBsAg < LLOQ and HBV DNA < LLOQ for target detected

HBsAg < LLOQ and HBV DNA < LLOQ for target not detected

HBsAg<LLOQ and HBV DNA≥LLOQ

HBsAg≥LLOQ and HBV DNA<2,000 IU/ml  

HBsAg≥LLOQ and HBV DNA<LLOQ**

HBsAg ≥ LLOQ and HBV DNA < LLOQ for target detected

HBsAg ≥ LLOQ and HBV DNA < LLOQ for target not detected

HBsAg ≥ LLOQ and HBV DNA < LLOQ for target detected and not detected

HBsAg ≥ LLOQ and LLOQ ≤ HBV DNA < 2,000 IU/mL

HBsAg ≥LLOQ and HBV DNA <2,000 IU/mL

HBsAg≥LLOQ and LLOQ ≤HBV DNA<2,000 IU/ml

HBsAg≥LLOQ and HBV DNA≥2,000 IU/ml

HBsAg<100 IU/mL and HBV DNA≥2,000 IU/ml

HBsAg≥100 IU/mL and HBV DNA≥2,000 IU/ml

HBsAg ≥LLOQ and HBV DNA ≥2,000 IU/mL

HBsAg <100 IU/mL and HBV DNA < LLOQ

HBsAg <100 IU/mL and HBV DNA≥2,000 IU/mL

HBsAg ≥ 100 IU/mL and HBV DNA ≥ 2,000 IU/ml

HBsAg <100 IU/mL and HBV DNA < 2000 IU/ml
** HBV DNA<LLOQ will be summarized by DNA target detected, TND and overall.
Due to the exploratory objectives of this Phase 2 study, additional blood marker 
reduction/seroclearance thresholds may be added at a later point in time according to the clinical 
interest.
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5.4.1.1.5.
Anti-HBe Antibodies
Participants who have positive and negative Anti-HBe values will be evaluated over time.
5.4.1.2.
Values and Change Over Time Endpoints
5.4.1.2.1.
HBV RNA and HBcrAg
Actual values and changes from baseline (log transformed value) over time in HBV RNA, and 
HBcrAg will be evaluated.
Change will be defined as: value at a given time point minus baseline value.
The change from baseline value to 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 by met the NA treatment completion criteria and stopped NA or 
did not meet and did not stop NA.
5.4.1.2.2.
Anti-HBs Antibodies
Actual values and change from baseline will be evaluated over time when anti-HBs antibodies are 
assessed.
Change from baseline is defined as: value at a given time point minus baseline value. Participants 
who have positive and negative Anti-HBs values will be evaluated over time.
5.4.1.2.3.
Liver Stiffness Measurements
Severity of liver disease at the end of study intervention and follow-up versus baseline will be 
evaluated by the actual values and changes in fibrosis according to Fibroscan liver stiffness 
measurements. Change will be defined as: value at a given time point minus baseline value.
5.4.1.3.
Endpoints for Correlation
5.4.1.3.1.
Association between several endpoints after the beginning of the 
consolidation phase
Correlations between the following endpoints will be evaluated for participants who received at 
least one dose of Pegylated Interferon: 
-
Maximum ALT increase (U/L) vs Maximum HBV DNA increase (log10 IU/mL) between 
Consolidation Baseline and FU Week 4
-
Maximum ALT increase (U/L) vs Maximum Neutrophils (10^9/L) decrease between 
Consolidation Baseline and FU Week 4
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-
Maximum ALT increase (U/L) vs Maximum HBsAg decrease (log10 IU/mL) between 
Consolidation Baseline and FU Week 4
-
Additional HBsAg decline (log10 IU/mL) at CW12 vs Maximum Neutrophils decrease
between Consolidation Baseline and FU Week 4
-
Additional HBsAg decline (log10 IU/mL) at CW12 vs Maximum ALT increase (U/L) 
between Consolidation Baseline and FU Week 4
To evaluate the additional HBsAg decline (log10 IU/mL) at CW12, a linear regression model using 
the four last HBsAg measures before Consolidation Baseline is performed to estimate Predicted 
value of HBsAg at CW12.
5.4.2.
Analysis Methods
Statistical analyses of all exploratory endpoints will use descriptive statistics. Treated analysis set 
will be used. The selected exploratory endpoints efficacy analyses will use combining the data 
from participants who received PegIFN-α2a but not JNJ-6379 in Cohort 1 with data of Cohort 2, 
the PegIFN-α2a ITT analysis set will be used. If applicable, additional statistical analyses 
(descriptive statistics and spaghetti plots) may be added for each of the following subgroups: 
participants who received at least one dose of JNJ-6379 and an induction phase duration ≤36 
weeks, participants who received at least one dose of JNJ-6379 and an induction phase duration >
36 weeks, participants who never received JNJ-6379. The mTreated and mPegIFN-α2a ITT will 
be used if relevant difference between the sets exists (see Section 2.3).
5.4.2.1.
Binary Endpoints
Please see the section 5.3.2.1.
5.4.2.1.1.
Treatment Failure
The number and proportion of off-treatment failure participants, as defined in Section 5.4.1.1.2,
will be summarized descriptively by cohort.
5.4.2.1.2.
Thresholds based on HBV RNA and HBcrAg Levels
The number and proportion of participants achieving the cut-offs as defined 5.4.1.1.3 will be 
summarized by cohort and analysis phase over time.
Cumulative percentage of participants achieving any given decrease from baseline in HBV RNA 
