Clinical trial NCT05275023
Conditions: Hepatitis B, Chronic
Sponsor: Janssen Research & Development, LLC
Start date: 2022-06-30; Completion date: 2024-05-31
Enrollment: 37 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study is to evaluate efficacy of the study intervention, based on hepatitis B surface antigen (HBsAg) levels at follow-up (FU) Week 24.

Detailed description:
JNJ-73763989 (JNJ-3989) is a small interfering ribonucleic acid (siRNA) targeting all hepatitis B virus (HBV) messenger ribonucleic acid (mRNAs). The programmed cell death protein receptor-1 (PD-1) inhibitor aims at preventing the interaction of PD-1 with its ligands. The purpose of this study to determine whether at least one of the combination regimens of JNJ-3989 + PD-1 inhibitor + Nucleos(t)ide analog (NA) is more efficacious than JNJ-3989 + NA treatment. This study will be conducted in 3 periods: screening period, treatment period and follow-up (FU) period. Safety assessments will include adverse events (AEs), serious AEs, clinical safety laboratory tests, electrocardiograms (ECGs), vital signs, and physical examinations. Total duration of individual participation will be up to 78 weeks (including screening period).

Arms: arm 1: Participants will receive JNJ-73763989 subcutaneous (SC) injections and single dose of programmed cell death protein receptor-1 (PD-1) inhibitor as intravenous (IV) infusion. Participants will also receive background treatment with NA (either tenofovir disoproxil, tenofovir alafenamide \[TAF\] or entecavir \[ETV\]). arm 2: Participants will receive JNJ-73763989 SC injections and multiple doses of PD-1 inhibitor as IV infusion. Participants will also receive background treatment with NA (either tenofovir disoproxil, TAF or ETV).
Interventions: intervention 1: JNJ-73763989 intervention 2: PD-1 inhibitor intervention 3: Tenofovir Disoproxil intervention 4: Tenofovir Alafenamide intervention 5: Entecavir
Intervention descriptions: intervention 1: JNJ-73763989 will be administered subcutaneously. intervention 2: PD-1 inhibitor will be administered as IV infusion. intervention 3: Tenofovir disoproxil film-coated tablets will be administered orally. intervention 4: TAF film-coated tablets will be administered orally. intervention 5: ETV film-coated tablets will be administered orally.

Protocol documents:
Prot_000.pdf: 
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
1
Status: Approved, Date: 30 June 2023
Janssen Research & Development *
Clinical Protocol
Intervention-specific Appendix 7 to Clinical Protocol PLATFORMPAHPB2001
A Phase 2 Open-label Trial to Evaluate Safety, Efficacy, Tolerability, and
Pharmacodynamics of a Combination of JNJ-73763989, Nucleos(t)ide Analogs, and a PD-1
Inhibitor in Chronic Hepatitis B Patients.
OCTOPUS-1Study
Protocol 73763989PAHPB2008; Phase 2
Version: Amendment 3
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.
EudraCT NUMBER: 2021-005132-33
Status: 
Approved
Date: 
30 June 2023
Prepared by: Janssen Research & Development, a division of Janssen Pharmaceutica NV
EDMS number: 
EDMS-RIM-511735, 6.0
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.
NCT05275023


JNJ-73763989 
Clinical Protocol 73763989PAHPB2008 Amendment 3
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
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Status: Approved, Date: 30 June 2023
PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLES
DOCUMENT HISTORY
Document 
Date
Amendment 3 
30 June 2023
Amendment 2  
28 March 2023
Amendment 1 
30 June 2022
Original Protocol 
21 December 2021
Amendment 3 (30 June 2023)
Overall Rationale for the Amendment: The main reason for the protocol amendment is the
discontinuation of PD-1 inhibitor (nivolumab) as study intervention as of 20 June 2023 as an urgent safety
measure (USM). Based on the observation of two cases of potential hyperthyroidism, the sponsor decided
on 20 June 2023, to halt further nivolumab dosing effective immediately. Both cases occurred in
participants in treatment arm 1 who were randomized to receive a single dose of nivolumab administered
at treatment week 16 of JNJ-3989 treatment. At treatment week 24, thyroid-stimulating hormone (TSH)
was reduced in both patients. While the first patient had normal free T3 and free T4 values and TSH values
returned to normal at follow-up visits, the second patient had fully suppressed TSH with elevation of free
T3 and free T4. The testing frequency for thyroid parameters in the Schedule of Activities will not be
changed. At the time of the USM, two participants in arm 2 were still scheduled for their third infusion with
nivolumab. Both planned infusions were cancelled via direct communication with the study sites. Treatment
with JNJ-3989 and/or nucleos(t)ide analog was continued as planned.
Also, additional clarifications were provided to the protocol sections about gastrointestinal adverse events
and hematologic abnormalities.
Section number 
and Name
Description of Change 
Brief Rationale
2.3.2.2 Potential Risks 
Discontinuation of PD-1 inhibitor (nivolumab) 
as study intervention as of 20 June 2023 for
the last two participants enrolled in treatment
arm 2 who still had outstanding doses of
nivolumab scheduled.
Two cases of potential
hyperthyroidism were observed
and therefore an urgent safety
measure was implemented.
5.4 Screen Failures 
It was clarified that the investigator will
generate screening and enrollment logs.
To align with the company’s
most recent protocol template.
8.3.6.2.1 Gastrointestinal 
Adverse Events 
It was clarified what is meant by lower
endoscopy. In addition, bowel perforation was
added as a contraindication to endoscopy.
For clarity and completeness
8.3.6.3.1 Hematologic 
Abnormalities 
Autoimmune hemolytic anemia was added to
the list of hematologic abnormalities reported
with nivolumab in the oncology setting
For completeness


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TABLE OF CONTENTS
PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLES............................................................. 2
TABLE OF CONTENTS ............................................................................................................................... 3
LIST OF IN-TEXT TABLES AND FIGURES................................................................................................ 6
1. 
PROTOCOL SUMMARY..................................................................................................................... 7
1.1. 
Synopsis........................................................................................................................................... 7
1.2. 
Schema.......................................................................................................................................... 18
1.3. 
Schedule of Activities..................................................................................................................... 19
1.3.1. 
Schedule of Activities –Screening Phase and Study Intervention Phase ................................. 19
1.3.2. 
Schedule of Activities –Follow-up Phase................................................................................... 25
2. 
INTRODUCTION................................................................................................................................ 28
2.1. 
Study Rationale.............................................................................................................................. 28
2.2. 
Background .................................................................................................................................... 32
2.2.1. 
Primary Pharmacology ............................................................................................................... 32
2.2.2. 
Nonclinical Studies ..................................................................................................................... 32
2.2.2.1. 
JNJ-3989................................................................................................................................. 32
2.2.2.2. 
Nivolumab................................................................................................................................ 35
2.2.2.3. 
Combination Nivolumab + JNJ-3989....................................................................................... 36
2.2.3. 
Clinical Studies ........................................................................................................................... 36
2.2.3.1. 
JNJ-3989................................................................................................................................. 36
2.2.3.2. 
Combination of JNJ-3989 and Entecavir, Tenofovir Disoproxil, or Tenofovir
Alafenamide............................................................................................................................. 38
2.3. 
Benefit-Risk Assessment............................................................................................................... 39
2.3.1. 
Benefits for Study Participation .................................................................................................. 39
2.3.1.1. 
Known Benefits........................................................................................................................ 39
2.3.1.2. 
Potential Benefits..................................................................................................................... 39
2.3.2. 
Risks for Study Participation....................................................................................................... 39
2.3.2.1. 
Known Risks............................................................................................................................ 39
2.3.2.2. 
Potential Risks......................................................................................................................... 40
2.3.3. 
Benefit-Risk Assessment for Study Participation ....................................................................... 41
3. 
OBJECTIVES AND ENDPOINTS ..................................................................................................... 43
4. 
STUDY DESIGN ................................................................................................................................ 45
4.1. 
Overall Design................................................................................................................................ 45
4.2. 
Scientific Rationale for Study Design............................................................................................. 47
4.2.1. 
Study-Specific Ethical Design Considerations ........................................................................... 47
4.3. 
Justification for Dose and Treatment Duration .............................................................................. 48
4.4. 
End of Study Definition................................................................................................................... 49
5. 
STUDY POPULATION ...................................................................................................................... 49
5.1. 
Inclusion Criteria............................................................................................................................ 50
5.2. 
Exclusion Criteria........................................................................................................................... 52
5.3. 
Lifestyle Considerations................................................................................................................. 57
5.4. 
Screen Failures.............................................................................................................................. 57
6. 
STUDY INTERVENTION AND CONCOMITANT THERAPY............................................................ 57
6.1. 
Study Intervention(s) Administered................................................................................................ 57
6.2. 
Preparation/Handling/Storage/Accountability ................................................................................ 59
6.3. 
Measures to Minimize Bias: Randomization and Blinding............................................................. 60
6.4. 
Study Intervention Compliance...................................................................................................... 60
6.5. 
Concomitant Therapy..................................................................................................................... 61
6.6. 
Dose Modification........................................................................................................................... 62
6.7. 
Continued Access to Study Intervention After the End of the Study ............................................. 62


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6.8. 
Treatment of Overdose .................................................................................................................. 62
6.9. 
Background Treatment................................................................................................................... 63
7.
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT
DISCONTINUATION/WITHDRAWAL............................................................................................... 64
7.1. 
Discontinuation of Study Intervention ............................................................................................ 64
7.1.1. 
Discontinuation of JNJ-3989....................................................................................................... 65
7.1.2. 
Discontinuation of Nivolumab..................................................................................................... 65
7.2. 
Participant Discontinuation/Withdrawal From the Study................................................................ 66
7.2.1. 
Withdrawal From the Use of Research Samples ....................................................................... 66
7.3. 
Lost to Follow-up............................................................................................................................ 67
8.
STUDY ASSESSMENTS AND PROCEDURES ............................................................................... 67
8.1. 
Efficacy Assessments .................................................................................................................... 68
8.1.1. 
Sequencing................................................................................................................................. 68
8.2. 
Safety Assessments....................................................................................................................... 69
8.2.1. 
Physical Examinations................................................................................................................ 69
8.2.2. 
Vital Signs................................................................................................................................... 69
8.2.3. 
Electrocardiograms..................................................................................................................... 69
8.2.4. 
Clinical Safety Laboratory Assessments .................................................................................... 69
8.2.5. 
Pregnancy Testing...................................................................................................................... 69
8.3. 
Adverse Events, Serious Adverse Events, and Other Safety Reporting ....................................... 70
8.3.1. 
Time Period and Frequency for Collecting Adverse Event and Serious Adverse Event
Information.................................................................................................................................. 70
8.3.2. 
Method of Detecting Adverse Events and Serious Adverse Events .......................................... 70
8.3.3. 
Follow-up of Adverse Events and Serious Adverse Events ....................................................... 70
8.3.4. 
Regulatory Reporting Requirements for Serious Adverse Events ............................................. 70
8.3.5. 
Pregnancy................................................................................................................................... 70
8.3.6. 
Guidelines for Management of Adverse Events of Special Interest Including Immune-
Related Adverse Events ............................................................................................................. 71
8.3.6.1. 
Intervention-emergent ALT/AST Elevations Including Immune-related Hepatic AEs ............. 71
8.3.6.2. 
Infusion-related Reactions and Other Immune-related Adverse Events................................. 73
8.3.6.2.1. 
Gastrointestinal Adverse Events.......................................................................................... 73
8.3.6.2.2. 
Neurological Adverse Events............................................................................................... 74
8.3.6.2.3. 
Pulmonary Adverse Events.................................................................................................. 75
8.3.6.2.4. 
Renal Adverse Events.......................................................................................................... 75
8.3.6.2.5. 
Endocrinopathies ................................................................................................................. 76
8.3.6.2.6. 
Rash..................................................................................................................................... 77
8.3.6.2.7. 
Uveitis and Visual Complaints.............................................................................................. 78
8.3.6.2.8. 
Lipase/Amylase Elevations .................................................................................................. 78
8.3.6.2.9. 
Infusion-related Reactions ................................................................................................... 79
8.3.6.2.10. 
Infections.............................................................................................................................. 79
8.3.6.3. 
Other Adverse Events of Special Interest Related to JNJ-3989............................................. 79
8.3.6.3.1. 
Hematologic Abnormalities .................................................................................................. 79
8.3.6.3.2. 
Injection Site Reactions........................................................................................................ 80
8.3.6.4. 
Other Adverse Events ............................................................................................................. 81
8.3.6.4.1. 
Acute Systemic Allergic Reactions....................................................................................... 81
8.4. 
Pharmacokinetics........................................................................................................................... 81
8.4.1. 
Evaluations ................................................................................................................................. 81
8.4.2. 
Analytical Procedures................................................................................................................. 81
8.4.3. 
Pharmacokinetic Parameters and Evaluations........................................................................... 82
8.5. 
Pharmacodynamics........................................................................................................................ 82
8.6. 
Host Genetics................................................................................................................................. 82
8.7. 
Exploratory Host Biomarkers ......................................................................................................... 83
8.8. 
Immune Assessments.................................................................................................................... 83
8.9. 
Medical Resource Utilization and Health Economics .................................................................... 84
9.
STATISTICAL CONSIDERATIONS.................................................................................................. 84


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9.1. 
Statistical Hypotheses.................................................................................................................... 84
9.2. 
Sample Size Determination ........................................................................................................... 85
9.3. 
Populations for Analysis Sets ........................................................................................................ 85
9.4. 
Statistical Analyses ........................................................................................................................ 85
9.4.1. 
General Considerations.............................................................................................................. 85
9.4.2. 
Efficacy Analyses........................................................................................................................ 85
9.4.2.1. 
Primary Endpoints ................................................................................................................... 86
9.4.2.2. 
Secondary Efficacy and Exploratory Endpoints ...................................................................... 86
9.4.2.3. 
Across ISAs Comparisons of Efficacy..................................................................................... 87
9.4.3. 
Safety Analyses.......................................................................................................................... 87
9.4.4. 
Other Analyses ........................................................................................................................... 87
9.5. 
Interim Analysis.............................................................................................................................. 89
10. SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS ............................ 90
10.1. 
Appendix 1: Abbreviations and Definitions .................................................................................... 90
10.2. 
Appendix 2: Clinical Laboratory Tests ........................................................................................... 93
10.3. 
Appendix 3: Regulatory, Ethical, and Study Oversight Considerations......................................... 95
10.3.1. 
Regulatory and Ethical Considerations ...................................................................................... 95
10.3.2. 
Financial Disclosure.................................................................................................................... 95
10.3.3. 
Informed Consent Process ......................................................................................................... 95
10.3.4. 
Data Protection ........................................................................................................................... 95
10.3.5. 
Long-Term Retention of Samples for Additional Future............................................................. 95
10.3.6. 
Committees Structure................................................................................................................. 96
10.3.7. 
Publication Policy/Dissemination of Clinical Study Data............................................................ 96
10.3.8. 
Data Quality Assurance.............................................................................................................. 96
10.3.9. 
Case Report Form Completion................................................................................................... 96
10.3.10. Source Documents ..................................................................................................................... 96
10.3.11. Monitoring ................................................................................................................................... 96
10.3.12. On-Site Audits............................................................................................................................. 96
10.3.13. Record Retention........................................................................................................................ 96
10.3.14. Study and Site Start and Closure ............................................................................................... 96
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................................................................................................................................. 97
10.4.1. 
Adverse Event Definitions and Classifications ........................................................................... 97
10.4.2. 
Attribution Definitions.................................................................................................................. 97
10.4.3. 
Severity Criteria.......................................................................................................................... 97
10.4.4. 
Special Reporting Situations ...................................................................................................... 97
10.4.5. 
Procedures ................................................................................................................................. 97
10.4.6. 
Product Quality Complaint Handling........................................................................................... 97
10.4.7. 
Contacting Sponsor Regarding Safety, Including Product Quality............................................. 97
10.5. 
Appendix 5: Contraceptive and Barrier Guidance ......................................................................... 98
10.6. 
Appendix 6: Rash Management................................................................................................... 100
10.7. 
Appendix 7: Cardiovascular Safety –Abnormalities.................................................................... 102
10.8. 
Appendix 8: DAIDS Table with Modifications (DAIDS [Modified]) ............................................... 103
10.9. 
Appendix 9: Study Conduct During a Natural Disaster................................................................ 129
10.10. Appendix 10: Protocol Amendment History................................................................................. 133
11. REFERENCES................................................................................................................................. 137
INVESTIGATOR AGREEMENT............................................................................................................... 139


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CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
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Status: Approved, Date: 30 June 2023
LIST OF IN-TEXT TABLES AND FIGURES
TABLES
Table 1: 
Animal-to-human Exposure Ratios at NOAEL for JNJ-3989.................................................... 35
Table 2: 
Description and Administration of Study Intervention............................................................... 58
Table 3: 
Disallowed Medication .............................................................................................................. 62
Table 4: 
Description and Administration of Background Treatment....................................................... 63
Table 5: 
Management of Immune-Related Hepatic Adverse Events...................................................... 72
Table 6: 
Management of Immune-Related Gastrointestinal Adverse Events......................................... 74
Table 7: 
Management of Neurological Adverse Events ......................................................................... 74
Table 8: 
Management of Pulmonary Adverse Events ............................................................................ 75
Table 9: 
Management of Renal Adverse Events .................................................................................... 76
Table 10: Management of Immune-Related Endocrinopathies ................................................................ 76
Table 11: Management of Uveitis and Visual Complaints ........................................................................ 78
Table 12: Management of Infusion-related Reactions.............................................................................. 79
Table 13: Management of Acute Systemic Allergic Reactions................................................................. 81
Table 14: Management of Rash Events by Severity Grade ................................................................... 100
FIGURES
Figure 1: Schematic Overview of the Study............................................................................................. 18
Figure 2: TMDD-IRM Predicted Liver Concentrations of JNJ-3989 (Left) and Corresponding
Predicted Change From Baseline (CFB) in HBsAg (Right) With (Red) and Without
(Cyan) Loading Dosing (200 mg JNJ-3989 Weekly for 4 Weeks) Prior to the 200 mg
JNJ-3989 Q4W Regimen.......................................................................................................... 29
Figure 3: Receptor Occupancy: (A) Nivolumab 0.1 mg/kg or 0.3 mg/kg, and (B) Nivolumab
0.3 mg/kg + GS-4774................................................................................................................ 30
Figure 4: Individual Patient Changes in HBsAg From Baseline to Week 12 (Left) or Week 24
(Right) by Nivolumab Treatment............................................................................................... 31


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1. 
PROTOCOL SUMMARY
1.1. 
Synopsis
A Phase 2 Open-label Trial to Evaluate Safety, Efficacy, Tolerability, and Pharmacodynamics of a
Combination of JNJ-73763989, Nucleos(t)ide Analogs, and a PD-1 Inhibitor in Chronic Hepatitis B
Patients.
Protocol 73763989PAHPB2008 is an intervention-specific appendix (ISA) to Master Protocol
PLATFORMPAHPB2001.
JNJ-73763989 (JNJ-3989) is a liver-targeted antiviral therapeutic for subcutaneous injection designed to
treat chronic hepatitis B virus (HBV) infection via a ribonucleic acid interference (RNAi) mechanism.
Engagement of the cellular RNAi machinery by JNJ-3989 results in specific cleavage of HBV RNA
transcripts, thereby reducing the levels of HBV proteins and the pre-genomic ribonucleic acid (pgRNA),
the precursor of viral relaxed circular deoxyribonucleic acid (rcDNA). The small interfering ribonucleic
acid (siRNA) triggers in JNJ-3989, JNJ-73763976 (JNJ-3976), and JNJ-73763924 (JNJ-3924), are designed
to target all HBV RNA transcripts derived from covalently closed circular deoxyribonucleic acid
(cccDNA), as well as transcripts derived from integrated HBV DNA. The latter has been suggested to be a
significant source of hepatitis B surface antigen (HBsAg) in hepatitis B e antigen (HBeAg)-negative
patients or patients on long-term (≥2 years) treatment with nucleos(t)ide analogs (NAs), the current standard
of care.
The programmed cell death protein receptor-1 (PD-1) inhibitor is nivolumab, which  is a human
immunoglobin G4 (IgG4) monoclonal antibody that binds to the PD-1 receptor, blocking the interaction
between PD-1 and its ligand PD-L1. Nivolumab is approved for the treatment of certain cancers and for
other indications at higher doses than intended in this study. The use of nivolumab in the treatment of HBV
is investigational.
Nucleos(t)ide analogs are approved treatments of chronic HBV infection.
The term “study intervention” throughout the protocol, refers to JNJ-3989 and
nivolumab.OBJECTIVES AND ENDPOINTS
Below is the list of objectives and endpoints that will be evaluated in this study, delineating the details in
alignment with the general objectives listed in the Master Protocol PLATFORMPAHPB2001. The details
specific for this ISA are highlighted (colored fill).
Objectives 
Endpoints
Primary
To evaluate efficacy of the study intervention, based on 
HBsAg levels at Follow-up Week 24 (FU Week 24). 
 
Proportion of participants who achieve HBsAg
seroclearance at FU Week 24.
Secondary
To characterize the safety and tolerability of the study 
intervention. 
 
Proportion of participants who experienced
adverse events (AEs) of interest.
 
Safety profile of JNJ-3989 with nivolumab
throughout the study (safety parameters include
but are not limited to the frequency and severity of
AEs and immune-related AEs, vital signs
measurements, physical examinations, clinical
laboratory values, and 12-lead electrocardiograms
[ECGs]).


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Objectives 
Endpoints
To evaluate efficacy in terms of changes in HBsAg 
levels from baseline over time during the study 
intervention and follow-up periods.
 
Change from baseline in HBsAg levels during the
study intervention and follow-up periods.
 
Proportion of participants with HBsAg levels
below/above different cut-offs over time.
To evaluate efficacy in terms of HBsAg 
seroclearance/seroconversion during the study 
intervention and follow-up periods (as defined in the 
Definitions of Terms).
 
Proportion 
of 
participants 
with 
HBsAg
seroclearance/seroconversion during the study
intervention and follow-up periods.
 
Time 
to 
achieve 
HBsAg 
seroclearance/
seroconversion.
To evaluate the efficacy as measured by blood markers 
(such as HBV DNA and HBeAg) during the study 
intervention and follow-up periods.
 
Change from baseline in HBV DNA levels during
the study intervention and follow-up periods.
 
Proportion of participants with HBV DNA and
HBeAg levels below/above different cut-offs over
time.
To evaluate the frequency of virologic breakthrough 
throughout the study. 
 
Proportion of participants with virological
breakthrough throughout the study.
To evaluate the pharmacokinetics (PK) of JNJ-3989 
(JNJ-3924 and JNJ-3976) and optionally of NA and/or 
nivolumab.
 
PK parameters of JNJ-3989 (JNJ-3924 and
JNJ‑3976).
 
Optionally, PK parameters of NA and/or
nivolumab.
Exploratory
To characterize the pharmacodynamics (PD) of 
JNJ-3989 with nivolumab including quantification of 
receptor occupancy (RO) on peripheral T-cells.
 
Relationship of various PK parameters with
selected efficacy and safety endpoints.
 
Quantification of nivolumab RO  on peripheral
CD3+ T-cells by flow cytometry on whole blood.
To explore changes in the severity of liver disease. 
 
Changes in fibrosis (according to Fibroscan liver
stiffness measurements) at end of study
intervention (EOSI) and the end of the follow-up
period versus baseline.
To explore HBV-specific T-cell responses throughout 
the study.*  
 
Changes from baseline in HBV-specific peripheral
blood T-cell responses over time.
To explore efficacy of the study intervention in terms 
of changes in HBV RNA and hepatitis B core-related 
antigen (HBcrAg) levels throughout the study.
 
Changes from baseline in HBV RNA and HBcrAg
levels over time.
To explore the HBV genome sequence throughout the 
study. 
 
Assessment of intervention associated mutations
over time.
To explore medical resource utilization to manage 
participants throughout the study. 
 
Number and duration of medical care encounters,
including surgeries, and other selected procedures
(inpatient and outpatient).
 
Duration of hospitalization (total days length of
stay, including duration by wards, eg, intensive
care unit).
 
Number and character of diagnostic and
therapeutic tests and procedures.


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Objectives 
Endpoints
 
Outpatient medical encounters and treatments
(including physician or emergency room visits,
tests and procedures, and medications).
*Peripheral blood mononuclear cell (PBMC) samples for immune analyses will be collected at selected sites only.
Hypothesis
The primary hypothesis of this study is that at least one of the combination regimens of
JNJ-3989+nivolumab+NA is more efficacious than JNJ-3989+NA treatment, as measured by the primary
efficacy endpoint (ie, the proportion of participants with HBsAg seroclearance at FU Week 24). Because
the study does not include a regimen arm without nivolumab, the hypothesis is formulated assuming a fixed
response rate for JNJ-3989+NA of 1% based on previous Study 73763989HPB2001 (REEF-1).
OVERALL DESIGN
This ISA describes a Phase 2 study of the combination regimen of JNJ-3989 with nivolumab and NA. It is
a companion document to the Master Protocol PLATFORMPAHPB2001, which describes the common
design elements of the Platform study in participants with chronic HBV infection. This ISA describes
specific and/or additional protocol elements applicable to this randomized, open-label, parallel, multicenter,
interventional study to evaluate safety, efficacy, tolerability, PK and PD of a combination of JNJ-3989,
nivolumab, and NAs in virologically suppressed chronic HBV-infected adult participants.
This open-label study will be conducted in 3 periods:
 
6-week Screening Period (if necessary, eg, for operational reasons, this can be extended to a
maximum of 8 weeks decided on a case-by-case basis and in agreement with the sponsor). During
the Screening Period, the participants will continue the same NA treatment they were receiving
before screening.
 
24-week Study Intervention Period:
o 
Arm 1: JNJ-3989 once a week (Q1W) for the first 4 weeks then once every 4 weeks (Q4W)
until Week 24 + nivolumab at Week 16 + NA once daily (QD)
o 
Arm 2: JNJ-3989 Q1W for the first 4 weeks then Q4W until Week 24 + nivolumab Q4W at
Weeks 16, 20, and 24 + NA QD.
 
48-week Follow-up Period: during which NA treatment will be continued.
At baseline, participants who meet the eligibility criteria will be randomized in a 1:1 ratio to Arm 1 or
Arm 2. Randomization will be stratified by absolute HBsAg level (<100 IU/mL, 100 to <1,000 IU/mL, and
≥1,000 IU/mL) at screening, as assessed by quantitative HBsAg assay.
Assessments and sampling will be done for efficacy (eg, HBsAg, HBeAg, and HBV DNA), safety (eg,
[S]AEs, immune-related AEs, laboratory evaluations, ECGs, vital signs, physical examinations), PK,
PK/PD, viral genome sequencing, PBMC, human leukocyte antigen (HLA) typing, immunogenicity and
pharmacogenomics, and for exploratory analysis of host and viral markers.
Participants will be considered to have completed the study if they have completed all the assessments of
the final study visit (ie, FU Week 48).
If a participant prematurely discontinues treatment with JNJ-3989 before Week 24, the participant will also
discontinue further treatment with nivolumab and will have an early withdrawal (WD) visit. Follow-up
assessments should be obtained as per the Schedule of Activities until 48 weeks after the end of JNJ-3989
treatment unless the participant withdraws consent. The NA treatment will be continued until the end of the
study.


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If a participant prematurely discontinues nivolumab, treatment with JNJ-3989 and NA should be continued
as planned, unless a treatment discontinuation rule for JNJ-3989 is also met. In that case, JNJ-3989 will
also be discontinued but NA treatment should be continued as planned.
If a participant withdraws prematurely from the study, the reason for withdrawal (if known) should be
documented. Participants who withdraw consent will be offered an optional safety follow-up visit to occur
on the day of consent withdrawal.
An internal Data Review Committee (DRC) will be commissioned for monitoring safety of participants
enrolled in this study. In addition, an Independent Flare Expert Panel (IFLEP) will be appointed.
NUMBER OF PARTICIPANTS
Initially, 44 (22 per arm) virologically suppressed, HBeAg negative, adult chronic hepatitis B participants
≥18 (or the legal age of consent in the jurisdiction in which the study is taking place) to <56 years of age
were planned to be enrolled in this study.
Due to the decision to not extend further enrollment beyond the planned enrollment period and proceed
with a reduced sample size, the final sample size is 37 (18 in Arm 1 and 19 in Arm 2).
INTERVENTION GROUPS AND DURATION
The total duration of individual participation will be up to 72 weeks (screening not included) with a 24-week
study intervention period and a 48-week follow-up period.
Description of Background Treatment
Background treatment consists of NAs tenofovir disoproxil (245 mg), tenofovir alafenamide (TAF)
(25 mg), or entecavir (ETV) (0.5 mg) given as oral tablets QD for approximately 76 weeks (screening
included).
Investigators should follow guidance detailed in the local prescribing information of NA.
Treatment Name 
Tenofovir disoproxil 
Tenofovir alafenamide 
(TAF)* 
Entecavir (ETV)
monohydrate
Type 
Drug 
Drug 
Drug
Dose Formulation 
Film-coated tablets 
Film-coated tablets 
Film-coated tablets
Unit Dose Strength(s) 
245 mg 
25 mg 
0.5 mg
Dosage Level(s) 
245 mg QD  
25 mg QD  
0.5 mg QD
Route of Administration 
Oral 
Oral 
Oral
* 
In countries where TAF is available, it will be one of the NA treatments options.


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Description of Study Intervention
Study intervention consists of:
 
JNJ-3989: 200 mg given by subcutaneous (SC) injections Q1W for the first 4 weeks then Q4W
until Week 24 (10 doses)
 
Nivolumab: 0.3 mg/kg, one single intravenous (IV) infusion at Week 16 for Arm 1 or 3 IV
infusions at Weeks 16, 20, and 24 for Arm 2.
Intervention Name 
JNJ-3989 
Nivolumab
Type 
Drug 
Drug
Dose Formulation  
Solution for injection (G001) 
Concentrate for solution for infusion
Unit Dose Strength(s) 
200 mg/mL 
40 mg/4 mL
Dosage Level(s) 
200 mg Q1W for the first 4 weeks, 
then Q4W until Week 24 
0.3 mg/kg (1 intravenous [IV]
infusion for Arm 1 or 3 IV infusions
Q4W for Arm 2)**
Route ofAdministration 
Subcutaneous injection* (preferably  
in the abdomen; upper arm or thigh is
also allowed)
IV infusion over 30 minutes
Use 
Investigational intervention  
Investigational intervention
Investigational Medicinal Product 
(IMP)
Yes 
Yes
Non-investigational Medicinal 
Product/ Auxiliary Medicinal
Product (NIMP/AxMP)
No 
No
Sourcing 
Provided centrally by the sponsor 
Provided centrally by the sponsor
Packaging and Labeling 
Each unit will be labeled with unique 
medication ID number 
Commercial supplies will be
sourced. Each unit will be labeled
with unique medication ID number
Food/Fasting Instructions 
Regardless of food intake 
Not Applicable
*Note: Administration into scar tissue or areas that are reddened, inflamed or swollen should be avoided. If injecting
into the abdomen, avoid a 5 cm diameter circle around the navel.
**Note: a tolerance of +/- 5% around the theoretical dose of 0.3 mg/kg will be applied to consider the necessary
rounding and standard practice for the preparation and intravenous administration of drugs dosed by weight.
EFFICACY EVALUATIONS
All efficacy assessments will be performed at predefined time points as specified in the Schedule of
Activities.
Qualitative and quantitative HBsAg and HBeAg, and quantitative HBcrAg as well as anti-hepatitis B
surface (HBs) and anti-hepatitis B e (HBe) antibodies will be determined using validated serologic assays
in a central laboratory. Samples for the determination of HBsAg, HBeAg, anti-HBs antibodies, and


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anti-HBe antibodies will be processed in real-time. Samples for the determination of HBcrAg can be
analyzed in batch and at the sponsor’s request.
HBV DNA and HBV RNA will be assessed at central laboratories using validated assays for the
quantification of HBV DNA and HBV RNA. Samples for the determination of HBV DNA will be processed
in real-time. Samples for the determination of HBV RNA can be analyzed in batch and at the sponsor’s
request.
In participants enrolled at a site with access to a Fibroscan device, Fibroscan assessments will be performed
at different time points to determine changes in fibrosis levels.
Samples may be used by the sponsor for additional exploratory assessments analyzing the serologic and
virologic characteristics of HBV infection and efficacy or safety of the study intervention.
Sequencing
Viral genome sequence analysis will be performed to evaluate mutations associated with the study
intervention.
SAFETY EVALUATIONS
Safety and tolerability (AEs, clinical safety laboratory assessments, ECGs, vital signs, and physical
examinations) will be evaluated as described in Section 8.2 and Section 8.3 of the Master Protocol
PLATFORMPAHPB2001 and at predefined time points as specified in the Schedule of Activities.
Adverse 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. Guidelines are in place for
management of AEs of Special Interest.
PHARMACOKINETIC EVALUATIONS
All participants will have sparse PK sampling during the study intervention period.
Blood samples will be collected for measurement of plasma concentrations of JNJ-3989 (ie, JNJ-3976 and
JNJ-3924) and NA, and serum concentrations of nivolumab at time points specified in the Schedule of
Activities. Bioanalysis of NA and nivolumab is optional at the discretion of the sponsor. Serum collected
for PK may additionally be used to evaluate safety or efficacy aspects that address concerns arising during
or after the study period.
PHARMACOKINETIC/PHARMACODYNAMIC EVALUATIONS
Relationships of individual PK parameters for JNJ-3976 and JNJ-3924, and optionally NA and/or
nivolumab, with RO, selected efficacy and/or safety endpoints may be evaluated, if applicable.
PHARMACODYNAMIC EVALUATIONS
Whole blood samples will be collected for assessment of nivolumab RO on circulating T-cells by flow
cytometry analysis.
Pharmacodynamic biomarkers will be evaluated in all participants pretreatment, on-treatment, and
posttreatment with study intervention as detailed in Section 8.5.
HOST GENETICS
An optional sample for HLA testing will be collected from participants who consent separately to this
component of the study.


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An optional pharmacogenomic (host DNA) blood sample may be collected (preferably at baseline) to allow
for host pharmacogenomic research, where local regulations permit. In addition, host DNA blood samples
to allow for epigenetic analyses will be collected in participants who consent. These samples could for
example be used to assess changes in frequencies of immune cells.
Complete host genomic testing may be done to search for links of specific genes to (HBV-related) liver
disease or to the PK, PD, efficacy, safety, or tolerability of the study intervention. These samples will only
be collected from participants who consent separately to this component of the study. Further, a participant
may withdraw such consent at any time without affecting their participation in other aspects of the study,
or their future participation in the Platform study.
In addition, other samples may be used for exploratory genetic or epigenetic research in participants
consenting separately to this part of the study. These samples can only be used to investigate the potential
association of genetic or epigenetic factors with efficacy, safety, or PK of the study intervention, or HBV
infection, or may be used to develop tests/assays related to the study intervention or HBV infection. No
genetic research will be performed on any sample in participants who have not provided the additional
separate consent for host genetic research.
EXPLORATORY HOST BIOMARKERS
The study includes collection of blood samples for exploratory analysis of host blood biomarkers at the
host RNA, protein, and cell level. Sampling will be performed at the time points indicated in the Schedule
of Activities. Leftovers of other samples might also be used for exploratory research of host and viral
markers.
Samples can only be used for research related to study intervention or HBV infection or may be used to
develop tests/assays related to study intervention or HBV infection.
A fine needle aspiration (FNA) biopsy sample may be collected from participants who consent separately
to this component of the study (as permitted by local regulations). If participants agree to undergo an
optional FNA biopsy of the liver, following local standard practice, the biopsy location will be identified
and/or guided with ultrasound and the FNA biopsy samples will be collected after application of local
anesthesia to allow for exploratory biomarker research.
IMMUNE ASSESSMENTS
At selected sites, PBMC samples for immune analyses will be collected during study intervention and
follow-up and will be analyzed centrally for HBV-specific responses by enzyme-linked immunospot
(ELISpot) and/or intracellular cytokine staining (ICS) after stimulation with HBV-specific antigens.
ELISpot detects T-cells that secrete gamma interferon (IFN-γ) in response to a specific antigenic
stimulation, whereas ICS determines the frequency of CD4+ and CD8+ T-cells secreting cytokines such as
IFN-γ, interleukin (IL)-2 and tumor necrosis factor (TNF)-α in response to a specific antigenic stimulation.
Additional PBMC samples may be taken in case of alanine aminotransferase (ALT) flares, upon discussion
with the sponsor, which may require an unscheduled visit.
Additional experiments may be performed to further phenotypically and functionally characterize PBMCs.
Leftover PBMC samples may be used at the sponsor’s discretion for additional exploratory research or to
explore new functional immune assays, or for immune assay optimalization.
Blood samples taken at the time points indicated in the Schedule of Activities, can also be used to explore
the emergence of antidrug antibodies to JNJ-3989 and/or nivolumab. Antidrug antibodies may be analyzed
using assays such as an enzyme-linked immunosorbent assay or functional assays.


