A Randomized, Double Blind, Placebo-controlled Phase 2b Study to Evaluate Efficacy, Pharmacokinetics, and Safety of 48-week Study Intervention With JNJ 73763989+JNJ 56136379+Nucleos(t)Ide Analog (NA) Regimen Compared to NA Alone in e Antigen Negative Virologically Suppressed Participants With Chronic Hepatitis B Virus Infection
Phase: PHASE2
Conditions: Hepatitis B, Chronic
Sponsor: Janssen Sciences Ireland UC

CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
1
Status: Approved,  Date: 26 November 2021
Janssen Research & Development *
Clinical Protocol
Intervention-specific Appendix 2 to Master Protocol PLATFORMPAHPB2001
AMENDMENT 3
A Randomized, Double-blind, Placebo-controlled Phase 2b Study to Evaluate Efficacy,
Pharmacokinetics, and Safety of 48-week Study Intervention With
JNJ-73763989+JNJ-56136379+Nucleos(t)ide Analog (NA) Regimen Compared to NA Alone
in e Antigen-negative Virologically Suppressed Participants With Chronic Hepatitis B
Virus Infection
REEF-2 Study
Protocol 73763989PAHPB2002; Phase 2b
AMENDMENT 4
JNJ-73763989 and JNJ-56136379
*Janssen Research & Development is a global organization that operates through different legal entities in
various countries. Therefore, the legal entity acting as the sponsor for Janssen Research & Development
studies may vary, such as, but not limited to Janssen Biotech, Inc.; Janssen Products, LP; Janssen
Biologics, BV; Janssen-Cilag International NV; Janssen, Inc; Janssen Pharmaceutica NV; Janssen
Sciences Ireland Unlimited Company; Janssen Biopharma Inc.; or Janssen Research & Development,
LLC. The term “sponsor” is used throughout the protocol to represent these various legal entities; the
sponsor is identified on the Contact Information page that accompanies the protocol. 
EudraCT NUMBER: 2019-002674-31
Status: 
Approved 
Date: 
26 November 2021
Prepared by: Janssen Research & Development, a division of Janssen Pharmaceutica NV
EDMS number: 
EDMS-ERI-188471315, 8.0
GCP Compliance: This study will be conducted in compliance with Good Clinical Practice, and applicable regulatory
requirements.
Confidentiality Statement
The information in this document contains trade secrets and commercial information that are privileged or confidential and
may not be disclosed unless such disclosure is required by applicable law or regulations. In any event, persons to whom the
information is disclosed must be informed that the information is privileged or confidential and may not be further disclosed
by them. These restrictions on disclosure will apply equally to all future information supplied to you that is indicated as
privileged or confidential.
NCT04129554

JNJ-73763989 and JNJ-56136379
Clinical Protocol 73763989PAHPB2002
AMENDMENT 4
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
2
Status: Approved,  Date: 26 November 2021
PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE
DOCUMENT HISTORY
Document 
Date
Amendment 4 
This document
Amendment 3 
30-September-2021
Amendment 2 
27-January-2020
Amendment 1 
26-Sept-2019
Original Protocol 
31-Jul-2019
Amendment 4 (This document)
Overall Rationale for the Amendment: The primary reason for this amendment is to update the
criteria for post-treatment monitoring and for nucleos(t)ide analog (NA) re-treatment for
participants who discontinued NA treatment at Week 48.
With Amendment 3, changes were introduced to the criteria for post-treatment monitoring and
NA re-treatment for patients who discontinued NA treatment. These changes were triggered by a
case of hepatitis B reactivation with subacute hepatic failure (initially reported as severe clinical
ALT flare) following NA treatment cessation as per protocol in the REEF-2
(73763989PAHPB2002) study which led to listing of the patient for high urgency liver
transplantation. The patient received a donor liver at Week 14 post-stopping NA and has since
then showed an uneventful post-operative recovery.
To further protect the safety of study participants, the current amendment includes additional
changes to the criteria for post-treatment monitoring and for NA re-treatment for participants
who discontinued NA treatment.
These changes are based on additional follow-up information from participants in the REEF-2
study who stopped all treatment including NA per protocol and is incorporating
recommendations from Health Authorities and the independent data monitoring committee.
Description of Change 
Brief Rationale 
Section Number and Name
Update of criteria for 
post-treatment monitoring and 
for NA re-treatment 
In further off-treatment analysis
of REEF-2 with all participants
having reached at least
12 weeks of follow-up post
stopping NA, some participants
show a pattern of fast increase
of HBV DNA followed by
significant elevations of ALT
that improved after re-starting
of NA treatment. Based on these
observations it was decided to
implement more conservative
rules for post-treatment
monitoring and re-treatment
criteria for all participants who
met NA treatment completion
criteria and stopped NA
treatment.
1.1 Synopsis
1.3.2 Schedule of Activities –Follow-up Phase
2.3.3 Benefit-risk Assessment for Study
Participation
4.2 Scientific Rationale for Study Design
6.7 NA Re-treatment Criteria and Monitoring
After Stopping of NA
10.13 Appendix 13: NA Re-treatment and
Monitoring After Stopping of NA
NCT04129554

JNJ-73763989 and JNJ-56136379
Clinical Protocol 73763989PAHPB2002
AMENDMENT 4
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
3
Status: Approved,  Date: 26 November 2021
Description of Change 
Brief Rationale 
Section Number and Name
Minor grammatical, formatting, 
or spelling changes were made.
Minor errors were noted 
Throughout the protocol
NCT04129554

JNJ-73763989 and JNJ-56136379
Clinical Protocol 73763989PAHPB2002
AMENDMENT 4
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
4
Status: Approved,  Date: 26 November 2021
TABLE OF CONTENTS
PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE ............................................................... 2
TABLE OF CONTENTS ............................................................................................................................... 4
LIST OF IN-TEXT TABLES AND FIGURES................................................................................................ 6
1. 
PROTOCOL SUMMARY..................................................................................................................... 7
1.1. 
Synopsis........................................................................................................................................... 7
1.2. 
Schema.......................................................................................................................................... 19
1.3. 
Schedule of Activities..................................................................................................................... 20
1.3.1. 
Schedule of Activities –Screening and Study Intervention Phase............................................. 20
1.3.2. 
Schedule of Activities –Follow-up Phase................................................................................... 25
2. 
INTRODUCTION................................................................................................................................ 29
2.1. 
Study Rationale.............................................................................................................................. 30
2.2. 
Background .................................................................................................................................... 31
2.2.1. 
JNJ-3989 and JNJ-6379............................................................................................................. 31
2.2.2. 
Combination of JNJ-3989 and JNJ-6379 with Entecavir, Tenofovir Disoproxil Fumarate,
or Tenofovir Alafenamide............................................................................................................ 41
2.3. 
Benefit-Risk Assessment............................................................................................................... 43
2.3.1. 
Benefits for Study Participation .................................................................................................. 43
2.3.1.1. 
Known Benefits........................................................................................................................ 43
2.3.1.2. 
Potential Benefits..................................................................................................................... 44
2.3.2. 
Risks for Study Participation....................................................................................................... 44
2.3.2.1. 
Known Risks............................................................................................................................ 44
2.3.2.2. 
Potential Risks......................................................................................................................... 44
2.3.2.2.1. 
Potential Risks for JNJ-3989................................................................................................ 44
2.3.2.2.2. 
Potential Risks for JNJ-6379................................................................................................ 45
2.3.3. 
Benefit-risk Assessment for Study Participation......................................................................... 46
3. 
OBJECTIVES AND ENDPOINTS ..................................................................................................... 47
4. 
STUDY DESIGN ................................................................................................................................ 50
4.1. 
Overall Design................................................................................................................................ 50
4.2. 
Scientific Rationale for Study Design............................................................................................. 53
4.2.1. 
Study-specific Ethical Design Considerations ............................................................................ 55
4.3. 
Justification for Dose...................................................................................................................... 55
4.3.1. 
JNJ-3989.................................................................................................................................... 55
4.3.2. 
JNJ-6379.................................................................................................................................... 55
4.4. 
End of Study Definition................................................................................................................... 56
4.4.1. 
Participant Completion................................................................................................................ 56
4.4.2. 
Study Completion (End of Study Definition)............................................................................... 56
5. 
STUDY POPULATION ...................................................................................................................... 56
5.1. 
Inclusion Criteria............................................................................................................................ 57
5.2. 
Exclusion Criteria........................................................................................................................... 59
5.3. 
Lifestyle Considerations................................................................................................................. 63
5.4. 
Screen Failures.............................................................................................................................. 64
6. 
STUDY INTERVENTION................................................................................................................... 65
6.1. 
Study Intervention(s) Administered................................................................................................ 65
6.2. 
Preparation/Handling/Storage/Accountability ................................................................................ 67
6.3. 
Measures to Minimize Bias: Randomization and Blinding............................................................. 68
6.4. 
Study Intervention Compliance...................................................................................................... 69
6.5. 
Concomitant Therapy..................................................................................................................... 69
NCT04129554

JNJ-73763989 and JNJ-56136379
Clinical Protocol 73763989PAHPB2002
AMENDMENT 4
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
5
Status: Approved,  Date: 26 November 2021
6.6. 
Study Intervention Completion at Week 48.................................................................................... 71
6.7. 
NA Re-treatment Criteria and Monitoring After Stopping of NA..................................................... 71
6.8. 
Intervention After the End of the Study.......................................................................................... 73
7. 
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT
DISCONTINUATION/WITHDRAWAL............................................................................................... 73
7.1. 
Discontinuation of Study Intervention ............................................................................................ 73
7.2. 
Participant Discontinuation/Withdrawal From the Study................................................................ 74
7.2.1. 
Withdrawal From the Use of Research Samples ....................................................................... 74
7.3. 
Lost to Follow-up............................................................................................................................ 74
8. 
STUDY ASSESSMENTS AND PROCEDURES ............................................................................... 74
8.1. 
Efficacy Assessments .................................................................................................................... 75
8.1.1. 
Sequencing................................................................................................................................. 76
8.1.2. 
Patient-reported Outcomes ........................................................................................................ 76
8.2. 
Safety Assessments....................................................................................................................... 77
8.2.1. 
Physical Examinations................................................................................................................ 78
8.2.2. 
Vital Signs................................................................................................................................... 78
8.2.3. 
Electrocardiograms..................................................................................................................... 78
8.2.4. 
Clinical Safety Laboratory Assessments .................................................................................... 78
8.3. 
Adverse Events and Serious Adverse Events ............................................................................... 78
8.3.1. 
Time Period and Frequency for Collecting Adverse Event and Serious Adverse Event
Information.................................................................................................................................. 78
8.3.2. 
Method of Detecting Adverse Events and Serious Adverse Events .......................................... 78
8.3.3. 
Follow-up of Adverse Events and Serious Adverse Events ....................................................... 78
8.3.4. 
Regulatory Reporting Requirements for Serious Adverse Events ............................................. 79
8.3.5. 
Pregnancy................................................................................................................................... 79
8.3.6. 
Adverse Events of Special Interest............................................................................................. 79
8.3.6.1. 
Rash ........................................................................................................................................ 79
8.3.6.1.1. 
Injection Site Reactions........................................................................................................ 80
8.3.6.2. 
Acute Systemic Allergic Reactions.......................................................................................... 80
8.3.6.3. 
Intervention-emergent ALT/AST Elevations............................................................................ 81
8.3.6.4. 
Renal Complications................................................................................................................ 82
8.3.6.5. 
Hematologic Abnormalities...................................................................................................... 82
8.4. 
Treatment of Overdose .................................................................................................................. 83
8.5. 
Pharmacokinetics........................................................................................................................... 83
8.6. 
Pharmacokinetic/Pharmacodynamic Evaluations.......................................................................... 84
8.7. 
Immune Assessments.................................................................................................................... 84
8.8. 
Host Genetics................................................................................................................................. 84
8.9. 
Exploratory Host Biomarkers ......................................................................................................... 85
9. 
STATISTICAL CONSIDERATIONS.................................................................................................. 85
9.1. 
Statistical Hypothesis..................................................................................................................... 85
9.2. 
Sample Size Determination ........................................................................................................... 86
9.3. 
Populations for Analyses................................................................................................................ 86
9.4. 
Statistical Analyses ........................................................................................................................ 86
9.4.1. 
Efficacy Analyses........................................................................................................................ 86
9.4.1.1. 
Primary Efficacy Endpoint (HBsAg Seroclearance 24 Weeks After Completion of All
Study Interventions at Week 48)............................................................................................. 87
9.4.1.2. 
Secondary and Exploratory Efficacy Endpoints ...................................................................... 87
9.4.1.3. 
Resistance Analyses ............................................................................................................... 89
9.4.1.4. 
Patient-reported Outcomes ..................................................................................................... 89
9.4.2. 
Safety Analyses.......................................................................................................................... 89
9.4.3. 
Other Analyses ........................................................................................................................... 89
9.5. 
Interim Analyses............................................................................................................................. 91
9.6. 
Independent Data Monitoring Committee ...................................................................................... 91
9.7. 
Independent Flare Expert Panel .................................................................................................... 92
NCT04129554

JNJ-73763989 and JNJ-56136379
Clinical Protocol 73763989PAHPB2002
AMENDMENT 4
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
6
Status: Approved,  Date: 26 November 2021
10. SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS ............................ 93
10.1. 
Appendix 1: Abbreviations and Definitions of Terms..................................................................... 93
10.2. 
Appendix 2: Clinical Laboratory Tests ........................................................................................... 96
10.3. 
Appendix 3: Regulatory, Ethical, and Study Oversight Considerations......................................... 97
REGULATORY AND ETHICAL CONSIDERATIONS................................................................................. 97
FINANCIAL DISCLOSURE......................................................................................................................... 97
INFORMED CONSENT PROCESS............................................................................................................ 97
DATA PROTECTION.................................................................................................................................. 97
LONG-TERM RETENTION OF SAMPLES FOR ADDITIONAL FUTURE RESEARCH ............................ 97
COMMITTEES STRUCTURE..................................................................................................................... 97
PUBLICATION POLICY/DISSEMINATION OF CLINICAL STUDY DATA................................................. 98
DATA QUALITY ASSURANCE................................................................................................................... 98
CASE REPORT FORM COMPLETION...................................................................................................... 98
SOURCE DOCUMENTS............................................................................................................................. 98
MONITORING............................................................................................................................................. 98
ON-SITE AUDITS ....................................................................................................................................... 98
RECORD RETENTION............................................................................................................................... 98
STUDY AND SITE START AND CLOSURE .............................................................................................. 98
10.4. 
Appendix 4: Adverse Events: Definitions and Procedures for Recording, Evaluating,
Follow-up, and Reporting............................................................................................................... 99
ADVERSE EVENT DEFINITIONS AND CLASSIFICATIONS .................................................................... 99
ATTRIBUTION DEFINITIONS .................................................................................................................... 99
SEVERITY CRITERIA................................................................................................................................. 99
SPECIAL REPORTING SITUATIONS........................................................................................................ 99
PROCEDURES........................................................................................................................................... 99
CONTACTING SPONSOR REGARDING SAFETY ................................................................................... 99
PRODUCT QUALITY COMPLAINT HANDLING ........................................................................................ 99
10.5. 
Appendix 5: Rash Management................................................................................................... 100
10.6. 
Appendix 6: Intervention-emergent ALT/AST Elevations ............................................................ 104
10.7. 
Appendix 7: Cardiovascular Safety –Abnormalities.................................................................... 105
10.8. 
Appendix 8: Contraceptive and Barrier Guidance and Collection of Pregnancy Information...... 106
10.9. 
Appendix 9: DAIDS Table ............................................................................................................ 108
10.10. Appendix 10: HBV-specific Self-stigma Scale ............................................................................. 131
10.11. Appendix 11: 5-Level EuroQol 5-Dimension Questionnaire (EQ-5D-5L).................................... 133
10.12. Appendix 12: Protocol Amendment History................................................................................. 136
10.13. Appendix 13: NA Re-treatment and Monitoring After Stopping of NA......................................... 144
11. REFERENCES................................................................................................................................. 145
INVESTIGATOR AGREEMENT............................................................................................................... 148
LIST OF IN-TEXT TABLES AND FIGURES
TABLES
Table 1: 
Animal/Human Exposure Ratios at NOAEL for JNJ-3989........................................................ 33
Table 2: 
Animal/Human Ratios at the NOAEL in Rat and Dog (Human Exposure at 250mg
JNJ-6379 Once Daily for 28 Days [Study 56136379HPB1001]).............................................. 34
Table 3: 
Disallowed Medication .............................................................................................................. 70
Table 4: 
Concomitant Medications to be Used With Caution ................................................................. 71
Table 5: 
Management of Rash Events by Severity Grade ................................................................... 100
FIGURES
Figure 1: Schematic Overview of the Study............................................................................................. 19
NCT04129554

JNJ-73763989 and JNJ-56136379
Clinical Protocol 73763989PAHPB2002
AMENDMENT 4
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
7
Status: Approved,  Date: 26 November 2021
1. 
PROTOCOL SUMMARY
1.1. 
Synopsis
Clinical Protocol 73763989PAHPB2002: A Randomized, Double-blind, Placebo-controlled Phase 2b
Study to Evaluate Efficacy, Pharmacokinetics, and Safety of 48-week Study Intervention With
JNJ-73763989+JNJ-56136379+Nucleos(t)ide Analog (NA) Regimen Compared to NA Alone in
e Antigen-negative Virologically Suppressed Participants With Chronic Hepatitis B Virus Infection.
Protocol 73763989PAHPB2002 is an intervention-specific appendix (ISA) to Master Protocol
PLATFORMPAHPB2001.
JNJ-73763989 (JNJ-3989) is a liver-targeted antiviral therapeutic for subcutaneous injection designed to
treat chronic hepatitis B virus (HBV) infection via a ribonucleic acid interference (RNAi) mechanism.
Engagement of the cellular RNAi machinery by JNJ-3989 results in specific cleavage of HBV ribonucleic
acid (RNA) transcripts, thereby reducing the levels of HBV proteins and the pre-genomic ribonucleic acid
(pgRNA), the precursor of viral relaxed circular deoxyribonucleic acid (DNA). The RNAi triggers
(JNJ-73763976 [JNJ-3976] and JNJ-73763924 [JNJ-3924]) in JNJ-3989 are designed to target all HBV
RNA transcripts derived from covalently closed circular DNA (cccDNA), as well as transcripts derived
from integrated viral DNA. The latter has been suggested to be a significant source of hepatitis B surface
antigen (HBsAg) in hepatitis B e antigen (HBeAg)-negative patients or patients on long-term treatment
with nucleos(t)ide analogs (NAs), the current standard of care.
JNJ-56136379 (JNJ-6379) is an orally administered capsid assembly modulator that is being developed
for the treatment of chronic HBV infection. JNJ-6379 binds to hepatitis B core protein and interferes with
the viral capsid assembly process, thereby preventing the polymerase-bound pgRNA encapsidation. This
results in the formation of HBV capsids, devoid of HBV DNA or RNA (non-functional capsids), and
ultimately in the inhibition of HBV replication. In addition, JNJ-6379 also acts at an early stage of the
viral life cycle by inhibiting the de-novo formation of cccDNA potentially by interfering with the capsid
disassembly process.
Study intervention refers to JNJ-3989 or placebo for JNJ-3989, JNJ-6379 or placebo for JNJ-6379, and
NA.
OBJECTIVES AND ENDPOINTS
Below is the list of objectives and endpoints that will be evaluated in this study, delineating the details in
alignment with the general objectives listed in the Master Protocol PLATFORMPAHPB2001. The details
specific for this ISA are highlighted (colored fill).
Objectives 
Endpoints
Primary
 
To evaluate the efficacy of 48-week study 
intervention 
with 
JNJ-3989+JNJ-6379+NA 
regimen compared to NA alone. 
 
Proportion of participants with HBsAg
seroclearance at Week 72 (ie, 24 weeks
after completion of all study interventions
at Week 48) without restarting NA
treatment.
Secondary
 
To evaluate the safety and tolerability of the 
study intervention throughout the study. 
 
Safety and tolerability including but not
limited to the proportion of participants
with (serious) adverse events ([S]AEs)
and abnormalities in clinical laboratory
tests 
(including 
hematology, 
blood
biochemistry, 
blood 
coagulation,
NCT04129554

NCT04129554

NCT04129554

JNJ-73763989 and JNJ-56136379
Clinical Protocol 73763989PAHPB2002
AMENDMENT 4
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
10
Status: Approved,  Date: 26 November 2021
Hypothesis
The primary hypothesis of this study is that the combination regimen of JNJ-3989+JNJ-6379+NA is more
efficacious than NA treatment alone, as measured by the primary efficacy endpoint, the proportion of
participants with HBsAg seroclearance at Week 72 (ie, 24 weeks after completion of all study
interventions at Week 48) without restarting NA treatment.
OVERALL DESIGN
This ISA describes a Phase 2b study of JNJ-3989 and JNJ-6379. It is a companion document to the
Master Protocol PLATFORMPAHPB2001, which describes the common design elements of the Platform
study  in participants with chronic hepatitis B (CHB). This ISA describes specific and/or additional
protocol elements applicable to this intervention cohort, in which participants will be treated with the
study intervention, JNJ-3989 and JNJ-6379 or placebos, in combination with NA.
The study described in this ISA is a Phase 2b, multicenter, randomized, double-blind, placebo-controlled,
2 parallel-group study to evaluate the efficacy of 48-week study intervention with
a JNJ-3989+JNJ-6379+NA regimen compared to NA treatment alone, assessed by HBsAg seroclearance
at Week 72 (ie, 24 weeks after completion of all study interventions at Week 48) without restarting NA
treatment in HBeAg-negative virologically  suppressed CHB-infected participants who received NA
treatment for at least 2 years prior to screening. All participants will stop all study interventions including
NAs at Week 48 and will be followed up until Week 96. After completing this study, participants may
have the option to enroll into a long-term follow-up study.
The study will be conducted in 3 phases: a screening phase (4 weeks), a study intervention phase
(48 weeks), and a follow-up phase (48 weeks). If necessary, eg, for operational reasons, the screening
phase may be extended up to a maximum of 6 weeks on a case-by-case basis and in agreement with the
sponsor. The duration of individual participation will be up to 102 weeks.
A target of 120 participants will be randomized in a 2:1 ratio to one of the following intervention arms
and will receive study intervention for 48 weeks:
 
Intervention Arm 1 (N=80): 200 mg JNJ-3989 (injection once monthly) +
250 mg JNJ-6379 (tablets once daily [qd]) +
NA* qd;
 
Intervention Arm 2 (N=40): placebo for JNJ-3989 (injection once monthly) +
placebo for JNJ-6379 (tablets qd) +
NA* qd.
* NA: entecavir (ETV), tenofovir disoproxil fumarate (TDF) or tenofovir alafenamide (TAF)
All participants who complete 48-week study intervention should stop all study interventions including
NAs at Week 48. Any relevant change in participant baseline status with regards to ALT, HBV DNA
levels and/or HBeAg status or any other event that in the opinion of the investigator could prevent
stopping NA should be discussed with the sponsor. After stopping all study interventions, participants
will be monitored closely during the 48-week follow-up phase and should restart NA treatment in
accordance with  the NA re-treatment criteria (see Section ‘NA Re-treatment Criteria and Monitoring
After Stopping of NA’ for more details).
The investigator should consider to re-start NA treatment per local standard of care at the EOS visit
(Follow-up Week 48) for participants who discontinued NA treatment at Week 48, who did not re-start
NA treatment during the follow-up phase, and who did not achieve and maintain HBsAg seroclearance.
NA will not be provided by the sponsor after the final study visit.
NCT04129554

JNJ-73763989 and JNJ-56136379
Clinical Protocol 73763989PAHPB2002
AMENDMENT 4
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
11
Status: Approved,  Date: 26 November 2021
The investigators and participants will remain blinded to intervention allocation until all participants have
reached Week 72 (or discontinued earlier), while the sponsor’s central study team will be unblinded at the
time of the Week 48 interim analysis (IA). Details on the central study team will be provided in the
Independent Data Monitoring Committee (IDMC) charter.
All participants who consent to participate in the intensive PK subgroup (optional) will undergo intensive
PK sampling (minimally 18 participants).
Participants will be considered to have completed the study if they have completed the assessments of the
end-of-study visit Follow-up Week 48 (Week 96).
An IDMC will be commissioned for this study. In addition, an Independent Flare Expert Panel (IFLEP)
will be appointed.
NA Re-treatment Criteria and Monitoring After Stopping of NA
After completing treatment with JNJ-3989, JNJ-6379 (or their matching placebos) and NA at Week 48 (or
after premature discontinuation), participants will be monitored closely during the follow-up phase.
After stopping NA treatment, participants should be monitored as follows:
 
Regular monitoring visits will be every 4 weeks during the follow-up phase in accordance with the
Schedule of Activities.
 
A post-treatment HBV DNA value of >20,000 IU/mL should trigger re-testing of ALT/AST,
HBV DNA, and total and direct bilirubin within a maximum of 7 days from receipt of the data and
further repeats as necessary (ie, weekly until HBV DNA returns to <20,000 IU/mL).
 
A post-treatment HBV DNA value of >2,000 IU/mL (but <20,000 IU/mL) should trigger a re-
test within 14 days from receipt of the data and further repeats as necessary (ie, every other
week until HBV DNA returns to <2,000 IU/mL).
 
A post-treatment ALT value of >5x ULN should trigger re-testing of ALT, AST, alkaline
phosphatase (ALP), total and direct bilirubin, INR, albumin, and HBV DNA on a weekly basis until
ALT and AST levels have returned to <5x ULN.
After stopping NA treatment, participants should restart NA treatment:
 
Immediately with signs of decreasing liver function based on laboratory findings (eg, INR, direct
bilirubin) or clinical assessment (eg, ascites, hepatic encephalopathy).
 
Immediately with an HBV DNA value of >100,000 IU/mL (irrespective of confirmation and/or ALT
increase).
 
With confirmed post-treatment HBeAg seroreversion (HBeAg positive after it was negative at NA
completion).
 
With confirmed* post-treatment increases in HBV DNA >2,000 IU/mL and ALT >5x ULN.
 
With confirmed* post-treatment increases in HBV DNA >20,000 IU/mL.
* At least 4 weeks apart –frequency of visits as described above.
Note: Additional re-testing and/or earlier restarting of NA treatment is at the investigator’s
discretion, even if the above cut-offs are not yet met.
NCT04129554

JNJ-73763989 and JNJ-56136379
Clinical Protocol 73763989PAHPB2002
AMENDMENT 4
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
12
Status: Approved,  Date: 26 November 2021
To avoid delays in decision making, sites are encouraged to run local re-testing in parallel with central
re-testing in the situations described above that require more frequent re-testing. Local test results are to
be collected in the CRF and/or source documents, including information on the HBV DNA assay used. In
addition, to avoid delays in NA re-treatment, it should be considered to dispense NA to participants who
potentially met the NA re-treatment criteria (eg, pending confirmation) and who will not be available to
come to the study site immediately at the time the confirmatory test results will become available. This
should ensure that the participant can immediately restart NA treatment if indicated, upon direct
confirmation by the investigator.
NUMBER OF PARTICIPANTS
A target of 120 HBeAg-negative virologically suppressed CHB-infected male and female participants,
18-65 years (inclusive) of age will be randomized in a 2:1 ratio to receive either JNJ-3989 and JNJ-6379
in combination with NA  (N=80) or their respective placebos in combination with NA  (N=40).
Randomization will be stratified by screening HBsAg level (<1,000 IU/mL or >1,000 IU/mL), race
(Asian versus non-Asian) and type of NA (TDF/TAF versus ETV).
NCT04129554

JNJ-73763989 and JNJ-56136379
Clinical Protocol 73763989PAHPB2002
AMENDMENT 4
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
13
Status: Approved,  Date: 26 November 2021
Description of Interventions
Intervention name 
JNJ-3989 
Placebo for 
JNJ-3989 
JNJ-6379 
Placebo for 
JNJ-6379 
Entecavir (ETV) 
monohydrate 
Tenofovir 
disoproxil 
fumarate (TDF) 
Tenofovir
alafenamide
(TAF)***
Dosage formulation 
Solution for 
injection  
Solution for 
injection 
Tablets 
Tablets 
Film-coated tablets 
Film-coated 
tablets 
Film-coated
tablets
Unit dose strength(s) 
200 mg/vial 
0.9% saline 
25 and 100 mg 
- 
0.5 mg 
300 mg** 
25 mg
Dosage regimen 
200 mg once 
every 4 weeks 
1 mL once every 
4 weeks 
250 mg qd 
qd 
Lamivudine-refractory 
patients:
1 mg* qd (but should
preferably be treated
with TDF or TAF
instead)
Other indications:
1 mg* qd (must be
agreed upon by the
sponsor)
300 mg qd 
25 mg qd
Route of 
administration 
Subcutaneous 
injection (in the 
abdomen) 
Subcutaneous 
injection (in the
abdomen)
Oral 
Oral 
Oral 
Oral 
Oral
Dosing instructions 
Regardless of 
food intake 
Regardless of 
food intake 
Regardless of 
food intake 
Regardless of 
food intake
On an empty stomach  
With food 
With food
qd: once daily
* 2 tablets of 0.5 mg
** 300 mg TDF is equivalent to tenofovir disoproxil 245 mg
*** In countries where TAF is available, it will be one of the NA treatment options.
NCT04129554

JNJ-73763989 and JNJ-56136379
Clinical Protocol 73763989PAHPB2002
AMENDMENT 4
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
14
Status: Approved,  Date: 26 November 2021
EFFICACY EVALUATIONS
All efficacy assessments will be performed at predefined time points as specified in the Schedule of
Activities.
Qualitative and quantitative HBsAg and HBeAg, and quantitative HBcrAg as well as anti-hepatitis B
surface (HBs) and anti-hepatitis B e (HBe) antibodies will be determined using validated serologic assays
in a central laboratory. Samples for the determination of HBsAg and HBeAg will be processed in real-
time. Samples for the determination of HBcrAg can be analyzed in batch and at the sponsor’s request.
HBV DNA and HBV RNA will be quantified at central laboratories using validated assays for the
quantification of HBV DNA and HBV RNA. Samples for the determination of HBV DNA will be
processed in real-time. Samples for the determination of HBV RNA can be analyzed in batch and at the
sponsor’s request.
In participants enrolled at a site with an on-site Fibroscan device, Fibroscan assessments will be
performed at different time points to determine changes in fibrosis levels.
Samples may be used by the sponsor for additional exploratory assessments analyzing the serologic and
virologic characteristics of HBV infection and efficacy or safety of the study intervention.
Sequencing
Viral genome sequence analysis will be performed to evaluate mutations associated with  the study
intervention.
Patient-reported Outcomes
The impact of HBV treatment on participants will be assessed using PROs at predefined time points. The
following PRO instruments will be used: HBV-specific self-stigma scale and EQ-5D-5L questionnaire.
The content validity of the HBV-specific self-stigma scale is currently being evaluated and the data
collected in this study will be used to assess the psychometric properties of this scale.
SAFETY ASSESSMENTS
Safety and tolerability  (AEs, clinical safety laboratory assessments, ECGs, vital signs and physical
examinations) will be evaluated as described in Section 8.2 of the Master Protocol
PLATFORMPAHPB2001 and at predefined time points as specified in the Schedule of Activities. In
addition, urine samples for urine chemistry and renal biomarkers will be collected.
Specific toxicity management plans are in place for follow-up of rash, injection site reactions, acute
systemic allergic reactions, ALT/aspartate aminotransferase elevations, and renal complications.
PHARMACOKINETICS
Plasma samples will be used to evaluate the PK of the study intervention. Samples collected for analyses
of the study intervention’s plasma concentrations may additionally be used to evaluate safety or efficacy
aspects.
All participants will have sparse PK sampling on Day 1 and at Weeks 4, 12, and 24 (and at early
withdrawal). All participants who consent to participate in the intensive PK subgroup (optional) will
undergo intensive PK sampling at Week 4 (minimally 18  participants). If necessary (eg, for operational
reasons), this visit may be scheduled at Week 8, 12, or 16.
Plasma concentration-time data for JNJ-3989 (ie, JNJ-3976 and JNJ-3924), JNJ-6379 and, optionally, NA
will be analyzed via population PK for all participants. Area under the plasma concentration-time curve
NCT04129554

JNJ-73763989 and JNJ-56136379
Clinical Protocol 73763989PAHPB2002
AMENDMENT 4
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
15
Status: Approved,  Date: 26 November 2021
over 24 hours (AUC24h) and plasma trough concentrations (C0h) will be estimated using empiric Bayes
estimation.
Plasma concentration-time data for JNJ-3989 (ie, JNJ-3976 and JNJ-3924), JNJ-6379 and, optionally, NA
will be analyzed via noncompartmental methods for all participants who underwent intensive PK
sampling. The main PK parameters will be AUC24h, maximum plasma concentration (Cmax), time to Cmax
(tmax), C0h, plasma concentration at the end of the dosing interval (τ) (Cτ), and minimum plasma
concentration (Cmin). Additional exposure parameters may be calculated if applicable.
Data from this study may be combined with other studies via population PK modelling to enable the
calculation of the above PK parameters also in participants who only underwent sparse PK sampling.
PHARMACOKINETIC/PHARMACODYNAMIC EVALUATIONS
Relationships of individual PK parameters (intensive PK and population PK, as applicable) for JNJ-3989
(ie, JNJ-3976 and JNJ-3924), JNJ-6379, and NA, as applicable, with selected efficacy and safety
endpoints will be evaluated.
IMMUNE EVALUATIONS
At selected sites, PBMC samples for immune analyses will be collected during study intervention and
follow-up and will be analyzed centrally for HBV-specific responses by enzyme-linked immunospot
(ELISpot) and/or intracellular cytokine staining (ICS) after stimulation with HBV-specific antigens.
Additional experiments may be performed to further phenotypically and functionally characterize PBMCs
using proliferation or cytotoxic assays or other methods such as cytometry by time of flight to evaluate
innate and adaptive immune responses. Leftover PBMC samples may be used at the sponsor’s discretion
for additional exploratory research related to HBV infection or study intervention (safety/efficacy).
Additional PBMC samples may be taken in case of ALT flares, upon discussion with the sponsor, which
may require an unscheduled visit.
HOST GENETICS
A pharmacogenomic (host DNA) blood sample should be collected at baseline to allow for host
pharmacogenomic research, where local regulations permit. In addition, host DNA blood samples to
allow for epigenetic analyses will be collected. These samples could for example be used to assess
changes in frequencies of immune cells such as myeloid derived suppressor cells. These samples will only
be collected from participants who consent separately to this component of the study.
In addition, other samples may be used for exploratory genetic or epigenetic research in participants
consenting separately to this part of the study. No genetic research will be performed on any sample in
participants who have not provided the additional separate consent for host genetic research. These
samples can only be used to investigate the potential association of genetic or epigenetic factors with
efficacy, safety, or PK of the study intervention, or HBV infection, or may be used to develop tests/assays
related to the study intervention or HBV infection.
EXPLORATORY HOST BIOMARKERS
The study includes collection of blood samples for exploratory analysis of host blood biomarkers at the
host RNA, protein, and cell level.
Samples can only be used for research related to study intervention or HBV infection or may be used to
develop tests/assays related to study intervention or HBV infection.
NCT04129554

