A Phase 2b, Multicenter, Double-blind, Active-controlled, Randomized Study to Investigate the Efficacy and Safety of Different Combination Regimens Including JNJ-73763989 and/or JNJ-56136379 for the Treatment of 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: 24 November 2021
Janssen Research & Development *
Clinical Protocol
A Phase 2b, Multicenter, Double-blind, Active-controlled, Randomized Study to
Investigate the Efficacy and Safety of Different Combination Regimens Including
JNJ-73763989 and/or JNJ-56136379 for the Treatment of Chronic Hepatitis B Virus
Infection
The REEF-1 Study
Protocol 73763989HPB2001; 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.
United States (US)sites of this study will be conducted under US Food & Drug Administration
Investigational New Drug regulations (21 CFR Part 312).
EudraCT NUMBER:2019-000622-22
Status: 
Approved 
Date: 
24 November 2021
Prepared by: Janssen Research & Development, a division of Janssen Pharmaceutica NV 
EDMS number: 
EDMS-ERI-180130107, 7.0
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.
NCT03982186

JNJ-73763989 and JNJ-56136379
Clinical Protocol 73763989HPB2001 AMENDMENT 4
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
2
Status: Approved,  Date: 24 November 2021
PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE
DOCUMENT HISTORY
Document 
Date
Amendment 4 
24-November-2021
Amendment 3 
30-September-2021
Amendment 2 
27-January-2020
Amendment 1 
14-November-2019
Original Protocol 
17-May-2019
Amendment 4(24 November 2021)
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
10.14 Appendix 14: NA Re-treatment and
Monitoring After Stopping of NA
Corrections were made to
footnote numbering
Minor errors were noted 
1.3.2 Schedule of Activities –Follow-up Phase 
NCT03982186

JNJ-73763989 and JNJ-56136379
Clinical Protocol 73763989HPB2001 AMENDMENT 4
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
3
Status: Approved,  Date: 24 November 2021
TABLE OF CONTENTS
PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE ............................................................... 2
TABLE OF CONTENTS ............................................................................................................................... 3
LIST OF IN-TEXT TABLES AND FIGURES................................................................................................ 5
1. 
PROTOCOL SUMMARY..................................................................................................................... 6
1.1. 
Synopsis........................................................................................................................................... 6
1.2. 
Schema.......................................................................................................................................... 21
1.3. 
Schedule of Activities..................................................................................................................... 22
1.3.1. 
Schedule of Activities –Screening and Study Intervention Phase............................................. 22
1.3.2. 
Schedule of Activities –Follow-up Phase................................................................................... 27
2. 
INTRODUCTION................................................................................................................................ 32
2.1. 
Study Rationale.............................................................................................................................. 34
2.2. 
Background .................................................................................................................................... 34
2.2.1. 
JNJ-3989 and JNJ-6379............................................................................................................. 34
2.2.2. 
Combination of JNJ-3989 and JNJ-6379 with Entecavir or Tenofovir Prodrugs
(Tenofovir Disoproxil Fumarate or Tenofovir Alafenamide)........................................................ 44
2.2.2.1. 
Overall Nonclinical Assessment of the Combination Therapy ................................................ 46
2.3. 
Benefit-risk Assessment................................................................................................................. 47
2.3.1. 
Benefits for Study Participation .................................................................................................. 47
2.3.1.1. 
Known Benefits........................................................................................................................ 47
2.3.1.2. 
Potential Benefits..................................................................................................................... 47
2.3.2. 
Risks for Study Participation....................................................................................................... 47
2.3.2.1. 
Known Risks............................................................................................................................ 47
2.3.2.2. 
Potential Risks......................................................................................................................... 47
2.3.3. 
Benefit-risk Assessment for Study Participation......................................................................... 49
3. 
OBJECTIVES AND ENDPOINTS ..................................................................................................... 51
4. 
STUDY DESIGN ................................................................................................................................ 54
4.1. 
Overall Design................................................................................................................................ 54
4.2. 
Scientific Rationale for Study Design............................................................................................. 56
4.2.1. 
Study-specific Ethical Design Considerations ............................................................................ 59
4.3. 
Justification for Dose...................................................................................................................... 59
4.3.1. 
JNJ-3989 .................................................................................................................................... 59
4.3.2. 
JNJ-6379 .................................................................................................................................... 60
4.4. 
End of Study Definition................................................................................................................... 61
5. 
STUDY POPULATION ...................................................................................................................... 61
5.1. 
Inclusion Criteria............................................................................................................................ 61
5.2. 
Exclusion Criteria........................................................................................................................... 64
5.3. 
Lifestyle Considerations................................................................................................................. 67
5.4. 
Screen Failures.............................................................................................................................. 67
6. 
STUDY INTERVENTION................................................................................................................... 69
6.1. 
Study Intervention(s) Administered................................................................................................ 69
6.2. 
Preparation/Handling/Storage/Accountability ................................................................................ 71
6.3. 
Measures to Minimize Bias: Randomization and Blinding............................................................. 72
6.4. 
Study Intervention Compliance...................................................................................................... 73
6.5. 
Concomitant Therapy..................................................................................................................... 74
6.6. 
Individual Participant NA Treatment Completion Criteria.............................................................. 76
6.7. 
NA Re-treatment Criteria and Monitoring After Stopping of NA..................................................... 77
6.8. 
Intervention After the End of the Study.......................................................................................... 78
NCT03982186

JNJ-73763989 and JNJ-56136379
Clinical Protocol 73763989HPB2001 AMENDMENT 4
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
4
Status: Approved,  Date: 24 November 2021
7. 
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT
DISCONTINUATION/WITHDRAWAL............................................................................................... 78
7.1. 
Discontinuation of Study Intervention ............................................................................................ 78
7.2. 
Participant Discontinuation/Withdrawal From the Study................................................................ 79
7.2.1. 
Withdrawal From the Use of Research Samples ....................................................................... 79
7.3. 
Lost to Follow-up............................................................................................................................ 80
8. 
STUDY ASSESSMENTS AND PROCEDURES ............................................................................... 80
8.1. 
Efficacy Assessments .................................................................................................................... 82
8.1.1. 
Sequencing................................................................................................................................. 83
8.1.2. 
Patient-reported Outcomes ........................................................................................................ 83
8.2. 
Safety Assessments....................................................................................................................... 85
8.2.1. 
Physical Examinations................................................................................................................ 85
8.2.2. 
Vital Signs................................................................................................................................... 85
8.2.3. 
Electrocardiograms..................................................................................................................... 86
8.2.4. 
Clinical Safety Laboratory Assessments .................................................................................... 86
8.3. 
Adverse Events and Serious Adverse Events ............................................................................... 87
8.3.1. 
Time Period and Frequency for Collecting Adverse Event and Serious Adverse Event
Information.................................................................................................................................. 87
8.3.2. 
Method of Detecting Adverse Events and Serious Adverse Events .......................................... 87
8.3.3. 
Follow-up of Adverse Events and Serious Adverse Events ....................................................... 88
8.3.4. 
Regulatory Reporting Requirements for Serious Adverse Events ............................................. 88
8.3.5. 
Pregnancy................................................................................................................................... 88
8.3.6. 
Specific Toxicities ....................................................................................................................... 88
8.3.6.1. 
Intervention-emergent ALT/AST Elevations............................................................................ 88
8.3.6.2. 
Rash ........................................................................................................................................ 89
8.3.6.3. 
Acute Systemic Allergic Reactions.......................................................................................... 90
8.3.6.4. 
Renal Complications................................................................................................................ 91
8.3.6.5. 
Hematologic Abnormalities...................................................................................................... 91
8.4. 
Treatment of Overdose .................................................................................................................. 92
8.5. 
Pharmacokinetics........................................................................................................................... 92
8.5.1. 
Evaluations ................................................................................................................................. 93
8.5.2. 
Analytical Procedures................................................................................................................. 93
8.5.3. 
Pharmacokinetic Parameters and Evaluations........................................................................... 93
8.6. 
Pharmacokinetics/Pharmacodynamics.......................................................................................... 93
8.7. 
Immune Assessments.................................................................................................................... 94
8.8. 
Host Genetics................................................................................................................................. 94
8.9. 
Host Biomarkers............................................................................................................................. 94
9. 
STATISTICAL CONSIDERATIONS.................................................................................................. 95
9.1. 
Statistical Hypotheses.................................................................................................................... 95
9.2. 
Sample Size Determination ........................................................................................................... 96
9.3. 
Populations for Analyses................................................................................................................ 98
9.4. 
Statistical Analyses ........................................................................................................................ 99
9.4.1. 
Efficacy Analyses........................................................................................................................ 99
9.4.1.1. 
Primary Efficacy Endpoint (Proportion of Participants Meeting the NA Treatment
Completion Criteria at Week 48) ............................................................................................. 99
9.4.1.2. 
Key Secondary Efficacy Endpoint of Functional Cure at Week 72 (HBsAg
Seroclearance 24 Weeks After Completion of All Study Intervention at Week 48)............... 100
9.4.1.3. 
Other Secondary and Exploratory Efficacy Endpoints .......................................................... 101
9.4.1.4. 
Resistance Analyses ............................................................................................................. 103
9.4.1.5. 
Patient-reported Outcome Analyses ..................................................................................... 103
9.4.2. 
Safety Analyses........................................................................................................................ 103
9.4.3. 
Other Analyses ......................................................................................................................... 104
9.5. 
Interim Analyses........................................................................................................................... 106
9.5.1. 
Independent Data Monitoring Committee................................................................................. 106
9.5.2. 
Independent Flare Expert Panel............................................................................................... 107
NCT03982186

JNJ-73763989 and JNJ-56136379
Clinical Protocol 73763989HPB2001 AMENDMENT 4
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
5
Status: Approved,  Date: 24 November 2021
10. SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS .......................... 108
10.1. 
Appendix 1: Abbreviations and Definitions of Terms................................................................... 108
10.2. 
Appendix 2: Clinical Laboratory Tests ......................................................................................... 111
10.3. 
Appendix 3: Regulatory, Ethical, and Study Oversight Considerations....................................... 113
10.4. 
Appendix 4: Adverse Events: Definitions and Procedures for Recording, Evaluating,
Follow-up, and Reporting............................................................................................................. 125
10.5. 
Appendix 5: Rash Management................................................................................................... 130
10.6. 
Appendix 6: Intervention-emergent ALT/AST Elevations ............................................................ 135
10.7. 
Appendix 7: Cardiovascular Safety –Abnormalities.................................................................... 136
10.8. 
Appendix 8: Contraceptive and Barrier Guidance ....................................................................... 137
10.9. 
Appendix 9: DAIDS Table ............................................................................................................ 140
10.10. Appendix 10: Hepatitis B Quality of Life Instrument .................................................................... 163
10.11. Appendix 11: HBV-specific Self-stigma PRO Scale .................................................................... 169
10.12. Appendix 12: Patient Global Impression of Change Scale.......................................................... 171
10.13. Appendix 13: Protocol Amendment History................................................................................. 172
10.14. Appendix 14: NA Re-treatment and Monitoring After Stopping of NA......................................... 181
11. REFERENCES................................................................................................................................. 182
INVESTIGATOR AGREEMENT............................................................................................................... 185
LIST OF IN-TEXT TABLES AND FIGURES
TABLES
Table 1: 
Various Stages of HBV Infection –Terminology and Characteristics (EASL 2017)7 ............... 32
Table 2: 
Animal/Human Exposure Ratios at NOAEL for JNJ-3989........................................................ 36
Table 3: 
Animal/Human Ratios at the NOAEL in Rat and Dog (Human Exposure at 250mg
JNJ-56136379 Once Daily for 28 Days [Study 56136379HPB1001]) ...................................... 37
Table 4: 
Disallowed Medication .............................................................................................................. 74
Table 5: 
Concomitant Medication to be Used With Caution................................................................... 75
Table 6: 
Power to Conclude a Positive Dose-response Under the Assumed Candidate
Dose-response Models............................................................................................................. 97
Table 7: 
Simulated-based Assessment of the Power of the Sequential Testing Strategy Under
a Variety of Scenarios (10,000 Runs/Scenario) ....................................................................... 98
Table 8: 
Meta-analysis of % HBsAg Seroclearance After 48 Weeks of Treatment.............................. 101
Table 9: 
Management of Rash Events by Severity Grade ................................................................... 130
FIGURES
Figure 1: Schematic Overview of the Study............................................................................................. 21
Figure 2: Candidate Dose-response Models on the Logit Scale ............................................................. 96
NCT03982186

JNJ-73763989 and JNJ-56136379
Clinical Protocol 73763989HPB2001 AMENDMENT 4
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
6
Status: Approved,  Date: 24 November 2021
1. 
PROTOCOL SUMMARY
1.1. 
Synopsis
A Phase 2b, Multicenter, Double-blind, Active-controlled, Randomized Study to Investigate the Efficacy
and Safety of Different Combination Regimens Including JNJ-73763989 and/or JNJ-56136379 for the
Treatment of Chronic Hepatitis B Virus Infection
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 ofHBV 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 in
JNJ-3989 injection 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
forthe 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, JNJ-6379 or placebo, and NA.
OBJECTIVES AND ENDPOINTS
The primary and secondary objectives and endpoints of this study are listed below.
Objectives 
Endpoints
Primary
 
To establish the dose-response relationship for
antiviral activity of 3 doses of JNJ-3989+NA and
to evaluate the efficacy of combination regimens
of JNJ-3989+NA (with and without JNJ-6379)
and of JNJ-6379+NA.
 
Proportion of participants meeting the NA
treatment completion criteria at Week 48 (see
Individual Participant NA Treatment Completion
Criteria).
Secondary
 
To evaluate the safety and tolerability of the study
intervention throughout the study.
 
Proportion of participants with (serious) adverse
events ([S]AEs) and abnormalities in clinical
laboratory tests (including hematology, blood
biochemistry, blood coagulation, urinalysis, urine
chemistry, and renal biomarkers), 12-lead
electrocardiograms (ECGs), and vital signs.
NCT03982186

JNJ-73763989 and JNJ-56136379
Clinical Protocol 73763989HPB2001 AMENDMENT 4
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
7
Status: Approved,  Date: 24 November 2021
Objectives 
Endpoints
 
To evaluate the efficacy of the study intervention 
during the follow-up phase*. 
 
Proportion 
of 
participants 
with 
HBsAg
seroclearance 24 weeks after completion of all
study intervention at Week 48.
 
Proportion 
of 
participants 
with 
HBsAg
seroclearance 48 weeks after completion of all
study intervention at Week 48.
 
Proportion of participants with HBV DNA
<lower limit of quantification (LLOQ) 24 and 48
weeks, respectively, after completion of all study
intervention at Week 48.
 
Proportion of participants meeting the NA
treatment completion criteria during follow-up.
 
Proportion 
of 
participants 
with 
HBsAg
seroclearance 24 and 48 weeks, respectively, after
completion of NA treatment at any time during
follow-up.
 
Frequency of flares.
 
Proportion 
of 
participants 
requiring 
NA
re-treatment during follow-up (see NA Re-
treatment Criteria and Monitoring After Stopping
of NA).
 
To evaluate efficacy as measured by blood 
markers (such as HBsAg, HBeAg,** HBV DNA, 
and alanine aminotransferase [ALT]) during 
study intervention and follow-up. 
 
Proportion of participants with (sustained)
reduction, suppression, and/or seroclearance
considering single and multiple markers (such as
HBsAg, HBeAg,** HBV DNA and ALT).
 
Proportion of participants with HBsAg and
HBeAg** seroconversion.
 
Change from  baseline over time in HBsAg,
HBeAg,** and HBV DNA.
 
Time 
to 
achieve 
HBsAg and 
HBeAg**
seroclearance.
 
Proportion of participants with HBsAg levels
and/or changes from baseline below/above
different cut-offs (eg, HBsAg <100 IU/mL or
>1 log10 IU/mL reduction in HBsAg from
baseline).
 
Proportion of HBeAg-positive participants with
HBeAg** levels and/or changes from baseline
below/above different cut-offs.
 
Proportion of participants with HBV DNA levels
and/or changes from baseline below/above
different cut-offs (eg, <LLOQ of the assay).
 
Proportion of participants with ALT decrease and
normalization.
 
To 
evaluate 
the 
frequency 
of 
virologic 
breakthrough. 
 
Proportion 
of 
participants 
with 
virologic
breakthrough.
NCT03982186

JNJ-73763989 and JNJ-56136379
Clinical Protocol 73763989HPB2001 AMENDMENT 4
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
8
Status: Approved,  Date: 24 November 2021
Objectives 
Endpoints
 
To evaluate the efficacy of NA re-treatment in 
participants who meet the criteria for NA 
re-treatment. 
 
Proportion of participants who reach HBV DNA
undetectability after re-start of NA treatment
during follow-up.
 
To evaluate the pharmacokinetics (PK) of 
JNJ-3989 (JNJ-3976 and JNJ-3924), JNJ-6379, 
and NA, as applicable.
 
PK parameters of JNJ-3989 (JNJ-3976 and JNJ-
3924), JNJ-6379, and NA, as applicable.
* The follow-up phase has a maximum duration of 96 weeks.
** in HBeAg-positive participants only
Hypothesis
Based on the primary efficacy endpoint, the proportion of participants meeting the NA treatment
completion criteria at Week 48, the primary hypotheses are as follows:
 
There is a positive dose-response signal across the 3 doses of JNJ-3989 (40, 100, and 200 mg) on the
background of NA compared with NA treatment alone (control Arm 6).
 
One or both combination regimens JNJ-3989+JNJ-6379+NA and JNJ-6379+NA are more
efficacious than NA treatment alone (control Arm 6).
 
The combination regimen of JNJ-3989 (100 mg)+JNJ-6379+NA is more efficacious than JNJ-3989
(100 mg)+NA and/or JNJ-6379+NA combination regimens.
OVERALL DESIGN
This is a Phase 2b, randomized, double-blind, double-dummy, active-controlled, dose-finding, parallel,
multicenter, interventional study in HBeAg-positive and -negative chronic HBV-infected participants
who (1) are currently not being treated for their HBV infection (including chronic hepatitis B [CHB]
treatment-naïve participants) or (2) who are virologically suppressed by current NA treatment (either
entecavir [ETV], tenofovir disoproxil fumarate [TDF], or tenofovir alafenamide [TAF]). The efficacy,
safety, and PK of the study intervention will be evaluated.
A target of 450 adult male and female participants, 18 (or the legal age of consent in the jurisdiction in
which the study is taking place) to 65 years of age (inclusive), will be randomized in a 2:2:2:2:1:1 ratio to
one of the following intervention arms:
 
Arm 1: 
JNJ-3989 (100 mg) + 
JNJ-6379 (250 mg qd) + 
NA* (N=90)
 
Arm 2: 
JNJ-3989 (200 mg) +  
Placebo +  
NA* (N=90)
 
Arm 3: 
JNJ-3989 (100 mg) +  
Placebo +  
NA* (N=90)
 
Arm 4: 
JNJ-3989 (40 mg) +  
Placebo +  
NA* (N=90)
 
Arm 5: 
Placebo +  
JNJ-6379 (250 mg qd) +  
NA* (N=45)
 
Arm 6 (control): 
Placebo +  
Placebo +  
NA* (N=45)
*NA: ETV, TDF, or TAF
After a fixed duration of 48 weeks, participants will complete treatment with JNJ-3989 and/or JNJ-6379.
If the NA treatment completion criteria (outlined below) are met based on clinical laboratory tests
performed at Week 44, treatment with NA will also be completed at Week 48 (ie, the next scheduled visit
after Week 44). Participants who meet the NA treatment completion criteria will be monitored closely
during the follow-up phase. NA treatment may need to be re-started based on protocol-defined NA
re-treatment criteria (see below).
NCT03982186

JNJ-73763989 and JNJ-56136379
Clinical Protocol 73763989HPB2001 AMENDMENT 4
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
9
Status: Approved,  Date: 24 November 2021
Randomization will be stratified by HBeAg status at screening (positive versus negative) and by treatment
history (not currently treated versus virologically suppressed).
The aim is to include 40% not currently treated participants of whom it is expected that 40% are
HBeAg-positive. As such subgroup enrollment may be closed prior to completion of study enrollment.
All efforts will be undertaken to include a sufficient number ofHBeAg-positive virologically suppressed
participants.
The study will be conducted in the following phases:
 
Screening phase: 4 weeks. If necessary, eg, for operational reasons, the screening phase may be
extended up to a maximum of 6 weeks on a case-by-case basis and in agreement with the sponsor.
 
Double-blind study intervention phase: from Day 1 (ie, baseline) up to Week 48.
 
Follow-up phase: for 48 weeks after the end of investigational intervention. For participants who
complete NA treatment during follow-up, the follow-up phase will be extended to 48 weeks after the
end of NA treatment. The follow-up phase has a maximum duration of 96 weeks.
The duration of individual study participation will be between 100 and 150 weeks.
At Week 48 or at time of early discontinuation, it will be communicated to the investigators whether the
participants were allocated to either an investigational arm (Arms 1 to 5) or the control arm (Arm 6) to
allow the correct follow-up visit schedule to be followed (see Schedule of Activities). Only at Week 72,
randomization codes (for Arms 1 to 5) will be fully disclosed to the investigators. The sponsor will be
fully unblinded for the primary analysis at Week 48 (see below).
Participants will be considered to have completed the study if they have completed the assessments of the
end of study visit ([Extended] Follow-up Week 48). After completing this study, participants may  be
invited to enroll into a long-term follow-up study.
An Independent Data Monitoring Committee (IDMC) will be commissioned for this study. In addition, an
Independent Flare Expert Panel (IFLEP) will be appointed.
Individual Participant NA Treatment Completion Criteria
After a fixed duration of 48 weeks, participants will complete treatment with JNJ-3989 and/or JNJ-6379.
If all of the following criteria are met based on clinical laboratory tests performed at Week 44, treatment
with NA will also be completed at Week 48 (ie, the next scheduled visit after Week 44):
 
The participant has ALT <3x upper limit of normal (ULN), AND
 
The participant has HBV DNA <LLOQ, AND
 
The participant is HBeAg-negative, AND
 
The participant has HBsAg <10 IU/mL.
Note: In case of ALT elevation ≥3x ULN at Week 44 the investigator must consider different potential
causes of increased ALT to ensure appropriate work up and management as needed. If the ALT elevation
is unrelated to HBV activity and/or <3x ULN by treatment Week 48, NA completion may be considered
at the discretion of the investigator and in consultation with the sponsor.
Participants who do not meet the above criteria at Week 48 should continue NA treatment during the
48-week follow-up. If the above criteria are met during the follow-up phase based on clinical laboratory
tests performed at or before Follow-up Week 42 (Follow-up Week 36 for Arm 6), NA treatment should be
stopped at or before Follow-up Week 48 (ie, the next scheduled visit after the laboratory test was
performed) and the follow-up schedule should be extended to 48 weeks after the end of NA treatment. If
NA treatment completion criteria are not met based on clinical laboratory tests performed at or before
NCT03982186

JNJ-73763989 and JNJ-56136379
Clinical Protocol 73763989HPB2001 AMENDMENT 4
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
10
Status: Approved,  Date: 24 November 2021
Follow-up Week 42 (Follow-up Week 36 for Arm 6), the follow-up phase will not be extended, but the
participant will continue NA treatment and complete the study at Follow-up Week 48.
The investigator should consider to re-start NA treatment per local standard of care at the EOS visit
([Extended] Follow-up Week 48) for participants who met the NA treatment completion criteria at Week
48 or during the follow-up phase, who did not re-start NA treatment during the follow-up phase, and who
did not achieve and maintain HBsAg seroclearance. NA will not be provided by the sponsor after the final
study visit.
If a participant prematurely discontinues investigational intervention  (before Week 48), follow-up
assessments should be obtained as per the Schedule of Activities until 48 weeks after the end of
investigational intervention unless the participant withdraws consent. In this case, NA treatment may be
continued or, in consultation with the sponsor, discontinued, based on the above-mentioned NA treatment
completion criteria.
NA Re-treatment Criteria and Monitoring After Stopping of NA
Participants who meet the NA treatment completion criteria outlined above will be monitored closely
during the follow-up phase.
After stopping NA treatment, participants should be monitored as follows:
 
Regular monitoring visits will be every 4 weeks during the follow-up phase in accordance with the
Schedule of Activities.
 
A post-treatment HBV DNA value of >20,000 IU/mL should trigger re-testing of ALT/AST, HBV
DNA, and total and direct bilirubin within a maximum of 7 days from receipt of the data and further
repeats as necessary (ie, weekly until HBV DNA returns to <20,000 IU/mL).
 
A post-treatment HBV DNA value of >2,000 IU/mL (but <20,000 IU/mL) should trigger a re-test
within 14 days from receipt of the data and further repeats as necessary (ie, every other week until
HBV DNA returns to <2,000 IU/mL).
 
A post-treatment ALT value of >5x ULN should trigger re-testing of ALT, AST, ALP, total and
direct bilirubin, International Normalized Ratio (INR), albumin, and HBV DNA on a weekly basis
until ALT and AST levels have returned to <5x ULN.
After stopping NA treatment, participants should re-start NA treatment:
 
Immediately with signs of decreasing liver function based on laboratory findings (eg, INR, direct
bilirubin) or clinical assessment (eg, ascites, hepatic encephalopathy).
 
Immediately with an HBV DNA value of >100,000 IU/mL (irrespective of confirmation and/or ALT
increase).
 
With confirmed post-treatment HBeAg seroreversion (HBeAg positive after it was negative at NA
completion).
 
With confirmed* post-treatment increases in HBV DNA >2,000 IU/mL and ALT >5x ULN.
 
With confirmed* post-treatment increases in HBV DNA >20,000 IU/mL.
*At least 4 weeks apart –frequency of visits as described above
Note: Additional re-testing and/or earlier restarting of NA treatment is at the investigator’s discretion,
even if the above cut-offs are not yet met.
To avoid delays in decision making, sites are encouraged to run local re-testing in parallel with central re-
testing in the situations described above that require more frequent re-testing. Local test results are to be
recorded in the CRF and/or source documents, including information on the HBV DNA assay used. In
NCT03982186

JNJ-73763989 and JNJ-56136379
Clinical Protocol 73763989HPB2001 AMENDMENT 4
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
11
Status: Approved,  Date: 24 November 2021
addition, to avoid delays in NA re-treatment, it should be considered to dispense NA to participants who
potentially met the NA re-treatment criteria (eg, pending confirmation) and who will not be available to
come to the study site immediately at the time the confirmatory test results will become available. This
should ensure that the participant can immediately re-start NA treatment if indicated, upon direct
confirmation by the investigator.
In case NA treatment is re-started, participants will be followed until the end of the study or until clinical
stabilization, whichever comes later.
Management of intervention-emergent ALT/aspartate aminotransferase (AST) elevations is discussed
below.
NUMBER OF PARTICIPANTS
A target of 450 male and female participants will be randomized.
NCT03982186

JNJ-73763989 and JNJ-56136379
Clinical Protocol 73763989HPB2001 AMENDMENT 4
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
12
Status: Approved,  Date: 24 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 
100 mg once 
every 4 weeks 
(Arms 1 and 3) 
200 mg once 
every 4 weeks 
(Arm 2)
40 mg once every 
4 weeks (Arm 4) 
0.5 mL once 
every 4 weeks 
(Arms 5 and 6) 
250 mg qd 
(Arms 1 
and 5) 
qd 
(Arms 2, 3, 4, 
and 6) 
Nucleoside-naïve 
patients:
0.5 mg qd
Lamivudine-
refractory patients:
1 mg* qd (but should
preferably be treated
with TDF or TAF
instead)
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.
NCT03982186

JNJ-73763989 and JNJ-56136379
Clinical Protocol 73763989HPB2001 AMENDMENT 4
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
13
Status: Approved,  Date: 24 November 2021
EFFICACY EVALUATIONS
Qualitative and quantitative HBsAg and HBeAg, and quantitative hepatitis B core-related antigen
(HBcrAg) as well as anti-HBs and anti-HBe antibodies will be determined using standard commercially
available serologic assays in a central laboratory. Samples for the determination of HBsAg and HBeAg
will be processed in real-time. Samples for the determination of HBcrAg can be analyzed in batch and at
the sponsor’s discretion.
HBV DNA and HBV RNA will be quantified at central laboratories using commercially available in vitro
nucleic acid amplification tests for the quantification of HBV DNA and HBV RNA. Samples for the
determination of HBV DNA will be processed in real-time. Samples for the determination of HBV RNA
can be analyzed in batch and at the sponsor’s discretion.
In participants enrolled at a site with an on-site Fibroscan device, Fibroscan assessments will be
performed to determine changes in fibrosis.
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 identify pre-existing baseline polymorphisms and to
evaluate emergence of mutations associated with JNJ-3989, JNJ-6379, and/or NA treatment.
Patient-reported Outcomes
The impact of study intervention on participants’ health-related quality of life (HRQoL), self-stigma
level, and impression of change will be assessed using patient-reported outcomes (PROs). The following
PRO instruments will be used: the Hepatitis B Quality of Life (HBQOL) scale, an HBV-specific
self-stigma PRO scale, and the Patient Global Impression of Change (PGIC) scale. Patient-reported
outcome data collected may also be used by the sponsor for additional exploratory assessments analyzing
the effect of study intervention on HRQoL, self-stigma, and impression of change, and for assessing the
psychometric properties of the PRO instruments.
SAFETY EVALUATIONS
Safety and tolerability will be assessed throughout the study from the time that the informed consent form
is signed until completion of the last study-related activity, which may include contact for follow-up of
safety. The evaluations of safety and tolerability will include monitoring of (S)AEs, physical
examinations (including body weight), vital signs measurements, triplicate 12-lead ECGs, and clinical
laboratory tests (including hematology, blood biochemistry, blood coagulation, urinalysis, urine
chemistry, and renal biomarkers). Any clinically relevant changes occurring during the study must be
recorded in the AE section of the case report form.
Specific toxicity management plans in line with the known pharmacological profile of the study
intervention (and the drug classes) evaluated in this study are implemented.
Management of Intervention-emergent ALT/AST Elevation
Elevated liver enzyme activity can be triggered by the underlying HBV disease as well as by the study
intervention.
Any intervention-emergent elevation of ALT  and/or aspartate aminotransferase (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, alkaline phosphatase (ALP),
NCT03982186

JNJ-73763989 and JNJ-56136379
Clinical Protocol 73763989HPB2001 AMENDMENT 4
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
14
Status: Approved,  Date: 24 November 2021
bilirubin (total and direct), INR, albumin, and HBV DNA. 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, investigational intervention should be discontinued. In both cases, NA treatment should be
continued. The participant will be monitored on a weekly basis until ALT  and/or AST  levels have
returned to 50% of the maximal value.
If the ALT and/or AST level is ≥3x ULN and ≥3x nadir and is associated with any of the following
laboratory results or clinical symptoms:
 
INR ≥1.5, OR
 
direct bilirubin >1.5x ULN, OR
 
serum albumin <3.0 g/dL, OR
 
ascites, hepatic encephalopathy, or liver-related symptoms (eg, severe fatigue, nausea, vomiting,
right upper quadrant pain in the absence of an alternative medical explanation), OR
 
other indication of reduced liver function
the participant should discontinue investigational intervention and should be monitored on a weekly basis
or as per good clinical practice until ALT and/or AST levels have returned to 50% of the maximal value
and, if present, liver-related symptoms have improved. NA treatment should be continued.
For the NA re-treatment criteria during follow-up, see above.
PHARMACOKINETIC EVALUATIONS
Plasma concentration-time data for JNJ-3989 (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 parameter will be the area of the concentration-time curve over the dosing
interval (tau) at steady-state (AUCtau). 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.
PHARMACOKINETICS/PHARMACODYNAMICS
Relationships of individual PK parameters (intensive PK and population PK, as applicable) for JNJ-3989
(JNJ-3976 and JNJ-3924) and/or JNJ-6379 and/or NA, as applicable, with selected efficacy and/or with
selected safety endpoints will be evaluated, if applicable.
IMMUNE EVALUATIONS
At selected sites, peripheral blood mononuclear cell (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
NCT03982186

JNJ-73763989 and JNJ-56136379
Clinical Protocol 73763989HPB2001 AMENDMENT 4
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
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Status: Approved,  Date: 24 November 2021
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 blood sample will be collected from participants who consent separately to this
component of the study to allow for pharmacogenomic research, as necessary (where local regulations
permit).
In addition, other samples may be used for exploratory genetic 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. Samples can only be
used to investigate the potential association of host genetic factors with efficacy, safety, or PK of study
intervention, or HBV infection, or may be used to develop tests/assays related to study intervention or
HBV infection.
HOST BIOMARKERS
The study includes collection of blood samples for exploratory analysis of host blood biomarkers at the
host RNA, protein, and cell level.
Samples can only be used for research related to study intervention or HBV infection or may be used to
develop tests/assays related to study intervention or HBV infection.
Blood samples will be taken that can be used to explore immunogenicity of JNJ-3989. The emergence of
antibodies to JNJ-3989 (antidrug antibodies) might be analyzed using assays such as an enzyme-linked
immunosorbent assay.
STATISTICAL METHODS
The primary analysis will be performed at the time when all participants have completed Week 48 or
discontinued earlier. The final analysis will be performed when all participants have completed the last
study visit or discontinued earlier.
Statistical Hypotheses
Based on the primary efficacy endpoint, the proportion of participants meeting the NA treatment
completion criteria at Week 48, the primary hypotheses are as follows:
 
There is a positive dose-response signal across the 3 doses of JNJ-3989 (40, 100, and 200 mg) on the
background of NA compared with NA treatment alone (control Arm 6).
 