and HBcrAg respectively at the end of induction, end of consolidation, and all FU time points, 
separately, will be presented graphically.
5.4.2.1.3.
Anti-HBe Antibodies
The number and proportion of participants having anti-HBe positive/negative values will be 
summarized by cohort and analysis phase over time.
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Shift tables in anti-HBe positive/negative values from baseline will be provided at each time point.
5.4.2.1.4.
Thresholds Based Multiple Markers for participants who completed 
NA Treatment
The number and proportion of participants who meet the blood marker reduction/seroclearance 
thresholds at all FU time points, respectively, after stopping all study interventions (including NA) 
and not having NA re-treated will be summarized descriptively by cohort for each marker and each 
threshold listed in Section 5.4.1.1.4.
5.4.2.2.
Values and Change Over Time Endpoints
5.4.2.2.1.
HBV RNA and HBcrAg 
The values of and changes from baseline in HBV RNA and HBcrAg, respectively, will be 
summarized only descriptively over time in a similar manner as for values and changes from 
baseline over time in HBsAg, and HBV DNA as described in Section 5.3.2.2.1, including the 
change from baseline value to nadir (i.e., maximum decrease for each participant) and the various 
graphical displays.
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.
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.
5.4.2.2.2.
Anti-HBs Antibodies
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 5.3.2.2.1.
Additionally, for all ITT participants with positive anti-HBs antibodies at baseline who will reach 
HbsAg seroclearance (as defined in Section 5.3.1.1.3), descriptive statistics will be calculated for 
the change of anti-HBs antibodies level from baseline at the timepoint when achieving the HbsAg 
seroclearance by cohort.  In an additional summary, the change of anti-HBs antibodies level from 
baseline at the specific timepoint (i.e., Week 12 of the consolidation phase, FU Week 4, Week 12, 
Week 24, Week 36 and Week 48) will be summarized descriptively for the subset of the
participants achieving HbsAg seroclearance at any time before or at that given timepoint by cohort.
Cross-tabulations overtime of quantitative versus qualitative anti-HBs values will also be 
presented.
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5.4.2.2.3.
Liver Stiffness Measurements 
Severity of liver disease at the end of consolidation phase and follow-up versus baseline will be 
evaluated by the changes in fibrosis according to Fibroscan liver stiffness measurements.
The changes from baseline at end of consolidation phase and end of follow-up will be summarized 
using descriptive statistics (n, mean, SE, 90% CI, median, minimum, maximum) by cohort
At each assessment time point, a frequency distribution of severity scores will be produced by 
cohort. A graphical display will also illustrate the findings.
5.4.2.3.
Endpoints for Correlation
5.4.2.3.1.
Association Between Baseline Characteristics/Viral Blood Markers 
and Selected Efficacy Variables
Correlations will be evaluated graphically using scatter plots, and heat maps displaying such 
potential associations by cohort and/or selected subgroups.
The following correlation coefficients will be calculated 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.
6.
SAFETY
All safety analyses will be performed using the safety analysis set. All assessments will be 
presented by analysis phase and cohort for safety analysis set. All summaries will be only 
descriptive, and no inferential methods will be used 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.
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 
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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 2.6.1 will apply.
6.1.2.
Analysis Methods
The adverse events will be summarized by cohort 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 an analysis phase, the AE will be attributed to that phase (treatment-emergent 
principle). For imputation of partially/fully missing dates please see Section 2.6.1. In case of a 
completely missing start date, the event is allocated to the induction study intervention phase, 
except if the end date of the AE falls before the first administration of study treatment in induction 
phase (Induction 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 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 2.5.2.
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 treatment or study 
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.
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Imputation rules:
In case continuous laboratory results are not numerically expressed, but as a character (e.g., ‘less 
than 2’, ‘>25’), these results will be numerically imputed as follows:

If the analysis result contains ‘<’ then the result will be multiplied by 0.999 (e.g., <6.1 becomes 
6.0939). 

