Conditions: Hepatitis B, Chronic
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 1
Healthy volunteers: no

Brief summary:
The purpose of this study is to evaluate the efficacy in terms of hepatitis B surface antigen (HBsAg) changes from baseline for the treatment regimens of 24 weeks of JNJ-73763989 + 24 weeks of nucleos(t)ide analog (NA) + 12 or 24 weeks of pegylated interferon alpha-2a (PegIFN-alpha-2a) (with immediate or delayed start of PegIFN-alpha-2a treatment).

Detailed description:
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. Combination treatment with JNJ-73763989 and NA has the potential to specifically decrease HBV viral antigen levels and inhibit viral replication. Since HBsAg is immune suppressive, the direct reduction of HBsAg levels by JNJ-73763989 is anticipated to contribute to the restoration of the immune response that is impaired in chronic HBV infection. Pegylated interferon (PegIFN) is an approved drug for the treatment of chronic HBV infection and after a finite treatment duration of 48 weeks results in slightly increased HBsAg seroclearance rates. The primary hypothesis of this study is that at least one of the combination regimens of JNJ-73763989+NA+PegIFN-alpha-2a is more efficacious than NA treatment alone (standard of care), as measured by the primary efficacy endpoint. This study will be conducted in 3 periods: Screening Period (4 weeks), Treatment Period (24 weeks) and Follow-up (FU) Period (48 weeks), starting at Week 24. Safety assessments will include adverse events (AEs), serious AEs, clinical safety laboratory tests, electrocardiograms (ECGs), vital signs, ophthalmologic examinations and physical examinations. Total duration of individual participation will be up to 76 weeks (including screening period).

Arms:
arm 1: Participants will receive JNJ-73763989 subcutaneous (SC) injection once every 4 weeks for 24 weeks plus NA treatment (either entecavir \[ETV\], tenofovir disoproxil or tenofovir alafenamide \[TAF\] tablets orally) once daily for 24 weeks plus PegIFN-alpha-2a SC injection once weekly for 24 weeks. arm 2: Participants will receive JNJ-73763989 SC injection once every 4 weeks for 24 weeks plus NA treatment (either ETV, tenofovir disoproxil, or TAF tablets orally) once daily for 24 weeks plus PegIFN-alpha-2a SC injection once weekly from Week 12 till Week 24. arm 3: Participants will receive JNJ-73763989 SC injection once every 4 weeks for 24 weeks plus NA treatment (either ETV, tenofovir disoproxil or TAF tablets orally) once daily for 24 weeks plus PegIFN-alpha-2a SC injection once weekly from baseline till Week 12.

Interventions: intervention 1: JNJ-73763989 intervention 2: PegIFN-alpha-2a intervention 3: Tenofovir disoproxil intervention 4: TAF intervention 5: ETV
Intervention descriptions: intervention 1: JNJ-73763989 will be administered subcutaneously once every 4 weeks. intervention 2: PegIFN-alpha-2a will be administered subcutaneously once weekly. intervention 3: Tenofovir disoproxil film-coated tablet will be administered orally once daily. intervention 4: TAF film-coated tablet will be administered orally once daily. intervention 5: ETV film-coated tablet will be administered orally once daily.

Protocol document:
Prot_000.pdf: 
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
1
Status: Approved,  Date:  6 October 2021
Janssen Research & Development *
Clinical Protocol
Intervention-specific Appendix6 to Clinical Protocol PLATFORMPAHPB2001
A Phase 2, Open-label, Multicenter Study to Assess Efficacy, Safety, Tolerability, and
Pharmacokinetics of Treatment With JNJ-73763989, Nucleos(t)ide Analogs, and Pegylated
Interferon Alpha-2a in Patients With Chronic Hepatitis B Virus Infection
The PENGUIN-2 Study
Protocol 73763989PAHPB2007; Phase 2
Amendment 1
JNJ-73763989
*Janssen Research & Development is a global organization that operates through different legal entities in
various countries. Therefore, the legal entity acting as the Sponsor for Janssen Research & Development
studies may vary, such as, but not limited to Janssen Biotech, Inc.; Janssen Products, LP; Janssen
Biologics, BV; Janssen-Cilag International NV; Janssen, Inc; Janssen Pharmaceutica NV; Janssen
Sciences Ireland UC; Janssen Biopharma Inc.; or Janssen Research & Development, LLC. The term
“Sponsor” is used throughout the protocol to represent these various legal entities; the Sponsor is
identified on the Contact Information page that accompanies the protocol.
United States (US)sites of this study will be conducted under US Food & Drug Administration
Investigational New Drug (IND) regulations (21 CFR Part 312).
IND: 142609
EudraCT NUMBER: 2021-002450-81
Status: 
Approved
Date: 
6 October 2021
Prepared by: Janssen Research & Development, a division of Janssen Pharmaceutica NV
EDMS number: 
EDMS-RIM-400304, 3.0
GCP Compliance: This study will be conducted in compliance with Good Clinical Practice, and applicable regulatory
requirements.
Confidentiality Statement
The information provided herein contains Company trade secrets, commercial or financial information that the Company
customarily holds close and treats as confidential.  The information is being provided under the assurance that the recipient
will maintain the confidentiality of the information under applicable statutes, regulations, rules, protective orders or
otherwise.
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JNJ-73763989 
Clinical Protocol 73763989PAHPB2007 Amendment 1
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
2
Status: Approved,  Date:  6 October 2021
PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE
DOCUMENT HISTORY
Document 
Date
Amendment 1 
This document
Original Protocol 
30 June 2021
Amendment 1 (This document)
Overall Rationale for the Amendment:
The primary reasons for this amendment are to include pre-specified nucleos(t)ide analog (NA) treatment
completion criteria, and to add a new  NA re-treatment criterion  and more frequent monitoring for
participants who meet the NA treatment completion criteria based on the Week 24 (or Follow-up Week 2)
results and discontinue NA treatment during follow-up.
A severe clinical alanine aminotransferase (ALT) flare following discontinuation of NA treatment was
reported in a virologically suppressed hepatitis B e antigen (HBeAg) negative participant on long-term
tenofovir disoproxil fumarate (TDF)treatment, who was randomized to the control arm (placebo + placebo
+ NA) in the REEF-2 (73763989PAHPB2002) study. The participant presented with hepatitis B virus
(HBV) DNA levels that increased rapidly, before any relevant changes in liver markers were noted.
Discontinuation of NA treatment followed the protocol-defined criteria and was in line with recent
European Association for the Study of the Liver (EASL) treatment guidelines (EASL 2017). Flares
following NA discontinuation are not unexpected, but the rapid evolution and clinical deterioration seen in
this participant who was anti-HBe antibody positive at screening and had no history or evidence of liver
cirrhosis was unforeseeable. Therefore, to protect safety of participants, the protocol was amended as
detailed below.
Other changes were made in this amendment to lower the limit of serum hepatitis B surface antigen
(HBsAg) for inclusion from 100 to 5 IU/mL at screening, to adjust the primary endpoint to assess the
proportion of participants with a reduction of at least 2 log10 IU/mL in HBsAg levels from baseline at Week
24, and to revise and add secondary objectives and endpoints to account for the introduction of NA
treatment completion criteria.
In addition, the pegylated interferon alpha-2a (PegIFN-α2a) eligibility criteria, the PegIFN-α2a
discontinuation criteria, and the monitoring of neuropsychiatric adverse events during PegIFN-α2a
treatment were amended to be consistent with the PegIFN-α2a prescribing information.
Other clarifications and corrections were also made as detailed below.
Description of Change 
Brief Rationale 
Section Number and Name
A new NA re-treatment criterion
was added for participants who
discontinued NA treatment during
follow-up.
To ensure that participants with
significant HBV DNA increases
during treatment free follow-up are
monitored more frequently and/or
immediately re-start NA treatment
irrespective of ALT levels.
1.1 Synopsis,
1.3 Schedule of Activities,
2.3.2.2 Potential Risks,
4.2 Scientific Rationale for Study
Design,
6.5.2 NA Re-treatment Criteria
During Follow-up,
6.6 Continued Access to Study
Intervention After the End of the
Study,
8.3.6.2 Intervention-emergent
ALT/AST Elevations,
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JNJ-73763989 
Clinical Protocol 73763989PAHPB2007 Amendment 1
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
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Status: Approved,  Date:  6 October 2021
Description of Change 
Brief Rationale 
Section Number and Name
10.7 Appendix 7: Intervention-
emergent ALT/AST Elevations ,
10.12 Appendix 12: NA Re-
treatment During Follow-up
Participants who discontinue NA 
treatment during follow-up, will be 
monitored more frequently, with a 
study visit at least once every 4 
weeks. The visit frequency for 
participants who continue NA 
treatment or have restarted NA 
treatment during the follow-up 
period and for whom the HBV 
DNA and ALT values are stable
remains at least once every 12
weeks.
For participants with increased
follow-up, the total blood volume to
be collected during the study will
increase.
To further protect the safety of 
participants. 
1.1 Synopsis,
1.2 Schema,
1.3 Schedule of Activities
4.1 Overall Design,
6.5.1 NA Treatment Completion ,
6.5.2 NA Re-treatment Criteria
During Follow-up,
8 STUDY ASSESSMENTS AND
PROCEDURES
NA treatment completion criteria, 
which take ALT, HBV DNA, 
HBeAg, and HBsAg levels into 
consideration, were added. 
If the NA treatment completion 
criteria are met based on the Week 
24 or Follow-up (FU) Week 2 
results, treatment with NA will be 
stopped at the next scheduled visit 
(ie, FU Week 2 or FU Week 4). 
Because of that, the FU Week 2 
visit becomes a mandatory visit. 
To ensure that only participants 
with a higher chance of achieving 
sustained off-treatment response are 
allowed to stop all study 
intervention. 
1.1 Synopsis,
1.2 Schema,
1.3 Schedule of Activities,
2.3.3 Benefit-Risk Assessment for
Study Participation,
4.1 Overall Design,
4.2 Scientific Rationale for Study
Design,
6.5.1 NA Treatment Completion ,
6.5.2 NA Re-treatment Criteria
During Follow-up,
8.1 Efficacy Assessments,
11 REFERENCES
Inclusion criterion A13 was 
updated to lower the limit of serum 
HBsAg for inclusion from 100 to 5 
IU/mL at screening.
To assess treatment response in 
participants with a wider range of
HBsAg levels at baseline.
5.1 Inclusion Criteria
The primary endpoint was adjusted 
to assess the proportion of 
participants with a reduction of at 
least 2 log10 IU/mL in HBsAg 
levels from baseline at Week 24. 
The sample size section and the 
efficacy analyses section were 
revised accordingly. 
To accommodate the updated 
Inclusion criterion A13. 
1.1 Synopsis,
3 OBJECTIVES AND
ENDPOINTS,
9.1 Statistical Hypotheses,
9.2 Sample Size Determination,
9.4.2.1 Primary Efficacy Endpoint,
9.4.2.3 Across ISAs Comparisons
of Efficacy
One secondary objective to assess 
the efficacy of the study 
intervention was revised and 1 new 
secondary objective and endpoint
was added.
To account for the newly 
introduced NA treatment 
completion criteria. 
1.1 Synopsis,
3 OBJECTIVES AND
ENDPOINTS
The PegIFN-α2a discontinuation 
criteria were updated to clarify that 
participants with moderate or 
severe depression or other 
psychiatric symptoms should
Upon Health Authority request and 
to be consistent with the PegIFN- 
α2a prescribing information  
1.3 Schedule of Activities,
5.2 Exclusion Criteria,
7.1 Discontinuation of Study
Intervention
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Status: Approved,  Date:  6 October 2021
Description of Change 
Brief Rationale 
Section Number and Name
immediately discontinue PegIFN-
α2a treatment.
In addition, participants will be
closely monitored for
neuropsychiatric adverse events
during the PegIFN-α2a treatment
period. Participants who develop a
neuropsychiatric adverse event
during PegIFN-α2a treatment will
be monitored closely until the
neuropsychiatric adverse event
resolves, by frequent (at least
weekly) follow-up phone calls.
Furthermore, exclusion criterion
A24 was amended to exclude
participants with depression or
psychiatric disorders that are not
adequately controlled on a stable
medication regimen.
An additional TSH/T4 assessment 
and ophthalmologic examination 
was added at Week 20. 
To ensure that participants in Arm 2 
have these assessments after
initiating PegIFN-α2a treatment.
1.3 Schedule of Activities
An additional hematology sample 
was added at Week 36. 
To ensure sufficient hematology 
assessments during follow-up visits
that are applicable to all
participants.
1.3 Schedule of Activities
At sites collecting peripheral blood 
mononuclear cell (PBMC) samples, 
additional PBMC samples will be 
collected at Week 4 and Week 8. 
To explore when the earliest 
changes in HBV-specific T cell
responses and/or other immune cell
changes, such as NK cells, can be
observed following combination
treatment of JNJ-3989, NA, and
PegIFN-α2a.
1.3 Schedule of Activities
Recommendations regarding the 
use of live vaccines during the 
study were added. 
Clarification regarding the use of 
live vaccines during the study  
6.8 Concomitant Therapy,
10.10 Appendix 10: Study Conduct
During a Natural Disaster
Exclusion criterion A06 concerning 
laboratory abnormalities at
screening was updated.
Clarification 
5.2 Exclusion Criteria
Exclusion criterion A01 was 
adapted to clarify that participants 
with a positive HIV-1 or HIV-2
antibody/antigen test at screening
should have a confirmatory HIV
RNA test, to rule out false positive
results. They can be enrolled if they
have a negative HIV RNA test at
screening.
It was also clarified that
participants with evidence of HIV-1
or HIV-2 infection who are on
antiretroviral treatment are
excluded. 
Clarification upon Health Authority 
request
5.2 Exclusion Criteria
It was clarified that a participant 
who prematurely discontinues 
PegIFN-α2a (ie, before Week 23
Clarification 
4.1 Overall Design,
6.5.1 NA Treatment Completion
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Status: Approved,  Date:  6 October 2021
Description of Change 
Brief Rationale 
Section Number and Name
[Arms 1 and 2] or before Week 11 
[Arm 3]) should continue treatment 
with JNJ-3989 and NA as planned. 
7 DISCONTINUATION OF
STUDY INTERVENTION AND
PARTICIPANT
DISCONTINUATION/WITHDRA
WAL,
7.1 Discontinuation of Study
Intervention
The contraceptive guidance from 
the Master Protocol was replaced 
by ISA-specific contraceptive 
guidance, which includes the 
following updates versus the Master
Protocol version: the list of
examples which are not allowed as
sole method of contraception during
the study and the footnote
concerning possible interaction
between hormonal contraception
and the study intervention have
been removed. Additional
clarifications were also made.
Upon Health Authority request and 
to align with the latest version of 
the sponsor’s protocol template. 
1.3 Schedule of Activities,
5.1 Inclusion Criteria,
10.5Appendix 5: Contraceptive
and Barrier Guidance
It was clarified that urine pregnancy 
tests for at-home use are to be 
provided during the Follow-up 
period to participants who continue 
NA treatment or have restarted NA
treatment during the follow-up
period (provided that their HBV
DNA and ALT values are stable).
To allow 4-weekly urine pregnancy 
testing in between scheduled site 
visits for participants with less
frequent follow-up.
1.3 Schedule of Activities,
8.2.5Pregnancy Testing
It was clarified that venous blood 
samples will be collected for 
measurement of JNJ-3989, NA, and 
PegIFN-α2a. Bioanalysis of NA 
and PegIFN-α2a is optional at the
discretion of the sponsor.
Clarification 
1.1 Synopsis,
1.3 Schedule of Activities,
4.1 Overall Design,
8.4.1 Evaluations
It was clarified that a copy of the 
dermatologist’s report, biopsy, 
and/or digital pictures if performed
for rash management, should be
made anonymous and provided to
the sponsor.
Clarification 
10.6 Appendix 6: Rash
Management
Minor grammatical, formatting, or 
spelling changes were made.
Minor errors were noted 
Throughout the protocol
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Clinical Protocol 73763989PAHPB2007 Amendment 1
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Status: Approved,  Date:  6 October 2021
TABLE OF CONTENTS
PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE ............................................................... 2
DOCUMENT HISTORY ................................................................................................................................ 2
TABLE OF CONTENTS ............................................................................................................................... 6
LIST OF IN-TEXT TABLES AND FIGURES................................................................................................ 9
1. 
PROTOCOL SUMMARY................................................................................................................... 10
1.1. 
Synopsis......................................................................................................................................... 10
1.2. 
Schema.......................................................................................................................................... 23
1.3. 
Schedule of Activities..................................................................................................................... 24
2. 
INTRODUCTION................................................................................................................................ 31
2.1. 
Study Rationale.............................................................................................................................. 31
2.2. 
Background .................................................................................................................................... 32
2.2.1. 
Primary Pharmacology ............................................................................................................... 32
2.2.2. 
Nonclinical Studies ..................................................................................................................... 33
2.2.2.1. 
JNJ-3989 ................................................................................................................................. 33
2.2.2.2. 
Combination of JNJ-3989 and Entecavir, Tenofovir Disoproxil, or Tenofovir
Alafenamide............................................................................................................................. 35
2.2.2.3. 
Combination of JNJ-3989 and PegIFN-α2a............................................................................ 36
2.2.3. 
Clinical Studies ........................................................................................................................... 37
2.2.3.1. 
JNJ-3989 ................................................................................................................................. 37
2.2.3.2. 
Combination of JNJ-3989 and Entecavir, Tenofovir Disoproxil, or Tenofovir
Alafenamide............................................................................................................................. 38
2.2.3.3. 
Combination of JNJ-3989 and PegIFN-α2a............................................................................ 39
2.3. 
Benefit-Risk Assessment............................................................................................................... 40
2.3.1. 
Benefits for Study Participation .................................................................................................. 40
2.3.1.1. 
Known Benefits........................................................................................................................ 40
2.3.1.2. 
Potential Benefits..................................................................................................................... 40
2.3.2. 
Risks for Study Participation....................................................................................................... 40
2.3.2.1. 
Known Risks............................................................................................................................ 40
2.3.2.2. 
Potential Risks......................................................................................................................... 41
2.3.2.2.1. 
Potential Risks for JNJ-3989................................................................................................ 41
2.3.2.2.2. 
Potential Risks for Entecavir, Tenofovir Disoproxil, Tenofovir Alafenamide, and
PegIFN-α2a.......................................................................................................................... 42
2.3.3. 
Benefit-Risk Assessment for Study Participation ....................................................................... 42
3. 
OBJECTIVES AND ENDPOINTS ..................................................................................................... 44
4. 
STUDY DESIGN ................................................................................................................................ 46
4.1. 
Overall Design................................................................................................................................ 46
4.2. 
Scientific Rationale for Study Design............................................................................................. 49
4.2.1. 
Study-Specific Ethical Design Considerations ........................................................................... 51
4.3. 
Justification for Dose and Treatment Duration .............................................................................. 51
4.4. 
End of Study Definition................................................................................................................... 52
5. 
STUDY POPULATION ...................................................................................................................... 52
5.1. 
Inclusion Criteria............................................................................................................................ 53
5.2. 
Exclusion Criteria........................................................................................................................... 55
5.3. 
Lifestyle Considerations................................................................................................................. 60
5.4. 
Screen Failures.............................................................................................................................. 60
6. 
STUDY INTERVENTION AND CONCOMITANT THERAPY............................................................ 61
6.1. 
Study Intervention(s) Administered................................................................................................ 61
6.2. 
Preparation/Handling/Storage/Accountability ................................................................................ 64
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6.3. 
Measures to Minimize Bias: Randomization and Blinding............................................................. 65
6.4. 
Study Intervention Compliance...................................................................................................... 66
6.5. 
Dose Modification........................................................................................................................... 66
6.5.1. 
NA Treatment Completion .......................................................................................................... 67
6.5.2. 
NA Re-treatment Criteria During Follow-up................................................................................ 68
6.6. 
Continued Access to Study Intervention After the End of the Study ............................................. 69
6.7. 
Treatment of Overdose .................................................................................................................. 69
6.8. 
Concomitant Therapy..................................................................................................................... 70
7. 
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT
DISCONTINUATION/WITHDRAWAL............................................................................................... 71
7.1. 
Discontinuation of Study Intervention ............................................................................................ 72
7.2. 
Participant Discontinuation/Withdrawal From the Study................................................................ 74
7.2.1. 
Withdrawal From the Use of Research Samples ....................................................................... 74
7.3. 
Lost to Follow-up............................................................................................................................ 74
8. 
STUDY ASSESSMENTS AND PROCEDURES ............................................................................... 74
8.1. 
Efficacy Assessments .................................................................................................................... 75
8.1.1. 
Sequencing................................................................................................................................. 75
8.2. 
Safety Assessments....................................................................................................................... 76
8.2.1. 
Physical Examinations................................................................................................................ 76
8.2.2. 
Vital Signs................................................................................................................................... 76
8.2.3. 
Electrocardiograms..................................................................................................................... 76
8.2.4. 
Clinical Safety Laboratory Assessments .................................................................................... 76
8.2.5. 
Pregnancy Testing...................................................................................................................... 76
8.2.6. 
Ophthalmologic Examinations.................................................................................................... 77
8.3. 
Adverse Events, Serious Adverse Events, and Other Safety Reporting ....................................... 77
8.3.1. 
Time Period and Frequency for Collecting Adverse Event and Serious Adverse Event
Information.................................................................................................................................. 77
8.3.2. 
Method of Detecting Adverse Events and Serious Adverse Events .......................................... 77
8.3.3. 
Follow-up of Adverse Events and Serious Adverse Events ....................................................... 77
8.3.4. 
Regulatory Reporting Requirements for Serious Adverse Events ............................................. 77
8.3.5. 
Pregnancy................................................................................................................................... 77
8.3.6. 
Adverse Events of Special Interest............................................................................................. 77
8.3.6.1. 
Injection Site Reactions........................................................................................................... 78
8.3.6.2. 
Intervention-emergent ALT/AST Elevations............................................................................ 78
8.3.6.3. 
Hematologic Abnormalities...................................................................................................... 79
8.3.7. 
Other Toxicities........................................................................................................................... 80
8.3.7.1. 
Rash ........................................................................................................................................ 80
8.3.7.2. 
Renal Complications................................................................................................................ 80
8.3.7.3. 
Acute Systemic Allergic Reactions.......................................................................................... 81
8.4. 
Pharmacokinetics........................................................................................................................... 81
8.4.1. 
Evaluations ................................................................................................................................. 82
8.4.2. 
Analytical Procedures................................................................................................................. 82
8.4.3. 
Pharmacokinetic Parameters and Evaluations........................................................................... 82
8.5. 
Host Genetics................................................................................................................................. 82
8.6. 
Exploratory Host Biomarkers ......................................................................................................... 83
8.7. 
Immune Assessments.................................................................................................................... 83
8.8. 
Medical Resource Utilization.......................................................................................................... 84
9. 
STATISTICAL CONSIDERATIONS.................................................................................................. 84
9.1. 
Statistical Hypotheses.................................................................................................................... 84
9.2. 
Sample Size Determination ........................................................................................................... 84
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 Efficacy Endpoint ....................................................................................................... 86
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Status: Approved,  Date:  6 October 2021
9.4.2.2. 
Secondary Efficacy and Exploratory Endpoints ...................................................................... 87
9.4.2.3. 
Across ISAs Comparisons of Efficacy..................................................................................... 87
9.4.3. 
Safety Analyses.......................................................................................................................... 88
9.4.4. 
Other Analyses ........................................................................................................................... 88
9.5. 
Interim Analysis.............................................................................................................................. 89
10. SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS ............................ 91
10.1. 
Appendix 1: Abbreviations and Definitions .................................................................................... 91
10.2. 
Appendix 2: Clinical Laboratory Tests ........................................................................................... 94
10.3. 
Appendix 3: Regulatory, Ethical, and Study Oversight Considerations......................................... 96
10.3.1. 
Regulatory and Ethical Considerations ...................................................................................... 96
10.3.2. 
Financial Disclosure.................................................................................................................... 96
10.3.3. 
Informed Consent Process ......................................................................................................... 96
10.3.4. 
Data Protection........................................................................................................................... 96
10.3.5. 
Long-Term Retention of Samples for Additional Future Research ............................................ 96
10.3.6. 
Committees Structure................................................................................................................. 96
10.3.7. 
Publication Policy/Dissemination of Clinical Study Data............................................................ 96
10.3.8. 
DataQuality Assurance.............................................................................................................. 96
10.3.9. 
Case Report Form Completion................................................................................................... 96
10.3.10. Source Documents ..................................................................................................................... 97
10.3.11. Monitoring ................................................................................................................................... 97
10.3.12. On-Site Audits............................................................................................................................. 97
10.3.13. Record Retention........................................................................................................................ 97
10.3.14. Study and Site Start and Closure ............................................................................................... 97
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................................................................................................................................. 98
10.4.1. 
Adverse Event Definitions and Classifications ........................................................................... 98
10.4.2. 
Attribution Definitions.................................................................................................................. 98
10.4.3. 
Severity Criteria.......................................................................................................................... 98
10.4.4. 
Special Reporting Situations ...................................................................................................... 98
10.4.5. 
Procedures ................................................................................................................................. 98
10.4.6. 
Product Quality Complaint Handling........................................................................................... 98
10.4.7. 
Contacting Sponsor Regarding Safety, Including Product Quality............................................. 98
10.5. 
Appendix 5: Contraceptive and Barrier Guidance ......................................................................... 99
10.6. 
Appendix 6: Rash Management................................................................................................... 101
10.7. 
Appendix 7: Intervention-emergent ALT/AST Elevations ............................................................ 104
10.8. 
Appendix 8: Cardiovascular Safety –Abnormalities.................................................................... 105
10.9. 
Appendix 9: DAIDS Table ............................................................................................................ 106
10.10. Appendix 10: Study Conduct During a Natural Disaster.............................................................. 128
10.11. Appendix 11: Protocol Amendment History................................................................................. 133
10.12. Appendix 12: NA Re-treatment During Follow-up........................................................................ 134
11. REFERENCES................................................................................................................................. 135
INVESTIGATOR AGREEMENT............................................................................................................... 137
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Status: Approved,  Date:  6 October 2021
LIST OF IN-TEXT TABLES AND FIGURES
TABLES
Table 1: 
Animal-to-human Exposure Ratios at NOAEL for JNJ-3989.................................................... 35
Table 2: 
PegIFN-α2a Hematological Dose Modification Guidelines....................................................... 67
Table 3: 
Disallowed Medication .............................................................................................................. 71
Table 4: 
Management of Rash Events by Severity Grade ................................................................... 101
FIGURES
Figure 1: Schematic Overview of the Study............................................................................................. 23
NCT05005507


JNJ-73763989 
Clinical Protocol 73763989PAHPB2007 Amendment 1
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
10
Status: Approved,  Date:  6 October 2021
1. 
PROTOCOL SUMMARY
1.1. 
Synopsis
Clinical Protocol 73763989PAHPB2007: A Phase 2, Open-label, Multicenter Study to Assess Efficacy,
Safety, Tolerability, and Pharmacokinetics of Treatment With JNJ-73763989, Nucleos(t)ide Analogs, and
Pegylated Interferon Alpha-2a in Patients With Chronic Hepatitis B Virus Infection.
Protocol 73763989PAHPB2007 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 RNA (siRNA)
triggers in JNJ-3989, JNJ-73763976 (JNJ-3976) and JNJ-73763924 (JNJ-3924), are designed to target all
HBV ribonucleic acid (RNA) transcripts derived from covalently closed circular deoxyribonucleic acid
(cccDNA), as well as transcripts derived from integrated HBV deoxyribonucleic acid (DNA). The latter
has been suggested to be a significant source of hepatitis B surface antigen (HBsAg) in hepatitis B e antigen
(HBeAg)-negative patients or patients on long-term (≥2 years) treatment with nucleos(t)ide analogs (NAs),
the current standard of care.
The term “study intervention” throughout the protocol, refers to JNJ-3989, nucleos(t)ide analog (NA), and
pegylated interferon alpha-2a (PegIFN-α2a)
OBJECTIVES AND ENDPOINTS
Below is the list of objectives and endpoints that will be evaluated in this study, delineating the details in
alignment with the general objectives listed in the Master Protocol PLATFORMPAHPB2001. The details
specific for this ISA are highlighted (colored fill).
Objectives 
Endpoints
Primary
 
To evaluate the efficacy in terms of HBsAg 
changes from baseline for the treatment 
regimens of 24 weeks of JNJ-3989 + 24 weeks 
of NA + 12 or 24 weeks of PegIFN-α2a (with 
immediate or delayed start of PegIFN-α2a
treatment), as compared to NA standard of
care treatment.
 