One or both combination regimens JNJ-3989+JNJ-6379+NA and JNJ-6379+NA are more
efficacious than NA treatment alone (control Arm 6).
 
The combination regimen of JNJ-3989 (100 mg)+JNJ-6379+NA is more efficacious than JNJ-3989
(100 mg)+NA and/or JNJ-6379+NA combination regimens.
After a positive dose-response signal is established with statistical significance using the Multiple
Comparison Procedure-Modeling (MCP-Mod) approach, then the testing procedure continues in a fixed
sequence, with the comparison of Arm 1 (JNJ-3989+JNJ-6379+NA) with control Arm 6
(Placebo+Placebo+NA) at a one-sided alpha of 0.05. If Arm 1 is found statistically superior to control
Arm 6, then the combination regimen JNJ-6379+NA (Arm 5) is compared to control Arm 6 at
0.05 one-sided alpha level.
NCT03982186

JNJ-73763989 and JNJ-56136379
Clinical Protocol 73763989HPB2001 AMENDMENT 4
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
16
Status: Approved,  Date: 24 November 2021
For the comparisons among regimens (Arm 1, 3, and 5), the statistical testing will control for the
one-sided Type I error of 0.05 separately and independently from the comparisons against the control arm
described above. The testing among the regimens (Arm 1, 3, and 5) will be performed using the min test
approach. The JNJ-3989+JNJ-6379+NA  (Arm 1) combination regimen will be declared statistically
superior to the dual regimens (Arm 3 and 5) if both tests of Arm 1 vs Arm 3 and Arm 1 vs Arm 5
demonstrate statistical significance at the one-sided 0.05 level.
Sample Size Determination
The total study sample size is 450 participants with a 2:2:2:2:1:1 randomization ratio, where
90 participants will be randomly allocated to each of the arms including a JNJ-3989 dose (Arms 1 to 4)
and 45 participants will be randomly assigned to each of the arms with no JNJ-3989 component (Arms 5
and 6). Statistical power to test a dose-response signal was assessed using the generalized version of the
MCP-Mod applied to the binary primary efficacy endpoint on the logit scale using data from Arms 2, 3,
and 4 (JNJ-3989 at 200, 100, and 40 mg dose, respectively +NA), and Arm 6 (Placebo+Placebo+NA) as
control.
The power to conclude a positive dose-response trend over the 3 JNJ-3989 doses on the background of
NA is ≥85% under all 5 candidate dose-response models for an absolute response rate of the highest dose
of JNJ-3989 of at least 25% (one-sided alpha level of 5%).
Assuming a response rate of 5% in control Arm 6, the sample size of 90 participants each in combination
Arms 1, 2, 3, and 4 and a sample size of 45 participants in combination Arm 5 (JNJ-6379+NA) and
control Arm 6, provides a statistical power ≥84% to detect a difference of ≥20% in the primary endpoint
between Arm 1 (JNJ-3989+JNJ-6379+NA) and control Arm 6, and power ≥76% for a difference ≥20%
between Arm 5 (JNJ-6379+NA) and control Arm 6, using a fixed sequence approach for controlling for
multiplicity.
The chosen study sample size and randomization allocation will also provide acceptable power levels for
the comparison of different combination regimens, ie, JNJ-3989+JNJ-6379+NA (Arm 1, 100-mg dose of
JNJ-3989) versus JNJ-3989+NA (Arm 3, 100-mg dose of JNJ-3989), and versus JNJ-6379+NA (Arm 5),
respectively. Based on the min test approach, Table 7 shows that the power levels vary depending on both
the rate difference between Arm 1 and Arm 3 as well as on the assumed rate for Arm 5. For example, for
the same delta of 25% between Arm 1 and Arm 3 and between Arm 1 and Arm 5, the power to observe a
statistically significant superiority of Arm 1 over the other 2 regimens is 87%.
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 any of the 6 intervention arms and received at least 1 dose of
study intervention will be included in the ITT set.
The baseline measurements are defined as the measurements taken closest to but before the first dose of
study intervention on Day 1.
Primary Efficacy Endpoint (Proportion of Participants Meeting the NA Treatment Completion Criteria
at Week 48)
A hybrid methodology that combines aspects of multiple testing with modeling techniques (MCP-Mod)
will be used for evaluating a dose-response trend and estimating the dose-response relationship of
3 JNJ-3989 doses in combination with NA versus NA treatment alone (control Arm 6).
Each of the dose-response shapes in the candidate set will be tested using the corresponding contrast t-test
statistic, employing a critical value derived for the maximum of the t-test statistics (based on the
associated multivariate t-distribution) to ensure appropriate multiplicity correction that preserves the
NCT03982186

JNJ-73763989 and JNJ-56136379
Clinical Protocol 73763989HPB2001 AMENDMENT 4
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
17
Status: Approved,  Date: 24 November 2021
one-sided Type I error rate at 0.05. A dose-response trend is established when the maximum of the t-test
statistics exceeds the critical value.
After establishing a significant dose-response signal, the testing procedures continue with the comparison
of the percentage of participants who completed the 48-week study intervention and qualified for stopping
NA treatment in Arms 1 and 5 against control Arm 6, respectively. The min test approach will be applied
to control for multiplicity of the comparisons among the combination regimens, as described above. The
Mantel-Haenszel (MH) test will be used in the pairwise comparisons at a one-sided alpha level of 0.05
adjusting for the randomization stratification factors of screening HBeAg status and treatment history.
The Wilson  test will be used at a one-sided alpha level of 0.05 with no adjustment for stratification
factors.
Key Secondary Efficacy Endpoint of Functional Cure at Week 72(HBsAg Seroclearance 24 Weeks
After Completion of All Study Intervention at Week 48)
The functional cure rate at Week 72 is defined as the proportion of participants with HBsAg seroclearance
24 weeks after completion of all study intervention at Week 48, including stopping NA treatment. It will
be used to support the JNJ-3989 dose selection and the regimen selection. The same multi-step testing
strategy as the one implemented for the primary efficacy endpoint (see above), using MCP-Mod and
additional treatment arms pairwise comparisons with NA control in a fixed sequence, as well as the min
test approach applied separately for between-regimen comparisons, will be used for this key secondary
endpoint. However, the comparisons with NA control in the testing strategy applied to this efficacy
endpoint will be made against the NA historical control benchmark of 5%, instead of the study NA
control arm (Arm 6).
To provide evidence of superior efficacy of the JNJ-3989+JNJ-6379+NA regimen against the
JNJ-3989+NA and JNJ-6379+NA combination regimens, respectively, those tests will be performed at a
one-sided 0.025 alpha level for regulatory consideration. This analysis aims to support the selection of the
combination drug therapy to be studied in confirmatory studies.
Other Secondary and Exploratory Efficacy Endpoints
Descriptive statistics will be used for all efficacy endpoints which will be summarized by intervention
arm. Comparisons among 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.
Graphic data displays will also be used to summarize the efficacy data by intervention arm and over time.
Resistance Analyses
The results of HBV viral sequencing will be evaluated by the sponsor virologist. Pretreatment amino acid
and/or nucleic acid substitutions in the HBV in all participants and relevant changes in the HBV in
participants not responding to study intervention will be tabulated and described.
Additional exploratory characterization of the HBV viral sequence and phenotype may be performed and
reported separately.
Patient-reported Outcome Analyses
Patient-reported outcome scores will be analyzed descriptively as mean scores over time, and (if
applicable) evaluated based on the proportion of participants experiencing a clinically important
improvement or worsening in PRO scores from  baseline during study intervention and follow-up.
Analyses will also be performed on PRO score changes from baseline at specific time points (Week 48,
NCT03982186

JNJ-73763989 and JNJ-56136379
Clinical Protocol 73763989HPB2001 AMENDMENT 4
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
18
Status: Approved,  Date: 24 November 2021
72, 96) and between Week 48 and later time points for different subgroups: participants who meet the NA
treatment completion criteria at Week 48 versus those who do not, and participants with versus
participants without HBsAg seroclearance 24 weeks and 48 weeks after completion of all study
intervention at Week 48.
Safety Analyses
The safety analysis set will be used for all safety analyses and includes all participants who received at
least one dose of study intervention.
The incidence of AEs will be summarized by body system and preferred term for each intervention arm
and study phase (ie, study intervention phase and follow-up phase). Values and changes from baseline
over time in clinical laboratory parameters, vital signs, and ECG parameters will be presented
descriptively (n, mean, standard deviation [SD], minimum, median, and maximum) by intervention arm.
The percentage of participants with abnormal clinical laboratory findings, vital signs, and ECG
parameters will be tabulated by intervention arm and study phase.
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-3989 (JNJ-3976 and JNJ-3924), JNJ-
6379 and/or NA, as applicable, and for the derived plasma PK parameters (noncompartmental analysis
and population PK analysis).
For each participant with intensive PK sampling, plasma concentration-time data of JNJ-3989 (JNJ-3976
and JNJ-3924), JNJ-6379, and/or 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. Pharmacokinetic parameters will be subjected to an exploratory graphical
analysis, including various transformations, to get a general overview.
Population PK analysis of plasma concentration-time data of JNJ-3989 (JNJ-3976 and JNJ-3924), JNJ-
6379, and/or NA (as applicable) will be performed using nonlinear mixed-effects modeling. Data may be
combined with those from selected studies to support a relevant structural model. Available baseline
participant characteristics (demographics, laboratory variables, genotypes, race, etc.) will be included in
the model as necessary. Individual estimates of PK parameters will be generated from the population PK
analysis for potential use in exposure-response analysis. 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-3989 (JNJ-3976 and JNJ-3924), JNJ-6379, 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.
Pharmacokinetic/Pharmacodynamic Analyses
Relationships of PK parameters for JNJ-3989 (JNJ-3976 and JNJ-3924), JNJ-6379, and/or NA (ETV,
TAF and/or tenofovir), as applicable, with selected efficacy and with selected safety endpoints will be
evaluated, applying graphical tools and, if feasible, statistical models.
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
NCT03982186

JNJ-73763989 and JNJ-56136379
Clinical Protocol 73763989HPB2001 AMENDMENT 4
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
19
Status: Approved,  Date: 24 November 2021
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 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 differences between participants. Analyses will be conducted at the sponsor’s discretion, will
always be under the sponsor’s supervision, and results will be presented either in the clinical study report
or a separate report.
Interim Analyses
Interim analyses (IAs) will be conducted to monitor safety and evaluate the time course of different
disease markers to support the sponsor’s internal decision-making, interactions with health authorities, as
well as inform decisions about additional studies and/or investigation of other treatment combinations.
The IAs are planned when:
 
All participants have completed Week 60 (ie, 12 weeks after completion of investigational
intervention at Week 48), or discontinued earlier.
 
All participants have completed Week 72 (ie, 24 weeks after completion of investigational
intervention at Week 48), or discontinued earlier.
 
All participants have completed Week 96 (ie, 48 weeks after completion of investigational
intervention at Week 48), or discontinued earlier.
One additional IA may be performed at the sponsor’s discretion when all participants, who completed NA
treatment at Week 48 of follow-up, have completed Week 120, ie, Week 24 of the extended follow-up, or
discontinued earlier, to support interactions with health authorities.
All IAs will be performed by the sponsor because occurring after the primary analysis, which will be
conducted at the time when all participants have completed Week 48 or discontinued earlier. Both
primary and interim analyses will be based on all data available at the predefined cut-off time, including
data at later time points for those participants who have reached subsequent visits.
Independent Data Monitoring Committee
An IDMC will be established for continuous monitoring of SAEs, AEs leading to discontinuation, and
ALT flares. In addition, the IDMC will review the unblinded results of the efficacy parameters measured
by different HBV disease blood markers (eg, HBV DNA, HBeAg, HBsAg, etc).
The IDMC will have access and use the totality of unblinded results to make recommendations, including
all safety and efficacy assessments available at a given interim milestone. Possible recommendations
include, but are not limited to, stopping the study or any of the study interventions for safety concerns.
The Sponsor Committee will review the time course of the different HBV disease blood markers to make
further decisions. Decision rules will be detailed and listed in the IDMC charter and will be non-binding.
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Status: Approved,  Date: 24 November 2021
Independent Flare Expert Panel
An IFLEP  will also be appointed. The IFLEP  is composed of 3 independent medical experts with
experience and expertise in hepatitis B and its treatment. The IFLEP  will monitor ALT flares and will
make recommendations regarding flare management based on an analysis of aggregate data.
In order to allow for an unbiased assessment, members of the committee will not serve as study
investigators or as members of the IDMC and will be blinded to the treatment assigned to each
participant.
Further details on the IFLEP process will be included in the IFLEP charter.
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Status: Approved,  Date: 24 November 2021
1.2. 
Schema
Figure 1: 
Schematic Overview of the Study
FU=follow-up; NA=nucleos(t)ide analog; IA=interim analysis; PA=primary analysis
*Participants not meeting NA treatment completion criteria at Week 48 continue NA treatment during follow-up
unless NA treatment completion criteria are met. HBsAg levels and NA treatment completion criteria will be
re-assessed at every follow-up visit.
**If NA treatment is completed during follow-up (based on NA treatment completion criteria), the follow-up
schedule will be extended to 48 weeks after the end of NA treatment.
Doses: JNJ-3989 40 mg, 100 mg, or 200 mg once every 4 weeks, JNJ-6379 250 mg qd, NA (ETV, TDF, or TAF)
according to the prescribing information.
Notes:
- 
After completing this study, participants may be invited to enroll into a long-term follow-up study.
- 
One additional IA may be performed at the sponsor’s discretion when all participants, who completed NA
treatment at Week 48 of follow-up, have completed Week 120, ie, Week 24 of the extended follow-up, or
discontinued earlier, to support interactions with health authorities.
- 
At Week 48 or at time of early discontinuation, it will be communicated to the investigators whether the
participants were allocated to either an investigational arm (Arms 1 to 5) or the control arm (Arm 6) to
allow the correct follow-up visit schedule to be followed (see Schedule of Activities). Only at Week 72,
randomization codes (for Arms 1 to 5) will be fully disclosed to the investigators. The sponsor will be fully
unblinded for the primary analysis at Week 48.
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Clinical Protocol 73763989HPB2001 AMENDMENT 4
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Status: Approved,  Date: 24 November 2021
j. 
Participants must have absence of signs of HCC or clinically relevant renal abnormalities on an abdominal ultrasound performed within 6 months prior to
screening or at the time of screening. In case of suspicious findings on conventional ultrasound the participant may still be eligible if HCC or clinically relevant
renal abnormalities have been ruled out by a more specific imaging procedure (contrast enhanced ultrasound, CT or MRI).
k. 
HBV genotype will be determined at baseline using standard genotyping assay if HBV DNA levels are sufficiently high. For participants with low HBV DNA
levels, available historical data on previous HBV genotype assessment will be collected in the CRF. Exploratory genotyping assays might be performed.
l. 
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.
m. At Week 48 or at time of early discontinuation, it will be communicated to the investigators whether the participants were allocated to either an investigational arm
(Arms 1 to 5) or the control arm (Arm 6). Only at Week 72, randomization codes (for Arms 1 to 5) will be fully disclosed to the investigators. The sponsor will be
fully unblinded for the primary analysis at Week 48.
n. 
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.
o. 
NA will be dispensed at Week 48 in case the participant does not meet the NA treatment completion criteria.
p. 
If the NA treatment completion criteria are met based on clinical laboratory tests performed at Week 44, treatment with NA will be completed at Week 48.
q. 
Complete physical examination, including height (at screening only), body weight, skin examination, and other body systems.
r. 
Symptom-directed physical examination, including body weight.
s. 
Vital signs include supine SBP, DBP, pulse rate, and body temperature.
t. 
All ECGs will be read centrally. Only on Day 1, an ECG will be collected and assessed locally prior to dosing. 
u. 
Biochemistry samples must be taken after fasting for at least 10 hours for measurement of phosphate, calcium, creatinine, and lipids.
v. 
Creatinine clearance (eGFR calculated by the CKD-EPI formula) will be assessed.
w. 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 ofthe 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 8.3.6.1
Intervention-emergent ALT/AST Elevations and Section 10.6 Appendix 6: Intervention-emergent ALT/AST Elevations.
x. 
Urine chemistry sample (quantitative measurement): creatinine, sodium, phosphate, glucose, protein, and albumin.
Urinalysis by dipstick: specific gravity, pH, glucose, protein, blood, ketones, bilirubin, urobilinogen, nitrite, leukocyte esterase, and microscopic analysis if needed.
In case of a positive dipstick result, a urine sample will be set aside for additional examination of the positive parameter at the central laboratory (eg, quantification
as applicable).
y. 
Urine sample for selected renal biomarkers including retinol binding protein and beta-2-microglobulin.
z. 
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.
aa. HBcrAg and HBV RNA samples may be batched and only selected samples may be tested at the sponsor’s discretion. Samples can be used for assessment of other
serologic/virologic markers of HBV.
bb. Sequencing at baseline (Day 1 predose) will be performed by default if HBV DNA levels are within the ranges required for the sequencing assay; other samples
may be sequenced based on the sponsor virologist’s request.
cc. Participants with undocumented (ie, no lab report) HBeAg status as part of their medical history must first complete HBeAg testing and have results reviewed by
the investigator to confirm if they qualify for study participation. Documented HBeAg status within 12 months prior to screening is acceptable.
dd. Quantitative HBeAg assessment will only be performed in participants who are defined HBeAg-positive at screening based on a qualitative HBeAg assay.
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JNJ-73763989 and JNJ-56136379
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Status: Approved,  Date: 24 November 2021
ee. Exploratory serology samples may be analyzed at the sponsor’s discretion. Samples may be used to assess virologic or serologic markers of HBV.
ff. 
All participants will have sparse PK sampling. For all samples, the time of the preceding 2 intakes of oral study intervention (JNJ-6379/placebo and NA) and the
time of PK sampling should be recorded. Sparse PK sampling is not required ifthe participant is part of the intensive PK subgroup and has an intensive PK
sampling at the same visit.
gg. 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.
hh. Only in case of early withdrawal.
ii. 
All participants who consent to participate in the intensive PK subgroup (optional) will undergo intensive PK sampling at Week 4. If necessary (eg, for operational
reasons), this visit may be scheduled at Week 8, 12, or 16. The study intervention should be taken on site and time of dosing should be recorded. Pharmacokinetic
samples will be taken predose and 15 minutes, 30 minutes, 1, 2, 3, 4, 6, 8,* 10,* and 24 hours postdose (*the 8 and 10 hours postdose samples are optional). All
efforts will be made to obtain the PK samples at the exact nominal time relative to dosing. However, samples obtained within 20% of the nominal time from dosing
(eg, within +/- 12 minutes of a 60-minute time point) will not be captured as a protocol deviation if the exact time of the sample collection is noted on the source
document and CRF.
jj. 
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, which
may require an unscheduled visit.
kk. The pharmacogenomic (DNA) sample should preferably be collected at baseline. This sample is optional and will only be collected from participants who consent
separately to this component of the study.
ll. 
PRO assessments will be performed by participants at sites where appropriate translations are available.
mm. A liver ultrasound is performed every 24 weeks from Day 1 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).42
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Status: Approved,  Date: 24 November 2021
b. 
Participants who withdraw consent during follow-up will be offered an optional safety follow-up visit to occur on the day of consent withdrawal. For the optional
safety follow-up visit, assessments are at the investigator’s discretion and could be similar to the early WD visit.
c. 
Participants in Arms 1 to 6 who discontinue NA treatment at Week 48 will be monitored more frequently, with a study visit at least once every 4 weeks. In case
NA re-treatment criteria are met, participants will switch to less frequent follow-up, provided that their HBV DNA and ALT values are stable.
d. 
If NA treatment completion criteria are met based on clinical laboratory tests performed at or before FU W42 (FU W36 for Arm 6 [NA continued]), NA treatment
should be stopped at or before Follow-up Week 48 (ie, the next scheduled visit after the laboratory test was performed) and the follow-up phase will be extended to
48 weeks after the end of NA treatment. If NA treatment completion criteria are not met based on clinical laboratory tests performed at or before FU W42
(FU W36 for Arm 6), the follow-up phase will not be extended, but the participant will continue NA treatment and complete the study at FU W48.
e. 
No JNJ-3989/JNJ-6379/placebo will be administered or dispensed during follow-up. Administration/Dispensation of NA is only applicable for participants who did
not meet the NA treatment completion criteria yet, or for those who met the NA re-treatment criteria. In between study visits, participants will take NA at home
and they will bring their NA treatment with them to each study visit. At study visits, the NA treatment should be taken on site.
f. 
For participants who take NA during follow-up.
g. 
Symptom-directed physical examination, including body weight.
h. 
Vital signs include supine SBP, DBP, pulse rate, and body temperature.
i. 
All ECGs will be read centrally.
j. 
Biochemistry samples must be taken after fasting for at least 10 hours for measurement of phosphate, calcium, creatinine, and lipids.
k. 
Creatinine clearance (eGFR calculated by the CKD-EPI formula) will be assessed.
l. 
ALT/AST elevations (ie, ALT and/or AST ≥3x ULN and ≥3x nadir [ie, lowest value during study participation]), should trigger an assessment of confounding
factors (alcohol intake, change in concomitant medication, and comorbidities)and a confirmatory visit, to be scheduled preferably within 7 days ofthe 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 8.3.6.1 Intervention-emergent ALT/AST
Elevations and Section 10.6 Appendix 6: Intervention-emergent ALT/AST Elevations.
m. Liver function tests only.
n. 
Urine chemistry sample (quantitative measurement): creatinine, sodium, phosphate, glucose, protein, and albumin.
Urinalysis by dipstick: specific gravity, pH, glucose, protein, blood, ketones, bilirubin, urobilinogen, nitrite, leukocyte esterase, and microscopic analysis if needed.
In case of a positive dipstick result, a urine sample will be set aside for additional examination of the positive parameter at the central laboratory (eg, quantification
as applicable).
o. 
Urine pregnancy tests for at-home use will be provided to the participants from (Extended) Follow-up Week 24 onwards as urine pregnancy test should be done at
least every 4 weeks. Results will be reported at the next visit. If a urine pregnancy test is positive, the investigator needs to be informed immediately by the
participant.
p. 
Only applicable to participants who are enrolled at a site with an on-site Fibroscan device.
q. 
HBcrAg and HBV RNA samples may be batched and only selected samples may be tested at the sponsor’s discretion. Samples can be used for assessment of other
serologic/virologic markers of HBV.
r. 
Samples may be sequenced based on the sponsor virologist’s request.
s. 
Exploratory serology samples may be analyzed at the sponsor’s discretion. Samples may be used to assess virologic or serologic markers of HBV.
t. 
PBMC samples may be collected at selected sites only. Additional PBMC samples may be taken in case of ALT flares, upon discussion with the sponsor, which
may require an unscheduled visit.
u. 
PRO assessments will be performed by participants at sites where appropriate translations are available.
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Status: Approved,  Date: 24 November 2021
v. 
A liver ultrasound is performed every 24 weeks from start of FU 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). Liver ultrasound evaluations for participants with increased risk of HCC should be
continued also every 24 weeks relative to baseline for participants who participate in the extended follow-up period.42
w. The investigator should consider to re-start NA treatment per local standard of care at the EOS visit ([Extended] Follow-up Week 48) for participants who met the
NA treatment completion criteria at Week 48 or during the follow-up phase, who did not re-start NA treatment during the follow-up phase, and who did not
achieve and maintain HBsAg seroclearance. NA will not be provided by the sponsor after the final study visit.
x. 
NA treatment should be re-started in accordance with the NA re-treatment criteria (see Section 6.7, NA Re-treatment Criteria and Monitoring After Stopping of
NA and Section 10.14 Appendix 14, for guidance after stopping NA treatment).
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Status: Approved,  Date: 24 November 2021
2. 
INTRODUCTION
Chronic Hepatitis B Infection
Hepatitis B virus (HBV) is a small deoxyribonucleic acid (DNA) virus that specifically infects
the human liver. It consists of a nucleocapsid in which the viral DNA is packed with hepatitis B
core protein (HBc) and a membraneous envelope containing hepatitis B surface antigen
(HBsAg). The acute phase of the infection (less than 6 months) is either followed by an immune
controlled state (spontaneous cure from the infection) or progresses to chronic hepatitis B (CHB)
(more than 6 months). Chronic HBV infection may lead to serious illnesses such as liver
cirrhosis and decompensation, and hepatocellular carcinoma (HCC), often with fatal outcome.35
The worldwide estimated prevalence of chronic HBV infection is 4.9% with about 292 million
people affected.29 Despite the availability of an efficacious prophylactic vaccine, yearly rates of
new infections remain high. Approximately 680,000 people per year worldwide die from
cirrhosis and HCC due to CHB.33
The natural course of HBV infection is the consequence of a complex interaction between the
virus and the host which in the chronic setting might evolve over a duration of decades. This is
associated with different disease phases or stages. The European Association for the Study of the
Liver (EASL) guidelines differentiate between chronic infection and chronic hepatitis (Table 1).
Table 1: 
Various Stages of HBV Infection –Terminology and Characteristics (EASL 2017)7
HBeAg-positive 
HBeAg-negative
Chronic infection Chronic hepatitis 
Chronic infection  Chronic hepatitis
HBsAg 
High  
High/intermediate 
Low  
Intermediate
HBeAg 
Positive 
Positive 
Negative 
Negative
HBV DNA  
>107 IU/mL 
104-107 IU/mL 
<2,000 IU/mL°° 
>2,000 IU/mL
ALT  
Normal 
Elevated 
Normal 
Elevated*
Liver disease 
None/minimal 
Moderate/severe 
None 
Moderate/severe
Old 
terminology  
Immune tolerant 
Immune reactive 
HBeAg-positive 
Inactive carrier 
HBeAg-negative chronic
hepatitis
ALT: alanine aminotransferase; DNA: deoxyribonucleic acid; EASL: European Association for the Study of the Liver;
HBeAg: hepatitis B e antigen; HBsAg: hepatitis B surface antigen; HBV: hepatitis B virus; IU/mL: International Units Per
Millilitre
*Persistently or intermittently. °°HBV deoxyribonucleic acid (DNA) levels can be between 2,000 and 20,000 IU/mL in some
patients without signs of chronic hepatitis.
Note that different definitions and naming of HBV disease phases may be used across different countries/regions.
According to the EASL treatment guidelines, the primary treatment goal for patients with CHB
is to improve survival and quality of life by preventing progression of liver disease, particularly
to cirrhosis, liver failure, and HCC. Risk factors associated with progression to advanced liver
disease are persistently elevated levels of HBV DNA and liver enzymes such as alanine
aminotransferase (ALT) in blood, male sex, older age, coinfection with hepatitis D virus (HDV),
hepatitis C virus (HCV), or human immunodeficiency virus (HIV), and coexistence of other liver
diseases (particularly fatty liver disease).6,7
Irrespective of the hepatitis B e antigen (HBeAg) status, antiviral therapy is recommended for all
patients with signs of active chronic hepatitis.3,7,30,35 Approved therapies for CHB are pegylated
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Status: Approved,  Date: 24 November 2021
interferon  (IFN) alpha and nucleos(t)ide analog inhibitors (ie, nucleos[t]ide analog [NA]
treatment) of the HBV polymerase/reverse transcriptase, the enzyme synthesizing HBV DNA
from pre-genomic ribonucleic acid (pgRNA).
Oral treatment with NAs is effective at suppressing viral DNA formation and lowering virus
concentration in the blood to levels below the lower limit of quantification (LLOQ) of the HBV
DNA assays commonly used. This is associated with normalization of liver enzymes and reduced
or halted progression of liver disease to cirrhosis and/or decompensation and even with
regression of cirrhotic transformation.5,17,22,25,38 While the risk of HCC development is reduced
as well, it is not eliminated.17,22,25
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”.21
Unfortunately, with currently available NA treatment strategies the rate of HBsAg seroclearance
remains very low (around 3%)even under long-term treatment.
Pegylated IFN is associated with a slightly higher rate of HBsAg seroclearance compared to NAs
and is recommended for a fixed treatment duration of 48 weeks, but is administered
subcutaneously and is associated with higher toxicity than NAs.27
With the low rate of functional cure with current treatments, and persistently high global
prevalence of HBV-associated mortality,7,35 there is a medical need for more effective finite
treatment options that lead to sustained HBsAg seroclearance ("functional cure"). In order to
achieve an effective finite treatment, combination of therapies with different mechanisms of
action, as is standard of care for other chronic viral infections like HCV and HIV, is deemed
required.
JNJ-73763989 and JNJ-56136379
JNJ-73763989 (JNJ-3989) is a liver-targeted antiviral therapeutic for subcutaneous injection
designed to treat chronic 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 pgRNA,
the precursor of viral relaxed circular DNA. The RNAi triggers in JNJ-3989 injection 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 HBsAg in HBeAg-negative patients or patients on
long-term treatment with NAs, the current standard of care.37
JNJ-56136379 (JNJ-6379) is an orally administered capsid assembly modulator (CAM) that is
being developed for the treatment of chronic HBV infection. JNJ-6379 binds to HBc and
interferes with the viral capsid assembly process, thereby preventing the polymerase-bound
pgRNA encapsidation. This results in the formation of HBV capsids, devoid of HBV DNA or
RNA (non-functional capsids), and ultimately in the inhibition of HBV replication. In addition,
JNJ-6379 also acts at an early stage of the viral life cycle by inhibiting the de-novo formation of
cccDNA potentially by interfering with the capsid disassembly process.
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JNJ-73763989 and JNJ-56136379
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Status: Approved,  Date: 24 November 2021
For the most comprehensive nonclinical and clinical information regarding JNJ-3989 and
JNJ-6379, refer to the latest version of the Investigator's Brochure (IB) and Addenda.13,14,15
The term “study intervention” throughout the protocol, refers to JNJ-3989 or placebo, JNJ-6379
or placebo, 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".
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 HCC) comparable to those achieved by patients with
self-limited HBV infection.
The efficacy and safety of finite treatment duration will be assessed with a fixed 48-week
treatment duration for JNJ-3989 and/or JNJ-6379 (in combination with NA treatment). The aim
is to also complete NA treatment after 48 weeks, based on pre-specified response criteria
outlined in Section 6.6.
The main goal of the study is to evaluate efficacy as measured by the proportion of participants
who completed 48-week study intervention and qualified for stopping NA treatment at Week 48.
In addition, off-treatment HBsAg seroclearance during follow-up (with focus on Follow-up
Weeks 24 and 48) as well as other measures for off-treatment (ie, HBV DNA suppression in the
presence of low HBsAg levels) and on-treatment response (eg, the kinetics of HBV DNA,
HBsAg and of other viral markers) will be assessed.
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 pharmacokinetics (PK) and toxicology studies are (being)
conducted for the combination.
JNJ-3989
Little potential for off-target inhibition of human gene expression in participants is expected,
based on in silico human genome database screening.
The nonclinical safety profile of JNJ-3989 has been evaluated through a series of in vitro and in
vivo studies. Repeat-dose subcutaneous toxicity studies of 2 weeks up to 24 or 37 weeks were
conducted in rat and monkey, respectively. In the 2-week studies, JNJ-3989 was administered
once weekly via subcutaneous injection at 30 up to 300 mg/kg. In the 24- or 37-week studies,
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Status: Approved,  Date: 24 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 study 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.16 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.16 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
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Status: Approved,  Date: 24 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 from EFD studies in pregnant
rats and rabbits, and human exposures after a single subcutaneous injection of 400 mg JNJ-3989
in human volunteers (Study AROHBV1001)(Table 2).
Table 2: 
Animal/Human Exposure Ratios at NOAEL for JNJ-3989
Sex 
NOAEL  
(mg/kg) 
C max 
(ng/mL) 
AUC  
b
(ng.h/mL) 
Ratio Total Concentration
Cmax 
A/H Ratio 
AUCb
A/H Ratio
JNJ-3976
Human exposure a 
4,282 
64,529 
- 
-
24-week 
ratc 
M 
41,100 
437,000 
9.6 
6.8
F 
43,100 
270,000 
10.1 
4.2
37-week 
monkeyd 
M 
73,200 
1,230,000 
17.1 
19.1
F 
65,800 
988,000 
15.4 
15.3
EFD rat 
F 
48,000 
501,000 
11.2 
7.8
EFD rabbit 
F 
26,600 
252,000 
6.2 
3.9
JNJ-3924
Human exposure a 
1,010 
14,771
24-week 
ratc 
M 
25,200 
271,000 
25.0 
18.3
F 
26,200 
163,000 
25.9 
11.0
37-week 
monkeyd 
M 
21,600 
383,000 
21.4 
25.9
F 
23,000 
392,000 
22.8 
26.5
EFD rat 
F 
31,200 
324,000 
30.9 
21.9
EFD rabbit 
F 
13,900 
133,000 
13.8  
9.0
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; EFD: embryofetal development; F: female;
M: male; NOAEL: no observed adverse effect level.
a 
single dose of 400 mg JNJ 3989 in healthy volunteers via subcutaneous injection (Study AROHBV1001).
b
AUC0-last for human exposure; AUC0-24h for animal exposures
c
once weekly dosing for 5 weeks, followed by once monthly dosing up to a total of24 weeks
d
once weekly dosing for 5 weeks followed by once monthly dosing, up to a total of 37 weeks
e
daily dosing during organogenesis (GD6 17 in pregnant rats and GD6 19 in pregnant rabbits)
JNJ-6379
Following 6 months of treatment in rats, the kidney and female reproductive tract (irregular
estrus 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 estrus cycle, from which they recovered at the end of the 9-week treatment-free period.
These irregular estrus 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.
CCI
NCT03982186