JNJ-73763989 and JNJ-56136379
Clinical Protocol 73763989PAHPB2002
AMENDMENT 4
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
16
Status: Approved,  Date: 26 November 2021
Blood samples will be taken that can be used to explore immunogenicity of JNJ-3989. The emergence of
antibodies to JNJ-3989 (antidrug antibodies) might be analyzed using assays such as an enzyme-linked
immunosorbent assay.
STATISTICAL METHODS
The primary analysis will be performed when all participants have completed Week 72 or discontinued
earlier. The final analysis will be performed when all participants have completed the last study visit
(Week 96) or discontinued earlier.
Sample Size Determination
The total study sample size is 120 participants who will be randomly assigned to one of the two
intervention arms in a 2:1 ratio (JNJ-3989+JNJ-6379+NA: placebo+placebo+NA). Statistical power to
test the primary hypothesis was assessed using the Mantel-Haenszel test with a 1-sided Type 1 error rate
of 0.05, assuming the observed percentage of participants with HBsAg seroclearance at Week 72 in the
placebo+placebo+NA arm to be 5%. The sample size of 80 participants in the investigational arm and 40
participants in the control arm provides >91% statistical power to detect a ≥20% difference in the primary
endpoint.
Efficacy Analyses
To evaluate the efficacy, the primary analysis set will be the Intent-to-treat (ITT) population. All
participants who were randomly assigned to an intervention arm and who received at least 1 dose of study
intervention within this ISA will be included in the ITT population. Participants will be analyzed
according to the study intervention they were randomly assigned to.
The baseline measurements are defined as the measurements taken closest to but before the first
administration of study intervention on Day 1.
Primary Efficacy Endpoint (HBsAg Seroclearance 24 Weeks After Completion of All Study
Interventions at Week 48)
The proportion of participants who achieved HBsAg seroclearance at Week 72 (24 weeks after
completion of 48 weeks of treatment with study intervention) without restarting NA treatment will be
compared between intervention arms at a 1-sided 0.05 alpha. The primary endpoint will be compared
between intervention arms using the stratum-adjusted Mantel-Haenszel difference in proportions, where
the stratification factors screening HBsAg level (<1,000 IU/mL or >1,000 IU/mL), race (Asian versus
non-Asian) and type of NA (TDF/TAF versus ETV) determine the strata. The associated 90% confidence
interval for the difference in proportions will also be calculated.
All participants who do not achieve HBsAg seroclearance at Week 72 and/or require NA re-treatment
between Week 48 and Week 72 are considered treatment non-responders for the purpose of the primary
endpoint analysis.
Secondary and Exploratory Efficacy Endpoints
Descriptive statistics will be used for all efficacy endpoints which will be summarized by intervention
arm and study phase. Comparisons between  intervention arms will be done with no adjustment for
multiplicity. Specific key selected endpoints may be analyzed using suitable categorical data approaches
(eg, Cochran-Mantel-Haenszel or logistic regression for proportions or other categorical type of
endpoint), longitudinal repeated measures models (eg, for continuous types of variables), or survival
analysis based on the Kaplan-Meier estimates (for time-to-event variables), as appropriate.
NCT04129554

JNJ-73763989 and JNJ-56136379
Clinical Protocol 73763989PAHPB2002
AMENDMENT 4
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
17
Status: Approved,  Date: 26 November 2021
Resistance Analyses
The results of HBV viral sequencing will be evaluated by the sponsor virologist. Relevant changes of
amino acid and/or nucleic acid variations (eg, substitutions) in the HBV genome will be tabulated and
described.
Additional exploratory characterization of the HBV viral sequence and phenotype may be performed and
reported separately.
Patient-reported Outcomes
The PRO scores will be analyzed descriptively as mean scores over time, and (if applicable) evaluated
based on the proportion of participants experiencing a clinically important improvement or worsening in
PRO scores from baseline during study intervention and follow-up. Analyses will also be performed on
PRO score changes from baseline at specific time points (Weeks 48, 72, 96) and between Week 48 and
later time points for different subgroups: participants with HBsAg seroclearance 24 weeks and 48 weeks
after completion of all study interventions at Week 48 without restarting NA treatment versus those
without HBsAg seroclearance at those time points.
The data collected in this study will be used to assess the psychometric properties of the HBV-specific
self-stigma scale. The psychometric analyses will be described in a separate document and results will be
presented in a separate report.
Safety Analyses
Safety analyses will be based on the safety population and are specified in Section 9.4.3 of the Master
Protocol PLATFORMPAHPB2001. All participants who received at least 1 dose of study intervention
within this ISA will be included in the safety population. Participants will be analyzed according to the
study intervention they actually received.
Safety will be evaluated by means of descriptive summaries of AEs including AEs of special interest to
any of the study interventions, clinical laboratory tests, ECGs, vital signs, and physical examinations. The
safety analysis will be done by study phase. Results will be presented in tabular format and/or graphically
by intervention arm and over time, as appropriate.
Other Analyses
Pharmacokinetic Analyses
Descriptive statistics (n, mean, standard deviation [SD], coefficient of variation [CV], geometric mean,
median, minimum, and maximum) will be calculated for the plasma concentrations of JNJ-6379,
JNJ-3976, JNJ-3924, and NA (ETV, tenofovir, and/or TAF), as applicable, and for the derived plasma PK
parameters for both noncompartmental and population PK analyses.
For each participant with intensive PK sampling, plasma concentration-time data of JNJ-6379, JNJ-3976,
JNJ-3924, and, optionally, NA will be graphically presented. Similarly, graphs of the mean plasma
concentration-time profiles and overlay graphs with combined individual plasma concentration-time
profiles will be produced. Plasma PK parameters in participants undergoing intensive PK sampling will
be calculated via noncompartmental methods for JNJ-6379, JNJ-3976, JNJ-3924, and, optionally, NA, as
applicable. The PK parameters will be Cmax, Cτ, and AUC24h. The PK parameters will be subjected to an
exploratory graphical analysis, including various transformations, to get a general overview.
Special attention will be paid to the plasma concentrations and PK parameters of those participants who
discontinued the study for an AE, or who experienced an AE ≥grade 3 or an SAE.
NCT04129554

JNJ-73763989 and JNJ-56136379
Clinical Protocol 73763989PAHPB2002
AMENDMENT 4
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
18
Status: Approved,  Date: 26 November 2021
Population PK analysis of plasma concentration-time data of JNJ-6379, JNJ-3976, JNJ-3924 and,
optionally, NA will be performed using nonlinear mixed-effects modeling. Data may be combined with
previous Phase 1 and/or 2 studies to support a relevant structural model. Available baseline characteristics
(eg, demographics, laboratory variables, genotypes) will be included in the model as necessary. For
operational reasons, a snapshot date for PK samples to be analyzed will be defined, if required. Samples
collected before this date will be analyzed for JNJ-6379, JNJ-3976, JNJ-3924, and/or NA (as applicable)
and will be included in the population PK analysis. Samples collected after the snapshot date will be
analyzed at a later date, and may be included in a population PK re-analysis when they become available
after database lock. Details will be given in a population PK analysis plan and results of the population
PK analysis will be presented in a separate report.
Pharmacokinetic/Pharmacodynamic Analyses
Relationships of PK parameters for JNJ-6379, JNJ-3976, JNJ-3924 and, optionally, NA (ETV, tenofovir,
and/or TAF) with selected efficacy and safety endpoints will be evaluated and graphically displayed.
Details will be described in the Statistically Analysis Plan.
Modeling of key PD parameters (eg, HBsAg, HBV DNA) may be performed using population PK/PD. If
PK/PD modeling of key efficacy endpoints is performed, treatment effect and possible covariates such as
disease progression will be investigated. Other biomarkers may be explored at the sponsor’s discretion.
Details of the PK/PD analyses will be described in a population PK/PD analysis plan and results will be
presented in a separate report.
Immune Analyses
Descriptive statistics (n, mean, SD, CV, geometric mean, median, minimum, and maximum) will be used
to describe the magnitude of the gamma interferon (IFN-γ) T-cell response or the CD4+ and CD8+ T-cell
responses (expressing at least 1 cytokine such as interleukin [IL]-2, tumor necrosis factor [TNF]-α or
IFN-γ specific to any HBV antigen) as defined by ELISpot and/or ICS, respectively. Changes from
baseline (if present) will also be tabulated for PBMCs during study intervention and follow-up. The
proportion (%) of CHB patients with positive responses based on the magnitude of the IFN-γ T-cell
response or the CD4+ or CD8+ T-cells expressing at least 1 of the cytokines amongst IL-2, TNF-α or
IFN-γ for 1 of the HBV antigens as defined by ELISpot and/or ICS, respectively, will be determined.
Pharmacogenomic Analyses
The statistical approach for analyzing the exploratory host DNA research, including epigenetic analyses,
may depend on the objective of the analyses (efficacy, safety, and PK) and possibly relevant genes at the
time of analysis. Analyses will be conducted at the sponsor’s discretion, will always be under the
sponsor’s supervision, and results will be presented either in the clinical study report or a separate report.
Host Biomarker Analyses
Statistical approaches to explore correlations between clinical outcome and blood biomarkers vary and
depend on the different data types of the applied technology platforms, as well as on the extent of
observed interindividual variability. Analyses will be conducted at the sponsor’s discretion, will always
be under the sponsor’s supervision, and results will be presented either in the clinical study report or a
separate report.
Interim Analyses
An IA will be conducted to assess safety and evaluate the time course of different disease markers to
support the sponsor’s interactions with health authorities, as well as to inform internal decisions about
additional studies and/or investigation of other treatment combinations. The IA is planned when  all
NCT04129554

NCT04129554

NCT04129554

NCT04129554

NCT04129554

JNJ-73763989 and JNJ-56136379
Clinical Protocol 73763989PAHPB2002
AMENDMENT 4
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
23
Status: Approved,  Date: 26 November 2021
e. 
Both the Platform Master ICF and the ISA ICF must be signed before the first study-related activity.
f. 
Minimum criteria for the availability of documentation supporting the eligibility criteria are described in the Source Documents section in Attachment 3 of the
Master Protocol PLATFORMPAHPB2001. Clinical status will be checked at screening and again before first dose of study intervention. If a participant’s clinical
status changes (including any available laboratory results or receipt of additional medical records) after screening but before the first dose of study intervention is
given such that he or she no longer meets all eligibility criteria, then the participant should be excluded from participation in the study.
g. 
Medical history also includes mode of HBV transmission, stage of liver fibrosis, and alcohol consumption. Historical HBV DNA, HBsAg, HBeAg, and ALT data,
if available, will be recorded in the CRF and/or the source document. Available historical data on a previous HBV genotype assessment will also be collected in
the CRF.
h. 
Liver disease staging assessments will be performed based on Fibroscan or liver biopsy results, obtained within 6 months (in case of Fibroscan) or within 2 years
(in case of liver biopsy) prior to screening or at the time of screening.
i. 
Participants must have absence of signs of cirrhosis or portal hypertension (absence of nodules, smooth liver contour, normal portal vein, spleen size <12 cm) and
absence of signs of HCC on an abdominal ultrasound performed within 6 months prior to screening or at the time of screening or clinically relevant renal
abnormalities. In case of suspicious findings on conventional ultrasound the participant may still be eligible if HCC or clinically relevant renal abnormalities have
been ruled out by a more specific imaging procedure (contrast enhanced ultrasound, CT or MRI).
j. 
In between study visits, participants will take oral study intervention at home and they will bring their study intervention with them to each study visit. At study
visits, the study intervention should be taken on site.
k. 
NA will be dispensed at Week 48 for intake during the follow-up phase in case the participant cannot stop NA treatment at Week 48.
l. 
Complete physical examination, including height (only at screening), body weight, skin examination, and other body systems.
m. Vital signs include supine SBP, DBP, pulse rate, and body temperature.
n. 
All ECGs will be read centrally. Only on Day 1, an ECG will be collected and assessed locally prior to dosing.
o. 
A liver ultrasound is recommended every 6 months for HCC screening in high-risk populations (ie, participants with a family history of HCC, Asian males
>40 years, Asian females >50 years; Africans and African Americans). The liver ultrasound does not need to be repeated at baseline if it was done within 6 months
prior to screening or at the time of screening.
p. 
Biochemistry samples must be taken after fasting for at least 10 hours for measurement of phosphate, calcium, creatinine, and lipids. If applicable, participants
should bring their study intervention with them to each visit and have that day’s intake at the site with breakfast.
q. 
Creatinine clearance (eGFR calculated by the CKD-EPI formula) will be assessed.
r. 
Intervention-emergent ALT/AST elevations (ie, ALT and/or AST ≥3x ULN and ≥3x nadir [ie, lowest value during study participation]), should trigger an
assessment of confounding factors (alcohol intake, change in concomitant medication, and comorbidities) and a confirmatory visit, to be scheduled preferably
within 7 days of the receipt of the initial ALT/AST results, to repeat laboratory testing of AFP, ALT, AST, ALP, bilirubin (total and direct), INR albumin, and
HBV DNA. Additional tests should be considered based on clinical judgement. For more details and further management guidance, refer to Section 8.3.6.3,
Intervention-emergent ALT/AST Elevations and Section 10.6, Appendix 6, Intervention-emergent ALT/AST Elevations.
s. 
Urinalysis by dipstick: specific gravity, pH, glucose, protein, blood, ketones, bilirubin, urobilinogen, nitrite, leukocyte esterase, and microscopic analysis if needed.
The dipstick reading should be done as soon as possible and in accordance with the manufacturer’s recommendation. In case of a positive dipstick result, a urine
sample will be set aside for additional examination of the positive parameter (eg, quantification as applicable).
t. 
Urine chemistry sample (quantitative measurement): creatinine, sodium, phosphate, glucose, protein, and albumin.
u. 
Urine sample for selected renal biomarkers including retinol binding protein and beta-2-microglobulin.
v. 
For postmenopausal women only: an FSH level in the postmenopausal range may be used to confirm a postmenopausal state in women not using hormonal
contraception or hormonal replacement therapy. However, in the absence of 12 months of amenorrhea, a single FSH measurement is insufficient to confirm a
woman is not of childbearing potential (see Section 10.8 Appendix 8: Contraceptive and Barrier Guidance and Collection of Pregnancy Information).
NCT04129554

JNJ-73763989 and JNJ-56136379
Clinical Protocol 73763989PAHPB2002
AMENDMENT 4
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
24
Status: Approved,  Date: 26 November 2021
w. Only applicable to participants who are enrolled at a site with an on-site Fibroscan device. A Fibroscan assessment will only be done at baseline if it was not done
at screening.
x. 
HBcrAg and HBV RNA samples may be batched and only selected samples may be tested at the sponsor’s request. Samples can be used for assessment of other
serologic/virologic markers of HBV.
y. 
Samples may be sequenced based on the sponsor virologist’s request, considering the HBV DNA levels.
z. 
Quantitative HBeAg assessment will only be performed in participants who become HBeAg-positive post baseline based on a qualitative HBeAg assay.
aa. Exploratory serology samples may be analyzed at the sponsor’s discretion. Samples may be used to assess virologic or serologic markers of HBV.
bb. All participants will have sparse PK sampling. For all samples, the date and time of the preceding 2 intakes of oral study intervention (JNJ-6379/placebo and NA),
the date and time of the previous JNJ-3989/placebo administration, and the date and time of PK sampling should be recorded. For participants in the intensive PK
subgroup, the sparse PK sample does not need to be collected at the time of an intensive PK visit.
cc. One sample at any time between 2 and 8 hours after JNJ-3989/placebo dosing. Before leaving the study site, the participant’s wellbeing should be confirmed.
dd. Only in case of early withdrawal.
ee. All participants who consent to participate in the intensive PK subgroup (optional) will undergo intensive PK sampling at Week 4 (minimally 18 participants). If
necessary (eg, for operational reasons), this visit may be scheduled at Week 8, 12, or 16. The study intervention should be taken on site and time of dosing should
be recorded. Pharmacokinetic samples will be taken predose and 15 minutes, 30 minutes, 1, 2, 3, 4, 6, 8,* 10,* and 24 hours postdose (*the 8 and 10 hours
postdose samples are optional). All efforts will be made to obtain the PK samples at the exact nominal time relative to dosing. However, samples obtained within
20% of the nominal time from dosing (eg, +/- 12 minutes of a 60-minute time point) will not be captured as a protocol deviation if the exact time of the sample
collection is noted on the source document and data collection record (eg, CRF).
ff. 
PBMC samples will be collected at selected sites only. Additional PBMC samples may be taken in case of ALT flares, upon discussion with the sponsor, and may
require an unscheduled visit.
gg. These samples are optional and will only be collected from participants who consent separately to this component of the study.
hh. Adverse events and concomitant medications will be monitored from the time a signed and dated ISA ICF is obtained until completion of the participant’s last
ISA-related procedure.
NCT04129554

NCT04129554

NCT04129554

NCT04129554

NCT04129554

JNJ-73763989 and JNJ-56136379
Clinical Protocol 73763989PAHPB2002
AMENDMENT 4
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
29
Status: Approved,  Date: 26 November 2021
2. 
INTRODUCTION
This intervention-specific appendix (ISA) describes a Phase 2b study of JNJ-73763989
(JNJ-3989) and JNJ-56136379 (JNJ-6379) in combination with a nucleos(t)ide analog (NA). It is
a companion document to the Master Protocol PLATFORMPAHPB2001, which describes the
common design elements of the Platform study in participants with chronic hepatitis B (CHB).
This ISA describes specific and/or additional protocol elements applicable to this intervention
cohort, in which participants will be treated with the study intervention, JNJ-3989 and JNJ-6379
or placebos, in combination with a NA (see Section 2.2.2).
JNJ-3989 is a liver-targeted antiviral therapeutic for subcutaneous injection designed to treat
chronic hepatitis B virus (HBV) infection via a ribonucleic acid interference (RNAi) mechanism.
Engagement of the cellular RNAi machinery by JNJ-3989 results in specific cleavage of HBV
ribonucleic acid (RNA) transcripts, thereby reducing the levels of HBV proteins and the
pre-genomic ribonucleic acid (pgRNA), the precursor of viral relaxed circular deoxyribonucleic
acid (DNA). The RNAi triggers (JNJ-73763976 [JNJ-3976] and JNJ-73763924 [JNJ-3924]) in
JNJ-3989 are designed to target all HBV RNA transcripts derived from covalently closed
circular DNA (cccDNA), as well as transcripts derived from integrated viral DNA. The latter has
been suggested to be a significant source of hepatitis B surface antigen (HBsAg) in hepatitis B
e antigen (HBeAg)-negative patients or patients on long-term treatment with NAs, the current
standard of care.37
JNJ-6379 is an orally administered capsid assembly modulator (CAM) that is being developed
for the treatment of chronic HBV infection. JNJ-6379 binds to hepatitis B core protein (HBc) and
interferes with the viral capsid assembly process, thereby preventing the polymerase-bound
pgRNA encapsidation. This results in the formation of HBV capsids, devoid of HBV DNA or
RNA (non-functional capsids), and ultimately in the inhibition of HBV replication. In addition,
JNJ-6379 also acts at an early stage of the viral life cycle by inhibiting the de-novo formation of
cccDNA potentially by interfering with the capsid disassembly process.
For the most comprehensive nonclinical and clinical information regarding JNJ-3989 and
JNJ-6379, refer to the latest version of the Investigator’s Brochure (IB)14,15 and Addendum.16
An introduction on HBV and the current treatment options is provided in Section 2 of the Master
Protocol PLATFORMPAHPB2001.
The term “study intervention” throughout the protocol, refers to JNJ-3989 or placebo for
JNJ-3989, JNJ-6379 or placebo for JNJ-6379, and NA.
The term “sponsor” used throughout this document refers to the entities listed in the Contact
Information page(s), which will be provided as a separate document.
The term “participant” throughout the protocol refers to the common term “subject”.
NCT04129554

JNJ-73763989 and JNJ-56136379
Clinical Protocol 73763989PAHPB2002
AMENDMENT 4
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
30
Status: Approved,  Date: 26 November 2021
2.1. 
Study Rationale
There is a medical need for effective finite treatment with long-term clinical benefits (ie, reduced
mortality and morbidity from cirrhosis and hepatocellular carcinoma [HCC]) in chronically
infected HBV patients under long-term NA therapy.
HBsAg seroclearance 24 weeks after end of treatment is currently considered to be associated
with the most thorough suppression of HBV replication and has been termed “functional cure”.24
With currently available NA treatment strategies the rate of HBsAg seroclearance remains very
low (around 3%), even under long-term treatment.5 To maintain suppression of HBV replication
and reduce liver injury, life-long treatment with HBV NAs is necessary in most patients, but this
approach is associated with potential non-adherence, possibly triggering relapse of symptomatic
hepatitis as well as emergence of drug resistance with limited re-treatment options.6,9,21,22,30,31,36
The development of new HBV regimens such as JNJ-3989 and JNJ-6379 with different
mechanisms of action seems a promising approach in increasing HBV functional cure, but
development of these agents requires appropriate comparison with current standard of care and
would need to be assessed prospectively in the setting of patients discontinuing NA therapy.
Recent studies explored the concept of stopping NAs in long-term suppressed patients. In some
of these studies, increased incidence of HBsAg seroclearance has been observed in HBeAg-
negative HBV patients off NA therapy (Reveal cohort).19 The landmark study ofHadziyannis in
33 HBeAg-negative patients showed that 39% of the patients who stopped 4-5 years of adefovir
therapy, had HBsAg loss during the follow-up period of 5.5 years.10 Other European studies have
reported that cessation of NA therapy can lead to HBsAg loss over time. In the FINITE study,
the percentage of patients with HBsAg loss increased from 11% (2 of 18) after 48 weeks to 31%
(4 of 13) after 144 weeks after stopping therapy.1 Similar results were reported after stopping 4
years or more of entecavir (ETV) or tenofovir disoproxil fumarate (TDF), with cumulative rates
of HBsAg loss reported to be 5% after 6 months, 16% after 12 months, and 25% after 18
months.28 A recent prespecified analysis of 2 TDF randomized controlled studies evaluated the
outcome after withdrawal of TDF and reported HBsAg loss in 5 (5%) of the 106 HBeAg-
negative patients who entered the 24-week treatment follow-up period.3
In a recent systematic review that included 25 studies mainly from Asia, identification of
predictors of virologic relapse and HBsAg loss after stopping NA led to conflicting results,
partly due to the heterogeneity of the studies and low rate of HBsAg loss (2%).29 Lower baseline
HBsAg level was the only statistical baseline factor for off-therapy HBsAg seroclearance in a
large cohort of 1075 HBeAg-negative patients in Taiwan.18 Studies conducted in Asia have
reported a lower estimated annual incidence of 1.78% of HBsAg loss highlighting potential
differences among Asians and Caucasians.18 A recent European retrospective, observational
cohort study that included 198 NA-treated CHB patients who stopped NA treatment after
HBeAg seroconversion showed 7-fold higher annual HBsAg seroclearance rates in Caucasian
patients compared to non-Caucasians.34
NCT04129554

JNJ-73763989 and JNJ-56136379
Clinical Protocol 73763989PAHPB2002
AMENDMENT 4
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
31
Status: Approved,  Date: 26 November 2021
After stopping NA treatment, it is expected that most of the patients will have rebound of HBV
DNA. This was reported in the Hadziyannis study where all patients had an initial rebound of
HBV DNA and 76% showed an alanine aminotransferase (ALT) flare suggesting that virologic
relapse might be an important trigger for immune response that could lead to subsequent HBsAg
loss. This was also reported in a recent prospective study showing that level of HBV DNA after
stopping NA was the most important factor for subsequent HBsAg decline.13 Therefore factors
that may influence virologic relapse should be taken into consideration. Some recent studies have
reported that patients treated with TDF experience virologic relapse significantly earlier than
those receiving ETV. In a randomized study of 220 HBeAg-negative Asian patients who stopped
treatment, 71% (47 of 66) treated with TDF had virologic relapse by Week 12, whereas 4.5% of
patients (7 of 154) treated with ETV had virologic relapse in the same period (p <0.0001), while
the overall virologic relapse rate was similar.12 Similarly, in a retrospective study that included
234 HBeAg-negative Asian patients who stopped treatment, median time to virologic relapse
was 18 weeks (TDF) versus 33 weeks (ETV).20
Given the reported influence of race (Asian versus non-Asian), type of NAs (TDF/tenofovir
alafenamide [TAF] versus ETV) and baseline HBsAg level on virologic relapse and
subsequently HBsAg seroclearance, those 3 elements will be included as stratification factors in
the current study.
The main goal of this Phase 2b study is to evaluate the efficacy of 48-week study intervention
with a JNJ-3989+JNJ-6379+NA regimen compared to NA alone, assessed by HBsAg
seroclearance at Week 72 (ie, 24 weeks after completion of all study interventions at Week 48)
without restarting NA treatment in HBeAg-negative virologically suppressed CHB-infected
participants who received NA treatment for at least 2 years prior to screening.
This study is also aiming at identifying baseline and on-treatment markers associated with
sustained off-treatment response.
2.2. 
Background
2.2.1. 
JNJ-3989 and JNJ-6379
Nonclinical Studies
Nonclinical assessments to support clinical development have been performed for the single
agents JNJ-3989 and JNJ-6379, and also for their combination (up to 3-month studies).
JNJ-3989
Little potential for off-target inhibition of human gene expression in participants is expected,
based on in silico human genome database screening.
The nonclinical safety profile of JNJ-3989 has been evaluated through a series of in vitro and in
vivo studies. Repeat-dose subcutaneous toxicity studies of 2 weeks up to 24 or 37 weeks were
conducted in rat and monkey, respectively. In the 2-week studies, JNJ-3989 was administered
once weekly via subcutaneous injection at 30 up to 300 mg/kg. In the 24- or 37-week studies,
NCT04129554

JNJ-73763989 and JNJ-56136379
Clinical Protocol 73763989PAHPB2002
AMENDMENT 4
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
32
Status: Approved,  Date: 26 November 2021
JNJ-3989 was administered once weekly for the first month, followed by once monthly thereafter
at 30 up to 180 mg/kg. JNJ-3989 was well tolerated in these studies.
In the 2-week and the 24-week studies in rat, JNJ-3989-related target organs were the liver, the
kidney, and the injection site. The mandibular and mesenteric lymph nodes were identified as
target organ in the 24-week study only. In the liver, hepatocyte alteration and hepatocyte mitosis,
accompanied by an increase in hepatocellular vacuoles, oval cell hyperplasia, Kupffer cell
vacuolation and/or increased liver weights were observed. The hepatocyte findings correlated to
increased alkaline phosphatase (ALP) activity levels seen in the 24-week study. Kidney findings
were characterized by cytoplasmic alteration of the cortical tubule epithelium. At the injection
site, mononuclear cell or vacuolated macrophage infiltrates, epidermal exudate, hemorrhages
and/or interstitial granules were observed. Macrophage vacuolation was observed in the sinus
spaces of the mandibular and mesenteric lymph nodes.
Liver findings persisted throughout the recovery period. Partial recovery was observed in the
kidney. No findings were present anymore at the injection sites and the lymph nodes at the end
of the recovery period.
All these changes likely represented the distribution, accumulation, and clearance of JNJ-3989
and were considered not to be adverse due to the nature of the findings and the low severity.
These are commonly described findings for N-acetylgalactosamine-conjugated RNAi.17 The no
observed adverse effect level (NOAEL) was therefore considered to be the highest dose tested,
ie,
mg/kg in the 24-week study.
In the 2-week study in monkey, apart from a minimally  increased ALP activity which was
considered not adverse, no JNJ-3989-related effects were observed. In the 37-week study,
JNJ-3989-related target organs were the liver, mandibular and/or mesenteric lymph nodes, and
the subcutaneous injection site. Findings included Kupffer cell basophilia/hypertrophy in the
liver, vacuolated macrophages in the lymph nodes, and macrophage infiltrates in the injection
site. Partial reversibility was observed for these findings. This likely represented the distribution,
accumulation, and clearance of JNJ-3989 and was considered not to be adverse due to the low
severity and/or nature of the findings. These are commonly described findings for
N-acetylgalactosamine-conjugated RNAi.17 A non-adverse minimally increased ALP activity
was observed at 180 mg/kg without a microscopic correlate. The NOAEL in the monkey was
considered to be the highest dose tested, ie,
mg/kg in the 37-week study.
In the embryofetal development (EFD) studies, JNJ-3989 was not teratogenic in rats and rabbits.
The fertility study showed no effects on parental and reproductive parameters in male and female
rats given JNJ-3989 up to a dose of 180 mg/kg/week.
JNJ-3989 was shown to be non-genotoxic when tested in the bacterial reverse mutation assay,
and in vitro and in vivo micronucleus test. Results of the non-Good Laboratory Practice (GLP) in
vitro studies demonstrated there is no potential for induction of the innate immune system
CCI
CCI
NCT04129554

JNJ-73763989 and JNJ-56136379
Clinical Protocol 73763989PAHPB2002
AMENDMENT 4
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
33
Status: Approved,  Date: 26 November 2021
(cytokine and complement activation), mitochondrial toxicity/cytotoxicity, or platelet
aggregation associated with JNJ-3989 exposure at concentrations up to 250 µg/mL.
The animal-to-human exposure ratios were calculated using rat and monkey exposures at
NOAEL from the 24-week and 37-week studies, respectively, and human exposures after a
single subcutaneous injection of 200 mg JNJ-3989 in human volunteers (Study AROHBV1001)
(Table 1).
Table 1: 
Animal/Human Exposure Ratios at NOAEL for JNJ-3989
Sex 
NOAEL  
(mg/kg) 
C max 
(ng/mL) 
AUC  
b
(ng.h/mL) 
Ratio Total Concentration
Cmax 
A/H Ratio 
AUCb
A/H Ratio
JNJ-3976
Human exposurea 
1,315 
20,136 
- 
-
24-week 
ratc 
M 
41,100 
437,000 
31.3 
21.7
F 
43,100 
270,000 
32.8 
13.4
37-week 
monkeyd 
M 
73,200 
1,230,000 
55.7 
61.1
F 
65,800 
988,000 
50.0 
49.1
JNJ-3924
Human exposurea 
363 
4,605
24-week 
ratc 
M 
25,200 
271,000 
69.4  
58.8
F 
26,200 
163,000 
72.2 
35.4
37-week 
monkeyd 
M 
21,600 
383,000 
59.5 
83.2
F 
23,000 
392,000 
63.4  
85.1
AUC: area under the plasma concentration time curve; AUC0-24h: area under the plasma concentration time curve from
administration to 24 h; AUC0-last: area under the plasma concentration time curve from administration to last quantifiable
sampling point; A/H: animal/human ratio; Cmax: maximum plasma concentration; F: female; M: male; NOAEL: no observed
adverse effect level.
a 
Single dose of 200 mg JNJ 3989 in healthy volunteers via subcutaneous injection (Study AROHBV1001; based on recent
clean dataset with data cutoff 29 October 2019. Clinical PK update will be included in next revision of the IB.).
b
AUC0-last for human exposure; AUC0-24h for animal exposures
c
Once weekly dosing for 4 weeks, followed by once monthly dosing, up to a total of 24 weeks
d
Once weekly dosing for 5 weeks followed by once monthly dosing, up to a total of 37 weeks
JNJ-6379
Following 6 months of treatment in rats, the kidney and female reproductive tract (irregular
estrous cycle) were identified as target organs. However, after further assessment of the kidney
findings and their clinical relevance, it is deemed unlikely that the retrograde nephropathy seen
in 1 out of 20 male rats following 6 months of dosing with JNJ-6379 at 100 mg eq./kg/day are
relevant for the clinical studies. The retrograde nephropathy was partially recovered after a
9-week recovery period. In the 6-month rat study, female rats (at 200 mg eq./kg/day) showed an
irregular estrous cycle, from which they recovered at the end of the 9-week treatment-free
period. These irregular estrous cycles were also apparent in the female fertility studies (main and
mechanistic). These changes were related to lowered hormone levels (luteinizing hormone,
progesterone, estradiol). JNJ-6379, however, did not affect female fertility. The fetal loss seen
during the early stages of pregnancy was considered to result from low hormone levels. In the
dog study, no changes were observed in the reproductive tract at higher exposures in dogs.
In the 9-month dog study, the target organs identified were the adrenal glands and bone marrow.
The adrenal glands did not show degenerative changes or loss of function and were therefore
CCI
NCT04129554