If analysis result contains ‘>’ then the result will be multiplied by 1.001 (e.g., >6.1 becomes 
6.1061).  

If analysis result contains ‘≤’ or ‘≥’ then only the numeric portion of the result will be used.
This also applies to normal limits expressed as such.
6.2.2.
Analysis Methods
Descriptive statistics (n, mean, SD, SE, minimum, median, and maximum) will be calculated for 
each laboratory analyte for observed values and changes from baseline at each scheduled time 
point by cohort and analysis phase on safety analysis set.
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 analysis 
phase and cohort.
The cross-tabulations of the worst toxicity grades over time versus baseline grade and the worst 
abnormalities versus baseline grade per parameter and per analysis phase will be presented 
including also the number of participants per worst grade and the number of participants per 
abnormality.
A tabulation of percentage and number of the participants who have treatment-emergent worst 
toxicity grades and treatment-emergent worst abnormalities per parameter and analysis phase will 
be included. The incidence table of worst toxicity grade abnormality in laboratory parameters will 
be also presented stratified by the subgroup of interests identified in Section 2.5.2.
Plots of mean (+/- SE) values and changes from baseline over time for selected laboratory 
parameters will be presented. Spaghetti-plots for selected laboratory parameters may be presented 
over time.
Additional spaghetti plots may be added for each of the following subgroups: participants who 
received at least one dose of JNJ-6379 and an induction phase duration ≤36 weeks, participants 
who received at least one dose of JNJ-6379 and an induction phase duration > 36 weeks, 
participants who never received JNJ-6379.
A listing including all parameters with at least one treatment-emergent toxicity or abnormality per 
participant (exclusion of urinalysis) will be generated.
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6.2.3.
Renal Safety
Renal safety parameters include the urine creatinine, serum creatinine, total urine protein, total 
urine albumin, urine protein to creatinine ratio (UPCR), urine albumin to creatinine ratio (UACR), 
retinol binding protein (RBP), beta-2-microglobulin, RBP to creatinine ratio, beta-2-microglobulin 
to creatinine ratio, urine fractional excretion of phosphate (FEPO4), Cystatin C. 
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%, 10-<30%, 30-
<50% and ≥50% decrease from baseline will be tabulated.
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]) as well as spaghetti plots 
will also be presented.
In addition, Cystatin C assessment is being performed as part of this study. eGFR will also be 
calculated by using the CKD-EPI Cystatin C equation. 
Differences between the two types of eGFR calculations will be assessed. Cross-tabulation of 
eGFR creatinine (<10%, 10-<30%, 30-<50% and ≥50% decrease from baseline) versus eGFR 
cystatin C (<10%, 10-<30%, 30-<50% and ≥50% decrease from baseline) will be presented over 
time.
6.2.3.1.1.
Proximal Renal Tubular Function Proteinuria by Quantitative
Assessment
Total urine protein, total urine albumin, UPCR and UACR will be summarized by cohort 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 cohort. The evolution 
over time of total urine protein and total urine albumin will also be presented.
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6.2.3.1.2.
Proteinuria by Urinalysis (Dipstick)
Treatment-emergent proteinuria by urinalysis (dipstick) over time will be summarized by cohort. 
Cross-tabulation of grades overtime versus baseline will also be presented.
6.2.3.1.3.
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 cohort 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 retinal binding protein 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
6.2.3.1.4.
Phosphate Excretion
Otherrenal biomarkers includeFEPO4 that will besummarized bycohort and visit using descriptive
statistics.
FEPO4 will be calculated as follows:

