Conditions: Hepatitis D, Chronic
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 52
Healthy volunteers: no

Brief summary:
The purpose of the study is to evaluate on-treatment efficacy against hepatitis D virus (HDV) of JNJ-73763989 + nucleos(t)ide analog (NA) regimen compared to NA alone.

Detailed description:

Arms:
arm 1: Participants will receive JNJ-73763989 subcutaneous (SC) injection every 4 weeks (Q4W) along with NA (entecavir \[ETV\], tenofovir disoproxil, or tenofovir alafenamide \[TAF\]) once daily for 144 Weeks in Part 1 and for at least 96 weeks in Part 2. arm 2: Participants will receive matching placebo to JNJ-73763989 SC injection Q4W along with NA (ETV, tenofovir disoproxil, or TAF) once daily for 52 Weeks followed by JNJ-73763989 SC injection Q4W along with NA once daily for 96 weeks in Part 1 and for at least 48 weeks in Part 2.

Interventions: intervention 1: JNJ-73763989 intervention 2: Placebo intervention 3: Entecavir (ETV) monohydrate intervention 4: Tenofovir disoproxil intervention 5: Tenofovir alafenamide (TAF)
Intervention descriptions: intervention 1: JNJ-73763989 will be administered as a SC injection. intervention 2: Matching placebo to JNJ-73763989 will be administered as a SC injection. intervention 3: ETV monohydrate film coated tablet will be administered orally. intervention 4: Tenofovir disoproxil film-coated tablet will be administered orally. intervention 5: TAF film coated tablet will be administered orally.

Protocol document:
Prot_000.pdf: 
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
1
Status: Approved,  Date:  27 March 2024
Janssen Research & Development *
Clinical Protocol
Protocol Title
A Phase 2, Multicenter, Randomized, Double-blind, Placebo‑controlled Study with Deferred
Active Treatment to Investigate the Efficacy, Safety, and Pharmacokinetics of JNJ‑73763989 +
Nucleos(t)ide Analog in Participants Co‑infected with Hepatitis B and Hepatitis D Virus
REEF-D
Protocol 73763989HPB2004; Phase 2
Version: Amendment 5
JNJ-73763989
*Janssen Research & Development is a global organization that operates through different legal entities in
various countries/territories. 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.
Studies conducted at sites in the United States (US) will be conducted under US Food & Drug
Administration Investigational New Drug (IND) regulations (21 CFR Part 312).
Studies conducted at sites in the European Economic Area (EEA) will be conducted under Regulation
[EU] No 536/2014.
Regulatory Agency Identifier Numbers:
IND: IND150393
EudraCT NUMBER: 2020-001249-37
EU TRIAL NUMBER: 2023-506763-33
Status: 
Approved
Date: 
27 March 2024
Prepared by: 
Janssen Research & Development, a division of Janssen Pharmaceutica NV
EDMS number: 
EDMS-RIM-39841, 9.0
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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JNJ-73763989  
Clinical Protocol 73763989HPB2004 Amendment 5
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
2
Status: Approved,  Date:  27 March 2024
PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE
DOCUMENT HISTORY
Document 
Date
Amendment 5 
27 March 2024
Amendment 4 
7 April 2023
Amendment 3 
6 December 2021
Amendment 2 
17 June 2021
Amendment 1 
6 August 2020
Original Protocol 
18 May 2020
Amendment 5 (27 March 2024)
Overall Rationale for the Amendment:
As described in Amendment 4 dated 7 April 2023, due to the strategic decision taken by the
sponsor to discontinue further investment in its hepatitis B and D discovery and development
programs, enrollment of new participants into the REEF-D study was not re-opened and the study
was modified to continue with the enrolled participants as planned.
The overall reason for the present amendment is to facilitate an early completion of the REEF-D
study by reducing the study duration for participants in Part 2 while ensuring that all participants
have the possibility to receive at least 48 weeks of JNJ-73763989 (JNJ-3989) treatment and
adequate follow-up. At the time of the present protocol amendment, all participants in Part 1 and
Part 2 are beyond the double-blind phase. All 22 participants in Part 1 have completed the
investigational study treatment. This amendment will not affect the participants in the follow-up
phase in Part 1 and will only affect the participants in Part 2. In Part 2, participants either have
completed the study (n 11), entered the open-label phase following the 52 weeks of double-blind
treatment (n 17), or are in the follow-up phase (n 2). Once the present amendment will be
approved and in effect at a given study site, the next planned visit for participants in the open-label
phase, but not earlier than Week 96 (Arm 1) and Week 100 (Arm 2), will be the end oftreatment
(EOT) visit. At this EOT visit, JNJ-3989 will not be administered and participants will continue
treatment with NA until the last study visit in the follow-up phase. All participants in Part 2 will
follow a reduced follow-up  phase of at least 24 weeks when the present amendment becomes
effective. The decision to reduce the study duration of Part 2 is due to the sponsor’s strategic
decision to discontinue the development of JNJ-3989 in chronic hepatitis D disease and is not
triggered by any safety findings.
The changes made to the clinical protocol 73763989HPB2004 as part of Protocol Amendment 5
are listed below, including the rationale of each change and a list of all applicable sections.
Changes made in previous protocol amendments are listed in Section 10.11, Appendix 11: Protocol
Amendment History.
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JNJ-73763989  
Clinical Protocol 73763989HPB2004 Amendment 5
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
3
Status: Approved,  Date:  27 March 2024
Section number 
and Name
Description of Change 
Brief Rationale
1.1 Synopsis 
Updated to reflect all the pertinent 
changes as described in rows below. 
Refer to overall rationale for the
amendment and rationale for
each section below.
1.3 Schedule of Activities 
Added modified SoA of open-label 
study intervention phase 
(Week 52-EOT) for conducting Part 2
of the study after Protocol
Amendment 5 is in effect.
Added SoA of reduced follow-up phase
(at least 24 weeks) for participants in
Part 2 at the time this amendment
becomes effective.
Refer to the overall rationale for
the amendment.
1.2 Schema 
4.1 Overall Design 
4.4 End of Study  
9 Statistical Considerations 
Updated study schema to align with the 
following modifications in Part 2 of the 
study: 
Treatment with JNJ-3989 will be 
stopped at the next planned visit 
(ie, EOT) but not earlier than Week 96 
(Arm 1) and Week 100 (Arm 2) when 
Protocol Amendment 5 is in effect. 
Follow-up will be reduced to 24 weeks 
for all Part 2 participants who have not 
reached FU Week 24 (including those
in the open-label phase) when the
amendment is in effect. Participants
who have reached FU Week 24 or later
will receive the EOS assessments at the
next planned visit.
Accordingly, the definition of EOS and
study completion is updated for Part 2.
Refer to the overall rationale for
the amendment.
The open-label phase in Part 2
was modified in a way that at
least 96 weeks of treatment with
JNJ-3989 in Arm 1 and
48 weeks of treatment with
JNJ-3989 in Arm 2 will be
ensured in the study
intervention phase.
2.3.3 Benefit-risk Assessments for 
Study Participation  
4.1 Overall Design  
6.3 Measures to Minimize Bias: 
Randomization and Blinding 
6.7 Concomitant Therapy  
8 Study Assessments and 
Procedures 
The time frame for open-label 
treatment with JNJ-3989, 
NA treatment, monitoring for
transaminase flares and for HBV/HDV
recurrence as well as recording of
concomitant therapy was updated in
accordance with the overall rationale
for the study amendment which now
includes different intervention and
follow-up periods across the study
parts.
Refer to the overall rationale for
the amendment.
2.3.3 Benefit-risk Assessments for 
Study Participation  
4.1 Overall Design  
4.2 Scientific Rationale for Study 
Design  
6.4 Study Intervention Compliance 
6.5 Re-treatment with NA during 
the Follow-up Phase 
The stopping criteria for NA treatment 
during the follow-up phase were 
removed for Part 2. 
Due to the reduced treatment
duration in Part 2 per protocol
amendment, the criteria for
discontinuation of NA treatment
will not be applicable.
Treatment with NA will be
continued until the end of the
study visit.
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JNJ-73763989  
Clinical Protocol 73763989HPB2004 Amendment 5
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
4
Status: Approved,  Date:  27 March 2024
Section number 
and Name
Description of Change 
Brief Rationale
3 Objectives and Endpoints 
Evaluation of PK of JNJ-3989 and the 
corresponding endpoint were removed 
from the ‘Other Secondary Objectives 
and Endpoints’. 
Sparse PK samples will be
analyzed for plasma
concentrations. Population PK
will not be conducted due to the
strategic decision taken by the
sponsor to discontinue further
investment in hepatitis.
9.5.2 Interim Analyses of Study 
Part 2 
The IA of Part 2 and any potential IAs 
that may be performed in the 
open-label phase were removed. 
Additional IAs will no longer be
necessary as the study duration
for Part 2 will be reduced and
no further interactions with
health authorities are planned.
9.5.4 Internal Data Review 
Committee 
10.3.6 Committees Structure 
The following was added: 
A DRC will be established for 
continuous monitoring of SAEs, AEs 
leading to discontinuation, and ALT 
flares when all participants have
completed double-blind phase and
IDMC has completed its review.
The transition of the safety
monitoring responsibilities from
IDMC to DRC after the
completion of the double-blind
phase was further clarified.
Throughout the protocol 
Changes to align with the sponsor’s 
current protocol template wording. 
Update to the most recent
template.
Throughout the protocol 
Minor grammatical, formatting, or 
spelling changes were made.
Minor errors were noted.
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JNJ-73763989  
Clinical Protocol 73763989HPB2004 Amendment 5
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
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Status: Approved,  Date:  27 March 2024
TABLE OF CONTENTS
PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE ............................................................... 2
TABLE OF CONTENTS ............................................................................................................................... 5
LIST OF IN-TEXT TABLES AND FIGURES................................................................................................ 8
1. 
PROTOCOL SUMMARY..................................................................................................................... 9
1.1. 
Synopsis........................................................................................................................................... 9
1.2. 
Schema.......................................................................................................................................... 27
1.3. 
Schedule of Activities..................................................................................................................... 28
1.3.1. 
Schedule of Activities –Screening and Double-blind Study Intervention Phase
(First 48Weeks)......................................................................................................................... 28
1.3.2. 
Schedule of Activities –Open-label Study Intervention Phase (Weeks 52 –EOT)................... 34
1.3.2.1. 
Schedule of Activities –Open-label Study Intervention Phase (Before Protocol
Amendment 5)......................................................................................................................... 34
1.3.2.2. 
Schedule of Activities –Open-label Study Intervention Phase (per Protocol
Amendment 5)......................................................................................................................... 39
1.3.3. 
Schedule of Activities –Follow-up Phase................................................................................... 44
1.3.3.1. 
Schedule of Activities –48-Week Follow-up Phase (Before Protocol Amendment 5)............ 44
1.3.3.2. 
Schedule of Activities –Reduced Follow-up Phase (per Protocol Amendment 5)................. 47
2. 
INTRODUCTION................................................................................................................................ 50
2.1. 
Study Rationale.............................................................................................................................. 52
2.2. 
Background .................................................................................................................................... 52
2.2.1. 
Primary Pharmacology ............................................................................................................... 52
2.2.2. 
Nonclinical Studies ..................................................................................................................... 53
2.2.3. 
Clinical Studies ........................................................................................................................... 55
2.3. 
Benefit-risk Assessment................................................................................................................. 57
2.3.1. 
Risks for Study Participation....................................................................................................... 57
2.3.1.1. 
Known Risks............................................................................................................................ 57
2.3.1.2. 
Potential Risks......................................................................................................................... 57
2.3.1.3. 
Risks Due to Study Procedures............................................................................................... 59
2.3.2. 
Benefits for Study Participation .................................................................................................. 59
2.3.2.1. 
Known Benefits........................................................................................................................ 59
2.3.2.2. 
Potential Benefits..................................................................................................................... 59
2.3.3. 
Benefit-risk Assessment for Study Participation......................................................................... 60
3. 
OBJECTIVES AND ENDPOINTS ..................................................................................................... 62
4. 
STUDY DESIGN ................................................................................................................................ 66
4.1. 
Overall Design................................................................................................................................ 66
4.2. 
Scientific Rationale for Study Design............................................................................................. 70
4.2.1. 
Study-specific Ethical Design Considerations ............................................................................ 73
4.3. 
Justification for Dose...................................................................................................................... 73
4.4. 
End of Study Definition................................................................................................................... 74
5. 
STUDY POPULATION ...................................................................................................................... 74
5.1. 
Inclusion Criteria............................................................................................................................ 75
5.2. 
Exclusion Criteria........................................................................................................................... 78
5.3. 
Lifestyle Considerations................................................................................................................. 82
5.4. 
Screen Failures.............................................................................................................................. 83
6. 
STUDY INTERVENTION AND CONCOMITANT THERAPY............................................................ 84
6.1. 
Study Interventions Administered .................................................................................................. 84
6.2. 
Preparation/Handling/Storage/Accountability ................................................................................ 85
6.3. 
Measures to Minimize Bias: Randomization and Blinding............................................................. 86
6.4. 
Study Intervention Compliance...................................................................................................... 87
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Clinical Protocol 73763989HPB2004 Amendment 5
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Status: Approved,  Date:  27 March 2024
6.5. 
Re-treatment With NA During the Follow-up Phase ...................................................................... 88
6.5.1. 
Re-treatment With NA................................................................................................................. 89
6.6. 
Treatment of Overdose .................................................................................................................. 89
6.7. 
Concomitant Therapy..................................................................................................................... 89
7. 
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT
DISCONTINUATION/WITHDRAWAL............................................................................................... 91
7.1. 
Discontinuation of Study Intervention ............................................................................................ 91
7.2. 
Participant Discontinuation/Withdrawal From the Study................................................................ 92
7.2.1. 
Withdrawal From the Use of Research Samples ....................................................................... 93
7.3. 
Lost to Follow-up............................................................................................................................ 94
8. 
STUDY ASSESSMENTS AND PROCEDURES ............................................................................... 94
8.1. 
Efficacy Assessments .................................................................................................................... 96
8.1.1. 
HBV and HDV Genotyping and Sequencing .............................................................................. 97
8.1.2. 
Core Liver Biopsy and Fine Needle Aspirate Biopsy (Optional with Separate Consent,
Part 2 Only)................................................................................................................................. 97
8.2. 
Safety Assessments....................................................................................................................... 98
8.2.1. 
Physical Examinations................................................................................................................ 99
8.2.2. 
Vital Signs................................................................................................................................... 99
8.2.3. 
Electrocardiograms..................................................................................................................... 99
8.2.4. 
Clinical Safety Laboratory Assessments .................................................................................. 100
8.2.5. 
Pregnancy Testing.................................................................................................................... 100
8.3. 
Adverse Events, Serious Adverse Events, and Other Safety Reporting ..................................... 100
8.3.1. 
Time Period and Frequency for Collecting Adverse Event and Serious Adverse Event
Information................................................................................................................................ 101
8.3.2. 
Method of Detecting Adverse Events and Serious Adverse Events ........................................ 102
8.3.3. 
Follow-up of Adverse Events and Serious Adverse Events ..................................................... 102
8.3.4. 
Regulatory Reporting Requirements for Serious Adverse Events ........................................... 102
8.3.5. 
Pregnancy................................................................................................................................. 103
8.3.6. 
Adverse Events of Special Interest........................................................................................... 103
8.3.6.1. 
Intervention-emergent ALT/AST Elevations.......................................................................... 103
8.3.6.2. 
Rash ...................................................................................................................................... 105
8.3.6.3. 
Acute Systemic Allergic Reactions........................................................................................ 106
8.3.6.4. 
Renal Complications.............................................................................................................. 107
8.3.6.5. 
Hematologic Abnormalities.................................................................................................... 107
8.3.6.6. 
Complications From Liver Biopsy.......................................................................................... 108
8.4. 
Pharmacokinetics......................................................................................................................... 108
8.4.1. 
Evaluations ............................................................................................................................... 108
8.4.2. 
Analytical Procedures............................................................................................................... 109
8.4.3. 
Pharmacokinetic Parameters and Evaluations......................................................................... 109
8.5. 
Pharmacokinetics/Pharmacodynamics........................................................................................ 109
8.6. 
Immune Assessments.................................................................................................................. 109
8.7. 
Host Genetics............................................................................................................................... 110
8.8. 
Host Biomarkers........................................................................................................................... 110
8.9. 
Medical Resource Utilization........................................................................................................ 111
9. 
STATISTICAL CONSIDERATIONS................................................................................................ 111
9.1. 
Statistical Hypotheses.................................................................................................................. 111
9.2. 
Sample Size Determination ......................................................................................................... 111
9.3. 
Participant Analysis Sets.............................................................................................................. 112
9.4. 
Statistical Analyses ...................................................................................................................... 112
9.4.1. 
General Considerations............................................................................................................ 112
9.4.2. 
Primary Endpoint ...................................................................................................................... 113
9.4.2.1. 
Primary Estimand .................................................................................................................. 113
9.4.2.2. 
Analysis of The Main Estimator............................................................................................. 115
9.4.3. 
Key Secondary Endpoints ........................................................................................................ 115
9.4.4. 
Other Efficacy Endpoints .......................................................................................................... 115
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JNJ-73763989  
Clinical Protocol 73763989HPB2004 Amendment 5
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
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Status: Approved,  Date:  27 March 2024
9.4.5. 
Resistance Analyses ................................................................................................................ 117
9.4.6. 
Safety Analyses........................................................................................................................ 117
9.4.7. 
Other Analyses ......................................................................................................................... 118
9.4.7.1. 
Pharmacokinetic Analyses .................................................................................................... 118
9.4.7.2. 
Pharmacokinetic/Pharmacodynamic Analyses ..................................................................... 119
9.4.7.3. 
Immune Analyses .................................................................................................................. 119
9.4.7.4. 
Pharmacogenomic Analyses................................................................................................. 119
9.4.7.5. 
Host Biomarkers Analyses .................................................................................................... 119
9.4.7.6. 
Medical Resource Utilization ................................................................................................. 120
9.5. 
Interim Analyses........................................................................................................................... 120
9.5.1. 
Interim Analyses of Study Part 1 .............................................................................................. 120
9.5.2. 
Interim Analysis of Study Part 2 ............................................................................................... 120
9.5.3. 
Independent Data Monitoring Committee................................................................................. 120
9.5.4. 
Internal Data Review Committee.............................................................................................. 121
9.5.5. 
Sponsor Committee.................................................................................................................. 121
9.5.6. 
Independent Flare Expert Panel............................................................................................... 122
10. SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS .......................... 123
10.1. 
Appendix 1: Abbreviations and Definitions .................................................................................. 123
10.2. 
Appendix 2: Clinical Laboratory Tests ......................................................................................... 126
10.3. 
Appendix 3: Regulatory, Ethical, and Study Oversight Considerations....................................... 128
10.3.1. 
Regulatory and Ethical Considerations .................................................................................... 128
10.3.2. 
Financial Disclosure.................................................................................................................. 131
10.3.3. 
Informed Consent Process ....................................................................................................... 131
10.3.4. 
Data Protection ......................................................................................................................... 132
10.3.5. 
Long-term Retention of Samples for Additional Future Research............................................ 133
10.3.6. 
Committees Structure............................................................................................................... 133
10.3.7. 
Publication Policy/Dissemination of Clinical Study Data.......................................................... 134
10.3.8. 
Data Quality Assurance............................................................................................................ 136
10.3.9. 
Case Report Form Completion................................................................................................. 136
10.3.10. Source Documents ................................................................................................................... 137
10.3.11. Monitoring ................................................................................................................................. 138
10.3.12. On-site Audits ........................................................................................................................... 138
10.3.13. Record Retention...................................................................................................................... 139
10.3.14. Study and Site Start and Closure ............................................................................................. 139
10.4. 
Appendix 4: Adverse Events, Serious Adverse Events, Product Quality Complaints, and
Other Safety Reporting: Definitions and Procedures for Recording, Evaluating, Follow-up,
and Reporting............................................................................................................................... 141
10.4.1. 
Adverse Event Definitions and Classifications ......................................................................... 141
10.4.2. 
Attribution Definitions................................................................................................................ 142
10.4.3. 
Severity Criteria........................................................................................................................ 143
10.4.4. 
Special Reporting Situations .................................................................................................... 143
10.4.5. 
Procedures ............................................................................................................................... 143
10.4.6. 
Product Quality Complaint Handling......................................................................................... 145
10.4.7. 
Contacting Sponsor Regarding Safety, Including Product Quality........................................... 145
10.5. 
Appendix 5: Rash Management................................................................................................... 146
10.6. 
Appendix 6: Intervention-emergent ALT/AST Elevations ............................................................ 150
10.7. 
Appendix 7: Cardiovascular Safety –Abnormalities.................................................................... 151
10.8. 
Appendix 8: Contraceptive and Barrier Guidance ....................................................................... 152
10.9. 
Appendix 9: DAIDS Table ............................................................................................................ 154
10.10. Appendix 10: COVID-19 APPENDIX........................................................................................... 178
10.10.1. Guidance on Study Conduct During the COVID-19 Pandemic................................................ 178
10.11. Appendix 11: Protocol Amendment History................................................................................. 182
11. REFERENCES................................................................................................................................. 207
INVESTIGATOR AGREEMENT............................................................................................................... 209
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LIST OF IN-TEXT TABLES AND FIGURES
TABLES
Table 1: 
Animal/Human Exposure Ratios at NOAEL for JNJ-3989........................................................ 55
Table 2: 
Disallowed Medication .............................................................................................................. 90
Table 3: 
Management of Rash Events by Severity Grade ................................................................... 146
FIGURES
Figure 1: Schematic Overview of the Study............................................................................................. 27
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Status: Approved,  Date:  27 March 2024
1. 
PROTOCOL SUMMARY
1.1. 
Synopsis
A Phase 2, Multicenter, Randomized, Double-blind, Placebo‑controlled Study with Deferred Active
Treatment to Investigate the Efficacy, Safety, and Pharmacokinetics of JNJ‑73763989 + Nucleos(t)ide
Analog in Participants Co‑infected with Hepatitis B and Hepatitis D Virus.
JNJ-73763989 (JNJ-3989) is a 2:1 molar mixture of 2 synthetic, double-stranded, N-acetylgalactosamine
(GalNac) conjugated RNAi triggers (JNJ-73763976 and JNJ-73763924, respectively). RNAi is a
naturally-occurring phenomenon by which short, double-stranded RNA oligonucleotides trigger a
sequence-specific down modulation of gene expression. The RNAi triggers in JNJ-3989 are designed to
target all hepatitis B virus (HBV) transcripts derived from covalently closed circular DNA (cccDNA) and
integrated viral DNA. This is made possible by the fact that all HBV transcripts expressed from cccDNA,
including the RNA transcript (pre-genomic ribonucleic acid [pgRNA]) that is used as a template for
replication of HBV DNA, are terminated by the same polyadenylation site and share a common sequence
region upstream of this site. One RNAi trigger (JNJ-73763924) in JNJ-3989 has its target within this
common sequence region and thus has the potential to knock down expression of all viral proteins as well
as the pgRNA expressed from cccDNA. The second RNAi trigger (JNJ-73763976), which targets the
HBsAg encoding region, was designed to knock down expression of hepatitis B surface antigen (HBsAg)
derived from integrated HBV DNA as well as all viral proteins derived from cccDNA with the exception
of HBV x protein. Silencing viral RNA will reduce HBV DNA and viral proteins, including HBsAg. Since
HBsAg is required for replication of hepatitis D virus (HDV), by allowing HDV to infect new cells,
reducing HBsAg levels is anticipated to lead to inhibition of HDV replication.
Study intervention refers to JNJ-3989 or placebo and nucleos(t)ide analog (NA).
BENEFIT-RISK ASSESSMENT
Overall, JNJ-3989 administration was generally safe and well tolerated in the completed and ongoing
studies, all of which except REEF-D are in CHB patients or healthy participants.
Alanine aminotransferase (ALT) elevations are considered an important potential risk for JNJ-3989. During
Part 1 of this study, in HBV/HDV co-infected participants, a higher frequency of ALT elevations was
observed when  receiving JNJ-3989 compared to placebo. This led to introduction of risk mitigation
measures, including stricter eligibility criteria (exclusion of participants with cirrhosis as well as
participants with high HDV RNA and in Part 2), more conservative criteria for JNJ-3989 discontinuation,
and more frequent monitoring.
Optional biopsy procedures will be performed during this study for research purposes, only in participants
who consented separately to this procedure. Risks and complications of these procedures may include pain
and discomfort, bleeding at the biopsy site, and infection and internal bleeding and/or puncture of other
internal organs (gall bladder, lung, intestine, or kidney) which can lead to serious complications
(uncommon –1 in 1,000 to 1 in 100) including the need for emergency surgery, blood transfusion, or
removal of organs. Deaths directly related to liver biopsy occur rarely (approximately 1 in every
10,000 biopsies).
The clinical benefit of JNJ-3989 remains to be established. Potential benefits include reduction of HBsAg
levels directly via JNJ-3989, leading to a reduced number of HDV particles and less de novo infections,
and inhibition of HDV replication and improved clinical outcomes. Treatment with JNJ-3989 in
combination with NAs might lead to HBsAg seroclearance which could result in complete elimination of
HDV (ie, cure). The combination of JNJ-3989 and NAs is also expected to intensify suppression of HBV
replication compared to NA alone, by further downregulating the levels of the HBV proteins and pgRNA,
which may allow a restoration of the host immune response and sustained HBsAg seroclearance
(ie, functional cure for HBV).
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Clinical Protocol 73763989HPB2004 Amendment 5
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
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Status: Approved,  Date:  27 March 2024
Based on the available data and proposed safety measures, the overall risk/benefit assessment for JNJ-3989
clinical studies is considered favorable. 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).
OBJECTIVES AND ENDPOINTS
The primary and secondary objectives and endpoints of this study are listed below.
Objectives 
Endpoints
Primary
To evaluate on-treatment efficacy against HDV 
of JNJ-3989 + NA regimen compared to NA 
alone. 
Proportion of participants with HDV RNA
≥2 log10 IU/mL decline from baseline or HDV
RNA target not detected (TND) in combination
with normal ALT at Week 48.
Key Secondary
To evaluate on-treatment efficacy of the 
JNJ-3989 +NA regimen in suppressing HDV 
replication as measured by HDV RNA. 
Proportion of participants with HDV RNA
≥2 log10 IU/mL decline from baseline or HDV
RNA TND at Week 48.
To evaluate efficacy of the JNJ-3989 + NA 
regimen on liver inflammation during study 
intervention phase.
Proportion of participants with normal ALT at
Week 48.
To evaluate the efficacy of the JNJ-3989 + NA 
regimen in terms of HBsAg response. 
Proportion of participants with HBsAg
seroclearance at Week 48.
To evaluate the efficacy of the JNJ-3989 +NA 
regimen on liver fibrosis. 
Proportion of participants with ≥2 kPa
reduction from baseline in liver stiffness
measurement (LSM) assessed by vibration-
controlled transient elastography (VCTE)
(FibroScan) at Week 48.
Other Secondary
To evaluate the efficacy of the JNJ-3989 +NA 
regimen during study intervention phase and 
follow-up phase. 
Proportion of participants with HDV RNA
≥2 log10 IU/mL decline from baseline or HDV
RNA TND in combination with normal ALT.
Proportion of participants with HDV RNA
≥2 log10 IU/mL decline from baseline in
combination with normal ALT.
Proportion of participants with HDV RNA
TND in combination with normal ALT.
Proportion of participants with HDV RNA
≥2 log10 IU/mL decline from baseline or HDV
RNA TND.
Proportion of participants with HDV RNA
≥2 log10 IU/mL decline from baseline.
NCT04535544


JNJ-73763989  
Clinical Protocol 73763989HPB2004 Amendment 5
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
11
Status: Approved,  Date:  27 March 2024
Objectives 
Endpoints
Proportion of participants with HDV RNA
TND.
Proportion of participants with normal ALT.
Time to reach HDV RNA ≥2 log10 IU/mL
decline or HDV RNA TND.
Changes from baseline in HDV RNA.
Changes from baseline in ALT.
To evaluate the safety and tolerability of the study
intervention throughout the study.
Proportion of participants with incidences of
(serious) 
adverse 
events 
(AEs) 
and
abnormalities in clinical laboratory tests
(including hematology, blood biochemistry,
blood coagulation, urinalysis, urine chemistry,
and 
renal 
biomarkers), 
12-lead
electrocardiograms (ECGs), vital signs, and
physical examination.
To evaluate the efficacy of the JNJ-3989 +NA
regimen  as measured by HBV blood markers
(such as HBsAg, HBeAg*, HBV DNA) during
study intervention and follow-up.
Proportion of participants with HBsAg
seroclearance and/or seroconversion.
Change from baseline over time in HBsAg,
HBeAg*, HBV DNA.
Proportion of participants with HBsAg,
HBeAg*, and/or HBV DNA levels or changes
from baseline below/above different cut-offs.
Time to reach efficacy thresholds such as
HBsAg <1 IU/mL.
To evaluate the frequency of HBV virologic
breakthrough throughout the study.
Proportion of participants with HBV DNA
virologic breakthrough.
To evaluate changes in liver fibrosis during study
intervention and follow-up.
Proportion of participants with ≥2 kPa
reduction from baseline in LSM assessed by
VCTE (FibroScan).
Change from baseline in LSM  over time
assessed by VCTE (FibroScan).
To evaluate the anti-HDV efficacy during the
follow-up phase.
Proportions of participants with sustained HDV
response off-treatment post end of JNJ-3989
treatment.
Proportions of participants with HDV relapse
post end of JNJ-3989 treatment.
To evaluate the anti-HBV efficacy during the
follow-up phase.
Proportions of participants with sustained HBV
response off-treatment post end of JNJ-3989
treatment.
NCT04535544


JNJ-73763989  
Clinical Protocol 73763989HPB2004 Amendment 5
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
12
Status: Approved,  Date:  27 March 2024
Objectives 
Endpoints
Proportions of participants with  HBV flare
(virologic, biochemical, and clinical) post end
of treatment.
* in HBeAg-positive participants only
Hypothesis
The original protocol had as primary hypothesis that the combination regimen of JNJ-3989 + NA is more
efficacious than NA treatment alone in reducing HDV replication and improving the associated liver
inflammation, as measured by the primary efficacy endpoint, the proportion of participants with HDV RNA
decline ≥2 log10 IU/mL from baseline or HDV RNA TND in combination with normal ALT at Week 48.
Due to the decision to stop enrollment at 30 participants in Part 2 of the study, the statistical analyses will
be descriptive.
OVERALL DESIGN
This is a 2-part, Phase 2, randomized, double-blind, placebo-controlled, parallel, multicenter, interventional
study with deferred active treatment to investigate the efficacy, safety, and PK of JNJ-3989 +nucleos(t)ide
analog (NA) in participants co-infected with HBV and HDV.
The study consists of 2 parts:
Part 1 will evaluate the safety, tolerability and antiviral activity of JNJ-3989 +NA in a small number
of participants (N=20), prior to enrolling a larger number of participants in Part 2. The primary aim of
Part 1 is to assess if the antiviral activity criteria to start Part 2 are met.
Part 2 (N=30) will evaluate the safety and efficacy of the JNJ-3989 +NA regimen in the treatment of
HBV/HDV co-infection.
Note that Part 2 of the study will only be initiated once the antiviral activity criteria in Part 1 have been
met, and if the results of Part 1 IA1 (when all participants of Part 1 have completed at least Week 16 or
discontinued earlier) support initiation of Part 2. The antiviral activity criteria are defined in the statistical
analysis plan (SAP). Participants in Part 1 may not participate in Part 2.
Before Protocol Amendment 5, Part 1 and Part 2 include 3 identical phases:
a 4-week screening phase (may be extended up to a maximum of 8 weeksa),
a 144-week study intervention phase (Arm 1) and 148-week study intervention phase (Arm 2). The
first 52 weeks of the intervention phase are double-blind followed by 92 and 96 weeks of open-label
treatment for participants in Arms 1 and 2, respectively.
a 48-week follow-up phase.
a If necessary (eg, for operational reasons), the screening phase may be extended up to a maximum of 8 weeks on a
case-by-case basis and in agreement with the sponsor. Depending on the duration of the screening phase, selected
screening assessments may have to be repeated prior to enrollment.
NCT04535544


JNJ-73763989  
Clinical Protocol 73763989HPB2004 Amendment 5
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
13
Status: Approved,  Date:  27 March 2024
Per Protocol Amendment 5, Part 2 will include modified phases after screening:
a 4-week screening phase (may be extended up to a maximum of 8 weeksa),
for both Arm 1 and Arm 2, the double-blind 52 weeks of intervention will be followed by an open-label
phase of at least 48 weeks of JNJ-3989 for all participants, including for those participants who were
randomized to placebo in the intervention phase. Arm 1 will have a total minimum of 96-week
intervention and Arm 2 a total minimum of 100-week intervention.
a reduced follow-up phase (at least 24 weeks):
for participants who have reached FU Week 24 or later when Protocol Amendment 5 is in effect,
the EOS assessments will be scheduled at the next planned visit; OR
for participants who have not reached FU Week 24 (including participants in the open-label
phase) when Protocol Amendment 5 is in effect, they will enter a 24-week follow-up phase.
The duration of individual study participation will be between 196 and 204 weeks for Part 1 and between
124 and 204 weeks for Part 2.
Before Protocol Amendment 5, at Week 144 (Arm 1) and Week 148 (Arm 2), treatment with JNJ-3989 will
be stopped in both parts. After Protocol Amendment 5 is in effect, treatment with JNJ-3989 will be stopped
in Part 2 at the next planned visit (ie, end oftreatment [EOT]) but not earlier than Week 96 (Arm 1) and
Week 100 (Arm 2).
Participants who complete treatment with JNJ-3989 at the end of the open-label phaseb in Part 1 and Part 2
will be closely monitored for transaminase flares and for HBV/HDV recurrence during the follow-up phase.
Before Protocol Amendment 5, for non-cirrhotic patients, NA treatment should be continued until the last
study visit (including the visit in the follow-up phase) unless confirmed HBsAg seroclearance, ALT <3x
upper limit of normal (ULN), and HBV DNA < lower limit of quantitation (LLOQ) is observed, in which
case NA treatment may be discontinued upon discussion with the sponsor. For cirrhotic patients, NA
treatment should be continued during the entire follow-up phase according to treatment guidelines.
Amongst the non-cirrhotic participants who stop treatment with NA, NA treatment will be restarted if any
of the following criteria are met:
If there are signs of decreasing liver function based on laboratory findings (INR or direct bilirubin) or
clinical assessment (follow guidance on study intervention discontinuation in case of an increase in
direct bilirubin >1.5x ULN in combination with INR ≥1.5x ULN or serum albumin <3.0 g/dL),
HBeAg seroreversion among participants who had previously experienced HBeAg loss,
Post-treatment values ofHBV DNA >2,000 IU/mL and ALT >5x ULN.
Post-treatment values ofHBV DNA >20,000 IU/mL.
Earlier restarting of NA treatment is at the investigator’s discretion, even if the above criteria are not met
yet.
a If necessary (eg, for operational reasons), the screening phase may be extended up to a maximum of 8 weeks on a
case-by-case basis and in agreement with the sponsor. Depending on the duration of the screening phase, selected
screening assessments may have to be repeated prior to enrollment.
b At Week 144 (Arms 1) or Week 148 (Arms 2) in Part 1 and Part 2 before Protocol Amendment 5; at Week 96 or
later (Arm 1) or Week 100 or later (Arm 2) in Part 2 after Protocol Amendment 5.
NCT04535544


JNJ-73763989  
Clinical Protocol 73763989HPB2004 Amendment 5
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
14
Status: Approved,  Date:  27 March 2024
Per Protocol Amendment 5, NA treatment will be continued in all participants in Part 2 until the last study
visit (including visit in the follow-up phase).
Part 1
Approximately 20 participants co-infected with HBV and HDV will be randomized in a 4:1 ratio to Arms 1
or 2.
Arm 1: 100 mg JNJ-3989 (subcutaneous [SC] injection every 4 weeks [Q4W]) + NA once daily (qd)
for 144 weeks (n=16; immediate active treatment arm);
Arm 2: placebo for JNJ-3989 (SC injection Q4W) + NA qd for 52 weeks, followed by 100 mg
JNJ-3989 (SC injection Q4W) + NA qd for 96 weeks (n=4; deferred active treatment arm).
NA=nucleos(t)ide analog=entecavir monohydrate (ETV), tenofovir disoproxil, or tenofovir alafenamide
(TAF). NA treatment is continued or started from Day 1 in both arms.
Part 2
Part 2 of the study will be initiated since the antiviral activitycriteria in Part 1 have been met, and the results
of Part 1 IA1 (when all participants of Part 1 have completed at least Week 16 or discontinued earlier)
support initiation of Part 2. Cirrhotic participants will be excluded from participation in Part 2 of the study.
Approximately 30 participants co-infected with HBV and HDV will be randomized in a 4:1 ratio to Arms 1
or 2.
Arm 1: 100 mg JNJ-3989 (SC injection Q4W) + NA qd for at least 96 weeks (approximately, n=24;
immediate active treatment arm);
Arm 2: placebo for JNJ-3989 (SC injection  Q4W) + NA qd for 52 weeks, followed by 100 mg
JNJ-3989 (SC injection Q4W) + NA qd for at least 48 weeks (approximately, n=6; deferred active
treatment arm).
NA= ETV, tenofovir disoproxil, or TAF. NA treatment is continued or started from Day 1 in both arms.
Study Details
This study consists of 2 parts. Part 1 (N=20) aims to observe antiviral anti-HDV activity in a limited number
of participants treated with the active regimen (ie, proof of concept) and to exclude futility before enrolling
a larger number of participants to be exposed to the 144-week treatment regimen of JNJ-3989 +NA. Part 1
IA1 will be conducted after all participants of Part 1 have completed at least Week 16 (or discontinued
earlier), to enable the Sponsor Committee to decide on the initiation of Part 2. A second IA of Part 1 (Part 1
IA2) will be conducted after all participants of Part 1 have completed at least Week 48 (or discontinued
earlier), to confirm the preliminary benefit-risk ratio of the investigational regimen with longer term data
on participants of Part 1.
Part 2 (N=30) will generate additional data. The randomization ratio will be fixed to 4:1 (active:control).
The conclusions of the study will be described separately on data from Part 1, Part 2, and pooled from Part 1
and Part 2 together (if applicable).
Randomization will be stratified by:
presence of compensated cirrhosis at screening (yes or no) (Part 1 only),
HDV RNA testing laboratory location (China versus outside ofChina), and
HBeAg status at screening (positive versus negative).
NCT04535544


JNJ-73763989  
Clinical Protocol 73763989HPB2004 Amendment 5
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
15
Status: Approved,  Date:  27 March 2024
Before Protocol Amendment 5, participants in Part 1 and Part 2 will be considered to have completed the
study if they have completed the end of study (EOS) assessments at Week 48 week of the follow-up phase
(ie, EOS visit at FU Week 48). After Protocol Amendment 5, the participants in Part 2 will be considered
to have completed the study if they have completed the EOS assessments assigned per Protocol
Amendment 5:
Participants who have not reached FU Week 24 (including participants in the open-label phase) when
Protocol Amendment 5 is in effect will enter the 24-week follow-up phase (ie, EOS visit at FU
Week 24).
Participants who have reached FU Week 24 or later when Protocol Amendment 5 is in effect will
receive the EOS assessments at the next planned visit (ie, EOS visit at FU Week 30 or later).
NUMBER OF PARTICIPANTS
In total for Part 1 and Part 2, 50 participants were planned to be enrolled in this study, specifically with a
target of 20 participants in Part 1 and 30 participants in Part 2. The minimum number of participants to be
enrolled will be 20 if futility is observed and Part 2 is not initiated.
Eligible participants will be aged ≥18 to 65 years and co-infected with HBV and HDV. Patients with
HBV/HDV co-infection will be eligible regardless of HBeAg status and treatment history. Patients with
compensated cirrhosis are allowed to be enrolled in Part 1 and patients with cirrhosis will be excluded from
Part 2 of this study.
NCT04535544


JNJ-73763989  
Clinical Protocol 73763989HPB2004 Amendment 5
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
16
Status: Approved,  Date:  27 March 2024
Description of Interventions
Intervention Name 
JNJ-3989 
Placebo for 
JNJ-3989
ETV monohydrate 
Tenofovir disoproxil 
TAFa
Type 
Drug 
Drug 
Drug 
Drug 
Drug
Dose Formulation 
Solution for injection  
Solution for injection  
Film-coated tablets 
Film-coated tablets 
Film-coated tablets
Unit Dose Strength(s) 
200 mg/mL 
0.9% saline 
0.5 mg 
245 mg 
25 mg
Dosage Regimen 
100 mg Q4W  
Q4W  
0.5 mg qd 
Lamivudine-refractory
participants:
1 mgb qd (but should
preferably be treated
with tenofovir
disoproxil or TAF
instead)
245 mg qd 
25 mg qd
Route of Administration 
Subcutaneous injection 
(in the abdomen) 
Subcutaneous injection 
(in the abdomen)
Oral 
Oral 
Oral
Use 
Investigational 
intervention  
Investigational 
intervention 
Background 
intervention  
Background 
intervention  
Background
intervention
IMP and NIMP 
IMP  
IMP  
IMP  
IMP  
IMP
Sourcing 
Provided centrally by 
the sponsor 
Provided centrally by 
the sponsor 
Provided centrally by 
the sponsor 
Provided centrally by 
the sponsor 
Provided centrally by
the sponsor
Packaging and Labeling 
Each unit will be 
labeled with unique 
medication ID number 
Each unit will be 
labeled with unique 
medication ID number 
Commercial supplies 
will be sourced and a 
clinical study label 
applied 
Commercial supplies 
will be sourced and a 
clinical study label 
applied 
Commercial supplies
will be sourced and a
clinical study label
applied
In child-resistant 
packaging 
In child-resistant 
packaging 
In child-resistant
packaging
Labels will contain information to meet the applicable regulatory requirements.
Food/Fasting Instructions 
Regardless of food 
intake 
Regardless of food 
intake 
Per the prescribing 
information 
Per the prescribing 
information  
Per the prescribing
information
ETV: entecavir; ID: identification; IMP: Investigational Medicinal Product; JNJ 3989: JNJ 73763989; NA: nucleos(t)ide analog; NIMP: Non investigational Medicinal Product; Q4W: once
every 4 weeks; qd: once daily; TAF: tenofovir alafenamide
a In countries where TAF is commercially available, it will be one of the NA treatment options.
b 2 tablets of 0.5 mg
NCT04535544


JNJ-73763989  
Clinical Protocol 73763989HPB2004 Amendment 5
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
17
Status: Approved,  Date:  27 March 2024
EFFICACY EVALUATIONS
HDV RNA will be quantified at central testing laboratory locations (China versus outside of China) using
a validated commercially available in vitro nucleic acid amplification tests for the quantification of HDV
RNA. Samples may be processed in real-time or could be analyzed in batch.
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 will be quantified at central laboratories using commercially available in vitro nucleic acid
amplification tests for the quantification of HBV DNA. Samples for the determination of HBV DNA will
be processed in real-time. HBV RNA will be quantified using a validated assay in a central laboratory.
Samples for the determination of HBV RNA can be analyzed in batch and at the sponsor’s discretion.
Liver stiffness measurement by VCTE (FibroScan) will be performed to determine changes in the liver
fibrosis.
Samples may be used by the sponsor for additional exploratory assessments analyzing the serologic and
virologic characteristics of HBV or HDV infection (including semi-quantitative anti-HDV IgM antibodies)
and efficacy or safety of the study intervention.
Sequencing
Viral genome sequence analysis may be performed to identify pre-existing baseline polymorphisms and to
evaluate emergence of mutations associated with JNJ-3989 and/or NA treatment.
Core Liver Biopsy and Fine Needle Aspirate Biopsy (Optional with Separate Consent, Part 2 only)
If participants agree to undergo an optional liver biopsy, percutaneous core liver biopsies and/or fine needle
aspirate biopsies (FNABs) will be performed preferentially at Week 0 and Week 24. Percutaneous core
liver biopsies will be prioritized over FNAB if only one sample can be collected.
SAFETY EVALUATIONS
Safety and tolerability will be assessed throughout the study from the time that the informed consent form
(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, vital signs measurements (including body weight), 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.
Adverse events of special interest in line with the known pharmacological profile of the study intervention
(and the drug classes) evaluated in this study are implemented.
NCT04535544


JNJ-73763989  
Clinical Protocol 73763989HPB2004 Amendment 5
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
18
Status: Approved,  Date:  27 March 2024
Any intervention-emergent elevation of ALT and/or AST ≥3x ULN and ≥2x 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 as specified below. Repeat laboratory values should include AFP, ALT, AST, ALP,
bilirubin (total and direct), INR, albumin, HBV DNA, and HDV RNA. Additional tests should be
considered based on clinical judgement. The confirmatory visit should be scheduled preferably within
3 days of the receipt of the initial ALT/AST results.
Weekly basis monitoring (or more frequently as long as values increase) until ALT/AST levels have
returned to <3x ULN or <2x nadir, and if present, liver-related symptoms have improved. With ALT and/or
AST values ≥3x ULN and ≥2x nadir, visit intervals may be extended to 14 days if values have been stable
or decreasing on three consecutive visits. The participant will be monitored (laboratory testing of ALT,
AST, ALP, bilirubin [total and direct], INR, albumin, HBV DNA, and HDV RNA) on a weekly basis or
more frequently until ALT and/or AST levels have returned to 50% of the maximal value.
Note: In case of urgency, local laboratory assessments could be considered. In case of IWRS participant
unblinding and if the investigator requires to be unblinded in case of an emergent safety event (ie, study
intervention discontinuation due to ALT flares) to allow further treatment of the participant, a sponsor
request can be made to have the investigator and sponsor unblinded to all HDV RNA and HBsAg data from
the double‑blind phase. Off-treatment local HDV RNA test can be done to exclude/assess for HDV driven
flare).
Management of intervention-emergent ALT and/or AST elevations:
JNJ-3989 treatment should be stopped, and NA treatment needs to be continued in the following situations:
Participants with liver cirrhosis:
Confirmed ALT/AST elevation >5x ULN and ≥2x nadir
ALT/AST elevation ≥3xULN and ≥2x nadir for >4 weeks.
If the ALT and/or AST level is ≥3x ULN and ≥2x nadir and is associated with any of the following
laboratory results or clinical symptoms:
o 
INR ≥1.5, OR
o 
direct bilirubin >1.5x ULN, OR
o 
serum albumin <3.0 g/dL, OR
o 
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
o 
other indication of reduced liver function.
Participants without liver cirrhosis:
Confirmed ALT/AST elevation >10x ULN and ≥2x nadir
First on-treatment ALT/AST elevation 3 to 5x ULN for >12 weeks
Second or following on-treatment ALT/AST elevation 3 to 5x ULN for >4 weeks
ALT/AST elevation >5 to 10x ULN for >4 weeks
NCT04535544


JNJ-73763989  
Clinical Protocol 73763989HPB2004 Amendment 5
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
19
Status: Approved,  Date:  27 March 2024
If the ALT and/or AST level is ≥3x ULN and ≥2x nadir and is associated with any of the following
laboratory results or clinical symptoms:
o 
INR ≥1.5, OR
o 
direct bilirubin >1.5x ULN, OR
o 
serum albumin <3.0 g/dL, OR
o 
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
o 
other indication of reduced liver function.
From Week 52 onwards, results of HBsAg and HDV RNA assessment will be reported to the investigators.
Management of flares observed in the follow-up phase after end of treatment:
In case of ALT flares that are observed during the follow-up phase, repeat laboratory values should include
AFP, ALT, AST, ALP, bilirubin (total and direct), INR, albumin, HBV DNA, and HDV RNA. The
participant should be monitored on a weekly basis (or more frequently as long as values increase) until ALT
and/or AST levels have returned to <3x ULN or <2x nadir. With ALT and/or AST values ≥3x ULN and
≥2x nadir, visit intervals may be extended to 14 days if values have been stable or decreasing on three
consecutive visits. For guidance on re-treatment with NA during the follow-up phase, refer to the
re-treatment criteria mentioned under Overall Design.
PHARMACOKINETIC EVALUATIONS
Sparse PK samples for JNJ-3989 will be collected and plasma concentration-time data for JNJ-3989
(JNJ-73763924 and JNJ-73763976) will be analyzed. Data from this study may be combined with data from
a selection of Phase 1 and 2 studies via population PK modeling.
PHARMACOKINETICS/PHARMACODYNAMICS
Relationships of individual PK parameters for JNJ-3989 (JNJ-73763924 and JNJ-73763976) with selected
efficacy and/or with selected safety endpoints may 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 may 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 HBV-specific T-cells that secrete gamma interferon (IFN-γ) in response to a
specific antigenic stimulation, whereas ICS determines the frequency of CD4+ and CD8+ HBV T-cells
secreting cytokines such as IFN-γ, interleukin (IL)-2 and tumor necrosis factor (TNF)-α in response to a
specific antigenic stimulation.
PBMC samples may also be analyzed for HDV-specific responses using ELISpot and ICS after stimulation
with HDV-specific antigens.
Additional experiments may be performed to further phenotypically and functionally characterize PBMCs
using proliferation or cytotoxic assays or other methods such as cytometry by time of flight to evaluate
innate and adaptive immune responses. Leftover PBMC samples may be used at the sponsor’s discretion
for additional exploratory research related to HBV or HDV infection or study intervention (safety/efficacy).
Additional PBMC samples may be taken until Week 48 in case of ALT flares, upon discussion with the
sponsor, which may require an unscheduled visit.
NCT04535544