JNJ-73763989 and JNJ-56136379
Clinical Protocol 73763989HPB2001 AMENDMENT 4
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
37
Status: Approved,  Date: 24 November 2021
In the 9-month dog study, the target organs identified were the adrenal glands and bone marrow.
The adrenal glands did not show degenerative changes or loss of function and were therefore
considered as non-adverse target organs. One female dog out of 4 dosed at 25 mg eq./kg/day (the
highest dose) was sacrificed on Day 61, after showing poor health condition. A JNJ-6379 plasma
level of 42,000 ng/mL was observed for this animal on Day 61, at approximately 24 hours after
last dosing. Pronounced clinical pathologic changes, including pancytopenia, were noted.
Marked increase in plasma cell-like cells was seen in the bone marrow during histopathologic
examination, resulting in a marked reduction of hematopoietic tissue and extramedullary
hematopoiesis in liver and spleen. The cause of the deteriorating condition was likely related to
changes in the bone marrow. A second dog in the same dose group with pancytopenia recovered
after a drug holiday and was re-exposed uneventfully.
In the EFD studies, JNJ-6379 was not teratogenic in rats and rabbits.
JNJ-6379 was not genotoxic in the in vitro micronucleus and Ames tests, and in the in vivo
micronucleus tests in rats.
Animal/human ratios at the NOAEL in rat and dog for human exposure at 250 mg JNJ-6379
once daily (qd) for 28 days are displayed in Table 3.
Table 3: 
Animal/Human Ratios at the NOAEL in Rat and Dog (Human Exposure at 250 mg
JNJ-56136379 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%).
CCI
CCI
NCT03982186

JNJ-73763989 and JNJ-56136379
Clinical Protocol 73763989HPB2001 AMENDMENT 4
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
38
Status: Approved,  Date: 24 November 2021
JNJ-3989 and JNJ-6379
A combination 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  (TOX13609) is
completed in male and female rats.
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, two 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.
Final data from the 28-day combination toxicity study in the rat are available (TOX13609). In
the 1-month combination study, JNJ-3989 was administered weekly via SC 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. JNJ-6379 was administered daily via oral gavage at a dose level of 100
mg/kg. Control animals received both vehicles via the respective routes.
JNJ-3989-related findings at 180 mg/kg included increased vacuolation of hepatocytes and/or
Kupffer cells, with correlating macroscopic pale discoloration and prominent lobular
architecture, single cell necrosis, increased mitosis, karyomegaly of low incidence in females,
and/or hypertrophy/hyperplasia of bile ducts  of low incidence in males in the liver, vacuolation
and basophilic granules in tubular epithelium of the kidney, macrophage vacuolation in lymph
nodes and/or sinus histiocytosis (mesenteric, axillary and/or popliteal), and mixed cell infiltrate
and infiltration of vacuolated macrophages with basophilic stippling in the administration site.
At 30 mg/kg increased vacuolation and increased mitosis in the liver, and mixed cell infiltrate in
the administration site with infiltration of vacuolated macrophages and basophilic stippling were
seen.
A minor increase in incidence and severity of decreased lymphoid cellularity in the thymus with
lower thymus weights was seen in females in the 180/100 mg/kg group, compared to what was
seen with the single agent JNJ-6379. The thymic change was considered non-adverse based on
the minor severity. All remaining findings in the groups dosed with  the combination of test
articles were in line with the findings recorded for the groups dosed with the single compounds.
Exposure to JNJ-6379 in terms of Cmax  and AUC0 24h  did not change significantly when dosed
together with JNJ-3989 vs. when dosed as a single agent. Exposure to both analytes of JNJ-3989
NCT03982186

JNJ-73763989 and JNJ-56136379
Clinical Protocol 73763989HPB2001 AMENDMENT 4
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
39
Status: Approved,  Date: 24 November 2021
in terms of Cmax  and AUC0 24h  did not change significantly when dosed together with JNJ-6379
vs. when dosed as a single agent.
Based on these results, the NOAEL was considered to be 
mg/kg after combination
therapy (JNJ-3989/JNJ-6379). At the NOAEL the mean Cmax  and AUC values for analyte
JNJ-3924 in males were 20,900 ng/mL and 178,000 ng∙h/mL, and for females 21,300 ng/mL and
141,000 ng∙h/mL, respectively. For analyte JNJ-3976, the mean Cmax  and AUC values in males
were 35,200 ng/mL and 279,000 ng∙h/mL, and for females 35,300 ng/mL and 218,000 ng∙h/mL,
respectively. Cmax  and AUC values for JNJ-6379 in males were 13,200 ng/mL and
181,000 ng∙h/mL, and for females 15,500 ng/mL and 206,000 ng∙h/mL, respectively, after 1
month of treatment.
In conclusion, weekly SC injection with JNJ-3989 at 30 or 180 mg/kg in combination with daily
administration of JNJ-6379 at 100 mg/kg (oral) for one month 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 and were considered not adverse.
There was no apparent interaction between JNJ-3989 and JNJ-6379.
Preliminary results of a 3-month combination toxicity study with JNJ-6379 and 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. For further information, refer to the IB
Addenda.40,41
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).
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
two compounds separately.
CCI
NCT03982186

JNJ-73763989 and JNJ-56136379
Clinical Protocol 73763989HPB2001 AMENDMENT 4
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
40
Status: Approved,  Date: 24 November 2021
JNJ-3989
Clinical data ofJNJ-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 entecavir (ETV) or tenofovir disoproxil fumarate
(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
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, on average, in pronounced HBsAg decline which was 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 of25 mg. Data on the 50 mg dose were still emerging at the time of
protocol writing. 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 participants is
also completed and clinical study report writing is currently ongoing (56136379HPB1005). In
addition, data are available from 148 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
NCT03982186

JNJ-73763989 and JNJ-56136379
Clinical Protocol 73763989HPB2001 AMENDMENT 4
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
41
Status: Approved,  Date: 24 November 2021
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 JNJ-6379 25 mg and 600 mg. Mean values for
terminal half-life (t1/2term) were comparable for the 25-mg to 300-mg dose levels, and averaged
between 93.3 hours and 110.5 hours. For the 600-mg dose group, the average t1/2term  was
141.3 hours. Mean values for the total apparent oral clearance (CL/F) were comparable for the
25-mg, 50-mg and 150-mg dose level, and appeared to decrease at higher dose levels. Mean
values of the apparent volume of distribution were generally comparable for the different dose
groups.
In Study 56136379HPB1002, study drug exposure levels using a novel tablet formulation,
containing hydroxypropylmethylcellulose E5 based spray-dried powder, were similar to
exposure levels observed in study 56136379HPB1001 using the original formulation, both in fed
conditions. The relative bioavailability of new 25-mg oral tablets of JNJ-6379 administered as a
150-mg dose under fasting and fed conditions, and of new 100-mg oral tablets of JNJ-6379
administered as a 300-mg dose under fasting conditions, was assessed in healthy adult
participants. Assuming proportionality, based on the geometric mean ratios between the 3x
100-mg dose, fasting (test) and the 6x 25-mg dose, fasting (reference) of the dose-normalized PK
parameters, Cmax  was 21.56% lower for the 100-mg tablet strength compared to the 25-mg tablet
strength, and AUC0 last and AUC∞ were similar. The median time to reach Cmax  (tmax) was around
1.75 hours when 150 mg JNJ-6379 was dosed as 6x 25-mg oral tablets, and around 3.00 hours
when 300 mg JNJ-6379 was dosed as 3x 100-mg oral tablets.
In Study 56136379HPB1005, the oral bioavailability of a single 300-mg dose of JNJ-6379
administered as a 100-mg tablet containing hydroxypropylmethylcellulose-acetate succinate
based spray-dried powder (test tablet) was assessed. All 14 healthy adult participants received a
300-mg dose of JNJ-6379 under fasted conditions. Preliminary PK analysis was performed and
mean Cmax  was 3,105 ng/mL, mean AUC0 72h  was 111,286 ng.h/mL and mean AUC∞ was
280,926 ng.h/mL. The median tmax  was around 3.00 hours. These preliminary PK parameter
values are comparable to the PK parameters obtained after administration of JNJ-6379
formulated as hydroxypropylmethylcellulose E5 based spray-dried powder tablet.
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.
NCT03982186

JNJ-73763989 and JNJ-56136379
Clinical Protocol 73763989HPB2001 AMENDMENT 4
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
42
Status: Approved,  Date: 24 November 2021
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 (AUCtau) increased between Day 6 (first dose of
JNJ-6379) and Day 20 as JNJ-6379 plasma concentrations accumulated due to the multiple-dose
regimen administered in this study. Steady-state was reached before Day 20. Plasma
concentration-time 
profiles 
of 
JNJ-6379 
were 
similar 
to 
those 
observed 
in
Study 56136379HPB1001.
Multiple Dose Studies in 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, novel data from Study 56136379HBP1002 with 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 JNJ-6379 170 mg 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.
NCT03982186

JNJ-73763989 and JNJ-56136379
Clinical Protocol 73763989HPB2001 AMENDMENT 4
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
43
Status: Approved,  Date: 24 November 2021
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 JNJ-6379 25 to
250 mg qd for 28 days, unblinded).
Available antiviral activity data for 4 weeks of treatment with JNJ-6379 in
Study 56136379HPB1001 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 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 included unblinded Week 24 data from 44 virologically
suppressed CHB participants of whom 33 received 75 mg qd JNJ-6379 and 11 received placebo
in addition to an NA. Interim analysis 3 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, 5/21 (23.8%) of participants on JNJ-6379 experienced a mean
reduction from baseline in HBV RNA of >2 log10 IU/mL versus 1/7 (14.3%) of participants on
placebo. HBV RNA levels at Week 24 were undetectable for 21/21 (100.0%) of participants on
JNJ-6379 and 4/7 (57.1%) of 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 viral breakthrough defined as confirmed on-treatment HBV DNA increase by
>1 log10 from nadir level or confirmed on-treatment HBV DNA level >200 IU/mL in participants
who had HBV DNA level below the LLOQ of the HBV DNA assay. All 5 participants with viral
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 viral 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 virological 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).
NCT03982186

JNJ-73763989 and JNJ-56136379
Clinical Protocol 73763989HPB2001 AMENDMENT 4
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
44
Status: Approved,  Date: 24 November 2021
In the monotherapy arm with 250 mg JNJ-6379, 1 participant experienced viral 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 implemented futility rule.
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
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 or Tenofovir
Prodrugs (Tenofovir Disoproxil Fumarate or Tenofovir Alafenamide)
Entecavir is an HBV NA reverse transcriptase inhibitor indicated for the treatment of chronic
HBV infection in adults and children at least 2 years of age with evidence of active viral
replication and either evidence of persistent elevations in serum aminotransferases (ALT or
aspartate aminotransferase [AST]) or histologically active disease. The most common adverse
reactions (≥3% of participants) are headache, fatigue, dizziness, and nausea.
Tenofovir disoproxil fumarate is a first-generation oral prodrug of tenofovir that is indicated for
the treatment of HBV infection 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 HIV type
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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 (TAF) is an HBV NA reverse transcriptase inhibitor that is indicated for
the treatment of chronic HBV infection in adults with compensated liver disease. It is an oral
prodrug of tenofovir. The most common adverse reactions (≥5% of participants) are headache,
abdominal pain, fatigue, cough, nausea, and back pain. Tenofovir alafenamide in combination
with other antiretrovirals is also indicated for the treatment of HIV-1 infection in adult and
pediatric patients.
For further information regarding ETV, TDF, and TAF, refer to the respective prescribing
information.
There is no common target organ between JNJ-6379 or JNJ-3989 and ETV.23
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.10,16 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).4,34 No kidney findings were observed in
dogs.
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Status: Approved,  Date: 24 November 2021
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,24 renal tubular epithelial karyomegaly was observed in rats, dogs, and monkeys. 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
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.8
2.2.2.1. 
Overall Nonclinical Assessment of the Combination Therapy
Based on the points listed below, no clinically relevant drug-drug interactions (DDIs) and no
specific concerns about additive or synergistic toxicities are expected in the kidneys 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
 
absence of synergistic or additive histology findings in the kidney observed in the 1-week
combination PK study with JNJ-6379 and JNJ-3989
 
available clinical data with JNJ-6379 (Jade study [56136379HPB2001]) up to 24 weeks
treatment on the absence of systematic 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
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Status: Approved,  Date: 24 November 2021
changes in clinical studies with dosing longer than 4 weeks (see Section  8.3.6.5). For further
information, refer to the IB Addenda.40,41
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.13,14
For the benefit-risk evaluation of ETV, TDF, and TAF, refer to the respective prescribing
information.
2.3.1. 
Benefits for Study Participation
2.3.1.1. 
Known Benefits
The clinical benefit of JNJ-3989 and JNJ-6379 remains to be established.
2.3.1.2. 
Potential Benefits
Results from clinical studies with JNJ-3989, JNJ-6379, 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 more profoundly block HBV replication 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.9,20,36 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.
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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 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. The fertility in male and
female rats is not impacted with JNJ-3989 up to a dose of 180 mg/kg/week.
Based on the difference in metabolic pathways and in vitro data indicating absence of impact of
JNJ-3989 on CYP enzymes and transporters, no clinically relevant interactions are anticipated
between JNJ-3989 and oral contraceptives.
Potential Genotoxicity
JNJ-3989 is considered to be devoid of genotoxic activity. Nonclinical carcinogenicity studies
have not been conducted.
Other Potential Toxicity/Events of Special Interest
JNJ-3989 is considered non-cytotoxic, did not activate human platelet aggregation, did not
activate the innate immune system to a significant degree in vitro, and did not activate
complement in vitro.
Viral Resistance
Treatment with JNJ-3989 may lead to viral resistance, but without impact to treatment with other
small interfering RNAs (siRNAs). Using these agents in combination, especially in combination
with ETV or TDF 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.
CCI
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Status: Approved,  Date: 24 November 2021
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-56136379 was not genotoxic in the in vitro and in vivo tests.
JNJ-56136379 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 ofinterest.
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.
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 participants with
chronic HBV infection. Most observed AEs were mild in severity and considered not related
CCI
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Status: Approved,  Date: 24 November 2021
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 ALT/AST
elevations, ISRs, renal complications, hematologic abnormalities, and events related to
cholesterol increase (Section 8.3.6, Specific Toxicities 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, Specific Toxicities).
 
Continued careful assessment of the safety, efficacy, and PK during treatment is included in
this study.
 
To minimize potential risk and stress to participants:
 
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 [SBP and DBP], pulse rate, and temperature), height (at
screening only), 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, Specific Toxicities).
 
An Independent Data Monitoring Committee (IDMC) and an Independent Flare Expert
Panel (IFLEP) 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 9.5, Interim Analyses).
 
Participants who meet the individual participant NA treatment completion criteria
(Section 6.6) will be monitored for 48 weeks after completing NA treatment with
frequent follow-up visits and pre-defined re-treatment criteria (Section 6.7).
 
The post-treatment monitoring and NA re-treatment criteria were further updated based
on findings from a case of post-treatment HBV reactivation with subacute hepatic
failure and assessment of additional REEF-2 study data (Section 6.7).
 
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, Specific Toxicities.
 
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).
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3. 
OBJECTIVES AND ENDPOINTS
Objectives 
Endpoints
Primary
 
To establish the dose-response relationship for 
antiviral activity of 3 doses of JNJ-3989+NA 
and to evaluate the efficacy of combination 
regimens of JNJ-3989+NA (with and without
JNJ-6379) and of JNJ-6379+NA.
 
Proportion of participants meeting the NA
treatment completion criteria at Week 48 (see
Section 6.6).
Secondary
 
To evaluate the safety and tolerability of the 
study intervention throughout the study. 
 
Proportion of participants with (S)AEs and
abnormalities in clinical laboratory tests
(including hematology, blood biochemistry,
blood coagulation, urinalysis, urine chemistry,
and renal biomarkers), 12-lead ECGs, and
vital signs.
 
To evaluate the efficacy of the study 
intervention during the follow-up phase.* 
 
Proportion of participants with HBsAg
seroclearance 24 weeks after completion of all
study intervention at Week 48.
 
Proportion of participants with HBsAg
seroclearance 48 weeks after completion of all
study intervention at Week 48.
 
Proportion of participants with HBV DNA
<LLOQ 24 and 48 weeks, respectively, after
completion of all study intervention at Week
48.
 
Proportion of participants meeting the NA
treatment 
completion 
criteria 
during
follow-up.
 
Proportion of participants with HBsAg
seroclearance 24 and 48 weeks, respectively,
after completion of NA treatment at any time
during follow-up.
 
Frequency of flares.
 
Proportion of participants requiring NA
re-treatment 
during 
follow-up 
(see
Section 6.7).
 
To evaluate efficacy as measured by blood 
markers (such as HBsAg, HBeAg,** HBV 
DNA, and ALT) during study intervention and 
follow-up. 
 
Proportion of participants with (sustained)
reduction, suppression, and/or seroclearance
considering single and multiple markers (such
as HBsAg, HBeAg,** HBV DNA and ALT).
 
Proportion of participants with HBsAg and
HBeAg** seroconversion.
 
Change from baseline over time in HBsAg,
HBeAg,** and HBV DNA.
 
Time to achieve HBsAg and HBeAg**
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Objectives 
Endpoints
seroclearance.
 
Proportion of participants with HBsAg levels
and/or changes from baseline below/above
different cut-offs (eg, HBsAg <100 IU/mL or
>1 log10 IU/mL reduction in HBsAg from
baseline).
 
Proportion of HBeAg-positive participants
with HBeAg** levels and/or changes from
baseline below/above different cut-offs.
 
Proportion of participants with HBV DNA
levels 
and/or 
changes 
from 
baseline
below/above different cut-offs (eg, <LLOQ of
the assay).
 
Proportion of participants with ALT decrease
and normalization.
 
To evaluate the frequency of virologic 
breakthrough. 
 
Proportion of participants with virologic
breakthrough.
 
To evaluate the efficacy of NA re-treatment in 
participants who meet the criteria for NA 
re-treatment. 
 
Proportion of participants who reach HBV
DNA undetectability after re-start of NA
treatment during follow-up.
 
To evaluate the PK of JNJ-3989 (JNJ-3976 
and JNJ-3924), JNJ-6379, and NA, as 
applicable.
 
PK parameters of JNJ-3989 (JNJ-3976 and
JNJ-3924), JNJ-6379, and NA, as applicable.
Exploratory
 
To explore changes in the severity of liver 
disease at the end of follow-up versus 
screening/baseline.
 
Changes in fibrosis (according to Fibroscan
liver stiffness measurements).
 
To explore the relationship between PK 
parameters (JNJ-3989 and/or JNJ-6379 and/or 
NA) and selected pharmacodynamic (PD) 
parameters of efficacy and/or safety, as 
applicable.
 
Relationship between various PK parameters
(JNJ-3989 and/or JNJ-6379 and/or NA) and
selected efficacy and/or safety endpoints, as
applicable.
 
To explore efficacy as measured by HBV 
RNA and HBcrAg during study intervention 
and follow-up.
 
Changes from baseline in HBV RNA and
HBcrAg levels.
 
Time to reach undetectability of HBV RNA
and HBcrAg.
 
To explore the impact of the baseline HBeAg 
and treatment status factors on efficacy as 
measured 
by 
primary 
and 
secondary
endpoints.
 
Proportion of participants meeting the NA
treatment completion criteria at Week 48.
 
Proportion of participants with HBsAg
seroclearance 24 weeks after completion of all
study intervention at Week 48.
 
Proportion of participants with HBsAg
seroclearance 48 weeks after completion of all
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Objectives 
Endpoints
study intervention at Week 48.
 
Proportion of participants with HBV DNA
<LLOQ 24 and 48 weeks, respectively, after
completion of all study intervention at Week
48.
 
Proportion of participants meeting the NA
treatment 
completion 
criteria 
during
follow-up.
 
Proportion of participants with HBsAg
seroclearance 24 and 48 weeks, respectively,
after completion of NA treatment at any time
during follow-up.
 
Frequency of flares.
 
Proportion of participants requiring NA
re-treatment during follow-up.
 
To explore the association between viral and 
host baseline factors with efficacy and safety. 
 
Correlation of viral and host baseline
characteristics (such as HBV genotype,
baseline HBV DNA levels, age, gender, body
mass index [BMI]) with selected efficacy and
safety variables.
 
To explore changes in the HBV genome 
sequence during study intervention and 
follow-up.
 
Emergence 
of 
intervention-associated
mutations.
 
To explore the effect of any baseline variation 
in the HBV genome on efficacy. 
 
Correlation of HBV genome sequence with
selected efficacy parameters.
 
To explore HBV-specific T-cell responses 
during study intervention and follow-up.*** 
 
Changes from baseline in HBV-specific
peripheral blood T-cell responses.
 
To explore the impact of study intervention on 
participants’ health-related quality of life 
(HRQoL), self-stigma, and impression of
change using 
patient-reported 
outcomes
(PROs) 
during 
study 
intervention 
and
follow-up. 
 
Changes over time in score on the Hepatitis B
Quality of Life (HBQOL) scale and subscales.
 
Changes over time in score on the
HBV-specific self-stigma PRO scale.
 
Participants’ impression of change on the
Patient Global Impression of Change (PGIC)
scale.
* The follow-up phase has a maximum duration of 96 weeks.
** in HBeAg-positive participants only
*** Peripheral blood mononuclear cell (PBMC) samples for immune analyses will be collected at selected
sites only.
Refer to Section 8, Study Assessments and Procedures for evaluations related to endpoints.
For a definition of terms, refer to Section 10.1, Appendix 1, Abbreviations and Definitions of
Terms.
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HYPOTHESIS
Based on the primary efficacy endpoint, the proportion of participants meeting the NA treatment
completion criteria at Week 48, the primary hypotheses are as follows:
 
There is a positive dose-response signal across the 3 doses of JNJ-3989 (40, 100, and
200 mg) on the background of NA compared with NA treatment alone (control Arm 6).
 
One or both combination regimens JNJ-3989+JNJ-6379+NA and JNJ-6379+NA are more
efficacious than NA treatment alone (control Arm 6).
 
The combination regimen of JNJ-3989 (100 mg)+JNJ-6379+NA is more efficacious than
JNJ-3989 (100 mg)+NA and/or JNJ-6379+NA combination regimens.
4. 
STUDY DESIGN
4.1. 
Overall Design
This is a Phase 2b, randomized, double-blind, double-dummy, active-controlled, dose-finding,
parallel, multicenter, interventional study  in  HBeAg-positive and -negative chronic
HBV-infected participants who (1) are currently not being treated for their HBV infection
(including CHB treatment-naïve participants) or (2) who are virologically suppressed by current
NA treatment (either ETV, TDF, TAF or approved tenofovir generics). The efficacy, safety, and
PK of the study intervention will be evaluated.
A target of 450 adult male and female participants, 18 (or the legal age of consent in the
jurisdiction in which the study is taking place) to 65 years of age (inclusive), will be randomized
in a 2:2:2:2:1:1 ratio to one of the following intervention arms:
 Arm 1: 
JNJ-3989 (100 mg)+ 
JNJ-6379 (250 mg qd)+ NA* (N 90)
 Arm 2: 
JNJ-3989 (200 mg)+ 
Placebo +  
NA* (N 90)
 Arm 3: 
JNJ-3989 (100 mg)+ 
Placebo +  
NA* (N 90)
 Arm 4: 
JNJ-3989 (40 mg)+ 
Placebo +  
NA* (N 90)
 Arm 5: 
Placebo +  
JNJ-6379 (250 mg qd) +  NA* (N 45)
 Arm 6 (control): 
Placebo +  
Placebo + 
NA* (N 45)
* NA: ETV, TDF, or TAF
After a fixed duration of 48 weeks, participants will complete treatment with JNJ-3989 and/or
JNJ-6379. If the NA treatment completion criteria (outlined in Section 6.6) are met based on
clinical laboratory tests performed at Week 44, treatment with NA will also be completed at
Week 48 (ie, the next scheduled visit after Week 44). Participants who meet the NA treatment
completion criteria will be monitored closely during the follow-up phase. NA treatment may
need to be re-started based on protocol-defined NA re-treatment criteria (see Section 6.7).
Randomization will be stratified by HBeAg status at screening (positive versus negative) and by
treatment history (not currently treated versus virologically suppressed).
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The aim is to include 40% not currently treated participants ofwhom it is expected that 40% are
HBeAg-positive. As such, enrollment of subgroups may be closed prior to completion of study
enrollment. All efforts will be undertaken to include a sufficient number of HBeAg-positive
virologically suppressed participants.
The study will be conducted in the following phases:
 
Screening phase: 4 weeks. If necessary, eg, for operational reasons, the screening phase
may be extended up to a maximum of 6 weeks on a case-by-case basis and in agreement
with the sponsor.
 
Double-blind study intervention phase:from Day 1 (ie, baseline) up to Week 48.
 