Based on unadjusted serum creatinine:
FEPO4 (%) = (SCr × UPO4) / (SPO4 × Ucr) × 100 (%)
Where SCr is serum creatinine concentration, UPO4 is urine phosphate concentration, SPO4 
is serum phosphate concentration, and Ucr is urine creatinine concentration.
The proportions of participants with FEPO4 ≤10% and >10% will be tabulated.
The baseline, post-baseline, and change from baseline in FEPO4 will be summarized by cohort
and visit using descriptive statistics. Median (Q1, Q3) change from baseline in FEPO4 over time 
will be plotted by cohort.
6.2.3.1.5.
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
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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 confirmed laboratory abnormality is defined as an abnormality observed at 2 consecutive 
postbaseline measurements or an abnormality observed at 1 post-baseline 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 are:
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).
6.2.4.
Electrocardiogram
6.2.4.1.
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: QTcF (msec) = QT (msec) / (RR (msec)/1000)1/3; 
if RR is missing, use QT (msec) * (HR(bpm)/60)1/3)
The abnormalities in ECG parameters will be determined according to the criteria specified in the 
Cardiovascular Safety – Abnormalities Table (see Clinical Protocol Appendix 7, Cardiovascular 
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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).
6.2.4.2.
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.
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 analysis phase and cohort 
on safety analysis set. 
Shift tables will be provided summarizing the shift in ECG values from baseline over time with 
respect to abnormality category (low, normal, high) for each parameter by cohort and analysis 
phase on safety analysis set. 
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A cross-tabulation of the worst abnormalities (on actual values) versus baseline per parameter by 
analysis phase will be presented including also the number of participants per abnormality. A 
tabulation of number and percentage 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 cohort and analysis 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 cohort.
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. 
6.2.5.
Vital Signs and Body Temperature
6.2.5.1.
Definitions
The following parameters measurements will be analyzed:

Supine pulse rate (bpm)

Supine systolic blood pressure (mmHg)

Supine diastolic blood pressure (mmHg)

Body temperature (℃)
The abnormalities in vital signs will be determined according to the criteria specified in the 
Cardiovascular Safety – Abnormalities Table (see Clinical Protocol Appendix 7).
An assessment is treatment-emergent 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).
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6.2.5.2.
Analysis Methods
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 by cohort and analysis 
phase on safety analysis set. 
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 
cohort and analysis phase on safety analysis set. 
A cross-tabulation of the worst abnormalities versus baseline per parameter and analysis 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 analysis 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.
Vital signs records with partial dates (any of day/month/year is missing) will not be used in the 
analysis but will be listed.
6.2.6.
Physical Examination
The complete physical examination including the head, neck, and thyroid findings and 
abnormalities will be listed.
7.
VIRAL GENOME SEQUENCE ANALYSIS
The sequencing of samples from participants in the 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 identify pre-existing baseline polymorphisms 
and to evaluate emergence of genetic variations (including substitutions) associated with 
JNJ-56136379, JNJ-3989, and/or NA 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 cohort with 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 
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
Number (%) of subjects with treatment-emergent and treatment-enriched substitutions on 
nucleotide level at post-baseline time points (as defined in Section 7.1) by substitution profile 

at the binding site positions of JNJ-3989 (overall and by HBV genotype (A, B, C, D, E, 
F, G, H, I and J)). 
The focus will be on substitutions at a time point, emerging and enriched variations and reversion 
to wild type or baseline state. The above summaries will be repeated for genetic variations (not 
needed for CSR). 
In the sequence analysis, sequences will be mapped to the respective genotype specific reference 
sequences after which nt changes and aa substitutions will be annotated compared to the respective 
genotype specific reference (see Table in Section 7.2). In addition, the X02763 (HBV genotype 
A), which is the master reference sequence of the HBV db, will be used as universal reference 
sequence. Focus of analysis and reporting of results will be on comparison versus 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 baseline nt changes and/or aa substitutions in terms of frequency of variant and impact on 
treatment outcome, a read frequency cut-off of ≥0.15 will be used. The analysis of treatment-
emergent nt changes or aa substitutions will consider nt changes or aa substitutions absent at 
baseline (<0.01 read frequency) but present at a read frequency of ≥0.15 at later time points. 
Virology analyses based on NGS data will also evaluate treatment-enriched nt changes and aa 
substitutions, defined as present at baseline with a read frequency ≥0.01 but <0.15 and with an 
increase in read frequency of at least 0.15 post-baseline. A minimum increase in read frequency 
of 0.15 compared to baseline excludes small, potentially technical variations in the read frequency 
of minority nt changes and aa substitutions which are not expected to have clinical relevance. In 
addition, for subjects with treatment failure nt changes and aa substitutions detected with a read 
frequency ≥0.01 at baseline, at time of failure and at end of study will be described in a listing. 
The persistence of treatment-emergent 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 (e.g., 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)
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In the JNJ-3989 binding pocket positions:

JNJ-3976  (S Trigger) 
o
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

JNJ-3924 (X Trigger)
o
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

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]) 