JNJ-73763989  
Clinical Protocol 73763989HPB2004 Amendment 5
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
20
Status: Approved,  Date:  27 March 2024
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 deemed 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 host DNA 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 or HDV infection, or may be used to develop tests/assays related to study intervention
or HBV or HDV infection.
HOST BIOMARKERS
The study includes collection of blood samples for exploratory analysis of host blood biomarkers (eg,
cytokines) at the host RNA, protein, and cell level. Exploratory serology samples may be used for this host
serum protein testing.
Samples can only be used for research related to study intervention or HBV or HDV infection or may be
used to develop tests/assays related to study intervention or HBV or HDV 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.
LIVER BIOPSY
Part 2 of the study includes the option to perform liver biopsies in participants who consented separately to
this procedure (only in sites and in selected countries where this is feasible, and after all relevant approvals
are in place and operational set-up is completed). Samples may be used to assess HDV and HBV markers
in the liver such as, but not limited to, HDAg and HDV RNA, HBsAg, pgRNA, total intracellular HBV
RNA and DNA, and HBcAg. Changes in the quantity and potentially changes in the spatial distribution of
these markers under JNJ-3989 treatment will be assessed.
Intrahepatic immune status at baseline and in response to treatment may be assessed. Both innate and
adaptive immune compartment may be characterized, by measuring the relative number of specific cells
and the expression of functional markers in each cell population using various single cell approaches, such
as single cell transcriptomics in FNABs and Immunofluorescence staining, and transcriptomics and
proteomics profiling in core needle biopsies. Depending on the latest platform developments (spatial
transcriptomics, in situ sequencing approaches etc.) methods for immune cells characterization might be
adjusted.
Remaining samples may be used for research on viral and host biomarkers and immune markers at the viral
and/or host RNA/DNA, protein, and cell level.
Samples can only be used for research related to JNJ-3989, chronic HBV or HDV infection, or chronic
HBV or HDV infection related disease or may be used to develop tests/assays related to JNJ-3989, NA, or
chronic HBV or HDV infection. These latter exploratory analyses will be performed at the sponsor’s
discretion and will always be under the sponsor’s supervision.
MEDICAL RESOURCE UTILIZATION
Medical resource utilization data, associated with medical encounters, will be collected in the case report
form (CRF) by the investigator and study-site personnel for all participants throughout the study.
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JNJ-73763989  
Clinical Protocol 73763989HPB2004 Amendment 5
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
21
Status: Approved,  Date:  27 March 2024
Protocol-mandated procedures, tests, and encounters are excluded. The data collected may be used to
conduct exploratory economic analyses and will include:
Number and type of medical visits (eg, in/out hospital, ER visit).
Number (proportion) of participants requiring hospitalization and duration of hospitalization (total
days length of stay, including duration by wards; eg, ICU).
Number and character of diagnostic and therapeutic tests and procedures (inpatient and outpatient).
STATISTICAL METHODS
The primary analysis in this study will be performed when all participants in the study (both parts if Part 2
has started) have reached Week 48 or have discontinued earlier.
The final analysis will be performed when all participants in the study (both parts if Part 2 of the study has
started) have reached the final study visit in the follow-up phase, or have discontinued earlier.
Statistical Hypothesis
The original protocol had as primary hypothesis of this study that the combination regimen of JNJ-3989 +
NA has superior efficacy compared to NA treatment alone in reducing HDV replication and improving the
associated liver inflammation, as measured by the primary efficacy endpoint at Week 48 (the proportion of
participants with HDV RNA decline ≥2 log10 IU/mL from baseline or HDV RNA TND in combination with
normal ALT at Week 48). Due to the decision to stop enrollment at 30 participants in Part 2 of the study
(see details in section below), the statistical analyses will be descriptive.
Sample Size Determination
The sample size in Part 1 (N=20) is primarily driven by the objectives of Part 1 to provide sufficient
evidence of safety and early antiviral activity of JNJ-3989 and to exclude futility of the regimen in a small
number of HBV/HDV co-infected participants before initiating the larger Part 2 of the study. No formal
statistical power calculations were conducted for Part 1.
A total sample size of 130 participants for Part 2 in the original protocol would yield a statistical power
>90% to detect a between-arm difference of ≥26% in the primary efficacy endpoint at Week 48, at a 1-sided
Type 1 error rate of 0.025, based on the test for the between-arm difference with normal approximation.
Per Protocol Amendment 4, the sample size in Part 2 was reduced to 30 participants.
In the original protocol, sample size re-estimation was planned at the single IA during Part 2 to allow for
an increase to a maximum of 170 participants in Part 2 for the conditional power at the end of the study to
be at least 80% in case the assumed 0.04 response rate for placebo was too conservative. Due to reduction
in sample size per Protocol Amendment 4, the single IA with sample size re-estimation was removed.
In the original protocol, the number of participants included in this study was planned to be a minimum of
approximately N=20 (if Part 2 is not initiated) or between a minimum of N=165 and a maximum of N=190
if Part 2 is initiated. Per Protocol Amendment 4, the planned number of participants included in the study
will be N=20 in Part 1 and N=30 in Part 2.
Efficacy Analyses
To evaluate the efficacy, the primary analysis set will be the Intent-to-treat (ITT) population, ie, all
participants who were randomly assigned to an intervention arm and who received at least 1 dose of study
intervention. Participants will be analyzed according to the study intervention they were randomly assigned
to.
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The baseline measurement is defined as the measurement taken closest to but before the first dose of study
intervention on Day 1.
Primary Estimand
The main analysis of the primary endpoint will be addressed by using the following estimand attributes:
1. Study Intervention:
Arm 1: JNJ-3989+NA
Arm 2: Placebo+ NA
2. Study population: Participants 18 to 65 years of age, inclusive, with HBV/HDV co-infection.
3. Variable: Response status defined as having HDV RNA decline ≥2 log10 IU/mL from baseline or
HDV RNA TND in combination with normal ALT at Week 48.
4. Intercurrent events (ICEs):
a. 
Treatment discontinuation prior to Week 48: if the participant discontinued treatment prior to
Week 48 then the participant will be considered as non-responder (composite strategy).
b. Selected major protocol deviations (identified as ICEs): participants who experienced major
protocol deviations considered ICE and who have missing ALT and/or HDV RNA data for the
primary endpoint at Week 48 will be considered as non-responders (composite strategy).
c. 
Deaths prior to Week 48 are handled in a composite strategy as participants who die prior to
Week 48 will be considered as non-responders.
5. Population level summary: Difference in proportion of responders between the 2 intervention arms
(Arm 1-Arm 2).
Note: The SAP will list the major protocol deviations used for the purpose of efficacy analyses and flag
those that are to be considered ICEs.
Assumptions:
Missing Data for HDV RNA and ALT are Missing At Random (MAR)
The treatment effect is homogeneous across strata.
Data Included
All available data from randomized participants that have received at least one dose is included (ITT
analysis set in Part 2), after taking into account all the ICEs and applying the ICE strategies.
Missing Data Handling Rules
Participants who withdraw from the study prior to Week 48 will be considered as non-responders.
If a participant remains in the study after early discontinuing treatment or after experiencing a major
protocol deviation (defined for the purpose of efficacy analyses and is an intercurrent event) and has missing
Week 48 value for HDV RNA and/or ALT, then the imputation to non-response will be applied. If the value
for the primary endpoint at Week 48 is available, then such data will be used to determine their response
status.
For the participants still in the study at Week 48 or for participants that have neither discontinued treatment
early nor experienced any major protocol violations (defined for the purpose of efficacy analyses and is an
intercurrent event), and, either HDV RNA or ALT values are missing at Week 48, the primary method to
handle missing data will be the Multiple Imputation (MI) approach, applied in a joint multivariate fashion
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to leverage the correlation between HDV RNA and ALT values over time. More details regarding the
multiple imputation multivariate model will be included in the SAP.
To challenge and assess the impact of the MAR assumption in presence of intercurrent events, different
approaches to handle missing data will be used as sensitivity analyses of the main estimator. One approach
is the tipping point analysis based on the Missing Not At Random (MNAR) assumption. As a supplementary
estimator, the analysis where all participants with missing HDV RNA and ALT values in the analysis
window of Week 48 in each arm are imputed as non-responders will be conducted, to provide a
comprehensive overview of the robustness for the assumption of MAR and the type of missing data.
Main Estimator
The proportion of responders will be compared between the 2 arms using, if possible, the stratum-adjusted
Mantel-Haenszel test on the difference of proportions, with the following stratification factors: presence of
compensated cirrhosis at screening (yes or no) (Part 1 only), HDV RNA testing laboratory location (China
versus outside of China), and HBeAg status at screening (positive versus negative).
Key Secondary Endpoints
The key secondary endpoints at Week 48 are defined as follows:
1. Proportion of participants with HDV RNA ≥2 log10IU/mL decline from baseline or HDV RNA TND
at Week 48.
2. Proportion of participants with normal ALT levels at Week 48.
3. Proportion of participants with HBsAg seroclearance at Week 48.
4. Proportion of participants with ≥2 kPa reduction from baseline in LSM assessed by VCTE (FibroScan)
at Week 48.
The 4 key secondary endpoints are binary and will be analyzed using, if possible, the stratum-adjusted
Mantel-Haenszel test similarly  to the primary efficacy endpoint with corresponding 95% CIs on the
difference of proportions.
Other Secondary and Exploratory Endpoints
Descriptive statistics will be used for all efficacy endpoints which will be summarized by intervention arm
over time and by study phase, using the whole study data as well as by stage. Specific endpoints may be
analyzed using suitable categorical data approaches (eg, Mantel-Haenszel test, logistic regression for
proportions or other categorical type of endpoint), longitudinal repeated measures or ANCOVA models
(eg, for continuous types of variables), or survival analysis based on  the Kaplan-Meier estimates (for
time-to-event variables), as appropriate.
The statistical inference to compare the efficacy between Arm 1 and Arm 2 as measured by the other
secondary endpoints at Week 48 will utilize the weighted inverse normal combination method as described
for the primary efficacy endpoint. No further adjustment for multiplicity will be made and no imputation
rule will be used in case of missing data.
Subgroup analyses will be conducted to evaluate the potential association between treatment outcome and
selected demographic and baseline characteristics (including but not limited to age, presence of
compensated cirrhosis at screening, HDV genotype, baseline values for HDV RNA, ALT, and HBsAg,
etc.). Multivariate model analyses with exploration of interaction terms might also be performed. The
primary and key secondary efficacy endpoints, respectively, will be analyzed by means of a logistic
regression model. Exploratory descriptive summaries will be displayed by subgroups with corresponding
95% CIs without multiplicity adjustment. Forest plots will be used for the graphical displays. Subgroup
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analyses, as exploratory, might be conducted both on Part 2 data only, and the 2 parts combined to leverage
the total sample size of the whole study (Part 1 and Part 2).
Graphic data displays will also be used to summarize the efficacy data by intervention arm and over time.
In addition, the potential association between HBsAg and HDV RNA will be explored graphically over
time.
Resistance Analyses
The results of HBV and potentially HDV viral sequencing will be evaluated by the sponsor virologist.
Relevant changes of amino acid and/or nucleic acid variations (eg, substitutions) in the HBV and/or HDV
genomes will be tabulated and described. Additional exploratory characterization of the HBV and/or HDV
viral sequence and phenotype may be performed and reported separately.
Safety Analyses
The Safety Analysis Set will be used for all safety analyses based on pooled data from Part 1 and Part 2 of
the study. In addition, part of the safety analysis may be reported by study part. Relevant analysis by study
part will be indicated in the SAP.
Safety will be evaluated by means of descriptive summaries of AEs, clinical laboratory tests, ECGs, vital
signs, and physical examinations. The safety analyses will be done for each analysis 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.
Other Analyses
Pharmacokinetic Analyses
Descriptive statistics (n, mean, standard deviation [SD], coefficient of variation [CV], geometric mean,
median, minimum, and maximum) will be calculated for the plasma concentrations of JNJ-3989
(ie, JNJ-73763924 and JNJ-73763976).
Population PK analysis of concentration-time data of JNJ-73763976, and JNJ-73763924 may be performed
using non-linear mixed effects modeling. Data may be combined with selected Phase 1 and/or 2 studies to
support a relevant structural model. 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-73763976 and
JNJ-73763924 and may 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. Available participant characteristics (eg, demographics, laboratory variables,
genotypes) will be included in the model as necessary.
Pharmacokinetic/Pharmacodynamic Analyses
Relationships of PK parameters for JNJ-3989 (JNJ-73763976 and JNJ-73763924), with selected efficacy
and safety endpoints may be evaluated and graphically displayed, if applicable.
Immune Analyses
Descriptive statistics (n, mean, SD, CV, geometric mean, median, minimum, and maximum) may 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 HDV and HBV antigen) as defined by
ELISpot and/or ICS, respectively. Changes from baseline (if present) may also be tabulated for PBMCs
during study intervention. The proportion (%) of patients with positive responses based on the magnitude
of the IFN- γ T-cell response or the percentage of CD4+ or CD8+ T-cells expressing one of the cytokines
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(eg, IL-2, TNF- α or IFN-γ) for at least 1 of the HDV and HBV antigens as defined by ELISpot and/or ICS,
respectively, may 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 (CSR) or a separate report.
Host Biomarker Analyses
Statistical approaches to explore correlations between clinical outcome and blood and liver biomarkers vary
and depend on the different data types of the applied technology platforms, as well as on the extent of
observed interindividual variability. Analyses will be conducted at the sponsor’s discretion, will always be
under the sponsor’s supervision, and results will be presented either in the CSR or a separate report.
Interim Analyses
Interim Analyses of Study Part 1
During the double-blind phase of Part 1, 2 IAs will be conducted by the sponsor. Part 1 IA1 will be
conducted after all participants of Part 1 have completed at least Week 16 (or discontinued earlier) to allow
a comprehensive review of ALT elevations observed during treatment. The sponsor will become unblinded
to Part 1 efficacy and safety data for this IA, to inform the decision of the Sponsor Committee for the
initiation of Part 2 in conjunction with the IDMC recommendations. Part 1 IA2 will be conducted after all
participants of Part 1 have completed at least Week 48 visit (or discontinued earlier).
From the moment of data unblinding for Part 1 IA1 onwards, the sponsor will remain unblinded to Part 1
data. The investigators, participants, site personnel, and operational sponsor team members involved with
the sites will remain blinded. For safety-related decisions, HDV RNA and HBsAg data may be discussed
with investigators on a case-by-case basis.
Interim Analysis of Study Part 2
The original protocol included an IA of Part 2 when all participants had reached Week 148, (EOT or
discontinued earlier). This IA of Part 2 was to be conducted to assess safety and evaluate the time course
of different disease markers and to support the sponsor’s interactions with health authorities. Due to the
decision to reduce the study duration of Part 2 and since interactions with health authorities are no longer
planned, the IA of Part 2 was removed per Protocol Amendment 5.
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 unblinded efficacy parameters measured by HBV/HDV disease
blood markers (eg, HDV RNA, HBV DNA, HBeAg, HBsAg) during the double-blind phase. During the
open-label phase, all data will be unblinded. When all participants are in the open-label phase or
discontinued earlier, the IDMC responsibilities will be covered by the internal Data Review Committee
(DRC) (see section below).
The IDMC members will be appointed before the start of the study to review unblinded interim data for
both safety and efficacy and formulate recommendation(s) to the sponsor Committee, who will make the
final decision(s). Possible recommendations of the IDMC include, but are not limited to, continuing the
study unchanged, stopping the study for safety concerns, or for futility or make a study amendment.
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The IDMC will consist of at least one medical expert in the relevant therapeutic area and at least
1 statistician. The IDMC role and responsibilities, communication flow with other stakeholders, and
procedures will be documented in the IDMC charter.
Internal Data Review Committee
A DRC will be established for continuous monitoring of SAEs, AEs leading to discontinuation, and ALT
flares when all participants have completed double-blind phase and IDMC has completed its review. This
committee will consist of at least one medical expert in the relevant therapeutic area (hepatology) and at
least one statistician; committee membership responsibilities, authorities, and procedures will be
documented in the DRC  charter. The committee will meet periodically to review data of the efficacy
parameters measured by different HBV and HDV disease blood markers (eg, HDV RNA, HBV DNA,
HBeAg, HBsAg, etc).
The DRC members will be appointed to review the interim data for both safety and efficacy and formulate
recommendation(s) to the Sponsor Committee (see section below), who will make the final decision(s).
Details on the roles and responsibilities of the DRC and Sponsor Committee, as well as the flows of
communication, will be documented in the DRC charter.
Sponsor Committee
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.
The Sponsor Committee will review selected efficacy and safety parameters to assess the predefined
antiviral activity criteria and decide to start Part 2 based on the results of the Part 1 IA1 (when all
participants ofPart 1 have completed at least Week 16 or discontinued earlier).
After Part 2 has commenced, all sponsor personnel, including the Sponsor Committee, will remain blinded
to subsequent IDMC data reviews during the double-blind phase. During the open-label phase, all data will
be unblinded. The efficacy monitoring will be conducted by the IDMC to protect the well-being of the
participants against unexpected absence of further HBV RNA decline and/or HDV RNA frequent rebound
contrary to the initial antiviral activity criteria.
The criteria to trigger the start of Part 2 and to exclude futility will be defined in terms of the antiviral
activity as measured by a predefined threshold of HDV RNA and HBsAg reduction from baseline and will
be paired with an assessment of the benefit-risk ratio based on the Part 1 IA1 data.
Independent Flare Expert Panel
An IFLEP will be appointed. The IFLEP is composed of 3 independent medical experts with experience
and expertise in HBV/HDV. The responsibilities of the IFLEP include: conduct regular review of all
relevant and available individual participant blinded study data related to ALT flares; determine and
adjudicate each ALT flare; and provide documentation of the final decision to IDMC. Adjudication review
cycles will match IDMC schedule and will be set up prior to planned IDMC review.
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 remain blinded to the treatment assigned to each participant up to the
time of Part 1 IA1, when the IFLEP will become unblinded to the Part 1 data. In Part 2, the IFLEP will also
be blinded to the treatment assigned to each participant up to unblinding of the Part 2 clinical data.
Further details on the IFLEP process will be included in the IFLEP charter.
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1.2. 
Schema
Figure 1: 
Schematic Overview of the Study
FU: follow-up; JNJ-3989: JNJ-73763989; n: number of participants; NA: nucleos(t)ide analog
* The antiviral activity assessments monitored in Part 1 of the study are described in Section 8.1.1.
# indicates the end of the intervention phase with JNJ-3989 treatment up until minimum Week 96 (Arm 1) and
minimum Week 100 (Arm 2) in Part 2 per Protocol Amendment 5. Participants who stop treatment with JNJ-3989
after Protocol Amendment 5 will enter a 24-week FU phase.
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JNJ-3989: JNJ-73763989; MRI: magnetic resonance imaging; NA: nucleos(t)ide analog; PBMC: peripheral blood mononuclear cells; PK: pharmacokinetic; RNA:
ribonucleic acid; SBP: systolic blood pressure; ULN: upper limit of normal; W: Week; WD: withdrawal.
a. 
Participants who discontinue JNJ-3989/placebo early will have an early WD visit, that should be scheduled as soon as possible, and will enter follow-up (as
specified in Section 1.3.3) unless they withdraw consent. In case these participants continue in the follow-up phase, the follow-up visits can be scheduled based on
WD visit date. Participants who withdraw consent will be offered an optional safety follow-up visit 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.
b. 
If necessary (eg, for operational reasons), the screening phase may be extended up to a maximum of 8 weeks on a case-by-case basis and in agreement with the
sponsor. Depending on the duration of the screening phase, selected screening assessments may have to be repeated prior to enrollment.
c. 
Day 1 samples are to be collected before the first dose of study intervention.
d. 
The ICF must be signed before the first study-related activity. Participants must sign a separate ICF if they agree to provide an optional DNA sample for
pharmacogenomic 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.
e. 
Minimum criteria for the availability of documentation supporting the eligibility criteria are described in the Source Documents section of Section 10.3,
Appendix 3: Regulatory, Ethical, and Study Oversight Considerations. Clinical status will be checked at screening and again before first dose of study intervention.
If a participant’s clinical status changes (including any available laboratory results or receipt of additional medical records that becomes available during the
screening phase) 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.
f. 
Medical history also includes mode of HBV and HDV transmission and stage of liver fibrosis. Historical HDV RNA, anti-HDV antibodies, and HBV DNA to be
reported in the CRF. HBsAg, HBeAg and ALT data, if available, to be recorded in source documents, but not in the CRF.
g. 
Liver disease staging assessments will be performed based on FibroScan or liver biopsy results, obtained within 6 months prior to screening or at the time of
screening (in case of FibroScan) or within 1 year prior to screening (in case of liver biopsy). If FibroScan is not available, acoustic radiation force impulse (ARFI)
may be used if standard practice at the site or if otherwise validated and agreed with the sponsor (refer to Section 5.1, Inclusion Criteria for more information).
h. 
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 MRI monitoring is used per patient’s standard of care, these MRI results may also be used. 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).
i. 
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.
j. 
HDV genotype may be determined by sequencing. For participants with low HDV RNA levels, available historical data on previous HDV genotype assessment
will be collected in the CRF. Exploratory genotyping assays might be performed.
k. 
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.
l. 
In between study visits, participants will take NA at home and they will bring their NA with them to each study visit.
m. Complete physical examination, including height (at screening only), skin examination, and other body systems.
n. 
A liver ultrasound is performed every 24 weeks from Day 1 for HCC screening in all participants. The liver ultrasound does not need to be repeated at baseline if it
was done 3 months prior to screening or at time of screening. If a liver ultrasound is required at baseline, it can be performed between the Day 1 and the Week 2
visit (visit days included). For any subsequent liver ultrasound, a window of 1 week is allowed before or after the scheduled visit. In case MRI monitoring is used
per patient’s standard of care, these MRI results may also be used.
o. 
Symptom-directed physical examination.
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p. 
Vital signs include supine SBP, DBP, pulse rate, body weight, and body temperature.
q. 
All ECGs will be read centrally. Only on Day 1, the ECG will also be read locally prior to dosing to assess eligibility.
r. 
All injection site reactions (ISRs; including ISRs below grade 1) will need to be recorded in the special events section of the CRF (see Section 8.3.6.2).
s. 
Biochemistry samples must be taken after fasting for at least 10 hours for measurement of phosphate, calcium, creatinine, and lipids.
t. 
Creatinine clearance (eGFR calculated by the CKD-EPI formula) will be assessed.
u. 
Intervention-emergent ALT/AST elevations (ie, ALT and/or AST ≥3x ULN and ≥2x 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 3 days of the receipt of the initial ALT/AST results, to repeat laboratory testing of AFP, ALT, AST, ALP, bilirubin (total and direct), INR, albumin, HBV
DNA, and HDV RNA. Note that in case of urgency, local laboratory assessments could be considered (except for HDV RNA and HBsAg to protect the blind).
Off-treatment local HDV RNA test can be done to exclude/assess for HDV driven flare. 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.
v. 
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).
w. Urine sample for selected renal biomarkers including retinol binding protein and beta-2-microglobulin.
x. 
A FibroScan assessment will only be done at baseline if it was not done at screening.
y. 
Only applicable to participants who are enrolled at a site with access to a FibroScan device.
z. 
At Week 52, participants of Arm 2 will switch to JNJ-3989 +NA, therefore, the FibroScan assessment at Week 48 is the baseline assessment for these participants.
aa. For sites in the US, HDV RNA tests used to determine the participant’s eligibility should be performed by a local laboratory.
bb. 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 and HDV.
cc. Sequencing at baseline (Day 1 predose) may be performed by default if HBV DNA levels and HDV RNA levels are within the ranges required for the sequencing
assay; other samples may be sequenced upon the sponsor virologist’s request. Samples might be used for exploratory analyses related to HBV/HDV or study
intervention.
dd. Quantitative HBeAg assessment will be performed throughout the study in participants who are HBeAg-positive at screening. In participants who are
HBeAg-negative at screening, quantitative HBeAg testing should only be performed starting from the first qualitative HBeAg test result being positive.
ee. Exploratory serology samples may be analyzed at the sponsor’s discretion. Samples may be used to assess virologic or serologic markers of HBV/HDV including
semi-quantitative anti-HDV IgM antibodies. These samples may also be used for host serum protein testing (eg, cytokines).
ff. 
All participants will have sparse PK sampling. For all samples, the time of the preceding 2 intakes of NA and the time of PK sampling should be recorded.
One sample at any time between 2 and 8 hours after JNJ-3989 dosing with collection of the time interval between last administration and blood draw. Before
leaving the study site, the participant’s well-being should be confirmed. In the event of special circumstances (eg, COVID-19 pandemic), the sample may be taken
between 15 minutes to less than 2 hours postdose but the sponsor should approve first.
gg. Antidrug antibodies samples should be collected prior to JNJ-3989 administration.
hh. PBMC samples will be collected at selected sites only and as operationally feasible. Additional PBMC samples may be taken until Week 48 in case of ALT flares,
upon discussion with the sponsor, which may require an unscheduled visit.
ii. 
The pharmacogenomic (host DNA) sample is optional and will only be collected from participants who consent separately to this component of the study. The
pharmacogenomic (host DNA) sample should preferably be collected at baseline.
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jj. 
The medical resource utilization data will include: (1) number and type of medical visits, (2) number (proportion) of participants requiring hospitalization and
duration of hospitalization, and (3) number and character of diagnostic and therapeutic tests and procedures (inpatient and outpatient). For more details, refer to
Section 8.9.
kk. The sample for HLA haplotyping should preferably be collected during the Day 1 visit, but may occur at any other study visit during the double-blind study
intervention phase.
ll. 
The preferable time points for collections are indicated but for post-baseline samples might be adapted at investigator’s discretion and in consultation with the
sponsor. Percutaneous core liver biopsy sample will be prioritized over FNAB if only one sample can be collected.
mm. Following local standard practice the biopsy location will be identified with ultrasound (which will also be used to rule out contraindicating conditions for a
biopsy) and after application of local anesthesia the FNAB samples and core liver biopsy samples will be collected. Prior to any on-treatment biopsy, a recent
(≤1 week) coagulation and hematology panel are required (pre-biopsy visit). Prior to the baseline or off-treatment biopsies, blood coagulation and platelets will be
assessed according to local practice. On-treatment (pre)biopsy can only occur during a regularly scheduled visit. It should be noted that antiplatelet aggregating
agents should be paused at least 9 days prior to liver biopsy procedures or according to local standard practice.
nn. If participants agree to undergo an optional liver biopsy, they must provide a separate consent at screening or at any time prior to the optional liver biopsy and
additional exclusion criteria apply (Section 5.2, Exclusion Criteria). Refusal to give consent for these optional liver biopsy samples does not exclude a participant
from participation in the study. Liver biopsies will be collected only in sites and in selected countries where this is feasible, and after all relevant approvals are in
place and operational set-up is completed.
oo. Total anti-HDV antibodies and anti-HDV IgM antibodies may be assessed (qualitative and semi-quantitative).
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Status: Approved,  Date:  27 March 2024
m. Intervention-emergent ALT/AST elevations (ie, ALT and/or AST ≥3x ULN and ≥2x 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 3 days of the receipt of the initial ALT/AST results, to repeat laboratory testing of AFP, ALT, AST, ALP, bilirubin (total and direct), INR, albumin, HBV
DNA, and HDV RNA. Note that in case of urgency, local laboratory assessments could be considered. (except for HDV RNA and HBsAg to protect the blind)
Off-treatment local HDV RNA test can be done to exclude/assess for HDV driven flare. 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.
n. 
Only applicable to participants who are enrolled at a site with an access to a FibroScan device.
o. 
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).
p. 
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 and HDV.
q. 
Samples may be sequenced upon on the sponsor virologist’s request. Samples might be used for exploratory analyses related to HBV/HDV or study intervention.
r. 
Quantitative HBeAg assessment will be performed throughout the study in participants who are HBeAg-positive at screening. In participants who are
HBeAg-negative at screening, quantitative HBeAg testing should only be performed starting from the first qualitative HBeAg test result being positive.
s. 
Exploratory serology samples may be analyzed at the sponsor’s discretion. Samples may be used to assess virologic or serologic markers of HBV/HDV including
semi-quantitative anti-HDV IgM antibodies. These samples may also be used for host serum protein testing (eg, cytokines).
t. 
All participants will have sparse PK sampling. For all samples, the time of the preceding 2 intakes of NA and the time of PK sampling should be recorded.
One sample at any time between 2 and 8 hours after JNJ-3989 dosing with collection of the time interval between last administration and blood draw. Before
leaving the study site, the participant’s well-being should be confirmed. In the event of special circumstances (eg, COVID-19 pandemic), the sample may be taken
between 15 minutes to less than 2 hours postdose but the sponsor should approve first.
u. 
The medical resource utilization data will include: (1) number and type of medical visits, (2) number (proportion) of participants requiring hospitalization and
duration of hospitalization, and (3) number and character of diagnostic and therapeutic tests and procedures (inpatient and outpatient). For more details, refer to
Section 8.9.
v. 
Antidrug antibodies samples should be collected prior to JNJ-3989 administration.
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Status: Approved,  Date:  27 March 2024
h. 
Vital signs include supine SBP, DBP, pulse rate, body weight, and body temperature.
i. 
All ECGs will be read centrally.
j. 
All injection site reactions (ISRs; including ISRs below grade 1) will need to be recorded in the special events section of the CRF.
k. 
Biochemistry samples must be taken after fasting for at least 10 hours for measurement of phosphate, calcium, creatinine, and lipids.
l. 
Creatinine clearance (eGFR calculated by the CKD-EPI formula) will be assessed.
m. Intervention-emergent ALT/AST elevations (ie, ALT and/or AST ≥3x ULN and ≥2x 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 3 days of the receipt of the initial ALT/AST results, to repeat laboratory testing of AFP, ALT, AST, ALP, bilirubin (total and direct), INR, albumin, HBV
DNA, and HDV RNA. Note that in case of urgency, local laboratory assessments could be considered. (except for HDV RNA and HBsAg to protect the blind)
Off-treatment local HDV RNA test can be done to exclude/assess for HDV driven flare. 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.
n. 
Only applicable to participants who are enrolled at a site with an access to a FibroScan device.
o. 
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).
p. 
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 and HDV.
q. 
Samples may be sequenced upon on the sponsor virologist’s request. Samples might be used for exploratory analyses related to HBV/HDV or study intervention.
r. 
Quantitative HBeAg assessment will be performed throughout the study in participants who are HBeAg-positive at screening. In participants who are
HBeAg-negative at screening, quantitative HBeAg testing should only be performed starting from the first qualitative HBeAg test result being positive.
s. 
Exploratory serology samples may be analyzed at the sponsor’s discretion. Samples may be used to assess virologic or serologic markers of HBV/HDV including
semi-quantitative anti-HDV IgM antibodies. These samples may also be used for host serum protein testing (eg, cytokines).
t. 
The medical resource utilization data will include: (1) number and type of medical visits, (2) number (proportion) of participants requiring hospitalization and
duration of hospitalization, and (3) number and character of diagnostic and therapeutic tests and procedures (inpatient and outpatient). For more details, refer to
Section 8.9, Medical Resource Utilization.
u. 
Procedures not applicable per Protocol Amendment 5.
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CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
46
Status: Approved,  Date:  27 March 2024
e. 
A liver ultrasound is performed every 24 weeks from start of FU for HCC screening in all participants. A window of 1 week is allowed before or after the
scheduled visit. In case MRI monitoring is used per patient’s standard of care, these MRI results may also be used.
f. 
Vital signs include supine SBP, DBP, pulse rate, body weight, and body temperature.
g. 
All ECGs will be read centrally.
h. 
Biochemistry samples must be taken after fasting for at least 10 hours for measurement of phosphate, calcium, creatinine, and lipids.
i. 
Creatinine clearance (eGFR calculated by the CKD-EPI formula) will be assessed.
j. 
ALT/AST elevations (ie, ALT and/or AST ≥3x ULN and ≥2x 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 3 days of the receipt of
the initial ALT/AST results, to repeat laboratory testing of AFP, ALT, AST, ALP, bilirubin (total and direct), INR, albumin, HBV DNA, and HDV RNA. Note that
in case of urgency, local laboratory assessments could be considered (except for HDV RNA and HBsAg to protect the blind). Off-treatment local HDV RNA test
can be done to exclude/assess for HDV driven flare. 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.
k. 
Liver function tests only.
l. 
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).
m. Urine pregnancy tests for at-home use will be provided to the participants from 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 urine pregnancy test is positive, the investigator needs to be informed immediately by the participant.
n. 
Only applicable to participants who are enrolled at a site with an access to a FibroScan device.
o. 
Only applicable to participants who stopped NA treatment.
p. 
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.
q. 
Samples may be sequenced upon on the sponsor virologist’s request. Samples might be used for exploratory analyses related to HBV/HDV or study intervention.
r. 
Exploratory serology samples may be analyzed at the sponsor’s discretion. Samples may be used to assess virologic or serologic markers of HBV/HDV including
semi-quantitative anti-HDV IgM antibodies. These samples may also be used for host serum protein testing (eg, cytokines).
s. 
The medical resource utilization data will include: (1) number and type of medical visits, (2) number (proportion) of participants requiring hospitalization and
duration of hospitalization, and (3) number and character of diagnostic and therapeutic tests and procedures (inpatient and outpatient). For more details, refer to
Section 8.9.
t. 
Quantitative HBeAg assessment will be performed throughout the study in participants who are HBeAg-positive at screening. In participants who are
HBeAg-negative at screening, quantitative HBeAg testing should only be performed starting from the first qualitative HBeAg test result being positive.
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Clinical Protocol 73763989HPB2004 Amendment 5
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
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Status: Approved,  Date:  27 March 2024
f. 
For participants who have not reached FU W24 (including those in the open-label phase) when Protocol Amendment 5 is in effect, liver ultrasound is performed at
the EOS visit (ie, FU W24) for HCC screening. A window of 1 week is allowed before or after the scheduled visit. In case MRI monitoring is used per patient’s
standard of care, this MRI result may also be used.
g. 
Vital signs include supine SBP, DBP, pulse rate, body weight, and body temperature.
h. 
All ECGs will be read centrally.
i. 
Biochemistry samples must be taken after fasting for at least 10 hours for measurement of phosphate, calcium, creatinine, and lipids.
j. 
Creatinine clearance (eGFR calculated by the CKD-EPI formula) will be assessed.
k. 
ALT/AST elevations (ie, ALT and/or AST ≥3x ULN and ≥2x 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 3 days of the receipt of
the initial ALT/AST results, to repeat laboratory testing of AFP, ALT, AST, ALP, bilirubin (total and direct), INR, albumin, HBV DNA, and HDV RNA. Note that
in case of urgency, local laboratory assessments could be considered (except for HDV RNA and HBsAg to protect the blind). Off-treatment local HDV RNA test
can be done to exclude/assess for HDV driven flare. 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.
l. 
Liver function tests only.
m. 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).
n. 
Urine pregnancy tests for at-home use will be provided to the participants from 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 urine pregnancy test is positive, the investigator needs to be informed immediately by the participant. The
procedures will not be applicable per Protocol Amendment 5.
o. 
Only applicable to participants who are enrolled at a site with an access to a FibroScan device.
p. 
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.
q. 
Samples may be sequenced upon on the sponsor virologist’s request. Samples might be used for exploratory analyses related to HBV/HDV or study intervention.
r. 
The medical resource utilization data will include: (1) number and type of medical visits, (2) number (proportion) of participants requiring hospitalization and
duration of hospitalization, and (3) number and character of diagnostic and therapeutic tests and procedures (inpatient and outpatient). For more details, refer to
Section 8.9, Medical Resource Utilization.
s. 
Quantitative HBeAg assessment will be performed throughout the study in participants who are HBeAg-positive at screening. In participants who are
HBeAg-negative at screening, quantitative HBeAg testing should only be performed starting from the first qualitative HBeAg test result being positive.
t. 
To be performed only in case ofearly discontinuation.
u. 
Procedures not applicable per Protocol Amendment 5.
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Status: Approved,  Date:  27 March 2024
2. 
INTRODUCTION
HBV/HDV Co-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 by the hepatitis B core
protein (HBc) surrounded by a membranous envelope containing hepatitis B surface antigen
(HBsAg). The acute phase of the infection (typically less than 6 months) is either followed by an
immune controlled state (spontaneous cure from the infection) or progression to chronic hepatitis
B (CHB) (persistence of the virus over 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.26
Hepatitis D virus (HDV) is a small single-stranded ribonucleic acid (RNA) virus. HDV requires
HBsAg to form infectious viral particles and therefore can only occur as a co-infection or
super-infection in HBsAg-positive CHB patients. Chronic HDV infection is considered the most
severe form of chronic viral hepatitis. Chronic HDV infection is life-threatening and debilitating
in the long-term as it can lead to cirrhosis, liver failure, and HCC.7 HDV infection is associated
with  more rapid progression of liver disease as well as increased frequency of HCC.25 The
mechanism in which HDV causes more severe hepatitis and a faster progression of fibrosis than
with HBV alone remains unclear.27
At least 13% of people with chronic HBV infection are co-infected with HDV, resulting in a total
of 48-60 million people infected with HDV worldwide.17 However, prevalence might be
underestimated due to limited testing and unreliable tests in older studies. A recent meta-analysis
reported a worldwide HBV/HDV co-infection prevalence of 62-72 million.5 Areas of high HDV
prevalence include Eastern and Mediterranean Europe, the Middle East, Central and North Asia,
the Amazon basin, and parts of Africa.5 In the EU, HDV infection affected approximately 4 in
10,000 people in 2015. This was equivalent to approximately 205,000 people and is within the
limits to qualify for orphan disease in the EU, which is set at 5 people in 10,000.19HDV prevalence
is thought to be relatively low in the United states (US) overall, but may be increased in certain
subpopulations, such as injecting drug users and people born or having lived in countries where
the disease is endemic. Population-based data from the UN Population Division World Population
Prospects 2019 and the WHO Global Hepatitis Report 2017 estimated that the anti-HDV antibody
prevalence among US born adults in the US is 0.04% and the prevalence of HBsAg 0.7%.21 Based
on the low prevalence in the US with <200,000 persons affected,18 hepatitis D is considered an
orphan disease. Therefore, drug products in development for the treatment of HDV infection may
be eligible for an orphan drug designation.10
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Status: Approved,  Date:  27 March 2024
Two types of HDV infection are defined according to the WHO: acute hepatitis due to co-infection
and superinfection.27
Acute hepatitis: simultaneous infection with HBV and HDV can lead to a mild-to-severe
or even fulminant hepatitis, but recovery is usually complete and development of chronic
hepatitis D (CHD) is rare (less than 5% of acute hepatitis).
Superinfection: HDV can infect a person already chronically infected with HBV. The
superinfection of HDV on chronic HBV accelerates progression to a more severe disease
in 70% 90% of patients (all ages). HDV superinfection accelerates progression to cirrhosis
almost a decade earlier than HBV mono-infected persons, although HDV suppresses HBV
replication.
At present there are no drugs approved for the treatment of chronic HDV infection. Pegylated
interferon-alpha (PegIFN-α) is used in chronic HDV infection but is associated with significant
toxicity and tolerability is poor in patients with decompensated cirrhosis. Treatment with
PegIFN-α results in “sustained” virologic response rates (defined as undetectable HDV RNA
levels 6 months after treatment) of 25%-30%.8,25 However, late virologic relapses after achieving
“sustained” virologic response are common following treatment with PegIFN-α, and it is not
known if HDV sustained clearance can be achieved in the setting of persistent HBsAg positivity.13
Although currently available HBV therapies are effective in suppressing HBV replication, the rate
of HBsAg reduction and/or loss remains low.22 In the absence of HBsAg loss, HDV infection may
persist. Therefore, therapies directly targeting HBsAg are expected to be of clinical benefit for
hepatitis D treatment as well.23
Suppression of HDV replication in combination with normal alanine aminotransferase (ALT)
levels are the primary goals of HDV treatment since this has been shown to lead to improved
clinical outcome.3 Consistent with this, the recent US Food and Drug Administration (FDA)’s draft
guidance on the treatment of chronic HDV infection recommends the following as surrogate
endpoint and primary endpoint for pivotal studies: a decline in virologic replication (eg, serum
HDV RNA target not detected [TND] and/or HDV RNA decline of >2 log10 IU/mL from baseline)
and an improvement in associated liver inflammation as evidenced by biochemical response
(eg, normal ALT).24
For the most comprehensive nonclinical and clinical information regarding JNJ-73763989
(JNJ-3989), refer to the latest version of the Investigator’s Brochure (IB) for JNJ-3989.
The term “study intervention” throughout the protocol, refers to JNJ-3989 or placebo, and
nucleos(t)ide analog (NA).
The term “sponsor” used throughout this document refers to the entities listed in the Contact
Information page(s), which will be provided as a separate document.
The term “participant” throughout the protocol refers to the common term “subject”.
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Status: Approved,  Date:  27 March 2024
2.1. 
Study Rationale
Infection with HDV leads to a chronic liver disease for which no effective treatment is approved.
HDV infection only occurs in the context of co-infection with HBV as it requires the presence of
HBsAg for HDV to form infectious viral particles.
There is a high unmet medical need for patients co-infected with HBV and HDV since co-infection
is associated with earlier development of liver cirrhosis, increased risk for development of HCC
and increased liver-related and overall mortality compared to HBV mono-infected. At present
there are no drugs approved for the treatment of chronic HDV infection. The currently available
therapeutic options for HDV infection  are suboptimal and untreated patients have a rapid
progression of disease.
JNJ-3989 is a small interfering RNA (siRNA) specifically engineered to silence all HBV viral
products including HBsAg derived from HBV covalently closed circular DNA (cccDNA) and
from HBV genes integrated in the host genome. In the Phase 1/2a Study AROHBV1001 with HBV
mono-infected patients, administration of JNJ-3989 has been associated with a significant decline
in HBsAg with 3 monthly doses. Ongoing studies are evaluating longer administration of JNJ-3989
in combination with NA with or without JNJ-56136379 (an orally administered capsid assembly
modulator).
Reduction of HBsAg levels directly via JNJ-3989 is expected to lead to a reduced number of
infectious HDV particles and less de novo infections ultimately leading to inhibition of HDV RNA
replication. Suppressing HDV RNA replication, the primary treatment goal in this study, is
associated with the normalization of liver enzymes and histological improvement of liver disease
which is expected to improve clinical outcomes.
2.2. 
Background
2.2.1. 
Primary Pharmacology
JNJ-3989 is a 2:1 molar mixture of 2 synthetic, double-stranded, N-acetylgalactosamine (GalNac)
conjugated RNAi triggers (JNJ-73763976 and JNJ-73763924, respectively). RNAi is a naturally-
occurring phenomenon by which short, double-stranded RNA oligonucleotides trigger a sequence-
specific down modulation of gene expression. The RNAi triggers in JNJ-3989 are designed to
target all HBV transcripts derived from cccDNA and integrated viral DNA. This is made possible
by the fact that all HBV transcripts expressed from cccDNA, including the RNA transcript
(pre-genomic ribonucleic acid [pgRNA]) that is used as a template for replication of HBV DNA,
are terminated by the same polyadenylation site and share a common sequence region upstream of
this site. One RNAi trigger (JNJ-73763924) in JNJ-3989 has its target within this common
sequence region and thus has the potential to knock down expression of all viral proteins as well
as the pgRNA expressed from cccDNA. The second RNAi trigger (JNJ-73763976), which targets
the HBsAg encoding region, was designed to knock down expression of HBsAg derived from
integrated HBV DNA as well as all viral proteins derived from cccDNA with the exception of
HBV x protein. Silencing viral RNA will reduce HBV DNA and viral proteins, including HBsAg.
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Status: Approved,  Date:  27 March 2024
Since HBsAg is required for replication of HDV, by allowing HDV to infect new cells, reducing
HBsAg levels is anticipated to lead to inhibition of HDV replication.
In mice transiently harboring the human HBV genome, treatment with JNJ-3989 led to dose-
dependent reductions of serum HBsAg, HBeAg, and HBV DNA. Multiple doses of JNJ-3989
resulted in additional and prolonged antigen and HBV DNA reductions in a stepwise fashion when
compared to a single dose. This was consistent with prolonged liver persistence of antisense
strands, which, when loaded into the RNA-induced silencing complex (RISC), exert the
pharmacologic RNAi activity. The ability of JNJ-3989 to reduce serum HBV DNA was additive
to synergistic with entecavir (ETV). ETV alone had no effect on serum HBsAg levels, and no
negative effect on the ability of JNJ-3989 to reduce serum HBsAg was observed when given in
combination.
2.2.2. 
Nonclinical Studies
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 (SC) 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 SC injection at 30 up to 300 mg/kg. In the 24- or 37-week studies, JNJ-3989 was
administered once weekly for the first month, followed by once monthly thereafter at 30 up to
180 mg/kg. JNJ-3989 was well tolerated in these studies.
In the 2-week and the 24-week 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 GalNac-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.
CCI
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Status: Approved,  Date:  27 March 2024
A second 24-week study in rats identified adverse findings: foci of cellular alteration in liver; likely
rat-specific; poorly differentiated injection site sarcoma, possibly spontaneous and/or associated
with repeated injections at the same location. These are not expected to translate to humans. The
animal-to-human exposure ratios are shown in Table 1.
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
SC 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.
The pre- and postnatal development study in rats showed no effects on pre- and postnatal
development, including no effects on sexual maturation, neurobehavioral assessments, or
reproductive performance of the F1 offspring at doses up to 120 mg/kg/administration. There was
negligible placental and/or lactational transfer.
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 in vitro studies
demonstrated there is no potential for induction of the innate immune system (cytokine and
complement activation), mitochondrial toxicity/cytotoxicity, or platelet aggregation associated
with JNJ-3989 exposure at concentrations up to 250 µg/mL.
The animal-to-human exposure ratios were calculated using rat and monkey exposures at NOAELs
from the 24-week studies in rat and the 37-week study in monkey, respectively, and human
exposures after a dose of 200 mg JNJ-3989 every 4 weeks (Q4W) in chronic HVB-infected
participants (73763989HPB2001) (Table 1), refer to the latest IB15 for the most comprehensive
results.
For rats, when combining the findings of the two 24-week studies, the most conservative NOAEL
over both studies is retained for calculations. This resulted in an NOAEL in male rats of
 mg/kg,
based on adverse findings at 
 mg/kg in the second 24-week study and a clean 
 mg/kg dose
in the first 24-week study, and an NOAEL in female rats of
 mg/kg, based on adverse findings
at
 mg/kg in the second 24-week study, and a clean
 mg/kg dose in the first 24-week study.
CCI
C
CCI
C
C
C
CI
C
CI
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Status: Approved,  Date:  27 March 2024
Table 1: 
Animal/Human Exposure Ratios at NOAEL for JNJ-3989
Ratio Total
Concentration
Sex 
NOAEL 
(mg/kg) 
Cmax 
(ng/mL) 
AUC0-24h  
(ng∙h/mL) 
Cmax 
A/H 
Ratio 
AUC
A/H
Ratio
JNJ-73763976 Human exposurea
1.031 
- 
-
24-week ratc
M 
23,500 
199,000 
22.8 
12.0
F 
12,200 
31,400 
11.8 
1.9
37-week monkeyc
M 
73,200 
1,230,000 
71.0 
74.2
F 
65,800 
988,000 
63.8 
59.6
JNJ-73763924 Human exposurea
212 
- 
-
24-week ratb
M 
14,400 
124,000 
67.9 
39.3
F 
7,780 
20,600 
36.7 
6.5
37-week monkeyc
M 
21,600 
383,000 
101.9 
121.3
F 
23,000 
392,000 
108.5 
124.1
a 
Q4W (Week 4, 8, 12 and 16) dose of 200 mg of JNJ 73763989 in chronic HBV infected participants (Study
73763989HPB2001).
b
Once weekly dosing for 5 weeks, followed by once monthly dosing up to a total of 24 weeks.
c
Once weekly dosing for 5 weeks, followed by once monthly dosing, up to a total of 37 weeks.
AUC0-24h  area under the plasma concentration time curve from administration to 24 h; A/H ratio  animal/human ratio;
F
female; M  male; Q4W  every 4 weeks; NOAEL: no observed adverse effect level; Cmax: maximum plasma concentration.
2.2.3. 
Clinical Studies
At the time of data cut-off for IB Edition 7 (15 February 2023)15, JNJ-3989 was being evaluated
in several clinical studies. Four Phase 1 studies were completed in different study populations:
healthy adult Japanese participants (Study 73763989HPB1001), adult participants with or without
hepatic impairment (Study 73763989HPB1002), healthy  adult Chinese participants
(Study 73763989HPB1004), and healthy adult participants (PK and relative bioavailability,
Study 73763989HPB1005). One Phase 1/2a study (Study AROHBV1001) in healthy adult
participants and in participants with CHB was also completed. Two Phase 2 studies were
completed 
in 
participants 
with 
CHB 
(Study  73763989HPB2001 
[REEF-1] 
and
Study 73763989PAHPB2002 [REEF-2]). In total, 107 healthy, 546 CHB participants, and
8 participants with moderately impaired hepatic function have been dosed with JNJ-3989 in the
completed 
Studies AROHBV1001, 
73763989HPB1001, 
73763989HPB1002,
73763989HPB1004, 73763989HPB1005, 73763989HPB2001, and 73763989PAHPB2002.
At the time of data cut-offfor IB Edition 7, clinical activities were ongoing in 3 Phase 1/1b studies:
PK in participants with or without renal impairment (Study 73763989HPB1003), safety and
tolerability of different formulations in healthy participants (Study 73763989HPB1008), and
efficacy in participants with CHB (OSPREY) (Study 73763989PAHPB1006). Four Phase 2
studies were ongoing in adult CHB participants: INSIGHT (Study 73763989HPB2003), REEF-IT
(Study 73763989PAHPB2005), PENGUIN (Study 73763989PAHPB2006), and OCTOPUS-1
(Study 73763989PAHPB2008). One Phase 2 study was ongoing in CHB/CHD co-infected
participants: REEF-D (Study 73763989HPB2004).
JNJ-3989 was generally safe and well tolerated with no deaths. The majority of serious adverse
events (SAEs) were considered not related to the study intervention. Adverse events (AEs) leading
CCI
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to study intervention discontinuation  were infrequent. Most AEs and laboratory abnormalities
were distributed across all dose levels and also occurred on placebo treatment.
At the time of initial protocol writing, efficacy was assessed using snapshot data through
26 March 2020. Antiviral activity data were available for 56 CHB participants who received 3 SC
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
numerically smaller mean decline was observed at the lower doses of 25 and 50 mg, mainly
apparent after end of JNJ-3989 dosing. 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. Refer to the latest IB15 for the most recent efficacy data.
Part 1 REEF-D Study Data (Study 73763989HPB2004)
Of the 22 participants with CHD enrolled into Part 1 of the REEF-D study, 17 were randomized
to treatment with JNJ-3989 100 mg + NA and 5 were randomized to placebo + NA. The predefined
antiviral activity criteria to start Part 2 of the study (at least 8 JNJ-3989 treated participants with
≥0.5 log reduction from baseline in HBsAg and HDV RNA and 4 of those with ≥1 log reduction
in HDV RNA) were met.
The second interim analysis (IA) was performed when all Part 1 participants (N 22) had reached
Week 48 or later, or discontinued earlier.
REEF-D Safety Data at Week 48for Part 1
At Week 48, 6/17 (35.3%) participants in the JNJ-3989 + NA arm were reported with a Grade ≥3
AE.
Adverse 
events 
were 
considered 
related 
to 
JNJ-3989 
by the 
investigator 
in
11/17 (64.7%) participants who received JNJ-3989 + NA treatment.
Among the adverse events of special interest (AESIs) defined in the study protocol, ALT/AST
elevations were reported in 13/17 (76.5%) participants in the JNJ-3989 + NA arm and no
participants in the placebo +NA arm. For 2 of these 13 participants, the ALT elevation criteria
according to the protocol were not met nor the discontinuation criteria for JNJ-3989.
One additional participant met the ALT elevation criteria and discontinued JNJ-3989, but the event
was not reported as an AE.
During follow-up, 4/11 (36.4%) participants in  the JNJ-3989 + NA arm reported treatment-
emergent AEs, which were AESIs (ie, ALT/AST elevations).
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No deaths were reported. Two (11.8%) participants in the JNJ-3989+NA arm experienced 3 SAEs:
ALT increased and AST increased in 1 (5.9%) participant, and transaminases increased in
1 (5.9%) participant, which lead to withdrawal from study drug.
Twelve of 22 (54.5%) participants enrolled in Part 1 experienced ALT elevations on treatment up
to the 48-week timepoint; all 12 were treated with JNJ-73763989 + NA. These ALT elevations
were Grade 3 in 5 participants and Grade 4 in 7 participants. The mean (SD) change from baseline
was 5.6 (80.05) U/L. The majority of these ALT elevations had a peak of ALT between
120 and 650 U/L. A single case marked a peak of 1,162 U/L, which showed levels below
1,000 U/L on confirmatory tests. None of the participants with ALT elevations showed signs of
decreased hepatic function, but 1 participant showed clinical symptoms of epigastric pain, nausea
and vomiting for 4 days during the peak of ALT elevation. Management of these acute elevations
was following protocol-defined criteria. Some of the cases showed a prolonged pattern of ALT
elevation for which no management criteria were provided in the protocol at the time of the event.
No clinically significant safety ECG or vital sign findings were observed.
REEF-D Efficacy Data at Week 48 for Part 1
In all JNJ-3989-treated participants, treatment with JNJ-3989 led to reductions in  HBsAg, and
subsequently, HDV RNA.
At Week 48, 4/17 (23.5%) participants in the JNJ-73763989 + NA and none in the NA arm
achieved the primary composite endpoint of HDV RNA decline from baseline of ≥2 log10 IU/mL
(or undetectable) and normal ALT. Among the 5 participants without ALT elevations in the
JNJ‑73763989+NA arm, 4/5 (80.0%) participants achieved the primary composite endpoint, of
which 2/5 (40.0%) participants had HDV RNA <LLOQ.
2.3. 
Benefit-risk Assessment
More detailed information about the known and expected benefits and risks of JNJ-3989 can be
found in the IB.15
2.3.1. 
Risks for Study Participation
2.3.1.1. 
Known Risks
Overall, JNJ-3989 administration was generally safe and well tolerated in the completed and
ongoing studies, all of which (except REEF-D) are in CHB patients or healthy participants.
2.3.1.2. 
Potential Risks
All therapies have the potential to cause adverse experiences.
Patients with positive HDV RNA, 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 HDV RNA, HBV DNA, and/or HBsAg.
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ALT elevations are considered an important potential risk for JNJ-3989. Two distinct patterns of
ALT elevations have been observed in participants receiving JNJ-3989: a rapidly rising and
resolving ALT elevation or a more sustained pattern of ALT elevation. During Parts 1 and 2 of
this study, the latter has been observed in HBV/HDV co-infected participants, when receiving
JNJ-3989 compared to placebo. In Part 2 of this study, the risk of confirmed ALT elevations was
higher in participants with HBsAg levels >10,000 IU/mL at screening or baseline. A causal
relationship between JNJ-3989 and ALT elevations is suspected. However, the mechanism for this
type of confirmed ALT elevations seen with JNJ-3989 in treatment of patients with HBV/HDV
co-infection is not yet understood.
The participants who are randomized to the deferred active treatment arm, could also be at
increased risk for liver disease progression during the 52 weeks of placebo +NA treatment.
Participants who are HBV DNA suppressed are at risk for hepatitis B reactivation if NA treatment
is discontinued. Reactivation of hepatitis B is defined by a sudden increase in HBV-DNA
replication in participants with previously inactive CHB (resolved HBV infection or virologically
suppressed). Although HBV reactivation can occur spontaneously, it can be triggered by
immunosuppressive therapy  (for autoimmune diseases or in the transplant setting), diseases
associated with an immunocompromised state (cancer, human immunodeficiency virus infection),
or the withdrawal of antiviral drugs.
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 cytochrome P450 (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.
Hematologic abnormalities and injection site reactions (ISRs) are AESIs for JNJ-3989 and are
routinely monitored in clinical trials. Other toxicities that are also monitored in this study as AESIs
include renal complications and events related to cholesterol increase.
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Viral Resistance
Treatment with JNJ-3989 may lead to viral resistance. This viral resistance is not expected to
impact the treatment with other siRNAs. Using JNJ-3989 in combination with ETV, tenofovir
alafenamide (TAF), or tenofovir disoproxil is expected to minimize the risk of emerging resistant
viral variants.
Please refer to Section 2.2, Background, for details on the safety results in the studies conducted
to date.
2.3.1.3. 
Risks Due to Study Procedures
Potential Risks and Inconvenience Associated with the Optional Liver Biopsy Procedures
Percutaneous core liver biopsies and fine needle aspiration biopsies (FNABs) will be performed
during this study for research purposes only in participants who consented separately to this
procedure. Liver biopsies will be collected only in sites and in selected countries where this is
feasible, and after all relevant approvals are in place and operational set-up is completed.
The risks and complications related to these procedures will be described in the informed consent
form (ICF) and may include:
Pain and discomfort located at or near the puncture site and radiating upwards toward the right
shoulder region, which may last for up to a few hours or rarely days after the procedure.
Bleeding at the biopsy site.
Infection and internal bleeding and/or puncture of other internal organs (gall bladder, lung,
intestine or kidney) which can lead to serious complications (uncommon 1 in 1,000 to 1 in
100) including the need for emergency surgery, blood transfusion, or removal of organs.
Deaths directly related to liver biopsy occur rarely (approximately 1 in every 10,000 biopsies).
2.3.2. 
Benefits for Study Participation
2.3.2.1. 
Known Benefits
The clinical benefit of JNJ-3989 remains to be established.
2.3.2.2. 
Potential Benefits
Results from clinical studies with JNJ-3989 and NAs may be useful for the development of a novel
therapeutic approach for chronic HBV/HDV co-infection.
Reduction of HBsAg levels directly via JNJ-3989 is expected to result in a reduced number of
infectious HDV particles and less de novo infections ultimately leading to inhibition of HDV
replication. Treatment with JNJ-3989 in combination with NAs might lead to HBsAg
seroclearance which could result in complete elimination of HDV (ie, cure). Reduced and complete
inhibition of HDV replication, is associated with the normalization of liver enzymes and
histological improvement of liver disease which is expected to improve clinical outcomes.
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In addition, the combination of JNJ-3989 and NAs is expected to intensify suppression of HBV
replication compared to NA alone, by further downregulating the levels of the HBV proteins and
pgRNA, the precursor of viral relaxed circular DNA. The inhibition of HBV proteins, including
HBsAg, may allow a restoration of the host immune response and could lead to sustained HBsAg
seroclearance (ie, functional cure for HBV).
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 clinical studies is considered favorable for the following reasons:
Overall, JNJ-3989 administration was safe and well tolerated in completed and ongoing
studies, all of which (except REEF-D) are in CHB patients or healthy participants.
Events of Special Interest are significant AEs that are judged to be of special interest
because of clinical importance, known class effects or based on nonclinical signals. Events
of Special Interest that will be carefully monitored during the study include ISRs,
ALT/AST elevations, renal complications, hematologic abnormalities, and events related
to cholesterol increase (Section 8.3.6, Adverse Events of Special Interest and Section 8.2.4,
Clinical Safety Laboratory Assessments). In addition, the following toxicities will also be
carefully monitored: rash and acute systemic allergic reactions (Section 8.3.6, Adverse
Events of Special Interest).
Continued careful assessment of the safety, efficacy, and PK during treatment is included
in this study.
To minimize potential risk and stress to participants, the following measures are in place:
- Utilization of selection criteria which exclude participants who may potentially be
at higher risk of an AE (see Section 5, Study Population).
Participants with liver cirrhosis are not eligible for Part 2 of the study.
Additional criteria based on HBsAg and HDV RNA levels will be used for
Part 2 to reduce the risk of ALT/AST elevations on-treatment.
- 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.
- Restriction of placebo +NA treatment to 52 weeks.
- Inclusion of treatment discontinuation criteria for signs of hepatic decompensation
(see Section 7.1).
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- Individuals showing signs of decreasing liver function during study conduct will
discontinue treatment with JNJ-3989/placebo and alternative treatment options
outside the study will be considered in discussion with the sponsor.
- At regular time points throughout the study (see Schedule of Activities), blood
samples for biochemistry, blood coagulation, and hematology and urine samples
for urinalysis, urine chemistry, and renal biomarkers will be collected. Vital signs
(systolic and diastolic blood pressure, pulse rate, body weight, and body
temperature), height (only at screening), and electrocardiograms (ECGs) will be
recorded throughout the study. Physical examinations will be performed and AEs
will be assessed (see Section 8.2, Safety Assessments). Events of Special Interest
will be closely monitored (Section 8.3.6, Adverse Events of Special Interest).
- An Independent Data Monitoring Committee (IDMC) will be established for
continuous monitoring of SAEs, AEs leading to discontinuation, and ALT flares to
ensure the continuing safety of the participants enrolled in the current study (see
Section 9.5.3, Independent Data Monitoring Committee). When all participants are
in the open-label phase or discontinued earlier, the IDMC responsibilities will be
covered by the internal Data Review Committee (DRC) (see Section 9.5.4, Internal
Data Review Committee). In addition, an Independent Flare Expert Panel (IFLEP)
will be appointed to characterize and adjudicate each ALT flare (see Section 9.5.6,
Independent Flare Expert Panel).
- All participants will continue NA treatment until the last study visit (including the
visit in follow-up phase for Part 1 and Part 2). NA will be provided as study
medication until the end of the study. Before Protocol Amendment 5, in case of
confirmed HBsAg seroclearance, ALT <3x ULN, and HBV DNA < lower limit of
quantitation  (LLOQ) in non-cirrhotic participants, NA treatment may be
discontinued upon discussion with the sponsor. NA treatment should be restarted
as specified in Section 6.5, Re-treatment With NA During the Follow-up Phase. Per
Protocol Amendment 5, NA treatment will be continued in all participants in Part 2
until the last study visit.
- JNJ-3989 will be administered using a proper SC technique to decrease the risk of
ISRs. ISRs will be managed as outlined in Section 8.3.6, Adverse Events of Special
Interest.
- Following local standard practice, the biopsy location will be identified with
ultrasound (which will also be used to rule out contraindicating conditions for a
biopsy). Prior to any on-treatment biopsy, a recent (≤1 week) coagulation and
hematology panel are required (pre-biopsy visit) to ensure normal platelet count
and normal coagulation parameters. Prior to the baseline or off-treatment biopsies,
blood coagulation and platelet count will be assessed according to local practice.
Site selection will be based on their experience in the performance of core liver
biopsies and FNABs.
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- Unblinding of the Part 2 double-blind phase laboratory data for HDV RNA and
HBsAg data (Day 1 to Week 48 visit) per investigator’s request at any time prior to
Week 48 visit to the investigator, in case this is required for medical/clinical patient
management.
- Unblinding of the double-blind phase in Part 2 for treatment allocation and all
laboratory data including HDV RNA and HBsAg data (Day 1 to Week 48 visit)
when a participant has completed the Week 48 visit or discontinued earlier, to the
investigator, site personnel, sponsor, and participants.
- In Part 2, participants with HBsAg values >10,000 IU/mL at screening or baseline,
who were assigned to Arm 1 (placebo), will not roll-over to the open-label phase
and will enter the follow-up phase (see Section 7.1).
Any clinically significant abnormalities persisting at the end of the study/early discontinuation will
be followed up by the investigator until resolution (return to baseline) or until stabilization (to be
agreed upon with the sponsor).
3. 
OBJECTIVES AND ENDPOINTS
Objectives 
Endpoints
Primary
To evaluate on-treatment efficacy against HDV
of JNJ-3989 + NA regimen compared to NA
alone.
Proportion of participants with HDV RNA
≥2 log10 IU/mL decline from baseline or HDV
RNA TND in combination with normal ALT at
Week 48.
Key Secondary
To evaluate on-treatment efficacy of the
JNJ-3989 +NA regimen in suppressing HDV
replication as measured by HDV RNA.
Proportion of participants with HDV RNA
≥2 log10 IU/mL decline from baseline or HDV
RNA TND at Week 48.
To evaluate efficacy of the JNJ-3989 +NA
regimen on liver inflammation during study
intervention phase.
Proportion of participants with normal ALT at
Week 48.
To evaluate the efficacy of the JNJ-3989 + NA
regimen in terms of HBsAg response.
Proportion 
of participants 
with 
HBsAg
seroclearance at Week 48.
To evaluate the efficacy of the JNJ-3989 +NA
regimen on liver fibrosis.
Proportion of participants with ≥2 kPa reduction
from baseline in liver stiffness measurement
(LSM) assessed by vibration-controlled transient
elastography (VCTE) (FibroScan) at Week 48.
Other Secondary
To evaluate the efficacy of the JNJ-3989 +NA
regimen during study intervention phase and
follow-up phase.
Proportion of participants with HDV RNA
≥2 log10 IU/mL decline from baseline or HDV
RNA TND in combination with normal ALT.
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Objectives 
Endpoints
Proportion of participants with HDV RNA
≥2 log10 IU/mL 
decline 
from 
baseline in
combination with normal ALT.
Proportion of participants with HDV RNA TND
in combination with normal ALT.
Proportion of participants with HDV RNA
≥2 log10 IU/mL decline from baseline or HDV
RNA TND.
Proportion of participants with HDV RNA
≥2 log10 IU/mL decline from baseline.
Proportion of participants with HDV RNA TND.
Proportion of participants with normal ALT.
Time to reach HDV RNA ≥2 log10 IU/mL decline
or HDV RNA TND.
Changes from baseline in HDV RNA.
Changes from baseline in ALT.
To evaluate the safety and tolerability of the study
intervention throughout the study.
Proportion of participants with incidences of
(S)AEs and abnormalities in clinical laboratory
tests (including hematology, blood biochemistry,
blood coagulation, urinalysis, urine chemistry,
and renal biomarkers), 12-lead ECGs, vital signs,
and physical examination.
To evaluate the efficacy of the JNJ-3989 +NA
regimen  as measured by HBV blood markers
(such as HBsAg, HBeAg*, HBV DNA) during
study intervention and follow-up.
Proportion 
of participants 
with 
HBsAg
seroclearance and/or seroconversion.
Change from baseline over time in HBsAg,
HBeAg*, HBV DNA.
Proportion of participants with HBsAg, HBeAg*,
and/or HBV DNA levels or changes from
baseline below/above different cut-offs.
Time to reach efficacy thresholds such as
HBsAg <1 IU/mL.
To evaluate the frequency of HBV virologic
breakthrough throughout the study.
Proportion of participants with HBV DNA
virologic breakthrough.
To evaluate changes in liver fibrosis during study
intervention and follow-up.
Proportion of participants with ≥2 kPa reduction
from baseline in LSM  assessed by VCTE
(FibroScan).
Change from baseline in LSM over time assessed
by VCTE (FibroScan).
To evaluate the anti-HDV efficacy during the
follow-up phase.
Proportions of participants with sustained HDV
response off-treatment post end of JNJ-3989
treatment.
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Objectives 
Endpoints
Proportions of participants with HDV relapse
post end of JNJ-3989 treatment.
To evaluate the anti-HBV efficacy during the
follow-up phase.
Proportions of participants with sustained HBV
response off-treatment post end of JNJ-3989
treatment.
Proportions of participants with  HBV flare
(virologic, biochemical, and clinical) post end of
treatment.
Exploratory
To explore the relationship between PK
parameters 
(JNJ-3989) 
and 
selected
pharmacodynamic (PD) parameters of efficacy
and/or safety, as applicable.
Relationship between various PK parameters
(JNJ-3989) and selected efficacy and/or safety
endpoints, as applicable.
To explore the relationship between HBsAg and
HDV RNA.
Correlation between HBsAg decline and HDV
RNA levels/changes.
To explore the impact of the viral and host
baseline characteristics on safety and efficacy.
Correlation 
of 
viral 
and 
host 
baseline
characteristics (such as HBV/HDV genotype,
baseline HBV DNA levels, baseline HDV RNA
levels, age, sex, body mass index [BMI]) with
selected efficacy and safety variables.
To explore the effect of any baseline variation in
the HBV and HDV (if feasible) genome on
efficacy.
Correlation of HBV and HDV genome sequence
with selected efficacy parameters.
To explore changes in the HBV and HDV (if
feasible) genome sequence during study
intervention and follow-up.
Emergence of intervention-associated mutations.
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 HBV-specific T-cell responses during
study intervention. **
Changes from baseline in peripheral blood T-cell
responses.
To explore medical resource utilization (MRU) to
manage participants during study intervention
and follow-up.
Number and type of medical visits.
Number (proportion) of participants requiring
hospitalization and duration of hospitalization
(total days length of stay, including duration by
wards; eg, ICU).
Number and character of diagnostic and
therapeutic tests and procedures.
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Objectives 
Endpoints
To explore liver viral responses during study
intervention.***
Changes from baseline in intrahepatic viral
parameters (such as HDV RNA, HDAg,
cccDNA, pgRNA, intrahepatic RNA, or HBsAg
in terms of copy number, or number of positive
cells).
Changes from baseline in intrahepatic cccDNA.
levels 
and 
transcriptional 
activity
(pgRNA/cccDNA ratio).
To explore liver immune responses during study
intervention.***
Changes between baseline and on-treatment liver
biopsy in intrahepatic immune response (eg,
CD45+ T-cells, CD4+ T-cells, CD8+ T-cells,
Natural Killer cells, and dendritic cells) in terms
of proportion of cells, cell types, and spatial
redistribution
To explore the relationship of intrahepatic
markers with blood markers (immune and viral).
Association between levels and changes in
intrahepatic and blood markers.
* in HBeAg-positive participants only
** Peripheral blood mononuclear cell (PBMC) samples for immune analyses will be collected at selected sites only
and as operationally feasible
*** If sufficient number of participants contribute to the liver biopsy collection
Refer to Section 8, Study Assessments and Procedures for evaluations related to endpoints.
HYPOTHESIS
The original protocol had as primary hypothesis that the combination regimen of JNJ-3989 + NA
is more efficacious than NA treatment alone in reducing HDV replication and improving the
associated liver inflammation, as measured by the primary efficacy endpoint, the proportion of
participants with HDV RNA decline ≥2 log10 IU/mL from baseline or HDV RNA TND in
combination with normal ALT at Week 48. Due to the decision to stop enrollment at
30 participants in Part 2 of the study, the statistical analyses will be descriptive.
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4. 
STUDY DESIGN
4.1. 
Overall Design
This is a 2-part, Phase 2, randomized, double-blind, placebo-controlled, parallel, multicenter,
interventional study with deferred active treatment to investigate the efficacy, safety, and PK of
JNJ-3989 + NA in participants co-infected with HBV and HDV.
The study consists of 2 parts:
Part 1 will evaluate the safety, tolerability and antiviral activity of JNJ-3989 +NA in a
small number of participants (N 20), prior to enrolling a larger number of participants in
Part 2. The primary aim of Part 1 is to assess if the antiviral activity criteria to start Part 2
are met.
Part 2 (N
30) will evaluate the safety and efficacy of the JNJ-3989 + NA regimen in the
treatment of HBV/HDV co-infection.
Note that Part 2 of the study will only be initiated once the antiviral activity criteria in Part 1
have been met, and ifthe results of Part 1 IA1 (when all participants of Part 1 have completed
at least Week 16 or discontinued earlier) support initiation of Part 2 (see Section 9.5). The
antiviral activity criteria are defined in the statistical analysis plan (SAP). Participants in Part 1
may not participate in Part 2.
In total for Part 1 and Part 2, 50 participants were planned to be enrolled, specifically with a target
of 20 participants in Part 1 and 30 participants in Part 2. The minimum number of participants to
be enrolled will be 20 if futility is observed and Part 2 is not initiated.
The conclusions of the study will be described separately on data from Part 1, Part 2, and pooled
from Part 1 and Part 2 together (if applicable).
An IDMC will be established for continuous monitoring of SAEs, AEs leading to discontinuation,
and ALT flares. In addition, the IDMC will support the Sponsor Committee in assessing whether
there is early evidence supporting antiviral activity criteria of JNJ-3989 +NA in reducing HDV
replication measured by HDV RNA reduction. Before Part 1 IA1, the Sponsor Committee, who is
not directly involved in the study conduct, will be involved in the unblinded review of selected
efficacy and safety parameters to decide when to trigger the start of Part 2. At the time ofthe Part 1
IA1 (when all participants of Part 1 have completed at least Week 16 or discontinued earlier), the
sponsor, including the Sponsor Committee, will become unblinded to the Part 1 data. Once Part 2
has commenced, all sponsor personnel, including the Sponsor Committee, will remain blinded to
subsequent IDMC data review during the double-blind phase. During the open-label phase, all data
will be unblinded. When all participants are in the open-label phase or discontinued earlier, the
IDMC responsibilities will be covered by the DRC (see Sections 9.5.4 and 10.3.6).
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Before Protocol Amendment 5, Part 1 and Part 2 include 3 identical phases:
a 4-week screening phase (may be extended up to a maximum of 8 weeksa),
a 144-week study intervention phase (Arm 1) and 148-week  study intervention phase
(Arm 2). The first 52 weeks of the intervention phase are double-blind followed by
92 and 96 weeks of open-label treatment for participants in Arms 1 and 2, respectively.
a 48-week follow-up phase.
Per Protocol Amendment 5, Part 2 will include modified phases after screening:
a 4-week screening phase (may be extended up to a maximum of 8 weeksa),
for both Arm 1 and Arm 2, the double-blind 52 weeks of intervention will be followed by
an open-label phase of at least 48 weeks of JNJ-3989 for all participants, including for
those participants who were randomized to placebo in the intervention phase. Arm 1 will
have a total minimum of 96-week intervention and Arm 2 a total minimum of 100-week
intervention.
a reduced follow-up phase (at least 24 weeks):
for participants who have reached FU Week 24 or later when Protocol Amendment 5 is
in effect, the EOS assessments will be scheduled at the next planned visit; OR
for participants who have not reached FU Week 24 (including participants in the
open-label phase) when Protocol Amendment 5 is in effect, they will enter a 24-week
follow-up phase.
The duration of individual study participation will be between 196 and 204 weeks for Part 1 and
between 124 and 204 weeks for Part 2.
Before Protocol Amendment 5, at Week 144 (Arm 1) and Week 148 (Arm 2), treatment with
JNJ-3989 will be stopped in both parts. After Protocol Amendment 5 is in effect, treatment with
JNJ-3989 will be stopped in Part 2 at the next planned visit (ie, EOT), but not earlier than Week 96
(Arm 1) and Week 100 (Arm 2).
Participants who complete treatment with JNJ-3989 at the end of the open-label phaseb in Part 1
and Part 2 will be closely monitored for transaminase flares and for HBV/HDV recurrence during
the follow-up phase.
Before Protocol Amendment 5, for non-cirrhotic patients, NA treatment should be continued until
the last study visit (including the visit at the follow-up phase) unless confirmed HBsAg
seroclearance, ALT <3x ULN, and HBV DNA <LLOQ is observed, in which case NA treatment
a If necessary (eg, for operational reasons), the screening phase may be extended up to a maximum of 8 weeks on a
case-by-case basis and in agreement with the sponsor. Depending on the duration of the screening phase, selected
screening assessments may have to be repeated prior to enrollment.
b At Week 144 (Arms 1) or Week 148 (Arms 2) in Part 1 and Part 2 before Protocol Amendment 5; at Week 96 or
later (Arm 1) or Week 100 or later (Arm 2) in Part 2 after Protocol Amendment 5.
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may be discontinued upon discussion with the sponsor. For cirrhotic patients, NA treatment should
be continued during the entire follow-up phase according to treatment guidelines. In the event of
signs of decreasing liver function, HBeAg seroconversion among participants who had previously
experienced HBeAg loss, post-treatment increases in HBV DNA >2,000 IU/mL and ALT >5x
ULN, or post-treatment increases in HBV DNA >20,000 IU/mL, NA treatment will be restarted
for the non-cirrhotic participants who stopped NA treatment after confirmed HBsAg
seroclearance, ALT <3x ULN, and HBV DNA <LLOQ (see Section 6.5, Re-treatment With NA
During the Follow-up Phase).
Per Protocol Amendment 5, NA treatment will be continued in all participants in Part 2 until the
last study visit (including visit in the follow-up phase).
Part 1
Approximately 20 participants co-infected with HBV and HDV will be randomized in a 4:1 ratio
to Arms 1 or 2.
Arm 1: 100 mg JNJ-3989 (SC injection Q4W) +NA once daily (qd) for 144 weeks (n 16;
immediate active treatment arm);
Arm 2: placebo for JNJ-3989 (SC injection Q4W) + NA qd for 52 weeks, followed by
100 mg JNJ-3989 (SC injection Q4W) + NA qd for 96 weeks (n 4; deferred active
treatment arm).
NA nucleos(t)ide analog
ETV, tenofovir disoproxil, or TAF. NA treatment is continued or
started from Day 1 in both arms.
Part 2
Part 2 of the study will be initiated since the antiviral activity criteria in Part 1 have been met, and
the results of Part 1 IA1 (when all participants of Part 1 have completed at least Week 16 or
discontinued earlier) support initiation of Part 2. Cirrhotic participants will be excluded from
participation in Part 2 of the study.
Approximately 30 participants co-infected with HBV and HDV will be randomized in a 4:1 ratio
to Arms 1 or 2.
Arm 1: 100 mg JNJ-3989 (SC injection Q4W) + NA qd for at least 96 weeks
(approximately, n 24; immediate active treatment arm);
Arm 2: placebo for JNJ-3989 (SC injection Q4W) + NA qd for 52 weeks, followed by
100 mg JNJ-3989 (SC injection Q4W) + NA qd for at least 48 weeks (approximately, n 6;
deferred active treatment arm).
NA  ETV, tenofovir disoproxil, or TAF. NA treatment is continued or started from Day 1 in
both arms.
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Study Details
In total across both Part 1 and Part 2, a target of approximately 50 participants, aged ≥18 to
65 years, co-infected with HDV and HBV will be enrolled in this study. If Part 2 is not initiated,
the number of participants will be approximately 20.
Patients with HBV/HDV co-infection will be eligible regardless of HBeAg status and treatment
history. Patients with compensated cirrhosis are only allowed to be enrolled in Part 1 of this study.
Cirrhotic patients will be excluded from participation in Part 2 of the study.
Randomization will be stratified by:
presence of compensated cirrhosis at screening (yes or no) (Part 1 only),
HDV RNA testing laboratory location (China versus outside of China) (Note: All sites in
China will utilize the laboratory testing in China and all sites in other countries will utilize the
laboratory outside of China), and
HBeAg status at screening (positive versus negative).
In those countries/sites where HDV testing is not part of standard of care, possible study candidates
can be prescreened for HDV testing (HDV RNA and/or anti-HDV antibody) after signing a
prescreening informed consent form (ICF). Results will be reviewed by the investigator to confirm
if they could qualify for study participation.
Participants will be considered to have completed the study if they have completed the assessments
of the end of study (EOS) visit as defined in Section 4.4.
Following assessments will be included in both parts of the study: blood sampling: efficacy
(eg, HDV RNA, HBsAg, HBeAg, HBV DNA), safety (eg, AEs, laboratory abnormalities, ECGs),
PK, PK/PD, viral genome sequencing/genotyping, immune analyses, HLA haplotyping,
exploratory biomarker, and pharmacogenomic analyses (see Section 8).
A pharmacogenomic blood sample will be collected from participants who consent separately to
this component of the study (see Section 8.7, Host Genetics).
Medical resource utilization will be assessed (see Section 8.9).
Clinical outcomes such as death, cirrhosis decompensation, or liver transplantation will be
captured.
The primary analysis of this study will be performed when all participants in the study (both parts
if Part 2 has started) have reached Week 48 or have discontinued earlier.
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The investigators, participants, and all site personnel will remain blinded to study intervention
allocation until a participant has completed the Week 48 visit or has discontinued earlier. When a
participant has completed the Week 48 visitor discontinued earlier, the investigator, site personnel,
sponsor, and participant will be unblinded for treatment allocation and all laboratory data,
including HDV RNA and HBsAgdata. AfterWeek 48, it will be communicated to the investigators
whether the participant was allocated to either the immediate active treatment (Arms 1) or the
deferred active treatment (Arms 2) to allow that the participant follows the correct visit schedule
during the open-label phase (see Section 1.3.2, Schedule of Activities 
 Open-label Study
Intervention Phase (Weeks 52 EOT)).
In case of premature discontinuation of JNJ-3989/placebo before the end of the study intervention
phase (ie, Week 144 [Arms 1] or Week 148 [Arms 2] in both parts before Amendment 5 and
Week 96 or later [Arm 1] or Week 100 or later [Arm 2] in Part 2 after Amendment 5), participants
will have an early withdrawal visit and will enter the follow-up phase as specified in Section 1.3.3,
unless they withdraw consent.
In addition  to the IDMC  and internal DRC, an IFLEP will be appointed (see