JNJ-73763989 and JNJ-56136379
Clinical Protocol 73763989PAHPB2002
AMENDMENT 4
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
34
Status: Approved,  Date: 26 November 2021
considered as non-adverse target organs. One female dog out of 4 dosed at 25 mg eq./kg/day (the
highest dose) was sacrificed on Day 61, after showing poor health condition. A JNJ-6379 plasma
level of 42,000 ng/mL was observed for this animal on Day 61, at approximately 24 hours after
last dosing. Pronounced clinical pathologic changes including pancytopenia were noted. Marked
increase in plasma cell-like cells was seen in the bone marrow during histopathologic
examination, resulting in a marked reduction of hematopoietic tissue and extramedullary
hematopoiesis in liver and spleen. The cause of the deteriorating condition was likely related to
changes in the bone marrow. A second dog in the same dose group with pancytopenia recovered
after a drug holiday and was re-exposed uneventfully.
In the EFD studies, JNJ-6379 was not teratogenic in rats and rabbits.
JNJ-6379 was not genotoxic in the in vitro micronucleus and Ames tests, and in the in vivo
micronucleus tests in rats.
Animal/human ratios at the NOAEL in rat and dog for human exposure at 250 mg JNJ-6379
once daily (qd) for 28 days are displayed in Table 2.
Table 2: 
Animal/Human Ratios at the NOAEL in Rat and Dog (Human Exposure at 250 mg JNJ-6379
Once Daily for 28 Days [Study 56136379HPB1001])
Sex 
NOAEL  
(mg eq./kg/day) 
Cmax 
(ng/mL) 
AUC0-24h  
(ng.h/mL) 
Ratio Total
Concentration
Ratio
Concentration
Corrected for
Plasma Protein
Bindingb
Cmax 
A/H 
Ratio 
AUC0-24h  
A/H 
Ratio 
Cmax 
A/H 
Ratio 
AUC0-24h
A/H
Ratio
Human exposurea 
13,798 
265,384 
- 
-
6M rat 
M 
7,540 
93,100 
0.6 
0.4  
0.9 
0.6
M 
13,600d 
180,000d 
1.0 
0.7 
1.7 
1.1
F 
19,900 
233,000 
1.4 
0.9 
2.4 
1.5
9M dog 
M 
30,000 
606,000 
2.2 
2.3 
3.3 
3.5
F 
22,500 
383,000 
1.6 
1.4 
2.5 
2.2
AUC: area under the plasma concentration time curve; AUC0-24h: area under the plasma concentration time curve from
administration to 24 h; A/H: animal/human ratio; Cmax: maximum plasma concentration; F: female; M: male; NOAEL: no
observed adverse effect level; qd: once daily.
a 
250 mg JNJ 6379 qd for 28 days (Study 56136379HPB1001).
b 
Ratio of the total Cmax or AUC corrected for species difference in plasma unbound fraction. Calculation: [animal Cmax or
AUC0-24h x animal free fraction] / [human Cmax or AUC0-24h x human free fraction].
c 
A dose of
 mg eq./kg/day in male rats is considered to be above the NOAEL due to kidney findings in male rats, which are
likely not relevant for human.
d 
The plasma Cmax of 13,600 ng/mL and AUC0-24h of 180,000 ng.h/mL in male rats at 100 mg eq./kg/day corresponds to an
unbound Cmax of 1,754 ng/mL and AUC0-24h of 23,220 ng.h/mL (fraction unbound rat plasma 12.9%). This unbound plasma
exposure will be achieved in humans at a total plasma Cmax of 22,784 ng/ml and AUC0-24h of 301,558 ng.h/mL (fraction
unbound in human plasma 7.7%).
JNJ-3989 and JNJ-6379
A combination pharmacokinetic (PK) study with JNJ-6379 and JNJ-3989 has been conducted in
male rats (N 3/group), and a GLP, 1-month combination repeat-dose toxicity study is ongoing in
male and female rats.
CCI
CCI
NCT04129554

JNJ-73763989 and JNJ-56136379
Clinical Protocol 73763989PAHPB2002
AMENDMENT 4
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
35
Status: Approved,  Date: 26 November 2021
In the combination PK study (FK13466), JNJ-6379 was administered orally at
100 mg eq./kg/day  for 8 days in combination with JNJ-3989 administered subcutaneously on
Days 0 and 7 at 30 or 180 mg/kg. In addition, 2 groups received JNJ-6379 alone (orally at 100
mg eq./kg/day for 8 days), or JNJ-3989 alone (at 180 mg/kg subcutaneously on Days 0 and 7).
Histopathological examinations were performed on the liver and kidney collected 25 hours
postdose on Day 7. No adverse findings for JNJ-3989, JNJ-6379 or for the combination were
noted. No additive or synergistic effects were noted when both compounds were coadministered.
When JNJ-6379 was administered in combination with JNJ-3989, mean maximum  plasma
concentration (Cmax) values and mean area under the plasma concentration-time curve (AUC)
values of JNJ-6379, JNJ-3976 and JNJ-3924 did not change significantly when compared to
dosing both compounds alone.
In the 1-month rat study, JNJ-3989 was administered weekly via subcutaneous injections at dose
levels of 30 and 180 mg/kg when given in combination with JNJ-6379, and at 180 mg/kg for the
monotherapy group. Control animals received both vehicles via the respective routes. JNJ-6379
was administered daily via oral gavage at a dose level of 100 mg/kg.
No treatment-related mortality occurred during the study. Also, no relevant clinical signs were
noted. Body weights and body weight gain were slightly decreased during the last weeks of
treatment in males at ≥30/100 mg/kg and in females at 180/100 mg/kg, with correlating lower
food intake at the high dose.
JNJ-3989 at 180 mg/kg presented vacuolation and basophilic granules in tubular epithelium of
the kidney. At 30 mg/kg no kidney changes were noted.
There were no differences in kidney morphologic alterations between rats dosed with the single
compound JNJ-3989, compared to the group dosed with the combination of the 2 compounds.
Crystals were observed in the urine of animals dosed with JNJ-6379 at 100 mg/kg, either alone
or in combination, with mainly males being affected, and correlating with significant amounts of
drug-related material in the urine (predominantly M7 but also unchanged drug).
No histopathology kidney findings were seen with JNJ-6379 at 100 mg/kg.
No drug-drug interaction (DDI) was seen in this study as well as in the previous study where the
2 compounds were given for 7 days.
In conclusion, daily oral administration of JNJ-6379 at 100 mg/kg in combination with weekly
subcutaneous injection with JNJ-3989 at 30 or 180 mg/kg for one month was well tolerated with
no clinical signs or treatment-related mortality. Changes in clinical pathology and histopathology
were mostly similar to the findings for the monotherapy groups dosed with JNJ-6379 at
100 mg/kg (per os) alone or with JNJ-3989 at 180 mg/kg (subcutaneous) alone. There were no
additive or synergistic changes noted in the kidneys or in clinical pathology.
NCT04129554

JNJ-73763989 and JNJ-56136379
Clinical Protocol 73763989PAHPB2002
AMENDMENT 4
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
36
Status: Approved,  Date: 26 November 2021
Preliminary results of a 3-month combination toxicity study with JNJ-6379 an JNJ-3989 in the
rat became available. In this study, the potential for toxicity of JNJ-6379 when given by daily
oral gavage, and of JNJ-3989 when given by intermittent SC injection, and of both test items
when given in combination, was assessed (TOX13608).
No test article-related mortalities were noted among animals dosed with JNJ-6379 alone, with
JNJ-3989 alone, or with JNJ-6379 + JNJ-3989 at 100/180 mg/kg.
One male rat dosed at 100/60 mg/kg JNJ-6379/JNJ-3989 was euthanized on Day 24 after
showing severe clinical signs in the morning (decreased activity, erected fur, pallor and cold to
touch). No clinical signs were noted for this animal until Day 23, and body weight and weight
gain were unaffected during the first 3 weeks of the study; The cause of moribundity was
considered to be a markedly decrease hematopoietic cellularity of the bone marrow with
pancytopenia including markedly reduced platelet counts and consequent hemorrhages and blood
loss. A relation to the treatment with JNJ-6379 and/or JNJ-3989 cannot be excluded. In addition,
a mild decrease in platelet counts was observed in females in the combination group
100/60 mg/kg and 100/180 mg/kg JNJ-6379/JNJ-3989.
No relevant changes on urinary biomarkers were detected in male and female rats given JNJ-
6379 at 100mg/kg/day (clusterin, albumin, ß2-microglobulin, Kidney Injury Molecule-1 (KIM-
1), Neutrophil Gelatinase Associated Lipocalin (NGAL) and cystatin-C).
For further information, refer to the IB Addenda.41,42
Clinical Studies
To date, no clinical information is available for the combination of JNJ-3989 with JNJ-6379. The
following sections provide an overview of the current clinical background information for the
2 compounds separately.
JNJ-3989
Clinical data of JNJ-3989 are available from the ongoing Phase 1/2a AROHBV1001 study with a
safety snapshot date of 26 March 2019. Twenty adult healthy participants have received single
subcutaneous injections of JNJ-3989 (35, 100, 200, 300, and 400 mg) and 72 adult CHB
participants have received multiple doses of JNJ-3989 (25, 50, 100, 200, 300, and 400 mg),
administered as 3 subcutaneous injections separated by either 7-day, 14-day, or 28-day intervals.
All participants either continued or started ETV or TDF on Day 1.
JNJ-3989 was generally safe and well tolerated with no deaths, serious adverse events (SAEs)
considered at least possibly related to the study intervention, or adverse events (AEs) leading to
study intervention discontinuation. All AEs were mild to moderate, with exception of 1 severe
blood creatine phosphokinase increased in 1 CHB participant. All reported injection site
reactions (ISRs) were mild. Adverse events and laboratory abnormalities were distributed across
all dose levels and also occurred on placebo treatment, except for mild ISRs, which were only
NCT04129554

JNJ-73763989 and JNJ-56136379
Clinical Protocol 73763989PAHPB2002
AMENDMENT 4
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
37
Status: Approved,  Date: 26 November 2021
reported in participants on JNJ-3989 treatment. Most reported laboratory abnormalities were
isolated incidences and resolved while on study treatment.
Efficacy was assessed using snapshot data through 02 May 2019. Antiviral activity data were
available for 56 CHB participants who received 3 subcutaneous injections of 25 to 400 mg
JNJ-3989 every 4 weeks. The antiviral activity data showed that administration of JNJ-3989 at
doses of 25 to 400 mg resulted in pronounced mean HBsAg declines which were generally
sustained at least until Day 168 (ie, 16 weeks after last dose) across all doses. No apparent dose
response was observed at doses between 100 and 400 mg JNJ-3989; a reduced mean decline was
observed at the lower dose of 25 mg. Data on the 50 mg dose is still emerging. Treatment status
(ie, virologically suppressed or not treated) did not seem to affect HBsAg changes. Other
measurable serological and virological markers (HBV DNA, HBV RNA, HBeAg, hepatitis B
core-related antigen [HBcrAg]) also showed responses to JNJ-3989, indicating that JNJ-3989
shows target activity on all detectable viral products.
JNJ-6379
At the time of protocol writing, 98 adult healthy and 41 CHB participants have been dosed with
JNJ-6379 in 4 completed Phase 1 studies (56136379HPB1001, 56136379HPB1002,
56136379HPB1003, and 56136379HPB1004). Another Phase 1 study in healthy adult
participants is also completed and clinical study report writing is currently ongoing
(56136379HPB1005). In addition, data are available from 148 adult CHB  participants in the
ongoing Phase 2a study, 56136379HPB2001, also referred to as Jade.
Human Pharmacokinetics and Product Metabolism
Single Dose Studies in Healthy Participants
In Study 56136379HPB1001, single ascending doses (25, 50, 150, 300 and 600 mg) of JNJ-6379
(or placebo) were administered under fasting conditions to healthy participants. No major
differences were observed in the shape of the mean JNJ-6379 plasma concentration-time curves
for the different dose levels. Mean and individual PK profiles showed minimal lag-time. A single
rather flat concentration peak was observed in the PK profiles of most participants. Plasma
concentrations in the terminal phase declined generally in parallel for all dose levels. The Cmax
and AUC from administration to 24 hours (AUC0 24h) increased proportionally with dose after
single-dose administration of JNJ-6379 doses of 25 mg to 300 mg and less than dose
proportionally at the dose of 600 mg. The AUC from administration to last quantifiable sampling
point (AUC0 last) and the AUC to last sampling point from time zero extrapolated to infinity
(AUC∞) increased proportionally between the JNJ-6379 25-mg and 600-mg dose levels. Mean
values for terminal half-life (t1/2term) were comparable for the 25-mg to 300-mg dose levels, and
averaged between 93.3 hours and 110.5 hours. For the 600-mg dose group, the average t1/2term
was 141.3 hours. Mean values for the total apparent oral clearance (CL/F) were comparable for
the 25-mg, 50-mg and 150-mg dose level, and appeared to decrease at higher dose levels. Mean
values of the apparent volume of distribution were generally comparable for the different dose
groups.
NCT04129554

JNJ-73763989 and JNJ-56136379
Clinical Protocol 73763989PAHPB2002
AMENDMENT 4
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
38
Status: Approved,  Date: 26 November 2021
In Study 56136379HPB1002, study drug exposure levels using a novel tablet formulation,
containing hydroxypropylmethylcellulose E5 based spray-dried powder, were similar to
exposure levels observed in study 56136379HPB1001 using the original formulation, both in fed
conditions. The relative bioavailability of new 25-mg oral tablets of JNJ-6379 administered as a
150-mg dose under fasting and fed conditions, and of new 100-mg oral tablets of JNJ-6379
administered as a 300-mg dose under fasting conditions, was assessed in healthy adult
participants. Assuming proportionality, based on the geometric mean ratios between the 3x
100-mg dose, fasting (test) and the 6x 25-mg dose, fasting (reference) of the dose-normalized PK
parameters, Cmax  was 21.56% lower for the 100-mg tablet strength compared to the 25-mg tablet
strength, and AUC0 last and AUC∞ were similar. The median time to reach Cmax  (tmax) was around
1.75 hours when 150 mg JNJ-6379 was dosed as 6x 25-mg oral tablets, and around 3.00 hours
when 300 mg JNJ-6379 was dosed as 3x 100-mg oral tablets.
In Study 56136379HPB1005, the oral bioavailability of a single 300-mg dose of JNJ-6379
administered as a 100-mg tablet containing hydroxypropylmethylcellulose-acetate succinate
based spray-dried powder (test tablet) was assessed. All 14 healthy adult participants received a
300-mg dose of JNJ-6379 under fasted conditions. Preliminary PK analysis was performed and
mean Cmax  was 3,105 ng/mL, mean AUC0 72h  was 111,286 ng.h/mL and mean AUC∞ was
280,926 ng.h/mL. The median tmax  was around 3.00 hours. These preliminary PK parameter
values are comparable to the PK parameters obtained after administration of JNJ-6379
formulated as hydroxypropylmethylcellulose E5 based spray-dried powder tablet.
Multiple Dose Studies in Healthy Participants
In Session 7 of Study 56136379HPB1001, participants received 150 mg JNJ-6379 twice daily
under fed conditions for the first 2 days of treatment, followed by 100 mg JNJ-6379 qd until
Day 12. JNJ-6379 plasma concentrations accumulated during the study (accumulation ratio of
approximately 6). The CL/F at steady-state and the t1/2term were similar to values observed after
single-dose administration, suggesting time-linear PK.
In Study 56136379HPB1004, participants received 250 mg of JNJ-6379 twice daily on Days 6
and 7 (fed conditions), followed by 170 mg qd on Day 8 to 25 in fed conditions (with exception
of Day 21). On Day 21, a single dose of JNJ-6379 170 mg and a single dose of
drospirenone/ethinylestradiol 3 mg/0.02 mg and a single dose of midazolam 2 mg were
administered under fasted conditions. Mean JNJ-6379 Cmax  and area under the plasma analyte
concentration-time curve over a dose interval (AUCτ) increased between Day 6 (first dose of
JNJ-6379) and Day 20 as JNJ-6379 plasma concentrations accumulated due to the multiple-dose
regimen administered in this study. Steady-state was reached before Day 20. Plasma
concentration-time 
profiles 
of 
JNJ-6379 
were 
similar 
to 
those 
observed 
in
Study 56136379HPB1001.
NCT04129554

JNJ-73763989 and JNJ-56136379
Clinical Protocol 73763989PAHPB2002
AMENDMENT 4
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
39
Status: Approved,  Date: 26 November 2021
Multiple Dose Studies in CHB Participants
In Sessions 8, 9, 10, 11, and A of Study 56136379HPB1001, treatment-naïve CHB-infected
participants were administered multiple-dose regimens (25, 75, 150, and 250 mg) of JNJ-6379
for 28 days. Pharmacokinetics of JNJ-6379 were not markedly different between healthy
participants and CHB participants. Mean JNJ-6379 exposures in CHB participants could be
predicted from data in healthy participants. The PK data show that exposure of JNJ-6379 in CHB
participants is dose proportional and CL/F is constant over time.
Food Interaction
Although Study 56136379HPB1001 suggested slightly higher exposure of JNJ-6379 in fed
conditions, data from Study 56136379HBP1002 with  a higher number of participants showed
that there is no food effect on JNJ-6379 exposure, and a preliminary PK analysis from
Study 56136379HBP1005 suggests the same.
Drug-drug Interaction
Oral contraceptives: When administered simultaneously with 3 mg drospirenone/0.02 mg
ethinylestradiol in Study 56136379HPB1004, JNJ-6379 increases the extent of exposure and
decreases the CL/F of ethinylestradiol while the peak plasma concentration decreased. In
contrast, JNJ-6379 has no clear effect on the extent of exposure and CL/F of drospirenone, a
cytochrome P450 (CYP)3A4 sensitive progestin: peak plasma concentration decreased while no
change in exposure and apparent clearance was observed. Consequently, oral contraceptives are
still considered to be effective when administered simultaneously with JNJ-6379. However, as a
precaution to avoid high exposure to ethinylestradiol, ethinylestradiol-containing contraceptives
are only allowed if the ethinylestradiol content is ≤20 µg.
Midazolam: In Study 56136379HPB1004, coadministration of 170 mg JNJ-6379 qd with oral
midazolam as a CYP3A4 probe substrate showed a reduction of 41.7% in Cmax  and 53.9% in
AUC of midazolam, implying that JNJ-6379 may induce the metabolism of CYP3A4 sensitive
substrates.
Efficacy Studies
Antiviral activity data are available from Part II of Study 56136379HPB1001 (final analysis,
57 treatment-naïve participants treated with multiple-dose regimens of 25 to 250 mg JNJ-6379
qd for 28 days, unblinded). Available antiviral activity data for 4 weeks of treatment with JNJ-
6379 in this study showed potent HBV DNA and RNA reductions but no changes in HBsAg,
indicating that longer treatments are needed.
Interim efficacy data are available from the Phase 2a Jade study. Interim analysis (IA) 2 (cut-off
date: 8 February 2019) includes Week 12 data from 64 CHB participants not treated at screening
of whom 26 received 75 mg qd JNJ-6379 monotherapy (open-label) and 38 received 75 mg qd
JNJ-6379 or placebo in addition to an NA (blinded). Interim analysis 2 also includes unblinded
Week 24 data from 44 virologically suppressed CHB participants of whom 33 received 75 mg qd
NCT04129554

JNJ-73763989 and JNJ-56136379
Clinical Protocol 73763989PAHPB2002
AMENDMENT 4
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
40
Status: Approved,  Date: 26 November 2021
JNJ-6379 and 11 received placebo in addition to an NA. Interim analysis 3 (cut-off date: 7
March 2019) includes blinded Week 12 data from 40 virologically suppressed CHB participants
who received 250 mg qd JNJ-6379 or placebo in addition to an NA.
The 12-week interim efficacy data in currently not treated participants on 75 mg JNJ-6379
monotherapy showed a mean reduction from baseline of HBV DNA of >3.5 log10 IU/mL at
Week 12. This decline was similar to the mean decline in participants treated with JNJ-6379 or
placebo in combination with an NA (data still blinded).
The 24-week interim efficacy data in virologically suppressed participants on 75 mg JNJ-6379
showed that most participants had HBV DNA levels below the limit of quantification at baseline.
At 24 weeks of treatment, 5 (23.8%) of 21 participants on JNJ-6379 experienced a mean
reduction from baseline in HBV RNA of >2 log10 IU/mL versus 1 (14.3%) of 7 participants on
placebo. HBV RNA levels at Week 24 were undetectable for 21 (100.0%) of 21 participants on
JNJ-6379 and 4 (57.1%) of 7 participants on placebo. No relevant mean changes from baseline in
HBsAg and HBeAg were noted so far.
In the monotherapy arm with 75 mg JNJ-6379, 5 of 28 participants (status after IA cut-off date)
experienced a virologic breakthrough defined as confirmed on-treatment HBV DNA increase by
>1 log10 from nadir level or confirmed on-treatment HBV DNA level >200 IU/mL in participants
who had HBV DNA level below the lower limit of quantification (LLOQ) of the HBV DNA
assay. All 5 participants with virologic breakthrough had an emerging core amino acid mutation
T33N, which is known to confer reduced JNJ-6379 activity in vitro. All 5 participants
discontinued JNJ-6379 and started NA treatment. An urgent safety measure was implemented to
discontinue JNJ-6379 treatment in all participants in this arm and offer NA treatment. No cases
of virologic breakthrough were observed in any of the arms combining JNJ-6379/placebo with
NA treatment. A futility rule was implemented in the 250 mg JNJ-6379 monotherapy arm (if
≥1 participant in the 250 mg monotherapy arm experiences virologic breakthrough during the
first 24 weeks of treatment, NA treatment will be added to JNJ-6379 treatment as soon as
possible for all remaining participants).
In the monotherapy arm with 250 mg JNJ-6379, 1 participant experienced virologic
breakthrough (status after IA cut-off date). The participant discontinued JNJ-6379 treatment and
started NA treatment at the withdrawal visit, due to meeting non-response criteria. NA treatment
will be added for all remaining participants in the JNJ-6379 250 mg monotherapy arm in
accordance with the futility rule mentioned above.
Safety Studies
Data from 4 completed Phase 1 studies (56136379HPB1001, 56136379HPB1002,
56136379HPB1003 and 56136379HPB1004) in healthy and CHB participants (N 98 and 41,
respectively), indicate that orally administered JNJ-6379 as single doses up to 600 mg or as
multiple doses (250 mg twice daily for 2 days followed by 170 mg qd for 18 days or 150 mg
twice daily for 2 days followed by 100 mg qd for 10 days) in healthy participants and as multiple
doses up to 250 mg for 28 days in  CHB participants was safe and well tolerated. No SAEs
NCT04129554

JNJ-73763989 and JNJ-56136379
Clinical Protocol 73763989PAHPB2002
AMENDMENT 4
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
41
Status: Approved,  Date: 26 November 2021
considered at least possibly related to the study intervention were reported. Most AEs were mild
and not considered treatment-related, with no dose-related trends. Those observations were
supported by the final safety data obtained for Phase 1 Study 56136379HPB1005, in which
14 healthy adult participants received single doses (300 mg) of JNJ-6379.
Safety data are also available from IAs 2 and 3 conducted for the Phase 2a Jade study, which
were mentioned above. There were no deaths, SAEs considered at least possibly related to the
study intervention, or AEs leading to discontinuation. Most AEs were grade 1 or 2 in severity.
The majority of reported AEs were considered unrelated to JNJ-6379 by the investigator. Grade
2 to 4 AEs considered at least possibly related to JNJ-6379 by the investigator were grade 2
asthenia (3 participants), grade 4 ALT increased, grade 2 headache, grade 2 vertigo, grade 3
anemia (corrected to grade 2 by the investigator after the IA cut-off date), grade 2 hypertension,
and grade 2 fatigue (all observed in 1 participant each).
Increased cholesterol is considered a laboratory abnormality of interest for JNJ-6379, based on
safety review from nonclinical and clinical trials. Cholesterol increased was reported as an AE in
4 (4.1%) participants on JNJ-6379 for the pooled Phase 1 studies, in 1 (2.4%) participant on
JNJ-6379 for the Phase 1 study 56136379HPB1005, and in none of the participants in the
Phase 2a Jade study.
2.2.2. 
Combination of JNJ-3989 and JNJ-6379 with Entecavir, Tenofovir
Disoproxil Fumarate, or Tenofovir Alafenamide
Entecavir monohydrate is an HBV NA reverse transcriptase inhibitor indicated for the treatment
of CHB in adults and children at least 2 years of age with evidence of active viral replication and
either evidence of persistent elevations in serum aminotransferases (ALT or aspartate
aminotransferase [AST]) or histologically active disease. The most common adverse reactions
(≥3% of participants) are headache, fatigue, dizziness, and nausea.
Tenofovir disoproxil fumarate is a first-generation oral prodrug of the NA tenofovir that is
indicated for the treatment of CHB  in adult and pediatric patients at least 12 years of age. In
addition, TDF in combination with other antiretrovirals is indicated for the treatment of human
immunodeficiency virus type 1 (HIV-1) infection in adult and pediatric patients at least 2 years
of age. The most common adverse reactions (≥10% of participants) are abdominal pain, nausea,
insomnia, pruritus, vomiting, dizziness, and pyrexia.
Tenofovir alafenamide is an ester prodrug of the NA tenofovir that is indicated for the treatment
of CHB in adults and that is characterized by a better safety profile than TDF. The most common
adverse reactions (≥10% of participants) is headache.
For further information regarding ETV, TDF, and TAF, refer to the respective currently
approved prescribing information.
There is no common target organ between JNJ-6379 or JNJ-3989 and ETV.27
NCT04129554

JNJ-73763989 and JNJ-56136379
Clinical Protocol 73763989PAHPB2002
AMENDMENT 4
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
42
Status: Approved,  Date: 26 November 2021
The single common toxicity target organ between JNJ-6379, JNJ-3989, and TDF or TAF is the
kidney.
In the chronic rat studies with JNJ-3989, slight alteration of the renal tubular epithelium was
characterized by basophilic stippling and/or microvacuolation of the cytoplasm of renal tubules
in the outer cortex in rats. These findings were not considered toxicologically meaningful since
they were related to compound accumulation, there was no evidence of cellular damage
(degeneration/necrosis) and there were no correlated clinical pathology indicators of changes in
renal function.11,17 These kidney findings have been observed in both the 2-week and 6-month
studies and did not worsen over time. No kidney findings were observed in monkeys.
In the chronic rat study (6 months) with JNJ-6379, retrograde nephropathy, secondary to
papillary or pelvic calculi/precipitates, was noted in male rats but not in dogs or female rats. This
finding is mainly due to precipitation or calculi formation in distal parts of the kidney/lower
urinary tract and is of limited relevance to man, due to differences in urinary composition and
functional anatomy between (male) rats and humans. In general, compounds or metabolites of
low solubility and high renal clearance may cause concretions in the kidneys/ urinary tract,
especially at high doses, as the urine concentrates in the distal nephron and supersaturation of the
compound can occur. Urinary pH, proteins and osmolality can also influence the formation of
urinary concretions. Male rat urine normally has a high concentration of protein and high
osmolality. In addition, rats may be predisposed to retrograde nephropathy because they are
known to experience spontaneous urine reflux during micturition or urinary bladder contraction,
and this reflux phenomenon can be increased or exacerbated by treatment induced obstructions.
The retrograde nephropathy in male rats correlated with increased urea and creatinine in plasma
and with urinary changes (red/brown discolored urine, increased volume, decreased pH, presence
of blood and white and red blood cells in sediment).4,32 No kidney findings were observed in
dogs.
In clinic, dosing JNJ-6379 with NA for 12 weeks, did not show any clinically relevant changes in
kidney parameters/glomerular function.
Although both compounds (JNJ-3989 and JNJ-6379) showed histological kidney findings in the
rat, the primary anatomical location, mechanism and severity are different. For JNJ-3989 the
renal findings are without anticipated clinical or clinicopathological consequences and located in
the proximal part of the nephron (outer cortex) and intra-cellular (not in the tubular lumen). For
JNJ-6379, the main findings are restricted to male rats and initiate in distal parts of the kidney
(renal pelvis/ papilla) and/or in the lumen of the lower urinary tract with secondary more
proximal changes due to reflux.
For TDF, renal tubular epithelial karyomegaly was observed in rats, dogs, and monkeys.26 In
dogs, the species most sensitive to TDF-related effects on the kidney, additional microscopic
alterations following chronic administration of TDF (10 mg/kg/day for 42 weeks) included
individual tubular cell necrosis, tubular dilatation, tubular degeneration/regeneration, pigment
accumulation, and interstitial nephritis. This was associated with biochemical changes such as
NCT04129554

JNJ-73763989 and JNJ-56136379
Clinical Protocol 73763989PAHPB2002
AMENDMENT 4
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
43
Status: Approved,  Date: 26 November 2021
slight elevation in serum creatinine, glucosuria, proteinuria, and increased urine volume. The
incidence and severity of nephrotoxicity was dose-related. Effects were reversible following
cessation of treatment. In Rhesus monkeys, biochemical and/or histopathologic evidence of
nephrotoxicity was observed at high doses. In rats, slight elevations in serum creatinine were
observed without any histopathology correlation.
For TAF, minimal renal cortical tubular karyomegaly and/or basophilia was seen in rats and
dogs. In addition, minimal renal cortical tubular degeneration/regeneration were reported in
dogs. No renal findings were reported in monkeys.7
Overall Nonclinical Assessment of the Combination Therapy
Based on the points listed below, no clinically relevant DDIs and no specific concerns about
additive or synergistic toxicities are expected in kidney when JNJ-6379 or JNJ-3989 are
combined with ETV, or TDF, or TAF:
 
available toxicology data described above (Sections 2.2.1 and 2.2.2)
 
in vitro drug transporters
 
metabolic interaction data
 
absence of relevant DDIs in the combination toxicity studies with JNJ-6379 and JNJ-3989
 
available clinical data with JNJ-6379 (Jade study [56136379HPB2001]) up to 24 weeks
treatment on the absence of changes in kidney parameters/glomerular function.
In addition, pancytopenia in 1 rat and a mild platelet decrease were observed in the combination
groups in the 3-month combination toxicity study (preliminary data, section 2.2.1). No
significant abnormalities of hematologic parameters have been observed in clinical studies to
date. The sponsor is implementing additional monitoring of significant on-treatment hematologic
changes in clinical studies with dosing longer than 4 weeks (see Section 8.3.6.5). For further
information, refer to the IB Addenda. 41,42
2.3. 
Benefit-Risk Assessment
More detailed information about the known and expected benefits and risks of JNJ-3989 and
JNJ-6379 may be found in the respective Ibs.14,15,16
For the benefit-risk evaluation of ETV, TDF, and TAF, refer to the respective prescribing
information and Summary of Product Characteristics.
2.3.1. 
Benefits for Study Participation
2.3.1.1. 
Known Benefits
The clinical benefit of JNJ-3989 and JNJ-6379 remains to be established.
NCT04129554

JNJ-73763989 and JNJ-56136379
Clinical Protocol 73763989PAHPB2002
AMENDMENT 4
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
44
Status: Approved,  Date: 26 November 2021
2.3.1.2. 
Potential Benefits
Results from clinical studies with JNJ-3989, JNJ-6379, and NAs may be useful for the
development of a novel therapeutic approach for chronic HBV infection.
The combination of JNJ-6379 and JNJ-3989 on a background of NAs would target different
stages of the viral life cycle. While NA treatment reduces HBV DNA to levels close to or below
the LLOQ of the HBV DNA assay, HBV replication is not completely inhibited, resulting in
replenishment of the cccDNA pool. The addition of JNJ-6379, which targets the HBV capsid
assembly (“primary” mode of action [MoA]) and the de novo cccDNA formation (“secondary”
MoA), is expected to block HBV replication more profoundly by inhibiting formation of HBV
RNA and DNA containing particles, and to inhibit de novo cccDNA formation, ultimately
leading to reduction in cccDNA levels/transcriptional activity  and HBsAg seroclearance
(“intensified viral suppression”). The addition of JNJ-3989 to an NA, or to JNJ-6379 in
combination with an NA, is expected to intensify viral suppression (further) by downregulating
levels of the HBV DNA precursor pgRNA. In addition, JNJ-3989 reduces levels of all viral
proteins including HBsAg, which is known to interfere with the host immune response.8,23,35 By
acting on both viral replication and by reducing barriers to the host immune-response, higher
functional cure rates may be achieved.
2.3.2. 
Risks for Study Participation
2.3.2.1. 
Known Risks
No known risks associated with JNJ-3989 or JNJ-6379 have been identified from clinical
observations so far in the Phase 1 and 2 studies. Injection site reactions were identified as
adverse drug reactions for JNJ-3989.
2.3.2.2. 
Potential Risks
All therapies have the potential to cause adverse experiences. In addition, the discontinuation of
NA treatment bares a risk of hepatitis B flares.
Patients with positive HBV DNA and positive HBsAg can always experience increases in liver
transaminases which may indicate immune activation and may result in the reduction of viral
parameters such as HBV DNA and/or HBsAg. Whether this occurs at higher frequency during or
after treatment with JNJ-6379 and JNJ-3989 is not known.
2.3.2.2.1. 
Potential Risks for JNJ-3989
Reproductive Risks and Pregnancy
In the EFD  studies, JNJ-3989 was not teratogenic in rats and rabbits. JNJ-3989 showed no
effects on fertility in rats.
Based on the difference in metabolic pathways and in vitro data indicating absence of impact of
JNJ-3989 on CYP enzymes and transporters, no clinically relevant interactions are anticipated
between JNJ-3989 and oral contraceptives.
NCT04129554

JNJ-73763989 and JNJ-56136379
Clinical Protocol 73763989PAHPB2002
AMENDMENT 4
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
45
Status: Approved,  Date: 26 November 2021
Potential Genotoxicity
JNJ-3989 is considered to be devoid of genotoxic activity. Nonclinical carcinogenicity studies
have not been conducted.
Other Potential Toxicity/Events of Special Interest
JNJ-3989 is considered non-cytotoxic, did not activate human platelet aggregation, did not
activate the innate immune system to a significant degree in vitro, and did not activate
complement in vitro.
Viral Resistance
Treatment with JNJ-3989 may also lead to viral resistance, but resistance to JNJ-3989 is not
anticipated to impact treatment with other small interfering RNAs (siRNAs). Using these agents
in combination, especially in combination with ETV, TDF, or TAF is expected to minimize the
risk of emerging resistant viral variants.
2.3.2.2.2. 
Potential Risks for JNJ-6379
Reproductive Risks and Pregnancy
In the fertility study in females, early embryonic development was affected: an increase in
pre- and post-implantation loss, reduction in implantation and live fetuses at 300 mg eq./kg/day.
The fetal loss seen during the early stages of pregnancy was considered the result of low
hormone levels (decreased luteinizing hormone, progesterone, estradiol) induced by treatment
with JNJ-6379.
In the EFD studies, JNJ-6379 was not teratogenic in rats and rabbits.
In the EFD  study in rats, fetal weights at 300 mg eq./kg/day were lowered, and there was
retarded ossification from 100 mg eq./kg/day onwards. The NOAEL for EFD was considered to
be
mg eq./kg/day. At this dose, the AUC0 24h was 84,000 ng.h/mL and the Cmax  was
5,190 ng/mL.
In the EFD study in rabbits, the NOAEL for EFD was considered to be the highest dose tested,
ie, 
mg eq./kg/day. At this dose, the AUC0 24h was 99,200 ng.h/mL and the Cmax was
6,880 ng/mL.
Potential Genotoxicity
JNJ-6379 was not genotoxic in the in vitro and in vivo tests.
JNJ-6379 did not affect male or female fertility. Carcinogenicity studies are not yet conducted.
Other Potential Toxicity/Events of Special Interest
Based on nonclinical findings in rats and dogs and based on clinical findings, increased
cholesterol was identified as a laboratory abnormality of interest.
CCI
CCI
NCT04129554

JNJ-73763989 and JNJ-56136379
Clinical Protocol 73763989PAHPB2002
AMENDMENT 4
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
46
Status: Approved,  Date: 26 November 2021
Viral Resistance
Treatment with JNJ-6379 may lead to emergence of viral variants with reduced susceptibility or
resistance to JNJ-6379. Based on nonclinical data, these variants remain susceptible to TDF and
ETV but might affect treatment options with CAMs in the future. All 5 participants with
virologic breakthrough  in the Jade study who received 75 mg JNJ-6379 monotherapy, had an
emerging core amino acid mutation T33N, which is known to confer reduced JNJ-6379 activity
in vitro (see Section 2.2.1 for the results of the IAs).
Drug-drug Interactions
Based on results from DDI study 56136379HPB1004 investigating the potential effect of
coadministration of JNJ-6379 with oral contraceptives, it is not anticipated that the efficacy of
oral contraceptives will be impacted during coadministration with JNJ-6379 since the exposure
of a progestin sensitive to CYP3A4 induction was not significantly affected by coadministration
of JNJ-6379. In contrast, it is anticipated that coadministration with ethinylestradiol-containing
contraceptives will result in an increased exposure to ethinylestradiol. Therefore, specific
requirements on the use of ethinylestradiol-containing contraceptives are included in Section 6.5,
Concomitant Therapy.
Please refer to Section 2.2, Background, for details on the safety results in the studies conducted
to date.
2.3.3. 
Benefit-risk Assessment for Study Participation
Based on the available data and proposed safety measures, the overall risk/benefit assessment for
JNJ-3989 and JNJ-6379 clinical studies is deemed acceptable for the following reasons:
 
At the time of protocol writing, JNJ-3989 was generally safe and well tolerated during the
ongoing Phase 1 Study AROHBV1001 (see Section 2.2.1, JNJ-3989 and JNJ-6379,
Subsection “Clinical Studies”). All but one AE were mild or moderate in severity. All ISRs,
identified as adverse drug reactions for JNJ-3989, were mild in intensity.
 