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
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 HBV reference sequences 
descriptive summaries will be performed by subgroups (HBeAg status at screening and HBV 
genotypes) by cohort. For comparison of amino acid or nucleotide levels to HBV genotype-
specific reference sequences, descriptive summaries will only be performed by HBV genotypes 
and by cohort.
7.5.1.
Baseline
The frequency of variant of baseline genetic variations, i.e., the number of subjects with baseline 
genetic variations, 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. 
Subgroup analysis by the presence of baseline genetic variations will be tabulated to evaluate the 
impact on treatment efficacy (efficacy categories including but not limited to functional cure, 
treatment failure). 
7.5.2.
Post-Baseline

Time of Virologic Breakthrough (if applicable)
For subjects with virologic breakthrough, the incidence of treatment emergent (NGS) and 
treatment enriched genetic variations (with primary focus on substitutions) will be tabulated in 
frequency outputs (n, %) and the genetic variations will be listed for all subjects with paired 
baseline and post-baseline sequencing data. 
The return to baseline for subjects with virologic breakthrough and treatment-emergent genetic 
variations at time of virologic breakthrough may be tabulated in frequency outputs based on NGS 
data, as well as the treatment-emergent genetic variations in subjects who did not return to baseline.

Time of End of Treatment
For subjects who don’t meet the NA treatment completion criteria, the incidence of treatment 
emergent and treatment enriched variants (with primary focus on substitutions) will be tabulated 
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in frequency outputs (n, %) and the genetic variations will be listed for all subjects with paired 
baseline and post-baseline sequencing data.
The return to baseline for subjects who don’t meet the NA treatment completion criteria and 
treatment-emergent genetic variations end of treatment may be tabulated in frequency outputs 
based on NGS data, as well as the treatment-emergent genetic variations in subjects who did not 
return to baseline.

Time of Virologic /Clinical Flare (if applicable)
For subjects with virologic/clinical flare, the incidence of treatment emergent (NGS) and treatment 
enriched genetic variations (with primary focus on substitutions) will be tabulated in frequency 
outputs (n, %) and the genetic variations will be listed for all subjects with paired baseline and 
post-baseline sequencing data. 
The return to baseline for subjects with virologic/clinical flare and treatment-emergent genetic 
variations at time of virologic/clinical flare may be tabulated in frequency outputs based on NGS 
data, as well as the treatment-emergent genetic variations in subjects who did not return to baseline.

Time of Re-treatment during Post-treatment Follow-up (if applicable)
For subjects who meet re-treatment criteria during follow-up, the incidence of treatment emergent 
and treatment enriched variants (with primary focus on substitutions) will be tabulated in 
frequency outputs (n, %) and the genetic variations will be listed for all subjects with paired 
baseline and post-baseline sequencing data.
The return to baseline for subjects who meet re-treatment criteria during follow-up and treatment-
emergent genetic variations at time of meeting the re-treatment criteria may be tabulated in 
frequency outputs based on NGS data, as well as the treatment-emergent genetic variations in 
subjects who did not return to baseline.