Sections 9.5.6 and 10.3.6).
In case a participant withdraws consent before completing the study, the reason (if known) should
be documented. Participants who withdraw consent will be offered an optional safety follow-up
visit 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 withdrawal visit.
The Coronavirus Disease 2019 (COVID-19) pandemic or similar pandemics may impact the
conduct of this clinical study, therefore additional guidance is provided in Section 10.10,
Appendix 10.
A diagram of the study design is provided in Section 1.2, Schema.
4.2. 
Scientific Rationale for Study Design
Study Population
Patients with HBV/HDV co-infection will be eligible regardless of HBeAg status and treatment
history.
Patients with compensated cirrhosis will only be enrolled in Part 1 of this study. Patients with
cirrhosis will be excluded from Part 2 of the study.
Blinding
Blinded treatment will be used to reduce potential bias during data collection and evaluation of
clinical endpoints.
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Randomization and Stratification
Randomization will be performed using a 4:1 ratio (immediate active treatment, ie, Arm 1:
deferred active treatment, ie, Arm 2), regardless of the study part, to minimize bias in the
assignment of participants to intervention arms, to increase the likelihood that known and unknown
participant attributes (eg, demographic and baseline characteristics) are evenly balanced across
treatment arms, and to enhance the validity of statistical comparisons across intervention arms.
The randomization ratio was determined to balance statistical efficiency considerations with high
unmet medical needs, patients’ perspectives, acceleration of the decision making based on an early
signal of antiviral activity to expand enrollment to a larger sample, and clinical and operational
feasibility considerations related to an orphan disease.
Randomization will be stratified by the presence of compensated cirrhosis at screening (yes or no,
Part 1 only), HDV RNA testing laboratory location (China versus outside of China), and HBeAg
status at screening (positive versus negative) in order to provide an evenly balanced representation
across the 2 arms.
Deferred Active Arms
To characterize efficacy and safety of the investigational treatment regimen, the study includes a
double-blind comparison of JNJ-3989 versus placebo on the background of NA treatment.
Participants on placebo will be switched to active JNJ-3989 treatment at Week 52. Participants in
both intervention arms will continue with JNJ-3989 +NA until Week 144 (Arm 1) and Week 148
(Arm 2) for Part 1 and until at least Week 96 (Arm 1) and Week 100 (Arm 2) for Part 2 in an
open-label fashion. The deferred active treatment design allows all participants in the study to
receive the JNJ-3989 +NA regimen while allowing for a valid comparison with placebo +NA and
a rigorous quantitative assessment of the treatment effect.
NA Treatment
All participants will receive NA treatment (ie, ETV, tenofovir disoproxil, or TAF) during the entire
treatment period to maximize the resistance barrier of the regimen and to ensure complete HBV
suppression since reduction in HDV replication can be associated with increased HBV replication.
Before Protocol Amendment 5, for non-cirrhotic patients, NA treatment should be continued until
the last study visit (including the visit in the follow-up phase) unless confirmed HBsAg
seroclearance, ALT <3x ULN, and HBV DNA <LLOQ is observed in which case NA treatment
may be discontinued upon discussion with the sponsor. For cirrhotic patients, NA treatment should
be continued during the entire follow-up phase according to treatment guidelines. Per Protocol
Amendment 5, NA treatment will be continued in all participants in Part 2 until the last study visit.
Providing the NA already in the deferred active arm from Day 1 onwards increases the validity
and robustness of the comparisons and ensures that NA will be given to all patients who have an
indication forNA treatment (ie, patients with cirrhosis and/or patients with detectable HBV DNA).
This approach is consistent with other HDV studies.
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Host DNA and Biomarker Collection
It is recognized that host 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 optional pharmacogenomic component is to
collect DNA to allow the identification of (epi)genetic factors that may influence the efficacy,
safety or PK of study intervention, or identify genetic factors associated with HBV/HDV infection,
or to develop assays for study intervention, or HBV/HDV infection.
Biomarker samples will be collected to allow evaluation of the mechanism of action  of
JNJ-3989 +NA or help to explain interindividual variability in clinical outcomes or may help to
identify population subgroups that respond differently to a treatment. The goal of the biomarker
analyses is to evaluate the safety, efficacy, and PK of study intervention and HBV infection or to
develop assays for study intervention or HBV/HDV 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.
Liver Biopsy
Collecting liver biopsy samples will allow to perform critical assessments of intrahepatic virologic
and immune events occurring in response to treatment with JNJ-3989 and NA, and to correlate the
findings in the liver with treatment response and to viral and immune blood markers. In addition,
these analyses are expected to improve the understanding of the molecular mechanisms of the
treatment interventions and to provide important insight into the HDV/HBV pathology.
Both core liver biopsies and FNABs will be optionally collected at selected sites for high
dimensional profiling of the liver tissue. The core biopsies will allow characterization of the
infected hepatocytes compartment and phenotyping of the major immune cell populations
(proportion of cells and spatial distribution). The liver tissue may be used to assess HDV and HBV
markers in the liver such as, but not limited to HDAg and HDV RNA, HBsAg, pgRNA, total
intracellular HBV RNA and DNA, and HBcAg. Changes in the quantity and potentially changes
in the spatial distribution of these markers under JNJ-3989 treatment will be assessed. Viral
genome (RNA or DNA) sequencing of the samples as well as assessment of HBV viral transcripts
and HBV DNA integrants in the host genome may be performed. This will also allow to compare
viral parameters assessed in the liver with viral parameters in the blood compartment.
FNABs may be profiled by single-cell transcriptomics approaches to better understand the innate
and adaptive immune cells composition and functional status11 (very few hepatocytes are expected
to be collected with fine needle aspirates). Hepatitis B virus-specific T-cells will be one of the
main targeted cell populations, detected and sorted by multimers binding assays. Downstream
transcriptomic profiling of collected HBV specific T-cells may be performed by T-cell receptor
sequencing and RNA sequencing.
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Remaining samples may be used for determination of liver JNJ-3989 and/or research on viral and
host biomarkers and immune markers at the viral and/or host RNA/DNA, protein, and cell level.
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.
Written consent may be obtained through various sources (eg, paper or electronic such as eConsent,
eSignature, or digital signature) as determined by regulations as well as study and/or participant
preferences.
At the time of protocol writing, there is no approved treatment for HBV/HDV co-infection.
Therapies that efficiently decrease HBsAg levels in patients with HBV/HDV co-infection,
eg, JNJ-3989, are expected to lead to suppression or inhibition of the HDV replication (as measured
by reduction of HDV RNA in blood). Complete suppression (ie, seroclearance) of HBsAg is
expected to lead to a sustained control of the HDV infection, either in response to chronic
suppression by continued treatment or by achieving HBV functional cure after completion of
therapy.
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 (less than standard blood donation
based upon recommendations of the World Health Organization [WHO], ie, 450 mL ± 10% for
participants weighing at least 50 kg over a period of 12 weeks for male participants and 16 weeks
for female participants) (Section 8.1)2.
4.3. 
Justification for Dose
100 mg Q4W JNJ-3989 will be administered SC. Treatment with JNJ-3989 (given as 3 SC
injections Q4W) has shown substantial reduction in HBsAg in the Phase 1/2a first in-human Study
AROHBV1001. No difference in tolerability and safety was noted between the different JNJ-3989
doses in the AROHBV1001 study. No apparent dose response in terms of HBsAg decline 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 slightly reduced mean decline in HBsAg
was observed at the lower doses of 25 mg and 50 mg. Given the absence of a dose response from
100 to 400 mg in the AROHBV1001 study and the extended treatment period of 144 weeks in a
population including participants with compensated cirrhosis, the 100 mg dose has been selected
for this study.
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4.4. 
End of Study Definition
End of Study Definition
The end of study  (EOS) is considered as the last visit (in the follow-up phase or early
discontinuation) for the last participant in the study. The final data from the study site will be sent
to the sponsor (or designee) after completion of the final participant visit at that study site, in the
time frame specified in the Clinical Trial Agreement.
Participant Study Completion Definition
Part 1
A participant will be considered to have completed the study if he or she has completed EOS
assessments at Week 48 of the follow-up phase (ie, EOS visit at FU Week 48).
Part 2
Before Protocol Amendment 5, a participant will be considered to have completed the study if he
or she has completed EOS assessments at Week 48 of the follow-up  phase (ie, EOS visit at
FU Week 48).
After Protocol Amendment 5, a participant will be considered to have completed the study if he or
she has completed the EOS assessments assigned per Protocol Amendment 5:
Participants who have not reached FU Week 24 (including those in the open-label phase) when
Protocol Amendment 5 is in effect will enter the 24-week follow-up phase with EOS visit
scheduled at FU Week 24.
Participants who have reached FU Week 24 or later when Protocol Amendment 5 is in effect
will receive the EOS assessments scheduled at the next planned visit (ie, EOS visit at FU
Week 30 or later).
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 8 weeks on a case-by-case basis and in agreement with the sponsor. Depending
on the duration of the screening phase, selected screening assessments may have to be repeated
prior to enrollment.
In those countries/sites where HDV testing is not part of standard of care, possible study candidates
can be prescreened for HDV testing (HDV RNA and/or anti-HDV antibody) after signing a
prescreening ICF. Results will be reviewed by the investigator to confirm if they could qualify for
study participation.
Retesting to assess eligibility will be allowed once, using an unscheduled visit during the screening
phase.
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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. 
male or female (according to their reproductive organs and functions assigned by
chromosomal complement).
2. 
Criterion modified per Amendment 1
2.1. 18 (or the legal age of consent in the jurisdiction in which the study is taking place,
provided that the legal age of consent is ≥18 years) to 65 years of age, inclusive.
3. 
medically stable on the basis of physical examination, medical history, vital signs, and
12-lead ECG performed at screening. Any abnormalities, must be consistent with the
underlying illness in the study population and this determination must be recorded in
the participant’s source documents and initialed by the investigator.
4. 
must have:
chronic hepatitis B infection either HBeAg positive or HBeAg negative and
either receiving NA treatment or no NA treatment. 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)
chronic HDV infection documented by positive HDV antibodies or HDV RNA
at screening. In addition, chronicity must be documented by positive HDV
antibodies or HDV RNA at least 3 months prior to screening.
5. 
Criterion modified per Amendment 3
5.1
a) For Part 1: must have HDV RNA values at screening ≥1,000 IU/mL.
b) For Part 2: must have HDV RNA values at screening ≥500 IU/mL, and
must have HBsAg values at screening ≤10,000 IU/mL.
Note: if HBsAg values are >10,000 IU/mL, the participant can only be enrolled
in case HDV RNA values at screening are ≤100,000 IU/mL.
6. 
Criterion modified per Amendment 1
6.1. must have ALT levels >ULN and <10x ULN at screening.
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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. 
Criterion modified per Amendment 1
8.1 Criterion modified per Amendment 3
8.2 Criterion modified per Amendment 4
8.3. must have presence or absence of compensated cirrhosis (Part 1) based on:
a. No cirrhosis: LSM <12.5 kPa by VCTE (FibroScan) within 6 months prior to
screening or at the time of screening or liver biopsy within 1 year prior to screening,
OR
b. Cirrhosis: LSM ≥12.5 kPa by VCTE (FibroScan) within 6 months prior to
screening or at the time of screening or liver biopsy within 1 year prior to screening;
and a Child-Pugh score A at screening.
Must have absence of cirrhosis (Part 2) based on:
c. LSM <12.5 kPa by VCTE (FibroScan) or histologic exclusion of cirrhosis (core
liver biopsy) within 6 months prior to screening or at the time of screening. In case
of discordant results, the biopsy readout will be taken for assessment of eligibility.
Note: If FibroScan is not available, acoustic radiation force impulse (ARFI) may be
used at screening if standard practice at the site or if otherwise validated and agreed
with the sponsor.
Note: Conventional imaging procedures (eg, conventional liver ultrasound, computed
tomography [CT] or magnetic resonance imaging [MRI]) and serum marker panels are
not acceptable for exclusion of cirrhosis.
9. 
must sign an ICF indicating that he or she understands the purpose of, and procedures
required for, the study and is willing to participate in the study.
10. 
must sign a separate ICF if he or she agrees to provide an optional DNA sample for
research (where local regulations permit). Refusal to give consent for the optional DNA
research sample does not exclude a participant from participation in the study.
11. 
a woman  of childbearing potential must have a negative highly sensitive serum
( -human chorionic gonadotropin [ -hCG]) at screening and a negative urine
pregnancy test on Day 1 before the first dose of study intervention.
12. 
a woman 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 (failure rate of <1% per year when used
consistently and correctly) for at least 30 days prior to screening and agrees to
remain on a highly effective method while receiving study intervention and until
90 days after last dose the end of relevant systemic exposure.
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Examples of highly effective methods of contraception are located in Section 10.8,
Appendix 8, Contraceptive Guidance and Barrier Guidance.
13. 
a woman must agree not to donate eggs (ova, oocytes) for the purposes of assisted
reproduction during the study and for a period of 90 days after the last dose of study
intervention.
14. 
a male participant must 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 of study intervention.
15. 
a male participant must agree not to donate sperm for the purpose of reproduction during
the study and for a minimum 90 days after receiving the last dose of study intervention.
16. 
In the investigator’s opinion, the participant is able to understand and comply with
protocol requirements, instructions, and lifestyle restrictions and be likely to complete
the procedures as planned for this study.
17 
Criterion added per Amendment 3
must provide separate consent if he or she agrees to provide an optional liver biopsy
sample (only in sites and in selected countries where this is feasible, and after all
relevant approvals are in place and operational set-up is completed) in Part 2 of the
study. Refusal to give consent for the optional liver biopsy sample does not exclude a
participant from participation in the study.
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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 Amendment 3
1.1 Participants with evidence of hepatitis A virus infection (hepatitis A antibody
immunoglobulin M [IgM]), hepatitis C virus (HCV) infection (HCV antibody), or
hepatitis E virus (HEV) infection (hepatitis E antibody IgM), or human
immunodeficiency virus type 1 (HIV-1) or HIV type 2 (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 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.
- Participants with a positive HIV-1 or HIV-2 antibody/antigen test at screening
should have a confirmatory HIV RNA test, to rule out false positive results. They
can be enrolled if they have a negative HIV RNA test at screening. Participants with
evidence of HIV-1 or HIV-2 infection who are on antiretroviral treatment are
excluded.
2. 
any of the following laboratory abnormalities within 12 months prior to screening or at
time of screening:
a. Total bilirubin >1.7x ULN,
b. Direct bilirubin >1.4x 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.
Note: Participants with uncomplicated splenomegaly may be enrolled after consultation
with the sponsor.
4. 
Criterion modified per Amendment 3
4.1 Child-Pugh score B or C  at screening (Part 1) and liver cirrhosis at screening
(Part 2).
5. 
evidence of liver disease of non-HDV or non-HBV etiology. This includes but is not
limited to hepatitis virus infections mentioned in exclusion criterion 1, drug- or
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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 non-HBV/HDV or non-viral liver disease considered clinically significant by
the investigator.
6. 
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).
7. 
Criterion modified per Amendment 3
7.1 Criterion modified per Amendment 4
7.2 One or more of the following laboratory abnormalities at screening as defined by
the Division of Acquired Immunodeficiency Syndrome (DAIDS) Toxicity Grading
Scale:
a. Estimated glomerular filtration rate (eGFR) ≥grade 3 (ie, <60 mL/min/1.73 m2) at
screening, calculated by the Chronic Kidney Disease Epidemiology Collaboration
(CKD-EPI) formula,
b. Total amylase ≥grade 3,
c. Lipase elevation ≥grade 3,
d. Hemoglobin ≤10.9 g/dL (males), ≤10.4 g/dL (females),
e. Platelet count ≤100,000/µL (Part 1),
Platelet count ≤140,000/µL (Part 2)
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, enhanced ultrasound, CT, or MRI)
during screening.
8. 
hemoglobin A1c >8% at screening.
9. 
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).
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10. 
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 interval ≥120 ms; PR interval >220 ms;
abnormal conduction; or any other clinically significant abnormalities on a 12-lead
ECG at screening.
11. 
a history of or current cardiac arrhythmias (eg, tachycardia at rest), history of risk
factors for Torsade de Pointes syndrome (eg, hypokalemia, family history of long QT
Syndrome) or history or other clinical evidence of significant or unstable cardiac disease
(eg, angina, congestive heart failure, myocardial infarction, diastolic dysfunction,
significant arrhythmia, coronary heart disease), moderate to severe valvular disease, or
uncontrolled hypertension at screening.
12. 
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.
13. 
any history of or current clinically significant skin disease requiring regular or periodic
treatment.
14. 
history of clinically relevant drug rash.
15. 
known allergies, hypersensitivity, or intolerance to JNJ-3989 or its excipients (refer to
the IB).15
16. 
contraindications to the use of ETV, tenofovir disoproxil, or TAF per local prescribing
information.
17. 
taken any disallowed therapies as noted in Section 6.7, Concomitant Therapy before the
planned first dose of study intervention.
18. 
received an investigational intervention (including investigational vaccines) or used any
invasive investigational medical device within 6 months before the planned first dose
of study intervention  or is currently enrolled in an investigational study with an
investigational intervention.
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19. 
received anti-HDV treatment (investigational or approved) and/or anti-HBV treatment
(investigational or approved IFN treatment) within 6 months before the planned first
dose of study intervention.
20. 
female participants who are pregnant, or breastfeeding, or planning to become pregnant
while enrolled in this study or within 90 days after the last dose of study intervention.
21. 
male participants who plan to father a child while enrolled in this study or within
90 days after the last dose of study intervention.
22. 
had major surgery, (eg, requiring general anesthesia) within 12 weeks before screening,
or will not have fully recovered from surgery, or has 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.
23. 
have received an organ transplant (except for skin, hair, or cornea transplants).
24. 
employee 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, as well as family
members of the employees or the investigator.
25. 
vulnerable participants (eg, incarcerated individuals, individuals under a legal
protection measure).
26. 
alcohol or drug abuse within 12 months of screening, judged by the investigator to
likely interfere with clinical assessments.
Additional exclusion criteria for optional liver biopsy:
27 
Criterion added per Amendment 3
Participants with presence of coagulopathy or bleeding disorder as indicated by
a. International normalized ratio (INR) ≥1.1x ULN;
b. Partial thromboplastin time >1.1x ULN;
c. Any signs of prolonged bleeding (>10 minutes).
28 
Criterion added per Amendment 3
Participants with presence of hemoglobinopathy (including sickle cell disease,
thalassemia).
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29 
Criterion added per Amendment 3
Participants who had a liver biopsy performed prior to screening that led to
complications and that in the opinion of the investigator would prohibit another liver
biopsy.
30 
Criterion added per Amendment 3
Participants with history of amyloidosis.
31 
Criterion added per Amendment 3
Participant refusal to accept blood transfusions.
32 
Criterion added per Amendment 3
Participants who use anticoagulants or antiplatelet aggregating agents that cannot be
paused prior to the liver biopsy procedures (as described in Section 6.7, Concomitant
Therapy).
NOTE: Investigators must 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 must be excluded
from participation in the study. Section 5.4, Screen Failures, describes options for retesting. The
required source documentation to support meeting the enrollment criteriaare 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. 
Refer to Section  6.7, Concomitant Therapy  for details regarding prohibited and
restricted therapy during the study.
2. 
Agree to follow all requirements that must be met during the study as noted in the
Inclusion and Exclusion Criteria (eg, contraceptive requirements).
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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. When available, the investigator may generate
screening and enrollment logs directly from an interactive web response system (IWRS).
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 of the sponsor.
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6. 
STUDY INTERVENTION AND CONCOMITANT THERAPY
6.1. 
Study Interventions Administered
Description of Interventions
Intervention Name 
JNJ-3989 
Placebo for JNJ-3989 
ETV monohydrate 
Tenofovir disoproxil 
TAFa
Type 
Drug 
Drug 
Drug 
Drug 
Drug
Dose Formulation 
Solution for injection  
Solution for injection  
Film-coated tablets 
Film-coated tablets 
Film-coated tablets
Unit Dose Strength(s) 
200 mg/mL 
0.9% saline 
0.5 mg 
245 mg 
25 mg
Dosage Regimen 
100 mg Q4W  
Q4W  
0.5 mg qd 
Lamivudine-refractory
participants:
1 mgb qd (but should
preferably be treated with
tenofovir disoproxil or TAF
instead)
245 mg qd 
25 mg qd
Route of Administration 
Subcutaneous injection 
(in the abdomen) 
Subcutaneous injection 
(in the abdomen)
Oral 
Oral 
Oral
Use 
Investigational 
intervention 
Investigational 
intervention  
Background intervention  
Background 
intervention  
Background
intervention
IMP and NIMP 
IMP  
IMP  
IMP  
IMP  
IMP
Sourcing 
Provided centrally by 
the sponsor 
Provided centrally by 
the sponsor 
Provided centrally by the 
sponsor 
Provided centrally by 
the sponsor 
Provided centrally by
the sponsor
Packaging and Labeling 
Each unit will be 
labeled with unique 
medication ID number 
Each unit will be 
labeled with unique 
medication ID number 
Commercial supplies will 
be sourced and a clinical 
study label applied 
Commercial supplies 
will be sourced and a 
clinical study label 
applied 
Commercial supplies
will be sourced and a
clinical study label
applied
In child-resistant packaging 
In child-resistant 
packaging 
In child-resistant
packaging
Labels will contain information to meet the applicable regulatory requirements.
Food/Fasting Instructions 
Regardless of food 
intake 
Regardless of food 
intake 
Per the prescribing 
information  
Per the prescribing 
information 
Per the prescribing
information
ETV: entecavir; ID: identification; IMP: Investigational Medicinal Product; JNJ 3989: JNJ 73763989; NA: nucleos(t)ide analog; NIMP: Non investigational Medicinal Product; Q4W: once
every 4 weeks; qd: once daily; TAF: tenofovir alafenamide
a In countries where TAF is commercially available, it will be one of the NA treatment options.
b 2 tablets of 0.5 mg
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Virologically suppressed participants who are already being treated with  ETV, tenofovir
disoproxil, or TAF at screening, will continue their current NA treatment. Participants who are not
receiving any HBV treatment at screening will receive tenofovir disoproxil during the study. If
clinically indicated, switching from one NA treatment (ETV, tenofovir disoproxil, or TAF) to
another NA treatment (ETV, tenofovir disoproxil, or TAF) during the study is allowed for all
participants after consultation with the sponsor.
Study intervention administration must be captured in the source documents and the case report
form (CRF). Study-site personnel will instruct participants on how to store study intervention (NA)
for at-home use as indicated for this protocol. JNJ-3989 will be manufactured and provided under
the responsibility of the sponsor. Refer to the IB for a list of excipients.15
For a definition of study intervention overdose, refer to Section 6.6, 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.
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 study intervention to the participant, and the return of study intervention from
the participant (if applicable), must be documented on the intervention  accountability form.
Participants must be instructed to return all original containers, whether empty or containing study
intervention. 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 as indicated on the
container label, and must be stored at the study site in a limited-access area or in a locked cabinet
under appropriate environmental conditions. Unused study intervention, and study intervention
returned by the participant, must be available for verification by the sponsor’s study site monitor
during on-site monitoring visits. The return to the sponsor of unused study intervention, or used
returned study intervention for destruction, will be documented on the intervention return form.
When the study site is an authorized destruction unit and study intervention supplies are destroyed
on-site, this must also be documented on the intervention return form.
Potentially hazardous materials such as used ampules, needles, syringes and vials containing
hazardous liquids, must be disposed of immediately in a safe manner and therefore will not be
retained for intervention accountability purposes.
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Study intervention must be dispensed under the supervision of the investigator or a qualified
member of the study-site personnel, or by a hospital/clinic pharmacist. Study intervention will be
supplied only to participants participating in the study. Returned study intervention must not be
dispensed again, even  to the same participant. 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.
Further guidance and information for the final disposition of unused study interventions are
provided in the Site Investigational Product Procedures Manual.
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 2 intervention arms of each part of the study with ratio 4:1 (JNJ-3989 +NA: placebo +NA)
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
the presence of compensated cirrhosis at screening (yes or no, Part 1 only), HDV RNA testing
laboratory location (China versus outside of China), and HBeAg status at screening (positive
versus negative). The 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
Blinded treatment will be used to reduce potential bias during data collection and evaluation of
clinical endpoints.
The investigators, participants, and all site personnel will remain blinded to study intervention
allocation until a participant has completed the Week 48 visit or has discontinued earlier. When a
participant has completed the Week 48 visitor discontinued earlier, the investigator, site personnel,
sponsor, and participants will be unblinded for treatment allocation  and all laboratory data,
including HDV RNA and HBsAgdata. AfterWeek 48, it will be communicatedto the investigators
whether the participant was allocated to either the immediate active arm (Arm 1) or the deferred
active arm (Arm 2) to allow that the participant follows the correct visit schedule during the
open-label phase (see Section 1.3.2, Schedule of Activities Open-label Study Intervention Phase
(Weeks 52 EOT)).
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As ofWeek 52 and up and until the end of the study intervention phase, study intervention will
be administered in open-label fashion to all participants and efficacy results (eg, HDV RNA and
HBsAg data) will be reported to the sites.
The Sponsor Committee will be unblinded to treatment allocation in the initial exploration of the
antiviral activity criteria in up to 16 participants randomized in Part 1, based on aggregate interim
data of HDV RNA and/or individual HDV RNA profiles and HBsAg data where the individual
participant identification will be masked. This is to assess whether the evaluation of antiviral
activity on a small number of participants warrants to expand enrollment to the remaining
30 participants (start of Part 2).
At the time of Part 1 IA1 (when all participants of Part 1 have completed at least Week 16 or
discontinued earlier), sponsor personnel and members of the IFLEP will become unblinded to the
Part 1 data. However, as soon as Part 2 commences, all sponsor personnel, including the Sponsor
Committee, and the members of the IFLEP  remain blinded to subsequent IDMC data reviews
during the double-blind phase. During the open-label phase, all data will be unblinded (see
Section 9.5). Study site personnel, investigators, participants, and operational sponsor team
members involved with the sites will have no access to any of the evaluations performed by either
the sponsor or the IDMC. For safety-related decisions, HDV RNA and HBsAg data may be
discussed with investigators on a case-by-case basis.
The investigator may in an emergency determine the identity of the study intervention by
contacting the IWRS. While the responsibility to break the study intervention code in emergency
situations resides solely with the investigator, it is recommended that the investigator contacts the
sponsor or its designee to discuss the particular situation, before breaking the blind, only if this
does not delay action with respect to treatment in an emergency situation. Telephone contact with
the sponsor or its designee will be available 24 hours per day, 7 days per week. In the event the
blind is broken, the sponsor must be informed as soon as possible. The date 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 case of IWRS participant unblinding and if the investigator requires to be unblinded in case of
an emergent safety event (ie, study intervention discontinuation due to ALT flares) to allow further
treatment of the participant, a sponsor request can be made to have the investigator and sponsor
unblinded to all HDV RNA and HBsAg data from the double‑blind phase.
During the blinded study treatment phase, HBV/HDV RNA, HBsAg, HBeAg, HBcrAg, anti-HBs,
and anti-Hbe antibody tests cannot be done locally.
6.4. 
Study Intervention Compliance
Preparation of JNJ-3989/placebo, including the necessary blinding, will be performed by an
unblinded preparer. JNJ-3989/placebo will be administered as a SC  injection by the blinded
administrator.
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An optional medication diary to document oral study intervention intake can be made available for
participants with an observed or known risk for study intervention non-compliance. The completed
diaries are reviewed by the site staff and discussed with the participants for compliance monitoring
and counseling. Completed diaries will be returned to the site staff to add to the source documents.
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.
If an injection of JNJ-3989 was missed, the injection should be given as soon as possible but
within 3 weeks after the scheduled time. Otherwise, the injection should be skipped, and the
next injection should be given at the next scheduled time point per the initial injection
schedule.
Note: All missed injections and significant delays should be discussed with the sponsor.
If a dose of NA is missed, the participant should follow the guidelines in the package insert.
If a participant’s study intervention intake is not according to the protocol, the investigator will
take the necessary measures to ensure future adherence to the protocol.
Per Protocol Amendment 5, NA treatment will be continued in all participants in Part 2 until the
last study visit.
If clinically indicated, switching from one NA treatment (ETV, tenofovir disoproxil, or TAF) to
another NA treatment (ETV, tenofovir disoproxil, or TAF) during the study is allowed for all
participants after consultation with the sponsor.
6.5. 
Re-treatment With NA During the Follow-up Phase
Participants who complete treatment with JNJ-3989 at the end of the open-label phasea in Part 1
and Part 2 will be closely monitored for transaminase flares and for HBV/HDV recurrence during
the follow-up phase.
Before Protocol Amendment 5, NA treatment should be continued during the entire follow-up
phase according to treatment guidelines for cirrhotic patients. For non-cirrhotic patients, NA
treatment should be continued until the last study visit (including the visit in the follow-up phase)
unless confirmed HBsAg seroclearance, ALT <3x ULN, and HBV DNA <LLOQ is observed, in
which case NA treatment may be discontinued upon discussion with the sponsor.
a At Week 144 (Arms 1) or Week 148 (Arms 2) in Part 1 and Part 2 before Protocol Amendment 5; at Week 96 or
later (Arm 1) or Week 100 or later (Arm 2) in Part 2 after Protocol Amendment 5
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Per Protocol Amendment 5, NA treatment will be continued in all participants in Part 2 until the
last study visit (including visit in the follow-up visit).
6.5.1. 
Re-treatment With NA
Amongst the non-cirrhotic participants who stop treatment with NA, NA treatment will be
restarted if any of the following criteria are met:
If there are signs of decreasing liver function based on laboratory findings (INR or direct
bilirubin) or clinical assessment.
HBeAg seroreversion among participants who had previously experienced HBeAg loss.
Post-treatment values ofHBV DNA >2,000 IU/mL and ALT >5x ULN
Post-treatment values ofHBV DNA >20,000 IU/mL.
Earlier restarting of NA treatment is at the investigator’s discretion, even if the above criteria are
not met yet.
Per Protocol Amendment 5, NA treatment will be continued in all participants in Part 2 until the
last study visit (including visit in the follow-up phase).
6.6. 
Treatment of Overdose
For this study, any dose of JNJ-3989 exceeding the protocol-specified dose with ≥25% (refer to
Section 6.1) will be considered an overdose. Any dose of NA greater than the prescribed dose
(refer to Section 6.1) will be considered 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 or modifications will be made by the investigator in
consultation with the Medical Monitor based on the clinical evaluation of the participant.
6.7. 
Concomitant Therapy
Pre-study therapies administered up to 30 days before first dose of study intervention, as well as
any prior IFN use, must be recorded at screening. If applicable, the participant’s last anti-HBV
and/or anti-HDV treatment prior to screening must also be recorded.
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Concomitant therapies must be recorded throughout the study, from signing of the ICF up to the
last study visit. Concomitant therapies must also be recorded beyond the last study visit only in
conjunction with new or worsening (S)Aes.
Note that locally approved COVID-19 vaccines (including those that received emergency use
authorization or conditional marketing authorization) are allowed throughout the study.
All COVID-19 vaccination-related data (eg, COVID-19 vaccination, AEs, AE management)
should be appropriately captured in the CRF and source documents. Refer to the COVID-19
vaccine prescribing information for more details.
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, or other specific categories of interest) 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 2.
Table 2: 
Disallowed Medication
Disallowed at any time prior to screening until end of follow-upa:
Any oligonucleotide-based treatment (eg, siRNA, nucleic acid polymers, 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-upa:
Any anti-HBV/HDV drug (including vaccines, interferons) other than the study intervention taken in the
context of this study.
Note: Study intervention taken in the context of this study (ETV, TD, TAF) is allowed. Prior hepatic
treatment with herbal or nutritional products is also allowed but should be stopped at screening.
Any investigational agent, investigational vaccine, invasive investigational medical device, or
investigational biological product (other than the study intervention taken in the context of this study)
Note: For investigational COVID-19 vaccines administered within 6 months prior to screening, an
exception will be made as long as the vaccine has been approved (or received emergency use authorization
or conditional marketing authorization) at the time of screening.
Disallowed from 6 months prior to baseline until end of follow-upa:
Any systemically (eg, intravenously, intramuscularly, orally, subcutaneously) administered medication
that directly or indirectly interferes with immune responses (eg, cyclosporine, interleukins, systemic
corticosteroids exceeding 5 mg of prednisolone equivalent/day).
Disallowed from 1 month prior to screening until end of follow-upa:
Any medication that reduces renal function or competes for active tubular secretion (eg cimetidine,
probenecid, quinidine).
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Table 2: 
Disallowed Medication
Disallowed from screening until end of follow-upa:
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.
a 
Refer to Section 4.1 for the end of follow-up definition before and after Protocol Amendment 5.
Note: The list of disallowed medication is not exhaustive; for products falling in one of the
categories and not mentioned by name, the sponsor should be contacted to determine whether the
product can be allowed.
Note:Anticoagulants are to be used with caution. Aspirin and other antiplatelet aggregating agents
are allowed. Further restrictions apply to participants undergoing optional liver biopsy procedures.
Antiplatelet aggregating agents should be paused at least 9 days prior to liver biopsy procedures
or according to local standard practice.
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, tenofovir disoproxil, and TAF should be consulted for any
additional prohibited medication.
The sponsor must be notified in advance (or as soon as possible thereafter) of any instances in
which prohibited therapies are administered.
7. 
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT
DISCONTINUATION/WITHDRAWAL
7.1. 
Discontinuation of Study Intervention
A participant’s investigational study intervention (JNJ-3989/placebo) must be discontinued if any
of the criteria listed below apply. In those cases, NA treatment should be continued.
The participant withdraws consent to receive study intervention.
The investigator believes that for safety reasons or tolerability reasons (eg, AE) it is in the
best interest of the participant to discontinue study 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) or an increase in direct bilirubin >1.5x ULN
in combination with INR ≥1.5x ULN or albumin <3.0 g/dL. In this case treatment with
JNJ-3989 should be discontinued and alternative treatment options (outside the study)
should be considered in discussion with the sponsor.
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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 that persists despite change of tenofovir disoproxil to ETV or TAF (if
the patient was receiving tenofovir disoproxil). 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.
The participant requires treatment with any of the disallowed medications listed in
Section 6.7 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. Injection with JNJ-3989 will be stopped if the NA change
does not result in a decrease in HBV DNA levels.
The participant has ALT/AST elevations, as described in Section 8.3.6.1,
Intervention-emergent ALT/AST Elevations.
Per IDMC recommendation, in Part 2, the participants with HBsAg values >10.000 IU/mL
at screening or baseline, who were assigned to Arm 1 (placebo), will not roll-over to the
open-label phase and will enter the follow-up phase.
The participant of the placebo group should discontinue study intervention (cannot start
JNJ-3989 in the open-label phase in Part 2, Arm 2) ifhe/she develops cirrhosis at the end
ofthe double-blind phase (based on the Week 48 FibroScan assessment).
If a participant discontinues study intervention for any reason before the end of the double-blind
phase, end-of-intervention assessments must 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 (see Section 1.3). 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.
A participant will be withdrawn from the study for any of the following reasons:
Lost to follow-up
Withdrawal of consent
Death
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When a participant withdraws before study completion, the reason for withdrawal is to be
documented in the CRF and in the source document. If the reason for withdrawal from the study
is withdrawal of consent then no additional assessments are allowed.
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 samples):
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 and may request
destruction of the previously collected samples, in which case the samples will be
destroyed and will not be used further. To initiate the sample 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 Samples While Remaining in the Main Study
The participant may withdraw consent for optional research sample 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 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 samples.
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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, immune,
biomarker, pharmacogenomic, safety, and MRU measurements applicable to this study.
All ECG assessments should preferably be conducted/completed before any tests, procedures, or
other consultations for that visit to prevent influencing participant perceptions.
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.
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. Other measurements may
be done earlier than specified timepoints if needed.
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 maximum amount of blood drawn from each participant in this study and during the follow-up
phase will not exceed 3,210 mL. Note that with the removal of several sample collections, the
amount of blood drawn, and the total blood volume needed will be less.
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Note: The total blood volume to be collected from each participant may vary, depending on several
factors (eg, treatment arm, unscheduled re-tests, re-sampling, individual and country/territory
variations). The maximum amount will only be reached for those participants who participate in
the collection of PBMC samples, and DNA sampling and who are treated within the study for the
maximal study duration of 148 weeks plus maximum 48 weeks of follow-up. This amount does
not include the local laboratory collection of samples required for the optional liver biopsy or any
local laboratory safety follow-up as the blood volume taken for these analyses will depend on the
local laboratory used.
Repeat or unscheduled samples may be taken for safety reasons or for technical issues with the
samples.
For participants in China, some exploratory assessments may not be collected.
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:
IB and any addenda for JNJ-3989,
Prescribing Information for ETV, tenofovir disoproxil, and TAF,
Pharmacy manual/study site investigational product and procedures manual,
Laboratory manual,
IWRS Manual,
CRF Completion Guidelines,
Sample ICF,
Participant diaries.
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8.1. 
Efficacy Assessments
Efficacy assessments will be performed at the time points indicated in the Schedule of Activities.
HDV RNA will be quantified at central testing laboratory locations (China versus outside of
China) using a validated commercially available in vitro nucleic acid amplification tests for the
quantification of HDV RNA. Samples may be processed in real-time or could be analyzed in batch.
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 will be quantified at central laboratories using commercially available in vitro nucleic
acid amplification tests for the quantification of HBV DNA. Samples for the determination of
HBV DNA will be processed in real-time. HBV RNA will be quantified using a validated assay in
a central laboratory. Samples for the determination of HBV RNA can be analyzed in batch and at
the sponsor’s discretion.
HBV DNA results will be provided to the investigator and the sponsor from screening until the
end of follow-up.
It is the responsibility of the investigator:
To monitor HBV DNA results and ensure that investigational intervention is discontinued
in participants with virologic breakthrough (see Section 7.1).
For each participant, the post-baseline HDV RNA, HBsAg, HBeAg, HBcrAg, anti-HBs, and
anti-Hbe antibody testing results from the Week 52 visit onwards will be provided to the
investigator for managing the participant’s safety. For Part 1, the sponsor will be unblinded to
Part 1 data from the moment of data unblinding for Part 1 IA1 onwards. For Part 2, the sponsor
will be blinded until the Week 52 visit. For safety-related decisions, Part 1 HDV RNA and HBsAg
data may be discussed with investigators on a case-by-case basis. When a participant has
completed the Week 48 visit or discontinued earlier, the investigator, site personnel, sponsor, and
participant will be unblinded for treatment allocation and all laboratory data, including HDV RNA
and HBsAg data.
Liver stiffness measurements will be performed by VCTE (FibroScan) to determine changes in the
liver fibrosis.1,4
Samples may be used by the sponsor for additional exploratory assessments analyzing the
serologic and virologic characteristics of HBV or HDV infection (including semi-quantitative
anti-HDV IgM antibodies) and efficacy or safety of the study intervention. During the blinded
study treatment phase, HBV/HDV RNA, HBsAg, HBeAg, HBcrAg, anti-HBs, and anti-HBe
antibody tests cannot be done locally.
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8.1.1. 
HBV and HDV Genotyping and Sequencing
HBV genotyping will be performed at baseline using a Line Probe Assay (LiPA assay) and/or
sequence-based method. HDV genotyping will be performed at baseline using sequence-based
methods.
Viral genome sequence analysis may be performed to identify pre-existing baseline
polymorphisms and to evaluate emergence of mutations associated with JNJ-3989 and/or NA
treatment.
Sequencing of the HBV genome will be performed to monitor HBV variants. 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.
Sequence analyses of the HDV genome might be performed.
Samples may be used by the sponsor for additional assessments analyzing the serologic and
virologic characteristics of HBV or HDV infection and efficacy and safety of the study
intervention, including viral genotypic and phenotypic assessments.
8.1.2. 
Core Liver Biopsy and Fine Needle Aspirate Biopsy (Optional with
Separate Consent, Part 2 Only)
Liver biopsies will be collected only in sites and in selected countries where this is feasible, and
after all relevant approvals are in place and operational set-up is completed.
If participants in Part 2 of the study agree to undergo an optional liver biopsy, percutaneous core
liver biopsies and FNABs will be performed preferentially at the time points indicated in the
Schedule of Activities (Week 0 and Week 24). Percutaneous core liver biopsies will be prioritized
over FNAB if only one sample can be collected.
Following local standard practice the biopsy location will be identified with ultrasound (which will
also be used to rule out contraindicating conditions for a biopsy) and after application of local
anesthesia the FNAB samples and core liver biopsy samples will be collected.
The core liver biopsy procedure should be preceded and followed by standard medical monitoring
according to local medical practice. This may include an overnight stay at the investigator’s
discretion.
Intrahepatic viral and host markers may be evaluated over time. Viral markers for HDV and HBV
in the liver such as, but not limited to, total intracellular HDV RNA and HDAg, HBV RNA and
DNA, HBeAg, HBsAg, and HBcAg. Changes in the quantity and potentially changes in the spatial
distribution of these markers under therapy may be assessed. Viral genome(s) or transcript
sequencing/analyses as well as assessment of HBV integrants in the host genome may be
performed.
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Intrahepatic virologic status at baseline and response to treatment will be assessed with a range of
methods. HDV RNA may be assessed by RT-PCR based methods. Hepatitis B virus cccDNA
levels may be assessed using quantitative polymerase chain reaction (qPCR) methods on a single
cell level using laser capture microdissection or bulk analyses. The exact protocol of cccDNA
measurement will be determined based on the latest method available considering the performance
characteristics and the validation status of the assay. Quantification of intracellular pre-genomic
HBV RNA can be used to determine transcriptional activity of HBV cccDNA by assessing the
ratio of pgRNA levels over cccDNA levels. Immunostaining approaches (for example for HBsAg,
HBcAg, HDAg) and in situ hybridization approach (HBV RNA, HDV RNA) may be applied to
evaluate the proportion of positive cells in each sample.
Intrahepatic immune status at baseline and in response to treatment may be assessed. Both innate
and adaptive immune compartment will may be characterized, by measuring the relative number
of specific cells and the expression of functional markers in each cell population using various
single cell approaches, such as single cell transcriptomics in FNABs and immunofluorescence
staining, and transcriptomics and proteomics profiling in core needle biopsies. Depending on the
latest platform developments (spatial transcriptomics, in situ sequencing approaches, etc.) methods
for immune cells characterization might be adjusted.
Hepatitis B virus-specific T-cells, although very rare in FNABs, may be characterized and counted
by multimers binding assays, staining, and sorting for positive cells. Downstream profiling of
collected HBV-specific T-cells may be performed by T-cell receptor sequencing and RNA
sequencing. Infiltrating immune cells will be used for the evaluation of innate and adaptive
immune responses, which can be compared to responses in PBMCs.
Immune and virologic markers in the liver and/or changes thereof under therapy will be used to
assess association with blood markers and/or treatment response and outcome.
Remaining samples may be used for research on viral and host biomarkers and immune markers
at the viral and/or host RNA/DNA, protein, and cell level.
Samples can only be used for research related to JNJ-3989, chronic HBV or HDV infection, or
chronic HBV or HDV infection related disease or may be used to develop tests/assays related to
JNJ-3989, NA, or chronic HBV or HDV infection. These latter exploratory analyses will be
performed at the sponsor’s discretion and will always be under the sponsor’s supervision.
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, vital signs measurements (including body weight), 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.
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Adverse events will be reported and followed by the investigator as specified in Section 8.3,
Adverse Events, Serious Adverse Events, and Other Safety Reporting and Section 10.4,
Appendix 4: Adverse Events, Serious Adverse Events, Product Quality Complaints, and Other
Safety Reporting: Definitions and Procedures for Recording, Evaluating, Follow-up, and
Reporting.
The AESIs 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, the internal DRC, 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], skin examination, and
other body systems) will be performed at screening, Week 24, and Week 48. A symptom-directed
physical examination 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, gastrointestinal system, and skin and mucous
membranes. A neurological and musculoskeletal examination will be performed, as well as an
examination of the lymph nodes. Height will be measured at the screening visit only.
8.2.2. 
Vital Signs
Temperature (tympanic or oral), body weight, pulse rate, and blood pressure will be assessed.
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.
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.
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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 and interpreted centrally. Preferably, all ECGs will be read and interpreted
under supervision of one and the same qualified person. Only on Day 1, the ECG will also be read
locally prior to dosing.
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 and hematology, coagulation and a urine sample 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.
8.2.5. 
Pregnancy Testing
An FSH test (postmenopausal women) will be performed at screening (Appendix 8). 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.
8.3. 
Adverse Events, Serious Adverse Events, and Other Safety Reporting
Timely, accurate, and complete reporting and analysis of safety information, including AE, SAEs,
and product quality complaint (PQC), from clinical studies are crucial for the protection of
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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.
In those countries/sites where HDV prescreening is performed, AEs and serious AEs related to
this blood collection procedures, as well as death from any cause, will be collected for 30 days
after the prescreening procedure.
Note: All reported AEs will be coded according to MedDRA. In addition, the following coding
conventions will be applied for the AEs reported by investigators as specified below:
AEs reporting ALT flare in relation to laboratory test elevation will be coded to the MedDRA
PT Alanine aminotransferase increased.
AEs reporting reactivation of hepatitis B in participants who are HBV DNA suppressed and
have, during the off-treatment period, a sudden HBV DNA increase (virologic flare) will be
coded to the MedDRA PT Hepatitis B reactivation.
AEs reporting viral breakthrough in the context of laboratory data will be coded to the
MedDRA PT Viral load increased.
For further details on AEs and SAEs (Definitions and Classifications; Attribution Definitions;
Severity Criteria; Special Reporting Situations; Procedures) as well as PQCs, refer to Section 10.4,
Appendix 4: Adverse Events, Serious Adverse Events, Product Quality Complaints, and Other
Safety Reporting: 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 study discontinuation or 30 days after completion of
the participant’s last study-related procedure, which may include contact for follow-up of safety.
The beforementioned AEs must be recorded on specific AE pages of the CRF. During the 30-day
period, SAEs, including those spontaneously reported to the investigator, must be reported using
the Serious Adverse Event Form. The sponsor will evaluate any safety information that is
spontaneously reported by an investigator beyond the time frame specified in the protocol.
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Serious Adverse Events
All SAEs occurring during the study must be reported to the appropriate sponsor contact person
by study-site personnel immediately, but no later than 24 hours of their knowledge of the event.
Information regarding SAEs will be transmitted to the sponsor using the Serious Adverse Event
Form, which must be completed and signed by a physician from the study site, and transmitted to
the sponsor immediately, but no later than within 24 hours. The initial and follow-up reports of a
SAE should be transmitted electronically or 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.
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
The investigator is obligated to perform or arrange for the conduct of supplemental measurements
and evaluations as medically indicated to elucidate the nature and causality of the AE or SAE as
fully as possible. This may include additional laboratory tests or investigations, histopathological
examinations, or consultation with other health care professionals.
AEs and the special reporting situation of pregnancy will be followed by the investigator as
specified in Appendix 4: Adverse Events, Serious Adverse Events, Product Quality Complaints,
and Other Safety Reporting: 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.
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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 Serious Adverse Event Form.
Any participant who becomes pregnant during the study must discontinue JNJ-3989.
Follow-up information regarding the outcome of the pregnancy for female participants who
become pregnant, or where the pregnancy was the result of a male participant and his partner, and
any postnatal sequelae in the infant will be required.
8.3.6. 
Adverse Events of Special Interest
Events of Special Interest are significant AEs that are judged to be of special interest because of
clinical importance, known class effects or based on nonclinical signals. Events of Special Interest
that will be carefully monitored during the study include ISRs, ALT/AST elevations, renal
complications, hematologic abnormalities, and events related to cholesterol increase
(Section 8.2.4, Clinical Safety Laboratory Assessments). In addition, the following toxicities will
also be carefully monitored: rash and acute systemic allergic reactions.
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
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 ≥2x 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 as specified below. Repeat laboratory values should include AFP,
ALT, AST, ALP, bilirubin (total and direct), INR, albumin, HBV DNA, and HDV RNA.
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 preferably within 3 days of the receipt of the initial ALT/AST results.
Weekly basis monitoring (or more frequently as long as values increase) until ALT/AST levels
have returned to <3x ULN or <2x nadir, and if present, liver related symptoms have improved.
With ALT and/or AST values ≥3x ULN and ≥2x nadir, visit intervals may be extended to 14 days
if values have been stable or decreasing on three consecutive visits. The participant will be
monitored (laboratory testing of ALT, AST, ALP, bilirubin [total and direct], INR, albumin,
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HBV DNA, and HDV RNA) on a weekly basis or more frequently until ALT and/or AST levels
have returned to 50% of the maximal value.
Note: In case of urgency, local laboratory assessments could be considered. In case of IWRS
participant unblinding and if the investigator requires to be unblinded in case of an emergent safety
event (ie, study intervention discontinuation due to ALT flares) to allow further treatment of the
participant, a sponsor request can be made to have the investigator and sponsor unblinded to all
HDV RNA and HBsAg data from the double‑blind phase. Off-treatment local HDV RNA test can
be done to exclude/assess for HDV-driven flare.
Management of intervention-emergent ALT and/or AST elevations:
JNJ-3989 treatment should be stopped, and NA treatment needs to be continued in the following
situations:
Participants with liver cirrhosis:
Confirmed ALT/AST elevation >5x ULN and ≥2x nadir
ALT/AST elevation ≥3xULN and ≥2x nadir for >4 weeks.
If the ALT and/or AST level is ≥3x ULN and ≥2x nadir and is associated with any of the
following laboratory results or clinical symptoms:
o INR ≥1.5, OR
o direct bilirubin >1.5x ULN, OR
o serum albumin <3.0 g/dL, OR
o 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
o other indication of reduced liver function.
Participants without liver cirrhosis:
Confirmed ALT/AST elevation >10x ULN and ≥2x nadir
First on-treatment ALT/AST elevation 3 to 5x ULN for >12 weeks
Second or following on-treatment ALT/AST elevation 3 to 5x ULN for >4 weeks
ALT/AST elevation >5 to 10x ULN for >4 weeks
If the ALT and/or AST level is ≥3x ULN and ≥2x nadir and is associated with any of the
following laboratory results or clinical symptoms:
o INR ≥1.5, OR
o direct bilirubin >1.5x ULN, OR
o serum albumin <3.0 g/dL, OR
o 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
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o other indication of reduced liver function.
From Week 52 onwards, results of HBsAg and HDV RNA assessment will be reported to the
investigators.
Management of flares observed in the follow-up phase after EOT:
In case of ALT flares that are observed during the follow-up phase, repeat laboratory values should
include AFP, ALT, AST, ALP, bilirubin (total and direct), INR, albumin, HBV DNA, and HDV
RNA. The participant should be monitored on a weekly basis (or more frequently as long as values
increase) until ALT and/or AST levels have returned to <3x ULN or <2x nadir. With ALT and/or
AST values ≥3x ULN and ≥2x nadir, visit intervals may be extended to 14 days if values have
been stable or decreasing on three consecutive visits. For guidance on re-treatment with NA during
the follow-up phase, refer to Section 6.5, Re-treatment With NA During the Follow-up Phase.
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 3 in
Section 10.5, Appendix 5: Rash Management.
When safety blood samples are drawn as per the rash management guidelines, these should be
processed by the local laboratory. The following parameters will need to be tested: AST, ALT,
sedimentation rate, complete blood cell count (including hemoglobin, hematocrit, red blood cell
[RBC] count, white blood cell [WBC] count, differential count [neutrophils, lymphocytes,
monocytes, eosinophils, and basophils], and platelet count), and creatinine. Relevant laboratory
assessment values are to be shared with the sponsor (if applicable and local regulations allow) as
per the “Instructions for Investigators for sharing of Digital Pictures and Local lab reports” and
should be de-identified.
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.
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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.
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. 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. Rechallenge is not allowed. The
participant’s NA treatment may be discontinued based on investigator judgement in consultation
with the sponsor.
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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, if
the abnormality is considered at least possibly related to JNJ-3989, 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
As already mentioned in Section 2.1, JNJ-3989 is also being developed in combination with
JNJ-6379.
Mild thrombocytopenia was observed in recently conducted nonclinical 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.
Review of laboratory data in the REEF-1 study showed a low number of hematologic laboratory
abnormalities and most were of Grade 1 or Grade 2 severity. Low absolute neutrophil count was
most frequently reported in the JNJ-3989 (200 mg) + NA arm (Grade 1: 4 [4.3%] participants and
Grade 2: 2 [2.1%] participants). Changes in hemoglobin and platelets in the
JNJ-3989 +NA +/- JNJ-6379 arms were comparable to the Placebo + NA arm. Few hematologic
laboratory abnormalities were also observed in the REEF-2 study (73763989PAHPB2002), which
were balanced between the active and placebo arms. In the Phase 1/2a AROHBV1001 study with
JNJ-3989, mild transient thrombocytopenia (Grade 1) was observed in 6 out of 84 participants
receiving 3 SC injections of JNJ-3989 alone over a period of up to 12 weeks with background of
NAs. The transient thrombocytopenia was not considered clinically significant. No
thrombocytopenia or pancytopenia was observed in 12 participants when JNJ-3989 and JNJ-6379
were given in combination over a 12-week period.
As these findings were not clearly attributed to JNJ-3989, JNJ-6379, or the combination of the
2 study interventions, measures for close monitoring of hematological changes during the study
are in place.
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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 2 consecutive visits.
In case of confirmed Grade 3 or Grade 4 hematologic abnormalities, discontinuation of
investigational study treatment (JNJ-3989) should be considered. In case of discontinuation,
NA treatment should be continued.
8.3.6.6. 
Complications From Liver Biopsy
Participants should be closely monitored for liver biopsy complications. Infection and internal
bleeding and/or puncture of other internal organs (gall bladder, lung, intestine or kidney) can lead
to serious complications (uncommon 1 in 1,000 to 1 in 100) including the need for emergency
surgery, blood transfusion or removal of organs. Deaths directly related to liver biopsy occur rarely
(approximately 1 in every 10,000 biopsies). Criteria for participant selection and laboratory
assessments are in place to minimize these risks. Additional investigations can be performed at the
investigator’s discretion. Participants must be treated as clinically appropriate.
8.4. 
Pharmacokinetics
Sparse PK samples for JNJ-3989 will be collected in all participants according to the Schedule of
Activities.
Plasma samples will be used to evaluate the PK of JNJ-3989 (JNJ-73763924 and JNJ-73763976).
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.
8.4.1. 
Evaluations
Venous blood samples will be collected for measurement of plasma concentrations of
JNJ-3989 (JNJ-73763924 and JNJ-73763976), at time points specified in the Schedule of
Activities.
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8.4.2. 
Analytical Procedures
Pharmacokinetics
At the sponsor’s discretion, a selection of plasma samples will be analyzed to determine
concentrations of JNJ-3989 (JNJ-73763924 and JNJ-73763976), using a validated, specific, and
sensitive liquid chromatography-mass spectrometry method or liquid chromatography
fluorescence method, as applicable, by or under the supervision of the sponsor.
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.
8.4.3. 
Pharmacokinetic Parameters and Evaluations
Sparse PK samples for JNJ-3989 will be collected and plasma concentration-time data for
JNJ-3989 (JNJ-73763924 and JNJ-73763976) will be analyzed. Data from this study may be
combined with data from a selection of Phase 1 and 2 studies via population PK modeling. If
performed, the population PK analysis will be described in a separate analysis plan and results will
be reported separately.
8.5. 
Pharmacokinetics/Pharmacodynamics
Relationships of individual PK parameters for JNJ-3989 (JNJ-73763924 and JNJ-73763976) with
selected efficacy and/or with selected safety endpoints may be evaluated, if applicable.
8.6. 
Immune Assessments
At selected sites, PBMC samples for immune analyses will be collected during study intervention
and may 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 HBV-specific T-cells that secrete gamma interferon (IFN-γ) in response
to a specific antigenic stimulation, whereas ICS determines the frequency of CD4+ and CD8+
HBV T-cells secreting cytokines such as IFN-γ, interleukin (IL)-2 and tumor necrosis factor
(TNF)-α in response to a specific antigenic stimulation.
PBMC samples may also be analyzed for HDV-specific responses using ELISpot and ICS after
stimulation with HDV-specific antigens.
Additional experiments may be performed to further phenotypically and functionally characterize
PBMCs using proliferation or cytotoxic assays or other methods such as cytometry by time of
flight to evaluate innate and adaptive immune responses. Leftover PBMC samples may be used at
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the sponsor’s discretion for additional exploratory research related to HBV or HDV infection or
study intervention (safety/efficacy).
Additional PBMC samples may be taken until Week 48 in case of ALT flares, upon discussion
with the sponsor, which may require an unscheduled visit.
8.7. 
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 deemed necessary (where
local regulations permit).
An optional pharmacogenomic (host DNA) blood sample may be collected (preferably at baseline)
to allow for host pharmacogenomic research, where local regulations permit. Complete host
genomic testing may be done to search for links of specific genes to (HBV/HDV-related) liver
disease or to the PK, PD, efficacy, safety, or tolerability of the study intervention. These samples
will only be collected from participants who consent separately to this component of the study.
Further, a participant may withdraw such consent at any time without affecting their participation
in other aspects of the study.
In addition, other samples may be used for exploratory genetic research in participants consenting
separately to this part of the study. No host DNA 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 or HDV infection, or may be used to develop
tests/assays related to study intervention or HBV or HDV infection.
8.8. 
Host Biomarkers
The study includes collection of blood samples for exploratory analysis of host blood biomarkers
(eg, cytokines) at the host RNA, protein, and cell level. Exploratory serology samples, which will
be collected in all participants at the time points indicated in the Schedule of Activities, may be
used for this host serum protein testing.
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.
Samples can only be used for research related to study intervention or HBV or HDV infection or
may be used to develop tests/assays related to study intervention or HBV or HDV infection.
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8.9. 
Medical Resource Utilization
Medical resource utilization data, associated with medical encounters, will be collected in the CRF
by the investigator and study-site personnel for all participants throughout the study.
Protocol-mandated procedures, tests, and encounters are excluded. The data collected may be used
to conduct exploratory economic analyses and will include:
Number and type of medical visits (eg, in/out hospital, ER visit).
Number (proportion) of participants requiring hospitalization and duration of hospitalization
(total days length of stay, including duration by wards; eg, ICU).
Number and character of diagnostic and therapeutic tests and procedures (inpatient and
outpatient).
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 SAP.
The primary analysis in this study will be performed when all participants in the study (both parts
if Part 2 has started) have reached Week 48 or have discontinued earlier.
The final analysis will be performed when all participants in the study (both parts if Part 2 of the
study has started) have reached the final study visit in the follow-up phase, or have discontinued
earlier.
9.1. 
Statistical Hypotheses
The original protocol had as primary hypothesis of this study that the combination regimen of
JNJ-3989 + NA  has superior efficacy compared to NA treatment alone in reducing HDV
replication and improving the associated liver inflammation, as measured by the primary efficacy
endpoint at Week 48 (the proportion of participants with HDV RNA decline ≥2 log10 IU/mL from
baseline or HDV RNA TND in combination with normal ALT at Week 48). Due to the decision
to stop enrollment at 30 participants in Part 2 of the study (see Section 9.2), the statistical analyses
will be descriptive.
9.2. 
Sample Size Determination
The sample size in Part 1 (N 20) is primarily driven by the objectives of Part 1 to provide sufficient
evidence of safety and early antiviral activity of JNJ-3989 and to exclude futility of the regimen
in a small number of HBV/HDV co-infected participants before initiating the larger Part 2 of the
study. No formal statistical power calculations were conducted for Part 1.
A total sample size of 130 participants for Part 2 in the original protocol would yield a statistical
power >90% to detect a between-arm difference of ≥26% in the primary efficacy endpoint at
Week 48, at a 1-sided Type 1 error rate of 0.025, based on the test for the between-arm difference
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in proportions with the normal approximation. Per Protocol Amendment 4, the sample size in
Part 2 was reduced to 30 participants.
In the original protocol, sample size re-estimation was planned at the single IA during Part 2 to
allow for an increase to a maximum of 170 participants in Part 2 for the conditional power at the
end of the study to be at least 80% in case the assumed 0.04 response rate for placebo was too
conservative. Due to reduction in sample size per Protocol Amendment 4, the single IA with
sample size re-estimation was removed.
In the original protocol, the number of participants included in this study was planned to be a
minimum of approximately N 20 (if Part 2 is not initiated) or between a minimum of N 165 and
a maximum of N 190 if Part 2 is initiated. Per Protocol Amendment 4, the planned number of
participants included in the study will be N 20 in Part 1 and N 30 in Part 2.
9.3. 
Participant Analysis Sets
For purposes of analysis, the following analysis sets are defined:
Analysis set 
Description
Screened 
All participants who signed the ICF.
Randomized 
All participants who were randomly assigned to an intervention arm in the study.
Intent-to-treat 
(ITT) 
All participants who were randomly assigned to an intervention arm and who received at
least 1 dose of study intervention. Participants will be analyzed according to the study
intervention they were randomly assigned to.
Modified intent- 
to-treat (mITT) 
All participants who were randomly assigned to an intervention arm and who received at
least 1 dose of study intervention, excluding those participants impacted by the COVID-19
pandemic, defined as those participants who, because of COVID-19 or similar pandemic-
related reasons, withdrew prematurely from the study prior to Week 48, or had no efficacy
assessment for the primary endpoint. COVID-19 or similar pandemic-related reasons may
include for example missed visits due to travel restrictions, shortage of lab kits at the
planned visit, missed collection of blood sample at key time points for the primary efficacy
endpoint, etc. Participants will be analyzed according to the study intervention they were
randomly assigned to.
Safety  
All participants who take at least 1 dose of study intervention. Participants will be analyzed
according to the study intervention they actually received.
9.4. 
Statistical Analyses
The SAP  will be finalized prior to study start and will include a more technical and detailed
description of the statistical analyses described in this section.
9.4.1. 
General Considerations
The primary analysis set for efficacy will be the ITT  set (defined in Section 9.3). All efficacy
summaries will be presented with descriptive statistics by intervention arm by study Parts 1 and 2,
as well as for the whole study data overall.
If the endpoint is continuous, the descriptive statistics will include the number of participants,
mean, standard deviation (SD), median, range and interquartile range. If the endpoint is binary or
categorical, the frequency distribution with the number and percentage of participants in  each
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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 presence of compensated cirrhosis at
screening (yes or no).
The baseline measurement is defined as the assessment taken the closest to but before the first
administration of study intervention on Day 1.
9.4.2. 
Primary Endpoint
The primary efficacy endpoint is defined as the proportion of participants with HDV RNA
≥2 log10 IU/mL decline from baseline or HDV RNA TND in combination with normal ALT levels
at Week 48.
9.4.2.1. 
Primary Estimand
The main analysis of the primary endpoint will be addressed by using the following estimand
attributes:
1. Study Intervention:
Arm 1: JNJ-3989 +NA
Arm 2: Placebo + NA
2. Study population: Participants 18 to 65 years of age, inclusive, with HBV/HDV co-infection
3. Variable: Response status defined as having HDV RNA decline ≥2 log10 IU/mL from
baseline or HDV RNA TND in combination with normal ALT at Week 48
4. Intercurrent events (ICEs):
a. Treatment discontinuation prior to Week 48: if the participant discontinued
treatment prior to Week 48 then the participant will be considered as non-responder
(composite strategy).
b. Selected major protocol deviations (identified as ICEs): participants who
experienced major protocol deviations considered ICE and who have missing ALT
and/or HDV RNA data for the primary endpoint at Week 48 will be considered as
non-responders (composite strategy).
c. Deaths prior to Week 48 are handled in a composite strategy as participants who
die prior to Week 48 will be considered as non-responders.
5. Population level summary: Difference in proportion of responders between the
2 intervention arms (Arm 1-Arm 2).
Note: The SAP will list the major protocol deviations used for the purpose of efficacy analyses
and flag those that are to be considered ICEs.
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Assumptions:
Missing Data for HDV RNA and ALT are Missing At Random (MAR)
The treatment effect is homogeneous across strata.
Data Included
All available data from randomized participants that have received at least one dose is included
(ITT analysis set in Part 2), after taking into account all the ICEs and applying the ICE strategies.
Missing Data Handling Rules
Participants who withdraw from the study prior to Week 48 will be considered as non-responders.
If a participant remains in the study after early discontinuing treatment or after experiencing a
major protocol deviation (defined for the purpose of efficacy analyses and is an intercurrent event)
and has missing Week 48 value for HDV RNA and/or ALT, then the imputation to non-response
will be applied. If the value for the primary endpoint at Week 48 is available, then such data will
be used to determine their response status.
For the participants still in the study at Week 48 or for participants that have neither discontinued
treatment early nor experienced any major protocol violations (defined for the purpose of efficacy
analyses and is an intercurrent event), and, either HDV RNA or ALT values are missing at
Week 48, the primary method to handle missing data will be the Multiple Imputation (MI)
approach, applied in a joint multivariate fashion to leverage the correlation between HDV RNA
and ALT values over time. More details regarding the multiple imputation multivariate model will
be included in the SAP.
To challenge and assess the impact of the MAR assumption in presence of intercurrent events,
different approaches to handle missing data will be used as sensitivity analyses of the main
estimator. Two sensitivity analyses will be conducted with different rules to handle missing HDV
RNA and/or ALT values at Week 48. One sensitivity analysis will be based on the tipping point
approach based on the Missing Not At Random (MNAR) assumption, and the other analysis will
use a single imputation method. For the latter, the Last Observation Carried Forward (LOCF) in
conjunction with the next available observation imputation approach will be used. The
non-missing value closest to Week 48 will be selected among the non-missing values for HDV
RNA and/or ALT which are no earlier than 12 weeks prior or no later than 4 weeks post Week 48.
If both HDV RNA and ALT values are missing at Week 48, the imputed values will be chosen at
the same timepoint. If 2 non-missing laboratory values are equidistant, the later observation will
be preferred.
As a supplementary estimator, the analysis where all participants with missing HDV RNA and
ALT values in the analysis window of Week 48 in each arm are imputed as non-responders will
be conducted to provide a comprehensive overview of the robustness for the assumption of MAR
and the type of missing data.
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The main estimator and statistical model are discussed in the next section. The estimator will be
presented for Part 2 data as well as for the whole study data.
9.4.2.2. 
Analysis of The Main Estimator
The proportion of responders will be compared between the 2 arms using, if possible, the
stratum-adjusted Mantel-Haenszel test on the difference of proportions, with the following
stratification factors: presence of compensated cirrhosis at screening (yes or no, for Part 1 only),
HDV RNA testing laboratory location (China versus outside of China), and HBeAg status at
screening (positive versus negative).
9.4.3. 
Key Secondary Endpoints
The key secondary endpoints at Week 48 are defined as follows:
1. Proportion of participants with HDV RNA ≥2 log10 IU/mL decline from baseline or HDV
RNA TND at Week 48.
2. Proportion of participants with normal ALT levels at Week 48.
3. Proportion of participants with HBsAg seroclearance at Week 48.
4. Proportion of participants with ≥2 kPa reduction from baseline in LSM assessed by VCTE
(FibroScan) at Week 48.
The 4 key secondary endpoints are binary and will be analyzed using, if possible, the
stratum-adjusted Mantel-Haenszel test similarly  to the primary efficacy endpoint with
corresponding 95% CIs on the difference of proportions between the 2 arms.
The estimand, estimator, and missing data handling rules will be constructed for and applied to
each of the key secondary efficacy endpoints in a similar fashion as described earlier for the
primary efficacy endpoint. The details are presented in the SAP.
9.4.4. 
Other Efficacy Endpoints
Descriptive statistics will be used for all efficacy endpoints which will be summarized by
intervention arm over time and by study phase, using the whole study data as well as by stage
(defined in Section 9.4.2.2). Specific endpoints may be analyzed using suitable categorical data
approaches (eg, Mantel-Haenszel test, logistic regression for proportions or other categorical type
of endpoint), longitudinal repeated measures or ANCOVA models (eg, for continuous types of
variables), or survival analysis based on the Kaplan-Meier estimates (for time-to-event variables),
as appropriate.
The statistical inference to compare the efficacy between Arm 1 and Arm 2 as measured by the
other secondary endpoints at Week 48 will utilize the weighted inverse normal combination
method as described for the primary efficacy endpoint. No further adjustment for multiplicity will
be made and no imputation rule will be used in case of missing data. More details are provided in
the SAP.
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The efficacy of JNJ-3989 +NA during study intervention and follow-up phases will be evaluated
in terms of the proportion of participants with
- HDV RNA ≥2 log10 IU/mL decline from baseline or HDV RNA TND in combination with
normal ALT,
- HDV RNA ≥2 log10 IU/mL decline from baseline in combination with normal ALT,
- HDV RNA TND in combination with normal ALT,
- HDV RNA ≥2 log10 IU/mL decline from baseline or HDV RNA TND,
- HDV RNA ≥2 log10 IU/mL decline from baseline,
- HDV RNA TND,
- Normal ALT,
- Off-treatment sustained HDV RNA response,
- Off-treatment sustained HDV RNA relapse,
will be tabulated by intervention arm as well as over time. The comparison among the intervention
arms for these endpoints at Week 48 will be done using MH chi-square test stratified by the
stratification factors and corresponding 95% CIs without adjustment for multiple intervals. The
time to reach HDV RNA ≥2 log10 IU/mL decline or HDV RNA TND will be summarized based
on Kaplan-Meier estimates in tables and graphs.
In addition, descriptive statistics on values and changes from baseline over time in HDV RNA and
ALT will be summarized by intervention arm.
The proportion of participants with HBsAg seroclearance/seroconversion during the study
intervention and follow-up phases will also be tabulated by intervention arm, and over time.
The proportion of participants with HBV virologic breakthrough, the proportion of participants
with HBV flare (virologic, biochemical, and clinical) post end of treatment, and the proportion of
participants with sustained HBV response off-treatment after stopping JNJ-3989 treatment will be
tabulated by intervention arm over time.
The change in the liver fibrosis from baseline measured by LSM according to VCTE (FibroScan)
at end of JNJ-3989 treatment and during follow-up will be tabulated by intervention arm over time.
In addition, subgroup analyses will be conducted to evaluate the potential association between
treatment outcome and selected demographic and baseline characteristics (including but not
limited to age, presence of compensated cirrhosis at screening, HDV genotype, baseline values for
HDV RNA, ALT, and HBsAg, etc). Multivariate model analyses with exploration of interaction
terms might also be performed. The primary and key secondary efficacy endpoints, respectively,
will be analyzed by means of a logistic regression model. Exploratory descriptive summaries will
be displayed by subgroups with corresponding 95% CIs without multiplicity adjustment. Forest
plots will be used for the graphical displays. Subgroup analyses, as exploratory, might be
conducted on Part 2 data alone as well as combined data (Part 1 and Part 2) to leverage the total
sample size of the entire study.
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The HBV blood markers such as HBsAg, HBeAg (for HBeAg-positive participants only), HBV
DNA during study intervention and follow-up will also be summarized and plotted in terms of
values and changes from baseline over time by intervention arm. The proportion of participants
with HBsAg, HBeAg (for HBeAg-positive participants only) and HBV DNA levels as well as
changes from baseline below/above different cut-offs will be analyzed as appropriate over time by
intervention arm. Time-to-event endpoints, such as time to reach HBsAg <1 IU/mL, will be
summarized based on Kaplan-Meier estimates in tables and graphs.
The proportion of participants who reach undetectability of HBV RNA and/or HBcrAg during the
study intervention and follow-up phases will also be tabulated by intervention arm. In addition,
time to undetectability will be summarized based on Kaplan-Meier estimates in tables and graphs.
Descriptive statistics on values and change from baseline in HBV RNA and HBcrAg levels will
be summarized by intervention arm.
Graphic data displays will also be used to summarize the efficacy data by intervention arm and
over time. In addition, the potential association between HBsAg and HDV RNA will be explored
graphically over time.
9.4.5. 
Resistance Analyses
The results of HBV and potentially HDV viral sequencing will be evaluated by the sponsor
virologist. Relevant changes of amino acid and/or nucleic acid variations (eg, substitutions) in the
HBV and/or HDV genomes will be tabulated and described. Additional exploratory
characterization of the HBV and/or HDV viral sequence and phenotype may be performed and
reported separately.
9.4.6. 
Safety Analyses
The Safety Analysis Set will be used for all safety analyses based on pooled data from Part 1 and
Part 2 of the study. In addition, selected safety analyses may be reported by study part. Such
descriptive analyses will be indicated in the SAP.
Safety will be evaluated by means of descriptive summaries of AEs, clinical laboratory tests,
ECGs, vital signs, and physical examinations. The safety analyses will be done for each analysis
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 (MedDRA). 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.
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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.
Clinical Laboratory Tests
Laboratory data will be summarized by type of 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 at baseline and for observed values and changes from baseline at each scheduled time
point. Frequency tabulations of the abnormalities will be made.
The ECG variables that will be analyzed are heart rate, PR interval, QRS interval, QT interval, and
corrected QT (QTc) interval corrected for heart rate according to Fridericia’s formula (QTcF).14
The percentage of participants with QTc interval >450 milliseconds, >480 milliseconds, or
>500 milliseconds will be summarized, as will the percentage of participants with QTc interval
increases from baseline >30 milliseconds or >60 milliseconds. 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, body weight, 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.
9.4.7. 
Other Analyses
9.4.7.1. 
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
(ie, JNJ-73763924 and JNJ-73763976).
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Population PK analysis of concentration-time data of JNJ-73763976 and JNJ-73763924 may be
performed using non-linear mixed effects modeling. Data may be combined with selected Phase 1
and/or 2 studies to support a relevant structural model. 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-73763976 and JNJ-73763924, and may 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. Available
participant characteristics (eg, demographics, laboratory variables, genotypes) will be included in
the model as necessary. Details will be given in a population PK analysis plan and results of the
population PK analysis, if applied, will be presented in a separate report.
9.4.7.2. 
Pharmacokinetic/Pharmacodynamic Analyses
Relationships of PK parameters for JNJ-3989 (JNJ-73763976 and JNJ-73763924), with selected
efficacy and safety endpoints may be evaluated and graphically displayed, if applicable.
Modeling of key PD parameters (eg, HBsAg, HDV RNA) may be performed using population
PK/PD. If PK/PD modeling of key efficacy endpoints is performed, treatment effect and possible
covariates may be investigated. Other biomarkers may be explored at the sponsor’s discretion.
Details will be described in a population PK/PD analysis plan and results of the PK/PD analysis,
if applied, will be presented in a separate report.
9.4.7.3. 
Immune Analyses
Descriptive statistics (n, mean, SD, CV, geometric mean, median, minimum, and maximum) may
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) may
also be tabulated for PBMCs during study intervention. The proportion (%) of patients with
positive responses based on the magnitude of the IFN-γ T-cell response or the percentage of CD4+
or CD8+ T-cells expressing one of the cytokines (eg, IL-2, TNF- α or IFN-γ) for at least 1 of the
HDV and HBV antigens as defined by ELISpot and/or ICS, respectively, may be determined.
9.4.7.4. 