No clinically significant safety concerns have previously been raised for JNJ-6379 based on
the safety information from studies in healthy adult participants and adult participants with
chronic HBV infection. Most observed AEs were mild in severity and considered not related
to JNJ-6379 by the investigator (see Section 2.2.1, JNJ-3989 and JNJ-6379, Subsection
“Clinical Studies”).
 
Events of Special Interest are significant AEs that are judged to be of special interest
because of clinical importance, known class effects or based on nonclinical signals. Events
of Special Interest that will be carefully monitored during the study include ISRs, ALT/AST
elevations, renal complications, hematologic abnormalities, and events related to cholesterol
increase (Section 8.3.6, Adverse Events of Special Interest and Section 8.2.4, Clinical Safety
Laboratory Assessments). In addition, the following toxicities will also be carefully
monitored: rash and acute systemic allergic reactions (Section 8.3.6, Adverse Events of
Special Interest).
 
Continued careful assessment of the safety, efficacy, and PK during treatment is included in
this study.
NCT04129554

JNJ-73763989 and JNJ-56136379
Clinical Protocol 73763989PAHPB2002
AMENDMENT 4
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
47
Status: Approved,  Date: 26 November 2021
 
To minimize potential risk and stress to participants, the following measures are in place:
 
Utilization of selection criteria which exclude participants who may potentially be at
higher risk of an AE (see Section 5, Study Population).
 
Utilization of withdrawal criteria (see Section 7, Discontinuation of Study Intervention
and Participant Discontinuation/Withdrawal). If a participant drops out due to
withdrawal of consent, he/she retains the option to participate in the safety follow-up
procedures.
 
At regular time points throughout the study (see Schedule of Activities), blood samples
for biochemistry, blood coagulation, and hematology and urine samples for urinalysis,
urine chemistry, and renal biomarkers will be collected. Vital signs (systolic and
diastolic blood pressure, pulse rate, and body temperature), height (only at screening),
body weight, and electrocardiograms (ECGs) will be recorded throughout the study.
Physical examinations will be performed and AEs will be assessed (see Section 8.2,
Safety Assessments). Events of Special Interest will be closely monitored
(Section 8.3.6, Adverse Events of Special Interest).
 
An Independent Data Monitoring Committee (IDMC) will be established for continuous
monitoring of SAEs, AEs leading to discontinuation, and ALT flares to ensure the
continuing safety of the participants enrolled in the current study (see Section 9.6,
Independent Data Monitoring Committee). In addition, an Independent Flare Expert
Panel (IFLEP) will be appointed to characterize and adjudicate each ALT flare (see
Section 9.7, Independent Flare Expert Panel).
 
After stopping treatment with NA and JNJ-3989 and JNJ-6379, participants will be
monitored closely during the follow-up phase, with frequent follow-up visits and
pre-defined NA re-treatment criteria in case of flares (Section 6.7, NA Re-treatment
Criteria and Monitoring After Stopping of NA).
 
The post-treatment monitoring and NA re-treatment criteria were further updated based
on findings from a case of post-treatment HBV reactivation with subacute hepatic
failure and assessment of additional REEF-2 study data (see Section 6.7).
 
JNJ-3989 will be administered using a proper subcutaneous technique to decrease the
risk of ISRs. ISRs will be managed as outlined in  Section  8.3.6, Adverse Events of
Special Interest.
 
Any clinically significant abnormalities persisting at the end of the study/early
discontinuation will be followed up by the investigator until resolution (return to
baseline) or until stabilization (to be agreed upon with the sponsor).
3. 
OBJECTIVES AND ENDPOINTS
Below is the list of objectives and endpoints that will be evaluated in this study, delineating the
details in alignment with the general objectives listed in the Master Protocol
PLATFORMPAHPB2001. The details specific for this ISA are highlighted (colored fill).
Objectives 
Endpoints
Primary
 
To evaluate the efficacy of 48-week study  
Proportion of participants with HBsAg
NCT04129554

NCT04129554

NCT04129554

NCT04129554

JNJ-73763989 and JNJ-56136379
Clinical Protocol 73763989PAHPB2002
AMENDMENT 4
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
51
Status: Approved,  Date: 26 November 2021
The study will be conducted in 3 phases: a screening phase (4 weeks), a study intervention phase
(48 weeks), and a follow-up phase (48 weeks). If necessary, eg, for operational reasons, the
screening phase may be extended up to a maximum of 6 weeks on a case-by-case basis and in
agreement with the sponsor. The duration of individual participation will be up to 102 weeks.
Participants will be randomized in a 2:1 ratio to one of the following intervention arms and will
receive study intervention for 48 weeks:
 
Intervention Arm 1 (N 80): 200 mg JNJ-3989 (injection once monthly) +
250 mg JNJ-6379 (tablets qd) +
NA* qd;
 
Intervention Arm 2 (N 40): placebo for JNJ-3989 (injection once monthly) +
placebo for JNJ-6379 (tablets qd) +
NA* qd.
* NA: ETV, TDF, or TAF
All participants who complete 48-week study intervention should stop all study interventions
including NAs at Week 48 (see Section 6.6, Study Intervention Completion at Week 48). After
stopping all study interventions, participants will be monitored closely during the 48-week
follow-up phase and should restart NA treatment in accordance with the NA re-treatment criteria
(see Section 6.7, NA Re-treatment Criteria and Monitoring After Stopping of NA, for more
details).
Randomization will be stratified by screening HBsAg level (<1,000 IU/mL or >1,000 IU/mL),
race (Asian versus non-Asian) and type of NA (TDF/TAF versus ETV).
The investigators and participants will remain blinded to intervention allocation until all
participants have reached Week 72 (or discontinued earlier), while the sponsor’s central study
team will be unblinded at the time of the Week 48 IA. Details on the central study team will be
provided in the IDMC charter.
Both the Platform Master informed consent form (ICF) and the ISA ICF must be signed before
the first study-related activity.
Safety and tolerability, including AEs, laboratory assessments, ECGs, vital signs, and physical
examination, will be assessed throughout the study from the time that the ISA ICF is signed until
the completion of the last study-related activity (see Section 8.2, Safety Assessments, and
Section 8.3, Adverse Events and Serious Adverse Events).
Samples for HBV genome sequencing will be taken at the time points indicated in the Schedule
of Activities (see Section 8.1.1, Sequencing). Sequencing of samples obtained may be triggered
by the sponsor’s virologist based on changes in HBV DNA levels observed in each individual
participant and the limits of the sequencing assay.
NCT04129554

JNJ-73763989 and JNJ-56136379
Clinical Protocol 73763989PAHPB2002
AMENDMENT 4
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
52
Status: Approved,  Date: 26 November 2021
The study includes collection of blood samples for exploratory analysis of viral markers (see
Section 8.1, Efficacy Assessments) and host blood biomarkers at the host RNA, protein, and cell
level (see Section 8.9, Host Biomarkers).
A population PK analysis will be performed based on the available data for JNJ-6379, JNJ-3976,
JNJ-3924 and, optionally, NA, potentially in combination with data from a selection of Phase 1
and/or 2 studies. PK parameters in participants undergoing intensive PK sampling (minimally
18 participants) will be calculated via noncompartmental methods (see Section 8.5,
Pharmacokinetics).
Peripheral blood mononuclear cell samples for immune analyses will be collected at selected
sites at the time points indicated in the Schedule of Activities (see Section 8.7, Immune
Assessments).
A pharmacogenomic blood sample will be collected from participants who consent separately to
this component of the study (see Section 8.8).
Two PRO instruments (the HBV-specific self-stigma scale and EQ-5D-5L questionnaire) will be
used to explore the impact of HBV treatment on participants (see Section 8.1.2, Patient-reported
Outcomes).
Participants will be considered to have completed the study if they have completed the
assessments of the end-of-study visit Follow-up Week 48 (Week 96).
If a participant discontinues study intervention before the end of the 48-week study intervention
phase, follow-up assessments should be obtained until 48 weeks after EOSI unless the participant
withdraws consent. NA treatment (either ETV, TDF or TAF as per local practice) should be
continued at this time as per local treatment guidelines.
If a participant withdraws before completing the study intervention, the reason for withdrawal (if
known) is to be documented in the case report form (CRF) and in the source document.
Participants who withdraw consent will be offered an optional safety follow-up visit.
The Schedule of Activities summarizes the frequency and timing of efficacy, safety, and other
assessments applicable to the Master Protocol PLATFORMPAHPB2001 and this ISA.
An  IDMC will be commissioned for this study  (Section 9.6, Independent Data Monitoring
Committee). In addition, an IFLEP will be appointed (Section 9.7, Independent Flare Expert
Panel).
A diagram of the study design is provided in Section 1.2, Schema.
NCT04129554

JNJ-73763989 and JNJ-56136379
Clinical Protocol 73763989PAHPB2002
AMENDMENT 4
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
53
Status: Approved,  Date: 26 November 2021
4.2. 
Scientific Rationale for Study Design
Study Population
Patients with CHB will be eligible if they are currently on NA treatment and are HBeAg
negative.
Patients with liver cirrhosis are excluded, as the goal of the study is to assess the potential of a
finite treatment to achieve functional cure, and discontinuation of treatment in patients with
cirrhosis is not current practice due to concerns about poor tolerability of liver flares associated
with increased viral replication. The safety of the combination regimen evaluated in this study
will first be established in patients without liver cirrhosis prior to initiating studies in patients
with more advanced liver disease.
Control Arm
The safety and tolerability of the investigational combination arm (Intervention Arm 1) will be
compared to those of standard of care NA (Intervention Arm 2).
The analysis of the primary efficacy endpoint and other secondary endpoints will be based on
comparison of the investigational combination arm with the control arm (see Section 9.4,
Statistical Analyses).
Randomization
Randomization will be used to minimize bias in the assignment of participants to intervention
arms, to increase the likelihood that known and unknown participant attributes (eg, demographic
and baseline characteristics) are evenly balanced across treatment arms, and to enhance the
validity of statistical comparisons across intervention arms.
Stratification Factors
Randomization will be stratified by screening HBsAg level (<1,000 IU/mL or >1,000 IU/mL),
race (Asian versus non-Asian), and type of NA (TDF/TAF  versus ETV) in order to provide a
reasonably balanced representation of the 3 baseline factors across the 2 intervention arms.
Blinding
The investigators and participants will remain blinded to intervention allocation until all
participants have reached Week 72 (or discontinued earlier), while the sponsor’s central study
team will be unblinded at the time of the Week 48 IA.
Blinded treatment will be used to reduce potential bias during data collection and evaluation of
clinical endpoints.
Follow-up Procedures and Criteria for Re-initiation of NA Treatment
To ensure safety of patients during the follow-up phase, an ALT flare management plan is in
place, including a high visit frequency for patients after completion of NA treatment (at
NCT04129554

JNJ-73763989 and JNJ-56136379
Clinical Protocol 73763989PAHPB2002
AMENDMENT 4
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
54
Status: Approved,  Date: 26 November 2021
Week 48), and weekly visits for patients with ALT/AST ≥3x upper limit of normal (ULN) and
≥3x nadir (ie, lowest value during study participation) until stabilization.
Increases in ALT and HBV DNA are frequently seen in patients after discontinuation of NA
treatment. These ALT elevations can be reflecting an activation of the host cellular immune
response and can as such lead to functional cure. Cases of fulminant HBV reactivation with fatal
outcome were described after cessation of NA treatment, but the vast majority of such cases were
described in patients with decompensated liver disease at the time of NA discontinuation. These
patients are not eligible to participate in the study. Still, a vigilant follow-up of patients during
this phase of the study is critical to ensure patient safety. Signs of decreased liver function or an
HBV DNA value of >100,000 IU/mL (irrespective of confirmation and/or ALT increase) will
trigger immediate re-initiation of NA treatment based on protocol-defined NA re-treatment
criteria (see Section 6.7, NA Re-treatment Criteria and Monitoring After Stopping of NA).
Re-initiation of NA treatment is also required in case of confirmed HBeAg seroreversion
(HBeAg positive after it was negative at NA completion), in case of confirmed* ALT increase
(>5x ULN) in combination with increased HBV DNA replication (>2,000 IU/mL), and in case of
confirmed* increased HBV DNA replication at higher levels (>20,000 IU/mL).
* At least 4 weeks apart
A post-treatment HBV DNA value of >20,000 IU/mL should trigger re-testing of ALT/AST,
HBV DNA, and total and direct bilirubin within a maximum of 7 days from receipt of the data
and further repeats as necessary (ie, weekly until HBV DNA returns to <20,000 IU/mL). A post-
treatment HBV DNA value of >2,000 IU/mL (but <20,000 IU/mL) should trigger a re-test within
14 days from receipt of the data and further repeats as necessary (ie, every other week until HBV
DNA returns to <2,000 IU/mL). A post-treatment ALT value of >5x ULN should trigger re-
testing of ALT, AST, ALP, total and direct bilirubin, INR, albumin, and HBV DNA on a weekly
basis until ALT and AST levels have returned to <5x ULN. Additional re-testing and/or earlier
restarting of NA treatment is at the investigator’s discretion, even if the above cut-offs are not
yet met.
To avoid delays in decision making, sites are encouraged to run local re-testing in parallel with
central re-testing in the situations described above that require more frequent re-testing. Local
test results are to be recorded in the CRF and/or source documents, including information on the
HBV DNA assay used. In addition, to avoid delays in NA re-treatment, it should be considered
to dispense NA to participants who potentially met the NA re-treatment criteria (eg, pending
confirmation) and who will not be available to come to the study site immediately at the time the
confirmatory test results will become available. This should ensure that the participant can
immediately restart NA treatment if indicated, upon direct confirmation by the investigator.
The decision to re-start NA treatment should take into consideration the dynamics of HBV DNA
and/or ALT values and should be discussed with the sponsor.
NA re-treatment and monitoring after stopping of NA are presented graphically in Section 10.13,
Appendix 13.
NCT04129554

JNJ-73763989 and JNJ-56136379
Clinical Protocol 73763989PAHPB2002
AMENDMENT 4
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
55
Status: Approved,  Date: 26 November 2021
Host DNA and Exploratory Host Biomarker Collection
Refer to Section 4.2 of the Master Protocol PLATFORMPAHPB2001.
4.2.1. 
Study-specific Ethical Design Considerations
Refer to Section 4.2.1 ofthe Master Protocol PLATFORMPAHPB2001.
The total blood volume to be collected is considered to be an acceptable amount of blood to be
collected over this time period from the population in this study.38
4.3. 
Justification for Dose
The proposed dose and treatment duration are selected to maximize the chance for patients to
achieve functional cure and are supported by scientific understanding of available data.
4.3.1. 
JNJ-3989
Clinical data of JNJ-3989 are available from the ongoing Phase 1/2a AROHBV1001 study with a
safety snapshot date of 26 March 2019. Twenty adult healthy participants have received single
subcutaneous injections of JNJ-3989 (35, 100, 200, 300, and 400 mg) and 72 adult CHB
participants have received multiple doses of JNJ-3989 (25, 50, 100, 200, 300, and 400 mg),
administered as 3 subcutaneous injections. The injections were separated by either 7-day
intervals (100, 200, and 300 mg doses), 14-day intervals (100 mg dose), or 28-day intervals (all
doses tested). All participants were started on ETV or TDF on Day 1. JNJ-3989 was generally
safe and well tolerated at all doses.
Efficacy was assessed using snapshot data through 02 May 2019. Antiviral activity data were
available for 56 CHB participants who received 3 subcutaneous injections of 25 to 400 mg
JNJ-3989 every 4 weeks. The antiviral activity data showed that administration of JNJ-3989 at
doses of 25 to 400 mg resulted in pronounced mean HBsAg declines which were generally
sustained at least until Day 168 (ie, 16 weeks after last dose) across all doses. No apparent dose
response was observed at doses between 100 and 400 mg JNJ-3989, suggesting that maximal
HBsAg reduction in this short-term study is reached with these doses. A reduced mean decline
was observed at the lower dose of 25 mg. Data on the 50 mg dose is still emerging.
A dose of 200 mg JNJ-3989 once monthly is chosen for the combination treatment regimen of
JNJ-3989+JNJ-6379+NA based on the observed decline in HBsAg in AROHBV1001 at this
dose over 3 injections, and the lack of dose response observed at higher doses.
4.3.2. 
JNJ-6379
A dose of 250 mg JNJ-6379 qd is chosen for this study.
A dose of 250 mg of JNJ-6379 is being considered to ensure maximal viral inhibition via
“primary” MoA (ie, interfering with the capsid assembly process). In addition, it ensures
sufficient high exposures to engage the “secondary” MoA (ie, inhibition of de novo cccDNA
formation). This dose selection is supported by translational PK/PD analyses and viral kinetic
modeling. Analyses of the HBV DNA data from the 4-week 56136379HPB1001 study showed a
NCT04129554

JNJ-73763989 and JNJ-56136379
Clinical Protocol 73763989PAHPB2002
AMENDMENT 4
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
56
Status: Approved,  Date: 26 November 2021
profound but slightly less substantial reduction of plasma HBV DNA, as a measure of the
“primary” MoA, in the 25 mg dose group compared to the 75 mg and higher dose groups,
suggesting that for JNJ-6379 maximum effect (Emax) in terms of HBV DNA inhibition via
primary MoA is approached starting from a dose of 75 mg onwards. Since it is not possible to
derive the engagement of the “secondary” MoA from the available short-term data, the in vitro
primary human hepatocyte 90% effective concentration values in the presence of serum proteins
obtained for both MoAs were used to translate from the “primary” to the “secondary” MoA.
Participants will be treated with JNJ-6379 for 48 weeks. Based on the MoA of JNJ-6379, it is
expected that continued complete suppression of virus production and de novo cccDNA
formation over many months is required to achieve reduction of the transcriptional active
cccDNA pool, which is considered a prerequisite for HBsAg reduction and/or seroclearance.
Interim analysis data are available from the ongoing Phase 2a Jade study in which the 250-mg
dose is being tested for 48 weeks. Blinded Week 12 data from 40 virologically suppressed CHB
participants who received 250 mg qd JNJ-6379 or placebo in addition to an NA showed that
there were no deaths, grade 4 AEs, or AEs leading to discontinuation. Most AEs were mild or
moderate in severity.
4.4. 
End of Study Definition
4.4.1. 
Participant Completion
A participant will be considered to have completed the study if he or she has completed
assessments at the final follow-up visit.
4.4.2. 
Study Completion (End of Study Definition)
The study is considered completed with the last visit for the last participant in the study. The
final data from the study site will be sent to the sponsor (or designee) after completion of the
final participant visit at that study site, in the time frame specified in the Clinical Trial
Agreement.
5. 
STUDY POPULATION
Screening for eligible participants will be performed within 4 weeks before administration of the
study intervention. If necessary, eg, for operational reasons, the screening phase may be
extended up to a maximum of 6 weeks on a case-by-case basis and in agreement with the
sponsor. Refer to Section 5.4, Screen Failures of the Master Protocol PLATFORMPAHPB2001
for conditions under which the repeat of any screening procedures is allowed.
The inclusion and exclusion criteria for enrolling participants in this study are described below.
If there is a question about these criteria, the investigator must consult with the appropriate
sponsor representative and resolve any issues before enrolling a participant in the study. Waivers
are not allowed.
NCT04129554

JNJ-73763989 and JNJ-56136379
Clinical Protocol 73763989PAHPB2002
AMENDMENT 4
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
57
Status: Approved,  Date: 26 November 2021
Each potential participant must satisfy all inclusion and exclusion criteria from the Master
Protocol PLATFORMPAHPB2001 (numbering prefixed by “M” in the list below) and all
additional intervention-specific inclusion and exclusion criteria (numbering prefixed by “A”).
The latter inclusion and exclusion criteria are highlighted (colored fill). For the few criteria from
the Master Protocol that are specified or more restricted in this ISA, the additional text is also
highlighted (colored fill).
5.1. 
Inclusion Criteria
Each potential participant must satisfy all of the following criteria to be enrolled in the study:
M01/ 
A01. 
Male or female participants ≥18 years of age (or the legal age of consent in the
jurisdiction in which the study is taking place) to ≤65 years of age.
M02. 
Participant must be medically stable based on physical examination, medical history,
vital signs, and 12-lead ECG performed at screening. If there are abnormalities, they
must be consistent with the underlying illness in the study population. This
determination must be recorded in the participant’s source documents and initialed by
the investigator.
M03/ 
A02. 
Participants must have HBV infection documented by serum HBsAg positivity at
screening. In addition, chronicity must be documented by any of the following at least
6 months prior to screening: serum HBsAg positivity, HBeAg or HBV DNA positivity,
ALT elevation above ULN without another cause than HBV infection, documented
transmission event, liver biopsy with changes consistent with chronic HBV, or should
be documented by absence of marker for acute infection such as positive
immunoglobulin M (IgM) anti-hepatitis B surface (HBs) and anti-HBc antibodies,
which can be tested at screening.
The participants should be virologically suppressed. They should:
o Be HBeAg-negative,
o Be on stable HBV treatment, defined as currently receiving NA treatment (ETV,
TDF, or TAF) for at least 24 months prior to screening and having been on the same
NA treatment regimen (at the same dose) as used in this study (see Section 6.1) for
at least 3 months at the time of screening, AND
o Have serum HBV DNA <60 IU/mL on 2 sequential measurements at least 6 months
apart (one of which is at screening), AND
o Have documented ALT  values <2.0x ULN on 2 sequential measurements at least
6 months apart (one of which is at screening).
M04. 
Participants must have a body mass index (weight in kg divided by the square of height
in meters) between 18.0 and 35.0 kg/m2, extremes included.
M05/ Participant must sign a Master ICF (specific for the Master Protocol
PLATFORMPAHPB2001) and an ICF specific for this ISA indicating that he or she
NCT04129554

JNJ-73763989 and JNJ-56136379
Clinical Protocol 73763989PAHPB2002
AMENDMENT 4
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
58
Status: Approved,  Date: 26 November 2021
A03. 
understands the purpose of, and procedures required for, the study and is willing to
participate in the study.
M06. 
Participant must sign a separate ICF  if he or she agrees to provide an optional DNA
sample for research (where local regulations permit). Refusal to give consent for the
optional DNA research sample does not exclude a participant from participation in the
study.
M07/ 
A04.
Criterion modified per Amendment 2.
M07/A04.1. Female participants must be (as defined in  Section 10.8 Appendix 8:
Contraceptive and Barrier Guidance and Collection of Pregnancy Information):
a. 
Not of childbearing potential, OR
b. 
Of childbearing potential and practicing a highly effective, preferably
user-independent method of contraception  at least 30 days prior to
screening (failure rate of <1% per year when used consistently and
correctly) and must agree to remain on a highly effective method while
receiving study intervention and until 90 days after last dose of study
intervention. Examples of highly effective methods of contraception are
provided in  Section 10.8 Appendix 8: Contraceptive and Barrier
Guidance and Collection of Pregnancy Information.
Note: Typical use failure rates may differ from those when used consistently and
correctly. Use should be consistent with local regulations regarding the use of
contraceptive methods for participants in clinical studies.
Note: Female participants of childbearing potential who are on a stable
treatment regimen with hormonal contraceptives (ie, same dose and not starting
or stopping hormonal contraceptive use for at least 30 days prior to screening)
should continue the same dose regimen until 90 days after the last dose of study
intervention. Ethinylestradiol-containing contraceptives are only allowed if the
ethinylestradiol content is ≤20 µg. Female participants stable on an
ethinylestradiol-containing regimen with a dose >20 µg who switch to an
ethinylestradiol-containing regimen with a dose ≤20 µg, should be on that new
regimen for at least 1 week before the first dose of study intervention. For
female participants of childbearing potential who will start a hormonal
contraceptive 
treatment 
during 
the 
study, 
ethinylestradiol-containing
contraceptives are not allowed.
M08. 
Female participants of childbearing potential must have a negative highly sensitive
serum pregnancy test (-human chorionic gonadotropin) at screening and a negative
urine pregnancy test on Day 1 before the first dose of study intervention.
M09. 
In the investigator’s opinion, the participant is able to understand and comply with
protocol requirements, instructions, and study restrictions (Section 5.3, Lifestyle
Considerations) and is likely to complete the study as planned in this ISA (including the
NCT04129554

NCT04129554

JNJ-73763989 and JNJ-56136379
Clinical Protocol 73763989PAHPB2002
AMENDMENT 4
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
60
Status: Approved,  Date: 26 November 2021
negative HCV RNA at screening and documented negative HCV RNA at
least 6 months prior to screening.
 Participants with a positive HDV antibody test may be enrolled after
discussion with the Sponsor if an active HDV co-infection can be ruled out
by documentation of negative HDV RNA.
 Participants with a positive IgM antibody test for HEV infection may be
enrolled after discussion with the Sponsor if an active HEV infection can be
ruled out by documentation of negative anti-HEV IgG.
M02. 
Criterion modified per Amendment 2.
M02.1. 
Participants with evidence of hepatic decompensation at any time
point prior to or at the time of screening:
a. Total bilirubin >1.5xULN,
b. Direct bilirubin >1.2xULN, OR
c. Prothrombin time >1.3xULN (unless caused by anticoagulation
therapy or vitamin K deficiency), OR
d. Serum albumin <3.2 g/dL, OR
e. History of clinical symptoms of hepatic decompensation (eg,
ascites, jaundice, hepatic encephalopathy or coagulopathy,
especially if resulting in a Child-Pugh classification B or C at the
time clinical symptoms present or at screening).
M03. 
History or evidence of clinical signs or symptoms of hepatic decompensation,
including but not limited to: portal hypertension, ascites, hepatic encephalopathy,
esophageal varices.
M04. 
Participants with evidence of liver disease of non-HBV etiology. This includes but is
not limited to hepatitis infections mentioned in exclusion criterion M01/A01, drug- or
alcohol-related liver disease, autoimmune hepatitis, hemochromatosis, Wilson’s
disease, α-1 antitrypsin deficiency, primary biliary cholangitis, primary sclerosing
cholangitis, Gilbert’s syndrome (mild cases are allowed, see exclusion criterion
M02a) or any other non-HBV liver disease considered clinically significant by the
investigator.
M05/ 
A02.
Criterion modified per Amendment 2.
M05.1/A02.1. Participants with history or signs of cirrhosis or portal hypertension
(nodules, no smooth liver contour, no normal portal vein, spleen size
≥12 cm) or signs of HCC on an abdominal ultrasound performed
within 6 months prior to screening or at the time of screening or
clinically relevant renal abnormalities. In case of suspicious findings
on conventional ultrasound the participant may still be eligible if HCC
or clinically relevant renal abnormalities have been ruled out by a more
NCT04129554

JNJ-73763989 and JNJ-56136379
Clinical Protocol 73763989PAHPB2002
AMENDMENT 4
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
61
Status: Approved,  Date: 26 November 2021
specific imaging procedure (contrast enhanced ultrasound, CT  or
MRI).
M06/ 
A03.
Criterion modified per Amendment 2.
M06.1/A03.1. Participants with one or more of the following laboratory abnormalities
at screening as defined by the Division of Acquired Immunodeficiency
Syndrome (DAIDS) Toxicity Grading Scale (see Section 10.9,
Appendix 9, DAIDS Table):
a. Estimated creatinine clearance ≥grade 3 (<60 mL/min) at
screening, 
calculated 
by 
the 
Chronic 
Kidney 
Disease
Epidemiology Collaboration (CKD-EPI) formula;
b. Pancreatic lipase elevation ≥grade 3;
c. Pancreatic amylase elevation ≥grade 3;
d. Hemoglobin ≤10.9 g/dL (males), ≤10.4 g/dL (females);
e. Platelet count ≤lower limit of normal (LLN);
f. Alpha-fetoprotein >100 ng/mL;
Note: Participants with alpha-fetoprotein >ULN but ≤100 ng/mL
may be eligible if HCC can be ruled out based on a sensitive
imaging study (eg, CT with contrast or MRI) during screening.
g. Any other laboratory abnormality considered to be clinically
significant by the investigator (also see inclusion criterion
M03/A02).
Note: Retesting of abnormal laboratory values that may lead to
exclusion will be allowed once without prior approval from the
sponsor. Retesting will take place at an unscheduled visit during
the screening phase. Participants with a normal value at retest may
be included.
M07. 
Participants with hemoglobin A1c >8% at screening.
M08. 
Participants with a history of malignancy within 5 years before screening (exceptions
are squamous and basal cell carcinomas of the skin and carcinoma in situ of the
cervix, or malignancy, which are considered cured with minimal risk of recurrence).
M09. 
Criterion modified per Amendment 2.
M09.1 
Participants with abnormal sinus rhythm (heart rate <45 or >100 beats
per minute [bpm]); QT interval corrected for heart rate according to
Fridericia’s formula (QTcF) >450 ms for males and >470 ms for
females; QRS interval ≥120 ms; PR interval >220 ms; abnormal
conduction; or any other clinically significant abnormalities on a 12-
NCT04129554

JNJ-73763989 and JNJ-56136379
Clinical Protocol 73763989PAHPB2002
AMENDMENT 4
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
62
Status: Approved,  Date: 26 November 2021
lead ECG at screening.
Note: Retesting of an abnormal ECG that may lead to exclusion will be
allowed once without prior asking approval from the sponsor.
Retesting will take place during an unscheduled visit in the screening
phase. Participants not meeting the above exclusion criterion at retest
may be included.
M10. 
Participants with a history of or current cardiac arrhythmias (eg, extrasystole,
tachycardia at rest), history of risk factors for Torsade de Pointes syndrome (eg,
hypokalemia, family history of long QT Syndrome) or history or other clinical
evidence of significant or unstable cardiac disease (eg, angina, congestive heart
failure, myocardial infarction, diastolic dysfunction, significant arrhythmia and/or
coronary heart disease), moderate to severe valvular disease, or uncontrolled
hypertension at screening.
M11. 
Participants with any current or previous illness for which, in the opinion of the
investigator and/or sponsor, participation would not be in the best interest of the
participant (eg, compromise the well-being) or that could prevent, limit, or confound
the protocol-specified assessments. This may include but is not limited to significant
vascular, pulmonary (eg, chronic obstructive pulmonary disease), gastrointestinal (eg,
significant diarrhea, gastric stasis, or constipation that in the investigator’s opinion
could influence drug absorption or bioavailability), endocrine (eg, thyroid disease),
neurologic, hematologic, rheumatologic, psychiatric, neoplastic, or metabolic
disturbances. Any condition possibly affecting drug absorption (eg, gastrectomy or
other significant gastrointestinal tract surgery, such as gastroenterostomy, small
bowel resection, or active enterostomy) will also lead to exclusion.
M12. 
Participants who have received an organ transplant (except for skin, hair, or cornea
transplants).
M13. 
Participants with any history of or current clinically significant skin disease requiring
regular or periodic treatment.
M14. 
Participants with clinically  relevant alcohol or drug abuse within 12 months of
screening.
M15. 
Participants with history of clinically relevant drug rash.
M16/ 
A04. 
Participants who have taken any disallowed therapies as noted in Section  6.5,
Concomitant Therapy before the planned first dose of study intervention.
M17. 
Participants having used any invasive investigational medical device within 3 months,
or having received an investigational intervention or a biological product,
immunoglobulin or other blood product not intended for the treatment of HBV within
6 months or 5 half-lives (whichever is longer), before the planned first dose of study
NCT04129554

NCT04129554

JNJ-73763989 and JNJ-56136379
Clinical Protocol 73763989PAHPB2002
AMENDMENT 4
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
64
Status: Approved,  Date: 26 November 2021
2. 
Agree to follow all requirements that must be met during the study  as noted in the
inclusion and exclusion Criteria of the Master Protocol PLATFORMPAHPB2001 and
of this ISA  (Section 5.1, Inclusion Criteria and 5.2, Exclusion Criteria in both
documents) (eg, contraceptive requirements).
5.4. 
Screen Failures
Refer to Section 5.4 of the Master Protocol PLATFORMPAHPB2001 for handling of screen
failures.
NCT04129554