Follow-up phase:for 48 weeks after the end of investigational intervention. For participants
who complete NA treatment during follow-up, the follow-up phase will be extended to
48 weeks after the end of NA treatment. The follow-up phase has a maximum duration of
96 weeks.
The duration of individual study participation will be between 100 and 150 weeks.
At Week 48 or at time of early discontinuation, it will be communicated to the investigators
whether the participants were allocated to either an investigational arm (Arms 1 to 5) or the
control arm (Arm 6)to allow the correct follow-up visit schedule to be followed (see Schedule of
Activities). Only at Week 72, randomization codes (for Arms 1 to 5) will be fully disclosed to the
investigators. The sponsor will be fully unblinded for the primary analysis at Week 48 (see
Section 9).
Participants will be considered to have completed the study if they have completed the
assessments of the end of study (EOS) visit ([Extended] Follow-up Week 48). After completing
this study, participants may be invited to enroll into a long-term follow-up study.
Efficacy will be evaluated using different parameters including HBsAg and HBeAg (see
Section 8.1).
Safety and tolerability, including (S)AEs, laboratory assessments, ECGs, vital signs, and
physical examination, will be assessed throughout the study from the time of signing the
informed consent form (ICF) until completion of the last study-related activity (see Section 8.2).
Three PRO instruments, including the HBQOL scale,32 an HBV-specific self-stigma PRO scale,
and the PGIC scale11,18 will be used to exploratively assess the impact of study intervention on
participants’ HRQoL, self-stigma level, and impression of change (see Section 8.1.2).
Samples for HBV genome sequencing will be taken at the time points indicated in the Schedule
of Activities (see Section 8.1.1).
A population PK analysis will be performed based on the available data for JNJ-3989, JNJ-6379
and, optionally, NA, potentially in combination with data from a selection of Phase 1 and 2
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studies. PK parameters in participants undergoing intensive PK sampling will be calculated via
noncompartmental methods (see Section 8.5).
Pharmacokinetic/pharmacodynamic relations will be explored (see Section 8.6).
Peripheral blood mononuclear cell (PBMC) samples for immune analyses will be collected at
selected sites at the time points indicated in the Schedule of Activities (see Section 8.7)
A pharmacogenomic blood sample will be collected from participants who consent separately to
this component of the study (see Section 8.8).
The study includes collection of blood samples for exploratory analysis of viral markers (see
Section 8.1) and host blood biomarkers at the host RNA, protein, and cell level (see Section 8.9).
If a participant prematurely discontinues investigational intervention  (before Week 48), the
participant will enter the follow-up phase and complete the follow-up schedule as per the
Schedule of Activities, unless the participant withdraws consent. In this case, NA treatment may
be continued or, in consultation with the sponsor, discontinued based on investigator judgement
or completed based on the NA treatment completion criteria (see Section 6.6).
If a participant withdraws consent before completing the study, the reason for withdrawal is to be
documented in the case report form (CRF) and in the source documents. Participants who
withdraw consent will be offered an optional safety follow-up visit.
An IDMC  will be commissioned for this study. In addition, an IFLEP  will be appointed (see
Section 9.5).
A diagram of the study design is provided in Section 1.2, Schema.
4.2. 
Scientific Rationale for Study Design
Study Population
Patients with CHB will be eligible if they have an indication for antiviral treatment according to
current treatment guidelines.
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 regimens evaluated in this study
will first be established in patients without liver cirrhosis prior to initiating studies in patients
with more advanced liver disease.
Randomization and Stratification Factors
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
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and baseline characteristics) are evenly balanced across intervention arms, and to enhance the
validity of statistical comparisons across intervention arms.
Randomization will be stratified by HBeAg status at screening (positive versus negative) and by
treatment history (not currently treated versus virologically suppressed). Two stratification
factors are considered maximally feasible. The two stratification factors selected, together with a
minimum HBsAg level of 100 IU/mL required for inclusion, will provide a reasonably balanced
representation of the 2 baseline factors across all intervention arms and will reduce the variability
of HBsAg across the treatment arms.
Double-blind, Placebo-controlled Safety Comparison
The safety profile of NAs as background regimen is well established. The safety of the different
investigational combinations will be characterized by comparing their tolerability to that of
standard of care in a double-blind manner.
Efficacy Comparison Versus Control Arm
The analysis of the primary efficacy endpoint and other secondary endpoints will be based on
comparisons of investigational combination arms with the control arm (see Section 9). Hence, it
is considered important that participants in control Arm 6 remain in the study for the full
duration of 96 weeks in order to support within-study efficacy measurements (including the
primary endpoint and kinetics of viral parameters).
Criteria for Completion of NA Treatment
NA treatment completion criteria (described in Section 6.6) are included to explore the
possibility of finite treatment. The treatment completion criteria which take ALT, HBV DNA,
HBeAg and HBsAg levels into consideration, have been selected to ensure that only subjects
with a chance of sustained off-treatment response are allowed to complete all study intervention.
Across a range of studies, HBsAg levels below 100 IU/mL are consistently associated with
favorable off-treatment response.19,26 The stringent HBsAg cutoff of 10 IU/mL for NA treatment
completion was chosen to account for the direct effect of JNJ-3989 on HBsAg levels.
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 Week 48
or later), and weekly visits for patients with ALT/AST ≥3x  upper limit of normal (ULN) and
≥3x nadir until stabilization.
Increases in ALT and HBV DNA are frequently seen in patients after discontinuation of NA
treatment. These ALT elevations can be reflecting an activation of the host cellular immune
response and can as such lead to functional cure. Cases of fulminant HBV reactivation with fatal
outcome were described after cessation of NA treatment, but the vast majority of such cases were
described in patients with decompensated liver disease at the time of NA discontinuation. These
patients are not eligible to participate in the study. Still, a vigilant follow-up of patients during
this phase of the study is critical to ensure patient safety. Increases in ALT that are accompanied
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by signs of decreased liver function, or an HBV DNA value of >100,000 IU/mL (irrespective of
confirmation and/or ALT increase), will trigger immediate re-initiation of NA treatment based
on protocol-defined NA re-treatment criteria (see Section 6.7).
Re-initiation of NA treatment is also required in case of confirmed HBeAg seroreversion
(HBeAg positive after it was negative at NA completion), in case of confirmed* ALT increase
(>5x ULN) in combination with increased HBV DNA replication (>2,000 IU/mL), and in case of
confirmed* increased HBV DNA replication at higher levels (>20,000 IU/mL).
* At least 4 weeks apart
A post-treatment HBV DNA value of >20,000 IU/mL should trigger re-testing of ALT/AST,
HBV DNA, and total and direct bilirubin within a maximum of 7 days from receipt of the data
and further repeats as necessary (ie, weekly until HBV DNA returns to <20,000 IU/mL). A post-
treatment HBV DNA value of >2,000 IU/mL (but <20,000 IU/mL) should trigger a re-test within
14 days from receipt of the data and further repeats as necessary (ie, every other week until HBV
DNA returns to <2,000 IU/mL). A post-treatment ALT value of >5x ULN should trigger re-
testing of ALT, AST, ALP, total and direct bilirubin, INR, albumin, and HBV DNA on a weekly
basis until ALT and AST levels have returned to <5x ULN. Additional re-testing and/or earlier
restarting of NA treatment is at the investigator’s discretion, even if the above cut-offs are not
yet met.
To avoid delays in decision making, sites are encouraged to run local re-testing in parallel with
central re-testing in the situations described above that require more frequent re-testing. Local
test results are to be recorded in the CRF and/or source documents, including information on the
HBV DNA assay used. In addition, to avoid delays in NA re-treatment, it should be
considered to dispense NA to participants who potentially met the NA re-treatment criteria (eg,
pending confirmation) and who will not be available to come to the study site immediately at the
time the confirmatory test results will become available. This should ensure that the participant
can immediately restart NA treatment if indicated, upon direct confirmation by the investigator.
The decision to re-start NA treatment should take into consideration the dynamics of HBV DNA
and/or ALT values and should be discussed with the sponsor.
NA re-treatment criteria during follow-up are presented graphically in Section 10.14,
Appendix 14.
Host DNA and Biomarker Collection
It is recognized that genetic variation can be an important contributory factor to interindividual
differences in intervention distribution and response and can also serve as a marker for disease
susceptibility and prognosis. Pharmacogenomic research may help to explain interindividual
variability in clinical outcomes and may help to identify population subgroups that respond
differently to an intervention. The goal of the pharmacogenomic component is to collect DNA to
allow the identification of genetic factors that may influence the efficacy, safety or PK of the
study intervention, to identify genetic factors associated with HBV infection, or to develop
assays for the study intervention or HBV infection.
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Biomarker samples will be collected to evaluate the mechanism of action of JNJ-3989 and
JNJ-6379 in combination with  NA  or help to explain interindividual variability in clinical
outcomes or may help to identify population subgroups that respond differently to an
intervention. The biomarker research can be used to address questions related to the safety, PK
and efficacy of the study intervention and HBV infection or to develop assays for the study
intervention or HBV infection.
Host DNA (pharmacogenomic) and biomarker samples may be used to help address emerging
issues and to enable the development of safer, more effective, and ultimately individualized
therapies.
4.2.1. 
Study-specific Ethical Design Considerations
Potential participants will be fully informed of the risks and requirements of the study and, during
the study, participants will be given any new information that may affect their decision to continue
participation. They will be told that their consent to participate in the study is voluntary and may be
withdrawn at any time with no reason given and without penalty or loss of benefits to which they
would otherwise be entitled. Only participants who are fully able to understand the risks, benefits,
and potential AEs of the study, and provide their consent voluntarily will be enrolled.
While all participants will receive the study intervention in combination with an approved
therapy for HBV infection, some ethical consideration should be given to the fact that
participants will not have access to potentially alternative or new effective therapies for the
duration of the study (intervention and follow-up phase) since they may not begin any other
approved or investigational therapies for treatment of HBV infection during this time.
Participants with worsening HBV infection can discontinue the study intervention at any time,
and the study intervention should be discontinued if a participant requires additional therapy for
HBV infection.
The total blood volume to be collected is considered to be an acceptable amount of blood to be
collected over this time period from the population in this study based upon the standard of the
American Red Cross standard blood donation.1
4.3. 
Justification for Dose
The proposed dose and treatment duration are selected to maximize the chance for patients to
achieve functional cure and are supported by scientific understanding of available data.
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 separated by either 7-day, 14-day, or 28-day intervals.
All participants were started on ETV or TDF on Day 1. JNJ-3989 was generally safe and well
tolerated at all doses.
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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, on average, in pronounced HBsAg decline which was 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 those doses. A reduced mean decline
was observed at the lower dose of 25 mg. Data on the 50 mg dose were still emerging at the time
of protocol writing.
Thus, for the current study, 3 doses of JNJ-3989 (ie, 40, 100, and 200 mg, administered every
4 weeks) were selected to study the effect of the different doses and a potential dose response
with longer treatment duration.
A dose of 100 mg JNJ-3989 is chosen  for the combination treatment regimen  of
JNJ-3989+JNJ-6379+NA as this is the most likely JNJ-3989 dose to be selected. Based on the
currently available HBsAg data, no discrimination between the 100 and 200 mg dose might be a
plausible scenario translated to the functional cure rate endpoint (ie, a maximum effect (Emax)
dose-response shape might be likely observed).
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
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 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
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there were no deaths, Grade 4 AEs, or AEs leading to discontinuation. Most AEs were mild or
moderate in severity.
4.4. 
End of Study Definition
End of Study Definition
The EOS is considered as the last visit ([Extended] Follow-up Week 48 or early discontinuation)
for the last participant in the study.
Study Completion Definition
A participant will be considered to have completed the study if he or she has completed
assessments at Week 48 of the (extended)follow-up phase.
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.
Retesting to assess eligibility will be allowed once, using an unscheduled visit during the
screening phase.
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.
5.1. 
Inclusion Criteria
Each potential participant must satisfy all of the following criteria to be enrolled in the study:
1. 
Adult male or female participants 18 (or the legal age of consent in the jurisdiction in
which the study is taking place) to 65 years of age, inclusive.
2. 
Participants must be medically stable, with the exception of HBV disease, on the basis
of 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.
3. 
Participants must have chronic HBV infection documented by serum HBsAg positivity
at screening. In addition, chronicity must be documented by serum HBsAg positivity at
least 6 months prior to screening or alternative markers of chronicity (HBeAg positivity
or HBV DNA positivity at least 6 months prior to screening, ALT elevation above ULN
at least 6 months prior to screening without another cause than HBV infection, liver
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biopsy, or documented transmission event at least 6 months prior to screening).
Note: if documentation of chronicity (as mentioned above) at least 6 months prior to
screening is not available, participants may be included if HBsAg positive and negative
for immunoglobulin M (IgM) antibodies to HBc antigen at screening.
4. 
Participants who are not currently treated  (defined as not having been on HBV
treatment, including NAs and IFN  products within 6 months prior to screening),
including treatment-naïve participants (defined as never having received HBV
treatment, including NAs and IFN products) should have:
a. Serum HBV DNA at screening 2,000 IU /mL for HBeAg-negative
participants and ≥20,000 IU/mL for HBeAg-positive participants, AND
b. ALT levels at screening <10x ULN AND >ULN on two measurements at least
3 months apart (one of which is at screening).
5. 
Virologically suppressed participants should:
a. be on stable HBV treatment, defined as currently receiving NA treatment
(ETV, TDF, or TAF) for at least 6 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
b. have serum HBV DNA <60 IU/mL on two measurements at least 6 months
apart (one of which is at screening), AND
c. have ALT values ≤2x ULN on two measurements at least 6 months apart (one
of which is at screening).
6. 
Participants must have HBsAg >100 IU/mL at screening.
7. 
Participants must have a BMI (weight in kg divided by the square of height in meters)
between 18.0 and 35.0 kg/m2, extremes included.
8. 
Participants must have:
a. Fibroscan liver stiffness measurement ≤9.0 kPa within 6 months prior to
screening or at the time of screening, OR
b. If a fibroscan result is not available: a liver biopsy result classified as
Metavir F0-F2 within 1 year prior to screening or at the time of screening.
Note: Other radiologic liver staging modalities (eg, acoustic radiation force impulse)
might be used if standard practice at the site or if otherwise validated and agreed with
the sponsor. Results should be equivalent to Metavir F0-F2.
Note: Conventional imaging procedures (eg, conventional liver ultrasound, computed
tomography [CT] or magnetic resonance imaging [MRI]) and serum marker panels are
not allowed to rule out severe fibrosis or cirrhosis.
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9. 
Participants must sign an ICF  indicating that they  understand the purpose of, and
procedures required for, the study and is willing to participate in the study.
10. 
Participants must sign a separate ICF if they agree 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.
11. 
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.
12. 
Criterion modified per Amendment 1
12.1 Female participants must be (as defined in Section 10.8, Appendix  8,
Contraceptive and Barrier Guidance)
a. Not of childbearing potential
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 agree
to remain on a highly effective method while receiving study intervention and
until 90 days after last dose.
Examples of highly effective methods of contraception are located in
Section 10.8, Appendix 8, Contraceptive and Barrier Guidance.
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.
13. 
Female participants must agree not to donate eggs (ova, oocytes) for the purposes of
assisted reproduction while receiving study intervention and until 90 days after the EOS.
14. 
Male participants must agree to wear a condom when engaging in any activity that
allows for passage of ejaculate to another person while receiving study intervention and
until 90 days after the last dose.
15. 
Male participants must agree not to donate sperm for the purpose of reproduction while
receiving study intervention and until 90 days after the EOS.
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16. 
In the investigator’s opinion, the participant must be able to understand and comply
with protocol requirements, instructions, and lifestyle restrictions (Section 5.3) and be
likely to complete the procedures as planned for this study.
5.2. 
Exclusion Criteria
Any potential participant who meets any of the following criteria will be excluded from
participating in the study:
1. 
Criterion modified per Amendments 1 and 2
1.1 Participants with evidence of hepatitis A virus infection (hepatitis A antibody IgM),
HCV infection (HCV antibody), HDV infection (HDV antibody) or hepatitis E virus
infection (hepatitis E antibody IgM), or HIV-1 or HIV-2 infection (confirmed by
antibodies) at screening.
Note:
- Participants with a positive HCV  antibody test can be enrolled if they have
negative HCV RNA at screening and documented negative HCV RNA at least 6
months prior to screening.
- 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.
2. 
Criterion modified per Amendment 1
2.1. Participants with any of the following laboratory abnormalities within 12 months
prior to screening or at the time of screening:
a. Total bilirubin >1.5x ULN,
b. Direct bilirubin >1.2x ULN,
c. Prothrombin time >1.3x ULN,
d. Serum albumin <3.2 g/dL.
3. 
History or evidence of clinical signs/symptoms of hepatic decompensation including but
not limited to: portal hypertension, ascites, hepatic encephalopathy, esophageal varices.
4. 
Participants with evidence of liver disease of non-HBV etiology. This includes but is
not limited to hepatitis virus infections mentioned in exclusion criterion 1, drug- or
alcohol-related liver disease, autoimmune hepatitis, hemochromatosis, Wilson’s disease,
α-1 antitrypsin deficiency, primary biliary cholangitis, primary sclerosing cholangitis,
Gilbert’s syndrome (mild cases are allowed, see exclusion criterion  2a), or any other
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non-HBV liver disease considered clinically significant by the investigator.
5. 
Criterion modified per Amendment 1
5.1 Participants with signs of HCC or clinically relevant renal abnormalities on an
abdominal ultrasound performed within 6 months prior to screening or at the time of
screening. In case of suspicious findings on conventional ultrasound the participant may
still be eligible if HCC or clinically relevant renal abnormalities has been ruled out by a
more specific imaging procedure (contrast enhanced ultrasound, CT or MRI).
6. 
Criterion modified per Amendment 1
6.1 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 glomerular filtration rate (eGFR)≥grade 3 (ie, <60 ml/min/1.73 m2)
at screening, calculated by the Chronic Kidney Disease Epidemiology
Collaboration (CKD-EPI) formula,
b. Pancreatic amylase ≥grade 3,
c. Lipase 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 (AFP) >100 ng/mL,
g. Any other laboratory abnormality considered to be clinically significant by the
investigator.
Note: Participants with AFP >ULN (but ≤100 ng/mL) may be eligible if HCC can be
ruled out based on a sensitive imaging study (eg, CT with contrast or MRI) during
screening.
7. 
Participants with hemoglobin A1c >8% at screening.
8. 
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 is considered cured with minimal risk of recurrence).
9. 
Participants with abnormal sinus rhythm (heart rate <45 or >100 beats per minute
[bpm]); QT interval corrected for heart rate according to Fridericia (QTcF) >450 ms for
male participants and >470 ms for female participants; QRS ≥120 ms; PR interval
>220 ms; abnormal conduction; or any other clinically significant abnormalities on a
12-lead ECG at screening.
10. 
Participants with a history of or current cardiac arrhythmias (eg, tachycardia at rest),
history of risk factors for Torsade de Pointes syndrome (eg, hypokalemia, family history
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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, coronary heart disease), moderate to severe valvular
disease, or uncontrolled hypertension at screening.
11. 
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.
12. 
Participants with any history of or current clinically significant skin disease requiring
regular or periodic treatment.
13. 
Participants with history of clinically relevant drug rash.
14. 
Criterion modified per Amendment 1
14.1 Participants with known allergies, hypersensitivity, or intolerance to JNJ-3989 and
JNJ-6379 or their excipients or excipients of the placebo content (refer to the
IB).13,14,15,39
15. 
Participants with contraindications to the use of ETV, TDF, or TAF per local prescribing
information.
16. 
Participants who have taken any disallowed therapies as noted in Section 6.5,
Concomitant Therapy before screening.
17. 
Participants having received an investigational intervention  (including investigational
vaccines) or used an invasive investigational medical device within 6 months before the
planned first dose of study intervention  or is currently enrolled in an investigational
clinical study with an investigational intervention.
18. 
Female participants who are pregnant, or breast-feeding, or planning to become
pregnant while enrolled in this study or within 90 days after the last dose of study
intervention.
19. 
Male participants who plan  to father a child while enrolled in this study or within
90 days after the last dose of study intervention.
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20. 
Participants who had major surgery, (eg, requiring general anesthesia), excluding
diagnostic surgery, within 12 weeks before screening, or will not have fully recovered
from surgery, or have surgery planned during the time the participant is expected to
participate in the study.
Note: Participants with planned surgical procedures to be conducted under local
anesthesia may participate.
21. 
Participants who have received an  organ transplant (except for skin, hair, or cornea
transplants).
22. 
Participants who are employees of the investigator or study site, with direct involvement
in the proposed study or other studies under the direction of that investigator or study
site, or a family member of an employee or the investigator.
23. 
Criterion modified per Amendment 1
23.1 Vulnerable participants (eg, incarcerated individuals, individuals under a legal
protection measure).
Note: Investigators should ensure that all study enrollment criteria have been met at screening. If
a participant’s clinical status changes (including any available laboratory results or receipt of
additional medical records) after screening but before the first dose of study intervention is given
such that he or she no longer meets all eligibility criteria, then the participant should be excluded
from participation in the study. The required source documentation to support meeting the
enrollment criteria are noted in Section 10.3, Appendix 3, Regulatory, Ethical, and Study
Oversight Considerations.
5.3. 
Lifestyle Considerations
Potential participants must be willing and able to adhere to the following lifestyle restrictions
during the course of the study to be eligible for participation:
1. 
Agree to follow all requirements outlined in Section 6.5, Concomitant Therapy
regarding prohibited and restricted therapy during the study.
2. 
Agree to follow all requirements that must be met during the study as noted in
Section 5.1, Inclusion Criteria and Section 5.2, Exclusion Criteria (eg, contraceptive
requirements).
5.4. 
Screen Failures
Participant Identification, Enrollment, and Screening Logs
The investigator agrees to complete a participant identification and enrollment log to permit easy
identification of each participant during and after the study. This document will be reviewed by
the sponsor study-site contact for completeness.
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The participant identification and enrollment log will be treated as confidential and will be filed
by the investigator in the study file. To ensure participant confidentiality, no copy will be made.
All reports and communications relating to the study will identify participants by participant
identification and age at initial informed consent. In cases where the participant is not
randomized into the study, the date seen and age at initial informed consent will be used.
Individuals who do not meet the criteria for participation in this study (screen failure) may not be
rescreened without agreement with the sponsor.
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6. 
STUDY INTERVENTION
6.1. 
Study Intervention(s) Administered
Description of Interventions
Intervention name 
JNJ-3989 
Placebo for
JNJ-3989 
JNJ-6379 
Placebo for 
JNJ-6379 
Entecavir (ETV) 
monohydrate 
Tenofovir 
disoproxil 
fumarate (TDF) 
Tenofovir
alafenamide
(TAF)***
Dosage formulation 
Solution for 
injection  
Solution for 
injection  
Tablets 
Tablets 
Film-coated tablets 
Film-coated 
tablets 
Film-coated
tablets
Unit dose strength(s) 
200 mg/vial 
0.9% saline 
25 and 100 mg 
0.5 mg 
300 mg** 
25 mg
Dosage regimen 
100 mg once 
every 4 weeks 
(Arms 1 and 3) 
200 mg once 
every 4 weeks 
(Arm 2)
40 mg once every 
4 weeks (Arm 4) 
0.5 mL once 
every 4 weeks 
(Arms 5 and 6) 
250 mg qd 
(Arms 1 
and 5) 
qd 
(Arms 2, 3, 4, 
and 6) 
Nucleoside-naïve 
patients:
0.5 mg qd
Lamivudine-
refractory patients:
1 mg* qd (but should
preferably be treated
with TDF or TAF
instead)
300 mg qd 
25 mg qd
Route of 
administration 
Subcutaneous 
injection (in the 
abdomen) 
Subcutaneous 
injection (in the
abdomen)
Oral 
Oral 
Oral 
Oral 
Oral
Dosing instructions 
Regardless of 
food intake 
Regardless of 
food intake 
Regardless of 
food intake 
Regardless of 
food intake 
On an empty 
stomach
With food 
With food
qd: once daily
* 2 tablets of 0.5 mg
** 300 mg TDF is equivalent to tenofovir disoproxil 245 mg.
*** In countries where TAF is available, it will be one of the NA treatment options.
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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.13,14,15
The placebo for JNJ-3989 will be a solution for subcutaneous 
. 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.
JNJ-3989/placebo injections will be administered 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
CCI
CC
CCI
CCI
CCI
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NA treatment will be provided by the sponsor through this study until the last study visit.
Investigators should follow guidance detailed in the respective prescribing information,
including special warnings and precaution for use.
Virologically suppressed participants who are already being treated with ETV, TDF, or TAF at
screening, will continue their current NA treatment. 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.
Participants who are not receiving any HBV treatment at screening will receive TDF during the
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 intervention 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. 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
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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.
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, 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. 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.
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
to 1 of 6 intervention arms with ratio 2:2:2:2:1:1 (Arms 1:2:3:4:5:6 as described in Section 4.1).
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 HBeAg status at screening (positive
versus negative) and by treatment history (not currently treated versus virologically suppressed).
The aim is to include 40% not currently treated participants of whom it is expected that 40% are
HBeAg-positive. As such, enrollment of subgroups may be closed prior to completion of study
enrollment. All efforts will be undertaken to include a sufficient number of HBeAg-positive
virologically suppressed participants. The interactive web response system (IWRS) will assign a
unique intervention  code, which will dictate the intervention assignment and matching study
intervention kit for the participant. The requestor must use his or her own user identification and
personal identification number when contacting the IWRS, and will then give the relevant
participant details to uniquely identify the participant.
Blinding
At Week 48 or at time of early discontinuation, it will be communicated to the investigators
whether the participants were allocated to either an investigational arm (Arms 1 to 5) or the
control arm (Arm 6)to allow the correct follow-up visit schedule to be followed (see Schedule of
Activities). Only at Week 72, the randomization codes (for Arms 1 to 5) will be fully disclosed to
the investigators.
The sponsor will be fully unblinded for the primary analysis at Week 48 (see Section 9).
Under normal circumstances, the blind should not be broken  for a participant until this
participant has completed Week 72 or discontinued earlier. The investigator may in an
emergency determine the identity of the intervention  by contacting the IWRS. While the
responsibility to break the intervention  code in emergency situations resides solely with the
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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 and reason for the unblinding must be
documented in the appropriate section of the CRF. The documentation received from the IWRS
indicating the code break must be retained with the participant’s source documents in a secure
manner.
In order to preserve the blinding during the study treatment phase, HBsAg, HBeAg, anti-HBs,
and anti-HBe antibody tests cannot be done locally.
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.
6.4. 
Study Intervention Compliance
JNJ-3989/placebo will be administered at the study site as a subcutaneous injection by qualified
study-site personnel who are unblinded to treatment assignment and who are independent from
any assessment activities with regard to the blinded study conduct. In order to protect the blind,
the participant should be asked to not look at the injection, and investigator and blinded study
personnel should not see the syringe and/or injection.
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 staffto add
to the source documents.
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.
 Ifan 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
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and the next injection should be given at the next scheduled time point per the initial
injection schedule.
 If a dose of NA is missed, the participant should follow the guidelines in the 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.
6.5. 
Concomitant Therapy
Prestudy therapies administered up to 30 days before the start of screening must be recorded at
screening. If applicable, the participant’s last anti-HBV treatment prior to screening must also be
recorded.
Concomitant therapies must be recorded throughout the study, from signing of the ICF up to the
last study visit. Concomitant therapies should also be recorded beyond the last study visit only in
conjunction with new or worsening (S)AEs.
All therapies (prescription or over-the-counter medications, including vaccines, vitamins, herbal
supplements; non-pharmacologic therapies such as electrical stimulation, acupuncture, special
diets, exercise regimens) different from the study intervention must be recorded in the CRF.
Recorded information will include a description of the type of therapy, duration of use, dosing
regimen, route of administration, and its indication. Modification of an effective pre-existing
therapy should not be made for the explicit purpose of entering a participant into the study.
An overview of disallowed medication is provided in Table 4.
Table 4: 
Disallowed Medication
Disallowed at any time prior to screening until end of follow-up:
 
Any CAM and oligonucleotide-based treatment (eg, siRNA and antisense oligonucleotides), 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:
 
For participants currently not being treated: Any anti-HBV drug (including vaccines)other than the study
intervention taken in the context of this study.
Note: Prior hepatic treatment with herbal or nutritional products is allowed but should be stopped at
screening.
 
Any systemically (eg, intravenously, intramuscularly, orally, subcutaneously) administered medication that
directly or indirectly interferes with immune responses (eg, cyclosporine, interleukins, IFN, systemic
corticosteroids exceeding 5 mg of prednisolone equivalent/day).
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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 P-glycoprotein transporter (eg, amiodarone, azithromycin clarithromycin, diltiazem,
dronedarone, erythromycin, felodipine, itraconazole, ketoconazole, quinidine, ritonavir, verapamil).
 
Inhibitors of breast cancer resistance protein (BCRP) transporter (eg, curcumin, cyclosporin A,
eltrombopag).
 
Any medication that reduces renal function or competes for active tubular secretion (eg cimetidine,
probenecid, quinidine).
 
Anticoagulants.
Note: aspirin and other antiplatelet agents are allowed.
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.
 
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 EOS intervention:
 
Ethinylestradiol-containing contraceptives with an ethinylestradiol content >20 µg.
Note: Starting treatment with ethinylestradiol-containing contraceptives during the study is not allowed.
An overview of concomitant medication that should be used with caution is described in Table 5.
Table 5: 
Concomitant Medication 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.
Note: The lists of disallowed medication and concomitant medication to be used with caution are
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.
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The sponsor must be notified in advance (or as soon as possible thereafter) of any instances in
which prohibited therapies are administered.
The prescribing information for ETV, TDF, and TAF should be consulted for any additional
prohibited medication.
6.6. 
Individual Participant NA Treatment Completion Criteria
After a fixed duration of 48 weeks, participants will complete treatment with JNJ-3989 and/or
JNJ-6379. If all of the following criteria are met based on clinical laboratory tests performed at
Week 44, treatment with NA will also be completed at Week 48 (ie, the next scheduled visit after
Week 44):
 
The participant has ALT <3x ULN, AND
 
The participant has HBV DNA <LLOQ, AND
 
The participant is HBeAg-negative, AND
 
The participant has HBsAg <10 IU/mL.
Note: In case of ALT elevation ≥3x ULN at Week 44 the investigator must consider different
potential causes of increased ALT to ensure appropriate work up and management as needed. If
the ALT elevation is unrelated to HBV activity and/or <3x ULN by treatment Week 48, NA
completion may be considered at the discretion of the investigator and in consultation with the
sponsor.
Participants who do not meet the above criteria at Week 48 should continue NA treatment during
the 48-week follow-up. If the above criteria are met during the follow-up phase based on clinical
laboratory tests performed at or before Follow-up Week 42 (Follow-up Week 36 for Arm 6), NA
treatment should be stopped at or before Follow-up Week 48 (ie, the next scheduled visit after
the laboratory test was performed) and the follow-up schedule should be extended to 48 weeks
after the end of NA treatment. If NA treatment completion criteria are not met based on clinical
laboratory tests performed at or before Follow-up Week 42 (Follow-up Week 36 for Arm 6), the
follow-up phase will not be extended, but the participant will continue NA treatment and
complete the study at Follow-up Week 48.
The investigator should consider to re-start NA treatment per local standard of care at the EOS
visit ([Extended] Follow-up Week 48) for participants who met the NA treatment completion
criteria at Week 48 or during the follow-up phase, who did not re-start NA treatment during the
follow-up phase, and who did not achieve and maintain HBsAg seroclearance. NA will not be
provided by the sponsor after the final study visit.
If a participant prematurely discontinues investigational intervention (before Week 48),
follow-up assessments should be obtained as per the Schedule of Activities until 48 weeks after
the end of investigational intervention unless the participant withdraws consent. In this case, NA
treatment may be continued or, in consultation with the sponsor, discontinued, based on the
above-mentioned NA treatment completion criteria.
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6.7. 
NA Re-treatment Criteria and Monitoring After Stopping of NA
Participants who meet the NA treatment completion criteria outlined in Section 6.6 will be
monitored closely during the follow-up phase.
After stopping NA treatment, participants should be monitored as follows:
 
Regular monitoring visits will be every 4 weeks during the follow-up phase in accordance
with the Schedule of Activities.
 
A post-treatment HBV DNA value of >20,000 IU/mL should trigger re-testing of ALT/AST,
HBV DNA, and total and direct bilirubin within a maximum of 7 days from receipt of the
data and further repeats as necessary (ie, weekly until HBV DNA returns to
<20,000 IU/mL).
 
A post-treatment HBV DNA value of >2,000 IU/mL (but <20,000 IU/mL) should trigger a
re-test within 14 days from receipt of the data and further repeats as necessary (ie, every
other week until HBV DNA returns to <2,000 IU/mL).
 
A post-treatment ALT value of >5x ULN should trigger re-testing of ALT, AST, ALP, total
and direct bilirubin, INR, albumin, and HBV DNA on a weekly basis until ALT and AST
levels have returned to <5x ULN.
After stopping NA treatment, participants should re-start NA treatment:
 
Immediately with signs of decreasing liver function based on laboratory findings (eg, INR,
direct bilirubin) or clinical assessment (eg, ascites, hepatic encephalopathy).
 
Immediately with an HBV DNA value of >100,000 IU/mL (irrespective of confirmation
and/or ALT increase).
 
With confirmed post-treatment HBeAg seroreversion (HBeAg positive after it was negative
at NA completion).
 
With confirmed* post-treatment increases in HBV DNA >2,000 IU/mL and ALT >5x ULN.
 
With confirmed* post-treatment increases in HBV DNA >20,000 IU/mL.
* At least 4 weeks apart frequency of visits as described above
Note: Additional re-testing and/or earlier restarting of NA treatment is at the investigator’s
discretion, even if the above cut-offs are not yet met.
To avoid delays in decision making, sites are encouraged to run local re-testing in parallel with
central re-testing in the situations described above that require more frequent re-testing. Local
test results are to be recorded in the CRF and/or source documents, including information on the
HBV DNA assay used. In addition, to avoid delays in NA re-treatment, it should be considered
to dispense NA to participants who potentially met the NA re-treatment criteria (eg, pending
confirmation) and who will not be available to come to the study site immediately at the time the
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confirmatory test results will become available. This should ensure that the participant can
immediately re-start NA treatment if indicated, upon direct confirmation by the investigator.
In case NA treatment is re-started, participants will be followed until the end of the study or until
clinical stabilization, whichever comes later.
NA re-treatment criteria and monitoring after stopping of NA  are presented graphically in
Section 10.14, Appendix 14.
Management of intervention-emergent ALT/AST elevations is discussed in Section 8.3.6.
6.8. 
Intervention After the End of the Study
Participants will be instructed that study intervention will not be made available to them after
they have completed/discontinued study intervention and that they should return to their primary
physician to determine standard of care.
The investigator should consider to re-start NA treatment per local standard of care at the EOS
visit ([Extended] Follow-up Week 48) for participants who met the NA treatment completion
criteria at Week 48 or during the follow-up phase, who did not re-start NA treatment during the
follow-up phase, and who did not achieve and maintain HBsAg seroclearance. NA will not be
provided by the sponsor after the final study visit.
7. 
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT
DISCONTINUATION/WITHDRAWAL
7.1. 
Discontinuation of Study Intervention
A participant’s investigational intervention  must be discontinued if any of the criteria listed
below apply. In those cases, NA treatment may be continued or, in consultation with the sponsor,
discontinued based on  investigator judgement or completed based on  the NA treatment
completion criteria (see Section 6.6).
 
The investigator believes that for safety or tolerability reasons (eg, AE) it is in the best
interest of the participant to discontinue investigational intervention.
 
The participant becomes pregnant.
 
The participant has a ≥grade 3 rash (see Section 10.5, Appendix 5, Rash Management) or
allergic reaction (see Section 8.3.6.3).
 
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 anytime,
according to the prescribing information. (see Section 8.3.6.4).
 
The participant has a confirmed QTcF prolongation (defined as a QTcF value of >500 ms, or
an increase from baseline of >60 ms) at any given time point.
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 
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.
 
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, changing the NA should be considered in
consultation with the sponsor.
 
The participant has ALT/AST elevations, as described in Section 8.3.6.1, Intervention-
emergent ALT/AST Elevations.
If a participant discontinues study intervention for any reason before Week 48, then the
end-of-intervention assessments should be obtained. The participant will enter the follow-up
phase and complete the follow-up schedule unless the participant withdraws consent. Participants
who withdraw consent will be offered an optional safety follow-up visit. Study intervention
assigned to the participant who discontinued study intervention may not be assigned to another
participant.
7.2. 
Participant Discontinuation/Withdrawal From the Study
A participant will NOT be automatically withdrawn  from the study if he or she has to
discontinue study intervention before Week 48.
A participant will be withdrawn from the study for any of the following reasons:
 
Lost to follow-up,
 
Withdrawal of consent,
 
Death.
If a participant withdraws before study  completion, the reason for withdrawal is to be
documented in the CRF and in the source documents. No additional participants will be enrolled
in case a participant withdraws from the study.
Withdrawal of Consent
A participant declining to return for scheduled visits does not necessarily constitute withdrawal
of consent. Alternate follow-up mechanisms that the participant agreed to when signing the
consent form apply as local regulations permit.
7.2.1. 
Withdrawal From the Use of Research Samples
A participant who withdraws from the study will have the following options regarding the
optional research samples (ie, host DNA sample):
 
The collected samples will be retained and used in accordance with the participant’s original
separate informed consent for optional research samples.
 