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 (CSR) or a separate
report.
9.4.7.5. 
Host Biomarkers Analyses
Statistical approaches to explore correlations between clinical outcome and blood and liver
biomarkers vary and depend on the different data types of the applied technology platforms, as
well as on the extent of observed interindividual variability. Analyses will be conducted at the
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sponsor’s discretion, will always be under the sponsor’s supervision, and results will be presented
either in the CSR or a separate report.
9.4.7.6. 
Medical Resource Utilization
Medical resource utilization data will be descriptively summarized by intervention arm.
9.5. 
Interim Analyses
9.5.1. 
Interim Analyses of Study Part 1
During the double-blind phase of Part 1, 2 IAs will be conducted by the sponsor.
Part 1 IA1: One IA will be conducted after all participants of Part 1 have completed at least
Week 16 (or discontinued earlier) to allow a comprehensive review of ALT elevations observed
during treatment. An in-depth understanding of the kinetics of virological parameters (eg, HDV
RNA, HBsAg, HBV DNA, etc) is critical to interpret the observed ALT elevations and their pattern
over time, in light of preliminary understanding the benefit-risk ratio of the investigational regimen
in HDV-infected participants. The sponsor will become unblinded to Part 1 efficacy and safety
data for this IA to inform the decision of the Sponsor Committee for the initiation of Part 2 in
conjunction with the IDMC recommendations.
From the moment of data unblinding for Part 1 IA1 onwards, the sponsor will remain unblinded
to Part 1 data. The investigators, participants, site personnel, and operational sponsor team
members involved with the sites will remain blinded. For safety-related decisions, HDV RNA and
HBsAg data may be discussed with investigators on a case-by-case basis.
Part 1 IA2: A second IA will be conducted after all participants of Part 1 have completed at least
Week 48 visit (or discontinued earlier).
9.5.2. 
Interim Analysis of Study Part 2
The original protocol included an IA of Part 2 when all participants had reached Week 148 (EOT
or discontinued earlier). This IA of Part 2 was to be conducted to assess safety and evaluate the
time course of different disease markers and to support the sponsor’s interactions with health
authorities. Due to the decision to reduce the study duration of Part 2 and since interactions with
health authorities are no longer planned, the IA of Part 2 was removed per Protocol Amendment
5.
9.5.3. 
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 unblinded efficacy parameters measured by
HBV/HDV disease blood markers (eg, HDV RNA, HBV DNA, HBeAg, HBsAg) during the
double-blind phase. During the open-label phase, all data will be unblinded. When all participants
are in the open-label phase or discontinued earlier, the IDMC responsibilities will be covered by
the internal DRC (see Section 9.5.4).
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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 (see
Section 9.5.5), who will make the final decision(s). Possible recommendations of the IDMC
include, but are not limited to, continuing the study unchanged, stopping the study for safety
concerns, or for futility or make a study amendment.
The IDMC will consist of at least one medical expert in the relevant therapeutic area and at least
one statistician. The IDMC role and responsibilities, communication flow with other stakeholders,
and procedures will be documented in the IDMC charter.
9.5.4. 
Internal Data Review Committee
A DRC will be established for continuous monitoring of SAEs, AEs leading to discontinuation,
and ALT flares when all participants have completed double-blind phase and IDMC has completed
its review. This committee will consist of at least one medical expert in the relevant therapeutic
area (hepatology) and at least one statistician; committee membership responsibilities, authorities,
and procedures will be documented in the DRC charter. The committee will meet periodically to
review data of the efficacy parameters measured by different HBV and HDV disease blood
markers (eg, HDV RNA, HBV DNA, HBeAg, HBsAg, etc).
The DRC members will be appointed to review the interim data for both safety and efficacy and
formulate recommendation(s) to the Sponsor Committee (see Section 9.5.5), who will make the
final decision(s). DRC and Sponsor Committee members will not be involved in the study conduct.
Details on the roles and responsibilities of the DRC and Sponsor Committee, as well as the flows
of communication, will be documented in the DRC charter.
9.5.5. 
Sponsor Committee
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.
The Sponsor Committee will review selected efficacy and safety parameters to assess the
predefined antiviral activity criteria and decide to start Part 2 based on the results of the Part 1 IA1
(when all participants of Part 1 have completed at least Week 16 or discontinued earlier).
After Part 2 has commenced, all sponsor personnel, including the Sponsor Committee, will remain
blinded to subsequent IDMC data reviews during the double-blind phase. During the open-label
phase, all data will be unblinded. The efficacy monitoring will be conducted by the IDMC to
protect the well-being of the participants against unexpected absence of further HBV RNA decline
and/or HDV RNA rebound contrary to the initial antiviral activity criteria.
The criteria to trigger the start of Part 2 and to exclude futility will be defined in terms of the
antiviral activity as measured by a predefined threshold of HDV RNA and HBsAg reduction from
baseline and will be paired with an assessment of the benefit-risk ratio based on the Part 1 IA1
data. Details will be provided only in the SAP to protect the study integrity and minimize the
operational bias.
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9.5.6. 
Independent Flare Expert Panel
An IFLEP will be appointed. The IFLEP is composed of 3 independent medical experts with
experience and expertise in HBV/HDV. The responsibilities of the IFLEP include: conduct regular
review of all relevant and available individual participant blinded study data related to ALT flares;
determine and adjudicate each ALT flare; and provide documentation of the final decision to
IDMC. Adjudication review cycles will match IDMC schedule and will be set up prior to planned
IDMC review.
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 remain blinded to the treatment assigned to each
participant up to the time of Part 1 IA1, when the IFLEP will become unblinded to the Part 1 data.
In Part 2, the IFLEP will also be blinded to the treatment assigned to each participant up to
unblinding of the Part 2 clinical data.
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
AE 
adverse event
AESI 
adverse event of special interest
AFP  
alpha-fetoprotein
ALP  
alkaline phosphatase
ALT  
alanine aminotransferase
AST 
aspartate aminotransferase
BMI 
body mass index
bpm  
beats per minute
cccDNA  
covalently closed circular deoxyribonucleic acid
CHB  
chronic hepatitis B
CHD  
chronic hepatitis D
CI 
confidence interval
CKD-EPI 
Chronic Kidney Disease Epidemiology Collaboration
CL/F  
total apparent oral clearance
Cmax  
maximum plasma concentration
CRF  
case report form(s) (paper or electronic as appropriate for this study)
CV  
coefficient of variation
CYP  
cytochrome P450
DAIDS  
Division of Acquired Immunodeficiency Syndrome
DBP  
diastolic blood pressure
DNA  
deoxyribonucleic acid
DRC  
Data Review Committee
ECG  
electrocardiogram
eDC  
electronic data capture
eGFR  
estimated glomerular filtration rate
ELISpot 
enzyme-linked immunospot
EOS  
end of study
EOT  
end of treatment
ETV  
entecavir
FDA  
Food and Drug Administration
FNAB  
fine needle aspirate biopsy
FOIA  
Freedom of Information Act
FSH  
follicle-stimulating hormone
GCP  
Good Clinical Practice
HBc 
hepatitis B core protein
HBcrAg 
hepatitis B core-related antigen
HBe 
hepatitis B e
HBeAg 
hepatitis B e antigen
HBs 
hepatitis B surface
HBsAg 
hepatitis B surface antigen
HBV  
hepatitis B virus
HCC  
hepatocellular carcinoma
HCV  
hepatitis C virus
HDV  
hepatitis D virus
HEV  
hepatitis E virus
HIV(-1) (-2) 
human immunodeficiency virus (type 1) (type 2)
HRQOL 
Health-Related Quality of life
IA  
interim analysis
IB  
Investigator’s Brochure
ICE 
intercurrent event
ICF  
informed consent form
ICH  
International Conference on Harmonisation
ICMJE 
International Committee of Medical Journal Editors
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ICS  
intracellular cytokine staining
IDMC  
Independent Data Monitoring Committee
IEC  
Independent Ethics Committee
IFLEP  
Independent Flare Expert Panel
IFN  
interferon
IFN-γ 
gamma interferon
Ig 
immunoglobulin
IgM  
immunoglobulin M
IL 
interleukin
IMP  
Investigational Medicinal Product
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 quantitation
LSM  
liver stiffness measurement
MAR  
Missing At Random
MCS  
Mental Component Summary
MedDRA  
Medical Dictionary for Regulatory Activities
MRI 
magnetic resonance imaging
MRU  
medical resource utilization
NA  
nucleos(t)ide analog
NIMP  
Non-Investigational Medicinal Product
NOAEL 
no observed adverse effect level
PBMC  
peripheral blood mononuclear cell
PCS  
Physical Component Summary
PD 
pharmacodynamic(s)
PegIFN-α 
pegylated interferon-alpha
pgRNA  
pre-genomic ribonucleic acid
PK 
pharmacokinetic(s)
PQC  
Product Quality Complaint
Q4W  
every 4 weeks
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
SC 
subcutaneous
SD 
standard deviation
SoA  
Schedule of Activities
siRNA  
small interfering RNA
SUSAR  
suspected unexpected serious adverse reaction
TAF  
tenofovir alafenamide
TNF  
tumor necrosis factor
ULN 
upper limit of normal
US  
United States
VCTE 
vibration-controlled transient elastography
WBC  
white blood cell
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Definitions of Terms
Electronic source 
system  
Contains data traditionally maintained in a hospital or clinic record to document medical
care or data recorded in a CRF as determined by the protocol. Data in this system may be
considered source documentation.
HBsAg seroclearance 
HBsAg negativity based on the assay used
HBsAg 
seroconversion
HBsAg negativity and anti-HBs antibody positivity
Virologic 
breakthrough  
Confirmed on-treatment HBV DNA increase by >1 log10 IU/mL from nadir or confirmed
on-treatment HBV DNA level >200 IU/mL in participants who had HBV DNA level
<LLOQ of the HBV DNA assay
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10.3. Appendix 3: Regulatory, Ethical, and Study Oversight Considerations
10.3.1. 
Regulatory and Ethical Considerations
Investigator Responsibilities
The investigator is responsible for ensuring that the study is performed in accordance with the
protocol, current International Conference on Harmonisation (ICH) guidelines on Good Clinical
Practice (GCP), and applicable regulatory and country- or territory-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 must 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/territory, 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
Sponsor-approved ICF (and any other written materials to be provided to the participants)
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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
Report of deaths of participants under the investigator’s care
Notification if a new investigator is responsible for the study at the site
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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 ofthe
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 (if applicable, the notification will be submitted through the head of
investigational institution).
Country/Territory Selection
This study will only be conducted in those countries/territories 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.
10.3.2. 
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.
10.3.3. 
Informed Consent Process
Each participant must give 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
must 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 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
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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 must 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
must personally date and sign the ICF after the oral consent of the participant is obtained.
10.3.4. 
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 information  about, and where
required per applicable regulations, 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, and regulatory inspection.
The informed consent also provides information to address the lawful transfer of the data to other
entities and to other countries/territories.
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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, or make requests
concerning his or her personal data in accordance with applicable data protection law. 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.
In the event of a data security breach, the sponsor will apply measures to adequately manage and
mitigate possible adverse effects taking into consideration the nature of the data security breach as
necessary to address other obligations such as notifying appropriate authorities in accordance with
applicable data protection law.
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.
10.3.5. 
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 the NAs (ETV,
tenofovir disoproxil, and TAF), to understand chronic HBV/HDV co-infection, to understand
differential intervention responders, and to develop tests/assays related to JNJ-3989 and the NAs
(ETV, tenofovir disoproxil, and TAF) and chronic HBV/HDV co-infection. The research may
begin at any time during the study or during 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).
10.3.6. 
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 efficacy parameters measured by different HBV/HDV disease blood markers (eg, HDV
RNA, HBV DNA, HBeAg, HBsAg) during the double-blind phase. During the open-label phase,
all data will be unblinded. When all participants are in the open-label phase or discontinued earlier,
the IDMC responsibilities will be covered by the internal DRC.
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.
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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.
Internal Data Review Committee
A DRC will be established for continuous monitoring of SAEs, AEs leading to discontinuation,
and ALT flares when all participants have completed double-blind phase and IDMC has completed
its review. This committee will consist of at least one medical expert in the relevant therapeutic
area (hepatology) and at least one statistician; committee membership responsibilities, authorities,
and procedures will be documented in the DRC charter. The committee will meet periodically to
review data of the efficacy parameters measured by different HBV and HDV disease blood
markers (eg, HDV RNA, HBV DNA, HBeAg, HBsAg, etc).
The DRC members will be appointed to review the interim data for both safety and efficacy and
formulate recommendation(s) to the Sponsor Committee, who will make the final decision(s). The
Sponsor Committee includes representatives from the sponsor’s Clinical, Biostatistics, Global
Medical Safety, and Virology departments. DRC and Sponsor Committee members will not be
involved in the study conduct. Details on the roles and responsibilities of the DRC and Sponsor
Committee, as well as the flows of communication, will be documented in the DRC charter.
Independent Flare Expert Panel
An IFLEP will also be appointed. The IFLEP is composed of 3 independent medical experts with
experience and expertise in HBV/HDV. 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 up to the time of Part 1 IA1, when the IFLEP will become unblinded to the Part 1 data.
In Part 2, the IFLEP will also be blinded to the treatment assigned to each participant up to
unblinding of the Part 2 clinical data.
Further details on the IFLEP process will be included in the IFLEP charter.
10.3.7. 
Publication Policy/Dissemination of Clinical Study Data
All information, including but not limited to information regarding JNJ-3989 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 the goals ofthis 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 thus may be disclosed as
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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 (CSR) 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 CSR has been issued
will be reported in a separate report and will not require a revision of the CSR.
Study participant identifiers will not be used in the 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 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.
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Registration of Clinical Studies and Disclosure of Results
The sponsor will register and disclose the interim results of clinical studies as required by law. The
disclosure of the study results will be performed after the EOS  in order to ensure the statistical
analyses are relevant.
10.3.8. 
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.
10.3.9. 
Case Report Form Completion
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 must 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:
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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.
10.3.10. 
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 the assessment by the investigator 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 must 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).
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
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eSource system but information collected through eSource may not be limited to that found in the
CRF.
10.3.11. 
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 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.
10.3.12. 
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 must immediately notify the sponsor if he or she has been
contacted by a regulatory agency concerning an upcoming inspection.
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10.3.13. 
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.
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.
10.3.14. 
Study and Site Start and Closure
First Act ofRecruitment
The first potential participant screened is considered the first act of recruitment and it becomes the
study start date.
Study/Site 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.
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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, Serious Adverse Events, Product Quality
Complaints, and Other Safety Reporting: Definitions and Procedures for
Recording, Evaluating, Follow-up, and Reporting
10.4.1. 
Adverse Event Definitions and Classifications
Adverse Event
An AE is any untoward medical occurrence in a clinical study participant administered a
pharmaceutical (investigational or non-investigational) product. An adverse event does not
necessarily have a causal relationship with the intervention. An adverse event 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 adverse event recording).
Serious Adverse Event
A serious adverse event based on ICH and EU 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 judgement must 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.
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If a serious and unexpected adverse event occurs for which there is evidence suggesting a causal
relationship between the study intervention and the event (eg, death from anaphylaxis), the event
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 adverse event is considered unlisted if the nature or severity is not consistent with the applicable
product reference safety information. For JNJ-3989, the expectedness of an adverse event will be
determined by whether or not it is listed in the IB. For ETV, tenofovir disoproxil, and TAF with a
marketing authorization, the expectedness of an adverse event will be determined by whether or
not it is listed in the local prescribing information.
10.4.2. 
Attribution Definitions
Assessment of Causality
The causal relationship to study intervention is assessed by the investigator and documented in the
Medical Records.
The assessment of causality must consider the following factors:
Temporal relationship
Clinical characteristics of event
Pharmacological plausibility
Confounding risk factors:
Concomitant medication
Underlying/concurrent disease
Family/social history
Challenge:
De-challenge: Did the reaction improve when the investigational product was withdrawn,
in the absence of any other treatment?
Re-challenge: What happens if participant is re-challenged with investigational product?
Other considerations: Participant characteristics and past medical history, and quality of
information
The following selection must be used to assess all AEs.
Related
There is a reasonable causal relationship between study intervention administration and the AE.
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Not Related
There is not a reasonable causal relationship between study intervention administration and the
AE.
10.4.3. 
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).
The investigator must use clinical judgement in assessing the severity of events not directly
experienced by the participant (eg, laboratory abnormalities).
10.4.4. 
Special Reporting Situations
Safety events of interest on a sponsor study intervention in an interventional studythat 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, intercepted medication error, or potential medication error involving a
Johnson & Johnson medicinal product (with or without patient exposure to the Johnson &
Johnson medicinal product, eg, product name confusion, product label confusion, intercepted
prescribing or dispensing errors)
Exposure to a sponsor study intervention from breastfeeding
Reporting of participant pregnancy or participant partner(s) pregnancy
Special reporting situations must be recorded in the CRF. Any special reporting situation that
meets the criteria of an SAE must be recorded on the serious adverse event page of the CRF.
10.4.5. 
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
adverse event to study therapy. All measures required for adverse event 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:
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Study number
Statement, in the local language(s), that the participant is participating in a clinical study
Investigator's name and 24hour 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
Serious Adverse Events
All SAEs that have not resolved by the end of the study, or that have not resolved upon  the
participant's discontinuation from 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)
Any event requiring hospitalization (or prolongation of hospitalization) that occurs during
participation in the study must be reported as a serious adverse event, except hospitalizations for
the following:
Hospitalizations not intended to treat an acute illness or adverse event (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 ICF, and where the
underlying condition for which the hospitalization was planned has not worsened, will not be
considered SAEs. Any adverse event that results in a prolongation of the originally planned
hospitalization is to be reported as a new serious adverse event.
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 a serious adverse event.
Information regarding SAEs will be transmitted to the sponsor using a serious adverse event
reporting form, which must be completed and signed by a physician from the study site, and
transmitted in a secure manner to the sponsor within 24 hours. The initial and follow-up reports of
a serious adverse event should be made by facsimile (fax). Telephone reporting should be the
exception and the reporter should be asked to complete the appropriate form(s) first.
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10.4.6. 
Product Quality Complaint Handling
Definition
A 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, reliability, or
performance of a distributed product, including its labeling, drug delivery system, or package
integrity. A PQC may have an impact on the safety and efficacy of the product. In addition, it
includes any technical complaints, defined as any complaint that indicates a potential quality issue
during manufacturing, packaging, release testing, stability monitoring, dose preparation, storage
or distribution of the product or the drug delivery system.
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.
A sample of the suspected product should be maintained under the correct storage conditions until
a shipment request is received from the sponsor.
10.4.7. 
Contacting Sponsor Regarding Safety, Including Product Quality
The names (and corresponding telephone numbers) of the individuals who must be contacted
regarding safety issues, PQC, or questions regarding the study 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 3: 
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
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Table 3: 
Management of Rash Events by Severity Grade
Definition 
Study
Intervention
Action
Activities by Daya
Referral to
Dermatologist and
Dermatology Activities
Grade 2 
rash 
(with or 
without 
pruritus)b 
Diffuse, 
maculopapular rash, or 
dry desquamation  
Study intervention
intake may be
continued at the
investigator’s
discretion
Day 0: required on-site visit (if a visit is not possible, telephone contact
with the participant should take place to collect information and give
advice on the necessary measures to be taken).
Safety laboratory assessments may be performed at the investigator’s
discretion (recommended).
Digital 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.
Referral to
dermatologist at the
discretion of the
investigatorc
Biopsy not required, but
may be performed at the
dermatologist’s
discretion
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Table 3: 
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 
ALT/AST 
>2×baseline value 
- Fever >38°C or 
100°F
- Eosinophils
>1.00×103/µL
- Serum sickness-
like reaction
Must permanently
discontinue
JNJ-3989; 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 3: 
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; 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 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.
Note:
Local laboratory assessments are to be used for rash management. Relevant laboratory assessment values are to be shared with the sponsor (if applicable and local
regulations allow) as per the “Instructions for Investigators for sharing of Digital Pictures and Local lab reports” and should be de-identified.
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
Note: please refer to Section 8.3.6.1, Intervention-emergent ALT/AST Elevations.
a: Additional tests may be considered based on clinical judgement in case of confirmed ALT flares
- Hepatitis A, 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
Appendix 4: Adverse Events, Serious Adverse Events, Product Quality Complaints, and Other
Safety Reporting: 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 follicle-stimulating hormone (FSH) level (>40 IU/L or mIU/mL) in the
postmenopausal range may be used to confirm a postmenopausal state in women not using
hormonal contraception or hormonal replacement therapy (HRT), however in the absence of
12 months of amenorrhea, a single FSH measurement is insufficient. 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 (for the purpose of this study)
Permanent sterilization methods include hysterectomy, bilateral salpingectomy, bilateral
tubal occlusion/ligation procedures, and bilateral oophorectomy.
Has congenital abnormalities resulting in sterility.
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 must 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 FOR MALE OR FEMALE
PARTICIPANTS DURING THE STUDY INCLUDE:
USER INDEPENDENT
Highly Effective Methods That Are User Independent Failure rate of <1% per year when used
consistently and correctly.
Implantable progestogen-only hormone contraception associated with inhibition of ovulation
Intrauterine device (IUD)
Intrauterine hormone-releasing system (IUS)
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 must be used.
Spermatogenesis cycle is approximately 74 days.)
USER DEPENDENT
Highly Effective Methods That Are User Dependent Failure rate of <1% per year when used
consistently and correctly.
Combined (estrogen- and progestogen-containing) hormonal contraception associated with
inhibition of ovulation
- oral
- intravaginal
- transdermal
- injectable
Progestogen-only hormone contraception associated with inhibition of ovulation
- oral
- injectable
Sexual abstinence
(Sexual abstinence is considered a highly effective method only if defined as refraining from
heterosexual intercourse during the entire period of risk associated with the study intervention.
The reliability of sexual abstinence needs to be evaluated in relation to the duration of the study
and the preferred and usual lifestyle of the participant.)
NOT ALLOWED METHODS UNLESS USED TOGETHER WITH HIGHLY EFFECTIVE
METHODS 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 spermicideb
Cap, diaphragm, or sponge with spermicide
A combination of male condom with either cap, diaphragm, or sponge with spermicide (double-
barrier methods)b
Periodic abstinence (calendar, symptothermal, post-ovulation methods)
Withdrawal (coitus-interruptus)
Spermicides alone
Lactational amenorrhea method (LAM)
a) Typical use failure rates may differ from those when used consistently and correctly. Use must be consistent
with local regulations regarding the use of contraceptive methods for participants in clinical studies.
b) Male condom and female condom must 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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10.10. Appendix 10: COVID-19 APPENDIX
10.10.1. 
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 to 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.
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
CSR.
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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/territory-specific regulatory requirements.
Screening and Randomization
Enrollment of new participants may continue based on the investigator’s assessment of risks
versus benefits, depending on the situation at a particular site, and the ability to monitor
participant safety.
Baseline visits for participants recently screened for this study should be postponed if the
current situation does not allow for an orderly conduct of the study.
Dispensing/Administration of Study Intervention
For participants able to visit the study site, but who request to reduce visit frequency, or for
whom limited access to the site is expected, an additional supply of oral study intervention can
be provided.
For participants unable to visit the study site, direct-to-patient (DTP) shipment or handover to
a caregiver or delegate of oral study intervention may be implemented, where allowed per local
regulations and if requested by the investigator. Where DTP shipments or handover to
delegates are deemed necessary, the process must be coordinated between the site and sponsor
staff following standard DTP procedures for arranging shipment and adhering to associated
approvals and documentation requirements.
JNJ-3989/placebo should always be administered at the study site or, if site visits are not
possible, at the participant’s home (in consultation with the sponsor and taking into
consideration participant safety). Of note, 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 a participant’s safety is considered at risk due to
study intervention, study intervention will be temporarily or permanently discontinued, while
every effort should be made to maintain follow-up on study. The benefit of continuing study
intervention should be assessed by the investigator for each individual participant, considering
the potential impact of reduced direct clinical supervision on participant safety.
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- If a participant develops a 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. Study intervention must be discontinued
if prohibited medication is used.
When a participant, for whom study intervention has been interrupted, recovers from
suspected or confirmed SARS-CoV-2 infection or related disease and all AEs related to
SARS-CoV-2 infection improve to Grade ≤1, the investigator should discuss with the
sponsor about resuming study intervention.
COVID-19 vaccination during the study:
Locally approved COVID-19 vaccines (including those that received emergency use authorization
or conditional marketing authorization) are allowed throughout the study.
All COVID-19 vaccination-related data (eg, COVID-19 vaccination, AEs, AE management)
should be appropriately captured in the CRF and source documents. Refer to the COVID-19
vaccine prescribing information for more details.
Study Visits and Assessments
If possible, central laboratory testing as outlined in the Schedule of Activities is to be
continued. If central laboratory tests cannot be performed, the use of a local laboratory is
allowed for study evaluations. A copy of the local laboratory report should be reviewed by the
investigator and filed with the source documents, along with reference ranges; to maintain
treatment blinding, HBV/HDV RNA, HBsAg, HBeAg, HBcrAg, 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)
JNJ-3989/placebo administration
Delivering oral study interventions
Any data related to AE, concomitant medication, vital signs, and ECGs will be reviewed and
assessed by the investigator.
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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 AEs (including injection site reactions), concomitant medications, study intervention
accountability. Key efficacy endpoint assessments should be performed as required and as
feasible. Participants will also be questioned regarding general health status to fulfill any
physical examination requirement. Procedures and timings should follow the Schedule of
Activities as closely as possible. Standard Adverse Event/Serious Adverse Event reporting
requirements apply.
Informed Consent
Consenting and re-consenting of participants for the measures taken (including also remote
consenting by phone or video consultation) will be performed as applicable and according to
local guidance for informed consent applicable during the COVID-19 pandemic. The process
is to be documented in the source documents.
Source Data Verification/Monitoring
In case on-site monitoring visits are not possible, the site monitor may contact the investigator
to arrange monitoring visits and activities remotely  (in accordance with site and local
requirements). Additional on-site monitoring visits may be needed in the future to catch up on
source data verification.
Site Audits
During the COVID-19 pandemic and at the impacted sites, study site GCP audits with direct
impact/engagement from the investigator and study site personnel would not be conducted in
order to comply with national, local, and/or organizational social distancing restrictions.
Additional quality assurance activities such as remote audits or focused review of study
related documents may take place with limited impact/engagement if possible.
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10.11. Appendix 11: Protocol Amendment History
The Protocol Amendment Summary of Changes Table for the current amendment is located
directly before the Table of Contents (TOC).
Amendment 4 (7 April 2023)
Overall Rationale for the Amendment:
Based on the observation that in Part 2 ofthe REEF-D study significant ALT elevations were more
frequently observed in participants with HBsAg levels >10,000 IU/mL at screening or at baseline
(irrespective of HDV RNA levels), a temporary halt of new enrollment into the study was
implemented in December 2022. Since there was no immediate risk to the safety of participants
already enrolled in the trial, treatment and monitoring of ongoing participants was continued as
per current protocol.
In February 2023, the Sponsor has taken the strategic decision to discontinue further investment
in its hepatitis B and D discovery and development programs. In light of this wider decision, which
was not driven by safety concerns with JNJ-73763989 (JNJ-3989), enrollment of new participants
into the REEF-D study will not be re-opened.
The overall reason for this amendment is to continue the study in a modified way for participants
already enrolled and to describe the reduced sample size in the study. Per IDMC recommendation,
it was added that in Part 2, participants with HBsAg values >10.000 IU/mL at screening or
baseline, who were assigned to Arm 1 (placebo), will not roll-over to the open-label phase and will
enter the follow-up phase. In addition, the stopping criteria for nucleos(t)ide analog(NA) treatment
at Week 144/148 have been updated upon HA request.
The changes made to the clinical protocol 73763989HPB2004 as part of Protocol Amendment 4
are listed below, including the rationale of each change and a list of all applicable sections.
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Section number
and Name
Description of Change 
Brief Rationale
1.1 Synopsis
1.2 Schema
4.1 Overall Design
4.2 Scientific Rationale for
Study Design
6.3 Measures to Minimize
Bias: Randomization and
Blinding
7.1 Discontinuation of
Study Intervention
9.2 Sample Size
Determination
9.4.1 General
Considerations
9.4.2.2 Analysis of The
Main Estimator
9.5.2 Interim Analysis of
Study Part 2
9.5.3 Independent Data
Monitoring Committee
The sample size of Part 2 was reduced. The
sample size re-estimation and related interim
analysis during the double-blind phase of
Part 2 were removed.
Figure 1 was updated to reflect the reduced
sample size in Part 2 of the study.
After the temporary halt of
enrollment, the sponsor decided
to not re-open enrollment and to
continue the study in a modified
way, ie, with reduced sample
size.
1.1 Synopsis
3 Objectives and Endpoints
4.1 Overall Design
8.1.1 HBV and HDV
Genotyping and Sequencing
9.1 Statistical Hypotheses
9.4.2.2 Analysis of The
Main Estimator
9.4.3 Key Secondary
Endpoints
9.4.4. Other Efficacy
Endpoints
9.4.7.2 Pharmacokinetic/
Pharmacodynamic Analyses
9.4.7.3 Immune Analyses
The study was changed from confirmatory to
descriptive.
It was clarified that, if possible, the proportion
of responders will be compared between the 2
arms using the stratum-adjusted
Mantel-Haenszel test on the difference of
proportions.
Several analyses were now made optional, ie,
subgroup analyses,
pharmacokinetic/pharmacodynamic analyses,
viral genome sequence analysis, and immune
analyses.
The study will be continued in a
modified way, ie, with reduced
sample size and reduced
statistical analyses.
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Section number
and Name
Description of Change 
Brief Rationale
1.1 Synopsis
1.3 Schedule of Activities
3 Objectives and Endpoints
8 Study Assessments and
Procedures
8.1.3 Patient Reported
Outcomes
9.4.6 Patient Reported
Outcomes (PRO)
10.10: Appendix 10:
Hepatitis B Quality of Life
Instrument
10.11 Appendix 11: Short
Form 36 version 2 (SF
36v2) 2010 Questionnaire
10.12 Appendix 12: 5 Level
EuroQol 5 Dimension
Questionnaire (EQ 5D 5L)
10.13.1 Guidance on Study
Conduct During the
COVID 19 Pandemic
10.13.2 Interview Version
of the Short Form 36
version 2 (SF 36v2) 2010
Questionnaire
10.13.3 Interview Version
of the 5 Level EuroQol
5 Dimension Questionnaire
(EQ5D5L)
PRO evaluations were removed. 
The study will be continued in a
modified way, ie, with reduced
sample size and reduced study
assessments.
1.1 Synopsis
1.3.3 Schedule of Activities
–Follow-up Phase
2.3.3 Benefit-risk
Assessment for Study
Participation
4.1 Overall Design
6.4 Study Intervention
Compliance
6.5 Re-treatment With NA
During the Follow-up Phase
6.6 Continued Access to
Study Intervention After the
End of the Study
8.3.6.1 Intervention-
emergent ALT/AST
Elevations
The re-treatment option for JNJ-3989 during
the follow-up phase was removed.
Removal of the posttrial access commitment
for JNJ-3989.
Sponsor has taken the strategic
decision to discontinue further
investment in its hepatitis B and
D discovery and development
programs (this decision was not
driven by safety concerns with
JNJ-3989). As the shelf life of
currently available batches is
limited, re-treatment with
JNJ-3989 during the follow-up
phase and posttrial access cannot
be offered.
2.3.3 Benefit-risk
Assessment for Study
Participation
7.1 Discontinuation of
Study Intervention
It was added that in Part 2, participants with
HBsAg values >10.000 IU/mL at screening or
baseline, who were assigned to Arm 1
(placebo), will not roll-over to the open-label
phase and will enter the follow-up phase.
Per IDMC recommendation to
protect the safety of the
participants.
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Section number
and Name
Description of Change 
Brief Rationale
1.1 Synopsis
1.3.2 Schedule of Activities
–Open-label Study
Intervention Phase (Weeks
52 –EOT)
1.3.3 Schedule of Activities
–Follow-up Phase
2.3.3 Benefit-Risk
Assessment for Study
Participation
4.1 Overall Design
4.2 Scientific Rationale for
Study Design
6.5 Re-treatment With
JNJ-3989 and/or NA During
the Follow-up Phase
The NA stopping criteria for non-cirrhotic
participants during the follow-up phase were
updated: 2 criteria were included in addition
to HBsAg seroclearance, ie ALT <3x ULN
and HBV DNA <LLOQ have to be achieved
to consider NA cessation.
Upon HA request, the stopping
criteria for NA treatment at
study Week 144/148 were
updated.
1.1 Synopsis
9.5.2 Interim Analysis of
Study Part 2
The number of interim analyses during the
open-label and follow-up phase of Part 2 was
reduced: the interim analysis at Week 96 in
the open-label phase and at Week 24 in the
follow-up phase were removed.
The remaining interim analysis
in the open-label phase of Part 2
at Week 148 (end of treatment),
in addition to the final analysis
(in the follow-up phase at
Week 48), provides sufficient
information to assess safety and
evaluate the time course of
different disease markers during
study conduct.
1.1 Synopsis
2.3.3 Benefit-risk
Assessment for Study
Participation
6.3 Measures to Minimize
Bias: Randomization and
Blinding
8.3.6.1 Intervention-
emergent ALT/AST
Elevations
It was added that in case of IWRS participant
unblinding and if the investigator requires to
be unblinded in case of an emergent safety
event (ie, study intervention discontinuation
due to ALT flares) to allow further treatment
of the participant, a sponsor request can be
made to have the investigator and sponsor
unblinded to all HDV RNA and HBsAg data
from the double‑blind phase.
To provide access of the double-
blind phase laboratory data for
HDV RNA and HBsAg to the
investigator if required for
medical/clinical patient
management.
4.1 Overall Design
6.3 Measures to Minimize
Bias: Randomization and
Blinding
8.1 Efficacy Assessments
It was added that when a participant has
completed the Week 48 visit or discontinued
earlier, the investigator, site personnel,
Sponsor, and participant will be unblinded for
treatment allocation and all laboratory data,
including HDV RNA and HBsAg data.
To provide access of the
double-blind phase laboratory
data for HDV RNA and HBsAg
when a participant has
completed the Week 48 visit or
has discontinued earlier. This
allows for a evaluation of the
effect of treatment or placebo on
HBV RNA and HBsAg on a
participant level for clinical
management.
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Section number
and Name
Description of Change 
Brief Rationale
1.1 Synopsis
2.3.3 Benefit-risk
Assessment for Study
Participation
4.1 Overall Design
6.3 Measures to Minimize
Bias: Randomization and
Blinding
8.2 Safety Assessments
9.5.3 Independent Data
Monitoring Committee
9.5.4 Internal Data Review
Committee
9.5.5 Sponsor Committee
9.5.6 Independent Flare
Expert Panel
10.3.6 Committees
Structure
Continuous monitoring of SAEs, AEs leading 
to discontinuation, and ALT flares and review  
ofunblinded efficacy parameters measured by  
HBV/HDV disease blood markers during the 
double-blind phase will be conducted by the
IDMC. When all participants enter in the
open-label phase, the IDMC responsibilities
will be covered by the internal DRC.
A description of the DRC was added to the
protocol.
It was added that in Part 2, the IFLEP will
also be blinded to the treatment assigned to
each participant up to unblinding of the Part 2
clinical data.
After unblinding of all data in
the open-label phase, there is no
need for a blinded data review
anymore.
1.1 Synopsis
1.3 Schedule of Activities
3 Objectives and Endpoints
8.4 Pharmacokinetics
8.4.1 Evaluations
8.4.2 Analytical Procedures
8.4.3 Pharmacokinetic
Parameters and Evaluations
8.5
Pharmacokinetics/Pharmaco
dynamics
8.4.7.1 Pharmacokinetic
Analyses
9.4.7.2
Pharmacokinetics/Pharmaco
dynamics Analyses
The blood sampling for sparse PK of NA and
blood sampling for intensive PK (PK
subgroup) was removed. Only blood sampling
for sparse PK of JNJ-3989 was kept. The
PK/PD analyses are now optional.
To reduce the burden for the
participants.
1.1 Synopsis
1.3 Schedule of Activities
8.6 Immune Assessments
9.4.7.3 Immune Analyses
A reduction in the number of samples for
immune monitoring (immune cells [PBMCs])
was 
implemented 
(ie, 
reduction 
from
9 timepoints to 2 timepoints [ie, the Day 1 and
Week 48 visits] for sample collection).
It was clarified that additional PBMC samples
may be taken until Week 48 in case of ALT
flares.
To reduce the burden for the
participants.
1.1 Synopsis
1.3 Schedule of Activities
4.1 Overall Design
8.7 Host Genetics
9.4.7.4 Pharmacogenomic
Analyses
The collection of pharmacogenomic samples
for epigenetic research was removed.
To reduce the burden for the
participants.
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Section number
and Name
Description of Change 
Brief Rationale
1.1 Synopsis
1.3.1 Schedule of Activities
–Screening and Double-
blind Study Intervention
Phase (First 48 Weeks)
8.1.2 Liver Biopsy and Fine
Needle Aspirate Biopsy
(Optional with Separate
Consent, Part 2 Only)
Removal of the optional biopsy sample
collections at an unscheduled visit.
To reduce the burden for the
participants.
1.3 Schedule of Activities 
8.8 Host Biomarkers 
The separate lines for host serum protein
sample collection were removed from the
SoA. It was explained in a footnote that
exploratory serology samples may be used for
host serum protein testing as well.
To reduce the burden for the
participants.
1.3 Schedule of Activities 
A reduction in the number of samples for HBV
and HDV virology and serology was
implemented.
The collection of exploratory biomarker
samples for whole blood RNA gene expression
and whole blood single cell profiling was
removed.
To reduce the burden for the
participants.
7.1 Discontinuation of 
Study Intervention  
It was clarified that participants of the placebo
group who develop cirrhosis at the end of the
double-blind phase (based on the Week 48
FibroScan assessment) will not be eligible to
receive JNJ-3989 during the open-label and
follow-up phase.
To protect the safety of the
participants.
1.3.1 Schedule of Activities 
–Screening and Double- 
blind Study Intervention
Phase (First 48 Weeks)
2.3.3 Benefit-Risk
Assessment for Study
Participation
The requirement for a platelet aggregation test
before FNAB collection was removed.
The platelet aggregation test is
not part of the recommended pre
fine needle aspiration work-up.
Clinical data shows no changes
in platelet numbers or function
after treatment with JNJ-3989.
1.1 Synopsis
1.3.1 Schedule of Activities
–Screening and Double-
blind Study Intervention
Phase (First 48 Weeks)
8.1 Efficacy Assessments
In addition to the qualitative anti-HDV
antibody test, semi-quantitative IgM and total
anti-HDV antibody data may be generated as
well.
To clarify that semi-quantitative
data for anti-HDV IgM and total
antibody may be obtained in
addition to the qualitative test
result.
1.3 Schedule of Activities 
The study protocol was updated to allow, in
addition to evaluation of HBV, evaluation of
virologic or serologic markers of HDV,
including total anti-HDV antibodies and anti-
HDV IgM antibodies throughout the study.
To clarify that exploratory
Hepatitis D related tests are
within the scope of this study.
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Section number 
and Name
Description of Change 
Brief Rationale
1.3 Schedule of Activities 
The language in footnotes a (for the double- 
blind phase, open-label phase, and follow-up
phase SoA) was adapted to reflect that an
early withdrawal visit should be scheduled as
soon as possible and that in case these
participants continue in the follow-up phase,
the follow-up visits can be scheduled based on
the withdrawal visit date.
Clarification.
2.3.1.2 Potential Risks 
It was added that also in Part 2 a more 
sustained pattern of ALT elevations was
observed and that in Part 2 of the study, the
risk ofALT elevations was higher in
participants with HBsAg levels >10,000
IU/mL at screening or baseline, and that a
causal relationship between JNJ-3989 and
ALT elevations is suspected, although the
mechanism for this type of confirmed ALT
elevations is not yet understood.
Clarification and update.
4.2.1 Study-specific Ethical 
Design Considerations 
Updated that 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, ie,
less than standard blood donation based upon
recommendations of the World Health
Organization, ie, 450 mL ± 10% for
participants weighing at least 50 kg over a
period of 12 weeks for male participants and
16 weeks for female participants, instead of
based upon the standard of the American Red
Cross.
Previous reference not valid
anymore.
7.2.1 Withdrawal From the 
Use of Research Samples 
For participants who withdraw consent for 
optional research samples (ie, host DNA 
samples), it was clarified that previously 
collected samples may be requested to be 
destructed, in which case no further use of the
samples will take place.
To clarify what to do with the
collected research samples in
case of withdrawal of consent
(aligned with ICF language).
8 Study Assessments and
Procedures
Updated that the maximum amount of blood
drawn from each participant in this study and
during the follow-up phase will not exceed
3,210 mL. Added that with the removal of
several sample collections, the amount of
blood drawn, and the total blood volume
needed will be less.
Updated to reflect removal of
several sample collections.
8.3 Adverse Events, Serious
Adverse Events, and Other
Safety Reporting
It was clarified that all reported AEs will be
coded according to MedDRA, with specific
examples regarding ‘alanine aminotransferase
increased’, ‘hepatitis B reactivation, and ‘viral
load increased’.
Clarification upon HA request
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Section number
and Name
Description of Change 
Brief Rationale
8.3.6.2 Rash
10.5 Appendix 5: Rash
Management
The sentence ‘The values of the local
laboratory assessments need to be transcribed
in the CRF by the study site personnel.’ Has
been replaced by ‘Relevant laboratory
assessment values are to be shared with the
sponsor (if applicable and local regulations
allow) as per the “Instructions for
Investigators for sharing of Digital Pictures
and Local lab reports” and should be de-
identified.’
Clarification.
1.1 Synopsis 
8.3.6.1 Intervention- 
emergent ALT/AST 
Elevations 
Re-insertion of the sentence: ‘The participant
will be monitored (laboratory testing of ALT,
AST, ALP, bilirubin [total and direct], INR,
albumin, HBV DNA, and HDV RNA) on a
weekly basis or more frequently until ALT
and/or AST levels have returned to 50% of the
maximal value.’.
Inadvertently deleted in
Amendment 3.
5.2 Exclusion Criteria 
The unit of platelet count was corrected in
exclusion criterion 7: /µL instead of /dL.
Correction ofan error.
7.1 Discontinuation of 
Study Intervention  
‘placebo’ was added as part of the
investigational study interventions to be
discontinued in case of compliance with the
listed criteria.
To correct that study
intervention discontinuation
applies to both JNJ-3989 and
placebo.
2.2 Background
2.3 Benefit-risk Assessment
8.3.6.5 Hematologic
Abnormalities
Sections were updated with the latest data
from the Investigator’s Brochure Edition 7.
To reflect the most up-to-date
info for background and benefit-
risk assessment.
1.3 Schedule of Activities
5.1 Inclusion Criteria
A note was added to clarify that if FibroScan
is not available at the study site, acoustic
radiation force impulse (ARFI) may be used at
screening.
To clarify that participants can
be enrolled using ARFI instead
of FibroScan to rule out liver
cirrhosis.
1.3.1 Schedule of Activities
–Screening and Double-
blind Study Intervention
Phase (First 48 Weeks)
1.3.2 Schedule of Activities
–Open-label Study
Intervention Phase (Weeks
52 –EOT)
The language on the quantitative HBeAg
assessment in footnotes dd (from the
double-blind phase SoA) and r (from the
open-label phase SoA) was aligned with
footnote t (from the follow-up phase SoA).
To align language throughout
the protocol.
6.7 Concomitant Therapy
10.10.1 Guidance on Study
Conduct During the
COVID-19 Pandemic
‘prescribing information’ was added to the
sentence ‘Refer to the COVID-19 vaccine
prescribing information for more details’.
For completeness.
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Section number 
and Name
Description of Change 
Brief Rationale
Throughout the protocol 
Changes to align with the sponsor’s current 
protocol template wording. 
Update to the most recent
template.
Throughout the protocol 
Minor grammatical, formatting, or spelling 
changes were made.
Minor errors were noted.
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Amendment 3 (6 December 2021)
Overall Rationale for the Amendment: Based on Part 1 interim study data, the sponsor in
consultation with IDMC has decided to start enrollment into Part 2 of the study. The
inclusion criteria for the participant population for Part 2 of the study have been updated.
In addition, the JNJ-3989 stopping criteria in case of ALT elevation have been updated for
Part 1 and Part 2 of the study. The Sponsor provided additional guidance to continue NA
treatment until the last study visit.
Based on review of the HBsAg and HDV RNA data, the Sponsor determined that the predefined
antiviral activity criteria for start of Part 2 of the study were met. In consultation with the IDMC
and based on review of the antiviral activity and safety data, it was decided to open Part 2 of the
study with changes to the inclusion criteria and to the safety management criteria for AST and/or
ALT increases.
Part 1 interim data showed that one group of patients experienced no/minimal ALT elevations
(<3x ULN) and had pronounced and consistent reductions of HDV RNA (1 to 3 log10 IU/mL at
last available time point in the Part 1 interim data). In patients with ALT flare (>3x ULN), the
HDV RNA kinetics were less consistent and did not show a clear benefit in terms of HDV RNA
decline in all of those patients.
Given the prolonged ALT  elevation seen in Part 1 of the study, mainly in participants with
compensated cirrhosis, and the reduced functional hepatic reserve in patients with cirrhosis, the
Sponsor decided that participants with liver cirrhosis will be excluded from Part 2 of the study.
Part 1 interim data showed a trend for a higher rate of ALT elevations in participants with high
HDV RNA and HBsAg baseline levels. To reduce the risk of experiencing ALT flares, the Sponsor
has updated the inclusion criteria for HBsAg and HDV RNA levels in Part 2 of the REEF-D study
to select participants with lower risk for potential occurrence of ALT elevations in Part 2 of the
study.
To further ensure the safety of the study participants the JNJ-3989 stopping criteria in case of ALT
elevations have been made more stringent.
The Sponsor also amended the protocol to continue NA treatment at Week 144/148. In case of
confirmed HBsAg seroclearance in non-cirrhotic participants, NA treatment may be discontinued
upon discussion with the sponsor. For non-cirrhotic participants who discontinued treatment with
NA, additional NA restart criteria were added. Furthermore, the Sponsor clarified that NA
treatment should be continued in case of early discontinuation of JNJ-3989.
The Sponsor included in Part 2 of the study the option for liver biopsies (only in sites and in
selected countries where this is feasible, and after all relevant approvals are in place and
operational set-up is completed) to allow a better understanding of the impact of JNJ-3989
treatment on viral and immune markers in the liver in these HBV/HDV co-infected participants.
Other changes, clarifications and corrections were also made as detailed below.
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Section number
and Name
Description of Change 
Brief Rationale
1.1 Synopsis
1.2 Schema
2.3.3 Benefit-risk
Assessment for
Study Participation
4.1 Overall Design
4.2 Scientific
Rationale for Study
Design
5.1 Inclusion
Criteria
5.2 Exclusion
Criteria
6.3 Measures to
Minimize Bias:
Randomization and
Blinding
9.4.2.2 Analysis of
The Main Estimator
The inclusion criteria have been updated to exclude 
participants with liver cirrhosis (LSM ≥12.5 kPa by 
VCTE [FibroScan] or core liver biopsy and platelet 
count ≤140,000/dL) from Part 2 of the study. 
Given the reduced functional
hepatic reserve in the cirrhotic
participant population and the
newly identified risk of on-
treatment ALT elevation, the
Sponsor decided that participants
with liver cirrhosis will be excluded
from Part 2 of the study to protect
the safety of participants.
1.1 Synopsis
3 OBJECTIVES
AND ENDPOINTS
9.4.3 Key
Secondary
Endpoints
The fixed sequence of key secondary endpoints
was adjusted. The third key secondary endpoint
‘Proportion of participants with ≥2 kPa reduction
from baseline in liver stiffness measurement (LSM)
assessed by vibration controlled transient
elastography (VCTE) (FibroScan) at Week 48.’ has
been moved to the fourth position.
Given participants with cirrhosis
are excluded from Part 2 of the
study, the probability of rejecting
the null hypothesis for this endpoint
will be reduced. Consequently, the
fixed sequence procedure for
multiple testing should be adjusted
by moving this endpoint to the last
position (4th).
2.3.3 Benefit-risk
Assessment for
Study Participation
5.1 Inclusion
Criteria
The inclusion criteria for Part 2 of the study have
been updated to include participants with HBsAg
levels of ≤10,000 IU/mL or with HBsAg levels of
>10,000 IU/mL if HDV RNA levels are
≤100,000 IU/mL
In addition, for Part 2 of the study, participants
must have HDV RNA values at screening ≥500
IU/mL.
Participants with HDV RNA and
HBsAg levels above the thresholds
at baseline were associated with
increased risk of ALT elevations
during treatment with JNJ-3989. To
reduce the risk of experiencing an
ALT flare, the Sponsor has updated
the inclusion criteria.
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Section number
and Name
Description of Change 
Brief Rationale
1.1 Synopsis;
1.3.1 Schedule of
Activities –
Screening and
Double-blind Study
Intervention Phase
(First 48 Weeks);
1.3.2 Schedule of
Activities –Open-
label Study
Intervention Phase
(Weeks 52 –EOT);
1.3.3 Schedule of
Activities –Follow-
up Phase;
6.5.2 Re-treatment
With JNJ-3989 +
NA
8.3.6.1 Intervention-
emergent ALT/AST
Elevations;
10.6 Appendix 6:
Intervention-
emergent ALT/AST
Elevations
The algorithm for the management of 
intervention-emergent ALT and/or AST elevations 
has been updated. 
The threshold value for defining the onset of an 
intervention-emergent ALT/AST elevation has 
become stricter, ie, from ‘≥3x ULN and
≥3x nadir’ to ‘≥3x ULN and ≥2x nadir’.
The threshold value for discontinuation of
JNJ-3989 for participants without cirrhosis has
been modified to ALT >10x ULN and ≥2x
nadir in the confirmatory sample and to ALT
>5x ULN and ≥2x nadir for participants with
cirrhosis.
Criteria for discontinuation of JNJ-3989 in case
of prolonged ALT elevation have been
updated to differentiate between participants
with compensated liver cirrhosis, and
participants without liver cirrhosis who
experience a first or second ALT flare.
Furthermore, the monitoring frequency for
participants who experience an ALT/AST flare has
been adjusted to weekly (or more frequently as
long as values increase) until ALT and/or AST
levels have returned to <3x ULN or <2x nadir, and
if present, liver-related symptoms have improved.
With ALT and/or AST values ≥3x ULN and ≥2x
nadir, visit intervals may be extended to 14 days if
values have been stable or decreasing on
3 consecutive visits.
In addition, the visit window for confirmatory
visits in case of any intervention-emergent
elevation of ALT and/or AST ≥3x ULN and ≥2x
nadir has been changed to “preferably within 3
days” of the receipt of the initial ALT/AST results.
To ensure the participant’s safety
and to gain a better understanding
of the outcome of ALT flares with
continued treatment as well as
HDV RNA kinetics after ALT
normalization.
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Section number
and Name
Description of Change 
Brief Rationale
1.1 Synopsis
1.3.2 Schedule of
Activities –Open-
label Study
Intervention Phase
(Weeks 52 –EOT)
1.3.3 Schedule of
Activities –Follow-
up Phase
2.3.3 Benefit-risk
Assessment for
Study Participation
4.1 Overall Design
4.2 Scientific
Rationale for Study
Design
6.5 Re treatment
With JNJ 3989
and/or NA During
the Follow up Phase
7.1 Discontinuation
of Study
Intervention
NA treatment has become mandatory for all study 
participants until the last study visit (FU Week 48). 
Only for non-cirrhotic participants, NA treatment 
can be discontinued during the Follow-up Phase of
the study in case of a confirmed HBsAg
seroclearance and upon discussion with the
Sponsor.
For non-cirrhotic participants who discontinued
treatment with NA, additional NA restart criteria
were added.
Furthermore, it has been clarified that NA
treatment should be continued in case of early
discontinuation of JNJ-3989.
Upon Health Authority Request and
to protect the safety of the
participants.
1.1 Synopsis;
1.3.1 Schedule of
Activities –
Screening and
Double-blind Study
Intervention Phase
(First 48 Weeks)
2.3.1.3 Risks Due to
Study Procedures
2.3.3 Benefit-risk
Assessment for
Study Participation
3 OBJECTIVES
AND ENDPOINTS
4.2 Scientific
Rationale for Study
Design
5.1 Inclusion
Criteria
5.2 Exclusion
Criteria
6.8 Concomitant
Therapy
8 STUDY
ASSESSMENTS
AND
PROCEDURES
8.1.2 Liver Biopsy
and Fine Needle
The study protocol was updated to include in Part 2
of the study the option to perform liver biopsies in
participants who consented separately to this
procedure.
To allow a better understanding of
the impact of JNJ-3989 treatment
on viral and immune markers in the
liver in HBV/HDV co-infected
participants.
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Section number
and Name
Description of Change 
Brief Rationale 
Aspirate Biopsy
(Optional with
Separate Consent,
Part 2 Only)
8.3.6.6
Complications From
Liver Biopsy
9.4.8 Other
Analyses
1.3.3 Schedule of 
Activities –Follow- 
up Phase 
Blood sampling for HBV DNA analysis was added
during FU W30 and FU W42 visits for the
non-cirrhotic participants who discontinue NA
treatment
To protect the safety of the
participants.
2.2 Background 
The subsection ‘Clinical Studies’ of the
background section of the protocol has been
updated with a short summary of the REEF-D Part
1 efficacy and safety data (ie, HDV RNA and ALT
results, respectively).
For completeness
6.8 Concomitant 
Therapy  
10.13 Appendix 13:
COVID-19
APPENDIX
Guidance was added on the concomitant use of
COVID-19 vaccines and JNJ-3989/NA.
Clarification added for
completeness.
8 STUDY
ASSESSMENTS
AND
PROCEDURES
The maximum amount of blood drawn from each
participant in this study and during the follow up
phase has been corrected (from 2500 mL to
3210 mL).
Correction of inconsistency.
6.7 Treatment of
Overdose
The definitions of an overdose for JNJ-3989 and
NA have been corrected.
Correction of inconsistencies.
6.8 Concomitant
Therapy
Anticoagulants have been removed from the list of
disallowed medication; instead, they are listed as
medication to be used with caution.
Preclinical and clinical data for
JNJ-3989 do not show evidence of
coagulopathy.
1.3.3 Schedule of
Activities –Follow-
up Phase
Footnote has been added to the HBeAg
quantitative testing in the SoA table for the follow-
up phase.
Clarification
1.3.1 Schedule of
Activities –
Screening and
Double-blind Study
Intervention Phase
(First 48 Weeks)
HDV RNA testing was added to footnote u of the
SoA.
Correction of inconsistency.
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Section number
and Name
Description of Change 
Brief Rationale
1.3.1 Schedule of
Activities –
Screening and
Double-blind Study
Intervention Phase
(First 48 Weeks)
1.3.2 Schedule of
Activities –Open-
label Study
Intervention Phase
(Weeks 52 –EOT)
1.3.3 Schedule of
Activities –Follow-
up Phase
It has been clarified that in case MRI monitoring is 
used per patient’s standard of care, MRI may be
used instead of abdominal ultrasound to follow-up
on HCC or clinically relevant renal abnormalities.
Clarification
1.3.3 Schedule of
Activities –Follow-
up Phase
In case of early treatment discontinuation, it has
been clarified that follow-up study visits are to be
scheduled relative to the last originally planned
JNJ-3989 treatment visit.
Clarification
6.3 Measures to
Minimize Bias:
Randomization and
Blinding
The sentence ‘Under normal circumstances, the
blind should not be broken until all participants
have completed the visit at which the primary
endpoint is assessed.’ has been removed as the
protocol text clearly states that at Week 52 it will
be communicated to investigators and participants
to which treatment arm they were allocated to
follow the correct visit schedule during the open-
label phase.
Correction of inconsistency
1.3.1 Schedule of
Activities –
Screening and
Double-blind Study
Intervention Phase
(First 48 Weeks)
1.3.2 Schedule of
Activities –Open-
label Study
Intervention Phase
(Weeks 52 –EOT)
It has been clarified that Antidrug antibodies
samples should be collected prior to JNJ-3989
administration.
Clarification.
1.3.1 Schedule of
Activities –
Screening and
Double-blind Study
Intervention Phase
(First 48 Weeks)
It has been clarified that a sample for HLA
haplotyping should preferably be collected during
the Day 1 visit, but may occur at any other study
visit during the double-blind study intervention
phase.
Clarification.
5.2 Exclusion
Criteria
Exclusion criterion 1 was adapted to clarify that
participants with a positive HIV-1 or HIV-2
antibody/antigen test at screening should have a
confirmatory HIV RNA test, to rule out false
Clarification.
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Section number
and Name
Description of Change 
Brief Rationale
positive results. They can be enrolled if they have a
negative HIV RNA test at screening.
It was also clarified that participants with evidence
of HIV-1 or HIV-2 infection who are on
antiretroviral treatment are excluded
1.1 Synopsis
6.1 Study
Interventions
Administered
The dosage regimen of ETV for nucleoside-naïve 
participants has been removed and replaced by a
dosage regimen for all participants.
Clarification.
1.3.1 Schedule of
Activities –
Screening and
Double-blind Study
Intervention Phase
(First 48 Weeks)
1.3.2 Schedule of
Activities –Open-
label Study
Intervention Phase
(Weeks 52 –EOT)
1.3.3 Schedule of
Activities –Follow-
up Phase
8.3.6.1 Intervention-
emergent ALT/AST
Elevations
It has been clarified that local laboratory
assessments could be considered for repeat
laboratory testing in case central laboratory testing
proves to be difficult or does not provide a result in
a timely manner (except for HDV RNA and
HBsAg assessment during treatment to protect the
blind). Off-treatment local HDV RNA test can be
done to exclude/assess for HDV driven flare.
Clarification.
5.1 Inclusion
Criteria
It has been clarified that conventional imaging
procedures and serum marker panels are not
acceptable for exclusion of cirrhosis.
Clarification.
1.3.2 Schedule of
Activities –Open-
label Study
Intervention Phase
(Weeks 52 –EOT)
1.3.3 Schedule of
Activities –Follow-
up Phase
It has been clarified that for liver ultrasound, a
window of 1 week is allowed before or after the
scheduled visit
Clarification.
Throughout the
protocol
Minor grammatical, formatting, or spelling
changes were made.
Minor errors were noted.
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Status: Approved,  Date:  27 March 2024
Amendment 2 (17 June 2021)
Overall Rationale for the Amendment: During conduct of Part 1 of this study, a higher-than-
expected proportion of participants (approximately 50% of 22 participants enrolled in Part 1)
experienced elevations of alanine aminotransferase (ALT) on treatment. Management of these
acute elevations is following protocol defined criteria but some of the cases show a prolonged
pattern of ALT elevation for which no management criteria were provided in the protocol.
To better characterize these observed ALT elevations and to protect participants from a potential
risk, the Sponsor, after consultation with the Independent Data Monitoring Committee (IDMC),
decided to implement the following changes:
1. Introduction of new discontinuation criteria
2. Sponsor unblinding for antiviral activity parameters to interpret the ALT flares
3. Planning an additional interim analysis (IA)
These changes were introduced with immediate effect to allow the Sponsor to provide guidance to
sites on study treatment discontinuation.
The additional IA is planned after all participants of Part 1 have completed at least Week 16 (or
discontinued earlier). This is taking the observed pattern of ALT elevations into account, where
all ALT elevations occurred at or before treatment Week 16.
Part 2 of this study will only be initiated after the results of the additional IA are available and
supporting initiation of Part 2.
Furthermore, a second IA during the double-blind phase of Part 1, after all participants of Part 1
have completed at least Week 48 (or discontinued earlier), was introduced, and additional
clarifications were made for study conduct and the planned statistical analyses.
Changes Related to the Observed ALT Elevations
Section number
and Name
Description of Change 
Brief Rationale 
1.1 Synopsis;
1.3.2 Schedule of
Activities –Open-
label Study
Intervention Phase
(Weeks 52 –EOT);
1.3.3 Schedule of
Activities –Follow-
up Phase
8.1 Efficacy
Assessments;
8.3.6.1 Intervention-
emergent ALT/AST
Elevations;
Criteria for discontinuation of JNJ-3989 in case of
prolonged elevation of ALT were added.
To allow accurate assessment of the
discontinuation criteria, HDV RNA samples will
be collected in case of intervention-emergent
ALT/AST flares, also prior to the Week 52 visit.
To ensure the safety of participants
during the treatment with JNJ-3989.
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Changes Related to the Observed ALT Elevations
Section number
and Name
Description of Change 
Brief Rationale
10.6 Appendix 6:
Intervention-
emergent ALT/AST
Elevations
1.1 Synopsis;
4.1 Overall Design;
6.3 Measures to
Minimize Bias:
Randomization and
Blinding;
9.5 Interim ;
9.5.4 Sponsor
Committee;
9.5.5 Independent
Flare Expert Panel;
10.3.6 Committees
Structure
Two IAs were added to the double-blind phase of
Part 1.
Part 1 IA1 was added to evaluate data from all
participants of Part 1 who have completed at least
Week 16 or discontinued earlier.
Part 1 IA2 was added to evaluate data from all
participants of Part 1 who have completed at least
Week 48 or discontinued earlier.
Sponsor personnel and members of the
Independent Flare Expert Panel (IFLEP) will
become unblinded to the Part 1 clinical data at the
time of Part 1 IA1. The investigators, participants,
site personnel, and operational Sponsor team
members involved with the sites will remain
blinded. For safety-related decisions, HDV RNA
and hepatitis B surface antigen (HBsAg) data may
be discussed with investigators on a case-by-case
basis.
The planned blinding of Part 2 will not be affected.
Part 1 IA1 is introduced to assess
and characterize ALT elevations
observed in hepatitis D virus
(HDV) infected participants of Part
1, and to inform the decision to start
Part 2.
Part 1 IA2 is introduced to continue
the comprehensive assessment of
the benefit-risk ratio of the
investigational regimen in HDV-
infected participants with longer
term data on participants of Part 1.
Additional Clarifications and Corrections
Section number
and Name
Description of Change 
Brief Rationale
4.1 Overall Design;
6.3 Measures to
Minimize Bias:
Randomization and
Blinding
It was clarified that unblinding will not occur at the 
time of early discontinuation for patients who
discontinue early, before the Week 52 visit.
Clarification
1.3.1 Schedule of
Activities –
Screening and
Double-blind Study
Intervention Phase
(First 48 Weeks)
Changes were made to avoid repetitive collection
of liver ultrasounds at baseline and to allow
flexibility in the scheduling of the ultrasound.
Clarification
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Additional Clarifications and Corrections
Section number
and Name
Description of Change 
Brief Rationale
1.1 Synopsis;
4.2 Scientific
Rationale for Study
Design;
6.3 Measures to
Minimize Bias:
Randomization and
Blinding;
9.2 Sample Size
Determination;
9.4.1 General
Considerations;
9.4.2.2 Analysis of
The Main Estimator;
9.5.2 Interim
Analyses of Study
Part 2
Text was added to clarify that the randomization 
ratio of 4:1 (active:control) will remain the same 
regardless of a potential sample size increase in 
Part 2, and that the determination of the exact fixed 
weights used to adjust the efficacy analyses for the
sample size re-estimation will be made prior to the
IA in Part 2.
Clarification on the fixed
randomization ratio and technical
details of the statistical method for
sample size re-estimation.
9.3 Populations for
Analysis Sets
A definition was added for the Modified intent-to-
treat (mITT) analysis set.
Address the potential impact of the
COVID-19 pandemic on the
efficacy analyses.
1.1 Synopsis;
9.4.1 General
Considerations;
9.4.2.1 Primary
Estimand
Clarified the definition of the main estimand and
its attributes for the primary efficacy endpoint.
Clarification of the attributes of the
estimand for the primary efficacy
endpoint in alignment with the
estimand framework in the ICH E9-
R1 guidance.
Throughout the
protocol
Minor grammatical, formatting, or spelling
changes were made.
Minor errors were noted.
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Status: Approved,  Date:  27 March 2024
Amendment 1 (6 August 2020)
Overall Rationale for the Amendment: This amendment is written to address comments from
Health Authorities, to allow for clarifications to be added, and for minor inconsistencies and errors
to be corrected.
Changes Requested by Health Authorities
Section number
and Name
Description of Change 
Brief Rationale 
5.1 Inclusion
Criteria
Inclusion criterion 6 was modified to include only
participants who have elevated ALT levels
(>ULN) at screening.
As normal ALT is part of the
primary endpoint for this study,
only participants with elevated ALT
levels at screening will be eligible
to participate. The threshold of
>ULN is aligned with similar
inclusion criteria of other drug
candidates in development for
treatment of HDV infection.
1.1 Synopsis Safety
Evaluations;
1.3 Schedule of
Activities;
8.3.6.1 Intervention-
emergent ALT/AST
Elevations;
10.6 Appendix 6:
Intervention-
emergent ALT/AST
Elevations;
11 REFERENCES
The frequency of monitoring participants who
experience intervention-emergent ALT/AST
elevations was changed to allow for more frequent
testing than on a weekly basis. It was highlighted
that confirmatory visits should take place “as soon
as possible within 7 days” of receipt of the initial
ALT/AST results and “on weekly basis or more
frequently” until ALT and/or AST levels have
returned to 50% of the maximal value.
Based on review of data from
chronic HBV patients by Fontana et
al,11 HBV patients who experience
an ALT flare may need more
frequent laboratory assessments
than once a week.
1.1 Synopsis Safety
Evaluations;
1.3.3 Schedule of
Activities –Follow-
up Phase;
8.3.6.1 Intervention-
emergent ALT/AST
Elevations;
10.6 Appendix 6:
Intervention-
emergent ALT/AST
Elevations
HDV RNA has been added to the list of laboratory
parameters to be measured at the confirmatory
study visits for participants who experience an
ALT flare.
Information on HDV RNA will be
made available to the IDMC at any
time during the study. HDV RNA
results will be made available to the
Sponsor and investigators from
primary analyses (Week 52)
onwards.
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Changes Requested by Health Authorities
Section number
and Name
Description of Change 
Brief Rationale
1.1 Synopsis
Overall Design;
Safety Evaluations;
1.3.3 Schedule of
Activities –Follow-
up Phase;
4.1 Overall Design;
6.4 Study
Intervention
Compliance;
6.5 Re treatment
With JNJ 3989
and/or NA During
the Follow up;
8.3.6.1 Intervention-
emergent ALT/AST
Elevations
A section was added on re-treatment with JNJ- 
3989 and/or NA during the follow-up phase in case 
of transaminase flares and HBV/HDV recurrence. 
The original protocol only
described management of on-
treatment transaminase flares. To
ensure the safety of participants
during the follow-up phase as well,
the management of off-treatment
flares was further expanded and the
possibility for re-treatment was
added, provided that the participant
fulfills the protocol-defined
re-treatment criteria.
8.3.1 Time Period
and Frequency for
Collecting Adverse
Event and Serious
Adverse Event
Information
The timing for reporting of SAEs using the Serious
Adverse Event Form has been corrected.
Correction of inconsistency.
6.3 Measures to
Minimize Bias:
Randomization and
Blinding
Additional wording was added with regards to
breaking the blind to clarify that unblinding of a
participant’s treatment should not be stalled or
delayed in case of an emergency.
Section was revised in order to
emphasize unambiguously that the
investigator has the primary right to
break the blind in order to treat a
participant in an emergency.
10.8 Appendix 8:
Contraceptive and
Barrier Guidance
The footnote on interactions with the study
intervention was removed from the Examples of
Contraceptives table.
No interaction is expected between
JNJ-3989 or NA and oral
contraceptives.
10.8 Appendix 8:
Contraceptive and
Barrier Guidance
The subtitle ‘Not Allowed as Sole Method of
Contraception During the Study’ in the Examples
of Contraceptives table was revised to clarify that
these methods should be used together with highly
effective methods of contraception.
Clarification that, although
frequently practiced, less effective
methods of contraception should
not be used without highly effective
methods of contraception.
1.1 Synopsis
Overall Design,
Statistical Methods;
4.1 Overall Design;
9.4 Statistical
Analyses;
9.4.1 General
Considerations;
9.4.2.1 Primary
Estimand;
Removed the inferentially seamless feature of the
study; stated a clear separation of efficacy analyses
by study parts, with use of Part 2 data only as the
pivotal part of the study.
To protect the study integrity and
allow the involvement of the
Sponsor Committee in making the
decision to initiate Part 2 based on
the assessment of antiviral activity
criteria in Part 1.
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Changes Requested by Health Authorities
Section number
and Name
Description of Change 
Brief Rationale
9.4.2.2 Analysis of
The Main Estimator;
9.4.3 Key
Secondary
Endpoints;
9.4.4 Other Efficacy
Endpoints;
9.4.7 Safety
Analyses;
9.5 Interim Analysis
1.1 Synopsis
Overall Design,
Number of
Participants;
Statistical Methods;
1.2 Schema;
4.1 Overall Design;
6.3 Measures to
Minimize Bias:
Randomization and
Blinding;
9.2 Sample Size
Determination;
11 REFERENCES
The text on sample size calculation was clarified
by adding the type of statistical test used, and the
justification for the assumptions made in the power
calculations and sample size re-estimation.
Changed the planned sample size of Part 2 to
145 participants with a potential increase to a
maximum of 170.
Clarification of assumptions for the
sample size calculation and update
of the sample size increase for Part
2 due to the inferential separation of
Part 1 from Part 2.
1.1 Synopsis
Statistical Methods;
9.4.2.1 Primary
Estimand;
9.4.2.2 Analysis of
The Main Estimator
Clarification of intercurrent events in the main
estimand definition for the primary efficacy
endpoint regarding the major protocol violations,
and update of the missing data handling rule in
presence of intercurrent events.
Addition of sensitivity and supplementary
estimators for the primary estimand.
‘Primary estimator’ was changed to ‘main
estimator’ in alignment with the SAP.
Alignment of the missing data
handling rule with the treatment
policy strategy proposed for
selected intercurrent events defined
in the primary estimand in
accordance with the ICH-E9-R1
guidance.
To evaluate the robustness of the
assumption of MAR and the type of
missing data.
Correction of inconsistency
between documents.
4.2 Scientific
Rationale for Study
Design
The rationale for choosing a 4:1 randomization
ratio was added.
Clarification.
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Additional Changes, Clarifications, and Corrections
Section number
and Name
Description of Change 
Brief Rationale
6.1 Study
Interventions
Administered
It was specified which NA treatment the 
participant should start (if treatment-naïve) or 
continue (if virologically suppressed) at baseline. 
Clarification was needed on which
NA treatment should be
administered during the study to
treatment-naïve participants,
virologically suppressed
participants, and participants who
experienced toxicity to either of the
NA treatment options prior to
screening.
1.1 Synopsis
Description of
Interventions;
6.1 Study
Interventions
Administered
A footnote was added to the Description of 
Interventions table, stating that TAF will be one of 
the NA treatment options in countries where TAF 
is commercially available.
Clarification that TAF will only be
an NA treatment option in countries
where it is commercially available.
5.1 Inclusion 
Criteria; 
5.2 Exclusion 
Criteria 
The timing for assessing the Child-Pugh score was
specified. In addition, the point-based indication
of the Child-Pugh score in the exclusion criteria
has been changed to a category-based indication
(ie, category A, B, or C) for consistency
throughout the protocol.
The timing for assessing the
Child-Pugh score was missing in
the original protocol.
5.1 Inclusion Criteria Wording was added to clarify that the minimum
age for inclusion in the study is 18 years, even if
the legal age of consent in the participating
country is <18 years.
Only participants ≥18 years to
≤65 years of age are eligible for
participation in this study. The
sentence “or the legal age of
consent in the jurisdiction in which
the study is taking place” had been
added to inclusion criterion 2 of the
protocol to exclude patients who
cannot legally consent by
themselves, as the legal age of
consent in some of the participating
countries is ≥19 years. For countries
with a legal age of consent of
<18 years, it was clarified that only
patients ≥18 years of age can be
enrolled in this study.
1.3.1 Schedule of
Activities –
Screening and
Double-blind Study
Intervention Phase
(First 48 Weeks)
The timing of liver biopsy for staging of liver
fibrosis at screening was corrected in the footnotes
of the Schedule of Activities.
Clarification that liver biopsy, if no
other method for staging of liver
fibrosis is available, is not
necessary to be done at screening.
The biopsy can still be done at
screening, unless it was done within
one year from screening.
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Additional Changes, Clarifications, and Corrections
Section number
and Name
Description of Change 
Brief Rationale
1.3.3 Schedule of
Activities –Follow-
up Phase
The early withdrawal (WD) visit has been added
to the Schedule of Activities for the follow-up
phase.
The early withdrawal (WD) visit
was erroneously missing from the
Schedule of Activities for the
follow-up phase.
1.1 Synopsis Safety
Evaluations;
1.3 Schedule of
Activities;
2.3.3 Benefit-Risk
Assessment for
Study Participation;
8.2 Safety
Assessments;
8.2.1 Physical
Examinations;
8.2.2 Vital Signs;
9.4.7 Safety
Analyses
Assessment of body weight has been categorized
under vital signs instead of under physical
examinations.
Alignment of time points for body
weight assessments with time points
for assessment of other vital signs.
6.8 Concomitant
Therapy
It was specified that any prior IFN use needs to be
recorded at screening.
Prior IFN use needs to be recorded
in the CRF in order to allow
analysis of the data by prior IFN
use.
6.8 Concomitant
Therapy
In the table with disallowed medication, IFN was
removed from the ‘disallowed from 6 months
prior to baseline until end of follow-up’ category
of medication.
IFN was erroneously listed in both
the ‘disallowed from 6 months prior
to screening until end of follow-up’
and the ‘disallowed from 6 months
prior to baseline until end of
follow-up’ categories of
medication.
6.8 Concomitant
Therapy
In the table with disallowed medication, nucleic
acid polymers were added to the ‘disallowed at
any time prior to screening until end of follow-up’
category of medication.
Nucleic acid polymers are another
example of oligonucleotide-based
treatment and are therefore
disallowed at any time prior to
screening until end of follow-up.
1.1 Synopsis Overall
Design, Safety
Evaluations;
1.3.1 Schedule of
Activities –
Screening and
Double-blind Study
Intervention Phase
(First 48 Weeks);
1.3.3 Schedule of
Activities –Follow-
up Phase;
A footnote was added to clarify that, for sites in
the US, HDV RNA tests used to determine the
participant’s eligibility for the study (inclusion
criteria) and to decide on JNJ-3989 re-treatment
during the follow-up phase should be performed
by a local laboratory.
Clarification.
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Additional Changes, Clarifications, and Corrections
Section number
and Name
Description of Change 
Brief Rationale
6.5.1 Re-treatment
With JNJ-3989;
8.3.6.1 Intervention-
emergent ALT/AST
Elevations
6.6 Continued
Access to Study
Intervention After
the End of the Study
The text was updated to reflect the possibility that
participants might have continued access to
JNJ-3989 after the end of the study through
compassionate use.
JNJ-3989 might be made available
after the end of the study through
compassionate use to allow access
for patients who are expected to
benefit from further treatment with
JNJ-3989.
4.1 Overall Design  
Definition of the primary analysis in this section
has been aligned with the same wording in other
sections of the protocol.
Correction of inconsistency.
1.1 Synopsis 
Pharmacokinetic 
Evaluations; 
8.4.3 
Pharmacokinetic 
Parameters and 
Evaluations
It was clarified that other PK parameters than
AUC may be calculated, if applicable. In addition,
it was specified that population PK modeling may
be used to enable the calculation of the PK
parameter AUC also in participants who only
underwent sparse PK sampling.
Clarification/specification of PK
parameters.
8.4
Pharmacokinetics
Text was added to clarify that intensive PK testing
is optional and will only be done for participants
who consent separately to the intensive PK study.
Clarification.
Throughout the
protocol
Minor grammatical, formatting, or spelling
changes were made.
Minor errors were noted.
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11. 
REFERENCES
1. Afdhal NH, Bacon BR, Patel K, et al. Accuracy of Fibroscan, compared with histology, in analysis of
liver fibrosis in patients with Hepatitis B or C: a United States multicentre study. Clin Gastroenerol
Hepatol. 2015;13(4):772-779.
2. WHO. 2012. Blood Donor Selection: Guidelines on Assessing Donor Suitability for Blood Donation.
4. General donor assessment. Available from: https://www.ncbi.nlm.nih.gov/books/NBK138219/.
3. Bogomolov P, Alexandrov A, Voronkova N, et al. Treatment of chronic hepatitis D with the entry
inhibitor myrcludex B: First results of a phase Ib/IIa study. J Hepatol. 2016;65(3):490-498.
4. Castéra L, Vergniol J, Foucher J, et al. Prospective comparison of transient elastography, Fibrotest,
APRI, and liver biopsy for the assessment of fibrosis in chronic hepatitis C. Gastroenterol.
2005;128:343-350.
5. Chen, HY, DT Shen, DZ Ji, et al. Prevalence and burden of Hepatitis D virus infection in the global
population: a systematic review and meta-analysis. Gut. 2019;68:512-521.
6. Cornberg M, Lok AS, Terrault NA. et al. Guidance for Design and Endpoints of Clinical Trials in
Chronic Hepatitis B—Report From the 2019 EASL-AASLD HBV Treatment Endpoints Conference.
Hepatology. 2020;71(3):1070-1092.
7. EMA. Orphan Designation. https://www.ema.europa.eu/en/human-regulatory/overview/orphan-
designation-overview. Accessed 16 December 2019.
8. Erhardt A, Gerlich W, Starke C, et al. Treatment of chronic hepatitis delta with pegylated interferon-
alpha2b. Liver Int. 2006;26(7):805-810.
9. European Association for the Study of the Liver (EASL) clinical practice guidelines on the
management of chronic hepatitis B virus infection. J Hepatol. 2017;67:370-398.
10. FDA. Orphan Drug Designation. https://www.fda.gov/industry/designating-orphan-product-drugs-
and-biological-products/orphan-drug-act-relevant-excerpts. Accessed 18 January 2020.
11. Fontana RJ, Avigan MI, Janssen HLA, et al. Liver safety assessment in clinical trials of new agents
for chronic hepatitis B. J Viral Hepat. 2020;27(2):96-109.
12. Gehring AJ, Protzer U. Targeting innate and adaptive immune responses to cure chronic HBV
infection. Gastroenterology. 2019;156(2):325-337.
13. Heidrich B, Yurdaydın C, Kabaçam G, et al. Late HDV RNA relapse after peginterferon alpha-based
therapy of chronic hepatitis delta. Hepatology. 2014;60(1):87-97.
14. International Conference on Harmonisation of Technical Requirements for Registration of
Pharmaceuticals for Human Use. ICH Harmonized Tripartite Guideline E14: Clinical evaluation of
QT/QTc interval prolongation and proarrhythmic potential for non-antiarrhythmic drugs.
ICH 12 May 2005.
15. Investigator’s Brochure: JNJ-73763989 Edition 7. Janssen Research & Development (April 2023).
16. Janas MM, Harbison CE, Perry VK, et al. The nonclinical safety profile of GalNac-conjugated RNAi
therapeutics in subacute studies. Toxicol Pathol. 2018;46(7):735-745.
17. Miao Z, Zhang S, Ou X, Li S, Ma Z, Wang W, Peppelenbosch MP, Liu J, Pan Q. Estimating the global
prevalence, disease progression, and clinical outcome of Hepatitis Delta Virus infection. J Infect Dis.
2020;221(10):1677-1687.
18. Patel, EU, CL Thio, D Boon, DL Thomas, and AAR Tobian. Prevalence of Hepatitis B and Hepatitis
D virus infections in the United States, 2011–2016, Clin Infect Dis. 2019; 69(4):709-528 712.
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19. Public 
summary 
of 
opinion 
on 
orphan 
designation 
for 
bulevirtide.
https://www.ema.europa.eu/en/documents/orphan-designation/eu/3/15/1500-public-summary-
opinion-orphan-designation-synthetic-47-amino-acid-n-myristoylated-lipopeptide en.pdf. Accessed
13 Dec 2019
20. Spiegel BMR, Bolus R, Han S, et al. Development and Validation of a Disease-Targeted Quality of
Life Instrument in Chronic Hepatitis B: The Hepatitis B Quality of Life Instrument, Version 1.0.
Hepatology. 2007;46(1):113-121.
21. Stockdale AJ, Kreuels B, Henrion MYR, Giorgi E, Kyomuhangi I, de Martel C, Hutin Y, Geretti AM.
The global prevalence of hepatitis D virus infection: systematic review and meta-analysis. J Hepatol.
2020; in press.
22. Tang LSY, Covert E, Wilson E, and Kottilil S. Chronic Hepatitis B infection: A Review. JAMA.
2018;319(17):1802-1813.
23. Terrault NA, Lok ASF, Mcmahon BJ, et al. Update on prevention, diagnosis, and treatment of chronic
hepatitis B: AASLD 2018 hepatitis B guidance. Hepatology. 2018;67(4):1560-1599.
24. US Department of Health and Human Services Food and Drug Administration Center for Drug
Evaluation and Research (CDER). Chronic Hepatitis D Virus Infection: Developing Drugs for
Treatment. Guidance for Industry. October 2019.
25. Wedemeyer H, Manns MP. Epidemiology, pathogenesis and management of hepatitis D: update and
challenges ahead. Nat Rev Gastroenterol Hepatol 2010;7:31-40.
26. WHO. 
Hepatitis 
B. 
http://www.who.int/news-room/fact-sheets/detail/hepatitis-b.
Accessed 9 December 2019
27. WHO. 
Hepatitis 
D. 
https://www.who.int/en/news-room/fact-sheets/detail/hepatitis-d.
Accessed 9 December 2019
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Status: Approved,  Date:  27 March 2024
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
NCT04535544


