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-naive Patients With HBeAg Positive Chronic Hepatitis B Virus Infection
Phase: PHASE2
Conditions: Hepatitis B, Chronic
Sponsor: Janssen Research & Development, LLC

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.
NCT04439539

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
NCT04439539

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
NCT04439539

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
NCT04439539

JNJ-73763989 and JNJ-56136379 
Clinical Protocol 73763989PAHPB2005
Amendment 7
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
5
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.
NCT04439539

NCT04439539

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.
NCT04439539

JNJ-73763989 and JNJ-56136379 
Clinical Protocol 73763989PAHPB2005
Amendment 7
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
23
Status: Approved,  Date: 25 November 2021
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.
NCT04439539

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NCT04439539

NCT04439539

JNJ-73763989 and JNJ-56136379 
Clinical Protocol 73763989PAHPB2005
Amendment 7
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Status: Approved,  Date: 25 November 2021
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.
NCT04439539

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NCT04439539

NCT04439539

NCT04439539

JNJ-73763989 and JNJ-56136379 
Clinical Protocol 73763989PAHPB2005
Amendment 7
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
35
Status: Approved,  Date: 25 November 2021
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.
NCT04439539

JNJ-73763989 and JNJ-56136379 
Clinical Protocol 73763989PAHPB2005
Amendment 7
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
36
Status: Approved,  Date: 25 November 2021
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.
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
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
NCT04439539

JNJ-73763989 and JNJ-56136379 
Clinical Protocol 73763989PAHPB2005
Amendment 7
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
38
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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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
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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NCT04439539

JNJ-73763989 and JNJ-56136379 
Clinical Protocol 73763989PAHPB2005
Amendment 7
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
40
Status: Approved,  Date: 25 November 2021
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-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
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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JNJ-73763989 and JNJ-56136379 
Clinical Protocol 73763989PAHPB2005
Amendment 7
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Status: Approved,  Date: 25 November 2021
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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JNJ-73763989 and JNJ-56136379 
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Status: Approved,  Date: 25 November 2021
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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 
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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NCT04439539

NCT04439539

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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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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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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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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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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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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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Status: Approved,  Date: 25 November 2021
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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JNJ-73763989 and JNJ-56136379 
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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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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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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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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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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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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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 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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CCI
CCI
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Scaling and Scoring Instructions
CCI
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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
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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Status: Approved,  Date: 25 November 2021
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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Status: Approved,  Date: 25 November 2021
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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Status: Approved,  Date: 25 November 2021
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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Status: Approved,  Date: 25 November 2021
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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Clinical Protocol 73763989PAHPB2005
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Status: Approved,  Date: 25 November 2021
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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Status: Approved,  Date: 25 November 2021
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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Status: Approved,  Date: 25 November 2021
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
NCT04439539

JNJ-73763989 and JNJ-56136379 
Clinical Protocol 73763989PAHPB2005
Amendment 7
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
178
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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Clinical Protocol 73763989PAHPB2005
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Status: Approved,  Date: 25 November 2021
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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Clinical Protocol 73763989PAHPB2005
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INVESTIGATOR AGREEMENT
I have read this protocol and agree that it contains all necessary details for carrying out this study. I will
conduct the study as outlined herein and will complete the study within the time designated.
I will provide copies of the protocol and all pertinent information to all individuals responsible to me who
assist in the conduct of this study. I will discuss this material with them to ensure that they are fully informed
regarding the study intervention, the conduct of the study, and the obligations of confidentiality.
Coordinating Investigator (where required):
Name (typed or printed):
Institution and Address:
Signature: 
Date:
(Day Month Year)
Principal (Site) Investigator:
Name (typed or printed):
Institution and Address:
Telephone Number:
Signature: 
Date:
(Day Month Year)
Sponsor's Responsible Medical Officer:
Name (typed or printed): 
Institution: 
Janssen Research & Development
Signature: 
[electronic signature appended at the end of the protocol] 
Date:
(Day Month Year)
Note: If the address or telephone number of the investigator changes during the study, written notification will be
provided by the investigator to the sponsor, and a protocol amendment will not be required.
PPD
NCT04439539

Signature
User 
Date 
Reason
 
25-Nov-2021 
17:23:18
(GMT)
Document Approval
PPD
NCT04439539