Proportion of participants with a reduction of
at least 2 log10 IU/mL in HBsAg levels from
baseline at Week 24 (end of study intervention
[EOSI]).
Secondary
 
To evaluate the safety and tolerability of the 
study intervention. 
 
Safety and tolerability including but not
limited to the proportion of participants with
(S)AEs 
and 
abnormalities 
in 
clinical
laboratory tests (including hematology, blood
biochemistry, blood coagulation, urinalysis,
urine chemistry, renal biomarkers), 12-lead
electrocardiograms (ECGs), vital signs, and
ophthalmologic and physical examinations
throughout the study.
NCT05005507


NCT05005507


NCT05005507


JNJ-73763989 
Clinical Protocol 73763989PAHPB2007 Amendment 1
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
13
Status: Approved,  Date:  6 October 2021
 
Treatment Period (24 weeks):
 
Arm 1 (N=34): JNJ-3989 for 24 weeks + NA for 24 weeks + PegIFN-α2a for 24 weeks.
 
Arm 2 (N=34): JNJ-3989 for 24 weeks + NA for 24 weeks + PegIFN-α2a from Week 12 till
Week 24.
 
Arm 3 (N=34): JNJ-3989 for 24 weeks + NA for 24 weeks + PegIFN-α2a from baseline till
Week 12.
 
Follow-up (FU) Period (48 weeks), starting at Week 24.
At baseline, participants who meet the eligibility criteria will be randomized in a 1:1:1 ratio to Arm 1, Arm
2, or Arm 3. Randomization will be stratified by absolute HBsAg level (<1,000 IU/mL versus >1,000
IU/mL) at baseline and country grouping as proxy for HBV genotype (GT) at enrollment, with 3 levels:
Poland (predominantly GT-A) versus Russia (predominantly GT-D) versus all other countries (other or
mixed GT prevalence)a. Participants in Arm 2 who no longer meet the PegIFN-α2a eligibility criteria at
Week 12, based on available laboratory or clinical data, will continue JNJ-3989 and NA treatment until
Week 24 without PegIFN-α2a.
All participants will receive the last dose of JNJ-3989 at Week 24 and the last dose of PegIFN-α2a at Week
23 (Arms 1 and 2) or Week 11 (Arm 3). They will start the FU Period after the Week 24 visit. If all of the
following NA treatment completion criteria are met based on the Week 24 results, treatment with NA will
be stopped at the next scheduled visit (ie, FU Week 2), otherwise NA treatment will continue during the
complete FU Period:
 
The participant has ALT <3x ULN, AND
 
The participant has HBV DNA <60 IU/mL at Week 24 and HBV DNA <LLOQ at the previous visit,
or HBV DNA <LLOQ at Week 24, AND
 
The participant is HBeAg-negative, AND
 
The participant has HBsAg <100 IU/mL.
Note: Participants who are close to meeting the protocol-defined NA treatment completion criteria with the
Week 24 results, and do meet the criteria based on the FU Week 2 results may be allowed to stop NA at
FU Week 4, after consultation with the Sponsor.
Participants who meet the protocol-defined NA treatment completion criteria based on the Week 24 or FU
Week 2 results will be monitored closely during the 48-week FU Period with a study visit at least once
every 4 weeks. NA treatment should be re-started in accordance with the NA re-treatment criteria (see
below for more details).
Study intervention consists of:
 
JNJ-3989: 200 mg subcutaneous injection every 4 weeks (Q4W)
 
NA: tenofovir disoproxil (245 mg), or tenofovir alafenamide (TAF) (25 mg), or entecavir (ETV) (0.5
mg) tablets orally, daily (QD)
 
PegIFN-α2a: 180 µg subcutaneous injection weekly (QW).
Assessments and sampling include efficacy (eg, HBsAg, HBeAg, and HBV DNA), safety (eg, [S]AEs, labs,
ECGs, vital signs, physical examinations), PK, PK/ PD, viral genome sequencing, PBMC, human leukocyte
a Kim BK, Revill PA, Ahn SH, et al. HBV genotypes: relevance to natural history, pathogenesis and treatment of
chronic hepatitis B. Antiviral Therapy. 2011;16:1169-1186
NCT05005507


JNJ-73763989 
Clinical Protocol 73763989PAHPB2007 Amendment 1
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
14
Status: Approved,  Date:  6 October 2021
antigen (HLA) typing, immunogenicity and pharmacogenomic samples, blood sampling for exploratory
analysis of host and viral markers, and medical resource utilization.
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).
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.
NA Re-treatment Criteria During Follow-up
Participants who meet the protocol-defined NA treatment completion criteria (based on the Week 24 or FU
Week 2 results) will be monitored closely during the follow-up period with a study visit at least once every
4 weeks. They should re-start NA treatment immediately in the event of:
 
Signs of decreasing liver function based on laboratory findings (eg, International Normalized Ratio
[INR], direct bilirubin) or clinical assessment (eg, ascites, hepatic encephalopathy).
 
HBV DNA value of >1,000,000 IU/mL (irrespective of confirmation and/or ALT increase).
Note: A post-treatment HBV DNA value of >100,000 IU/mL should trigger re-testing of
ALT/AST, HBV DNA, and total and direct bilirubin within a maximum of 7 days from receipt of
the data and further repeats as necessary (ie, weekly until HBV DNA returns to <100,000 IU/mL).
A post-treatment HBV DNA value of >20,000 IU/mL (but <100,000 IU/mL) should trigger a re-
test within 14 days. At all times, additional re-testing of the above parameters should be performed
at the investigator’s discretion.
In addition, re-start of NA treatment should be considered in the following cases:
 
Confirmed post-treatment HBeAg seroreversion (HBeAg positive after it was negative at NA
completion), OR
 
Confirmed (at least 4 weeks apart) post-treatment increases in HBV DNA >2,000 IU/mL and ALT
>5x upper limit of normal (ULN), OR
Note: A post-treatment ALT value of >5x ULN should trigger re-testing of ALT, AST, ALP, total
and direct bilirubin, INR, albumin, and HBV DNA on a weekly basis until ALT and AST levels
have returned to <5x ULN. At all times, additional re-testing of these parameters should be
performed at the investigator’s discretion.
 
Confirmed (at least 4 weeks apart) post-treatment increases in HBV DNA >20,000 IU/mL.
The decision to re-start NA treatment should take into consideration the dynamics of HBsAg, HBV DNA
and/or ALT values and should be discussed with the Sponsor.
To avoid delays in decision making, sites are encouraged to run local re-testing in parallel with central re-
testing in the situations described above that require more frequent re-testing. Local test results are to be
recorded in the CRF and/or source documents, including information on the HBV DNA assay used. In
addition, to avoid delays in NA re-treatment, it should be considered to dispense NA to participants who
potentially met the NA re-treatment criteria (eg, pending confirmation) and who will not be available to
come to the study site immediately at the time the confirmatory test results will become available. This
should ensure that the participant can immediately re-start NA treatment if indicated, upon direct
confirmation by the investigator.
In case NA treatment is re-started, participants will be followed until the end of the study or until clinical
stabilization, whichever comes later.
NCT05005507


JNJ-73763989 
Clinical Protocol 73763989PAHPB2007 Amendment 1
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
15
Status: Approved,  Date:  6 October 2021
NUMBER OF PARTICIPANTS
Approximately  102 long-term (≥2 years of NA treatment) 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 65 years of age (inclusive) will be enrolled in this study.
NCT05005507


JNJ-73763989 
Clinical Protocol 73763989PAHPB2007 Amendment 1
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
16
Status: Approved,  Date:  6 October 2021
DESCRIPTION OF INTERVENTIONS
Intervention Name 
JNJ-3989 
PegIFN-α2a 
Tenofovir disoproxil 
Tenofovir alafenamide 
(TAF)* 
Entecavir (ETV)
monohydrate
Type 
Drug 
Drug 
Drug 
Drug 
Drug
Dose Formulation 
Solution for injection  
Solution for injection  
Film coated tablets 
Film coated tablets 
Film coated tablets
Unit Dose Strength(s) 
200 mg/mL 
180 µg/0.5 mL 
245 mg 
25 mg 
0.5 mg
Dosage Level(s) 
200 mg once every 4 
weeks (Q4W) 
180 µg once weekly 
(QW)
245 mg QD  
25 mg QD  
0.5 mg QD
Route of Administration 
Subcutaneous injection 
(preferably in the 
abdomen) 
Subcutaneous injection 
(in the thigh or
abdomen)
Oral 
Oral 
Oral
Use 
Investigational 
intervention  
Investigational 
intervention
Background intervention  Background intervention  Background intervention
Investigational Medicinal 
Product (IMP)
Yes 
Yes 
Yes 
Yes 
Yes
Non-investigational Medicinal 
Product/ Auxiliary Medicinal
Product (NIMP/AxMP)
No 
No 
No 
No 
No
Sourcing 
Provided centrally by the 
Sponsor 
Provided centrally by the 
Sponsor 
Provided centrally by the 
Sponsor 
Provided centrally by the 
Sponsor 
Provided centrally by the
Sponsor
Packaging and Labeling 
Each unit will be labeled 
with unique medication 
ID number 
Commercial supplies 
will be sourced. Each 
unit will be labeled with 
unique medication ID 
number. 
Commercial supplies 
will be sourced. Each 
unit will be labeled with 
unique medication ID 
number. 
Commercial supplies 
will be sourced. Each 
unit will be labeled with 
unique medication ID 
number. 
Commercial supplies
will be sourced. Each
unit will be labeled with
unique medication ID
number.
In child resistant 
packaging 
In child resistant 
packaging 
In child resistant 
packaging 
In child resistant
packaging
Food/Fasting Instructions 
Regardless of food 
intake 
Per the prescribing 
information  
Per the prescribing 
information  
Per the prescribing 
information  
Per the prescribing
information
Q4W: once every 4 weeks; QD: once daily; QW: once weekly.
* In countries where TAF is available, it will be one of the NA treatment options.
NCT05005507


JNJ-73763989 
Clinical Protocol 73763989PAHPB2007 Amendment 1
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
17
Status: Approved,  Date:  6 October 2021
EFFICACY EVALUATIONS
All efficacy assessments will be performed at predefined time points as specified in the Schedule of
Activities.
Qualitative and quantitative HBsAg and HBeAg, and quantitative HBcrAg as well as anti-hepatitis B
surface (HBs) and anti-hepatitis B e (HBe) antibodies will be determined using validated serologic assays
in a central laboratory. Samples for the determination of HBsAg and HBeAg will be processed in real-time.
Samples for the determination of HBcrAg can be analyzed in batch and at the Sponsor’s request.
HBV DNA and HBV RNA will be 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. In
addition, ophthalmologic examinations will be performed at the time points specified in the Schedule of
Activities.
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 
injection 
site 
reactions (ISRs), 
alanine
aminotransferase/aspartate aminotransferase (ALT/AST) elevations, and hematologic abnormalities. In
addition, the following toxicities will also be carefully monitored: rash, renal complications, and acute
systemic allergic reactions.
PHARMACOKINETIC EVALUATIONS
All participants will have sparse PK sampling during the treatment period.
Venous blood samples will be collected for measurement of plasma or serum (as applicable) concentrations
of JNJ-3989 (ie, JNJ-3976 and JNJ-3924), NA and PegIFN-α2a, at time points specified in the Schedule of
Activities. Bioanalysis of NA and PegIFN-α2a is optional at the discretion of the sponsor.
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 PegIFN-
α2a, with selected efficacy and/or safety endpoints may be evaluated, ifapplicable.
NCT05005507


JNJ-73763989 
Clinical Protocol 73763989PAHPB2007 Amendment 1
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
18
Status: Approved,  Date:  6 October 2021
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. These samples could for example be used to assess
changes in frequencies of immune cells such as myeloid-derived suppressor cells (MDSCs). 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.
These analyses will be performed at the Sponsor’s discretion, will always be under the Sponsor’s
supervision, and may be reported separately.
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 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
using proliferation or cytotoxic assays or other methods such as cytometry by time of flight to evaluate
innate and adaptive immune responses. Leftover PBMC samples may be used at the Sponsor’s discretion
for additional exploratory research (eg, assessment of other immune cells such as natural killer (NK)-cells,
MDSCs, dendritic cells [DCs], and B-cells) related to HBV infection or study intervention
(safety/efficacy), 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 optionally to PegIFN-α2a. Antidrug antibodies may
NCT05005507


JNJ-73763989 
Clinical Protocol 73763989PAHPB2007 Amendment 1
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
19
Status: Approved,  Date:  6 October 2021
be analyzed using assays such as an enzyme-linked immunosorbent assay or functional assays. The analyses
may also include gene expression and cytokine analyses assessing markers such as interferon-stimulated
genes (ISGs), IFN-α, and interferon γ-induced protein 10 (IP-10).
Medical Resource Utilization
Medical resource utilization data, associated with medical encounters, will be collected in the CRF by the
investigator and study site personnel for all participants throughout the study. Protocol-mandated
procedures, tests, and encounters are excluded. The data collected may be used to conduct exploratory
economic analyses and will include:
 
Number and 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 Determination
A sample size of 30 participants per arm yields >95% statistical power to detect a ≥30% difference in at
least one arm in the proportions of participants with a reduction of at least 2 log10 IU/mL in HBsAg levels
from baseline at Week 24 versus a fixed proportion of ≤2%, assumed for external control (NA treatment).
Statistical power to test the primary hypothesis was assessed for each of the intervention arms, separately,
using an exact test for single proportion with a one-sided Type 1 error rate of 0.05 and applying the
Hochberg procedure for multiple comparisons adjustment. The assumed external control value is based on
the data of the NA control arm in virologically suppressed HBeAg negative participants in study
73763989HPB2001 (REEF-1).
The total study sample size is 102 participants (34 per arm) with 1:1:1 randomization ratio to one of the
three intervention arms, assuming an approximate 10% attrition rate.
For the secondary set of pairwise comparisons of the primary efficacy endpoint among the 3 study
intervention arms (Arm1 versus Arm 2, Arm 1 versus Arm 3, and Arm 2 versus Arm 3), the planned sample
size yields about 68% power to detect a significant difference of 30%, assuming the lowest response rate at
Week 24 to be 50% in one of the intervention arms, and 80% in one or both of the other 2 arms. The one-
sided Type 1 error rate of 0.05 will be controlled for multiplicity by the Hochberg procedure.
Efficacy Analyses
The primary efficacy analysis will be performed when all participants have completed the Week 24 (EOSI)
visit or discontinued earlier. The final analysis will be performed when all participants have completed the
last study visit at Week 72 (FU Week 48) or discontinued earlier.
To evaluate the efficacy, the primary analysis set will be the Full Analysis Set (FAS; ie, 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). The IFN-FAS set will be used for sensitivity analyses of selected efficacy
endpoints. (ie, all participants who were randomly assigned to an intervention arm in this ISA and received
at least 1 dose of PegIFN-α2a within this ISA).
NCT05005507


JNJ-73763989 
Clinical Protocol 73763989PAHPB2007 Amendment 1
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
20
Status: Approved,  Date:  6 October 2021
Primary Efficacy Endpoint
The proportion of participants who achieved a reduction of at least 2 log10 IU/mL in HBsAg levels from
baseline at Week 24 will be summarized for each treatment arm paired 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 2% at a one-sided Type 1
error rate of 0.05 and applying the Hochberg procedure for adjusting for multiple comparisons.
The Mantel-Haenszel (MH) test adjusted for the randomization stratification factors will be used in a
secondary analysis comparing the primary endpoint between the study intervention arms at a one-sided
alpha level of 0.05and applying the Hochberg procedure for multiple comparisons adjustment.
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 will 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, waterfall, and radar plots) will also be
used to summarize the efficacy data by intervention arm and over time.
Across ISAs Comparisons of Efficacy
To further evaluate the impact of potential differences between ISAs, a virtual control armwill be generated
for this ISA. Virtual control efficacy data will be defined as IFN-free regimen with JNJ-3989+NA at the
dose level used in this ISA. Creating a virtual control arm by fitting the PK/PD model to the available
HBsAg data can be performed for subjects with  serum HBsAg >100 IU/mL at screening. The same
approach may also be considered for subjects with serum HBsAg ≤100 IU/mL at screening, but as these
subjects were typically not included in previous JNJ-3989 studies, the feasibility of this approach will be
assessed based on the current analysis results.
For each participant in Arm 2 of this ISA, the HBsAg data for “virtual” control subjects will be generated
using an appropriate longitudinal model (eg, kinetic pharmacodynamic model [KPD] or PK/PD model)
developed and validated based on the data from the 73763989HPB2001 (REEF-1) study. In Arm 2, the first
12 weeks of HBsAg data under treatment with JNJ-3989+NA alone will enable to estimate individual
parameters (ie, Empirical Bayes Estimates) describing each participant's specific HBsAg temporal kinetics.
These individual parameters will be used further to extrapolate each participant’s individual HBsAg values
over time, as if that participant had been treated with JNJ-3989+NA regimen (matching the same JNJ-3989
dose level) but without receiving PegIFN-α2a treatment. The observed HBsAg levels post PegIFN-α2a
intake will be directly compared to virtual control model-generated data for this arm. Due to the
randomization, the virtual control subjects derived for Arm 2 can be considered exchangeable with the
participants of the other arms in this ISA. Therefore, the summary statistics at the group level of the virtual
control subjects for Arm 2 constitute a virtual control arm for the other arms.
In addition, indirect comparisons of the primary endpoint between different regimens across ISAs will be
performed in an exploratory fashion by selecting the similar subgroup of participants in other ISAs who
match the most important inclusion/exclusion criteria and demographic characteristics in this ISA, such as
for example the virologically suppressed participants who are HBeAg negative at screening.
More details on this approach and its application to secondary endpoints will be provided in a separate
analysis plan document.
NCT05005507


JNJ-73763989 
Clinical Protocol 73763989PAHPB2007 Amendment 1
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
21
Status: Approved,  Date:  6 October 2021
Safety Analyses
Safety analyses will be based on the safety population.
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 overall and 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
PegIFN-α2a may be performed using non-linear mixed effects modeling. Data may be combined with
selected Phase 1 and/or 2 studies to support a relevant structural model. Available participant characteristics
(eg, demographics, laboratory variables, genotypes) will be included in the model as necessary. Details will
be given in a population PK analysis plan and results of the population PK analysis, if applied, will be
presented in a separate report.
Pharmacokinetic/Pharmacodynamic Analyses
Relationships of PK parameters for JNJ-3976 and JNJ-3924, and, optionally, for NA and PegIFN-α2a with
selected efficacy and with selected 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.
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.
NCT05005507


JNJ-73763989 
Clinical Protocol 73763989PAHPB2007 Amendment 1
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
22
Status: Approved,  Date:  6 October 2021
Immune Analyses
Descriptive statistics (n, mean, standard deviation [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, tumor necrosis factor [TNF]-α or IFN-γ specific to any HBV antigen) as defined by
ELISpot and/or ICS, respectively. Changes from baseline (or positivity treshold) 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.
Interim Analyses
Interim analyses (IA) 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.
The IAs are planned when:
 
Approximately 50% of the randomized participants have completed Week 12 or discontinued earlier.
 
Approximately 50% of the randomized participants have completed Week 24 or discontinued earlier.
 
All randomized participants have completed Week 36 (FU Week 12) or discontinued earlier.
 
All randomized participants have completed Week 48 (FU Week 24) or discontinued earlier.
 