Signature
User 
Date 
Reason
 
30-Mar-2024
19:40:32
(GMT)
Document Approval
PPD
NCT04535544

SAP_001.pdf: 
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
1
Status: Approved, Date: 09 August 2023
Janssen Research & Development
Statistical Analysis Plan
A Phase 2, Multicenter, Randomized, Double-blind, Placebo‑controlled Study with 
Deferred Active Treatment to Investigate the Efficacy, Safety, and Pharmacokinetics of 
JNJ‑73763989+ Nucleos(t)ide Analog in Participants Co‑infected with Hepatitis B and 
Hepatitis D Virus
The REEF-D Study
Protocol 73763989HPB2004; Phase 2
AMENDMENT 5
JNJ-73763989 
Status:
Approved
Date:
09-August-2023
Prepared by:
Janssen Research & Development, a division of Janssen Pharmaceutics BV
Document No.: EDMS-RIM-54024, 7.0
Compliance: The study described in this report was performed according to the principles of Good Clinical Practice (GCP). 
Confidentiality Statement
The information provided herein contains Company trade secrets, commercial or financial information that the Company 
customarily holds close and treats as confidential.  The information is being provided under the assurance that the recipient
will maintain the confidentiality of the information under applicable statutes, regulations, rules, protective orders or 
otherwise.
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JNJ-73763989   
Statistical Analysis Plan 73763989HPB2004
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
2
Status: Approved, Date: 09 August 2023
TABLE OF CONTENTS
TABLE OF CONTENTS ............................................................................................................................... 2
LIST OF IN-TEXT TABLES.......................................................................................................................... 6
LIST OF IN-TEXT FIGURES ........................................................................................................................ 6
AMENDMENT HISTORY.............................................................................................................................. 7
ABBREVIATIONS ...................................................................................................................................... 17
1.
INTRODUCTION................................................................................................................................ 19
1.1.
Trial Objectives and Endpoints ...................................................................................................... 19
1.2.
Trial Design .................................................................................................................................... 22
1.3.
Statistical Hypotheses for Trial Objectives..................................................................................... 23
1.4.
Sample Size Justification ............................................................................................................... 24
1.5.
Randomization and Blinding .......................................................................................................... 24
2.
GENERAL ANALYSIS DEFINITIONS .............................................................................................. 25
2.1.
Analysis Phases and Visit Windows .............................................................................................. 25
2.1.1.
Analysis Phase ........................................................................................................................... 25
2.1.2.
Relative Day by Study Phase ..................................................................................................... 26
2.1.2.1.
Double-Blind Study Intervention Relative Day ........................................................................ 27
2.1.2.2.
Follow Up Relative Day ........................................................................................................... 27
2.1.3.
Analysis Visits and Time Points.................................................................................................. 27
2.2.
Baseline ......................................................................................................................................... 29
2.3.
Analysis Sets.................................................................................................................................. 30
2.4.
Definition of Subgroups.................................................................................................................. 30
2.4.1.
Subgroups for Efficacy Analyses................................................................................................ 30
2.4.2.
Subgroups for Safety Analyses .................................................................................................. 32
2.5.
Missing and Partial Dates Imputation Rules .................................................................................. 32
2.5.1.
Adverse Event Onset Date and Resolution Date ....................................................................... 32
2.5.2.
HBV and HDV Diagnosis and Infection Dates............................................................................ 33
2.5.3.
NA and IFN Treatment Dates Prior to Study Entry..................................................................... 33
2.5.4.
Concomitant Medication Dates................................................................................................... 33
2.5.5.
Dates of Alcohol Consumptions ................................................................................................. 34
3.
INTERIM ANALYSIS AND DATA MONITORING COMMITTEE REVIEW....................................... 34
3.1.
Independent Data Monitoring Committee and Sponsor Committee.............................................. 34
3.1.1.
Internal Data Review Committee................................................................................................ 35
3.2.
Independent Flares Expert Panel .................................................................................................. 35
3.3.
Data Reviews and Interim Analyses .............................................................................................. 36
3.3.1.
Data Reviews.............................................................................................................................. 36
3.3.2.
Interim, Primary and Final Analyses........................................................................................... 38
3.3.2.1.
IAs During the Double-Blind Treatment Phase ....................................................................... 39
3.3.2.1.1.
Part 1 IA1 ............................................................................................................................. 39
3.3.2.1.2.
Part 1 IA2 ............................................................................................................................. 39
3.3.2.2.
IA at the end of Open-label Phase .......................................................................................... 40
3.3.3.
Rule to Start Part 2 of the Study or Determine Futility ............................................................... 40
4.
SUBJECT INFORMATION................................................................................................................ 42
4.1.
Disposition Information................................................................................................................... 42
4.2.
Demographic and Baseline Characteristics................................................................................... 42
4.2.1.
Baseline Characteristics ............................................................................................................. 43
4.2.2.
Demographic Characteristics ..................................................................................................... 45
4.3.
Medical History............................................................................................................................... 46
4.4.
Prior and Concomitant Medications ............................................................................................... 46
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4.5.
Protocol Deviations ........................................................................................................................ 46
4.6.
Extent of Exposure......................................................................................................................... 46
4.7.
Treatment Compliance................................................................................................................... 48
5.
EFFICACY ......................................................................................................................................... 48
5.1.
Analysis Specifications................................................................................................................... 49
5.1.1.
Virology Data Handling Rules..................................................................................................... 49
5.2.
Primary and Final Analyses ........................................................................................................... 51
5.3.
Primary Efficacy Endpoint.............................................................................................................. 51
5.3.1.
Definition..................................................................................................................................... 51
5.3.2.
Main Estimand for the Primary Endpoint.................................................................................... 51
5.3.2.1.
Main Estimator of the Main Estimand for the Primary Endpoint.............................................. 52
5.3.2.1.1.
Analysis Methods ................................................................................................................. 52
5.3.2.1.2.
Data Included ....................................................................................................................... 52
5.3.2.1.3.
Assumptions......................................................................................................................... 52
5.3.2.1.4.
Missing Data Handling Rule................................................................................................. 52
5.3.2.2.
Sensitivity Estimators of the Main Estimand for the Primary Endpoint ................................... 53
5.3.2.2.1.
Sensitivity Estimator of the Main Estimand (Missing as Non-Response) for the 
Primary Endpoint.................................................................................................................. 53
5.3.2.2.1.1.
Assumptions...................................................................................................................... 53
5.3.2.2.1.2.
Missing Data Handling Rule.............................................................................................. 53
5.3.2.3.
Supplementary Estimators of the Main Estimand for the Primary Endpoint ........................... 53
5.3.2.3.1.
Supplementary Estimator (mITT + Missing as Non-Response) of the Main 
Estimand for the Primary Endpoint ...................................................................................... 54
5.3.2.3.2.
Data Included ....................................................................................................................... 54
5.3.2.3.3.
Assumptions......................................................................................................................... 54
5.3.2.3.4.
Missing Data Handling Rule................................................................................................. 54
5.3.3.
Subgroup analyses..................................................................................................................... 54
5.4.
Key Secondary Endpoints  (KSE) .................................................................................................. 54
5.4.1.
KSE1: HDV RNA Decline from Baseline ≥2 log10 IU/mL or HDV RNA TND at Week 48........... 55
5.4.1.1.
Definition.................................................................................................................................. 55
5.4.1.2.
Main Estimand for the KSE1 ................................................................................................... 55
5.4.1.2.1.
Main Estimator of the Main Estimand for the KSE1............................................................. 56
5.4.1.2.1.1.
Analysis Methods.............................................................................................................. 56
5.4.1.2.1.2.
Data Included.................................................................................................................... 56
5.4.1.2.1.3.
Assumptions...................................................................................................................... 56
5.4.1.2.1.4.
Missing Data Handling Rule.............................................................................................. 56
5.4.1.2.2.
Sensitivity Estimators of the Main Estimand for the KSE1 .................................................. 56
5.4.1.2.2.1.
Sensitivity Estimator of the Main Estimand (Missing as Non-Response) for the 
KSE1 ................................................................................................................................. 57
5.4.1.2.3.
Supplementary Estimators of the Main Estimand for the KSE1 .......................................... 57
5.4.2.
KSE2: Normal ALT at Week 48.................................................................................................. 57
5.4.2.1.
Definition.................................................................................................................................. 57
5.4.2.2.
Main Estimand for the KSE2 ................................................................................................... 57
5.4.2.2.1.
Main Estimator of the Main Estimand for the KSE2............................................................. 58
5.4.2.2.1.1.
Analysis Methods.............................................................................................................. 58
5.4.2.2.1.2.
Data Included.................................................................................................................... 58
5.4.2.2.1.3.
Assumptions...................................................................................................................... 58
5.4.2.2.1.4.
Missing Data Handling Rule.............................................................................................. 58
5.4.2.2.2.
Sensitivity Estimators of the Main Estimand for the KSE2 .................................................. 59
5.4.2.2.2.1.
Sensitivity Estimatorof the Main Estimand (Missing as Non-Response) for the 
KSE2 ................................................................................................................................. 59
5.4.2.2.3.
Supplementary Estimators of the Main Estimand for the KSE2 .......................................... 59
5.4.2.2.4.
Main Estimator of the Supplementary Estimand for the KSE2 ............................................ 60
5.4.2.2.4.1.
Analysis Methods.............................................................................................................. 60
5.4.2.2.4.2.
Data Included.................................................................................................................... 60
5.4.2.2.4.3.
Assumptions...................................................................................................................... 60
5.4.2.2.4.4.
Missing Data Handling Rule.............................................................................................. 60
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Status: Approved, Date: 09 August 2023
5.4.3.
KSE3: HBsAg Seroclearance at Week 48.................................................................................. 60
5.4.3.1.
Definition.................................................................................................................................. 60
5.4.3.2.
Main Estimand for the KSE3 ................................................................................................... 60
5.4.3.2.1.
Main Estimator of the Main Estimand for the KSE3............................................................. 61
5.4.3.2.1.1.
Analysis Methods.............................................................................................................. 61
5.4.3.2.1.2.
Data Included.................................................................................................................... 61
5.4.3.2.1.3.
Assumptions...................................................................................................................... 61
5.4.3.2.1.4.
Missing Data Handling Rule.............................................................................................. 61
5.4.4.
KSE4 : Reduction in LSM From baseline to Week 48................................................................ 62
5.4.4.1.
Definition.................................................................................................................................. 62
5.4.4.2.
Main Estimand for the KSE4 ................................................................................................... 62
5.4.4.2.1.
Main Estimator of the Main Estimand for the KSE4............................................................. 63
5.4.4.2.1.1.
Analysis Methods.............................................................................................................. 63
5.4.4.2.1.2.
Data Included.................................................................................................................... 63
5.4.4.2.1.3.
Assumptions...................................................................................................................... 63
5.4.4.2.1.4.
Missing Data Handling Rule.............................................................................................. 63
5.4.5.
Subgroup analyses..................................................................................................................... 64
5.5.
Other Secondary Endpoints........................................................................................................... 64
5.5.1.
Definition..................................................................................................................................... 65
5.5.1.1.
Binary Endpoints ..................................................................................................................... 65
5.5.1.1.1.
HDV RNA Decline and Normal ALT..................................................................................... 65
5.5.1.1.2.
HDV RNA Cut-offs ............................................................................................................... 65
5.5.1.1.3.
Virologic HDV RNA Breakthrough ....................................................................................... 66
5.5.1.1.4.
JNJ-3989 Off-Treatment HDV RNA Relapses..................................................................... 66
5.5.1.1.5.
JNJ-3989 Off-treatment HDV Clinical Flares ....................................................................... 66
5.5.1.1.6.
JNJ-3989 Off-treatment Sustained HDV Response............................................................. 67
5.5.1.1.7.
HBsAg Seroclearance.......................................................................................................... 67
5.5.1.1.8.
HBsAg Seroconversion........................................................................................................ 67
5.5.1.1.9.
Virologic HBV Breakthrough ................................................................................................ 68
5.5.1.1.10.
HBsAg, HBeAg and HBV DNA Cut-offs............................................................................... 68
5.5.1.1.11.
HBV Flares........................................................................................................................... 69
5.5.1.1.12.
ALT/AST Elevations ............................................................................................................. 71
5.5.1.1.13.
Liver Stiffness Measurement................................................................................................ 71
5.5.1.2.
Values and Changes Over Time ............................................................................................. 72
5.5.1.3.
Time to Event Endpoints ......................................................................................................... 72
5.5.1.3.1.
Time to Event Endpoints Based on Parameters Used in Key Secondary Endpoints.......... 72
5.5.1.3.1.1.
Time to HDV RNA ≥2 log10 IU/mL Decline or HDV RNA TND or <LLOQ........................ 72
5.5.1.3.1.2.
Time to HDV RNA ≥2 log10 IU/mL Decline....................................................................... 73
5.5.1.3.1.3.
Time to HDV RNA TND or <LLOQ ................................................................................... 73
5.5.1.3.1.4.
Time to Normal ALT Levels .............................................................................................. 73
5.5.1.3.1.5.
Time to HBsAg Thresholds ............................................................................................... 73
5.5.1.3.2.
Time to Event Endpoints Based on Other Parameters........................................................ 73
5.5.1.3.2.1.
Time to JNJ-3989 Off-Treatment HDV Relapse ............................................................... 73
5.5.1.4.
Additional Efficacy Endpoints Relative to The Actual Duration of JNJ-3989 Treatment......... 73
5.5.2.
Analysis Methods........................................................................................................................ 75
5.5.2.1.
Binary Endpoints ..................................................................................................................... 75
5.5.2.1.1.
HDV RNA ............................................................................................................................. 76
5.5.2.1.2.
HBsAg Seroclearance.......................................................................................................... 76
5.5.2.1.3.
HBsAg Seroconversion........................................................................................................ 76
5.5.2.1.4.
HBV Flares........................................................................................................................... 76
5.5.2.1.5.
HBV DNA Cut-offs................................................................................................................ 76
5.5.2.2.
Values and Change Over Time ............................................................................................... 77
5.5.2.2.1.
HDV RNA ............................................................................................................................. 77
5.5.2.2.1.1.
Change from Baseline to Nadirs....................................................................................... 77
5.5.2.2.1.2.
Change from Baseline Over Time..................................................................................... 77
5.5.2.2.2.
ALT....................................................................................................................................... 77
5.5.2.2.3.
HBsAg, HBeAg and HBV DNA............................................................................................. 78
5.5.2.2.3.1.
Change from Baseline to Nadir......................................................................................... 78
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Statistical Analysis Plan 73763989HPB2004
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Status: Approved, Date: 09 August 2023
5.5.2.2.3.2.
Change from Baseline Over Time..................................................................................... 78
5.5.2.2.3.3.
Qualitative versus Quantitative Values ............................................................................. 78
5.5.2.2.4.
Liver Stiffness Measurement................................................................................................ 78
5.5.2.3.
Time to Event Endpoints ......................................................................................................... 78
5.6.
Exploratory Endpoints.................................................................................................................... 78
5.6.1.
Definitions ................................................................................................................................... 79
5.6.1.1.
Binary Endpoints ..................................................................................................................... 79
5.6.1.1.1.
HDV RNA Decline and Normal ALT..................................................................................... 79
5.6.1.1.2.
HDV RNA Cutoffs................................................................................................................. 79
5.6.1.1.3.
HBV RNA and HBcrAg......................................................................................................... 80
5.6.1.1.4.
HBV DNA Cutoffs................................................................................................................. 80
5.6.1.1.5.
HBsAg Seroclearance.......................................................................................................... 80
5.6.1.2.
Value and Change Over Time................................................................................................. 81
5.6.1.3.
Time to Event Endpoints ......................................................................................................... 81
5.6.1.3.1.
Time to Undetectability of HBcrAg ....................................................................................... 81
5.6.1.3.2.
Time to Appearance of Anti-HBs Antibodies........................................................................ 81
5.6.1.3.3.
Time to Appearance of Anti-HBe Antibodies ....................................................................... 81
5.6.1.4.
Relationship between HBsAg and HDV RNA.......................................................................... 81
5.6.1.5.
Relationship Between Baseline characteristics and Efficacy Endpoints................................. 82
5.6.1.6.
Liver Viral Response ............................................................................................................... 82
5.6.1.7.
Liver Immune Response.......................................................................................................... 83
5.6.1.8.
Relationship Between On-Treatment ALT Elevations, Efficacy and Safety Endpoints, 
and Baseline Characteristics................................................................................................... 83
5.6.2.
Analysis Methods........................................................................................................................ 83
5.6.2.1.
Binary Endpoints ..................................................................................................................... 83
5.6.2.1.1.
HDV RNA Cutoffs................................................................................................................. 83
5.6.2.1.2.
HBsAg Seroclearance.......................................................................................................... 84
5.6.2.2.
Value and Change Over Time................................................................................................. 84
5.6.2.2.1.
HBV RNA and HBcrAg......................................................................................................... 84
5.6.2.2.2.
Anti-HBs Antibodies ............................................................................................................. 84
5.6.2.2.3.
Anti-HBe Antibodies ............................................................................................................. 85
5.6.2.3.
Time to Event Endpoints ......................................................................................................... 85
5.6.2.4.
Relationship between HBsAg and HDV RNA.......................................................................... 85
5.6.2.5.
Relationship Between Baseline Characteristics and Efficacy Endpoints ................................ 85
5.6.2.6.
Liver Viral Response ............................................................................................................... 85
5.6.2.7.
Liver Immune Response.......................................................................................................... 86
6.
SAFETY............................................................................................................................................. 86
6.1.
Adverse Events .............................................................................................................................. 86
6.1.1.
Definitions ................................................................................................................................... 86
6.1.2.
Analysis Methods........................................................................................................................ 86
6.1.3.
Adverse Events of Special Interest............................................................................................. 87
6.2.
Clinical Laboratory Tests................................................................................................................ 88
6.2.1.
Definitions ................................................................................................................................... 88
6.2.2.
Analysis Methods........................................................................................................................ 89
6.3.
Renal Safety................................................................................................................................... 90
6.3.1.
eGFR .......................................................................................................................................... 90
6.3.2.
Proximal Renal Tubular Function ............................................................................................... 90
6.4.
Electrocardiogram.......................................................................................................................... 92
6.4.1.
Definitions ................................................................................................................................... 92
6.4.2.
Analysis Methods........................................................................................................................ 93
6.5.
Vital Signs and Body Temperature ................................................................................................ 94
6.5.1.
Definitions ................................................................................................................................... 94
6.5.2.
Analysis Methods........................................................................................................................ 95
6.6.
Physical Examination..................................................................................................................... 95
7.
VIRAL GENOME SEQUENCE ANALYSIS AND GENOTYPING..................................................... 95
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JNJ-73763989   
Statistical Analysis Plan 73763989HPB2004
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
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Status: Approved, Date: 09 August 2023
REFERENCES............................................................................................................................................ 96
ATTACHMENTS......................................................................................................................................... 97
Attachment 1: 
Selected Major Protocol Deviations for Analysis Purposes ....................................... 97
attachment 2: 
Adverse events of special interest list of preferred terms. ......................................... 99
Attachment 3:
Justification of the Decision Rule to start Part 2....................................................... 105
LIST OF IN-TEXT TABLES
Table 1:
Analysis Phases Start and End Dates...................................................................................... 26
Table 2:
Analysis Time Point and Time Intervals by Analysis Phase..................................................... 28
Table 3:
Overview of Times of Unblinding and Data Summaries and Analyses at Planned Data 
Review Milestones and IAs....................................................................................................... 37
Table 4:
Data Handling Rules for HDV and HBV Virology and Serology Assessments........................ 50
Table 5:
Correspondence between timepoints for Arm 1 and Open Label timepoints for Arm 2........... 74
Table 6:
Laboratory Parameters ............................................................................................................. 88
LIST OF IN-TEXT FIGURES
Figure 1:
Median and [20%, 90%] credible interval of the posterior distribution of the proportion 
of participants meeting the antiviral activity criteria to start Part 2. ........................................ 106
Figure 2:
Probability of the outcome of the decision rule as a function of the percentage of  
participants meeting the criteria to start Part 2 ....................................................................... 107
Figure 3:
Probability of the outcome of the decision rule as a function of the percentage of 
participants meeting the primary endpoint for different values of the probability that a 
participant who meets the antiviral activity criteria will attain the primary endpoint................ 108
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Statistical Analysis Plan 73763989HPB2004
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
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Status: Approved, Date: 09 August 2023
AMENDMENT HISTORY
Document History
Document
Date
Amendment 6
04 August 2023
Amendment 5
15 June 2023
Amendment 4
15 March 2022
Amendment 3
08 July 2021
Amendment 2
24 February 2021 
Amendment 1
12 August 2020
Original SAP
27 May 2020
Amendment 6
Overall rationale for the Amendments: This is an administrative amendment to add in 
Sections 5.6.1.6 and 5.6.1.7 that were inadvertently removed during last amendment as well as to 
fix the date of approval in the footer. 
Amendment 5
Overall rationale for the Amendments: Based on the observation that in Part 2 of the REEF-D 
study significant ALT elevations were more frequently observed in participants with HBsAg levels 
>10,000 IU/mL at screening or at baseline (irrespective of HDV RNA levels), a temporary halt of 
new enrollment into the study was implemented in December 2022. Since there was no immediate 
risk to the safety of participants already enrolled in the trial, treatment and monitoring of ongoing 
participants was continued as per current protocol.
This amendment aligns the Statistical Analysis Plan (SAP) with Protocol Amendment #4 issued 
on April 7, 2023 which was submitted in context of the Sponsor’s strategic decision to discontinue 
further investment in its hepatitis B and D discovery and development programs. In light of this 
decision, which was not driven by safety concerns with JNJ-73763989 (JNJ-3989), enrollment of 
new participants into the REFF-D study will not be reopened. 
The overall reason for this amendment is to continue the study in a modified way for participants 
already enrolled and to describe the reduced sample size in the study. The hypothesis test is no 
longer going to be performed and the analyses in the study will be descriptive. Per IDMC 
recommendation, it was added that in Part 2, participants with HBsAg values >10.000 IU/mL at 
screening or baseline, who were assigned to Arm 1 (placebo), will not roll-over to the open-label 
phase and will enter the follow-up phase. In addition, the stopping criteria for nucleos(t)ide analog 
(NA) treatment at Week 144/148 have been updated upon HA request.
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JNJ-73763989   
Statistical Analysis Plan 73763989HPB2004
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
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Status: Approved, Date: 09 August 2023
Main Changes
Section Number and Name
Description of Change
Rationale
Throughout the SAP
Sample size for Part 2 was reduced from 
145 to 30 patients
The enrollment in the study was stopped so 
the final Part 2 sample size is 30.
Throughout the SAP
Interim Analysis for Sample Size Re-
Estimation has been removed from the 
SAP.
Due to stopped enrollment, the sample size 
re-estimation is no longer relevant. 
Throughout the SAP
Removed sections on Type I error rate.
The study is now a descriptive study so no 
Type I error control is required.
Throughout the SAP
Removed wording on multiplicity 
adjustment
Due to stopped enrollment, the study will 
only have descriptive analyses
5.5.1.1.12 ALT/AST 
Elevations
5.5.1.1.11 HBV Flares
Updated Flare definitions 
Clarification
5.3. Primary Efficacy 
Endpoint
5.4. Key Secondary Endpoints
Removed sensitivity estimators and per 
protocol analyses.
Due to stopped enrollment, the study will 
only have descriptive analyses.
2.4. Definition of Subgroups 
5.3.3. Subgroup Analyses
Removed some of the subgroup analyses.
Due to stopped enrollment and smaller 
sample size, some of the subgroup analyses 
are no longer needed.
5.6.1.6. Relationship 
Between On-Treatment ALT 
Elevations, Efficacy and 
Safety Endpoints, and 
Baseline Characteristics
Added analyses on the relationship 
between On-Treatment ALT elevations 
and Efficacy and Safety Endpoints, and 
Baseline Characteristics
Due to safety concern and ALT Flares, new 
analyses were included 
5.1.1.
Virology Data 
Handling Rules
Changed Imputation Rules for laboratory 
values and LLOQ Values
The focus of the analyses for HBV DNA 
are on < LLOQ. New assay with lower 
LLOQ value is used for HBV DNA from 
Jne 2023 and therefore LLOQ value was 
updated. 
Throughout the SAP
Other changes, clarifications, and 
corrections made throughout the 
document.
To be aligned with other SAPs within the 
Hepatitis B project
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JNJ-73763989   
Statistical Analysis Plan 73763989HPB2004
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
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Status: Approved, Date: 09 August 2023
Amendment 4
Overall rationale for the Amendment: This amendment aims to align the Statistical Analysis 
Plan (SAP) to the Protocol Amendment #3 issued on December 6, 2021 which was submitted in 
the context of data supporting start of Part 2. Protocol amendment #3 introduces updated inclusion 
criteria for the population enrolled in Part 2: cirrhotic participants will no longer be enrolled and 
adapted inclusion criteria for HBsAg and HDV RNA are provided. In addition, guidance to 
continue NA treatment until the last study visit and the discontinuation criteria of prolonged ALT 
elevation (as recommended by FDA) is introduced. 
Protocol Amendment #3 also includes optional liver biopsies for Part 2 participants to allow a 
better understanding of the impact of JNJ-3989 treatment on viral and immune markers in the liver 
in these HBV/HDV co-infected participants, described as new exploratory endpoints. This 
amendment provides details on the analyses for those endpoints.
Additional changes are implemented for the simulations related to the sample re-estimation IA 
planned during the double-blind phase of Part 2 as the enrollment rate has been updated for Part 2 
from 0.23 to 0.27 patient/site/month.
Main Changes
Section Number and Name
Description of Change
Rationale
Section 1.2 Trial Design
Section 1.5 Randomization 
and Blinding
Section 5.3 Primary Efficacy 
Endpoint
Section 5.4 Key Secondary 
Endpoints (KSE)
Stratification 
factor 
“Presence 
of 
compensated cirrhosis” removed from the 
statistical models for both primary and 
key secondary endpoints.
This stratification factor is no longer 
relevant to be included into the 
statistical models since all Part 2 
participant randomized in the study 
are non-cirrhotic.
Section 5.4.3 KSE3: HBsAg 
Seroclearance at Week 48
Section 5.4.4  KSE4 : 
Reduction in LSM From 
baseline to Week 48
Positions are switched for the last two 
key secondary endpoints 
-
3rd KSE is Proportion of participants 
with HBsAg seroclearance at Week 
48
-
4th KSE is Proportion of participants 
with ≥2 kPa reduction from baseline 
in LSM at Week 48.
Since all Part 2 participants are non-
cirrhotic, it will be more difficult to 
reach significance for the proportion 
of participants with ≥2 kPa 
reduction from baseline in LSM. 
Consequently, this endpoint is now 
ranked at the last position as per 
fixed sequence approach. 
Section 5.5 Other Secondary 
Endpoints
on / off treatment and nadir definitions 
are moved into this section and 
additional definitions are included:
The naming convention for on/off 
treatment should remain consistent 
across the program. Consequently, 
for HDV endpoints (whose on-
treatment period refers to the period 
NCT04535544


JNJ-73763989   
Statistical Analysis Plan 73763989HPB2004
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
10
Status: Approved, Date: 09 August 2023
Main Changes
Section Number and Name
Description of Change
Rationale
-
JNJ3989 on-treatment
-
JNJ-3989 off-treatment
-
JNJ-3989 on-treatment nadir
-
JNJ-3989 off-treatment nadir
when the participant receives JNJ-
3989 regardless of continuing NA 
treatment), a JNJ-3989-specific 
convention should be used to 
differentiate those terms from the 
standard HBV convention.
Section 5.5.1.1.12
ALT/AST Elevations
Section added
The treatment discontinuation 
criteria required by the FDA as 
prolonged 3xULN and 2xnadir is 
defined as “ALT elevation”. 
Section 5.6.1.6 Liver Immune 
Response
Section 5.6.1.7 Liver Immune 
Response
Section Error! Reference 
source not found. Error! 
Reference source not found.
Section 5.6.2.6 Liver Immune 
Response
Section 5.6.2.7 Liver Immune 
Response
Section Error! Reference 
source not found. Error! 
Reference source not found.
Sections added 
Align with the additional 
intrahepatic exploratory endpoints 
described in the protocol amendment 
3. 
Error! Reference source not 
found. : Error! Reference 
source not found.
Simulation results updated as per the 
current recruitment rate of 0.27 
patients/site/month.
Clarification
Throughout the SAP
Minor grammatical, formatting or 
spelling changes were made
Minor errors were noted
NCT04535544