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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.
Protocol-mandated procedures, tests, and encounters are excluded. The data collected may be used to
conduct exploratory economic analyses and will include:
 
Number and duration of medical care encounters, including surgeries, and other selected procedures
(inpatient and outpatient)
 
Duration of hospitalization (total days length of stay, including duration by wards, eg, intensive care
unit)
 
Number and character of diagnostic and therapeutic tests and procedures
 
Outpatient medical encounters and treatments (including physician or emergency room visits, tests
and procedures, and medications).
STATISTICAL METHODS
Sample Size DeterminationAccording to the initial protocol, the study aimed to have a sample size of 20
participants per intervention arm which  yielded ≥85% statistical power to detect a ≥15% and ≥20%
difference for the proportions of participants with HBsAg seroclearance at FU Week 24 in the
2 intervention arms, respectively, vs a fixed proportion of ≤1%. Statistical power to test the primary
hypothesis was assessed for each of the intervention arms, using an exact test for a single proportion with
a one-sided Type 1 error rate of 0.05 and applying the Hochberg procedure for multiple comparisons
adjustment. The fixed rate assumed for the external active control (JNJ-3989 [200 mg]+NA treatment) is
based on the data of Study 73763989HPB2001 (REEF-1).
The total study sample size was adjusted to 44 participants (22 per arm), with 1:1 randomization ratio to
each of the intervention arms, to account for an approximate 10% attrition rate.
Due to the decision to not extend further enrollment beyond the planned enrollment period and proceed
with a reduced sample size, the final sample size is 37 (18 in Arm 1 and 19 in Arm 2). Under the same
assumptions and methods of the initial protocol, an approximate sample size of 16 participants per
intervention arm (assuming 10% attrition) yields ≥75% statistical power to detect the same differences in
HBsAg seroclearance at FU Week 24.
Efficacy Analyses
The primary efficacy analysis will be performed when all participants have completed the FU Week 24
visit or discontinued earlier. The final analysis will be performed when all participants have completed the
final study visit at FU Week 48 or discontinued earlier.
To evaluate the efficacy, the primary analysis set will be the Full Analysis Set (FAS) (see Section 9.3,
Populations for Analysis Sets). The Full Analysis Set for nivolumab (FAS-N) will be used for sensitivity
analyses of selected efficacy endpoints.
Primary Efficacy Endpoint
The proportion of participants who achieved HBsAg seroclearance at FU Week 24 will be summarized for
each intervention arm paired together with a two-sided, single arm 90% confidence interval (CI) based on
the Clopper-Pearson method. The statistical comparison will be conducted using an exact binomial test
against a fixed external control value of 1% at a one-sided Type 1 error rate of 0.05 and applying the
Hochberg procedure for adjusting for multiple comparisons.


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Association of the stratification factors and other demographic and baseline disease characteristics with the
primary endpoint may be explored using logistic regression analyses and classification and regression tree
analysis (CART).
The Mantel-Haenszel test adjusted for the randomization stratification factors will be used in a secondary
analysis comparing the primary endpoint between the 2 study intervention arms at a one-sided alpha level
of 0.05.
Secondary Efficacy and Exploratory Endpoints
Descriptive statistics will be used for all efficacy endpoints, which will be summarized by intervention arm
and by study period. Comparisons between intervention arms and 90% CIs may be done with no adjustment
for multiplicity. Specific key selected endpoints may be analyzed using suitable categorical data approaches
(eg, Mantel-Haenszel or logistic regression for proportions or other categorical type of endpoint),
longitudinal repeated measures models (eg, for continuous types of variables), or survival analysis based
on the Kaplan-Meier estimates (for time-to-event variables), as appropriate. Details will be described in the
Statistical Analysis Plan (SAP).
Graphic data displays of different type (eg, bar charts, line plots, and waterfall plots) will also be used to
summarize the efficacy data by intervention arm and over time.
Across ISAs Comparisons of Efficacy
Indirect comparisons between different regimens across multiple ISAs may be performed in an exploratory
fashion by selecting the similar subgroup of participants who match the most important inclusion/exclusion
criteria and demographic characteristics of this ISA.
More details on this approach and its application to secondary endpoints will be provided in a separate
document (eg, SAP or the Modeling and Simulation Report).
Safety Analyses
Safety analyses will be based on the safety population. Safety will be evaluated by means of descriptive
summaries of AEs including AEs of Special Interest to any of the study interventions, clinical laboratory
tests, ECGs, vital signs, and physical examinations. The safety analysis will be done by study period.
Results will be presented in tabular format and/or graphically by intervention arm and over time, as
appropriate.
Other Analyses
Pharmacokinetic Analyses
Population PK analysis of concentration-time data of JNJ-3976 and JNJ-3924, and, optionally, of NA and/or
nivolumab may be performed using non-linear mixed effects modeling. Data may be combined with
selected Phase 1 and/or 2 studies to support a relevant structural model. Available participant characteristics
(eg, demographics, laboratory variables, genotypes) will be included in the model as necessary. Details will
be given in a population PK analysis plan and results of the population PK analysis, if applied, will be
presented in a separate report.
Pharmacokinetic/Pharmacodynamic Analyses
Relationships of PK parameters for JNJ-3976 and JNJ-3924, and, optionally, for NA and/or nivolumab,
with RO, selected efficacy and/or safety endpoints may be evaluated and graphically displayed, if
applicable.
Modeling of key PD parameters (eg, HBsAg, HBV DNA) may be performed using population PK/PD. If
PK/PD modeling of key efficacy endpoints is performed, treatment effect and possible covariates may be


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investigated. Other biomarkers may be explored at the sponsor’s discretion. If applicable, the results will
be described in a separate report.
Pharmacodynamic Analyses
Descriptive statistics by treatment will be used to summarize PD parameters at each applicable time point.
Statistics include sample size (n), mean, standard deviation (SD), coefficient of variation (CV), geometric
mean, median, minimum, and maximum. Additional PD analyses may be performed, as deemed necessary.
Resistance Analysis
The results of HBV viral sequencing will be evaluated by the sponsor virologist. Relevant changes of amino
acid and/or nucleic acid variations (eg, substitutions) in the HBV genome will be tabulated and described.
Additional exploratory characterization of the HBV viral sequence and phenotype may be performed and
reported separately.
Pharmacogenomic Analyses
The statistical approach for analyzing the exploratory host DNA research samples, including epigenetic
analyses, may depend on the objective of the analyses (eg, efficacy, safety, and/or PK) and possibly relevant
genes at the time of analysis. Analyses will be conducted at the sponsor’s discretion, will always be under
the sponsor’s supervision, and results will be presented either in the clinical study report or a separate report.
Host Biomarker Analyses
Statistical approaches to explore correlations between clinical outcome and blood biomarkers vary and
depend on the different data types of the applied technology platforms, as well as on the extent of observed
interindividual variability. Analyses will be conducted at the sponsor’s discretion, will always be under the
sponsor’s supervision, and results will be presented either in the clinical study report or a separate report.
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 (or positivity threshold) may also be tabulated for PBMCs during
study intervention and follow-up. The proportion (%) of chronic HBV-infected patients with detectable
responses based on the magnitude of the IFN-γ T-cell response or the CD4+ or CD8+ T-cells expressing at
least 1 of the cytokines amongst IL-2, TNF α or IFN-γ for 1 of the HBV antigens as defined by ELISpot
and/or ICS, respectively, will be determined.
Medical Resource Utilization
Medical resource utilization data will be descriptively summarized by intervention arm over time.
Interim Analyses
Interim analyses (IAs) will be conducted to assess safety and evaluate the time course of different safety
and efficacy markers to support the sponsor’s interactions with health authorities, as well as to inform
internal decisions about additional studies and/or investigation of other treatment combinations.


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Optional IAs are planned when:
 
All randomized participants have completed Week 24 or discontinued earlier.
 
All randomized participants have completed FU Week 12 or discontinued earlier.
Depending on the enrollment rate, any of the above IAs may be skipped if it is too close to the predicted
timing of any adjacent interim cut-offs and additional IAs may be performed by the sponsor to support
interactions with health authorities.
The study is open-label, and the sponsor will conduct IA(s). Hence, the study team and the DRC will have
access to the IA results, while the investigators and participants will not.
Interim analyses will be based on all data available at the predefined cut-off time points and may include
data at later time points for those participants who have reached subsequent visits.






















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2. 
INTRODUCTION
JNJ-73763989 (JNJ-3989) is a liver-targeted antiviral therapeutic for subcutaneous (SC) injection
designed to treat chronic hepatitis B virus (HBV) infection via a ribonucleic acid interference
(RNAi) mechanism. Engagement of the cellular RNAi machinery by JNJ-3989 results in specific
cleavage of HBV RNA transcripts, thereby reducing the levels of HBV proteins and the
pre-genomic ribonucleic acid (pgRNA), the precursor of viral relaxed circular deoxyribonucleic
acid (rcDNA). The small interfering ribonucleic acid(siRNA) triggers in JNJ-3989, JNJ-73763976
(JNJ-3976), and JNJ-73763924 (JNJ-3924), are designed to target all HBV RNA transcripts
derived from covalently closed circular deoxyribonucleic acid (cccDNA), as well as transcripts
derived from integrated HBV DNA. The latter has been suggested to be a significant source of
hepatitis B surface antigen (HBsAg) in hepatitis B e antigen (HBeAg) negative patients or patients
on long-term (≥2 years) treatment with nucleos(t)ide analogs (NAs), the current standard of care.
(Wooddell 2017)
The programmed cell death protein receptor-1 (PD-1) inhibitor is nivolumab, which is a human
immunoglobulin G4 (IgG4) monoclonal antibody that binds to the PD-1 receptor, blocking the
interaction between PD-1 and its ligand PD-L1. Nivolumab is approved for the treatment of certain
cancers at higher doses than intended in this study. The use of nivolumab in the treatment of HBV
is investigational.
The nucleos(t)ide analogs (NAs) are approved treatments of chronic HBV infection.
For the most comprehensive nonclinical and clinical information regarding JNJ-3989, refer to the
latest version of the Investigator’s Brochure (IB) and Addenda for JNJ-3989 (IB JNJ-3989). For
nonclinical and clinical information regarding nivolumab  and NA, refer to the respective
prescribing information.
The term “study intervention” throughout the protocol, refers to JNJ-3989 and nivolumab as
defined in Section 6.1, Study Intervention(s) Administered.
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.
2.1. 
Study Rationale
Combination treatment with JNJ-3989 and NA has shown  to specifically decrease HBV viral
antigen levels and inhibit viral replication. Since hepatitis B surface antigen (HBsAg) is immune-
suppressive, the direct reduction of HBsAg levels by JNJ-3989 is aimed at contributing to the
restoration of the immune response that is impaired in chronic HBV infection. The restoration of
immune response may not be sufficient and therefore addition of immunomodulatory agents is
being investigated.


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The current study is designed to assess efficacy and safety of a treatment regimen of 24 weeks of
JNJ-3989 (200 mg administered Q1W for the first 4 weeks then Q4W until Week 24), in
combination with 1 or 3 doses of nivolumab every 4 weeks (Q4W) as of Week 16 and with NA.
Virologically suppressed chronic HBV-infected HBeAg negative patients will be enrolled in this
study.
The primary objective of the study will be to explore the proportion of participants who achieve
HBsAg seroclearance at Follow-up (FU) Week 24. The complete follow-up period will be
48 weeks.
Pharmacokinetic-pharmacodynamic (PK/PD) modeling of JNJ-3989 using a transporter-mediated
drug disposition (TMDD) and indirect response model (IRM) based on REEF-1 data suggests that
applying a loading dose (Q1W) regimen for JNJ-3989 will result in higher liver concentrations
more rapidly than with a Q4W dosing regimen. Higher liver concentrations are expected to result
in a more pronounced and faster decline in HBsAg and may improve the likelihood of achieving
functional cure. Figure 2 illustrates the model-predicted liver concentrations of JNJ-3989 and
corresponding predicted change from baseline in HBsAg, comparing a 200 mg JNJ-3989 Q4W
regimen with a 200 mg JNJ-3989 loading dose regimen (Q1W for the first 4 weeks and then Q4W).
The deterministic prediction was performed using a typical subject of the REEF-1 study, being
virologically suppressed and HBeAg negative, representative of the (median) population.
Figure 2: 
TMDD-IRM Predicted Liver Concentrations of JNJ-3989 (Left) and Corresponding Predicted
Change From Baseline (CFB) in HBsAg (Right) With (Red) and Without (Cyan) Loading
Dosing (200 mg JNJ-3989 Weekly for 4 Weeks) Prior to the 200 mg JNJ-3989 Q4W Regimen


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A major barrier to achieving functional cure of HBV is the dysfunctional immune response to viral
infection. In patients with chronic hepatitis B (CHB), HBV antigen-specific T-cells are depleted
or exhausted and therefore, incapable of controlling and eliminating virus. HBsAg-specific B-cells
are also deficient in producing antibodies. The primary cause of immune dysfunction is excessive
antigen (eg, HBsAg) stimulation from ongoing viral replication which induces epigenetic
reprogramming of CD8+ T-cells and subsequently increased expression of multiple inhibitory
receptors, such as PD-1. Expression of the corresponding ligands (eg, PDL-1) is also increased. In
vitro, checkpoint blockade with PD(L)-1 inhibitors can reinvigorate cytokine production  of the
immune dysfunction from HBV and proliferation potential of exhausted T-cells (Yang 2021).
In 51 CHB patients with advanced hepatocellular carcinoma (HCC) treated with the humanized
monoclonal antibody (mAb, IgG4) PD-1 inhibitor nivolumab dosed 3 mg/kg every 2 weeks (Q2W)
during the dose expansion phase of CHECKMATE 040, 3 patients (6%) had ≥1 log10 decline in
HBsAg – there were no HBsAg seroconversions or HBV reactivation in this cohort
(El-Khoueiry 2017).
In the initial dose-ranging study of nivolumab, doses of 0.1 to 10 mg/kg IV were used –no serious
adverse events (SAEs), fewer treatment-related Grade 3-4 adverse events (AEs), and no
autoimmune disorders were reported in cancer patients who received single or multiple doses
<1 mg/kg IV (Brahmer 2010, Topalian 2012). Based on these data, Gane 2019 evaluated
single-dose nivolumab 0.1 or 0.3 mg/kg IV alone or with GS-4774 (therapeutic HBV vaccine) in
virologically suppressed CHB patients who were HBeAg negative on current anti-HBV treatment.
Maximum receptor occupancy (RO) measured in peripheral blood mononuclear cell (PBMCs) was
68.9-88.2% across the 2 doses, similar to levels seen in prior evaluations of nivolumab (from 0.1
to 10 mg/kg) and were maintained up to Day 43 post-dose (see Figure 3).
Figure 3: 
Receptor Occupancy: (A) Nivolumab 0.1 mg/kg or 0.3 mg/kg, and (B) Nivolumab 0.3 mg/kg +
GS-4774


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No difference in HBsAg was observed after 12 weeks in the 2 patients dosed 0.1 mg/kg IV. The
mean (95% confidence interval [CI]) change in HBsAg from baseline to Week 12 was -0.30 (-0.46
to -0.14) log10 IU/mL for 12 patients treated with nivolumab 0.3 mg/kg IV and -0.16 (-0.33 to
0.01) log10 IU/mL for 10 patients treated with nivolumab 0.3 mg/kg IV and GS-4774 40 yeast units
(YU); change in HBsAg from baseline to Week 24 was -0.48 (-0.83 to -0.13) and -0.25 (-0.64 to
0.13), respectively. Individual change in HBsAg is shown in Figure 4 (Gane 2019).
Figure 4: 
Individual Patient Changes in HBsAg From Baseline to Week 12 (Left) or Week 24 (Right) by
Nivolumab Treatment
AEs were reported in 15 patients: 1 (50%) receiving nivolumab 0.1 mg/kg IV, 7 (58%) receiving
nivolumab 0.3 mg/kg IV, and 7 (70%) receiving nivolumab 0.3 mg/kg IV with GS-4774 40 YU.
Most AEs were Grade 1 in severity and were considered not related to nivolumab. One patient
receiving GS-4774 + nivolumab 0.3 mg/kg experienced an AE (injection site pain) considered by
the investigator as related to GS-4774, and 3 patients receiving nivolumab 0.3 mg/kg experienced
an AE (mild fatigue, mild headache, mild cough [1 patient each]) considered by the investigator
as related to nivolumab. The most common AEs were fatigue (3 patients [nivolumab 0.3 mg/kg
group]), upper respiratory tract infection (2 patients [GS-4774 + nivolumab 0.3 mg/kg group]),
and nasal congestion (2 patients [GS-4774 + nivolumab 0.3 mg/kg group]). There were no Grade 3
or 4 AEs or SAEs. There were no AEs of autoimmune disorders (eg, pneumonitis, colitis, rash, or
endocrinopathies). One patient in the 0.3 mg/kg nivolumab group had a baseline alanine
aminotransferase (ALT) of 49 IU/mL which increased to 275 IU/mL at Week 4 (Grade 3 elevation)
after nivolumab administration before returning to 54 IU/mL by the end of study. The ALT
elevation was accompanied by a 3-log10 reduction in HBsAg level and subsequent HBsAg
seroconversion.
Two other patients (1 in the nivolumab 0.3 mg/kg group and 1 in the GS-4774 + nivolumab group)
experienced Grade 1 ALT elevations with peak ALT values of 59 IU/mL  and 61 IU/mL,
respectively, both accompanied by >0.5 log10 reduction in serum HBsAg levels at 24 weeks. The
association of these transient ALT elevations with HBsAg responses in all 3 patients suggested
that these were immune-mediated HBV flares rather than de novo autoimmune hepatitis.
There were no clinically significant abnormal findings for electrocardiograms or vital signs
(Gane 2019).


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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-3976 and JNJ-3924, 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 (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-3924) 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-3976), 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.
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
2.2.2.1. 
JNJ-3989
Little potential for off-target inhibition of human gene expression in participants is expected, based
on in silico human genome database screening.
The nonclinical safety profile of JNJ-3989 has been evaluated through a series of in vitro and in
vivo studies. Repeat-dose SC toxicity studies up to 24 or 37 weeks were conducted in  rat and
monkey, respectively. In the 24- or 37-week studies, JNJ-3989 was administered once weekly
(QW) for the first month, followed by once monthly thereafter. JNJ-3989 was well tolerated in
these studies.
Target organs/tissues in rats are the liver, injection site, kidney, and macrophages (in testes, lymph
nodes, injection site) and in monkeys are the liver, injection site, and macrophages (lymph nodes,
injection site). Most of the observed study intervention-related microscopic changes in these
tissues/organs are well-known modality-related findings (Janas 2018a, Janas 2018b) related to


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intracellular presence of siRNA. Additionally, adverse findings were noted in the liver and
subcutaneous injection site in rats.
Slight alteration of the renal tubular epithelium in rats was characterized by the presence of
basophilic granules and/or microvacuolation of the cytoplasm of renal tubules in the outer cortex.
After a recovery period of 4 months in rats, most of the kidney findings noted at the end of
treatment hadfully (tubular vacuolation) or partially (basophilic granules) resolved. These findings
were considered not toxicologically meaningful since they were related to compound accumulation
and were largely in line with published data for GalNAC-conjugated siRNA compounds
(Henry 2012; Janas 2018a). There was no evidence of cellular damage (degeneration/necrosis) and
no correlation to clinical pathology indicators of changes in renal function.
After 6 months of dosing with JNJ-3989 in both rat studies (Studies 8381085 and TOX13822),
livers showed basophilic granules in Kupffer cells and hepatocytes, hepatocellular vacuolation,
single-cell necrosis (SCN), increased mitoses, karyomegaly, and/or cytoplasmic alteration, but
also an increased incidence/severity of foci of cellular alteration (FCA), oval cell proliferation and
cholangiofibrosis. These findings accompanied with increased alkaline phosphatase (ALP) activity
levels. The FCA (in combination with the magnitude of other microscopic findings in the liver)
were considered adverse in males at ≥180 mg/kg and in females at ≥60 mg/kg. Following a
4-month treatment-free period, there was no clear evidence of recovery of the FCA in females
(also no progression).
At supra-pharmacologic doses, GalNAc-siRNA compounds are known to induce modality-related
liver findings in the rat. These findings include basophilic granules in hepatocytes and Kupffer
cells, Kupffer cell hyperplasia, hepatocellular vacuolation, degeneration, and SCN, and are
commonly associated with signs of regeneration, such as increased mitosis and karyomegaly. This
may be accompanied by mild increases in hepatic transaminases related to accumulation of
GalNAc-siRNA in the liver (Janas 2018b). Sensitivity to hepatic injury including SCN and
sequelae as a result of GalNAc-siRNA accumulations are described to be largely specific to rats
because they are not seen or occur at lower severity in other species (Janas 2018a). The hypothesis
for the presence of FCA in rat livers is that at continuously high compound exposure/accumulation
in hepatocytes, primary hepatotoxic events (supported by presence of SCN) occur at a higher
incidence/severity in rats. This leads to secondary regenerative proliferative responses (mitoses,
karyomegaly, oval cell proliferation), ultimately leading to FCA, which are potentially
preneoplastic findings (Holsapple 2006; Cattley 2013). While the mechanism for the species
differences is not known, the cascade of hepatotoxic events does not appear to occur in non-human
primates (NHPs), as supported by the 9-month chronic study (Study 8381086) and data from other
GalNAc-siRNA (Givlaari 2019; Janas 2018b). Such liver findings were not observed in NHPs
(Study 8381086) despite exhibiting higher liver concentrations, confirming the higher sensitivity
of rats to liver toxicities induced by JNJ-3989. As reported, NHPs are considered a more relevant
species for testing pharmacologically-related toxicity and potency of RNAi therapeutics as they
present better genomic homology with humans (Ebeling 2011; Janas 2018a; Setten 2019).


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The subcutaneous injection of JNJ-3989 in rats resulted in chronic vacuolated macrophage
response (phagocytosis of siRNA), mononuclear cell infiltration, and a low incidence of fibrosis
at the end of the dosing period caused by the chronic SC  presence of the compound, while in
monkey only minimal infiltrates of macrophages were observed. In one male rat of the 300 mg/kg
dose group (highest dose tested, Study TOX13822), a poorly differentiated sarcoma was noted at
the left flank during the recovery period. This was not seen in males up to 180 mg/kg,
corresponding to a rat/human plasma area under the plasma concentration-time curve (AUC) ratio
of 59x and 21x for JNJ-3924 and JNJ-3976, respectively (human exposures originating from Study
AROHBV1001). Subcutaneous sarcomas can occur spontaneously in rodents or can be induced
by SC injection by a range of non-carcinogenic agents after varying periods oftime. They can be
induced in laboratory rodents by implanted chemical or inert substances and are typically
associated with agents that elicit a tissue response characterized by severe inflammation, tissue
damage, a macrophage response, fibroblastic proliferation and fibroplasia (Greaves 2012). The
rats in this study were repeatedly injected at the same location (ie, 10 injections in the left flank).
In the embryofetal development (EFD) studies, JNJ-3989 was not teratogenic in rats and rabbits.
The fertility study showed no effects on parental and reproductive parameters in male and female
rats given JNJ-3989 up to a dose of 180 mg/kg/week.
JNJ-3989 was shown to be non-genotoxic when tested in the bacterial reverse mutation assay, and
in vitro and in vivo micronucleus test.
Results of the non-Good Laboratory Practice (non-GLP) in vitro studies demonstrated there is no
potential for induction of the innate immune system (cytokine and complement activation),
mitochondrial toxicity/cytotoxicity, or platelet aggregation associated with JNJ-3989 exposure at
concentrations up to 250 μg/mL.
The animal-to-human exposure ratios were calculated using rat and monkey exposures at no
observed adverse effect levels (NOAELs) from the 24-week studies in rat and the 37-week study
in monkey, respectively, and human exposures after a single SC injection of 200 mg JNJ-3989 in
human participants (AROHBV1001) (Table 1).
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 a NOAEL in male rats of 
and a NOAEL in female rats of
CCI
CCI


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Table 1: 
Animal-to-human Exposure Ratios at NOAEL for JNJ-3989
Ratio Total Concentration
Sex 
NOAEL  
(mg/kg) 
C max 
(ng/mL) 
AUC  
a
(ng∙h/mL) 
Cmax
A/H Ratio 
AUCa
A/H Ratio
JNJ-3976 
Human exposureb 
1,315 
20,136 
- 
-
24-week ratc 
M 
 
23,500 
199,000 
17.9 
9.9
F 
 
12,200 
31,400 
9.3 
1.6
37-week monkeyd 
M 
 
73,200 
1,230,000 
55.7 
61.1
F 
 
65,800 
988,000 
50.0 
49.1
JNJ-3924 
Human exposureb 
363 
4,605 
- 
-
24-week ratc 
M 
 
14,400 
124,000 
39.6 
26.9
F 
 
7,780 
20,600 
21.4 
4.5
37-week monkeyd 
M 
 
21,600 
383,000 
59.5 
83.2
F 
 
23,000 
392,000 
63.4 
85.1
AUC: area under the plasma concentration-time curve; AUC0-24h = area under the plasma concentration-time curve from
administration to 24 h; AUC0-last = area under the plasma concentration-time curve from administration to last quantifiable
sampling point; A/H ratio = animal/human ratio; Cmax: maximum plasma concentration; F = female; M = male.
Source: 24-week rat study (Study 8381085); 24-week monkey (Study 8381086)
a 
AUC0-last for human exposure; AUC0-24h for rat exposures; AUC0-24h for monkey exposures.
b 
Single dose of 200 mg JNJ-3989 in healthy participants via subcutaneous injection (Study AROHBV1001; based on clean
dataset with data cut-off date 29 October 2019).
c 
Once weekly dosing for 5 weeks, followed by once monthly dosing up to a total of 24 weeks.
d 
Once weekly dosing for 5 weeks, followed by once monthly dosing, up to a total of 37 weeks.
For further information, refer to the latest version of the IB for JNJ-3989 (IB JNJ-3989).
2.2.2.2. 
Nivolumab
Nivolumab is a fully human IgG4 monoclonal antibody targeting PD-1. Nivolumab is able to bind
PD-1 from both humans and cynomolgus monkeys and to prevent the interaction of PD-1 with its
ligands, PD-L1 and PD-L2. This interaction plays an important role in the maintenance of
self-tolerance and the prevention of unnecessary tissue damage following immune activation after
acute infection by downregulating the immune response. General toxicology studies with
nivolumab administered either weekly (4-week study) or twice weekly (13-week study) were
conducted in cynomolgus monkeys to investigate the safety of nivolumab. In both monkey studies,
exposure of nivolumab at all dose levels tested exceeded that measured in humans at the intended
clinical dose and schedule of 3 mg/kg once every 2 weeks. Toxicities noted in these monkey
studies were limited to mild increases in monocytic and lymphocytic infiltration in tissues. These
changes are consistent with the pharmacologic activity of the antibody: blocking signaling through
the immune-inhibitory PD-1 pathway. Immunophenotyping performed on samples from monkeys
administered nivolumab during the 13-week study showed a trend towards increases in the
percentage of CD4+ and CD8+ effector and central memory cells; this trend was clearer for the
CD8+ T-cell population. Monkeys did not develop any clear signs of the autoimmune toxicity seen
in clinical trials with nivolumab; however, the generalized lymphocytic infiltration and increases
in memory T-cells do hint at the possibility of these types of toxicities. Given nivolumab’s
mechanism of action, the possibility exists that greater exposure in treated monkeys would result
in a more serious inflammatory pattern closer to that seen clinically (Memorandum 2014).
C
C
C
C
C
C
C
C


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2.2.2.3. 
Combination Nivolumab + JNJ-3989
Due to the distinct mechanism of action and safety profile of JNJ-3989 and nivolumab, it is not
expected that they will have additive or synergistic effects on toxicology parameters. Therefore, a
combination study with these 2 compounds is not warranted.
2.2.3. 
Clinical Studies
2.2.3.1. 
JNJ-3989
At the time ofprotocol writing, JNJ-3989 is being evaluated in 13 clinical studies. Three Phase 1
studies 
(Study 
73763989HPB1001 
in 
healthy 
adult 
Japanese 
participants,
Study 73763989HPB1002 in adult participants with or without hepatic impairment, and
Study 73763989HPB1004 in healthy adult Chinese participants) and one Phase 1/2a study
(Study AROHBV1001) with a single ascending dose part in healthy adult participants and a
multiple ascending dose part in adult participants with chronic HBV infection are completed.
Conduct of the following studies is ongoing: 2 Phase 1 studies (73763989HPB1003 [renal
impairment], 73763989HPB1005 [relative bioavailability], and 73763989PAHPB1006
[OSPREY], 5 Phase 2 studies (Studies 73763989HPB2001 [REEF-1], 73763989PAHPB2002
[REEF-2], 
73763989PAHPB2003 
[INSIGHT], 
73763989PAHPB2005 
[REEF-IT],
73763989PAHPB2006 [PENGUIN], and 73763989PAHPB2007 [PENGUIN-2]) in adult chronic
HBV-infected participants, and 1 Phase 2 study (Study 73763989HPB2004 [REEF-D]) in adult
participants co-infected with hepatitis B and D virus. In total, 64 healthy, 84 chronic HBV-infected
participants, and 8 participants with moderately impaired hepatic function have been dosed with
JNJ-3989 in completed Studies AROHBV1001, 73763989HPB1001, 73763989HPB1002, and
73763989HPB1004.
Across these completed studies, JNJ-3989 was generally safe and well tolerated with no deaths,
SAEs considered at least possibly related to the study intervention, or AEs leading to study
intervention discontinuation. All treatment-emergent AEs were mild to moderate, with exception
of 1 severe blood creatine phosphokinase increased in 1 chronic HBV-infected participant. All
reported injection site reactions (ISRs) were mild. Adverse events and laboratory abnormalities
were distributed across all dose levels and occurred also on placebo treatment, except for mild
ISRs, which were only reported in participants on JNJ-3989 treatment. Most reported laboratory
abnormalities were isolated incidences and resolved while on study intervention.
In the primary REEF-1 analysis (Week 48, end of treatment), the primary endpoint (ie, proportion
of participants meeting NA completion criteria at Week 48 [assessments performed at Week 44]:
HBsAg <10 IU/mL, <3x  upper limit of normal [ULN] ALT, HBV DNA < lower limit of
quantification [LLOQ] and HBeAg negative) was most commonly met in the HBeAg negative
virologically suppressed subgroup for all regimens containing JNJ-3989. The numerically largest
NA treatment completion rate was observed in the virologically suppressed HBeAg negative
subgroup (200 mg dose group). The main reason for not meeting the primary endpoint criteria in
the HBeAg positive subgroup was the persistence of HBeAg positivity.


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A dose-response pattern was shown across the 3 dose levels of JNJ-3989 in mean HBsAg (log10)
decline from baseline over time. Overall, mean HBsAg levels in treatment arms containing
JNJ-3989 show the greatest magnitude of decline during the first 24 weeks.
In the REEF-1 Week 48 analysis, no deaths were reported. Ten SAEs were reported of which
2 were considered related to study drug by the investigator. Two participants experienced SAEs
related to study treatment: 1 ALT/aspartate aminotransferase (AST) increased in the triple regimen
(JNJ-3989 100 mg + JNJ-6379 250 mg QD [capsid assembly modulator] + NA) arm and 1 CK
elevation reported as rhabdomyolysis in the JNJ-3989 200 mg + NA arm. The CK elevation was
confounded by recent strenuous exercise. The elevated CK levels returned to normal and did not
recur with subsequent administrations of study treatment.
Overall, 5 (1.1%) participants discontinued investigational treatment due to an AE:
2/95 participants in the triple regimen arm, 2/93 participants in the JNJ-3989 40mg + NA arm, and
1/48 participant in the JNJ-6379 + NA arm.
Of the 29 (6.2%) participants who experienced any Grade 3 or 4 AEs, the largest incidence was
observed in the in JNJ-6379+NA arm (14.6% [7/48]) and the triple regimen arm (7.4% [7/95]).
The most frequent (8 participants) Grade 3 or 4 AEs were alanine aminotransferase increased:
3 participants each in the triple regimen arm and the JNJ-6379 + NA arm, and 2 participants in the
JNJ-3989 200 mg + NA.
Events related to renal function were the most frequently reported AE of Special Interest (14.7%
[14/95] in triple regimen arm and 8.3% [4/48] in JNJ-6379 + NA arm), followed by ISRs (10.8%
[10/93] in JNJ-3989 100mg + NA arm) and ALT/AST elevations (8.3% [4/48] in JNJ-6379 + NA
arm and 7.4% [7/95] in triple regimen arm).
Laboratory Abnormalities and Grade 3/4 ALT Elevations
No eGFR Grade 4 abnormalities were observed. No meaningful changes over time in mean
estimated glomerular filtration rate based on serum creatinine (eGFRcr) are seen in JNJ-3989 +
NA regimens.
Overall, around 5% of the participants experienced AEs or laboratory abnormalities related to
hematologic abnormalities, the majority of mild to moderate severity. The hematologic
abnormalities resolved on continued JNJ-3989 + NA treatment.
Treatment-emergent increases in mean ALT values were mild and remained within the normal
range in all treatment arms. Currently not treated participants were required to have ALT >ULN
at study entry to be eligible while virologically suppressed participants were required to have ALT
≤2x ULN. In currently not treated participants, an increase of mean ALT values early on treatment
was observed, followed by a gradual reduction towards normal values across all treatment arms.


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For the virologically suppressed participants an immediate increase of mean ALT values is seen
in both arms containing JNJ-6379 and a delayed and gradual increase is seen in JNJ-3989 200 mg
group.
Thirteen cases of ALT flare (3.1% [13 of 425]) (confirmed treatment-emergent elevation of ALT
and/or AST ≥3x ULN and ≥3x nadir) were observed across the active treatment arms, primarily in
currently not treated participants (11 of 13). No ALT flares were observed in the control arm.
Seven ALT flares were observed in the JNJ-3989 200 mg + NA arm (7.3% [7 of 96]), followed by
2 flares each in the JNJ-3989 (100 mg) + NA (2.2% [2 of 93]), JNJ-3989 (100 mg) + JNJ-6379
(250 mg) + NA (2.1% [2 of 95]) and the JNJ-6379 250 mg + NA arms (4.1% [2 of 48]). Majority
of the ALT flares occurred early during the study (61.5% [8 of 13]), between 1-12 weeks, one
ALT flare occurred between 13-24 weeks (7.7% [1 of 13]) and the remainder occurred between
25-48 weeks (30.7% [4 of13]). Declines in virologic parameters were similar between participants
with and without ALT flare. The ALT elevations were without concurrent bilirubin elevations or
signs and symptoms of hepatic dysfunction. All ALT flares resolved or stabilized on continued
treatment.
2.2.3.2. 
Combination of JNJ-3989 and Entecavir, Tenofovir Disoproxil, or
Tenofovir Alafenamide
Entecavir monohydrate is an HBV NA reverse transcriptase inhibitor indicated for the treatment
of chronic HBV infection in adults and children at least 2 years of age with evidence of active viral
replication and either evidence of persistent elevations in serum aminotransferases (ALT or AST)
or histologically active disease. The most common adverse reactions (≥3% of participants) are
headache, fatigue, dizziness, and nausea.
There is no common target organ toxicity between JNJ-3989 and ETV (Memorandum 2005). The
single common toxicity target organ between JNJ-3989 and tenofovir disoproxil or tenofovir
alafenamide (TAF) is the kidney.
Tenofovir disoproxil (available in several salt forms including tenofovir disoproxil fumarate and
tenofovir disoproxil maleate) is a first-generation oral prodrug of the NA tenofovir that is indicated
for the treatment of chronic HBV infection in adult and pediatric patients at least 12 years of age.
In addition, tenofovir disoproxil in combination with other antiretrovirals is indicated for the
treatment of human immunodeficiency virus type 1 (HIV-1) infection in adult and pediatric
patients at least 2 years of age. The most common adverse reactions (≥10% of participants) are
abdominal pain, nausea, insomnia, pruritus, vomiting, dizziness, and pyrexia.
Tenofovir alafenamide is an ester prodrug of the NA tenofovir that is indicated for the treatment
of chronic HBV infection in adults and that is characterized by a better safety profile than tenofovir
disoproxil. The most common adverse reaction (≥10% of participants) is headache. The single
common toxicity target organ between JNJ-3989 and tenofovir disoproxil or TAF is the kidney
(IB JNJ-3989).
For further information regarding ETV, tenofovir disoproxil, and TAF, refer to the respective
currently approved prescribing information.