All randomized participants have completed Week 60 (FU Week 36) 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 cutoffs 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 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.
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1.2. 
Schema
Figure 1: 
Schematic Overview of the Study
ALT: alanine aminotransferase; DNA: deoxyribonucleic acid; EOS: end of study; EOSI: end of study intervention; FU: follow-up; HBeAg: hepatitis B e antigen; HBV:
hepatitis B virus; JNJ-3989: JNJ-73763989; N: number of participants; NA: nucleos(t)ide analog; PegIFN-α2a: pegylated interferon alpha-2a; Q4W: every 4 weeks; QD:
once daily; QW: once weekly; Rand: randomization.
a 
If all of the NA treatment completion criteria (see Section 6.5.1, NA Treatment Completion, for more details) are met based on the Week 24 results, NA will be
stopped at the next scheduled visit (ie, FU Week 2), otherwise NA treatment will continue during the complete FU period.
Note: Participants who are close to meeting the protocol-defined NA treatment completion criteria with the Week 24 results, and do meet the criteria based on the
FU Week 2 results may be allowed to stop NA at FU Week 4, after consultation with the Sponsor.
Participants who meet the protocol-defined NA treatment completion criteria will be monitored closely during the 48-week FU Period with a study visit at least
once every 4 weeks. NA treatment should be re-started in accordance with the NA re-treatment criteria (see Section 6.5.2, NA Re-treatment Criteria During
Follow-up, for more details).
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qq. All participants will have sparse PK sampling for JNJ 3989, NA, and PegIFN α2a at any time between 2 and 6 hours post dose, and an optional sample for JNJ 3989, NA, and
PegIFN α2a may be taken 6 to 24 hours post dose. Bioanalysis of NA and PegIFN α2a is optional at the discretion of the sponsor.
For all samples, the date and time of the preceding 2 intakes of NA, the date and time of the previous JNJ 3989 and PegIFN α2a administration, as applicable, and the date and time
of PK sampling should be recorded. Before leaving the study site, the participant’s well being should be confirmed.
rr. 
Sample to be collected before and 4 6 hours after administration of study intervention (JNJ 3989 and PegIFN α2a)on Day 1 (Arms 1 and 3) or Week 12 (Arm 2).
ss. 
These samples are optional and will only be collected from participants who consent separately to this component of the study. The exploratory host genotyping sample should
preferably be collected at baseline.
tt. 
PBMC samples will be collected at selected sites only. Additional PBMC samples may be taken in case of ALT flares, upon discussion with the Sponsor, and may require an
unscheduled visit. If a PBMC sample has been taken within the last 4 weeks prior to the unscheduled visit, no new PBMC sample is to be collected.
uu. Adverse events and concomitant medications will be monitored from the time a signed and dated ISA ICF is obtained until completion of the participant’s last ISA related procedure.
vv. Includes close monitoring for neuropsychiatric adverse events during the PegIFN α2a treatment period. Participants who develop a neuropsychiatric adverse event during PegIFN
α2a treatment, will be monitored closely until the neuropsychiatric adverse event resolves, with frequent (at least weekly) follow up phone calls.
ww. A post treatment HBV DNA value of >100,000 IU/mL should trigger re testing of ALT/AST, HBV DNA, and total and direct bilirubin within a maximum of 7 days from receipt of
the data and further repeats as necessary (ie, weekly until HBV DNA returns to <100,000 IU/mL). A post treatment HBV DNA value of >20,000 IU/mL (but <100,000 IU/mL)
should trigger a re test within 14 days. A post treatment ALT value of >5x ULN should trigger re testing of ALT, AST, ALP, total and direct bilirubin, INR, albumin, and HBV
DNA on a weekly basis until ALT and AST levels have returned to <5x ULN. At all times, additional re testing of the above parameters should be performed at the investigator’s
discretion. In these situations that require more frequent re testing, sites are encouraged to run local re testing in parallel with central re testing. Local test results are to be recorded
in the CRF and/or source documents, including information on the HBV DNA assay used.
NA treatment should be re started in accordance with the NA re treatment criteria (see Section 6.5.2, NA Re treatment Criteria During Follow up, for more details). NA treatment
should be re started immediately in the event of signs of decreasing liver function based on laboratory findings (eg, INR, direct bilirubin) or clinical assessment (eg, ascites, hepatic
encephalopathy), or an HBV DNA value of >1,000,000 IU/mL (irrespective of confirmation and/or ALT increase).
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2. 
INTRODUCTION
This intervention-specific appendix (ISA) describes a Phase 2 study of JNJ-73763989 (JNJ-3989)
in combination with a nucleos(t)ide analog (NA)and pegylated interferon alpha-2a (PegIFN-α2a).
It is a companion document to the Master Protocol PLATFORMPAHPB2001, which describes the
Sponsor’s Platform study in participants with chronic HBV infection. This ISA describes specific
and/or additional protocol elements applicable to this intervention cohort.
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 RNA (siRNA) triggers in JNJ-3989, JNJ-73763976 (JNJ-3976) and JNJ-73763924
(JNJ-3924), are designed to target all HBV ribonucleic acid (RNA) transcripts derived from
covalently closed circular deoxyribonucleic acid (cccDNA), as well as transcripts derived from
integrated HBV deoxyribonucleic acid (DNA). The latter has been suggested to be a significant
source of hepatitis B surface antigen (HBsAg) in hepatitis B e antigen (HBeAg)-negative patients
or patients on long-term (≥2 years) treatment with NAs, the current standard of care (Wooddell
2017).
Select NAs and PegIFN-α2a 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)for JNJ-3989 (IB JNJ-3989). For nonclinical and
clinical information regarding NA and PegIFN-α2a, refer to their respective prescribing
information.
An introduction on HBV and the current treatment options is provided in Section 2 of the Master
Protocol PLATFORMPAHPB2001.
The term “study intervention” throughout the protocol, refers to JNJ-3989, NA, and PegIFN-α2a
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 the potential to specifically decrease HBV viral
antigen levels and inhibit viral replication. Since HBsAg is immune suppressive, the direct
reduction of HBsAg levels by JNJ-3989 is anticipated to contribute to the restoration of the
immune response that is impaired in chronic HBV infection.
PegIFN is an approved drug for the treatment of chronic HBV infection and after a finite treatment
duration of 48 weeks results in slightly increased HBsAg seroclearance rates compared to NA
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alone (Slaets 2020). PegIFN with its dual mode of action (direct antiviral effect [Belloni 2012,
Lucifora 2014, Xu 2010, Yan 2015] and immune boosting effect [Gill 2016]) is expected to
contribute to additional HBsAg decline and restoration of immune response including natural killer
(NK) cell activation.
The current study is designed to assess efficacy and safety of a treatment regimen of 24 weeks of
JNJ-3989 and NA, and 3 different treatment schedules for PegIFN-α2a. PegIFN-α2a will be
administered during the complete 24-week treatment period for participants in Arm 1, during the
second half of the treatment period (Week 12 till Week 24) for participants in Arm 2, and during
the first half (from baseline till Week 12) for participants in Arm 3.
Long-term (≥2 years of NA treatment) virologically suppressed, HBeAg-negative, chronic HBV-
infected, adult patients will be enrolled.
The primary objective of the study will be to assess the effect of the study intervention
(JNJ-3989+NA+PegIFN-α2a) versus NA standard of care treatment on HBsAg levels at end of
study intervention (EOSI) at Week 24. In addition, off-treatment efficacy will be explored to
evaluate if the study intervention results in functional cure in patients with chronic HBV infection,
defined as HBsAg seroclearance 24-weeks after EOSI. The complete follow-up (FU) Period will
be 48 weeks, starting at EOSI.
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
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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 subcutaneous 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 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
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 suprapharmacologic 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
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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)
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 subcutaneous 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 subcutaneous injection by a range of non-carcinogenic agents after varying periods of time.
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),
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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 subcutaneous 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
mg/kg,
and a NOAEL in female rats of
 mg/kg.
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 offdate 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. 
Combination of JNJ-3989 and Entecavir, Tenofovir Disoproxil, or
Tenofovir Alafenamide
There is no common target organ 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.
In the chronic rat studies with JNJ-3989, slight alteration of the renal tubular epithelium was
characterized by basophilic stippling and/or microvacuolation of the cytoplasm of renal tubules in
the outer cortex in rats. These findings were not considered toxicologically meaningful since they
were related to compound accumulation, there was no evidence of cellular damage
(degeneration/necrosis) and there were no correlated clinical pathology indicators of changes in
CCI
CC
CCI
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renal function (Henry 2012; Janas 2018a). These kidney findings have been observed in both the
2-week and 6-month studies and did not worsen over time. No kidney findings were observed in
monkeys.
For tenofovir disoproxil, renal tubular epithelial karyomegaly was observed in rats, dogs, and
monkeys (Memorandum 2001). In dogs, the species most sensitive to tenofovir disoproxil-related
effects on the kidney, additional microscopic alterations following chronic administration of
tenofovir disoproxil (10 mg/kg/day for 42 weeks) included individual tubular cell necrosis, tubular
dilatation, tubular degeneration/regeneration, pigment accumulation, and interstitial nephritis. This
was associated with biochemical changes such as slight elevation in serum creatinine, glucosuria,
proteinuria, and increased urine volume. The incidence and severity of nephrotoxicity was dose
related. Effects were reversible following cessation of treatment. In Rhesus monkeys, biochemical
and/or histopathologic evidence of nephrotoxicity was observed at high doses. In rats, slight
elevations in serum creatinine were observed without any histopathology correlation
For TAF, minimal renal cortical tubular karyomegaly and/or basophilia was seen in rats and dogs.
In addition, minimal renal cortical tubular degeneration/regeneration were reported in dogs. No
renal findings were reported in monkeys (EMA Vemlidy 2020).
Based on the available toxicology data, there are no specific concerns about additive or synergistic
toxicities in the kidney when JNJ-3989 is combined with ETV, tenofovir disoproxil, or TAF. In
addition, no clinically relevant drug-drug interactions (DDIs) are expected when JNJ-3989 is
combined with ETV, or tenofovir disoproxil, or TAF.
2.2.2.3. 
Combination of JNJ-3989 and PegIFN-α2a
A 3-month combination toxicity study of JNJ-3989 and PegIFN-α2a (Pegasys®) was conducted
in male and female Cynomolgus monkeys (Study TOX14273). JNJ-3989 was administered at 60
or 180 mg/kg (SC, monthly) in combination with PegIFN-α2a at 0.015 mg/kg (SC, twice weekly).
In addition, 180 mg/kg JNJ-3989 (SC, monthly) or PegIFN-α2a (0.015 mg/kg; SC, twice weekly)
were dosed in monotherapy groups. The study was conducted in monkeys as the toxicity profile
of both PegIFN-α2a and JNJ-3989 were known in monkeys (rat studies were not performed with
PegIFN-α2a).
There were no test item-related mortalities. JNJ-3989 (alone or combined with PegIFN-α2a) was
well tolerated and did not induce effects on clinical signs, body weight, food consumption,
ophthalmoscopic examination, electrocardiology evaluation, coagulation, clinical chemistry or
urinalysis parameters, as well as organ weight and macroscopic examination.
Transient local reactions (edema and erythema) were observed at the administration site at 60
and/or 180 mg/kg JNJ-3989. These reactions were also observed with PegIFN-α2a alone and
incidentally in control females (erythema only). They were not correlated with microscopic
findings.
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Administration of JNJ-3989 alone or combined with PegIFN-α2a elicited minimal to mild,
transient (on Day 30 only), non-dose-related increases in neutrophils and total WBCs. Similar
findings were observed in the group administered 0.015 mg/kg PegIFN-α2a alone.
The combination of JNJ-3989 with PegIFN-α2a did not induce any further effects on biomarkers
(interferon gamma inducible protein 10 and interferon alpha) than the increases observed with
PegIFN-α2a treatment alone on Day 1.
JNJ-3989-related microscopic findings were observed in the lymph nodes (minimal to mild
vacuolation of macrophages) at ≥60 mg/kg and in the liver (minimal hypertrophy of Kupffer cells)
at 180 mg/kg in single agent and combination groups. The microscopic changes were comparable
between the animals administered with JNJ-3989 alone or combined with PegIFN-α2a indicating
an absence of synergistic effect.
In conclusion, the intermittent SC administration of JNJ-3989 up to 180 mg/kg given alone or
combined with PegIFN-α2a for 3 months was well tolerated in Cynomolgus monkeys at up to 180
mg/kg. Treatment only induced transient local reactions at the injection site, transient
hematological changes and microscopic findings in liver and lymph nodes, all considered as non-
adverse. In addition, the administration of PegIFN-α2a in combination with test item did not
amplify any toxicological effect. Based on these results, there were no additive or synergistic
effects on the toxicity profile and no drug-drug interactions when JNJ-3989 is combined with
PegIFN-α2a.
For further information, refer to the latest version of the IB for JNJ-3989 (IB JNJ-3989).
2.2.3. 
Clinical Studies
2.2.3.1. 
JNJ-3989
At the time of protocol writing, JNJ-3989 is being evaluated in 11 clinical studies. Two Phase 1
studies (Study 73763989HPB1001 in healthy adult Japanese participants and Study
73763989HPB1002 in adult participants with or without hepatic impairment) 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: 3 Phase 1 studies (Study 73763989HPB1004 in
healthy 
adult 
Chinese 
participants, 
73763989HPB1003 
[renal 
impairment] 
and
73763989HPB1005 [relative bioavailability]), 4 Phase 2 studies (Studies 73763989HPB2001
[REEF-1], 
73763989PAHPB2002 [REEF-2], 
73763989PAHPB2005 [REEF-IT], 
and
73763989PAHPB2006 [PENGUIN]) in adult chronic HBV-infected participants, and 1 Phase 2
study (Study 73763989HPB2004 [REEF-D]) in adult participants coinfected with hepatitis B and
D virus. In total, 46 healthy, 84 chronic HBV-infected participants, and 8 participants with
moderately impaired hepatic function have been dosed with JNJ-3989 in Studies AROHBV1001,
73763989HPB1001, and 73763989HPB1002.
Across studies, JNJ-3989 was generally safe and well tolerated with no deaths, serious adverse
events (SAEs) considered at least possibly related to the study intervention, or adverse events
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(AEs) leading to study intervention discontinuation. All AEs were mild to moderate, with
exception of 1 severe blood creatine phosphokinase increased in 1 chronic HBV-infected
participant. All reported injection site reactions (ISRs) were mild. Adverse events and laboratory
abnormalities were distributed across all dose levels and also occurred on placebo treatment,
except for mild ISRs, which were only reported in participants on JNJ-3989 treatment. Most
reported laboratory abnormalities were isolated incidences and resolved while on study
intervention.
Up to 48-week hematology data from the ongoing Phase 2 clinical study REEF-1 are available and
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.
Antiviral activity data are available for 56 chronic HBV-infected participants from Study
AROHBV1001, who received 3 subcutaneous injections of 25 to 400 mg JNJ-3989 every 4 weeks
(Q4W). The antiviral activity data showed that administration of JNJ-3989 at doses of 25 to 400
mg resulted, on average, in pronounced HBsAg decline which was generally sustained at least
until Day 168 (ie, 16 weeks after last dose) across all doses. No apparent dose response was
observed at doses between 100 and 400 mg JNJ-3989; a numerically smaller mean decline was
observed at the lower doses of 25 and 50 mg, mainly apparent after end of JNJ-3989 dosing.
Treatment status (ie, virologically suppressed or not treated) did not seem to affect HBsAg
changes. Other measurable serological and virological markers (HBV DNA, HBV RNA, HBeAg,
hepatitis B Core-related antigen [HBcrAg]) also showed responses to JNJ-3989, indicating that
JNJ-3989 shows target activity on all detectable viral products.
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 (alanine
aminotransferase [ALT] or aspartate aminotransferase [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.
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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 (see Section 2.2.2.2, Combination of JNJ-3989 and Entecavir, Tenofovir Disoproxil, or
Tenofovir Alafenamide).
Clinical data from the Phase 1/2a AROHBV1001 study (see Section 2.2.3.1, JNJ-3989) showed
that dosing JNJ-3989 with NA for 12 weeks did not result in any clinically relevant changes in
kidney parameters/glomerular function.
For further information regarding ETV, tenofovir disoproxil, and TAF, refer to the respective
currently approved prescribing information.
Overall Assessment of the Combination Therapy
Based on the points listed below, no clinically relevant DDIs and no specific concerns about
additive or synergistic toxicities in the kidney are expected when JNJ-3989 is combined with ETV,
or tenofovir disoproxil, or TAF:
 
Available toxicology data (Section  2.2.2.2, Combination of JNJ-3989 and Entecavir,
Tenofovir Disoproxil, or Tenofovir Alafenamide).
 
No clinically relevant changes in kidney parameters/glomerular function for JNJ-3989 + NA
in the completed Phase 1/2a Study AROHBV1001 (Section 2.2.3.2, Combination With
Entecavir, Tenofovir Disoproxil, or Tenofovir Alafenamide).
2.2.3.3. 
Combination of JNJ-3989 and PegIFN-α2a
PegIFN-α2a is a covalent conjugate of recombinant alfa-2a interferon that is indicated for the
treatment of chronic HBV infection  in  adult and pediatric patients at least 3 years of age. In
addition, PegIFN-α2a in combination with other medicinal products is indicated for the treatment
of chronic hepatitis C virus (HCV)-infection in adult and pediatric patients at least 5 years of age
and not treated before. The most common adverse reactions (≥10% of participants) are anorexia,
anxiety, headache, concentration impairment, dyspnea, cough, alopecia, dermatitis, pruritis, dry
skin, myalgia, arthralgia, asthenia, pyrexia, and fatigue. For further information regarding PegIFN-
α2a, refer to the currently approved prescribing information.
Treatment with PegIFN-α2a has been associated with decreases in platelet count (common adverse
reaction). Of the 84 adult chronic HBV-infected participants that received 3 subcutaneous
injections of JNJ-3989 in the Phase 1/2a AROHBV1001 study (see Section 2.2.3.1, JNJ-3989), 6
participants developed Grade 1 platelet reduction with no general trend towards a continuous
decline.
No pharmacokinetic (PK)interaction is expected between JNJ-3989 and PegIFN-α2a based on the
known pharmacologic profile of JNJ-3989 (IB JNJ-3989; Yeh 2019).
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At the time of protocol writing, 2 clinical studies using the combination of JNJ-3989 and PegIFN-
α2a are ongoing: REEF-IT and PENGUIN. Nonclinical studies to investigate the effect on platelet
count decreases were completed and results are summarized in Section 2.2.2.1, JNJ-3989. Up to
48-week hematology data from the ongoing Phase 2 clinical study REEF-1 are available and
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.
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 the benefit-risk evaluation of ETV, tenofovir disoproxil, TAF, and PegIFN-α2a, refer to the
respective prescribing information and Summary of Product Characteristics.
2.3.1. 
Benefits for Study Participation
2.3.1.1. 
Known Benefits
The clinical benefit of JNJ-3989 remains to be established.
2.3.1.2. 
Potential Benefits
Results from clinical studies with JNJ-3989, NAs, and PegIFN-α2a 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 lower limit of quantification (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 levels of the HBV DNA precursor pgRNA. In addition, JNJ-3989 reduces levels
of all viral proteins including HBsAg, which is known to interfere with the host immune 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.
The addition of PegIFN-α2a (12 or 24 weeks, with immediate or delayed start)to the regimen may
lead to further improvement of the immune response (such as reactivation of NK-cells) and
ultimately could lead to immune control of HBV (ie, functional cure). In addition, PegIFN-α2a has
shown to have direct antiviral effects on HBV which could also contribute to the efficacy of the
regimen. By adding PegIFN-α2a to the regimen, higher functional cure rates may be achieved.
2.3.2. 
Risks for Study Participation
2.3.2.1. 
Known Risks
Injection site reactions were the most frequently observed AEs assessed as related to JNJ-3989 by
the investigator.
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The side effect profile of PegIFN-α2a is well established and includes, but is not limited to,
neuropsychiatric, autoimmune, ischemic, ophthalmologic, hematological, and infectious
disorders. Exacerbations of hepatitis during hepatitis B therapy are common and characterized by
transient and potentially severe increases in serum ALT. Marked increases in ALT were sometimes
accompanied by bilirubin elevation and other liver test abnormalities. In many, but not all cases,
these disorders resolve after stopping PegIFN-α2a therapy. For a full list of known risks for
PegIFN-α2a, refer to the respective prescribing information and Summary of Product
Characteristics.
2.3.2.2. 
Potential Risks
All therapies have the potential to cause adverse experiences. In addition, the discontinuation of
NA treatment bares a risk of hepatitis B flares.
Please refer to Section 2.2, Background, for details on the safety results in the studies conducted
to date.
2.3.2.2.1. 
Potential Risks for JNJ-3989
ALT Elevations:
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 every 4 weeks, compared to 0% of participants treated with NA and 0% to 2%
of participants treated with lower doses of JNJ-3989. The majority of the ALT flares resolved
rapidly on continued treatment; 1 was considered serious. In REEF-D, an ongoing study with
HBV/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.
Reproductive Risks and Pregnancy
In the EFD studies, JNJ-3989 was not teratogenic in rats and rabbits. The fertility in male and
female rats is not impacted with JNJ-3989 up to a dose of 180 mg/kg/week.
Based on the difference in metabolic pathways and in vitro data indicating absence of impact of
JNJ-3989 on cytochrome P450 [CYP] enzymes and transporters, no clinically relevant interactions
are anticipated between JNJ-3989 and oral contraceptives.
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Potential Genotoxicity
JNJ-3989 is considered to be devoid of genotoxic activity. Nonclinical carcinogenicity studies
have not been conducted.
Other Potential Toxicity/Events of Special Interest
JNJ-3989 is considered non-cytotoxic, did not activate human platelet aggregation, did not activate
the innate immune system to a significant degree in vitro, and did not activate complement in vitro.
Viral Resistance
Treatment with JNJ-3989 may lead to viral resistance, but resistance to JNJ-3989 is not anticipated
to impact treatment with other siRNAs, unless they would have an overlapping trigger binding
region. Note that none of the siRNAs in development have overlapping regions. Using these agents
in combination, especially in combination with ETV or tenofovir, is expected to minimize the risk
of emerging resistant viral variants.
2.3.2.2.2. 
Potential Risks for Entecavir, Tenofovir Disoproxil, Tenofovir
Alafenamide, and PegIFN-α2a
For the general potential risks of ETV, tenofovir disoproxil, TAF, and PegIFN-α2a, refer to the
respective prescribing information and Summary of Product Characteristics.
Risks specific for this study design are listed below:
 
PegIFN-α2a might increase the immunogenicity of JNJ-3989.
 
Combination of PegIFN-α2a and JNJ-3989 might increase the risk of hematologic
abnormalities and/or of bone marrow suppression.
2.3.3. 
Benefit-Risk Assessment for Study Participation
Based on the available data and proposed safety measures, the overall risk/benefit assessment for
JNJ-3989 clinical studies is deemed acceptable for the following reasons:
 
JNJ-3989 was generally safe and well tolerated during the Phase 1/2a Study AROHBV1001
(see Section 2.2.3.1, JNJ-3989). All but one AE were mild or moderate in severity. All ISRs,
identified as adverse drug reactions for JNJ-3989, were mild in intensity.
 
Based on pre-clinical and clinical data available today, the combination of JNJ-3989, NA
(ETV, tenofovir disoproxil, or TAF), and PegIFN-α2a is considered safe. Data from
nonclinical combination toxicity studies (Section 2.2.2.3, Combination of JNJ-3989 and
PegIFN-α2a) confirmed that combination of PegIFN-α2a with JNJ-3989 did not induce any
synergistic or additive effect in monkeys up to 3 months oftreatment. Fourty-eight (48)-week
hematology data of ongoing Phase 2 clinical study REEF-1 (Section 2.2.3.3, Combination of
JNJ-3989 and PegIFN-α2a)has been reviewed and no safety concern has been identified.
 
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 for JNJ-3989 that will be carefully monitored during the study include ISRs,
ALT/AST elevations, and hematologic abnormalities (see Section 8.3.6, Adverse Events of
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Special Interest). In addition, the following toxicities will also be carefully monitored: rash,
renal complications, and acute systemic allergic reactions (Section 8.3.7, Other Toxicities).
 
Continued careful assessment of the safety, efficacy, and PK during treatment is included in
this study.
 
To minimize potential risk and stress to participants, the following measures are in place:
 
Utilization of selection criteria which exclude participants who may potentially be at
higher risk of an AE (see Section 5, Study Population).
 
Utilization of withdrawal criteria (see Section 7, Discontinuation of Study Intervention
and Participant Discontinuation/Withdrawal). If a participant drops out due to withdrawal
of consent, he/she retains the option to participate in the safety follow-up procedures.
 
At regular time points throughout the study (see Schedule of Activities), blood samples
for biochemistry, blood coagulation, and hematology and urine samples for urinalysis,
urine chemistry, and renal biomarkers will be collected. Vital signs (systolic and diastolic
blood pressure, pulse rate, and body temperature), height (only at screening), body
weight, and electrocardiograms (ECGs) will be recorded throughout the study. Physical
and ophthalmologic examinations will be performed and AEs will be assessed (see
Section 8.2, Safety Assessments). Events of Special Interest will be closely monitored
(Section 8.3.6, Adverse Events of Special Interest).
 
The impact of PegIFN-α2a addition to JNJ-3989 on ALT elevations is not known  in
context of HBV monoinfection. Strict rules for management of ALT elevation are in place
(refer to Section 8.3.6.2, Intervention-emergent ALT/AST Elevations).
 
An internal Data Review Committee (DRC) will be established for continuous monitoring
of SAEs, AEs leading to discontinuation, and ALT flares to ensure the continuing safety
of the participants enrolled in the current study. 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 monitored closely during the 48-week FU Period, with frequent
follow-up visits. Participants who completed NA treatment after meeting the NA
treatment completion criteria (Section 6.5.1, NA Treatment Completion) based on the
Week 24 (EOSI) or FU Week 2 results, should re-start NA treatment if pre-defined NA
re-treatment criteria are met (Section 6.5.2, NA Re-treatment Criteria During Follow-up).
 
JNJ-3989 will be administered using a proper subcutaneous technique to decrease the risk
of ISRs. ISRs will be managed as outlined in Section 8.3.6, Adverse Events of Special
Interest.
 
Any clinically significant abnormalities persisting at the end of the study/early
discontinuation will be followed up by the investigator until resolution (return to baseline)
or until stabilization (to be agreed upon with the Sponsor).
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Refer to Section 8, Study Assessments and Procedures for evaluations related to endpoints.
For the definitions of terms, refer to Section 10.1, Appendix 1: Abbreviations and Definitions.
HYPOTHESIS
The primary hypothesis of this study is that at least one of the combination regimens of
JNJ-3989+NA+PegIFN-α2a is more efficacious than NA treatment alone (standard of care), as
measured by the primary efficacy endpoint, the proportion of participants with a reduction of at
least 2 log10 IU/mL in HBsAg levels from baseline at Week 24. Because the study does not include
a control arm, the hypothesis is formulated assuming a fixed external NA control response rate of
2% in terms of the primary efficacy endpoint.
4. 
STUDY DESIGN
4.1. 
Overall Design
This ISA describes a Phase 2 study of the combination regimen of JNJ-3989 with NA and different
durations ofPegIFN-α2a, and with an immediate or delayed start of PegIFN-α2a treatment. 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 open-label, 3-arm,
multicenter, interventional study to evaluate the efficacy, safety, tolerability, and PK of the
combination of JNJ-3989, NAs, and PegIFN-α2a in long-term (≥2 years of NA treatment)
virologically suppressed, HBeAg-negative, chronic HBV-infected, adult participants.
Approximately  102 long-term (≥2 years of NA treatment) 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 65 years of age (inclusive) will be enrolled in
this study.
This open-label study will be conducted in 3 periods:
 
Screening Period (4 weeks [if necessary, eg, 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]).
 
Treatment Period (24 weeks):
o 
Arm 1 (N 34): JNJ-3989 for 24 weeks + NA for 24 weeks + PegIFN-α2a for
24 weeks.
o 
Arm 2 (N 34): JNJ-3989 for 24 weeks + NA for 24 weeks + PegIFN-α2a from
Week 12 till Week 24.
o 
Arm 3 (N 34): JNJ-3989 for 24 weeks + NA for 24 weeks + PegIFN-α2a from
baseline till Week 12.
 
Follow-up (FU) Period (48 weeks), starting at Week 24.
At baseline, participants who meet the eligibility criteria will be randomized in a 1:1:1 ratio to
Arm 1, Arm 2, or Arm 3. Randomization will be stratified byabsolute HBsAg level (<1,000 IU/mL
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versus >1,000 IU/mL) at baseline and country grouping as proxy for HBV genotype (GT) at
enrollment, with 3 levels: Poland (predominantly GT-A) versus Russia (predominantly GT-D)
versus all other countries (other or mixed GT prevalence)(Kim 2011). Participants in Arm 2 who
no longer meet the PegIFN-α2a eligibility criteria (see Exclusion Criterion A24 in Section 5.2,
Exclusion Criteria) at Week 12, based on available laboratory  or clinical data, will continue
JNJ-3989 and NA treatment until Week 24 without PegIFN-α2a.
All participants will receive the last dose of JNJ-3989 at Week 24 and the last dose of PegIFN-α2a
at Week 23 (Arms 1 and 2) or Week 11 (Arm 3). They will start the FU Period after the Week 24
visit. If the protocol-defined NA treatment completion criteria (see Section 6.5.1, NA Treatment
Completion, for more details) are met based on the Week 24 results, NA will be stopped at the
next scheduled visit (ie, FU Week 2), otherwise NA treatment will continue during the complete
FU Period. Note: Participants who are close to meeting the protocol-defined NA treatment
completion criteria with the Week 24 results, and do meet the criteria based on the FU Week 2
results may be allowed to stop NA at FU Week 4, after consultation with the Sponsor.
Participants who meet the protocol-defined NA treatment completion criteria will be monitored
closely during the 48-week FU Period with a study visit at least once every 4 weeks. NA treatment
should be re-started in accordance with the NA re-treatment criteria (see Section 6.5.2, NA Re-
treatment Criteria During Follow-up, for more details).
Study intervention consists of:
 
JNJ-3989: 200 mg subcutaneous injection Q4W
 
NA: tenofovir disoproxil (245 mg), or TAF (25 mg), or ETV (0.5 mg) tablets p.o. QD
 
PegIFN-α2a: 180 µg subcutaneous injection QW.
Both the Platform Master informed consent form (ICF) and the ISA ICF must be signed before the
first study-related activity takes place.
Assessments and sampling include: 
 
Safety and tolerability, based on AEs, laboratory assessments, ECGs, vital signs,
ophthalmologic and physical examination, will be assessed throughout the study from the time
that the ISA ICF is signed until the completion of the last study-related activity (see
Section 8.2, Safety Assessments, and Section 8.3, Adverse Events and Serious Adverse
Events).
 
Efficacy will be evaluated using different parameters including HBsAg, HBeAg, and HBV
DNA (see Section 8.1, Efficacy Assessments).
 
Samples for HBV genome sequencing will be taken at the time points indicated in the
Schedule of Activities (see Section 8.1.1, Sequencing). 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.
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 
The study includes collection of blood samples for exploratory analysis of viral markers (see
Section 8.1, Efficacy Assessments) and host blood biomarkers at the host RNA, protein, and
cell level (see Section 8.6, Exploratory Host Biomarkers).
 
All participants will have sparse PK sampling during the treatment period. Venous blood
samples will be collected for measurement of plasma or serum (as applicable) concentrations
of JNJ-3989 (ie, JNJ-3976 and JNJ-3924), NA and PegIFN-α2a, at time points specified in
the Schedule of Activities. Bioanalysis of NA and PegIFN-α2a is optional at the discretion of
the sponsor (see Section 8.4, Pharmacokinetics).
 
Peripheral blood mononuclear cell (PBMC) samples for immune analyses will be collected at
selected sites at the time points indicated in the Schedule of Activities (see Section 8.7,
Immune Assessments).
 
Optional samples for human leukocyte antigen (HLA) testing, pharmacogenomics, and
epigenetics will be collected from participants who consent separately to this component of
the study (see Section 8.5, Host Genetics).
 