JNJ-73763989 and JNJ-56136379
Clinical Protocol 73763989PAHPB2002
AMENDMENT 4
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
65
Status: Approved,  Date: 26 November 2021
6. 
STUDY INTERVENTION
6.1. 
Study Intervention(s) Administered
Description of Interventions
Intervention name 
JNJ-3989 
Placebo for
JNJ-3989 
JNJ-6379 
Placebo for 
JNJ-6379 
Entecavir (ETV) 
monohydrate 
Tenofovir 
disoproxil 
fumarate (TDF) 
Tenofovir
alafenamide
(TAF)***
Dosage formulation 
Solution for 
injection  
Solution for 
injection 
Tablets 
Tablets 
Film-coated tablets 
Film-coated 
tablets 
Film-coated
tablets
Unit dose strength(s) 
200 mg/vial 
0.9% saline 
25 and 100 mg 
- 
0.5 mg 
300 mg** 
25 mg
Dosage regimen 
200 mg once 
every 4 weeks 
1 mL once every 
4 weeks 
250 mg qd 
qd 
Lamivudine-refractory 
patients:
1 mg* qd (but should
preferably be treated
with TDF or TAF
instead)
Other indications:
1 mg* qd (must be
agreed upon by the
sponsor)
300 mg qd 
25 mg qd
Route of 
administration 
Subcutaneous 
injection (in the 
abdomen) 
Subcutaneous 
injection (in the
abdomen)
Oral 
Oral 
Oral 
Oral 
Oral
Dosing instructions 
Regardless of 
food intake 
Regardless of 
food intake 
Regardless of 
food intake 
Regardless of 
food intake
On an empty stomach  
With food 
With food
qd: once daily
* 2 tablets of 0.5 mg
** 300 mg TDF is equivalent to tenofovir disoproxil 245 mg
*** In countries where TAF is available, it will be one of the NA treatment options.
NCT04129554

JNJ-73763989 and JNJ-56136379
Clinical Protocol 73763989PAHPB2002
AMENDMENT 4
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
66
Status: Approved,  Date: 26 November 2021
Physical Description of Study Interventions
The JNJ-3989 supplied for this study will be provided as an aqueous clear, colorless to light
yellow solution with 200 mg/mL of JNJ-3989 for subcutaneous injection
.
The JNJ-6379 supplied for this study is formulated as oral tablets containing 
mg (
) and
mg (
) JNJ-56136379-AAA. The JNJ-6379 tablets should be swallowed as a whole.
JNJ-3989 and JNJ-6379 will be provided under the responsibility of the sponsor. Refer to the iBs
for a list of excipients.14,15,16
The placebo for JNJ-3989 will be a solution for subcutaneous injection 
. The matching placebo for JNJ-6379 consists of the oral tablets without active drug
substance (
 [placebo for 
mg] and 
 [placebo for 
mg]).
The NAs ETV, TDF, and TAF are formulated as oral film-coated tablets of 0.5-mg, 300-mg, and
25-mg strength, respectively.
Packaging and Labeling
All study interventions will be packaged with each unit labeled with a unique medication ID
number. Packaging and labeling of JNJ-3989, the corresponding placebo, and the NAs will be
done in an open-label way.
Commercial supplies of NAs and sodium chloride will be sourced and a clinical study label will be
applied.
Study intervention labels will contain information to meet the applicable regulatory requirements.
JNJ-6379 and matching placebo will be dispensed in child-resistant packaging. NA treatment may
also be repackaged into child-resistant packaging if this is not already the case.
No study interventions can be repacked or relabeled without prior approval from the sponsor.
Study Intervention Administration
Study intervention administration must be captured in the source documents and the CRF.
JNJ-3989/placebo injections will be administered subcutaneously (preferably in the abdomen) at
the study site.
In between study visits, participants will take their oral study intervention (JNJ-6379/placebo/NA
treatment) at home and they will bring their oral study intervention with them to each study visit.
At study visits, the oral study intervention should be taken on site to allow biochemistry and
renal biomarker samples to be taken in fasted conditions.
CCI
CCI
CCI
CCI
CCI
CC
CCI
CC
CCI
CCI
NCT04129554

JNJ-73763989 and JNJ-56136379
Clinical Protocol 73763989PAHPB2002
AMENDMENT 4
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
67
Status: Approved,  Date: 26 November 2021
NA treatment will be provided by the sponsor. Investigators should follow guidance detailed in
the respective prescribing information, including special warnings and precaution for use.
During the study, participants will continue the same NA treatment they were receiving at time of
screening (and during at least 3 months prior to screening). In case participants experienced
toxicity to ETV, TDF, or TAF prior to screening, they should be treated with one of the other two
NAs during this study.
If clinically indicated, switching from one NA treatment (ETV, TDF, or TAF) to another NA
treatment (ETV, TDF, or TAF) during the study is allowed for all participants after consultation
with the sponsor.
For a definition of study intervention overdose, refer to Section 8.4, Treatment of Overdose.
6.2. 
Preparation/Handling/Storage/Accountability
Preparation/Handling/Storage
All study interventions must be stored as specified on the product-specific labeling.
Study-site personnel will instruct participants on how to store JNJ-6379/placebo/NA treatment
for at-home use as indicated for this protocol.
Refer to the pharmacy manual/study site investigational product and procedures manual for
additional guidance on study intervention preparation, handling, and storage.
Accountability
The investigator is responsible for ensuring that all study intervention received at the site is
inventoried and accounted for throughout the study. The dispensing of JNJ-6379/placebo and
NA to the participant, and the return of JNJ-6379/placebo and NA from the participant, must be
documented on the intervention accountability form. Participants must be instructed to return all
original containers, whether empty or containing study intervention. The JNJ-3989/placebo
injections administered to the participant must be documented on the intervention accountability
form. All study intervention will be stored and disposed of according to the sponsor’s
instructions. The investigator agrees neither to dispense the study intervention from, nor store it
at, any site other than the study sites agreed upon with the sponsor. Study-site personnel must not
combine contents of the study intervention containers.
Study intervention must be handled in strict accordance with the protocol and the container label,
and must be stored at the study site in a limited-access area or in a locked cabinet under
appropriate environmental conditions. Unused study intervention, and study intervention
returned by the participant, must be available for verification by the sponsor’s study site monitor
during on-site monitoring visits. The return to the sponsor of unused study intervention, or used
returned study intervention for destruction, will be documented on the intervention return form.
When the study site is an authorized destruction unit and study intervention supplies are
destroyed on-site, this must also be documented on the intervention return form.
NCT04129554

JNJ-73763989 and JNJ-56136379
Clinical Protocol 73763989PAHPB2002
AMENDMENT 4
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
68
Status: Approved,  Date: 26 November 2021
Study intervention should be dispensed under the supervision of the investigator or a qualified
member of the study-site personnel, or by a hospital/clinic pharmacist. Study intervention will be
supplied only to participants of this study. Returned study intervention must not be dispensed
again, not even to the same participant. An intermediate study intervention compliance check is
not considered to be a re-dispensing. Study intervention may not be relabeled or reassigned for
use by other participants in the study.
6.3. 
Measures to Minimize Bias: Randomization and Blinding
Intervention Allocation
Procedures for Randomization and Stratification
Central randomization will be implemented in this study. Participants will be randomly assigned
in a 2:1 ratio to 1 of 2 intervention arms (JNJ-3989+JNJ-6379+NA:placebo+placebo+NA).
Randomization will be based on a computer-generated randomization schedule prepared before
the study by or under the supervision of the sponsor. The randomization will be balanced by
using randomly permuted blocks and will be stratified by screening HBsAg level (<1,000 IU/mL
or >1,000 IU/mL), race (Asian versus non-Asian) and type of NA (TDF/TAF versus ETV).
For more information on the interactive web response system (IWRS), refer to Section 6.3 of the
Master Protocol PLATFORMPAHPB2001.
Blinding
The investigators and participants will remain blinded to intervention allocation until all
participants have reached Week 72 (or discontinued earlier), while the sponsor’s central study
team will be unblinded at the time of the Week 48 IA.
Under normal circumstances, the blind should not be broken until all participants have completed
Week 72 or discontinued earlier. The investigator may in an emergency determine the identity of
the study intervention by contacting the IWRS. While the responsibility to break the study
intervention code in emergency situations resides solely with the investigator, it is recommended
that the investigator contacts the sponsor or its designee to discuss the particular situation, before
breaking the blind, only if this does not delay action with respect to treatment in an emergency
situation. Telephone contact with the sponsor or its designee will be available 24 hours per day, 7
days per week. In the event the blind is broken, the sponsor must be informed as soon as
possible. The date, time, and reason for the unblinding must be documented by the IWRS, in the
appropriate section of the CRF, and in the source document. The documentation received from
the IWRS indicating the code break must be retained with the participant’s source documents in
a secure manner.
Sponsor personnel involved in the pharmacokinetic and pharmacodynamic modeling will have
access to the pharmacokinetic and pharmacodynamic data before formal unblinding. Sponsor
personnel involved in trial conduct, data management, and statistics will not have access to these
data.
NCT04129554

JNJ-73763989 and JNJ-56136379
Clinical Protocol 73763989PAHPB2002
AMENDMENT 4
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
69
Status: Approved,  Date: 26 November 2021
Participants who have had their study intervention assignment unblinded should continue study
intervention intake (unless instructed otherwise) and should return for scheduled evaluations.
In order to preserve the blinding during the study treatment phase, HBsAg, HBeAg, anti-HBs,
and anti-HBe antibody tests cannot be done locally.
For more information on blinding, refer to Section 6.3 of the Master Protocol
PLATFORMPAHPB2001.
6.4. 
Study Intervention Compliance
JNJ-3989/placebo will be administered at the study site as a subcutaneous injection by qualified
study-site personnel to assure compliance with study requirements.
If an injection of JNJ-3989 was missed, the injection should be given as soon as possible but
within 3 weeks after the scheduled time. Otherwise, the injection should be skipped, and the next
injection should be given at the next scheduled time point per the initial injection schedule.
The participants will be requested to bring unused oral study interventions and empty packaging
to the study site at each visit.
Every effort should be made to have the participant take the oral study interventions as indicated
in the Schedule of Activities. In case a dose of JNJ-6379/placebo was missed, the dose should be
given as soon as possible but within 12 hours after the scheduled time. Otherwise, the dose
should be skipped and the next dose should be given at the next scheduled time point per the
initial dosing schedule. If more than 3 consecutive doses are missed, the investigator should be
contacted and the case should be discussed with the sponsor. If a dose of NA is missed, the
participant should follow the guidelines in the package insert.
If a participant’s study intervention intake is not according to the protocol, the investigator will
take the necessary measures to ensure future adherence to the protocol.
An optional medication diary to document oral study intervention intake can be made available
for participants with an observed or known risk for study intervention non-compliance. The
completed diaries are reviewed by the site staff and discussed with the participants for
compliance monitoring and counseling. Completed diaries will be returned to the site staff to add
to the source documents.
6.5. 
Concomitant Therapy
Overviews of ISA-specific disallowed medication and concomitant medications that should be
used with caution are provided in Table 3 and Table 4, respectively. For general concomitant
therapy considerations, refer to Section 6.5 ofthe Master Protocol PLATFORMPAHPB2001.
NCT04129554

JNJ-73763989 and JNJ-56136379
Clinical Protocol 73763989PAHPB2002
AMENDMENT 4
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
70
Status: Approved,  Date: 26 November 2021
Table 3: 
Disallowed Medication
Disallowed at any time prior to screening until end of follow-up:
 
Any CAM and oligonucleotide-based HBV treatment (eg, siRNA and antisense oligonucleotides), other
than the study intervention taken in the context of this study.
Disallowed from 6 months prior to screening until end of follow-up:
 
Any investigational agent, investigational vaccine, invasive investigational medical device, or
investigational biological product (other than the study intervention taken in the context of this study).
Disallowed from 6 months prior to baseline until end of follow-up:
 
Any systemically (eg, intravenously, intramuscularly, orally, subcutaneously) administered medication that
directly or indirectly interferes with immune responses (eg, cyclosporine, interleukins, IFN, programmed
death-[ligand] 1 inhibitors, systemic corticosteroids exceeding 5 mg of prednisolone equivalent/day).
Disallowed from 1 month prior to screening until end of follow-up:
 
Moderate and potent inhibitors of CYP3A4 (eg, azole anti-fungals, macrolide antibiotics, diltiazem,
verapamil).
 
Moderate and potent inducers of CYP3A4 (anti-epileptics: eg, carbamazepine, oxcarbazepine,
[fos]phenytoin, and phenobarbital; anti-tuberculosis drugs: rifabutin, rifampin, and rifapentine; other:
bosentan, modafinil).
 
Inhibitors of breast cancer resistance protein (BCRP) transporter (eg, curcumin, cyclosporine A,
eltrombopag) or P-glycoprotein transporter (eg, amiodarone, azithromycin clarithromycin, diltiazem,
dronedarone, erythromycin, felodipine, itraconazole, ketoconazole, quinidine, ritonavir, verapamil).
 
Any medication that reduces renal function or competes for active tubular secretion (eg cimetidine,
probenecid, quinidine).
Disallowed from screening until end of follow-up:
 
Products containing Hypericum perforatum (St. John’s wort).
 
Any anti-HBV drug (including vaccines) other than the study intervention taken in the context of this study.
Note:  NA standard ofcare treatment is allowed.
 
Biotin (>1 mg daily dose), either taken alone or as part of a multivitamin formulation.
Note: The use of other vitamins is allowed.
 
Topical steroids (>7 days) under occlusive dressing.
Disallowed from 1 week prior to baseline until 12 weeks after EOSI:
 
Ethinylestradiol-containing contraceptives with an ethinylestradiol content >20 µg.
Note: Starting treatment with ethinylestradiol-containing contraceptives during the study is not allowed.
NCT04129554

JNJ-73763989 and JNJ-56136379
Clinical Protocol 73763989PAHPB2002
AMENDMENT 4
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
71
Status: Approved,  Date: 26 November 2021
Table 4: 
Concomitant Medications to be Used With Caution
The following concomitant medications are allowed but should be used with caution with monitoring of AEs
and desired efficacy. Alternative medications or adjusted doses should be considered.
 
Analgesics: ergoloid mesylates, ergotamine tartrate, dihydroergotamine and methylergonovine.
 
Calcium channel blockers: eg, amlodipine, bepridil, nicardipine, nifedipine, and nisoldipine.
 
Lipid-lowering drugs: eg, atorvastatin, lovastatin, pitavastatin, pravastatin, rosuvastatin, simvastatin.
 
Phosphodiesterase 5 inhibitors: sildenafil, vardenafil, tadalafil.
 
Sedatives/anxiolytics: midazolam, triazolam.
 
Acid-reducing agents: antacids (eg, aluminium and magnesium hydroxide) (recommended to separate
antacid and oral study intervention administration by 4 hours).
 
Ethinylestradiol-containing contraceptives:
o 
Only allowed if on a stable treatment regimen for ≥3 months prior to screening and the
ethinylestradiol content is ≤20 µg.
o 
Female participants stable on an ethinylestradiol-containing regimen with a dose >20 µg who
switch to an ethinylestradiol-containing regimen with a dose ≤20 µg, should be on that new
regimen for at least 1 week before the first dose of study intervention.
 
Hormone replacement therapy in postmenopausal women: allowed if on a stable treatment regimen (ie,
same dose and not starting or stopping for 2 weeks prior to baseline until 12 weeks after EOS
intervention). Applicable procedures and treatment guidance based on package inserts should be respected.
 
Anticoagulants.
Note: aspirin and other antiplatelet agents are allowed.
Note: The list of disallowed concomitant medication and medication to be used with caution is
not exhaustive; for products falling in one of the categories and not mentioned by name, the
sponsor should be contacted to determine whether the product can be allowed.
The prescribing information for ETV, TDF, and TAF should be consulted for any additional
prohibited medication.
Medications requiring subcutaneous injection (other than JNJ-3989/placebo; eg, insulin) should
be administered away from the JNJ-3989 injection site.
6.6. 
Study Intervention Completion at Week 48
All participants should stop all study interventions (JNJ-3989, JNJ-6379, and NA  or both
placebos and NA) at Week 48.
Any relevant change in participant baseline status with regards to ALT, HBV DNA levels and/or
HBeAg status or any other event that in the opinion of the investigator could prevent stopping
NA should be discussed with the sponsor.
For participants who cannot stop NA treatment, follow-up assessments will be obtained until
Week 96.
6.7. 
NA Re-treatment Criteria and Monitoring After Stopping of NA
After completing treatment with JNJ-3989, JNJ-6379 (or their matching placebos) and NA at
Week 48 (or after premature discontinuation), participants will be monitored closely during the
follow-up phase.
NCT04129554

JNJ-73763989 and JNJ-56136379
Clinical Protocol 73763989PAHPB2002
AMENDMENT 4
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
72
Status: Approved,  Date: 26 November 2021
After stopping NA treatment, participants should be monitored as follows:
 Regular monitoring visits will be every 4 weeks during the follow-up phase in accordance
with the Schedule of Activities.
 A post-treatment HBV DNA value of >20,000 IU/mL should trigger re-testing of ALT/AST,
HBV DNA, and total and direct bilirubin within a maximum of 7 days from receipt of the
data and further repeats as necessary (ie, weekly until HBV DNA returns to <20,000 IU/mL).
 A post-treatment HBV DNA value of >2,000 IU/mL (but <20,000 IU/mL) should trigger a
re-test within 14 days from receipt of the data and further repeats as necessary (ie, every
other week until HBV DNA returns to <2,000 IU/mL).
 A post-treatment ALT value of >5x ULN should trigger re-testing of ALT, AST, alkaline
phosphatase (ALP), total and direct bilirubin, INR, albumin, and HBV DNA on a weekly
basis until ALT and AST levels have returned to <5x ULN.
After stopping NA treatment, participants should restart NA treatment:
 
Immediately with signs of decreasing liver function based on laboratory findings (eg, INR,
direct bilirubin) or clinical assessment (eg, ascites, hepatic encephalopathy).
 
Immediately with an HBV DNA value of >100,000 IU/mL (irrespective of confirmation
and/or ALT increase).
 
With confirmed post-treatment HBeAg seroreversion (HBeAg positive after it was negative
at NA completion).
 
With confirmed* post-treatment increases in HBV DNA >2,000 IU/mL and ALT >5x ULN.
 
With confirmed* post-treatment increases in HBV DNA >20,000 IU/mL.
* At least 4 weeks apart frequency of visits as described above.
Note: Additional re-testing and/or earlier restarting of NA treatment is at the investigator’s
discretion, even if the above cut-offs are not yet met.
To avoid delays in decision making, sites are encouraged to run local re-testing in parallel with
central re-testing in the situations described above that require more frequent re-testing. Local
test results are to be collected in the CRF and/or source documents, including information on the
HBV DNA assay used. In addition, to avoid delays in NA re-treatment, it should be considered
to dispense NA to participants who potentially met the NA re-treatment criteria (eg, pending
confirmation) and who will not be available to come to the study site immediately at the time the
confirmatory test results will become available. This should ensure that the participant can
immediately re-start NA treatment if indicated, upon direct confirmation by the investigator.
Management of intervention-emergent ALT/AST elevations is discussed in Section 8.3.6.3,
Intervention-emergent ALT/AST Elevations.
NA re-treatment criteria and monitoring after stopping of NA  are presented graphically in
Section 10.13, Appendix 13.
NCT04129554

JNJ-73763989 and JNJ-56136379
Clinical Protocol 73763989PAHPB2002
AMENDMENT 4
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
73
Status: Approved,  Date: 26 November 2021
6.8. 
Intervention After the End of the Study
Refer to Section 6.7 of the Master Protocol PLATFORMPAHPB2001.
The investigator should consider to re-start NA treatment per local standard of care at the EOS
visit (Follow-up Week 48) for participants who discontinued NA treatment at Week 48, who did
not re-start NA treatment during the follow-up phase, and who did not achieve and maintain
HBsAg seroclearance. NA will not be provided by the sponsor after the final study visit.
7. 
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT
DISCONTINUATION/WITHDRAWAL
If a participant discontinues study intervention for any reason before Week 48, the participant
will have an early withdrawal visit and will enter follow-up unless he/she withdraws consent. If
the reason for withdrawal from the study is withdrawal of consent, then the participant will be
offered an optional safety follow-up visit. Study intervention assigned to the participant who
discontinued study intervention may not be assigned to another participant.
7.1. 
Discontinuation of Study Intervention
JNJ-3989 and JNJ-6379 (or matching placebos) must be discontinued before Week 48 for all
reasons listed in Section 7.1 of the Master Protocol PLATFORMPAHPB2001 and for all
additional intervention-specific reasons. All the discontinuation criteria are listed below and the
intervention-specific criteria are highlighted (colored fill). For the few criteria from the Master
Protocol that are specified or more restricted in this ISA, the changes compared to the Master
Protocol are also highlighted (colored fill). When JNJ-3989 or JNJ-6379 (or the matching
placebos) are discontinued, NA treatment may be continued or, in consultation with the sponsor,
discontinued based on investigator judgement.
The discontinuation criteria are:
 
The investigator believes that for safety or tolerability reasons (eg, AE) it is in the best
interest of the participant to discontinue JNJ-3989 and JNJ-6379 (or matching placebos).
 
The participant becomes pregnant.
 
The participant has a ≥grade 3 rash or allergic reaction.
 
The participant has signs of hepatic decompensation (ie, clinical evidence of ascites,
bleeding varices, or hepatic encephalopathy).
 
The participant has a confirmed ≥grade 3 estimated glomerular filtration rate (eGFR)
abnormality and a drop from baseline of >10 mL/min/1.73 m2, considered at least possibly
related to JNJ-3989 or JNJ-6379. Change of NA treatment should be considered according
to the prescribing information.
 
The participant has a QTcF prolongation (defined as a QTcF value of >500 ms, or an
increase from baseline of >60 ms) at any given time point.
 
The participant requires ≥7 days of treatment with any of the disallowed medications listed
in Section 6.5 and does not intend to discontinue treatment with the disallowed medication.
NCT04129554

JNJ-73763989 and JNJ-56136379
Clinical Protocol 73763989PAHPB2002
AMENDMENT 4
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
74
Status: Approved,  Date: 26 November 2021
 
The participant has confirmed HBV virologic breakthrough (ie, confirmed on-treatment
HBV DNA increase by >1 log10 IU/mL from nadir or confirmed on-treatment HBV DNA
level >200 IU/mL in participants who had HBV DNA level <LLOQ of the HBV DNA
assay). In case of virologic breakthrough, the investigator in consultation with the sponsor
should consider changing the NA (to an NA that is not cross-resistant to the current NA,
after evaluation of all data available). In case of virologic breakthrough, the same
assessments will be done at an unscheduled visit as will be done in case of an ALT flare, but
no PBMC sample will be taken (see Section 8.3.6.3 and Schedule of Activities).
 
The participant has ALT/AST elevations, as described in  Section 8.3.6.3,
Intervention-emergent ALT/AST Elevations.
Note: The grades are based on the DAIDS Toxicity Grading Scale (see Section 10.9,
Appendix 9, DAIDS Table).
7.2. 
Participant Discontinuation/Withdrawal From the Study
In case a participant is withdrawn from the study intervention cohort for any of the reasons listed
in Section 7.2 of the Master Protocol PLATFORMPAHPB2001, additional participants will not
be entered.
7.2.1. 
Withdrawal From the Use of Research Samples
Refer to Section 7.2.1 of the Master Protocol PLATFORMPAHPB2001.
7.3. 
Lost to Follow-up
Refer to Section 7.3 of the Master Protocol PLATFORMPAHPB2001.
8. 
STUDY ASSESSMENTS AND PROCEDURES
Overview
Refer to Section 8 of the Master Protocol PLATFORMPAHPB2001.
The PRO assessments and ECGs should be completed before any tests, procedures or other
consultations for that visit.
The total blood volume to be collected from each participant during planned assessments for the
entire study will be approximately 1200 mL. In addition, PBMC samples (at selected sites only;
approximately 300 mL), optional exploratory host genotyping and epigenetic research samples
(approximately 60 mL) and optional intensive PK samples (approximately 66 mL) may be
collected.
Note: The total blood volume to be collected from each participant may vary, depending on
several factors (eg, unscheduled re-tests, re-sampling, individual variations).
Sample Collection and Handling
Refer to Section 8 of the Master Protocol PLATFORMPAHPB2001.
NCT04129554

JNJ-73763989 and JNJ-56136379
Clinical Protocol 73763989PAHPB2002
AMENDMENT 4
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
75
Status: Approved,  Date: 26 November 2021
Study-specific Materials
In addition to the items described in Section 8 of the Master Protocol PLATFORMPAHPB2001,
the investigator will be provided with the following supplies:
 
A binder with the PRO instruments,
 
Prescribing Information for ETV, TDF, and TAF,
 
Contact information page(s).
8.1. 
Efficacy Assessments
All efficacy assessments will be performed at predefined time points as specified in the Schedule
of Activities.
Qualitative and quantitative HBsAg and HBeAg, and quantitative HBcrAg as well as anti-HBs
and anti-hepatitis B e (HBe) antibodies will be determined using validated serologic assays in a
central laboratory. Samples for the determination of HBsAg and HBeAg will be processed in
real-time. Samples for the determination of HBcrAg can be analyzed in batch and at the
sponsor’s request.
HBV DNA and HBV RNA will be quantified at central laboratories using validated assays for
the quantification of HBV DNA and HBV RNA. Samples for the determination of HBV DNA
will be processed in real-time. Samples for the determination of HBV RNA can be analyzed in
batch and at the sponsor’s request.
HBeAg and anti-HBe antibody testing results from the Week 44 visit onwards will be provided
for each participant to the investigator and the sponsor at the next visit (ie, from the Week 48
visit onwards). HBsAg and anti-HBs testing results from the Week 44 visit onwards will be
provided for each participant to the investigator from FU Week 2 onwards. The blinded post-
baseline results collected prior to the Week 44 visit will be provided to the investigator at the end
of the study to complete the participant’s medical records. Note that screening and Day 1 predose
results are not blinded. HBV DNA results will be provided to the investigator and the sponsor
from screening until the end of follow-up. In order to preserve the blinding during the study
treatment phase, HBsAg, HBeAg, anti-HBs, and anti-HBe antibody tests cannot be done locally.
It is the responsibility of the investigator:
 
To monitor HBV DNA results and ensure that JNJ-3989 and JNJ-6379 (or the matching
placebos) are discontinued in participants with confirmed virologic breakthrough  (see
Section 7.1, Discontinuation of Study Intervention),
 
To assess if NA treatment cannot be stopped at Week 48 due to any relevant change in
participant baseline status with regards to ALT, HBV DNA levels and/or HBeAg status or
any other event (see Section 6.6, Study Intervention Completion at Week 48),
 
To assess whether restart of NA treatment during follow-up is needed (see Section 6.7, NA
Re-treatment Criteria and Monitoring After Stopping of NA).
NCT04129554

JNJ-73763989 and JNJ-56136379
Clinical Protocol 73763989PAHPB2002
AMENDMENT 4
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
76
Status: Approved,  Date: 26 November 2021
In participants enrolled at a site with an on-site Fibroscan device, Fibroscan assessments will be
performed at different time points to determine changes in fibrosis levels.
Samples may be used by the sponsor for additional exploratory assessments analyzing the
serologic and virologic characteristics of HBV infection and efficacy or safety of the study
intervention.
8.1.1. 
Sequencing
Viral genome sequence analysis will be performed to evaluate mutations associated with the
study intervention.
Sequencing of the HBV genome will be performed to monitor HBV variants present at the time
points indicated in the Schedule of Activities. The sequencing of samples may be triggered by
the sponsor virologist based on changes in HBV DNA levels observed in each individual
participant and the limits of the sequencing assay.
Samples may be used by the sponsor for additional assessments analyzing the serologic and
virologic characteristics of the HBV infection and efficacy of the study intervention, including
viral genotypic and phenotypic assessments.
8.1.2. 
Patient-reported Outcomes
The impact of HBV treatment on participants will be assessed using PROs at predefined time
points (see Schedule of Activities). The following PRO instruments will be used: HBV-specific
self-stigma scale and EQ-5D-5L questionnaire.
The PRO assessments will be performed by all participants. Participants should complete these
assessments in their native language or if there is no version available in their native language, a
version in a language in which the participant is fluent and literate. It is preferable that
participants are able to read and write to complete the assessments by themselves. If a participant
is unable to read or has visual or other physical limitations that make it difficult to read or
complete the assessments, trained study-site personnel may read the questions and responses
aloud exactly as they appear on the assessment and record the participant’s responses.
Study-site personnel will record in the CRF whether the PRO  assessments were performed
during the study visit.
The participant should be provided a quiet place to complete the PRO assessments, and
instructed how to complete the PRO assessments. When deciding which answer to report,
participants should not receive any help from anyone accompanying them (such as family
members and friends) or study-site personnel; the responses should reflect the participant’s
interpretation and response.
Participants’ responses to the PRO questionnaires will not be reported as AEs or SAEs.
HBV-specific Self-stigma Scale, Version 1.0
NCT04129554

JNJ-73763989 and JNJ-56136379
Clinical Protocol 73763989PAHPB2002
AMENDMENT 4
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
77
Status: Approved,  Date: 26 November 2021
The HBV-specific self-stigma scale is an HBV-specific PRO instrument designed to assess the
experience and impact of self-stigma. The current version consists of 37 items. The items cover
aspects of self-stigma such as a) devaluation, inferiority, and worthlessness, b) marginalization
and alienation, c) secrecy and concealment, d) shame and guilt, and e) withdrawal and social
isolation. Each of the 37 items is graded on a 5-point Likert scale (1 “Never”, 2 “Rarely”,
3 “Sometimes”, 4 “Often”, and 5 “Always”). It takes less than 15 minutes to complete the
scale. The content validity of the scale is currently being evaluated and the data collected in this
study will be used to assess the psychometric properties of the scale.33,39
The HBV-specific self-stigma scale version 1.0 is provided in Section 10.10, Appendix 10,
HBV-specific Self-stigma Scale.
5-Level EuroQol 5-Dimension Questionnaire
The EQ-5D-5L questionnaire is a brief, 2-page, generic health-related quality-of-life assessment
that evaluates a subject’s self-rated health state on 5 dimensions (mobility, self-care, usual
activities, pain/discomfort, anxiety/depression). Additionally, a VAS records the subject’s
self-rated health on a vertical VAS where the endpoints are labelled ‘best imaginable health
state’ (100) and ‘worst imaginable health state’ (0). This information can be used as a
quantitative measure of health outcome as judged by the subject. EQ-5D scores include the
following:
 
EQ-5D Valuation Index score (a weighted scoring ofthe 5 dimension scores with a possible
range from 0 to 1);
 
EQ-5D VAS score (with a possible range from 0 [worst imaginable health] to 100 [best
imaginable health]);
 
EQ-5D descriptive system scores (5 scores reflecting each of the 5 dimensions ranging from
0 [no limitation] to 4 [incapacity]).
It takes about 2 minutes to complete the EQ-5D-5L questionnaire.
A representative example of the EQ-5D-5L questionnaire is provided in Section 10.11,
Appendix 11, 5-Level EuroQol 5-Dimension Questionnaire (EQ-5D-5L).
8.2. 
Safety Assessments
Safety and tolerability (AEs, clinical safety laboratory assessments, ECGs, vital signs and
physical examinations) will be evaluated as described in Section 8.2 of the Master Protocol
PLATFORMPAHPB2001 and at predefined time points as specified in the Schedule of
Activities.
Additional clinical safety laboratory assessments specific for this protocol are described in
Section 10.2, Appendix 2, Clinical Laboratory Tests.
NCT04129554

JNJ-73763989 and JNJ-56136379
Clinical Protocol 73763989PAHPB2002
AMENDMENT 4
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
78
Status: Approved,  Date: 26 November 2021
8.2.1. 
Physical Examinations
Refer to Section 8.2.1 ofthe Master Protocol PLATFORMPAHPB2001.
8.2.2. 
Vital Signs
Refer to Section 8.2.2 of the Master Protocol PLATFORMPAHPB2001.
Clinically relevant abnormalities in vital signs are defined in Section 10.7, Appendix 7,
Cardiovascular Safety Abnormalities.
8.2.3. 
Electrocardiograms
Refer to Section 8.2.3 of the Master Protocol PLATFORMPAHPB2001.
Clinically relevant abnormalities in ECG  are defined in Section 10.7, Appendix 7,
Cardiovascular Safety Abnormalities.
8.2.4. 
Clinical Safety Laboratory Assessments
Refer to Section 8.2.4 ofthe Master Protocol PLATFORMPAHPB2001.
In addition, urine samples for urine chemistry and renal biomarkers will be collected as noted in
Section 10.2, Appendix 2, Clinical Laboratory Tests.
For this study, the laboratory abnormality of cholesterol increase is identified as laboratory
abnormality of interest.
8.3. 
Adverse Events and Serious Adverse Events
Adverse events and SAEs will be evaluated as described in Section 8.3 of the Master Protocol
PLATFORMPAHPB2001, including handling of pregnancy described in Section 8.3.5.
For further details on AEs and SAEs (Definitions and Classifications; Attribution Definitions;
Severity Criteria; Special Reporting Situations; Procedures) as well as product quality
complaints, refer to Attachment 4 of the Master Protocol PLATFORMPAHPB2001.
8.3.1. 
Time Period and Frequency for Collecting Adverse Event and Serious
Adverse Event Information
Refer to Section 8.3.1 of the Master Protocol PLATFORMPAHPB2001.
8.3.2. 
Method of Detecting Adverse Events and Serious Adverse Events
Refer to Section 8.3.2 of the Master Protocol PLATFORMPAHPB2001.
8.3.3. 
Follow-up of Adverse Events and Serious Adverse Events
Refer to Section 8.3.3 ofthe Master Protocol PLATFORMPAHPB2001.
NCT04129554