JNJ-73763989   
Statistical Analysis Plan 73763989HPB2004
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
11
Status: Approved, Date: 09 August 2023
Amendment 3 
Overall rationale for the Amendment: This amendment aims to align the Statistical Analysis 
Plan (SAP) to the protocol Amendment #2 issued on June 18, 2021 which introduced two interim 
analyses (IA) during the Part 1 of the study. The first IA (Part 1 IA1) will occur after all participants 
of Part 1 have completed at least Week 16 (or discontinued earlier) and the second one (Part 1 
IA2) when all participants of Part 1 have completed at least Week 48 (or discontinued earlier). In 
addition, the unblinding of the sponsor, including the Sponsor Committee, for conducting and 
reviewing of results of the Part 1 IA1 and IA2 was introduced in this amendment.
During the conduct of Part 1 of this study, a higher than-expected proportion of participants 
(approximately 50% of 22 participants enrolled in Part 1 at the time of this amendment) 
experienced elevations of alanine aminotransferase (ALT) on treatment. Management of these 
acute elevations has been following the protocol defined criteria but some of the cases showed a 
prolonged pattern of ALT elevation for which no management criteria were provided in the 
protocol. To better characterize these observed ALT elevations and to protect participants from a 
potential risk, the Sponsor, after consultation with the Independent Data Monitoring Committee 
(IDMC), decided to implement the following changes:
1. Introduction of new treatment discontinuation criteria
2. Sponsor unblinding for review of antiviral activity parameters to interpret the ALT flares
3. Addition of two interim analyses (IA) of study Part 1 data
The first IA (Part 1 IA1) is planned after all participants of Part 1 have completed at least Week 
16 (or discontinued earlier). This timepoint was chosen based on the observed pattern of ALT 
elevations occurring at or before treatment Week 16. 
Part 2 of this study will only be initiated after the conduct of Part 1 IA1 and conditional upon the 
IA1 results. The knowledge of a more complete characterization of ALT elevations in Part 1 will 
be critical to decide on the start of Part 2 while ensuring the protection of the participants’ safety, 
and to guide management of potential ALT elevations in Part 2 by the investigators.
A second IA during the double-blind phase of Part 1 (Part 1 IA2), after all participants of Part 1 
have completed at least Week 48 (or discontinued earlier), was introduced to continue the 
comprehensive assessment of the benefit-risk ratio of the investigational regimen in hepatitis D 
virus (HDV) infected participants with longer term data on participants of Part 1.
Additional changes are implemented to correct and/or clarify technical details for the sample re-
estimation IA planned during the double-blind phase of Part 2.
NCT04535544


JNJ-73763989   
Statistical Analysis Plan 73763989HPB2004
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
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Status: Approved, Date: 09 August 2023
Main Changes
Section Number and Name
Description of Change
Rationale
Section 1.2 Trial Design
Section 3.1 Independent Data 
Monitoring Committee and 
Sponsor Committee
Section 3.2 Independent Flares 
Expert Panel
Section 3.3 Data Reviews and 
Interim Analyses
Added the two IAs during the double-
blinded treatment phase of Part 1 and 
modified the wording accordingly across 
the relevant sections. 
Align the data review and interim analyses 
processes to assess and characterize ALT 
elevations observed in approximately 50% 
of the randomized HDV-infected 
participants of Part 1.
Section 1.2 Trial Design
Section 1.5 Randomization 
and Blinding
Section Error! Reference 
source not found. Error! 
Reference source not found.
Clarification of the randomization ratio 
of 4:1 (JNJ-3989+NA : placebo+NA) to
remain the same regardless of a potential 
sample size increase in Part 2, and of the 
exact fixed weights used to adjust the 
efficacy analyses for the sample size re-
estimation will be made prior to the IA in 
Part 2. Correction in the formula for the 
sample-size re-estimation.
Clarification on the fixed randomization 
ratio and technical details of the statistical 
method for sample size re-estimation.
Section 5.1.1 Virology Data 
Handling Rules
Updated ULOQ for HBsAg and HBeAg
Correction
Section 5.5.1.1.3 Virologic 
HDV RNA Breakthrough
Section 5.5.1.1.9 Virologic 
HBV Breakthrough
Updated definition of both HDV RNA 
and HBV DNA virologic breakthroughs
Correction
Throughout the SAP
Minor grammatical, formatting or 
spelling changes were made
Minor errors were noted
Amendment 2 
Overall rationale for the Amendment: This amendment addresses the expansion of the estimand 
framework for all analyses of the primary endpoint and key secondary endpoints following the 
ICH E9-R1 guidance including the per-protocol analysis. In addition, improved alignment with 
other clinical trials SAP within the JNJ-3989 development program is made with regards to 
clarification of endpoints (eg. definition of flares), addition of subgroup variables and safety 
analyses, as well as inclusion of sensitivity estimators based on additional missing data handling 
rules.
NCT04535544


JNJ-73763989   
Statistical Analysis Plan 73763989HPB2004
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
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Status: Approved, Date: 09 August 2023
Main Changes
Section Number and Name
Description of Change
Rationale
Section 2.3 Analysis Sets
0 attachments
Attachment 1: 
Selected 
Major Protocol Deviations 
for Analysis Purposes
Added definition of 4 Per Protocol 
analyses sets: PP1, PP2, PP3 and PP4. 
Exclusion criteria and definition of 
intercurrent events for each PPs added in 
0.
Clarify the appropriate intercurrent events 
within the corresponding estimand to 
conduct a per-protocol analysis of primary 
and key secondary endpoints.
Section 5.3 Primary Efficacy 
Endpoint and 5.4 Key 
Secondary Endpoints
Expanded text in the estimand section. 
Updated intercurrent events and added 
missing data handling rules. 
Added supplementary estimands and 
sensitivity estimators.
Improve the structure of the efficacy 
analyses of the primary endpoint and key 
secondary endpoints in alignment with the 
estimand framework following the ICH E9-
R1 guidance. Correction of some 
intercurrent events.
Clarifications, Additions, Corrections
Section Number and Name
Description of Change
Rationale
Section 2.1.1 Analysis 
Phase
Updated the definition of start and end 
dates for each analysis phase.
Correction.
Section 2.1.2 Relative Day 
by Study Phase
Removed Open Label Relative Day.
Alignment of open-label analysis windows
with the week/day labels in the protocol 
Time & Events Schedule as defined relative 
to Double Blind Day 1.
Section 2.4.1 Subgroups for 
Efficacy Analyses
Added new subgroup variables and 
categories.
For completeness and alignment with other 
clinical trials SAP within the JNJ-3989 
development program.
Section 3.3.1 Data Reviews
Updated Table 3 by limiting the output for 
the IA for sample size re-estimation to the 
primary efficacy endpoint analysis.
Correction.
Section 3.3.3 Rule to Start 
Part 2 of the Study or
Determine Futility
Added the qualification “On-treatment” to 
the lab values used in the criteria defining 
antiviral activity.
Clarification 
Section 4.6 Extent of 
Exposure
Updated derivation of durations of 
exposure.
Clarification and consistency with the 
wording used in Section 2.1.1 Analysis 
Phase
Section 5.1.1 Virology Data 
Handling Rules
LLOQ and imputed values updated for 
HDV RNA and HBV RNA.
Updates from external vendors on assay 
properties on RNA quantification.
NCT04535544


JNJ-73763989   
Statistical Analysis Plan 73763989HPB2004
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Status: Approved, Date: 09 August 2023
Clarifications, Additions, Corrections
Section Number and Name
Description of Change
Rationale
Section 5.5.1.1.4 JNJ-3989 
Off-Treatment HDV RNA
Relapses
Updated with additional definitions of off-
treatment HDV RNA relapses
Clarification of approach to define different 
off-treatment HDV relapses based on HDV 
RNA value at End of Treatment visit.
Section 5.5.1.1.11 HBV 
Flares
Updated definition of virologic, 
biochemical and clinical flares by adding 
start and end dates for each type of flares. 
Clarification of approach to identify distinct 
flare events over time.
Section 5.5.1.3.1 Time to 
Event Endpoints Based on 
Parameters Used in Key 
Secondary Endpoints
Analyses of time to event endpoints 
changed to overall during the study instead 
of by analysis phase.
Clarification.
Section 5.5.1.4 Additional 
Efficacy Endpoints Relative
to The Actual Duration of
JNJ-3989 Treatment and 
Section 5.6.1.3 Time to 
Event Endpoints
Added Table 5:
Correspondence between 
timepoints for Arm 1 and Open Label
timepoints for Arm 2 for the analysis based 
on actual duration of treatment exposure.
Alignment of time points to match the 
exposure to JNJ-3989+NA between the 2 
arms, given the deferred active treatment 
design.
Section 5.6 Exploratory 
Endpoints
Added exploratory analyses for HDV 
RNA, HBV DNA and HBsAg
Added for accounting 
Section 6.2.1 Definitions
Added imputation rules for laboratory data
in the event of “<”, “>”, “≥” and “≤” being 
contained in the character result value.
Clarification
Section Error! Reference 
source not found. Error! 
Reference source not 
found.
Added definitions of HBV genetic and 
viral variations as well as parameters of 
interest with accompanying analyses.
Added for completeness
Section Error! Reference 
source not found. Error! 
Reference source not 
found.
Updated the calculation of the HBQOL 
total and subitems scores.
Correction
0 attachments
Attachment 1: 
Selected 
Major Protocol 
Deviations for Analysis 
Purposes
Updated the list of major protocol 
deviations for the purpose of the efficacy 
analyses.
Alignment of the major deviations to the 
detailed estimands definition and expanded 
list of intercurrent events.
0 attachment 2: Adverse 
events of special interest list 
of preferred terms.
Added attachment 2 to identify the 
preferred terms for the identification of 
adverse events of special interest.
Added for completeness
NCT04535544


JNJ-73763989   
Statistical Analysis Plan 73763989HPB2004
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Status: Approved, Date: 09 August 2023
Clarifications, Additions, Corrections
Section Number and Name
Description of Change
Rationale
Throughout the document
Clarification of text.
Typographical corrections or improved 
language for clarity and precision
Amendment 1
Overall rationale for the Amendment: Following the FDA’s response to the protocol and SAP 
submission, the study team agreed to amend the SAP to align with FDA recommendations, mainly 
Furthermore, clarifications, additions and corrections were made throughout the SAP.
Main Changes
Section Number and Name
Description of Change
Rationale
Section 5.3.2.2 Supplementary 
Estimator
Supplementary estimator added for 
the primary estimand where all 
subjects with missing HDV RNA 
and ALT values in the analysis 
window of Week 48 are imputed as 
non-responders
To 
evaluate 
the 
robustness 
of 
the
assumption of MAR and the type of
missing data.
Sections 0 Supplementary Estimand 
(Per-protocol analysis)
Supplementary estimand for the 
Per-Protocol analysis set
To define the PP analyses according to the 
estimand framework
Sections 1.2 Trial Design, 3 Interim 
Analysis,  4 Subject Information, 
Error! Reference source not 
found. Level of significance, 5.3
Primary Efficacy Endpoint, 5.4 Key 
Secondary Endpoints, 5.5 Other 
Secondary Endpoints, 5.6
Exploratory Endpoints, 6 Safety
Removed the inferentially seamless 
feature of the study; stated a clear 
separation of efficacy analyses by 
study parts, with use of Part 2 data 
only as the pivotal part of the study.
To protect the study integrity and allow 
the involvement of the Sponsor 
Committee in making the decision to 
initiate Part 2 based on the assessment of 
antiviral activity criteria in Part 1.
Sections 5.3 Primary Efficacy 
Endpoint, 5.4 Key Secondary 
Endpoints, 
Clarification of intercurrent events 
in the main estimand definition for 
the primary efficacy endpoint
regarding the major protocol 
deviations, and update of the 
missing data handling rule in 
presence of intercurrent events.
Alignment of the missing data handling 
rule with the treatment policy strategy 
proposed for selected intercurrent events 
defined in the primary estimand in 
accordance with the ICH-E9-R1 guidance.
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Status: Approved, Date: 09 August 2023
Clarifications, Additions, Corrections
Section Number and Name
Description of Change
Rationale
Section 1.4 Sample Size 
Justification
The text on sample size calculation 
was clarified by adding the type of 
statistical 
test 
used, 
and 
the
justification for the assumptions 
made in the power calculations and 
sample size re-estimation. Changed 
the planned sample size of Part 2 to
145 participants with a potential 
increase to a maximum of 170.
Clarification of assumptions for the sample 
size calculation and update of the sample 
size increase for Part 2 due to the inferential 
separation of Part 1 from Part 2.
Section 2.1.1 Analysis Phase
Updated the definition for end of 
Double Blind Study Intervention 
Phase
Correction
Section 2.4.1 Subgroups for 
Efficacy Analyses
Section 5.3.3
Subgroup analysis based on prior 
exposure to PegIFN-α added
Pooling of Part 1 and Part 2 data for 
explorations of subgroups 
To align with EUnetHTA recommendation 
to account for prior use of PegIFN-α as 
potential subgroup of interest for primary 
and key secondary endpoints.
To leverage the whole study data.
Section 2.4.2 Subgroups for Safety 
Analyses
Comment “To team: do we also 
need duration?]” removed 
Correction
Section Error! Reference source 
not found. Level of Significance
References for the use of median-
unbiased estimate were updated 
To correct a typo and to include an 
additional relevant reference 
Section 5.1.1 Virology Data 
Handling Rules
ULOQ for HBsAg updated to 
124,925 IU/mL without dilution
To align rules with other clinical trials 
within Hepatitis B therapeutic area.
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ABBREVIATIONS
ADY
analysis relative day
AE
adverse event
AESI
adverse event of special interest
ALT
alanine aminotransferase
AST
aspartate aminotransferase
ATC
anatomic and therapeutic class
BMI
body mass index
CHB
chronic hepatitis B
CI
confidence interval
CKD
Chronic Kidney Disease
CRF
case report form
DAIDS
division of acquired immunodeficiency syndrome
DB
double-blind
DR
data review
DRC
data review committee
ECG
electrocardiogram
EOS
end of study
EOT
end of treatment
eCRF
electronic case report form
ETV
entecavir
FU
follow-up
HBQOL
hepatitis B Quality of Life 
HBcrAg
hepatitis B core-related antigen 
HBe
hepatitis B envelope
HBs
hepatitis B surface
HBeAg
hepatitis B envelope antigen
HBsAg
hepatitis B surface antigen
HBV
hepatitis B virus
HBV DNA
hepatitis B virus deoxyribonucleic acid
HBV RNA
hepatitis B virus ribonucleic acid
HIV-1(-2)
human immunodeficiency virus type 1 (type 2)
HDV RNA
hepatitis D virus ribonucleic acid
HRQoL
Heart-Related Quality of Life
ICS
intracellular cytokine staining
IDMC
independent data monitoring committee
iFLEP
independent flares expert panel
IA
interim analysis
IFN
interferon
IQR
interquartile range
IRT
item response theory
ISR
injection site reaction
ITT
Intent-to-treat
IU/mL
international units per milliliter
IWRS
interactive website response system
KSE
Key Secondary Endpoint
LiPA
line probe assay
LLOQ
lower limit of quantification
LOCF
last observation carried forward
LSM
liver stiffness measurement
MAR
missing at random
MCAR
missing completely at random
MCS
mental component summary
MCT
multiple contrast test
MedDRA
medical dictionary for regulatory activities
MH
Mantel-Haenszel
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MI
multiple imputation
mITT
modified intent-to-treat
MNAR
missing not at random
MSE
missing score estimation
NA
nucleos(t)ide analog
NGS
next generation sequencing
OL
open-label
PBMC
peripheral blood mononuclear cell
PC
precore
PCS
physical component summary
pegIFN
peginterferon
PD
pharmacodynamic(s)
PK
pharmacokinetic(s)
PRO
patient-reported outcomes
Q4W
every 4 weeks
qd
once daily
QTcF
QT interval corrected for heart rate according to Fridericia
RR
Interval between R wave of one heartbeat and R wave of preceding heartbeat
RT
reference timepoint
SAE
serious adverse event
SAP
statistical analysis plan
SD
standard deviation
SC
sponsor committee
TEAE
treatment-emergent adverse event
TAF
tenofovir alafenamide
TD
target detected
TeD
tenofovir disoproxil
TND
target not detected
TNF
tumor necrosis factor
ULN 
upper limit of normal
VCTE
vibration-controlled transient elastography
WBC
white blood cell
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Status: Approved, Date: 09 August 2023
1.
INTRODUCTION
This statistical analysis plan (SAP) for the 73763989HPB2004 phase 2 trial describes the statistical 
analyses and definitions to assess the efficacy and safety of the study intervention with JNJ-
73763989 (100 mg every 4 weeks [Q4W]) and Nucleos(t)ide analogs (NA) in participants 
co-infected with hepatitis B virus (HBV) and hepatitis D virus (HDV). In this document the 
abbreviation JNJ-3989 is used to refer to the treatments JNJ-73763989. This SAP to be interpreted 
in conjunction with the clinical protocol amendment 4 finalized on 07 April 2023.
This is a 2-part, Phase 2, randomized, double-blind, placebo-controlled deferred active treatment, 
parallel, multicenter, interventional study comprising a proof-of-concept Part 1 followed by Part 2. 
Part 1 will provide the data to evaluate the safety, tolerability, and HDV anti-viral activity signal 
of JNJ-3989+NA in a small number of participants (N=20), prior to enrolling a further number of 
participants in Part 2. The Part 2 of the study was originally planned with N = 145, however, as of 
protocol Amendment 4, sample size was reduced to 30 participants due to stopped enrollment. 
Monitoring of the safety and efficacy in terms of HDV RNA and HBsAg data in the JNJ-3989+NA 
arm aims to exclude futility of the regimen and initiate Part 2.
Part 2 will provide additional evidence of safety and efficacy of the JNJ-3989 regimen in the 
treatment of HBV/HDV co-infection.
An independent data monitoring committee (IDMC) will be commissioned for this study to 
monitor data on a regular basis to ensure the continuing safety, efficacy and well-being of the 
participants enrolled in this study (see Section 3.1). 
Details of the pharmacokinetic (PK) and pharmacokinetic/pharmacodynamics (PK/PD) analyses 
will be described in a separate analysis and modeling plan.
1.1.
Trial Objectives and Endpoints
Objectives
Endpoints
Primary
To evaluate on-treatment efficacy against HDV 
of JNJ-3989 + NA regimen compared to NA 
alone.

Proportion of participants with HDV RNA 
≥2 log10 IU/mL decline from baseline or HDV 
RNA TND in combination with normal ALT at 
Week 48. 
Key Secondary
To evaluate on-treatment efficacy of the 
JNJ-3989 + NA regimen in suppressing HDV 
replication as measured by HDV RNA.

Proportion of participants with HDV RNA 
≥2 log10 IU/mL decline from baseline or HDV 
RNA TND at Week 48.
To evaluate efficacy of the JNJ-3989 + NA 
regimen on liver inflammation during study 
intervention phase.

Proportion of participants with normal ALT at 
Week 48.
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Objectives
Endpoints
To evaluate the efficacy of the JNJ-3989 + NA 
regimen in terms of HBsAg response.

Proportion
of 
participants 
with 
HBsAg 
seroclearance at Week 48.
To evaluate the efficacy of the JNJ-3989 + NA 
regimen on liver fibrosis.

Proportion of participants with ≥2 kPa reduction 
from baseline in liver stiffness measurement 
(LSM) assessed by vibration-controlled transient 
elastography (VCTE) (FibroScan) at Week 48.
Other Secondary
To evaluate the efficacy of the JNJ-3989 + NA 
regimen during study intervention phase and 
follow-up phase.

Proportion of participants with HDV RNA 
≥2 log10 IU/mL decline from baseline or HDV 
RNA TND in combination with normal ALT. 

Proportion of participants with HDV RNA 
≥2 log10 IU/mL 
decline 
from 
baseline 
in 
combination with normal ALT. 

Proportion of participants with HDV RNA TND 
in combination with normal ALT.

Proportion of participants with HDV RNA 
≥2 log10 IU/mL decline from baseline or HDV 
RNA TND.

Proportion of participants with HDV RNA 
≥2 log10 IU/mL decline from baseline.

Proportion of participants with HDV RNA TND.

Proportion of participants with normal ALT.

Time to reach HDV RNA ≥2 log10 IU/mL decline 
or HDV RNA TND.

Changes from baseline in HDV RNA.

Changes from baseline in ALT.
To evaluate the safety and tolerability of the study 
intervention throughout the study.

Proportion of participants with incidences of 
(S)AEs and abnormalities in clinical laboratory 
tests (including hematology, blood biochemistry, 
blood coagulation, urinalysis, urine chemistry, 
and renal biomarkers), 12-lead ECGs, vital signs, 
and physical examination.
To evaluate the efficacy of the JNJ-3989 + NA 
regimen as measured by HBV blood markers 
(such as HBsAg, HBeAg*, HBV DNA) during 
study intervention and follow-up.

Proportion 
of 
participants 
with 
HBsAg 
seroclearance and/or seroconversion. 

Change from baseline over time in HBsAg, 
HBeAg*, HBV DNA.

Proportion of participants with HBsAg, HBeAg*, 
and/or HBV DNA levels or changes from 
baseline below/above different cut-offs.

Time to reach efficacy thresholds such as 
HBsAg <1 IU/mL.
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Objectives
Endpoints
To evaluate the frequency of HBV virologic 
breakthrough throughout the study.

Proportion of participants with HBV DNA 
virologic breakthrough. 
To evaluate the PK of JNJ-3989 throughout the 
study.

PK parameters of JNJ-3989 (JNJ-73763924 and 
JNJ-73763976). 
To evaluate changes in liver fibrosis during study 
intervention and follow-up.

Proportion of participants with ≥2 kPa reduction 
from baseline in Liver Stiffness Measurement
(LSM) assessed by VCTE (FibroScan).

Change from baseline in LSM over time assessed 
by VCTE (FibroScan).
To evaluate the anti-HDV efficacy during the 
follow-up phase.

Proportions of participants with sustained HDV 
response off-treatment post end of JNJ-3989 
treatment. 

Proportions of participants with HDV relapse 
post end of JNJ-3989 treatment.
To evaluate the anti-HBV efficacy during the 
follow-up phase.

Proportions of participants with sustained HBV 
response off-treatment post end of JNJ-3989 
treatment. 

Proportions of participants with HBV flare 
(virologic, biochemical, and clinical) post end of 
treatment.
Exploratory
To explore the relationship between PK 
parameters 
(JNJ-3989) 
and 
selected 
pharmacodynamic (PD) parameters of efficacy 
and/or safety, as applicable.

Relationship between various PK parameters 
(JNJ-3989) and selected efficacy and/or safety 
endpoints, as applicable.
To explore the relationship between HBsAg and 
HDV RNA.

Correlation between HBsAg decline and HDV 
RNA levels/changes. 
To explore the impact of the viral and host 
baseline characteristics on safety and efficacy. 

Correlation 
of 
viral 
and 
host 
baseline 
characteristics (such as HBV/HDV genotype, 
baseline HBV DNA levels, baseline HDV RNA 
levels, age, sex, body mass index [BMI]) with 
selected efficacy and safety variables.
To explore the effect of any baseline variation in 
the HBV and HDV (if feasible) genome on 
efficacy.

Correlation of HBV and HDV genome sequence 
with selected efficacy parameters.
To explore changes in the HBV and HDV (if 
feasible)
genome 
sequence 
during 
study 
intervention and follow-up.

Emergence of intervention-associated mutations.
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Objectives
Endpoints
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 HBV-specific T-cell responses during 
study intervention. **

Changes from baseline in peripheral blood T-cell 
responses.
To explore medical resource utilization (MRU) to 
manage participants during study intervention 
and follow-up. 

Number and type of medical visits.

Number (proportion) of participants requiring 
hospitalization and duration of hospitalization 
(total days length of stay, including duration by 
wards; eg, intensive care unit (ICU).

Number and character of diagnostic and 
therapeutic tests and procedures.
To explore liver viral responses during study 
intervention.***

Changes from baseline in intrahepatic viral 
parameters (such as HDV RNA, HDAg, 
cccDNA, pgRNA, intrahepatic RNA, or HBsAg 
in terms of copy number, or number of positive 
cells).

Changes from baseline in intrahepatic cccDNA.

Levels 
and 
transcriptional 
activity 
(pgRNA/cccDNA ratio).
To explore liver immune responses during study 
intervention.***

Changes between baseline and on-treatment liver 
biopsy in intrahepatic immune response (eg, 
CD45+ T-cells, CD4+ T-cells, CD8+ T-cells, 
Natural Killer cells, and dendritic cells) in terms 
of proportion of cells, cell types, and spatial 
redistribution
To explore the relationship of intrahepatic 
markers with blood markers (immune and viral).

Association between levels and changes in 
intrahepatic and blood markers.
*: in HBeAg-positive participants only
** Peripheral blood mononuclear cell (PBMC) samples for immune analyses will be collected at selected sites only
and as operationally feasible 
*** If sufficient number of participants contribute to the liver biopsy collection
1.2.
Trial Design
Prior Protocol Amendment #4 the study was planned to include 2 parts, Part 1 (approximately 
N=20) with proof of concept objectives and Part 2 (approximately N=145) with confirmatory 
objectives. As of Protocol Amendment #4, Part 2 sample size was reduced to 30 participants which 
triggered modifications of objectives of Part 2 from confirmatory to exploratory. 
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Part 2 of the study will only be initiated once the antiviral activity criteria in Part 1 have been met
and after evaluation of the results of the first IA during the double-blind phase of Part 1. Cirrhotic 
participants will be excluded from participation in Part 2 of the study.
Each part includes 3 phases: a 4-week screening phase (may be extended up to a maximum of 6 
weeks), 144-weeks study intervention phase (Arm 1) and 148-weeks study intervention phase 
(Arm 2), 48-week follow-up phase. The first 52 weeks of the intervention phase are double-blind 
followed by 96 weeks of open-label (OL) treatment.
In each part the participants will be randomized in a 4:1 ratio to Arms 1:2.

Arm 1: 100 mg JNJ-3989 (subcutaneous [SC] injection every 4 weeks [Q4W]) + NA qd for 
144 weeks; 

Arm 2: placebo for JNJ-3989 (SC injection Q4W) + NA qd for 52 weeks, followed by 100 
mg JNJ-3989 (SC injection Q4W) + NA qd for 96 weeks (control deferred active treatment 
arm). 
Randomization will be stratified by presence of compensated cirrhosis at screening (yes or no)
(Part 1 only), HDV RNA testing laboratory location (China versus outside China) (all sites in 
China will utilize the laboratory testing in China and all sites in other countries will utilize the 
laboratory outside of China), and HBeAg status at screening (positive versus negative).
Prior Protocol Amendment #4, if safety was confirmed and futility excluded in Part 1, the total 
number of participants in this study was planned to be approximately 165 participants (specifically 
with a target of approximately 20 participants in Part 1, and 145 participants [up to a maximum of 
170 participants] in Part 2), aged ≥18 to 65 years of age, co-infected with HDV and HBV. An 
interim analysis (IA) during DB study intervention phase was planned to re-assess the sample size
in Part 2 and potentially increase it to maintain the statistical power at minimum at 80%. The 
maximum total sample size allowed for Part 2 of this study was 170. A reduction in sample size 
was not allowed, hence the minimum sample size for Part 2 was the planned number of 145 
participants (see Section 1.4). The confirmatory conclusions of the study would be based on data 
from Part 2 only (145 participants, or, if recommended by IDMC, up to 170 participants). As Per 
Protocol Amendment #4, the total sample size of the study is 52, with 22 participants in Part 1 and 
30 participants in Part 2. Data from Part 1 and Part 2 will be reported both separately and together 
to contribute to the overall benefit/risk ratio assessment of the regimen. 
1.3.
Statistical Hypotheses for Trial Objectives
The original protocol had as primary hypothesis of this study that the combination regimen of JNJ-
3989 + NA has superior efficacy compared to NA treatment alone in reducing HDV replication 
and improving the associated liver inflammation, as measured by the primary efficacy endpoint at 
Week 48 (the proportion of participants with HDV RNA decline ≥2 log10 IU/mL from baseline 
or HDV RNA TND in combination with normal ALT at Week 48). Due to the decision to stop 
enrollment at 30 participants in Part 2 of the study (see Section 1.2), the primary study hypothesis 
can no longer be tested with sufficient power, and hence the statistical analyses will be descriptive.
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1.4.
Sample Size Justification
A total sample size of 130 participants for Part 2 in the original protocol would have yielded a 
statistical power >90% to detect a between-arm difference of ≥26% in the primary efficacy 
endpoint at Week 48, at a 1-sided Type 1 error rate of 0.025, based on the test for the between-arm 
difference in proportions with the normal approximation. Per Protocol Amendment 4, the sample 
size in Part 2 was reduced to 30 participants. In the original protocol, sample size re-estimation 
was planned at the single IA during Part 2 to allow for an increase to a maximum of 170 
participants in Part 2 for the conditional power at the end of the study to be at least 80% in case 
the assumed 0.04 response rate for placebo was too conservative. Due to reduction in sample size 
per Protocol Amendment 4, the single IA with sample size re-estimation was removed. In the 
original protocol, the number of participants included in this study was planned to be a minimum 
of approximately N=20 (if Part 2 is not initiated) or between a minimum of N=165 and a maximum 
of N=190 if Part 2 is initiated. Per Protocol Amendment 4, the planned number of participants 
included in the study will be N=20 in Part 1 and N=30 in Part 2. 
1.5.
Randomization and Blinding
Randomization and Stratification
Randomization will be performed using a 4:1 ratio (Active regimen from the start Arm1 : Placebo/ 
deferred treatment Arm 2), regardless of the study part, to minimize bias in the assignment of 
participants to intervention arms, to increase the likelihood that known and unknown participant 
attributes (eg, demographic and baseline characteristics) are evenly balanced across treatment 
arms, and to enhance the validity of statistical comparisons across intervention arms.
Randomization will be stratified by presence of compensated cirrhosis at screening (yes or no)
(Part 1 only), HDV RNA testing laboratory location (China versus outside China), and HBeAg 
status at baseline (positive versus negative) in order to provide an evenly balanced representation 
across the 2 arms.
Blinding
Blinded treatment will be used to reduce potential bias during data collection and evaluation of 
clinical endpoints. 
The investigators, participants and all site personnel will remain blinded to study intervention 
allocation until Week 52 (Part 1) and Week 48 (Part 2). After Week 52 (Part 1) and Week 48 
(Part 2), it will be communicated to the investigators whether the participants were allocated to 
either the investigational arm (Arm 1) or the control arm (Arm 2) to allow the correct open-label 
and follow-up visits schedule to be followed (see Schedules of Activities). For each participant, 
all HDV RNA, HBsAg, HBeAg, HBcrAg, anti-HBs, and anti-HBe antibody testing individual 
results will be provided to the investigator and the sponsor for managing the participant’s safety.
After Week 52 and up and until Week 144, study intervention will be administered in open-label 
fashion to all participants (except Part 2 participants allocated to Placebo+NA who had HBsAg 
>10,000 IU/mL at screening or baseline).
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Prior to Part 1 IA1 (see Section 3.3.2.1.1), the Sponsor Committee will review unblinded 
aggregated interim data of HDV RNA, HBsAg, ALT, AST, total and direct bilirubin, HBV DNA 
and individual patient profiles for the values/changes from baseline over time for all participants 
in Part 1 including those randomized to the placebo+NA arm. 
Part 1 IA1 will include the review of all unblinded efficacy and safety results by the Sponsor 
Committee and the decision whether the Part 2 can be initiated based on the review of the antiviral 
activity criteria in conjunction with ALT elevations and other safety data, taking into consideration 
the IDMC recommendations. From the moment of unblinding for this IA onwards, the Sponsor 
Committee will remain unblinded to Part 1 data.  
The Study Team will become unblinded at the time of the IA1 of Part 1, throughout IA2 of Part 1 
until completion of Part 1, but will remain blinded to all data of Part 2 until the end of double-
blind phase (each individual participant will be unblinded after they reach Week 48 or discontinue 
earlier). 
2.
GENERAL ANALYSIS DEFINITIONS
The SAP will use throughout the document the following definitions:

Study treatment refers to: JNJ-3989, placebo, or NA [entecavir (ETV), tenofovir disoproxil
(TD), or tenofovir alafenamide fumarate (TAF)]

Study agent refers to: JNJ-3989 or placebo

Study intervention arm refers to: 
o
Arm 1: JNJ-3989 (100 mg) + NA
o
Arm 2: Placebo + NA
2.1.
Analysis Phases and Visit Windows
2.1.1.
Analysis Phase
The analysis phases are defined in Table 1 below.
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Table 1:
Analysis Phases Start and End Dates
Analysis phase
Start date
End date
Screening
The date of signing the informed 
consent 
1 day before the first study agent intake 
Double-Blind 
(DB) Study 
Intervention
Date of first study agent intake
If participant did not withdraw from the study and
did not discontinue treatment early prior to the 
projected/actual Week 52 Visit date:
Min(Date of Week 52 study agent intake – 1 day, cut-off 
date*)
Otherwise:
[Min (Early study withdrawal visit date, study agent 
discontinuation date) + 5 daysa]
or cut-off date*, 
whichever occurs first
Open-Label 
(OL) Study 
Intervention
If participant has a 
projected/actual Week 52 Visit 
date:

End date of DB study 
intervention phase + 1 
day
Otherwise:

Missing
If participant did not withdraw from the study prior 
to the projected/actual Week 144 (Arm 1)/Week 148 
(Arm 2) Visit date and did not discontinue treatment 
early prior to the projected/actual Week 140 (Arm 
1)/Week 144 (Arm 2) Visit date:
[Min (Date of Week 144 Visit (for Arm 1) or / Date of 
Week 148 Visit (for Arm 2) )+ 5 daysa ] or cut-off date*, 
whichever occurs first
if participant withdrew from the study or 
discontinued treatment between projected/actual 
Week 52 Visit date + 1 day and projected/actual Week 
144 (Arm 1)/Week 148 (Arm 2) Visit date:
[Min (Early study withdrawal visit date, study agent 
discontinuation date)+ 5 daysa ] or cut-off date*, 
whichever occurs first
Follow-up
If participant did not withdraw 
informed consent during DB or 
OL study intervention phases
Max (End date of DB study 
intervention phase, End date of 
OL study intervention phase) + 1 
day
Otherwise:
Missing
If participant entered the Follow-up phase: 
Max [early study withdrawal visit date, study completion 
date] or cut-off date, whichever occurs first. 
Otherwise:
Missing
*Cut-off dates will be defined to match the prespecified timepoints for IDMC safety monitoring, interim analysis, the 
primary analysis and the final analysis, respectively.
a :
Addition of 5 days is only applicable for Adverse Events and Concomitant Medications
2.1.2.
Relative Day by Study Phase
An analysis relative day (ADY) will be calculated for all assessments at all visits for each 
participant.
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2.1.2.1.
Double-Blind Study Intervention Relative Day
The Double-Blind (DB) Study intervention start date (DB Day 1) is defined as the date of first 
study agent intake. All efficacy and safety assessments during the DB study intervention phase
will be assigned a day relative to this date.
The study day in the Double-Blind intervention phase (DB ADY) is defined as:
DB ADY=visit date – DB start date+1
for visits on or after Day 1, and 
DB ADY=visit date – DB start date
for visits before DB Day 1 (Screening phase).
There is no ‘Day 0’.
2.1.2.2.
Follow Up Relative Day
Follow Up (FU) start date (FU Day 1) is defined in Table 1. All efficacy and safety assessments 
during the FU phase will be assigned a day relative to this date.
The FU study day in the FU treatment phase (ADY) is defined as:
FU ADY=visit date – FU start date+1
2.1.3.
Analysis Visits and Time Points
All visits for all assessments (safety, efficacy or PK) will be uniquely allocated within each phase 
to an analysis time point based on the analysis relative day (ADY) compared with the target days
based on Table 2. All assignments will be made in chronological order.  Once a visit is assigned 
to a visit window (time interval in Table 2), it will no longer be used for a later time point except 
for the end of treatment (EOT) and the end of study (EOS) visits. If two or more visits fall within 
the same interval in the same phase, only one measurement will be selected for the analysis time 
point per phase in order to have only one evaluation per participant. The following rules will be 
applied: 
1.
The measurement closest to the target day in that phase will be used. 
2.
If the measurements fall equidistant from the target day, the last measurement in chronological 
order within the interval will be used per phase.
3.
If there are two or more measurements on the same day, then the last measurement in 
chronological order will be used. If the time of the assessment is not available the highest 
record/sequence number will be selected.
The listings will include all measurements, also those multiple assessments within the same visit 
window/phase. 
End of treatment (i.e. EOT) and end of study (i.e. EOS) time points will be included in all analysis 
over time unless stated otherwise.
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Note: For the selection of the patient-reported outcome (PRO) measurements the above algorithm 
needs to be performed on the entire questionnaire (filled in at a specific date and time) and not on 
the individual questions /items (i.e., not mixing answers from different questionnaires)
Table 2 provides the analysis time points, time intervals for each visit per analysis phase.
Table 2:
Analysis Time Point and Time Intervals by Analysis Phase
Phase
Target 
day
Analysi
s time 
point
(Week)
Analysis time 
point
(label)
Time interval (days) 
for Arm 1
Time interval (days) 
for Arm 2(a)
Screening
-28 to -1
    -1
Screening
<0
Double-Blind 
(DB) Study 
Intervention
1
0
Baseline
Pre-dose ; 1
15
2
Week 2
[2,22]
29
4
Week 4
[23, 43]
57
8
Week 8
[44, 71]
85
12
Week 12
[72, 99]
113
16
Week 16
[100, 127]
141
20
Week 20
[128, 155]
169
24
Week 24
[156, 183]
197
28
Week 28
[184, 211]
225
32
Week 32
[212, 239]
253
36
Week 36
[240, 267]
281
40
Week 40
[268, 295]
309
44
Week 44
[296, 323]
337
48
Week 48
[324,351]
Open-Label 
(OL) Study 
Intervention
365
52
Week 52
[352, 372]
379
54
Week 54
[373, 386]
393
56
Week 56
[386, 407]
421
60
Week 60
[408, 435]
449
64
Week 64
[436, 463]
477
68
Week 68
[464, 491]
505
72
Week 72
[492, 519]
533
76
Week 76
[520, 547]
561
80
Week 80
[548, 575]
589
84
Week 84
[576, 603]
617
88
Week 88
[604, 631]
645
92
Week 92
[632, 659]
673
96
Week 96
[660, 687]
701
100
Week 100
[688, 715]
729
104
Week 104
[716, 743]
757
108
Week 108
[744, 771]
785
112
Week 112
[772, 799]
813
116
Week 116
[800, 827]
841
120
Week 120
[828, 855]
869
124
Week 124
[856, 883]
897
128
Week 128
[884, 911]
925
132
Week 132
[912, 939]
953
136
Week 136
[940, 967]
981
140
Week 140
[968, 995]
1009
144
Week 144 (b)
Not Applicable
[996, 1023]
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Status: Approved, Date: 09 August 2023
Phase
Target 
day
Analysi
s time 
point
(Week)
Analysis time 
point
(label)
Time interval (days) 
for Arm 1
Time interval (days) 
for Arm 2(a)
last visit 
during the 
interventio
n phase
149*
EOT(b)
Follow-Up (FU)
15
150
Follow-up 
Week 2
[1, 22]
29
152
Follow-up 
Week 4
[23,36]
43
154
Follow-up 
Week 6
[37, 50]
57
156
Follow-up 
Week 8
[51, 71]
85
160
Follow-up 
Week 12
[72, 99]
113
164
Follow-up 
Week 16
[100, 127]
141
168
Follow-up 
Week 20
[128, 155]
169
172
Follow-up 
Week 24
[156, 190]
211
178
Follow-up 
Week 30
[191,  232]
253
184
Follow-up 
Week 36
[233, 274]
295
190
Follow-up 
Week 42
[275, 316]
337
196
Follow-up 
Week 48
[317, +∞]
last visit in 
the study
999*
EOS
(a)
Participants randomized to Arm 2 (placebo + NA) will have additional assessments during the OL phase at Week 54 and Week 144. See 
Protocol Section 1.3.2 for more details 
(b)
For participants who completed the OL phase (see Table 1), EOT corresponds to Week 144 Visit Date for Arm 1 and Week 148 for Arm 
2 
*End of treatment (EOT) visit will be the last post-baseline visit in double-blind or open-label phase, and End of study (EOS) visit (last 
available data during the follow-up) will be the last visit in the study.
2.2.
Baseline
In general, the baseline assessment is defined as the last observed non-missing measurement before 
the date and time of the first administration of any of study treatments. 
In case the first administration time is missing, the first observed measurement on DB Day 1 will 
be used as the baseline measurement. If no observed measurement on DB Day 1, the last observed 
measurement before DB Day 1 will be used as the baseline assessment.
An additional reference timepoint (RT) will be used for an additional analysis of selected efficacy 
endpoints for Part 2 relative to the actual duration of treatment with JNJ-3989 as motivated by the 
deferred treatment design. This is described in Section 5.5.1.4.
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2.3.
Analysis Sets
Due to the issues caused by the pandemic Coronavirus Disease (COVID-19), the study team had 
decided to add the Modified Intent-to-treat analysis set (mITT) as defined below. It will be used 
for the efficacy analyses instead of the ITT in case of significant impact of future pandemics on 
the conduct and data collection for this study. The assessment of the impact will be made beforethe 
primary analysis of Part 2, however, the mITT is tentatively planned to be used if 6 or more 
participants are affected.
All randomized analysis set: All participants who were randomly assigned to an intervention arm
in the study. Participants will be analyzed according to the study intervention they were randomly 
assigned to.
Intent-to-Treat analysis set (ITT): All participants who were randomly assigned to an intervention 
arm and who received at least 1 dose of study intervention. Participants will be analyzed according 
to the study intervention they were randomly assigned to.
Modified Intent-to-Treat analysis set (mITT): All participants who were randomized in the study
and received at least one dose of study treatment excluding those participants impacted by the 
pandemic defined as those participants who, because of COVID-19 or similar pandemics related 
reasons, withdrew prematurely from the study prior to Week 48, or had no efficacy assessment for 
the primary endpoint. COVID-19 or similar pandemics related reasons may include for example 
missed visits due to travel restriction, shortage of lab kits at the planned visit, missed collection of 
blood sample at key time points for the primary efficacy endpoint, etc. Participants will be 
analyzed according to the study intervention they were randomly assigned to.
Safety analysis set: All participants who take at least 1 dose of study intervention. Participants 
will be analyzed according to the study intervention they actually received.
Pharmacokinetics analysis set (PK): The PK analysis set is defined as subjects who have received 
at least 1 dose of any of the study treatments and have at least 1 valid blood sample drawn for PK 
analysis.
2.4.
Definition of Subgroups
Subgroup analyses will be performed if at least 5 participants fall into the category.
2.4.1.
Subgroups for Efficacy Analyses

Sex: Male, Female

Age categories: 18 years - ≤30 years, > 30 years -≤ 45 years, > 45 years-≤60 years, > 60 
years

Duration of NA at Baseline: ≤2 years, > 2 years Race: Asian, non-Asian

NA Treatment history at screening 
o
Yes
o
No
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
Presence of compensated cirrhosis at screening (yes or no) (Part 1 only)

HDV RNA level at baseline:
o
< 1000 IU/mL vs ≥1000 IU/mL
o
< 10,000 IU/mL vs ≥10,000 IU/mL
o
< 100,000 IU/mL vs ≥100,000 IU/mL

HBeAg status at screening (positive vs negative)

HBV DNA level at baseline: 
o
<LLOQ
o
≥LLOQ
o
< 200 IU/mL vs ≥200 IU/mL
o
< 2,000 IU/mL vs ≥2,000 IU/mL

HBV RNA level at baseline:
o
TND
o
Detectable

HBsAg level at baseline: 
o
<1,000 IU/mL

≥1,000 IU/mL-<10,000 IU/mL
o
≥10,000 IU/mL

HBcrAg level at baseline:
o
<3 log10 U/mL
o
≥3 log10 U/mL-<4 log10 U/mL
o
≥4 log10 U/mL

HBsAg Antibody (Anti-HBs) level at baseline:
o
<LLOQ
o
<10 mIU/mL
o
≥10 mIU/mL

Alanine transferase (ALT) at baseline: ≤ 1.0xULN, > 1.0xULN - <2.5xULN, ≥2.5xULN

Combination of HDV RNA and HBsAg at screening:
o
< 100,000 IU/mL/< 10,000 IU/mL
o
≥100,000 IU/mL/< 10,000 IU/mL
o
< 100,000 IU/mL/ ≥10,000 IU/mL
o
≥100,000 IU/mL/≥10,000 IU/mL
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2.4.2.
Subgroups for Safety Analyses

Age categories: 18 years - ≤30 years, > 30 years - ≤ 45 years, > 45 years - ≤60 years, > 60 
years

Presence of compensated cirrhosis at screening (yes or no) (Part 1 only)

Type of NA at baseline 
o
TeD
o
TAF
o
ETV
o
None

Duration of NA at screening: ≤ 2 years, > 2 years to ≤4 years, > 4 years to ≤8 years, > 8 years
2.5.
Missing and Partial Dates Imputation Rules
For analysis and reporting purposes, missing or partial dates in adverse event (AE onset date; AE 
end date), diagnosis and infection dates, concomitant therapies (start date; end date) and NA/IFN
prior to baseline/study entry dates will be imputed according to the rules in the following 
subsections. The original, non-imputed, dates will be used only in listings.
2.5.1.
Adverse Event Onset Date and Resolution Date
Partial AE onset dates will be imputed as follows:

If the AE onset date is missing the day only, it will be set to:
o
The first day of the month when the AE occurred, if month and year of the AE onset date 
is different than the month and year of the first administration of study treatment date.
o
The day of the first study treatment administration, if the month and year of the AE onset 
date is the same as the month and year of the first study treatment administration but the 
month/year of the AE resolution date is different.
o
The earliest between the day of the first study treatment administration date and day of AE 
resolution date, if month/year of the AE onset are the same as both the month and year of 
the first study drug administration and the AE resolution date.

If the AE onset date is missing both day and month, it will be set to the earliest of:
o
January 1 of the year of onset, as long as this date is on or after the first study drug 
administration.
o
Month and day of the first study treatment administration, if this date is in the same year 
of AE onset date.
o
December 31 if the AE onset date year is prior to the year of the first study drug 
administration. 
o
The AE resolution date.

Completely missing onset dates will not be imputed.
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Partial AE resolution dates not marked as ongoing will be imputed as follows:

If the resolution date of an AE is missing the day only, it will be set to the earliest of the last 
day of that month or the day of the date of death, if the participant died in that month.

If the resolution date of an AE is missing both day and month, it will be set to the earliest of 
December 31 of that year or the day and month of the date of death, if the participant died in 
that year.

Completely missing resolution dates will not be imputed.
2.5.2.
HBV and HDV Diagnosis and Infection Dates
If the reported date is partially missing, the following imputation rules will be applied:

the 15th of the month, if only the day is missing.

the 30th of June, if only the year is available.

No imputation if completely missing.
2.5.3.
NA and IFN Treatment Dates Prior to Study Entry
In case of partially missing NA and IFN start/end dates recorded as medical history (i.e prior to 
study entry), the following imputation rules will be applied:

the 15th of the month, if only the day is missing.

the 30th of June, if only the year is available.

if the imputed start date is after the NA end date, further adjustment of the imputed start date 
is required. It will be imputed as the NA end date
No imputation if completely missing
2.5.4.
Concomitant Medication Dates
In case of partially missing concomitant medication start/end dates, the following imputation rules 
will be applied:

the 15th of the month, if only the day is missing.

the 30th of June, if only the year is available.

if the imputed start date is after the concomitant medication end date, further adjustment of 
the imputed start date is required. It will be imputed as the concomitant medication end date

No imputation if completely missing.
If the medication was taken prior to study start (Day 1) based on eCRF question, and the imputed 
start date is after first treatment date, further adjustment of the imputed start date is required. It 
will be imputed as the day prior to first treatment date.
If the medication was taken after study start (Day 1) based on eCRF question, and the imputed 
start date is prior to first dosing date, the imputed start date will be further adjusted to be the first 
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study treatment dosing date. The partially missing medication end date will be imputed following 
the rule described at the beginning of this section to ensure it is on or after first dosing date, and 
after its start date.
In case of a completely missing start date, the concomitant therapy will be considered as having 
started before the trial, unless the eCRF indicates that the medication was taken after study start. 
In case of a completely missing end date, the concomitant therapy will be considered as ongoing 
at the end of the trial, unless the eCRF indicates as not ongoing.
2.5.5.
Dates of Alcohol Consumptions
In case of partially missing start/end dates, the following imputation rules will be applied:

the 15th of the month, if only the day is missing.

the 30th of June, if only the year is available.

if the imputed start date is after the end date, further adjustment of the imputed start date is 
required. It will be imputed as the end date
if end date is completely missing and marked as Ongoing then impute with randomization date.  
Otherwise, no imputation if completely missing
3.
INTERIM ANALYSIS AND DATA MONITORING COMMITTEE REVIEW
3.1.
Independent Data Monitoring Committee and Sponsor Committee
An IDMC will monitor data on a regular basis to ensure the continuing safety, efficacy and well-
being of the participants enrolled in this study. The IDMC will review the 2 interim analyses data
of Part 1.
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 SC, who will make the 
final decision(s). Possible recommendations of the IDMC include, but are not limited to, 
continuing the study unchanged, stopping the study for safety concerns, or for futility or make a 
study amendment. 
The IDMC will consist of at least one medical expert in the relevant therapeutic area and at least
one statistician. The IDMC role and responsibilities, communication flow with other stakeholders 
(such as SC and Statistical Support Group), and procedures will be documented in its charter. 
The SC includes representatives from the sponsor’s Clinical, Biostatistics, Global Medical Safety 
and Virology departments who are not involved in the study conduct.
The Sponsor Committee will be unblinded in the initial evaluation of the antiviral activity criteria 
in up to all the participants randomized in Part 1 of the study based on aggregate interim data of 
HDV RNA and HBsAg and/or individual HDV RNA and HBsAg profiles.
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Prior to Part 1 IA1 (see Section 3.3.2.1.1), the Sponsor Committee will review unblinded 
aggregated interim data of HDV RNA, HBsAg, ALT, AST, total and direct bilirubin, HBV DNA 
and individual patient profiles for the values/changes from baseline over time for all participants 
in Part 1 including those randomized to the placebo+NA arm. 
Part 1 IA1 will include the review of all unblinded efficacy and safety results by the Sponsor 
Committee and decision whether the Part 2 can be initiated based on the review of the antiviral 
activity criteria (Section 3.3.3) in conjunction with ALT elevations and other safety data, and the 
recommendations from the IDMC. From the moment of unblinding for this IA onwards, the 
Sponsor Committee will remain unblinded to Part 1 data.  
After Part 2 has commenced, all Sponsor personnel, including the Sponsor Committee, will remain 
blinded to all Part 2 data and any subsequent IDMC data reviews concerning Part 2 until the end 
of the double-blind phase of Part 2 of the study. Only the IDMC will remain unblinded for Part 2 
data during the double-blind phase of each individual patient.
After enrolment has been expanded beyond the participants in Part 1, the efficacy monitoring will 
be conducted by the IDMC using all the data available at that time to protect the well-being of the 
participants against unexpected absence of further HDV RNA decline and/or HDV RNA 
rebound/breakthrough contrary to the initial antiviral activity signal. 
The criteria to assess the antiviral activity or to declare futility will be based on predefined 
thresholds for HDV RNA and HBsAg reductions from baseline. Details are provided in 
Section 3.3.3.
3.1.1.
Internal Data Review Committee
The Members of the Sponsor Committee will form a newly established Internal Data Review 
Committee (DRC) which replaces the IDMC once all patients have completed the double-blind 
phase. The DRC will monitor SAEs, AEs leading to discontinuation, and ALT flares during the 
open-label and follow-up phases of the study. The committee will meet periodically to review data 
of the efficacy parameters measured by different HBV and HDV disease blood markers (eg, HDV 
RNA, HBV DNA, HBeAg, HBsAg, etc). DRC members will not be involved in the study conduct.
3.2.
Independent Flares Expert Panel
An independent flare expert panel (IFLEP) will be appointed. The IFLEP is composed of 
3 independent medical experts with experience and expertise in HBV/HDV. The responsibilities 
of the IFLEP include: conduct regular review of all relevant and available individual participant 
blinded study data related to ALT flares; determine and adjudicate each ALT flare; and provide 
documentation of the final decision to IDMC. Adjudication review cycles will match IDMC 
schedule and will be set up ideally 2 weeks before IDMC. 
In order to allow for an unbiased assessment, members of the committee will not serve as study 
investigators or as members of the IDMC. They will be unblinded to treatment assignment for all 
Part 1 participants from the time of Part1 IA1 and will remain blinded to the treatment assigned to 
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each participant of Part 2. Further details on the IFLEP process will be included in the IFLEP 
charter.
HBV Flares are defined in Section 5.5.1.1.11.
3.3.
Data Reviews and Interim Analyses
The IDMC will conduct unblinded periodic safety data reviews to ensure the continuing safety of 
the study participants during the entire course of the study. 
The primary aim of Part 1 is to assess if the antiviral activity criteria to start Part 2 are met and to 
exclude futility of the regimen JNJ-3989+NA. As introduced in Section 3.1, the IDMC will also 
periodically review unblinded efficacy parameters measured by different HDV and HBV disease 
blood markers (e.g., HDV RNA, HBV DNA, HBsAg, and HBeAg) to support the detection of 
anti-HDV viral activity and to protect the well-being of the participants against the eventuality of 
lack of sufficient efficacy after Part 2 of the study has started enrolling.
3.3.1.
Data Reviews
The IDMC will periodically review unblinded cumulative safety and efficacy data at the following 
timepoints:
Reviews by the IDMC before Part 2 has started (up to approximately 20 participants randomized 
into the study)

The first data review (DR) will be performed after approximately 8 participants completed 8 
weeks of treatment.

Thereafter, data reviews will occur approximately every 4 weeks.
Reviews by the Sponsor Committee and selected Study Team members before Part 2 has started
It is worth noting that during this period, the SC will perform every 2 weeks an unblinded review 
of accruing HDV RNA and HBsAg data to assess the antiviral activity based on criteria defined in 
Section 3.3.3. 
Due to the higher than expected rate of ALT elevations observed among several participants 
randomized in Part 1, even if the antiviral activity criteria are met, the Sponsor Committee will not 
initiate Part 2 yet, and continue to review the Part 1 data (see Section 3.3.2.1.1). The Sponsor 
Committee will make the decision to start Part 2 based on data from or after Part 1 IA1, jointly 
with the IDMC and unblinded Study team members, based on the preliminary evaluation of the 
benefit/risk ratio of the investigational treatment regimen. 
For safety-related decisions and participant’s safety management, selected unblinded data (e.g. 
HDV RNA and hepatitis B surface antigen [HBsAg]) and treatment assignment will be available 
to selected team members to instruct the sites to discontinue study treatment in patients receiving 
active treatment and meeting the additional discontinuation criteria defined in the Protocol 
Amendment #2.
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Reviews by the IDMC after Part 2 has started (enrollment extended beyond the first approximately 
20 participants)

The first data review will be performed after approximately 12 weeks since the start of Part 2 
(enrollment expanded to >20 participants).

Data reviews will occur approximately every 8 weeks up until decision in Protocol 
Amendment #4 to stop the enrollment. 

Thereafter, data reviews will occur approximately quarterly.
It is worth noting that after the decision is made (either to start Part 2 or declare futility), the SC
and selected study team members will not review any Part 2 data any longer, and will remain 
blinded to all Part 2 data (Section 1.5) for the rest of the study up to the end of the double-blind 
phase for each individual patient (see Section 5.2).Safety data comprising AEs, SAEs, AEs of 
special interest, laboratory data, and any other data applicable for the study, will be summarized, 
plotted and provided as appropriate.
HDV RNA, HBV DNA, HBsAg, and HBeAg values and changes from baseline will be 
summarized by intervention arm over time. Count and proportions of participants achieving given 
cutoffs in absolute values and/or reductions from baseline will be summarized descriptively. 
The overview of data domains and specific endpoints that will be provided to the IDMC for review 
is provided in Table 3. Details on the type of summaries and analyses of both efficacy and safety 
variables are described in the following sections.
Table 3:
Overview of Times of Unblinding and Data Summaries and Analyses at Planned Data Review 
Milestones and IAs
DR’s
Before 
Part 2 
starts
IA1 
Part1(1)  
IA2
Part1
(2)
DR’s
After Part 2 
has started 
and 
quarterly
Primary 
Analysis 
Open 
Label 
IAs
UNBLINDING
IDMC
X
X
X
X
X
X
X
Sponsor Committee/DRC(3)
X
X
X
X
X
Study Team
X(4)
X(4)
X
X
DATA DOMAINS FOR 
ANALYSIS
Subject Information 
Baseline & Demographic 
characteristics
X
X
X
X
X
X
Disposition and Study Populations 
X
X
X
X
X
X
X
Extent of Exposure 
X
X
X
X
X
X
Safety 
TEAEs, SAEs, AE of interest, fatal 
AEs, AEs causing treatment 
discontinuation
X
X
X
X
X
X
Laboratory Tests
X
X
X
X
X
X
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DR’s
Before 
Part 2 
starts
IA1 
Part1(1)  
IA2
Part1
(2)
DR’s
After Part 2 
has started 
and 
quarterly
Primary 
Analysis 
Open 
Label 
IAs
ECG
X
X
X
X
X
X
Vital signs
X
X
X
X
X
X
Efficacy
Primary efficacy endpoint
X
X
X
X
X
X
Key secondary efficacy endpoints
X
X
X
X
Values and changes over time in 
HDV RNA,  HBV DNA, HBsAg 
and HBeAg
X
X
X
X
X
X
Proportion of participants with 
HDV RNA reduction ≥ 0.5 log10
IU/mL, ≥1 log10 IU/mL, ≥ 2 log10 
IU/mL
X
X
X
X
X
X
Proportion of participants with 
HDV RNA <LLOQ and TND
X
X
X
X
X
X
Proportion of participants with 
HBsAg reduction ≥0.5 log10 IU/mL, 
≥1  log10 IU/mL and ≥2  log10 
IU/mL
X
X
X
X
X
X
Values and changes over time ALT 
X
X
X
X
X
X
Proportion of participants with 
normal ALT
X
X
X
X
X
X
Virologic breakthrough HDV
X
X
X
X
X
X
Virologic breakthrough HBV
X
X
X
X
X
X
Flares: Viral, Biochemical, Clinical 
X
X
X
X
X
X
(1) Part 1 IA1 will be performed when all participants will have completed at least Week 16 or discontinued earlier
(2) Part 1 IA2 will be performed when all participants will have completed at least Week 48 or discontinued earlier
(3) Prior to Part 1 IA1, the Sponsor Committee will review unblinded aggregated interim data of HDV RNA, HBsAg, 
ALT, AST, total and direct bilirubin, HBV DNA and individual patient profiles for the values/changes from baseline 
over time for all participants in Part 1 including those randomized to the placebo+NA arm. At time of Part 1 IA1, the 
Sponsor Committee will review all unblinded efficacy and safety results from Part 1 IA1.
(4) Operational Study team members involved with and at the sites will remain blinded together with investigators 
and participants.
3.3.2.
Interim, Primary and Final Analyses
During the Double-Blind Treatment Phase:
Part 1 : 
Part 1 IA1: One IA will be conducted after all participants of Part 1 have completed at least Week 
16 (or discontinued earlier), to enable initiation of Part 2. At the time of this first IA in Part 1, 
members of the Study team [as described in Table 3, footnote 5)] will be unblinded to the Part 1 
clinical data.
Part 1 IA2: This IA will be conducted by the Sponsor after all participants of Part 1 have completed 
at least Week 48 visit (or discontinued earlier) to continue a comprehensive assessment of the 
benefit-risk ratio of the investigational regimen in HDV-infected participants with longer term data 
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on participants in Part 1. All Sponsor personnel unblinded for Part 1 IA1 will also be unblinded 
for Part 1 IA2.
Part 2 : 
During the Open-label follow-up phase:
One IA will be conducted after all participants have finished open-label phase or discontinued 
earlier to assess safety and evaluate the time course of different disease markers to support the 
sponsor’s interactions with health authorities.
The primary analysis of this study will be performed when the last participant in the study has 
reached study visit Week 48 or has discontinued earlier. 
The final analysis will be performed when all participants in the study (both parts if Part 2 of the 
study has started) have reached the final study visit FU Week 48 or have discontinued earlier.
3.3.2.1.
IAs During the Double-Blind Treatment Phase
3.3.2.1.1.
Part 1 IA1
This IA will be conducted by the Sponsor and will provide unblinded aggregated summaries and 
individual profiles for selected unblinded safety and virology activity parameters (including, but 
not limited to, HDV RNA and HBsAg data) after all participants in Part 1 have completed at least 
Week 16 or discontinued earlier. It will allow a more in-depth assessment of the benefit-risk ratio 
of the investigational regimen by the Sponsor and the IDMC to better characterize the observed 
ALT elevations and to decide whether or not Part 2 can be initiated. This decision may be also 
based on data available after the Part 1 IA1 cut-off. The Sponsor will be unblinded to the Part 1 
clinical data although the investigators, participants, site personnel, and operational Sponsor team 
members involved with the sites will remain blinded. Following this IA, the Sponsor (as defined 
above, i.e excluding the operational team) will be unblinded to the rest of Part 1 data.
3.3.2.1.2.
Part 1 IA2
After all participants in Part 1 have completed at least Week 48 (or discontinued earlier), a second 
IA of Part 1 data will be performed by the Sponsor to evaluate additional safety and efficacy data 
for the participants in Part 1 to monitor the benefit/risk ratio of the investigated regimen, regardless 
whether or not Part 2 has been initiated. While the Study Team, Sponsor Committee and IDMC 
will be unblinded to Part1 IA2, the investigators, participants, site personnel, and operational 
Sponsor team members involved with the sites will remain blinded. For safety-related decisions 
and participant’s safety management, selected unblinded virology activity data (e.g. HDV RNA 
and hepatitis B surface antigen [HBsAg]) may be discussed with investigators on a case by case 
basis).
In case Part 2 has started prior to the timing of this IA of Part 1, there is no impact on keeping the 
blind of Part 2. All Sponsor personnel, including the Sponsor Committee, will remain blinded to 
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all Part 2 data, any subsequent IDMC data reviews concerning Part 2 until the end of the double-
blind phase for each individual patient.
3.3.2.2.
IA at the end of Open-label Phase
The IA at the end of the open-label phase of the study is planned when all participants have 
reached: 

Week 144 (Arm 1) and Week 148 (Arm 2), that is, end of treatment [EOT], or discontinued 
earlier.
Additional IAs may be performed by the sponsor in the open-label phase, given the long duration 
of the study and the uncertainty of the exact timing of future interactions with health authorities 
relative to the actual completion of enrollment and time of execution of the primary efficacy 
analysis. 
3.3.3.
Rule to Start Part 2 of the Study or Determine Futility
The SC will be unblinded to treatment allocation in the exploration of antiviral activity criteria in 
Part 1 based on aggregate interim data of HDV RNA and HBsAg, as well as individual HDV RNA 
and HBsAg profiles. This is to assess whether the initial and early evaluation of antiviral activity 
warrants the enrollment of participants beyond the subjects in Part 1. 
Due to the higher than expected rate of ALT elevations observed during the double-blind treatment 
phase among several participants in Part 1, the Sponsor has amended the protocol to introduce Part 
1 IAs to allow a better characterization of the acute ALT elevations. Hence, the SC decision to 
initiate Part 2 will not be made before the review of the results of Part 1 IA1, which will include 
unblinded safety and virology activity data.
However, as soon as Part 2 commences, the SC and Sponsor personnel will be blinded to all Part 
2 data. Study site personnel, investigators and participants will have no access to any of the HDV 
RNA and HBsAg evaluations performed by the IDMC at any time during Part 2.
The SC will use the rule described below to decide whether antiviral activity can be declared, as 
well as to declare futility if Step 4 is reached. The decision outcome will depend on the timing 
when the rule is met or not, and after the evaluation of the results of Part 1 IA1.
Antiviral activity criteria to start Part 2
At least 8 participants in Arm 1 have: 
a
On-treatment HDV RNA reduction from baseline at any time ≥ 0.5 log10 and
b
On-treatment HBsAg reduction from baseline at any time ≥0.5 log10 and
c
(≥ 4 participants have on-treatment HDV RNA reduction from baseline at any time ≥ 1 log10)
or (≥4 participants have on-treatment HDV RNA continuous decline at least at the last 2 
timepoints)
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Step 1 – When the first 8 participants randomized to Arm 1 have at least 8 weeks of data assess
the antiviral activity criteria a) and b) and c). If criteria a) and b) and c) are met, start Part 2.
Otherwise, go to Step 2.
Step 2- If the criteria a) and b) and c) are not met at Step 1, repeat the review of HDV RNA and 
HBsAg incremental data available every 2 weeks and make a decision as described in Step 1. If 
Part 2 has not started by the time 16 participants in Arm 1 have reached Week 36, go to Step 3.
Step 3 – If criteria a) and b) and c) have not been met when all 16 participants randomized to 
active Arm 1 have at least 36 weeks of data, the decision to start Part 2 of the study will be based 
on the following more detailed rule:

If 4 or fewer participants out of 16 meet the two criteria a) and b) described above, then Part 2 
will not start

If 5-7 out of 16 participants meet the 2 criteria a) and b) described above, then Part 2 might be 
started depending on a further review of the individual longitudinal profiles of HDV RNA and 
HBsAg of all participants. The totality of the HDV RNA and HBsAg data for the participants 
so far in the study will be taken into account to properly evaluate the magnitude of change and 
variability over time of the blood markers for each individual.
Step 4 – If Part 2 has not started based on data at Step 3, repeat the review of HDV RNA and 
HBsAg incremental data available every 2 weeks and make a decision following the rule described 
in Step 3. If the detailed rule described in Step 3 has not been met by the time when 16 participants 
randomized to active Arm 1 have at least 44 weeks of data, the study will be stopped for futility.
The antiviral activity criteria become the futility criteria if the antiviral activity is not observed by 
Week 44 in the 16 participants randomized to JNJ-3989+NA in Part 1. It is worth noting that if the 
treatment appears ineffective, the futility is declared to avoid that up to 20 participants will be 
treated for much longer than 1 year. 
Since the data for Part 1 and Part 2 are analyzed separately there will be no penalty on the alpha 
level of one-sided 0.025, used in the efficacy comparisons as described in the rest of this document.
If Part 2 of the study begins, the SC will stop reviewing any Part 2 data and remain blinded to any 
Part 2 data for the rest of the study up to the time of the primary analysis (see Section 5.2). 
However, the IDMC will continue monitoring the efficacy data, as well as safety, for both the first 
20 subjects randomized in Part 1 and the accruing participants in Part 2. The IDMC will start their 
review of the HDV and HBV markers 12 weeks after opening of Part 2. This is to ensure the well-
being of all participants and avoid HDV RNA rebound/ or unexpected absence/insufficient 
efficacy trends in terms of HDV RNA/HBsAg declines after Part 2 has been opened and more data 
will be available. The primary efficacy endpoint will not be reviewed by the IDMC.
Details on the operating characteristics of the antiviral activity criteria to start Part 2 and futility 
rule are presented in 0.
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4.
SUBJECT INFORMATION
All the summaries will be done on the ITT analysis set unless specified otherwise. Subject 
information analyses will be reported by study Parts 1 and 2, as well as for the whole study overall.
4.1.
Disposition Information
The number and percentage of participants who are screened, screened failure and reason for that 
screening failure will be tabulated. Only an all participants group (total N) will be provided.
A summary of the number of participants randomized, randomized and not treated, in the safety, 
ITT, and mITT sets, respectively, will be summarized by intervention arm. Summaries will be 
repeated also by DB, OL and FU study phase. 
Completion/withdrawal information, study disposition and treatment disposition will be 
summarized for the ITT, mITT and safety sets (only for ITT and mITT sets if the safety set is 
identical to ITT). 
An overview of the study disposition will be provided by intervention arm and overall. The number 
and percentage of participants who completed or discontinued (or are ongoing [except the final 
analysis]) and the number and percentage of participants for each study discontinuation reason will
be summarized. The number and percentage of participants under each phase (i.e. double-blind/ 
open-label study intervention phase, follow-up phase) will also be tabulated.  
An overview of the treatment disposition will be provided. The number and percentage of 
participants who completed or discontinued study treatment or were ongoing at the time of the 
data reviews or IAs cutoff (except the final analysis) will be presented by treatment and 
intervention arm and phase. The incidences of treatment discontinuation reasons will also be 
summarized by study intervention arm for each treatment and overall and by phase. 
A listing including information (i.e. the date of last study visit, the last study phase and time point 
[phase and week], the date of discontinuation and the reason) on participants which prematurely 
discontinue from the study and/or study treatment will be included. Information on the NA 
treatment, discontinuation and/or re-treatment will also be included.
4.2.
Demographic and Baseline Characteristics
Tabulations of demographic and baseline characteristics will be presented by intervention arm and 
overall for the ITT and mITT analysis sets. Continuous variables will be summarized by 
descriptive statistics including the number of participants, mean, standard deviation, median and
range. Categorical/binary variables will be summarized by counts and percentages.
Additional summaries will be presented by the 3 randomization stratification factors (by presence 
of compensated cirrhosis at screening, and HDV RNA testing laboratory location, and HBeAg 
status at screening. The randomization stratification factors are reported by IWRS and also entered 
in the Electronic Case Report Form (eCRF). A cross–tabulation of the stratification factors 
collected by the IWRS vs. eCRF will also be provided by intervention arm to identify any 
mismatch. In case of discrepancies between the 2 sources, the randomization factors as entered in 
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the eCRF will be used in the analyses/summaries. If the eCRF data is missing, then the IWRS data 
will be used.
4.2.1.
Baseline Characteristics
For the viral activity parameters (e.g. HDV RNA, HBeAg, HBsAg, HBV DNA, HBV RNA, 
HBcrAg, anti-HBs antibody, anti-HBe antibody), baseline values are used unless specified 
differently.