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Based on available clinical and nonclinical data, no clinically relevant drug-drug interactions are
expected between JNJ-3989, nivolumab, and NAs. No specific concerns about additive or
synergistic toxicities in the kidney are expected when JNJ-3989 is combined with ETV, tenofovir
disoproxil, or TAF.
2.3. 
Benefit-Risk Assessment
More detailed information about the known and expected benefits and risks of JNJ-3989 may be
found in the IB  (IB JNJ-3989). For nivolumab and NA, refer to the respective prescribing
information.
Weekly dosing of JNJ-3989 was tested in study AROHBV1001 at doses ranging from 100 mg to
300 mg Q1W for 3 doses and no safety concerns were identified. For more details, refer to the IB
(IB JNJ-3989).
2.3.1. 
Benefits for Study Participation
2.3.1.1. 
Known Benefits
The clinical benefit of JNJ-3989 remains to be established.
2.3.1.2. 
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 infection.
JNJ-3989 on a background of NAs would target different stages of the viral life cycle. While NA
treatment reduces HBV DNA to levels close to or below the LLOQ of the HBV DNA assay, HBV
replication is not completely inhibited, resulting in replenishment of the cccDNA pool. The
addition of JNJ-3989 is expected to intensify viral suppression by downregulating pgRNA levels
and therefore also HBV DNA. In addition, JNJ-3989 reduces levels of all viral proteins including
HBsAg, which is known to interfere with the host immune responses (Fang 2015; Li 2018;
Wang 2013). By acting on both viral replication and by reducing barriers to the host immune
responses, higher functional cure rates may be achieved.
Gane et al has shown, among the 12 participants who received one dose of 0.3 mg/kg nivolumab,
92% (11/12) had a reduction in HBsAg from baseline during the study. One participant achieved
a ≥0.5 log10 IU/mL decrease in HBsAg at Week 12 that continued to decline and became
undetectable at Week 16 and had an associated ALT flare from Week 3 to Week 8. This participant
developed an anti-HBs response 10 weeks after the end of the study, which is the ultimate goal of
HBV treatment.
2.3.2. 
Risks for Study Participation
2.3.2.1. 
Known Risks
In the AROHBV1001 study, ISRs were the most frequently observed AEs assessed by the
investigator as related to JNJ-3989 administered subcutaneously.


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Immune checkpoint inhibitors (ICIs), such as anti-PD-1 monoclonal antibodies, target proteins
that enhance the response of the immune system to tumor cells or HBV-infected hepatocytes. By
stimulating the endogenous immune system however, there is the potential for adverse effects on
other tissues by way of immune cell activation and inflammatory mechanisms. The potential
immune-related AEs (irAEs) require close and more frequent monitoring, and early intervention
such as administration of corticosteroids.
Safety risks for nivolumab are based on results from nonclinical toxicology studies and oncology
clinical studies conducted with nivolumab, the known mechanism of action of nivolumab (ie,
anti-PD-1 antibody), and the route of administration. irAEs and infusion-related reactions (IRRs)
have been identified as important identified risks for nivolumab (ie, immune-related pneumonitis,
immune-related colitis, immune-related hepatitis, immune-related nephritis and renal dysfunction,
immune-related endocrinopathies, immune-related skin adverse reactions, other irAEs, and severe
infusion reactions (NSPC).
The safety profile of nivolumab is manageable with the majority of AEs being Grade 1 or Grade 2
in severity based on the National Cancer Institute Common Terminology Criteria for Adverse
Events (NCI-CTCAE). irAEs typically resolve after systemic treatment with corticosteroids or
discontinuation of nivolumab treatment. Immune-related endocrinopathies such as
hypothyroidism and adrenal insufficiency may require endocrine replacement therapy.
Treatment with anti-PD-1 medications is associated with a risk of HBV reactivation in CHB
patients. This risk is reduced with concurrent NA treatment or continuation of ongoing NA
treatment.
In a case series of cancer patients with HIV, HBV, or hepatitis C virus (HCV) infection treated
with ICI therapy including chemotherapy plus immunotherapy, it was found that the safety and
efficacy profile of ICI therapy is similar to that observed in those without chronic viral illness,
suggesting that ICI therapy is a safe and effective treatment option for patients with HIV, HBV,
or HCV infection suffering from advanced-stage cancer (Shah 2019).
2.3.2.2. 
Potential Risks
All therapies have the potential to cause adverse experiences.
Patients with positive HBV DNA and positive HBsAg can always experience increases in liver
transaminases which may indicate immune activation and may result in the reduction of viral
parameters such as HBV DNA and/or HBsAg. Whether this occurs at higher frequency during or
after treatment with JNJ-3989 is not known.
ALT elevation is considered an important potential risk for JNJ-3989. Two distinct patterns of
ALT elevations have been observed: a rapidly rising and resolving ALT elevation, or a sustained
pattern of ALT elevation. In a Phase 2 study involving chronic HBV-infected participants
(REEF-1), ALT flares (ALT ≥3x ULN and ≥3x nadir) were observed in 7% of participants treated
with 200 mg JNJ-3989 Q4W, compared to 0% of participants treated with NA and 0% to 2% of
participants treated with lower doses of JNJ-3989.Those ALT flares seen primarily early during


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treatment with JNJ-3989, were observed in currently not treated HBeAg positive participants. The
majority of the ALT flares resolved rapidly on continued treatment; 1 was considered serious. In
REEF-D, an ongoing study with HBV/hepatitis D virus (HDV) co-infected participants, 10 out of
22 (45%) participants have developed ALT elevations. Study treatment assignment remains
blinded. Three participants have experienced prolonged elevation of ALT. In 2 participants the
ALT elevation was considered serious. ALT elevation has led to discontinuation of blinded study
treatment in 2 participants. A causal association of ALT elevations with JNJ-3989 has not been
confirmed and the underlying mechanism for ALT elevations being more frequent in context of
HBV HDV co-infection is not yet understood.
Important potential risks of nivolumab include embryofetal toxicity and immunogenicity (NSPC).
Optional fine needle aspiration (FNA) biopsy of the liver will be performed during this study only
for participants who consent to this procedure. The related risks and complications will be
described in a separate informed consent form (ICF) and may include pain and discomfort located
at or near the puncture site (Tang 2003). No complications were seen in a series of more than
1000 FNA biopsies performed as part of monitoring of liver allografts (Lautenschlager 1991).
During the conduct of this OCTOPUS-1 study, two cases of possible hyperthyroidism were
reported. Both cases occurred in participants in treatment Arm 1 who were randomized to receive
a single dose of nivolumab administered at treatment week 16 of JNJ-73763989 treatment. At
treatment week 24, thyroid-stimulating hormone (TSH) was reduced in both patients. While the
first patient had normal free T3 and free T4 and TSH values returned to normal at follow-up visits,
the second patient had fully suppressed TSH with elevation of free T3 and free T4. In light of this
observation, the Sponsor decided on 20 June 2023 to not further expose any patients in the
OCTOPUS-1 study to nivolumab. Two patients were concerned by this USM and did not receive
their third dose of nivolumab.
Please refer to Section 2.2, Background, for details on the safety results in the studies conducted
to date.
2.3.3. 
Benefit-Risk Assessment for Study Participation
Based on the available data and proposed safety measures, the overall risk/benefit assessment for
JNJ-3989 and nivolumab clinical studies is deemed acceptable for the following reasons:
 
Efficacy and safety of JNJ-3989 with NA as assessed in CHB patients in the REEF-1 study
over a 48-week period was generally considered safe and well tolerated. Robust reductions of
HBsAg levels were seen in all JNJ-3989 arms, however, HBsAg seroclearance occurred only
in a few participants. In the current study, JNJ-3989 is being combined with nivolumab, a
PD-1 inhibitor, which may lead to higher seroclearance rates.
 
The toxicities associated with JNJ-3989, nivolumab and NAs are manageable with guidance
provided in this protocol, the IB, and approved prescribing information. ALT/AST elevations
is an important potential risk associated for JNJ-3989 and has been observed in the REEF-1
study. These ALT/AST elevations were not associated with signs of reduced liver function.
Nivolumab is a PD-1 inhibitor administered intravenously and is associated with irAEs and


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IRRs. Nivolumab may cause fetal harm when administered to pregnant women. NAs are
established treatment for chronic hepatitis B and well tolerated; discontinuation of NA
treatment may lead to reactivation of hepatitis.
 
Continued careful assessment of the safety, efficacy, and PK during treatment is included in
this study.
 
Events of Special Interest are significant AEs that are judged to be of special interest because
of clinical importance, known class effects or based on nonclinical signals. Events of Special
Interest that will be carefully monitored during the study include ALT/AST elevations
including immune-related hepatic AEs, IRRs and other irAEs (including gastrointestinal AEs,
neurological AEs, pulmonary AEs, renal AEs, endocrinopathies, rash, uveitis and visual
complaints, lipase/amylase elevations, and infection; see Section 8.3.6.1 and Section 8.3.6.2).
Other AEs of Special Interest related to JNJ-3989 that will be carefully monitored during the
study include hematological abnormalities and ISRs (see Section 8.3.6.3).
 
To minimize potential risk and stress to participants, the following measures are in place:
 
Utilization of selection criteria which exclude participants who may potentially be at
higher risk of an AE (see Section 5, Study Population).
 
Utilization of withdrawal criteria (see Section 7, Discontinuation of Study Intervention
and Participant Discontinuation/Withdrawal). If a participant drops out due to withdrawal
of consent, he/she will be offered an optional safety follow-up visit.
 
At regular time points throughout the study (see Schedule of Activities), blood samples
for biochemistry, blood coagulation, and hematology and urine samples for urinalysis,
urine chemistry, and renal biomarkers will be collected. Vital signs (systolic and diastolic
blood pressure, pulse rate, and body temperature), height (only at screening), body
weight, and electrocardiograms (ECGs) will be recorded throughout the study. Physical
examinations will be performed, and AEs will be assessed (see Section 8.2, Safety
Assessments). AEs of Special Interest will be closely monitored (Section 8.3.6,
Guidelines for Management of Adverse Events of Special Interest Including
Immune-Related Adverse Events).
 
An internal Data Review Committee (DRC) will be established forcontinuous monitoring
of safety data including SAEs, AEs leading to discontinuation, and ALT flares to ensure
the continuing safety of the participants enrolled in the current study. In addition, an
Independent Flare Expert Panel (IFLEP) will be appointed to characterize and adjudicate
each ALT flare. See Section 10.3.6, Committees Structure.
 
Participants will be regularly monitored for HBV reactivation and virologic
breakthroughs throughout the study.
 
Participants will be monitored closely during the 48-week follow-up period, with frequent
follow-up visits.
 
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, Guidelines for Management of
Adverse Events of Special Interest Including Immune-Related Adverse Events.
Nivolumab will be administered by IV  infusion and participants will be carefully
monitored for IRRs.


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 
Female participants will be monitored for pregnancy due to risk of embryofetal toxicity
associated with PD-1 inhibitors. Participants of childbearing potential are required to use
a highly effective user-independent contraceptive method while receiving study
intervention and until 5 months after the last dose of study intervention.
 
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).
More detailed information about the benefits and risks of JNJ-3989 may be found in the IB. For
nivolumab and NA, refer to the respective prescribing information.
3. 
OBJECTIVES AND ENDPOINTS
Below is the list of objectives and endpoints that will be evaluated in this study, delineating the
details in alignment with the general objectives listed in the Master Protocol
PLATFORMPAHPB2001. The details specific for this ISA are highlighted (colored fill).
Objectives 
Endpoints
Primary
To evaluate efficacy of the study intervention, 
based on HBsAg levels at FU Week 24. 
 
Proportion of participants who achieve
HBsAg seroclearance at FU Week 24.
Secondary
To characterize the safety and tolerability of 
the study intervention. 
 
Proportion 
of 
participants 
who
experienced AEs of interest.
 
Safety  profile 
of JNJ-3989 
with
nivolumab throughout the study (safety
parameters include but are not limited to
the frequency and severity of AEs and
immune-related 
AEs, 
vital 
signs
measurements, physical examinations,
clinical laboratory values, and 12-lead
electrocardiograms [ECGs]).
To evaluate efficacy in terms of changes in
HBsAg levels from baseline over time during
the study intervention and follow-up periods.
 
Change from baseline in HBsAg levels
during the study intervention and
follow-up periods.
 
Proportion of participants with HBsAg
levels below/above different cut-offs over
time.
To evaluate efficacy in terms of HBsAg
seroclearance/seroconversion during the study
intervention and follow-up periods (as defined
in the Definitions of Terms).
 
Proportion of participants with HBsAg
seroclearance/seroconversion during the
study intervention and follow-up periods.
 
Time to achieve HBsAg seroclearance/
seroconversion.


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Objectives 
Endpoints
To evaluate the efficacy as measured by blood 
markers (such as HBV DNA and HBeAg) 
during the study intervention and follow-up 
period. 
 
Change from baseline in HBV DNA
levels during the study intervention and
follow-up periods.
 
Proportion of participants with HBV DNA
and HBeAg levels below/above different
cut-offs over time.
To evaluate the frequency of virologic
breakthrough throughout the study.
 
Proportion of participants with virological
breakthrough throughout the study.
To evaluate the pharmacokinetics (PK) of
JNJ-3989 (JNJ-3924 and JNJ-3976), and
optionally of NA and/or nivolumab.
 
PK parameters of JNJ-3989 (JNJ-3924
and JNJ‑3976).
 
Optionally, PK parameters of NA and/or
nivolumab.
Exploratory
To characterize the pharmacodynamics (PD)
of JNJ-3989 with nivolumab including
quantification of RO on peripheral T-cells.
 
Relationship of various PK parameters
with 
selected 
efficacy 
and 
safety
endpoints.
 
Quantification of nivolumab RO on
peripheral 
CD3+ 
T-cells 
by flow
cytometry on whole blood.
To explore changes in the severity of liver
disease.
 
Changes in fibrosis (according to
Fibroscan liver stiffness measurements) at
end of study intervention (EOSI) and the
end of the follow-up  period versus
baseline.
To explore HBV-specific T-cell responses
throughout the study.*
 
Changes from baseline in HBV-specific
peripheral blood T-cell responses over
time.
To explore efficacy of the study intervention
in terms of changes in HBV RNA and
hepatitis B core-related antigen (HBcrAg)
levels throughout the study.
 
Changes from baseline in HBV RNA and
HBcrAg levels over time.
To explore the HBV genome sequence
throughout the study.
 
Assessment of intervention-associated
mutations over time.


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Objectives 
Endpoints
To explore medical resource utilization to 
manage participants throughout the study. 
 
Number and duration of medical care
encounters, including surgeries, and other
selected 
procedures 
(inpatient 
and
outpatient).
 
Duration of hospitalization (total days
length of stay, including duration by
wards, eg, intensive care unit).
 
Number and character of diagnostic and
therapeutic tests and procedures.
 
Outpatient 
medical 
encounters 
and
treatments 
(including 
physician 
or
emergency 
room 
visits, 
tests 
and
procedures, and medications).
*PBMC samples for immune analyses will be collected at selected sites only.
Refer to Section 8, Study Assessments and Procedures for evaluations related to endpoints.
HYPOTHESIS
The primary hypothesis of this study is that at least one of the combination regimens of
JNJ-3989+nivolumab+NA is more efficacious than JNJ-3989+NA treatment, as measured by the
primary efficacy endpoint (ie, the proportion of participants with HBsAg seroclearance at FU
Week 24). Because the study does not include a regimen arm without nivolumab, the hypothesis
is formulated assuming a fixed response rate for JNJ-3989+NA of 1% based on previous
Study 73763989HPB2001 (REEF-1).
4. 
STUDY DESIGN
4.1. 
Overall Design
This ISA describes a Phase 2 study of the combination regimen of JNJ-3989 with nivolumab and
NA. It is a companion document to the Master Protocol PLATFORMPAHPB2001, which
describes the common design elements of the Platform study in participants with chronic HBV
infection. This ISA describes specific and/or additional protocol elements applicable to this
randomized, open-label, parallel, multicenter, interventional study  to evaluate safety, efficacy,
tolerability, PK and PD of a combination of JNJ-3989, nivolumab, and NAs in virologically
suppressed chronic HBV-infected adult participants.
Initially, a target of approximately 44  virologically suppressed, HBeAg negative, adult chronic
hepatitis B participants ≥18 (or the legal age of consent in the jurisdiction in which the study is
taking place) to <56 years of age were planned to be randomly assigned in this study with
22 participants planned per arm.
Due to the decision to not extend further enrollment beyond the planned enrollment period and
proceed with a reduced sample size, the final sample size is 37 (18 in Arm 1 and 19 in Arm 2).


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This open-label study will be conducted in 3 periods:
 
6-week Screening Period (if necessary, eg, for operational reasons, this can be extended
to a maximum of 8 weeks decided on a case-by-case basis and in agreement with the
sponsor). During the Screening Period, the participants will continue the same NA
treatment they were receiving before screening.
 
24-week Study Intervention Period:
o 
Arm 1: JNJ-3989 Q1W for the first 4 weeks and then Q4W until Week 24 +
nivolumab at Week 16 + NA QD
o 
Arm 2: JNJ-3989 Q1W for the first 4 weeks and then Q4W until Week 24 +
nivolumab Q4W at Weeks 16, 20, 24 + NA QD.
 
48-week Follow-up Period, during which NA treatment will be continued.
At baseline, participants who meet the eligibility criteria will be randomized in a 1:1 ratio to Arm 1
or Arm 2. Randomization will be stratified by absolute HBsAg level (<100 IU/mL, 100 to
<1,000 IU/mL, and ≥1,000 IU/mL) at screening, as assessed by quantitative HBsAg assay.
Background treatment consists of:
- NA: tenofovir disoproxil (245 mg), TAF (25 mg), or ETV (0.5 mg) given as oral tablets
QD for approximately 76 weeks (screening included).
Study intervention consists of:
 
JNJ-3989: 200 mg given by SC injections Q1W for the first 4 weeks and then Q4W until
Week 24 (10 doses)
 
Nivolumab: 0.3 mg/kg, one single IV infusion at Week 16 for Arm 1 or 3 IV infusions at
Weeks 16, 20, and 24 for Arm 2.
Assessments and sampling will be done for efficacy (eg, HBsAg, HBeAg, and HBV DNA), safety
(eg, [S]AEs, irAEs, laboratory evaluations, ECGs, vital signs, physical examinations), PK, PK/PD,
viral genome sequencing, PBMC, human leukocyte antigen (HLA) typing, immunogenicity and
pharmacogenomics, and for exploratory analysis of host and viral markers.
The total duration of individual participation will be up to 72 weeks (screening not included).
Participants will be considered to have completed the study if they have completed all the
assessments of the final study visit (ie, FU Week 48).
If a participant prematurely discontinues treatment with JNJ-3989 before Week 24, the participant
will also discontinue further treatment with nivolumab and will have an early withdrawal (WD)
visit. Follow-up assessments should be obtained as per the Schedule of Activities until 48 weeks
after the end of JNJ-3989 treatment, unless the participant withdraws consent. The NA treatment
will be continued until the end of the study.


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If a participant prematurely discontinues nivolumab, treatment with JNJ-3989 and NA should be
continued as planned, unless a treatment discontinuation rule for JNJ-3989 is also met. In that case,
JNJ-3989 will also be discontinued but NA treatment should be continued as planned.
If a participant withdraws prematurely from the study, the reason for withdrawal (if known) should
be documented. Participants who withdraw consent will be offered an optional safety follow-up
visit to occur on the day of consent withdrawal.
An internal DRC will be commissioned for monitoring safety of participants enrolled in this study.
In addition, an IFLEP will be appointed. Refer to Committees Structure in Appendix 3: Regulatory,
Ethical, and Study Oversight Considerations for details.
A diagram of the study design is provided in Section 1.2, Schema.
4.2. 
Scientific Rationale for Study Design
Randomization
Randomization will be used to minimize bias in the assignment of participants to intervention
arms, to increase the likelihood that known and unknown participant attributes (eg, demographic
and baseline characteristics) are evenly balanced across intervention  arms, and to enhance the
validity of statistical comparisons across intervention arms. Randomization will occur at baseline.
Stratification Factors
Randomization will be stratified by absolute HBsAg level (<100 IU/mL, 100 to <1,000 IU/mL,
and ≥1,000 IU/mL) at screening, as assessed by quantitative HBsAg assay.
Host DNA and Exploratory Host Biomarker Collection
Refer to Section 4.2 of the Master Protocol PLATFORMPAHPB2001.
Optional FNA biopsy samples may be collected to assess intrahepatic immune responses which
can be compared to responses in PBMCs.
4.2.1. 
Study-Specific Ethical Design Considerations
Refer to Section 4.2.1 of the Master Protocol PLATFORMPAHPB2001. Differences with the
Master Protocol PLATFORMPAHPB2001 are highlighted (colored fill).
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
patient preferences.
FNA biopsies may be performed during this study only for participants who consent to this
procedure. The risks and complications related to these procedures are described in Section 2.3.2.2.
These risks and complications will be described in the ICF and will be clearly explained to
potential participants prior to enrollment.


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4.3. 
Justification for Dose and Treatment Duration
The proposed dose and treatment duration for JNJ-3989 are selected to maximize the chance for
patients to achieve functional cure and are supported by scientific understanding of available data.
The same dose (ie, 200 mg of JNJ-3989) is currently being tested in ongoing Phase 2b studies.
Clinical data on PK, PD, safety, and efficacy of JNJ-3989 are available from the completed
Phase 1/2a AROHBV1001 study. Twenty adult healthy participants received single SC injections
of JNJ-3989 (35, 100, 200, 300, and 400 mg) and 84 adult chronic HBV-infected participants
received multiple doses of JNJ-3989 (25, 50, 100, 200, 300, and 400 mg), administered as 3 SC
injections separated by either 7-day, 14-day, or 28-day intervals. All participants either continued
or started on ETV or tenofovir disoproxil on Day 1.
JNJ-3989 was generally safe and well tolerated at all doses. No clinically relevant safety signal
was identified.
Antiviral activity data are available for 56 chronic HBV-infected participants who received 3 SC
injections of 25 to 400 mg JNJ-3989 Q4W (Gane 2019; Yuen 2019; IB JNJ-3989). In general,
mean HBsAg declines reached nadir at Day 113 (ie, 8 weeks after last JNJ-3989 injection). Mean
HBsAg levels remained suppressed (below baseline levels) at least until Day 392 (ie, 9 months
after last dose) in a substantial proportion of patients. The HBsAg levels at Day 392 were variable
with some patients having HBsAg levels close to baseline levels while a substantial proportion of
patients still had HBsAg levels >1 log10 IU/mL lower than the baseline levels. JNJ-3989 showed
activity on other viral markers (HBV DNA, HBV RNA, HBeAg and HBcrAg), frequently with
sustained reduction at least until Day 362. No apparent dose-response was observed at doses
between 100 mg and 400 mg JNJ-3989, a numerically smaller mean decline was observed at the
lower doses of 25 mg and 50 mg, mainly apparent after end of JNJ-3989 dosing.
Clinical data on efficacy and safety of JNJ-3989 are available from the Phase 2b
73763989HPB2001 (REEF-1) study. One of the objectives of this ongoing study is to assess the
dose-response relationship for antiviral activity of 3 doses (40 mg, 100 mg and 200 mg,
administered Q4W) of JNJ-3989 in combination with NA.
A dose of 200 mg JNJ-3989 is chosen based on the dose-response pattern that was observed across
the 3 dose levels of JNJ-3989 in mean HBsAg (log10) decline from baseline over time in
Study REEF-1. Furthermore, a dose of 200 mg JNJ-3989 is chosen based on the observed decline
in HBsAg in Study AROHBV1001 at this dose over 3 injections, and the lack of a substantial
incremental efficacy response at higher doses.
A JNJ-3989 dosing interval of Q1W for the first 4 weeks and then Q4W until Week 24 is chosen
based on PK/PD modeling of JNJ-3989 using a TMDD and IRM based on REEF-1 data,
suggesting that a loading dose (Q1W) regimen  for JNJ-3989 will result in higher liver
concentrations more rapidly than a Q4W dosing regimen. Higher liver concentrations are expected
to result in a more pronounced and faster decline in HBsAg and may improve the likelihood of
achieving functional cure.


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The proposed dose of nivolumab, 0.3 mg/kg, is based on available data for the use of nivolumab
in CHB patients (refer to Section 2.1 for further information). The frequency of dosing in Arm 2,
Q4W, is based on the estimated geometric mean half-life of nivolumab (25 days) and frequency
of administration for its approved indications in oncology (for more details, refer to the nivolumab
prescribing information).
4.4. 
End of Study Definition
End of Study Definition
The end of study is considered as the last scheduled study visit (FU Week 48 or early
discontinuation) for the last participant in the study. The final data from the study site will be sent
to the sponsor (or designee) after completion of the final participant visit at that study site, in the
time frame specified in the Clinical Trial Agreement.
Participant Study Completion Definition
A participant will be considered to have completed the study if the participant has completed
assessments of the final study visit (ie, FU Week 48).
5. 
STUDY POPULATION
Screening for eligible participants will be performed within 42 days before administration of the
study intervention. If necessary, eg, for operational reasons, the Screening Period may be extended
up to a maximum of 8 weeks decided on a case-by-case basis and in agreement with the sponsor.
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.
Exceptional and limited retesting of abnormal screening values that lead to exclusion is allowed
once, using an unscheduled visit during the Screening Period (to reassess eligibility).
For a discussion of the statistical considerations of participant selection, refer to Section 9.2,
Sample Size Determination.
Each potential participant must satisfy all inclusion and exclusion criteria from the Master Protocol
PLATFORMPAHPB2001 (numbering prefixed by “M” in the list below) and all additional
intervention-specific inclusion and exclusion criteria (numbering prefixed by “A” in the list
below). The latter inclusion and exclusion criteria are highlighted (colored fill). For the few criteria
from the Master Protocol that are specified or more restricted in this ISA, the additional text is also
highlighted (colored fill).


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5.1. 
Inclusion Criteria
Each potential participant must satisfy all of the following criteria to be enrolled in the study:
A01 (adapted 
from M01) 
Adult male or female participants ≥18 (or the legal age of consent in the jurisdiction in
which the study is taking place) to <56 years of age.
M02 
Participants must be medically stable based on physical examination, medical history,
vital signs, and 12-lead ECG performed at screening. If there are abnormalities, they
must be consistent with the underlying illness in the study population. This determination
must be recorded in the participant’s source documents and initialed by the investigator.
A03 (adapted 
from M03a) 
Participants must have chronic HBV infection. HBV infection must be documented by
serum HBsAg positivity at screening. In addition, chronicity must be documented by any
of the following, at least 6 months prior to screening: serum HBsAg positivity, HBeAg
positivity or HBV DNA positivity, ALT elevation >ULN without another cause than
HBV infection, documented transmission event, liver biopsy with changes consistent
with chronic HBV, or absence of marker for acute HBV infection at screening such as
positive immunoglobulin M (IgM) anti-HBc antibodies.
Participants should:
 
Be HBeAg negative at screening, AND
 
Be on stable HBV treatment, defined as currently receiving NA treatment
(ie, entecavir, tenofovir disoproxil, or tenofovir alafenamide) for at least 12 months
prior to screening, and having been on the same NA treatment regimen (at the same
dose) as used in this study (see Table 4) for at least 3 months at the time of screening,
AND
 
Have serum HBV DNA <60 IU/mL on 2 sequential measurements at least 6 months
apart (one of which is at screening), AND
 
Have documented ALT values <2.0x ULN on 2 sequential measurements at least
6 months apart (one of which is at screening).
A04 (adapted 
from M04) 
Participants must have a body mass index (BMI; weight in kg divided by the square of
height in meters) between 18.0 and 30.0 kg/m2, extremes included.
A05 (adapted 
from M05) 
Participants must sign a Master ICF (specific for the Master Protocol
PLATFORMPAHPB2001) and must sign an ICF specific for this intervention cohort,
indicating that he or she understands the purpose of, and procedures required for, the
study and is willing to participate in the study.
A06 (adapted 
from M06) 
Participants must sign a separate ICF if he or she agrees to provide additional optional
DNA samples and/or FNA biopsy samples for research (where local regulations permit).
Refusal to give consent for the optional DNA and/or FNA biopsy research samples does
not exclude a participant from participation in the study.






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A02 
(adapted 
from M02)
Participants with evidence of hepatic decompensation at any time point prior to or at the
time of screening:
a. 
Total bilirubin >1.5x ULNa, OR
b. Direct bilirubin >1.2x ULN b, OR
c. 
Prothrombin time >1.3x ULN (unless caused by anticoagulation therapy or vitamin
K deficiency)b, OR
d. Serum albumin <3.2 g/dLb.
M03 
History or evidence of clinical signs or symptoms of hepatic decompensation, including
but not limited to: portal hypertension, ascites, hepatic encephalopathy, esophageal
varices.
M04 
Participants with evidence of liver disease of non-HBV etiology. This includes but is not
limited to hepatitis infections mentioned in exclusion criterion A01, drug- or
alcohol-related liver disease, autoimmune hepatitis, hemochromatosis, Wilson’s disease,
α-1 antitrypsin deficiency, primary biliary cholangitis, primary sclerosing cholangitis,
Gilbert’s syndrome (mild cases are allowed) or any other non-HBV liver disease
considered clinically significant by the investigator.
A05 
(adapted 
from M05) 
Participants with history or signs of cirrhosis or portal hypertension (nodules, no smooth
liver contour, no normal portal vein, spleen size ≥12 cm) or signs of HCC or clinically
relevant renal abnormalities on an abdominal ultrasound performed within 3 months prior
to screening or at the time of screening. In case of suspicious findings on conventional
ultrasound the participant may still be eligible if HCC or clinically relevant renal
abnormalities have been ruled out by a more specific imaging procedure
(contrast-enhanced ultrasound, CT or MRI).
A06 
(adapted
from M06)
Criterion modified per Amendment 1:
A06.1 Participants with one or more of the following laboratory abnormalities at screening
as defined by the Division of Acquired Immunodeficiency Syndrome (DAIDS) Toxicity
Grading Scale (see Section 10.8, Appendix 8: DAIDS Table with Modifications):
a. 
Estimated glomerular filtration rate based on serum creatinine (eGFRcr) ≥Grade 3
(ie, <60 mL/min/1.73 m2) at screening, calculated by the Chronic Kidney Disease
Epidemiology Collaboration (CKD-EPI) formula;
b. Pancreatic lipase elevation ≥Grade 3;
c. 
Pancreatic amylase elevation ≥Grade 3;
d. Hemoglobin ≤10.9 g/dL (males), ≤10.4 g/dL (females);
e. 
Platelet count ≤lower limit of normal (LLN);
f. 
Absolute neutrophil count <1,500/mm  
3 (<1,000/mm3 for participants of African
ancestry);
g. Alpha-fetoprotein (AFP) >100 ng/mL;
a Unless explained by a clinical setting that is not hepatic decompensation.


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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, contrast-enhanced ultrasound, CT
or MRI) during screening.
h. Abnormal thyroid function (including TSH, free triiodothyronine [T3] and free
thyroxine [T4])
i. 
Positive autoantibody test results for at least one of the following:
o Anti-nuclear antibodies (ANA) titer ≥1:80;
o Anti-smooth muscle antibodies (ASMA) titer ≥1:80;
o Anti-mitochondrial antibodies (AMA) titer ≥1:80;
o Anti-thyroid peroxidase antibodies ≥35 IU/mL;
o Anti-Neutrophil Cytoplasmic Antibody (ANCA) titer ≥1:20;
o Rheumatoid factor ≥14 IU/mL.
Note:In case of ≥2 positive tests but below the exclusionary cut-off, participant may
be enrolled if approved by the sponsor before randomization.
j. 
Any other laboratory abnormality considered to be clinically significant by the
investigator (also see exclusion criterion A02).
M07 
Participants with hemoglobin A1c >8% at screening.
M08 
Participants with a history of malignancy within 5 years before screening (exceptions are
squamous and basal cell carcinomas of the skin and carcinoma in situ of the cervix, or
malignancy, which are considered cured with minimal risk of recurrence).
M09 
Participants with abnormal sinus rhythm (heart rate <45 or >100 beats per minute [bpm]);
QT interval corrected for heart rate according to Fridericia’s formula (QTcF) >450 ms for
males and >470 ms for females; QRS interval ≥120 ms; PR interval >220 ms; or any other
clinically significant abnormalities on a 12-lead ECG at screening (eg, significant
abnormal conduction).
M10 
Participants with a history of or current cardiac arrhythmias (eg, significant extrasystole
patterns, tachycardia at rest), history of risk factors for Torsade de Pointes syndrome
(eg, hypokalemia, family history of long QT Syndrome) or history or other clinical
evidence of significant or unstable cardiac disease (eg, angina, congestive heart failure,
myocardial infarction, diastolic dysfunction, significant arrhythmia and/or coronary heart
disease), moderate to severe valvular disease, or uncontrolled hypertension at screening.


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M11  
Participants with any current or previous illness for which, in the opinion of the
investigator and/or sponsor, participation would not be in the best interest of the participant
(eg, compromise the well-being) or that could prevent, limit, or confound the
protocol-specified assessments. This may include but is not limited to significant vascular,
pulmonary (eg, chronic obstructive pulmonary disease), gastrointestinal (eg, significant
diarrhea, gastric stasis, or constipation that in the investigator’s opinion could influence
drug absorption or bioavailability), endocrine (eg, thyroid disease), neurologic,
hematologic, rheumatologic, psychiatric, neoplastic, or metabolic disturbances. Any
condition possibly affecting drug absorption (eg, gastrectomy or other significant
gastrointestinal tract surgery, such as gastroenterostomy, small bowel resection, or active
enterostomy) will also lead to exclusion.
M12  
Participants who have received an organ transplant (except for skin, hair, or cornea
transplants).
M13 
Participants with any history of or current clinically significant skin disease requiring
regular or periodic treatment.
M14  
Participants with clinically relevant alcohol or drug abuse within 12 months of screening.
M15 
Participants with history of clinically relevant drug rash.
M16 
Participants who have taken any disallowed therapies as noted in Section 6.5, Concomitant
Therapy before screening.
A17 
(adapted 
from M17) 
Participants having used any invasive investigational medical device within 6 months or
having received an investigational intervention or a biological product, immunoglobulin
or other blood product not intended for the treatment of HBV within 6 months or
5 half-lives (whichever is longer), before the planned first dose of study intervention, or is
currently enrolled in an interventional clinical study with an investigational product.
A18 
(adapted 
from M18)
Female participants who are pregnant, or breast-feeding, or planning to become pregnant
while enrolled in this study, until 5 months after last dose of study intervention.
A19 
(adapted 
from M19)
Male participants who plan to father a child while enrolled in this study, until 5 months
after last dose of study intervention.
M20 
Participants who had major surgery (eg, requiring general anesthesia), excluding
diagnostic surgery, within 12 weeks before screening; or will not have fully recovered
from surgery; or have surgery planned during the time of expected participation in the
study.
Note:Participants with planned surgical procedures to be conducted under local anesthesia
may participate.




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5.3. 
Lifestyle Considerations
Potential participants must be willing and able to adhere to the following lifestyle restrictions
during the study to be eligible for participation:
1. 
Agree to follow all requirements outlined in Section  6.5, Concomitant Therapy,
regarding prohibited and restricted therapy during the study.
2. 
Agree to follow all requirements that must be met during the study as noted in the
Inclusion and Exclusion Criteria (eg, contraceptive requirements).
5.4. 
Screen Failures
Refer to Section 5.4 of the Master Protocol PLATFORMPAHPB2001 for handling of screen
failures and use of participant identification, enrollment, and screening logs.
This study will use IWRS. The investigator will generate screening and enrollment logs directly
from IWRS.
6. 
STUDY INTERVENTION AND CONCOMITANT THERAPY
6.1. 
Study Intervention(s) Administered
Description of Study Intervention
The JNJ-3989 supplied for this study will be provided as an aqueous clear, colorless to light yellow
solution with 200 mg/mL of JNJ-3989 for SC injection, containing 0.5 mM sodium phosphate
monobasic and 0.5 mM sodium phosphate dibasic in water as inactive ingredients (formulation
G001). JNJ-3989 will be manufactured and provided under the responsibility of the sponsor. Refer
to the IB for a list of excipients (IB JNJ-3989).
The nivolumab formulated as concentrate for solution for infusion will be supplied for this study
by the sponsor as a 40 mg/4 mL solution for IV infusion. Refer to the prescribing information for
a list of excipients.


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Table 2: 
Description and Administration of Study Intervention
Intervention Name 
JNJ-3989 
Nivolumab
Type 
Drug 
Drug
Dose Formulation  
Solution for injection (G001) 
Concentrate for solution for infusion
Unit Dose Strength(s) 
200 mg/mL  
40 mg/4 mL
Dosage Level(s) 
200 mg Q1W for the first 4 weeks, 
then once every Q4W until Week 24 
0.3 mg/kg (1 intravenous [IV] infusion
for Arm 1 or 3 IV infusions Q4W for
Arm 2)**
Route of Administration 
Subcutaneous injection* (preferably 
in the abdomen; upper arm or thigh
is also allowed)
IV infusion over 30 minutes
Use 
Investigational intervention  
Investigational intervention
Investigational Medicinal Product 
(IMP)
Yes 
Yes
Non-investigational Medicinal 
Product/ Auxiliary Medicinal
Product (NIMP/AxMP)
No 
No
Sourcing 
Provided centrally by the sponsor 
Provided centrally by the sponsor
Packaging and Labeling 
Each unit will be labeled with unique 
medication ID number 
Commercial supplies will be sourced.
Each unit will be labeled with unique
medication ID number
Food/Fasting Instructions 
Regardless of food intake 
Not Applicable
*Note: Administration into scar tissue or areas that are reddened, inflamed or swollen should be avoided. If injecting
into the abdomen, avoid a 5 cm diameter circle around the navel.
**Note: a tolerance of +/- 5% around the theoretical dose of 0.3 mg/kg will be applied to consider the necessary
rounding and standard practice for the preparation and intravenous administration of drugs dosed by weight.
Packaging and Labeling of Study Intervention
All study interventions will be packaged with each unit labeled with a unique medication ID
number. Packaging and labeling of JNJ-3989 and nivolumab will be done in an open-label way.
Commercial supplies of nivolumab will be sourced, and a clinical study  label will be applied.
Study intervention labels will contain information to meet the applicable regulatory requirements.
No study interventions can be repacked or relabeled without prior approval from the sponsor.
Study Intervention Administration
Study intervention administration must be captured in the source documents and the case report
form (CRF).
JNJ-3989 injections will be administered SC (preferably in the abdomen) at the study site and the
approximate location should be recorded.