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. 
7.5.3.
Over the Study Period
For all subjects, listings with relevant baseline disease and demographic characteristics, session 
info, all genetic variations at baseline, at time of virologic breakthrough (if applicable), at end of 
induction phase, at the end of consolidation phase and at end of FU will be presented. 
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.
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7.6.
HBV genotype
Plasma samples for HBV genotyping were taken at screening and tested using the INNO-LiPA 
HBV genotyping assay. In addition, plasma samples were taken at baseline to determine the HBV 
genotype using the HBV full genome sequence and phylogenetic analysis.
The number and percentage of subjects by HBV genotype for study analysis will be tabulated. In 
addition, cross-tabulations per HBV genotype will compare the HBV genotypes determined by the
INNO-LiPA HBV genotyping assay and by using the HBV full genome sequence.
8.
OTHER ANALYSIS
8.1.
Pharmacokinetics 
Descriptive statistics (n, mean, SD, SE, coefficient of variation [CV], geometric mean, median, 
minimum, and maximum) will be calculated for the plasma or serum concentrations of JNJ-3989 
(ie, JNJ-3976 and JNJ-3924) and, optionally, JNJ-6379 NA and/or PegIFN-α2a, as applicable, and 
for the derived PK parameters for noncompartmental PK analysis.
For each participant with intensive PK sampling, concentration-time data of JNJ-3976, and JNJ-
3924, and optionally JNJ-6379, NA and/or PegIFN-α2a will be graphically presented. Similarly, 
graphs of the mean concentration-time profiles and overlay graphs with combined individual 
concentration-time profiles will be produced. PK parameters in participants undergoing intensive 
PK sampling will be calculated via noncompartmental methods for JNJ-3976, and JNJ-3924, and 
optionally of JNJ-6379, NA and PegIFN-α2a, as applicable. The PK parameters will be Cmax, C24h, 
and AUC24h. The PK parameters will be subjected to an exploratory graphical analysis, including 
various transformations, to get a general overview.
To assess the effect of PegIFN-α2a on JNJ-3989, the PK parameters of JNJ-3976, and JNJ-3924 
coadministered with PegIFN-α2a at Week 8 (or 4) of the consolidation phase will be compared to 
those of JNJ-3976, and JNJ-3924 at Week 24 (or 28 or 32) of the induction phase as reference. 
The primary PK parameters are Cmax and AUC24h on the logarithmic scale. A mixed effects model 
will be fitted to log-transformed PK parameters with phase (induction or consolidation) as a fixed 
effect and subject as a random effect.
Special attention will be paid to the 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 concentration-time data of JNJ-3976, and JNJ-3924, and, optionally, of 
JNJ-6379, NA and/or PegIFN-α2a may be performed using non-linear mixed effects modeling. 
Data may be combined with selected Phase 1 and/or 2 studies to support a relevant structural 
model. Available participant characteristics (e.g., demographics, laboratory variables, genotypes) 
will be included in the model as necessary. Details will be given in a population PK analysis plan 
and results of the population PK analysis, if applied, will be presented in a separate report.
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8.2.
Pharmacokinetic/Pharmacodynamic Relationships 
Relationships of PK parameters for JNJ-3989, JNJ-3924, and, optionally, of JNJ-6379, Nas and/or 
PegIFN-α2a, 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.
Effect of PegIFN-α2a coadministration on the PK of JNJ-3976, JNJ-3924, and JNJ-6379 if 
applicable, will be presented in a separate report.
8.3.
Immune Analyses
Descriptive statistics (n, mean, SD, SE, CV, geometric mean, median, minimum, and maximum) 
may 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) may 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, may be determined. Changes from baseline in HBV-specific peripheral 
blood T-cell responses may be summarized and tabulated. 
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 may be 
presented. The spaghetti plots may be used to show the patient profiles per time point for each 
assay. A graph showing the median and IQR over time by cohort may be presented. A bar chart 
may 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 may 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 may be presented to reflect the mean magnitude of each combination.
9.
PATIENT-REPORTED OUTCOMES
The impact of HBV/HDV treatment on participants will be assessed using PROs at predefined 
time points. The following PRO instruments will be used: Hepatitis B Quality of Life (HBQOL), 
Short Form 36 version 2 (SF-36), and EQ-5D-5L. All PRO analyses will be performed using the 
ITT analysis set.
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9.1.
Hepatitis B Quality of Life Instrument (HBQOL)
9.1.1.
Definition
The HBQOL version 1 is a 31-item disease-specific instrument designed to measure HRQoL for 
participants with CHB.
Each item is scored on a 5-level response scale ranging from 1 through 5. Each response is 
transformed along a 0 to 100-point scale, where lower scores denote less HRQOL impact, and 
higher scores denote more HRQOL impact (i.e., 0=best score; 100=worst score), as follows:
Level 1 – 0 points
Level 2 – 25 points
Level 3 – 50 points
Level 4 – 75 points
Level 5 – 100 points
The items are combined to form 7 subscales, as follows:
Psychological Well-Being (8 Items): Anxious (F6), Frustrated (F4), Sad (F3), Angry (F7), Less 
Enjoyable (F10), Scared (F13), Bad (F9), Isolated (F8)
Anticipation Anxiety (6 Items): Concern Failure (C1), Concern Cancer (C2), Concern Worsen 
(C15), Concern Serious (C12), Concern Survival (C9), Concern Flare (C5)
Vitality (5 Items): Tiredness (P1), Worn Out (F5), Muscle Aches (P3), Memory Problems (P2), 
Unproductive (F12)
Stigma (6 Items): Concern Embarrassed (C14), Ashamed (F1), Concern Self-Conscious (C10), 
Concern Socially Isolated (C11), Concern Boss (C3), Stigmatized (F2)
Vulnerability (3 Items): Concern Eat (C13), Concern Sick Easily (C6), Concern Medicines (C8)
Transmission (3 Items): Concern Transmit Sex (C7), Concern Transmit Child (C4), Sex Difficult 
(F11)
Viral Response (4 Items): Concern Transmit Sex (C7), Concern Transmit Child (C4), Concern 
Eat (C13), Concern Medicines (C8)
Each subscale score is simply calculated as the average score among the items included in that 
subscale. In addition to the 7 subscales, there is a single global score that reflects the results on all 
31 items. The global score is the average score among all the items in the HBQOL. Responses are
transformed along a 0 to 100-point scale, where lower scores denote less HRQOL impact, and
higher scores denote more HRQOL impact (i.e., 0=best score; 100=worst score).
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For example, consider these sample scores for items in the vulnerability scale:
Item Number
Item Name
Raw Score
Scaled Score
C13
Concern eat
2
25
C6
Concern sick easily
4
75
C8
Concern medicines
3
50
Average
50
The score on this subscale is 50 out of a possible score of 100, where higher scores denote more 
severe negative impact of HBV on HRQOL.
9.1.2.
Analysis Methods
Descriptive statistics of the actual values and change from baseline values at each timepoint 
(including baseline, Week 24, end of induction, end of consolidation phase, FU Week 24 and FU 
Week48) for the derived scores will be displayed for subscales/domains and global score by 
analysis phase and by cohort. The proportion of participants experiencing a clinically important
improvement or worsening from baseline (if applicable) at each timepoint will be calculated by 
analysis phase and by cohort. Clinically important improvement = change from baseline >= 10, 
Clinically important worsening = change from baseline <= -10. Other change from baseline values 
will be categorized as ‘No clinically important change’. Analyses will also be performed on the 
changes from baseline at specific time points (end of consolidation phase, FU Week 24 and FU 
Week 48) as appropriate for different subgroups: participants with HBsAg seroclearance 24 weeks 
and 48 weeks after completion of consolidation phase treatment, in patients stopping NA (at FU 
Week 2) without restarting NA treatment, versus those without HBsAg seroclearance at those time 
points.
9.2.
Short Form 36 version 2
9.2.1.
Definition
The SF-36 is a 36-item generic PRO instrument designed to measure physical and mental health 
status. Participants self-report on items that have between 2-6 response options per item using 
Likert-type responses (e.g., none of the time, some of the time). The SF-36 is scored and interpreted 
using two summary scores – Physical Component Summary (PCS) and Mental Component 
Summary (MCS) – and eight domain subscales:

PF: Physical functioning

RP: Role limitations due to physical health problems

BP: Bodily pain

SF: Social functioning

MH: General mental health, covering psychological distress & well-being

RE: Role limitations due to emotional problems

VT: Vitality, energy and fatigue

GH: General health perceptions
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Although SF-36v2 PCS and MCS scores include information from all 8 SF-36 domain subscales, 
the PCS score gives more weight to physical aspects of health status as represented in the Physical 
functioning, Physical role limitations, Pain, and General health perception domain scores. The 
MCS score gives more weight to the emotional and mental and social aspects of health status as 
assessed by the Vitality, Social function, Social role limitations, and Mental health domain scores.
A scoring algorithm will be used to convert the raw scores into the eight dimensions listedabove. 
The total domain scores of domain scales will be transformed into a range from zero where the 
respondent has the worst possible health to 100 where the respondent is in the best possible health. 
The scores (0-100) will then be standardized using means and standard deviation from 2009 U.S. 
general population and converted to norm-based scores using a T-score transformation (mean = 
50, SD = 10). The two component scores will be derived as linear combination of the standardized 
(2009 U.S. norm) scores using weights from principal component analysis. Each component score 
will be transformed to the corresponding PCS T-score and MCS T-score (mean = 50 and SD = 10)
The domain scale scores, and component summary scores will be calculated using the Quality 
Metric Health Outcomes™ Scoring Software, version 4.5.1 or a later version and the OPTUM 
scoring software (Third Party vendor). In case of missingness the Full Missing Score Estimation 
(MSE) method or Item Response Theory (IRT) will be used, if applicable, for imputation of 
missing values (Maruish, 2011).
9.2.2.
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 derived PCS, MCS and 8 domain 
scores will be displayed by analysis phase and by cohort.
The number (and percentage) of participants with clinically important improvement/ worsening 
will be presented for SF-36 v2 components (PCS score, MCS score and 8 domain scores (T-
scores):

Clinical Important Improvement = change from baseline ≥5

Clinical Important Worsening = change from baseline ≤-5.