Medical resource utilization will be assessed (see Section 8.8, Medical Resource Utilization).
The Schedule of Activities summarizes the frequency and timing of efficacy, safety, and other
assessments applicable to the Master Protocol PLATFORMPAHPB2001 and this ISA.
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).
If a participant prematurely discontinues JNJ-3989 (ie, before Week 24), the participant will have
an early WD visit and will enter the 48-week follow-up period as per the Schedule of Activities,
unless the participant withdraws consent.
If a participant prematurely discontinues PegIFN-α2a (ie, before Week 23 [Arms 1 and 2] or before
Week 11 [Arm 3]), treatment with JNJ-3989 and NA should be continued as planned.
If a participant withdraws prematurely from the study, the reason for withdrawal (if known) should
be documented in the case report form (CRF) and in the source document. Participants who
withdraw consent will be offered an optional safety follow-up visit 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. See Section 10.3.6, Committees Structure.
The Coronavirus Disease 2019 (COVID-19) pandemic or similar pandemics may impact the
conduct of this clinical study, therefore additional guidance is provided in Section 10.10,
Appendix 10: Study Conduct During a Natural Disaster.
A diagram of the study design is provided in Section 1.2, Schema.
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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 treatment 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 (<1,000 IU/mL versus >1,000 IU/mL)
at baseline and country grouping as proxy for HBV GT at enrollment, with 3 levels: Poland
(predominantly GT-A) versus Russia (predominantly GT-D) versus all other countries (other or
mixed GT prevalence) (Kim 2011). The two stratification factors selected will provide a
reasonably balanced representation of 2 baseline factors across all intervention arms.
Addition of PegIFN-α2a to Treatment Regimen
The combination of the treatment regimen of JNJ-3989 + NA with PegIFN-α2a is based on
2 different properties of IFN-α: a direct antiviral effect and an immune boosting effect. The
direct antiviral activity against HBV replication, and in some cases HBsAg production, was
demonstrated for PegIFN-α2a (Belloni 2012, Lucifora 2014, Xu 2010, Yan 2015). In addition,
IFN-α is expected to act as immune booster with potential to reactivate NK-cells (Gill 2016).
Addition of PegIFN-α2a (for 12 weeks [during the first or second half of the treatment period for
Arms 3 and 2, respectively] or during the complete 24 week treatment period [Arm 1]) to the
treatment regimen is expected to enhance antiviral activity of JNJ-3989 + NA and may lead to a
shorter overall treatment duration (ie, 24 weeks) and might improve functional cure rates.
Criteria for NA Treatment Completion
All participants will receive the last dose of JNJ-3989 at Week 24 and the last dose of PegIFN-α2a
at Week 23 (Arms 1 and 2) or Week 11 (Arm 3). They will start the FU Period after the Week 24
visit. If the protocol-defined NA treatment completion criteria (described in Section 6.5.1, NA
Treatment Completion) are met based on the Week 24 results, treatment with NA will be stopped
at the next scheduled visit (ie, FU Week 2), otherwise NA treatment will continue during the
complete FU Period. Note: Participants who are close to meeting the protocol-defined NA
treatment completion criteria with the Week 24 results, and do meet the criteria based on the FU
Week 2 results may be allowed to stop NA at FU Week 4, after consultation with the Sponsor.
The NA treatment completion criteria which take ALT, HBV DNA, HBeAg, and HBsAg levels
into consideration, have been selected to ensure that only participants with a higher chance of
achieving sustained off-treatment response are allowed to stop all study intervention. Across a
range of studies, HBsAg levels at end of treatment below 100 IU/mL were consistently associated
with favorable off-treatment response (Jeng 2018; Papatheodoridis 2018).
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Participants will be monitored closely during the 48-week FU Period and participants who
completed NA treatment should re-start NA treatment if NA re-treatment criteria are met (see
Section 6.5.2, NA Re-treatment Criteria During Follow-up, for more details).
Follow-up Procedures and Criteria for Re-initiation of NA Treatment
To ensure safety of patients during the FU Period, an ALT flare management plan is in place,
including weekly visits for patients with ALT/AST ≥3x  ULN and ≥3x nadir (ie, lowest value
during study participation) until stabilization.
Increases in ALT and HBV DNA are frequently seen in  patients after discontinuation of NA
treatment. These ALT elevations may be reflecting an activation of the host cellular immune
response and can as such lead to functional cure. Cases of fulminant HBV reactivation with fatal
outcome were described after cessation of NA treatment, but the vast majority of such cases were
described in patients with cirrhosis or decompensated liver disease at the time of NA
discontinuation. These patients are not eligible to participate in the study. Still, a vigilant follow-
up of patients during this phase of the study is critical to ensure patient safety. Signs of decreased
liver function, or an HBV DNA value of >1,000,000 IU/mL (irrespective of confirmation and/or
ALT increase), will trigger immediate re-initiation of NA treatment based on protocol-defined NA
re-treatment criteria (see Section 6.5.2, NA Re-treatment Criteria During Follow-up).
In the absence of signs of decompensation or an HBV DNA value of >1,000,000 IU/mL, the
decision to re-start NA treatment should take into account that a too early re-initiation might reduce
the chances of achieving functional cure. Re-initiation of NA treatment should be considered in
case of confirmed HBeAg seroreversion (HBeAg positive after it was negative at NA completion),
in case of confirmed ALT increase (>5x ULN) in combination with increased HBV DNA
replication (>2,000 IU/mL), and in case of confirmed increased HBV DNA replication at higher
levels (>20,000 IU/mL). If the kinetics of the ALT increase permit it, the confirmatory test should
be performed at least 4 weeks after the initial test, except in the situations described below.
A post-treatment HBV DNA value of >100,000 IU/mL should trigger re-testing of ALT/AST,
HBV DNA, and total and direct bilirubin within a maximum of 7 days from receipt of the data and
further repeats as necessary (ie, weekly until HBV DNA returns to <100,000 IU/mL). A post-
treatment HBV DNA value of >20,000 IU/mL (but <100,000 IU/mL) should trigger a re-test
within 14 days. A post-treatment ALT value of >5x ULN should trigger re-testing of ALT, AST,
ALP, total and direct bilirubin, INR, albumin, and HBV DNA on a weekly basis until ALT and
AST levels have returned to <5x ULN. At all times, additional re-testing of the above parameters
should be performed at the investigator’s discretion.
To avoid delays in decision making, sites are encouraged to run local re-testing in parallel with
central re-testing in the situations described above that require more frequent re-testing. Local test
results are to be recorded in the CRF and/or source documents, including information on the HBV
DNA assay used. In addition, to avoid delays in NA re-treatment, it should be considered to
dispense NA to participants who potentially met the NA re-treatment criteria (eg, pending
confirmation) and who will not be available to come to the study site immediately at the time the
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confirmatory test results will become available. This should ensure that the participant can
immediately restart NA treatment if indicated, upon direct confirmation by the investigator.
The decision to re-start NA treatment should take into consideration the dynamics of HBV DNA
and/or ALT values and should be discussed with the sponsor.
NA re-treatment criteria during follow-up are presented graphically in Section 10.12, Appendix
12.
Host DNA and Exploratory Host Biomarker Collection
Refer to Section 4.2 of the Master Protocol PLATFORMPAHPB2001.
4.2.1. 
Study-Specific Ethical Design Considerations
Refer to Section 4.2.1 of the Master Protocol PLATFORMPAHPB2001.
The total blood volume to be collected (see Section 8) is considered to be an acceptable amount of
blood to be collected over this time period from the population in this study.
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
REEF-1 
(73763989HPB2001), 
REEF-2 
(73763989PAHPB2002), 
REEF-IT
(73763989PAHPB2005), and Penguin (73763989PAHPB2006). Addition of short-term
PegIFN-α2a (12 or 24 weeks, with immediate or delayed start) to the treatment regimen is expected
to enhance antiviral activity of JNJ-3989 + NA and may lead to a shorter overall treatment duration
(ie, 24 weeks) needed to achieve functional cure.
Clinical data on PK, PD, safety, and efficacy of JNJ-3989 are available from the Phase 1/2a
AROHBV1001 study. The study has been completed and the final study report is available.
Twenty adult healthy participants have received single subcutaneous injections of JNJ-3989 (35,
100, 200, 300, and 400 mg) and 84 adult chronic HBV-infected participants have received multiple
doses of JNJ-3989 (25, 50, 100, 200, 300, and 400 mg), administered as 3 subcutaneous injections
separated by either 7-day, 14-day, or 28-day intervals. All participants either continued or started
on ETV or tenofovir disoproxil on Day 1.
JNJ-3989 was generally safe and well tolerated at all doses. No clinically relevant safety signal
was identified.
Antiviral activity data were available for 56 chronic HBV-infected participants who received
3 subcutaneous injections of 25 to 400 mg JNJ-3989 Q4W (Gane 2019; Yuen 2019; IB JNJ-3989).
In general, mean HBsAg declines reached nadir at Day 113 (ie, 8 weeks after last JNJ-3989). Mean
HBsAg levels remained suppressed (below baseline levels) at least until Day 392 (ie, 9 months
after last dose) in a substantial proportion of patients. The HBsAg levels at Day 392 were variable
with some patients having HBsAg levels close to baseline levels while a substantial proportion of
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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 25mg and 50 mg, mainly apparent after end of JNJ-3989 dosing.
A dose of 200 mg JNJ-3989 Q4W is chosen based on the observed decline in HBsAg in
Study AROHBV1001 at this dose over 3 injections, and the lack of a substantial incremental
efficacy response at higher doses.
4.4. 
End of Study Definition
End of Study Definition
The EOS is considered as the last visit (FU Week 48 or early discontinuation) for the last
participant in the study. The final data from the study site will be sent to the Sponsor (or designee)
after completion of the final participant visit at that study site, in the time frame specified in the
Clinical Trial Agreement.
Study Completion Definition
A participant will be considered to have completed the study if he or she has completed the
assessments of the EOS visit (ie, FU Week 48).
5. 
STUDY POPULATION
Screening for eligible participants will be performed within 4 weeks before administration of the
study intervention. If necessary, eg, for operational reasons, the Screening Period may be extended
up to a maximum of 8 weeks on a case-by-case basis and in agreement with the Sponsor. Refer to
Section 5.4, Screen Failures, of the Master Protocol PLATFORMPAHPB2001 for conditions
under which the repeat of any screening procedures is allowed.
Note: Retesting to assess eligibility will be allowed once, using an unscheduled visit during the
screening period.
The inclusion and exclusion criteria for enrolling participants in this study are described below. If
there is a question about these criteria, the investigator must consult with the appropriate Sponsor
representative and resolve any issues before enrolling a participant in the study. Waivers are not
allowed.
For a discussion of the statistical considerations of participant selection, refer to Section 9.2,
Sample Size Determination.
Each potential participant must satisfy all inclusion and exclusion criteria from the Master Protocol
PLATFORMPAHPB2001 (numbering prefixed by “M” in the list below) 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
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from the Master Protocol that are specified or more restricted in this ISA, the additional text is also
highlighted (colored fill).
5.1. 
Inclusion Criteria
Each potential participant must satisfy all of the following criteria to be enrolled in the study:
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 65 years of age, inclusive.
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 above
ULN without another cause than HBV infection, documented transmission event.
If none of the above are available, the following ways of documenting chronicity
are acceptable at the time of screening: liver biopsy with changes consistent with
chronic HBV, or absence of marker for acute HBV infection such as positive
immunoglobulin M (IgM) anti-hepatitis B surface (HBs) and anti-HBc antibodies.
Participants should:
 be HBeAg-negative, AND
 be anti-HBe antibody-positive, AND
 be on stable HBV treatment, defined as currently receiving NA treatment for at
least 2 years prior to screening, and having been on the same NA treatment
regimen (at the same dose) as used in this study for at least 3 months at the time
of screening, AND
 have documented 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).
M04 
Participants must have a body mass index (BMI; weight in kg divided by the square
of height in meters) between 18.0 and 35.0 kg/m2, extremes included.
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Participants with a positive IgM antibody test for HEV infection may be
enrolled after discussion with the Sponsor if an active HEV infection can be
ruled out by documentation of negative anti-HEV immunoglobulin G (IgG).a
 
Participants with a positive HIV-1 or HIV-2 antibody/antigen test at screening
should have a confirmatory HIV RNA test, to rule out false positive results.
They  can  be enrolled if they have a negative HIV RNA test at screening.
Participants with evidence of HIV-1 or HIV-2 infection who are on
antiretroviral treatment are excluded. 
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 ULNb, OR
b. Direct bilirubin >1.2x ULNb, 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
hepatocellular carcinoma (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).
a Negative HEV RNA may also be acceptable to rule out active HEV infection depending on local standard practices.
b Unless explained by a clinical setting that is not hepatic decompensation.
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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 10.9, Appendix 9: DAIDS Table):
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. Alpha-fetoprotein (AFP) >100 ng/mL;
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.
g. 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; abnormal conduction; or any other clinically significant
abnormalities on a 12-lead ECG at screening.
Note: Retesting of an abnormal ECG that may lead to exclusion will be allowed
once without prior asking approval from the Sponsor. Retesting will take place
during an unscheduled visit in the screening phase. Participants not meeting the
above exclusion criterion at retest may be included.
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M10 
Participants with a history of or current cardiac arrhythmias (eg, extrasystole,
tachycardia at rest), history of risk factors for Torsade de Pointes syndrome
(eg, hypokalemia, family history of long QT Syndrome) or history or other clinical
evidence of significant or unstable cardiac disease (eg, angina, congestive heart
failure, myocardial infarction, diastolic dysfunction, significant arrhythmia and/or
coronary heart disease), moderate to severe valvular disease, or uncontrolled
hypertension at screening.
M11  
Participants with any current or previous illness for which, in the opinion of the
investigator and/or Sponsor, participation would not be in the best interest of the
participant (eg, compromise the well-being) or that could prevent, limit, or
confound the protocol-specified assessments. This may include but is not limited
to significant vascular, pulmonary (eg, chronic obstructive pulmonary disease),
gastrointestinal (eg, significant diarrhea, gastric stasis, or constipation that in the
investigator’s opinion could influence drug absorption or bioavailability),
endocrine (eg, thyroid disease), neurologic, hematologic, rheumatologic,
psychiatric, neoplastic, or metabolic disturbances. Any condition possibly
affecting drug absorption (eg, gastrectomy or other significant gastrointestinal tract
surgery, such as gastroenterostomy, small bowel resection, or active enterostomy)
will also lead to exclusion.
M12 
Participants who have received an organ transplant (except for skin, hair, or cornea
transplants).
M13 
Participants with any history of or current clinically significant skin disease
requiring regular or periodic treatment.
M14  
Participants with clinically relevant alcohol or drug abuse within 12 months of
screening.
M15 
Participants with history of clinically relevant drug rash.
A16 
(adapted 
from M16) 
Participants who have taken any disallowed therapies as noted in Section 6.8,
Concomitant Therapy, before screening or baseline. Participants who have taken
IFN within the last 3 years prior to screening. Participants with lamivudine-
refractory chronic hepatitis B.
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.
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6. 
STUDY INTERVENTION AND CONCOMITANT THERAPY
6.1. 
Study Intervention(s) Administered
Description of Interventions
Intervention Name 
JNJ-3989 
PegIFN-α2a 
Tenofovir disoproxil 
Tenofovir alafenamide 
(TAF)* 
Entecavir (ETV)
monohydrate
Type 
Drug 
Drug 
Drug 
Drug 
Drug
Dose Formulation 
Solution for injection  
Solution for injection  
Film coated tablets 
Film coated tablets 
Film coated tablets
Unit Dose Strength(s) 
200 mg/mL 
180 µg/0.5 mL 
245 mg 
25 mg 
0.5 mg
Dosage Level(s) 
200 mg once every 4 
weeks (Q4W) 
180 µg once weekly 
(QW)
245 mg QD  
25 mg QD  
0.5 mg QD
Route of Administration 
Subcutaneous injection 
(preferably in the 
abdomen) 
Subcutaneous injection 
(in the thigh or
abdomen)
Oral 
Oral 
Oral
Use 
Investigational 
intervention  
Investigational 
intervention
Background intervention  Background intervention  Background intervention
Investigational Medicinal 
Product (IMP)
Yes 
Yes 
Yes 
Yes 
Yes
Non-investigational Medicinal 
Product/ Auxiliary Medicinal
Product (NIMP/AxMP)
No 
No 
No 
No 
No
Sourcing 
Provided centrally by the 
Sponsor 
Provided centrally by the 
Sponsor 
Provided centrally by the 
Sponsor 
Provided centrally by the 
Sponsor 
Provided centrally by the
Sponsor
Packaging and Labeling 
Each unit will be labeled 
with unique medication 
ID number 
Commercial supplies 
will be sourced. Each 
unit will be labeled with 
unique medication ID 
number. 
Commercial supplies 
will be sourced. Each 
unit will be labeled with 
unique medication ID 
number. 
Commercial supplies 
will be sourced. Each 
unit will be labeled with 
unique medication ID 
number. 
Commercial supplies
will be sourced. Each
unit will be labeled with
unique medication ID
number.
In child resistant
packaging
In child resistant
packaging
In child resistant
packaging
In child resistant
packaging
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Intervention Name 
JNJ-3989 
PegIFN-α2a 
Tenofovir disoproxil 
Tenofovir alafenamide 
(TAF)* 
Entecavir (ETV)
monohydrate
Food/Fasting Instructions 
Regardless of food 
intake 
Per the prescribing 
information  
Per the prescribing 
information  
Per the prescribing 
information  
Per the prescribing
information
Q4W: once every 4 weeks; QD: once daily; QW: once weekly.
* In countries where TAF is available, it will be one of the NA treatment options.
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Physical Description of Study Interventions
The JNJ-3989 supplied for this study will be provided as an aqueous clear, colorless to light yellow
solution with 200 mg/mL of JNJ-3989 for subcutaneous injection
).
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 NAs ETV, tenofovir disoproxil, and TAF formulated as oral film-coated tablets of 0.5-mg,
245-mg, and 25-mg strength, respectively, will be provided by the Sponsor. Refer to the
prescribing information for a list of excipients.
PegIFN-α2a formulated as solution for subcutaneous injection in a prefilled syringe with
180 µg/0.5 mL of PegIFN-α2a, will be provided by the Sponsor. Refer to the prescribing
information for a list of excipients.
Packaging and Labeling
All study interventions will be packaged with each unit labeled with a unique medication ID
number. Packaging and labeling of JNJ-3989, the NAs, and PegIFN-α2a will be done in an
open-label way. Commercial supplies of NAs and PegIFN-α2a will be sourced and a clinical study
label will be applied. Study intervention labels will contain information to meet the applicable
regulatory requirements.
NA and PegIFN-α2a treatment may be repackaged into child-resistant packaging if this is not
already the case.
No study interventions can be repacked or relabeled without prior approval from the Sponsor.
Study Intervention Administration
Study intervention administration must be captured in the source documents and the CRF.
JNJ-3989 injections will be administered subcutaneously (preferably in the abdomen)at the study
site.
NA and PegIFN-α2a treatment will be provided by the Sponsor. Investigators should follow
guidance detailed in the respective prescribing information, including special warnings and
precaution for use.
In between study visits, participants will take their oral study intervention (NA) at home and they
will bring their oral study intervention with them to each study visit. Study site personnel will
instruct participants on how to take their oral study intervention at home. At study visits, the oral
study intervention should be taken on site to allow biochemistry and renal biomarker samples to
be taken in fasted conditions.
CCI
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During the study, participants will continue the same NA treatment (ETV, tenofovir disoproxil, or
TAF) 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 two 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.
For PegIFN-α2a, the first administration must be performed at the study site by the investigator or
his/her designee. Thereafter, weekly administration should preferably be done on the same day of
the week in the evening by self-injection.a Study site personnel will instruct participants on how
to self-administer, where applicable, their PegIFN-α2a injections at home. Used PegIFN-α2a
syringes should be separated from the needle via the sharps container and then placed into their
original box and returned to the site at the next study visit, if allowed per local guidelines and
regulations. The used needles in the sharps container will be returned to the study site after
completion of the Treatment Period or disposed of following local standard procedures. If desired,
participants can also choose to have the weekly administration of PegIFN-α2a performed at the
study site irrespective of the time of day.
JNJ-3989 and PegIFN-α2a should be injected subcutaneously and the approximate location should
be recorded. If both are injected in the abdomen, different areas of the abdomen should be used.
For a definition of study intervention overdose, refer to Section 6.7, Treatment of Overdose.
6.2. 
Preparation/Handling/Storage/Accountability
Preparation/Handling/Storage
All study intervention must be stored as specified on the product-specific labeling.
Study site personnel will instruct participants on how to store study intervention for at home use as
indicated for this protocol.
Refer to the pharmacy manual/study site investigational product and procedures manual for
additional guidance on study intervention preparation, handling, and storage.
Accountability
The investigator is responsible for ensuring that all study intervention received at the site is
inventoried and accounted for throughout the study. The dispensing of NA and PegIFN-α2a (if
self-administered) to the participant, and the return of NA, and PegIFN-α2a (if self-administered)
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
a For countries that do not allow PegIFN-α2a self-injection: weekly administration of PegIFN-α2a must be performed
at the study site by the investigator or his/her designee.
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intervention. The JNJ-3989 and PegIFN-α2a injections administered to the participant at the study
site must be documented on the intervention accountability form. All study intervention will be
stored and disposed of according to the Sponsor’s instructions. Study site personnel must not
combine contents of the study intervention containers.
Study intervention must be handled in strict accordance with the protocol and the container label,
and must be stored at the study site in a limited-access area or in a locked cabinet under appropriate
environmental conditions. Unused study intervention, and study intervention returned by the
participant, must be available for verification by the Sponsor’s study site monitor during on-site
monitoring visits. The return to the Sponsor of unused study intervention, or used 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, and
vials, should be disposed of immediately in a safe manner and therefore will not be retained for
intervention accountability purposes. Details on handling of used PegIFN-α2a syringes are
described in Section 6.1, Study Intervention(s) Administered.
Study intervention should be dispensed under the supervision of the investigator or a qualified
member of the study site personnel, or by a hospital/clinic pharmacist. Study intervention will be
supplied only to participants participating in the study. Returned study intervention must not be
dispensed again, even to the same participant. Whenever a participant brings his or her study
intervention to the study site for pill count, this is not seen as a return of supplies. Study
intervention may not be relabeled or reassigned for use by other participants. The investigator
agrees neither to dispense the study intervention from, nor store it at, any site other than the study
sites agreed upon with the Sponsor. Further guidance and information for the final disposition of
unused study interventions are provided in the Study Reference Manual.
6.3. 
Measures to Minimize Bias: Randomization and Blinding
Intervention Allocation
Procedures for Randomization and Stratification
Participants will be randomly assigned to 1 of 3 intervention  groups based on a computer-
generated randomization schedule at baseline under the supervision of the Sponsor. The
randomization will be balanced by using randomly permuted blocks and will be stratified by
absolute HBsAg level (<1,000 IU/mL versus >1,000 IU/mL) at baseline and country grouping as
proxy for HBV GT at enrollment, with 3 levels: Poland (predominantly GT-A) versus Russia
(predominantly GT-D) versus all other countries (other or mixed GT prevalence) (Kim 2011).
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.
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For more information on the interactive web response system (IWRS), refer to Section 6.3 of the
Master Protocol PLATFORMPAHPB2001.
Blinding
As this is an open-label study, blinding procedures are not applicable.
6.4. 
Study Intervention Compliance
JNJ-3989 will be administered at the study site as a subcutaneous injection by qualified study site
personnel to assure compliance with study requirements.
The participants will be requested to bring unused study interventions and empty packaging to the
study site at each visit.
Every effort should be made to have the participant take the study interventions as indicated in the
Schedule of Activities.
 
If an injection of JNJ-3989 was missed, the injection should be given as soon as possible but
within 3 weeks after the scheduled time. Otherwise, the injection should be skipped and the
next injection should be given at the next scheduled time point per the initial injection
schedule.
 
If a dose of NA is missed, the participant should follow the guidelines in the prescribing
information.
 
If an injection of PegIFN-α2a is missed, the participant should follow the guidelines in the
prescribing information.
If a participant’s study intervention intake is not according to the protocol, the investigator will
take the necessary measures to ensure future adherence to the protocol.
An optional medication diary to document oral study intervention intake can be made available for
participants with an observed or known risk for study intervention non-compliance. The completed
diaries are reviewed by the site staff and discussed with the participants for compliance monitoring
and counseling. Completed diaries will be returned to the site staff to add to the source documents.
Participants who are administering PegIFN-α2a by self-injectiona will be requested to complete a
self-injection tracker. The completed self-injection trackers are reviewed by the site staff and
discussed with the participants for compliance monitoring and counseling. Completed
self-injection trackers will be returned to the site staff who will transcribe the data into the CRF.
6.5. 
Dose Modification
Dose modifications of JNJ-3989 and NA (increase or decrease of dose level) are not permitted.
For PegIFN-α2a, dose adjustment guidelines are recommended for participants who develop
a Not applicable for participants in countries that do not allow PegIFN-α2a self-injection, where weekly administration
of PegIFN-α2a must be performed at the study site by the investigator or his/her designee.
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laboratory abnormalities during PegIFN-α2a treatment, as recommended in the locally approved
prescribing information for PegIFN-α2a. The Pegasys USPI has been provided as an example in
Table 2 below.
Table 2: 
PegIFN-α2a Hematological Dose Modification Guidelines
Laboratory Values 
Recommended Dose
ANC <750 cells/mm³ 
Reduce to 135µg
ANC <500 cells/mm³ 
Discontinue treatment until ANC values return to more than 1,000 cells/mm³.
Reinstitute at 90µg and monitor ANC.
Platelet <50,000 cells/mm³ 
Reduce to 90µg
Platelet <25,000 cells/mm³ 
Discontinue treatment
ANC: absolute neutrophil count
Source: Pegasys USPI
For participants who prematurely discontinue PegIFN-α2a, treatment with PegIFN-α2a may be
restarted according to the recommendations from the locally approved prescribing information for
PegIFN-α2a.
6.5.1. 
NA Treatment Completion
All participants will receive the last dose of JNJ-3989 at Week 24 and the last dose of PegIFN-α2a
at Week 23 (Arms 1 and 2) or Week 11 (Arm 3). They will start the FU Period after the Week 24
visit. If all of the following NA treatment completion criteria are met based on the Week 24 results,
treatment with NA will be stopped at the next scheduled visit (ie, FU Week 2):
 
The participant has ALT <3x ULN, AND
 
The participant has HBV DNA <60 IU/mL at Week 24 and HBV DNA <LLOQ at the previous
visit, or HBV DNA <LLOQ at Week 24, AND
 
The participant is HBeAg-negative, AND
 
The participant has HBsAg <100 IU/mL.
Note: Participants who are close to meeting the protocol-defined NA treatment completion criteria
with the Week 24 results, and do meet the criteria based on the FU Week 2 results may be allowed
to stop NA at FU Week 4, after consultation with the Sponsor. In case of ALT elevation ≥3x ULN
at Week 24, the investigator must consider different potential causes of increased ALT to ensure
appropriate work up and management as needed. If the ALT elevation is unrelated to HBV activity
and/or <3x ULN by FU Week 2, NA completion may be considered at the discretion of the
investigator and in consultation with the sponsor.
Participants who do not meet the above criteria based on the Week 24 or FU Week 2 results should
continue NA treatment during the 48-week FU Period.
Participants who meet the above-mentioned NA treatment completion criteria will be monitored
closely during the 48-week FU Period with a study visit at least once every 4 weeks. NA treatment
should be re-started in accordance with the NA re-treatment criteria (see Section 6.5.2, NA Re-
treatment Criteria During Follow-up, for more details).
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The investigator should consider to re-start NA treatment per local standard of care at the EOS
visit (Follow-up Week 48) for participants who met the NA treatment completion criteria based
on the Week 24 (or FU Week 2) results, who did not re-start NA treatment during the follow-up
phase, and who did not achieve and maintain HBsAg seroclearance. NA will not be provided by
the sponsor after the final study visit.
If a participant prematurely discontinues JNJ-3989 (ie, before Week 24), 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. NA treatment may be continued or, in
consultation with the sponsor, discontinued, based on the above-mentioned NA treatment
completion criteria.
If a participant prematurely discontinues PegIFN-α2a (ie, before Week 23 [Arms 1 and 2] or before
Week 11 [Arm 3]), treatment with JNJ-3989 and NA should be continued as planned.
6.5.2. 
NA Re-treatment Criteria During Follow-up
Participants who meet the protocol-defined NA treatment completion criteria based on the Week
24 (or FU Week 2) results should complete NA treatmentat FU Week 2 (or FU Week 4)as outlined
in Section 6.5.1, NA Treatment Completion, and will be monitored closely during the follow-up
period with a study visit at least once every 4 weeks. They  should re-start NA treatment
immediately in the event of:
 
Signs of decreasing liver function based on laboratory findings (eg, International Normalized
Ratio [INR], direct bilirubin) or clinical assessment (eg, ascites, hepatic encephalopathy).
 