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Prior to starting nivolumab treatment, the participant’s most recent ALT value (tested by local or
central lab) should be <3x ULN with no change in autoimmune status. In case the administration
of nivolumab would not be in the interest of the participant, this should be discussed with the
sponsor.
Nivolumab injections will be administered as an IV infusion at the study site. The duration of the
IV infusion will be approximately 30 minutes.
When both JNJ-3989 and nivolumab are administered at the same visit, JNJ-3989 should be
administered first (preferably in abdomen) followed within approximately  30 minutes by  IV
infusion of nivolumab.
For a definition of study intervention overdose, refer to Section 6.8, 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. The study intervention
administered to the participant must be documented on the intervention accountability form. All
study intervention will be stored and disposed of according to the sponsor's instructions. Studysite
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 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 containing hazardous liquids, such as used ampules, needles,
syringes and vials, 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. 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 intervention is provided
in the Study Reference Manual.
6.3. 
Measures to Minimize Bias: Randomization and Blinding
Intervention Allocation
Procedures for Randomization and Stratification
Participants will be randomly assigned to 1 of 2 intervention  groups 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 absolute HBsAg level (<100 IU/mL, 100 to <1,000 IU/mL, and ≥1,000 IU/mL) at
screening, as assessed by quantitative HBsAg assay. Based on this randomization code, the study
intervention will be packaged and labeled for each participant. Participant numbers will be
preprinted on the study intervention labels and assigned as participants qualify for the study and
are assigned to intervention.
For more information on the interactive web response system (IWRS), refer to Section 6.3 of the
Master Protocol PLATFORMPAHPB2001.
Blinding
As this is an open-label study, blinding procedures are not applicable.
6.4. 
Study Intervention Compliance
JNJ-3989 and nivolumab will be administered at the study site by qualified study site personnel as
an SC injection and IV infusion, respectively, to assure compliance with study requirements. The
details of each administration will be recorded in the source document and CRF (including date,
start and stop times of the IV infusion or SC injection, volume prepared, and volume administered).
The dose of study intervention and study participant identification will be confirmed at the time of
dosing by a member of the study site personnel other than the person administering the study
intervention. The study intervention may not be used for any purpose other than that outlined in
this protocol, including other human studies, animal investigations, or in vitro testing. Study site
personnel will maintain a log of all study interventions administered. Study intervention supplies
for each participant will be inventoried and accounted for.
Every effort should be made to have the study interventions administered as indicated in the
Schedule of Activities, especially during the first 4 weeks of dosing.


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If a SC injection of JNJ-3989 was missed during the loading dose period (Week 1-4), the injection
should be given as soon as possible but within 3 days after the scheduled time and with a minimum
of 3 days between injections. Otherwise, the dose should be skipped and the next dose should be
given at the next scheduled time point per the initial dosing schedule.
If after the loading dose period a SC injection of JNJ-3989 was missed or an IV infusion of
nivolumab was missed, the injection or infusion should be given as soon as possible but within
2 weeks after the scheduled time. Otherwise, the dose should be skipped and the next dose should
be given at the next scheduled time point per the initial dosing schedule.
In case of ALT elevation ≥3x ULN during the first 4 weeks of dosing, administration of JNJ-3989
should be discussed with the sponsor.
If a participant’s study intervention intake is not according to the protocol, the investigator will
take the necessary measures to ensure future adherence to the protocol.
6.5. 
Concomitant Therapy
For general concomitant therapy considerations, refer to Section 6.5 of the Master Protocol
PLATFORMPAHPB2001.
An overview of ISA-specific disallowed medication is provided in Table 3.
For participants who consent to complete the optional FNA biopsy of the liver, any anticoagulants
and antiplatelets are disallowed from baseline to at least 2 weeks after the completion of the last
FNA biopsy. Use of low-dose aspirin is allowed except during the 7 days period preceding the
FNA biopsies.
Note that locally approved COVID-19 vaccines (including those that received emergency use
authorization or conditional marketing authorization) are allowed throughout the study, with the
exception of the second dose of Sputnik V (which contains rAd5). Sputnik light which is the first
dose of Sputnik V (with rAd26) is allowed.
During nivolumab treatment, the following recommendations should be applied to accommodate
COVID-19 vaccination:
 
COVID-19 vaccine and nivolumab should not be administered on the same day. If required,
nivolumab administration can be delayed by 2-5 days.
 
The next nivolumab administration should be performed at the scheduled time.
 
If required, skipping a nivolumab administration may be considered after consultation with
the sponsor.
All COVID-19 vaccination-related data (eg, COVID-19 vaccination, AEs, AE management)
should be appropriately captured in the CRF and source documents. Refer to the COVID-19
vaccine and/or nivolumab prescribing information for more details.


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Table 3: 
Disallowed Medication
Disallowed from 12 months prior to screening until end of follow-up:
 
IFN.
 
Any oligonucleotide-based treatment (eg, siRNA, nucleic acid polymers, antisense oligonucleotides),
other than the study intervention taken in the context of this study.
 
Any prior treatment with an anti-PD-1 antibody, anti-PD-L1 antibody or anti-PD-L2 antibody, other than
the study intervention taken in the context of this study.
Disallowed from 6 months prior to screening until end of follow-up:
 
Any investigational agent, investigational vaccine, invasive investigational medical device, or
investigational biological product (other than the study intervention taken in the context of this study).
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.
 Any systemically (eg, intravenously, intramuscularly, orally, subcutaneously) administered medication
that directly or indirectly interferes with immune responses (eg, cyclosporine, interleukins, systemic
corticosteroids at doses exceeding 5 mg/day of prednisone or its equivalent). Use of systemic
immunosuppressive medications for the management of irAEs, ISRs, or IRRs, or in participants with
contrast allergies is acceptable, ie, it will not be considered a protocol deviation, but it will lead to
nivolumab discontinuation and/or JNJ-3989 discontinuation if criteria relative to the use of prohibited
medication (including systemic corticosteroids) detailed in Sections 7.1.1 and 7.1.2 are met. In addition,
use of inhaled, topical, local, and intranasal corticosteroids is permitted.
Disallowed from screening until end of follow-up:
 
Any anti-HBV drug (including vaccines) other than the study intervention and the NA background
regimen taken in the context of this study.
Notes:
o 
Prior hepatic treatment with herbal or nutritional products is allowed but should be stopped at
screening.
 
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.
The prescribing information for ETV, tenofovir disoproxil, TAF, and nivolumab should be
consulted for any additional prohibited medication.
Medications other than JNJ-3989 requiring SC injection (eg, insulin) should be administered away
from the JNJ-3989 injection sites.
6.6. 
Dose Modification
Any dose/dosage adjustment must be overseen by medically-qualified study site personnel
(principal or subinvestigator unless an immediate safety risk appears to be present).
6.7. 
Continued Access to Study Intervention After the End of the Study
Refer to Section 6.7 of the Master Protocol PLATFORMPAHPB2001.
6.8. 
Treatment of Overdose
For this study, any dose of JNJ-3989 exceeding the protocol-specified dose with ≥25% and any
dose of nivolumab  exceeding the protocol-specified dose (0.3 mg/kg) with >5%; refer to
Section 6.1, Study Intervention(s) Administered), will be considered an overdose.


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In the event of an overdose, the investigator or treating physician should:
 
Contact the Medical Monitor immediately.
 
Evaluate the participant to determine, in consultation with the Medical Monitor, whether study
intervention must be interrupted or whether the dose should be reduced.
 
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.
6.9. 
Background Treatment
The NAs tenofovir disoproxil, TAF, and ETV are formulated as oral film-coated tablets of 245-mg,
25-mg, and 0.5-mg strength, respectively. Refer to the prescribing information for a list of
excipients.
Table 4: 
Description and Administration of Background Treatment
Treatment Name 
Tenofovir disoproxil 
Tenofovir alafenamide 
(TAF)* 
Entecavir (ETV)
monohydrate
Type 
Drug 
Drug 
Drug
Dose Formulation 
Film-coated tablets 
Film-coated tablets 
Film-coated tablets
Unit Dose 
Strength(s)
245 mg 
25 mg 
0.5 mg
Dosage Level(s) 
245 mg QD  
25 mg QD  
0.5 mg QD
Route of 
Administration
Oral 
Oral 
Oral
* In countries where TAF is available, it will be one of the NA treatments options.
Investigators should follow guidance detailed in the local prescribing information of NA, including
special warnings and precaution for use.
Participants are instructed to take their NA at home in between study visits, and to bring their NA
with them to each study visit. Study site personnel will instruct participants on how to take their
NA at home and how to store NA for at-home use. At study visits, the NA should be taken on site
to allow biochemistry and renal biomarker samples to be taken in fasted conditions.
NA prescription should follow the standard of care. Compliance will be assessed by the
investigator based on participant interview.


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During the study, participants will continue the same NA treatment (ETV, tenofovir disoproxil, or
TAF) at the same dose they were receiving at the time of screening (and during at least 3 months
prior to screening). In case participants experienced toxicity to ETV, tenofovir disoproxil, or TAF
prior to screening, they should be treated with one of the other 2 NAs during this 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 after consultation with
the sponsor. NA combination treatment is not allowed in this study.
7. 
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT
DISCONTINUATION/WITHDRAWAL
If a participant prematurely discontinues treatment with all study intervention (ie, before Week
24), the participant will have an early WD visit and will enter the 48-week follow-up period, unless
the participant withdraws consent from study participation. NA treatment will be continued until
the end of the study.
If the reason for withdrawal from the study is withdrawal of consent, then the participant will be
offered an optional safety follow-up visit (to occur on the day of consent withdrawal). Study
intervention assigned to the participant who discontinued study intervention should not be assigned
to another participant.
7.1. 
Discontinuation of Study Intervention
Treatment with JNJ-3989 and/or nivolumab must be discontinued if any of the discontinuation
criteria listed in Sections 7.1.1 and 7.1.2 are met. Criteria specific for this ISA are highlighted
(colored fill). For the few criteria from the Master Protocol that are specified or more restricted in
this ISA, the changes compared to the Master Protocol are also highlighted (colored fill).
 If JNJ-3989 and/or nivolumab are discontinued, NA treatment should be continued until
study completion.
 If JNJ-3989 is discontinued, further treatment with nivolumab should also be discontinued.
 If nivolumab  is discontinued, treatment with JNJ-3989 and NA should be continued as
planned unless a treatment discontinuation rule for JNJ-3989 is also met. In that case,
JNJ-3989 will also be discontinued, but NA treatment should be continued as planned.
No rechallenge is allowed after discontinuation of study intervention (JNJ-3989 and/or
nivolumab).
Note: The grades are based on the DAIDS Toxicity Grading Scale and NCI-CTCAE (see
Section 10.8, Appendix 8: DAIDS Table with Modifications).


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7.1.1. 
Discontinuation of JNJ-3989
Treatment with JNJ-3989 must be discontinued ifany of the following occurs:
 
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 JNJ-3989.
 
The participant becomes pregnant.
 
The participant has ≥Grade 3 rash (see Section 10.6, Appendix 6: Rash Management).
 
The participant has ≥Grade 3 allergic reaction or worsening of Grade 2 allergic reaction (see
Section 8.3.6.4.1, Acute Systemic Allergic Reactions).
 
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. Alternative treatment options
(outside the study) should be considered in consultation with the sponsor.
 
The participant has treatment-emergent ALT/AST elevations, as described in Section 8.3.6.1,
Intervention-emergent ALT/AST Elevations including immune-related hepatic AEs.
 
The participant has a confirmed ≥Grade 3 eGFR abnormality and a drop from baseline of
>10 mL/min/1.73 m2, based on creatinine (calculated by the CKD-EPI formula), that persists
despite changing tenofovir disoproxil to ETV or TAF (if the participant was receiving
tenofovir disoproxil) and that is considered at least possibly related to JNJ-3989.
 
The participant has a QTcF prolongation (defined as a QTcF value of >500 ms, or an increase
from baseline of >60 ms) at any given time point.
 
The participant requires ≥7 days oftreatment with any of the disallowed medications listed in
Section 6.5, Concomitant Therapy, 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). If
virologic breakthrough occurs during nivolumab administration, this does not automatically
lead to stop of JNJ-3989 and/or nivolumab, but should be assessed/discussed with the sponsor.
In case of virologic breakthrough, a viral sequencing sample maybe collected at the next visit.
7.1.2. 
Discontinuation of Nivolumab
Treatment with nivolumab should be discontinued if any of the following occurs:
 
Participant meets any of the JNJ-3989 discontinuation criteria listed in Section 7.1.1.
 
The investigator believes that for safety reasons or tolerability reasons (eg, AE) it is in the
best interest of the participant to discontinue nivolumab.


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 
Participant experiences an irAE that requires systemic treatment with corticosteroids (refer to
Section 8.3.6.2, Infusion-related Reactions and Other Immune-related AEs) or has
treatment-emergent 
ALT/AST 
elevations, 
as 
described 
in 
Section 
8.3.6.1,
Intervention-emergent ALT/AST Elevations including immune-related hepatic AEs.
 
Participant experiences Grade 3 or 4 irAE.
 
Participant experiences Grade 3 or 4 IRR.
7.2. 
Participant Discontinuation/Withdrawal From the Study
In case a participant is withdrawn from the study intervention cohort for any of the reasons listed
in Section 7.2 of the Master Protocol PLATFORMPAHPB2001, additional participants will not
be entered.
Withdrawal of Consent
A participant declining to return for scheduled visits does not necessarily constitute withdrawal of
consent. Alternate follow-up mechanisms that the participant agreed to when signing the consent
form apply as local regulations permit.
7.2.1. 
Withdrawal From the Use of Research Samples
Withdrawal From the Study
A participant who withdraws from the ISA/Platform study will have the following options
regarding the optional research samples (ie, pharmacogenomic and FNA samples):
 The collected samples will be retained and used in accordance with the participant's original
informed consent for optional research samples.
 The participant may withdraw consent for optional research samples, in which case the samples
will be destroyed and no further testing will take place. To initiate the sample 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 ISA/Platform
Study
The participant may withdraw consent for optional research samples (ie, pharmacogenomic and/or
FNA samples) while remaining in the study. In such a case, the participant will have to indicate:
 Whether he/she withdraws from further collection only, and he/she agrees the previously
collected samples will be retained and used in accordance with the participant's original
informed consent for optional research samples.


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 Or if he/she also requires that previously collected samples are destroyed and no further testing
is done. The sample destruction process will proceed as described above.
Withdrawal From the Use of Samples in Future Research
The participant may withdraw consent for use of samples for future research (refer to the
paragraphs on long-term retention of samples for additional future research in Attachment 3 of the
Master protocol). In such a case, samples will be destroyed after they are no longer needed for the
clinical study. Details of the sample retention for future research are presented in the main ICF,
and in the separate ICF for optional research samples.
7.3. 
Lost to Follow-up
Refer to Section 7.3 of the Master Protocol PLATFORMPAHPB2001.
8. 
STUDY ASSESSMENTS AND PROCEDURES
Overview
Refer to Section 8 of the Master Protocol PLATFORMPAHPB2001.
The Schedule of Activities summarizes the frequency and timing of efficacy, safety, PK, PD,
pharmacogenomic, biomarker, medical resource utilization, and immune assessments applicable
to this study.
The total blood volume to be collected from each participant during planned assessments for the
entire study will be up to approximately 875 mL. In addition, PBMC samples (at selected sites
only; approximately 250 mL) and optional pharmacogenomic samples (approximately 15 mL)
may be collected.
Sample Collection and Handling
Refer to Section 8 of the Master Protocol PLATFORMPAHPB2001.
Study-Specific Materials
In addition to the items described in Section 8 of the Master Protocol PLATFORMPAHPB2001,
the investigator will be provided with the following supplies:
 
Prescribing Information for ETV, tenofovir disoproxil, and TAF, and nivolumab.
 
Contact information page(s).


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8.1. 
Efficacy Assessments
All efficacy assessments will be performed at predefined time points as specified in the Schedule
of Activities.
Qualitative and quantitative HBsAg and HBeAg, and quantitative HBcrAg as well as
anti-hepatitis B surface (HBs) and anti-hepatitis B e (HBe) antibodies will be determined using
validated serologic assays in a central laboratory. Samples for the determination of HBsAg,
HBeAg, anti-HBs antibodies, and anti-HBe antibodies will be processed in real-time. Samples for
the determination of HBcrAg can be analyzed in batch and at the sponsor’s request.
HBV DNA and HBV RNA will be assessed at central laboratories using validated assays for the
quantification of HBV DNA and HBV RNA. Samples for the determination of HBV DNA will be
processed in real-time. Samples for the determination of HBV RNA can be analyzed in batch and
at the sponsor’s request.
HBV DNA, HBsAg, HBeAg, anti-HBs, and anti-HBe antibody testing results will be provided to
the investigator and the sponsor from screening until the end of follow-up.
It is the responsibility of the investigator:
 
To monitor HBV DNA results and assess whether JNJ-3989 is discontinued in participants
with confirmed virologic breakthrough (see Section 7.1, Discontinuation of Study
Intervention).
In participants enrolled at a site with access to a Fibroscan device, Fibroscan assessments will be
performed at different time points to determine changes in fibrosis levels.
Samples may be used by the sponsor for additional exploratory assessments analyzing the
serologic and virologic characteristics of HBV infection and efficacy or safety of the study
intervention.
8.1.1. 
Sequencing
Viral genome sequence analysis will be performed to evaluate mutations associated with the study
intervention.
Sequencing of the HBV genome may be performed to monitor HBV variants using any of the
virology/serology samples collected at the time points indicated in the Schedule of Activities.
Samples may be sequenced based on the sponsor virologist’s request, considering the HBV DNA
levels. In case of a virologic breakthrough/flare, additional samples for viral sequencing may be
taken.
Samples may be used by the sponsor for additional assessments analyzing the serologic and
virologic characteristics of the HBV infection and efficacy of the study intervention, including
viral genotypic and phenotypic assessments.


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8.2. 
Safety Assessments
Safety and tolerability (AEs, clinical safety laboratory assessments, ECGs, vital signs and physical
examinations) will be evaluated as described in Section 8.2 and Section 8.3 of the Master Protocol
PLATFORMPAHPB2001 and at predefined time points as specified in the Schedule of Activities.
Additional clinical safety laboratory assessments specific for this protocol are described in
Section 10.2, Appendix 2: Clinical Laboratory Tests.
The study will include the following evaluations of safety and tolerability according to the time
points provided in the Schedule of Activities.
8.2.1. 
Physical Examinations
Refer to Section 8.2.1 of the Master Protocol PLATFORMPAHPB2001.
In addition, physical examination will include neck and thyroid gland check.
8.2.2. 
Vital Signs
Refer to Section 8.2.2 of the Master Protocol PLATFORMPAHPB2001.
Clinically relevant abnormalities in vital signs are defined in Section 10.7, Appendix 7:
Cardiovascular Safety –Abnormalities.
8.2.3. 
Electrocardiograms
Refer to Section 8.2.3 of the Master Protocol PLATFORMPAHPB2001.
Clinically relevant abnormalities in ECG are defined in Section 10.7, Appendix 7: Cardiovascular
Safety –Abnormalities.
8.2.4. 
Clinical Safety Laboratory Assessments
Refer to Section 8.2.4 of the Master Protocol PLATFORMPAHPB2001.
In addition, urine samples for urine chemistry and renal biomarkers will be collected as noted in
Section 10.2, Appendix 2: Clinical Laboratory Tests.
8.2.5. 
Pregnancy Testing
For women of childbearing potential, a negative screening serum pregnancy test and a negative
baseline urine pregnancy test must be obtained before the first dose of study intervention on Day 1.
Urine pregnancy tests should be done at least every 4 weeks, preferably during a scheduled site
visit. Pregnancy tests for at-home use may be provided to the participants from FU Week 24
onwards to allow 4-weekly urine pregnancy testing in between scheduled site visits. If positive,
the participant should contact the site immediately.


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8.3. 
Adverse Events, Serious Adverse Events, and Other Safety Reporting
Adverse events and SAEs will be evaluated as described in Section 8.3 of the Master Protocol
PLATFORMPAHPB2001, including handling of pregnancy described in Section 8.3.5.
Further details on AEs, SAEs, and Product Quality Complaints (PQCs) can be found in
Attachment 4 of the Master Protocol PLATFORMPAHPB2001.
Note: All reported AEs will be coded according to the Medical Dictionary for Regulatory
Activities (MedDRA). In addition, the following coding conventions will be applied for the AEs
reported by investigators as specified below:
 
AE reporting an ALT flare in relation to laboratory test elevation will be coded to the
MedDRA preferred term alanine aminotransferase increased.
 
AE reporting a reactivation of hepatitis B in patients who are HBV DNA suppressed and have,
when a patient is off NA treatmenta, a sudden HBV DNA increase (virologic flare) will be
coded to MedDRA preferred term hepatitis B reactivation.
 
AE reporting a viral breakthrough in the context of laboratory data will be coded to the
MedDRA preferred term viral load increased.
8.3.1. 
Time Period and Frequency for Collecting Adverse Event and Serious
Adverse Event Information
Refer to Section 8.3.1 of the Master Protocol PLATFORMPAHPB2001.
8.3.2. 
Method of Detecting Adverse Events and Serious Adverse Events
Refer to Section 8.3.2 of the Master Protocol PLATFORMPAHPB2001.
8.3.3. 
Follow-up of Adverse Events and Serious Adverse Events
Adverse events 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
Refer to Section 8.3.4 of the Master Protocol PLATFORMPAHPB2001.
8.3.5. 
Pregnancy
Refer to Section 8.3.5 of the Master Protocol PLATFORMPAHPB2001. Differences with the
Master Protocol PLATFORMPAHPB2001 are highlighted (colored fill).
a Note that in the current study, participants will continue their NA background regimen during the study intervention
and the follow-up periods.


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Follow-up information regarding the outcome of the pregnancy for female participants who
become pregnant, or where the pregnancy was the result of male participant and his partner, and
any postnatal sequelae in the infant will be required.
8.3.6. 
Guidelines for Management of Adverse Events of Special Interest
Including Immune-Related Adverse Events
Adverse events of interest are significant AEs that are judged to be of special interest because of
clinical importance, known class effects or based on nonclinical signals. Immune-related AEs of
interest that will be carefully monitored during the study include ALT/AST elevations including
immune-related hepatic AEs, IRRs and other irAEs (including gastrointestinal AEs, neurological
AEs, pulmonary AEs, renal AEs, endocrinopathies, rash, uveitis and visual complaints,
lipase/amylase elevations, and infection). Other AEs of Special Interest related to JNJ-3989 that
will be carefully monitored during the study include hematological abnormalities and ISRs.
AEs of Special Interest should be identified and reported to the sponsor’s Medical Monitor and
reported as an SAE if SAE criteria are met.
8.3.6.1. 
Intervention-emergent ALT/AST Elevations Including Immune-related
Hepatic AEs
Elevated liver enzyme activity can be triggered by the underlying HBV disease as well as
potentially by the study intervention. Management of intervention-emergent ALT/AST elevations
is described below.
Hepatic AEs, including elevated liver function tests and, infrequently, drug-induced-liver-injuries
(DILI) have been observed following treatment with anti-PD-1 therapies. Early recognition and
treatment of elevated liver function tests and DILI are critical to their management. Participants
should be advised to seek medical evaluation if they notice jaundice (yellow appearance of skin or
sclera) or if they develop bruising, bleeding, or right-sided abdominal pain. Investigators should
monitor liver function tests (included in chemistry laboratory test) during the study.
Any treatment-emergent elevation of ALT and/or AST ≥3x ULN and ≥3x nadir (ie, lowest value
during study participation) should trigger an assessment of confounding factors (alcohol intake,
change in concomitant medication, and comorbidities), and should trigger a confirmatory study
visit to repeat laboratory testing of ALT, AST, ALP, bilirubin (total and direct), INR, albumin,
HBV DNA. After nivolumab initiation, antinuclear antibodies, anti-smooth muscle antibodies,
anti-neutrophil cytoplasmic antibodies, and gamma globulin should be added as part of the
confirmatory laboratory testing to assess potential immune-related hepatic AEs. Additional tests
should be considered based on clinical judgement: Hepatitis A, Delta, C, E: IgM anti-HAV; delta
IgM, IgG and polymerase chain reaction (PCR), HCV RNA, IgM and IgG anti-HEV, HEV RNA;
CMV, herpes simplex virus (HSV), Epstein-Barr virus (EBV) infection; IgM and IgG anti-CMV,
IgM and IgG anti-HSV; IgM and IgG anti-EBV, PCR; HIV; Ig electrophoresis. The confirmatory
visit should be scheduled as soon as possible within 7 days of the receipt of the initial ALT/AST
results. Additional PBMC and AFP samples may be taken in case of ALT flares, upon discussion
with the sponsor, which may require an unscheduled visit.


















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In the Phase 1/2a AROHBV1001 study with JNJ-3989, mild (Grade 1) transient thrombocytopenia
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 was given in combination with JNJ-6379 over a 12-week period in the same study.
Based on the nonclinical findings, any relevant abnormalities in hematologic parameters will be
carefully monitored as described below:
 
Platelet counts: <100,000 cells/mm3 (at least Grade 2 [DAIDS]) 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).
 
Neutrophil count: Treatment-emergent reduction to at least Grade 2 (DAIDS).
In case any 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 (platelet count, hemoglobin,
and neutrophil count), discontinuation of JNJ-3989 (and nivolumab if applicable) should be
considered. In case of discontinuation, NA treatment should be continued.
8.3.6.3.2. 
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. Evaluations will be recorded in the source documents and 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 Section 10.8, Appendix 8: DAIDS Table with Modifications.
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 made anonymous and provided to the sponsor.




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8.4.3. 
Pharmacokinetic Parameters and Evaluations
Parameters
Based on the individual plasma concentration-time data, using the actual dose taken and the actual
sampling times, PK parameters and exposure information of JNJ-3989 and optionally NA and/or
nivolumab will be derived using population PK modeling. Baseline covariates (eg, body weight,
age, sex, creatinine clearance [CrCL], race) may be included in the model, if relevant.
Pharmacokinetic/Pharmacodynamic Evaluations
Relationships of individual PK parameters for JNJ-3924 and JNJ-3976, and optionally NA and/or
nivolumab, with RO, selected efficacy and/or safety endpoints may be evaluated, if applicable.
8.5. 
Pharmacodynamics
Whole blood samples will be collected for assessment of nivolumab RO on circulating T-cells by
flow cytometry analysis.
Pharmacodynamic biomarkers will be evaluated in all participants pretreatment, on-treatment, and
posttreatment with study intervention as shown in Schedule of Activities in Section 1.3.1 and
Section 1.3.2.
Refer to laboratory manuals for sample collection requirements.
8.6. 
Host Genetics
An optional sample for HLA testing will be collected from participants who consent separately to
this component of the study.
An optional pharmacogenomic (host DNA) blood sample may be collected (preferably at baseline)
to allow for host pharmacogenomic research, where local regulations permit. In addition, host
DNA blood samples to allow for epigenetic analyses will be collected in participants who consent.
These samples could for example be used to assess changes in frequencies of immune cells.
Complete host genomic testing may be done to search for links of specific genes to (HBV-related)
liver disease or to the PK, PD, efficacy, safety, or tolerability of the study intervention. These
samples will only be collected from participants who consent separately to this component of the
study. Further, a participant may withdraw such consent at any time without affecting their
participation in other aspects of the study, or their future participation in the Platform study (see
Section 7.2.1 of the Master Protocol PLATFORMPAHPB2001).
In addition, other samples may be used for exploratory genetic or epigenetic research in
participants consenting separately to this part of the study. These samples can only be used to
investigate the potential association of genetic or epigenetic factors with efficacy, safety, or PK of
the study intervention, or HBV infection, or may be used to develop tests/assays related to the
study intervention or HBV infection. No genetic research will be performed on any sample in
participants who have not provided the additional separate consent for host genetic research.


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These analyses will be performed at the sponsor’s discretion, will always be under the sponsor’s
supervision, and may be reported separately.
8.7. 
Exploratory Host Biomarkers
The study includes collection of blood samples for exploratory analysis of host blood biomarkers
at the host RNA, protein, and cell level. Sampling will be performed at the time points indicated
in the Schedule of Activities. Leftovers of other samples might also be used for exploratory
research of host and viral markers.
Samples can only be used for research related to study intervention or HBV infection or may be
used to develop tests/assays related to study intervention or HBV infection.
A FNA biopsy sample may be collected from participants who consent separately to this
component of the study (as permitted by local regulations). If participants agree to undergo an
optional FNA biopsy of the liver, following local standard practice, the biopsy location will be
identified and/or guided with ultrasound and the FNA biopsy samples will be collected after
application of local anesthesia to allow for exploratory biomarker research.
The FNA 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. Prior to each to FNA biopsy, a recent (≤2 weeks) coagulation and hematology panel
are required to ensure normal platelet count and normal coagulation parameters. The use of local
laboratories may be allowed at the investigator’s discretion. Optional FNA biopsy will only be
completed at selected sites that have expertise and capacity to perform FNA biopsy. Intrahepatic
immune response to treatment will be assessed in FNA biopsy samples.
Infiltrating immune cells will be used for the evaluation of immune responses, which can be
compared to responses in PBMCs.
These analyses will be performed at the sponsor’s discretion, will always be under the sponsor’s
supervision, and may be reported separately.
More information is provided in Section 8.8 of the Master Protocol PLATFORMPAHPB2001.
8.8. 
Immune Assessments
At selected sites, PBMC samples for immune analyses will be collected during study intervention
and follow-up and will be analyzed centrally for HBV-specific responses by enzyme-linked
immunospot (ELISpot) and/or intracellular cytokine staining (ICS) after stimulation with
HBV-specific antigens. ELISpot detects T-cells that secrete gamma interferon (IFN-γ) in response
to a specific antigenic stimulation, whereas ICS determines the frequency of CD4+ and CD8+
T-cells secreting cytokines such as IFN-γ, interleukin (IL)-2 and TNF-α in response to a specific
antigenic stimulation.
Additional PBMC samples may be taken in case of ALT flares, upon discussion with the sponsor,
which may require an unscheduled visit.


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Additional experiments may be performed to further phenotypically and functionally characterize
PBMCs. Leftover PBMC samples may be used at the sponsor’s discretion for additional
exploratory research or to explore new functional immune assays, or for immune assay
optimalization.
Blood samples taken at the time points indicated in the Schedule of Activities, can also be used to
explore the emergence of antidrug antibodies to JNJ-3989 and/or nivolumab. Antidrug antibodies
may be analyzed using assays such as an enzyme-linked immunosorbent assay or functional
assays.
These analyses will be performed at the sponsor’s discretion, will always be under the sponsor’s
supervision, and may be reported separately.
8.9. 
Medical Resource Utilization and Health Economics
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 duration of medical care encounters, including surgeries, and other selected
procedures (inpatient and outpatient).
 
Duration of hospitalization (total days length of stay, including duration by wards,
eg, intensive care unit).
 
Number and character of diagnostic and therapeutic tests and procedures.
 
Outpatient medical encounters and treatments (including physician or emergency room visits,
tests and procedures, and medications).
9. 
STATISTICAL CONSIDERATIONS
Statistical analysis will be done by the sponsor or under the authority of the sponsor. A general
description of the statistical methods to be used to analyze the efficacy and safety data is outlined
below. Specific details will be provided in the Statistical Analysis Plan (SAP).
9.1. 
Statistical Hypotheses
The primary hypothesis of this study is that at least one of the combination regimens of
JNJ-3989+nivolumab+NA is more efficacious than JNJ-3989+NA treatment, as measured by the
primary efficacy endpoint (ie, the proportion of participants with HBsAg seroclearance at FU
Week 24). Because the study does not include a regimen arm without nivolumab, the hypothesis
is formulated assuming a fixed response rate for JNJ-3989+NA of 1% based on previous
Study 73763989HPB2001 (REEF-1).


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9.2. 
Sample Size Determination
According to the initial protocol, the study aimed to have a sample size of 20 participants per
intervention arm which yielded ≥85% statistical power to detect a ≥15% and ≥20% difference for
the proportions of participants with HBsAg seroclearance at FU Week 24 in the 2 intervention
arms, respectively, vs a fixed proportion of ≤1%. Statistical power to test the primary hypothesis
was assessed for each of the intervention arms, using an exact test for a single proportion with a
one-sided Type 1 error rate of 0.05 and applying the Hochberg procedure for multiple comparisons
adjustment. The fixed rate assumed for the external active control (JNJ-3989 [200 mg]+NA
treatment) is based on the data of Study 73763989HPB2001 (REEF-1).
The total study sample size was adjusted to 44 participants (22 per arm), with 1:1 randomization
ratio to each of the intervention arms, to account for an approximate 10% attrition rate.
Due to the decision to not extend further enrollment beyond the planned enrollment period and
proceed with a reduced sample size, the final sample size is 37 (18 in Arm 1 and 19 in Arm 2).
Under the same assumptions and methods of the initial protocol, an approximate sample size of 16
participants per intervention arm (assuming 10% attrition) yields ≥75% statistical power to detect
the same differences in HBsAg seroclearance at FU Week 24.
9.3. 
Populations for Analysis Sets
For purposes of analysis, the following populations are defined:
Screened 
All participants who signed the ICF for the Master Protocol and the ICF specific for this ISA.
Enrolled 
All participants who were enrolled in this ISA.
Full Analysis Set 
(FAS) 
All participants who were randomly assigned to an intervention arm in this ISA and received
at least 1 dose of study intervention within this ISA. Participants will be analyzed according
to the study intervention they were randomly assigned to.
Full Analysis Set 
for nivolumab 
(FAS-N) 
All participants who were randomly assigned to an intervention arm in this ISA and received
at least 1 dose of nivolumab within this ISA. Participants will be analyzed according to the
study intervention they were randomly assigned to.
Safety  
All participants who received at least 1 dose of study intervention within this ISA.
Participants will be analyzed according to the study intervention they actually received.
9.4. 
Statistical Analyses
The SAP will include a more technical and detailed description of the statistical analyses described
in this section. This section is a summary of the planned statistical analyses of the most important
endpoints including primary and key secondary endpoints.
9.4.1. 
General Considerations
Refer to Section 9.4.1 of the Master Protocol PLATFORMPAHPB2001.
9.4.2. 
Efficacy Analyses
The primary efficacy analysis will be performed when all participants have completed the FU
Week 24 visit or discontinued earlier. The final analysis will be performed when all participants
have completed the final study visit at FU Week 48 or discontinued earlier.


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To evaluate the efficacy, the primary analysis set will be the Full Analysis Set (see Section 9.3,
Populations for Analysis Sets). The FAS-N set will be used for sensitivity analyses of selected
efficacy endpoints.
All efficacy summaries will be presented with descriptive statistics and 90% CIs by intervention
arm, when applicable. If the endpoint is continuous, the descriptive statistics will include the
number of participants, mean, standard deviation (SD), median, and range. If the endpoint is binary
or categorical, the frequency distribution with the number and percentage of participants in each
category will be calculated. For time-to-event variables, a summary table based on the Kaplan-
Meier method 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 the
randomization stratification factor (ie, absolute HBsAg value at baseline [<100 IU/mL, 100 to
<1,000 IU/mL, and ≥1,000 IU/mL]).
The baseline measurements are defined as the measurements taken closest to, but before, the first
administration of study intervention on Day 1, unless otherwise specified.
9.4.2.1. 
Primary Endpoints
The proportion of participants who achieved HBsAg seroclearance at FU Week 24 will be
summarized for each intervention arm paired together with a two-sided, single arm 90% CI based
on the Clopper-Pearson method. The statistical comparison will be conducted using an exact
binomial test against a fixed external control value of 1% at a one-sided Type 1 error rate of0.05
and applying the Hochberg procedure for adjusting for multiple comparisons.
Association of the stratification factors and other demographic and baseline disease characteristics
with the primary endpoint may be explored using logistic regression analyses and classification
and regression tree analysis (CART).
The Mantel-Haenszel test adjusted for the randomization stratification factors will be used in a
secondary analysis comparing the primary endpoint between the 2 study intervention arms at a
one-sided alpha level of 0.05.
9.4.2.2. 
Secondary Efficacy and Exploratory Endpoints
Descriptive statistics will be used for all efficacy endpoints, which will be summarized by
intervention arm and by study period. Comparisons between intervention arms and 90% CIs may
be done with no adjustment for multiplicity. Specific key selected endpoints may be analyzed
using suitable categorical data approaches (eg, Mantel-Haenszel or logistic regression for
proportions or other categorical type of endpoint), longitudinal repeated measures models (eg, for
continuous types of variables), or survival analysis based on the Kaplan-Meier estimates (for
time-to-event variables), as appropriate. Details will be described in the SAP.
Graphic data displays of different type (eg, bar charts, line plots, and waterfall plots) will also be
used to summarize the efficacy data by intervention arm and over time.