The participant may withdraw consent for optional research samples, in which case the
samples will be destroyed and no further testing will take place. To initiate the sample
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destruction process, the investigator must notify the sponsor study site contact of withdrawal
of consent for the optional research samples and to request sample destruction. The sponsor
study site contact will, in turn, contact the biomarker representative to execute sample
destruction. If requested, the investigator will receive written confirmation from the sponsor
that the samples have been destroyed.
Withdrawal From the Optional Research Sample (ie, host DNA)While Remaining in the
Main Study
The participant may withdraw consent for optional research samples while remaining in the
study. In such a case, the optional research samples will be destroyed. The sample destruction
process will proceed as described above.
Withdrawal From the Use of Samples in Future Research
The participant may withdraw consent for use of samples for future research (refer to Long-Term
Retention of Samples for Additional Future Research in Section 10.3, Appendix 3, Regulatory,
Ethical, and Study Oversight Considerations). In such a case, samples will be destroyed after
they are no longer needed for the clinical study. Details of the sample retention for research are
presented in the main ICF and in the separate ICF for optional research sample.
7.3. 
Lost to Follow-up
A participant will be considered lost to follow-up if he or she repeatedly fails to return for
scheduled visits and is unable to be contacted by the study site. A participant cannot be deemed
lost to follow-up until all reasonable efforts made by the study-site personnel to contact the
participant are deemed futile. The following actions must be taken if a participant fails to return
to the study site for a required study visit:
 
The study-site personnel must attempt to contact the participant to reschedule the missed
visit as soon as possible, to counsel the participant on the importance of maintaining the
assigned visit schedule, to ascertain whether the participant wishes to or should continue in
the study.
 
Before a participant is deemed lost to follow up, the investigator or designee must make
every reasonable effort to regain contact with the participant (where possible, 3 telephone
calls, e-mails, fax, and, if necessary, a certified letter to the participant’s last known mailing
address, or local equivalent methods). These contact attempts should be documented in the
participant’s medical records.
 
Should the participant continue to be unreachable, they will be considered to have
withdrawn from the study.
8. 
STUDY ASSESSMENTS AND PROCEDURES
Overview
The Schedule of Activities summarizes the frequency and timing of efficacy, PK, PD, immune,
biomarker, pharmacogenomic, safety, and PRO measurements applicable to this study.
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All PRO assessments and ECGs should be conducted/completed before any tests, procedures, or
other consultations for that visit.
Actual dates and times of assessments will be recorded in the source documentation and CRF.
Blood collections for PK assessments should be kept as close to the specified time as possible.
Samples obtained within 20% of the nominal time from dosing (eg, within +/- 12 minutes of a
60-minute time point) will not be captured as a protocol deviation if the exact time of the sample
collection is noted on the source document and CRF.
Additional serum or urine pregnancy tests may be performed, as determined necessary by the
investigator or required by local regulation, to establish the absence of pregnancy at any time
during the participation in the study.
The total blood volume to be collected from each participant will be approximately 335 mL
during the first 12 weeks of the intervention phase and including the screening visit. Between
Week 16 and Week 48, the total blood volume will be approximately 350 mL. During the
(extended) follow-up phase, up to approximately 430 mL of blood will 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, follow-up visits that
are only applicable for participants who completed NA treatment during the follow-up period),
but mainly driven by potential participation in the 48 weeks extended follow-up (see
Section 6.6).
In addition, for PBMC samples, which will be collected at selected sites only, 180-240 mL blood
will be collected. Optional intensive PK samples (approximately 66 mL)may be collected.
Repeat or unscheduled samples may be taken for safety reasons or for technical issues with the
samples.
Sample Collection and Handling
The actual dates and times of sample collection must be recorded in the CRF or laboratory
requisition form.
Refer to the Schedule of Activities for the timing and frequency of all sample collections.
Instructions for the collection, handling, storage, and shipment of samples are found in the
laboratory manual that will be provided. Collection, handling, storage, and shipment of samples
must be under the specified, and where applicable, controlled temperature conditions as indicated
in the laboratory manual.
Study-specific Materials
The investigator will be provided with the following supplies:
 
Investigator’s Brochure and any addenda for JNJ-3989 and JNJ-6379,
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 
Prescribing Information for ETV, TDF, and TAF,
 
Pharmacy manual/study site investigational product and procedures manual,
 
Laboratory manual,
 
PRO instruments,
 
IWRS Manual,
 
CRF Completion Guidelines,
 
Sample ICF.
8.1. 
Efficacy Assessments
Efficacy assessments will be performed at the time points indicated in the Schedule of Activities.
Qualitative and quantitative HBsAg and HBeAg, and quantitative HBcrAg as well as
anti-hepatitis B surface (HBs) and anti-hepatitis B e (HBe) antibodies will be determined using
standard commercially available serologic assays in a central laboratory. Samples for the
determination of HBsAg and HBeAg will be processed in real-time. Samples for the
determination of HBcrAg can be analyzed in batch and at the sponsor’s discretion.
HBV DNA and HBV RNA will be quantified at central laboratories using commercially
available in vitro nucleic acid amplification tests for the quantification of HBV DNA and HBV
RNA. Samples for the determination of HBV DNA will be processed in real-time. Samples for
the determination of HBV RNA can be analyzed in batch and at the sponsor’s discretion.
HBsAg, HBeAg, anti-HBs, 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). HBV DNA results will be provided to the investigator and
the sponsor from screening until the end of follow-up. 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. 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 investigational intervention is discontinued
in participants with virologic breakthrough (see Section 7.1),
 To assess if NA treatment completion criteria are met (see Section 6.6),
 To assess whether re-start of NA treatment during follow-up is needed (see Section 6.7).
In participants enrolled at a site with an on-site Fibroscan device, Fibroscan assessments will be
performed to determine changes in fibrosis.
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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 identify pre-existing baseline
polymorphisms and to evaluate emergence of mutations associated with JNJ-3989, JNJ-6379,
and/or NA treatment.
Sequencing of the HBV genome will be performed to monitor HBV variants present at the time
points indicated in the Schedule of Activities. Samples at baseline will be sequenced by default if
HBV DNA levels are within the ranges required for the sequencing assay. The sequencing of
samples after baseline 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 HBV infection and efficacy and safety of the study intervention,
including viral genotypic and phenotypic assessments.
8.1.2. 
Patient-reported Outcomes
The impact of study intervention on participants’ HRQoL, self-stigma level, and impression of
change will be assessed using PROs at predefined time points. The following PRO instruments
will be used: the HBQOL scale, an HBV-specific self-stigma PRO scale, and the PGIC scale.
Patient-reported outcome data collected may also be used by the sponsor for additional
exploratory assessments analyzing the effect of study intervention on HRQoL, self-stigma, and
impression of change, and for assessing the psychometric properties of the PRO instruments.
Patient-reported outcome assessments will be performed by all participants at sites where
appropriate translations are available. 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. 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.
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Hepatitis B Quality of Life Instrument, Version 1.0
The HBQOL32 version 1 is a 31-item disease-specific instrument designed to measure HRQoL
for participants with  CHB. The instrument includes 7 subscales/domains, including
psychological well-being, anticipation anxiety, vitality, stigma, vulnerability, transmission, and
viral response. Each of the 31 items is scored on a 5-level response scale. Each subscale score is
simply calculated as the average score among the items included in that subscale. In addition to
the 7 subscales, there is a single global score that reflects the results on all 31 items. The global
score is the average score among all the items in the HBQOL. Responses are transformed along a
0 to 100-point scale, where lower scores denote less HRQoL impact, and higher scores denote
more HRQoL impact (ie, 0 best score; 100 worst score).
It takes about 10 minutes to complete the HBQOL version 1.
See Section 10.10, Appendix 10, Hepatitis B Quality of Life Instrument for a representative
example of the HBQOL version 1.
HBV-specific Self-stigma PRO Scale, Version 1.0
The HBV-specific self-stigma scale is an hepatitis B-specific PRO instrument designed to assess
the experience and impact of self-stigma. The current version consists of 37 items. The items
cover aspects of self-stigma such as a) devaluation, inferiority, and worthlessness,
b)marginalization and alienation, c) secrecy and concealment, d) shame and guilt, and
e)withdrawal and social isolation. Each of the 37 items is graded on a 5-point Likert scale
(1 “Never”, 2 “Rarely”, 3 “Sometimes”, 4 “Often”, and 5 “Always”). 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.
The HBV-specific self-stigma PRO scale version 1 is provided in Section 10.11, Appendix 11,
HBV-specific Self-stigma PRO Scale.
Patient Global Impression of Change Scale, Version 1.0
The PGIC scale11,18 is a single-item PRO scale aimed at assessing the participant’s perceptions of
change (improvement or worsening) in how they feel overall compared to the beginning of the
study. Response options include: “Much better”, “Better”, “A little better”, “No change”, “A
little worse”, “Worse”, “Much worse”. It takes less than a minute to complete the scale. The
PGIC responses will be used as anchors to perform responder analyses and to evaluate the ability
to detect change for the HBQOL and the HBV-specific self-stigma PRO scale.
The PGIC scale version 1 is provided in Section 10.12, Appendix 12, Patient Global Impression
of Change Scale.
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8.2. 
Safety Assessments
Safety and tolerability will be assessed throughout the study from the time that the ICF is signed
until completion of the last study-related activity, which may include contact for follow-up of
safety. The evaluations of safety and tolerability will include monitoring of (S)AEs, physical
examinations (including body weight), vital signs measurements, triplicate 12-lead ECGs, and
clinical laboratory tests (including hematology, blood biochemistry, blood coagulation,
urinalysis, urine chemistry, and renal biomarkers) at predefined time points as specified in the
Schedule of Activities. Any clinically relevant changes occurring during the study must be
recorded in the Adverse Event section of the CRF.
AEs will be reported and followed by the investigator as specified in Section 8.3, Adverse
Events and Serious Adverse Events and Section 10.4, Appendix 4, Adverse Events: Definitions
and Procedures for Recording, Evaluating, Follow-Up, and Reporting.
Specific toxicity management plans in line with the known pharmacological profile of the study
intervention (and the drug classes) evaluated in this study are implemented (Section 8.3.6).
Any clinically significant abnormalities persisting at the end of the study/early withdrawal will
be followed by the investigator until resolution or until a clinically stable condition is reached.
Details regarding the IDMC and the IFLEP are provided in Section 9.5 and in the Committees
Structure in Section 10.3, Appendix 3, Regulatory, Ethical, and Study Oversight Considerations.
8.2.1. 
Physical Examinations
A complete physical examination (including height [at screening only], body weight, skin
examination, and other body systems) will be performed at screening, Week 24, and Week 48. A
symptom-directed physical examination (including body weight) will be performed at the time
points indicated in the Schedule of Activities.
A complete physical examination includes the following: general appearance, eyes, ears, nose,
throat, cardiovascular system, respiratory system, gastro-intestinal system, and skin and mucous
membranes. A neurological and musculoskeletal examination will be performed, as well as an
examination of the lymph nodes. Body weight and temperature will be measured. Height will be
measured at the screening visit only.
8.2.2. 
Vital Signs
Temperature, pulse rate, and supine SBP and DBP will be assessed at the time points indicated in
the Schedule of Activities.
Blood pressure and pulse rate measurements will be assessed with a completely automated
device. All values will preferably be registered on a built-in recorder so that measurements are
observer independent. Manual techniques will be used only if an automated device is not
available.
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Blood pressure and pulse rate measurements should be preceded by at least 5 minutes of rest in a
quiet setting without distractions (eg, television, cell phones).
Clinically relevant abnormalities in vital signs are defined in  Section 10.7, Appendix  7,
Cardiovascular Safety Abnormalities.
8.2.3. 
Electrocardiograms
Twelve-lead triplicate ECGs will be collected at the time points indicated in the Schedule of
Activities and when clinically indicated.
During the collection of ECGs, participants should be in a quiet setting without distractions (eg,
television, cell phones). Participants should rest in a supine position for at least 5 minutes before
ECG collection and should refrain from talking or moving arms or legs.
At each time point at which triplicate ECGs are required, 3 individual ECG tracings should be
obtained as closely as possible in succession, but no more than 2 minutes apart. The full set of
triplicates should be completed in less than 10 minutes.
Evaluation of the triplicate 12-lead ECGs will be based on the mean value of the triplicate
parameters.
All ECGs will be read centrally. Preferably, all ECGs will be read and interpreted under
supervision of one and the same qualified person. Day 1, pre-dose ECG assessment will also be
done locally on-site to determine eligibility.
Clinically relevant abnormalities in ECG are defined in Section 10.7, Appendix  7,
Cardiovascular Safety Abnormalities.
8.2.4. 
Clinical Safety Laboratory Assessments
Blood samples for serum chemistry, hematology, and coagulation, and a urine sample for
urinalysis, urine chemistry, and renal biomarkers will be collected as noted in Section 10.2,
Appendix 2, Clinical Laboratory Tests. The investigator must review the laboratory results,
document this review, and record any clinically relevant changes occurring during the study in
the AE section of the CRF. The laboratory reports must be filed with the source documents.
Participants need to have fasted for at least 10 hours before biochemistry samples are taken for
measurement of phosphate, calcium, creatinine, and lipids. Participants are to bring their oral
study intervention with them to each study visit and have that day’s intake at the site.
If a grade 3 or grade 4 laboratory abnormality occurs, that is considered to be clinically
significant by the investigator, a confirmatory test must be performed preferably within 48 hours
but no later than 72 hours after the results have become available.
For this study, the laboratory abnormality of cholesterol increase is identified as laboratory
abnormality of interest.
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8.3. 
Adverse Events and Serious Adverse Events
Timely, accurate, and complete reporting and analysis of safety information from clinical studies
are crucial for the protection of participants, investigators, and the sponsor, and are mandated by
regulatory agencies worldwide. The sponsor has established Standard Operating Procedures in
conformity with regulatory requirements worldwide to ensure appropriate reporting of safety
information; all clinical studies conducted by the sponsor or its affiliates will be conducted in
accordance with those procedures.
Adverse events will be reported by the participant (or, when appropriate, by a caregiver,
surrogate) for the duration of the study.
For further details on AEs and SAEs (Definitions and Classifications; Attribution Definitions;
Severity Criteria; Special Reporting Situations; Procedures) as well as product quality
complaints, refer to Section 10.4, Appendix 4, Adverse Events: Definitions and Procedures for
Recording, Evaluating, Follow-Up, and Reporting.
8.3.1. 
Time Period and Frequency for Collecting Adverse Event and Serious
Adverse Event Information
All Adverse Events
All AEs and special reporting situations, whether serious or non-serious, will be reported from
the time a signed and dated ICF is obtained until completion  of the participant’s last
study-related procedure, which may include contact for follow-up of safety. Serious AEs,
including those spontaneously reported to the investigator within 30 days after the last dose of
study intervention, must be reported using the SAE Form. The sponsor will evaluate any safety
information that is spontaneously reported by an investigator beyond the time frame specified in
the protocol.
Serious Adverse Events
All SAEs occurring during the study must be reported to the appropriate sponsor contact person
by study-site personnel within 24 hours of their knowledge of the event.
Information regarding SAEs will be transmitted to the sponsor using the SAE Form, which must
be completed and signed by a physician from the study site, and transmitted to the sponsor
within 24 hours. The initial and follow-up reports of an SAE should be made by facsimile (fax).
8.3.2. 
Method of Detecting Adverse Events and Serious Adverse Events
Care will be taken not to introduce bias when detecting AEs or SAEs. Open-ended and
nonleading verbal questioning of the participant is the preferred method to inquire about AE
occurrence.
Solicited Adverse Events
Solicited AEs are predefined local (at the injection site) and systemic events for which the
participant is specifically questioned.
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Unsolicited Adverse Events
Unsolicited AEs are all AEs for which the participant is not specifically questioned.
8.3.3. 
Follow-up of Adverse Events and Serious Adverse Events
AEs, including pregnancy, will be followed by the investigator as specified in Section 10.4,
Appendix 4, Adverse Events: Definitions and Procedures for Recording, Evaluating, Follow-up,
and Reporting.
8.3.4. 
Regulatory Reporting Requirements for Serious Adverse Events
The sponsor assumes responsibility for appropriate reporting of AEs to the regulatory authorities.
The sponsor will also report to the investigator (and the head of the investigational institute
where required) all suspected unexpected serious adverse reactions (SUSARs). The investigator
(or sponsor where required) must report SUSARs to the appropriate Independent Ethics
Committee/Institutional Review Board (IEC/IRB) that approved the protocol unless otherwise
required and documented by the IEC/IRB. A SUSAR will be reported to regulatory authorities
unblinded. Participating investigators and IEC/IRB will receive a blinded SUSAR summary,
unless otherwise specified.
8.3.5. 
Pregnancy
All initial reports of pregnancy in female participants or partners of male participants must be
reported to the sponsor by the study-site personnel within 24 hours of their knowledge of the
event using the appropriate pregnancy notification form. Abnormal pregnancy outcomes (eg,
spontaneous abortion, fetal death, stillbirth, congenital anomalies, ectopic pregnancy) are
considered SAEs and must be reported using the SAE Form. Any participant who becomes
pregnant during the study must discontinue further investigational intervention.
Follow-up information regarding the outcome of the pregnancy and any postnatal sequelae in the
infant will be required.
8.3.6. 
Specific Toxicities
For participants reporting ALT/AST elevations, rash, ISRs, acute systemic allergic reactions, 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. 
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
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study visit to repeat laboratory testing of AFP, ALT, AST, ALP, bilirubin (total and direct), INR,
albumin, and HBV DNA. Additional tests should be considered based on clinical judgement
(refer to Section 10.6, Appendix 6: Intervention-emergent ALT/AST Elevations). The
confirmatory visit should be scheduled as soon as possible, preferably within 7 days of the
receipt of the initial ALT/AST results. In case the repeat laboratory testing shows an isolated
ALT/AST elevation (ie, with stable albumin, bilirubin [total and direct], and INR) the participant
may continue study intervention. In case of confirmed ALT elevation >1,000 U/L and >3x the
baseline value, investigational intervention 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 50% of the maximal value.
If the ALT  and/or AST level is ≥3x ULN and ≥3x nadir and is associated with any of the
following laboratory results or clinical symptoms:
 INR ≥1.5, OR
 direct bilirubin >1.5x ULN, OR
 serum albumin <3.0 g/dL, OR
 ascites, hepatic encephalopathy, or liver-related symptoms (eg, severe fatigue, nausea,
vomiting, right upper quadrant pain in the absence of an alternative medical explanation),
OR
 other indication of reduced liver function
the participant should discontinue investigational intervention and should be monitored on a
weekly basis or as per good clinical practice until ALT and/or AST levels have returned to 50%
of the maximal value 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 during follow-up are presented in Section 6.7.
8.3.6.2. 
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 9 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
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[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, the study intervention
needs to be permanently discontinued. 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.
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.
8.3.6.3. 
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.
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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. Rechallenge is not allowed. The participant’s NA
treatment may be discontinued based on investigator judgement in consultation with the sponsor.
Grade 3 (Generalized Urticaria, Angioedema With Intervention Indicated, or Symptoms of
Mild Bronchospasm) and Grade 4 (Acute Anaphylaxis, Life-Threatening Bronchospasm,
or Laryngeal Edema)
Participants will permanently discontinue the intake of JNJ-3989 and JNJ-6379. 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.
8.3.6.4. 
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, if the abnormality is considered at least possibly related to JNJ-3989 or JNJ-6379,
and should be followed appropriately until resolution of 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. A second dog in the same dose group with pancytopenia recovered
after a drug holiday and was re-exposed uneventfully.
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-week 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.
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Status: Approved,  Date: 24 November 2021
Based on the non-clinical findings, any relevant abnormalities in hematologic parameters will be
carefully monitored as described below:
 
Platelet counts: <100,000 cells/mm3 or <100 GI/L or reduction from baseline by at least 50%
 
Hemoglobin: Decrease of at least 2 g/dL from baseline or at least Grade 2 (DAIDS)
 
Reticulocytes: Reduction to <0.5% of the RBC count
 
Neutrophil count: Treatment emergent reduction to at least Grade 2 (DAIDS)
In case any one of the above criteria are met, a confirmatory visit should be scheduled as soon as
possible, preferably within 7 days of the receipt of the initial results. Confirmation of the results
will trigger weekly or biweekly (every other week) unscheduled visits until improvement or
stabilization of the respective parameter(s). Stabilization is defined as no further significant
reduction over two consecutive visits.
In case of confirmed Grade 3 or Grade 4 hematologic abnormalities, discontinuation of
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. 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 ofJNJ-3989 (ie, JNJ-3976 and JNJ-3924) and/or
JNJ-6379 and/or NA (ETV, TAF, or tenofovir), as applicable. Plasma collected for PK may
additionally be used to evaluate safety or efficacy aspects that address concerns arising during or
after the study period, or for analysis of plasma concentrations of co-medications.
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CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
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Status: Approved,  Date: 24 November 2021
8.5.1. 
Evaluations
Venous blood samples will be collected for measurement of plasma concentrations of JNJ-3989
(ie, JNJ-3976 and JNJ-3924) and/or JNJ-6379 and/or NA (ETV, TAF, or tenofovir), as
applicable, at time points specified in the Schedule of Activities.
All participants will have sparse PK sampling. Participants who consent to participate in the
intensive PK subgroup (optional)will also undergo intensive PK sampling.
8.5.2. 
Analytical Procedures
Pharmacokinetics
At the sponsor’s discretion, a selection of plasma samples may  be analyzed to determine
concentrations of JNJ-3989 (ie, JNJ-3976 and JNJ-3924) and/or JNJ-6379 and/or NA as
applicable, using a validated liquid chromatography-mass spectrometry method or liquid
chromatography-fluorescence method, as applicable, by or under the supervision of the sponsor.
Plasma PK samples may be stored for future exploratory  analysis of protein binding or the
metabolite profile. Genetic analyses will not be performed on these plasma samples. Participant
confidentiality will be maintained.
To allow selection of samples, the bioanalytical laboratory will receive randomization lists per
IA and/or upon request of the bioanalytical scientist. Unblinding of the treatment code will be
performed at the bioanalytical laboratory only and will be subjected to a procedure that will
ensure that codes will not be revealed to anyone involved in the execution of the study.
8.5.3. 
Pharmacokinetic Parameters and Evaluations
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 parameter will be the area under the plasma
concentration-time curve over the dosing interval (tau) at steady-state (AUCtau). Additional
exposure parameters may be calculated if applicable.
Data from this study may be combined with data from a selection of Phase 1 and 2 studies via
population PK modelling to enable the calculation of the above PK parameters also in
participants who only underwent sparse PK sampling. If performed, the population PK analysis
will be described in a separate analysis plan and results will be reported separately.
8.6. 
Pharmacokinetics/Pharmacodynamics
Relationships of individual PK parameters (intensive PK and population PK, as applicable) for
JNJ-3989 (ie, JNJ-3976 and JNJ-3924) and/or JNJ-6379 and/or NA, as applicable, with selected
efficacy and/or with selected safety endpoints will be evaluated, if applicable.
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CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
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Status: Approved,  Date: 24 November 2021
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)-αin 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 blood sample will be collected from participants who consent separately to
this component of the study to allow for pharmacogenomic research, as necessary (where local
regulations permit).
In addition, other samples may be used for exploratory genetic 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. Samples can only be used to investigate the potential association of host genetic factors
with efficacy, safety, or PK of study intervention, or HBV infection, or may be used to develop
tests/assays related to study intervention or HBV infection.
8.9. 
Host Biomarkers
The study includes collection of blood samples for exploratory analysis of host blood biomarkers
at the host RNA, protein, and cell level. Sampling will be performed in all participants at the
time points indicated in the Schedule of Activities.
Samples can only be used for research related to study intervention or HBV infection or may be
used to develop tests/assays related to study intervention or HBV infection.
Blood samples will be taken at the time points indicated in the Schedule of Activities which can
be used to explore immunogenicity of JNJ-3989. The emergence of antibodies to JNJ-3989
(antidrug antibodies) might be analyzed using assays such as an enzyme-linked immunosorbent
assay.
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Status: Approved,  Date: 24 November 2021
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).
The primary analysis will be performed at the time when all participants have completed
Week 48 or discontinued earlier. The final analysis will be performed when all participants have
completed the last study visit or discontinued earlier. For the IAs, please refer to Section 9.5.
9.1. 
Statistical Hypotheses
Based on the primary efficacy endpoint, the proportion of participants meeting the NA treatment
completion criteria at Week 48, the primary hypotheses are as follows:
 
There is a positive dose-response signal across the 3 doses of JNJ-3989 (40, 100, and
200 mg) on the background of NA compared with NA treatment alone (control Arm 6).
 
One or both combination regimens JNJ-3989+JNJ-6379+NA and JNJ-6379+NA are more
efficacious than NA treatment alone (control Arm 6).
 
The combination regimen of JNJ-3989 (100 mg)+JNJ-6379+NA is more efficacious than
JNJ-3989 (100 mg)+NA and/or JNJ-6379+NA combination regimens.
A hybrid methodology that combines aspects of multiple testing with modeling techniques
(Multiple Comparison Procedure-Modeling [MCP-Mod]) will be used for declaring a
dose-response trend at 0.05 one-sided significance level and estimating the dose-response
relationship of JNJ-3989 doses +NA versus control Arm 6 (Placebo+Placebo+NA). Because the
primary efficacy endpoint is binary, the generalized MCP-Mod approach will be used on the
logit scale.28 A significant dose-response signal is declared if one or more prespecified models
(see Figure 2) have been found to be significant (multiple contrast test approach). The
statistically significant models form a model pool used to estimate the dose-response relationship
and select a dose (modeling step).
After a positive dose-response signal is established with statistical significance, then the testing
procedure 
continues 
in 
a fixed 
sequence, 
with 
the 
comparison 
of 
Arm 
1
(JNJ-3989+JNJ-6379+NA) with control Arm 6 at a one-sided alpha of 0.05. If Arm 1 is found
statistically superior to control Arm 6, then the combination regimen JNJ-6379+NA (Arm 5) is
compared to control Arm 6 at 0.05 one-sided alpha level. The Mantel-Haenszel (MH) test for the
difference of 2 proportions adjusted for the 2 randomization stratification factors will be applied.
For the comparisons among regimens (Arm 1, 3, and 5), the statistical testing will control for the
one-sided Type I error of 0.05 separately and independently from the comparisons against the
control arm described above. The testing among the regimens (Arm 1, 3, and 5) will be
performed using the min test approach. The JNJ-3989+JNJ-6379+NA  (Arm 1) combination
regimen will be declared statistically superior to the dual regimens (Arm 3 and 5) if both tests of
Arm 1 vs Arm 3 and Arm 1 vs Arm 5 demonstrate statistical significance at the one-sided 0.05
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CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
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Status: Approved,  Date: 24 November 2021
level. The MH test for the difference of 2 proportions adjusted for the 2 randomization
stratification factors will be applied.
9.2. 
Sample Size Determination
The total study sample size is 450 participants with a 2:2:2:2:1:1 randomization ratio, where
90 participants will be randomly allocated to each of the arms including a JNJ-3989 dose
(Arms 1 to 4) and 45 participants will be randomly assigned to each of the arms with no
JNJ-3989 component (Arms 5 and 6).
Statistical power to test a dose-response signal was assessed using the generalized version of the
MCP-Mod approach28 applied to the binary primary efficacy endpoint on the logit scale for
Arms 2, 3 and 4 (JNJ-3989 at 200, 100, and 40 mg dose, respectively  +NA), and Arm 6
(Placebo+Placebo+NA) as control.
Five different assumptions were made for the dose-response relationship on the logit scale (see
Figure 2) over the 3 doses of JNJ-3989 (40 mg, 100 mg and 200 mg) +NA.
Figure 2: 
Candidate Dose-response Models on the Logit Scale
Assuming a response rate for the highest dose of JNJ-3989 of at least 25%, and a one-sided alpha
level of 5%, the power to conclude a positive dose-response trend over the 3 JNJ-3989 doses on
the background of NA is ≥85% under all candidate models (see Table 6).
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JNJ-73763989 and JNJ-56136379
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Status: Approved,  Date: 24 November 2021
Table 6: 
Power to Conclude a Positive Dose-response Under the Assumed Candidate Dose-response
Models
Response Rate 
for the 
Highest
JNJ-3989
Dose
Emax  
(ED50=5 mg) 
Emax  
(ED50=100 mg) 
Linear 
SigEmax  
(ED50=110 mg, h=8.0) 
Exponential
(δ = 40)
20%  
0.582 
0.794 
0.877 
0.930 
0.949
25% 
0.851 
0.953 
0.978 
0.991 
0.994
30% 
0.956 
0.992 
0.999 
0.999 
1.000
ED50: dose that produces half of Emax; Emax: maximum effect; SigEmax: sigmoid Emax
The operational characteristics of the sequential testing approach as described in Section 9.1 are
summarized in Table 7 for a variety of scenarios. In all scenarios, the primary endpoint response
rate of the JNJ-3989 100 mg +NA  arm  is set between 25% and 35% whereas the rate of
JNJ-6379+NA and the combination regimen JNJ-3989 100-mg dose+JNJ-6379+NA vary. Under
these scenarios, the probability to find a significant signal (max trend test for positive
dose-response) is ≥87% for an absolute response rate in the 100 mg dose of JNJ-3989 (Arm 3) of
at least 25 %.
Simulations were conducted using the normal approximation test for the difference in binomial
proportions to determine the power level in the comparison of the primary efficacy endpoint
among the combination regimens at one-sided alpha of 0.05.
Assuming a response rate of 5% in control Arm 6, the sample size of 90 participants each in
combination Arms 1, 2, 3, and 4 and a sample size of 45 participants in combination Arm 5
(JNJ-6379+NA) and control Arm 6, provides a statistical power ≥84% to detect a difference of
≥20% in the primary endpoint between Arm 1 (JNJ-3989+JNJ-6379+NA) and control Arm 6,
and power ≥76% for a difference ≥20% between Arm 5 (JNJ-6379+NA) and control Arm 6
(Table 7), using a fixed sequence approach for controlling for multiplicity.
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Status: Approved,  Date: 24 November 2021
Table 7: 
Simulated-based Assessment of the Power of the Sequential Testing Strategy Under a Variety of
Scenarios (10,000 Runs/Scenario)
Response Rates 
Comparisons vs. NA Control 
Arm 6 vs. 
Comparisons Among Regimens
Arm 1 vs.
JNJ-3989+ 
JNJ-6379+ 
NA  
Arm 1 
(N=90) 
JNJ-3989 
+NA  
Arm 3 
(N=90) 
JNJ-6379 
+NA  
Arm 5  
(N=45) 
Deltaa 
MCT  JNJ-3989+ 
JNJ-6379+ 
NAb
   Arm 1 
JNJ-6379+ 
NAb 
   Arm 5 
JNJ-3989+NA  
  