HBV DNA value of >1,000,000 IU/mL (irrespective of confirmation and/or ALT increase).
Note: A post-treatment HBV DNA value of >100,000 IU/mL should trigger re-testing of
ALT/AST, HBV DNA, and total and direct bilirubin within a maximum of 7 days from
receipt of the data and further repeats as necessary (ie, weekly until HBV DNA returns to
<100,000 IU/mL). A post-treatment HBV DNA value of >20,000 IU/mL (but <100,000
IU/mL) should trigger a re-test within 14 days. At all times, additional re-testing of the
above parameters should be performed at the investigator’s discretion.
In addition, re-start of NA treatment should be considered in the following cases:
 
Confirmed post-treatment HBeAg seroreversion (HBeAg positive after it was negative at NA
completion), OR
 
Confirmed (at least 4 weeks apart) post-treatment increases in HBV DNA >2,000 IU/mL and
ALT >5x ULN, OR
Note: A post-treatment ALT value of >5x ULN should trigger re-testing of ALT, AST,
ALP, total and direct bilirubin, INR, albumin, and HBV DNA on a weekly basis until ALT
and AST levels have returned to <5x ULN. At all times, additional re-testing of these
parameters should be performed at the investigator’s discretion.
 
Confirmed (at least 4 weeks apart) post-treatment increases in HBV DNA >20,000 IU/mL.
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The decision to re-start NA treatment should take into consideration the dynamics of HBsAg, HBV
DNA and/or ALT values and should be discussed with the Sponsor.
To avoid delays in decision making, sites are encouraged to run local re-testing in parallel with
central re-testing in the situations described above that require more frequent re-testing. Local test
results are to be recorded in the CRF and/or source documents, including information on the HBV
DNA assay used. In addition, to avoid delays in NA re-treatment, it should be considered to
dispense NA to participants who potentially met the NA re-treatment criteria (eg, pending
confirmation) and who will not be available to come to the study site immediately at the time the
confirmatory test results will become available. This should ensure that the participant can
immediately re-start NA treatment if indicated, upon direct confirmation by the investigator.
In case NA treatment is re-started, participants will be followed until the end of the study or until
clinical stabilization, whichever comes later.
NA re-treatment criteria during follow-up are presented graphically in Section 10.12, Appendix
12.
Management of intervention-emergent ALT/AST elevations is discussed in Section 8.3.6.2,
Intervention-emergent ALT/AST Elevations.
6.6. 
Continued Access to Study Intervention After the End of the Study
Refer to Section 6.7 of the Master Protocol PLATFORMPAHPB2001.
The investigator should consider to re-start NA treatment per local standard of care at the EOS
visit (Follow-up Week 48) for participants who met the NA treatment completion criteria based
on the Week 24 (of FU Week 2) results, who did not re-start NA treatment during the follow-up
phase, and who did not achieve and maintain HBsAg seroclearance. NA will not be provided by
the sponsor after the final study visit.
6.7. 
Treatment of Overdose
For this study, any dose of JNJ-3989 exceeding the protocol-specified dose with ≥25% and any
dose of NA (ETV, tenofovir disoproxil, or TAF) greater than the prescribed dose (refer to Section
6.1, Study Intervention(s) Administered), will be considered an overdose. Any dose of PegIFN-
α2a greater than the prescribed dose will be considered an overdose. The Sponsor does not
recommend specific treatment for an overdose.
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 should be interrupted or whether the dose should be reduced.
 
Closely monitor the participant for AE/SAE and laboratory abnormalities.
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 
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.
6.8. 
Concomitant Therapy
An overview of ISA-specific disallowed medication is provided in Table 3.
Local guidelines on the use of live vaccines in participants receiving PegIFN-α2a should be
followed, including for the second dose of Sputnik V (which contains rAd5, with a theoretical risk
of replication competence). Sputnik Light, which is the first dose of Sputnik V (with rAd26) is not
considered a live vaccine. See below for further guidance on the use of COVID-19 vaccines.
Note that locally approved COVID-19 vaccines (including those that received emergency use
authorization or conditional marketing authorization) are allowed throughout the study. For
participants receiving PegIFN-α2a the following recommendations should be applied to
accommodate COVID-19 vaccination during the Treatment Period:
 
COVID-19 vaccine and PegIFN-α2a should not be administered on the same day.
 
If required, PegIFN-α2a injection can be delayed up to 2 days. The next PegIFN-α2a injection
should be administered at the scheduled time.
 
If required, skipping a PegIFN-α2a injection may be considered after consultation with the
Sponsor.
 
Vaccination with Sputnik V should take above-mentioned consideration about live vaccines
into account.
All COVID-19 vaccination-related data (eg, COVID-19 vaccination, AEs, AE management)
should be appropriately captured in the CRF and source documents. Refer to the COVID-19
vaccine and/or PegIFN-α2a prescribing information for more details.
For general concomitant therapy considerations, refer to Section 6.5 of the Master Protocol
PLATFORMPAHPB2001.
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Table 3: 
Disallowed Medication
Disallowed from 3 years prior to screening until end of follow-up:
 
IFN, other than the PegIFN-α2a taken in the context of this study.
Disallowed from 1 year prior to baseline until end of follow-up:
 
Any oligonucleotide-based treatment (eg, siRNA, nucleic acid polymers, antisense oligonucleotides),
other than the study intervention taken in the context of this study.
Disallowed from 6 months prior to screening until end of follow-up:
 
Any investigational agent, investigational vaccine, invasive investigational medical device, or
investigational biological product (other than the study intervention taken in the context of this study).
Note: For investigational COVID-19 vaccines administered within 6 months prior to screening, an
exception will be made as long as the vaccine has been approved (or received emergency use authorization
or conditional marketing authorization) at the time of screening.
Disallowed from 6 months prior to baseline until end of follow-up:
 
Any systemically (eg, intravenously, intramuscularly, orally, subcutaneously) administered medication
that directly or indirectly interferes with immune responses (eg, cyclosporine, interleukins, systemic
corticosteroids exceeding 5 mg of prednisolone equivalent/day).
Disallowed from screening until end of follow-up:
 
Any anti-HBV drug (including vaccines) other than the study intervention taken in the context of this
study.
Notes:
o 
NA standard of care treatment is allowed between screening and baseline.
o Prior hepatic treatment with herbal or nutritional products is allowed but should be stopped at
screening.
Disallowed from screening until end of study intervention:
 
Products containing Hypericum perforatum (St. John’s wort).
 
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 PegIFN-α2a should be
consulted for any additional prohibited medication. In case of flu-like symptoms after
administration of PegIFN-α2a, acetaminophen/paracetamol up to a maximum of 2 g per 24 hours
and a maximum of 6 g per week is allowed.
Medications requiring subcutaneous injection (other than JNJ-3989 and PegIFN-α2a; eg, insulin)
should be administered in a different location than the JNJ-3989 and PegIFN-α2a injection sites.
7. 
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT
DISCONTINUATION/WITHDRAWAL
If a participant prematurely discontinues JNJ-3989 (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.
If a participant prematurely discontinues PegIFN-α2a (ie, before Week 23 [Arms 1 and 2] or before
Week 11 [Arm 3]), treatment with JNJ-3989 and NA should be continued as planned.
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In case of virologic breakthrough, a viral sequencing sample will be collected during an
unscheduled visit within 7 days of the DNA increase.
 
The participant has ALT/AST elevations, as described in Section 8.3.6.2,
Intervention-emergent ALT/AST Elevations.
Note: The grades are based on the DAIDS Toxicity Grading Scale (see Section 10.9, Appendix 9:
DAIDS Table).
In addition, PegIFN-α2a must immediately be discontinued for any of the following reasons:
 
Participant has platelet count <25,000 cells/mm3.
 
Participant has ANC <500 cells/mm3.
Note: PegIFN-α2a treatment can be restarted when ANC values return to more than
1,000 cells/mm³ (see details in Section 6.5, Dose Modification)
 
Participant develops evidence of hepatic decompensation during treatment, or ALT increase
clinically significant or accompanied by direct bilirubin increase.
 
Participant develops thyroid disorders or diabetes during treatment and cannot be controlled
with medication.
 
Participant develops new or worsening ophthalmologic disorders.
 
Participant develops any deterioration of cardiovascular status.
 
Participant develops serious, acute hypersensitivity reaction (eg, urticaria, angioedema,
bronchoconstriction, anaphylaxis).
 
Participant develops serious infection (bacterial, viral, fungal) and sepsis.
 
Participant develops persistent or unexplained pulmonary infiltrates or pulmonary function
impairment.
 
Participant with onset or worsening of psoriatic lesion.
 
Participant develops moderate or severe depression, or other psychiatric symptoms (for mild
depression, treatment discontinuation may be considered).
Note: Participants who develop a neuropsychiatric AE during PegIFN-α2a treatment, will be
monitored closely until the neuropsychiatric AE resolves, with frequent (at least weekly)
follow-up phone calls.
 
Participant develops colitis symptoms (such as but not limited to abdominal pain, bloody
diarrhea, and fever).
 
Participant develops symptoms or signs suggestive of pancreatitis.
For participants who prematurely discontinue PegIFN-α2a, treatment with PegIFN-α2a may be
restarted according to the recommendations from the locally approved prescribing information for
PegIFN-α2a.
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7.2. 
Participant Discontinuation/Withdrawal From the Study
In case a participant is withdrawn from the study intervention cohort for any of the reasons listed
in Section 7.2 of the Master Protocol PLATFORMPAHPB2001, additional participants will not
be entered.
Withdrawal of Consent
A participant declining to return for scheduled visits does not necessarily constitute withdrawal of
consent. Alternate follow-up mechanisms that the participant agreed to when signing the consent
form apply as local regulations permit.
7.2.1. 
Withdrawal From the Use of Research Samples
Refer to Section 7.2.1 of the Master Protocol PLATFORMPAHPB2001.
7.3. 
Lost to Follow-up
Refer to Section 7.3 of the Master Protocol PLATFORMPAHPB2001.
8. 
STUDY ASSESSMENTS AND PROCEDURES
Overview
Refer to Section 8 of the Master Protocol PLATFORMPAHPB2001.
The total blood volume to be collected from each participant during planned assessments for the
entire study will be up to approximately 1050 mL.a  In addition, PBMC samples (at selected sites
only; approximately 450 mL)andoptional pharmacogenomic samples (approximately 25mL) may
be collected.
Note: The total blood volume to be collected from each participant may vary, depending on several
factors (eg, unscheduled re-tests, unscheduled sampling for safety management, re-sampling,
individual variations, follow-up visits that are not mandatory for participants who continue NA
treatment or have restarted NA treatment during the follow-up period).
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, TAF, and PegIFN-α2a.
 
Contact information page(s).
a For participants in Japan only: the total blood volume to be collected during planned assessments for the entire study
will be approximately 920 mL due to additional hematology assessments.
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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 and HBeAg will
be processed in real-time. Samples for the determination of HBcrAg can be analyzed in batch and
at the Sponsor’s request.
HBV DNA and HBV RNA will be 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 (and PegIFN-α2a if applicable)
are discontinued in participants with confirmed virologic breakthrough (see Section 7.1,
Discontinuation of Study Intervention).
 
To assess if the protocol-defined NA treatment completion criteria are met (see Section 6.5.1,
NA Treatment Completion).
 
To assess whether re-start of NA treatment during follow-up is needed (see Section 6.5.2, NA
Re-treatment Criteria During Follow-up).
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 will be performed to monitor HBV variants present 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.
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Samples may be used by the Sponsor for additional assessments analyzing the serologic and
virologic characteristics of the HBV infection and efficacy of the study intervention, including
viral genotypic and phenotypic assessments.
8.2. 
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.
In addition, ophthalmologic examinations will be performed at the time points specified in the
Schedule of Activities.
Additional clinical safety laboratory assessments specific for this protocol are described in
Section 10.2, Appendix 2: Clinical Laboratory Tests.
8.2.1. 
Physical Examinations
Refer to Section 8.2.1 of the Master Protocol PLATFORMPAHPB2001.
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 10.8, Appendix 8:
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 10.8, Appendix 8: 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. Given the less frequent follow-up of participants who continue NA treatment or have
restarted NA treatment during the follow-up period (provided that their HBV DNA and ALT
values are stable), pregnancy tests for at-home use may be provided to these participants from
Follow-up Week 4 onwards to allow 4-weekly urine pregnancy testing in between scheduled site
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visits. Participants will report the results to the study site personnel at the next visit, and these will
be added to the source documents. If positive, the participant should contact the site immediately.
8.2.6. 
Ophthalmologic Examinations
Ophthalmologic examinations (including fundoscopy) will be performed at the time points
specified in the Schedule of Activities. Any participant experiencing a decrease or loss of vision
at any time point during study participation, must have a prompt ophthalmologic examination.
Medical records of the examination should be collected and assessed by the investigator.
8.3. 
Adverse Events, Serious Adverse Events, and Other Safety Reporting
Adverse events and SAEs will be evaluated as described in Section 8.3 of the Master Protocol
PLATFORMPAHPB2001, including handling of pregnancy described in Section 8.3.5.
For further details on AEs and SAEs (Definitions and Classifications; Attribution Definitions;
Severity Criteria; Special Reporting Situations; Procedures) as well as product quality complaints,
refer to Attachment 4 of the Master Protocol PLATFORMPAHPB2001.
8.3.1. 
Time Period and Frequency for Collecting Adverse Event and Serious
Adverse Event Information
Refer to Section 8.3.1 of the Master Protocol PLATFORMPAHPB2001.
8.3.2. 
Method of Detecting Adverse Events and Serious Adverse Events
Refer to Section 8.3.2 of the Master Protocol PLATFORMPAHPB2001.
8.3.3. 
Follow-up of Adverse Events and Serious Adverse Events
Refer to Section 8.3.3 of the Master Protocol PLATFORMPAHPB2001.
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.
8.3.6. 
Adverse Events of Special Interest
Events of Special Interest are significant AEs that are judged to be of special interest because of
clinical importance, known class effects or based on nonclinical signals. Events of Special Interest
for JNJ-3989 that will be carefully monitored during the study include ISRs, ALT/AST elevations,
and hematologic abnormalities.
For participants reporting ISRs, ALT/AST elevations, or hematologic abnormalities as specified
in the DAIDS Toxicity Grading Scale (see Section 10.9, Appendix 9: DAIDS Table), the following
should be done.
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8.3.6.1. 
Injection Site Reactions
At the time points specified in the Schedule of Activities or at an unscheduled visit if needed, an
evaluation of the injection site will be performed based on participant’s description and/or physical
examination. 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 the DAIDS scale (see Section 10.9, Appendix 9: DAIDS Table).
All ISRs (including ISRs below Grade 1) will need to be recorded in the special events section of
the CRF.
Digital pictures will be taken when considered appropriate; all efforts should be made to collect
images in case of Grade 3 and 4 ISRs. Digital pictures will only be taken and collected from
participants who consent separately to this component of the study. If digital pictures are required,
they should be de-identified and provided to the Sponsor.
8.3.6.2. 
Intervention-emergent ALT/AST Elevations
Elevated liver enzyme activity can be triggered by the underlying HBV disease as well as by the
study intervention.
Management of intervention-emergent ALT/AST elevations is presented graphically in
Section 10.7, Appendix 7: Intervention-emergent ALT/AST Elevations, and is described below.
Any intervention-emergent elevation of ALT and/or AST ≥3x ULN and ≥3x nadir (ie, lowest value
during study participation) should trigger an assessment of confounding factors (alcohol intake,
change in concomitant medication, and comorbidities) and should trigger a confirmatory study
visit to repeat laboratory testing of AFP, ALT, AST, ALP, bilirubin (total and direct), INR,
albumin, and HBV DNA. Additional tests should be considered based on clinical judgement (refer
to Section 10.7, Appendix 7: Intervention-emergent ALT/AST Elevations). This confirmatory visit
should be scheduled as soon as possible within 7 days of the receipt of the initial ALT/AST results.
In case the repeat laboratory testing shows an isolated ALT/AST elevation (ie, with stable albumin,
bilirubin [total and direct], and INR) the participant may continue study intervention. In case of
confirmed ALT elevation >1,000 U/L and ≥3x the baseline value, JNJ-3989 (and PegIFN-α2a if
applicable) should be discontinued. In both cases, NA treatment should be continued. The
participant will be monitored (laboratory testing of AFP, ALT, AST, ALP, bilirubin [total and
direct], INR, albumin, and HBV DNA) on a weekly basis or more frequently until ALT and AST
levels have returned to <5x ULN and HBV DNA is <20,000 IU/mL. 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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If the ALT and/or AST level is ≥3x ULN and ≥3x nadir and is associated with any of the following
laboratory results or clinical symptoms:
 
INR ≥1.5, OR
 
direct bilirubin >1.5x ULN, OR
 
serum albumin <3.0 g/dL, OR
 
ascites, hepatic encephalopathy, or liver-related symptoms (eg, severe fatigue, nausea,
vomiting, right upper quadrant pain in the absence of an alternative medical explanation), OR
 
other indication of reduced liver function,
the participant should discontinue JNJ-3989 (and PegIFN-α2a if applicable) and should be
monitored on a weekly basis or more frequently, or as per good clinical practice, until ALT and
AST levels have returned to <5x ULN, HBV DNA is <20,000 IU/mL and, if present, liver-related
symptoms have improved. NA treatment should be continued. Additional tests can be considered
based on clinical judgement (refer to Section 10.7, Appendix 7: Intervention-emergent ALT/AST
Elevations).
In case of prolonged ALT elevation >3x ULN AND >2x nadir, which lasts at least 12 weeks, the
decision to continue JNJ-3989 and/or PegIFN-α2a should be based upon virologic parameters (eg,
HBsAg, HBV DNA) and should be made in consultation with the sponsor.
PegIFN-α2a may need to be discontinued in clinically significant cases of ALT increase or in
combined increase of ALT and direct bilirubin. Refer to the prescribing information for
PegIFN-α2a (Pegasys SmPC or Pegasys USPI).
8.3.6.3. 
Hematologic Abnormalities
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 subcutaneous 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 non-clinical 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
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stabilization of the respective parameter(s). Stabilization is defined as no further significant
reduction over two consecutive visits.
In case of confirmed Grade 3 or Grade 4 hematologic abnormalities, discontinuation of JNJ-3989
(and PegIFN-α2a if applicable) should be considered. In case of discontinuation, NA treatment
should be continued.
8.3.7. 
Other Toxicities
The following toxicities will be carefully monitored: rash, renal complications, and acute systemic
allergic reactions.
For participants reporting rash, renal complications, or acute systemic allergic reactions as
specified in the DAIDS Toxicity Grading Scale (see Section 10.9, Appendix 9: DAIDS Table), the
following should be done.
8.3.7.1. 
Rash
Participants should be informed that they should contact their doctor immediately when they
notice any generalized skin reaction. This skin reaction should be evaluated in the clinic the
same day (if possible) or the next possible day.
All rash events should be captured in the AE section of the CRF. Separate Rash pages will be
completed in case of a rash event.
Monitoring of the evolution of rash events will be performed as described in Table 4 in
Section 10.6, Appendix 6: Rash Management.
When safety blood samples are drawn as per the rash management guidelines, these should be
processed by the local laboratory. The following parameters will need to be tested: AST, ALT,
sedimentation rate, complete blood cell count (including hemoglobin, hematocrit, RBC count,
WBC count, differential count [neutrophils, lymphocytes, monocytes, eosinophils, and basophils],
and platelet count), and creatinine. The values of the local laboratory assessments need to be
transcribed in the CRF by the study site personnel.
The participant may be treated symptomatically until the rash resolves. Oral antihistamines (eg,
cetirizine, levocetirizine) and/or topical corticosteroids may provide symptomatic relief but
effectiveness of these measures has not been established. If systemic corticosteroids exceeding
5mg of prednisolone equivalent/day are required for treatment of rash, JNJ-3989 (and PegIFN-
α2a if applicable) need to be permanently discontinued. NAs can be continued. If the rash is
considered to be most likely due to concomitant illness or non-study interventions, standard
management, including discontinuation of the likely causative agent, should be undertaken.
8.3.7.2. 
Renal Complications
If renal complications develop, participants should be closely monitored for disturbances in
creatinine clearance. Additional investigations can be performed at the investigator’s discretion.
Participants must be treated as clinically appropriate.
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Participants who develop confirmed Grade 3 or 4 eGFR abnormalities with reduction from
baseline by at least 10 mL/min/1.73 m2 will change their NA from tenofovir disoproxil to ETV or
TAF (if the patient was receiving tenofovir disoproxil), according to the prescribing information.
If the abnormality persists despite change of NA or if the patient is not receiving tenofovir
disoproxil, he or she will permanently discontinue the intake of JNJ-3989 (and PegIFN-α2a if
applicable) if considered at least possibly related to JNJ-3989 (or PegIFN-α2a if applicable) and
should be followed appropriately until resolution of the AE or toxicity. Rechallenge is not allowed.
8.3.7.3. 
Acute Systemic Allergic Reactions
Grade 1 (Localized Urticaria [Wheals] With no Medical Intervention Indicated)
Participants may continue the intake ofstudy interventions.
Cetirizine, levocetirizine, topical corticosteroids or antipruritic agents may be prescribed.
Participants should be advised to contact the investigator immediately if there is any worsening of
the acute systemic allergic reaction.
Grade 2 (Localized Urticaria With Intervention Indicated, or Mild Angioedema With no
Intervention Indicated)
Participants may continue the intake of study interventions.
Cetirizine, levocetirizine, topical corticosteroids or antipruritic agents may be prescribed.
Participants should be advised to contact the investigator immediately if there is any worsening of
the acute systemic allergic reaction, in which case the participant will permanently discontinue the
intake of JNJ-3989 (and PegIFN-α2a if applicable). Rechallenge is not allowed. The participant’s
NA treatment may be discontinued based on investigator judgement in consultation with the
Sponsor.
Grade 3 (Generalized Urticaria, Angioedema With Intervention Indicated, or Symptoms of
Mild Bronchospasm) and Grade 4 (Acute Anaphylaxis, Life-threatening Bronchospasm, or
Laryngeal Edema)
Participants will permanently discontinue the intake of JNJ-3989 (and PegIFN-α2a if applicable).
Rechallenge is not allowed. The participant’s NA treatment may be discontinued based on
investigator judgement in consultation with the Sponsor.
Participants will be treated as clinically appropriate. Participants should be followed until
resolution of the AE and standard management should be undertaken.
8.4. 
Pharmacokinetics
Plasma or serum samples, as applicable, will be used to evaluate the PK of JNJ-3989. Serum
collected for PK may additionally be used to evaluate safety or efficacy aspects that address
concerns arising during or after the study period.
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8.4.1. 
Evaluations
All participants will have sparse PK sampling during the treatment period.
Venous blood samples will be collected for measurement of plasma or serum (as applicable)
concentrations of JNJ-3989 (ie, JNJ-3976 and JNJ-3924), NA and PegIFN-α2a, at time points
specified in the Schedule of Activities. Bioanalysis of NA and PegIFN-α2a is optional at the
discretion of the sponsor.
8.4.2. 
Analytical Procedures
Pharmacokinetics
At the Sponsor’s discretion, a selection of samples may be analyzed to determine concentrations
of JNJ-3989 (ie, JNJ-3976 and JNJ-3924)and optionally NA and/or PegIFN-α2a using a validated,
specific, and sensitive liquid chromatography-mass spectrometry method or liquid
chromatography fluorescence method, as applicable, by or under the supervision of the Sponsor.
PK samples may be stored for future exploratory analysis of protein binding or the metabolite
profile. Genetic analyses will not be performed on these samples. Participant confidentiality will
be maintained.
8.4.3. 
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 may  be derived using
population PK modelling. Baseline covariates (eg, body weight, age, sex, CrCL, race) may be
included in the model, if relevant.
Pharmacokinetic/Pharmacodynamic Evaluations
Relationships of individual PK parameters for JNJ-3976 and JNJ-3924, and optionally NA and/or
PegIFN-α2a, with selected efficacy and/or safety endpoints may be evaluated, if applicable.
8.5. 
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. These samples could for
example be used to assess changes in frequencies of immune cells such as myeloid-derived
suppressor cells (MDSCs). 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
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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.
These analyses will be performed at the Sponsor’s discretion, will always be under the Sponsor’s
supervision, and may be reported separately.
8.6. 
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.
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.
8.7. 
Immune Assessments
At selected sites, PBMC samples for immune analyses will be collected during study intervention
and follow-up and will be analyzed centrally for HBV-specific responses by enzyme-linked
immunospot (ELISpot) and/or intracellular cytokine staining (ICS) after stimulation with
HBV-specific antigens. ELISpot detects T-cells that secrete gamma interferon (IFN-γ)in response
to a specific antigenic stimulation, whereas ICS determines the frequency of CD4+ and CD8+
T-cells secreting cytokines such as IFN-γ, interleukin (IL)-2 and tumor necrosis factor (TNF)-α in
response to a specific antigenic stimulation.
Additional PBMC samples may be taken in case of 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 using proliferation or cytotoxic assays or other methods such as cytometry by time of
flight to evaluate innate and adaptive immune responses. Leftover PBMC samples may be used at
the Sponsor’s discretion for additional exploratory research (eg, assessment of other immune cells
such as NK-cells, MDSCs, dendritic cells [DCs], and B-cells) related to HBV infection or study
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intervention (safety/efficacy), 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 optionally to PegIFN-α2a. Antidrug
antibodies may be analyzed using assays such as an enzyme-linked immunosorbent assay or
functional assays. The analyses may also include gene expression and cytokine analyses assessing
markers such as interferon-stimulated genes (ISGs), IFN-α, and interferon γ-induced protein 10
(IP-10).
These analyses will be performed at the Sponsor’s discretion, will always be under the Sponsor’s
supervision, and may be reported separately.
8.8. 
Medical Resource Utilization
Medical resource utilization data, associated with medical encounters, will be collected in the CRF
by the investigator and study site personnel for all participants throughout the study. Protocol-
mandated procedures, tests, and encounters are excluded. The data collected may be used to
conduct exploratory economic analyses and will include:
 