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9.4.2.3. 
Across ISAs Comparisons of Efficacy
Indirect comparisons between different regimens across multiple ISAs may be performed in an
exploratoryfashion by selecting the similar subgroup of participants who match the most important
inclusion/exclusion criteria and demographic characteristics of this ISA.
More details on this approach and its application to secondary endpoints will be provided, if
applicable, in a separate document (eg, SAP or the Modeling and Simulation Report).
9.4.3. 
Safety Analyses
Safety analyses will be based on the safety population (see Section 9.3, Populations for Analysis
Sets) and are specified in Section 9.4.3 of the Master Protocol PLATFORMPAHPB2001.
Safety will be evaluated by means of descriptive summaries of AE including AEs of Special
Interest to any of the study interventions, clinical laboratory tests, ECGs, vital signs, and physical
examinations. The safety analysis will be done by study period. Results will be presented in tabular
format and/or graphically by intervention arm and over time, as appropriate.
Indirect descriptive comparisons of selected safety endpoints between different regimens across
different ISAs will be performed in an exploratory fashion by selecting the similar subgroup of
participants who match the most important inclusion/exclusion criteria and demographic
characteristics of this ISA population.
9.4.4. 
Other Analyses
Pharmacokinetic Analyses
Population PK analysis of concentration-time data of JNJ-3976 and JNJ-3924, and, optionally, of
NA and/or nivolumab may be performed using non-linear mixed effects modeling. Data may be
combined with selected Phase 1 and/or 2 studies to support a relevant structural model. Available
participant characteristics (eg, demographics, laboratory variables, genotypes) will be included in
the model as necessary. Details will be given in a population PK analysis plan and results of the
population PK analysis, if applied, will be presented in a separate report.
Pharmacokinetic/Pharmacodynamic Analyses
Relationships of PK parameters for JNJ-3976 and JNJ-3924, and, optionally, for NA and/or
nivolumab, with RO, selected efficacy and/or safety endpoints may be evaluated and graphically
displayed, if applicable.
Modeling of key PD parameters (eg, HBsAg, HBV DNA) may be performed using population
PK/PD. If PK/PD modeling of key efficacy endpoints is performed, treatment effect and possible
covariates may be investigated. Other biomarkers may be explored at the sponsor’s discretion. If
applicable, the results will be described in a separate report.


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Pharmacodynamic Analyses
Descriptive statistics by treatment will be used to summarize PD parameters at each applicable
time point. Statistics include sample size (n), mean, SD, coefficient of variation (CV), geometric
mean, median, minimum, and maximum. Additional PD analyses may be performed, as deemed
necessary.
Resistance Analysis
The results of HBV viral sequencing will be evaluated by the sponsor virologist. Relevant changes
of amino acid and/or nucleic acid variations (eg, substitutions) in the HBV genome will be
tabulated and described.
Additional exploratory characterization of the HBV viral sequence and phenotype may be
performed and reported separately.
Pharmacogenomic Analysis
The statistical approach for analyzing the exploratory host DNA research samples, including
epigenetic analyses, may depend on the objective of the analyses (eg, efficacy, safety, and/or PK)
and possibly relevant genes at the time of analysis. Analyses will be conducted at the sponsor’s
discretion, will always be under the sponsor’s supervision, and results will be presented either in
the clinical study report or a separate report.
Host Biomarker Analysis
Statistical approaches to explore correlations between clinical outcome and blood biomarkers vary
and depend on the different data types of the applied technology platforms, as well as on the extent
of observed interindividual variability. Analyses will be conducted at the sponsor’s discretion, will
always be under the sponsor's supervision, and results will be presented either in the clinical study
report or a separate report.
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 (or positivity
threshold) may also be tabulated for PBMCs during study intervention and follow-up. The
proportion (%) of chronic HBV-infected patients with detectable responses based on the
magnitude of the IFN-γ T-cell response or the CD4+ or CD8+ T-cells expressing at least 1 of the
cytokines amongst IL-2, TNF-α or IFN-γ for 1 of the HBV antigens as defined by ELISpot and/or
ICS, respectively, will be determined.
Medical Resource Utilization
Medical resource utilization data will be descriptively summarized by intervention arm over time.


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9.5. 
Interim Analysis
Interim analyses (IAs) will be conducted to assess safety and evaluate the time course of different
safety and efficacy markers to support the sponsor’s interactions with health authorities, as well as
to inform internal decisions about additional studies and/or investigation of other treatment
combinations.
Optional IAs are planned when:
 
All randomized participants have completed Week 24 or discontinued earlier.
 
All randomized participants have completed FU Week 12 or discontinued earlier.
Depending on the enrollment rate, any of the above IAs may be skipped if it is too close to the
predicted timing of any adjacent interim cut-offs and additional IAs may be performed by the
sponsor to support interactions with health authorities.
The study is open-label, and the sponsor will conduct the IA(s). Hence, the study team and the
DRC will have access to the IA results, while the investigators and patients will not.
Interim analyses will be based on all data available at the predefined cut-off time points and may
include data at later time points for those participants who have reached subsequent visits.
More details are provided in Section 9.5 of the Master Protocol PLATFORMPAHPB2001.












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10.3. Appendix 3: Regulatory, Ethical, and Study Oversight Considerations
10.3.1. 
Regulatory and Ethical Considerations
Refer to Attachment 3 of the Master Protocol PLATFORMPAHPB2001.
10.3.2. 
Financial Disclosure
Refer to Attachment 3 of the Master Protocol PLATFORMPAHPB2001.
10.3.3. 
Informed Consent Process
Refer to Attachment 3 of the Master Protocol PLATFORMPAHPB2001.
Each participant must give consent according to local requirements after the nature of the study
has been fully explained.
Participants will be asked for consent to provide optional host DNA samples and/or FNA biopsy
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.
10.3.4. 
Data Protection
Refer to Attachment 3 of the Master Protocol PLATFORMPAHPB2001.
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.
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.
10.3.5. 
Long-Term Retention of Samples for Additional Future
Refer to Attachment 3 of the Master Protocol PLATFORMPAHPB2001.


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10.3.6. 
Committees Structure
Data Review Committee
The internal DRC established for the Platform study will review interim data and formulate
recommendations to protect the safety and well-being of the participants. Description of the DRC
is provided in Section 9.6 of the Master Protocol PLATFORMPAHPB2001. The possible
recommendations and role of the DRC will be further detailed in the DRC charter for this ISA.
Independent Flare Expert Panel
An IFLEP will be appointed. The IFLEP is composed of 3 independent medical experts with
experience and expertise in HBV and its treatment. The IFLEP will monitor ALT flares and will
make recommendations regarding flare management based on an analysis of aggregate data.
In order to allow for an unbiased assessment, members of the committee will not serve as study
investigators or as members of the DRC.
Further details on the IFLEP process will be included in the IFLEP charter.
10.3.7. 
Publication Policy/Dissemination of Clinical Study Data
Refer to Attachment 3 of the Master Protocol PLATFORMPAHPB2001.
10.3.8. 
Data Quality Assurance
Refer to Attachment 3 of the Master Protocol PLATFORMPAHPB2001.
10.3.9. 
Case Report Form Completion
Refer to Attachment 3 of the Master Protocol PLATFORMPAHPB2001.
10.3.10. 
Source Documents
Refer to Attachment 3 of the Master Protocol PLATFORMPAHPB2001.
10.3.11. 
Monitoring
Refer to Attachment 3 of the Master Protocol PLATFORMPAHPB2001.
10.3.12. 
On-Site Audits
Refer to Attachment 3 of the Master Protocol PLATFORMPAHPB2001.
10.3.13. 
Record Retention
Refer to Attachment 3 of the Master Protocol PLATFORMPAHPB2001.
10.3.14. 
Study and Site Start and Closure
Refer to Attachment 3 of the Master Protocol PLATFORMPAHPB2001.
The first participant screened is considered the first act of recruitment and it becomes the study
start date.


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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
Refer to Attachment 4 of the Master Protocol PLATFORMPAHPB2001.
10.4.2. 
Attribution Definitions
Refer to Attachment 4 of the Master Protocol PLATFORMPAHPB2001.
10.4.3. 
Severity Criteria
Refer to Attachment 4 of the Master Protocol PLATFORMPAHPB2001.
10.4.4. 
Special Reporting Situations
Refer to Attachment 4 of the Master Protocol PLATFORMPAHPB2001.
A participant pregnancy or participant partner(s) pregnancy is also considered a special reporting
situation in this ISA.
10.4.5. 
Procedures
Refer to Attachment 4 of the Master Protocol PLATFORMPAHPB2001.
10.4.6. 
Product Quality Complaint Handling
Refer to Attachment 4 of the Master Protocol PLATFORMPAHPB2001.
10.4.7. 
Contacting Sponsor Regarding Safety, Including Product Quality
Refer to Attachment 4 of the Master Protocol PLATFORMPAHPB2001.


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10.5. Appendix 5: 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, or bilateral salpingectomy, or
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 must 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 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)
 Tubal closure (eg, bilateral tubal occlusion, bilateral tubal ligation)
 Azoospermic partner (vasectomized or due to medical cause)
(Vasectomized partner is a highly effective contraceptive method provided that the partner is the
sole sexual partner of the woman of childbearing potential and the absence of sperm has been
confirmed. If not, additional highly effective method of contraception must be used.
Spermatogenesis cycle is approximately 74 days.)
USER DEPENDENTb
Highly Effective Methods That Are User Dependent Failure rate of <1% per year when used
consistently and correctly.
 Combined (estrogen- and progestogen-containing) hormonal contraception associated with
inhibition of ovulation
 oral
 intravaginal
 transdermal
 injectable
 Progestogen-only hormone contraception associated with inhibition of ovulation
 oral
 injectable
 Sexual abstinence
(Sexual abstinence is considered a highly effective method only if defined as refraining from
heterosexual intercourse during the entire period of risk associated with the study intervention.
The reliability of sexual abstinence needs to be evaluated in relation to the duration of the study
and the preferred and usual lifestyle of the participant.)
a. Typical use failure rates may differ from those when used consistently and correctly. Use must
be consistent with local regulations regarding the use of contraceptive methods for
participants in clinical studies.
b. User-dependent, highly effective forms of contraception are not acceptable as the sole method
ofcontraception for female study participants of childbearing potential. They are acceptable
as the sole method of contraception only for female partners of male study participants.


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10.6. Appendix 6: Rash Management
Table 14: 
Management of Rash Events by Severity Grade
Activities by Daya
In case of suspicion of immune-related rash events
Grade 1 rash
(with or without pruritus)b
Day 0: Optional on-site visit for initial rash evaluation may be performed at the
investigator’s discretion.
Safety laboratory assessments may be performed at the investigator’s discretion
(recommended if visit occurs).
Digital picturesc of skin lesions may be taken at the investigator’s discretion.
Day 1 and thereafter: Appropriate follow-up visits at the investigator’s
discretion until resolution of rash.
Safety laboratory assessments and digital picturesc of skin lesions may be
performed at the investigator’s discretion.
Study intervention may be continued at the investigator’s discretion
Treat with topical emollients and/or mild-moderate potency
topical corticosteroids.
Counsel patients to avoid skin irritants and sun exposure
Grade 2 rash
(with or without pruritus)b
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).
The participant may be referred to a dermatologist at the investigator’s discretiond,
who may perform a biopsy.
Digital picturesc of skin lesions may be taken at the investigator’s discretion.
Digital picturesc of skin lesions are recommended in case consultation of a
dermatologist is required.
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 picturesc of skin lesions may be taken at the investigator’s discretion.
Study intervention may be continued at the investigator’s discretion
Immediately: Symptomatic therapy (eg, antihistamines, topical
steroids)
Persistence ≥2 weeks or recurrence: consider skin biopsy;
consider 0.5-1.0 mg/kg/d methylprednisolone IV or oral
equivalent; consider prophylactic antibiotics
Improvement to ≤Grade 1: taper steroids over at least 4 weeks
Worsening to >Grade 2: treat as Grade 3-4
In case of treatment with systemic corticosteroids initiated,
nivolumab must be discontinued.


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Table 14: 
Management of Rash Events by Severity Grade
Activities by Daya
In case of suspicion of immune-related rash events
Grade 3 rashb
Day 0: Required on-site visit.
Safety laboratory assessments required to be performed.
Referral to a dermatologist requiredd, who may perform a biopsy.
Digital picturesc of skin lesions may be taken at the investigator’s discretion
(recommended).
Day 1 and thereafter: Appropriate follow-up required until resolution of rash or
until clinical stability is reached.
Safety laboratory assessments and photography (digital picturesc of skin lesions)
are recommended to be performed until the rash severity resolves to Grade 2 or
Grade 1.
Must permanently discontinue study intervention; no rechallenge allowed
Immediately: consult dermatologist; consider skin biopsy; start
0.5-1.0 mg/kg methylprednisolone IV or IV equivalent; add
prophylactic antibiotics
Improvement to ≤Grade 1: taper steroids over at least 4 weeks
Grade 4 rash  
Day 0: required on-site visit. 
Safety laboratory assessments required to be performed. 
Referral to a dermatologist requiredd and biopsy to be performed as soon as
possible after onset of rash.
Digital picturesc of skin lesions may be taken at the investigator’s discretion
(recommended).
Day 1 and thereafter: appropriate follow-up required until resolution of rash or
until clinical stability is reached.
Safety laboratory assessments and photography (digital picturesc of skin lesions)
are recommended to be performed until the rash severity resolves to Grade 2 or
Grade 1.
Must permanently discontinue study intervention; no rechallenge allowed
Immediately: referral to a dermatologist requiredd; biopsy to be
performed as soon as possible after onset of rash; start
1.0-2.0 mg/kg/d methylprednisolone IV or IV equivalent; add
prophylactic antibiotics
Improvement to ≤Grade 1: taper steroids over at least 4 weeks
AE: adverse event; ALT: alanine aminotransferase; AST: aspartate aminotransferase; NA: nucleos(t)ide analog.
a 
Day 0 of the rash is the first day of investigator assessment and not the first day of rash as reported by the participant. The initial visit should be conducted as soon as possible after
the participant contacts the investigator to report the AE (ie, preferably on Day 0). The initial visit and subsequent visits to manage the rash may require unscheduled visit(s).
b 
The participant should be advised to contact the investigator immediately if there is any worsening of the rash, if any systemic signs or symptoms appear, or if mucosal involvement
develops. In case the rash evolves to a higher grade than that first observed, management of the rash should follow the guidelines indicated for the higher grade.
c 
Digital pictures to be taken at the clinical site upon consent of the participant.
d 
If applicable, dermatologist visit should occur preferably within 24 hours after onset of rash.
Notes:
 
Local laboratory assessments are to be used for rash management. The values of the local laboratory assessments need to be transcribed in the CRF by the study site personnel.
 
A copy of the dermatologist’s report, biopsy, and/or digital pictures if performed, should be made anonymous and will be provided to the sponsor.
 
The grades are based on the DAIDS Toxicity Grading Scale and NCI-CTCAE (see Section 10.8, Appendix 8: DAIDS Table with Modifications).


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


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10.8. Appendix 8: DAIDS Table with Modifications (DAIDS [Modified])
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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10.9. Appendix 9: Study Conduct During a Natural Disaster
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, isolation or quarantine ofparticipants and
study site personnel; travel restrictions/limited access to public places, including hospitals; study
site personnel being unavailable, isolated, or reassigned to critical tasks.
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. If, at any time, a participant’s travel to the study site is considered to be
dangerous, study participation may be interrupted, and study follow-up conducted. If it becomes
necessary to discontinue participation in the study, the procedures outlined in the protocol for
discontinuing study intervention will be followed.
If, as a result of the COVID-19 pandemic scheduled visits cannot be conducted in person at the
study site, they 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 after consultation with the participant, investigator, and the sponsor. Missed
assessments/visits will be captured in the clinical trial management system for protocol deviations.
Discontinuations of study intervention and withdrawal from the study should be documented with
the prefix “COVID-19-related” in the CRF.
The sponsor will continue to monitor the conduct and progress of the clinical study, and any
changes will be communicated to the sites and to the health authorities according to local guidance.
Modifications made to the study conduct as a result of the COVID-19 should be summarized in
the clinical study report.
If the participant has tested positive for the COVID-19, the investigator should contact the
sponsor’s responsible medical officer to discuss plans for administration of study intervention,
performing. study assessments, and follow-up. Modifications made to the study conduct as a result
of the COVID-19 should be summarized in the clinical study report.


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GUIDANCE SPECIFIC TO THIS PROTOCOL
The following emergency provisions are meant to ensure participant safety on study while site
capabilities are compromised by COVID-19-related restrictions. Remote medical consultation and
alternatives to study intervention dispensing, administration, and clinical laboratory assessments
may allow continued study participation for participants in this trial. Before implementing any of
these emergency provisions, the sponsor should be consulted to perform a benefit-risk analysis
and to ensure the measures are executed and documented correctly.
As restrictions are lifted and the acute phase of the COVID-19 pandemic resolves, sites should
revert to original protocol conduct as soon as feasible and in accordance with any country-specific
regulatory requirements.
Screening and Randomization:
 Enrollment of new participants may continue based on the investigator’s assessment 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 and NA Background Regimen:
 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 NA background treatment,
where allowed per local regulations, can be provided.
 For participants unable to visit the study site, shipment or handover to a caregiver or delegate
of NA background treatment, may be implemented, where allowed per local regulations and if
requested by the treating study physician. Where shipments or handover to delegates are
deemed necessary, the process must be coordinated between the site and participant for
arranging shipment and adhering to associated approvals and documentation requirements.
 JNJ-3989 and nivolumab should always be administered by a nurse at the study site or, if site
visits are not possible, at the participant’s home. Refer to Section 6.4, Study Intervention
Compliance, in case a scheduled administration of study intervention (JNJ-3989 and
nivolumab) or NA background treatment is missed.
Continuation of Study Intervention and/or NA Background Treatment:
 Any issue with continuation and/or provision of study intervention  and/or NA background
treatment should be discussed with the sponsor and should be well documented.
 Study intervention should be continued if, in the assessment of the investigator, it does not
result in risk to the participant. If at any time the participant’s safety is considered at risk due
to study intervention, study intervention will be temporarily or permanently discontinued,
while every effort should be made to maintain follow-up on study. The benefit of continuing
study intervention should be assessed by the investigator for each individual participant,
considering the potential impact of reduced direct clinical supervision on participant safety.


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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(s)
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 with the exception of the
second dose of Sputnik V.
During nivolumab treatment, the following recommendations should be applied to accommodate
COVID-19 vaccination:
 
COVID-19 vaccine and nivolumab should not be administered on the same day. If required,
nivolumab administration can be delayed by 2-5 days.
 
The next nivolumab administration should be performed at the scheduled time.
 
If required, skipping a nivolumab administration may be considered after consultation with
the sponsor.
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 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).
 Performing electrocardiograms (ECGs).
 If JNJ-3989 is administered at the patient’s home, it will need to be done by a nurse (who
received study-specific training).


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 Any data related to AEs, concomitant medication, vital signs, and ECGs will be reviewed and
assessed by the investigator.
 In addition, participants may have tele-health visits conducted by qualified site personnel via
phone or video conversation as per local regulation. Assessments may include review of AEs
(including ISRs), concomitant medications, and study intervention accountability. 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 AE/serious adverse event (SAE) reporting requirements apply.
 Ultrasound (and Fibroscan where applicable) should be done as close as possible to the time
points specified in the Schedule of Activities. However, if this is not possible due to
COVID-19-related restrictions, the imaging test should be performed as soon as possible.
Informed Consent:
 Consenting and re-consenting of participants (including also remote consenting by phone or
video consultation) will be performed as applicable for the measures taken 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 activities remotely (in accordance with site and local requirements).
Additional on-site monitoring visits may be needed in the future to catch up on source data
verification.
Site Audits:
 During the COVID-19 pandemic and at the impacted sites, study site Good Clinical Practice
(GCP) audits with direct impact/engagement from the investigator and study site personnel
would not be conducted in order to comply with national, local, and/or organizational social
distancing restrictions. Additional quality assurance activities such as remote audits or focused
review of study-related documents may take place with limited impact/engagement if possible.


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10.10. Appendix 10: Protocol Amendment History
Amendment 2 (28 March 2023)
Overall Rationale for the Amendment: The main reason for the protocol amendment is that due to
difficult recruitment a strategic decision was taken to not extend further enrollment beyond the planned
enrollment period and continue the study with a reduced sample size. There is no change in the benefit/risk
for the participants.
Section number
and Name
Description of Change 
Brief Rationale
1.1. Synopsis
1.2. Schema
4.1. Overall Design
9.2. Sample Size
Determination
Reduction of sample size. 
Due to difficult recruitment.
1.1. Synopsis
9.5. Interim Analysis
Reduction of number of planned interim
analyses.
The remaining optional interim
analyses at Week 24 and FU
Week 12, in addition to the final
analysis (at FU Week 48),
provide sufficient information to
assess safety and evaluate the
time course of different safety
and efficacy markers during
study conduct.
1.3.1. Schedule of Activities
–Screening Phase and
Study Intervention Phase
1.3.2. Schedule of Activities
–Follow-up Phase
8.7. Exploratory Host
Biomarkers
Removed the sentence: ‘For participants’
convenience, the coagulation test may be
collected at the visit preceding the scheduled
FNA biopsy.’
Correction.
1.3.2. Schedule of Activities
–Follow-up Phase
8. STUDY
ASSESSMENTS AND
PROCEDURES
Reduction of samples collection and analyses
during the follow-up period. Therefore, the
total blood volume was updated accordingly.
Protocol simplification without
impacting participant’s safety
and maintaining scientific value.
1.1. Synopsis
6.1. Study Intervention(s)
Administered
6.8. Treatment of Overdose
Added flexibility for nivolumab dosing and
updated the overdose definition.
To consider the necessary
rounding and standard practice
for the preparation and
intravenous administration of
drugs dosed by weight.
2.3.2.1. Known Risks 
Added: ‘Treatment with anti-PD-1
medications is associated with a risk of HBV
reactivation in CHB patients. This risk is
reduced with concurrent NA treatment or
continuation of ongoing NA treatment.’
Clarification. 
2.3.3. Benefit-Risk 
Assessment for Study 
Participation  
Added: ‘Participants will be regularly 
monitored for HBV reactivation and virologic
breakthroughs throughout the study.’
Clarification.
5.2. Exclusion Criteria 
Exclusion criteria M09 and M10 were further 
clarified.
Clarification.
7.1.1. Discontinuation of 
JNJ-3989 
Added: ‘based on creatinine (calculated by the 
CKD-EPI formula)’.
Clarification.
8.2.1. Physical 
Examinations
Added thyroid check to physical examination. 
Clarification.


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Section number 
and Name
Description of Change 
Brief Rationale
8.3. Adverse Events, 
Serious Adverse Events, 
and Other Safety Reporting
Added coding conventions for the AEs 
reported by investigators.
Clarification.
8.3.6.3.1. Hematologic 
Abnormalities 
Added hematological abnormalities for 
nivolumab when used in the oncology setting.
Clarification.
10.8. Appendix 8: DAIDS 
Table with Modifications 
(DAIDS [Modified]) 
Updated the CTCAE Severity Grading for 
irAEs table by adding severity grading for
myocarditis.
For investigator convenience.
11. REFERENCES  
Update of IB version. 
Update of IB version
INVESTIGATOR 
AGREEMENT  
Update of Sponsor’s Responsible Medical 
Officer. 
Update of Sponsor’s
Responsible Medical Officer.
Throughout the protocol 
Minor grammatical, formatting, or spelling 
changes were made.
Minor errors were noted.
Amendment 1(30 June 2022)
Overall Rationale for the Amendment: The rationale of this amendment is to allow inclusion of
participants with low titers of autoantibodies, to remove certain procedures, to implement changes regarding
immune-related gastro-intestinal adverse event management based on Health Authority feedback and
clarifications of sampling collection.
Section number 
and Name
Description of Change 
Brief Rationale
1.1. Synopsis
1.3.1. Schedule of Activities
–Screening Phase and
Study Intervention Phase
4.1. Overall Design
5. STUDY POPULATION
Text added to indicate the screening duration extension to
6 weeks (42 days)
To take into account
the turnaround time
for certain screening
tests
1.3.1. Schedule of Activities
–Screening Phase and
Study Intervention Phase
1.3.2. Schedule of Activities
–Follow-up Phase
5.2. Exclusion Criteria
10.2. Appendix 2: Clinical
Laboratory Tests
Text was added to provide a full list of autoantibodies to
be tested and their respective exclusionary cut-off
To allow inclusion
of participants with
low titers of
autoantibodies.
Autoantibodies may
be found in
otherwise healthy
participants
1.1. Synopsis
1.3.1. Schedule of Activities
–Screening Phase and
Study Intervention Phase
1.3.2. Schedule of Activities
–Follow-up Phase
3. OBJECTIVES AND
ENDPOINTS
8.5. Pharmacodynamics
Functional receptor occupancy (RO) assay was removed
Time points for RO assay for Arm 1 and Arm 2,
previously provided in Table 14 (removed), were added to
the Schedule of Activities
Comparative
functional RO data
is not available for
nivolumab
For clarification
1.3.1. Schedule of Activities
–Screening Phase and
Study Intervention Phase
8.4.1. Evaluations
Text was added to clarify blood sampling for sparse PK  
For clarification


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Section number 
and Name
Description of Change 
Brief Rationale
1.3.2. Schedule of Activities 
–Follow-up Phase 
Text was added in the footnote of Schedule of Activities to 
clarify that participants who discontinued study
prematurely will have an early withdrawal visit
For clarification
1.3.1. Schedule of Activities 
–Screening Phase and 
Study Intervention Phase 
1.3.2. Schedule of Activities 
–Follow-up Phase 
8.7. Exploratory Host 
Biomarkers
Removal of the platelet aggregation test 
Platelet aggregation
test is not part of the
recommended pre
fine needle
aspiration (FNA)
work-up
5.2. Exclusion Criteria 
Text was added to exclude participants with absolute 
neutrophil count <1,500/mm3 (<1,000/mm3 for 
participants of African ancestry)
Nivolumab may
induce neutropenia
7.2.1. Withdrawal From the 
Use of Research Samples 
Text was added to align with guidance regarding 
management of optional research samples 
To not destroy
samples already
collected in case of
participant
withdrawal if the
participant agrees to
have his/her samples
further stored and
analyzed
8. STUDY 
ASSESSMENTS AND 
PROCEDURES  
Text was added to reflect adjustment of total blood, 
peripheral blood mononuclear cell (PBMC) and 
pharmacogenomic sample volumes 
Blood volumes were
adjusted to reflect
total volumes
collected during the
study
8.3.6.1. Intervention- 
emergent ALT/AST 
Elevations Including 
Immune-related Hepatic 
AEs 
Table 5 
Text was updated to clarify mandatory histologic 
assessment in case of potential immune-related hepatic AE 
The histologic
assessment as a
prerequisite to
initiate
corticosteroids and
stop nivolumab was
made not mandatory
to avoid delay in
potential irAE
management
8.3.6.2.1. Gastrointestinal 
Adverse Events 
Text was added to specify medical assessment for 
treatment-emergent colitis ≥Grade 2 
To align with
American society of
clinical oncology
(ASCO) guidelines
for the management
of immune-related
Adverse Events in
patients treated with
Immune Checkpoint
Inhibitor therapy
1.1. Synopsis 
9.5. Interim Analysis 
Text was added to indicate an additional interim analysis 
when all randomized participants have completed 
Week 24 or discontinued earlier 
Optimization of the
interim analysis
schedule
10.2. Appendix 2: Clinical 
Laboratory Tests
Table updated to add C-reactive protein (CRP) 
For clarification
10.9. Appendix 9: Study 
Conduct During a Natural 
Disaster 
Text was revised to clarify nucleos(t)ide analog (NA) 
background treatment and remove reference to 
direct-to-patients process. 
Clarification of NA
background
treatment


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Section number 
and Name
Description of Change 
Brief Rationale
7.1.2. Discontinuation of 
Nivolumab 
Text was added to include discontinuation of nivolumab 
by the investigator for safety reasons
For completeness
10.1. Appendix 1: 
Abbreviations and
Definitions
Abbreviation and definition list updated 
For completeness
Throughout the protocol 
Minor grammatical, spelling changes or formatting 
changes were made 
Minor errors were
noted


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11. 
REFERENCES
Clinical Protocol Amendment 2: 73763989HPB2001 (REEF-1). Janssen Research & Development (January 2020).
Clinical Protocol Amendment 2: 73763989PAHPB2002 (REEF-2). Intervention-specific Appendix 2 to Master
Protocol PLATFORMPAHPB2001. Janssen Research & Development (January 2020).
Clinical Protocol Amendment 2: 73763989PAHPB2006 (PENGUIN). Intervention-specific Appendix 4 to Master
Protocol PLATFORMPAHPB2001. Janssen Research & Development (May 2021).
Brahmer JR, Drake CG, Wollner I, et al. Phase I study of single-agent anti-programmed death-1 (MDX-1106) in
refractory solid tumors: safety, clinical activity, pharmacodynamics, and immunologic correlates. J Clin Oncol
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Cattley RC and Cullen JM. Chapter 45: Liver and Gall Bladder. Haschek and Rousseaux’s. Handbook of
Toxicologic Pathology, Third Ed., 2013.
Ebeling M, Kung E, See A, et al. Genome-based analysis of the nonhuman primate Macaca fascicularis as a model
for drug safety assessment. Genome Res. 2011; 21:1746-1756.
El-Khoueiry AB, Sangro B, Yau T, et al. Nivolumab in patients with advanced hepatocellular carcinoma
(CheckMate 040): an open-label, non- comparative, phase 1/2 dose escalation and expansion trial. Lancet. 2017;
389(10088):2492-2502.
Fang Z, Li J, Yu X, et al. Polarization of monocytic myeloid-derived suppressor cells by hepatitis B surface antigen
is mediated via ERK/IL-6/STAT3 signaling feedback and restrains the activation of T cells in chronic hepatitis B
virus infection. J Immunol. 2015;195(10):4873-4483.
Gane E, Daniel JV, Anna EB, et al. Anti-PD-1 blockade with nivolumab with and without therapeutic vaccination
for virally suppressed chronic hepatitis B: A pilot study. J Hepatol 2019;71:900-907-
Givlaari (givosiran; NDA212194) NDA/BLA Multi-Disciplinary Review and Evaluation, Center for Drug
Evaluation and Research. 20 November 2019.
Greaves P. Chapter 2: Integumentary system- skin and subcutaneous tissue (pages 39-42). Histopathology of
preclinical toxicity studies: Interpretation and relevance in drug safety studies, Fourth editioned., 2012.
Henry SP, Johnson M, Zanardi TA, et al. Renal uptake and tolerability of a 2’-O-methoxyethyl modified antisense
oligonucleotide (ISIS 113715) in monkey. Toxicology. 2012;301(1-3):13-20.
Holsapple MP, Pitot HC, Cohen SM, et al. Mode of action in relevance of rodent liver tumors to human cancer risk.
Toxicol Sci, 2006; 89(1):51-56.
Investigator’s Brochure: JNJ-73763989 (IB JNJ-3989) Edition 6 Janssen Research & Development (8 April 2022).
Janas MM, Harbison CE, Perry VK, et al. The nonclinical safety profile of GalNac-conjugated RNAi therapeutics in
subacute studies. Toxicol Pathol. 2018a;46(7):735-745.
Janas MM, Schlegel MK, Harbison CE, et al. Selection of GalNAc-conjugated siRNAs with limited off-target-
driven rat hepatotoxicity. Nat Commun, 2018b;9(1):723.
Lautenschlager I, Höckerstedt K, Häyry P. Fine-needle aspiration biopsy in the monitoring of liver allografts.
Transpl Int. 1991;4(1):54-61.
Li H, Zhai N, Wang Z, et al. Regulatory NK cells mediated between immunosuppressive monocytes and
dysfunctional T cells in chronic HBV infection. Gut. 2018;67(11):2035-2044.
Memorandum to Advisory Committee Members and Guests from Entecavir Review Team. Briefing document for
NDA 21-797, entecavir 0.5 and 1 mg tablets and NDA 21-798, entecavir oral solution 0.05 mg/mL,
10 February 2005.
Memorandum to the file for BLA 125554 OPDIVO (nivolumab). Approvability of Pharmacology and Toxicology.
Bristol-Myers Squibb Company; 04 December 2014.
Nivolumab Summary of Product Characteristics (NSPC). Uxbridge, United Kingdom: Bristol-Myers Squibb Pharma
EEIG. https://www.ema.europa.eu/en/documents/product-information/nivolumab-bms-epar-product-
information_en.pdf. Accessed 23 March 2023.