      Arm 3 
JNJ-6379+ 
NA
 
    Arm 5 
Min Test
Both
Arm 3 and
Arm 5 c
0.25 
0.25 
0.25 
0 
0.876 
0.841 
0.765 
0.052 
0.045 
0.008
0.27 
0.27 
0.27 
0 
0.918 
0.897 
0.841 
0.051 
0.049 
0.010
0.3 
0.3 
0.30 
0 
0.958 
0.947 
0.915 
0.052 
0.047 
0.010
0.35 
0.35 
0.35 
0 
0.975 
0.973 
0.963 
0.050 
0.048 
0.009
0.25 
0.25 
0.10 
0 
0.881 
0.850 
0.200 
0.050 
0.686 
0.047
0.4 
0.25 
0.10 
0.15 
0.88 
0.88 
0.199 
0.699 
0.990 
0.698
0.45 
0.25 
0.10 
0.20 
0.881 
0.881 
0.197 
0.882 
0.998 
0.882
0.5 
0.25 
0.10 
0.25 
0.877 
0.877 
0.196 
0.972 
1.000 
0.972
0.4 
0.25 
0.25 
0.15 
0.877 
0.877 
0.792 
0.692 
0.528 
0.423
0.45 
0.25 
0.25 
0.20 
0.878 
0.878 
0.790 
0.880 
0.739 
0.680
0.5 
0.25 
0.25 
0.25 
0.873 
0.873 
0.790 
0.970 
0.889 
0.871
0.45 
0.30 
0.30 
0.15 
0.959 
0.959 
0.923 
0.676 
0.510 
0.409
0.5 
0.30 
0.30 
0.20 
0.956 
0.956 
0.921 
0.880 
0.718 
0.666
MCT: Multiple Contrast Test; NA: nucleos(t)ide analog
a Delta difference in primary endpoint response rate between JNJ 3989 (100 mg)+JNJ 6379+NA and JNJ 3989(100 mg) +NA
b Versus control Arm 6 with assumed response rate of 5%
c Min Test: probability that Arm 1 is statistically superior to both Arm 3 and Arm 5
Note: in this table “JNJ 3989” always refers to the JNJ 3989 100 mg dose
The chosen study sample size and randomization allocation will also provide acceptable power
levels for the comparison of different combination regimens, ie, JNJ-3989+JNJ-6379+NA
(Arm 1, 100-mg dose of JNJ-3989) versus JNJ-3989+NA (Arm 3, 100-mg dose of JNJ-3989),
and versus JNJ-6379+NA (Arm 5), respectively (Table 7). Based on the min test approach, Table
7 shows that the power levels vary depending on both the rate difference between Arm 1 and
Arm 3 and the assumed rate for Arm 5. For example, for the same delta of 25% between Arm 1
and Arm 3 and between Arm 1 and Arm 5, the power to conclude that Arm 1 is statistically
superior to Arm 3 and Arm 5 is 87%, assuming a response rate of 25% in both Arm 3 and 5.
9.3. 
Populations for Analyses
For purposes of analysis, the following populations are defined:
Population 
Description
Randomized 
All participants who were randomized in the study
Intent-to-treat (ITT) 
All participants who were randomly assigned to any of the 6 intervention arms and received
at least 1 dose of study intervention.
Safety  
All participants who received at least 1 dose of study intervention.
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Status: Approved,  Date: 24 November 2021
9.4. 
Statistical Analyses
9.4.1. 
Efficacy Analyses
To evaluate the efficacy, the primary analysis set will be the ITT population. Participants will be
analyzed according to the study intervention they were randomly assigned to.
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, and range. If the endpoint is binary or categorical, the
frequency distribution with the number and percentage of participants in each category will be
calculated. For time-to-event variables, a summary table including number of participants
included in the analysis, number of participants censored, 25th  and 75th  percentiles and median
time-to event will be shown by intervention arm. Graphic displays will also be used to
summarize the data. Summaries will also be presented by randomization stratification factors,
HBeAg status at screening and treatment history.
The baseline measurements are defined as the measurements taken closest to but before the first
dose of study intervention on Day 1.
Inferential analyses will be specified for each of the endpoints in the following sections. In
general, comparisons between intervention arms will be accompanied by appropriate confidence
intervals (CIs).
9.4.1.1. 
Primary Efficacy Endpoint (Proportion of Participants Meeting the NA
Treatment Completion Criteria at Week 48)
A hybrid methodology that combines aspects of multiple testing with modeling techniques
(MCP-Mod) will be used for evaluating a dose-response trend and estimating the dose-response
relationship of 3 JNJ-3989 doses in combination with NA versus NA treatment alone (control
Arm 6). Because the primary efficacy endpoint is binary, the generalized MCP-Mod approach
will be used on the logit scale. A significant dose-response signal is declared if one or more
prespecified models have been found to be significant (multiple contrast test approach). The
statistically significant models form a model pool used to estimate the dose-response relationship
and select a dose (modeling step).
A set of 5 candidate models (see Figure 2) will be used to cover a suitable range of possible
dose-response shapes in terms of the logit of the primary efficacy endpoint, the proportion of
participants meeting the NA treatment completion criteria at Week 48.
Each of the dose-response shapes in the candidate set will be tested using the corresponding
contrast t-test statistic, employing a critical value derived for the maximum of the t-test statistics
(based on the associated multivariate t-distribution) to ensure appropriate multiplicity correction
that preserves the one-sided Type I error rate at 0.05. A dose-response trend is established when
the maximum of the t-test statistics exceeds the critical value.
After establishing a significant dose-response signal, the testing procedures continue with the
comparison of the percentage of participants who completed the 48-week study intervention and
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Status: Approved,  Date: 24 November 2021
qualified for stopping NA treatment in Arms 1 and 5 against control Arm 6, respectively. The
Mantel-Haenszel (MH) test will be used in the pairwise comparisons at a one-sided alpha level
of 0.05 adjusting for the randomization stratification factors of screening HBeAg status and
treatment history. The Wilson  test will be used at a one-sided alpha level of 0.05 with no
adjustment for stratification factors as a secondary analysis.
The testing among the regimens (Arm 1 vs. Arm 3, and Arm 1 vs. Arm 5) will be performed
using the min test approach. The JNJ-3989+JNJ-6379+NA (Arm 1) combination regimen will be
declared statistically superior to the dual regimens (Arm 3 and 5) if both tests of Arm 1 vs Arm 3
and Arm 1 vs Arm 5 demonstrate statistical significance at the one-sided 0.05 level. The MH test
for the difference of 2 proportions adjusted for the 2 randomization stratification factors will be
applied to all pairwise comparisons.
As a secondary analysis, the primary efficacy endpoint will be compared between intervention
arms in a logistic regression model with factors for treatment arm, treatment status and HBeAg
status at screening. The potential impact of each intervention-by-randomization factor interaction
will be assessed by comparing the model with and without interaction terms. Appropriate
90% CIs will be also calculated without multiplicity adjustment. Exploratory subgroup
summaries will be displayed graphically in forest plots.
9.4.1.2. 
Key Secondary Efficacy Endpoint of Functional Cure at Week 72
(HBsAg Seroclearance 24 Weeks After Completion of All Study
Intervention at Week 48)
The functional cure rate at Week 72 is defined as the proportion of participants with HBsAg
seroclearance 24 weeks after completion of all study intervention at Week 48, including stopping
NA treatment. It will be used to support the JNJ-3989 dose selection and the regimen selection.
The same multi-step testing strategy as the one implemented for the primary efficacy endpoint
(see Section 9.4.1.1), using MCP-Mod and additional treatment arms pairwise comparisons with
NA control in a fixed sequence, as well as the min test approach separately for between-regimen
comparisons, will be used for this key secondary endpoint. However, the comparisons with NA
control in the testing strategy applied to this efficacy endpoint will be made against the NA
historical control benchmark of 5%, instead of the study NA control arm (Arm 6).
To provide evidence of superior efficacy of the JNJ-3989+JNJ-6379+NA regimen against the
JNJ-3989+NA and JNJ-6379+NA combination regimens, respectively, those tests will be
performed at a one-sided 0.025 alpha level for regulatory consideration. This analysis aims to
support the selection of the combination drug therapy to be studied in confirmatory studies.
Additionally, the functional cure efficacy endpoint will be summarized for the control Arm 6
with the point estimate paired with its 90% CI using the Clopper-Pearson exact method to assess
the consistency with the assumed historical control value.
As a secondary analysis, this key secondary endpoint will be compared between intervention
arms in a logistic regression model with factors for treatment arm, treatment status and HBeAg
status at screening. The potential impact of each randomization factor will be assessed by
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comparing the model with and without treatment-by-randomization interaction terms.
Appropriate 90% CIs will be also calculated without multiplicity adjustment. Exploratory
subgroup summaries will be displayed graphically in forest plots.
The comparison of functional cure rate at Week 72 against a historical control value is to
leverage the large amount of historical data available for more than 15 years of NA treatment,
where consistently low HBsAg loss rates were reported across different patient subpopulations
characterized by different baseline HBeAg status and treatment history status. The choice of 5%
as the historical control percentage for the HBsAg seroclearance 24 weeks after completion of all
study intervention at Week 48 is based on the results of a meta-analysis31 of the HBsAg
seroclearance rates after 48 weeks of treatment with NA (ETV, TDF or TAF) in 3 different
subgroups based on treatment history and HBeAg status (see Table 8).
Table 8: 
Meta-analysis of % HBsAg Seroclearance After 48 Weeks of Treatment
Meta analytic (Predictive) Distribution  
Heterogeneity
assessment
Cohorts 
N 
mean  
95% CI 
95% PI 
Qp 
I²
Not currently
treated
and
HBeAg positive
24 
2,410 
0.67 
[0.29, 1.56] 
[0.11, 4.17] 
0.050 
34.6 
Not currently 
treated
and
HBeAg negative
20 
2,864 
0.19 
[0.04, 0.84] 
[0.01, 3.33] 
0.108 
29.3
NA suppressed 
any HBeAg status
13 
679 
0.15 
[0.02, 1.06] 
[0.02, 1.06] 
0.987 
0.0
CI  confidence interval, PI  prediction interval, Qp  p value of Cochrane’s Q statistic for heterogeneity
Note: Meta analysis results (data on file). Preliminary results presented at the 68th Annual Meeting of the American Association
for the Study of Liver Diseases (2017).31 Draft publication in progress.
Although there was some variability between subgroups as well as trial heterogeneity, the mean
percentage of HBsAg seroclearance after 48 weeks of treatment with NA was consistently low
(<1%). The upper limit of the 95% prediction interval (PI) based on the meta-analytical
predictive probability distribution was the largest (4.17%) in the subgroup of treatment-naïve
HBeAg-positive patients. As the current study will enroll patients in all subgroups of treatment
history and HBeAg status, the value of 5% can be considered a conservative estimate for
percentage of HBsAg seroclearance after 48 weeks of NA treatment.
Given that the percentage of HBsAg seroclearance at the end of 48 weeks of NA treatment is not
expected to differ substantially from that percentage 24 weeks later, the 5% value derived from
this meta-analysis provides an adequate and conservative historical control treatment estimate of
this efficacy endpoint.
9.4.1.3. 
Other Secondary and Exploratory Efficacy Endpoints
Descriptive statistics will be used for all efficacy endpoints which will be summarized by
intervention arm. Comparisons among intervention arms will be done with no adjustment for
multiplicity. Specific key selected endpoints may be analyzed using suitable categorical data
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approaches (eg, Cochran-Mantel-Haenszel [CMH] 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.
The efficacy of the study intervention during the follow-up phase will be evaluated. The
proportion of participants with HBsAg seroclearance 48 weeks after completion of all study
intervention at Week 48, the proportion of participants with HBV DNA <LLOQ 24 and
48 weeks after completion of all study intervention at Week 48, the proportion of participants
meeting the NA treatment completion criteria during follow-up, the proportion of participants
with HBsAg seroclearance 24 and 48 weeks after completion of NA treatment at any time during
follow-up, the frequency of flares, and the proportion of participants requiring NA re-treatment
during follow-up will be tabulated by intervention arm. The comparison among the intervention
arms will be done using CMH chi-square test stratified by HBeAg status at screening (positive
versus negative) and treatment history (naïve or NA suppressed) and corresponding 90% CIs
without adjustment for multiple intervals.
The proportion of participants who reach HBV DNA undetectability after re-start of NA
treatment during follow-up will also be tabulated by intervention arm and the comparison among
the intervention arms will be done using the CMH chi-square test as described above.
The blood markers (such as HBsAg, HBeAg, HBV DNA, and ALT) during study intervention
and follow-up will also be summarized by treatment arm over time and plotted. The proportion
of participants with (sustained) reduction, suppression, and/or seroclearance considering single
and multiple markers (such as HBsAg, HBeAg, HBV DNA, and ALT) will be summarized
during follow-up. The proportion of participants with HBsAg and HBeAg seroconversion will be
tabulated by intervention arm. Descriptive statistics on values and changes from baseline over
time in HBsAg, HBeAg, and HBV DNA will be summarized by intervention arm. Additional
summaries will be provided by the randomization stratification factors (HBeAg status at
screening and treatment history).
The time to achieve HBsAg and HBeAg seroclearance will be summarized based on
Kaplan-Meier estimates in tables and graphs. The proportion of participants with HBsAg levels
and/or changes from baseline below/above different cut-offs, the proportion of HBeAg-positive
participants with HBeAg 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. The proportion of participants with virologic breakthrough will be summarized by
intervention arm.
Graphic data displays will also be used to summarize the efficacy data by intervention arm and
over time.
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In addition, the potential association between treatment outcome and baseline factors (including
but not limited to HBeAg status at screening, treatment history, baseline HBsAg levels, 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.
9.4.1.4. 
Resistance Analyses
The results of HBV viral sequencing will be evaluated by the sponsor virologist. Pretreatment
amino acid and/or nucleic acid substitutions in the HBV in all participants and relevant changes
in the HBV in participants not responding to study intervention will be tabulated and described.
Additional exploratory characterization of the HBV viral sequence and phenotype may be
performed and reported separately.
9.4.1.5. 
Patient-reported Outcome Analyses
Patient-reported outcome scores will be analyzed descriptively as mean scores over time, and (if
applicable) evaluated based on the proportion of participants experiencing a clinically important
improvement or worsening in PRO scores from baseline during study intervention and
follow-up. Analyses will also be performed on PRO score changes from baseline at specific time
points (Week 48, 72, 96) and between Week 48 and later time points for different subgroups:
participants who meet the NA treatment completion criteria at Week 48 versus those who do not,
and participants with versus participants without HBsAg seroclearance 24 weeks and 48 weeks
after completion of all study intervention at Week 48. Further details will be provided in the
SAP.
9.4.2. 
Safety Analyses
The safety analysis set will be used for all safety analyses.
Safety will be evaluated by means of descriptive summaries of AEs, clinical laboratory tests,
ECGs, vital signs, and physical examinations. The safety analysis will be done for each study
phase separately (ie, study intervention phase and follow-up phase). Results will be presented in
tabular format and/or graphically by intervention arm and over time, as appropriate.
Adverse Events
The verbatim terms used in the CRF by investigators to identify AEs will be coded using the
Medical Dictionary for Regulatory Activities. Intervention-emergent AEs are AEs with onset
during the intervention phase or that are a consequence of a pre-existing condition that has
worsened since baseline. All reported intervention-emergent AEs will be included in the
analysis. For each AE, the percentage of participants who experience at least 1 occurrence of the
given event will be summarized. AEs of interest will be analyzed separately.
Frequency tabulations, listings, or participant narratives may be provided, as appropriate, for
those participants who die, who discontinue study intervention due to an AE, or who experience
a severe or a serious AE.
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Clinical Laboratory Tests
Laboratory data will be summarized by laboratory test. Descriptive statistics (n, mean, SD,
minimum, median, and maximum) will be calculated for each laboratory analyte for observed
values and changes from baseline at each scheduled time point by intervention arm and study
phase. A graphical presentation of changes from baseline over time in selected laboratory tests
will be also used by intervention arm.
The laboratory abnormalities will be determined according to the criteria specified in the DAIDS
Toxicity Grading Scale (see Section 10.9, Appendix 9, DAIDS Table) or in accordance with the
normal ranges of the clinical laboratory if no gradings are available. The number and percentage
of the participants who experience (worst) laboratory abnormalities will be tabulated by
intervention arm and study phase. Shifts in toxicity grades will be cross-tabulated by intervention
arm and study phase.
Electrocardiogram
Electrocardiogram data will be summarized by ECG parameter. Descriptive statistics will be
calculated for observed values and changes from baseline at each scheduled time point by
intervention arm. Frequency tabulations of the abnormalities will be made.
The ECG variables that will be analyzed are heart rate, PR interval, QRS interval, RR interval,
QT interval, and QT interval corrected for heart rate according to Fridericia’s (QTcF).12
The percentage of participants with QTc interval >450 ms, >480 ms, or >500 ms will be
summarized, as will the percentage of participants with QTc interval increases from baseline
>30 ms or >60 ms. Shifts in QTc interval categories will be cross-tabulated by intervention arm
and study phase.
All clinically relevant abnormalities in ECG waveform that are changes from the baseline
readings will be reported (eg, changes in T-wave morphology or the occurrence of U-waves).
Vital Signs
Descriptive statistics of temperature, pulse rate, and supine SBP and DBP will be calculated for
observed values and changes from baseline at each scheduled time point. The percentage of
participants with values beyond clinically important limits will be summarized by intervention
arm.
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-3976,
JNJ-3924, JNJ-6379 and/or NA, as applicable, and for the derived plasma PK parameters
(noncompartmental analysis and population PK analysis).
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For each participant with intensive PK sampling, plasma concentration-time data of JNJ-3976,
JNJ-3924, JNJ-6379, and/or 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. Pharmacokinetic parameters will be subjected to an
exploratory graphical analysis, including various transformations, to get a general overview.
Population PK analysis of plasma concentration-time data of JNJ-3976, JNJ-3924, JNJ-6379,
and/or NA (as applicable) will be performed using nonlinear mixed-effects modeling. Data may
be combined with those from selected studies to support a relevant structural model. Available
baseline participant characteristics (demographics, laboratory variables, genotypes, race, etc.)
will be included in the model as necessary. Individual estimates of PK parameters will be
generated from the population PK analysis for potential use in exposure-response analysis. 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-3989 (ie, JNJ-3976 and JNJ-3924),
JNJ-6379, 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 of the
population PK analysis will be described in a separate analysis plan and results will be reported
separately.
Pharmacokinetic/Pharmacodynamic Analyses
Relationships of PK parameters for JNJ-3976, JNJ-3924, JNJ-6379, and/or NA (ETV, TAF
and/or tenofovir), as applicable, with selected efficacy and with selected safety endpoints will be
evaluated, applying graphical tools and, if feasible, statistical models.
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
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.
Analyses will be conducted at the sponsor’s discretion.
Pharmacogenomic Analyses
The statistical approach for analyzing the exploratory host DNA research may depend on the
objective of the analyses (efficacy, safety, and PK) and possibly relevant genes at the time of
analysis. Analyses will be conducted at the sponsor’s discretion, will always be under the
sponsor’s supervision, and results will be presented either in the clinical study report or a
separate report.
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Host Biomarkers 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 differences between participants. Analyses will be conducted at the sponsor’s
discretion, will always be under the sponsor’s supervision, and results will be presented either in
the clinical study report or a separate report.
9.5. 
Interim Analyses
Interim analyses will be conducted to monitor safety and evaluate the time course of different
disease markers to support the sponsor’s internal decision-making, interactions with health
authorities, as well as inform decisions about additional studies and/or investigation of other
treatment combinations. The IAs are planned when:
 
All participants have completed Week 60 (ie, 12 weeks after completion of investigational
intervention at Week 48), or discontinued earlier.
 
All participants have completed Week 72 (ie, 24 weeks after completion of investigational
intervention at Week 48), or discontinued earlier.
 
All participants have completed Week 96 (ie, 48 weeks after completion of investigational
intervention at Week 48), or discontinued earlier.
One additional IA may be performed at the sponsor’s discretion when all participants, who
completed NA treatment at Week 48 of follow-up, have completed Week 120, ie, Week 24 of the
extended follow-up, or discontinued earlier, to support interactions with health authorities.
All IAs will be performed by the sponsor because occurring after the primary analysis, which
will be conducted at the time when all participants have completed Week 48 or discontinued
earlier. Both primary and interim analyses will be based on all data available at the predefined
cut-off time, including data at later time points for those participants who have reached
subsequent visits.
Detailed approaches to define the decision rules, and the methods for IA of the safety and
efficacy endpoints of interest will be described in the IA SAP.
9.5.1. 
Independent Data Monitoring Committee
An IDMC will be established for continuous monitoring of SAEs, AEs leading to
discontinuation, and ALT flares. In addition, the IDMC will review the unblinded results of
efficacy parameters measured by different HBV disease blood markers (eg, HBV DNA, HBeAg,
HBsAg, etc).
The IDMC will have access and use the totality of unblinded results to make recommendations,
including all safety and efficacy assessments available at a given interim milestone. Possible
recommendations include, but are not limited to, stopping the study or any of the study
interventions for safety concerns. The Sponsor Committee will review the time course of the
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different HBV disease blood markers to make further decisions. Decision rules will be detailed
and listed in the IDMC charter and will be non-binding.
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). 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.
9.5.2. 
Independent Flare Expert Panel
An IFLEP will also be appointed. The IFLEP is composed of 3 independent medical experts with
experience and expertise in hepatitis B and its treatment. The IFLEP will monitor ALT flares and
will make recommendations regarding flare management based on an analysis of aggregate data.
In order to allow for an unbiased assessment, members of the committee will not serve as study
investigators or as members of the IDMC and will be blinded to the treatment assigned to each
participant.
Further details on the IFLEP process will be included in the IFLEP charter.
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10. 
SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS
10.1. Appendix 1: Abbreviations and Definitions of Terms
AE 
adverse event
AFP  
alpha-fetoprotein
A/H  
animal/human ratio
ALP  
alkaline phosphatase
ALT  
alanine aminotransferase
AST  
aspartate aminotransferase
AUC  
area under the plasma concentration-time curve
AUC0-xh 
area under the plasma concentration-time curve from administration to x h
AUC0-last 
area under the plasma concentration-time curve from administration to last quantifiable sampling
point
AUCtau  
area under the plasma concentration-time curve over the dosing interval (tau) at steady-state
AUC∞ 
area under the plasma concentration-time curve to last sampling point from time zero extrapolated
to infinity
BCRP  
breast cancer resistance protein
BMI 
body mass index
bpm  
beats per minute
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
CMH  
Cochran-Mantel-Haenszel
CRF  
case report form
CT  
computed tomography
CV  
coefficient of variation
CYP  
cytochrome P450
DAIDS  
Division of Acquired Immunodeficiency Syndrome
DBP  
diastolic blood pressure
DDI 
drug-drug interaction
DNA  
deoxyribonucleic acid
EASL 
European Association for the Study of the Liver
ECG  
electrocardiogram
ED50 
dose that produces half of Emax
eDC  
electronic data capture
EFD  
embryofetal development
eGFR  
estimated glomerular filtration rate
ELISpot 
enzyme-linked immunospot
Emax  
maximum effect
Ext FU Wx  
Extended Follow-up Week x
EOS  
end of study
ETV  
entecavir
FSH  
Follicle-stimulating hormone
FU Wx  
Follow-up Week x
GCP  
Good Clinical Practice
GLP  
Good Laboratory Practice
HBc 
hepatitis B core protein
HBQOL 
Hepatitis B Quality of Life
HBcrAg 
hepatitis B core-related antigen
HBe 
hepatitis B e
HBeAg 
hepatitis B e antigen
HBs 
hepatitis B surface
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HBsAg 
hepatitis B surface antigen
HBV  
hepatitis B virus
HCC  
hepatocellular carcinoma
HCV  
hepatitis C virus
HDV  
hepatitis D virus
HIV-1(-2) 
human immunodeficiency virus type 1 (type 2)
HRQoL 
health-related quality of life
HRT  
hormonal replacement therapy
IA  
interim analysis
IB  
Investigator’s Brochure
ICF  
informed consent form
ICH  
International Council for Harmonisation of Technical Requirements for Pharmaceuticals for
Human Use
ICMJE 
International Committee of Medical Journal Editors
ICS  
intracellular cytokine staining
IDMC  
Independent Data Monitoring Committee
IEC  
Independent Ethics Committee
IFLEP  
Independent Flare Expert Panel
IFN  
interferon
IFN-γ 
gamma interferon
IgM  
immunoglobulin M
IL 
interleukin
INR  
International Normalized Ratio
IRB  
Institutional Review Board
ISR  
injection site reaction
ITT  
Intent-to-treat
IU/mL 
International Units Per Milliliter
IWRS  
interactive web response system
LLN  
lower limit of normal
LLOQ  
lower limit of quantification
MCP-Mod 
Multiple Comparison Procedure-Modeling
MCT  
Multiple Contrast Test
MH  
Mantel-Haenszel
MoA  
mode of action
MRI 
magnetic resonance imaging
NA  
nucleos(t)ide analog
NOAEL 
no observed adverse effect level
PD 
pharmacodynamic(s)
PGIC  
Patient Global Impression of Change
PK 
pharmacokinetic(s)
PBMC  
peripheral blood mononuclear cell
pgRNA  
pre-genomic ribonucleic acid
PI 
prediction interval
PQC  
Product Quality Complaint
PRO  
patient-reported outcome
qd 
once daily
QTcF  
QT interval corrected for heart rate according to Fridericia
RBC  
red blood cell
RNA  
ribonucleic acid
RNAi 
ribonucleic acid interference
SAE 
serious adverse event
SAP  
Statistical Analysis Plan
SBP 
systolic blood pressure
SD 
standard deviation
SigEmax  
sigmoid Emax
siRNA  
small interfering RNA
SUSAR  
suspected unexpected serious adverse reaction
t1/2term  
terminal half-life
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tmax  
time to reach the maximum plasma concentration
TAF  
tenofovir alafenamide
TDF  
tenofovir disoproxil fumarate
TNF  
tumor necrosis factor
ULN 
upper limit of normal
US  
United States
WBC  
white blood cell
Definitions of Terms
Study intervention  
JNJ-73763989 or placebo, JNJ-56136379 or placebo, and NA (either ETV, TDF, or TAF)
Functional cure 
HBsAg seroclearance 24 weeks after end of treatment
HBsAg or HBeAg 
seroclearance
HBsAg or HBeAg negativity, respectively, based on the assay used
HBsAg or HBeAg 
seroconversion
HBsAg or HBeAg negativity and anti-HBs or anti-HBe antibody positivity, respectively
Virologic 
breakthrough  
Confirmed on-treatment HBV DNA increase by >1 log10 IU/mL from nadir or confirmed
on-treatment HBV DNA level >200 IU/mL in participants who had HBV DNA level
<LLOQ of the HBV DNA assay
ALT/AST nadir 
Lowest ALT/AST value during study participation
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applicable).
Urine
Chemistry
(quantitative
measurement)
Creatinine
Sodium
Phosphate
Glucose
Protein
Albumin
Renal
Biomarkers
Retinol binding protein
Beta-2-microglobulin
Note: These renal biomarkers are to assess proximal renal tubular function.
Other
Screening Tests
 
Serum pregnancy testing for women of childbearing potential at screening.
 
Urine pregnancy testing for women of childbearing potential at the time points
indicated in the Schedule of Activities.
 
Follicle-stimulating hormone (FSH) testing for postmenopausal women at
screening.
 
Testing for hepatitis A, B, C, D, and E virus and HIV-1 and -2 at screening.
 
Testing for HBsAg, HBeAg, HBcrAg, and anti-HBs and anti-HBe antibodies at
the time points indicated in the Schedule of Activities.
 
Determination of coagulation parameters will be performed at the time points
indicated in the Schedule of Activities. INR will be calculated by the central
laboratory.
 
Alpha-fetoprotein at screening.
Other optional
tests in
response to
ALT flare
(refer to
Section 10.6
Appendix 6:
Intervention-
emergent
ALT/AST
Elevations)
Testing for HIV-1 and -2, and hepatitis A, C, and E
Testing for CMV, HSV, EBV infection
Ig-Electrophoresis
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10.3. Appendix 3: Regulatory, Ethical, and Study Oversight Considerations
REGULATORY AND ETHICAL CONSIDERATIONS
Investigator Responsibilities
The investigator is responsible for ensuring that the study is performed in accordance with the
protocol, current International Council for Harmonisation of Technical Requirements for
Pharmaceuticals for Human Use (ICH) guidelines on Good Clinical Practice (GCP), and
applicable regulatory and country-specific requirements.
Good Clinical Practice is an international ethical and scientific quality standard for designing,
conducting, recording, and reporting studies that involve the participation of human participants.
Compliance with this standard provides public assurance that the rights, safety, and well-being of
study participants are protected, consistent with the principles that originated in the Declaration
of Helsinki, and that the study data are credible.
Protocol Amendments
Neither the investigator nor the sponsor will modify this protocol without a formal amendment
by the sponsor. All protocol amendments must be issued by the sponsor, and signed and dated by
the investigator. Protocol amendments must not be implemented without prior IEC/IRB
approval, or when the relevant competent authority has raised any grounds for non-acceptance,
except when necessary to eliminate immediate hazards to the participants, in which case the
amendment must be promptly submitted to the IEC/IRB and relevant competent authority.
Documentation of amendment approval by the investigator and IEC/IRB must be provided to the
sponsor. When the change(s) involve only logistic or administrative aspects of the study, the
IEC/IRB (where required) only needs to be notified.
During the course of the study, in situations where a departure from the protocol is unavoidable,
the investigator or other physician in attendance will contact the appropriate sponsor
representative listed in the Contact Information page(s), which will be provided as a separate
document. Except in emergency situations, this contact should be made before implementing any
departure from the protocol. In all cases, contact with the sponsor must be made as soon as
possible to discuss the situation and agree on an appropriate course of action. The data recorded
in the CRF and source documents will reflect any departure from the protocol, and the source
documents will describe this departure and the circumstances requiring it.
Regulatory Approval/Notification
This protocol and any amendment(s) must be submitted to the appropriate regulatory authorities
in each respective country, if applicable. A study may not be initiated until all local regulatory
requirements are met.
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Required Prestudy Documentation
The following documents must be provided to the sponsor before shipment of study intervention
to the study site:
 
Protocol and amendment(s), if any, signed and dated by the principal investigator
 
A copy of the dated and signed (or sealed, where appropriate per local regulations), written
IEC/IRB approval of the protocol, amendments, ICF, any recruiting materials, and if
applicable, participant compensation programs. This approval must clearly identify the
specific protocol by title and number and must be signed (or sealed, where appropriate per
local regulations) by the chairman or authorized designee.
 
Name and address of the IEC/IRB, including a current list of the IEC/IRB members and
their function, with a statement that it is organized and operates according to GCP and the
applicable laws and regulations. If accompanied by a letter of explanation, or equivalent,
from the IEC/IRB, a general statement may be substituted for this list. If an investigator or a
member of the study-site personnel is a member of the IEC/IRB, documentation must be
obtained to state that this person did not participate in the deliberations or in the
vote/opinion of the study.
 