Duration of HBV infection (Years) = (date of randomization – date of HBV infection 
+1)/365.25; rounded to 1 decimal

Time since HBV diagnosis (Years) = (date of randomization –
date of HBV 
diagnosis+1)/365.25; rounded to 1 decimal

Mode of HBV infection: Sexual transmission, intravenously injectable drug use, blood 
transfusion, hemophilia-associated injection, occupational exposure, mother to child 
transmission, unknown and other.

Duration of HDV infection (Years) = (date of randomization – date of HDV infection 
+1)/365.25; rounded to 1 decimal

Time since HDV diagnosis (Years) = (date of randomization –
date of HDV 
diagnosis+1)/365.25; rounded to 1 decimal

Mode of HDV infection: co-infection, super-infection, Other, Unknown.

Presence of compensated cirrhosis at screening: Yes, No

Has never received HBV treatment (only for currently not treated participants): Yes, No

Type of NA at baseline: TeD, TAF, ETV, None

NA Treatment history at screening:
o
Yes
o
No

Duration of NA at baseline (Years) = (Sum of all NA treatment duration [prior to 
randomization])/365.25; rounded to 1 decimal; calculated as: end date – start date +1. If for 
the latest NA treatment an end date is missing, randomization date is used.

HDV RNA at baseline (quantitative: IU/mL and log10 IU/mL)

HDV RNA category at baseline:
o
Participants with HDV RNA < LLOQ
o
Participants with HDV RNA < LLOQ TND
o
Participants with HDV RNA < LLOQ TD
o
Participants with HDV RNA < 500 IU /mL
o
Participants with HDV RNA ≥ 500 IU /mL
o
Participants with HDV RNA < 10000 IU/mL
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o
Participants with HDV RNA > 10000 IU/mL and <100000 IU/mL
o
Participants with HDV RNA ≥100000 IU/mL

Liver Stiffness Measurement (LSM) at baseline (quantitative)

LSM category at baseline: 2 kPa - < 7.1 kPa, ≥7.1 kPa - < 9.5 kPa, ≥ 9.5 kPa - < 12.5 kPa, ≥ 
12.5 kPa

HBeAg status at screening: positive, negative

HBeAg at baseline (quantitative): values in IU/mL and log10 IU/mL (for HBeAg positive 
participants only)

HBsAg at baseline (quantitative): values in IU/mL and log10 IU/mL  

HBsAg category at baseline (quantitative: IU/mL):
o
Participants with HBsAg <500 IU/mL 
o
Participants with HBsAg <1,000 IU/mL
o
Participants with HBsAg <10,000 IU/mL
o
Participants with HBsAg ≥10,000 IU/mL

HBV DNA at baseline (quantitative): values in IU/mL and log10 IU/mL

HBV DNA category at baseline (quantitative: IU/mL):
o
Participants with HBV DNA < LLOQ (20 IU/mL or 10 IU/mL for the new assay) 
o
Participants with HBV DNA < 60 IU/mL
o
Participants with HBV DNA < 2,000 IU/mL 
o
Participants with HBV DNA < 20,000 IU/mL
o
Participants with HBV DNA ≥ 20,000 IU/mL

HBV RNA (quantitative): values in copies/mL and log10 copies/mL

HBV RNA category at baseline (quantitative: copies/mL):
o
Participants with HBV RNA < LOD
o
Participants with HBV RNA < LLOQ
o
Participants with HBV RNA ≥LLOQ

Hepatitis B core related antigen (HBcrAg) at baseline (quantitative): values in log U/mL

HBcrAg category at baseline (quantitative: log10 U/mL):
o
Participants with HBcrAg <3 log10 U/mL
o
Participants with HBcrAg≥3 log10 U/mL-<4 log10 U/mL
o
Participants with HBcrAg≥4 log10 U/mL

HBsAg Antibody (Anti-HBs) category at baseline (quantitative: mIU/mL):
o
Participants with Anti-HBs<10 mIU/mL
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o
Participants with Anti-HBs≥10 mIU/mL

HBeAg Antibody (Anti-HBe) status at baseline (qualitative): Positive, Negative, Borderline

Anti-HDV status at baseline: Positive, Negative 

Alanine aminotransferase (ALT) at baseline:
o
Baseline ALT values (U/L)
o
Baseline ALT toxicity grade according to DAIDS
o
Baseline ALT categorization (≤ 1.0xULN, > 1.0xULN to <2.5xULN, ≥ 2.5xULN)

Stage of liver fibrosis: F0, F1, F3 or F4

HBV genotype (using the INNO-LiPA or sequence based HBV genotying data): Genotype A, 
B, C, D, E, F, G, H, I, J and Unknown 
4.2.2.
Demographic Characteristics
The following demographic characteristics will be summarized by study intervention arm and 
overall. 

Sex: Male, Female

Age (years)

Age categories: 18 years - ≤30 years, > 30 years -≤ 45 years, > 45 years-≤60 years, > 60 
years

Race: American Indian or Alaska Native, Asian (Japanese, Other Asian), Black or African 
American, Native Hawaiian or Other Pacific Islander, White, Not reported, Unknown
o
In case the participant is Asian provide subgroup: Asian Indian, Chinese, Filipino, 
Japanese, Korean, Vietnamese, Other Asian

Ethnicity: Hispanic or Latino, Not Hispanic or Latino, Not Reported, Unknown

Region: Asia (China, Japan, and Other Asian Country), Europe, North America, South 
America

Height at baseline (cm)

Weight at baseline (kg)

Body mass index (BMI) at baseline (kg/m2) = weight at baseline (kg) / (height at baseline 
(m))2 (rounded to 1 decimal)

Body mass index group: Underweight <18.5, Normal ≥18.5-<25, Overweight ≥25-<30 and 
Obese ≥30           

History of Tobacco use: Yes/No 

Type of Substance (Beer, Wine, Distilled Spirits): Current/Former/Never 

Type of Substance (Beer, Wine, Distilled Spirits) Duration (Months) = (stop date – start date 
+1)/30.4375; rounded to 1 decimal 
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4.3.
Medical History
A tabulation of the general medical history coded terms will be provided by body system class and 
by intervention arm.
4.4.
Prior and Concomitant Medications
All medications will be coded using the World Health Organization-Drug Dictionary. Tabulations 
will include prior and concomitant medications which are defined as follows:
(i)
Prior medications are defined as medications with a start date occurring before the date 
of DB Day 1 regardless of when dosing of the medication ended. 
(ii)
Concomitant medications are defined as medications received on or after Day 1, 
medication that was received before initial dosing and continued after initial dosing of 
the study interventions, or medication with missing stop date.  
Medication that started before the Day 1 and continued afterwards will be summarized both as 
prior and, separately, as concomitant medication. All concomitant medications will be allocated to 
one or multiple analysis phases depending on their start date and end date and also taking into 
account the eCRF flag to indicate if it is taken before/after study start or still ongoing.
A frequency tabulation of prior medications, and concomitant medications will be shown by 
Anatomical Therapeutic Chemical (ATC) class level 2, level 4 and preferred terms by intervention 
arm. In addition, the concomitant medications will be summarized by analysis phase. A listing of 
prior medications and concomitant medications respectively, will be also provided.
4.5.
Protocol Deviations
Major protocol deviations will be based on clinical review, but not limited to, the following 
criteria: (1) entered but did not satisfy inclusion/exclusion criteria, (2) received wrong treatment 
or incorrect dose, (3) received a disallowed concomitant treatment, (4) developed withdrawal 
criteria but not withdrawn, (5) other. Protocol deviations will be closely monitored during the 
execution of the study and the final set of protocol deviation criteria will be finalized before the 
primary analysis database lock.
All major protocol deviations will be tabulated by coded term by intervention arm for the ITT 
analysis set. A listing of the major protocol deviations will be also presented.
In addition, the use of the mITT analysis set in the efficacy analyses will be determined based on
the impact of the COVID-19 or similar pandemics prior to database lock for the first IA (i.e. IA 
during the DB intervention phase for sample size re-estimation). The number and percentage of 
participants in ITT vs mITT will be summarized by intervention arm.
4.6.
Extent of Exposure
Extent of exposure to study treatments will be summarized and presented based on the safety 
analysis set. The total duration of exposure during the DB and OL study intervention phases will 
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be calculated by each study treatment (JNJ-3989/placebo and NA) separately and summarized 
descriptively by intervention arm. The duration of treatment with NA will be summarized also for 
the follow up phase for participants with presence of compensated cirrhosis at screening by 
intervention arm. 
Because of the different route and frequency of treatment administration across the 2 study 
treatments (for JNJ-3989/placebo one subcutaneous injection once every 4 weeks, and for NA 
once daily tablet), the total duration of exposure (weeks) will be calculated by analysis phase for 
each agent as follows:

For the DB study intervention phase:
o
JNJ-3989/placebo: [Min ((Date of last injection in the DB intervention phase +27 days),
Early study withdrawal visit date, cut-off date) – date of first injection in the DB phase 
+ 1] / 7
o
NA: [Min (Date of the last NA administration in the DB phase, Date of discontinuation 
from NA, Early study withdrawal visit date, cut-off date) - first drug administration 
date in the DB phase + 1] / 7

For the OL study intervention phase (only for participants with non-missing OL phase start 
date, as defined in Section 2.1.1):
o
JNJ-3989: [Min ((Date of last injection in the OL phase +27 days), Early study 
withdrawal visit date, cut-off date) – Week 52 study agent intake date + 1] / 7 
o
NA: [Min (Date of the last NA administration in the OL phase, Date of discontinuation 
from NA, Early study withdrawal visit date, cut-off date) - Week 52 NA intake date + 
1] / 7
Cutoff dates will be defined to match the prespecified timepoints for IDMC periodical data reviews, 
interim analyses and the primary and final analyses, respectively (see Section 3.3).
The number and percentage of participants who skipped any dose of JNJ-3989/placebo or NA will 
be summarized separately for each study treatment by intervention arm during the DB and OL 
study intervention phases, separately. Additionally, the number and percentage of participants who 
missed 2 or more consecutive JNJ-3989/placebo injections, or who missed more than 5 doses of 
NA within a four-week period will be presented.
For NA treatment, the total duration of exposure will be calculated separately for the DB, OL and 
FU study phases. 

For the FU study phase:
o
NA: [Min (Date of the last NA administration in the FU study phase, Date of 
discontinuation from NA, Date of trial disposition, Date of clinical cut-off) - first drug 
administration date in the FU phase + 1] / 7
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Those participants who stopped NA treatment at Week 144/Week 148 and never restarted NA 
treatment thereafter will be counted as having zero weeks of NA exposure during the FU study
phase.
4.7.
Treatment Compliance
Treatment compliance will be summarized for the safety analysis set by intervention arm for each 
study treatment except NA.
DB Treatment compliance (%) is defined as follows.
For JNJ-3989/placebo: (Total number of injections received/ 13) * 100%
OL Treatment compliance (%) is defined as follows.
For JNJ-3989 in Arm 1: (Total number of injections received/ 23) * 100%
For JNJ-3989 in Arm 2: (Total number of injections received/ 24) * 100%
5.
EFFICACY
The primary analysis set will be the ITT analysis set (see definition in Section 2.3), unless specified 
otherwise. Efficacy assessments over time will be performed at the analysis time points defined in 
Section 2.1.3. However, the use of the mITT analysis set (instead of ITT) in the efficacy analyses 
will be determined based on the impact of the COVID-19 or similar pandemics and assessed prior 
to the database lock for the first IA during DB study intervention phase.
All efficacy data will be summarized by study Parts 1 and 2, as well as for the whole study data 
overall:
-
For DB study intervention phase: by study intervention arm over time (when applicable), as 
well as by study part (1 and 2).
-
For OL study intervention and Follow-up phases: by study intervention arm over time and by 
study part 1 and 2. Additional selected efficacy analyses will be conducted to compare the OL 
study intervention data from Week 52 to Week 148 in Arm 2 with data from the first 96 weeks 
of DB study intervention in Arm 1 (i.e same duration of exposure toJNJ-3989+NA in both 
arms). See Section 5.5.1.4 for more details.
Subgroup analyses will be conducted on Part 2 data alone as well as combined data (Part 1 and 
Part 2) to leverage the total sample size of the entire study. Subgroup analyses will be performed 
if their size is at least 10% of the total sample size. All analyses will be presented only in a 
descriptive fashion.
For OL intervention and FU study phases, all efficacy data will be presented only descriptively,
and no formal testing will be performed. 
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5.1.
Analysis Specifications
In general, continuous variables will be summarized using descriptive statistics including the 
number of participants, mean, standard deviation (SD), two-sided 95% confidence interval (CI),
median, and range). Binary or categorical variables will be summarized using the number and 
percentage of participants in each category. For time-to-event variables, a summary table including 
number of participants included in the analysis, number of participants censored, 25th and 75th
percentiles and median time-to event will be shown. Descriptive summaries will be provided by 
stratification factors presence of compensated cirrhosis at screening (yes or no) (Part 1 only), HDV 
RNA testing laboratory location (China versus outside China), and HBeAg status at screening 
(positive vs negative). Graphic displays will also be used to summarize the data.
5.1.1.
Virology Data Handling Rules
Those measurements collected from screening visit to the end of study will be handled according 
to the following rules in Table 4.
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Table 4:
Data Handling Rules for HDV and HBV Virology and Serology Assessments
Key: NA=Not applicable
(a) LLOQ/2
(b) ULOQ+(ULOQ/10)
(c) If the original result > ULOQ, then take the re-test value (i.e. diluted result). If the diluted result is not 
available, use the imputed value indicated in this table
All other viral activity data with values <LLOQ which are not included in the data handling rules 
above will be imputed by the absolute value divided by 2.
HDV 
parameter
LLOQ
ULOQ
Imputed Values
   If value< LLOQ              If value> ULOQ
HDV RNA
For outside of 
China :
LLOQ = 63 
IU/mL
LOD = 14 IU/mL
NA
For outside of China :
Main imputation: 
If <LLOQ 
31.5 IU/mL
Exploratory Imputation: 
If LLOQ TD: 31.5 IU/ml
If LLOQ TND: 15.75 
IU/ml(a)
NA
HBV 
parameter
LLOQ
ULOQ
Imputed Values
   If value< LLOQ              If value> ULOQ
HBsAg
0.05 IU/mL
124,925.00  IU/mL
w/o dilution
249,750.00  IU/mL 
with dilution
0.025 IU/mL (a)
137,417.5  IU/mL(b)(c)
w/o dilution
274,725.00  IU/mL (c)
with dilution
HBeAg
0.11 IU/mL
1,400.00 IU/mL w/o 
dilution
7,000.00 IU/mL with 
dilution
0.055 IU/mL (a)
1,540.00IU/mL(b) (c) w/o 
dilution
7,700.00 IU/mL (c) with 
dilution
HBcrAg
3.0 log10 U/mL
7.0 log10 U/mLw/o 
dilution
9.0 log10 U/mL with 
dilution
2.7 log10 U/mL
7.7 log10 U/mL(b)(c)
w/o dilution
9.9 log10 U/mL (b)
with dilution
HBV DNA
20 IU/mL For 
Roche CAP/CTM
Assay
10IU/mL for 
Roche COBAS 
6800 assay
170,000,000 IU/mL 
w/o dilution
If < LLOQ: 5 IU/mL
187,000,000(b)(c) w/o 
dilution
HBV RNA
LLOQ = 2.939
log10 cp/mL (i.e 
869 cp/mL)
LOD = 1.398 
log10 cp/mL (i.e 
25 cp/mL)
NA
If < LOD or target not 
detected then 1.114 log10 
cp/mL (13 cp/mL)
NA
Anti-HBs
5mIU/mL
10000.0 mIU/mL
2.5 mIU/mL(a)
11000.0 mIU/mL (b)
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5.2.
Primary and Final Analyses
The primary analysis of this study will be performed when the last participant in the study has 
reached study visit Week 48 or has discontinued earlier.
The final analysis will be performed when all participants in the study (both parts if Part 2 of the 
study has started) have reached the final study visit FU Week 48 or have discontinued earlier.
5.3.
Primary Efficacy Endpoint
5.3.1.
Definition
The primary efficacy endpoint is defined as the proportion of participants with normal ALT
(defined as ALT < ULN with ULN = 34 U/L for female and 43 U/L for male) in combination with 
HDV RNA ≥2 log10 IU/mL decline from baseline and/or HDV RNA TND at Week 48. 
5.3.2.
Main Estimand for the Primary Endpoint
Primary Study Objective: To evaluate the efficacy of JNJ-3989 + NA regimen versus Placebo + 
NA in reducing HDV replication and associated liver inflammation.
Scientific question: in the adult non-cirrhotic population co-infected with HBV and HDV, what 
is the benefit of JNJ-3989 (100mg Q4W) in combination with NA compared with Placebo + NA 
for 48 weeks in reducing HDV replication measured by HDV RNA and liver inflammation
measured by ALT?
The main estimand for the primary endpoint is characterized by the following attributes:
A) Study Intervention:

Arm 1: JNJ-3989 + NA

Arm 2: Placebo + NA 
B) Study population: Non-cirrhotic patients 18 to 65 years of age, inclusive, with HBV/HDV 
co-infection
C) Variable: Response status defined as having HDV RNA decline ≥2 log10 IU/mL from 
baseline or HDV RNA TND in combination with normal ALT at Week 48 
D) Intercurrent events (ICEs):

Treatment discontinuation prior to Week 48: if the participant discontinued treatment prior 
to Week 48 then the participant will be considered as non-responder (composite strategy).

Selected major protocol deviations affecting efficacy: 0 identifies deviations considered 
ICE. Participants with such deviations and who have missing ALT and/or HDV RNA data
for the primary endpoint at Week 48 will be considered as non-responders (composite 
strategy). 

Deaths prior to Week 48 are handled in a composite strategy as participants who die prior 
to Week 48 will be considered as non-responders.
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Status: Approved, Date: 09 August 2023
E) Population level summary: Difference in proportion of responders defined by the primary 
endpoint between the two intervention arms (Arm 1 – Arm 2).
5.3.2.1.
Main Estimator of the Main Estimand for the Primary Endpoint
5.3.2.1.1.
Analysis Methods 
Statistical Model
The proportion of responders will be compared between the 2 arms using the stratum-adjusted 
Mantel-Haenszel (MH) test on the difference of proportions, with the following stratification 
factors: HDV RNA testing laboratory location (China versus outside China) and HBeAg status at 
screening (positive vs negative). 
5.3.2.1.2.
Data Included
All available data from randomized participants that have received at least one dose are included 
(ITT analysis set in Part 2), after taking into account all the ICEs and applying the ICE strategies 
in Section 5.3.2.
5.3.2.1.3.
Assumptions

Missing Data for HDV RNA and ALT are Missing At Random (MAR)

The treatment effect is homogeneous across strata 
5.3.2.1.4.
Missing Data Handling Rule

Participants who withdraw from the study prior to Week 48 will be considered as non-
responders. 

For participants who remain in the study at Week 48 after experiencing a major protocol 
deviation defined for the purpose of efficacy analyses, which is an ICE, and have missing 
HDV RNA and/or ALT values at Week 48, then the imputation to non-response will be 
applied. If the value for the primary endpoint at Week 48 is available, then such data will be 
used to determine their response status.

For participants who remain the study at Week 48 and have had no major protocol deviations 
defined as ICE and have the values of HDV RNA and ALT available, such data will be used 
to determine their response status.

For participants who remain in the study at Week 48 and who have not experienced any major 
protocol deviations defined for the purpose of efficacy analyses as ICE, and has missing HDV 
RNA and/or ALT values missing at Week 48, then the primary method to handle missing data 
will be the Multiple Imputation (MI) approach3 under the assumption of MAR, applied in a 
joint fashion to leverage the correlation between HDV RNA and ALT values over time.
The multiple imputation (MI) model will use all available data and be applied to the continuous 
HDV RNA and ALT values (not the binary endpoint). Of note, also the pre-ICE data for those 
subjects who experienced an ICE will be included in the MI model; but for these subjects the 
response status will be applied according to the ICE strategies before running the MI model.
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The model will include treatment, the 3 randomization factors, the available non-missing log-
transformed HDV RNA data (values < LLOQ, < LOD TND or < LOD TD will be first substituted 
following the main rules described in Table 4, ALT values for each scheduled time point (Week) 
and the following demographic and baseline characteristics4,6: age, gender, and baseline value for 
HDV RNA level, ALT level, HBsAg level, and HBV DNA level.
Depending on the amount of missing data, the number of imputed datasets to be generated will be 
10 and will be adjusted appropriately to ensure robustness in the results 5.
5.3.2.2.
Sensitivity Estimators of the Main Estimand for the Primary Endpoint
Sensitivity analyses will be conducted by constructing a different sensitivity estimator for the 
primary estimand as defined in Section 5.3.2. The estimator will use Missing as Non-Responsedata 
imputation rule.
5.3.2.2.1.
Sensitivity Estimator of the Main Estimand (Missing as Non-
Response) for the Primary Endpoint
For this sensitivity estimator, the same statistical model (stratum-adjusted MH test) and data 
included will be used as for the main estimator (Section 5.3.2.1). The assumption for missing data 
and the rule to handle missing data have changed.
5.3.2.2.1.1.
Assumptions

Missing Data for HDV RNA and ALT are Missing Not At Random (MNAR)

The treatment effect is homogeneous across strata
5.3.2.2.1.2.
Missing Data Handling Rule
Participants who withdraw from the study prior to Week 48 will be considered as non-responders. 
All participants with missing data for the determination of the primary endpoint will be imputed 
as non-responders.
5.3.2.3.
Supplementary Estimators of the Main Estimand for the Primary 
Endpoint
Supplementary analysis to better interpret the primary analysis results will be conducted by 
constructing additional estimator for the main estimand of the primary endpoint as defined in 
Section 5.3.2. This estimator will be based on the mITT set (instead of ITT) for participants in Part 
2. To provide a comprehensive interpretation of the study results and the impact of COVID-19 
pandemic, the following supplementary estimator will utilize the mITT analysis set for participants 
in Part 2. The supplementary estimator analysis will only be performed if there is a difference of 
more than 5% from ITT to mITT.
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5.3.2.3.1.
Supplementary Estimator (mITT + Missing as Non-Response) of the 
Main Estimand for the Primary Endpoint
For this supplementary estimator, the same estimand defined in Section 5.3.2, statistical model 
(stratum-adjusted MH test) and assumptions will be used as for the main estimator 
(Section 5.3.2.1).  
5.3.2.3.2.
Data Included
All available data from mITT analysis set in Part 2, after taking into account all the ICEs and 
applying the ICE strategies specified in the previous Section 5.3.2, will be included.
5.3.2.3.3.
Assumptions

Missing Data for HDV RNA and ALT are Missing Not At Random (MNAR)

The treatment effect is homogeneous across strata 
5.3.2.3.4.
Missing Data Handling Rule
The missing data approach will follow the missing as non-response approach as described in 
Section 5.3.2.2.1.2.
5.3.3.
Subgroup analyses 
Subgroup analyses will be performed on the primary endpoint by the subgroups defined in 
Section 2.4.1. Subgroup analyses, as exploratory, will be conducted on Part 2 data alone as well 
as combined data (Part 1 and Part 2) to leverage the total sample size of the entire study. They will 
only be performed if their size is more than 10% of the total sample size. 
The potential association between the primary efficacy endpoint and the selected demographic and 
baseline characteristics (in Section 2.4.1) will be explored using a logistic regression model which 
will be estimated for each subgroup variable, one at a time. The factors in each model will be 
treatment arm, the randomization stratification factors, the subgroup variable, and the treatment-
by-stage and treatment-by-subgroup variable as the interaction-terms. The Firth's penalized 
likelihood method9,10 (as implemented in SAS PROC LOGISTIC) will be used in the logistic 
regression to reduce possible bias which could arise in the presence of a zero-response rate in one 
or more subgroup levels and/or intervention arms. 
Corresponding 95% CIs will be also calculated. A forest plot will present graphically the endpoint 
estimates resulting from the models described above, by treatment arm and the prespecified 
subgroup levels, with the corresponding 95% CIs.
5.4.
Key Secondary Endpoints (KSE)
All key secondary endpoints will be summarized individually by intervention arm, stage and study 
parts (Parts 1 and 2, as well as for the whole study data overall). The statistical analysis will follow 
the estimand and estimators framework as described in the following sections. Testing will be 
performed by providing adjusted p-values as per Section Error! Reference source not found..
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5.4.1.
KSE1: HDV RNA Decline from Baseline ≥2 log10 IU/mL or HDV RNA 
TND at Week 48 
5.4.1.1.
Definition
The first key secondary efficacy endpoint (KSE 1) is defined as the proportion of participants with 
HDV RNA decline ≥2 log10 IU/mL from baseline or HDV RNA TND at Week 48.
5.4.1.2.
Main Estimand for the KSE1
Study Objective: To evaluate the efficacy of JNJ-3989 + NA regimen versus Placebo + NA in 
reducing HDV replication.
Scientific question: in the adult population co-infected with HBV and HDV, what is the benefit 
of JNJ-3989 (100mg Q4W) in combination with NA compared with Placebo + NA for 48 weeks 
in reducing HDV replication?
The main analysis of this endpoint will be addressed by using the following estimand attributes: 
A) Study Intervention:

Arm 1: JNJ-3989+NA

Arm 2: NA alone
B) Study population: Non-cirrhotic patients 18 to 65 years of age, inclusive, with HBV/HDV co-
infection. 
C) Variable: Response status defined as having HDV RNA decline ≥2 log10 IU/mL from 
baseline or HDV RNA TND at Week 48
D) Intercurrent events:

Treatment discontinuation prior to Week 48: if the participant discontinued treatment prior 
to Week 48 then the participant will be considered as non-responder (composite strategy).

Selected major protocol deviations affecting efficacy: 0 identifies deviations considered as 
ICEs. Participants with such deviations and who have missing data for HDV RNA at Week 
48 will be considered as non-responders (composite strategy). 

Deaths prior to Week 48 are handled in a composite strategy as participants who die prior 
to Week 48 will be considered as non-responders.
E) Population level summary: Difference in proportion of responders defined by KSE 1 between 
the two intervention arms.
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5.4.1.2.1.
Main Estimator of the Main Estimand for the KSE1
5.4.1.2.1.1.
Analysis Methods
Statistical Model
The same stratum-adjusted MH test on the difference of proportions as described for the main 
estimator of the main estimand for the primary endpoint will be used (see Section 5.3.2.1).
5.4.1.2.1.2.
Data Included
All available data from ITT analysis set in Part 2, after taking into account all the ICEs and 
applying the ICE strategies specified in the previous Section 5.4.1.2, will be included.
5.4.1.2.1.3.
Assumptions

Missing Data for HDV RNA are Missing At Random (MAR)

The treatment effect is homogeneous across strata 
5.4.1.2.1.4.
Missing Data Handling Rule

Participants who withdraw from the study prior to Week 48 will be considered as non-
responders. 

For participants who remain in the study at Week 48 after experiencing a major protocol 
deviation defined for the purpose of efficacy analyses, which is an ICE, and have missing 
HDV RNA at Week 48, then the imputation to non-response will be applied. If the value for 
the primary endpoint at Week 48 is available, then such data will be used to determine their 
response status.

For participants who remain the study at Week 48 and have had no major protocol deviations 
defined as ICE and have the values of HDV RNA available, such data will be used to 
determine their response status.

For the participants who remain in the study at Week 48 and who have not experienced any 
major protocol deviations defined for the purpose of efficacy analyses as ICE, and has missing
HDV RNA values missing at Week 48, then missing data will be imputed by the values 
obtained from the MI model performed for the main estimator of the primary efficacy endpoint 
to leverage the correlations between HDV RNA and ALT values (see Section 5.3.2.1.4). Once 
the HDV RNA values at Week 48 are obtained, the binary key secondary endpoint will be 
derived and analyzed as described in Section 5.3.2.1.
5.4.1.2.2.
Sensitivity Estimators of the Main Estimand for the KSE1
Sensitivity analyses will be conducted by constructing a sensitivity estimator for the main estimand 
of KSE1 as defined in Section 5.4.1.2. This sensitivity estimator will be similar to the one defined 
for the main estimand of the primary endpoint, i.e it will use Missing as Non-Response data 
imputation rule.
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5.4.1.2.2.1.
Sensitivity Estimator of the Main Estimand (Missing as Non-
Response) for the KSE1
For this sensitivity estimator, the same statistical model (stratum-adjusted MH test) and data 
included will be used as for the main estimator (Section 5.4.1.2.1). The assumption for missing 
data and the rule to handle missing data have changed.
5.4.1.2.2.1.1.
Assumptions

Missing Data for HDV RNA are Missing Not At Random (MNAR)

The treatment effect is homogeneous across strata
5.4.1.2.2.1.2.
Missing Data Handling Rule
Participants who withdraw from the study prior to Week 48 will be considered as non-responders. 
All participants with missing HDV RNA data for the determination of the KSE1 will be imputed 
as non-responders.
5.4.1.2.3.
Supplementary Estimators of the Main Estimand for the KSE1
Supplementary analyses to better interpret the results will be conducted by constructing additional 
estimator for the main estimand of the KSE1 as defined in Section 5.4.1.2. This supplementary 
estimators will be similar to the sensitivity estimator of the main estimand (Section 5.4.1.2.2) but 
based on the mITT set (instead of ITT) for participants in Part 2: mITT + Missing as Non-Response 
(Supplementary Estimator). The supplementary estimator analysis will only be performed if there 
is a difference of more than 5% from ITT to mITT.
5.4.2.
KSE2: Normal ALT at Week 48 
5.4.2.1.
Definition
The second key secondary efficacy endpoint is defined as the proportion of participants with 
normal ALT at Week 48.
5.4.2.2.
Main Estimand for the KSE2
Study Objective: To evaluate the efficacy of JNJ-3989 + NA regimen versus Placebo + NA in 
reducing liver inflammation.
Scientific question: in the adult population co-infected with HBV and HDV, what is the benefit 
of JNJ-3989 (100mg Q4W) in combination with NA for 48 weeks in reducing liver inflammation?
The main analysis of this endpoint will be addressed by using the following estimand attributes: 
A) Study Intervention:

Arm 1: JNJ-3989+NA

Arm 2: NA alone
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B) Study population: Non-cirrhotic patients 18 to 65 years of age, inclusive, with HBV/HDV co-
infection. 
C) Variable: Response status defined as having normal ALT at Week 48
D) Intercurrent events:

Treatment discontinuation prior to Week 48 if the participant discontinued treatment prior 
to Week 48 then the participant will be considered as non-responder (composite strategy).

Selected major protocol deviations affecting efficacy: 0 identifies deviations considered as 
ICEs. Participants with such deviations and who have missing data for ALT at Week 48 
will be considered as non-responders (composite strategy). 

Deaths prior to Week 48 are handled in a composite strategy as participants who die prior 
to Week 48 will be considered as non-responders.
E) Population level summary: Difference in proportion of responders defined by KSE2 between 
the two intervention arms.
5.4.2.2.1.
Main Estimator of the Main Estimand for the KSE2
5.4.2.2.1.1.
Analysis Methods
Statistical Model
The same stratum-adjusted MH test on the difference of proportions as described for the main 
estimator of the main estimand for the primary endpoint will be used (see Section 5.3.2.1).
5.4.2.2.1.2.
Data Included
All available data from ITT analysis set in Part 2, after taking into account all the ICEs and 
applying the ICE strategies specified in the previous Section 5.4.2.2, will be included.
5.4.2.2.1.3.
Assumptions

Missing Data for ALT are Missing At Random (MAR)

The treatment effect is homogeneous across strata 
5.4.2.2.1.4.
Missing Data Handling Rule

Participants who withdraw from the study prior to Week 48 will be considered as non-
responders. 

For participants who remain in the study at Week 48 after experiencing a major protocol 
deviation defined for the purpose of efficacy analyses, which is an ICE, and have missing 
ALT at Week 48, then the imputation to non-response will be applied. If the ALT value for 
the KSE2 at Week 48 is available, then such data will be used to determine their response 
status.
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
For participants who remain the study at Week 48, have had no major protocol deviations 
defined as ICE and have the values of ALT available, such data will be used to determine their 
response status.

For the participants who remain in the study at Week 48 and who have not experienced any 
major protocol deviations defined for the purpose of efficacy analyses as ICE, and has missing 
ALT values missing at Week 48, then missing data will be imputed by the values obtained 
from the MI model performed for the main estimator of the primary efficacy endpoint to 
leverage the correlations between HDV RNA and ALT values (see Section 5.3.2.1.4). Once 
the ALT values at Week 48 are obtained, the binary key secondary endpoint will be derived 
and analyzed as described in Section 5.3.2.1.
5.4.2.2.2.
Sensitivity Estimators of the Main Estimand for the KSE2
Sensitivity analyses will be conducted by constructing a sensitivity estimator for the main estimand 
of KSE2 as defined in Section 5.4.2.2. This sensitivity estimator will be similar to the one defined 
for the main estimand of the primary endpoint, i.e it will use different Missing as Non-Response
data imputation .
5.4.2.2.2.1.
Sensitivity Estimatorof the Main Estimand (Missing as Non-
Response) for the KSE2
For this sensitivity estimator, the same statistical model (stratum-adjusted MH test) and data 
included will be used as for the main estimator (Section 5.4.2.2.1). The assumption for missing 
data and the rule to handle missing data have changed.
5.4.2.2.2.1.1.
Assumptions

Missing Data for ALT are Missing Not At Random (MNAR)

The treatment effect is homogeneous across strata
5.4.2.2.2.1.2.
Missing Data Handling Rule
Participants who withdraw from the study prior to Week48 will be considered as non-responders. 
All participants with missing ALT data for the determination of the KSE2 will be imputed as non-
responders.
5.4.2.2.3.
Supplementary Estimators of the Main Estimand for the KSE2
Supplementary analysis to better interpret the results will be conducted by constructing additional 
estimator for the main estimand of the KSE2 as defined in Section 5.4.2.2. This supplementary 
estimator will be similar to the sensitivity estimator of the main estimand (5.4.2.2.2) but based on 
the mITT set (instead of ITT) for participants in Part 2 : mITT + Missing as Non-Response 
(Supplementary Estimator). The supplementary estimator analysis will only be performed if there 
is a difference of more than 5% from ITT to mITT.
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5.4.2.2.4.
Main Estimator of the Supplementary Estimand for the KSE2
5.4.2.2.4.1.
Analysis Methods 
Statistical Model
Similar stratum-adjusted MH test on the difference of proportions as described for the main 
estimator of the main estimand will be used (see section 5.4.1.2.1).
5.4.2.2.4.2.
Data Included
All available data from randomized participants in Part 2 that are included in the mITT analysis 
set will be used, after taking into account the ICEs and applying the ICE strategies specified in 
Section 5.4.2.2.
5.4.2.2.4.3.
Assumptions

The treatment effect is homogeneous across strata 
5.4.2.2.4.4.
Missing Data Handling Rule
Participants who withdraw from the study prior to Week 48 will be considered non-responders. 
For the participants who remain in the study at Week 48 and who have not experienced an ICE as 
listed in 0, but with ALT values missing at Week 48, then the method to handle missing data will 
be the imputation to non-responder. 
5.4.3.
KSE3: HBsAg Seroclearance at Week 48
5.4.3.1.
Definition
The third key secondary efficacy endpoint is defined as the proportion of participants with HBsAg 
seroclearance i.e. with HBsAg (quantitative) < LLOQ (see Table 4) at Week 48.
5.4.3.2.
Main Estimand for the KSE3
Study Objective: To evaluate the efficacy of JNJ-3989 + NA regimen versus Placebo + NA in 
reducing HBsAg levels.
Scientific question: in the adult population co-infected with HBV and HDV, what is the benefit 
of JNJ-3989 (100mg Q4W) in combination with NA compared with Placebo + NA for 48 weeks 
in reducing HBsAg levels?
The main analysis of this endpoint will be addressed by using the following estimand attributes: 
A) Study Intervention:

Arm 1: JNJ-3989+NA

Arm 2: NA alone
B) Study population: Non-cirrhotic patients 18 to 65 years of age, inclusive, with HBV/HDV 
co-infection. 
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C) Variable: HBsAg level at Week 48
D) Intercurrent events:

Treatment discontinuation prior to Week 48: if the participant discontinued treatment prior 
to Week 48 then the participant will be considered as non-responder (composite strategy).

Selected major protocol deviations affecting efficacy: 0 identifies deviations considered 
as ICEs. Participants with such deviations and who have missing data for HBsAg at Week 
48 will be considered as non-responders (composite strategy). 

Deaths prior to Week 48 are handled in a composite strategy as participants who die prior 
to Week 48 will be considered as non-responders.
E) Population level summary: Difference in proportion of participants with HBsAg 
seroclearance at Week 48 between the two intervention arms.
5.4.3.2.1.
Main Estimator of the Main Estimand for the KSE3
5.4.3.2.1.1.
Analysis Methods
Statistical Model
The same stratum-adjusted MH test on the difference of proportions as described for the main 
estimator of the main estimand for the primary endpoint will be used (see Section 5.3.2.1).
5.4.3.2.1.2.
Data Included
All available data from ITT analysis set in Part 2, after taking into account all the ICEs and 
applying the ICE strategies specified in the previous Section 5.4.3.2, will be included.
5.4.3.2.1.3.
Assumptions

Missing Data for HBsAg are Missing At Random (MAR)

The treatment effect is homogeneous across strata. 
5.4.3.2.1.4.
Missing Data Handling Rule

Participants who withdraw from the study prior to Week 48 will be considered as non-
responders. 

For participants who remain in the study at Week 48 after experiencing a major protocol 
deviation defined for the purpose of efficacy analyses, which is an ICE, and have missing 
HBsAg at Week 48, then the imputation to non-response will be applied. If the HBsAg value 
for the KSE4 at Week 48 is available, then such data will be used to determine their response 
status.

For participants who remain the study at Week 48, have had no major protocol deviations 
defined as ICE and have the values of HBsAg available, such data will be used to determine 
their response status.
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
For the participants who remain in the study at Week 48 and who have not experienced any 
major protocol deviations defined for the purpose of efficacy analyses as ICE, and have
missing HBsAg values missing at Week 48, missing data will be imputed using a MI model.
The MI model will use all available data and be applied to the continuous HBsAg values (not the 
binary endpoint). Of note, also the pre-ICE data for those subjects who experienced an ICE will 
be included in the MI model; but for these subjects the response status will be applied according 
to the ICE strategies before running the MI model.
The MI model will include treatment, the 3 randomization factors, the available non-missing log-
transformed HBsAg (values < LLOQ will be first substituted following rules described in Table 
4) for each scheduled time point (Week) and the following demographic and baseline 
characteristics4,6: age, gender, and baseline value for HDV RNA level, ALT level, HBsAg level, 
and HBV DNA level.
The details on the implementation of this MI model will follow the same steps as described in 
Section 5.3.2.1.4. 
5.4.4.
KSE4 : Reduction in LSM From baseline to Week 48
5.4.4.1.
Definition
The fourth key secondary efficacy endpoint is defined as the proportion of participants with LSM
reduction ≥2kPa from baseline to Week 48 as assessed by vibration-controlled transient 
elastography (VCTE) (FibroScan).
5.4.4.2.
Main Estimand for the KSE4
Study Objective: To evaluate the efficacy of JNJ-3989 + NA regimen versus Placebo + NA in 
reducing liver fibrosis.
Scientific question: in the adult population co-infected with HBV and HDV, what is the benefit 
of JNJ-3989 (100mg Q4W) in combination with NA compared with Placebo + NA for 48 weeks 
in reducing liver fibrosis determined using LSM?
The main analysis of this endpoint will be addressed by using the following estimand attributes: 
A) Study Intervention:

Arm 1: JNJ-3989+NA

Arm 2: NA alone
B) Study population: Non-cirrhotic patients 18 to 65 years of age, inclusive, with HBV/HDV 
co-infection
C) Variable: Response status defined as having reduction in LSM from baseline ≥ 2 kPa at Week 
48 as assessed by VCTE (Fibroscan)
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D) Intercurrent events:

Treatment discontinuation prior to Week 48: if the participant discontinued treatment prior 
to Week 48 then the participant will be considered as non-responder (composite strategy).

Selected major protocol deviations affecting efficacy: 0 identifies deviations considered 
as ICEs. Participants with such deviations and who have missing data for LSM at Week 
48 will be considered as non-responders (composite strategy). 

Deaths prior to Week 48 are handled in a composite strategy as participants who die prior 
to Week 48 will be considered as non-responders.
E) Population level summary: Difference in proportion of responders defined by KSE3 between 
the two intervention arms.
5.4.4.2.1.
Main Estimator of the Main Estimand for the KSE4
5.4.4.2.1.1.
Analysis Methods
Statistical Model
The same stratum-adjusted MH test on the difference of proportions as described for the main 
estimator of the main estimand for the primary endpoint will be used (see Section 5.3.2.1).
5.4.4.2.1.2.
Data Included
All available data from ITT analysis set in Part 2, after taking into account all the ICEs and 
applying the ICE strategies specified in the previous Section 5.4.4.2, will be included.
5.4.4.2.1.3.
Assumptions

Missing Data for LSM are Missing At Random (MAR)12

The treatment effect is homogeneous across strata. 
5.4.4.2.1.4.
Missing Data Handling Rule

Participants who withdraw from the study prior to Week 48 will be considered as non-
responders. 

For participants who remain in the study at Week 48 after experiencing a major protocol 
deviation defined for the purpose of efficacy analyses, which is an ICE, and have missing 
LSM at Week 48, then the imputation to non-response will be applied. If the LSM value for 
the KSE3 at Week 48 is available, then such data will be used to determine their response 
status.

For participants who remain the study at Week 48 and have had no major protocol deviations 
defined as ICE and have the values of LSM available, such data will be used to determine 
their response status.

For the participants who remain in the study at Week 48 and who have not experienced any 
major protocol deviations defined for the purpose of efficacy analyses as ICE, and has missing 
LSM values at Week 48, then they will be considered as non-responder (composite strategy).
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5.4.5.
Subgroup analyses 
Subgroup analyses will be performed on the key secondary endpoints by the subgroup variables
listed in Section 2.4.1. The same analysis as defined in Section 5.3.3 will be performed.
5.5.
Other Secondary Endpoints
Other secondary endpoints will be summarized descriptively by intervention arm, by study phase
(unless specified otherwise), timepoint and study part. No imputation rule will be used in case of 
missing data and the analysis will be based on observed cases. Statistical analyses of selected other 
secondary endpoints will be done with no adjustment for multiplicity.
The following on and off-treatment periods will be used for all secondary efficacy endpoints:
-
For all HBV endpoints:
o
On-treatment will be defined as the time periods in which the participant receives 
any of the study interventions (JNJ-3989/placebo and/or NA). 
o
Off-treatment will be defined as the periods when the participants do not receive any 
of the study interventions (JNJ-3989/placebo and NA).
-
For all HDV endpoints:
o
JNJ-3989 on-treatment will be defined as the time period in which the participant 
receives JNJ-3989/placebo (regardless of continuing NA treatment).
o
JNJ-3989 off-treatment will be defined as the time period in which the participant is 
not receiving JNJ-3989 (regardless of continuing NA treatment).
The following on and off-treatment nadirs will be used for all secondary efficacy endpoints:
o
On-treatment nadir will be defined as the lowest value during the on-treatment 
period up to the time of assessment.
o
JNJ-3989 on-treatment nadir will be defined as the lowest value during the JNJ-
3989 on-treatment period up to the time of assessment.
o
Off-treatment nadir will be defined as the lowest value during the off-treatment 
period up to the time of assessment.
o
JNJ-3989 off-treatment nadir will be defined as the lowest value during the JNJ-
3989 off-treatment period up to the time of assessment.
o
Overall nadir will be defined as the lowest value collected during the study up to the 
time of assessment.
A confirmed criteria means that the criteria should be fulfilled at 2 or more consecutive time points 
or at the last observed time point.
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5.5.1.
Definition
5.5.1.1.
Binary Endpoints
The number and proportion of participants experiencing the endpoints defined in the following 
subsections will be calculated and summarized as specified in Section 5.5.2.1.
5.5.1.1.1.
HDV RNA Decline and Normal ALT
The following individual and combined endpoints related to HDV RNA decline and normal ALT
will be evaluated over time during the study intervention and follow-up phases:

HDV RNA ≥2 log10 IU/mL decline from baseline or TND in combination with normal ALT.

HDV RNA ≥2 log10 IU/mL decline from baseline or HDV RNA TND.

HDV RNA ≥2 log10 IU/mL decline from baseline in combination with normal ALT.

HDV RNA ≥2 log10 IU/mL decline from baseline or < LLOQ in combination with normal 
ALT.

HDV RNA ≥2 log10 IU/mL decline from baseline or < LLOQ 

HDV RNA TND in combination with normal ALT.

HDV RNA < LLOQ in combination with normal ALT.

HDV RNA ≥2 log10 IU/mL decline from baseline.

HDV RNA TND.

HDV RNA < LLOQ

ALT categorization (≤ 1.0xULN, > 1.0xULN to <2.5xULN, ≥ 2.5xULN)
Those endpoints will be analyzed as observed case without imputation (for combined endpoints, 
in case one of the two individual parameters is missing for a specific timepoint, the endpoint will 
be considered missing for that timepoint).
5.5.1.1.2.
HDV RNA Cut-offs
HDV RNA will be analyzed over time using binary endpoints on both absolute values and 
reductions from baseline
The cutoffs for HDV RNA absolute values are as follows: 

<LLOQ
o
<LLOQ TND
o
<LLOQ TD

> LLOQ

< 2,000 IU/mL

< 10,000 IU/mL
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
The cutoffs for HDV RNA reductions from baseline are as follows:

≥1 log10 IU/mL

≥2 log10 IU/mL

≥3 log10 IU/mL

≥4 log10 IU/mL
5.5.1.1.3.
Virologic HDV RNA Breakthrough
Two types of HDV RNA breakthroughs will be defined using 2 distinct thresholds:
Confirmed JNJ-3989 on-treatment increase in HDV RNA of >1log10 IU/mL from JNJ-3989 on-
treatment nadir in participants who did not have HDV RNA JNJ-3989 on-treatment nadir < LLOQ 
or confirmed >1log10 IU/mL (i.e., 630 IU/ml) above LLOQ of the HDV RNA assay in participants 
who had HDV RNA JNJ-3989 on-treatment nadir <LLOQ.
Confirmed JNJ-3989 on-treatment increase in HDV RNA of >2log10 IU/mL from JNJ-3989 on-
treatment nadir in participants who did not have HDV RNA JNJ-3989 on-treatment nadir < LLOQ
or confirmed >2log10 IU/mL above LLOQ of the HDV RNA assay in participants who had HDV 
RNA JNJ-3989 on-treatment nadir <LLOQ.
5.5.1.1.4.
JNJ-3989 Off-Treatment HDV RNA Relapses
JNJ-3989 off-treatment HDV RNA relapse will be defined using 2 distinct rules:
1) In participants with HDV RNA <LLOQ (i.e., 630 IU/ml) at EOT: Confirmed increase in HDV 
RNA of > 1 log10 IU/mL above the LLOQ JNJ-3989 off-treatment.
2) In participants with HDV RNA >LLOQ at EOT: Confirmed increase in HDV RNA of > 1 log10
IU/mL from EOT HDV RNA value JNJ-3989 off-treatment.
5.5.1.1.5.
JNJ-3989 Off-treatment HDV Clinical Flares
An JNJ-3989 off-treatment HDV clinical flare is defined as a confirmed increase in HDV RNA of 
> 1 log10 IU/mL above the LLOQ JNJ-3989 off-treatment and confirmed ALT and/or AST >=3x 
ULN and >=3x JNJ-3989 off-treatment nadir during the follow-up phase.
The start date of an JNJ-3989 off-treatment HDV clinical flare is defined as the minimum date 
between the date when the confirmed HDV RNA criterion is met and start date of the JNJ-3989 
off-treatment biochemical flare.
The end date of a JNJ-3989 off-treatment HDV clinical flare is defined as either:
-
The maximum date between HDV RNA increase returns to ≤1 log10 IU/mL and the date when 
a 50% reduction from the peak ALT and/or AST level is reached.
-
Or the date of JNJ-3989 treatment restart, whichever comes first.

1 (Yes)= confirmed HDV RNA of > 1 log10 IU/mL above the LLOQ JNJ-3989 off-
treatment and confirmed ALT and/or AST≥3x ULN and ≥3x JNJ-3989 off-treatment nadir 
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
0 (No) = otherwise

2 (Not applicable) = no JNJ-3989 off-treatment HDV RNA and/or ALT/AST quantitative 
measurements available.
5.5.1.1.6.
JNJ-3989 Off-treatment Sustained HDV Response 
A JNJ-3989 off-treatment sustained HDV response is defined by having HDV RNA TND during 
the FU phase after stopping JNJ-3989 regardless of continuing NA treatment. 
Alternative JNJ-3989 off-treatment sustained HDV responses will be evaluated using the 
following definitions:

Having HDV RNA < LLOQ during the FU phase

Having HDV RNA TND with normal ALT during the FU phase

Having HDV RNA < LLOQ and normal ALT during the FU phase

HDV RNA > 2 log10 IU/mL decline from baseline and normal ALT during the FU phase.
Participants with missing HDV RNA at a specific timepoint will be considered as non-responders 
for that timepoint. No imputation rule will be used in case of missing data.
5.5.1.1.7.
HBsAg Seroclearance
HBsAg seroclearance (i.e quantitative HBsAg < LLOQ) will be evaluated at all time points when 
assessed, and analyzed as observed case without imputation, with emphasis at the following time 
points:

At Week 48 (Also defined as KSE 4, see section 5.4.3)

Week 96

Week 144/EOT

FU Week 24 

FU Week 48 
Of note, HBsAg seroclearance may be achieved prior to the FU Week 12, 24, 36, or 48, 
respectively, but must be observed at the given week of interest.
Note that HBsAg seroclearance at Week 48 is used for one of the key secondary endpoints and 
specific imputation rules applied. However, for this analysis over time, HBsAg data at Week 48
will be treated similarly to the other timepoints, i.e no imputation will be done in case of missing 
value.
5.5.1.1.8.
HBsAg Seroconversion
Seroconversion of HBsAg is defined as having achieved HBsAg seroclearance and appearance of 
anti-HBs antibodies.
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The seroconversion will only be assessed at the time points when the anti-HBs antibodies 
assessment is available. If the HBsAg value is missing at that specific time point, then the non-
missing lab test closest to that specific timepoint will be used. If the non-missing lab test before 
and after the specific timepoint fall equidistant from the target timepoint, the later one will be used 
to impute the missing value.
Appearance of anti-HBs antibodies is defined as a baseline anti-HBs antibodies (quantitative) 
<LLOQ and a post-baseline assessment ≥LLOQ. A sensitivity analysis will be conducted using 
the threshold of 10 mIU/mL, i.e. appearance of anti-HBs antibodies is defined as a baseline anti-
HBs antibodies (quantitative) <10 mIU/mL and a post-baseline assessment ≥10 mIU/mL.
5.5.1.1.9.
Virologic HBV Breakthrough
Virologic HBV breakthrough is defined as having a confirmed on-treatment HBV DNA increase 
by >1 log10 from on-treatment nadir level in participants who did not have on-treatment HBV DNA 
<LLOQ or a confirmed on-treatment HBV DNA level >200 IU/mL in participants who had on-
treatment HBV DNA <LLOQ. 
In addition, participants who experience a virologic breakthrough followed by on-treatment 
biochemical flare (see Section 5.5.1.1.11) will be evaluated.
5.5.1.1.10.
HBsAg, HBeAg and HBV DNA Cut-offs
HBsAg, HBeAg (only for participants HBeAg-positive at screening) and HBV DNA will be 
analyzed over time using binary endpoints on both absolute values, change (log10 transformed) 
and reductions (log10 transformed) on from baseline.
The cutoffs for HBsAg absolute values are as follows:

<1000 IU/mL

<100 IU/mL

<10 IU/mL

<1 IU/mL

< LLOQ (0.05 IU/mL)

The cutoffs for HBsAg reductions from baseline are as follows:

≥1 log10 IU/mL 

≥2 log10 IU/mL 

≥3 log10 IU/mL 

≥4 log10 IU/mL 
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The cutoffs for HBeAg absolute values are as follows:

< 10 IU/mL

< 1 IU/mL

< LLOQ (0.11 IU/mL) 
The cutoffs for HBeAg reductions from baseline are as follows:

≥0.5 log10 IU/mL

≥1 log10 IU/mL

≥2 log10 IU/mL

≥3 log10 IU/mL
The cutoffs for HBV DNA absolute values are as follows: 

<LLOQ

< 2000 IU/mL

> 2000 IU/mL

The cutoffs for HBV DNA reduction from baseline are as follows: 

≥1 log10 IU/mL

≥2 log10 IU/mL

≥3 log10 IU/mL

≥4 log10 IU/mL
5.5.1.1.11.
HBV Flares
The criteria based on blood markers/lab tests for each of the flare types are defined as below.
a) HBV Virologic flare is defined as follows:
Derivation 1. This derivation of virologic flare will be assessed only for those participants 
who are off-treatment and had HBV DNA<LLOQ at the last observed point on-treatment.
The start date of a confirmed virologic flare is defined as the first date of two consecutive visits 
with HBV DNA > 200 IU/mL. The end date of the same confirmed virologic flare is defined 
as the first date when HBV DNA value returns to ≤200 IU/mL or the date of treatment restart 
(ie JNJ-3989 and/or NA), whichever comes first. Each virologic flare will be categorized based 
on the confirmed (ie two consecutive values) peak HBV DNA above any of the three thresholds 
within the start and end date of that flare as follows: 20,000 IU/mL 2,000 IU/mL and 200 
IU/mL.
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
1 (Yes) = confirmed HBV DNA > peak threshold

0 (No) = at least one off-treatment HBV DNA measurement available and not meeting the 
criteria of confirmed HBV DNA > peak threshold.

2 (Not applicable) = no off-treatment HBV DNA quantitative measurements available.
Derivation 2. This derivation of virologic flare will be assessed only for those participants 
who are off-treatment and had HBV DNA ≥LLOQ at the last observed point on-treatment.
The start date of a confirmed virologic flare is defined as the first date of two consecutive visits 
with HBV DNA log10 increase > 1 log10 from EOT. The end date of the same confirmed 
virologic flare is defined as the first date when HBV DNA log10 increase from EOT returns 
to ≤1 log10 or the date of treatment restart (ie JNJ-3989 and/or NA), whichever comes first. 
Each virologic flare will be categorized based on the confirmed (ie, two consecutive values) 
peak HBV DNA increase above any of the three thresholds within the start and end date of that 
flare as follows: 1 log10, 2log10, 3 log10.

(Yes) = confirmed HBV DNA increase from EOT > peak threshold

0 (No) = at least one off-treatment HBV DNA measurement available and not meeting the 
criteria of confirmed HBV DNA increase from EOT > peak threshold.

2 (Not applicable) = no off-treatment HBV DNA quantitative measurements available.
b) Off-treatment HBV biochemical flare is defined as follows:
The start date of a confirmed off-treatment biochemical flare is defined as the first date of two 
consecutive visits with ALT and/or AST ≥3x ULN and ≥3x nadir (ie, lowest value observed 
up to the start of the flare). The end date of the same off-treatment biochemical flare is defined 
as the first date when there is a 50% reduction from the peak ALT and/or AST level or the date 
of treatment restart (ie JNJ-3989 and/or NA), whichever comes first.

1 (Yes) = confirmed ALT and/or AST ≥3x ULN and ≥3x nadir (ie, lowest value observed 
up to the start of the flare)

0 (No) = otherwise
c) On-treatment HBV biochemical flare is defined as follows:
The start date of a confirmed on-treatment biochemical flare is defined as the first date of two 
consecutive visits with ALT and/or AST ≥3x ULN and ≥3x nadir  (ie, lowest value observed up 
to the start of the flare). The end date of the same on-treatment biochemical flare is defined as the 
first date when there is a 50% reduction from the peak ALT and/or AST level, regardless of 
stopping JNJ-3989 and/or NA.

1 (Yes) = confirmed ALT and/or AST ≥3x ULN and ≥3x nadir (ie, lowest value observed up 
to the start of the flare)

0 (No) = otherwise
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d) HBV Clinical flare is defined as follows:
A HBV clinical flare occurs either when a HBV virologic flare and off-treatment HBV 
biochemical flare overlap in time or when a HBV biochemical flare starts within 4 weeks 
following the end of a HBV virologic flare.
The start date of a HBV clinical flare is defined as the minimum start date of the HBV virologic 
flare and HBV biochemical flare. The end date of a HBV clinical flare is defined as the 
maximum end date of the HBV virologic flare and HBV biochemical flare, ie, the later date 
between HBV DNA returns to ≤ 200 IU/mL (or ≤1 log10) and 50% reduction from the peak 
ALT and/or AST level reached during the HBV biochemical flare.