JNJ-73763989 and JNJ-56136379
Clinical Protocol 73763989PAHPB2002
AMENDMENT 4
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
79
Status: Approved,  Date: 26 November 2021
8.3.4. 
Regulatory Reporting Requirements for Serious Adverse Events
Refer to Section 8.3.4 ofthe Master Protocol PLATFORMPAHPB2001.
8.3.5. 
Pregnancy
Refer to Section 8.3.5 of the Master Protocol PLATFORMPAHPB2001.
8.3.6. 
Adverse Events of Special Interest
Events of Special Interest are significant AEs that are judged to be of special interest because of
clinical importance, known class effects or based on nonclinical signals. Events of Special
Interest that will be carefully monitored during the study include ISRs, ALT/AST elevations,
renal complications, and events related to cholesterol increase (Section 8.2.4, Clinical Safety
Laboratory Assessments). In addition, the following toxicities will also be carefully monitored:
rash and acute systemic allergic reactions.
For participants reporting rash, ISRs, acute systemic allergic reactions, ALT/AST elevations, and
renal complications as specified in the DAIDS Toxicity Grading Scale (see Section 10.9,
Appendix 9, DAIDS Table), the following should be done.
8.3.6.1. 
Rash
Participants should be informed that they should contact their doctor immediately when
they notice any generalized skin reaction. This skin reaction should be evaluated in the
clinic the same day (if possible) or the next day.
All rash events should be captured in the AE section of the CRF. A separate Rash page will be
completed in case of a rash event.
Monitoring of the evolution of rash events will be performed as described in Table 5 in
Section 10.5, Appendix 5, Rash Management.
When safety blood samples are drawn as per the rash management guidelines, these should be
processed by the local laboratory. The following parameters will need to be tested: AST, ALT,
sedimentation rate, complete blood cell count (including hemoglobin, hematocrit, red blood cell
[RBC] count, white blood cell [WBC] count, differential count [neutrophils, lymphocytes,
monocytes, eosinophils, and basophils], and platelet count), and creatinine. The values of the
local laboratory assessments need to be transcribed in the CRF by the study site personnel.
The participant may be treated symptomatically until the rash resolves. Oral antihistamines
(eg, cetirizine, levocetirizine) and/or topical corticosteroids may provide symptomatic relief but
effectiveness of these measures has not been established. If systemic corticosteroids exceeding
5 mg of prednisolone equivalent/day are required for treatment of rash, JNJ-3989 and JNJ-6379
(or placebos) need to be permanently discontinued. NAs can be continued. If the rash is
considered to be most likely due to concomitant illness or non-study drugs, standard
management, including discontinuation of the likely causative agent, should be undertaken.
NCT04129554

JNJ-73763989 and JNJ-56136379
Clinical Protocol 73763989PAHPB2002
AMENDMENT 4
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
80
Status: Approved,  Date: 26 November 2021
8.3.6.1.1. 
Injection Site Reactions
At the time points specified in the Schedule of Activities or at an unscheduled visit if needed, an
evaluation of the injection site will be performed based on participant’s description and/or
physical examination. Evaluation will include at a minimum the time of occurrence, time of
resolution and a description of the abnormality including its maximal diameter. For each ISR,
information on pain, erythema, induration and pruritus should be obtained as specified in the
DAIDS scale (see Section 10.9, Appendix 9, DAIDS Table).
All ISRs (including ISRs below grade 1) will need to be recorded in the special events section of
the CRF.
Digital pictures will be taken when considered appropriate; all efforts should be made to collect
images in case of grade 3 and 4 ISRs. Digital pictures will only be taken and collected from
participants who consent separately to this component of the study. If digital pictures are
required, they should be de-identified and provided to the sponsor.
8.3.6.2. 
Acute Systemic Allergic Reactions
Grade 1 (Localized Urticaria [Wheals] With no Medical Intervention Indicated)
Participants may continue the intake of study interventions.
Cetirizine, levocetirizine, topical corticosteroids or antipruritic agents may be prescribed.
Participants should be advised to contact the investigator immediately if there is any worsening
of the acute systemic allergic reaction.
Grade 2 (Localized Urticaria With Intervention Indicated, or Mild Angioedema With no
Intervention Indicated)
Participants may continue the intake of study interventions.
Cetirizine, levocetirizine, topical corticosteroids or antipruritic agents may be prescribed.
Participants should be advised to contact the investigator immediately if there is any worsening
of the acute systemic allergic reaction, in which case the participant will permanently discontinue
the intake of JNJ-3989 and JNJ-6379 (or placebos). Rechallenge is not allowed. The participant’s
NA treatment may be discontinued based on investigator judgement in consultation with the
sponsor.
NCT04129554

JNJ-73763989 and JNJ-56136379
Clinical Protocol 73763989PAHPB2002
AMENDMENT 4
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
81
Status: Approved,  Date: 26 November 2021
Grade 3 (Generalized Urticaria, Angioedema With Intervention Indicated, or Symptoms of
Mild Bronchospasm) and Grade 4 (Acute Anaphylaxis, Life-threatening Bronchospasm, or
Laryngeal Edema)
Participants will permanently discontinue the intake of JNJ-3989 and JNJ-6379 (or placebos).
Rechallenge is not allowed. The participant’s NA treatment may be discontinued based on
investigator judgement in consultation with the sponsor.
Participants will be treated as clinically appropriate. Participants should be followed until
resolution of the AE and standard management should be undertaken.
8.3.6.3. 
Intervention-emergent ALT/AST Elevations
Elevated liver enzyme activity can be triggered by the underlying HBV disease as well as by the
study intervention.
Management of intervention-emergent ALT/AST elevations is presented graphically in
Section 10.6, Appendix 6, Intervention-emergent ALT/AST Elevations and is described below.
Any intervention-emergent elevation of ALT and/or AST ≥3x ULN and ≥3x nadir (ie, lowest
value during study participation) should trigger an assessment of confounding factors (alcohol
intake, change in concomitant medication, and comorbidities) and should trigger a confirmatory
study visit to repeat laboratory testing of AFP, ALT, AST, ALP, bilirubin (total and direct), INR,
albumin, and HBV DNA. Additional tests should be considered based on clinical judgement
(Refer to 10.6, Appendix 6, Intervention-emergent ALT/AST Elevations). The confirmatory visit
should be scheduled as soon as possible, preferably within 7 days of the receipt of the initial
ALT/AST results. In case the repeat laboratory testing shows an isolated ALT/AST elevation (ie,
with stable albumin, bilirubin [total and direct], and INR) the participant may continue study
intervention. In case of confirmed ALT elevation >1,000 U/L and ≥3x baseline value, JNJ-3989
and JNJ-6379 (or their matching placebos) should be discontinued. In both cases, NA treatment
should be continued. The participant will be monitored (laboratory testing of ALT, AST, ALP,
bilirubin [total and direct], INR, albumin, and HBV DNA) on a weekly basis until ALT and/or
AST levels have returned to <5x ULN and HBV DNA is <20,000 IU/mL.
If the ALT and/or AST level is ≥3x ULN and ≥3x nadir and is associated with any of the
following laboratory results or clinical symptoms:
 
INR ≥1.5, OR
 
direct bilirubin >1.5x ULN, OR
 
serum albumin <3.0 g/dL, OR
 
ascites, hepatic encephalopathy, or liver-related symptoms (eg, severe fatigue, nausea,
vomiting, right upper quadrant pain in the absence of an alternative medical explanation),
OR
 
other indication of reduced liver function
NCT04129554

JNJ-73763989 and JNJ-56136379
Clinical Protocol 73763989PAHPB2002
AMENDMENT 4
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
82
Status: Approved,  Date: 26 November 2021
the participant should discontinue JNJ-3989 and JNJ-6379 (or their matching placebos) and
should be monitored on a weekly basis or as per good clinical practice until ALT and/or AST
levels have returned to <5x ULN and HBV DNA is <20,000 IU/mL and, if present, liver-related
symptoms have improved. NA treatment should be continued. Additional tests can be considered
based on clinical judgement.
The NA re-treatment criteria and monitoring after stopping of NA are presented in Section 6.7.
8.3.6.4. 
Renal Complications
If renal complications develop, participants should be closely  monitored for disturbances in
creatinine clearance. Additional investigations can be performed at the investigator’s discretion.
Participants must be treated as clinically appropriate.
Participants who develop confirmed grade 3 or 4 eGFR abnormalities with reduction from
baseline by at least 10 mL/min/1.73 m2 will permanently discontinue the intake of JNJ-3989 and
JNJ-6379 (or placebos) if considered at least possibly  related to JNJ-3989 or JNJ-6379 and
should be followed appropriately until resolution of the AE or toxicity. Rechallenge is not
allowed. Change of NA treatment should be considered according to the prescribing information.
8.3.6.5. 
Hematologic Abnormalities
Mild thrombocytopenia was observed in recently conducted non-clinical toxicology studies with
the combination of JNJ-3989 and JNJ-6379. In addition, in a 3-month combination study with
80 rats, 1 rat developed pancytopenia related to bone marrow depletion after 23 days of dosing.
Previously, in a 9-month dog study in 24 dogs treated with JNJ-6379 alone, pancytopenia which
correlated with a marked increase in plasma cell-like cells in the bone marrow was observed in
1 dog after 60 days of dosing.
No thrombocytopenia or pancytopenia has been observed in the ongoing Jade study
(56136379HPB2001) investigating JNJ-6379/Placebo with or without NA treatment. All 232
participants have completed at least 24 weeks of study treatment. In the Phase 1/2a
AROHBV1001 study with JNJ-3989, mild transient thrombocytopenia (Grade 1) was observed
in 6 out of 84 participants receiving 3 SC injections of JNJ-3989 alone over a period of up to 12
weeks with background of NAs. The transient thrombocytopenia was not considered clinically
significant. No thrombocytopenia or pancytopenia was observed in 12 patients when JNJ-3989
and JNJ-6379 were given in combination over a 12-week period.
Based on the non-clinical findings, any relevant abnormalities in hematologic parameters will be
carefully monitored as described below:
 
Platelet counts: <100,000 cells/mm3 or <100 GI/L or reduction from baseline by at least 50%
 
Hemoglobin: Decrease of at least 2 g/dL from baseline or at least Grade 2 (DAIDS)
 
Reticulocytes: Reduction to <0.5% of the RBC count
 
Neutrophil count: Treatment emergent reduction to at least Grade 2 (DAIDS)
NCT04129554

JNJ-73763989 and JNJ-56136379
Clinical Protocol 73763989PAHPB2002
AMENDMENT 4
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
83
Status: Approved,  Date: 26 November 2021
In case any one of the above criteria are met, a confirmatory visit should be scheduled as soon as
possible, preferably within 7 days of the receipt of the initial results. Confirmation of the results
will trigger weekly or biweekly (every other week) unscheduled visits until improvement or
stabilization of the respective parameter(s). Stabilization is defined as no further significant
reduction over two consecutive visits.
In case of confirmed Grade 3 or Grade 4 hematologic abnormalities, discontinuation of
investigational study treatment (JNJ-3989 and/or JNJ-6379/placebo) should be considered. In
case of discontinuation, NA treatment should be continued.
8.4. 
Treatment of Overdose
For this study, any dose of JNJ-3989 and JNJ-6379 greater than  the protocol-specified dose
(refer to Section 6.1) will be considered an overdose; any dose of NA (ETV, TDF or TAF)
greater than the prescribed dose will be considered an overdose. The sponsor does not
recommend specific intervention for an overdose.
In the event of an overdose, the investigator or treating physician should:
 
Contact the Medical Monitor immediately.
 
Closely monitor the participant for AE/SAE and laboratory abnormalities.
 
Obtain a plasma sample for PK analysis as soon as possible from the date of the last dose of
study intervention if requested by the Medical Monitor (determined on a case-by-case basis).
 
Document the quantity of the excess dose as well as the duration of the overdosing in the
CRF.
Decisions regarding dose interruptions will be made by the investigator in consultation with the
Medical Monitor based on the clinical evaluation of the participant.
8.5. 
Pharmacokinetics
Plasma samples will be used to evaluate the PK of the study intervention. Samples collected for
analyses of the study intervention’s plasma concentrations may additionally be used to evaluate
safety or efficacy aspects.
All participants will have sparse PK sampling on Day 1 and at Weeks 4, 12, and 24 (and at early
withdrawal). All participants who consent to participate in the intensive PK subgroup (optional)
will undergo intensive PK sampling at Week 4 (minimally 18 participants). If necessary (eg, for
operational reasons), this visit may be scheduled at Week 8, 12, or 16.
Plasma concentration-time data for JNJ-3989 (ie, JNJ-3976 and JNJ-3924), JNJ-6379 and,
optionally, NA will be analyzed via population PK for all participants. Area under the plasma
concentration-time curve over 24 hours (AUC24h) and plasma trough concentrations (C0h) will be
estimated using empiric Bayes estimation.
NCT04129554

JNJ-73763989 and JNJ-56136379
Clinical Protocol 73763989PAHPB2002
AMENDMENT 4
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
84
Status: Approved,  Date: 26 November 2021
Plasma concentration-time data for JNJ-3989 (ie, JNJ-3976 and JNJ-3924), JNJ-6379 and,
optionally, NA will be analyzed via noncompartmental methods for all participants who
underwent intensive PK sampling. The main PK parameters will be AUC24h, Cmax, tmax, C0h,
plasma concentration at the end of the dosing interval (τ) (Cτ), and minimum plasma
concentration (Cmin). Additional exposure parameters may be calculated if applicable.
Data from this study may be combined with other studies via population PK modelling to enable
the calculation of the above PK parameters also in participants who only underwent sparse PK
sampling.
8.6. 
Pharmacokinetic/Pharmacodynamic Evaluations
Relationships of individual PK parameters (intensive PK and population PK, as applicable) for
JNJ-3989 (ie, JNJ-3976 and JNJ-3924), JNJ-6379, and NA, as applicable, with selected efficacy
and safety endpoints will be evaluated.
8.7. 
Immune Assessments
At selected sites, PBMC samples for immune analyses will be collected during study
intervention and follow-up and will be analyzed centrally for HBV-specific responses by
enzyme-linked immunospot (ELISpot) and/or intracellular cytokine staining (ICS) after
stimulation with HBV-specific antigens. ELISpot detects T-cells that secrete gamma interferon
(IFN-γ) in response to a specific antigenic stimulation, whereas ICS determines the frequency of
CD4+ and CD8+ T-cells secreting cytokines such as IFN-γ, interleukin (IL)-2 and tumor
necrosis factor (TNF)-α in response to a specific antigenic stimulation.
Additional experiments may be performed to further phenotypically and functionally
characterize PBMCs using proliferation or cytotoxic assays or other methods such as cytometry
by time of flight to evaluate innate and adaptive immune responses. Leftover PBMC samples
may be used at the sponsor’s discretion for additional exploratory research related to HBV
infection or study intervention (safety/efficacy).
Additional PBMC samples may be taken in case of ALT flares, upon discussion with the
sponsor, which may require an unscheduled visit.
8.8. 
Host Genetics
A pharmacogenomic (host DNA) blood sample should be collected at baseline to allow for host
pharmacogenomic research, where local regulations permit. In addition, host DNA blood
samples to allow for epigenetic analyses will be collected. These samples could for example be
used to assess changes in frequencies of immune cells such as myeloid derived suppressor cells.
These samples will only be collected from participants who consent separately to this component
of the study. Complete host genomic testing may be done to search for links of specific genes to
(HBV-related) liver disease or to the PK, PD, efficacy, safety, or tolerability of the study
intervention. Only host DNA research related to the study interventions under this protocol or to
chronic HBV infection will be performed. Further, a participant may withdraw such consent at
NCT04129554

JNJ-73763989 and JNJ-56136379
Clinical Protocol 73763989PAHPB2002
AMENDMENT 4
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
85
Status: Approved,  Date: 26 November 2021
any time without affecting their participation in other aspects of the study, or their future
participation in the Platform study (see Section 7.2.1 of the Master Protocol
PLATFORMPAHPB2001).
In addition, other samples may be used for exploratory genetic or epigenetic research in
participants consenting separately to this part of the study. No genetic research will be performed
on any sample in participants who have not provided the additional separate consent for host
genetic research. These samples can only be used to investigate the potential association of
genetic or epigenetic factors with efficacy, safety, or PK of the study intervention, or HBV
infection, or may be used to develop tests/assays related to the study intervention or HBV
infection.
These analyses will be performed at the sponsor’s discretion, will always be under the sponsor’s
supervision, and may be reported separately.
8.9. 
Exploratory Host Biomarkers
The study includes collection of blood samples for exploratory analysis of host blood biomarkers
at the host RNA, protein, and cell level. Sampling will be performed at the time points indicated
in the Schedule of Activities. Leftovers of other samples might also be used for exploratory
research of host and viral markers.
Samples can only be used for research related to study intervention or HBV infection or may be
used to develop tests/assays related to study intervention or HBV infection.
Blood samples will be taken at the time points indicated in the Schedule of Activities which can
be used to explore immunogenicity of JNJ-3989. The emergence of antibodies to JNJ-3989
(antidrug antibodies) might be analyzed using assays such as an enzyme-linked immunosorbent
assay.
These analyses will be performed at the sponsor’s discretion, will always be under the sponsor’s
supervision, and may be reported separately from the main study report.
More information is provided in Section 8.8 ofthe Master Protocol PLATFORMPAHPB2001.
9. 
STATISTICAL CONSIDERATIONS
Statistical analysis will be done by the sponsor or under the authority of the sponsor. A general
description of the statistical methods to be used to analyze the efficacy and safety data is outlined
below. Specific details will be provided in the Statistical Analysis Plan (SAP).
9.1. 
Statistical Hypothesis
The primary hypothesis of this study is that the combination regimen of JNJ-3989+JNJ-
6379+NA is more efficacious than NA treatment alone, as measured by the primary efficacy
endpoint, the proportion of participants with HBsAg seroclearance at Week 72 (ie, 24 weeks
after completion of all study interventions at Week 48) without restarting NA treatment.
NCT04129554

JNJ-73763989 and JNJ-56136379
Clinical Protocol 73763989PAHPB2002
AMENDMENT 4
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
86
Status: Approved,  Date: 26 November 2021
9.2. 
Sample Size Determination
The total study sample size is 120 participants who will be randomly assigned to one of the two
intervention  arms in a 2:1 ratio (JNJ-3989+JNJ-6379+NA: placebo+placebo+NA). Statistical
power to test the primary hypothesis was assessed using the Mantel-Haenszel test with a 1-sided
Type 1 error rate of 0.05, assuming the observed percentage of participants with HBsAg
seroclearance at Week 72 in the placebo+placebo+NA arm to be 5%. The sample size of
80 participants in the investigational arm and 40 participants in the control arm provides >91%
statistical power to detect a ≥20% difference in the primary endpoint.
The 2:1 randomization ratio (N 80:40, JNJ-3989+JNJ-6379+NA:placebo+placebo+NA) was
chosen to balance statistical and clinical considerations as it provides adequate evidence of
efficacy and safety, with the benefit of offering study participants a higher chance to receive
investigational treatment. Safety will be compared between arms descriptively only, and no
inferential testing is planned.
9.3. 
Populations for Analyses
For purposes of analysis, the following populations are defined:
Population 
Description
Screened 
All participants who signed the ICF for the Master Protocol and this ISA
Enrolled 
All participants who were randomly assigned to an intervention arm in this ISA
Intent-to-treat 
(ITT) 
All participants who were randomly assigned to an intervention arm and who received at
least 1 dose of study intervention within this ISA. Participants will be analyzed according to
the study intervention they were randomly assigned to.
Safety  
All participants who received at least 1 dose of study intervention within this ISA.
Participants will be analyzed according to the study intervention they actually received.
9.4. 
Statistical Analyses
9.4.1. 
Efficacy Analyses
The primary efficacy analysis will be performed when all participants have completed Week 72
or discontinued earlier. The final analysis will be performed when all participants have
completed the last study visit (Week 96) or discontinued earlier.
To evaluate the efficacy, the primary analysis set will be the Intent-to-treat (ITT) population
(defined in Section 9.3).
All efficacy summaries will be presented with descriptive statistics by intervention arm. If the
endpoint is continuous, the descriptive statistics will include the number of participants, mean,
standard deviation (SD), median, range and interquartile range. If the endpoint is binary or
categorical, the frequency distribution with the number and percentage of participants in each
category will be calculated. For time-to-event variables, a summary table including number of
participants included in the analysis, number of participants censored, 25th  and 75th  percentiles
and median time-to-event will be shown by intervention arm. Graphic displays will also be used
to summarize the data. Summaries will also be presented by randomization stratification factors,
NCT04129554

JNJ-73763989 and JNJ-56136379
Clinical Protocol 73763989PAHPB2002
AMENDMENT 4
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
87
Status: Approved,  Date: 26 November 2021
screening HBsAg level (<1,000 IU/mL or >1,000 IU/mL), race (Asian versus non-Asian) and
type of NA (TDF/TAF versus ETV).
The baseline measurements are defined as the measurements taken closest to but before the first
administration of study intervention on Day 1.
9.4.1.1. 
Primary Efficacy Endpoint (HBsAg Seroclearance 24 Weeks After
Completion of All Study Interventions at Week 48)
The proportion of participants who achieved HBsAg seroclearance at Week 72 (24 weeks after
completion of 48 weeks of treatment with study interventions) without restarting NA treatment
will be compared between intervention arms at a 1-sided 0.05 alpha. The primary endpoint will
be compared between intervention arms using the stratum-adjusted Mantel-Haenszel difference
in proportions,25 where the stratification factors screening HBsAg level (<1,000 IU/mL or
>1,000 IU/mL), race (Asian versus non-Asian) and type of NA (TDF/TAF  versus ETV)
determine the strata. The associated 90% confidence interval (CI) for the difference in
proportions will also be calculated.
All participants who do not achieve HBsAg seroclearance at Week 72 and/or require NA
re-treatment between Week 48 and Week 72 are considered treatment non-responders for the
purpose of the primary endpoint analysis. In addition, participants who withdraw from treatment
prior to Week 48 or from the study prior to Week 72 will be defined as non-responder. If the
HBsAg value at Week 72 is missing, the non-missing value closest to Week 72 within the
window of Weeks 60-84 (12 weeks prior/after Week 72) will be used.
Additional analyses may be performed on the primary efficacy endpoint using the Bayesian
methodology to leverage the Platform framework. Posterior probabilities will be calculated for
the treatment difference in the primary efficacy endpoint. This Bayesian analysis may
incorporate historical data and/or data from other ISAs that may enter the Platform study in the
future. Details on the Bayesian approach will be provided in the Modelling and Simulation
Report.
9.4.1.2. 
Secondary and Exploratory Efficacy Endpoints
Descriptive statistics will be used for all efficacy endpoints which will be summarized by
intervention arm and study phase. Comparisons between intervention arms will be done with no
adjustment for multiplicity. Specific key selected endpoints may be analyzed using suitable
categorical data approaches (eg, Cochran-Mantel-Haenszel or logistic regression for proportions
or other categorical type of endpoint), longitudinal repeated measures models (eg, for continuous
types of variables), or survival analysis based on the Kaplan-Meier estimates (for time-to-event
variables), as appropriate. Details will be described in the SAP.
To evaluate the efficacy at the end of treatment, the proportion of participants with HBsAg
seroclearance and the proportion of participants with HBV DNA <LLOQ  at Week 48,
respectively, will be tabulated by study intervention arm. Between arm comparisons for both
endpoints will be evaluated using the stratum-adjusted Mantel-Haenszel difference in
NCT04129554

JNJ-73763989 and JNJ-56136379
Clinical Protocol 73763989PAHPB2002
AMENDMENT 4
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
88
Status: Approved,  Date: 26 November 2021
proportions, where the stratification factors screening HBsAg level (<1,000 IU/mL or
≥1,000 IU/mL), race (Asian versus non-Asian) and type of NA (TDF/TAF  versus ETV)
determine the strata and corresponding 90% cIs.
The efficacy of the study intervention during the follow-up phase will also be evaluated. The
proportion of participants with HBsAg seroclearance at Week 96 without restarting NA
treatment, the proportion of participants with HBV DNA <LLOQ at Weeks 72 and 96,
respectively, the proportion of participants achieving partial response (HBV suppression without
restarting NA treatment) at different time points during follow-up, the proportion of participants
with flares (virologic, biochemical, and clinical), and the proportion of participants requiring NA
re-treatment during follow-up will be tabulated by intervention arm. The comparison between
the intervention arms will be done using the stratum-adjusted Mantel-Haenszel difference in
proportions, as described above. A similar analysis will be conducted for the proportion of
participants with HBsAg seroclearance 24 and 48 weeks, respectively, after stopping all study
interventions without restarting NA treatment.
The proportion of participants who reach HBV DNA <LLOQ and/or ALT normalization after
restart of NA treatment during follow-up will also be tabulated by intervention arm and the
comparison  between  the intervention arms will be done using the Mantel-Haenszel test for
difference in proportions as described above.
The blood markers (such as HBsAg, HBV DNA, and ALT) during study intervention and
follow-up will also be summarized by intervention arm over time and plotted. The proportion of
participants with virologic breakthrough (on treatment) and the proportion of participants with
(sustained) reduction, suppression, and/or seroclearance during follow-up considering single and
multiple markers (such as HBsAg, HBV DNA, and ALT) will be summarized by intervention
arm. The proportion of participants with HBsAg seroconversion will be tabulated by intervention
arm. Descriptive statistics on values and changes from baseline over time in HBsAg and HBV
DNA will be summarized by intervention arm. Additional summaries will be provided by the
randomization stratification factors (screening HBsAg level [<1,000 IU/mL or >1,000 IU/mL],
race [Asian versus non-Asian] and type of NA [TDF/TAF versus ETV]).
The time to achieve first HBsAg seroclearance will be summarized based on Kaplan-Meier
estimates in tables and graphs and compared between study interventions using the log rank test.
The proportion of participants with HBsAg levels and/or changes from baseline below/above
different cut-offs, and the proportion of participants with HBV DNA levels and/or changes from
baseline below/above different cut-offs will be analyzed as appropriate by intervention arm and
over time. The proportion of participants with ALT decrease and normalization will be tabulated
by intervention arm.
Graphic data displays will also be used to summarize the efficacy data by intervention arm and
over time.
In addition, the potential association between treatment outcome and baseline factors (including
but not limited to screening HBsAg level [<1,000 IU/mL or ≥1,000 IU/mL], race [Asian versus
NCT04129554

JNJ-73763989 and JNJ-56136379
Clinical Protocol 73763989PAHPB2002
AMENDMENT 4
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
89
Status: Approved,  Date: 26 November 2021
non-Asian] and type of NA [TDF/TAF versus ETV], and other HBV and host characteristics)
will be explored by multivariate analyses and exploration of interaction terms.2 Exploratory
subgroup summaries will be displayed graphically in forest plots.
9.4.1.3. 
Resistance Analyses
The results of HBV viral sequencing will be evaluated by the sponsor virologist. Relevant
changes of amino acid and/or nucleic acid variations (eg, substitutions) in the HBV genome will
be tabulated and described.
Additional exploratory characterization of the HBV viral sequence and phenotype may be
performed and reported separately.
9.4.1.4. 
Patient-reported Outcomes
The PRO  scores will be analyzed descriptively as mean scores over time, and (if applicable)
evaluated based on the proportion of participants experiencing a clinically important
improvement or worsening in PRO scores from baseline during study intervention and
follow-up. Analyses will also be performed on PRO score changes from baseline at specific time
points (Weeks 48, 72, 96) and between Week 48 and later time points for different subgroups:
participants with HBsAg seroclearance 24 weeks and 48 weeks after completion of all study
interventions at Week 48 without restarting NA treatment versus those without HBsAg
seroclearance at those time points. Further details will be provided in the SAP.
The data collected in this study will be used to assess the psychometric properties of the
HBV-specific self-stigma scale. The psychometric analyses will be described in a separate
document and results will be presented in a separate report.
9.4.2. 
Safety Analyses
The safety analyses will be based on the safety population  (defined in Section 9.3) and are
specified in Section 9.4.3 of the Master Protocol PLATFORMPAHPB2001.
Safety will be evaluated by means of descriptive summaries of AEs including AEs of special
interest to any of the study interventions, clinical laboratory tests, ECGs, vital signs, and physical
examinations. The safety analysis will be done by  study phase. Results will be presented in
tabular format and/or graphically by intervention arm and over time, as appropriate.
9.4.3. 
Other Analyses
Pharmacokinetic Analyses
Descriptive statistics (n, mean, SD, coefficient of variation [CV], geometric mean, median,
minimum, and maximum) will be calculated for the plasma concentrations of JNJ-6379,
JNJ-3976, JNJ-3924, and NA (ETV, tenofovir, and/or TAF), as applicable, and for the derived
plasma PK parameters for both noncompartmental and population PK analyses.
NCT04129554

JNJ-73763989 and JNJ-56136379
Clinical Protocol 73763989PAHPB2002
AMENDMENT 4
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
90
Status: Approved,  Date: 26 November 2021
For each participant with intensive PK sampling, plasma concentration-time data of JNJ-6379,
JNJ-3976, JNJ-3924, and, optionally, NA will be graphically presented. Similarly, graphs of the
mean plasma concentration-time profiles and overlay graphs with combined individual plasma
concentration-time profiles will be produced. Plasma PK parameters in participants undergoing
intensive PK sampling will be calculated via noncompartmental methods for JNJ-6379,
JNJ-3976, JNJ-3924, and, optionally, NA, as applicable. The PK parameters will be Cmax, Cτ, and
AUC24h. The PK parameters will be subjected to an exploratory graphical analysis, including
various transformations, to get a general overview.
Special attention will be paid to the plasma concentrations and PK parameters of those
participants who discontinued the study for an AE, or who experienced an AE ≥grade 3 or an
SAE.
Population PK analysis of plasma concentration-time data of JNJ-6379, JNJ-3976, JNJ-3924 and,
optionally, NA will be performed using nonlinear mixed-effects modeling. Data may be
combined with previous Phase 1 and/or 2 studies to support a relevant structural model.
Available baseline characteristics (eg, demographics, laboratory variables, genotypes) will be
included in the model as necessary. For operational reasons, a snapshot date for PK samples to
be analyzed will be defined, if required. Samples collected before this date will be analyzed for
JNJ-6379, JNJ-3976, JNJ-3924, and/or NA (as applicable) and will be included in the population
PK analysis. Samples collected after the snapshot date will be analyzed at a later date, and may
be included in a population PK re-analysis when they become available after database lock.
Details will be given in a population PK analysis plan and the results of the population PK
analysis will be presented in a separate report.
Pharmacokinetic/Pharmacodynamic Analyses
Relationships of PK parameters for JNJ-6379, JNJ-3976, JNJ-3924 and, optionally, NA (ETV,
tenofovir, and/or TAF) with selected efficacy and safety endpoints will be evaluated and
graphically displayed. Details will be described in the SAP.
Modeling of key PD parameters (eg, HBsAg, HBV DNA) may be performed using population
PK/PD. If PK/PD modeling of key efficacy endpoints is performed, treatment effect and possible
covariates such as disease progression will be investigated. Other biomarkers may be explored at
the sponsor’s discretion. Details of the PK/PD analyses will be described in a population PK/PD
analysis plan and results will be presented in a separate report.
Immune Analyses
Descriptive statistics (n, mean, SD, CV, geometric mean, median, minimum, and maximum) will
be used to describe the magnitude of the IFN-γ T-cell response or the CD4+ and CD8+ T-cell
responses (expressing at least 1 cytokine such as IL-2, TNF-α or IFN-γ specific to any HBV
antigen) as defined by ELISpot and/or ICS, respectively. Changes from baseline (if present) will
also be tabulated for PBMCs during study intervention and follow-up. The proportion (%) of
CHB patients with positive responses based on the magnitude of the IFN-γ T-cell response or the
NCT04129554

JNJ-73763989 and JNJ-56136379
Clinical Protocol 73763989PAHPB2002
AMENDMENT 4
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
91
Status: Approved,  Date: 26 November 2021
CD4+ or CD8+ T-cells expressing at least 1 of the cytokines amongst IL-2, TNF-α or IFN-γ for
1 of the HBV antigens as defined by ELISpot and/or ICS, respectively, will be determined.
Pharmacogenomic Analyses
The statistical approach for analyzing the exploratory host DNA research, including epigenetic
analyses, may depend on the objective of the analyses (efficacy, safety, and PK) and possibly
relevant genes at the time of analysis. Analyses will be conducted at the sponsor’s discretion,
will always be under the sponsor’s supervision, and results will be presented either in the clinical
study report or a separate report.
Host Biomarker Analyses
Statistical approaches to explore correlations between clinical outcome and blood biomarkers
vary and depend on the different data types of the applied technology platforms, as well as on the
extent of observed interindividual variability. Analyses will be conducted at the sponsor’s
discretion, will always be under the sponsor’s supervision, and results will be presented either in
the clinical study report or a separate report.
9.5. 
Interim Analyses
An IA  will be conducted to assess safety and evaluate the time course of different disease
markers to support the sponsor’s interactions with health authorities, as well as to inform internal
decisions about additional studies and/or investigation of other treatment combinations. The IA
is planned when all participants have completed Week 48 or discontinued earlier. The sponsor’s
central study team will be unblinded at this IA. Details on this team will be provided in the
IDMC charter.
Up to two additional IAs may be performed by the sponsor between Week 48 and the primary
analysis at Week 72, to support interactions with health authorities.
Both primary and interim analyses will be based on all data available at the predefined cut-off
time points, and may include data at later time points for those participants who have reached
subsequent visits.
More details are provided in Section 9.5 of the Master Protocol PLATFORMPAHPB2001.
9.6. 
Independent Data Monitoring Committee
At the analysis time points specified above and at regular intervals, an IDMC will meet and
review unblinded data to ensure the continuing safety of the participants enrolled in the study. In
addition, at the analysis time points specified above, the IDMC will also review the unblinded
results of selected efficacy parameters measured by different HBV disease blood markers (eg,
HBV DNA, HBsAg, etc).
The IDMC members will be appointed before the start of the study to review unblinded interim
data for both safety and efficacy and formulate recommendation(s) to the Sponsor Committee,
who will make the final decision(s). Possible recommendations of the IDMC include, but are not
NCT04129554

JNJ-73763989 and JNJ-56136379
Clinical Protocol 73763989PAHPB2002
AMENDMENT 4
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
92
Status: Approved,  Date: 26 November 2021
limited to, stopping the study for safety concerns, or study amendments. The Sponsor Committee
includes representatives from the sponsor’s Clinical, Biostatistics, Global Medical Safety and
Virology departments who are not involved in the study conduct.
Details on the roles and responsibilities of the IDMC and Sponsor Committee, as well as the
flows of communication, will be documented in the IDMC charter.
More details are provided in Section 9.6 of the Master Protocol PLATFORMPAHPB2001.
9.7. 
Independent Flare Expert Panel
An IFLEP will be appointed. The IFLEP  is composed of 3 independent medical experts with
experience and expertise in HBV and its treatment. The responsibilities of the IFLEP include:
conduct regular review of all relevant and available individual participant blinded study data
related to ALT flares; determine and adjudicate each ALT flare; and provide documentation of
the final decision to IDMC. Adjudication review cycles will match IDMC schedule and will be
set up ideally 2 weeks before IDMC.
In order to allow for an unbiased assessment, members of the committee will not serve as study
investigators or as members of the IDMC and will be blinded to the treatment assigned to each
participant.
Further details on the IFLEP process will be included in the IFLEP charter.
NCT04129554