Regulatory authority approval or notification, if applicable
 
Signed and dated statement of investigator (eg, Form FDA 1572), if applicable
 
Documentation of investigator qualifications (eg, curriculum vitae)
 
Completed investigator financial disclosure form from the principal investigator, where
required
 
Signed and dated clinical trial agreement, which includes the financial agreement
 
Any other documentation required by local regulations
The following documents must be provided to the sponsor before enrollment of the first
participant:
 
Completed investigator financial disclosure forms from all subinvestigators
 
Documentation of subinvestigator qualifications (eg, curriculum vitae)
 
Name and address of any local laboratory conducting tests for the study, and a dated copy of
current laboratory normal ranges for these tests, if applicable
 
Local laboratory documentation demonstrating competence and test reliability
(eg, accreditation/license), if applicable
Independent Ethics Committee or Institutional Review Board
Before the start of the study, the investigator (or sponsor where required) will provide the
IEC/IRB with current and complete copies of the following documents (as required by local
regulations):
 
Final protocol and, if applicable, amendments
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 
Sponsor-approved ICF (and any other written materials to be provided to the participants)
 
IB (or equivalent information) and amendments/addenda
 
Sponsor-approved participant recruiting materials
 
Information on compensation for study-related injuries or payment to participants for
participation in the study, if applicable
 
Investigator's curriculum vitae or equivalent information (unless not required, as
documented by the IEC/IRB)
 
Information regarding funding, name of the sponsor, institutional affiliations, other potential
conflicts of interest, and incentives for participants
 
Any other documents that the IEC/IRB requests to fulfill its obligation
This study  will be undertaken only after the IEC/IRB has given full approval of the final
protocol, amendments (if any, excluding the ones that are purely administrative, with no
consequences for participants, data or study conduct, unless required locally), the ICF, applicable
recruiting materials, and participant compensation programs, and the sponsor has received a copy
of this approval. This approval letter must be dated and must clearly identify the IEC/IRB and
the documents being approved.
Approval for the collection of optional samples for research and for the corresponding ICF must
be obtained from the IEC/IRB. Approval for the protocol can be obtained independent of this
optional research component.
During the study the investigator (or sponsor where required) will send the following documents
and updates to the IEC/IRB for their review and approval, where appropriate:
 
Protocol amendments (excluding the ones that are purely administrative, with no
consequences for participants, data or study conduct)
 
Revision(s) to ICF and any other written materials to be provided to participants
 
If applicable, new or revised participant recruiting materials approved by the sponsor
 
Revisions to compensation for study-related injuries or payment to participants for
participation in the study, if applicable
 
New edition(s) of the IB and amendments/addenda
 
Summaries of the status of the study at intervals stipulated in guidelines of the IEC/IRB (at
least annually)
 
Reports of AEs that are serious, unlisted/unexpected, and associated with the study
intervention
 
New information that may adversely affect the safety of the participants or the conduct of
the study
 
Deviations from or changes to the protocol to eliminate immediate hazards to the
participants
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 
Report of deaths of participants under the investigator's care
 
Notification if a new investigator is responsible for the study at the site
 
Development Safety Update Report and Line Listings, where applicable
 
Any other requirements of the IEC/IRB
For all protocol amendments (excluding the ones that are purely administrative, with no
consequences for participants, data or study conduct), the amendment and applicable ICF
revisions must be submitted promptly to the IEC/IRB for review and approval before
implementation of the change(s).
At least once a year, the IEC/IRB will be asked to review and reapprove this study, where
required.
At the end of the study, the investigator (or sponsor where required) will notify the IEC/IRB
about the study completion.
Country Selection
This study will only be conducted in those countries where the intent is to launch or otherwise
help ensure access to the developed product if the need for the product persists, unless explicitly
addressed as a specific ethical consideration in Section  4.2.1, Study-Specific Ethical Design
Considerations.
Other Ethical Considerations
For study-specific ethical design considerations, refer to Section 4.2.1.
FINANCIAL DISCLOSURE
Investigators and subinvestigators will provide the sponsor with sufficient, accurate financial
information in accordance with local regulations to allow the sponsor to submit complete and
accurate financial certification or disclosure statements to the appropriate regulatory authorities.
Investigators are responsible for providing information on financial interests during the course of
the study and for 1 year after completion of the study.
INFORMED CONSENT PROCESS
Each participant must give written consent according to local requirements after the nature of the
study has been fully explained. The ICF(s) must be signed before performance of any
study-related activity. The ICF(s) that is/are used must be approved by both the sponsor and by
the reviewing IEC/IRB and be in a language that the participant can read and understand. The
informed consent should be in accordance with principles that originated in the Declaration of
Helsinki, current ICH and GCP guidelines, applicable regulatory requirements, and sponsor
policy.
Before enrollment in the study, the investigator or an authorized member of the study-site
personnel must explain to potential participants the aims, methods, reasonably anticipated
benefits, and potential hazards of the study, and any discomfort participation in the study may
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entail. Participants will be informed that their participation is voluntary and that they may
withdraw consent to participate at any time. They will be informed that choosing not to
participate will not affect the care the participant will receive for the treatment of his or her
disease. Participants will be told that alternative treatments are available if they refuse to take
part and that such refusal will not prejudice future treatment. Finally, they will be told that the
investigator will maintain a participant identification register for the purposes of long-term
follow up if needed and that their records may be accessed by health authorities and authorized
sponsor personnel without violating the confidentiality of the participant, to the extent permitted
by the applicable law(s) or regulations. By signing the ICF the participant is authorizing such
access. It also denotes that the participant agrees to allow his or her study physician to recontact
the participant for the purpose of obtaining consent for additional safety evaluations, and
subsequent disease-related treatments, if needed.
The participant will be given sufficient time to read the ICF and the opportunity to ask questions.
After this explanation and before entry into the study, consent should be appropriately recorded
by means of the participant's personally dated signature. After having obtained the consent, a
copy of the ICF must be given to the participant.
Participants will be asked for consent to provide optional host DNA samples for research (where
local regulations permit). After informed consent for the study is appropriately obtained, the
participant will be asked to sign and personally date a separate ICF indicating agreement to
participate in the optional research component. Refusal to participate in the optional research will
not result in ineligibility for the study. A copy of this signed ICF will be given to the participant.
If the participant is unable to read or write, an impartial witness should be present for the entire
informed consent process (which includes reading and explaining all written information) and
should personally date and sign the ICF after the oral consent of the participant is obtained.
DATA PROTECTION
Privacy of Personal Data
The collection and processing of personal data from participants enrolled in this study will be
limited to those data that are necessary to fulfill the objectives of the study.
These data must be collected and processed with adequate precautions to ensure confidentiality
and compliance with applicable data privacy protection laws and regulations. Appropriate
technical and organizational measures to protect the personal data against unauthorized
disclosures or access, accidental or unlawful destruction, or accidental loss or alteration must be
put in place. Sponsor personnel whose responsibilities require access to personal data agree to
keep the identity of participants confidential.
The informed consent obtained from the participant includes explicit consent for the processing
of personal data and for the investigator/institution to allow direct access to his or her original
medical records (source data/documents) for study-related monitoring, audit, IEC/IRB review,
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and regulatory inspection. This consent also addresses the transfer of the data to other entities
and to other countries.
The participant has the right to request through the investigator access to his or her personal data
and the right to request rectification of any data that are not correct or complete. Reasonable
steps will be taken  to respond to such a request, taking into consideration the nature of the
request, the conditions of the study, and the applicable laws and regulations.
Exploratory DNA, PK/PD, and biomarker research is not conducted under standards appropriate
for the return of data to participants. In addition, the sponsor cannot make decisions as to the
significance of any findings resulting from exploratory research. Therefore, exploratory research
data will not be returned to participants or investigators, unless required by law or local
regulations. Privacy and confidentiality of data generated in the future on stored samples will be
protected by the same standards applicable to all other clinical data.
LONG-TERM RETENTION OF SAMPLES FOR ADDITIONAL FUTURE RESEARCH
Samples collected in this study may be stored for up to 15 years (or according to local
regulations) for additional research. Samples will only be used to understand JNJ-3989 and
JNJ-6379, and the NAs (ETV, TDF, and TAF), to understand chronic HBV infection, to
understand differential intervention responders, and to develop tests/assays related to JNJ-3989
and JNJ-6379, the NAs (ETV, TDF, and TAF), and chronic HBV infection. The research may
begin at any time during the study or the post-study storage period.
Stored samples will be coded throughout the sample storage and analysis process and will not be
labeled with personal identifiers. Participants may withdraw their consent for their samples to be
stored for research (refer to Section 7.2.1, Withdrawal From the Use of Research Samples).
COMMITTEES STRUCTURE
Independent Data Monitoring Committee
An IDMC will be established for continuous monitoring of SAEs, AEs leading to
discontinuation, and ALT flares. In addition, at prespecified IA time points, the IDMC will
review the unblinded results of the IAs of efficacy parameters measured by different HBV
disease blood markers (eg, HBV DNA, HBeAg, 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). 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.
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Independent Flare Expert Panel
An IFLEP will also be appointed. The IFLEP is composed of 3 independent medical experts with
experience and expertise in hepatitis B and its treatment. The IFLEP will monitor ALT flares and
will make recommendations regarding flare management based on an analysis of aggregate data.
In order to allow for an unbiased assessment, members of the committee will not serve as study
investigators or as members of the 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
All information, including but not limited to information regarding JNJ-3989 and JNJ-6379 or
the sponsor's operations (eg, patent application, formulas, manufacturing processes, basic
scientific data, prior clinical data, formulation information) supplied by the sponsor to the
investigator and not previously published, and any data, including pharmacogenomic or
exploratory  biomarker research data, generated as a result of this study, are considered
confidential and remain the sole property of the sponsor. The investigator agrees to maintain this
information in confidence and use this information only to accomplish this study and will not use
it for other purposes without the sponsor's prior written consent.
The investigator understands that the information developed in the study will be used by the
sponsor in connection with the continued development ofJNJ-3989 and JNJ-6379, and thus may
be disclosed as required to other clinical investigators or regulatory agencies. To permit the
information derived from the clinical studies to be used, the investigator is obligated to provide
the sponsor with all data obtained in the study.
The results of the study will be reported in a Clinical Study Report generated by the sponsor and
will contain data from all study sites that participated in the study as per protocol. Recruitment
performance or specific expertise related to the nature and the key assessment parameters of the
study will be used to determine a coordinating investigator for the study. Results of
pharmacogenomic or exploratory biomarker analyses performed after the Clinical Study Report
has been issued will be reported in a separate report and will not require a revision of the Clinical
Study Report.
Study participant identifiers will not be used in publication of results. Any work created in
connection with performance of the study and contained in the data that can benefit from
copyright protection (except any publication by the investigator as provided for below) shall be
the property of the sponsor as author and owner of copyright in such work.
Consistent with Good Publication Practices and International Committee of Medical Journal
Editors (ICMJE) guidelines, the sponsor shall have the right to publish such primary
(multicenter) data and information without approval from the investigator. The investigator has
the right to publish study site-specific data after the primary data are published. If an investigator
wishes to publish information from the study, a copy of the manuscript must be provided to the
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sponsor for review at least 60 days before submission for publication or presentation. Expedited
reviews will be arranged for abstracts, poster presentations, or other materials. If requested by
the sponsor in writing, the investigator will withhold such publication for up to an additional
60 days to allow for filing of a patent application. In the event that issues arise regarding
scientific integrity or regulatory compliance, the sponsor will review these issues with the
investigator. The sponsor will not mandate modifications to scientific content and does not have
the right to suppress information. For multicenter study designs and sub-study approaches,
secondary results generally should not be published before the primary endpoints of a study have
been published. Similarly, investigators will recognize the integrity of a multicenter study by not
submitting for publication data derived from the individual study site until the combined results
from the completed study have been submitted for publication, within 18 months after the study
end date, or the sponsor confirms there will be no multicenter study publication. Authorship of
publications resulting from this study will be based on the guidelines on authorship, such as
those described in the ICMJE Recommendations for the Conduct, Reporting, Editing and
Publication of Scholarly Work in Medical Journals, which state that the named authors must
have made a significant contribution to the conception or design of the work; or the acquisition,
analysis, or interpretation of the data for the work; and drafted the work or revised it critically for
important intellectual content; and given final approval of the version  to be published; and
agreed to be accountable for all aspects of the work in  ensuring that questions related to the
accuracy or integrity of any part of the work are appropriately investigated and resolved.
Registration of Clinical Studies and Disclosure of Results
The sponsor will register and disclose the existence of and the results of clinical studies as
required by law. The disclosure of the final study results will be performed after the EOS  in
order to ensure the statistical analyses are relevant.
DATA QUALITY ASSURANCE
Data Quality Assurance/Quality Control
Steps to be taken to ensure the accuracy and reliability of data include the selection of qualified
investigators and appropriate study sites, review of protocol procedures with the investigator and
study-site personnel before the study, periodic monitoring visits by the sponsor, and direct
transmission of clinical laboratory data from a central laboratory into the sponsor's data base.
Written instructions will be provided for collection, handling, storage, and shipment of samples.
Guidelines for CRF completion will be provided and reviewed with study-site personnel before
the start of the study.
The sponsor will review CRF for accuracy and completeness during on-site monitoring visits and
after transmission to the sponsor; any discrepancies will be resolved with the investigator or
designee, as appropriate. After upload of the data into the study database they will be verified for
accuracy and consistency with the data sources.
CASE REPORT FORM COMPLETION
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Case report forms are prepared and provided by the sponsor for each participant in electronic
format. All data relating to the study must be recorded in CRF. All CRF entries, corrections, and
alterations must be made by the investigator or authorized study-site personnel. The investigator
must verify that all data entries in the CRF are accurate and correct.
The study data will be transcribed by study-site personnel from the source documents onto an
electronic CRF, if applicable. Study-specific data will be transmitted in a secure manner to the
sponsor.
Worksheets may be used for the capture of some data to facilitate completion of the CRF. Any
such worksheets will become part of the participant's source documents. Data must be entered
into CRF in English. The CRF must be completed as soon as possible after a participant visit and
the forms should be available for review at the next scheduled monitoring visit.
All participative measurements (eg, pain scale information or other questionnaires) will be
completed by the same individual who made the initial baseline determinations whenever
possible.
If necessary, queries will be generated in the electronic data capture (eDC) tool. If corrections to
a CRF are needed after the initial entry into the CRF, this can be done in either of the following
ways:
 Investigator and study-site personnel can make corrections in the eDC tool at their own
initiative or as a response to an auto query (generated by the eDC tool).
 Sponsor or sponsor delegate can generate a query for resolution by the investigator and
study-site personnel.
SOURCE DOCUMENTS
At a minimum, source documents consistent in the type and level of detail with that commonly
recorded at the study site as a basis for standard medical care must be available for the following:
participant identification, eligibility, and study identification; study discussion and date of signed
informed consent; dates of visits; results of safety and efficacy parameters as required by the
protocol; record of all AEs and follow-up of AEs; concomitant medication; intervention
receipt/dispensing/return records; study intervention  administration information; and date of
study completion and reason for early discontinuation of study intervention or withdrawal from
the study, if applicable.
The author of an entry in the source documents should be identifiable.
Specific details required as source data for the study and source data collection methods will be
reviewed with the investigator before the study and will be described in the monitoring
guidelines (or other equivalent document).
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The following data will be recorded directly into the CRF and will be considered source data:
 Race
 Blood pressure and pulse/heart rate
 Height and weight
 Details of physical examination
The minimum source documentation requirements for Section 5.1, Inclusion Criteria and
Section 5.2, Exclusion Criteria that specify a need for documented medical history are as
follows:
 Referral letter from treating physician or
 Complete history of medical notes at the site
 Discharge summaries
Inclusion and exclusion criteria not requiring documented medical history must be verified at a
minimum by participant interview or other protocol required assessment (eg, physical
examination, laboratory assessment) and documented in the source documents.
An eSource system may be utilized, which contains data traditionally maintained in a hospital or
clinic record to document medical care (eg, electronic source documents) as well as the clinical
study-specific data fields as determined by the protocol. This data is electronically extracted for
use by the sponsor. If eSource is utilized, references made to the CRF in the protocol include the
eSource system but information collected through eSource may not be limited to that found in
the CRF.
MONITORING
The sponsor will use a combination of monitoring techniques (central, remote, or on-site
monitoring)to monitor this study. 
The sponsor will perform on-site monitoring visits as frequently as necessary. The monitor will
record dates of the visits in a study site visit log that will be kept at the study site. The first
post-initiation visit will be made as soon as possible after enrollment has begun. At these visits,
the monitor will compare the data entered into the CRF with the source documents
(eg, hospital/clinic/physician’s office medical records); a sample may be reviewed. The nature
and location of all source documents will be identified to ensure that all sources of original data
required to complete the CRF are known to the sponsor and study-site personnel and are
accessible for verification by the sponsor study-site contact. If electronic records are maintained
at the study site, the method of verification must be discussed with the study-site personnel.
Direct access to source documents (medical records) must be allowed for the purpose of
verifying that the recorded data are consistent with the original source data. Findings from this
review will be discussed with the study-site personnel. The sponsor expects that, during
monitoring visits, the relevant study-site personnel will be available, the source documents will
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be accessible, and a suitable environment will be provided for review of study-related
documents. The monitor will meet with the investigator on a regular basis during the study to
provide feedback on the study conduct.
In addition to on-site monitoring visits, remote contacts can occur. It is expected that during
these remote contacts, study-site personnel will be available to provide an update on the progress
of the study at the site.
Central monitoring will take place for data identified by the sponsor as requiring central review.
ON-SITE AUDITS
Representatives of the sponsor's clinical quality assurance department may visit the study site at
any time during or after completion of the study to conduct an audit of the study in compliance
with regulatory guidelines and company policy. These audits will require access to all study
records, including source documents, for inspection. Participant privacy must, however, be
respected. The investigator and study-site personnel are responsible for being present and
available for consultation during routinely scheduled study-site audit visits conducted by the
sponsor or its designees.
Similar auditing procedures may also be conducted by agents of any regulatory body, either as
part of a national GCP compliance program or to review the results of this study in support of a
regulatory submission. The investigator should immediately notify the sponsor if he or she has
been contacted by a regulatory agency concerning an upcoming inspection.
RECORD RETENTION
In compliance with the ICH/GCP guidelines, the investigator/institution will maintain all CRF
and all source documents that support the data collected from each participant, as well as all
study documents as specified in ICH/GCP Section 8, Essential Documents for the Conduct of a
Clinical Trial, and all study documents as specified by the applicable regulatory requirement(s).
The investigator/institution will take measures to prevent accidental or premature destruction of
these documents.
Essential documents must be retained until at least 2 years after the last approval of a marketing
application in an ICH region and until there are no pending or contemplated marketing
applications in an ICH region  or until at least 2 years have elapsed since the formal
discontinuation of clinical development of the investigational product. These documents will be
retained for a longer period if required by the applicable regulatory requirements or by an
agreement with the sponsor. It is the responsibility of the sponsor to inform the
investigator/institution as to when these documents no longer need to be retained.
If the responsible investigator retires, relocates, or for other reasons withdraws from the
responsibility of keeping the study records, custody must be transferred to a person who will
accept the responsibility. The sponsor must be notified in writing of the name and address of the
new custodian. Under no circumstance shall the investigator relocate or dispose of any study
documents before having obtained written approval from the sponsor.
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If it becomes necessary for the sponsor or the appropriate regulatory authority to review any
documentation relating to this study, the investigator/institution must permit access to such
reports.
STUDY AND SITE START AND CLOSURE
First Act of Recruitment
The first site open is considered the first act of recruitment and it becomes the study start date.
Study Termination
The sponsor reserves the right to close the study site or terminate the study at any time for any
reason at the sole discretion of the sponsor. Study sites will be closed upon study completion. A
study site is considered closed when all required documents and study supplies have been
collected and a study-site closure visit has been performed.
The investigator may initiate study-site closure at any time, provided there is reasonable cause
and sufficient notice is given in advance of the intended termination.
Reasons for the early closure of a study site by the sponsor or investigator may include but are
not limited to:
 Failure of the investigator to comply with the protocol, the requirements of the IEC/IRB or
local health authorities, the sponsor's procedures, or GCP guidelines
 Inadequate recruitment of participants by the investigator
 Discontinuation of further study intervention development
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10.4. Appendix 4: Adverse Events: Definitions and Procedures for Recording,
Evaluating, Follow-up, and Reporting
ADVERSE EVENT DEFINITIONS AND CLASSIFICATIONS
Adverse Event
An AE is any untoward medical occurrence in a clinical study participant administered a
medicinal (investigational or non-investigational) product. An AE does not necessarily have a
causal relationship with the intervention. An AE can therefore be any unfavorable and
unintended sign (including an abnormal finding), symptom, or disease temporally associated
with the use of a medicinal (investigational or non-investigational) product, whether or not
related to that medicinal (investigational or non-investigational) product (Definition per ICH).
This includes any occurrence that is new in onset or aggravated in severity or frequency from the
baseline condition, or abnormal results of diagnostic procedures, including laboratory test
abnormalities.
Note: The sponsor collects AEs starting with the signing of the ICF (refer to All Adverse Events
under Section  8.3.1, Time Period and Frequency for Collecting Adverse Events and Serious
Adverse Events Information, for time of last AE recording).
Serious Adverse Event
An SAE based on ICH and European Union  Guidelines on Pharmacovigilance for Medicinal
Products for Human Use is any untoward medical occurrence that at any dose:
 
Results in death
 
Is life-threatening
(The participant was at risk of death at the time of the event. It does not refer to an event that
hypothetically might have caused death if it were more severe.)
 
Requires inpatient hospitalization or prolongation of existing hospitalization
 
Results in persistent or significant disability/incapacity
 
Is a congenital anomaly/birth defect
 
Is a suspected transmission of any infectious agent via a medicinal product
 
Is Medically Important*
*Medical and scientific judgment should be exercised in deciding whether expedited reporting is
also appropriate in other situations, such as important medical events that may not be
immediately life threatening or result in death or hospitalization but may jeopardize the
participant or may require intervention to prevent one of the other outcomes listed in the
definition above. These should usually be considered serious.
If a serious and unexpected AE occurs for which there is evidence suggesting a causal
relationship between the study intervention and the event (eg, death from anaphylaxis), the event
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must be reported as a serious and unexpected suspected adverse reaction even if it is a
component of the study endpoint (eg, all-cause mortality).
Unlisted (Unexpected) Adverse Event/Reference Safety Information
An AE is considered unlisted if the nature or severity is not consistent with the applicable
product reference safety information. For JNJ-3989 and JNJ-6379, the expectedness of an AE
will be determined by whether or not it is listed in the IB. For ETV, TDF, and TAF  with a
marketing authorization, the expectedness of an AE will be determined by whether or not it is
listed in the package insert/summary of product characteristics.
Adverse Event Associated With the Use of the Intervention
An AE is considered associated with the use of the intervention  if the attribution is possible,
probable, or very likely by the definitions listed below (see Attribution Definitions).
ATTRIBUTION DEFINITIONS
Not Related
An AE that is not related to the use of the intervention.
Doubtful
An AE for which an alternative explanation is more likely, eg, concomitant treatment(s),
concomitant disease(s), or the relationship in time suggests that a causal relationship is unlikely.
Possible
An AE that might be due to the use of the intervention. An alternative explanation,
eg, concomitant treatment(s), concomitant disease(s), is inconclusive. The relationship in time is
reasonable; therefore, the causal relationship cannot be excluded.
Probable
An AE that might be due to the use of the intervention. The relationship in time is suggestive
(eg, confirmed by dechallenge). An alternative explanation is less likely, eg, concomitant
treatment(s), concomitant disease(s).
Very Likely
An AE that is listed as a possible adverse reaction and cannot be reasonably explained by an
alternative explanation, eg, concomitant treatment(s), concomitant disease(s). The relationship in
time is very suggestive (eg, it is confirmed by dechallenge and rechallenge).
SEVERITY CRITERIA
An assessment of severity grade will be made by the investigator using the general categorical
descriptors outlined in the DAIDS Toxicity Grading Scale (see Section 10.9, Appendix 9,
DAIDS Table).
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The investigator should use clinical judgment in assessing the severity of events not directly
experienced by the participant (eg, laboratory abnormalities).
SPECIAL REPORTING SITUATIONS
Safety events of interest on a sponsor study intervention in an interventional study  that may
require expedited reporting or safety evaluation include, but are not limited to:
 
Overdose of a sponsor study intervention
 
Suspected abuse/misuse of a sponsor study intervention
 
Accidental or occupational exposure to a sponsor study intervention
 
Medication error involving a sponsor product (with or without participant/patient exposure
to the sponsor study intervention, eg, name confusion)
 
Exposure to a sponsor study intervention from breastfeeding
Special reporting situations should be recorded in the CRF. Any special reporting situation that
meets the criteria of an SAE should be recorded on the SAE page of the CRF.
PROCEDURES
All Adverse Events
All AEs, regardless of seriousness, severity, or presumed relationship to study intervention, must
be recorded using medical terminology in the source document and the CRF. Whenever possible,
diagnoses should be given when signs and symptoms are due to a common etiology (eg, cough,
runny nose, sneezing, sore throat, and head congestion should be reported as "upper respiratory
infection"). Investigators must record in the CRF their opinion concerning the relationship of the
AE to study therapy. All measures required for AE management must be recorded in the source
document and reported according to sponsor instructions.
For all studies with an outpatient phase, including open-label studies, the participant must be
provided with a "wallet (study) card" and instructed to carry this card with them for the duration
of the study indicating the following:
 
Study number
 
Statement, in the local language(s), that the participant is participating in a clinical study
 
Investigator's name and 24-hour contact telephone number
 
Local sponsor's name and 24-hour contact telephone number (for medical personnel only)
 
Site number
 
Participant number
 
Any other information that is required to do an emergency breaking of the blind
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Serious Adverse Events
All SAEs that have not resolved by the end of the study, or that have not resolved upon
discontinuation of the participant's participation in the study, must be followed until any of the
following occurs:
 
The event resolves
 
The event stabilizes
 
The event returns to baseline, if a baseline value/status is available
 
The event can be attributed to agents other than the study intervention or to factors unrelated
to study conduct
 
It becomes unlikely that any additional information can be obtained (participant or health
care practitioner refusal to provide additional information, lost to follow-up after
demonstration of due diligence with follow-up efforts)
Suspected transmission of an infectious agent by a medicinal product will be reported as an SAE.
Any event requiring hospitalization (or prolongation of hospitalization) that occurs during the
course of a participant's participation in a study must be reported as an  SAE, except
hospitalizations for the following:
 
Hospitalizations not intended to treat an acute illness or AE (eg, social reasons such as
pending placement in long-term care facility)
 
Surgery or procedure planned before entry into the study (must be documented in the CRF).
Note: Hospitalizations that were planned before the signing of the ICFs, and where the
underlying condition for which the hospitalization was planned has not worsened, will not
be considered SAEs. Any AE that results in a prolongation of the originally planned
hospitalization is to be reported as a new SAE.
The cause of death of a participant in a study, whether or not the event is expected or associated
with the study intervention, is considered an SAE.
CONTACTING SPONSOR REGARDING SAFETY
The names (and corresponding telephone numbers) of the individuals who should be contacted
regarding safety issues or questions regarding the study are listed in the Contact Information
page(s), which will be provided as a separate document.
PRODUCT QUALITY COMPLAINT HANDLING
A product quality complaint (PQC) is defined as any suspicion of a product defect related to
manufacturing, labeling, or packaging, ie, any dissatisfaction relative to the identity, quality,
durability, or reliability of a product, including its labeling or package integrity. A PQC may have
an impact on the safety and efficacy of the product. Timely, accurate, and complete reporting and
analysis of PQC information from studies are crucial for the protection of participants,
investigators, and the sponsor, and are mandated by regulatory agencies worldwide. The sponsor
has established procedures in conformity with regulatory requirements worldwide to ensure
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appropriate reporting of PQC information; all studies conducted by the sponsor or its affiliates
will be conducted in accordance with those procedures.
Procedures
All initial PQCs must be reported to the sponsor by the study-site personnel within 24 hours after
being made aware of the event.
If the defect is combined with an  SAE, the study-site personnel must report the PQC to the
sponsor according to the SAE reporting timelines (refer to Section 8.3.1, Time Period and
Frequency for Collecting Adverse Event and Serious Adverse Event Information). A sample of
the suspected product should be maintained for further investigation if requested by the sponsor.
Contacting Sponsor Regarding Product Quality
The names (and corresponding telephone numbers) of the individuals who should be contacted
regarding product quality issues are listed in the Contact Information page(s), which will be
provided as a separate document.
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10.5. Appendix 5: Rash Management
Table 9: 
Management of Rash Events by Severity Grade
Definition 
Study Intervention
Action
Activities by Daya
Referral to
Dermatologist and
Dermatology
Activities
Grade 1 rash
(with or without pruritus)b
Erythema 
Study intervention
intake may be
continued at the
investigator’s
discretion
Day 0: optional on site visit for initial
rash evaluation may be performed at
the investigator’s discretion.
Safety laboratory assessments may be
performed at the investigator’s
discretion (recommended if visit
occurs).
Digital pictures* of skin lesions may be
taken at the investigator’s discretion.
Determine if participant was adhering
to the recommended sun-protective
measures. If appropriate, provide sun
protection counseling.
Day 1 and thereafter: appropriate
follow-up visits at the investigator’s
discretion until resolution of rash.
Safety laboratory assessments and
photography (digital pictures* of skin
lesions) may be performed at the
investigator’s discretion.
* Digital pictures to be taken at the
clinical site upon consent of the
participant.
Not required
Grade 2 rash
(with or without pruritus)b
Diffuse, maculopapular rash,
or dry desquamation
Study intervention
intake may be
continued at the
investigator’s
discretion
Day 0: required on-site visit (if a visit
is not possible, telephone contact with
the participant should take place to
collect information and give advice on
the necessary measures to be taken).
Referral to
dermatologist at the
discretion of the
investigatorc
Biopsy not required,
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Table 9: 
Management of Rash Events by Severity Grade
Definition 
Study Intervention
Action
Activities by Daya
Referral to
Dermatologist and
Dermatology
Activities
Safety laboratory assessments may be
performed at the investigator’s
discretion (recommended).
Digital pictures* of skin lesions may be
taken at the investigator’s discretion.
Digital pictures* of skin lesions are
recommended in case consultation of a
dermatologist is required. Determine if
participant was adhering to the
recommended sun-protective measures.
If appropriate, provide sun protection
counseling.
Day 1 and thereafter: appropriate
follow-up visits at the investigator’s
discretion until resolution of rash or
until clinical stability is reached.
Safety laboratory assessments are
required on Day 1 and are required
thereafter only if the previous values
were abnormal (but may be performed
at the investigator’s discretion). If the
rash progresses to a higher grade,
safety laboratory assessments of the
higher grade should be followed.
Digital pictures* of skin lesions may be
taken at the investigator’s discretion.
* Digital pictures to be taken at the
clinical site upon consent of the
participant.
but may be performed
at the dermatologist’s
discretion
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Table 9: 
Management of Rash Events by Severity Grade
Definition 
Study Intervention
Action
Activities by Daya
Referral to
Dermatologist and
Dermatology
Activities
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; no
rechallenge allowed
NA treatment may be
discontinued based
on investigator
judgement in
consultation with the
sponsor
Day 0: required on-site visit.
Safety laboratory assessments required
to be performed.
Digital pictures* of skin lesions may be
taken at the investigator’s discretion
(recommended).
Determine if participant was adhering
to the recommended sun-protective
measures. If appropriate, provide sun
protection counseling.
Day 1: required on-site visit.
Safety laboratory assessments required
to be performed.
Digital pictures* of skin lesions may be
taken at the investigator’s discretion
(recommended).
Further visit(s): appropriate follow-up
required until resolution of rash or until
clinical stability is reached.
Safety laboratory assessments and
photography (digital pictures* of skin
lesions) are recommended to be
performed until the rash severity
resolves to grade 2 or grade 1.
* Digital pictures to be taken at the
clinical site upon consent of the
participant.
Requiredc
Biopsy not required,
but may be performed
at the dermatologist’s
discretion.
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Table 9: 
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; no
rechallenge allowed
NA treatment may
be discontinued
based on investigator
judgement in
consultation with the
sponsor
Day 0: required on-site visit.
Safety laboratory assessments required
to be performed.
Digital pictures* of skin lesions may be
taken at the investigator’s discretion
(recommended).
Determine if participant was adhering
to the recommended sun-protective
measures. If appropriate, provide sun
protection counseling.
Day 1: required on-site visit.
Safety laboratory assessments required
to be performed.
Digital pictures* of skin lesions may be
taken at the investigator’s discretion
(recommended).
Further visit(s): appropriate follow-up
required until resolution of rash or until
clinical stability is reached.
Safety laboratory assessments and
photography (digital pictures* of skin
lesions) are recommended to be
performed until the rash severity
resolves to grade 2 or grade 1.
* Digital pictures to be taken at the
clinical site upon consent of the
participant.
Requiredc
Biopsy required and to
be performed as soon
as possible after the
onset of the rash.
AE: adverse event; ALT: alanine aminotransferase; AST: aspartate aminotransferase; NA: nucleos(t)ide analog.
a 
Day 0 of the rash is the first day of investigator assessment and not the first day of rash as reported by the participant. The initial visit should be conducted as soon as
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Table 9: 
Management of Rash Events by Severity Grade
Definition 
Study Intervention 
Action 
Activities by Daya 
Referral to
Dermatologist and
Dermatology
Activities
possible after the participant contacts the investigator to report the AE (ie, preferably on Day 0). The initial visit and subsequent visits to manage the rash may
require unscheduled visit(s).
b 
The participant should be advised to contact the investigator immediately if there is any worsening of the rash, if any systemic signs or symptoms appear, or if
mucosal involvement develops. In case the rash evolves to a higher grade than that first observed, management of the rash should follow the guidelines indicated for
the higher grade.
c 
If applicable, dermatologist visit should occur preferably within 24 hours after onset of rash.
Notes:
 Local laboratory assessments are to be used for rash management. The values of the local laboratory assessments need to be transcribed in the eCRF by the study site
personnel.
 Digital pictures that are collected, dermatological consultation reports or biopsy reports that become available, should be de-identified and provided to the sponsor.
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10.6. Appendix 6: Intervention-emergent ALT/AST Elevations
a: Additional tests may be considered based on clinical judgement in case of confirmed ALT flares
- Hepatitis A, Delta, C, E: IgM anti-HAV; delta IgM, IgG & PCR, HCV RNA, IgM & IgG anti-HEV, HEV RNA
- CMV, HSV, EBV infection: IgM & IgG anti-CMV, IgM & IgG anti-HSV; IgM & IgG anti-EBV, PCR
- HIV
- Ig –Electrophoresis
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10.7. Appendix 7: Cardiovascular Safety –Abnormalities
ECG
All important abnormalities from the ECG readings will be listed.
Abnormality Code 
ECG parameter
Heart Rate 
PR  
QRS  
QTcorrected
Abnormalities on actual values
Abnormally low  
<45 bpm  
NAP  
- 
-
Abnormally high  
120 bpm  
>220 ms 
120 ms 
-
Borderline prolonged QT 
- 
- 
- 
450 ms < QTc ≤480 ms
Prolonged QT  
- 
- 
- 
480 ms < QTc <500 ms
Pathologically prolonged QT 
- 
- 
- 
QTc >500 ms
Abnormalities on changes from baseline (∆QTc)
Normal QTc change 
- 
- 
- 
∆QTc <30 ms
Borderline QTc change 
- 
- 
- 
30 ms < ∆QTc <60 ms
Abnormally high QTc change 
- 
- 
- 
∆QTc >60 ms
ECG: electrocardiogram; NAP = not applicable
For absolute QTc parameters the categories are defined based on the ICH E14 GuidanceFa
Vital Signsb
The following abnormalities will be defined for vital signs:
Abnormality Code 
Vital Signs parameter
Pulse 
DBP  
SBP
Abnormalities on actual values
Abnormally low  
45 bpm  
50 mmHg 
90 mmHg
Grade 1 or mild 
- 
>90 mmHg - <100 mmHg 
>140 mmHg - <160 mmHg
Grade 2 or moderate 
- 
100 mmHg - <110 mmHg 
160 mmHg - <180 mmHg
Grade 3 or severe 
- 
110 mmHg 
180 mmHg
Abnormally high  
120 bpm  
- 
-
DBP: diastolic blood pressure; SBP: systolic blood pressure
a The clinical evaluation of QT/QTc interval prolongation and proarrhythmic potential for non-antiarrhythmic drugs
CHMP/ICH/2/04, May 2005.
b The classification of AEs related to hypotension and hypertension will be done according to the DAIDS grading
scale.
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10.8. Appendix 8: Contraceptive and Barrier Guidance
Participants must follow contraceptive measures as outlined in Section  5.1, Inclusion Criteria.
Pregnancy information will be collected and reported as noted in Section 8.3.5, Pregnancy and
Section 10.4, Appendix 4, Adverse Events: Definitions and Procedures for Recording,
Evaluating, Follow-up, and Reporting.
Definitions
Woman of Childbearing Potential (WOCBP)
A woman is considered fertile following menarche and until becoming postmenopausal unless
permanently sterile (see below).
Woman Not of Childbearing Potential
 
premenarchal
A premenarchal state is one in which menarche has not yet occurred.
 