Number and 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+NA+PegIFN-α2a is more efficacious than NA treatment alone (standard of care), as
measured by the primary efficacy endpoint, the proportion of participants who achieved a
reduction of at least 2 log10 IU/mL in HBsAg levels from baseline at Week 24. Because the study
does not include a control arm, the hypothesis is formulated assuming a fixed external NA control
response rate of 2% in terms of the primary efficacy endpoint.
9.2. 
Sample Size Determination
A sample size of 30 participants per arm yields >95% statistical power to detect a ≥30% difference
in at least one arm in the proportions of participants with a reduction of at least 2 log10 IU/mL in
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HBsAg levels from baseline at Week 24 versus a fixed proportion of ≤2%, assumed for external
control (NA treatment). Statistical power to test the primary hypothesis was assessed for each of
the intervention arms, separately, 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 assumed external control value is based on the data of the NA control arm in virologically
suppressed HBeAg negative participants in study 73763989HPB2001 (REEF-1).
The total study sample size is 102 participants (34 per arm) with 1:1:1 randomization ratio to one
of the three intervention arms, assuming an approximate 10% attrition rate.
For the secondary set of pairwise comparisons of the primary efficacy endpoint among the 3 study
intervention arms (Arm 1 versus Arm 2, Arm 1 versus Arm 3, and Arm 2 versus Arm 3) and using
a 2-sample binomial test, the planned sample size yields about 68% power to detect a significant
difference of at least 30%. This is assuming the lowest response rate at Week 24 to be 50% in one
of the intervention arms, and 80% in one or both of the other 2 arms and applying the Hochberg
procedure to control the 1-sided Type 1 error rate at 0.05 level. The assumption of 50% response
rate was derived from the analysis of 73763989HPB2001 (REEF-1) on-treatment data.
9.3. 
Populations for Analysis Sets
For purposes of analysis, the following populations are defined:
Population 
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.
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.
IFN-FAS  
All participants who were randomly assigned to an intervention arm in this ISA and received
at least 1 dose of PegIFN-α2a 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 statistical analysis plan 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 Week 24
(EOSI) visit or discontinued earlier. The final analysis will be performed when all participants
have completed the last study visit at Week 72 (FU Week 48) or discontinued earlier.
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To evaluate the efficacy, the primary analysis set will be the FAS (see Section 9.3, Populations for
Analysis Sets). The IFN-FAS set will be used for sensitivity analyses of selected efficacy
endpoints.
All efficacy summaries will be presented with descriptive statistics and 90% confidence intervals
(CI) 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 factors (ie, country grouping as proxy for HBV
genotype (GT) at enrollment and absolute HBsAg value at baseline [<1,000 IU/mL versus >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 Efficacy Endpoint
The proportion of participants who achieved a reduction of at least 2 log10 IU/mL in HBsAg levels
from baseline at Week 24 will be summarized for each treatment 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 2% at a one-sided Type 1 error rate of 0.05 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 will be explored using logistic regression analyses and classification
and regression tree analysis (CART).
The Mantel-Haenszel (MH) test adjusted for the randomization stratification factors will be used
in a secondary analysis comparing the primary endpoint between the study intervention arms at a
one-sided alpha level of 0.05 and applying the Hochberg procedure for multiple comparisons
adjustment.
The primary efficacy endpoint will be compared between Arm 2 and the “virtual” model-generated
IFN-free JNJ-3989 control participants in Arm 2 using the McNemar test for the difference
between paired matched case-control binomial proportions at 0.05 one-sided Type 1 error rate.
The associated 2-sided 90% CI will be estimated to accompany the point estimate of the difference
in proportions. No multiplicity adjustment will be used in this exploratory statistical comparison.
Description of the virtual control generated data for Arm 2 is described in Section 9.4.2.3, Across
ISAs Comparisons of Efficacy.
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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 will
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, waterfall, and radar plots) will
also be used to summarize the efficacy data by intervention arm and over time.
9.4.2.3. 
Across ISAs Comparisons of Efficacy
Indirect comparisons between different regimens across multiple 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, such as for example the
virologically suppressed participants who are HBeAg negative at screening across
73763989PAHPB2007 (this ISA), 73763989PAHPB2002 (REEF-2), and 73763989PAHPB2006
(PENGUIN) ISAs.
To further evaluate the impact of potential differences between ISAs, a virtual control arm will be
generated for this ISA. Virtual control efficacy data will be defined as IFN-free regimen with
JNJ-3989+NA at the dose level used in this ISA. Creating a virtual control arm by fitting the
PK/PD model to the available HBsAg data can be performed for subjects with serum HBsAg >100
IU/mL at screening. The same approach may also be considered for subjects with serum HBsAg
≤100 IU/mL at screening, but as these subjects were typically not included in previous JNJ-3989
studies, the feasibility of this approach will be assessed based on the current analysis results.
For each participant in Arm 2 of this ISA, the HBsAg data for “virtual” control subjects will be
generated using an appropriate longitudinal model (eg, kinetic pharmacodynamic model [KPD] or
PK/PD model) developed and validated based on the data from the 73763989HPB2001 (REEF-1)
study. In Arm 2, the first 12 weeks of HBsAg data under treatment with JNJ-3989+NA alone will
enable to estimate individual parameters (ie, Empirical Bayes Estimates) describing each
participant's specific HBsAg temporal kinetics. These individual parameters will be used further
to extrapolate each participant’s individual HBsAg values over time, as if that participant had been
treated with JNJ-3989+NA regimen (matching the same JNJ-3989 dose level) but without
receiving PegIFN-α2a treatment. The observed HBsAg levels post PegIFN-α2a intake in Arm 2
will be directly compared to virtual control model-generated data for this arm. Due to the
randomization, the virtual control subjects derived for Arm 2 can be considered exchangeable with
the participants of the other arms in this ISA. Therefore, the estimates of HBsAg efficacy endpoints
at the group level of the virtual control subjects for Arm 2 will also be compared to the other arms
in this ISA.
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The evaluation of the comparisons within this ISA (virtual within-participant control versus
regimens in this ISA) against the results from comparing the regimens in this ISA with those in
the 73763989PAHPB2006 (PENGUIN) and 73763989PAHPB2002 (REEF-2) ISAs will provide
an additional efficacy assessment of the treatment benefit of PegIFN-α2a.
More details on this approach and its application to secondary endpoints will be provided in a
separate analysis plan 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 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 overall and 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 analysis
Population PK analysis of concentration-time data of JNJ-3976 and JNJ-3924, and, optionally, of
NA and PegIFN-α2a may be performed using non-linear mixed effects modeling. Data may be
combined with selected Phase 1 and/or 2 studies to support a relevant structural model. Available
participant characteristics (eg, demographics, laboratory variables, genotypes) will be included in
the model as necessary. Details will be given in a population PK analysis plan and results of the
population PK analysis, if applied, will be presented in a separate report.
Pharmacokinetic/pharmacodynamic analysis
Relationships of PK parameters for JNJ-3976 and JNJ-3924, and, optionally, for NA and PegIFN-
α2a with selected efficacy and with selected 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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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.
Immune analysis
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 treshold) 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.
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.
Medical Resource Utilization
Medical resource utilization data will be descriptively summarized by intervention arm over time.
9.5. 
Interim Analysis
Interim analyses (IA) 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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The IAs are planned when:
 
Approximately 50% of the randomized participants have completed Week  12 or
discontinued earlier.
 
Approximately 50% of the randomized participants have completed Week 24 or
discontinued earlier.
 
All randomized participants have completed Week 36 (FU Week 12) or discontinued
earlier.
 
All randomized participants have completed Week 48 (FU Week 24) or discontinued
earlier.
 
All randomized participants have completed Week 60 (FU Week 36) 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 cutoffs, 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 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. 
SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS
10.1. Appendix 1: Abbreviations and Definitions
AE 
adverse event
AFP  
alpha-fetoprotein
ALP  
alkaline phosphatase
ALT  
alanine aminotransferase
ANC  
absolute neutrophil count
AST  
aspartate aminotransferase
AUC∞ 
area under the plasma concentration time curve to last sampling point from time zero extrapolated to infinity
AUCτ 
area under the plasma concentration time curve over the dosing interval (τ)
AUC0-last 
area under the plasma concentration time curve from administration to last quantifiable sampling point
AUC0-xh  
area under the plasma concentration time curve from administration to x hours
BMI 
body mass index
bpm  
beats per minute
C24h  
plasma concentration 24 hours after administration
CAM(-N) 
(Class N) capsid assembly modulator
cccDNA  
covalently closed circular deoxyribonucleic acid
CI 
confidence interval
CKD-EPI 
Chronic Kidney Disease Epidemiology Collaboration
CL/F  
total apparent oral clearance
Cmax  
maximum plasma concentration
CRF  
case report form
CT  
computed tomography
CV  
coefficient of variation
CYP  
cytochrome P450
DAIDS  
Division of Acquired Immunodeficiency Syndrome
DC  
dendritic cell
DDI 
drug-drug interaction
DNA  
deoxyribonucleic acid
DRC  
Data Review Committee
EC90 
90% effective concentration
ECG  
electrocardiogram
EFD  
embryofetal development
eGFRcr 
estimated glomerular filtration rate based on serum creatinine
eGFRcys 
estimated glomerular filtration rate based on cystatin C
ELISpot 
enzyme-linked immunospot
EOS  
end of study
EOSI 
end of study intervention
ETV  
entecavir
FAS  
full analysis set
FC 
functional cure
FOIA  
Freedom of Information Act
FU 
follow-up
GLDH  
glutamate dehydrogenase
GT  
genotype
HBc 
hepatitis B core protein
HBcrAg 
hepatitis B core-related antigen
HBe 
hepatitis B e
HBeAg 
hepatitis B e antigen
HBs 
hepatitis B surface protein
HBsAg 
hepatitis B surface antigen
HBV  
hepatitis B virus
HCC  
hepatocellular carcinoma
HCV  
hepatitis C virus
HDV  
hepatitis D virus
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HEV  
hepatitis E virus
HIV(-1/2) 
human immunodeficiency virus (type 1/2)
HLA  
human leukocyte antigen
IA  
interim analysis
IB  
Investigator’s Brochure
ICF  
informed consent form
ICS  
intracellular cytokine staining
IFLEP  
Independent Flare Expert Panel
IFN(-α/γ) 
(alpha/gamma) interferon
IFN-FAS  
interferon full analysis set
IgG  
immunoglobulin G
IgM  
immunoglobulin M
IL 
interleukin
IMP  
investigational medicinal product
INR  
International Normalized Ratio
ISA  
intervention-specific appendix
ISR  
injection site reaction
KPD  
kinetic pharmacodynamic model
LLN  
lower limit of normal
LLOQ  
lower limit of quantification
MDSC  
myeloid-derived suppressor cell
MoA  
mode of action
MRI 
magnetic resonance imaging
MRU  
medical resource utilization
NA  
nucleos(t)ide analog
NIMP  
non-investigational medicinal product
NK  
natural killer
NOAEL 
no observed adverse effect level
PBMC  
peripheral blood mononuclear cell
PD 
pharmacodynamic(s)
PegIFN-α2a 
pegylated interferon alpha-2a
pgRNA  
pre-genomic ribonucleic acid
PK 
pharmacokinetic(s)
PoC  
proof of concept
Q4W  
every 4 weeks
QW 
weekly
QD 
once daily
QTcF  
QT interval corrected for heart rate according to Fridericia’s formula
RBC  
red blood cell
rcDNA  
relaxed circular deoxyribonucleic acid
RNAi 
ribonucleic acid interference
SAE 
serious adverse event
SAP  
Statistical Analysis Plan
SD 
standard deviation
SDM  
site-directed mutant
SE 
standard error
siRNA  
small interfering ribonucleic acid
t1/2term  
terminal half-life
T4 
thyroxine
TAF  
tenofovir alafenamide
TEAE 
treatment-emergent adverse event
tmax  
time to reach Cmax
TND  
target not detected
TNF  
tumor necrosis factor
TSH  
thyroid stimulating hormone
WBC  
white blood cell
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Definitions of Terms
ALT/AST nadir 
Lowest ALT/AST value during study participation
End of study 
intervention (EOSI)
Time of the last administration of study intervention
Functional cure (FC) 
HBsAg seroclearance at 24-weeks after EOSI
HBsAg or HBeAg 
seroclearance
HBsAg or HBeAg negativity, respectively, based on the assay used
HBsAg or HBeAg 
seroconversion
HBsAg or HBeAg negativity and anti-HBs or anti-HBe antibody positivity, respectively
IC50 
half maximal inhibitory concentration
Study intervention  
JNJ-73763989 (JNJ-3989), NA (either ETV, tenofovir disoproxil, or TAF), and
PegIFN-α2a
Virologic breakthrough  
Confirmed on-treatment HBV DNA increase by >1 log10 IU/mL from nadir or
confirmed on-treatment HBV DNA level >200 IU/mL in participants who had HBV
DNA level <LLOQ of the HBV DNA assay.
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10.3. Appendix 3: Regulatory, Ethical, and Study Oversight Considerations
10.3.1. 
Regulatory and Ethical Considerations
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.
10.3.4. 
Data Protection
Refer to Attachment 3 of the Master Protocol PLATFORMPAHPB2001.
10.3.5. 
Long-Term Retention of Samples for Additional Future Research
Refer to Attachment 3 of the Master Protocol PLATFORMPAHPB2001.
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.
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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.
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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.
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. Pregnancy information
will be collected and reported as noted in Section 8.3.5.
Definitions
Woman of Childbearing Potential (WOCBP)
A woman is considered fertile following menarche and until becoming postmenopausal unless
permanently sterile (see below).
Woman Not of Childbearing Potential
 
premenarchal
A premenarchal state is one in which menarche has not yet occurred.
 
postmenopausal
A postmenopausal state is defined as no menses for 12 months without an alternative medical
cause. A high follicle-stimulating hormone (FSH) level (>40 IU/L or mIU/mL) in the
postmenopausal range may be used to confirm a postmenopausal state in women not using
hormonal contraception or hormonal replacement therapy (HRT). However, in the absence of
12 months of amenorrhea, a single FSH measurement is insufficient to confirm a woman is
not of childbearing potential. If there is a question about menopausal status in women on HRT,
the woman will be required to use one of the non-estrogen-containing hormonal highly
effective contraceptive methods if she wishes to continue HRT during the study.
 
permanently sterile
Permanent sterilization methods include hysterectomy, bilateral salpingectomy, or bilateral
oophorectomy.
Note: If the childbearing potential changes after start of the study (eg, a premenarchal woman
experiences menarche) or the risk of pregnancy changes (eg, a woman who is not heterosexually
active becomes active), a woman must begin a highly effective method of contraception, as
described throughout the inclusion criteria.
If reproductive status is questionable, additional evaluation should be considered.
Contraceptive (birth control) use by men or women should be consistent with local regulations
regarding the acceptable methods of contraception for those participating in clinical studies.
Examples of Contraceptives
EXAMPLES OF CONTRACEPTIVESa ALLOWED DURING THE STUDY INCLUDE:
USER INDEPENDENT
Highly Effective Methods That Are User Independent Failure rate of <1% per year when used
consistently and correctly.
 Implantable progestogen-only hormone contraception associated with inhibition of ovulation
 Intrauterine device (IUD)
 Intrauterine hormone-releasing system (IUS)
 Tubal closure (eg, bilateral tubal occlusion, bilateral tubal ligation)
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 Azoospermic partner (vasectomized or due to medical cause)
(Vasectomized partner is a highly effective contraceptive methodprovided that the partner is the
sole sexual partner of the woman of childbearing potential and the absence of sperm has been
confirmed. If not, additional highly effective method of contraception should be used.
Spermatogenesis cycle is approximately 74 days.)
USER DEPENDENT
Highly Effective Methods That Are User Dependent Failure rate of <1% per year when used
consistently and correctly.
 Combined (estrogen- and progestogen-containing) hormonal contraception associated with
inhibition of ovulation
 oral
 intravaginal
 transdermal
 injectable
 Progestogen-only hormone contraception associated with inhibition of ovulation
 oral
 injectable
 Sexual abstinence
(Sexual abstinence is considered a highly effective method only if defined as refraining from
heterosexual intercourse during the entire period of risk associated with the study intervention.
The reliability of sexual abstinence needs to be evaluated in relation to the duration of the study
and the preferred and usual lifestyle of the participant.)
a) Typical use failure rates may differ from those when used consistently and correctly. Use should be
consistent with local regulations regarding the use of contraceptive methods for participants in
clinical studies.
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10.6. Appendix 6: Rash Management
Table 4: 
Management of Rash Events by Severity Grade
Definition 
Study
Intervention
Action
Activities by Daya
Referral to
Dermatologist and
Dermatology
Activities
Grade 1 rash
(with or
without
pruritus)b
Erythema 
Study
intervention
intake may be
continued at the
investigator’s
discretion
Day 0: optional on-site visit for initial rash evaluation may be performed
at the investigator’s discretion.
Safety laboratory assessments may be performed at the investigator’s
discretion (recommended if visit occurs).
Digital picturesc of skin lesions may be taken at the investigator’s
discretion.
Determine if participant was adhering to the recommended sun-
protective measures. If appropriate, provide sun protection counseling.
Day 1 and thereafter: appropriate follow-up visits at the investigator’s
discretion until resolution of rash.
Safety laboratory assessments and photography (digital picturesc of skin
lesions) may be performed at the investigator’s discretion.
Not required
Grade 2 rash
(with or without
pruritus)b
Diffuse, maculopapular
rash, or dry
desquamation
Study
intervention
intake may be
continued at the
investigator’s
discretion
Day 0: required on-site visit (if a visit is not possible, telephone contact
with the participant should take place to collect information and give
advice on the necessary measures to be taken).
Safety laboratory assessments may be performed at the investigator’s
discretion (recommended).
Digital picturesc of skin lesions may be taken at the investigator’s
discretion. Digital picturesc of skin lesions are recommended in case
consultation of a dermatologist is required. Determine if participant was
adhering to the recommended sun-protective measures. If appropriate,
provide sun protection counseling.
Day 1 and thereafter: appropriate follow-up visits at the investigator’s
discretion until resolution of rash or until clinical stability is reached.
Safety laboratory assessments are required on Day 1 and are required
thereafter only if the previous values were abnormal (but may be
Referral to
dermatologist at the
discretion of the
investigatord
Biopsy not required,
but may be
performed at the
dermatologist’s
discretion
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Table 4: 
Management of Rash Events by Severity Grade
Definition 
Study
Intervention
Action
Activities by Daya 
Referral to
Dermatologist and
Dermatology
Activities
performed at the investigator’s discretion). If the rash progresses to a
higher grade, safety laboratory assessments of the higher grade should be
followed.
Digital picturesc of skin lesions may be taken at the investigator’s
discretion.
Grade 3 rashb 
Vesiculation, moist
desquamation, or
ulceration OR
Any cutaneous event
with 1 of the following:
- Elevations in
AST/ALT
>2×baseline value
- Fever >38°C or
100°F
- Eosinophils
>1.00×103/µL
- Serum sickness-like
reaction
Must permanently
discontinue
JNJ-3989 and
JNJ-6379 and
PegIFN-α2a; no
rechallenge
allowed
NA treatment
may be
discontinued
based on
investigator
judgement in
consultation with
the Sponsor
Day 0: required on-site visit.
Safety laboratory assessments required to be performed.
Digital picturesc of skin lesions may be taken at the investigator’s
discretion (recommended).
Determine if participant was adhering to the recommended sun-
protective measures. If appropriate, provide sun protection counseling.
Day 1: required on-site visit.
Safety laboratory assessments required to be performed.
Digital picturesc of skin lesions may be taken at the investigator’s
discretion (recommended).
Further visit(s): appropriate follow-up required until resolution of rash or
until clinical stability is reached.
Safety laboratory assessments and photography (digital picturesc of skin
lesions) are recommended to be performed until the rash severity
resolves to Grade 2 or Grade 1.
Requiredd
Biopsy not required,
but may be
performed at the
dermatologist’s
discretion.
Grade 4 rash 
Exfoliative dermatitis
OR
Mucous membrane
involvement in at least
2 distinct sites OR
Erythema multiforme
major OR
Must permanently
discontinue
JNJ-3989 and
JNJ-6379 and
PegIFN-α2a; no
rechallenge
allowed
Day 0: required on-site visit.
Safety laboratory assessments required to be performed.
Digital picturesc of skin lesions may be taken at the investigator’s
discretion (recommended).
Determine if participant was adhering to the recommended sun-
protective measures. If appropriate, provide sun protection counseling.
Requiredd
Biopsy required and
to be performed as
soon as possible
after the onset of
the rash.
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Table 4: 
Management of Rash Events by Severity Grade
Definition 
Study
Intervention
Action
Activities by Daya
Referral to
Dermatologist and
Dermatology
Activities
Stevens-Johnson 
syndrome OR  
Toxic epidermal
necrolysis OR
Necrosis requiring 
surgery  
NA treatment 
may be
discontinued
based on
investigator
judgement in
consultation with
the Sponsor
Day 1: required on-site visit.
Safety laboratory assessments required to be performed.
Digital picturesc of skin lesions may be taken at the investigator’s
discretion (recommended).
Further visit(s): appropriate follow-up required until resolution of rash or
until clinical stability is reached.
Safety laboratory assessments and photography (digital picturesc of skin
lesions) are recommended to be performed until the rash severity
resolves to Grade 2 or Grade 1.
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.
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10.7. Appendix 7: Intervention-emergent ALT/AST Elevations
Note: In case of prolonged ALT elevation >3x ULN AND >2x nadir, which lasts at least 12 weeks, the decision to continue JNJ-3989 and/or PegIFN-α2a should be
based upon virologic parameters (eg, HBsAg, HBV DNA) and should be made in consultation with the sponsor (refer to Section 8.3.6.2, Intervention-emergent
ALT/AST Elevations)
a Additional tests may be considered based on clinical judgement in case of confirmed ALT flares:
 
Hepatitis A, Delta, C, E: IgM anti-HAV; delta IgM, IgG and PCR, HCV RNA, IgM and IgG anti-HEV, HEV RNA
 
CMV, HSV, EBV infection: IgM and IgG anti-CMV, IgM and IgG anti-HSV; IgM and IgG anti-EBV, PCR
 