JNJ-73763989 and JNJ-56136379
Clinical Protocol 73763989PAHPB2002
AMENDMENT 4
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
93
Status: Approved,  Date: 26 November 2021
10. 
SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS
10.1. Appendix 1: Abbreviations and Definitions of Terms
Abbreviations
AE 
adverse event
A/H  
animal/human ratio
AFP  
Alpha-fetoprotein
ALP  
alkaline phosphatase
ALT  
alanine aminotransferase
AST  
aspartate aminotransferase
AUC  
area under the plasma concentration-time curve
AUC0-xh 
area under the plasma concentration-time curve from administration to x hours
AUC0-last 
area under the plasma concentration-time curve from administration to last quantifiable sampling
point
AUC∞ 
area under the plasma concentration-time curve to last sampling point from time zero extrapolated
to infinity
AUCτ 
area under the plasma concentration-time curve over the dosing interval (τ)
bpm  
beats per minute
C0h  
plasma trough concentration
CAM  
capsid assembly modulator
cccDNA  
covalently closed circular deoxyribonucleic acid
CHB  
chronic hepatitis B
CI 
confidence interval
CKD-EPI 
Chronic Kidney Disease Epidemiology Collaboration
CL/F  
total apparent oral clearance
Cmax  
maximum plasma concentration
Cmin  
minimum plasma concentration
CRF  
case report form
CT  
computed tomography
Cτ 
plasma concentration at the end of the dosing interval (τ)
CV  
coefficient of variation
CYP  
cytochrome P450
DAIDS  
Division of Acquired Immunodeficiency Syndrome
DBP  
diastolic blood pressure
DDI 
drug-drug interaction
DNA  
deoxyribonucleic acid
ECG  
electrocardiogram
EFD  
embryofetal development
eGFR  
estimated glomerular filtration rate
ELISpot 
enzyme-linked immunospot
Emax  
maximum effect
EOSI 
end-of-study intervention
EQ-5D-5L 
5-Level EuroQol 5-Dimension
ETV  
entecavir
GCP  
Good Clinical Practice
GLP  
Good Laboratory Practice
HBc 
hepatitis B core protein
HBcrAg 
hepatitis B core-related antigen
HBe(Ag) 
hepatitis B e (antigen)
HBs(Ag) 
hepatitis B surface (antigen)
HBV  
hepatitis B virus
HCC  
hepatocellular carcinoma
HCV  
hepatitis C virus
HDV  
hepatitis D virus
HEV  
hepatitis E virus
NCT04129554

JNJ-73763989 and JNJ-56136379
Clinical Protocol 73763989PAHPB2002
AMENDMENT 4
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
94
Status: Approved,  Date: 26 November 2021
HIV(-1/2) 
human immunodeficiency virus (type 1/2)
IA  
interim analysis
IB  
Investigator’s Brochure
ICF  
informed consent form
ICH  
International Council for Harmonisation of Technical Requirements for Pharmaceuticals for
Human Use
ICS  
intracellular cytokine staining
IDMC  
Independent Data Monitoring Committee
IFLEP  
Independent Flare Expert Panel
IFN-γ 
gamma interferon
IgG  
immunoglobulin G
IgM  
immunoglobulin M
IL 
Interleukin
INR  
International Normalized Ratio
ISA  
intervention-specific appendix
ISR  
injection site reaction
ITT  
Intent-to-treat
IWRS  
interactive web response system
LLN  
lower limit ofnormal
LLOQ  
lower limit of quantification
MoA  
mode of action
MRI 
magnetic resonance imaging
NA  
nucleos(t)ide analog
NOAEL 
no observed adverse effect level
PBMC  
peripheral blood mononuclear cell
PD 
pharmacodynamic(s)
pgRNA  
pre-genomic ribonucleic acid
PK 
pharmacokinetic(s)
PRO  
patient-reported outcome(s)
qd 
once daily
QTcF  
QT interval corrected for heart rate according to Fridericia’s formula
RBC  
red blood cell
RNA  
ribonucleic acid
RNAi 
ribonucleic acid interference
SAE 
serious adverse event
SAP  
Statistical Analysis Plan
SBP 
systolic blood pressure
SD 
standard deviation
siRNA  
small interfering ribonucleic acid
t1/2term  
terminal half-life
TAF  
tenofovir alafenamide
tmax  
time to reach Cmax
TDF  
tenofovir disoproxil fumarate
TNF  
tumor necrosis factor
ULN  
upper limit of normal
VAS  
Visual Analog Scale
WBC  
white blood cell
Definitions of Terms
ALT/AST nadir 
Lowest ALT/AST value during study participation
End-of-study intervention 
(EOSI)
Time of the last administration of study intervention
HBsAg seroclearance 
HBsAg negativity based on the assay used
HBsAg seroconversion 
HBsAg negativity and anti-HBs antibody positivity
Intervention cohort 
Cohorts of adult participants with chronic hepatitis B virus infection who receive a
NCT04129554

JNJ-73763989 and JNJ-56136379
Clinical Protocol 73763989PAHPB2002
AMENDMENT 4
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
95
Status: Approved,  Date: 26 November 2021
specific study intervention within this Platform study, and in whom the efficacy and
safety of that intervention is evaluated
Study intervention  
JNJ-73763989 or placebo, JNJ-56136379 or placebo, and NA (either ETV, TDF, or
TAF)
Study intervention phase 
48-week phase from randomization to last administration of study intervention
Virologic breakthrough  
Confirmed on-treatment HBV DNA increase by >1 log10 IU/mL from nadir or
confirmed on-treatment HBV DNA level >200 IU/mL in participants who had HBV
DNA level <LLOQ of the HBV DNA assay
NCT04129554

NCT04129554

JNJ-73763989 and JNJ-56136379
Clinical Protocol 73763989PAHPB2002
AMENDMENT 4
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
97
Status: Approved,  Date: 26 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
Independent Data Monitoring Committee
At the analysis time points specified above and at regular intervals, an IDMC  will meet and
review unblinded data to ensure the continuing safety of the participants enrolled in the study. In
addition, at the analysis time points specified above, the IDMC will also review the unblinded
results of selected efficacy parameters measured by different HBV disease blood markers (eg,
HBV DNA, HBsAg, etc).
The IDMC members will be appointed before the start of the study to review unblinded interim
data for both safety and efficacy and formulate recommendation(s) to the Sponsor Committee,
who will make the final decision(s). Possible recommendations of the IDMC include, but are not
limited to, stopping the study for safety concerns, or study amendments. The Sponsor Committee
includes representatives from the sponsor’s Clinical, Biostatistics, Global Medical Safety and
Virology departments who are not involved in the study conduct.
Details on the roles and responsibilities of the IDMC and Sponsor Committee, as well as the
flows of communication, will be documented in the IDMC charter.
More details are provided in Attachment 3 of the Master Protocol PLATFORMPAHPB2001.
Independent Flare Expert Panel
An IFLEP will be appointed. The IFLEP is composed of 3 independent medical experts with
experience and expertise in HBV and its treatment. The responsibilities of the IFLEP include:
conduct regular review of all relevant and available individual participant blinded study data
related to ALT flares; determine and adjudicate each ALT flare; and provide documentation of
NCT04129554

JNJ-73763989 and JNJ-56136379
Clinical Protocol 73763989PAHPB2002
AMENDMENT 4
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
98
Status: Approved,  Date: 26 November 2021
the final decision to IDMC. Adjudication review cycles will match IDMC schedule and will be
set up ideally 2 weeks before IDMC.
In order to allow for an unbiased assessment, members of the committee will not serve as study
investigators or as members of the IDMC and will be blinded to the treatment assigned to each
participant.
Further details on the IFLEP process will be included in the IFLEP charter.
PUBLICATION POLICY/DISSEMINATION OF CLINICAL STUDY DATA
Refer to Attachment 3 of the Master Protocol PLATFORMPAHPB2001.
DATA QUALITY ASSURANCE
Refer to Attachment 3 of the Master Protocol PLATFORMPAHPB2001.
CASE REPORT FORM COMPLETION
Refer to Attachment 3 of the Master Protocol PLATFORMPAHPB2001.
SOURCE DOCUMENTS
Refer to Attachment 3 of the Master Protocol PLATFORMPAHPB2001.
MONITORING
Refer to Attachment 3 of the Master Protocol PLATFORMPAHPB2001.
ON-SITE AUDITS
Refer to Attachment 3 of the Master Protocol PLATFORMPAHPB2001.
RECORD RETENTION
Refer to Attachment 3 of the Master Protocol PLATFORMPAHPB2001.
STUDY AND SITE START AND CLOSURE
First Act of Recruitment
The first site open is considered the first act of recruitment and it becomes the study start date.
Study Termination
Refer to Attachment 3 of the Master Protocol PLATFORMPAHPB2001.
NCT04129554

JNJ-73763989 and JNJ-56136379
Clinical Protocol 73763989PAHPB2002
AMENDMENT 4
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
99
Status: Approved,  Date: 26 November 2021
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.
NCT04129554

JNJ-73763989 and JNJ-56136379
Clinical Protocol 73763989PAHPB2002
AMENDMENT 4
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
100
Status: Approved,  Date: 26 November 2021
10.5. Appendix 5: Rash Management
Table 5: 
Management of Rash Events by Severity Grade
Definition 
Study Intervention 
Action
Activities by Daya
Referral to
Dermatologist and
Dermatology
Activities
Grade 1 rash
(with or
without
pruritus)b
Erythema 
Study intervention
intake may be
continued at the
investigator’s
discretion
Day 0: optional on-site visit for initial rash evaluation
may be performed at the investigator’s discretion.
Safety laboratory assessments may be performed at the
investigator’s discretion (recommended if visit occurs).
Digital picturesc of skin lesions may be taken at the
investigator’s discretion.
Determine if participant was adhering to the
recommended sun-protective measures. If appropriate,
provide sun protection counseling.
Day 1 and thereafter: appropriate follow-up visits at the
investigator’s discretion until resolution of rash.
Safety laboratory assessments and photography (digital
picturesc of skin lesions) may be performed at the
investigator’s discretion.
Not required
Grade 2 rash
(with or without
pruritus)b
Diffuse, maculopapular rash,
or dry desquamation
Study intervention
intake may be
continued at the
investigator’s
discretion
Day 0: required on-site visit (if a visit is not possible,
telephone contact with the participant should take place to
collect information and give advice on the necessary
measures to be taken).
Safety laboratory assessments may be performed at the
investigator’s discretion (recommended).
Digital picturesc of skin lesions may be taken at the
investigator’s discretion. Digital picturesc of skin lesions
are recommended in case consultation of a dermatologist
is required. Determine if participant was adhering to the
recommended sun-protective measures. If appropriate,
provide sun protection counseling.
Day 1 and thereafter: appropriate follow-up visits at the
investigator’s discretion until resolution of rash or until
Referral to
dermatologist at the
discretion of the
investigatord
Biopsy not required,
but may be performed
at the dermatologist’s
discretion
NCT04129554

JNJ-73763989 and JNJ-56136379
Clinical Protocol 73763989PAHPB2002
AMENDMENT 4
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
101
Status: Approved,  Date: 26 November 2021
Table 5: 
Management of Rash Events by Severity Grade
Definition 
Study Intervention
Action
Activities by Daya 
Referral to
Dermatologist and
Dermatology
Activities
clinical stability is reached.
Safety laboratory assessments are required on Day 1 and
are required thereafter only if the previous values were
abnormal (but may be performed at the investigator’s
discretion). If the rash progresses to a higher grade, safety
laboratory assessments of the higher grade should be
followed.
Digital picturesc of skin lesions may be taken at the
investigator’s discretion.
Grade 3 rashb 
Vesiculation, moist
desquamation, or ulceration
OR
Any cutaneous event with 1
of the following:
- Elevations in AST/ALT
>2×baseline value
- Fever >38°C or 100°F
- Eosinophils
>1.00×103/µL
- Serum sickness-like
reaction
Must permanently
discontinue
JNJ-3989 and
JNJ-6379 (or
placebos); no
rechallenge allowed
NA treatment may be
discontinued based
on investigator
judgement in
consultation with the
sponsor
Day 0: required on-site visit.
Safety laboratory assessments required to be performed.
Digital picturesc of skin lesions may be taken at the
investigator’s discretion (recommended).
Determine if participant was adhering to the
recommended sun-protective measures. If appropriate,
provide sun protection counseling.
Day 1: required on-site visit.
Safety laboratory assessments required to be performed.
Digital picturesc of skin lesions may be taken at the
investigator’s discretion (recommended).
Further visit(s): appropriate follow-up required until
resolution of rash or until clinical stability is reached.
Safety laboratory assessments and photography (digital
picturesc of skin lesions) are recommended to be
performed until the rash severity resolves to grade 2 or
grade 1.
Requiredd
Biopsy not required,
but may be performed
at the dermatologist’s
discretion.
NCT04129554

JNJ-73763989 and JNJ-56136379
Clinical Protocol 73763989PAHPB2002
AMENDMENT 4
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
102
Status: Approved,  Date: 26 November 2021
Table 5: 
Management of Rash Events by Severity Grade
Definition 
Study Intervention
Action
Activities by Daya
Referral to
Dermatologist and
Dermatology
Activities
Grade 4 rash 
Exfoliative dermatitis OR  
Mucous membrane
involvement in at least
2 distinct sites OR
Erythema multiforme major 
OR
Stevens-Johnson syndrome 
OR  
Toxic epidermal necrolysis
OR
Necrosis requiring surgery
Must permanently 
discontinue
JNJ-3989 and
JNJ-6379 (or
placebos); no
rechallenge allowed
NA treatment may
be discontinued 
based on investigator
judgement in
consultation with the
sponsor
Day 0: required on-site visit. 
Safety laboratory assessments required to be performed. 
Digital picturesc of skin lesions may be taken at the
investigator’s discretion (recommended).
Determine if participant was adhering to the
recommended sun-protective measures. If appropriate,
provide sun protection counseling.
Day 1: required on-site visit.
Safety laboratory assessments required to be performed.
Digital picturesc of skin lesions may be taken at the
investigator’s discretion (recommended).
Further visit(s): appropriate follow-up required until
resolution of rash or until clinical stability is reached.
Safety laboratory assessments and photography (digital
picturesc of skin lesions) are recommended to be
performed until the rash severity resolves to grade 2 or
grade 1.
Requiredd
Biopsy required and to
be performed as soon
as possible after the
onset of the rash.
AE: adverse event; ALT: alanine aminotransferase; AST: aspartate aminotransferase; NA: nucleos(t)ide analog.
a 
Day 0 of the rash is the first day of investigator assessment and not the first day of rash as reported by the participant. The initial visit should be conducted as
soon as possible after the participant contacts the investigator to report the AE (ie, preferably on Day 0). The initial visit and subsequent visits to manage the
rash may require unscheduled visit(s).
b 
The participant should be advised to contact the investigator immediately if there is any worsening of the rash, if any systemic signs or symptoms appear, or if
mucosal involvement develops. In case the rash evolves to a higher grade than that first observed, management of the rash should follow the guidelines
indicated for the higher grade.
c 
Digital pictures to be taken at the clinical site upon consent of the participant.
d 
If applicable, dermatologist visit should occur preferably within 24 hours after onset of rash.
NCT04129554

JNJ-73763989 and JNJ-56136379
Clinical Protocol 73763989PAHPB2002
AMENDMENT 4
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
103
Status: Approved,  Date: 26 November 2021
Notes:
 
Local laboratory assessments are to be used for rash management. The values of the local laboratory assessments need to be transcribed in the CRF by the study
site personnel.
 
If a copy of the dermatologist's report, biopsy, and/or digital pictures are required, they should be deidentified and will be provided to sponsor.
NCT04129554

JNJ-73763989 and JNJ-56136379
Clinical Protocol 73763989PAHPB2002
AMENDMENT 4
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
104
Status: Approved,  Date: 26 November 2021
10.6. Appendix 6: Intervention-emergent ALT/AST Elevations
a Additional tests may be considered based on clinical judgement in case of confirmed ALT flares:
 
Hepatitis A, Delta, C, E: IgM anti-HAV; delta IgM, IgG and PCR, HCV RNA, IgM and IgG anti-HEV, HEV RNA
 
CMV, HSV, EBV infection: IgM and IgG anti-CMV, IgM and IgG anti-HSV; IgM and IgG anti-EBV, PCR
 
HIV
 
Ig-Electrophoresis
NCT04129554

JNJ-73763989 and JNJ-56136379
Clinical Protocol 73763989PAHPB2002
AMENDMENT 4
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
105
Status: Approved,  Date: 26 November 2021
10.7. Appendix 7: Cardiovascular Safety –Abnormalities
ECG
All important abnormalities from the ECG readings will be listed.
Abnormality Code 
ECG parameter
Heart Rate 
PR  
QRS  
QTcorrected
Abnormalities on actual values
Abnormally low  
<45 bpm  
NAP  
- 
-
Abnormally high  
120 bpm  
>220 ms 
120 ms 
-
Borderline prolonged QT 
- 
- 
- 
450 ms < QTc ≤480 ms
Prolonged QT  
- 
- 
- 
480 ms < QTc <500 ms
Pathologically prolonged QT 
- 
- 
- 
QTc >500 ms
Abnormalities on changes from baseline (∆QTc)
Normal QTc change 
- 
- 
- 
∆QTc <30 ms
Borderline QTc change 
- 
- 
- 
30 ms < ∆QTc <60 ms
Abnormally high QTc change 
- 
- 
- 
∆QTc >60 ms
ECG: electrocardiogram; NAP = not applicable
For absolute QTc parameters the categories are defined based on the International Council for Harmonisation of
Technical Requirements for Pharmaceuticals for Human Use (ICH) E14 GuidanceFa
Vital Signsb
The following abnormalities will be defined for vital signs:
Abnormality Code 
Vital Signs parameter
Pulse 
DBP  
SBP
Abnormalities on actual values
Abnormally low  
45 bpm  
50 mmHg 
90 mmHg
Grade 1 or mild 
- 
>90 mmHg - <100 mmHg 
>140 mmHg - <160 mmHg
Grade 2 or moderate 
- 
100 mmHg - <110 mmHg 
160 mmHg - <180 mmHg
Grade 3 or severe 
- 
110 mmHg 
180 mmHg
Abnormally high  
120 bpm  
- 
-
DBP: diastolic blood pressure; SBP: systolic blood pressure
a The clinical evaluation of QT/QTc interval prolongation and proarrhythmic potential for non-antiarrhythmic drugs
CHMP/ICH/2/04, May 2005.
b The classification of AEs related to hypotension and hypertension will be done according to the DAIDS grading
scale.
NCT04129554

JNJ-73763989 and JNJ-56136379
Clinical Protocol 73763989PAHPB2002
AMENDMENT 4
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
106
Status: Approved,  Date: 26 November 2021
10.8. Appendix 8: Contraceptive and Barrier Guidance and Collection of
Pregnancy Information
Participants must follow contraceptive measures as outlined in Section 5.1. Pregnancy
information will be collected and reported as noted in Section 8.3.5.
Definitions
Woman of Childbearing Potential (WOCBP)
A woman is considered fertile following menarche and until becoming postmenopausal unless
permanently sterile (see below).
Woman Not of Childbearing Potential
 
premenarchal
A premenarchal state is one in which menarche has not yet occurred.
 
postmenopausal
A postmenopausal state is defined as no menses for 12 months without an alternative
medical cause. A high follicle-stimulating hormone (FSH) level (>40 IU/L or mIU/mL) in
the postmenopausal range may be used to confirm a postmenopausal state in women not
using hormonal contraception or hormonal replacement therapy (HRT). However, in the
absence of 12 months of amenorrhea, a single FSH measurement is insufficient to confirm a
woman is not of childbearing potential. If there is a question about menopausal status in
women on HRT, the woman will be required to use one of the non-estrogen-containing
hormonal highly effective contraceptive methods if she wishes to continue HRT during the
study.
 
permanently sterile
Permanent sterilization methods include hysterectomy, bilateral salpingectomy, or bilateral
oophorectomy.
Note: If the childbearing potential changes after start of the study (eg, a premenarchal woman
experiences menarche) or the risk of pregnancy changes (eg, a woman who is not heterosexually
active becomes active), a woman must begin a highly effective method of contraception, as
described throughout the inclusion criteria.
If reproductive status is questionable, additional evaluation should be considered.
Contraceptive (birth control) use by men or women should be consistent with local regulations
regarding the acceptable methods of contraception for those participating in clinical studies.
Examples of Contraceptives
EXAMPLES OF CONTRACEPTIVESa ALLOWED DURING THE STUDY INCLUDE:
USER INDEPENDENT
Highly Effective Methods That Are User Independent Failure rate of <1% per year when used
consistently and correctly.
 Implantable progestogen-only hormone contraception associated with inhibition of ovulation
 Intrauterine device (IUD)
NCT04129554

JNJ-73763989 and JNJ-56136379
Clinical Protocol 73763989PAHPB2002
AMENDMENT 4
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
107
Status: Approved,  Date: 26 November 2021
 Intrauterine hormone-releasing system (IUS)
 Tubal closure (eg, bilateral tubal occlusion, bilateral tubal ligation)
 Azoospermic partner (vasectomized or due to medical cause)
(Vasectomized partner is a highly effective contraceptive method provided that the partner is the
sole sexual partner of the woman of childbearing potential and the absence of sperm has been
confirmed. If not, additional highly effective method of contraception should be used.
Spermatogenesis cycle is approximately 74 days.)
USER DEPENDENT
Highly Effective Methods That Are User Dependent Failure rate of <1% per year when used
consistently and correctly.
 Combined (estrogen- and progestogen-containing) hormonal contraception associated with
inhibition of ovulation
oral
intravaginal
transdermal
injectable
 Progestogen-only hormone contraception associated with inhibition of ovulation
oral
injectable
 Sexual abstinence
(Sexual abstinence is considered a highly effective method only if defined as refraining from
heterosexual intercourse during the entire period of risk associated with the study intervention.
The reliability of sexual abstinence needs to be evaluated in relation to the duration of the study
and the preferred and usual lifestyle of the participant.)
a) Typical use failure rates may differ from those when used consistently and correctly. Use should be
consistent with local regulations regarding the use of contraceptive methods for participants in
clinical studies.
NCT04129554

JNJ-73763989 and JNJ-56136379
Clinical Protocol 73763989PAHPB2002
AMENDMENT 4
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
108
Status: Approved,  Date: 26 November 2021
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.
NCT04129554

NCT04129554

NCT04129554

NCT04129554

NCT04129554

NCT04129554

NCT04129554

NCT04129554

NCT04129554

NCT04129554

NCT04129554

NCT04129554

NCT04129554

NCT04129554

NCT04129554

NCT04129554

NCT04129554

NCT04129554

NCT04129554

NCT04129554

NCT04129554

NCT04129554

NCT04129554

NCT04129554

JNJ-73763989 and JNJ-56136379
Clinical Protocol 73763989PAHPB2002
AMENDMENT 4
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
132
Status: Approved,  Date: 26 November 2021
25. Hepatitis B has had a damaging effect on my education
                               
26. My family life has been disrupted because I have hepatitis B
                               
27. I have stopped socialising with some people because of their reactions to
me having hepatitis B
                               
28. Some people have treated me differently because I have hepatitis B
                               
29. People discriminated against me because I have hepatitis B
                               
30. I felt like people were avoiding touching me because of my hepatitis B
                               
31. I worried that people would reject me when they found out I have
hepatitis B
                               
32. I have been hurt by how people reacted because I have hepatitis B
                               
33. I felt frustrated by other people’s lack of understanding of hepatitis B
                               
34. I was not afraid to tell people I had hepatitis B
                               
35. I was comfortable with others knowing I have hepatitis B
                               
36. I was ashamed to seek medical care because of my hepatitis B
                               
37. I was afraid to seek medical care because of my hepatitis B
                               
NCT04129554

JNJ-73763989 and JNJ-56136379
Clinical Protocol 73763989PAHPB2002
AMENDMENT 4
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
133
Status: Approved,  Date: 26 November 2021
10.11. Appendix 11: 5-Level EuroQol 5-Dimension Questionnaire (EQ-5D-5L)
Note: This appendix provides a representative example of the questionnaire that will be used in
this study. The site should always use the most recently provided version of the questionnaire.
Health Questionnaire
English version for the UK
UK(English) © 2009 EuroQol Group. EQ 5D™ is a trade mark of the EuroQol Group
NCT04129554

JNJ-73763989 and JNJ-56136379
Clinical Protocol 73763989PAHPB2002
AMENDMENT 4
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
134
Status: Approved,  Date: 26 November 2021
Under each heading, please check the ONE box that best describes your health TODAY.
MOBILITY
I have no problems in walking about 

I have slight problems in walking about 

I have moderate problems in walkingabout 

I have severe problems in walking about 

I am unable to walk about 

SELF-CARE
I have no problems washing or dressing myself 

I have slight problems washing or dressing myself 

I have moderate problems washing or dressing myself 

I have severe problems washing or dressing myself 

I am unable to wash or dress myself 

USUAL ACTIVITIES (e.g. work, study, housework,
family or leisure activities)
I have no problems doing my usual activities 

I have slight problems doing my usual activities 

I have moderate problems doing my usual activities 

I have severe problems doing my usual activities 

I am unable to do my usual activities 

PAIN / DISCOMFORT
I have no pain or discomfort 

I have slight pain or discomfort 

I have moderate pain or discomfort 

I have severe pain or discomfort 

I have extreme pain or discomfort 

ANXIETY / DEPRESSION
I am not anxious or depressed 

I am slightly anxious or depressed 

I am moderately anxious or depressed 

I am severely anxious or depressed 

I am extremely anxious or depressed 

UK(English) © 2009 EuroQol Group. EQ 5D™ is a trade mark of the EuroQol Group
NCT04129554

JNJ-73763989 and JNJ-56136379
Clinical Protocol 73763989PAHPB2002
AMENDMENT 4
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
135
Status: Approved,  Date: 26 November 2021
 We would like to know how good or bad your health is TODAY.
 This scale is numbered from 0 to 100.
 100 means the best health you can imagine.
0 means the worst health you can imagine.
 Mark an X on the scale to indicate how your health is TODAY.
 Now, please write the number you marked on the scale in the box
below.
YOUR HEALTH TODAY 
UK(English) © 2009 EuroQol Group. EQ 5D™ is a trade mark of the EuroQol Group
10
0
20
30
40
50
60
80
70
90
100
5
15
25
35
45
55
75
65
85
95
The best health 
you can imagine
The worst health
you can imagine
NCT04129554

JNJ-73763989 and JNJ-56136379
Clinical Protocol 73763989PAHPB2002
AMENDMENT 4
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
136
Status: Approved,  Date: 26 November 2021
10.12. Appendix 12: Protocol Amendment History
The Protocol Amendment Summary of Changes Table for the current amendment is located
directly before the Table of Contents (TOC).
Amendment 3(30 September 2021)
Overall Rationale for the Amendment:
The primary reason for this amendment is to add a new NA re-treatment criterion   and to include more
frequent monitoring for participants who discontinued NA treatment at Week 48 or during follow-up.
A severe clinical alanine aminotransferase (ALT) flare following discontinuation of NA treatment was
reported in a virologically suppressed HBeAg negative participant on long-term tenofovir disoproxil
fumarate (TDF) treatment, who was randomized to the control arm (placebo + placebo + NA) in the
REEF-2 (73763989PAHPB2002) study. The participant presented with HBV DNA levels that increased
rapidly, before any relevant changes in liver markers were noted. Discontinuation of NA treatment
followed the protocol-defined criteria and was in line with recent European Association for the Study of
the Liver (EASL) treatment guidelines5. Flares following NA discontinuation are not unexpected, but the
rapid evolution and clinical deterioration seen in this participant who was anti-HBe antibody positive at
screening and had no history or evidence of liver cirrhosis was unforeseeable. Therefore, to protect safety
of participants, the protocol was amended as detailed below.
Other clarifications and corrections were also made as detailed below.
Description of Change 
Brief Rationale 
Section Number and Name
A new NA re-treatment 
criterion was added for 
participants who discontinued 
NA treatment at Week 48. 
To ensure that participants with 
significant HBV DNA increases 
during treatment free follow-up 
are monitored at least weekly 
and/or immediately re-start NA 
treatment irrespective of ALT 
levels. 
1.1 Synopsis
1.3.2 Schedule of Activities –Follow-up Phase
2.3.2.2 Potential Risks
4.2 Scientific Rationale for Study Design
6.7 NA Re-treatment Criteria During Follow-up
8.3.6.3 Intervention-emergent ALT/AST
Elevations
6.8 Intervention After the End of the Study
10.13 Appendix 13: NA Re-treatment During
Follow-up
Participants who discontinued 
NA treatment at Week 48 , will 
be monitored more frequently, 
with a study visit at least once 
every 4 weeks. The visit
frequency for participants who
continue NA treatment or have
restarted NA treatment during
the follow-up period and for
whom the HBV DNA and ALT
values are stable remains
unchanged. For participants
with increased follow-up, the
total blood volume to be
collected during the study will
increase.
To further protect the safety of 
participants. 
1.1 Synopsis
1.3.2 Schedule of Activities –Follow-up Phase
8 STUDY ASSESSMENTS AND
PROCEDURES
Clarifications were made to the 
urine pregnancy testing during
follow-up.
Clarification. 
1.3.2 Schedule of Activities –Follow-up Phase
Clarifications were made 
Clarification. 
1.3.2 Schedule of Activities –Follow-up Phase
NCT04129554

JNJ-73763989 and JNJ-56136379
Clinical Protocol 73763989PAHPB2002
AMENDMENT 4
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
137
Status: Approved,  Date: 26 November 2021
Description of Change 
Brief Rationale 
Section Number and Name
concerning the optional safety
follow-up visit for participants
who withdraw consent during
follow-up.
The contraceptive guidance 
from the Master Protocol was 
replaced by ISA-specific 
contraceptive guidance, which 
includes the following updates 
versus the Master Protocol 
version: the list of examples
which are not allowed as sole
method of contraception during
the study and the footnote
concerning possible interaction
between hormonal
contraception and the study
intervention have been
removed. Additional
clarifications were also made.
Upon Health Authority request 
and to align with the latest 
version of the sponsor’s 
protocol template. 
1.3.1 Schedule of Activities –Screening and
Study Intervention Phase
5.1 Inclusion Criteria
10.8 Appendix 8: Contraceptive and Barrier
Guidance and Collection of Pregnancy
Information
The formulations numbers for 
JNJ-6379 were corrected and
formulation numbers for
placebo were added.
Correction. 
6.1 Study Intervention(s) Administered
Minor grammatical, formatting, 
or spelling changes were made.
Minor errors were noted 
Throughout the protocol
NCT04129554

JNJ-73763989 and JNJ-56136379
Clinical Protocol 73763989PAHPB2002
AMENDMENT 4
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
138
Status: Approved,  Date: 26 November 2021
Amendment 2 (27 January 2020)
Overall Rationale for the Amendment: Based on a nonclinical finding from the preliminary
results of the 3-Month Combination toxicity study with JNJ-6379 and JNJ-3989 in the rat, the
protocol was amended to include hematologic abnormalities as an event of special interest, to
trigger a mandatory higher visit frequency with unscheduled visits in case of significant on-
treatment reduction in hematologic parameters, and to include treatment discontinuation criteria
in relation to hematological abnormalities as precautionary measures. No significant
abnormalities of hematologic parameters have been observed in clinical trials to date.
Furthermore, clarifications, additions and corrections were made throughout the protocol.
Main Changes
Section Number
and Name
Description of Change 
Brief Rationale 
2.3.3 Benefit-risk
Assessment for
Study Participation
8.3.6.5 Hematologic
Abnormalities
Addition of management of
hematologic abnormalities
In response to a serious and unexpected adverse
nonclinical finding, any relevant abnormalities in
hematologic parameters will be carefully monitored
to trigger a mandatory higher visit frequency in case
of significant on-treatment reduction in hematologic
parameters to ensure closer follow-up.
2.2.1 JNJ-3989 and
JNJ-6379
Preclinical update: Addition of
preliminary results from 3-month
combination toxicity study with
JNJ-3989 and JNJ-6379
Preliminary results of the 3-month combination
toxicity study with JNJ-6379 and JNJ-3989 in the
rat include an update on the sacrifice of one male rat
receiving JNJ-6379 orally at 100 mg/kg/day and
JNJ-3989 SC at 60 mg/kg related to bone marrow
depletion with pancytopenia including marked
thrombocytopenia.
Clarifications, Additions and Corrections
1.3.1 Schedule of
Activities –
Screening and Study
Intervention Phase
Addition of HBeAg (qualitative) 
assessment at Week 44 
Negative HBeAg status needs to be confirmed at
Week 48 before stopping NA treatment based on the
Week 44 result using the qualitative HBeAg assay
8.1 Efficacy
Assessments
Blinding of post-baseline (Day1)
HBsAg results to investigators and
participants until follow-up
Week 2
All participants who complete the Week 48 visit,
should stop all study interventions including NAs at
Week 48. HBsAg level is part of the primary
endpoint. In order to avoid any bias, HBsAg results
will be made available after stopping NA and from
FU Week 2 visit onwards.
1.3.1 Schedule of
Activities –
Screening and Study
Intervention Phase
1.3.2 Schedule of
Activities –Follow-
up Phase
10.6 Appendix 6:
Intervention-
emergent ALT/AST
Elevations
Addition of Alpha-fetoprotein
measurement every 24 weeks and
in case of ALT flares
Alpha-fetoprotein is of interest to link to liver
ultrasound assessment for the screening of HCC
every 6 months. In addition, alpha-fetoprotein has
been reported to be associated with HBsAg decline.
Thus, it is relevant to assess this marker.
1.3.1 Schedule of
Activities –
Language was added for
participants in the intensive PK
To avoid unnecessary duplication of PK sampling
for participants in the intensive PK subgroup.
NCT04129554