Other changes from baseline values are categorized as ‘No Clinically Important Change’.
9.3.
5-Level EuroQol 5-Dimension Questionnaire
9.3.1.
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).
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The EQ-5D-5L questionnaire will be analyzed in 3 ways:

EQ-5D descriptive system scores (5 scores reflecting each of the 5 dimensions).
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)).
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 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.
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. 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.
9.3.2.
Analysis Methods
For the EQ-5D descriptive system, descriptive statistics on the actual value and change from 
baseline will be presented by analysis phase and by cohort.
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 as appropriate for different subgroups: participants with HBsAg seroclearance 24 
weeks and 48 weeks after completion of consolidation phase treatment, in patients stopping NA 
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(at FU Week 2) without restarting NA treatment, versus those without HBsAg seroclearance at 
those time points.
The clinically 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).
9.4.
Patient Global Impression of Change Scale (PGIC)
9.4.1.
Definition
The PGIC scale is a single-item PRO scale aimed at assessing the participant’s perceptions of
change (improvement or worsening) in how they feel overall compared to the beginning of the 
study. Response options include: “Much better”, “Better”, “A little better”, “No change”, “A little 
worse”, “Worse”, “Much worse”.
9.4.2.
Analysis Methods
The tabulation of the number and percentage of participants at each response level will be
displayed per time point by analysis phase and by cohort. 
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10.
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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.
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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-
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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
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Honaker J, King G et al.. Amelia II: A Program for Missing Data. Journal of Statistical Software, 45, 7, Pp. 1-
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Inker LA, Schmid CH, Tighiouart H, Eckfeldt JH, Feldman HI, Greene T, Kusek JW, Manzi J, Van Lente F, 
Zhang YL, Coresh J, Levey AS; CKD-EPI Investigators. Estimating glomerular filtration rate from serum 
creatinine and cystatin C. N Engl J Med. 2012 Jul 5;367(1):20-9. 
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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.
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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.
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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.
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Lui K.J., Kelly C. A Revisit on Tests for Homogeneity of the Risk Difference, Biometrics, 2000; 56:309-315.
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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.
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Maruish M. E. (Ed.). User’s manual for the SF-36v2 Health Survey (3rd ed.). Lincoln, RI:QualityMetric
Incorporated.
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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.
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Ratitch B., Lipkovitch I., O’Kelly M. (2013), Combining Analysis Results from Multiply Imputed Categorical 
Data, PhasrmaSUG, Paper SP03.
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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.
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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 v25.1)
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 v25.1)
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
Renal tubular necrosis
Urine output decreased
Nephropathy
Nephropathy toxic
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Adverse Event of Special 
Interest
Source
Preferred Term
Glomerulonephropathy
Nephrolithiasis
Cholesterol increase
Dyslipidaemia (SMQ), (MedDRA v25.1)
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
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 v25.1)
Aplastic anaemia
Autoimmune aplastic anaemia
Bicytopenia
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Adverse Event of Special 
Interest
Source
Preferred Term
Bone marrow failure
Cytopenia
Febrile bone marrow aplasia
Full blood count decreased
Gelatinous transformation of the bone 
marrow
Immune-mediated pancytopenia
Pancytopenia
Panmyelopathy
Aspiration bone marrow abnormal
Biopsy bone marrow abnormal
Full Blood count abnormal
Blood disorder
Bone marrow disorder
Bone marrow infiltration
Bone marrow myelogram abnormal
Bone marrow necrosis
Haematotoxicity
Myelodysplastic syndrome
Myelodysplastic syndrome transformation
Myelofibrosis
Myeloid metaplasia
Plasmablast count decreased
Scan bone marrow abnormal
(Modified) Haematopoietic erythropenia (SMQ), (MedDRA 
v25.1)
Aplasia pure red cell
Aplastic anaemia
Erythroblast count decreased
Erythroid maturation arrest
Erythropenia
Hypoplastic anaemia
Microcytic anaemia
Proerythroblast count decreased
Red blood cell count decreased
Reticulocyte count decreased
Reticulocytopenia
Anaemia
Erythroblast count abnormal
Erythropoiesis abnormal
Haematocrit abnormal
Haematocrit decreased
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Adverse Event of Special 
Interest
Source
Preferred Term
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
(Modified) Haematopoietic leukopenia (SMQ), (MedDRA 
v25.1)
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
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
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Adverse Event of Special 
Interest
Source
Preferred Term
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
White blood cell count abnormal
White blood cell disorder
(Modified) Haematopoietic thrombocytopenia (SMQ), 
(MedDRA v25.1)
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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