HIV-1 and -2
 
Ig-Electrophoresis
 
PBMC sampling
 
AFP testing
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10.8. Appendix 8: 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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10.9. Appendix 9: DAIDS Table
DIVISION OF AIDS (DAIDS) TABLE FOR GRADING THE SEVERITY OF ADULT
AND PEDIATRIC ADVERSE EVENTS, VERSION 2.1, PUBLISH DATE: JULY, 2017
The DAIDS grading table is a descriptive terminology to be utilized for AE reporting in this study.
A grading (severity) scale is provided for each AE term.
General Instructions
Grading Adult and Pediatric Adverse Events
When a single parameter is not appropriate for grading an AE in both adult and pediatric
populations, separate parameters with specified age ranges are provided. If there is no distinction
between adult and pediatric populations, the listed parameter should be used for grading an AE in
both populations.
Determining Severity Grade for Parameters Between Grades
If the severity of an AE could fall under either 1 of 2 grades (eg, the severity of an AE could be
either Grade 2 or Grade 3), sites should select the higher of the 2 grades.
Laboratory normal ranges should be taken into consideration to assign gradings to a laboratory
value.
Definitions
Basic self-care functions 
Adults: activities such as bathing, dressing, toileting,
transfer/movement, continence, and feeding
Young children: activities that are age and culturally appropriate
(eg, feeding self with culturally appropriate eating implements)
Usual social & functional 
activities 
Activities which adults and children perform on a routine basis and
those which are part of regular activities of daily living, for
example:
Adults: adaptive tasks and desirable activities, such as going to
work, shopping, cooking, use of transportation, or pursuing a
hobby
Young Children: activities that are age and culturally appropriate
(eg, social interactions, play activities, learning tasks)
Intervention  
Medical, surgical, or other procedures recommended or provided
by a healthcare professional for the treatment of an AE.
Estimating Severity Grade for Parameters not Identified in the Grading Table
The functional table below should be used to grade the severity of an AE that is not specifically
identified in the grading table. In addition, all deaths related to an AE are to be classified as
Grade 5.
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10.10. Appendix 10: Study Conduct During a Natural Disaster
GUIDANCE ON STUDY CONDUCT DURING THE COVID-19 PANDEMIC
It is recognized that the Coronavirus Disease 2019 (COVID-19) pandemic may have an impact on
the conduct of this clinical study due to, for example, self-isolation/quarantine by participants and
study site personnel; travel restrictions/limited access to public places, including hospitals; study
site personnel being reassigned to critical tasks.
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 via COVID-19 Appendix 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 interventions and withdrawal from the study should
be documented with the prefix “COVID-19-related” in the CRF.
The Sponsor will continue to monitor the conduct and progress of the clinical study, and any
changes will be communicated to the sites and to the health authorities according to local guidance. 
If a participant has tested positive for COVID-19, the investigator should contact the Sponsor’s
responsible medical officer to discuss plans for study intervention and follow-up. Modifications
made to the study conduct as a result of the COVID-19 pandemic should be summarized in the
clinical study report.
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GUIDANCE SPECIFIC TO THIS PROTOCOL
The following emergency provisions are meant to ensure participant safety on study while site
capabilities are compromised by COVID-19-related restrictions. Remote medical consultation and
alternatives to study intervention dispensing, administration, and clinical laboratory assessments
may allow continued study participation for participants in this trial. Before implementing any of
these emergency provisions, the Sponsor should be consulted to perform a benefit-risk analysis
and to ensure the measures are executed and documented correctly.
As restrictions are lifted and the acute phase of the COVID-19 pandemic resolves, sites should
revert to original protocol conduct as soon as feasible and in accordance with any country-specific
regulatory requirements.
Screening and Randomization:
 Enrollment of new participants may continue based on the investigator’s assessment of risks
versus benefits, depending on the situation at a particular site, and the ability to monitor
participant safety.
 Baseline visits for participants recently screened for this study should be postponed if the
current situation does not allow for an orderly conduct of the study.
Dispensing/Administration of Study Intervention:
 For participants able to visit the study site, but who request to reduce visit frequency, or for
whom limited access to the site is expected, an additional supply of oral study intervention, as
well as PegIFN-α2a where allowed per local regulationsa, can be provided.
 For participants unable to visit the study site, direct-to-patient (DTP) shipment or handover to
a caregiveror delegate of oral study intervention, as well as PegIFN-α2a, may be implemented,
where allowed per local regulationsa and if requested by the treating study physician. Where
DTP shipments or handover to delegates are deemed necessary, the process must be
coordinated between the site and Sponsor staff following standard DTP procedures for
arranging shipment and adhering to associated approvals and documentation requirements.
 JNJ-3989 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, NA, or PegIFN-α2a) is
missed.
Continuation of Study Intervention:
 Any issue with continuation and/or provision of study intervention should be discussed with
the Sponsor and should be well documented.
 Study intervention should be continued if, in the assessment of the investigator, it does not
result in risk to the participant. If at any time the participant’s safety is considered at risk due
to study intervention, study intervention will be temporarily or permanently discontinued,
a Delivering PegIFN-α2a is not applicable for sites in countries that do not allow PegIFN-α2a self-injection.
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while every effort should be made to maintain follow-up on study. The benefit of continuing
study intervention should be assessed by the investigator for each individual participant,
considering the potential impact of reduced direct clinical supervision on participant safety.
 If a participant develops a SARS-CoV-2 infection, the investigator should contact the Sponsor
to discuss plans for study intervention and follow-up. A decision to continue study intervention
should be made by the investigator depending on symptoms and concomitant medication(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 adverse events (AEs)related to
SARS-CoV-2 infection improve to Grade ≤1, the investigator should discuss with the Sponsor
about resuming study intervention.
COVID-19 vaccination during the study:
Local guidelines on the use of live vaccines in participants receiving PegIFN-α2a should be
followed, including for the second dose of Sputnik V (which contains rAd5, with a theoretical risk
of replication competence). Sputnik Light, which is the first dose of Sputnik V (with rAd26) is not
considered a live vaccine. See below for further guidance on the use of COVID-19 vaccines.
Locally approved COVID-19 vaccines (including those that received emergency use authorization
or conditional marketing authorization) are allowed throughout the study. For participants
receiving PegIFN-α2a, the following recommendations should be applied to accommodate
COVID-19 vaccination during the treatment period:
 COVID-19 vaccine and PegIFN-α2a should not be administered on the same day.
 If required, PegIFN-α2a injection can be delayed up to 2 days. The next PegIFN-α2a
injection should be administered at the scheduled time.
 If required, skipping a PegIFN-α2a injection may be considered after consultation with the
Sponsor.
 Vaccination with Sputnik V should take above-mentioned consideration about live
vaccines into account.
All COVID-19 vaccination-related data (eg, COVID-19 vaccination, AEs, AE management)
should be appropriately captured in the CRF and source documents. Refer to the COVID-19
vaccine and/or PegIFN-α2a prescribing information for more details.
Study Visits and Assessments:
 If possible, central laboratory testing as outlined in the Schedule of Activities is to be
continued. If central laboratory tests cannot be performed, the use of a local laboratory is
allowed for study evaluations. A copy of the local laboratory report should be reviewed by the
investigator and filed with the source documents, along with reference ranges.
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 To safely maintain participants on study intervention while site capabilities are compromised
by COVID-19-related restrictions, study visits may be performed by a nurse (who received
study-specific training) at the patient’s home (home health nurse) until such time that on-site
visits can be resumed. The following activities may be completed as required per the Schedule
of Activities and as feasible:
 Sampling, processing and shipping of laboratory samples (as described above).
 Checking study compliance: medication diary (if available), intake of oral study
intervention, storage of oral study intervention, review of the PegIFN α2a self-injection
tracker (if applicable).
 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).
 Delivering oral study interventions, as well as PegIFN-α2a where allowed per local
regulations.a
 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 injection site reactions), 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.
a Delivering PegIFN-α2a is not applicable for sites in countries that do not allow PegIFN-α2a self-injection.
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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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10.11. Appendix 11: Protocol Amendment History
The Protocol Amendment Summary of Changes Table for the current amendment is located
directly before the Table of Contents (TOC).
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10.12. Appendix 12: NA Re-treatment During Follow-up
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11. 
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Gane E, Locarnini S, Lim TH, et al. Dose Response with the RNA Interference Therapy JNJ-3989 Combined with
Nucleos(t)ide Analogue Treatment in Expanded Cohorts of Patients with Chronic Hepatitis B. The Liver Meeting,
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8400-1c0495271e35. Accessed 18 August 2020.
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therapeutics in subacute studies. Toxicologic Pathology. 2018;46(7):735-745.
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.Li H, Zhai N, Wang Z, et al. Regulatory NK cells mediated between immunosuppressive monocytes and
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Slaets L, De Ridder F, Lenz O, Beumont Maria, Meyvisch P, Verbinnen T. Systematic review with meta-analysis:
hepatitis B surface antigen decline and seroclearance in chronic hepatitis B patients on nucleos(t)ide analogues or
pegylated interferon therapy. GastroHep. 2020;00:1–11.
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production in monocytes/macrophages by interfering with JNK activation. J Immunol. 2013;190(10):5142-5151.
Wooddell CI, Yuen MF, Chan HL, et al. RNAi-based treatment of chronically infected patients and chimpanzees
reveals that integrated hepatitis B virus DNA is a source of HBsAg. Sci. Transl. Med. 2017;9(409).
Xu C, Guo H, Pan XB, et al. Interferons accelerate decay of replication-competent nucleocapsids of hepatitis B
virus. J Virol. 2010 Sep;84(18):9332-40. doi: 10.1128/JVI.00918-10. Epub 2010 Jul 7. PMID: 20610715; PMCID:
PMC2937652.
Yan R, Zhao X, Cai D, et al. The Interferon-Inducible Protein Tetherin Inhibits Hepatitis B Virus Virion Secretion. J
Virol. 2015 Sep;89(18):9200-12. doi: 10.1128/JVI.00933-15. Epub 2015 Jun 24. PMID: 26109732; PMCID:
PMC4542364.
Yeh ML, Huang JF, Dai CY, Yu ML, Chuang WL. Pharmacokinetics and pharmacodynamics of pegylated
interferon for the treatment of hepatitis B. Expert Opin Drug Metab Toxicol. 2019;15(10):779-785.
Yuen MF, Locarnini S, Given B, et al. First Clinical Experience with RNA Interference-based Triple Combination
Therapy in Chronic Hepatitis B: JNJ-3989, JNJ-6379 and a Nucleos(t)ide Analogue. The Liver Meeting, Boston
November 2019, Poster LP4. Available at: http://ir.arrowheadpharma.com/static-files/6d7edbe7-c5a2-46c5-9990-
a9cdfec854a9. Accessed 18 August 2020.
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INVESTIGATOR AGREEMENT
I have read this protocol and agree that it contains all necessary details for carrying out this study. I will
conduct the study as outlined herein and will complete the study within the time designated.
I will provide copies of the protocol and all pertinent information to all individuals responsible to me who
assist in the conduct of this study. I will discuss this material with them to ensure that they are fully informed
regarding the study intervention, the conduct of the study, and the obligations of confidentiality.
Coordinating Investigator (where required):
Name (typed or printed):
Institution and Address:
Signature: 
Date:
(Day Month Year)
Principal (Site) Investigator:
Name (typed or printed):
Institution and Address:
Telephone Number:
Signature: 
Date:
(Day Month Year)
Sponsor's Responsible Medical Officer:
Name (typed or printed): 
Institution: 
Janssen Research & Development
Signature: 
electronic signature appended at the end of the protocol 
Date:
(Day Month Year)
Note: If the address or telephone number of the investigator changes during the study, written notification will be
provided by the investigator to the Sponsor, and a protocol amendment will not be required.
PPD
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Signature
User 
Date 
Reason
06-Oct-2021
14:36:43
(GMT)
Document Approval
PPD
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SAP_001.pdf: 
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
1
Status: Approved, Date: 06 January 2022
Janssen Research & Development
Statistical Analysis Plan
A Phase 2, Open-label, Multicenter Study to Assess Efficacy, Safety, Tolerability, and 
Pharmacokinetics of Treatment With JNJ-73763989, Nucleos(t)ide Analogs, and Pegylated 
Interferon Alpha-2a in Patients With Chronic Hepatitis B Virus Infection
The PENGUIN-2 Study
Protocol 73763989PAHPB2007; Phase 2
JNJ-73763989  
Status:
Approved
Date:
06 January 2022
Prepared by:
Janssen Research & Development, a division of Janssen Pharmaceutica NV  
Document No.: EDMS-RIM-563836, 1.0
Compliance: The study described in this report was performed according to the principles of Good Clinical Practice (GCP). 
Confidentiality Statement
The information provided herein contains Company trade secrets, commercial or financial information that the Company 
customarily holds close and treats as confidential.  The information is being provided under the assurance that the recipient
will maintain the confidentiality of the information under applicable statutes, regulations, rules, protective orders or 
otherwise.
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Status: Approved, Date: 06 January 2022
TABLE OF CONTENTS
TABLE OF CONTENTS ............................................................................................................................... 2
VERSION HISTORY..................................................................................................................................... 6
1.
INTRODUCTION.................................................................................................................................. 7
1.1.
Objectives and Endpoints ................................................................................................................ 7
1.2.
Study Design.................................................................................................................................... 9
2.
STATISTICAL HYPOTHESES.......................................................................................................... 11
3.
SAMPLE SIZE DETERMINATION.................................................................................................... 11
4.
POPULATIONS (ANALYSIS SETS) FOR ANALYSIS..................................................................... 12
5.
STATISTICAL ANALYSES............................................................................................................... 13
5.1.
General Considerations ................................................................................................................. 13
5.1.1.
Analysis Phase ........................................................................................................................... 14
5.1.2.
Relative Day by Study Phase ..................................................................................................... 15
5.1.2.1.
Treatment Period Relative Day ............................................................................................... 15
5.1.2.2.
Follow Up Relative Day ........................................................................................................... 15
5.1.3.
Visit Windows ............................................................................................................................. 15
5.1.4.
Baseline ...................................................................................................................................... 16
5.1.5.
Analysis Specifications ............................................................................................................... 17
5.1.6.
Additional Reference Timepoints................................................................................................ 17
5.1.7.
Level of Significance................................................................................................................... 17
5.1.8.
Missing and Partial Dates Imputation Rules............................................................................... 17
5.1.8.1.
Adverse Event Onset Date and Resolution Date .................................................................... 18
5.1.8.2.
HBV Diagnosis and Infection Dates ........................................................................................ 18
5.1.8.3.
Concomitant Medication Dates................................................................................................ 18
5.1.8.4.
Dates of Alcohol Consumptions .............................................................................................. 19
5.1.9.
Data Handling Rules................................................................................................................... 19
5.2.
Participant Dispositions.................................................................................................................. 20
5.3.
Primary Efficacy Endpoint.............................................................................................................. 21
5.3.1.
Definition..................................................................................................................................... 21
5.3.2.
Main Estimand for the Primary Endpoint.................................................................................... 21
5.3.2.1.
Main Estimator......................................................................................................................... 22
5.3.2.1.1.
Analysis Methods ................................................................................................................. 22
5.3.2.1.1.1.
Scientific Question of Interest Part a: Comparison vs Fixed Control................................ 22
5.3.2.1.1.2.
Scientific Question of Interest Part b: Comparison Amongst Regimens .......................... 23
5.3.2.1.2.
Data Included ....................................................................................................................... 23
5.3.2.1.3.
Assumptions......................................................................................................................... 23
5.3.2.1.4.
Missing Data Handling Rule................................................................................................. 23
5.3.2.2.
Sensitivity Estimators of the Main Estimand ........................................................................... 23
5.3.2.2.1.
Sensitivity Estimator 1 of the Main Estimand (Homogeneity Assumption) .......................... 23
5.3.2.2.1.1.
Assumptions...................................................................................................................... 24
5.3.2.2.1.2.
Analysis Methods.............................................................................................................. 24
5.3.2.2.2.
Sensitivity Estimator 2 of the Main Estimand (Observed Case Analysis)............................ 24
5.3.2.2.2.1.
Assumptions...................................................................................................................... 24
5.3.2.2.2.2.
Missing Data Handling Rule.............................................................................................. 24
5.3.2.2.3.
Sensitivity Estimator 3 of the Main Estimand (LOCF).......................................................... 24
5.3.2.2.3.1.
Assumptions...................................................................................................................... 25
5.3.2.2.3.2.
Missing Data Handling Rule.............................................................................................. 25
5.3.3.
Supplementary Estimand for the Primary Endpoint (Per-Protocol Analysis Set)....................... 25
5.3.3.1.
Main Estimator of the Supplementary Estimand ..................................................................... 26
5.3.3.1.1.
Analysis Methods ................................................................................................................. 26
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Status: Approved, Date: 06 January 2022
5.3.3.1.2.
Data Included ....................................................................................................................... 26
5.3.3.1.3.
Assumptions......................................................................................................................... 26
5.3.3.1.4.
Missing Data Handling Rule................................................................................................. 26
5.3.4.
Hochberg Procedure................................................................................................................... 26
5.3.5.
Subgroup Analyses of Primary Efficacy Endpoint ...................................................................... 27
5.3.6.
Comparisons Between Arm 2 and Model-Based Virtual IFN-Free JNJ-3989+NA 
Regimen Control......................................................................................................................... 27
5.4.
Secondary Efficacy Endpoints ....................................................................................................... 28
5.4.1.
Definitions ................................................................................................................................... 29
5.4.1.1.
Binary Endpoints ..................................................................................................................... 29
5.4.1.1.1.
NA Treatment Completion Criteria....................................................................................... 29
5.4.1.1.2.
NA Re-Treatment During Follow-up..................................................................................... 29
5.4.1.1.3.
HBsAg Cut-offs..................................................................................................................... 29
5.4.1.1.4.
HBsAg Seroclearance.......................................................................................................... 30
5.4.1.1.4.1.
On Treatment.................................................................................................................... 30
5.4.1.1.4.2.
Off Treatment.................................................................................................................... 30
5.4.1.1.5.
Functional Cure.................................................................................................................... 30
5.4.1.1.6.
Treatment Failure................................................................................................................. 30
5.4.1.1.7.
HBsAg Seroconversion........................................................................................................ 31
5.4.1.1.8.
HBeAg Cut-offs .................................................................................................................... 31
5.4.1.1.9.
HBV DNA Cut-offs................................................................................................................ 31
5.4.1.1.10.
Suppressed HBV DNA ......................................................................................................... 31
5.4.1.1.11.
ALT Normalization................................................................................................................ 31
5.4.1.1.12.
Partial Cure .......................................................................................................................... 32
5.4.1.1.13.
Virologic Breakthrough......................................................................................................... 32
5.4.1.1.14.
Flares ................................................................................................................................... 32
5.4.1.2.
Continuous Endpoints ............................................................................................................. 34
5.4.1.2.1.
HBsAg, HBeAg, HBV DNA and ALT.................................................................................... 34
5.4.1.3.
Time to Event Endpoints ......................................................................................................... 34
5.4.1.3.1.
Time to First HBsAg Seroclearance..................................................................................... 34
5.4.1.3.2.
Time to First HBsAg Seroconversion................................................................................... 35
5.4.1.3.3.
Time to HBV DNA < LLOQ .................................................................................................. 35
5.4.1.3.4.
Time to First Virologic Breakthrough.................................................................................... 35
5.4.1.3.5.
Time to First Flare ................................................................................................................ 35
5.4.2.
Analysis Methods........................................................................................................................ 36
5.4.2.1.
Binary Endpoints ..................................................................................................................... 36
5.4.2.1.1.
LOCF Imputation Method..................................................................................................... 36
5.4.2.1.2.
NA Treatment Completion Criteria at Week 24 and During FU........................................... 37
5.4.2.1.3.
NA Re-Treatment Criteria During FU................................................................................... 37
5.4.2.1.4.
HBsAg Cut-offs..................................................................................................................... 37
5.4.2.1.5.
HBsAg Seroclearance.......................................................................................................... 38
5.4.2.1.5.1.
On Treatment.................................................................................................................... 38
5.4.2.1.5.2.
Off Treatment.................................................................................................................... 38
5.4.2.1.5.3.
Functional Cure................................................................................................................. 38
5.4.2.1.6.
Treatment Failure................................................................................................................. 38
5.4.2.1.7.
HBsAg Seroconversion........................................................................................................ 38
5.4.2.1.8.
HBeAg Cut-offs .................................................................................................................... 39
5.4.2.1.9.
HBV DNA Cut-offs................................................................................................................ 39
5.4.2.1.10.
Suppressed HBV DNA ......................................................................................................... 39
5.4.2.1.11.
ALT Normalization................................................................................................................ 40
5.4.2.1.12.
Partial Cure .......................................................................................................................... 40
5.4.2.1.13.
Virologic Breakthrough......................................................................................................... 40
5.4.2.1.14.
Flares ................................................................................................................................... 40
5.4.2.2.
Continuous Endpoints ............................................................................................................. 41
5.4.2.2.1.
HBsAg, HBeAg, HBV DNA and ALT.................................................................................... 41
5.4.2.3.
Time to Event Endpoints ......................................................................................................... 42
5.5.
Exploratory Endpoints.................................................................................................................... 42
5.5.1.
Definitions ................................................................................................................................... 42
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Status: Approved, Date: 06 January 2022
5.5.1.1.
Binary Endpoints ..................................................................................................................... 42
5.5.1.1.1.
Liver Stiffness Measurement................................................................................................ 42
5.5.1.1.2.
HBV RNA Cut-offs................................................................................................................ 43
5.5.1.1.3.
HBcrAg Cut-offs ................................................................................................................... 43
5.5.1.1.4.
Anti-HBe Antibodies ............................................................................................................. 43
5.5.1.2.
Continuous Endpoints ............................................................................................................. 43
5.5.1.2.1.
Liver Stiffness Measurement................................................................................................ 43
5.5.1.2.2.
HBV RNA and HBcrAg......................................................................................................... 43
5.5.1.2.3.
Anti-HBs Antibodies ............................................................................................................. 44
5.5.1.3.
Time to Event Endpoints ......................................................................................................... 44
5.5.1.3.1.
Time to First HBV RNA<LOD............................................................................................... 44
5.5.1.3.2.
Time to First HBcrAg Undetectability ................................................................................... 44
5.5.1.3.3.
Time to Appearance of Anti-HBs Antibodies........................................................................ 44
5.5.1.3.4.
Time to Appearance of Anti-HBe Antibodies ....................................................................... 45
5.5.1.4.
Endpoints for Correlation......................................................................................................... 45
5.5.1.4.1.
Association Between Baseline Characteristics/Viral Blood Markers and Selected 
Efficacy Variables................................................................................................................. 45
5.5.2.
Analysis Methods........................................................................................................................ 46
5.5.2.1.
Binary Endpoints ..................................................................................................................... 47
5.5.2.1.1.
Liver Stiffness Measurement................................................................................................ 47
5.5.2.1.2.
HBV RNA Cut-offs................................................................................................................ 47
5.5.2.1.3.
HBcrAg Cut-offs ................................................................................................................... 47
5.5.2.1.4.
Anti-HBe Antibodies ............................................................................................................. 47
5.5.2.2.
Continuous Endpoints ............................................................................................................. 47
5.5.2.2.1.
Liver Stiffness Measurement................................................................................................ 47
5.5.2.2.2.
HBV RNA and HBcrAg......................................................................................................... 48
5.5.2.2.3.
Anti-HBs Antibodies ............................................................................................................. 48
5.5.2.3.
Time to Event Endpoints ......................................................................................................... 48
5.5.2.4.
Endpoints for Correlation......................................................................................................... 48
5.5.2.4.1.
Association Between Baseline Characteristics/Viral Blood Markers and Selected 
Efficacy Variables................................................................................................................. 48
5.6.
Safety Analyses ............................................................................................................................. 49
5.6.1.
Extent of Exposure ..................................................................................................................... 49
5.6.2.
Adverse Events........................................................................................................................... 50
5.6.3.
Additional Safety Assessments .................................................................................................. 51
5.6.3.1.
Clinical Laboratory Tests......................................................................................................... 51
5.6.3.2.
Renal Safety ............................................................................................................................ 53
5.6.3.2.1.
eGFR.................................................................................................................................... 54
5.6.3.2.2.
Proximal Renal Tubular Function......................................................................................... 55
5.6.3.3.
Vital Signs................................................................................................................................ 56
5.6.3.4.
Electrocardiogram ................................................................................................................... 57
5.6.3.5.
Physical and Ophthalmic Examinations .................................................................................. 59
5.7.
Other Analyses............................................................................................................................... 59
5.7.1.
Pharmacokinetics ....................................................................................................................... 59
5.7.2.
Pharmacokinetic/Pharmacodynamic Relationships ................................................................... 59
5.7.3.
Immune Analyses ....................................................................................................................... 60
5.7.4.
Viral Genome Sequence Analysis .............................................................................................. 60
5.7.4.1.
Time Points and Samples........................................................................................................ 61
5.7.4.2.
Definitions................................................................................................................................ 61
5.7.4.3.
Parameters to Analyze ............................................................................................................ 62
5.7.4.4.
Positions & Genetic Variations of Interest............................................................................... 63
5.7.4.5.
Analysis Methods .................................................................................................................... 64
5.7.4.5.1.
Post-Baseline ....................................................................................................................... 64
5.7.4.5.2.
Over the Study Period.......................................................................................................... 65
5.7.5.
HBV genotype............................................................................................................................. 65
5.7.6.
Health Economics....................................................................................................................... 65
5.7.7.
Definition of Subgroups .............................................................................................................. 65
5.7.7.1.
Subgroups for Efficacy Analyses............................................................................................. 65
NCT05005507


JNJ-73763989
Statistical Analysis Plan 73763989PAHPB2007
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
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Status: Approved, Date: 06 January 2022
5.7.7.2.
Subgroups for Safety Analyses ............................................................................................... 66
5.8.
Data Review Committee and Interim Analyses ............................................................................. 66
5.8.1.
Data Review Committee............................................................................................................. 66
5.8.2.
Independent Flare Expert Panel................................................................................................. 66
5.8.3.
Data Reviews and Interim Analyses........................................................................................... 67
5.8.3.1.
Data Reviews........................................................................................................................... 67
5.8.3.2.
Interim Analyses ...................................................................................................................... 67
5.8.3.3.
Overview of Data Reviews, Interim, Primary and Final Analyses ........................................... 68
6.
SUPPORTING DOCUMENTATION .................................................................................................. 70
6.1.
Appendix 1 List of Abbreviations.................................................................................................... 70
6.2.
Appendix 2 Changes to Protocol-Planned Analyses ..................................................................... 72
6.3.
Appendix 3 Demographics and Baseline Characteristics.............................................................. 73
6.3.1.
Demographics............................................................................................................................. 73
6.3.2.
Baseline Characteristics ............................................................................................................. 73
6.4.
Appendix 4 Protocol Deviations ..................................................................................................... 75
6.5.
Appendix 5 Prior and Concomitant Medications............................................................................ 89
6.6.
Appendix 6 Medical History ........................................................................................................... 90
6.7.
Appendix 7 Intervention Compliance ............................................................................................. 91
6.8.
Appendix 8 Adverse Events of Special Interest............................................................................. 92
6.9.
Appendix 9 Medications of Special Interest................................................................................... 98
6.10.
Appendix 10 Laboratory Toxicity Grading.................................................................................... 100
7.
REFERENCES................................................................................................................................. 101
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JNJ-73763989
Statistical Analysis Plan 73763989PAHPB2007
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Status: Approved, Date: 06 January 2022
VERSION HISTORY
Table 1:
SAP Version History Summary
SAP Version
Approval Date
Change
Rationale
1
Not Applicable
Initial release
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NCT05005507


NCT05005507


JNJ-73763989
Statistical Analysis Plan 73763989PAHPB2007
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
10
Status: Approved, Date: 06 January 2022
A schematic overview of the trial is presented in Figure 1.
Figure 1:
Schematic Overview of the Study
ALT: alanine aminotransferase; DNA: deoxyribonucleic acid; EOS: end of study; EOSI: end of study intervention; 
FU: follow-up; HBeAg: hepatitis B e antigen; HBV: hepatitis B virus; JNJ-3989: JNJ-73763989; N: number of 
participants; NA: nucleos(t)ide analog; PegIFN-α2a: pegylated interferon alpha-2a; Q4W: every 4 weeks; QD: once 
daily; QW: once weekly; Rand: randomization.
a
If all of the NA treatment completion criteria (see Clinical Protocol Section 6.5.1, NA Treatment Completion, for more 
details) are met based on the Week 24 results, NA will be stopped at the next scheduled visit (ie, FU Week 2), otherwise NA 
treatment will continue during the complete FU period.
Note: Participants who are close to meeting the protocol-defined NA treatment completion criteria with the Week 24 results, and 
do meet the criteria based on the FU Week 2 results may be allowed to stop NA at FU Week 4, after consultation with the Sponsor.
Participants who meet the protocol-defined NA treatment completion criteria will be monitored closely during the 48-week FU 
Period with a study visit at least once every 4 weeks. NA treatment should be re-started in accordance with the NA re-treatment 
criteria are met (see Clinical Protocol Section 6.5.2, NA Re-treatment Criteria During Follow-up, for more details).
At baseline, participants who meet the eligibility criteria will be randomized in a 1:1:1 ratio to 
Arm 1, Arm 2, or Arm 3. Randomization will be stratified by absolute HBsAg level (<1,000 IU/mL 
versus >1,000 IU/mL) at baseline and country grouping as proxy for HBV genotype (GT) at 
enrollment, with 3 levels: Poland (predominantly GT-A) versus Russia (predominantly GT-D) 
versus all other countries (other or mixed GT prevalence). Participants in Arm 2 who no longer 
meet the PegIFN-α2a eligibility criteria (see Exclusion Criterion A24 in Clinical Protocol Section 
5.2, Exclusion Criteria) at Week 12, based on available laboratory or clinical data, will continue 
JNJ-3989 and NA treatment until Week 24 without PegIFN-α2a.
All participants will receive the last dose of JNJ-3989 at Week 24 and the last dose of PegIFN-α2a 
at Week 23 (Arms 1 and 2) or Week 11 (Arm 3). They will start the FU period after the Week 24 
visit. If the protocol-defined NA treatment completion criteria (Section 5.4.1.1.1) are met based
on the Week 24 results, treatment with NA will be stopped at the next scheduled visit (ie, FU 
NCT05005507