JNJ-73763989 and JNJ-56136379
Clinical Protocol 73763989PAHPB2002
AMENDMENT 4
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
139
Status: Approved,  Date: 26 November 2021
Screening and Study
Intervention Phase
subgroup, such that the sparse PK
sample does not need to be
collected at the time of an
intensive PK visit.
1.3.1 Schedule of
Activities –
Screening and Study
Intervention Phase
1.3.2 Schedule of
Activities –Follow-
up Phase
8 STUDY
ASSESSMENTS
AND
PROCEDURES
The recommendation regarding
the order of assessments in case of
multiple assessments at the same
time point was removed (refer to
Master protocol
PLATFORMPAHPB2001
amendment 2).
For more flexibility in timing of the assessments.
The PRO assessment and ECGs should be
prioritized, but the order of the other assessments is
of less importance.
1.3.1 Schedule of
Activities –
Screening and Study
Intervention Phase,
5.2 Exclusion
Criteria
Updated language, explaining that
the abdominal ultrasound 6
months prior to screening or at
screening will also be used to rule
out any clinically relevant renal
abnormalities.
Additional safety measure.
1.3.1 Schedule of
Activities –
Screening and Study
Intervention Phase
Updated footnote for liver
ultrasound assessment at baseline
Liver ultrasound is performed every 6 months to
monitor for development of HCC in participants
with increased risk for HCC. No need to repeat liver
ultrasound assessment at baseline if done within 6
months
1.3.2 Schedule of
Activities –Follow-
up Phase
Visit windows for follow-up
Week 2 and Week 4 were updated
Visit windows for follow-up Week 2 and Week 4
were increased from +/-2 days to +/-4 days to allow
sufficient time for laboratory results to come in,
especially HBeAg results, in order to assess re-
treatment criteria.
5.1 Inclusion
Criteria
A timeframe was added for female
participants of childbearing
potential to use a highly effective
method of contraception for at
least 30 days prior to screening.
The minimum time period for contraceptive use
prior to screening ensures adequate protection of
females of childbearing potential.
5.2 Exclusion
Criteria
The note in exclusion criterion
M01/A01 was modified to allow
participants with positive HCV,
HDV or HEV antibody test to
enroll if an active infection can be
ruled out (refer to Master protocol
PLATFORMPAHPB2001
amendment 2).
To only exclude patients with active infection. Some
patients may carry antibodies after an acute
infection, which never developed into a chronic
infection.
5.2 Exclusion
Criteria
Exclusion criterion M02 was
modified to include ‘total bilirubin
>1.5x ULN’. In addition, the
reference to benign cause such as
Gilbert’s disease was removed for
‘direct bilirubin’ (refer to Master
protocol
PLATFORMPAHPB2001
amendment 2).
For clarification as no threshold for total bilirubin
was included.
For correction as Gilbert’s syndrome is often
associated with increased indirect bilirubin, not
direct bilirubin.
5.2 Exclusion
Criteria
Pancreatic amylase elevation
≥grade 3 was added in exclusion
criterion M06/A03 (refer to
Master protocol
Additional safety measure.
NCT04129554

JNJ-73763989 and JNJ-56136379
Clinical Protocol 73763989PAHPB2002
AMENDMENT 4
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
140
Status: Approved,  Date: 26 November 2021
PLATFORMPAHPB2001
amendment 2).
5.2 Exclusion
Criteria
Exclusion criterion M09 was
updated to exclude participants
with PR interval >220 ms instead
of >200 ms
To align with ongoing HBV protocols with
JNJ-3989 where a less restrictive cutoff was
selected.
1.1 Synopsis/
Description of
Interventions
6.1 Study
Intervention(s)
Administered
Specification on which NA
treatments are available for the
study was adapted.
To account for import restrictions with regards to
tenofovir alafenamide (TAF) in some participating
countries as well as indications other than
lamivudine-resistant for ETV 1 mg.
6.4 Study
Intervention
Compliance
Instructions for handling of missed
or delayed injections with
JNJ-3989 were added.
For completeness, to ensure adequate treatment in
case of missed or delayed injections with JNJ-3989.
6.5 Concomitant
Therapy
Over-the-counter products, herbal
medications and dietary
supplements were removed from
the disallowed concomitant
medication list.
For clarification. Only products containing
Hypericum perforatum are disallowed.
7.1 Discontinuation
of Study
Intervention
This section was updated to
describe that only participants who
have taken the disallowed
concomitant medication for ≥7
days and have no intention to
discontinue the concomitant
medication will be discontinued
from the study intervention.
To avoid accidental intake of disallowed
concomitant medication triggering the
discontinuation of study intervention.
8.3.6.3 Intervention-
emergent ALT/AST
Elevations
10.2 Appendix 2:
Clinical Laboratory
Tests
10.6 Appendix 6:
Intervention-
emergent ALT/AST
Elevations
Added wording for ALT/AST
elevations management, added
baseline value as reference for
stopping criteria, and ensure that
all relevant liver tests are
performed
For closer patient safety monitoring and
management
8.3.6.1.1 Injection
Site Reactions
10.5 Appendix 5:
Rash Management
It was specified that digital
pictures can only be taken if the
participant has specifically
consented to this.
Language on the collection of
digital pictures was updated to
describe that if digital pictures are
required, they should be de-
identified and will be provided to
the sponsor.
To protect the participant’s privacy.
To clarify that the pictures are optional and explain
the proper steps to follow.
NCT04129554

JNJ-73763989 and JNJ-56136379
Clinical Protocol 73763989PAHPB2002
AMENDMENT 4
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
141
Status: Approved,  Date: 26 November 2021
6.3 Measures to
Minimize Bias:
Randomization and
Blinding
Added language explaining that
persons involved in PK and viral
load modeling will have access to
the PK and viral load data before
formal unblinding, while persons
involved in trial conduct, data
management and statistics will not
have access to these data.
To allow the sponsor to make informed portfolio
decisions for further development of the compound
while protecting the blind prior to the primary
analysis.
6.3 Measures to
Minimize Bias:
Randomization and
Blinding
8.1 Efficacy
Assessments
Addition of “In order to preserve
the blinding during the study
treatment phase, HbsAg, HbeAg,
anti-HBs, and anti-Hbe antibody
tests cannot be done locally.”
Clarification to avoid local unblinding via
assessment of these parameters
6.5 Concomitant
Therapy –Table 3
NA standard of care treatment is
not part of “any anti HBV drug
that are disallowed from screening
until end of follow-up”
Clarification
1.3.1 Schedule of
Activities –
Screening and Study
Intervention Phase
ECG at baseline needs to be
performed and assessed locally
prior to dosing but are not part of
eligibility criteria assessed after
screening.
Clarification
1.1 Synopsis/
Description of
Interventions
6.1 Study
Intervention(s)
Administered
Subcutaneous injection of
JNJ-3989 is now unambiguously
described to be administered in the
abdomen, instead of by
preference.
For clarification and consistency in approach.
1.1 Synopsis/
Description of
Interventions
1.2 Schema
6.1 Study
Intervention(s)
Administered
“Once monthly” in the dosage
regimen of JNJ-3989 was replaced
by “once every 4 weeks”.
For clarification
7.1 Discontinuation
of Study
Intervention
8.3.6.4 Renal
Complications
The relationship for
discontinuation criterion for a
confirmed ≥grade 3 eGFR
abnormality and a drop from
baseline of >10 mL/min/1.73 m²
was clarified to refer specifically
to JNJ-3989 and JNJ-6379 instead
of investigational intervention.
For clarification
8.3.6.1.1 Injection
Site Reactions
Wording was modified such that
all ISRs will need to be reported in
the CRF, but not by default as an
AE.
For clarification
5.1 Inclusion
Criteria
Update alphanumeric code IC
A07/M09 to A07/M10 as male
contraception requirement is IC 10
in Master Platform Protocol
Correction
2.2.1 JNJ-3989 and
JNJ-6379
Limited updates were made to the
nonclinical sections where
relevant
Correction
NCT04129554

JNJ-73763989 and JNJ-56136379
Clinical Protocol 73763989PAHPB2002
AMENDMENT 4
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
142
Status: Approved,  Date: 26 November 2021
2.3.2.2.1 Potential
Risks for JNJ-3989
2.3.2.2.2 Potential
Risks for JNJ-6379
Potential risk on viral resistance to
JNJ-3989 was moved to Section
2.3.2.2.1 as appropriate.
Correction
8 STUDY
ASSESSMENTS
AND
PROCEDURES
Approximations of total blood
volumes were modified.
A note was added with regards to
total blood volume.
Correction
To clarify that the total blood volume to be collected
from each participant may vary.
1.3.1 Schedule of
Activities –
Screening and Study
Intervention Phase
A time window was added for
intensive PK sampling.
For completeness
2.2.1 JNJ-3989 and
JNJ-6379
Clarification of fertility study  
For completeness
5.2 Exclusion
Criteria
Individuals under a legal 
protection measure were added to
criterion #M22 as an additional
example of vulnerable participants
(refer to Master protocol
PLATFORMPAHPB2001
amendment 2).
For completeness
1.1 Synopsis/
Description of
Interventions
6.1 Study
Intervention(s)
Administered
The volume of the placebo for 
JNJ-3989 was added to the dosage
regimen.
For completeness
1.3.1 Schedule of
Activities –
Screening and Study
Intervention Phase
2.3.2.2.1 Potential
Risks for JNJ-3989
6.1 Study
Intervention(s)
Administered
6.5 Concomitant
Therapy
7.1 Discontinuation
of Study
Intervention
10.1 Appendix 1:
Abbreviations and
Definitions of Terms
10.9 Appendix 9:
DAIDS Table
Minor grammatical, formatting, or
spelling changes were made.
Minor errors corrected.
NCT04129554

JNJ-73763989 and JNJ-56136379
Clinical Protocol 73763989PAHPB2002
AMENDMENT 4
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
143
Status: Approved,  Date: 26 November 2021
Amendment 1 (26 September 2019)
Overall Rationale for the Amendment: Following Health Authority (HA) feedback under the Voluntary
Harmonisation Procedure, the protocol was amended as specified below.
Section Number 
and Name
Description of Change 
Brief Rationale
1.1 Synopsis,
9.4.1.1 Primary
Efficacy Endpoint
(HBsAg
Seroclearance 24
Weeks After
Completion of All
Study Interventions
at Week 48)
Methods for handling missing data were added to
the protocol.
Per HA request, instead of referring
to the SAP, the approach to handle
missing data in the primary analysis
of the primary efficacy endpoint
was added.
5.1 Inclusion
Criteria
Numbering of the inclusion criteria was updated
due to addition of an inclusion criterion to the
master protocol.
Formatting
5.2 Exclusion
Criteria, 11
REFERENCES
Exclusion criterion #7 was amended to also include
known allergies, hypersensitivity, or intolerance to
placebo content.
Per HA feedback, exclusion
criterion #7 was corrected to also
include placebo content.
6.1 Study
Intervention(s)
Administered
It was clarified that during treatment with ETV,
TDF or TAF, guidance per the respective
prescribing information should be followed, in
particular with reference to special warnings and
precautions for use.
For consistency and completeness
and per HA feedback, reference to
the prescribing information of
ETV, TDF, and TAF was added for
guidance during NA treatment.
6.3 Measures to
Minimize Bias:
Randomization and
Blinding
Wording on unblinding was updated to clarify that
the investigator will contact the sponsor before
unblinding but only if this does not delay action
with respect to treatment in case of emergency.
The protocol currently recommends
the investigator contact the sponsor
before breaking the blind if
possible. The text was updated to
emphasize participant safety per
HA feedback.
6.5 Concomitant
Therapy
More general recommendation to consider
alternative medications or adjusted doses was
provided in Table 4 (Concomitant Medications to
be Used With Caution).
As JNJ-6379 is a mild inducer of
CYP3A, CYP3A substrates are
included in the table of concomitant
medications to be used with caution
(Table 4). More general
recommendation to consider
alternative medications or adjusted
doses was provided in this table per
HA request.
NCT04129554

JNJ-73763989 and JNJ-56136379
Clinical Protocol 73763989PAHPB2002
AMENDMENT 4
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
144
Status: Approved,  Date: 26 November 2021
10.13. Appendix 13: NA Re-treatment and Monitoring After Stopping of NA
NCT04129554

JNJ-73763989 and JNJ-56136379
Clinical Protocol 73763989PAHPB2002
AMENDMENT 4
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
145
Status: Approved,  Date: 26 November 2021
11. 
REFERENCES
1. Berg T, Simon K-G, Mauss S, Schott E, Heyne R, Klass DM, et al. Long-term response after stopping tenofovir
disoproxil fumarate in non-cirrhotic HBeAg-negative patients—FINITE study. J Hepatol. 2017;67:918-924.
2. Brooks ST, Whitely E, Egger M, Smith GD, Mulheran PA, Peters TJ. Subgroup analyses in randomized trials:
risks of subgroup-specific analyses; power and sample size for the interaction test. J Clin Epidemiol.
2004;57(3):229-236.
3. Buti M, Wong DK, Gane E, et al. Safety and efficacy of stopping tenofovir disoproxil fumarate in patients with
chronic hepatitis B following at least 8 years of therapy: a prespecified follow-up analysis of two randomized
trials. Lancet Gastroenterol Hepatol. 2019;4(4):296-304.
4. Cohen SM, Johansson SL, Arnold LL, Lawson TA. Urinary tract calculi and thresholds in carcinogenesis. Food
and Chem Tox. 2002;40:793-799.
5. European Association for the Study of the Liver. EASL Clinical Practice Guidelines on the management of
hepatitis B virus infection. J Hepatol. 2017;67:370–398.
6. European Association for the Study of the Liver. EASL clinical practice guidelines: management of chronic
hepatitis B virus infection. J Hepatol. 2012;57(1):167–185.
7. European Medicines Agency (EMA). Assessment report Vemlidy (Tenofovir alafenamide).
https://www.ema.europa.eu/documents/assessment-report/vemlidy-epar-public-assessment-report en.pdf.
10 November 2016. Accessed 29 January 2019.
8. Fang Z, Li J, Yu X, et al. Polarization of monocytic myeloid-derived suppressor cells by hepatitis B surface
antigen is mediated via ERK/IL-6/STAT3 signaling feedback and restrains the activation of T cells in chronic
hepatitis B virus infection. J Immunol. 2015;195(10):4873-4483.
9. Ford N, Scourse R, Lemoine M, et al. Adherence to Nucleos(t)ide Analogue Therapies for Chronic Hepatitis B
Infection: A systematic review and meta-analysis. Hepatol Commun. 2018;2(10):1160-1116.
10. Hadziyannis SJ, Sevastianos,V, Rapti I, Vassilopoulos D, Hadziyannis E. Sustained responses and loss of
HBsAg in HBeAg-negative patients with chronic hepatitis B who stop longterm treatment with adefovir.
Gastroenterology. 2012;143:629-636.
11. Henry SP, Johnson M, Zanardi TA, Fey R, Auyeung D, Lappin PB, Levin AA. Renal uptake and tolerability of
a 2’-O-methoxyethyl modified antisense oligonucleotide (ISIS 113715) in monkey. Toxicology.
2012;301(1-3):13-20.
12. Höner Zu Siederdissen C, Hui AJ, Sukeepaisarnjaroen W, et al. Contrasting timing of virological relapse after
discontinuation of tenofovir or entecavir in hepatitis B e antigen–negative patients. J Infect Dis.
2018;218(9):1480-1484.
13. Höner Zu Siederdissen C, Rinker F, Maasoumy B, et al. Viral and host responses after stopping long-term
nucleos(t)ide analogue therapy in HBeAg-negative chronic hepatitis B. J Infect Dis. 2016;214(10):1492-1497.
14. Investigator’s Brochure: JNJ-73763989 Edition 3. Janssen Research & Development (May 2019).
15. Investigator’s Brochure: JNJ-56136379 Edition 4. Janssen Research & Development (Feb 2019).
16. Investigator’s Brochure: JNJ-56136379 Edition 4, Addendum 1. Janssen Research & Development (May 2019).
17. Janas MM, Harbison CE, Perry VK, et al. The nonclinical safety profile ofGalNac-conjugated RNAi
therapeutics in subacute studies. Toxicologic Pathology. 2018;46(7):735-745.
18. Jeng WJ, Chen YC, Chien RN, Sheen IS, Liaw YF. Incidence and predictors of hepatitis B surface antigen
seroclearance after cessation of nucleos(t)ide analogue therapy in hepatitis B e antigen-negative chronic
hepatitis B. Hepatology. 2018;68(2):425-434.
19. Jeng W-J, Yang H-I, Chen Y-C, et al. Increased incidence of HBsAg seroclearance in HBeAg negative chronic
hepatitis B patients discontinued Nuc therapy comparing to natural course –a propensity score matched study. J
Hepatol. 2018;68 Suppl 1:S88.
20. Kuo MT, Hu TH, Hung CH, et al. Hepatitis B virus relapse rates in chronic hepatitis B patients who discontinue
either entecavir or tenofovir. Aliment Pharmacol Ther. 2019;49(2):218-228.
NCT04129554

JNJ-73763989 and JNJ-56136379
Clinical Protocol 73763989PAHPB2002
AMENDMENT 4
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
146
Status: Approved,  Date: 26 November 2021
21. Lee M, Keeffe EB. Study of adherence comes to the treatment of chronic hepatitis B. J Hepatol. 2011;54:6–8.
22. Lesmana LA, Leung NWY, Mahachai V, et al. Hepatitis B: Overview of the burden of disease in the
Asia-Pacific region. Liver International. 2006;26:3–10.
23. Li H, Zhai N, Wang Z, et al. Regulatory NK cells mediated between immunosuppressive monocytes and
dysfunctional T cells in chronic HBV infection. Gut. 2018;67(11):2035-2044.
24. Lok AS, Zoulim F, Dusheiko G, Ghany MG. Hepatitis B cure: from discovery to regulatory approval.
J Hepatol. 2017;67(4):847-861.
25. Mantel N and Haenszel W. Statistical aspects of the analysis of data from retrospective studies of disease. J Natl
Cancer Inst. 1959;22:719-748.
26. Memorandum to Advisory Committee Members and Guests from Tenofovir Review Team. Background
Package for NDA 21-356: VIREAD (tenofovir disoproxil fumarate), 6 September 2001.
27. Memorandum to Advisory Committee Members and Guests from Entecavir Review Team. Briefing document
for NDA 21-797, entecavir 0.5 and 1 mg tablets and NDA 21-798, entecavir oral solution 0.05 mg/mL,
10 February 2005.
28. Papatheodoridis GV, Rigopoulou EI, Papatheodoridi M, et al. DARING-B: discontinuation of effective
entecavir or tenofovir disoproxil fumarate long-term therapy before HBsAg loss in non-cirrhotic
HBeAg-negative chronic hepatitis B. Antivir Ther. 2018;23(8):677-685.
29. Papatheodoridis G, Vlachogiannakos I, Cholongitas E, et al. Discontinuation of oral antivirals in chronic
hepatitis B: a systematic review. Hepatology. 2016;63(5):1481-1492.
30. Scaglione SJ, Lok AS. Effectiveness of hepatitis B treatment in clinical practice. Gastroenterology.
2012;142:1360-1368.
31. Sorrell MF, Belongia EA, Costa J, et al. National Institutes of Health Consensus Development Conference
Statement: Management of hepatitis B. Ann Intern Med. 2009;150:104–110.
32. Tannehill-Gregg SH, Dominick MA, Reisinger AJ, et al. Strain-related Differences in Urine Composition of
Male Rats of Potential Relevance to Urolithiasis. Toxicol Pathol. 2009;37:293-305.
33. US Food and Drug Administration. Guidance for Industry. Patient-Reported Outcome Measures: Use in
Medical Product Development to Support Labeling Claims. 2019. Available on:
https://www.fda.gov/regulatory-information/search-fda-guidance-documents/patient-reported-outcome-
measure-use-medical-product-development-support-labeling-claims. Accessed on 4 June 2019.
34. Van Hees S, Chi H, Hansen B, et al. Sustained off-treatment viral control is associated with high hepatitis B
surface antigen seroclearance rates in Caucasian patients with nucleos(t)ide analogue–induced HBeAg
seroconversion. J Viral Hepat. 2019;26(6):766–769.
35. Wang S, Chen Z, Hu C, et al. Hepatitis B virus surface antigen selectively inhibits TLR2 ligand-induced IL-12
production in monocytes/macrophages by interfering with JNK activation. J Immunol.
2013;190(10):5142-5151.
36. Woo G, Tomlinson G, Nishikawa Y, et al. TDF and ETV are the most effective antiviral agents for chronic
hepatitis B: A systematic review and Bayesian meta-analyses. Gastroenterology. 2010;139:1218–1229.
37. Wooddell CI, Yuen MF, Chan HL, et al. RNAi-based treatment of chronically infected patients and
chimpanzees reveals that integrated hepatitis B virus DNA is a source of HBsAg. Sci Transl Med. 2017;9(409).
38. World Health Organization. WHO Requirements for the Collection, Processing and Quality Control of Blood,
Blood Components and Plasma Derivatives. WHO Technical Report Series No. 840, Annex 2 (Adopted by
ECBS 1992). Available from: https://www.who.int/bloodproducts/publications/WHO TRS 840 A2.pdf.
Accessed 10 July 2019.
39. Zumbo BD, Chan EKH. Validity and Validation in Social, Behavioral, and Health Sciences. Springer Press;
2014.
40. Investigator’s Brochure: JNJ-56136379 Edition 4, Addendum 2. Janssen Research & Development (Sep 2019).
NCT04129554

JNJ-73763989 and JNJ-56136379
Clinical Protocol 73763989PAHPB2002
AMENDMENT 4
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
147
Status: Approved,  Date: 26 November 2021
41. Investigator’s Brochure: JNJ-73763989 Edition 3, Addendum 1. Janssen Research & Development
(January 2020).
42. Investigator’s Brochure: JNJ-56136379 Edition 4, Addendum 3. Janssen Research & Development (January
2020).
NCT04129554

JNJ-73763989 and JNJ-56136379
Clinical Protocol 73763989PAHPB2002
AMENDMENT 4
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
148
Status: Approved,  Date: 26 November 2021
INVESTIGATOR AGREEMENT
I have read this protocol and agree that it, in conjunction with the accompanying Master Protocol,
contains all necessary details for carrying out this study. I will conduct the study as outlined herein and
will complete the study within the time designated.
I will provide copies of the protocol and all pertinent information to all individuals responsible to me who
assist in the conduct of this study. I will discuss this material with them to ensure that they are fully
informed regarding the study intervention, the conduct of the study, and the obligations of confidentiality.
Coordinating Investigator (where required):
Name (typed or printed):
Institution and Address:
Signature: 
Date:
(Day Month Year)
Principal (Site) Investigator:
Name (typed or printed):
Institution and Address:
Telephone Number:
Signature: 
Date:
(Day Month Year)
Sponsor's Responsible Medical Officer:
Name (typed or printed): 
Institution: 
Janssen Research & Development
Signature: 
electronic signature appended at the end of the protocol 
Date:
(Day Month Year)
Note: If the address or telephone number of the investigator changes during the course of the study, written
notification will be provided by the investigator to the sponsor, and a protocol amendment will not be required.
PPD
NCT04129554

Signature
User 
Date 
Reason
26-Nov-2021
15:32:04
(GMT)
Document Approval
PPD
NCT04129554

CONFIDENTIAL – FOIA Exemptions Apply in U.S.
1
Status: Approved,  Date: 25 May 2020
Janssen Research & Development *
Clinical Protocol
COVID-19 Appendix
Intervention-specific Appendix 2 to Master Protocol PLATFORMPAHPB2001
A Randomized, Double blind, Placebo-controlled Phase 2b Study to Evaluate Efficacy, 
Pharmacokinetics, and Safety of 48-week Study Intervention With 
JNJ-73763989+JNJ-56136379+Nucleos(t)ide Analog (NA) Regimen Compared to NA Alone 
in e Antigen-negative Virologically Suppressed Participants With Chronic Hepatitis B 
Virus Infection
REEF-2 study
Protocol 73763989PAHPB2002; Phase 2b
JNJ-73763989 and JNJ-56136379  
*Janssen Research & Development is a global organization that operates through different legal entities in
various countries. Therefore, the legal entity acting as the sponsor for Janssen Research & Development
studies may vary, such as, but not limited to Janssen Biotech, Inc.; Janssen Products, LP; Janssen Biologics,
BV; Janssen-Cilag International NV; Janssen, Inc; Janssen Pharmaceutica NV; Janssen Sciences Ireland
UC; Janssen Biopharma Inc.; or Janssen Research & Development, LLC. The term “sponsor” is used
throughout the protocol to represent these various legal entities; the sponsor is identified on the Contact
Information page that accompanies the protocol.
United States (US) sites of this study will be conducted under US Food & Drug Administration
Investigational New Drug (IND) regulations (21 CFR Part 312).
EudraCT NUMBER: 2019-002674-31
Status:
Approved  
Date:
25 May 2020
Prepared by:
Janssen Research & Development, a division of Janssen Pharmaceutica NV  
EDMS number:
EDMS-RIM-66038, 2.0
THIS APPENDIX APPLIES TO ALL CURRENT APPROVED VERSIONS OF PROTOCOL
73763989PAHPB2002 (EDMS-ERI-188471315)
GCP Compliance: This study will be conducted in compliance with Good Clinical Practice, and applicable regulatory 
requirements. 
Confidentiality Statement
The information provided herein contains Company trade secrets, commercial or financial information that the Company
customarily holds close and treats as confidential.  The information is being provided under the assurance that the recipient
will maintain the confidentiality of the information under applicable statutes, regulations, rules, protective orders or 
otherwise.
NCT04129554

COVID-19 Appendix
JNJ-73763989
Clinical Protocol 73763989PAHPB2002
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
2
Status: Approved,  Date: 25 May 2020
COVID-19 APPENDIX
GUIDANCE ON STUDY CONDUCT DURING THE COVID-19 PANDEMIC
It is recognized that the Coronavirus Disease 2019 (COVID-19) pandemic may have an impact on 
the conduct of this clinical study due to, for example, self-isolation/quarantine by participants and 
study-site personnel; travel restrictions/limited access to public places, including hospitals; study 
site personnel being reassigned to critical tasks.
In alignment with recent health authority guidance, the sponsor is providing options for study-
related participant management in the event of disruption to the conduct of the study. This guidance 
does not supersede any local or government requirements or the clinical judgement of the 
investigator to protect the health and well-being of participants and site staff and maintain 
oversight of delegated trial activities. If, at any time, a participant’s safety is considered at risk, 
study intervention will be discontinued, and study follow-up will be conducted.
Scheduled visits that cannot be conducted in person at the study site will be performed to the extent 
possible remotely/virtually or delayed until such time that on-site visits can be resumed. At each 
contact, participants will be interviewed to collect safety data. Key efficacy endpoint assessments 
should be performed if required and as feasible. Participants will also be questioned regarding 
general health status to fulfill any physical examination requirement. 
Every effort should be made to adhere to protocol-specified assessments for participants on study 
intervention, including follow-up. Modifications to protocol-required assessments may be 
permitted via COVID-19 Appendix after consultation with the participant, investigator, or the 
sponsor. Missed assessments/visits will be captured in the clinical trial management system for 
protocol deviations. Discontinuations of study interventions and withdrawal from the study should 
be documented with the prefix “COVID-19-related” in the case report form (CRF). 
The sponsor will continue to monitor the conduct and progress of the clinical study, and any 
changes will be communicated to the sites and to the health authorities according to local guidance. 
If a participant has tested positive for COVID-19, the investigator should contact the sponsor’s
responsible medical officer to discuss plans for study intervention and follow-up. Modifications 
made to the study conduct as a result of the COVID-19 pandemic should be summarized in the 
clinical study report.
NCT04129554

COVID-19 Appendix
JNJ-73763989
Clinical Protocol 73763989PAHPB2002
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
3
Status: Approved,  Date: 25 May 2020
GUIDANCE SPECIFIC TO THIS PROTOCOL
The following emergency provisions are meant to ensure participant safety on study while site 
capabilities are compromised by COVID-19 related restrictions. Remote medical consultation and 
alternatives to study intervention dispensing, administration, and clinical laboratory assessments 
may allow continued study participation for participants in this trial. Before implementing any of 
these emergency provisions, the sponsor should be consulted to perform a benefit-risk analysis 
and to ensure the measures are executed and documented correctly.
As restrictions are lifted and the acute phase of the COVID-19 pandemic resolves, sites should 
revert to original protocol conduct as soon as feasible and in accordance with any country-specific 
regulatory requirements.
Screening and Randomization:

Enrollment of new participants may continue based on the investigator’s assessment of risks 
versus benefits, depending on the situation at a particular site, and the ability to monitor 
participant safety. 

Baseline visits for participants recently screened for this study should be postponed if the 
current situation does not allow for an orderly conduct of the study.
Dispensing/administration of study intervention:

For participants able to visit the study site, but who request to reduce visit frequency, or for 
whom limited access to the site is expected, an additional supply of oral study intervention can 
be provided.

For participants unable to visit the study site, direct-to-patient (DTP) shipment or handover to 
a caregiver or delegate of oral study intervention may be implemented, where allowed per local 
regulations and if requested by the investigator. Where DTP shipments or handover to 
delegates are deemed necessary, the process must be coordinated between the site and sponsor
staff following DTP procedures for arranging shipment and adhering to associated approvals 
and documentation requirements.

JNJ-3989/placebo should always be administered by an unblinded nurse at the study site or, if 
site visits are not possible, at the participant’s home. Per protocol amendment 1, if a scheduled 
injection of JNJ-3989/placebo was missed, the injection should be given as soon as possible 
but within 3 weeks after the scheduled time. Otherwise, the injection should be skipped and 
the next injection should be given at the next scheduled time point per the initial injection 
schedule.
Continuation of study intervention: 

Any issue with continuation and/or provision of study intervention should be discussed with 
the sponsor and should be well documented.

Study intervention should be continued if, in the assessment of the investigator, it does not 
result in risk to the participant. If at any time the participant’s safety is considered at risk due 
to study intervention, study intervention will be temporarily or permanently discontinued, 
while every effort should be made to maintain follow-up on study. The benefit of continuing 
NCT04129554

COVID-19 Appendix
JNJ-73763989
Clinical Protocol 73763989PAHPB2002
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
4
Status: Approved,  Date: 25 May 2020
study intervention should be assessed by the investigator for each individual participant, 
considering the potential impact of reduced direct clinical supervision on participant safety.

If a participant develops a SARS-CoV-2 infection, the investigator should contact the 
sponsor to discuss plans for study intervention and follow-up. A decision to continue study 
intervention should be made by the investigator depending on symptoms and concomitant 
medication used for the treatment of COVID-19. 

When a participant, for whom study intervention has been interrupted, recovers from 
suspected or confirmed SARS-CoV-2 infection or related disease and all AEs related to 
SARS-CoV-2 infection improve to Grade ≤1, the investigator should discuss with the 
sponsor about resuming study intervention.
Study visits and assessments:

If possible, central laboratory testing as outlined in the Schedule of Activities is to be 
continued. If central laboratory tests cannot be performed, the use of a local laboratory is 
allowed for study evaluations. A copy of the local laboratory report should be reviewed by the 
investigator and filed with the source documents, along with reference ranges; to maintain 
treatment blinding, HBsAg, HBeAg, anti-HBs and anti-HBe antibody tests during the study 
intervention phase cannot be done locally (unless instructed otherwise by the sponsor).

To safely maintain participants on study intervention while site capabilities are compromised 
by COVID-19-related restrictions, study visits may be performed by a nurse (who received 
study-specific training) at the patient’s home (home health nurse) until such time that on-site 
visits can be resumed. The following activities may be completed as required per the Schedule 
of Activities and as feasible:

Sampling, processing and shipping of laboratory samples (as described above). 

Checking study compliance: medication diary (if available), intake of oral study 
intervention, storage of oral study intervention

Performing ECGs

Collecting patient-reported outcomes (where appropriate translations and licensing are 
available)

If JNJ-3989/placebo is administered at the patient’s home, it will need to be done by an 
unblinded nurse (who received study-specific training)

Delivering oral study interventions

Any data related to adverse events, concomitant medication, vital signs, and ECGs will be 
reviewed and assessed by the investigator.

In addition, participants may have tele-health visits conducted by blinded qualified site 
personnel via phone or video conversation as per local regulation. Assessments may include 
review of adverse events (including injection site reactions), concomitant medications, study 
intervention accountability. Participants will also be questioned regarding general health status 
to fulfill any physical examination requirement. Patient-reported outcomes may be collected 
(where appropriate translations and licensing are available) following the Site Assisted 
Administration Process Guidance.
NCT04129554

COVID-19 Appendix
JNJ-73763989
Clinical Protocol 73763989PAHPB2002
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
5
Status: Approved,  Date: 25 May 2020

Procedures and timings should follow the Schedule of Activities as closely as possible. 
Standard Adverse Event/Serious Adverse Event reporting requirements apply.
Informed consent:

Consenting and re-consenting of participants for the measures taken (including also remote 
consenting by phone or video consultation) will be performed as applicable and according to 
local guidance for informed consent applicable during the COVID-19 pandemic. The process 
is to be documented in the source documents.
Source data verification/monitoring:

In case on-site monitoring visits are not possible, the site monitor may contact the investigator 
to arrange monitoring visits and activities remotely (in accordance with site and local 
requirements). Additional on-site monitoring visits may be needed in the future to catch up on 
source data verification. 
Site audits:

During the COVID-19 pandemic and at the impacted sites, study site GCP audits with direct 
impact/engagement from the investigator and study site personnel would not be conducted in 
order to comply with national, local, and/or organizational social distancing restrictions. 
Additional quality assurance activities such as remote audits or focused review of study related 
documents may take place with limited impact/engagement if possible.
NCT04129554

COVID-19 Appendix
JNJ-73763989
Clinical Protocol 73763989PAHPB2002
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
6
Status: Approved,  Date: 25 May 2020
INVESTIGATOR AGREEMENT
I have read this document and agree that it contains all necessary details for carrying out this study. 
I will conduct the study as outlined herein and will complete the study within the time designated.
I will provide copies of the protocol and all pertinent information to all individuals responsible to 
me who assist in the conduct of this study. I will discuss this material with them to ensure that they 
are fully informed regarding the study intervention, the conduct of the study, and the obligations 
of confidentiality.
Coordinating Investigator (where required):
Name (typed or printed):
Institution and Address:
Signature:
Date:
(Day Month Year)
Principal (Site) Investigator:
Name (typed or printed):
Institution and Address:
Telephone Number:
Signature:
Date:
(Day Month Year)
Sponsor's Responsible Medical Officer:
Name (typed or printed):
Institution:
Janssen Research & Development
Signature:
electronic signature appended at the end of the protocol
Date:
(Day Month Year)
Note: If the address or telephone number of the investigator changes during the course of the study, written 
notification will be provided by the investigator to the sponsor, and a protocol amendment will not be required.
PPD
NCT04129554

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