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Status: Approved, Date: 30 June 2023
Nivolumab US Package Insert (NUSPI). Princeton, NJ: Bristol-Myers Squibb Company.
https://packageinserts.bms.com/pi/pi_opdivo.pdf. Accessed 23 March 2023.
Setten RL, Rossi JJ and Han S-P. The current state and future directions of RNAi-based therapeutics. Nat Rev Drug
Discov. 2019;18(6):421-446.
Shah NJ, Al-Shbool G, BlackburnM, et al. Safety and efficacy of immune checkpoint inhibitors (ICIs) in cancer
patients with HIV, hepatitis B, or hepatitis C viral infection. J Immunother Cancer. 2019;7(1):353.
Tang TJ, Janssen HLA, Kusters JG, et al. The intrahepatic immune response during chronic hepatitis B infection can
be monitored by the fine-needle aspiration biopsy technique. FEMS Immunol Med Microbiol. 2003;39(1):69-72.
Topalian SL, Hodi FS, Brahmer JR, et al. Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. N
Engl J Med 2012;366(26):2443-2454.
Wang S, Chen Z, Hu C, et al. Hepatitis B virus surface antigen selectively inhibits TLR2 ligand-induced IL-12
production in monocytes/macrophages by interfering with JNK activation. J Immunol. 2013;190(10):5142-5151.
Wooddell CI, Yuen M-F, Chan HKL, et al. RNAi-Based Treatment of Chronically Infected Patients and
Chimpanzees Implicates Integrated Hepatitis B Virus DNA as a Source of HBsAg. Sci. Transl. Med. 2017; 9(409).
Yang S, Zeng W, Zhang J, et al. Restoration of a functional antiviral immune response to chronic HBV infection by
reducing viral antigen load: if not sufficient, is it necessary? Emerg Microbes Infect. 2021;10(1):1545-1554.
Yuen M-F, Gane JE, Kim DJ, et al. Antiviral Activity, Safety, and Pharmacokinetics of Capsid Assembly Modulator
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INVESTIGATOR AGREEMENT
I have read this protocol and agree that in conjunction with the accompanying Master Protocol, it contains
all necessary details for carrying out this study. I will conduct the study as outlined herein and will complete
the study within the time designated.
I will provide copies of the protocol and all pertinent information to all individuals responsible to me who
assist in the conduct of this study. I will discuss this material with them to ensure that they are fully informed
regarding the study intervention, the conduct of the study, and the obligations of confidentiality.
Coordinating Investigator (where required):
Name (typed or printed):
Institution and Address:
Signature: 
Date:
(Day Month Year)
Principal (Site) Investigator:
Name (typed or printed):
Institution and Address:
Telephone Number:
Signature: 
Date:
(Day Month Year)
Sponsor's Responsible Medical Officer:
Name (typed or printed): 
Institution: 
Janssen Research & Development
Signature: electronic signature appended at the end of the protocol 
Date:
(Day Month Year)
Note: If the address or telephone number of the investigator changes during the study, written notification will be
provided by the investigator to the sponsor, and a protocol amendment will not be required.
PPD


Signature
User 
Date 
Reason
30-Jun-2023
16:06:26
(GMT)
Document Approval
PPD

SAP_001.pdf: 
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
1
Status: Approved, Date: 10 June 2024
Janssen Research & Development
Statistical Analysis Plan
Intervention-specific Appendix 7 to Clinical Protocol PLATFORMHPB2001
A Phase 2 Open-label Trial to Evaluate Safety, Efficacy, Tolerability, and 
Pharmacodynamics of a Combination of JNJ-73763989, Nucleos(t)ide Analogs, and a PD-1 
Inhibitor in Chronic Hepatitis B Patients.
OCTOPUS-1 Study
Protocol 73763989PAHPB2008; Phase 2
JNJ-73763989  
Status:
Approved
Date:
10 June 2024
Prepared by:
Janssen Research & Development, a division of Janssen Pharmaceutica NV  
Document No.: EDMS- RIM-669752, 2.0
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.
NCT05275023


JNJ-73763989
Statistical Analysis Plan 73763989PAHPB2008
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2
Status: Approved, Date: 10 June 2024
TABLE OF CONTENTS
TABLE OF CONTENTS ............................................................................................................................... 2
1.
INTRODUCTION.................................................................................................................................. 9
1.1.
Objectives and Endpoints ................................................................................................................ 9
1.2.
Study Design.................................................................................................................................. 11
2.
STATISTICAL HYPOTHESES.......................................................................................................... 13
3.
SAMPLE SIZE DETERMINATION.................................................................................................... 13
4.
POPULATIONS (ANALYSIS SETS) FOR ANALYSIS..................................................................... 13
5.
STATISTICAL ANALYSES............................................................................................................... 15
5.1.
General Considerations ................................................................................................................. 15
5.1.1.
Analysis Phase ........................................................................................................................... 15
5.1.2.
Relative Day by Study Phase ..................................................................................................... 16
5.1.2.1.
Study Intervention Relative Day .............................................................................................. 16
5.1.2.2.
Nivolumab Relative Day .......................................................................................................... 16
5.1.2.3.
Follow Up Relative Day ........................................................................................................... 16
5.1.3.
Visit Windows ............................................................................................................................. 16
5.1.4.
Baseline ...................................................................................................................................... 18
5.1.5.
Analysis Specifications ............................................................................................................... 18
5.1.6.
Additional Reference Timepoints................................................................................................ 18
5.1.6.1.
Nivo RT.................................................................................................................................... 18
5.1.6.2.
W24 RT.................................................................................................................................... 18
5.1.6.3.
FUW4 RT................................................................................................................................. 18
5.1.7.
Level of Significance................................................................................................................... 19
5.1.8.
Missing and Partial Dates Imputation Rules............................................................................... 19
5.1.8.1.
Adverse Event Onset Date and Resolution Date .................................................................... 19
5.1.8.2.
HBV Diagnosis and Infection Dates ........................................................................................ 20
5.1.8.3.
Concomitant Medication Dates................................................................................................ 20
5.1.8.4.
Dates of Alcohol Consumptions .............................................................................................. 21
5.1.9.
Data Handling Rules................................................................................................................... 21
5.2.
Participant Dispositions.................................................................................................................. 22
5.3.
Primary Efficacy Endpoint.............................................................................................................. 23
5.3.1.
Definition..................................................................................................................................... 23
5.3.2.
Main Estimand for the Primary Endpoint.................................................................................... 23
5.3.2.1.
Main Estimator......................................................................................................................... 24
5.3.2.1.1.
Analysis Methods ................................................................................................................. 24
5.3.2.1.1.1.
Comparison vs Fixed External Control ............................................................................. 24
5.3.2.1.1.2.
Comparison Amongst Regimens ...................................................................................... 24
5.3.2.1.2.
Data Included ....................................................................................................................... 24
5.3.2.1.3.
Assumptions......................................................................................................................... 24
5.3.2.1.4.
Missing Data Handling Rule................................................................................................. 24
5.3.2.2.
Sensitivity Estimators of the Main Estimand ........................................................................... 25
5.3.2.2.1.
Sensitivity Estimator 1 of the Main Estimand (Homogeneity Assumption) .......................... 25
5.3.2.2.1.1.
Assumptions...................................................................................................................... 25
5.3.2.2.1.2.
Analysis Methods.............................................................................................................. 25
5.3.2.2.2.
Sensitivity Estimator 2 of the Main Estimand (Observed Case Analysis)............................ 26
5.3.2.2.2.1.
Assumptions...................................................................................................................... 26
5.3.2.2.2.2.
Missing Data Handling Rule.............................................................................................. 26
5.3.2.2.3.
Sensitivity Estimator 3 of the Main Estimand (LOCF).......................................................... 26
5.3.2.2.3.1.
Assumptions...................................................................................................................... 26
5.3.2.2.3.2.
Missing Data Handling Rule.............................................................................................. 26
5.3.3.
Supplementary Estimand for the Primary Endpoint (Per-Protocol Analysis Set)....................... 27


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5.3.3.1.
Main Estimator of the Supplementary Estimand ..................................................................... 27
5.3.3.1.1.
Analysis Methods ................................................................................................................. 27
5.3.3.1.2.
Data Included ....................................................................................................................... 27
5.3.3.1.3.
Assumptions......................................................................................................................... 28
5.3.3.1.4.
Missing Data Handling Rule................................................................................................. 28
5.3.4.
Hochberg Procedure................................................................................................................... 28
5.4.
Secondary Efficacy Endpoints ....................................................................................................... 28
5.4.1.
Definitions ................................................................................................................................... 29
5.4.1.1.
Binary Endpoints ..................................................................................................................... 29
5.4.1.1.1.
HBsAg Cut-offs..................................................................................................................... 29
5.4.1.1.2.
HBsAg Seroclearance.......................................................................................................... 29
5.4.1.1.3.
HBsAg Seroconversion........................................................................................................ 30
5.4.1.1.4.
HBeAg Cut-offs .................................................................................................................... 30
5.4.1.1.5.
HBV DNA Cut-offs................................................................................................................ 30
5.4.1.1.6.
Suppressed HBV DNA ......................................................................................................... 30
5.4.1.1.7.
ALT Normalization................................................................................................................ 30
5.4.1.1.8.
Virologic Breakthrough......................................................................................................... 31
5.4.1.1.9.
Flares ................................................................................................................................... 31
5.4.1.2.
Continuous Endpoints ............................................................................................................. 31
5.4.1.2.1.
HBsAg, HBeAg, HBV DNA and ALT.................................................................................... 31
5.4.2.
Analysis Methods........................................................................................................................ 32
5.4.2.1.
Binary Endpoints ..................................................................................................................... 32
5.4.2.1.1.
LOCF Imputation Method..................................................................................................... 32
5.4.2.1.2.
HBsAg Seroconversion........................................................................................................ 33
5.4.2.1.3.
Suppressed HBV DNA ......................................................................................................... 33
5.4.2.1.4.
Flares ................................................................................................................................... 33
5.4.2.2.
Continuous Endpoints ............................................................................................................. 34
5.4.2.2.1.
HBsAg, HBeAg, HBV DNA and ALT.................................................................................... 34
5.5.
Exploratory Endpoints.................................................................................................................... 35
5.5.1.
Definitions ................................................................................................................................... 35
5.5.1.1.
Binary Endpoints ..................................................................................................................... 35
5.5.1.1.1.
Sustained HBsAg Response................................................................................................ 35
5.5.1.1.2.
Liver Stiffness Measurement................................................................................................ 35
5.5.1.1.3.
HBV RNA Cut-offs................................................................................................................ 36
5.5.1.1.4.
HBcrAg Cut-offs ................................................................................................................... 36
5.5.1.2.
Continuous Endpoints ............................................................................................................. 36
5.5.1.2.1.
Liver Stiffness Measurement................................................................................................ 36
5.5.1.2.2.
HBV RNA and HBcrAg......................................................................................................... 36
5.5.2.
Analysis Methods........................................................................................................................ 37
5.5.2.1.
Binary Endpoints ..................................................................................................................... 37
5.5.2.2.
Continuous Endpoints ............................................................................................................. 37
5.5.2.2.1.
Liver Stiffness Measurement................................................................................................ 37
5.5.2.2.2.
Anti-HBs Antibodies ............................................................................................................. 37
5.6.
Safety Analyses ............................................................................................................................. 38
5.6.1.
Extent of Exposure ..................................................................................................................... 38
5.6.2.
Adverse Events........................................................................................................................... 39
5.6.3.
Additional Safety Assessments .................................................................................................. 40
5.6.3.1.
Clinical Laboratory Tests......................................................................................................... 40
5.6.3.2.
Renal Safety ............................................................................................................................ 43
5.6.3.2.1.
eGFR Creatinine and eGFR Cystatin C............................................................................... 43
5.6.3.2.2.
Proximal Renal Tubular Function......................................................................................... 44
5.6.3.3.
Vital Signs................................................................................................................................ 45
5.6.3.4.
Electrocardiogram ................................................................................................................... 46
5.6.3.5.
Physical and Ophthalmic Examinations .................................................................................. 48
5.7.
Other Analyses............................................................................................................................... 48
5.7.1.
Pharmacokinetics ....................................................................................................................... 48
5.7.2.
Pharmacokinetic/Pharmacodynamic Relationships ................................................................... 48
5.7.3.
Receptor Occupancy .................................................................................................................. 49


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5.7.4.
Immune Analyses ....................................................................................................................... 49
5.7.5.
Viral Genome Sequence Analysis .............................................................................................. 49
5.8.
Data Review Committee and Interim Analyses ............................................................................. 50
5.8.1.
Data Review Committee............................................................................................................. 50
5.8.2.
Independent Flare Expert Panel................................................................................................. 50
5.8.3.
Data Reviews and Interim Analyses........................................................................................... 50
5.8.3.1.
Data Reviews........................................................................................................................... 50
5.8.3.2.
Interim Analyses ...................................................................................................................... 51
5.8.3.3.
Overview of Data Reviews, Interim, Primary and Final Analyses ........................................... 51
6.
SUPPORTING DOCUMENTATION .................................................................................................. 53
6.1.
Appendix 1 List of Abbreviations.................................................................................................... 53
6.2.
Appendix 2 Changes to Protocol-Planned Analyses ..................................................................... 55
6.3.
Appendix 3 Demographics and Baseline Characteristics.............................................................. 56
6.3.1.
Demographics............................................................................................................................. 56
6.3.2.
Baseline Characteristics ............................................................................................................. 56
6.4.
Appendix 4 Protocol Deviations ..................................................................................................... 58
6.5.
Appendix 5 Prior and Concomitant Medications............................................................................ 71
6.6.
Appendix 6 Medical History ........................................................................................................... 72
6.7.
Appendix 7 Intervention Compliance ............................................................................................. 73
6.8.
Appendix 8 Adverse Events of Special Interest............................................................................. 74
6.9.
Appendix 9 Medications of Special Interest................................................................................... 81
6.10.
Appendix 10 Laboratory Toxicity Grading...................................................................................... 83
7.
REFERENCES................................................................................................................................... 84


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VERSION HISTORY
Document History
Document
Date
Original SAP
20 September 2022
Amendment 1
23 August 2023
Amendment 2
10 June 2024
Amendment 2 (10 June 2024)
The main purpose of this SAP amendment is to document changes in the scope of the final 
analyses, based on results of the primary analysis.
Section number and Name
Description 
of Change
Brief Rationale
5.3.6. Comparisons 
Between Arm 1, 2 and 
Model-Based Virtual 
Nivolumab-Free JNJ-
3989+NA Regimen Control
Section 
Removed.
Virtual Control analysis is no longer of interest.
5.4.1.2. Continuous 
Endpoints
Section 
Updated.
Change from baseline value to the nadir is of 
interest only in HBsAg.
5.4.2.1.1. HBsAg Cut-offs 
and 5.4.2.1.4. HBeAg Cut-
offs
Section 
Removed.
Cross-Tabulation for Quantitative Result vs. 
Qualitative Result Over Time for HBsAg and 
HBeAg removed as according to the protocol, 
qualitative HBsAg and HBeAg are only 
collected at screening and baseline.
5.4.2.2.1. HBsAg, HBeAg, 
HBV DNA and ALT
Section 
Updated.

Waterfall plots of changes from 
Reference Timepoints in HBsAg 
removed

Descriptive statistics of changes from 
RTs in ALT removed

Changes from baseline analyses are 
removed for HBV DNA

Changes from baseline outputs are only 
displayed in the log 10 scale for all viral 
parameters

Change from Nivolumab RT and 
Follow-up Week 4 RT are of interest 
only for HBsAg


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Section number and Name
Description 
of Change
Brief Rationale
5.5.1.3. and 5.5.2.3. 
Endpoints for Correlation
Section 
Removed.
Endpoints for Correlation is no longer of 
interest.
5.5.2.2.2. HBV RNA and 
HBcrAg
Section 
Removed.
Change from baseline value to the nadir is of 
interest only in HBsAg.
5.3.5. Subgroup Analyses of 
Primary Efficacy Endpoint  
and 5.7.6. Definition of 
Subgroups
Section 
Removed.
Subgroup Analysis is removed due to low 
number of observed events of interest.
Amendment 1 
Overall rationale of this SAP Amendment: The main reason for this SAP amendment was to 
align with the protocol amendment 2 that was performed due to difficult recruitment. Therefore,
a strategic decision was taken to not extend further enrollment beyond the planned enrollment 
period and continue the study with a reduced sample size. In the meantime, there has been a new 
amendment (amendment 3 – 30 June 2023) of the protocol filed. The main reason for the
protocol amendment 3 was the discontinuation of PD-1 inhibitor (nivolumab) as study 
intervention as of 20 June 2023 as an urgent safety measure (USM). Based on the observation of 
two cases of potential hyperthyroidism, the sponsor decided on 20 June 2023, to halt further 
nivolumab dosing effective immediately. Treatment with JNJ-3989 and/or nucleos(t)ide analog 
was continued as planned. The impact of this amendment 3 has been discussed and it has been 
agreed that this does not affect the Statistical Analysis Plan. 
Section number and Name
Description of Change
Brief Rationale
1.2. Study Design
3. Sample Size 
Determination
Reduction of
sample size.
Due to difficult
recruitment.
5.1.9. Data Handling Rules
Revised ULOQ and Imputed Values 
data cutpoints for HBsAg, HBeAg 
and HBcrAg.
Updated guidelines for the 
imputation of HBV DNA.
Improved for clarity 
and precision.
5.5.1.1.5. Anti-HBe 
Antibodies
5.5.1.2.3. Anti-HBs 
Antibodies
Analysis removed.
Qualitative anti-HBs 
results are not 
collected.


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Section number and Name
Description of Change
Brief Rationale
5.8.3.1. Data Reviews
Change in frequency and timing of 
Data Reviews.
Change in the scope of 
the study.
5.8.3.2. Interim Analysis
Reduction of number of planned
interim analyses. They may be done 
instead of will be done.
Change in the scope of
the study.
5.5.1.3.1. Association 
between Baseline 
Characteristics/ Viral Blood 
Markers and Selected 
Efficacy Variables
Analysis of Correlations between 
baseline characteristics and HBV 
blood markers may be done instead 
of will be done and at a later time 
point in a post hoc nature.
Clarification.
5.4.1.1.1. HBsAg Cut-offs
Number of categories reduced
Clarification.
5.4.2. Analysis Methods
Analysis of Secondary Endpoints 
may be done instead of will be done.
Clarification.
5.7.3. Receptor Occupancy
Section Added.
Added for 
completeness.
5.4.1.3. Time to Event 
Endpoints
5.4.2.3. Time to Event 
Endpoints
5.5.1.3. Time to Event 
Endpoints
5.5.2.3. Time to Event 
Endpoints
Time to event endpoints have been 
removed.
Time to event 
endpoints are no longer
of interest.
5.7.4. Immune Analysis
Immune Analysis may be done 
instead of will be done.
Clarification.
5.7.4. Viral Genome 
Sequence Analysis 
Removed subsections. This analysis 
may be done instead of will be done.
Subsections were 
removed to simplify the 
analysis.
Health Economics
Section Removed.
Clarification.
HBV genotype
Section Removed.
Clarification.
Throughout the SAP
Minor grammatical, formatting, or 
spelling changes were made.
Typographical 
corrections or improved 
language for clarity and 
precision.
5.7.6. Definition of 
Subgroups
Removed some subgroups.
Considering the small 
sample size, it was 


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Section number and Name
Description of Change
Brief Rationale
decided to remove 
some subgroups.
6.4. Appendix 4 Protocol 
Deviations
List was updated to incorporate the 
updated list as per protocol 
amendment #3.
For completeness


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1.
INTRODUCTION
The statistical analysis plan (SAP) for the 73763989PAHPB2008 phase 2 trial describes the 
statistical analyses,
and definitions to assess the efficacy, safety, tolerability, and 
pharmacodynamics of the combination of JNJ-73763989 (JNJ-3989), nucleos(t)ide analogs (NAs), 
and nivolumab in virologically suppressed, HBeAg-negative, chronic HBV-infected (CHB), adult 
participants < 56 years of age. 
This study is part of the platform trial PLATFORMPAHPB2001 in participants with CHB. The 
protocol for 73763989PAHPB2008 constitutes the Intervention Specific Appendix 7 that describes 
all the specific and/or additional features of this study complementing the common design 
elements of the platform trial described in the Master Protocol.
This SAP is to be interpreted in conjunction with the clinical trial protocol amendment 1 finalized 
on 30 June 2022, and with the Master Protocol Amendment-3 for PLATFORMPAHPB2001 
finalized on 21 January 2021.
Details on pharmacokinetic (PK) and pharmacokinetic/pharmacodynamic (PK/PD) analyses will 
be described in a separate analysis and modelling plan.  
1.1.
Objectives and Endpoints 
Objectives
Endpoints
Primary

To evaluate efficacy of the study intervention, 
based on HBsAg levels at FU Week 24.

Proportion of participants who achieve 
HBsAg seroclearance at FU Week 24.
Secondary

To characterize the safety and tolerability of 
the study intervention.

Proportion of participants who experienced 
AEs of interest.

Safety profile of JNJ-3989 with nivolumab 
throughout the study (safety parameters 
include but are not limited to the frequency 
and severity of AEs and immune-related AEs, 
vital 
signs 
measurements, 
physical 
examinations, clinical laboratory values, and 
12-lead electrocardiograms [ECGs]).

To evaluate efficacy in terms of changes in 
HBsAg levels from baseline over time during 
the study intervention and follow-up periods. 

Change from baseline in HBsAg levels during 
the study intervention and follow-up periods.

Proportion of participants with HBsAg levels 
below/above different cut-offs over time.

To evaluate efficacy in terms of HBsAg 
seroclearance/seroconversion 
during 
the 
study intervention and follow-up periods.

Proportion of participants with HBsAg 
seroclearance/seroconversion 
during 
the 
study intervention and follow-up periods.

Time to achieve HBsAg seroclearance/ 
seroconversion.


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Objectives
Endpoints

To evaluate the efficacy as measured by blood 
markers (such as HBV DNA and HBeAg) 
during the study intervention and follow-up 
period.

Change from baseline in HBV DNA levels 
during the study intervention and follow-up 
periods.

Proportion of participants with HBV DNA 
and HBeAg levels below/above different cut-
offs over time.

To evaluate the frequency of virologic 
breakthrough throughout the study.

Proportion of participants with virological 
breakthrough throughout the study.

To evaluate the pharmacokinetics (PK) of 
JNJ-3989 (JNJ-3924 and JNJ-3976), and 
optionally of NA and/or nivolumab.

PK parameters of JNJ-3989 (JNJ-3924 and 
JNJ‑3976).

Optionally, PK parameters of NA and/or 
nivolumab.
Exploratory

To characterize the pharmacodynamics (PD) 
of JNJ-3989 with nivolumab including 
quantification of Receptor Occupancy (RO)
on peripheral T-cells.

Relationship of various PK parameters with 
selected efficacy and safety endpoints.

Quantification of nivolumab RO on peripheral 
CD3+ T-cells by flow cytometry on whole 
blood.

To explore changes in the severity of liver 
disease.

Changes in fibrosis (according to Fibroscan 
liver stiffness measurements) at end of study 
intervention (EOSI) and the end of the follow-
up period versus baseline.

To explore HBV-specific T-cell responses 
throughout the study.

Changes from baseline in HBV-specific 
peripheral blood T-cell responses over time.

To explore efficacy of the study intervention 
in terms of changes in HBV RNA and 
hepatitis B core-related antigen (HBcrAg) 
levels throughout the study.

Changes from baseline in HBV RNA and 
HBcrAg levels over time.

To explore the HBV genome sequence 
throughout the study.

Assessment 
of 
intervention-associated 
mutations over time.

To explore medical resource utilization to 
manage participants throughout the study.

Number and duration of medical care 
encounters, including surgeries, and other 
selected procedures (inpatient and outpatient).

Duration of hospitalization (total days length 
of stay, including duration by wards, e.g. 
intensive care unit).

Number and character of diagnostic and 
therapeutic tests and procedures.

Outpatient medical encounters and treatments 
(including physician or emergency room 
visits, tests and procedures, and medications).
a
Peripheral blood mononuclear cell (PBMC) samples for immune analyses will be collected at selected sites only.


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1.2.
Study Design
This is a Phase 2, open-label, 2-arm, multicenter study to assess efficacy, safety, tolerability, PK 
and PD of a combination of JNJ-3989, nivolumab, and NAs in virologically suppressed, HBeAg-
negative, chronic HBV-infected, adult participants.
Initially a target of approximately 44 virologically suppressed, HBeAg-negative chronic HBV-
infected adult participants ≥18 (or the legal age of consent in the jurisdiction in which the study is 
taking place) to <56 years of age were planned to be enrolled in this study. 
Due to the decision to not extend further enrollment beyond the planned enrollment period and
proceed with a reduced sample size, the final sample size is 37 (18 in Arm 1 and 19 in Arm 2).
This open-label study will be conducted in 3 periods:

Screening Period (6 weeks [if necessary, e.g. for operational reasons, can be extended to a 
maximum of 8 weeks decided on a case-by-case basis and in agreement with the Sponsor]).

Study intervention (24 weeks): 

Arm 1: JNJ-3989 Q1W for the first 4 weeks and then Q4W until Week 24 + nivolumab 
at Week 16 + NA QD

Arm 2: JNJ-3989 Q1W for the first 4 weeks and then Q4W until Week 24 + nivolumab 
Q4W at Weeks 16, 20, 24 + NA QD

Follow-up (FU) Period (48 weeks), during which NA treatment will be continued.
The total duration of individual participation will be up to 72 weeks (screening not included). 
Participants will be considered to have completed the study if they have completed all the 
assessments of the end of study (EOS) visit (ie, FU Week 48).


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A schematic overview of the trial is presented in Figure 1.
Figure 1: 
Schematic Overview of the Study
FU: follow-up; JNJ-3989: JNJ-73763989; n: number of participants; NA: nucleos(t)ide analog; Q1W: once weekly;
Q4W: every 4 weeks; QD: once daily.
Note: In red: number of participants per arm according to the initial design. In blue: the actual sample size.
At baseline, participants who meet the eligibility criteria will be randomized in a 1:1 ratio to Arm 1 
or Arm 2. Randomization will be stratified by absolute HBsAg level (<100 IU/mL, 100 to 
<1,000 IU/mL, and ≥1,000 IU/mL) at screening, as assessed by quantitative HBsAg assay.
If a participant prematurely discontinues treatment with JNJ-3989 before Week 24, the participant 
will also discontinue further treatment with nivolumab and will have an early withdrawal (WD) 
visit. Follow-up assessments should be obtained as per the Schedule of Activities (see Clinical 
Protocol Section 1.3) until 48 weeks after the end of JNJ-3989 treatment, unless the participant 
withdraws consent. The NA treatment will be continued until the end of the study.
If a participant prematurely discontinues nivolumab, treatment with JNJ-3989 and NA should be 
continued as planned, unless a treatment discontinuation rule for JNJ-3989 is also met. In that case, 
JNJ-3989 will also be discontinued but NA treatment should be continued as planned.
If a participant withdraws prematurely from the study, the reason for withdrawal (if known) should 
be documented. Participants who withdraw consent will be offered an optional safety follow-up 
visit to occur on the day of consent withdrawal.


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An internal Data Review Committee (DRC) will be commissioned for monitoring safety of 
participants enrolled in this study. In addition, an Independent Flare Expert Panel (IFLEP) will be 
appointed. 
2.
STATISTICAL HYPOTHESES
The primary hypothesis of this study is that at least one of the combination regimens of 
JNJ-3989+nivolumab+NA is more efficacious than JNJ-3989+NA treatment, as measured by the 
primary efficacy endpoint (ie, the proportion of participants with HBsAg seroclearance at FU 
Week 24). Because the study does not include a regimen arm without nivolumab, the hypothesis 
is formulated assuming a fixed response rate for JNJ-3989+NA of 1% based on previous study 
73763989HPB2001 (REEF-1).
3.
SAMPLE SIZE DETERMINATION
According to the initial protocol, a sample size of 20 participants per intervention arm which
yielded ≥85% statistical power to detect a ≥15% and ≥20% difference for the proportions of 
participants with HBsAg seroclearance at FU Week 24 in the 2 intervention arms, respectively, vs 
a fixed proportion of 1%. Statistical power to test the primary hypothesis was assessed for each of 
the intervention arms, using an exact test for a single proportion with a one-sided Type 1 error rate 
of 0.05 and applying the Hochberg procedure for multiple comparisons adjustment. The fixed rate 
assumed for the external active control (JNJ-3989 [200 mg]+NA treatment) is based on the data 
of study 73763989HPB2001 (REEF-1).
The total study sample size was adjusted to 44 participants (22 per arm) with 1:1 randomization 
ratio to each of the intervention arms, to account for an approximate 10% attrition rate.
Due to the decision to not extend further enrollment beyond the planned enrollment period and 
proceed with a reduced sample size, the final sample size is 37 (18 in Arm 1 and 19 in Arm 2). 
Under the same assumptions and methods of the initial protocol, an approximate sample size of 
16 participants per intervention arm (assuming 10% attrition) yields ≥75% statistical power to 
detect the same differences in HBsAg seroclearance at FU Week 24.
4.
POPULATIONS (ANALYSIS SETS) FOR ANALYSIS
Due to a potential impact of Coronavirus Disease (COVID-19) pandemics on the study data 
collection, study intervention adherence and study conduct, the modified Full Analysis Set 
(mFAS) and modified FAS-N (mFAS-N) are defined to target the estimation of effects without the 
pandemic-related influences. 
The primary set for efficacy analyses will be the FAS, and for the safety analyses the safety set. 
The FAS-N and modified FAS/FAS-N analysis sets will be used if there is a relevant difference 
from the FAS (>5% of participants in total). Analysis sets for analysis are described in Table 1


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Table 1: 
Analysis Sets for Analysis
Analysis Sets
Description
Screened
All participants who signed the ICF for the Master 
Protocol and the ICF specific for this ISA.
Enrolled
All participants who were enrolled in this ISA.
Randomized
The randomized analysis set includes all participants 
who were randomized in the study.
Full Analysis Set (FAS)
All participants who were randomly assigned to an 
intervention arm in this ISA and received at least 1 dose 
of study intervention within this ISA. Participants will 
be analyzed according to the study intervention they 
were randomly assigned to.
Modified FAS (mFAS)
All participants who were randomly assigned to an 
intervention arm in this ISA and received at least 1 dose 
of study intervention within this ISA excluding those
participants who, because of COVID-19 or similar 
pandemics related reasons, withdrew prematurely from 
the study prior to FU Week 24, or had no efficacy 
assessment for the primary endpoint. 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.
Full Analysis Set for nivolumab (FAS-N)
All participants who were randomly assigned to an 
intervention arm in this ISA and received at least 1 dose 
of nivolumab within this ISA. Participants will be 
analyzed according to the study intervention they were 
randomly assigned to.
Modified FAS-N (mFAS-N)
All participants who were randomly assigned to an 
intervention arm in this ISA and received at least 1 dose 
of nivolumab within this ISA excluding those 
participants who, because of COVID-19 or similar 
pandemics related reasons, withdrew prematurely from 
the study prior to FU Week 24, or had no efficacy 
assessment for the primary endpoint. 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
All participants who received at least 1 dose of study 
intervention within this ISA. Participants will be 
analyzed according to the study intervention they 
actually received.
Per Protocol Analysis Set (PP)
All participants in the FAS who do not have any of the
selected major protocol deviations that may affect the 
assessment of efficacy in terms of the
primary endpoint at FU Week 24. The selected major 
protocol deviations for efficacy analysis
purposes that will be used to identify the participants 
included in the PP set are described in Section 6.4. 
Pharmacokinetics Analysis Set
All participants who received at least 1 dose of study 
intervention and have at least 1 valid blood sample 
drawn for PK analysis.


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5.
STATISTICAL ANALYSES
5.1.
General Considerations
The SAP will use throughout the document the following definitions:

Study agent refers to: JNJ-3989, and nivolumab

Study intervention arm refers to:

Arm 1: JNJ-3989 + nivolumab (1 infusion) + NA

Arm 2: JNJ-3989 + nivolumab (3 infusions) + NA
5.1.1.
Analysis Phase
The analyses phases are defined in Table 2 below.
Table 2: 
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
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 24 
Visit date:
Min [Date of Week 24 study agent 
intake + 5 daysa, cut-off dateb]
Otherwise:
Max [Early study withdrawal visit 
date, study agent discontinuation 
date] + 5 daysa or cut-off dateb, 
whichever occurs first
Follow-up
Participants 
who 
did 
not 
withdraw 
informed 
consent 
during study intervention phase:
End of study intervention phase + 1 
day
Otherwise: missing
Max [study discontinuation date, 
study completion date] or cut-off 
dateb, whichever occurs first
a 
Addition of 5 days is only applicable for Adverse Events and Concomitant Medications.
b
Cut-off dates will be defined to match the prespecified timepoints for DRC safety monitoring, interim 
analyses, the primary and the final analyses, respectively.


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5.1.2.
Relative Day by Study Phase
An analysis relative day (ADY) will be calculated for all assessments at all visits for each 
participant by study phase.
5.1.2.1.
Study Intervention Relative Day
Study Intervention (SI) start date (SI Day 1) is defined in Table 2. All efficacy and safety 
assessments during the study intervention period will be assigned an analysis day relative to this 
date.
The study day in the study intervention period (SI ADY) is defined as: 
  = 
  −   + 1
for visits on or after study intervention period Day 1, and 
  = 
  −  
for visits before SI Day 1 (Screening phase).
There is no ‘SI Day 0’.
5.1.2.2.
Nivolumab Relative Day
Nivolumab start date (NV Day 1) is defined as the date of the first Nivolumab administration. 
Efficacy and safety assessments during the study intervention (after receiving Nivolumab) and FU 
phase will be assigned a day relative to this date. The study day is defined as:
  = 
  −   + 1
for visits on or after NV Day 1.
5.1.2.3.
Follow Up Relative Day
Follow-up (FU) start date (FU Day 1) is defined in Table 2. Efficacy and safety assessments during 
the FU phase will be assigned a day relative to this date. The FU study day in the FU phase (ADY) 
is defined as:
  = 
  −   + 1
for visits on or after FU Day 1.
5.1.3.
Visit Windows
As participants do not always adhere to the protocol visit schedule, the following rules are applied 
to assign actual visits to analysis visits. 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 day based on Table 3. All assignments will be made in 
chronological order. Once a visit date is assigned to a visit window, it will no longer be used for a 


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later time point except for the end of study intervention period (EOSI) and end of study (EOS) 
visits. If a participant has 2 or more actual visits in 1 visit window, the visit closest to the target 
day will be used as the protocol visit for that visit window. The other additional visit(s) will not be 
used in the summaries or analyses, but they can be used for determination of clinically important 
endpoints. If 2 actual visits are equidistant from the target day within a visit window, the later visit 
is used. 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 and spaghetti plots will include all measurements, also those multiple assessments 
with the same visit window/phase.
End of study intervention (EOSI) and end of study (EOS) time points will be included in all 
analyses over time unless otherwise stated.
Table 3 provides the analysis time points and time intervals for each visit per analysis phase.
Table 3: 
Visit Windows
Analysis phase
Target Day
Analysis time point 
(Week)
Analysis time point 
(label)
Time interval 
(days)
Screening
-∞
-1
Screening
<0
Study 
Intervention
period
1
0
Baseline
Pre-dose: 1
8
1
Week 1
[2, 11]
15
2
Week 2
[12, 18]
22
3
Week 3
[19, 25]
29
4
Week 4
[26, 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]
Last visit in study 
intervention period
25a
EOSIa
Follow-up
29
28
Follow-up Week 4
[1, 43]
57
32
Follow-up Week 8
[44, 71]
85
36
Follow-up Week 12
[72, 99]
113
40
Follow-up Week 16
[100, 127]
141
44
Follow-up Week 20
[128, 155] 
169
48
Follow-up Week 24
[156, 197]
225
56
Follow-up Week 32
[198, 253]
281
64
Follow-up Week 40
[254, 309]
337
72
Follow-up Week 48
[310, +∞]
Last visit in the 
study
999b
EOSb
a
End of study intervention (EOSI) visit will be the last post-baseline visit in study intervention period.
b 
End of study (EOS) visit (last available data during the follow-up visit) will be the last visit in the study.


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5.1.4.
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 agents.
In case the first administration measurement time is missing, the first observed measurement on 
SI Day 1 will be used as the baseline measurement. If no observed measurement on Day 1, the last 
observed measurement before Day 1 will be used as the baseline assessment.
5.1.5.
Analysis Specifications
In general, continuous variables will be summarized using descriptive statistics including the 
number of participants, mean, standard error (SE), standard deviation (SD), two-sided 90% 
confidence interval (CI), median, and range. The 90% CI for continuous endpoints is constructed 
using the t-distribution. Binary or categorical variables will be summarized using the number and 
percentage of participants in each category and 90% CI using Clopper-Pearson exact method for 
the simple sample proportion (Newcombe RG,1998). For time-to-event variables, using the 
Kaplan-Meier approach, a summary table including number of participants included in the 
analysis, number of participants censored, 25th and 75th percentiles, median time-to-event and 90% 
CI will be shown. Graphic displays will also be used to summarize the data.
5.1.6.
Additional Reference Timepoints
Three additional Reference Timepoints (RT) will be used for additional analyses of selected 
efficacy endpoints.
5.1.6.1.
Nivo RT
The Nivo RT is defined as the last observed non-missing measurement before the date and time of 
the first Nivolumab administration. In case the first administration measurement time is missing, 
the first observed measurement on NV Day 1 (Nivolumab relative day 1) will be used as the 
nivolumab reference measurement. If no observed measurement on NV Day 1, the last observed 
measurement before NV Day 1 will be used as the nivolumab reference assessment.
The Nivo RT will be used for additional analyses for selected efficacy endpoints after Week 16 of 
study intervention period and FU phase.
5.1.6.2.
W24 RT
The W24 RT is defined as the last observed non-missing measurement at the time of stopping JNJ-
3989 administration at Week 24. This RT will be used for additional analyses for selected efficacy 
endpoints for FU phase.
5.1.6.3.
FUW4 RT
The Follow up Week 4 RT (FUW4 RT) is defined as the last observed non-missing measurement 
at the FU Week 4 visit (4 weeks after the last JNJ-3989 administration). In case the measurement 
is missing at FU Week 4, the first non-missing measurement after FU Week 4 will be used as FU 
Week 4 reference assessment.


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The FUW4 RT will be used for additional analyses for selected efficacy endpoints during FU 
phase.
5.1.7.
Level of Significance
For the primary efficacy endpoint analysis, the statistical comparison will be conducted using an 
exact binomial test against a fixed external control value of 1% at a one-sided Type 1 error rate of 
0.05 and applying the Hochberg procedure for adjusting for multiple comparisons (see 
Section 5.3.4).
For the comparisons between the intervention arms (Arms 1,2), the Mantel-Haenszel test adjusting 
for the stratification factor will be used in a secondary analysis to compare the primary endpoint 
between the intervention arms at a one-sided alpha level of 0.05.
For all other efficacy analyses, only two-sided 90% CIs will be provided with no adjustment for 
multiplicity, unless otherwise specified.
5.1.8.
Missing and Partial Dates Imputation Rules
For analysis and reporting purposes, missing or partial dates in adverse event (AE onset date; AE 
end date), HBV diagnosis and infection dates, concomitant therapies (start date; end date) will be 
imputed according to the rules in the following subsections. The original, non-imputed, dates will 
be used only in listings.
5.1.8.1.
Adverse Event Onset Date and Resolution Date
Partial AE onset dates will be imputed as follows:

If the AE onset date is missing the day only, it will be set to:

The first day of the month when the AE occurred, if month/year of the AE onset date is 
different than the month/year of the first administration of study agent date.

The day of the first study agent administration, if the month/year of the AE onset date is 
the same as the month/year of the first study agent administration but the month/year of 
the AE resolution date is different.

The earliest between the day of the first study agent administration date and day of AE 
resolution date, if month/year of the AE onset are the same as both the month/year of the 
first study drug administration and the AE resolution date.

If the AE onset date is missing both day and month, it will be set to the earliest of:

January 1 of the year of onset, as long as this date is on or after the first study drug 
administration.

Month and day of the first study agent administration, if this date is in the same year of 
AE onset date.

December 31 if the AE onset date year is prior to the year of the first study drug 
administration. 

The AE resolution date.


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
Completely missing onset dates will not be imputed.
Partial AE resolution dates not marked as ongoing will be imputed as follows:

If the resolution date of an AE is missing the day only, it will be set to the earliest of the last 
day of that month or the day of the date of death, if the participant died in that month.

If the resolution date of an AE is missing both day and month, it will be set to the earliest of 
December 31 of that year or the day and month of the date of death, if the participant died in 
that year.

Completely missing resolution dates will not be imputed.
5.1.8.2.
HBV Diagnosis and Infection Dates
If the reported date is partially missing, the following imputation rules will be applied:

the 15th of the month, if only the day is missing.

the 30th of June, if only the year is available.

No imputation if completely missing.
5.1.8.3.
Concomitant Medication Dates
In case of partially missing concomitant medication start/end dates, the following imputation rules 
will be applied:

the 15th of the month, if only the day is missing.

the 30th of June, if only the year is available.

If the imputed start date is after the concomitant medication end date, further adjustment of 
the imputed start date is required. It will be imputed as the concomitant medication end date.

No imputation if completely missing.
If the medication was taken prior to study start (SI 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 dosing date.
If the medication was taken after study start (SI Day 1) based on eCRF question, and the imputed 
start date is prior to first dosing date, the imputed start date will be further adjusted to be the first 
study agent 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 indicating 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 indicating not ongoing. 


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5.1.8.4.
Dates of Alcohol Consumptions
In case of partially missing start/end dates, the following imputation rules will be applied:

the 15th of the month, if only the day is missing.

the 30th of June, if only the year is available.