postmenopausal
A postmenopausal state is defined as no menses for 12 months without an alternative
medical cause. A high FSH level (>40 IU/L or mIU/mL) in the postmenopausal range may
be used to confirm a postmenopausal state in women not using hormonal contraception or
hormonal replacement therapy (HRT), however in the absence of 12 months of amenorrhea,
a single FSH measurement is insufficient.
If there is a question about menopausal status in women on HRT, the woman will be
required to use one of the non-estrogen-containing hormonal highly effective contraceptive
methods if she wishes to continue HRT during the study.
 
permanently sterile
Permanent sterilization methods include hysterectomy, bilateral salpingectomy, and bilateral
oophorectomy.
Note: If the childbearing potential changes after start of the study (eg, a premenarchal woman
experiences menarche) or the risk of pregnancy changes (eg, a woman who is not heterosexually
active becomes active), a woman must begin a highly effective method of contraception, as
described throughout the inclusion criteria.
If reproductive status is questionable, additional evaluation should be considered.
Contraceptive (birth control) use by men or women should be consistent with local regulations
regarding the acceptable methods of contraception for those participating in clinical studies.
Typical use failure rates may differ from those when used consistently and correctly. Use should
be consistent with local regulations regarding the use of contraceptive methods for participants in
clinical studies.
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Examples of Contraceptives
EXAMPLES OF CONTRACEPTIVESa ALLOWED DURING THE STUDY INCLUDE:
USER INDEPENDENT
Highly Effective Methods That Are User Independent Failure rate of <1% per year when used
consistently and correctly.
 Implantable progestogen-only hormone contraception associated with inhibition of ovulationb
 Intrauterine device
 Intrauterine hormone-releasing system
 Bilateral tubal occlusion
 Vasectomized partner
(Vasectomized partner is a highly effective contraceptive method provided that the partner is the
sole sexual partner of the woman of childbearing potential and the absence of sperm has been
confirmed. If not, additional highly effective method of contraception should be used.
Spermatogenesis cycle is approximately 74 days.)
USER DEPENDENT
Highly Effective Methods That Are User Dependent Failure rate of <1% per year when used
consistently and correctly.
 Combined (estrogen- and progestogen-containing) hormonal contraception associated with
inhibition of ovulationb
 oral
 intravaginal
 transdermal
 injectable
 Progestogen-only hormone contraception associated with inhibition of ovulationb
 oral
 injectable
 Sexual abstinence
(Sexual abstinence is considered a highly effective method only if defined as refraining from
heterosexual intercourse during the entire period of risk associated with the study intervention.
The reliability of sexual abstinence needs to be evaluated in relation to the duration of the study
and the preferred and usual lifestyle of the participant.)
NOT ALLOWED AS SOLE METHOD OF CONTRACEPTION DURING THE STUDY (not
considered to be highly effective - failure rate of 1% per year)
 Progestogen-only oral hormonal contraception where inhibition of ovulation is not the primary
mode of action.
 Male or female condom with or without spermicidec
 Cap, diaphragm, or sponge with spermicide
 A combination of male condom with either cap, diaphragm, or sponge with spermicide
(double-barrier methods)c
 Periodic abstinence (calendar, symptothermal, post-ovulation methods)
 Withdrawal (coitus-interruptus)
 Spermicides alone
 Lactational amenorrhea method
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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.
b Hormonal contraception may be susceptible to interaction with the study intervention, which may
reduce the efficacy of the contraceptive method. In addition, consider if the hormonal contraception
may interact with the study intervention.
c Male condom and female condom should not be used together (due to risk of failure with friction).
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10.9. Appendix 9: DAIDS Table
DIVISION OF AIDS (DAIDS) TABLE FOR GRADING THE SEVERITY OF ADULT
AND PEDIATRIC ADVERSE EVENTS, VERSION 2.1, PUBLISH DATE: JULY, 2017
The DAIDS grading table is a descriptive terminology to be utilized for AE reporting in this
study. A grading (severity) scale is provided for each AE term.
General Instructions
Grading Adult and Pediatric Adverse Events
When a single parameter is not appropriate for grading an AE in both adult and pediatric
populations, separate parameters with specified age ranges are provided. If there is no distinction
between adult and pediatric populations, the listed parameter should be used for grading an AE
in both populations.
Determining Severity Grade for Parameters Between Grades
If the severity of an AE could fall under either 1 of 2 grades (eg, the severity of an AE could be
either grade 2 or grade 3), sites should select the higher of the 2 grades.
Laboratory normal ranges should be taken into consideration to assign gradings to a laboratory
value.
Definitions
Basic self-care functions 
Adults: activities such as bathing, dressing, toileting,
transfer/movement, continence, and feeding
Young children: activities that are age and culturally appropriate
(eg, feeding self with culturally appropriate eating implements)
Usual social & functional 
activities 
Activities which adults and children perform on a routine basis and
those which are part of regular activities of daily living, for
example:
Adults: adaptive tasks and desirable activities, such as going to
work, shopping, cooking, use of transportation, or pursuing a
hobby
Young Children: activities that are age and culturally appropriate
(eg, social interactions, play activities, learning tasks)
Intervention  
Medical, surgical, or other procedures recommended or provided
by a healthcare professional for the treatment of an AE.
Estimating Severity Grade for Parameters not Identified in the Grading Table
The functional table below should be used to grade the severity of an AE that is not specifically
identified in the grading table. In addition, all deaths related to an AE are to be classified as
grade 5.
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Scaling and Scoring Instructions
There are 31 scored items included in the HB-QOL, including 13 items regarding how HBV
makes patients feel socially or mentally (F1-F13), 15 items regarding HBV-related concerns
(C1-C15), and 3 items regarding HBV-related physical impacts.
Each item is scored on a 5-level response scale ranging from 1 through 5. Each response is
transformed along a 0 to 100-point scale, where lower scores denote less HRQOL impact, and
higher scores denote more HRQOL impact (i.e. 0=best score; 100=worst score), as follows:
Level 1 –0 points
Level 2 –25 points
Level 3 –50 points
Level 4 –75 points
Level 5 –100 points
The items are combined to form 7 subscales, as follows:
Psychological Well-Being (8 Items)
Anxious (F6)
Frustrated (F4)
Sad (F3)
Angry (F7)
Less Enjoyable (F10)
Scared (F13)
Bad (F19)
Isolated (F8)
Anticipation Anxiety (6 Items)
Concern Failure (C1)
Concern Cancer (C2)
Concern Worsen (C15)
Concern Serious (C12)
Concern Survival (C9)
Concern Flare (C5)
Vitality (5 Items)
Tiredness (P1)
Worn Out (F5)
Muscle Aches (P3)
Memory Problems (P2)
Unproductive (F13)
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Stigma (6 Items)
Concern Embarrassed (C14)
Ashamed (F1)
Concern Self-Conscious (C10)
Concern Socially Isolated (C11)
Concern Boss (C3)
Stigmatized (F2)
Vulnerability (3 Items)
Concern Eat (C13)
Concern Sick Easily (C6)
Concern Medicines (C8)
Transmission (3 Items)
Concern Transmit Sex (C7)
Concern Transmit Child (C4)
Sex Difficult (F11)
Viral Response (4 Items)
Concern Transmit Sex (C7)
Concern Transmit Child (C4)
Concern Eat (C13)
Concern Medicines (C8)
In addition, there is a single global score that reflects the results on all 31 items.
Each subscale score is simply calculated as the average score among the items included in that
subscale. The global score is simply the average score among all the items in the HBQOL.
For example, consider these sample scores for items in the vulnerability scale:
Item Number 
Item Name 
Raw Score 
Scaled Score
C13 
Concern eat 
2 
25
C6 
Concern sick easily 
4 
75
C8 
Concern medicines 
3 
50
Average 
50
The score on this subscale is 50 out of a possible score of 100, where higher scores denote
more severe negative impact of HBV on HRQOL.
NCT03982186

NCT03982186

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CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
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Status: Approved,  Date: 24 November 2021
27. I have stopped socialising with some people because of their reactions to
me having hepatitis B
                               
28. Some people have treated me differently because I have hepatitis B
                               
29. People discriminated against me because I have hepatitis B
                               
30. I felt like people were avoiding touching me because of my hepatitis B
                               
31. I worried that people would reject me when they found out I have
hepatitis B
                               
32. I have been hurt by how people reacted because I have hepatitis B
                               
33. I felt frustrated by other people’s lack of understanding of hepatitis B
                               
34. I was not afraid to tell people I had hepatitis B
                               
35. I was comfortable with others knowing I have hepatitis B
                               
36. I was ashamed to seek medical care because of my hepatitis B
                               
37. I was afraid to seek medical care because of my hepatitis B
                               
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10.12. Appendix 12: Patient Global Impression of Change Scale
Please select how you feel about yourself now in comparison to how you felt about
yourself at the beginning of this study.  (Select one response)
 Much better
 Better
 A little better
 No change
 A little worse
 Worse
 Much worse
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10.13. Appendix 13: 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 nucleos(t)ide analog (NA) re-treatment criterion
for participants who discontinued NA treatment at Week 48 or during the follow-up phase, and to include
more frequent monitoring for participants who discontinued NA treatment.
A severe clinical alanine aminotransferase (ALT) flare following discontinuation of NA treatment was
reported in a virologically suppressed hepatitis B e antigen (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 hepatitis B
virus (HBV) DNA levels that increased rapidly, before any relevant changes in liver markers were noted.
Discontinuation of NA treatment followed the protocol-defined criteria and was in line with recent
European Association for the Study of the Liver (EASL) treatment guidelines.7 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 or
during the follow-up phase.
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,
6.6 Individual Participant NA Treatment
Completion Criteria,
6.7 NA Re-treatment Criteria ,
6.8 Intervention After the End of the Study
10.14 Appendix 14: NA Re-treatment
Participants who discontinue
NA treatment at Week 48 or
during the follow-up phase
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,
6.7 NA Re-treatment Criteria ,
8 STUDY ASSESSMENTS AND
PROCEDURES
Clarifications were made to the
urine pregnancy testing during
(extended) follow-up.
Clarification  
1.3.2 Schedule of Activities –Follow-up Phase
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JNJ-73763989 and JNJ-56136379
Clinical Protocol 73763989HPB2001 AMENDMENT 4
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Status: Approved,  Date: 24 November 2021
Description of Change 
Brief Rationale 
Section Number and Name
Clarifications were made 
concerning the optional safety
follow-up visit for participants
who withdraw consent during
follow-up.
Clarification  
1.3.2 Schedule of Activities –Follow-up Phase
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
and template updates were
made.
Minor errors were noted 
Throughout the protocol
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 
2.2.2.1 Overall Nonclinical 
Assessment of the Combination 
Therapy  
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 subcutaneous at 60 mg/kg
related to bone marrow depletion
with pancytopenia including marked
thrombocytopenia.
10.2. Appendix 2: Clinical 
Laboratory Tests 
Addition of reticulocyte count and 
reticulocyte index to all study visits 
To allow for early detection of
changes in hematologic parameters.
Clarifications, Additions, and Corrections
Section Number and Name 
Description of Change 
Brief Rationale
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 is not part of eligibility
Clarification
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Status: Approved,  Date: 24 November 2021
Clarifications, Additions, and Corrections
Section Number and Name 
Description of Change 
Brief Rationale
criteria assessed after screening.
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 
Add alpha-fetoprotein measurement 
every 24 weeks and at the time 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.
8.3.6.1 Intervention-emergent 
ALT/AST Elevations 
10.2 Appendix 2: Clinical Laboratory 
Tests 
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
10.6 Appendix 6: Intervention- 
emergent ALT/AST Elevations 
Added Appendix 6. Consequently, 
all subsequent appendices are
renumbered.
Clarification
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 timing of the PRO assessments 
and the ECGs was changed. 
The PRO assessments and ECGs
should be prioritized, but the order
of the other assessments is
of less importance.
5.1 Inclusion Criteria 
5.2 Exclusion Criteria 
The note “Retesting to assess
eligibility will be allowed once,
using an unscheduled visit during
the screening phase.” was moved up
as it applies to both inclusion as well
as exclusion criteria.
Clarification
5.2 Exclusion Criteria 
The note in exclusion criterion 1 was
modified to allow participants with
positive HCV, HDV or HEV
antibody test to enroll if an active
infection can be ruled out.
To only exclude patients with active
infection. Some patients may carry
antibodies after an acute infection,
which never developed into a
chronic infection.
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
2.3.2.2.1 Potential Risks for 
JNJ-3989 
Potential risk on viral resistance to
JNJ-3989 was moved from Section
2.3.2.2.2 to Section 2.3.2.2.1 as
appropriate.
Correction
8.3.5 Pregnancy  
Discontinuation of “study
intervention” during pregnancy has
been updated to “investigational
intervention”
Correction
2.2.1 JNJ-3989 and JNJ-6379 
Limited updates were made to the
nonclinical sections where relevant
Correction
2.3.2.2.1 Potential Risks for 
JNJ-3989 
The sentence “The fertility in male
and female rats is not impacted with
JNJ-3989 up to a dose of
Correction
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Status: Approved,  Date: 24 November 2021
Clarifications, Additions, and Corrections
Section Number and Name 
Description of Change 
Brief Rationale
180 mg/kg/week.” was moved from
Potential Genotoxicity to
Reproductive Risks and Pregnancy
10.2 Appendix 2: Clinical Laboratory 
Tests 
Timing of the reflex testing of 
pancreatic amylase in case of
amylase or lipase increase has been
changed from “post-screening” to
“screening onwards”
Correction
8 STUDY ASSESSMENTS AND 
PROCEDURES  
A time window was added for 
intensive PK sampling and “within
12 minutes” was changed to +/- 12
minutes for clarity”
For completeness and consistency
1.1 Synopsis 
3 OBJECTIVES AND ENDPOINTS  
8.5 Pharmacokinetics 
8.5.1 Evaluations 
8.5.2 Analytical Procedures
8.5.3 Pharmacokinetic Parameters
and Evaluations
8.6
Pharmacokinetics/Pharmacodynamics
9.4.3 Other Analyses
Addition of "(JNJ-3976 and JNJ- 
3924)" and changed ‘JNJ-3989’ to
‘JNJ-3976 and JNJ-3924’ where
applicable
For completeness
6.1 Study Intervention(s)
Administered
Formulation numbers were added for
JNJ-3989 and for the 25 mg and 100
mg JNJ-6379 tablets.
Clarification
1.3.1 Schedule of Activities –
Screening and Study Intervention
Phase
Minor grammatical, formatting, or
spelling changes were made.
Minor errors corrected.
Amendment 1 (14 November 2019)
Overall Rationale for the Amendment: Pursuant to Health Authority (HA) and Independent Ethics
Committee (IEC)/Institutional Review Board (IRB) feedback, the protocol was amended as specified
below. Furthermore, clarifications, additions and corrections were made throughout the protocol.
HA and IEC/IRC Feedback
Description of Change 
Brief Rationale 
Section Number
and Name
A liver ultrasound was added in participants 
with increased risk for HCC, every 24 
weeks during the study intervention phase 
and (extended) follow-up. 
To monitor for development of HCC in 
participants with increased risk for 
HCC.42 
1.3.1 Schedule of
Activities –Screening
and Study Intervention
Phase, 1.3.2 Schedule of
Activities –Follow-up
Phase
A timeframe of at least 30 days prior to 
screening was added for the use of a highly 
effective method of contraception by female 
participants of childbearing potential. 
The minimum time period for 
contraceptive use prior to screening
ensures adequate protection of females
of childbearing potential.
5.1 Inclusion Criteria
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Status: Approved,  Date: 24 November 2021
Exclusion criterion #14 was updated to also
include known allergies, hypersensitivity, or
intolerance to excipients of the placebo
formulations.
For completeness, to safeguard all 
patients, including those on placebo,
who may react to certain content of the
formulations.
5.2 Exclusion Criteria
Individuals under a legal protection measure
were added to criterion #26 as an additional
example of vulnerable participants.
For completeness 
5.2 Exclusion Criteria
Description of the unblinding procedure for
the investigator was updated to ensure that
discussion with the sponsor is not delaying
action with respect to treatment in case of
emergency.
For clarity  
6.3 Measures to Minimize
Bias: Randomization and
Blinding
BCRP inhibitors (eg, curcumin, cyclosporin
A, and eltrombopag) were added to the list
of disallowed concomitant medications.
JNJ-6379 is a substrate of BCRP. 
6.5 Concomitant Therapy
The description of the control of the Type I
error rate for multiple testing in the analysis
of the primary efficacy endpoint and the key
secondary efficacy endpoint was clarified.
In line with this clarification, the simulation
results for the statistical power levels
achieved with the planned sample size have
been updated.
To clarify that the control of the Type I
error rate at one-sided 0.05 level is
conducted separately and independently
for the comparisons against the control
arm as opposed to the comparisons
among the active combination
regimens.
1.1 Synopsis,
3 OBJECTIVES AND
ENDPOINTS
9.1 Statistical
Hypotheses, 9.2 Sample
Size Determination,
9.4 Statistical Analyses
Clarifications and Additions
Description of Change 
Brief Rationale 
Section Number
and Name
A time frame of maximal 12 months was 
added for documented HBeAg status as part 
of the medical history at prescreening. 
Within 12 months prior to screening is 
acceptable to assess documented 
HBeAg status as part of the medical 
history at prescreening. 
1.3.1 Schedule of
Activities –Screening
and Study Intervention
Phase
A time window was added for intensive PK 
sampling. 
For completeness 
1.3.1 Schedule of
Activities –Screening
and Study Intervention
Phase
Language was added for participants in the 
intensive PK subgroup, such that the sparse 
PK sample does not need to be collected at 
the time of an intensive PK visit. 
To avoid unnecessary duplication of PK 
sampling for participants in the 
intensive PK subgroup. 
1.3.1 Schedule of
Activities –Screening
and Study Intervention
Phase
Quantitative HBeAg assessment will be 
performed for all participants during FU, 
instead of only those who are defined 
HBeAg-positive at screening.
For completeness 
1.3.2 Schedule of
Activities –Follow-up
Phase
The recommendation regarding the order of 
assessments in case of multiple assessments 
at the same time point was removed. 
For more flexibility in timing of the 
assessments. The PRO assessment 
should be prioritized, but the order of 
the other assessments is not deemed 
important. 
1.3.1 Schedule of
Activities –Screening
and Study Intervention
Phase,
1.3.2 Schedule of
Activities –Follow-up
Phase,
8.2.3 Electrocardiograms
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Status: Approved,  Date: 24 November 2021
Clarifications and Additions
Description of Change 
Brief Rationale 
Section Number
and Name
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. 
To evaluate for the presence of 
structural kidney disease. 
1.3.1 Schedule of
Activities –Screening
and Study Intervention
Phase,
5.2 Exclusion Criteria
Final data from the 28-day combination 
toxicity study in rats are added. 
For completeness 
2.2.1 JNJ-3989 and JNJ-
6379,
2.3.2.2.1 Potential Risks
for JNJ-3989
Approved tenofovir generics were added as 
an acceptable NA treatment option.
For completeness 
4.1 Overall Design
The note in exclusion criterion #1 was 
modified to allow participants with positive 
anti-HCV antibody test to enroll, if they 
have negative HCV RNA at screening and 
documented negative HCV RNA at least 6
months prior to screening and/or
documentation of prior HCV treatment.
To identify patients with resolved HCV 
infection (spontaneously or after
treatment) who can participate in this
study.
5.2 Exclusion Criteria
Exclusion criterion #2 was adapted to 
describe that the listed laboratory
abnormalities are exclusionary within 12
months prior to screening but also at the
time of screening.
For clarity  
5.2 Exclusion Criteria
Added language to explain that rescreening 
is not allowed without the sponsor’s
approval.
For clarity  
5.4 Screen Failures
Subcutaneous injection of JNJ-3989 is now 
unambiguously described to be administered 
in the abdomen, instead of by preference. 
For clarity and consistency in approach. 1.1 Synopsis,
6.1 Study Intervention(s)
Administered
The volume of the placebo for JNJ-3989 
was added to the dosage regimen. 
For completeness 
1.1 Synopsis,
6.1 Study Intervention(s)
Administered
“Once monthly” in the dosage regimen of 
JNJ-3989 was adjusted to “once every 
4 weeks”. 
For clarity  
1.1 Synopsis,
1.2 Schema,
6.1 Study Intervention(s)
Administered
Specification on NA treatments available for 
the study was adapted. 
To account for import restrictions with 
regards to tenofovir alafenamide (TAF) 
in some participating countries and 
clarify that TAF will only be one of the
NA options in the countries where it is
available.
1.1 Synopsis,
6.1 Study Intervention(s)
Administered
Language was added instructing 
investigators to follow guidance during NA 
treatment as detailed in the respective
prescribing information, in particular with
reference to special warnings and
precautions for use.
For completeness 
6.1 Study Intervention(s)
Administered
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.
6.4 Study Intervention
Compliance
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Status: Approved,  Date: 24 November 2021
Clarifications and Additions
Description of Change 
Brief Rationale 
Section Number
and Name
Table 5 (Concomitant Medications to be 
Used With Caution) was adapted to provide
more general recommendations regarding
alternative medications or adjusted doses.
For clarity  
6.5 Concomitant Therapy
Over-the-counter products, herbal 
medications and dietary supplements were 
removed from the disallowed concomitant
medication list.
For clarity. Only products containing 
Hypericum perforatum are disallowed.
6.5 Concomitant Therapy
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.
7.1 Discontinuation of
Study Intervention
The discontinuation criterion for a 
confirmed ≥grade 3 eGFR abnormality and 
a drop from baseline of >10 mL/min/1.73 
m² was adjusted to include the relationship 
to the investigational intervention and to 
propose consideration of changing NA 
treatment. 
Multiple conditions, including 
treatment with TDF can lead to eGFR 
abnormalities. Therefore, the 
relationship to the investigational 
intervention should be taken into
consideration before treatment
discontinuation and a switch from TDF
to ETV or TAF should be considered as
the first step.
7.1 Discontinuation of
Study Intervention,
8.3.6.4 Renal
Complications
The word ‘optional’ was removed for 
PBMC samples. 
A note was added with regards to total blood 
volume. 
To clarify that PBMC samples are only 
taken at selected sites and at these sites, 
PBMC samples will be collected from 
all subjects.
To clarify that the total blood volume to
be collected from each participant may
vary, depending on the timing of
potential participation in the extended
FU.
8 STUDY
ASSESSMENTS AND
PROCEDURES
Management of grade 3 and 4 laboratory 
abnormalities is adapted to request a repeat 
analysis (within 72 hours) only in case the
abnormality is considered to be clinically
significant.
To avoid unnecessary, unscheduled 
visits. 
8.2.4 Clinical Safety
Laboratory Assessments
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.
Wording was modified such that all ISRs
will need to be reported in the CRF, but not
by default as an AE.
To protect the participant’s privacy. 
To clarify that the pictures are optional
and explain the proper steps to follow.
For clarity
8.3.6.2 Rash,
10.5 Appendix 5: Rash
Management
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Status: Approved,  Date: 24 November 2021
Clarifications and Additions
Description of Change 
Brief Rationale 
Section Number
and Name
Added language specifying sponsor staff 
that will also have access to PK and 
pharmacodynamic unblinded data during 
study conduct (for PK and 
pharmacodynamic modeling) in addition to 
the IDMC. 
It was specified that the IDMC can monitor 
unblinded safety and efficacy data on a 
continuous basis. 
Unblinded PK and pharmacodynamic 
data will be used for compound 
development decision making. 
For completeness 
1.1 Synopsis,
6.3 Measures to Minimize
Bias: Randomization and
Blinding
9.5.1 Independent Data
Monitoring Committee
10.3 Appendix 3:
Regulatory, Ethical, and
Study Oversight
Considerations
A statistical test for the difference in 
proportions, adjusted for the randomization 
stratification factors, has been added. 
To take into account the randomization 
stratification factors of screening 
HBeAg status and treatment history in 
the analysis of the primary and the 
secondary efficacy endpoints. For 
completeness of the inferential analysis. 
1.1 Synopsis,
9.1 Statistical
Hypotheses,
9.4.1 Efficacy Analyses
10.1 Appendix 1:
Abbreviations and
Definitions of Terms
‘Bilateral tubal occlusion/ligation 
procedures’ was removed from the 
definition of ‘permanently sterile’. 
In line with the updated guidance from 
the Clinical Trials Facilitation and 
Coordination Group (CTFG), the 
definition of ‘permanently sterile’ was
updated.
10.8 Appendix 8:
Contraceptive and Barrier
Guidance
Corrections
Description of Change 
Brief Rationale 
Section Number
and Name
Urinalysis assessment was moved from FU 
Week 48 to FU Week 4. 
Correction, as safety analysis of the 
treatment phase will be done up to 
4 weeks after end of investigational 
treatment.
1.3.2 Schedule of
Activities –Follow-up
Phase
Approximations of total blood volumes 
were modified. 
Correction  
8 STUDY
ASSESSMENTS AND
PROCEDURES
The term relapse is replaced by flare across 
the document. 
Relapse implies a lack of efficacy while 
some increases in ALT and/or HBV 
DNA might occur in patients with 
favorable response to treatment. 
Increases that do not lead to treatment 
action (discontinuation if during the 
treatment phase or re-start if during the 
follow up phase) will be referred to as 
flares instead of relapses. As such, a 
distinction will be made in the analysis
to differentiate between frequency of
patients with flares and frequency of
patients that meet criteria to re-start
treatment during follow up.
1.1 Synopsis,
2.3.3 Benefit-risk
Assessment for Study
Participation,
3 OBJECTIVES AND
ENDPOINTS,
9.4.1.3 Other Secondary
and Exploratory Efficacy
Endpoints,
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Corrections
Description of Change 
Brief Rationale 
Section Number
and Name
Minor grammatical, formatting, or spelling 
changes were made. 
Minor errors corrected. 
1.1 Synopsis,
3 OBJECTIVES AND
ENDPOINTS,
5.1 Inclusion Criteria
5.2 Exclusion Criteria,
7.1 Discontinuation of
Study Intervention,
9.4.1.2 Key Secondary
Efficacy Endpoint of
Functional Cure at Week
72 (HBsAg Seroclearance
24 Weeks After
Completion of All Study
Intervention at Week 48)
9.4.1.3 Other Secondary
and Exploratory Efficacy
Endpoints,
10.3 Appendix 3:
Regulatory, Ethical, and
Study Oversight
Considerations,
10.9 Appendix 9: DAIDS
Table
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10.14. Appendix 14: NA Re-treatment and Monitoring After Stopping of NA
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11. 
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INVESTIGATOR AGREEMENT
I have read this protocol and agree that it contains all necessary details for carrying out this study. I will
conduct the study as outlined herein and will complete the study within the time designated.
I will provide copies of the protocol and all pertinent information to all individuals responsible to me who
assist in the conduct of this study. I will discuss this material with them to ensure that they are fully
informed regarding the study intervention, the conduct of the study, and the obligations of confidentiality.
Coordinating Investigator (where required):
Name (typed or printed):
Institution and Address:
Signature: 
Date:
(Day Month Year)
Principal (Site) Investigator:
Name (typed or printed):
Institution and Address:
Telephone Number:
Signature: 
Date:
(Day Month Year)
Sponsor's Responsible Medical Officer:
Name (typed or printed): 
Institution: 
Janssen Research & Development
Signature: 
electronic signature appended at the end of the protocol 
Date:
(Day Month Year)
Note: If the address or telephone number of the investigator changes during the course of the study, written
notification will be provided by the investigator to the sponsor, and a protocol amendment will not be required.
PPD
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Signature
User 
Date 
Reason
 
25-Nov-2021 
08:31:01
(GMT)
Document Approval
PPD
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1
Status: Approved,  Date: 15 May 2020
Janssen Research & Development *
Clinical Protocol
COVID-19 Appendix
Protocol Title
A Phase 2b, Multicenter, Double-blind, Active-controlled, Randomized Study to 
Investigate the Efficacy and Safety of Different Combination Regimens Including 
JNJ-73763989 and/or JNJ-56136379 for the Treatment of Chronic Hepatitis B Virus 
Infection
The REEF-1 study
Protocol 73763989HPB2001; 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: 2019-000622-22
Status:
Approved  
Date:
15 May 2020
Prepared by:
Janssen Research & Development, a division of Janssen Pharmaceutica NV  
EDMS number:
EDMS-RIM-48855, 1.0
THIS APPENDIX APPLIES TO ALL CURRENT APPROVED VERSIONS OF PROTOCOL
73763989HPB2001 (EDMS-ERI-180130107)
GCP Compliance: This study will be conducted in compliance with Good Clinical Practice, and applicable regulatory 
requirements. 
Confidentiality Statement
The information provided herein contains Company trade secrets, commercial or financial information that the Company 
customarily holds close and treats as confidential.  The information is being provided under the assurance that the recipient
will maintain the confidentiality of the information under applicable statutes, regulations, rules, protective orders or 
otherwise.
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Status: Approved,  Date: 15 May 2020
COVID-19 APPENDIX
GUIDANCE ON STUDY CONDUCT DURING THE COVID-19 PANDEMIC
It is recognized that the Coronavirus Disease 2019 (COVID-19) pandemic may have an impact on 
the conduct of this clinical study due to, for example, self-isolation/quarantine by participants and 
study-site personnel; travel restrictions/limited access to public places, including hospitals; study 
site personnel being reassigned to critical tasks.
In alignment with recent health authority guidance, the sponsor is providing options for study-
related participant management in the event of disruption to the conduct of the study. This guidance 
does not supersede any local or government requirements or the clinical judgement of the 
investigator to protect the health and well-being of participants and site staff and maintain 
oversight of delegated trial activities. If, at any time, a participant’s safety is considered at risk, 
study intervention will be discontinued, and study follow-up will be conducted.
Scheduled visits that cannot be conducted in person at the study site will be performed to the extent 
possible remotely/virtually or delayed until such time that on-site visits can be resumed. At each 
contact, participants will be interviewed to collect safety data. Key efficacy endpoint assessments 
should be performed if required and as feasible. Participants will also be questioned regarding 
general health status to fulfill any physical examination requirement. 
Every effort should be made to adhere to protocol-specified assessments for participants on study 
intervention, including follow-up. Modifications to protocol-required assessments may be 
permitted via COVID-19 Appendix after consultation with the participant, investigator, or the 
sponsor. Missed assessments/visits will be captured in the clinical trial management system for 
protocol deviations. Discontinuations of study interventions and withdrawal from the study should 
be documented with the prefix “COVID-19-related” in the case report form (CRF). 
The sponsor will continue to monitor the conduct and progress of the clinical study, and any 
changes will be communicated to the sites and to the health authorities according to local guidance. 
If a participant has tested positive for COVID-19, the investigator should contact the sponsor’s 
responsible medical officer to discuss plans for study intervention and follow-up. Modifications 
made to the study conduct as a result of the COVID-19 pandemic should be summarized in the 
clinical study report.
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Status: Approved,  Date: 15 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.
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 
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 
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Status: Approved,  Date: 15 May 2020
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.

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.
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Status: Approved,  Date: 15 May 2020
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.
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Clinical Protocol 73763989HPB2001
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
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Status: Approved,  Date: 15 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
NCT03982186

Signature
User
Date
Reason
18-May-2020
08:08:56
(GMT)
Document Approval
PPD
NCT03982186