1 (Yes)= confirmed HBV DNA > peak threshold (for derivation 1 of virologic flare) or 
HBV DNA increase from end of treatment > peak threshold (for derivation 2 of virologic 
flare) and confirmed ALT and/or AST≥3x ULN and ≥3x nadir  (ie, lowest value observed 
up to the start of the flare)

0 (No) = otherwise
The HBV virologic and clinical flares will be assessed only off-treatment, while biochemical 
flares will be identified on-treatment and off-treatment, respectively. On-treatment virologic 
flares are described as virologic HBV breakthrough in Section 5.5.1.1.9.
5.5.1.1.12.
ALT/AST Elevations
ALT/AST elevation is defined as follows:
The start date of a confirmed ALT/AST elevation is defined as the first date of two consecutive 
visits with ALT and/or AST ≥3x ULN and ≥2x  nadir (ie, lowest value observed up to the start of 
the flare). The end date of the same ALT/AST elevation is defined as the first date when ALT 
(and/or AST) < 3xULN or ALT (and/or AST) < 2x  nadir  (ie, lowest value observed up to the start 
of the flare) whichever comes first.

1 (Yes) = confirmed ALT and/or AST ≥3x ULN and ≥2x nadir (ie, lowest value observed up 
to the start of the flare)

0 (No) = otherwise
5.5.1.1.13.
Liver Stiffness Measurement 
The proportion of participants with the following LSM changes from baseline (both in terms of 
reductions and increases) will be evaluated over time:

≥ 1 kPa

≥ 2 kPa

≥ 4 kPa

≥ 6 kPa
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Only participants from sites with available VCTE (Fibroscan) will be included in the analysis. 
Within these participants, missing LSM (in kPa) at a specific timepoint will be considered as non-
responders for that timepoint.
5.5.1.2.
Values and Changes Over Time 
Change from baseline is defined as the value at a given time point minus the baseline value.
Actual values (original unit and log10 transformed values, where applicable) and changes from 
baseline (log10 transformed values, where applicable) will be derived for the following parameters:
HDV virology:

HDV RNA (original unit and log10 transformed values)
Liver inflammation 

ALT
Liver Fibrosis:

Liver stiffness measurement assessed by vibration-controlled transient elastography 
(FibroScan)
HBV virology and serology:

HBsAg (original unit and log10 transformed values)

HBeAg (only for participants HBeAg-positive at screening; original unit and log10
transformed values)

HBV RNA (original unit and log10 transformed values)

HBV DNA (original unit and log10 transformed values)
5.5.1.3.
Time to Event Endpoints
5.5.1.3.1.
Time to Event Endpoints Based on Parameters Used in Key 
Secondary Endpoints 
All time to event endpoints will analyzed throughout the entire study (and not by study phase) 
using DB day 1 as reference timepoint by study part.
5.5.1.3.1.1.
Time to HDV RNA ≥2 log10 IU/mL Decline or HDV RNA TND or <LLOQ
Time to reach HDV RNA ≥2log10 IU/mL decline or HDV RNA TND is defined as the number of 
days between the date of first study intervention intake and the date of the first occurrence of HDV 
RNA ≥2log10 IU/mL decline or HDV RNA TND, whichever event is first (i.e. min [the date of 
the first HDV RNA ≥2log10 IU/mL decline, date of the first time HDV RNA is TND] – the date 
of first study intervention intake + 1). The participants who withdrew early from the study before 
achieving such event, or who did not achieve it at the time of the cut-off date for the analysis will
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be censored at the last available HDV RNA assessment during the study or the cut-off date, 
whichever comes first.
5.5.1.3.1.2.
Time to HDV RNA ≥2 log10 IU/mL Decline
The same derivation and censoring rules as in Section 5.5.1.3.1.1 apply for the time to reach HDV 
RNA decline≥2log10 IU/mL, which will be calculated using the date of first HDV RNA 
decline≥2log10 IU/mL.
5.5.1.3.1.3.
Time to HDV RNA TND or <LLOQ
The same derivation and censoring rules as in Section 5.5.1.3.1.1 apply for the time to reach HDV 
RNA TND and time to reach HDV RNA < LLOQ, which will be calculated using the date of first 
HDV RNA TND and date of first HDV RNA < LLOQ respectively.
5.5.1.3.1.4.
Time to Normal ALT Levels 
The same derivation and censoring rules as in Section 5.5.1.3.1.1 apply for the time to reach normal 
ALT (i.e. ALT value ≤ULN), which will be calculated using the first date of normal ALT value.
5.5.1.3.1.5.
Time to HBsAg Thresholds
The following thresholds will be evaluated:

HBsAg < LLOQ (i.e seroclearance)

HBsAg < 1 IU/mL

HBsAg < 10 IU/mL

HBsAg < 100 IU/mL

HBsAg decline ≥2 log10IU/mL
The same derivation and censoring rules as in Section 5.5.1.3.1.1 apply for the time to reach 
HBsAg thresholds, which will be calculated using the date of first occurrence of the given HBsAg 
threshold.
5.5.1.3.2.
Time to Event Endpoints Based on Other Parameters 
5.5.1.3.2.1.
Time to JNJ-3989 Off-Treatment HDV Relapse
It is defined as the number of days between the date of EOT and the date of the first occurrence of 
JNJ-3989 off-treatment HDV relapse as defined in Section 5.5.1.1.4. The participants who 
withdrew during the FU phase before the end of the study and before achieving the event or without 
achieving it will be censored at the last available HDV RNA assessment during the FU phase.
5.5.1.4.
Additional Efficacy Endpoints Relative to The Actual Duration of JNJ-
3989 Treatment
This section intends to evaluate some selected efficacy endpoints over time conditional upon the 
same treatment duration with JNJ-3989 across the 2 arms based on Part 2 data. For example, DB 
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Week 24 for Arm 1 corresponds to Week 76 for Arm 2 (Week 52+24, See Table 2), as participants 
in Arm 2 start treatment with JNJ-3989 at Week 52 when they switch over to the active regimen. 
For each DB Week X for Arm 1 data, the corresponding Week 52+X for Arm 2 data will be 
considered, as described in Table 5:
Table 5:
Correspondence between timepoints for Arm 1 and Open Label timepoints for Arm 2
Analysis Time point for Arm 1
(label)
Matching Analysis OL Timepoint for Arm 2 (label)
Baseline
Week 52
Week 2
Week 54
Week 4
Week 56
Week 8
Week 60
Week 12
Week 64
Week 16
Week 68
Week 20
Week 72
Week 24
Week 76
Week 28
Week 80
Week 32
Week 84
Week 36
Week 88
Week 40
Week 92
Week 44
Week 96
Week 48
Week 100
Week 52
Week 104
Week 56
Week 108
Week 60
Week 112
Week 64
Week 116
Week 68
Week 120
Week 72
Week 124
Week 76
Week 128
Week 80
Week 132
Week 84
Week 136
Week 88
Week 140
Week 92
Week 144
Week 96
EOT (only for OL completers)
When applicable, the reference timepoint (RT) for those analyses will be baseline (DB Day 1) for 
Arm 1 and Week 52 for Arm 2. 
The following endpoints will be presented for those time points during the open-label phase in 
Arm 2 that match the treatment duration in Arm 1 during the double-blind phase, because of the 
deferred active trial design, as per Table 5.
The selected endpoints are:

Proportion of participants with HDV RNA ≥ 2 log10 IU/mL decline from RT or HDV RNA 
TND in combination with normal ALT

Proportion of participants with HDV RNA ≥ 2 log10 IU/mL decline from RT or HDV RNA < 
LLOQ in combination with normal ALT
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
Proportion of participants with HDV RNA ≥ 2 log10 IU/mL decline from RT or HDV RNA 
TND 

Proportion of participants with HDV RNA TND

Proportion of participants with HDV RNA <LLOQ

Proportion of participants with normal ALT

Proportion of participants with LSM reduction ≥ 2 kPa from RT

Proportion of participants with HBsAg seroclearance i.e. with HBsAg < LLOQ, with HBsAg 
< 1 IU/mL and < 10 IU/mL

Change from RT in HDV RNA

Change from RT in ALT

Change from RT in HBsAg

Change from RT in LSM 
5.5.2.
Analysis Methods
All secondary efficacy data will be summarized by study Parts 1 and 2, as well as for the whole 
study data overall.
All other secondary endpoints at Week 48 will be analyzed and summarized as described in 
Section 5. No adjustment for multiple endpoints will be made. 
All secondary endpoints evaluated at all other time points different than Week 48 during the study 
will be summarized descriptively by intervention arm, by phase and time point. No imputation rule 
will be used in case of missing data and the analysis will be based on observed cases.
5.5.2.1.
Binary Endpoints
The binary endpoints will be analyzed using the stratum-adjusted MH test similar to the primary 
efficacy endpoint with corresponding 95% CIs on the difference of proportions.
The number and proportion of participants achieving the endpoints defined in Section 5.5.1.1 will 
be summarized over time with associated 95% CI. Between-arm difference in proportions with 
95% CI will also be provided for all timepoints. 
Bar charts will be provided for proportions in each intervention arm.
Cumulative percentage of participants achieving any given decrease from baseline at Week 48 in 
selected virology markers (e.g. HBsAg, HBV DNA etc.) will be presented graphically.
Subsections below describe the additional analyses planned for only those specific other secondary 
binary endpoints that require further evaluations. 
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5.5.2.1.1.
HDV RNA
In addition to the summaries described in Section 5.5.2.1, shift tables in HDV RNA categories 
from baseline will be provided. 
In an additional summary, the proportions will be calculated based on the number of participants 
who have achieved HBsAg seroclearance at the FU weeks of interest after stopping JNJ-3989.
regardless of continuing NA.
5.5.2.1.2.
HBsAg Seroclearance
The proportion of participants who achieve HBsAg seroclearance will be summarized over time 
for all time points.
5.5.2.1.3.
HBsAg Seroconversion.
For all participants achieving HBsAg seroconversion, descriptive statistics will be calculated for 
the level of anti-HBs antibodies at the timepoint when achieving the HBsAg seroconversion by 
intervention arm. In an additional summary, the level of anti-HBs antibodies will be summarized 
over time for the subset of the participants achieving HBsAg seroconversion at any time before or 
at that given timepoint by intervention arm.
Furthermore, the number and proportion of participants with appearance of anti-HBs antibodies 
and without HBsAg seroclearance will also be summarized.
5.5.2.1.4.
HBV Flares
The incidence rate will be calculated and summarized for each type of on-treatment or off-
treatment flares (virologic, biochemical and clinical) separately, as well as the overall incidence 
of participants experiencing at least one flare, regardless of type. Additionally, for each participant 
the total number of flares the participant experienced will be counted by type. Such counts will be 
used to summarize the distribution of the total number of flares by type and by intervention arm.
For on-treatment biochemical flares, the incidence of flares causing treatment discontinuation will 
be summarized. Further, for off-treatment flares, the count and percentage of participants who 
experienced a flare followed by NA re-treatment will be summarized by flare type. Similarly, the 
incidence of flares followed by the achievement of HBsAg seroclearance (at any time) will be 
summarized by flare type. Flares that are associated with signs of liver decompensation will be 
provided in a listing.
5.5.2.1.5.
HBV DNA Cut-offs
The proportion of participants achieving HBV DNA cutoffs described in Section 5.5.1.1.10 will 
be summarized over time for all time points.
In an additional summary, the proportions will be calculated based on the number of participants 
who have achieved HBV DNA cutoffs at the FU weeks of interest after stopping all study 
interventions including NA.
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5.5.2.2.
Values and Change Over Time 
Continuous variables will be summarized using descriptive statistics including the number of 
participants in the analysis, mean, standard deviation (SD), two-sided 95% CIs, median, and range.
Descriptive statistics on actual values (original unit and log10 transformed values, when 
appropriate) and changes from baseline (log10 transformed values when appropriate) will be 
summarized over time. Mean (+/- SE) plots of the actual values and the change from baseline 
(log10 transformed when appropriate) will be presented over time.
Spaghetti plots for both absolute values and changes from baseline will be presented over time and 
by selected subgroups for efficacy (see Section 2.4.1).
Subsections below describe the additional analyses planned for specific continuous endpoints.
5.5.2.2.1.
HDV RNA
5.5.2.2.1.1.
Change from Baseline to Nadirs
The following change from baseline value to nadir values (defined in Section 5.5) in HDV RNA
will be summarized descriptively and displayed graphically via box plots by intervention arm.
-
Change from baseline to JNJ-3989 on-treatment nadir
-
Change from baseline to overall nadir.
5.5.2.2.1.2.
Change from Baseline Over Time
Change from baseline based on log10 transformed values for quantitative HDV RNA to leverage 
the longitudinal data during the DB study intervention phase will be analyzed using mixed effects 
model for repeated measures [MMRM]) including intervention arm, analysis time point (week), 3 
randomization stratification factors (presence of compensated cirrhosis at screening [yes or no], 
HDV RNA testing laboratory location (China versus outside China), and HBeAg status at 
screening [positive vs negative]) as fixed effects and baseline HDV RNA (continuous) as covariate. 
In addition, the above model will be augmented with an intervention arm-by-analysis week 
interaction term (i.e. treatment-by-time interaction term) to evaluate the change of treatment effect 
over time. The covariance structure will include a random intercept at the level of the participant 
to capture between-participant variability, while within-participant variability will be captured 
with an unstructured (type=UN) covariance matrix. In case of convergence problems, simpler 
variance-covariance structures such as Toeplitz or AR (1) will be considered. The selection of any 
of these structures will be determined after exploration of the observed correlation structure. The 
LS mean of change from baseline, standard error (SE), 95% CI and p-values will be provided.
5.5.2.2.2.
ALT
Change from baseline in ALT over time will be analyzed using similar MMRM as described in 
Section 5.5.2.2.1 using baseline ALT (continuous) as covariate. The LS mean of change from 
baseline, standard error (SE), 95% CI and p-values will be provided.
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5.5.2.2.3.
HBsAg, HBeAg and HBV DNA
5.5.2.2.3.1.
Change from Baseline to Nadir
The following change from baseline value to nadir values (JNJ3989 on-treatment and overall, 
respectively, as described in Section 5.5) in HBsAg, HBeAg (only for HBeAg-positive participants 
at screening) and HBV DNA will be summarized descriptively and box plots of the changes to 
nadirs in each blood marker will display the distribution.
5.5.2.2.3.2.
Change from Baseline Over Time
Descriptive statistics on actual values (original unit and log10 transformed values) and changes 
from baseline (log10 transformed values) over time in each HBV blood marker will be summarized. 
For HBsAg and HBV DNA, respectively, the comparison between intervention arms to leverage 
the longitudinal data during the DB study intervention phase will be done using similar MMRM 
as described in Section 5.5.2.2.1 using baseline value (quantitative) as covariate.
Waterfall plots for changes from baseline of HBsAg, HBeAg, and HBV DNA will also be 
presented by intervention arm at selected timepoints: Week 48, 72, 96, 120 and 144 (for Study 
Part 2).
5.5.2.2.3.3.
Qualitative versus Quantitative Values
Cross-tabulations overtime of quantitative versus qualitative HBsAg and HBeAg values, 
respectively, will also be presented.
5.5.2.2.4.
Liver Stiffness Measurement
The change from baseline in LSM will be compared between intervention arms at Week 48 using 
ANCOVA with intervention arm, randomization stratification factors as main effects in the model
and baseline score as covariate.
At each assessment time point, a frequency distribution of severity scores will be produced. A 
graphical display will also illustrate the findings. In addition, a waterfall plot will be produced to 
display the individual changes from baseline in LSM.
5.5.2.3.
Time to Event Endpoints
The Kaplan-Meier method will be used to estimate and plot the cumulative incidence by each 
intervention arm. The log-rank test will be performed to compare the intervention arms. The 
median time with 95% CI will be estimated using Kaplan-Meier method. This analysis method
will apply to all time-to-events variables defined in Section 5.5.1.3. 
5.6.
Exploratory Endpoints
All exploratory endpoints will be summarized descriptively by intervention arm, phase, time point 
and study part. No imputation rule will be used in case of missing data and the analysis will be 
based on observed cases.
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5.6.1.
Definitions
5.6.1.1.
Binary Endpoints
5.6.1.1.1.
HDV RNA Decline and Normal ALT
All endpoints described in Section 5.5.1.1.1 which include HDV RNA TND will be evaluated by 
replacing TND by < LLOQ for assay sensitivity purpose:

HDV RNA ≥2 log10 IU/mL decline from baseline or < LLOQ in combination with normal 
ALT.

HDV RNA ≥2 log10 IU/mL decline from baseline or HDV RNA < LLOQ.

HDV RNA < LLOQ in combination with Normal ALT.

HDV RNA < LLOQ.
Additionally, some of the HDV RNA endpoints above may also be evaluated using the exploratory 
imputation rules defined in Table 4.
Those endpoints will be analyzed as observed case without imputation (for combined endpoints, 
in case one of the two individual parameters is missing for a specific timepoint, the endpoint will 
be considered missing for this timepoint).
5.6.1.1.2.
HDV RNA Cutoffs
HDV RNA will be evaluated when assessed at the following time points:

12 weeks after stopping JNJ-3989 (regardless of continuing NA treatment and when JNJ-3989 
was stopped) without restarting JNJ-3989 treatment, 

24 weeks after stopping JNJ-3989 (regardless of continuing NA treatment and when JNJ-3989 
was stopped)) without restarting JNJ-3989 treatment, 

36 weeks after stopping JNJ-3989 (regardless of continuing NA treatment and when JNJ-3989 
was stopped)) without restarting JNJ-3989 treatment, 

48 weeks after stopping JNJ-3989 (regardless of continuing NA treatment and when JNJ-3989 
was stopped)) without restarting JNJ-3989 treatment, 
For each timepoint, the following cutoffs on actual values will be evaluated:

LLOQ
o
<LLOQ TND
o
<LLOQ TD

> LLOQ

< 100 IU/mL

< 2,000 IU/mL
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5.6.1.1.3.
HBV RNA and HBcrAg
The cutoffs for HBV RNA level are as follows: 

< LOD

< LLOQ
The cutoffs for HBV RNA change from baseline are as follows:

decrease by ≥1 log10 IU/mL

decrease by ≥2 log10 IU/mL

decrease by ≥3 log10 IU/mL
The cutoffs for HBcrAg level are as follows:

<3.0 Log10 U/mL

<4.0 Log10 U/mL
The cutoffs for HBcrAg change from baseline are as follows:

decrease by ≥1 log10 IU/mL

decrease by ≥2 log10 IU/mL

decrease by ≥3 log10 IU/mL

decrease by ≥4 log10 IU/mL
5.6.1.1.4.
HBV DNA Cutoffs
HBV DNA <LLOQ will be also evaluated when assessed at the following time points:

12 weeks after stopping JNJ-3989 (regardless of continuing NA treatment and when JNJ-3989 
was stopped) without restarting JNJ-3989 treatment,24 weeks after stopping JNJ-3989 
(regardless of continuing NA treatment and when JNJ-3989 was stopped) without restarting 
JNJ-3989 treatment,

36 weeks after stopping JNJ-3989 (regardless of continuing NA treatment and when JNJ-3989 
was stopped) without restarting JNJ-3989 treatment, 48 weeks after stopping JNJ-3989 
(regardless of continuing NA treatment and when JNJ-3989 was stopped) without restarting 
JNJ-3989 treatment
5.6.1.1.5.
HBsAg Seroclearance
Participants achieving HBsAg seroclearance (HBsAg <LLOQ) will be evaluated when HBsAg 
assessed at the following time points:

12 weeks after stopping JNJ-3989 (regardless of continuing NA treatment and when JNJ-3989 
was stopped) without restarting JNJ-3989 treatment,24 weeks after stopping JNJ-3989 
(regardless of continuing NA treatment and when JNJ-3989 was stopped) without restarting 
JNJ-3989 treatment,36 weeks after stopping JNJ-3989 (regardless of continuing NA treatment 
and when JNJ-3989 was stopped) without restarting JNJ-3989 treatment,48 weeks after 
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stopping JNJ-3989 (regardless of continuing NA treatment and when JNJ-3989 was stopped) 
without restarting JNJ-3989 treatment,
5.6.1.2.
Value and Change Over Time
Change from baseline is defined as the value at a given time point minus the baseline value.
Actual values (original unit and log10 transformed values, where applicable) and changes from 
baseline (log10 transformed values, where applicable) over time will be summarized by 
intervention arm and phase for the following variable:
-
HBV RNA (original unit and log10 transformed)
-
HBcrAg (original unit and log10 transformed)
-
Anti-HBs antibodies
5.6.1.3.
Time to Event Endpoints
The analyses will be performed if at least 10% of the participants experience the events.
5.6.1.3.1.
Time to Undetectability of HBcrAg 
The same derivation and censoring rules as in Section 5.5.1.3.1.1 apply for the time to 
undetectability of HBcrAg, which will be calculated using the date of first HBcrAg TND.
Only the participants with HBcrAg values ≥LLOQ+ 0.5 log10 U/mL (i.e. ≥3.5 log10 U/mL) at 
baseline will be included in this analysis.
5.6.1.3.2.
Time to Appearance of Anti-HBs Antibodies
Appearance of anti-HBs antibodies is defined as a baseline anti-HBs (quantitative) <LLOQ and a 
post-baseline assessment ≥LLOQ. 
The same derivation and censoring rules as in Section 5.5.1.3.1.1 apply for the time to appearance
of anti-HBs antibodies, which will be calculated using the date of first appearance as defined 
above.
5.6.1.3.3.
Time to Appearance of Anti-HBe Antibodies
Appearance of anti-HBe antibodies is defined as a baseline anti-HBe antibodies (qualitative) with 
a "NEGATIVE" result and a post-baseline assessment with “POSITIVE” result. 
The same derivation and censoring rules as in Section 5.5.1.3.1.1 apply for the time to appearance 
of anti-HBe antibodies, which will be calculated using the date of first appearance as defined 
above.
5.6.1.4.
Relationship between HBsAg and HDV RNA
HBsAg levels and decline from baseline (in log10 transformed values) and HDV RNA levels and 
change from baseline (in log10 transformed values) during study intervention and follow-up will 
be used to analyze a potential relationship between the two markers.
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In case either HBsAg or HDV RNA is missing at a specific timepoint, no imputation will be 
performed.
Correlations between HBsAg and HDV RNA markers may be evaluated. The list of HBsAg and 
HDV RNA endpoints, including but not limited to, are defined below. Note, that these analyses 
may be performed if sufficient data are collected on patients and will only be performed at a later 
time point in a post hoc nature.
Off-Treatment Clinical HDV Flares (Yes/No)

HBsAg value and change from baseline (absolute and 
log10 values) at End of Treatment of JNJ-3989.

HBsAg seroclearance at End of Treatment of JNJ-
3989- . (Yes/No)
5.6.1.5.
Relationship Between Baseline characteristics and Efficacy 
Endpoints
The relationship between efficacy endpoints at Week 48 and selected baseline characteristics 
defined in the list of subgroup variables for efficacy (see Section 2.4.1) will be evaluated as part 
of the subgroup analyses in Sections 5.3.3 and 5.4.5. In addition, an analysis of correlation at Week 
48 will be performed to evaluate the relationship between endpoints at Week 48 (HDV RNA 
decline from baseline, change from baseline in ALT, change in HBsAg, change in LSM) and 
selected baseline characteristics. This analysis will use continuous variables only. More details are 
provided in Section 5.6.2.5.
In addition, the relationship between efficacy endpoints and on-treatment predictive outcomes at 
early visits (such as HDV RNA reduction ≥2 log10 from baseline, normal ALT, LSM reduction, 
HBsAg seroclearance etc) will also be explored.
5.6.1.6.
Liver Viral Response 
In case a sufficient number of participants agrees to undergo the optional liver biopsy at baseline 
and/or Week 24, the following endpoints will be evaluated:

Change from baseline at Week 24 in intrahepatic HDV RNA (semi-quantitative: negative, low, 
middle, high expression)

Change from baseline at Week 24 in intrahepatic HDAg (semi-quantitative: negative, low, 
middle, high expression)

Change from baseline at Week 24 in number and proportion of pgRNA-positive hepatocytes 

Change from baseline at Week 24 in number and proportion of HBsAg-positive hepatocytes 

Change from baseline at Week 24 in number and proportion of silent hepatocytes

Change from baseline at Week 24 in pgRNA levels (copies/cell)

Change from baseline at Week 24 in intrahepatic HBsAg (semi-quantitative: negative, low, 
middle, high expression)
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
Change from baseline at Week 24 in intrahepatic HBV RNA (semi-quantitative: negative, low, 
middle, high expression)
Additional endpoints may be added if sufficient biopsy data are available for the analysis.
5.6.1.7.
Liver Immune Response 
In case a sufficient number of participants agrees to undergo the optional liver biopsy at baseline 
and/or Week 24, the following immune cells may be evaluated:

CD45 positive cells,

CD4 positive cells,

CD8 positive cells,

Natural Killer (NK) cells,

T-cells,

Dendritic cells
5.6.1.8.
Relationship Between On-Treatment ALT Elevations, Efficacy and 
Safety Endpoints, and Baseline Characteristics
The relationship between On-Treatment ALT elevations will be evaluated. The following 
relationships will be evaluated:

Efficacy outcomes by ALT Elevation Status: HBsAg, HBeAg, HDV RNA, HBV DNA, 
HBcrAg, Liver stiffness measurement

Safety outcomes by ALT/AST Elevation Status: Direct Bilirubin, Total Bilirubin, Individual 
GFR, Platelets, Cholesterol, INR (ratio), Hemoglobin, Eosinophils, Albumin, LDH, 
Prothrombin time, Alkaline Phosphatase, GGT, Alpha Fetoprotein, 

Tables of ALT elevation status by HBsAg, HBeAg, HDV RNA, HBV DNA, HBV RNA, type 
of NA, race, BMI, age, anti-HDV IgM, Fibroscan at Baseline

ALT values over time by HBsAg, HBeAg, HDV RNA, HBV DNA, HBV RNA, type of NA
or none, race, BMI, age, anti-HDV IgM, Fibroscan at Baseline (Cut-offs or Categories)
5.6.2.
Analysis Methods
5.6.2.1.
Binary Endpoints
Descriptive summaries including 95% CI and graphical displays will be provided for the 
exploratory binary endpoints.
5.6.2.1.1.
HDV RNA Cutoffs
The proportion of participants with HDV RNA  < or ≥ cutoffs defined in Section 5.6.1.1.2 will be 
evaluated at each of the following off-treatment time points: 12, 24, 36 and 48 weeks, respectively, 
after stopping JNJ-3989.
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In an additional summary, these proportions will be calculated with the denominator including 
only those participants who have reached the off-treatment time points (week 12, 24, 36 or 48) and 
have stopped JNJ-3989 and have not restarted JNJ-3989, regardless of continuing NA treatment 
prior to the time point of interest
5.6.2.1.2.
HBsAg Seroclearance
The proportion of participants achieving HBsAg seroclearance will be evaluated at each of the
following off-treatment time points: 12, 24, 36 and 48 weeks, respectively, after stopping all study 
interventions and without restarting JNJ-3989.
In an additional summary, these proportions will be calculated with the denominator including 
only those participants who have reached the off-treatment time points (week 12, 24, 36 or 48) and 
have stopped JNJ-3989 and have not restarted JNJ-3989 , regardless of continuing NA treatment 
prior to the time point of interest.
5.6.2.2.
Value and Change Over Time
Similar summaries and graphical displays as described in Section 5.5.2.2 will be provided for the 
exploratory continuous endpoints.
Subsections below describe the additional analyses specific to individual continuous exploratory 
endpoints. 
5.6.2.2.1.
HBV RNA and HBcrAg  
HBcrAg will be summarized by NA treatment history (Yes/No) and overall, while HBV RNA will 
only be summarized by NA treatment history.
The values of and changes from baseline in HBV RNA and HBcrAg, respectively, will be 
summarized only descriptively over time in a similar manner as for values and changes from 
baseline over time in HBsAg, HBeAg, and HBV DNA as described in Section 5.5.2.2.3, including 
the change from baseline value to nadir values (both on and off treatment) and the various graphical 
displays. 
Waterfall plots for changes from baseline in HBV RNA and HBcrAg will also be presented.
5.6.2.2.2.
Anti-HBs Antibodies
For participants with positive anti-HBs antibodies at baseline who will reach HBsAg seroclearance 
(as defined in Section 5.4.3.1), descriptive statistics will be calculated for the change (increase) of 
anti-HBs antibodies level from baseline at the timepoint when achieving the HBsAg seroclearance 
by intervention arm. In an additional summary, the change of anti-HBs antibodies level from 
baseline at Week 48 will be summarized descriptively for the subset of the participants achieving 
HBsAg seroclearance at any time before or at that given timepoint by intervention arm.
If available, cross-tabulations overtime of quantitative versus qualitative anti-HBs values, 
respectively, will also be presented.
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5.6.2.2.3.
Anti-HBe Antibodies
The number and proportion of positive and negative values in anti-HBe antibodies will be 
summarized over time.
Shift tables from baseline will also be provided over time.
5.6.2.3.
Time to Event Endpoints
The time to event endpoints defined in Section 5.6.1.3 will be analyzed using the Kaplan Meier 
method and Log-Rank test similarly to the time to event endpoints described in the Section 5.5.2.3. 
No Cox model will be provided for the time to event exploratory endpoints.
5.6.2.4.
Relationship between HBsAg and HDV RNA
The relationship between HBsAg and HDV RNA will be explored over time during the 
intervention and FU phases by providing the following scatterplots and heat maps :
The following correlation coefficients will be calculated by study intervention arm for the different 
correlation scenarios:

Pearson’s correlation coefficient for two continuous variables. 

Phi correlation coefficient for two binary variables. 

Point biserial correlation coefficient for one binary variable and one continuous variable. 
Potential relationship on the selected subgroups defined in Section 2.4.1 will also be explored 
using the same graphical approach. Graphical display combining individual profiles for HDV RNA 
and HBsAg over time (and mean by intervention arm) will also be provided. 
5.6.2.5.
Relationship Between Baseline Characteristics and Efficacy 
Endpoints
The analysis of correlation between each secondary endpoint at Week 48 and selected subgroup 
variables for efficacy (see Section 2.4.1 for the list of variables) will be performed using the 
correlation coefficients described in Section 5.6.2.4 , scatter plots and heat plots.
Analysis of correlation and graphical displays will also be used to explore the relationship between 
efficacy endpoints and predictive outcomes at early visits.
5.6.2.6.
Liver Viral Response 
Descriptive statistics on actual values at baseline and Week 24 and changes from baseline at Week 
24 may be summarized for the list of parameters described in Section 5.6.1.6 if sufficient biopsy 
data on Part 2 subjects are collected.
Number of cells may be expressed in original unit and proportions, or ratios may be provided in 
both original and log10 transformed scales. Change from baseline may be provided in log10 
transformed unit. In addition, graphical displays e.g spaghetti plots, scatter plot, box plots may be 
provided.
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5.6.2.7.
Liver Immune Response 
Descriptive statistics on actual values at baseline and Week 24 and changes from baseline at Week 
24 will be summarized for the list of parameters described in Section 5.6.1.7 if sufficient biopsy 
data on Part 2 subjects are collected.
In addition, graphical displays e.g spaghetti plots, scatter plot, box plots may be provided.
Additional immune cells may be evaluated depending on data availability and clinical interest. 
Spatial distribution for each cell type at baseline and Week 40 may be graphically evaluated.
6.
SAFETY
The Safety Analysis Set will be used for all safety analyses based on pooled data from Part 1 and 
Part 2 of the study. In addition, selected safety analyses may be reported by study part.
All assessments will be presented by analysis phase and study intervention, unless other specified. 
All summaries will be descriptive, and no inferential methods will be used to compare intervention 
arms for safety.
Safety and tolerability will be assessed by evaluating treatment emergent-adverse events (TEAEs), 
physical examinations, vital signs measurements, clinical laboratory tests (including hematology, 
blood biochemistry, blood coagulation, and urinalysis), and ECGs.
Continuous parameters will be summarized using the following statistics: number of observations, 
mean, standard deviation (SD), standard error (SE), minimum, median and maximum, unless 
specified otherwise. Frequencies and percentages will be used for summarizing categorical 
(discrete) data.
As a result of the IDMC ongoing periodic safety data reviews to ensure the continuing safety of 
study participants, additional safety analyses may be generated at the discretion of the Sponsor.
6.1.
Adverse Events
6.1.1.
Definitions
The verbatim terms used in the CRF by investigators to identify adverse events will be coded using 
the Medical Dictionary for Regulatory Activities (MedDRA version 21.1 or higher). Treatment-
emergent AEs (TEAE) are all AEs with a start date on or after the first administration of study 
treatment or any ongoing event that worsens in severity, intensity or frequency after the first 
administration of study treatment. If the event date and/or resolution date is recorded as partial or 
completely missing, then the imputation rules described in Section 2.5.1 will apply.
6.1.2.
Analysis Methods
The adverse events will be summarized by intervention arm and by analysis phase. Adverse events 
will be allocated to phases based on their start date. If the start date of an event falls between (or 
on) the start and stop date of a study phase, the AE will be attributed to that phase (treatment-
emergent principle). For imputation of partially/fully missing dates please see Section 2.5.1. In 
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case of a completely missing start date, the event is allocated to the double-blind study intervention 
phase, except if the end date of the AE falls before the first administration of study treatment (DB 
Day 1).
An overview table will summarize the incidence of TEAEs classified in the following categories: 
AEs, serious AEs, related AEs, AEs leading to treatment discontinuation, COVID-19 AEs (serious 
and non-serious) and fatal AEs by presenting by intervention arm the number and percentage of 
participants who experienced at least one of such AE. The overview AEs table will be also 
presented stratified by the subgroup of interests identified in Section 2.4.2.
AE relationship to study treatment is grouped into either related or not related category. A related 
AE is defined as with possible, probable, or very likely relationship with study treatment; not 
related, otherwise.
All adverse events will be presented in a descending order by incidence based on all participants 
(Total column). The following TEAEs tables will be included in the analysis:

All TEAEs

Serious TEAEs

At least grade 3 TEAEs

At least grade 2 TEAEs and related

TEAEs leading to treatment discontinuation 

Related TEAEs
All serious TEAE, related TEAE, TEAE leading to death, TEAE leading to discontinuation, TEAE 
of at least grade 3, or AESIs will be listed separately. Listings will include all information collected 
on the Adverse Event CRF pages (e.g. information on time of onset, duration of events, time of 
resolution, concomitant therapies and relationship to study treatment).
For participants reporting rash, a listing with specific grade will be provided and Rash 
questionnaire will be tabulated by study intervention arm and overall.
6.1.3.
Adverse Events of Special Interest
Incidence of treatment-emergent adverse events of special interest will be summarized by 
intervention arm and analysis phase. The adverse events of special interest include:

ALT/AST elevations

Injection Site Reactions

Renal complications

Hematologic abnormalities (platelet count, hemoglobin, reticulocytes, neutrophil count)

Cholesterol increase
The list of all preferred terms belonging to ALT/AST elevations, renal complications, cholesterol 
increase, and hematologic abnormalities is provided in 0. Injection site reactions will be identified 
using the eCRF Injection Site Reaction form.
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The laboratory abnormalities will be determined according to the criteria specified in the DAIDS 
Toxicity Grading Scale (see Clinical Protocol Appendix 8, DAIDS Table) or in accordance with 
the normal ranges of the clinical laboratory if no gradings are available.
An assessment is treatment-emergent if the toxicity grade/abnormality worsened as compared to 
the grade/abnormality at baseline; this also includes the shift from abnormally high to abnormally 
low and vice-versa. Post-reference toxicities/abnormalities are always treatment-emergent with 
regard to missing toxicities/abnormalities at baseline. The abnormalities ‘Abnormally high’ and 
‘Abnormally low’ are considered equally important.
For each lab parameter, a worst-case analysis will be performed by using the worst abnormality 
and/or worst toxicity grade lab value and time point per participant. The worst toxicity case is the 
value associated to the highest toxicity grade and is derived per parameter and toxicity direction 
(low / high). Worst-case will be derived within each phase, including unscheduled assessments.
For abnormalities, in case the same subject has both abnormalities (low and high) for the same lab 
test within the same phase, the participant will be counted in the analysis for both toxicity 
directions (abnormally high and low).
Imputation rules:
In case continuous laboratory results are not numerically expressed, but as a character (e.g. ‘less 
than 2’, ‘>25’), these results will be numerically imputed as follows:

If the analysis result contains '<' then the result will be multiplied by 0.999 (e.g. <6.1 becomes 
6.0939). 

If analysis result contains '>' then the result will be multiplied by 1.001 (e.g. >6.1 becomes 
6.1061).  

If analysis result contains '≤' or '≥' then only the numeric portion of the result will be used.
This also applies to normal limits expressed as such.
6.2.2.
Analysis Methods
Descriptive statistics (n, mean, SD, minimum, median, and maximum) will be calculated for each 
laboratory analyte for observed values and changes from baseline at each scheduled time point by 
intervention arm and study phase.
Shift tables will be provided summarizing the shift in laboratory values from baseline over time 
with respect to abnormality criteria (low, normal, high) for each laboratory parameter by study 
phase.
The cross-tabulations of the worst toxicity grades over time versus baseline grade and the worst 
abnormalities versus baseline grade per parameter and per analysis phase will be presented 
including also the number of participants per worst grade and the number of participants per 
abnormality.
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A tabulation of percentage and number of the participants who have treatment-emergent worst 
toxicity grades and treatment-emergent worst abnormalities per parameter and analysis phase will 
be included. The incidence table of worst toxicity grade abnormality in laboratory parameters will 
be also presented stratified by the subgroup of interests identified in Section 2.4.2.
Plots of mean (+/- SE) values and changes from baseline over time for alanine transferase (ALT), 
aspartate aminotransferase (AST), alkaline phosphatase, hemoglobin, neutrophils, platelets, 
bilirubin (direct and indirect), lipase, amylase/pancreatic amylase, activated partial thromboplastin 
time, prothrombin time and phosphate will be presented by intervention arm. Spaghetti-plots for 
selected laboratory parameters may be presented by intervention arm over time (with Week shown 
on x-axis).
A listing including all parameters with at least one treatment-emergent toxicity or abnormality per 
participant (exclusion of urinalysis) will be generated. 
6.3.
Renal Safety
6.3.1.
eGFR
Stages of eGFR at baseline versus the minimum post-baseline eGFR value and the last available 
value will be summarized by count and percent of participants. Stage of Chronic Kidney Disease 
(CKD) are defined as follows: 1 (Normal): eGFR ≥ 90; 2 (Mild): eGFR 60-89; 3 (Moderate): eGFR 
30-59; 4 (Severe): eGFR <30.
In addition to the above, the number and proportion of participants with a < 10%, 10-<30%, 30-
<50% and ≥50% decrease from baseline will be tabulated.
Scatter plots of GFR versus other renal biomarkers (total urine protein, total urine albumin, urine 
protein to creatinine ratio [UPCR], urine albumin to creatinine ratio [UACR], retinol binding 
protein (RBP) and beta-2-microglobulin, RBP to creatinine ratio and beta-2-microglobulin to 
creatinine ratio, and urine fractional excretion of phosphate [FEPO4]) as well as spaghetti plots 
will also be presented.
6.3.2.
Proximal Renal Tubular Function
Proteinuria by Quantitative Assessment
Total urine protein, total urine albumin, UPCR and UACR will be summarized by intervention 
arm and visit using descriptive statistics. 
The number and proportion of participants with UACR and UPCR results in the following 
categories over time will be tabulated:

UACR: < 30, ≥ 30 to 300, >300 mg/g

UPCR: < 200 mg/g versus ≥200 mg/g
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Median (Q1, Q3) percent change from baseline over time will be plotted by intervention arm.
The evolution over time of total urine protein and total urine albumin will also be presented.
Proteinuria by Urinalysis (Dipstick)
Treatment-emergent proteinuria by urinalysis (dipstick) over time will be summarized by 
intervention arm. Cross-tabulation of grades overtime versus baseline will also be presented.
Other Renal Biomarkers
Selected renal biomarkers RBP and beta-2-microglobulin, RBP to creatinine ratio and beta-2-
microglobulin to creatinine ratio will be summarized by intervention arm and visit using 
descriptive statistics. 
The proportions of participants with beta-2-microglobulin to creatinine ratio <=343.5 μg/g and 
>343.5 μg /g will be tabulated.
The number and proportion of participants with retinal binding protein to creatinine ratio results 
in the following categories overtime will be tabulated:

< 50 years of age: < 130 mcg/g creatinine, ≥ 130 mcg/g creatinine

≥ 50 years of age: < 172 mcg/g creatinine, ≥ 172 mcg/g creatinine
Phosphate excretion
Other renal biomarkers include FEPO4 that will be summarized by intervention arm and visit using 
descriptive statistics.
FEPO4 will be calculated as follows:

Based on unadjusted serum creatinine:
FEPO4 (%) = (SCr × UPO4) / (SPO4 × UCr) × 100 (%)
Where SCr is serum creatinine concentration, UPO4 is urine phosphate concentration, SPO4 is serum 
phosphate concentration, and UCr is urine creatinine concentration.
The proportions of participants with FEPO4 <=10% and >10% will be tabulated.
The baseline, post-baseline, and change from baseline in FEPO4 will be summarized by 
intervention arm and visit using descriptive statistics. Median (Q1, Q3) change from baseline in 
FEPO4 over time will be plotted by intervention arm. 
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Subclinical renal proximal tubulopathy
Potential Markers of Renal Proximal Tubulopathy are:
1.
Confirmed increase in serum creatinine ≥ 0.40 mg/dL from baseline. 
2.
Confirmed ≥ 2 grade level increase from baseline in graded proteinuria
3.
Confirmed ≥ 1 grade level increase from baseline in graded hypophosphatemia
4.
Confirmed ≥ 1 grade level increase from baseline in graded glycosuria concurrent with serum 
glucose <=100 mg/dL (normoglycemic glycosuria)
A confirmed laboratory abnormality is defined as an abnormality observed at 2 consecutive post-
baseline measurements or an abnormality observed at 1 measurement followed by study drug 
discontinuation
A subclinical renal proximal tubulopathy will be defined as confirmed abnormalities in any 2 out 
of the 4 renal parameters (serum creatinine and one or more of the 3 other markers of tubular 
dysfunction).
Baseline Subclinical renal proximal tubulopathy
Potential Markers of Renal Proximal Tubulopathy at Baseline
1.
Grade ≥ 1 serum creatinine 
2.
Grade ≥ 2 proteinuria
3.
Grade ≥ 1 hypophosphatemia
4.
Grade ≥ 1 glycosuria concurrent with serum glucose <=100 mg/dL (normoglycemic 
glycosuria)
A baseline subclinical renal proximal tubulopathy will be defined as abnormalities in any 2 out of 
the 4 renal parameters (serum creatinine + 1 or more of the 3 other markers of tubular dysfunction).
6.4.
Electrocardiogram
6.4.1.
Definitions
Evaluation of the triplicate 12-lead ECGs will be based on the mean value of the triplicate 
parameters and the abnormalities will be defined on the triplicate means. 
The following ECG parameters measurements will be analyzed:

PR interval (ms)

Heart Rate (bpm)

QT interval (ms)

QRS duration (ms)

QTc Corrected (Fridericia’s formula QTcF)
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The abnormalities in ECG parameters will be determined according to the criteria specified in the 
Cardiovascular Safety – Abnormalities Table (see Clinical Protocol Appendix 6, Cardiovascular 
Safety- Abnormalities Table). Abnormalities on actual values are provided for HR, PR, QRS and 
QTcF. Additional abnormalities on change from baseline will be provided for QTcF. No 
abnormalities will be defined for actual uncorrected QT values. Uncorrected QT ≥ 500 ms will be 
flagged and only shown in listings.
An assessment is treatment-emergent if /abnormality worsened as compared to the abnormality at 
baseline; this also includes the shift from abnormally high to abnormally low and vice-versa. Post-
reference abnormalities are always treatment-emergent with regard to missing abnormalities at 
baseline. The abnormally high values (i.e. abnormally high, borderline prolonged, prolonged, 
pathologically prolonged) versus the abnormally low values are considered equally important.
Abnormalities defined on changes from baseline are always treatment-emergent.
For each parameter, a “worst-case” analysis will be performed by using the worst abnormality 
and time point per participant. Worst-case will be derived within each phase, including 
unscheduled assessments. In case the same subject has both abnormalities (low and high) for the 
same test within the same phase, the participant will be counted in the analysis for both 
abnormality directions (abnormally high and low).
6.4.2.
Analysis Methods
Only data from the vendor ERT will be analyzed. All other ECG data will be listed.
For the time points on which triplicate ECGs apply, a rounded mean value to the next integer per 
triplet will be calculated per time point before any further handling. This rounded mean value will 
be used through the entire analysis also in case of 1 or 2 missing values.
ECG records with partial dates (any of day/month/year is missing) will not be used in analysis, 
except in the listings. The following imputation rules will be applied.
If heart rate (HR) is missing, it will be calculated using RR (if available) and rounded to the integer 
value (see formula below) before any further handling if applicable. 
60
)
(
)
(
1000
bpm
HR
ms
RR

HR from the vital signs section (i.e. pulse) will not be used in this ECG analysis section. RR values 
(if available) will only be listed. Recalculated HR values will be flagged.
Descriptive statistics will be calculated for observed values and changes from baseline per 
parameter (all parameters except for RR) at each scheduled time point by intervention arm. 
Shift tables will be provided summarizing the shift in ECG values from baseline over time with 
respect to abnormality category (low, normal, high) for each parameter by study phase.
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A cross-tabulation of the worst abnormalities (on actual values) versus baseline per parameter by 
study phase will be presented including also the number of participants per abnormality. A 
tabulation of number and percentage of the participants who have treatment-emergent worst 
abnormalities per parameter (i.e. for HR, PR, QRS and QTcF) and analysis phase will also be 
presented. 
A cross-tabulation of the worst change from baseline abnormalities (i.e. for QTcF) versus the 
baseline category per parameter will be presented by intervention arm and study phase.

Frequency tabulations of categorized corrected QT/QTc change from baseline (<=30 msec, 
>30- <=60 msec, >60 msec) and categorized corrected QT/QTc interval values (<=450 msec, 
>450- <=480 msec, >480-<= 500 msec, >500 msec) per timepoint will be presented by 
intervention arm.

Listings including all parameters for participants with at least one treatment-emergent 
abnormality (on actual values or change from baseline), including all findings (e.g. 
interpretation, rhythm, or technical findings) for participants with uncorrected QT values ≥ 
500 ms will be provided separately. 
6.5.
Vital Signs and Body Temperature
6.5.1.
Definitions
The following parameters measurements will be analyzed:

Supine pulse rate (bpm)

Supine systolic blood pressure (mmHg)

Supine diastolic blood pressure (mmHg)

Body temperature (℃)
The abnormalities in vital signs (not applicable for body temperature) will be determined according 
to the criteria specified in the Cardiovascular Safety – Abnormalities Table (see Clinical Protocol 
Appendix 7).
An assessment is treatment-emergent if abnormality worsened as compared to the abnormality at 
baseline; this also includes the shift from abnormally high to abnormally low and vice-versa. Post-
baseline abnormalities are always treatment-emergent with regard to missing abnormalities at 
baseline. The abnormally high values (i.e. abnormally high, grade 1 or mild, grade 2 or moderate, 
grade 3 or severe) versus the abnormally low values are considered equally important.
For each parameter, a “worst-case” analysis will be performed by using the worst abnormality and 
time point per participant. Worst-case will be derived within each phase, including unscheduled 
assessments. In case the same subject has both abnormalities (low and high) for the same test 
within the same phase, the participant will be counted in the analysis for both abnormality 
directions (abnormally high and low).
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6.5.2.
Analysis Methods
Vital signs records with partial dates (any of day/month/year is missing) will not be used in the 
analysis but will be listed.
Descriptive statistics of continuous vital sign parameters and body temperature will be calculated 
for observed values and changes from baseline at each scheduled time point.
Shift tables will be provided summarizing the shift in vital sign and body temperature values from
baseline over time with respect to abnormality criteria (low, normal, high) for each parameter by 
study phase.
A cross-tabulation of the worst abnormalities versus baseline per parameter and study phase will 
be presented including also the number of participants per abnormality, the number of participants 
with treatment emergent abnormalities per abnormality.

A tabulation of percentage and number of the participants who have treatment-emergent worst 
abnormalities per parameter and study phase will be included.

A listing including all parameters for participants with at least one treatment-emergent 
abnormality (on actual values or change from baseline) is provided. Additional vital signs 
assessments corresponding to the rash eCRF pages will be only listed as applicable.
6.6.
Physical Examination
The physical examination findings and abnormalities will be listed.
7.
VIRAL GENOME SEQUENCE ANALYSIS AND GENOTYPING
Viral genome sequence analysis may be performed to identify pre-existing baseline 
polymorphisms and to evaluate emergence of genetic variations (including substitutions) 
associated with JNJ-3989, and/or ETV, TDF or TAF treatment on both nucleotide and/or amino 
acid level. The sequencing of samples may be triggered by the sponsor virologist based on changes 
in HBV DNA or HDV RNA levels observed in each individual participant and the limits of the 
sequencing assay. Virology results will be presented by specified timepoints and genetic region 
and position of interest. A separate virology report may be prepared.
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REFERENCES
1.
Wedemeyer H, Bogomolov P, Blank A, et al. Final results of a multicenter, open-label phase 2b clinical trial to 
assess safety and efficacy of Myrcludex B in combination with Tenofovir in patients with chronic HBV/HDV  
co-infection. J Hepatol. 2018;68:S3.
2.
Wedemeyer H, Yurdaydìn C, Dalekos GN, et al. Peginterferon plus adefovir versus either drug alone for 
hepatitis delta. N Engl J Med. 2011;364(4):322-31.
3.
Ratitch B., Lipkovitch I., O’Kelly M. (2013), Combining Analysis Results from Multiply Imputed Categorical 
Data, PhasrmaSUG, Paper SP03.
4.
King G., Honaker J., Joseph A., et al. Analyzing Incomplete Political Science Data: An Alternative Algorithm 
for Multiple Imputation. American Political Science Review, Vol. 95:49-69.
5.
Graham JW, Olchowski A E, Gilreath T D, How Many Imputations are Really Needed? Some Practical 
Clarifications of Multiple Imputation Theory, Prev Sci . 2007 Sep;8(3):206-13
6.
Honaker J, King G et al.. Amelia II: A Program for Missing Data. Journal of Statistical Software, 45, 7, Pp. 
1-47.
7.
Lui K.J., Kelly C. A Revisit on Tests for Homogeneity of the Risk Difference, Biometrics, 2000; 56:309-315.
8.
Barnes A., Mallinckrodt C. et al. The impact of missing data and how it is handled on the rate of false-positive 
results in drug development. Pharmaceut. Statist. 2008; 7: 215–225
9.
Firth, D. (1993), Bias Reduction of Maximum Likelihood Estimates, Biometrika, 80, 27–38.
10.
Heinze, G. and Schemper, M. (2002), A Solution to the Problem of Separation in Logistic Regression, 
Statistics in Medicine, 21, 2409–2419.
11.
Maruish, M. E. (Ed.). User’s manual for the SF-36v2 Health Survey (3rd ed.). Lincoln, RI:QualityMetric 
Incorporated
12.
Cornberg M, Lok AS, Terrault NA. et al. Guidance for Design and Endpoints of Clinical Trials in Chronic 
Hepatitis B—Report From the 2019 EASL-AASLD HBV Treatment Endpoints Conference. Hepatology. 
2020;71(3):1070-1092.
13.
Bourne, C. R., Finn, M. G., & Zlotnick, A. (2006). Global structural changes in hepatitis B virus capsids 
induced by the assembly effector HAP1. Journal of virology, 80(22), 11055-11061.
14.
Klumpp, K., Lam, A. M., Lukacs, C., Vogel, R., Ren, S., Espiritu, C., ... & Efimov, A. (2015). High-resolution 
crystal structure of a hepatitis B virus replication inhibitor bound to the viral core protein. Proceedings of the 
National Academy of Sciences, 112(49), 15196-15201.
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attachment 2: Adverse events of special interest list of preferred terms.
Adverse Event of 
Special Interest
Source
Preferred Term
ALT/AST 
elevation
(Modified) Liver related investigations, 
signs and symptoms (SMQ) narrow, (as 
per MedDRA version used for the 
analysis)
Alanine aminotransferase abnormal
Alanine aminotransferase increased
Aspartate aminotransferase abnormal
Aspartate aminotransferase increased
Hepatic enzyme abnormal
Hepatic enzyme increased
Hepatic function abnormal
Hypertransaminasaemia
Liver function test abnormal
Liver function test increased
Transaminases abnormal
Transaminases increased
Renal 
Complications
(Modified) Acute renal failure (SMQ) 
broad (as per MedDRA version used for 
the analysis)
Acute kidney injury
Anuria
Nephropathy toxic
Oliguria
Renal failure
Renal impairment
Subacute kidney injury
Blood creatinine abnormal
Blood creatinine increased
Creatinine renal clearance abnormal
Creatinine renal clearance decreased
Creatinine urine abnormal
Creatinine urine decreased
Crystal nephropathy
Glomerular filtration rate abnormal
Glomerular filtration rate decreased
Nephritis
Proteinuria
Renal function test abnormal
Renal tubular disorder
Renal tubular dysfunction
Renal tubular injury
Renal tubular necrosis
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Adverse Event of 
Special Interest
Source
Preferred Term
Urine output decreased
Nephropathy
Nephropathy toxic
Glomerulonephropathy
Nephrolithiasis
Cholesterol 
increase
Dyslipidaemia (SMQ), (as per MedDRA 
version used for the analysis)
Blood cholesterol abnormal
Blood cholesterol esterase increased
Blood cholesterol increased
Dyslipidaemia
High density lipoprotein abnormal
High density lipoprotein decreased
High density lipoprotein increased
Hypercholesterolaemia
Hyperlipidaemia
Hypo HDL cholesterolaemia
Intermediate density lipoprotein 
decreased
Intermediate density lipoprotein 
increased
LDL/HDL ratio decreased
LDL/HDL ratio increased
Lipid metabolism disorder
Lipids abnormal
Lipids increased
Lipoprotein abnormal
Lipoprotein increased
Low density lipoprotein abnormal
Low density lipoprotein decreased
Low density lipoprotein increased
Non-high-density lipoprotein 
cholesterol decreased
Non-high-density lipoprotein 
cholesterol increased
Primary hypercholesterolaemia
Remnant hyperlipidaemia
Remnant-like lipoprotein particles 
increased
Total cholesterol/HDL ratio abnormal
Total cholesterol/HDL ratio decreased
Total cholesterol/HDL ratio increased
Very low density lipoprotein abnormal
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Adverse Event of 
Special Interest
Source
Preferred Term
Very low density lipoprotein decreased
Very low density lipoprotein increased
Hematologic 
abnormalities
(Modified)  Haematopoietic cytopenias 
affecting more than one type of blood cell 
(SMQ), (as per MedDRA version used for 
the analysis)
Aplastic anaemia
Autoimmune aplastic anaemia
Bicytopenia
Bone marrow failure
Cytopenia
Febrile bone marrow aplasia
Full blood count decreased
Gelatinous transformation of the bone 
marrow
Immune-mediated pancytopenia
Pancytopenia
Panmyelopathy
Aspiration bone marrow abnormal
Biopsy bone marrow abnormal
Blood count abnormal
Blood disorder
Bone marrow disorder
Bone marrow infiltration
Bone marrow myelogram abnormal
Bone marrow necrosis
Bone marrow toxicity
Haematotoxicity
Myelodysplastic syndrome
Myelodysplastic syndrome 
transformation
Myelofibrosis
Myeloid metaplasia
Plasmablast count decreased
Scan bone marrow abnormal
Hematologic 
abnormalities
(Modified) Haematopoietic erythropenia 
(SMQ), (as per MedDRA version used for 
the analysis)
Aplasia pure red cell
Aplastic anaemia
Erythroblast count decreased
Erythroid maturation arrest
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Adverse Event of 
Special Interest
Source
Preferred Term
Erythropenia
Hypoplastic anaemia
Microcytic anaemia
Proerythroblast count decreased
Red blood cell count decreased
Reticulocyte count decreased
Reticulocytopenia
Anaemia
Erythroblast count abnormal
Erythropoiesis abnormal
Haematocrit abnormal
Haematocrit decreased
Haemoglobin abnormal
Haemoglobin decreased
Leukoerythroblastic anaemia
Normochromic anaemia
Normochromic normocytic anaemia
Normocytic anaemia
Proerythroblast count abnormal
Red blood cell count abnormal
Reticulocyte count abnormal
Reticulocyte percentage decreased
Hematologic 
abnormalities
(Modified)  Haematopoietic leukopenia 
(SMQ), (as per MedDRA version used for 
the analysis)
Agranulocytosis
Band neutrophil count decreased
Band neutrophil percentage decreased
Basophil count decreased
Basophilopenia
B-lymphocyte count decreased
Cyclic neutropenia
Eosinopenia
Eosinophil count decreased
Febrile neutropenia
Granulocyte count decreased
Granulocytes maturation arrest
Granulocytopenia
Idiopathic neutropenia
Leukopenia
Lymphocyte count decreased
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Adverse Event of 
Special Interest
Source
Preferred Term
Lymphopenia
Metamyelocyte count decreased
Monoblast count decreased
Monocyte count decreased
Monocytopenia
Myeloblast count decreased
Myelocyte count decreased
Neutropenia
Neutropenic infection
Neutropenic sepsis
Neutrophil count decreased
Promyelocyte count decreased
Pure white cell aplasia
T-lymphocyte count decreased
White blood cell count decreased
Basophil count abnormal
Basophil percentage decreased
B-lymphocyte abnormalities
B-lymphocyte count abnormal
Differential white blood cell count 
abnormal
Eosinophil count abnormal
Eosinophil percentage decreased
Full blood count abnormal
Granulocytes abnormal
Leukopenia neonatal
Lymphocyte count abnormal
Lymphocyte percentage abnormal
Lymphocyte percentage decreased
Monocyte count abnormal
Monocyte percentage decreased
Mononuclear cell count decreased
Myeloblast percentage decreased
Myelocyte percentage decreased
Myeloid maturation arrest
Neutrophil count abnormal
Neutrophil percentage decreased
Plasma cell disorder
Plasma cells absent
White blood cell analysis abnormal
White blood cell count abnormal
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Status: Approved, Date: 09 August 2023
Adverse Event of 
Special Interest
Source
Preferred Term
White blood cell disorder
Hematologic 
abnormalities
(Modified) Haematopoietic 
thrombocytopenia (SMQ), (as per 
MedDRA version used for the analysis)
Acquired amegakaryocytic 
thrombocytopenia
Megakaryocytes decreased
Platelet count decreased
Platelet maturation arrest
Platelet production decreased
Platelet toxicity
Thrombocytopenia
Megakaryocytes abnormal
Platelet count abnormal
Platelet disorder
Plateletcrit abnormal
Plateletcrit decreased
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Status: Approved, Date: 09 August 2023
Attachment 3: Justification of the Decision Rule to start Part 2 
The antiviral activity criteria to decide if /when to trigger Part 2 (Section 3.3.3) are based on the 
expectation that early declines of HBsAg and HDV RNA will eventually lead to achieve response 
in terms of  the primary endpoint at Week 48 (defined in Section 5.3.1) with JNJ-3989+NA 
treatment. However, the magnitude of the correlation between the early changes (at Week 8, 12, 
24, etc.) and the Week 48 primary time point is currently not known for the investigational 
treatment regimen in this study. This correlation will primarily depend on the positive predictive 
probability of the early declines of HDV RNA and HBsAg for the primary endpoint response 
status, i.e. the probability that a participant who meets the antiviral activity criteria will eventually 
achieve responder status for the primary endpoint. In addition, it is assumed that all participants 
who do not meet the antiviral activity criteria will be non-responders for the primary endpoint. 
Initially, the positive predictive probability is assumed to be 0.75. As the study targets a response 
rate of 30% in Arm 1, this translates into a target value of 40% for the percentage of participants 
meeting the antiviral activity criteria. 
The performance of the proposed decision rule was evaluated by two different metrics:

Lower bound and upper bound of an asymmetric credible interval (20%, 90%) of the posterior 
distribution of the proportion of participants who meet the criteria for each potential outcome 
after which the decision rule is applied (using a non-informative prior distribution, 
beta[0.5,0.5]). 

The probability of the each of the 3 different decisions (decide to start Part 2 in Step 1 or Step 
2; consider starting Part 2 in Step 3 or decide not to start Part 2 in Step 3) as a function of the 
true percentage of participants meeting the criteria varying from 0% to 100%. This was 
obtained through simulation (10,000 replicates for each scenario).
The decision to start Part 2 can be taken as early as after the first 8 participants randomized to Arm 
1 (JNJ-3989+NA) have data for at least 8 weeks and all of them meet the antiviral activity criteria. 
At the other extreme, it can also happen that the threshold of 8 participants is only reached after 
the total number of 16 participants on the investigational regimen in Part 1 have completed at least 
36 weeks. In all possible scenarios where Part 2 would be triggered, the lower bound of the credible 
interval exceeds 40% (Figure 1, panel A). This implies that in each case where the decision rule 
will lead to the start of Part 2, the available data from Part 1 indicate that the probability that the 
proportion of participants meeting the criteria is in the region of interest (>40%) is at least 80%. 
On the other hand, if the number of participants meeting criteria a) and b) is ≤4 out of 16, the upper 
bound of the credible interval excludes the region of interest (<40%) and therefore it is not 
warranted to start Part 2 (Figure 1, panel B). Otherwise, the evidence of the data in Part 1 is 
considered inconclusive. In such case, the decision to start of Part 2 may then be based on a further 
exploration of the individual longitudinal profiles of HDV RNA and HBsAg of all participants up 
to at least Week 36.
The operational characteristics of the decision rule in relation to the true, but unknown, proportion 
of participants meeting the criteria is shown in Figure 2. The probability to start Part 2 exceeds 
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Status: Approved, Date: 09 August 2023
80% when the true proportion of participants meeting the criteria is higher than 57%. Conversely, 
if the true proportion is less than 20%, the probability not to start Part 2 exceeds 80%. 
As the predictive probability of the early HDV RNA and HBsAg declines is not known, a 
sensitivity analysis was performed by assuming different values for the positive predictive 
probability of the early reductions in HDV RNA and HBsAg. The results are shown in (Figure 2). 
Here the probability for the different decisions are now plotted against the response rate (i.e. the 
percentage of participants achieving the primary endpoint). When the positive predictive 
probability is less than 0.75, the assumption made above, each value of the response rate now maps 
to a higher value of the percentage of participants meeting the antiviral activity criteria. 
Consequently, the curves shift to the left in comparison to Figure 2. When the positive predictive 
probability is less than 0.5, there is now a high chance of starting Part 2 when the response rate is 
in the region of 10% to 30%. However, the likelihood to start Part 2 is strongly reduced when the 
response rate is less than 10%, even with a predictive value as low as 0.3
In conclusion, the proposed decision rule has acceptable operational characteristics in terms of the 
probability to start Part 2 over a broad range of the unknown predictive value of the early declines 
in HDV RNA and HBsAg and the uncertainty around the primary efficacy endpoint response rate.
Figure 1:
Median and [20%, 90%] credible interval of the posterior distribution of the proportion of 
participants meeting the antiviral activity criteria to start Part 2.
Panel A
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Status: Approved, Date: 09 August 2023
Panel B
Figure 2:
Probability of the outcome of the decision rule as a function of the percentage of  participants 
meeting the criteria to start Part 2
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Status: Approved, Date: 09 August 2023
Figure 3:
Probability of the outcome of the decision rule as a function of the percentage of participants 
meeting the primary endpoint for different values of the probability that a participant who 
meets the antiviral activity criteria will attain the primary endpoint.
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