If the imputed start date is after the end date, further adjustment of the imputed start date is 
required. It will be imputed as the end date.

If end date is completely missing and marked as Ongoing then impute with randomization 
date. Otherwise, no imputation if completely missing.
5.1.9.
Data Handling Rules
Those measurements collected from screening visit to the end of study will be handled according 
to the following rules summarized in Table 4.
Table 4: 
Data Handling Rules for HBV Virology and Serology Assessments
HBV parameter
LLOQ
ULOQ
Imputed Values
If value< LLOQ
If value> ULOQ
HBsAg
0.05 IU/mL
249,750.00 IU/mL 
with dilution
0.025 IU/mL (a)
274,725.00IU/mL (b) with 
dilution
HBeAg
0.11 IU/mL
7,000.00 IU/mL 
with dilution
0.055 IU/mL (a)
7,700.00 IU/mL(b) with 
dilution
HBcrAg*
3.0 log10 U/mL
9.0 log10 U/mL 
with dilution
2.7 log10 U/mL
9.9 log10 U/mL (b)
with dilution
HBV DNA
20 IU/mL
170,000,000 
IU/mL w/o 
dilution
If target detected: 
15 IU/mL**
If target not 
detected: 5 
IU/mL**
187,000,000(b)(c) IU/mL 
w/o dilution
HBV RNA*
LLOQ = 2.939
log10 cp/mL
(i.e. 869 cp/mL)
LOD = 1.398 
log10 cp/mL 
(i.e. 25 cp/mL)
NAP
If <LOD or target 
not detected then 
1.114 log10 cp/mL 
(13 cp/mL)
NAP
Anti-HBs
5 mIU/mL
10000.0 mIU/mL
2.5 mIU/mL(a)
11000.0 mIU/mL (b)


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Table 4: 
Data Handling Rules for HBV Virology and Serology Assessments
HBV parameter
LLOQ
ULOQ
Imputed Values
If value< LLOQ
If value> ULOQ
* As new assays become available different data handling rules may apply.
** For HBV DNA spaghetti plots showing absolute values, the imputed value will be 15 IU/mL. For all other 
tables, listings and figures, the main analysis will be performed using 15 IU/mL to impute HBV 
DNA<LLOQ 
and the two methods of imputation may be used as exploratory analysis.
Key: NAP=Not applicable
(a) LLOQ/2
(b) ULOQ+(ULOQ/10)
(c) If the original result > ULOQ, then take the re-test value (i.e., diluted result). If the diluted result is not 
available, use the imputed value indicated in this table.
All other viral activity data with values <LLOQ which are not included in the data handling rules 
above will be imputed by the absolute value divided by 2.
5.2.
Participant Dispositions
All the summaries will be done on the FAS analysis set unless specified otherwise.  
Screened participants and reason for screen failures will be summarized overall.
The number of participants in the following disposition categories will be summarized throughout 
the study by intervention group and overall:

Participants randomized

Participants who received any study intervention (JNJ-3989, Nivolumab)

Participants in each study analysis phase

Participants who completed the study

Participants who completed study intervention but dropped off during follow-up

Participants who discontinued any study intervention

Reasons for discontinuation of any study intervention

Participants who terminated study prematurely

Reasons for termination of study
A listing of participants will be provided for the following categories:

Participants who discontinued any study intervention

Participants who terminated study prematurely

Participants who were randomized yet did not receive study intervention.


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5.3.
Primary Efficacy Endpoint
5.3.1.
Definition
The primary endpoint is the proportion of participants who achieved HBsAg seroclearance
(HBsAg<LLOQ) at FU Week 24. 
5.3.2.
Main Estimand for the Primary Endpoint
Study Objective: To evaluate the efficacy in terms of HBsAg seroclearance for the treatment 
regimens of JNJ-3989 + nivolumab at Week 16 + NA (Arm 1), and JNJ-3989 + nivolumab at 
Weeks 16, 20, 24 + NA (Arm 2), as compared to JNJ-3989 + NA.
Scientific Question of Interest: in HBeAg negative virologically suppressed adult population 
with chronic HBV infection
a) Comparison vs fixed external control: what is the benefit of JNJ-3989 + nivolumab (1 or 3 
infusions) + NA compared with a fixed external proportion of 1% for JNJ-3989 + NA,
measured by proportion of participants achieving HBsAg seroclearance at FU Week 24?
b) Comparison amongst regimens: what is the difference between JNJ-3989 + nivolumab 
(1 infusion) + NA and JNJ-3989 + nivolumab (3 infusions) + NA, measured by proportion 
of participants achieving HBsAg seroclearance at FU Week 24?
The attributes for the main estimand for the primary endpoint are:
A) Study Intervention Arms:

Arm 1: JNJ-3989 + nivolumab (1 infusion) + NA

Arm 2: JNJ-3989 + nivolumab (3 infusions) + NA
B) Study Population: HBeAg-negative chronic HBV-infected adult patients who are 
virologically suppressed by being treated with NA.
C) Variable: Individual participant response status defined as whether an individual 
participant achieved HBsAg seroclearance at FU Week 24 (responders) as detailed in 
Section 5.3.1.
D) Intercurrent events:

Treatment discontinuation prior to Week 24: if the participant discontinued treatment 
prior to Week 24 then s/he will be considered non-responder (composite strategy).

Major protocol deviations affecting efficacy: Table 9 identifies the deviations considered 
intercurrent event. Participants with such deviations and who have missing data for the 
endpoint will be considered as non-responders (composite strategy). For all other 
deviations not considered intercurrent events, the data are used regardless of the 
occurrence of major protocol deviations (treatment policy strategy).


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
Deaths prior to FU Week 24 are handled in a composite strategy as participants who die 
prior to FU Week 24 will be considered as non-responders.
E) Population-level summary:
a. Primary (comparison vs fixed external proportion): Difference in proportion 
of participants with HBsAg seroclearance at FU Week 24 using a fixed external
proportion of 1%.
b. Secondary (comparison amongst regimens): Difference in proportion of 
participants with HBsAg seroclearance at FU Week 24 between study 
intervention arms.
5.3.2.1.
Main Estimator
5.3.2.1.1.
Analysis Methods
5.3.2.1.1.1. Comparison vs Fixed External Control
The main estimator is constructed by using an exact binomial test against a fixed external control 
value of 1% at a one-sided Type 1 error rate of 0.05 and applying the Hochberg procedure for 
adjusting for multiple comparisons (Section 5.3.4).
5.3.2.1.1.2. Comparison Amongst Regimens
The main estimator is constructed by using the Mantel-Haenszel test (Mantel N. et al., 1959) 
adjusted for the randomization stratification factor (HBsAg level at screening [<100 IU/mL, 100 
to <1,000 IU/mL, and ≥1,000 IU/mL]) to compare the primary endpoint between the intervention 
arms at a one-sided alpha level of 0.05.
5.3.2.1.2.
Data Included
The main analysis of the primary endpoint will be conducted using the FAS. The FAS-N and 
modified FAS/FAS-N analysis sets will be used if there is a relevant difference from the FAS 
(>5% of participants in total).
FU Week 24 response status data from the selected population analysis set, after taking into 
account all the intercurrent events and applying the intercurrent event strategies in Section 5.3.2, 
will be included.
5.3.2.1.3.
Assumptions

Missing Data for HBsAg are Missing Not at Random (MNAR)

The treatment effect is homogeneous across strata
5.3.2.1.4.
Missing Data Handling Rule
Participants who withdraw from the study prior to FU Week 24 will be considered as non-
responders.


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If a participant remains in the study after experiencing a major protocol deviation (defined for the 
purpose of efficacy analyses and is an intercurrent event) and has missing FU Week 24 value, then 
the imputation to non-response will be applied. If the value for the endpoint at FU Week 24 is 
available, then such data will be used to determine their response status.
For the participants still in the study at FU Week 24 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 HBsAg values missing at FU Week 
24, then the primary method to handle missing data will be the missing as non-responder (MANR).
5.3.2.2.
Sensitivity Estimators of the Main Estimand
Sensitivity analyses will be conducted by constructing three sensitivity estimators for the main 
estimand as defined in Section 5.3.2. 
5.3.2.2.1.
Sensitivity Estimator 1 of the Main Estimand (Homogeneity 
Assumption)
Homogeneity will be assessed for scientific question of interest part b, comparison amongst 
regimens. For this sensitivity estimator 1, the same included data, missing data assumption, and 
missing data handling rule (MANR) as well as the same approach to control the Type I error rate 
(Section 5.3.2.1) will be applied. The assumption for homogeneity of treatment effect across the 
stratification factor will be tested and, if heterogeneity is found statistically significant, a different 
statistical model will be used to define the sensitivity estimator. 
5.3.2.2.1.1. Assumptions

Missing Data for HBsAg are Missing Not at Random (MNAR)

The treatment effect is non-homogeneous across strata
5.3.2.2.1.2. Analysis Methods 
Homogeneity of treatment effect for each stratification factor separately will be tested using the 
weighted least squares chi-squared statistic (Lui K. J. et al., 2000) for one-way homogeneity. Tests 
of homogeneity will be assessed at the one-sided 10% level of significance. 
Any heterogeneity found to be statistically significant will be explored using the following 
statistical model.
Statistical model: A logistic regression model on the primary efficacy endpoint using the  
randomization stratification factor and interaction terms. The model will include intervention arm, 
HBsAg level at screening (<100 IU/mL, 100 to <1,000 IU/mL or ≥1,000 IU/mL), as factors, and 
the intervention arm-by-factor interaction terms.


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5.3.2.2.2.
Sensitivity Estimator 2 of the Main Estimand (Observed Case 
Analysis)
For this sensitivity estimator 2, the same statistical model, 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.
5.3.2.2.2.1. Assumptions

Missing Data for HBsAg are Missing Completely at Random (MCAR) (Barnes A. et al., 2008)

The treatment effect is homogeneous across strata
5.3.2.2.2.2. Missing Data Handling Rule
For sensitivity estimator 2, participants who withdrew from the study prior to Week 24 will not be 
included in the analysis. After taking into account all the intercurrent events and applying the 
intercurrent event strategies specified in Section 5.3.2, if a participant who did not experience any 
ICEs has missing response status for the primary endpoint then this participant will not be used 
for the analysis.
5.3.2.2.3.
Sensitivity Estimator 3 of the Main Estimand (LOCF)
For this sensitivity estimator 3, the same statistical model, 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.
5.3.2.2.3.1. Assumptions

Missing Data for HBsAg are MCAR (Barnes A. et al., 2008)

The treatment effect is homogeneous across strata
5.3.2.2.3.2. Missing Data Handling Rule
For sensitivity estimator 3, participants who withdraw from the study prior to FU Week 24 will be 
considered as non-responders. After taking into account all the intercurrent events and applying 
the intercurrent event strategies specified in Section 5.3.2, if a participant who did not experience 
any ICEs has missing response status for the primary endpoint then the LOCF approach will be 
used as follows.
If the HBsAg value at FU Week 24 is missing, the LOCF in conjunction with the next available 
observation imputation approach will be used. The non-missing value closest to FU Week 24 will 
be selected among the non-missing values which are no earlier than 12 weeks prior to FU Week 
24 or no later than 12 weeks after FU Week 24. If 2 non-missing laboratory values are equidistant, 
the later observation will be preferred. If a participant who did not experience any ICE and does 
not have HBsAg data within the analysis window of ±12 weeks around FU Week 24 assessment 
will be considered as non-responder.


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5.3.3.
Supplementary Estimand for the Primary Endpoint (Per-Protocol 
Analysis Set)
The attributes for the supplementary estimand for the primary endpoint are:
A) Study Intervention Arms:

Arm 1: JNJ-3989 + nivolumab (1 infusion) + NA

Arm 2: JNJ-3989 + nivolumab (3 infusions) + NA
B) Study Population: HBeAg-negative chronic HBV-infected adult patients who are 
virologically suppressed by being treated with NA.
C) Variable: Individual participant response status defined as whether an individual 
participant achieved HBsAg seroclearance at FU Week 24 (responders) as defined in 
Section 5.3.1.
D) Intercurrent events:

Treatment discontinuation prior to Week 24: if the participant discontinued treatment 
prior to Week 24 then s/he will be considered non-responder (composite strategy).

Deaths prior to FU Week 24 are handled in a composite strategy as participants who die 
prior to FU Week 24 will be considered as non-responders.
E) Population-level summary:
a. Primary (comparison vs fixed external proportion): Difference in proportion 
of participants with HBsAg seroclearance at FU Week 24 using a fixed external 
proportion of 1%.
b. Secondary (comparison amongst regimens): Difference in proportion of 
participants with HBsAg seroclearance at FU Week 24 between study 
intervention arms.
5.3.3.1.
Main Estimator of the Supplementary Estimand
5.3.3.1.1.
Analysis Methods
Similar methods as described for the main estimator of the main estimand will be used 
(Section 5.3.2.1.1).
5.3.3.1.2.
Data Included
FU Week 24 response status data from randomized participants that are included in the PP analysis 
set will be used, after taking into account the intercurrent events and applying the intercurrent 
event strategies specified in Section 5.3.3.


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To complement this analysis because of its inherent bias and allow a better interpretation of the 
results, the proportions of participants excluded from the PP analysis set will be summarized by 
intervention arm and by type of major protocol deviation.
5.3.3.1.3.
Assumptions

Missing Data for HBsAg are MANR

The treatment effect is homogeneous across strata.
5.3.3.1.4.
Missing Data Handling Rule
Participants who withdraw from the study prior to FU Week 24 will be considered non-responders. 
For the participants still in the study at FU Week 24 or for participants that have neither 
discontinued treatment early nor experienced any major protocol violations as listed in Table 9, 
but HBsAg values missing at FU Week 24, then the primary method to handle missing data will 
be the imputation to non-responder.
5.3.4.
Hochberg Procedure
Consider testing the family of hypotheses , i = 1, . . . , k. 
Let  , i = 1, . . . , k, denote the sample p-values of tests for  ,  = 1, … . . ,  , computed without 
multiplicity adjustment. Let [1], . . . , [k] denote the random indices such that 
["] ≤⋯≤[&] . 
That is, [] is the anti-rank of  among " , … , & . 
Hochberg’s step-up method proceeds as follows. 
Step 1. If [&] < , reject [],  = 1, … . . ,  , and stop; otherwise go to Step 2. 
Step 2. If [&("] < /2, reject [],  = 1, … . . ,  −1, and stop; otherwise go to Step 3. 
· · · 
Step k. If ["] < / , reject [],  = 1, and stop.
5.4.
Secondary Efficacy Endpoints
See Section 1.1 for a list of the secondary endpoints. All secondary endpoints will be analyzed 
using observed case data. Additional analyses with specific imputation methods for missing data 
are added for selected endpoints.


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5.4.1.
Definitions
5.4.1.1.
Binary Endpoints
5.4.1.1.1.
HBsAg Cut-offs
The cut-offs for HBsAg level are as follows (yes vs no):

<1000 IU/mL

<100 IU/mL

<10 IU/mL

<1 IU/mL

<LLOQ (0.05 IU/mL)
The cut-offs for HBsAg change from baseline and Nivo RT are as follows (yes vs no):

decrease by ≥0.5 log10 IU/mL 

decrease by ≥1 log10 IU/mL 

decrease by ≥2 log10 IU/mL 

decrease by ≥3 log10 IU/mL 

decrease by ≥4 log10 IU/mL 
The cut-offs for HBsAg change from FUW4 RT are as follows (yes vs no):

increase by ≤0.2 log10 IU/mL 

increase by ≤0.5 log10 IU/mL 

increase by ≤1 log10 IU/mL 

decrease by > 0.2 log10 IU/mL

within +/- 0.2 log10 IU/mL
5.4.1.1.2.
HBsAg Seroclearance
Seroclearance of HBsAg is defined as a (quantitative) HBsAg level <LLOQ (see Table 4). HBsAg 
seroclearance can be observed prior to the time point assessed but must be observed at the given 
week of interest.
HBsAg seroclearance will be evaluated over all time points when assessed, with emphasis at Week
24, FU Week 12, FU Week 32 and FU Week 48.
For the analyses of seroclearance at the time points mentioned above, participants with HBsAg 
seroclearance at the respective time points will be considered as having achieved this endpoint.


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5.4.1.1.3.
HBsAg Seroconversion
Seroconversion of HBsAg is defined as having achieved HBsAg seroclearance and appearance of 
anti-HBs antibodies.
The seroconversion will only be assessed at the time points when the anti-HBs antibodies 
assessment is available. 
Appearance of anti-HBs antibodies is defined as a baseline anti-HBs antibodies (quantitative) 
<LLOQ and a post-baseline assessment ≥LLOQ. An additional seroconversion will be applied 
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.
5.4.1.1.4.
HBeAg Cut-offs
The cut-offs for HBeAg level are as follows (yes vs no):

< LLOQ

<1 IU/mL

<10 IU/mL
5.4.1.1.5.
HBV DNA Cut-offs
The cut-offs for HBV DNA are as follows (yes vs no):

< LLOQ for target detected or not detected

< LLOQ for target not detected

< LLOQ for target detected

<60 IU/mL

<200 IU/mL

<2000 IU/mL

<20000 IU/mL
5.4.1.1.6.
Suppressed HBV DNA
HBV DNA < LLOQ (HBV DNA detectable or HBV DNA TND) and HBV DNA < 60 IU/mL will 
be evaluated over all time points when assessed, with emphasis at Week 24, FU Week 12, FU 
Week 24, FU Week 32 and FU Week 48.
5.4.1.1.7.
ALT Normalization
ALT elevation at baseline is defined as ALT≥ULN. A participant with ALT elevation at baseline 
achieves ALT normalization if his/her ALT value post-baseline is <ULN at any given time point.
Participants who achieve ALT normalization on treatment will be evaluated over time.


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5.4.1.1.8.
Virologic Breakthrough
HBV virological breakthrough is defined as having a confirmed on-treatment HBV DNA increase 
by >1 log10 from nadir level (lowest level reached during treatment) in participants who didn’t 
have on-treatment HBV DNA level below the lower limit of quantification (LLOQ) or a confirmed 
on-treatment HBV DNA level >200 IU/mL in participants who had on-treatment HBV DNA level 
below the lower limit of quantification (LLOQ). Confirmed HBV DNA increase/level means that 
the criterion should be fulfilled at 2 or more consecutive time points or at the last observed time 
points or at the last observed on-treatment time point. On-treatment will be defined as the time 
period in which the participant receives any of the study interventions (including NA).
In addition, participants who experience a virologic breakthrough followed by on-treatment 
biochemical flare will be evaluated.
5.4.1.1.9.
Flares
The criteria based on blood markers/lab tests for each of the flare types are defined below.
On-treatment Biochemical flare is defined as follows:
The start date of a confirmed on-treatment biochemical flare is defined as the first date of two 
consecutive visits with ALT and/or AST≥3x ULN and ≥3x nadir (i.e. lowest value observed up to 
the start of the flare) while the participant receives any of the study interventions. The end date of 
the same on-treatment biochemical flare is defined as the first date when there is a 50% reduction 
from the peak ALT and/or AST level & <3x ULN, regardless of stopping the study interventions.

1 (Yes) = confirmed** ALT and/or AST ≥3x ULN and ≥3x nadir (i.e. lowest value observed 
up to the start of the flare)

0 (No) = otherwise
** Confirmed means that the criterion should be fulfilled at 2 or more consecutive time points or at 
the last observed time point.
5.4.1.2.
Continuous Endpoints
5.4.1.2.1.
HBsAg, HBeAg, HBV DNA and ALT
Actual values (original unit and/or log10 transformed values), changes from baseline (log10
transformed values) and change from RTs over time in HBsAg will be evaluated, and actual values 
(original unit and/or log10 transformed values), over time in HBeAg, HBV DNA and ALT will be 
evaluated.
Change from baseline is defined as the value at a given time point minus baseline value.
The change from baseline value to the nadir (i.e. maximum decrease for each participant) in 
HBsAg will be evaluated at 3 intervals: during study intervention nadir (first 24 weeks), during 
follow-up nadir, and entire study nadir.


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5.4.2.
Analysis Methods
Summaries and graphs will be provided for each intervention arm and analysis phase, unless 
specified otherwise.
Statistical comparisons of the secondary endpoints among intervention arms may be done with no 
adjustment for multiplicity.
All secondary endpoints will be analyzed based on the observed case data. Additional analyses 
with specific imputation methods for missing data are added for selected endpoints.
Inferential and descriptive subgroup analyses may not be performed if there are not enough data
to perform the analyses.
5.4.2.1.
Binary Endpoints
The count and proportion (%) of participants achieving the endpoints defined in Section 5.4.1.1
will be summarized.  The associated 90% CI will be included for the following endpoints:

HBsAg seroclearance

HBsAg seroconversion

Suppressed HBV DNA

ALT Normalization

Virologic Breakthrough

Flares
For all time points, binary endpoints will be analyzed using the observed case data. LOCF 
(Section 5.4.2.1.1) will be used for HBsAg seroclearance and Suppressed HBV DNA analyses at 
Week 24, FU Week 12, FU Week 24, FU Week 32 and FU Week 48.
The HBsAg seroclearance analyses at Week 24, FU Week 12, FU Week 24, FU Week 32 and FU 
Week 48 will be compared between treatment arms using a 2-sided 90% CI of the difference in 
proportions between the treatment groups (Arm 1 minus Arm 2) that will be constructed using a 
Mantel-Haenszel test controlling for stratification factor.
For single arm, point and 90% CI estimates, the Clopper Pearson method will be used. 
Subsections below describe the additional analyses planned for only those specific other secondary 
binary endpoints that require further evaluations.
5.4.2.1.1.
LOCF Imputation Method

If the lab value at Week 24 is missing, the LOCF approach will be used with the condition
that no value earlier than Week 20 may be carried forward.

If the lab value at FU Week 12 is missing, the LOCF in conjunction with the next available 
observation imputation approach will be used. The available non-missing lab test closest to 


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FU Week 12 which is no earlier than FU Week 4 and no later than FU Week 24 will be 
imputed. If the non-missing lab value before and after the specific timepoint fall equidistant 
from the target timepoint, the later one will be used to impute the missing value.

If the lab value at FU Week 24 is missing, the LOCF in conjunction with the next available 
observation imputation approach will be used. The available non-missing lab test closest to 
FU Week 24 which is no earlier than FU Week 12 and no later than FU Week 32 will be 
imputed. If the non-missing lab value before and after the specific timepoint fall equidistant 
from the target timepoint, the later one will be used to impute the missing value.

If the lab value at FU Week 32 is missing, the LOCF in conjunction with the next available 
observation imputation approach will be used. The available non-missing lab test closest to 
FU Week 32 which is no earlier than FU Week 24 and no later than FU Week 48 will be 
imputed. If the non-missing lab value before and after the specific timepoint fall equidistant 
from the target timepoint, the later one will be used to impute the missing value.

If the lab value at FU Week 48 is missing, the LOCF approach will be used with the condition 
that no value earlier than FU Week 32 may be carried forward.
5.4.2.1.2.
HBsAg Seroconversion
For participants achieving HBsAg seroconversion, descriptive statistics will be calculated for the 
level of anti-HBs antibodies at the timepoint when achieving the HBsAg seroconversion.  In an 
additional summary, the level of anti-HBs antibodies at the specific timepoint will be summarized 
for the subset of the participants achieving HBsAg seroconversion at any time before or at that 
given timepoint.
In addition, the count and proportion of participants (and associated 90% CI) with appearance of 
anti-HBs antibodies but without seroclearance of HBsAg will also be summarized by intervention 
arm and analysis phase.
5.4.2.1.3.
Suppressed HBV DNA
The number of occurrences each participant has HBV DNA <LLOQ (overall and separately for 
HBV DNA detectable and HBV DNA TND) will be determined and summarized by intervention 
arm using frequency distributions and descriptive statistics. Additionally, the number of 
occurrences will be displayed graphically.
The same analyses will also be performed for HBV DNA < 60 IU/mL.
5.4.2.1.4.
Flares
The incidence rate will be calculated and summarized for on-treatment biochemical flares by 
intervention arm. 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 intervention arm.
The number and percentage of participants with ALT flares will be calculated by the peak ALT 
value during the flare using the following cut-offs: 


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
<3 x ULN

≥3-<5 x ULN

≥5-<10 x ULN

≥10 x ULN.
The incidence rate of flares will also be calculated before and after week 12.
For on-treatment biochemical flares, the incidence of flares causing treatment discontinuation will 
be summarized by intervention arm. Similarly, the incidence of flares followed by the achievement 
of HBsAg seroclearance (at any time) will be summarized by flare type and intervention arm.
Flares that are associated with signs of liver decompensation will be provided in a listing.
5.4.2.2.
Continuous Endpoints
5.4.2.2.1.
HBsAg, HBeAg, HBV DNA and ALT
Descriptive statistics on actual values (original unit and/or log10 transformed values) over time in 
HBsAg, HBeAg, HBV DNA, and ALT (original unit) will be summarized by intervention arm.
Changes from baseline (log10 transformed values) over time in HBsAg, HBeAg, and ALT (original 
unit) and changes from RTs (log10 transformed) over time in HBsAg will be summarized by 
intervention arm. Mean (+/- SE) plots of the actual values in HBsAg, HBV DNA and ALT (original 
unit) and change from baseline (log10 transformed)) will be presented over time in HBsAg and 
ALT (original unit) - by intervention arm and analysis phase. Change from RTs (log10 transformed) 
will be presented over time in HBsAg by intervention arm and analysis phase The change from 
baseline value to the nadirs (i.e. maximum decrease for each participant) in HBsAg will be 
summarized descriptively by intervention arm. Box plots of the changes to nadirs in HBsAg will 
display the distribution by intervention arm.
Change from baseline based on log10 transform for quantitative HBsAg, HBeAg and HBV DNA 
will be analyzed using mixed effects model for repeated measures [MMRM]) including 
intervention arm, analysis time point (week), and the randomization stratification factor (ie, 
absolute HBsAg value at screening [<100 IU/mL, 100 to <1,000 IU/mL versus >1,000 IU/mL]) as 
fixed effects. 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), 90% confidence interval (CI)
and p-values will be provided.
Descriptive statistics on actual values (original unit and log10 transformed values) in HBsAg, 
HBeAg and HBV DNA and changes from baseline (log10 transformed values) at end of treatment


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in HBsAg, HBeAg and will be summarized by study intervention arm by outcome response (i.e. 
by HBsAg seroclearance at FU Week 24 and FU Week 48).
Waterfall plots for actual values, changes from baseline of HBsAg will also be presented.
Descriptive statistics of the absolute values, changes from baseline over time in ALT will be 
summarized by intervention arm and analysis phase for those participants who had ALT elevation 
at baseline. An additional summary of descriptive statistics of the ALT absolute values and 
changes from baseline over time will be summarized by intervention arm and analysis phase for 
those participants who had ALT values within the normal range at baseline.
5.5.
Exploratory Endpoints
5.5.1.
Definitions
5.5.1.1.
Binary Endpoints
5.5.1.1.1.
Sustained HBsAg Response
The definitions of sustained response are as follows (yes/no):
Definition 1: 

For participants with follow-up week 48 data: Participants who have a > 1 log decline in 
HBsAg at follow-up week 48 and have an HBsAg <1000 IU/mL at follow-up week 48.

For participants without follow-up week 48 data: HBsAg values have a > 2 log decline at 
follow-up week 24 or >1.5 log decline at follow-up week 40 (most recent value used) 
compared to baseline and have an HBsAg <1000 IU/mL at the last available timepoint.
Definition 2: For participants with a >1 log decline in HBsAg from baseline at last follow-up 
visit: Among the most recent three visits, the difference between log HBsAg at 2 of 3 last visit 
and 1 of 3 last visit is <0.2, and the difference between log HBsAg at 3 of 3 last visit and 1 of 3 
last visit is <0.2.
Definition 3: For participants with a >1 log decline in HBsAg from baseline at last follow-up 
visit: Among the most recent three visits, the difference between log HBsAg at 2 of 3 last visit 
and 1 of 3 last visit is <0.2, and the difference between log HBsAg at 3 of 3 last visit and 1 of 3 
last visit is <0.2 and have an HBsAg <1000 IU/mL at the last available timepoint.
Due to the exploratory objectives of this Phase 2 study, additional sustained HBsAg response 
definitions may be explored according to the clinical interest.
5.5.1.1.2.
Liver Stiffness Measurement
The following liver stiffness measurements (LSM) changes from baseline (in terms of reductions) 
will be evaluated over time at Week 24, FU Week 24 and FU Week 48:

≥ 2 kPa

≥ 4 kPa


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
≥ 6 kPa
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. 
5.5.1.1.3.
HBV RNA Cut-offs
The cut-offs for HBV RNA are as follows (yes vs no):

TND

< LOD

< LLOQ

<1000 copies/mL
The cut-offs for HBV RNA change from baseline are as follows (yes vs no):

decrease by ≥ 1.0 log copies/mL

decrease by ≥ 2.0 log copies/mL

decrease by ≥ 3.0 log copies/mL
5.5.1.1.4.
HBcrAg Cut-offs
The cut-offs for HBcrAg are as follows (yes vs no):

< 3.0 log U/mL

< 4.0 log U/mL
The cut-offs for HBcrAg change from baseline are as follows (yes vs no):

decrease by ≥ 1.0 log U/mL

decrease by ≥ 2.0 log U/mL

decrease by ≥ 3.0 log U/mL

decrease by ≥ 4.0 log U/mL
5.5.1.2.
Continuous Endpoints
5.5.1.2.1.
Liver Stiffness Measurement
Severity of liver disease at the end of study intervention and follow-up versus baseline will be 
evaluated by the changes in fibrosis over time according to Fibroscan LSM.
Change from baseline is defined as the value at a given time point minus baseline value.
5.5.1.2.2.
HBV RNA and HBcrAg
Actual values, changes from baseline (log transformed value) over time in HBV RNA and HBcrAg 
will be evaluated.


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Change from baseline is defined as the value at a given time point minus baseline value.
5.5.2.
Analysis Methods
Summaries and graphs will be provided for each intervention arm and analysis phase, unless 
specified otherwise.
Statistical comparisons of all exploratory endpoints among intervention arms will be done with no 
adjustment for multiplicity.
All exploratory endpoints will be analyzed based on the observed case data.
Inferential and descriptive subgroup analyses may not be performed if there are not enough data
to perform the analyses.
5.5.2.1.
Binary Endpoints
The count and proportion (%) of participants achieving the endpoints defined in Section 5.4.2.1
will be summarized.  The associated 90% CI may also be included.
5.5.2.2.
Continuous Endpoints
The methods of analysis of the continuous exploratory endpoints will be the same as those 
described in Section 5.4.2.2.
Waterfall plots for changes from baseline HBcrAg and fibrosis will also be presented.
Subsections below describe the additional analyses planned for only those specific exploratory
endpoints that require further evaluations.
5.5.2.2.1.
Liver Stiffness Measurement
The changes from baseline at Week 24, FU Week 24, and FU Week 48 will be summarized using 
descriptive statistics (n, mean, SD, SE, 90% CI, median, minimum, maximum) by intervention 
arm. The comparison among intervention arms will be done using ANCOVA with intervention 
arm, randomization stratification factor as main effects and baseline score as covariate.
At each assessment time point, a frequency distribution of severity scores will be produced.
5.5.2.2.2.
Anti-HBs Antibodies
For all participants with positive anti-HBs antibodies at baseline who will reach HBsAg 
seroclearance (as defined in Section 5.4.1.1.2), descriptive statistics will be calculated for the 
change of anti-HBs antibodies level from baseline at the timepoint and subsequent timepoints
when achieving the HBsAg seroclearance.  In an additional summary, the change of anti-HBs 
antibodies level from baseline at the specific timepoint and subsequent timepoints will be 
summarized descriptively for the subset of the participants achieving HBsAg seroclearance at any 
time before or at that given timepoint.


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5.6.
Safety Analyses
Summaries will be provided on the overall population and by intervention arm and analysis phase 
unless specified otherwise.
Safety and tolerability will be assessed by evaluating treatment emergent-adverse events (TEAEs), 
immune related AEs, physical examinations, vital signs measurements, clinical laboratory tests 
(including hematology, blood biochemistry, blood coagulation, and urinalysis), renal biomarkers
and ECGs.
For all continuous safety variables, descriptive statistics by intervention group will include the N, 
mean, standard deviation, standard error, median, minimum, and maximum. Categorical variables 
will be summarized by intervention group using frequency counts and percentages.
5.6.1.
Extent of Exposure
The number and percentage of participants who receive each study agent within a study
intervention will be summarized. 
Descriptive statistics for duration of each study agent within a study intervention (N, mean, SD, 
SE, median, and range (minimum, maximum)) during the study intervention period will be 
summarized. 
Because of the different route and frequency of treatment administration across the 3 agents (for 
JNJ-3989 one subcutaneous injection every week for the first 4 weeks and then once every 4 
weeks, for nivolumab one intravenous infusion at Week 16 in Arm 1 and Week 16, 20 and 24 in 
Arm 2, and for NA once daily tablet) the total duration for each study agent as follows:

JNJ-3989: 

Discontinuation of JNJ-3989 before Week 4:
o
[Min ((Date of last JNJ-3989 (loading dose) injection +6 days), Date of trial 
disposition, cut-off date) – Date of first JNJ-3989 injection+ 1] / 7  
o
Otherwise: [Min ((Date of last JNJ-3989 injection + 27 days), Date of trial 
disposition, cut-off date) – Date of first JNJ-3989 injection + 1] / 7  

Nivolumab: [Min (Date of the last nivolumab infusion + 27 days, Date of trial disposition, 
cut-off date) – Date of first nivolumab infusion + 1] /7
Cutoff dates will be defined to match the prespecified timepoints for interim analyses and the 
primary analysis, respectively (Section 5.8).
The number and percentage of participants who skipped any dose of JNJ-3989 or nivolumab will 
be summarized separately for each study intervention by intervention arm during the study
intervention period. Additionally, the number and percentage of participants who missed 2 or more 
JNJ-3989 injections, or who missed 1 or more nivolumab infusion will be presented.
Study intervention compliance will be summarized descriptively. See Appendix 7 Intervention 
Compliance for further details.


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5.6.2.
Adverse Events
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 25.0). Any AE occurring at 
or after the initial administration of study intervention is considered to be treatment emergent. If 
the event occurs on the day of the initial administration of study intervention, and either event time 
or time of administration are missing, then the event will be assumed to be treatment emergent. If 
the event date is recorded as partial or completely missing, then the event will be considered to be 
treatment emergent unless it is known to be prior to the first administration of study intervention
based on partial onset date or resolution date. All reported treatment-emergent adverse events will 
be included in the analysis.  For each adverse event, the number and percentage of participants
who experience at least 1 occurrence of the given event will be summarized by intervention arm.
Summary tables will be provided for treatment-emergent adverse events:

AEs

Serious AEs (SAEs)

AEs leading to discontinuation of any study agent within a study intervention

AEs by relationship to each study agent within a study intervention

AEs leading to dose interruption/dose modification of each study agent within a study 
intervention.

AEs leading to systemic corticosteroid administration.
In addition to the summary tables, listings will be provided for participants who:

Had SAEs

Had AEs leading to discontinuation of each study agent within a study intervention 
For participants reporting rash, a listing with specific grade will be provided.
Incidence of treatment-emergent adverse events of special interest will be summarized by analysis 
phase and overall
The adverse events of special interest include:

Immune related AEs

ALT/AST elevations

Injection Site Reactions Related to JNJ-3989

Infusion Reactions Related to nivolumab

Renal Complications

Hematologic Abnormalities (platelet count, hemoglobin, reticulocytes, neutrophil count)


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The list of all preferred terms belonging to ALT/AST elevation, renal complications, and 
hematologic abnormalities is provided in Table 10 Appendix 8. Injection and infusion site 
reactions will be identified using the eCRF Injection Site Reaction Assessment form for JNJ-3989 
and Infusion-related reactions for Nivolumab. Immune related AEs will be also identified using 
the eCRF Adverse events/Serious AEs form based on the related question.
A listing of participants who died will be provided.
5.6.3.
Additional Safety Assessments
5.6.3.1.
Clinical Laboratory Tests
Laboratory data will be summarized by category of laboratory test. The different categories and 
laboratory tests used in the analysis are listed in Table 5.
Table 5: 
Laboratory Parameters
Laboratory 
Assessments
Parameters
Hematology
Platelet count
Red blood cell count
Hemoglobin
Hematocrit
RBC Indices:
MCV
MCH
% Reticulocytes
White Blood Cell (WBC) 
count with Differential:
Neutrophils
Lymphocytes
Monocytes
Eosinophils
Basophils
Note: A WBC evaluation may include any abnormal cells, which will then be
reported by the laboratory. A RBC evaluation may include abnormalities in the
RBC count, RBC parameters, or RBC morphology, which will then be reported 
by the laboratory. In addition, any other abnormal cells in a blood smear will also 
be reported.
Hematology 
Coagulation
Activated partial thromboplastin time
Prothrombin Intl. normalized ratio
Prothrombin time 
Clinical Chemistry
Sodium
Potassium
Chloride
Bicarbonate
Blood urea nitrogen (BUN)
Creatinine
Cystatin C 
Glucose 
Aspartate aminotransferase (AST)/Serum 
glutamic-oxaloacetic
Alanine aminotransferase (ALT) /Serum 
glutamic-oxaloacetic
Gamma-glutamyltransferase (GGT)
Fibrinogen (on blood)
eGFR calculation based on Creatinine 
(by CKD EPI formula, eGFRcr)
eGFR calculation based on Cystatin C 
(by CKD EPI formula, eGFRcys)
Total, direct, indirect bilirubin
Alkaline phosphatase (ALP)
Creatine phosphokinase (CPK)
Lactic acid dehydrogenase (LDH)
Uric acid
Calcium
Phosphate
Albumin
Total protein
Total cholesterol
High-density lipoprotein cholesterol
Low-density lipoprotein cholesterol
Triglycerides
Magnesium
Lipase
Amylase (reflex testing of pancreatic 
amylase should be done in case of 


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Table 5: 
Laboratory Parameters
Laboratory 
Assessments
Parameters
amylase or lipase increase from 
screening onwards)
Routine Urinalysis
Dipstick
Specific gravity
pH
Glucose
Protein
Blood
Ketones
Bilirubin
Urobilinogen
Nitrite
Leukocyte esterase
Sediment (if dipstick result is 
abnormal)
Red blood cells
White blood cells
Epithelial cells
Crystals
Casts
Bacteria
In case of a positive dipstick result, a urine sample will be set aside for additional 
examination of the positive parameter (e.g. quantification as applicable).
Urine Chemistry 
(quantitative 
measurement)
Creatinine
Sodium
Phosphate
Glucose
Protein
Albumin
Renal Biomarkers
Retinol binding protein
Beta-2-microglobulin
Note: Other biomarkers might be measured.
Other Tests
Autoantibodies: anti-nuclear antibodies [ANA], anti-smooth muscle antibodies 
[ASMA], anti-mitochondrial antibodies [AMA], anti-Neutrophil Cytoplasmic 
antibodies [ANCA], anti-thyroid peroxidase antibodies and rheumatoid factor
Thyroid function tests: TSH, T3 and T4
Clinical laboratory tests will be displayed for the participants included in the safety analysis set.
Descriptive statistics and graphical displays will be presented for all chemistry, hematology, and 
urinalysis laboratory tests at scheduled time points.
Change from baseline over time will be summarized for chemistry, hematology, urinalysis tests
and renal biomarkers and displayed.
Abnormality criteria (based on the criteria specified in the Modified DAIDS Toxicity Grade Scale 
(see Clinical Protocol Appendix 8, DAIDS Table with Modifications (DAIDS [Modified]))) will 
be applied to baseline and postbaseline values or in accordance with the normal ranges of the 
clinical laboratory if no gradings are available.
Postbaseline abnormalities will be compared with their corresponding baseline result:

For toxicity grades, treatment emergent (TE) will be concluded if the postbaseline grade is 
worse than the baseline grade.


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
For abnormalities based on normal range and/or criteria: If the postbaseline value is above the 
upper limit and the baseline value is below the upper limit (e.g. Normal or Low), then the 
postbaseline abnormality will be considered TE. The same applies to the postbaseline value 
being below the lower limit with the baseline value being above the lower limit (e.g. Normal 
or High).

If the baseline value is missing, a postbaseline abnormality will always be considered as TE.
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 
(hypo/hyper). Worst-case will be derived withing each analysis phase, including unscheduled 
assessments. For abnormalities, in case the same participant 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).
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.
Shift tables will be provided summarizing the shift in laboratory values from baseline over time
with respect to abnormality criteria (low, normal, high) for each laboratory parameter by analysis 
phase.
The cross-tabulations of the worst toxicity grades over time versus baseline grade and the worst 
abnormalities versus baseline grade per parameter and per analysis phase will be presented 
including also the number of participants per worst grade and the number of participants per 
abnormality.
A tabulation of percentage and number of the participants who have treatment-emergent worst 
toxicity grades and treatment-emergent worst abnormalities per parameter and analysis phase will 
be included.
Plots of mean (+/- SE) values and changes from baseline over time for selected laboratory 
parameters will be presented by intervention arm. Spaghetti-plots for selected laboratory 
parameters will be presented over time by intervention arm (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. 


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5.6.3.2.
Renal Safety
Renal safety parameters include the urine creatinine, serum creatinine, urine glucose, total urine 
protein, total urine albumin, urine protein to creatinine ratio (UPCR), urine albumin to creatinine 
ratio (UACR), retinol binding protein (RBP), beta-2-microglobulin, RBP to creatinine ratio, beta-
2-microglobulin to creatinine ratio, urine fractional excretion of phosphate (FEPO4), Cystatin C, 
eGFR based on Creatinine (eGFRcr), eGFR based on Cystatin C (eGFRcys).
Descriptive statistics (n, mean, SD, SE, minimum, median, and maximum) will be calculated for 
each parameter for observed values and changes from baseline at each scheduled time point by 
intervention arm and analysis phase.
Plots of mean (+/- SE) values and changes from baseline over time for the renal safety parameters 
will be presented.
A confirmed eGFRcr Grade ≥3 is defined as a Grade 3 or higher at 2 consecutive post-baseline 
measurements or an abnormality observed at 1 measurement followed by study drug 
discontinuation.
A listing including all renal safety parameters for participants with at least one treatment-emergent 
eGFRcr Grade 3 or higher will be generated.  Another listing will be generated with renal safety 
parameters for participants who had a confirmed eGFRcr Grade 3 or higher.
5.6.3.2.1.
eGFR Creatinine and eGFR Cystatin C
The following analyses will be done for both eGFRcr and eGFRcys
Stages of eGFR at baseline versus the minimum post-baseline eGFR value and the last available 
value will be summarized by count and percent of participants. Kidney disease stages are defined 
as follows: 1 (Normal): eGFR ≥ 90; 2 (Mild): eGFR 60-89; 3 (Moderate): eGFR 30-59; 4 (Severe): 
eGFR <30.
In addition to the above, the number and proportion of participants with a 10-<30%, 30-<50% and 
≥50% decrease from baseline will be tabulated.
Scatter plots of eGFR 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 be presented.
In addition, cystatin C assessment is being performed as part of this study. eGFRcys will also be 
calculated by using the CKD-EPI cystatin C equation. 
Differences between the two types of GFR calculation will be assessed. Cross-tabulation of 
eGFRcr (<10%, 10-<30%, 30-<50% and ≥50% decrease from baseline) versus eGFRcys (<10%, 
10-<30%, 30-<50% and ≥50% decrease from baseline) will be presented over time.


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5.6.3.2.2.
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
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 number and proportion of participants with beta-2-microglobulin to creatinine ratio ≤343.5 
μg/g and >343.5 μg/g will be tabulated over time.
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 (%)


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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. 
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 post-baseline measurement followed by 
study drug discontinuation.
A subclinical renal proximal tubulopathy will be defined as confirmed abnormalities in any 2 out 
of the 4 renal parameters (serum creatinine and one or more of the 3 other markers of tubular 
dysfunction).
Baseline Subclinical renal proximal tubulopathy
Potential Markers of Renal Proximal Tubulopathy at Baseline
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 2 out of the 
4 renal parameters (serum creatinine + 1 or more of the 3 other markers of tubular dysfunction). 
5.6.3.3.
Vital Signs
The following parameters measurements will be analyzed:

Supine pulse rate (bpm)


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
Supine systolic blood pressure (mmHg)

Supine diastolic blood pressure (mmHg)

Body temperature (℃)
The abnormalities in vital signs will be determined according to the criteria specified in the 
Cardiovascular Safety – Abnormalities Table (see Clinical Protocol Appendix 7).
An assessment is treatment-emergent if abnormality worsened as compared to the abnormality at 
baseline; this also includes the shift from abnormally high to abnormally low and vice-versa. Post-
baseline abnormalities are always treatment-emergent with regard to missing abnormalities at 
baseline. The abnormally high values (i.e. abnormally high, grade 1 or mild, grade 2 or moderate, 
grade 3 or severe) versus the abnormally low values are considered equally important.
For each parameter, a “worst-case” analysis will be performed by using the worst abnormality and 
time point per participant. Worst-case will be derived within each analysis phase, including 
unscheduled assessments. In case the same participant 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).
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
analysis phase.
A cross-tabulation of the worst abnormalities versus baseline per parameter and analysis phase 
will be presented including also the number of participants per abnormality, the number of 
participants with treatment emergent abnormalities per abnormality.
A tabulation of percentage and number of the participants who have treatment-emergent worst 
abnormalities per parameter and analysis phase will be included. 
A listing including all parameters for participants with at least one treatment-emergent abnormality 
(on actual values or change from baseline) is provided. Additional vital signs assessments 
corresponding to the rash eCRF pages will be only listed as applicable.
The physical examination findings and abnormalities will be listed.
5.6.3.4.
Electrocardiogram
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.


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The ECG parameters that will be analyzed are heart rate (bpm), PR interval (ms), RR interval (ms), 
QRS interval (ms), QT interval (ms), and corrected QT (QTc) interval using the following 
correction methods: 
Fridericia’s formula: QTcF (msec) = QT (msec) / (RR (msec)/1000)1/3; if RR is missing, use QT 
(msec) * (HR(bpm)/60)1/3;
The abnormalities in ECG parameters will be determined according to the criteria specified in the 
Cardiovascular Safety – Abnormalities Table (see Clinical Protocol Appendix 7, Cardiovascular 
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 analysis phase, including 
unscheduled assessments. In case the same participant 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).
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.


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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 and 
analysis phase. 
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 analysis phase.
A cross-tabulation of the worst abnormalities (on actual values) versus baseline per parameter by 
analysis phase will be presented including also the number of participants per abnormality. A 
tabulation of number and percentage of the participants who have treatment-emergent worst 
abnormalities per parameter (i.e. for HR, PR, QRS and QTcF) and analysis phase will also be 
presented. 
A cross-tabulation of the worst change from baseline abnormalities (i.e. for QTcF) versus the
baseline category per parameter will be presented by intervention arm and analysis phase.
Frequency tabulations of categorized corrected QT/QTc change from baseline (≤30 msec, >30-
≤60 msec, >60 msec) and categorized corrected QT/QTc interval values (≤450 msec, >450- ≤480 
msec, >480-≤ 500 msec, >500 msec) per timepoint will be presented by 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.
5.6.3.5.
Physical and Ophthalmic Examinations
The physical and ophthalmic examination findings and abnormalities will be listed. A listing of 
participants who experienced a decrease or loss of vision at any timepoint during study will be 
provided.
5.7.
Other Analyses
5.7.1.
Pharmacokinetics
Population PK analysis of plasma concentration-time data of JNJ-73763976 (JNJ-3976), and JNJ-
73763924 (JNJ-3924) may be performed using non-linear mixed effects modeling. Data from the 
current study may be combined with prior information available from Phase 1 and/or 2 studies to 
support a relevant structural model. Available participant characteristics (e.g. demographics, 
laboratory variables, genotypes) may be included in the model as necessary. If a population PK 
analysis is conducted, the results will be presented in a separate report.
5.7.2.
Pharmacokinetic/Pharmacodynamic Relationships
Relationships of PK parameters for JNJ-3976 and JNJ-3924, and, optionally, for NA and/or 
nivolumab with RO, selected efficacy and with selected safety endpoints may be evaluated and 
graphically displayed, if applicable. 


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Modeling of key PD parameters (e.g. HBsAg, HBV DNA) may be performed using population 
PK/PD. If PK/PD modeling of key efficacy endpoints is performed, treatment effect and possible 
covariates may be investigated. Other biomarkers may be explored at the Sponsor’s discretion. If 
applicable, the results will be described in a separate report.
5.7.3.
Receptor Occupancy
Individual Receptor Occupancy values may be provided in a listing and summarized by descriptive 
statistics (n, mean, SD, geometric mean, median, minimum, and maximum and IQ range).
Individual and summarized RO results may be graphically presented by intervention arm and 
selected time points.
5.7.4.
Immune Analyses
Descriptive statistics (n, mean, SD, coefficient of variation [CV], geometric mean, median, 
minimum, and maximum) may be used to describe the magnitude of the gamma interferon (IFN-
γ) T-cell response or the CD4+ and CD8+ T-cell responses (expressing at least 1 cytokine such as 
interleukin [IL]-2, TNF-α or IFN-γ specific to any HBV antigen) as defined by ELISpot and/or 
ICS, respectively. Changes from baseline (or positivity threshold) may also be tabulated for 
PBMCs during study intervention and follow-up. The proportion (%) of chronic HBV-infected
patients with detectable responses based on the magnitude of the IFN-γ T-cell response or the 
CD4+ or CD8+ T-cells expressing at least 1 of the cytokines amongst IL-2, TNF-α or IFN-γ for 1 
of the HBV antigens as defined by ELISpot and/or ICS, respectively, may be determined. Changes 
from baseline (or positivity threshold) in HBV-specific peripheral blood T-cell responses may be 
summarized and tabulated.
Graphs showing the individual participant values as dots, together with horizontal lines indicating 
the corresponding median and interquartile range (IQR) per time point for each assay will be
presented. The spaghetti plots may be used to show the patient profiles per time point for each
assay. A graph showing the median and IQR over time by intervention arm will be presented. A 
bar chart may be used to show the breadth of response (i.e. HBV-specific immune response rate 
for combinations of peptide pools).
For intracellular cytokine staining (ICS), for all cytokine combinations (IFN-γ and/or TNF-α 
and/or IL-2), pie charts may be presented to reflect the distribution of each of the cytokine
combinations (i.e. the proportion of a specific cytokine combination of the CD4 or CD8 T-cells 
secreting at least one cytokine), and bar charts may be presented to reflect the mean magnitude of 
each combination.
5.7.5.
Viral Genome Sequence Analysis
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-56136379, JNJ-3989, and/or ETV or TD treatment on both nucleotide and/or 
amino acid level.


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The sequencing of samples may be triggered by the sponsor virologist based on changes in HBV 
DNA levels observed in each individual participant and the limits of the sequencing assay.
Virology results may be presented by specified timepoints and genetic region and position of 
interest. A separate virology report may be prepared. 
5.8.
Data Review Committee and Interim Analyses
5.8.1.
Data Review Committee
The internal DRC will conduct periodic data review to ensure the continuing safety of the study 
participants during the entire course of the study. The DRC will also review the results of the 
primary and interim analyses (IAs) comprising cumulative safety and selected efficacy endpoints 
for providing the sponsor with further insight and interpretation of the data. Details on the roles 
and responsibilities of the DRC, as well as data reviews and the flows of communication, are 
documented in the DRC charter. Description of the DRC is provided in Section 9.6 of the Master 
Protocol PLATFORMPAHPB2001.
5.8.2.
Independent Flare Expert Panel
An IFLEP is appointed. The IFLEP is composed of 3 independent medical experts with experience 
and expertise in HBV and its treatment. The IFLEP will monitor ALT flares and will make 
recommendations regarding flare management based on an analysis of aggregate data.
In order to allow for an unbiased assessment, members of the committee will not serve as study 
investigators or as members of the DRC.
Further details on the IFLEP process is included in the IFLEP charter.
5.8.3.
Data Reviews and Interim Analyses
The DRC will conduct periodic safety data reviews (DRs) to ensure the continuing safety of the 
study participants during the entire course of the study.
5.8.3.1.
Data Reviews
The DRC will periodically review unblinded cumulative safety and efficacy data at the following 
timepoints:

DR1: All randomized participants have completed Week 4 or discontinued earlier.

Additional data reviews will occur quarterly after the first review for 2023 and then every 6 
months. If the timing of a data review is close to the cutoff point for any of the interim 
analyses, then only the closest IA will take place.
Safety data comprising AEs, SAEs, AEs of special interest, laboratory data, electrocardiogram 
(ECG) data and any other data applicable for the study, will be summarized, plotted and provided 
as appropriate.


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Besides the safety variables listed above, selected efficacy parameters for review may include 
values and changes from baseline over time in HBV disease blood markers (such as HBsAg, 
HBeAg, HBV DNA and ALT), proportion of participants with virologic breakthrough and flares.
5.8.3.2.
Interim Analyses
Interim analyses (IAs) may be conducted to assess safety and efficacy to support the sponsor’s 
interactions with health authorities, as well as to inform decisions about additional studies and/or 
investigation of other treatment combinations. The optional IAs are planned when:

All randomized participants have completed Week 24 or discontinued earlier.

All randomized participants have completed FU Week 12 or discontinued earlier.
Depending on the enrollment rate, any of the above IAs may be skipped if it is too close to the 
predicted timing of any adjacent interim cut-offs and additional IAs may be performed by the 
sponsor to support interactions with health authorities.
The primary analysis will be conducted at the time when all participants have completed FU Week 
24 or discontinued earlier.
Both primary and interim analyses will be based on all data available at the prespecified cut-off 
time points and may include data at later time points for those participants who have reached 
subsequent visits.
The final analysis will be conducted at the time when all participants have completed the last study 
visit (FU Week 48) or discontinued earlier.
5.8.3.3.
Overview of Data Reviews, Interim, Primary and Final Analyses
The overview of data domains and specific endpoints that will be provided to the DRC for 
review is presented in Table 6. Details on the type of summaries and analyses of both efficacy 
and safety variables are described in the following sections.


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Table 6: 
Overview of Data Summaries and Analyses to be Provided to the DRC at Data Reviews, 
Interim, Primary and Final Analyses
DR1/ 
Week 4 
(approx. 
N=37)
DR approx. 
every 8 
weeks
IA1/ Week 
24 (N=37)
IA2/ FU 
Week 12 
(approx. 
N=37)
Primary
analysis/ 
FU Week 
24 
(N=37)
Final 
analysis/ 
Week 72 
(N=37)
Participant information
Baseline & Demographic characteristics
X
X
X
X
X
X
Disposition and Study Populations
X
X
X
X
X
X
Extent of Exposure
X
X
X
X
X
X
Safety
TEAEs, SAEs, AE of special interest, fatal AEs, 
AEs causing treatment discontinuation
X
X
X
X
X
X
Laboratory tests
X
X
X
X
X
X
ECG
X
X
X
X
X
X
Vital signs
X
X
X
X
X
X
Efficacy
Proportion of participants with HBsAg 
seroclearance
X
X
X
X
X
Values and Changes over time in HBsAg, 
HBeAg, HBV DNA and ALT
X**
X**
X
X
X
X
Proportion of participants with HBsAg, HBeAg, 
HBV DNA and ALT below/above different 
cutoffs
X**
X**
X
X
X
X
Other secondary efficacy endpoints
X
X
X
X
X
Exploratory endpoints
X
X
X
X
X
Virologic breakthrough
X
X
X
X
X
X
Flares
X
X
X
X
X
X
PK*
X
X
X
X
Immune response*
X
X
RO*
X
X
X
X
* If there are available data to analyze.
**Only HBsAg will be analyzed for  
Data Reviews.


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6.
SUPPORTING DOCUMENTATION
6.1.
Appendix 1 List of Abbreviations
aa
amino acid
AE
adverse event
ALT
alanine aminotransferase
ANCOVA
analysis of covariance
AST
aspartate aminotransferase
ATC
anatomic and therapeutic class
AUC
area under the curve
BMI
body mass index
BUN
blood urea nitrogen
CI
confidence interval
Cmax
maximum concentration
CPK
creatinine phosphokinase
CRF
case report form
CSR
Clinical Study Report
CV
coefficient of variation
DAIDS
division of acquired immunodeficiency syndrome
db
database
DR
data review
DRC
Data Review Committee
ECG
electrocardiogram
eCRF
electronic case report form
eGFR
estimated glomerular filtration rate
eGFRcr
estimated glomerular filtration rate calculated based on Creatinine
eGFRcys
estimated glomerular filtration rate calculated based on Cystatin C
EOS
end of study
EOSI
end of study intervention
ETV
entecavir
FAS
full analysis set
FC
functional cure
FEPO4
urine fractional excretion of phosphate
FU
follow-up
GGT
Gamma-glutamyltransferase
HBcrAg
hepatitis B core-related antigen
HBs
hepatitis B surface
HbeAg
hepatitis B envelope antigen
HBsAg
hepatitis B surface antigen
HBV
hepatitis B virus
HBV DNA
hepatitis B virus deoxyribonucleic acid 
HBV RNA
hepatitis B virus ribonucleic acid 
IA
interim analysis
ICS
intracellular cytokine staining
iFLEP
independent flares expert panel
IFN-N
Nivolumab full analysis set
IQR
interquartile range
IRT
item response theory
ISR
injection site reaction
IU/mL
international units per milliliter
IV
intravenous
IWRS
interactive website response system
LiPA
line probe assay
LLOQ
lower limit of quantification
LOCF
last observation carried forward
LSM
liver stiffness measurement
MCS
mental component summary


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MedDRA
medical dictionary for regulatory activities 
MANR
missing as non-responder
MCAR
missing completely at random
mFAS
modified full analysis set
MH
Mantel-Haenszel
MI
multiple imputation
mIFN-FAS
modified PegIFN-α2a full analysis set
MNAR
missing not at random
MRU
medical resource utilization
NA
nucleos(t)ide analog
NCBI
National Center for Biotechnology Information
NGS
next generation sequencing
nt
nucleotide
PBMC
peripheral blood mononuclear cell
PC
precore
PCS
physical component summary
PD
pharmacodynamic(s)
PK
pharmacokinetic(s)
PP
per protocol
Q4W
every 4 weeks
qd
once daily
QTc
corrected QC interval
QTcF
QT interval corrected for heart rate according to Fridericia
QW
once weekly
RR
Interval between R wave of one heartbeat and R wave of preceding heartbeat 
RT
reference timepoint
RO
receptor occupancy
SAE
serious adverse event
SAP
statistical analysis plan
SCr
serum creatinine
SD
standard deviation
SEB 
staphylococcal enterotoxin assay
SPO4
serum phosphate
T4
thyroxine
TAF
tenofovir alafenamide
TD
target detected
TEAE
treatment-emergent adverse event
TeD
tenofovir disoproxil
Tmax
time to maximum concentration
TND
target not detected
TNF
tumor necrosis factor
TSH
thyroid stimulating hormone
ULN
upper limit of normal
ULOQ
upper limit of quantification
UPCR
USM                    
urine protein to creatinine ratio
Urgent Safety Issue
VAS
Visual Analog Scale
WBC
white blood cell


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6.2.
Appendix 2 Changes to Protocol-Planned Analyses
Changes to protocol-planned analyses are documented in this SAP.


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6.3.
Appendix 3 Demographics and Baseline Characteristics
The number of participants in each analysis set will be summarized and listed by intervention 
group, and overall. In addition, the distribution of participants by region, country, and site ID will 
be presented unless otherwise noted.
6.3.1.
Demographics
Table 7 presents a list of the demographic variables that will be summarized by intervention group, 
and overall for the FAS.  
Table 7: 
Demographic Variables
Continuous Variables:
Summary Type
Age (years)
Descriptive statistics (N, mean, 
standard deviation [SD], median 
and range [minimum and 
maximum], and IQ range).
Weight at baseline (kg)
Height at baseline (cm)
Body Mass Index (BMI) at baseline (kg/m2)
Number of drinks containing alcohol (weekly period)
Period of time using substances (beer, wine, distilled spirits) in 
months derived as = (stop date – start date+1)/30.4375; rounded to 1 
decimal point
Categorical Variables
Age (≤45 years, >45 years)
Frequency distribution with the 
number and percentage of 
participants in each category.
Sex (male, female, undifferentiated)
Racea (American Indian or Alaska Native, Asian, Black or African 
American, Native Hawaiian or other Pacific Islander, White,
Multiple)
Ethnicity (Hispanic or Latino, not Hispanic or Latino)
BMI at baseline (underweight <18.5 kg/m2, normal ≥18.5-<25 kg/m2, 
overweight ≥25-<30 kg/m2, obese ≥30 kg/m2)
History of tobacco use (Yes, No)
Type of substance use (beer, wine, distilled spirits): current, former, 
never
a
If multiple race categories are indicated, the Race is recorded as 'Multiple'
6.3.2.
Baseline Characteristics
Table 8 presents a list of the baseline characteristics variables that will be summarized by 
intervention group, and overall for the FAS.  
Table 8: 
Baseline Characteristics Variables
Continuous Variables
Summary Type
HBV history 
Descriptive statistics (N, mean, 
standard deviation [SD], median 
and range [minimum and 
maximum], and IQ range).
Duration of HBV infection (years) = (date of randomization – date of 
HBV infection +1)/365.25; rounded to 1 decimal point
Time since HBV diagnosis (Years) = (date of randomization – date of 
HBV diagnosis+1)/365.25; rounded to 1 decimal point
Duration of NA at baseline (years)= (Sum of all NA treatment duration 
[prior and current])/365.25; rounded to 1 decimal; calculated as: end 
date – start date +1. If the end date is missing for latest NA treatment, 
then the randomization date is used.


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Table 8: 
Baseline Characteristics Variables
Continuous Variables
Summary Type
HBV viral activity and serology parameters
HBeAg at baseline in IU/mL and log10 IU/mL 
HBsAg at baseline in IU/mL and log10 IU/mL 
HBV DNA at baseline in IU/mL and log10 IU/mL
HBV RNA at baseline: values in copies/mL and log10 copies/mL
HBcrAg at baseline in log10 U/mL
HBsAg Antibody (Anti-HBs) at baseline in mIU/mL and log10
mIU/mL
Liver Stiffness Measurement at baseline (kPa)
Categorical Variables
Summary Type
HBV history
Frequency distribution with the 
number and percentage of 
participants in each category.
Mode of HBV infection: Sexual contact, injection needle reuse, blood 
transfusion, occupational exposure, vertical transmission, unknown 
and other
Type of NA at baseline: TeD, TAF, ETV
HBV viral activity and serology parameters
HBsAg category at baseline (IU/mL): <100, ≥ 100 - < 1,000, ≥ 1000 -
< 10,000, ≥ 10,000 - < 100,000, ≥ 100,000 
HBV DNA category at baseline (IU/mL): < LLOQ Target detected 
(TD) or not detected (TND), < LLOQ TD, < LLOQ TND, ≥ LLOQ -
< 60, ≥60 
HBV RNA category at baseline (copies/mL): TND, < LOD, < LLOQ, 
≥ LLOQ - < 1,000, ≥ 1,000 
HBcrAg category at baseline (log U/mL): < 3, ≥ 3 - < 4, ≥ 4
HBsAg Antibody (Anti-HBs) status at baseline: Positive, Negative
HBsAg Antibody (Anti-HBs) category at baseline (mIU/mL): < 10, ≥ 
10
HBeAg Antibody (Anti-HBe) status: Positive, Negative
Baseline ALT toxicity grade according to DAIDS
Baseline ALT categorization: ≤ 1.0xULN, > 1.0xULN to <2xULN, ≥ 
2xULN




























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6.5.
Appendix 5 Prior and Concomitant Medications
Prior and Concomitant medications will be coded using the World Health Organization Drug 
Dictionary (WHO-DD). Prior medications are defined as any therapy used before the day of first 
dose (partial or complete) of study intervention. Concomitant medications are defined as any 
therapy used on or after the same day as the first dose of study intervention, including those that 
started before and continue on after the first dose of study intervention.
Summaries of concomitant medications will be presented by ATC class level 2, level 4 and 
preferred term, intervention arm, analysis phase and overall. The proportion of participants who 
receive each concomitant medication will be summarized as well as the proportion of participants 
who receive at least 1 concomitant medication. 
Prior medications will be summarized by intervention arm and overall, and ATC class level 2, 
level 4 and preferred term.


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6.6.
Appendix 6 Medical History
A tabulation of the general medical history coded terms will be provided by body system class, 
intervention arm and overall.


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6.7.
Appendix 7 Intervention Compliance
Compliance will be summarized for the safety analysis set by intervention arm for each study agent
(i.e. excluding NA).
Treatment compliance is defined as follows.

For JNJ-3989: (Total number of injections received/10) * 100%

For nivolumab: (Total number of infusions received/ Total number of infusions supposed to 
be received a) * 100%
a For participants in Arm 1, 1 infusion should be administered. For participants in Arm 2, a 
total of 3 infusions should be administered.


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6.8.
Appendix 8 Adverse Events of Special Interest
Adverse events of special interest list of MedDRA preferred terms.
Table 10: 
Adverse Events of Special Interest and Preferred Terms
Adverse 
Event of 
Special 
Interest
Source
Preferred Term
ALT/AST 
elevation
(Modified) Liver 
related investigations, 
signs and symptoms 
(SMQ) narrow, 
(MedDRA v25.0)
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
Acute renal failure 
(SMQ) narrow
(MedDRA v25.0)
Acute kidney injury
Acute phosphate nephropathy
Anuria
Azotaemia
Continuous haemodiafiltration
Dialysis
Foetal renal impairment
Haemodialysis
Haemofiltration
Neonatal anuria
Nephropathy toxic
Oliguria
Peritoneal dialysis
Prerenal failure
Renal failure
Renal failure neonatal
Renal impairment
Renal impairment neonatal
Subacute kidney injury
Acute renal failure 
(SMQ) broad
(MedDRA v25.0)
Albuminuria
Blood creatinine abnormal
Blood creatinine increased
Blood urea abnormal


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Table 10: 
Adverse Events of Special Interest and Preferred Terms
Adverse 
Event of 
Special 
Interest
Source
Preferred Term
Blood urea increased
Blood urea nitrogen/creatinine ratio increased
Creatinine renal clearance abnormal
Creatinine renal clearance decreased
Creatinine urine abnormal
Creatinine urine decreased
Crystal nephropathy
Fractional excretion of sodium
Glomerular filtration rate abnormal
Glomerular filtration rate decreased
Hypercreatininaemia
Hyponatriuria
Intradialytic parenteral nutrition
Kidney injury molecule-1
Nephritis
Neutrophil gelatinase-associated lipocalin increased
Oedema due to renal disease
Protein urine present
Proteinuria
Renal function test abnormal
Renal transplant
Renal tubular disorder
Renal tubular dysfunction
Renal tubular injury
Renal tubular necrosis
Tubulointerstitial nephritis
Urea renal clearance decreased
Urine output decreased
Tubulointerstitial 
diseases narrow
(MedDRA v25.0)
Acidosis hyperchloraemic
Acquired aminoaciduria
Acute phosphate nephropathy
Aminoaciduria
Beta-N-acetyl-D-glucosaminidase increased
Crystal nephropathy
Eosinophils urine present
Fanconi syndrome acquired
Hyperphosphaturia
Isosthenuria
Metabolic nephropathy
Nephritis allergic


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Table 10: 
Adverse Events of Special Interest and Preferred Terms
Adverse 
Event of 
Special 
Interest
Source
Preferred Term
Nephrogenic diabetes insipidus
Nephropathy toxic
Renal glycosuria
Renal papillary necrosis
Renal phospholipidosis
Renal tubular acidosis
Renal tubular atrophy
Renal tubular disorder
Renal tubular dysfunction
Tubulointerstitial nephritis
Tubulointerstitial nephritis and uveitis syndrome
Urine phosphorus increased
Urine retinol binding protein increased
Tubulointerstitial 
diseases broad
(MedDRA v25.0)
Albumin urine present
Albuminuria
Blood chloride increased
Blood uric acid decreased
Crystal urine present
Crystalluria
Cylindruria
Haematuria
Haemoglobin urine present
Haemoglobinuria
Hypercalcaemic nephropathy
Hyperchloraemia
Kidney fibrosis
Kidney small
Microalbuminuria
pH urine abnormal
pH urine increased
Polyuria
Potassium wasting nephropathy
Protein urine present
Proteinuria
Red blood cells urine positive
Renal atrophy
Renal tubular injury
Renal tubular necrosis
Sterile pyuria


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Table 10: 
Adverse Events of Special Interest and Preferred Terms
Adverse 
Event of 
Special 
Interest
Source
Preferred Term
Urinary casts present
Urine phosphorus abnormal
Hematologic 
abnormalities
(Modified)  
Haematopoietic 
cytopenias affecting 
more than one type of 
blood cell (SMQ), 
(MedDRA v25.0)
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 cytopenia
Myelosuppression
Pancytopenia
Panmyelopathy
Aspiration bone marrow abnormal
Biopsy bone marrow abnormal
Blood disorder
Bone marrow disorder
Bone marrow infiltration
Bone marrow myelogram abnormal
Bone marrow necrosis
Congenital aplastic anaemia
Haematotoxicity
Myelodysplastic syndrome
Myelodysplastic syndrome transformation
Myelofibrosis
Myeloid metaplasia
Plasmablast count decreased
Primary myelofibrosis
Scan bone marrow abnormal
(Modified) 
Haematopoietic 
erythropenia (SMQ), 
(MedDRA v25.0)
Anaemia macrocytic
Aplasia pure red cell
Aplastic anaemia
Erythroblast count decreased
Erythroid maturation arrest
Erythropenia
Hypoplastic anaemia


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Table 10: 
Adverse Events of Special Interest and Preferred Terms
Adverse 
Event of 
Special 
Interest
Source
Preferred Term
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
(Modified)  
Haematopoietic 
leukopenia (SMQ), 
(MedDRA v25.0)
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
Granulocyte percentage decreased
Granulocytes maturation arrest
Granulocytopenia
Idiopathic neutropenia
Leukopenia
Lymphocyte count decreased
Lymphopenia
Metamyelocyte count decreased


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Table 10: 
Adverse Events of Special Interest and Preferred Terms
Adverse 
Event of 
Special 
Interest
Source
Preferred Term
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
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
T-lymphocyte count abnormal
White blood cell analysis abnormal
White blood cell count abnormal
White blood cell disorder


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Table 10: 
Adverse Events of Special Interest and Preferred Terms
Adverse 
Event of 
Special 
Interest
Source
Preferred Term
(Modified) 
Haematopoietic 
thrombocytopenia 
(SMQ), (MedDRA 
v25.0)
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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6.9.
Appendix 9 Medications of Special Interest
Table 11: Medications of Special Interest
Concomitant 
Medication 
Special Interest 
Category
Concomitant 
Medication Special 
Interest ATC level 1
Standard ATC Name (level 
2)
Standard Medication 
Name/group (ATC level 3, 4 or 
5)
Systemic 
corticosteroids
Systemic hormonal 
preparations, excl. Sex 
hormones and insulins 
(H)
Corticosteroids for systemic 
use (H02)
H02A: Corticosteroids for 
systemic use, Plain
H02B: Corticosteroids for 
systemic use, Combinations
Miscellaneous 
hepatotoxic 
medications
Nervous system (N)
Anesthetics, general (N01)
Halothane (N01AB01)
Dermatology (D)
Antipsoriatics (D05)
Etretinate (D05BB01)
Antiinfectives 
for 
systemic use (J)
Antivirals for systemic use 
(J05)
Protease inhibitors (J05AE)
Lopinavir and ritonavir: 
J05AR10
Darunavir and cobicistat: 
J05AR14
Atazanavir and cobicistat: 
J05AR15
emtricitabine, tenofovir 
alafenamide, darunavir and 
cobicistat :J05AR22
Atazanavir and ritonavir: 
J05AR23
Darunavir and ritonavir: 
J05AR26
Alimentary tract and 
metabolism (A)
Drugs for acid related 
disorders (A02)
Omeprazole: A02BC01
Musculo-skeletal 
system (M)
Muscle relaxant (M03)
Dantrolene (M03CA01)
Antiparasitic products, 
insecticides 
and 
repellents (P)
Ectoparasiticides, incl. 
scabicides, insecticides and 
repellents (P03)
Disulfiram, combinations 
(P03AA54)
Musculo-skeletal 
system (M) 
Antiinflammatory and 
antirheumatic products
(M01)
Gold preparations (M01CB)
Systemic 
hormonal 
preparations, excl. Sex 
hormones and insulins 
(H)
Thyroid therapy (H03)
Propylthiouracil (H03BA02)
Immunosuppressive 
medications for the 
management 
of 
immune-related 
Systemic hormonal 
preparations, excl. Sex 
hormones and insulins 
(H)
Corticosteroids for systemic 
use (H02)
H02A: Corticosteroids for 
systemic use, Plain
H02B: Corticosteroids for 
systemic use, Combinations


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Table 11: Medications of Special Interest
Concomitant 
Medication 
Special Interest 
Category
Concomitant 
Medication Special 
Interest ATC level 1
Standard ATC Name (level 
2)
Standard Medication 
Name/group (ATC level 3, 4 or 
5)
AEs, injection site 
reactions 
or 
infusion-related 
reactions 
Antineoplastic and 
immunomodulating 
agents (L)
Immunosuppressants (L04)
L04AB Tumor necrosis factor 
alpha (TNF-α) inhibitors
Antineoplastic 
and 
immunomodulating 
agents (L)
Immunosuppressants (L04)
L04AA06:
mycophenolic acid
The method of analysis of the medications of special interest will be the same as the analysis 
described in Section 6.5.


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6.10.
Appendix 10 Laboratory Toxicity Grading
The laboratory abnormalities will be determined according to the criteria specified in the DAIDS
Toxicity Grading Scale (see Clinical Protocol Appendix 8, DAIDS Table with Modifications 
(DAIDS [Modified]) or in accordance with the normal ranges of the clinical laboratory if no 
gradings are available.


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7.
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Lui K.J., Kelly C. A Revisit on Tests for Homogeneity of the Risk Difference, Biometrics, 
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