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Status: Approved, Date: 06 January 2022
Week 2), otherwise NA treatment will continue during the complete FU period. Note: Participants 
who are close to meeting the protocol-defined NA treatment completion criteria with the Week 24
results, and do meet the criteria at FU Week 2 results may be allowed to stop NA at FU Week 4, 
upon prior discussion with the Sponsor.
The NA treatment completion criteria which take ALT, HBV DNA, HBeAg, and HBsAg levels 
into consideration, have been selected to ensure that only participants with a higher chance of 
achieving sustained off-treatment response are allowed to stop all study intervention. Participants 
who meet the protocol-defined NA treatment completion criteria will be monitored closely during 
the 48-week FU Period and participants should re-start NA treatment if NA re-treatment criteria 
are met (see Clinical Protocol Section 6.5.2, NA Re-treatment Criteria During Follow-up, for more 
details).
If a participant prematurely discontinues JNJ-3989 (ie, before Week 24), the participant will have 
an early WD visit and will enter the 48-week follow-up period as per the Schedule of Activities, 
unless the participant withdraws consent. 
If a participant prematurely discontinues PegIFN-α2a (ie, before Week 23 [Arms 1 and 2] or before 
Week 11 [Arm 3]), treatment with JNJ-3989 and NA should be continued as planned.
If a participant withdraws prematurely from the study, the reason for withdrawal (if known) should 
be documented in the case report form (CRF) and in the source document. Participants who 
withdraw consent will be offered an optional safety follow-up visit 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. 
2.
STATISTICAL HYPOTHESES
The primary hypothesis of this study is that at least one of the combination regimens of 
JNJ-3989+NA+PegIFN-α2a is more efficacious than NA treatment alone (standard of care), as 
measured by the primary efficacy endpoint, the proportion of participants who achieved a 
reduction of at least 2 log10 in HBsAg levels from baseline at Week 24. Because the study does 
not include a control arm, the hypothesis is formulated assuming a fixed external NA control 
response rate of 2% in terms of the primary efficacy endpoint.
3.
SAMPLE SIZE DETERMINATION
A sample size of 30 participants per arm yields >95% statistical power to detect a ≥30% difference 
in at least one arm in the proportions of participants with a reduction of at least 2 log10 in HBsAg 
levels from baseline at Week 24 versus a fixed proportion of ≤2%, assumed for external control 
(NA treatment). Statistical power to test the primary hypothesis was assessed for each of the 
intervention arms, separately, 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 
NCT05005507


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Status: Approved, Date: 06 January 2022
assumed external control value is based on the data of the NA control arm in virologically 
suppressed HBeAg negative participants in study 73763989HPB2001 (REEF-1).
The total study sample size is 102 participants (34 per arm) with 1:1:1 randomization ratio to one 
of the three intervention arms, assuming an approximate 10% attrition rate.
For the secondary set of pairwise comparisons of the primary efficacy endpoint among the 3 study 
intervention arms (Arm 1 versus Arm 2, Arm 1 versus Arm 3, and Arm 2 versus Arm 3) and using 
a 2-sample binomial test, the planned sample size yields about 68% power to detect a significant 
difference of at least 30%. This is assuming the lowest response rate at Week 24 to be 50% in one 
of the intervention arms, and 80% in one or both of the other 2 arms and applying the Hochberg 
procedure to control the 1-sided Type 1 error rate at 0.05 level. The assumption of 50% response 
rate was derived from the analysis of 73763989HPB2001 (REEF-1) on-treatment data.
4.
POPULATIONS (ANALYSIS SETS) FOR ANALYSIS
Due to a potential impact of future Coronavirus Disease (COVID-19) pandemics on the study data 
collection, study treatment adherence and study conduct, the modified Full Analysis Set (mFAS) 
and modified IFN-FAS (mIFN-FAS) 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 IFN-FAS and modified FAS/IFN-FAS analysis sets will be used if there is a relevant 
difference from the FAS (>5% of participants in total).
Table 2:
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
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 Week 24 (EOSI), 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.
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Analysis Sets
Description
IFN-FAS
All participants who were randomly assigned to an 
intervention arm in this ISA and received at least 1 dose 
of PegIFN-α2a within this ISA. Participants will be 
analyzed according to the study intervention they were 
randomly assigned to.
Modified IFN-FAS
All participants who were randomly assigned to an 
intervention arm in this ISA and received at least 1 dose 
of PegIFN-α2a within this ISA excluding those 
participants who, because of COVID-19 or similar 
pandemics related reasons, withdrew prematurely from 
the study prior to Week 24 (EOSI), 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 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. 
Participants will be analyzed according to the study 
intervention they were randomly assigned to.
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.
5.
STATISTICAL ANALYSES
5.1.
General Considerations
The SAP will use throughout the document the following definitions:

Study treatment refers to: JNJ-3989, NA, and PegIFN-α2a

Study agent refers to: JNJ-3989, NA, and PegIFN-α2a

Study intervention arm refers to:

Arm 1: JNJ-3989 for 24 weeks + NA for 24 weeks + PegIFN-α2a for 24 weeks.

Arm 2: JNJ-3989 for 24 weeks + NA for 24 weeks + PegIFN-α2a from Week 12 till 
Week 24.

Arm 3: JNJ-3989 for 24 weeks + NA for 24 weeks + PegIFN-α2a from baseline till 
Week 12.
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5.1.1.
Analysis Phase
The analyses phases are defined in Table 3 below.
Table 3:
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
Treatment period
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 – 1 day, 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 treatment period:
End of treatment period + 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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Status: Approved, Date: 06 January 2022
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.
Treatment Period Relative Day
Treatment period (TP) start date (TP Day 1) is defined in Table 3. All efficacy and safety 
assessments during the treatment period will be assigned an analysis day relative to this date.
The study day in the treatment period phase (TP ADY) is defined as: 
  = 
  −   + 1
for visits on or after treatment period Day 1, and 
  = 
  −  
for visits before TP Day 0 (Screening phase).
There is no ‘TP Day 0’.
5.1.2.2.
Follow Up Relative Day
Follow-up (FU) start date (FU Day 1) is defined in Table 3. 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 4. 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 
later time point except for the end of treatment period 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.
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JNJ-73763989
Statistical Analysis Plan 73763989PAHPB2007
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Status: Approved, Date: 06 January 2022
The listings will include all measurements, also those multiple assessments with the same visit 
window/phase.
End of treatment (EOT) and end of study (EOS) time points will be included in all analyses over 
time unless otherwise stated.
Table 4 provides the analysis time points and time intervals for each visit per analysis phase.
Table 4:
Visit Windows
Analysis phase
Target Day
Analysis time point 
(Week)
Analysis time point 
(label)
Time interval 
(days)
Screening
-∞
-1
Screening
<0
Treatment period
1
0
Baseline
Pre-dose: 1
15
2
Week 2
[2, 22]
29
4
Week 4
[23, 43]
57
8
Week 8
[44, 71]
85
12
Week 12
[72, 92]
99
14
Week 14
[93, 106]
113
16
Week 16
[107, 127]
141
20
Week 20
[128, 155]
169
24
Week 24
[156, 183]
Last visit in 
treatment period
25a
EOTa
Follow-up
15
26
Follow-up Week 2
[1, 22]
29
28
Follow-up Week 4
[23, 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, 183]
197
52
Follow-up Week 28
[184, 211]
225
56
Follow-up Week 32
[212, 239]
253
60
Follow-up Week 36
[240, 267]
281
64
Follow-up Week 40
[268, 295]
309
68
Follow-up Week 44
[296, 323]
337
72
Follow-up Week 48
[324, +∞]
Last visit in the 
study
999b
EOSb
a End of treatment (EOT) visit will be the last post-baseline visit in treatment period.
b End of study (EOS) visit (last available data during the follow-up visit) will be the last visit in the study.
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 
TP 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.
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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 (RTs) will be used for additional analyses of selected 
efficacy endpoints.
The PegIFN RT is defined as the last observed non-missing measurement before the first PegIFN-
α2a for Arm 2. This RT will be used for additional analyses for selected efficacy endpoints after 
Week 12 of treatment period and FU phase.
The NA RT is defined as the last observed non-missing measurement before the start of FU phase 
for participants who met the NA completion criteria at the EOT. This RT will be used for additional 
analyses for selected efficacy endpoints for FU phase.
The JNJ-3989 RT is defined as the last observed non-missing measurement at the time of stopping 
JNJ-3989. This RT will be used for additional analyses for selected efficacy endpoints for 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 2% at a one-sided Type 1 error rate of 
0.05 and applying the Hochberg procedure for adjusting for multiple comparisons. For the 
comparisons between the intervention arms (Arms 1,2,3), the Mantel-Haenszel test adjusting for 
the stratification factors 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 and applying the Hochberg 
procedure for multiple comparisons adjustment.
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.
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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 treatment date.

The day of the first study treatment administration, if the month/year of the AE onset date 
is the same as the month/year of the first study treatment administration but the 
month/year of the AE resolution date is different.

The earliest between the day of the first study treatment administration date and day of 
AE resolution date, if month/year of the AE onset are the same as both the month/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 treatment 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.

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:
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
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 (TP 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 (TP 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 treatment dosing date. The partially missing medication end date will be imputed following 
the rule described at the beginning of this section to ensure it is on or after first dosing date, and 
after its start date.

In case of a completely missing start date, the concomitant therapy will be considered as 
having started before the trial, unless the eCRF 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. 
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 5.
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Table 5:
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
124,925.00 IU/mL 
w/o dilution 
249,750.00 IU/mL 
with dilution
0.025 IU/mL (a)
137,417.50 IU/mL w/o 
dilution (b)
274,725.00IU/mL (b) with 
dilution
HBeAg
0.11 IU/mL
1,400.00 IU/mL 
w/o dilution
7,000.00 IU/mL 
with dilution
0.055 IU/mL (a)
1,540.00 IU/mL(b) w/o 
dilution
7,700.00 IU/mL(b) with 
dilution
HBcrAg*
3.0 log10 U/mL
7.0 log10 U/mL 
w/o dilution
9.0 log10 U/mL 
with dilution
2.7 log10 U/mL
7.7 log10 U/mL(b)(c)
w/o dilution
9.9 log10 U/mL (b)
with dilution
HBV DNA
20 IU/mL
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 
(i.e. 13 cp/mL)
NAP
Anti-HBs
5 mIU/mL
10,000.0 mIU/mL
2.5 mIU/mL(a)
11,000.0 mIU/mL (b)
* As new assays become available different data handling rules may apply.
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:
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
Participants randomized

Participants who received any study intervention (JNJ-3989, PegIFN-α2a, NA)

Participants in each study analysis phase

Participants who completed the study

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 unblinded during the study period

Participants who were randomized yet did not receive study intervention.
5.3.
Primary Efficacy Endpoint
5.3.1.
Definition
The primary endpoint is the proportion of participants with a reduction of at least 2 log10 IU/mL 
in HBsAg levels from baseline at Week 24 (EOSI). 
5.3.2.
Main Estimand for the Primary Endpoint
Study Objective: To evaluate the efficacy in terms of HBsAg changes from baseline for the 
treatment regimens of 24 weeks of JNJ-3989 + 24 weeks of NA + 12 or 24 weeks of PegIFN-α2a 
(with immediate or delayed start of PegIFN-α2a treatment), as compared to NA standard of care 
treatment.
Scientific Question of Interest: in HBeAg negative virologically suppressed adult population 
with chronic HBV infection
a) Comparison vs fixed control: what is the benefit of JNJ-3989 + 24 weeks of NA + 12 or 24 
weeks of PegIFN-α2a in terms of reduction of at least 2 log10 IU/mL in HBsAg levels from 
baseline at Week 24 compared with fixed proportion 2% for NA (standard of care 
treatment)?
b) Comparison amongst regimens: what is the benefit of JNJ-3989 + 24 weeks of NA + 12 or 
24 weeks of PegIFN-α2a in terms of reduction of at least 2 log10 IU/mL in HBsAg levels 
from baseline at Week 24 compared amongst regimens (Arm 1 versus Arm 2, Arm 1 versus 
Arm 3, and Arm 2 versus Arm 3)?
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A) Study Intervention:
o
Arm 1: JNJ-3989 for 24 weeks + NA for 24 weeks + PegIFN-α2a for 24 weeks.
o
Arm 2: JNJ-3989 for 24 weeks + NA for 24 weeks + PegIFN-α2a from Week 12 till 
Week 24.
o
Arm 3: JNJ-3989 for 24 weeks + NA for 24 weeks + PegIFN-α2a from baseline till 
Week 12.
B) Study Population: HBeAg-negative chronic HBV-infected adult patients who are 
virologically suppressed by being treated with NA.
C) Variable: Response status defined as participants with reduction of at least 2 log10 IU/mL 
in HBsAg levels from baseline at Week 24 (responders) as in Section 5.3.1.
D) Intercurrent events:
o
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).
o
Major protocol deviations affecting efficacy: Table 13 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).
o
Deaths prior to Week 24 are handled in a composite strategy as participants who die 
prior to Week 24 will be considered as non-responders.
E) Population-level summary:
a. Primary (comparison vs fixed proportion): Difference in proportion of 
participants with reduction of at least 2 log10 IU/mL in HBsAg levels from 
baseline at Week 24 using a fixed proportion of 2%.
b. Secondary (comparison amongst regimens): Difference in proportion of 
participants with reduction of at least 2 log10 IU/mL in HBsAg levels from 
baseline at 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. Scientific Question of Interest Part a: Comparison vs Fixed Control
The main estimator is constructed by using an exact binomial test against a fixed external control 
value of 2% 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).
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5.3.2.1.1.2. Scientific Question of Interest Part b: Comparison Amongst Regimens
The main estimator is constructed by using the Mantel-Haenszel test (Mantel N. et al., 1959) 
adjusted for the randomization stratification factors (HBsAg level at baseline [<1,000 IU/mL,
≥1,000 IU/mL] and country grouping at enrollment [Poland, Russia, all other countries]) to 
compare the primary endpoint between the intervention arms at a one-sided alpha level of 0.05 
and applying the Hochberg procedure for multiple comparisons adjustment.
5.3.2.1.2.
Data Included
The main analysis of the primary endpoint will be conducted using the FAS. The IFN-FAS and 
modified FAS/IFN-FAS analysis sets will be used if there is a relevant difference from the FAS 
(>5% of participants in total).
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 Week 24 will be considered as non-responders.
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 Week 24 value, then the 
imputation to non-response will be applied. If the value for the endpoint at Week 24 is available, 
then such data will be used to determine their response status.
For the participants still in the study at 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 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 
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stratification factors will be tested and, if heterogeneity is found statistically significant, a different 
statistical model is 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 2
randomization stratification factors and interaction terms. The model will include intervention arm, 
HBsAg level at baseline (<1,000 IU/mL or ≥1,000 IU/mL), and country grouping at enrollment 
(Poland, Russia, all other countries) as factors, and the intervention arm-by-factor interaction 
terms.
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 subject 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.
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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 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 subject 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 Week 24 is missing, the non-missing closest to Week 24 within the window 
of 4 weeks prior/after Week 24 visit will be used. If 2 non-missing laboratory values are 
equidistant, the later observation will be preferred. Participants who do not have data within the 
analysis window of ±4 weeks around Week 24 assessment will be defined as non-responders.
5.3.3.
Supplementary Estimand for the Primary Endpoint (Per-Protocol 
Analysis Set)
A) Study Intervention:
o
Arm 1: JNJ-3989 for 24 weeks + NA for 24 weeks + PegIFN-α2a for 24 weeks.
o
Arm 2: JNJ-3989 for 24 weeks + NA for 24 weeks + PegIFN-α2a from Week 12 till 
Week 24.
o
Arm 3: JNJ-3989 for 24 weeks + NA for 24 weeks + PegIFN-α2a from baseline till 
Week 12.
B) Study Population: HBeAg-negative chronic HBV-infected adult patients who are 
virologically suppressed by being treated with NA.
C) Variable: Response status defined as participants with reduction of at least 2 log10 IU/mL 
in HBsAg levels from baseline at Week 24 (responders) as in Section 5.3.1.
D) Intercurrent events:
o
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).
o
Deaths prior to Week 24 are handled in a composite strategy as participants who die 
prior to Week 24 will be considered as non-responders.
E) Population-level summary:
a. Primary (comparison vs fixed proportion): Difference in proportion of 
participants with reduction of at least 2 log10 IU/mL in HBsAg levels from 
baseline at Week 24 using a fixed proportion of 2%.
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b. Secondary (comparison amongst regimens): Difference in proportion of 
participants with reduction of at least 2 log10 IU/mL in HBsAg levels from 
baseline at 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
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.
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 Week 24 will be considered non-responders. 
For the participants still in the study at Week 24 or for participants that have neither discontinued 
treatment early nor experienced any major protocol violations as listed at Table 13, but HBsAg 
values missing at 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 [$] < , reject [],  = 1, … . . , , and stop; otherwise go to Step 2. 
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Step 2. If [$& ] < /2, reject [],  = 1, … . . ,  −1, and stop; otherwise go to Step 3. 
· · · 
Step k. If [ ] < /, reject [],  = 1, and stop.
5.3.5.
Subgroup Analyses of Primary Efficacy Endpoint
The potential association between the primary endpoint and the randomization stratification factors 
will be assessed by a logistic regression model (Brooks ST. et al., 2004) and exploration of the 
interaction terms using observed case data. The model will include intervention arm, country 
grouping as proxy for HBV genotype at enrollment (Poland (predominantly GT-A) vs Russia 
(predominantly GT-D) vs all other countries (other or mixed GT prevalence)), absolute HBsAg 
value at baseline (<1,000 IU/mL vs ≥1,000 IU/mL), as factors, and the interaction of intervention 
arm-by-country grouping, and intervention arm-by-HBsAg value at baseline as interaction terms. 
The primary endpoint estimates for each intervention arm will be derived from this model and 
presented graphically with their 90% CI in a forest plot.
In addition, for assessment of internal consistency and investigation of homogeneity of the 
treatment effect in the primary efficacy endpoint across other subgroups (as defined in 
Section 5.7.7.1), similarly to what is described above, a logistic regression model (Brooks ST. et 
al., 2004) will be estimated for each subgroup variable at a time. The factors in the model will be 
intervention arm, the subgroup variable, and the two randomization stratification factors (country 
grouping as proxy for HBV genotype at enrollment [Poland (predominantly GT-A) vs Russia 
(predominantly GT-D) vs all other countries (other or mixed GT prevalence)], absolute HBsAg 
value at baseline [<1,000 IU/mL vs ≥1,000 IU/mL]), and the intervention arm-by-subgroup 
interaction term. Corresponding 90% CIs will be also calculated without multiplicity adjustment 
for each intervention arm. Statistical analysis of treatment heterogeneity between subgroups will 
be conducted by assessing the significance of the interaction term (Brooks ST. et al., 2004). The 
forest plot will present graphically the primary endpoint estimate, its 90% CI resulting from the 
model across intervention arms by the prespecified subgroups.
The primary efficacy endpoint will be summarized also descriptively using the number and 
percentage of participants in each intervention arm, by each subgroup of interest (Section 5.7.7.1).
In addition, the tabulation of count and percentage of responders will be calculated for the 
combination of the 2 randomization stratification factors of country grouping-by-HBsAg at 
baseline categories.
5.3.6.
Comparisons Between Arm 2 and Model-Based Virtual IFN-Free JNJ-
3989+NA Regimen Control
As study participants were not randomized across those ISAs ongoing at the time of writing this 
SAP, because of the staggered ISAs initiation, any imbalance in baseline characteristics, beyond 
matching the key inclusion/exclusion criteria, may introduce potential bias in the treatment effect 
estimation. Such additional sources of variability could be driven by country effect, HBV 
genotype, time effect (e.g. time of the participant’s enrollment into an ISA), impact of the COVID-
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19 pandemic on protocol compliance, as well as by the different combination regimens and the 
different JNJ-3989 treatment durations across ISAs. To address these concerns another analysis of 
the primary efficacy endpoint will be performed constructing “virtual” IFN-free JNJ-3989 control 
participants for the participants in this ISA (Arm 2). Virtual control HBsAg data are defined as 
IFN-free regimen with JNJ-3989+NA, at the JNJ-3989 dose level used in this ISA. For each 
participant in Arm 2 of this ISA, the HBsAg data for “virtual” control subjects will be generated 
using an appropriate longitudinal model (e.g. kinetic pharmacodynamic model [KPD] or PK/PD 
model) developed and validated based on the data from the JNJ73763989HPB2001 (REEF-1) 
study. In Arm 2, the first 12 weeks of HBsAg data under treatment with JNJ-3989+NA alone will 
enable to estimate individual parameters (ie, Empirical Bayes Estimates) describing each 
participant’s specific HBsAg temporal kinetics. These individual parameters will be used further 
to extrapolate each participant’s individual HBsAg values over time, as if that participant had been 
treated with JNJ-3989 +NA regimen but without receiving PegIFN-α2a for the entire 24-week 
treatment. The observed HBsAg levels post PegIFN-α2a intake in Arm 2 will be directly compared 
to virtual control model-generated HBsAg data for this arm. Of Note: the model-based prediction 
of HBsAg between weeks 12-24 for each individual in Arm2 assumes that (i) the individual’s 
HBsAg dynamics follow the general path of the population-level HBsAg turnover model, and (ii) 
assumes absence of immune-related effects.
Single-arm estimate of the primary endpoint response rate (study intervention arm and virtual 
control-arm): The estimated primary endpoint response rate will be calculated for the virtual 
control arm, and 90% CI will be estimated using Clopper-Pearson exact method for a single sample 
proportion. The same Clopper Pearson method will also apply to estimate the 90% CI around the 
response rate for the Arm 2 of this ISA.
Matched-control paired difference in the primary endpoint response rate (study intervention 
arm vs. virtual control-arm): The proportion of responders estimated for participants in this ISA 
will be compared with the proportion of responders obtained for the virtual IFN-free JNJ-3989 
control participants model-generated using the McNemar test for the difference between paired 
matched case-control binomial proportions at 0.05 one-sided Type 1 error rate. The associated 
90% CI will be estimated to accompany the point estimate of the difference in proportions. 
No multiplicity adjustment will be used in this exploratory statistical comparison.
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.
NA Treatment Completion Criteria 
NA treatment completion criteria are defined based on the Week 24 results as follows:

ALT <3x ULN, and 

HBV DNA <60 IU/mL at Week 24 and HBV DNA<LLOQ at the previous visit, or HBV 
DNA< LLOQ at Week 24, and

HBeAg-negative, and

HBsAg <100 IU/mL 
Note: Participants who are close to meeting the protocol-defined NA treatment completion criteria 
with the Week 24 results, and do meet the criteria based on the FU Week 2 results may be allowed 
to stop NA at FU Week 4, after consultation with the Sponsor. In case of ALT elevation ≥3x ULN 
at Week 24, the investigator must consider different potential causes of increased ALT to ensure 
appropriate work up and management as needed. If the ALT elevation is unrelated to HBV activity
and/or <3x ULN by FU Week 2, NA completion may be considered at the discretion of the 
investigator and in consultation with the sponsor.
The NA completion criteria will be assessed based on clinical laboratory tests and summarized 
based on the Week 24 (EOSI) or FU Week 2 results, and during the FU phase.
5.4.1.1.2.
NA Re-Treatment During Follow-up
Participants who actually re-started NA treatment during the follow-up phase will be identified 
based on the ‘Study Drug Administration for NA’ CRF page.
Participants who meet the NA re-treatment criteria will be identified on the CRF page of ‘NA Re-
treatment Criteria Assessment’. Each sub-criteria will also be evaluated.
5.4.1.1.3.
HBsAg Cut-offs
The cut-offs for HBsAg level are as follows:

<1000 IU/mL

<500 IU/mL

<100 IU/mL

<10 IU/mL

<1 IU/mL

<LLOQ (0.05 IU/mL)
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The cut-offs for HBsAg change from baseline and RTs are as follow:

decrease by ≥0.3 log10 IU/mL 

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 
5.4.1.1.4.
HBsAg Seroclearance
Seroclearance of HBsAg is defined as a (quantitative) HBsAg level <LLOQ (see Table 5). HBsAg 
seroclearance can be observed prior to the time point assessed but must be observed at the given 
week of interest.
5.4.1.1.4.1. On Treatment
HBsAg seroclearance will be evaluated over time during the study intervention phase.
5.4.1.1.4.2. Off Treatment
HBsAg seroclearance will be evaluated over time at each of the FU timepoints separately, with 
emphasis at FU Weeks 12, 24, 36 and 48 (i.e. 12, 24, 36, 48 weeks after completion of all study 
interventions at Week 24) and without restarting NA treatment.
For the analyses of seroclearance at the time points mentioned above, participants with HBsAg 
seroclearance at the respective time points (and without restarting NA treatment during the interval 
between the time of stopping the study intervention up to the analysis time point (FU Week 12, 
24, 36 and 48)) will be considered as having achieved this endpoint.
5.4.1.1.5.
Functional Cure
Functional cure will be evaluated at each of the following time points separately: FU Week 12, 24, 
36 and 48. A participant will be defined as having achieved functional cure (FC) if he/she has:

had HBsAg seroclearance at the given week of interest, and

not required NA re-treatment between Week 24 and the given follow-up week of interest.
It can be noted that a participant may achieve HBsAg seroclearance prior to the week of interest, 
but the HBsAg level<LLOQ has to be shown at the given week of interest to be counted as 
responder.
5.4.1.1.6.
Treatment Failure
A participant will be defined as on-treatment failure if he/she didn’t have a reduction from baseline 
of at least 2 log10 IU/mL levels at Week 24. 
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5.4.1.1.7.
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.
5.4.1.1.8.
HBeAg Cut-offs
The cut-offs for HBeAg level are as follows:

≥LLOQ

< LLOQ (0.11 IU/mL) 
5.4.1.1.9.
HBV DNA Cut-offs
The cut-offs for HBV DNA are as follows:

< LLOQ for target detected and not detected

< LLOQ for target not detected

< LLOQ for target detected

<60 IU/mL

<100 IU/mL

<200 IU/mL

<1000 IU/mL 

<2000 IU/mL

<20000 IU/mL
5.4.1.1.10.
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 FU Weeks 12, 24, 36 and 48 (i.e. 
12, 24, 36, 48 weeks after completion of all study interventions at Week 24), and without restarting 
NA treatment.
5.4.1.1.11.
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.
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Participants who achieve ALT normalization on treatment and off treatment but without restarting 
NA treatment will be evaluated over time.
Participants who were retreated with NA and who have ALT≥ULN before NA re-treatment and 
reach ALT normalization after NA re-treatment during follow-up will be evaluated.
Additionally, for those participants who restarted NA treatment during the follow-up, the 
participants who reach ALT<ULN and who have ALT less than their nadir value will be evaluated.
5.4.1.1.12.
Partial Cure
Partial cure will be evaluated at each of the following time points separately: FU Week 12, 24, 36
and 48. A participant will be defined as having achieved partial cure if he/she has:

Stopped all study interventions at any time, and

had HBV DNA level < 2,000 IU/ml at the given follow-up week of interest, and

had HBsAg ≥LLOQ at the given week of interest, and

not required NA re-treatment after stopping all study interventions.
Of note, HBV DNA level < 2,000 IU/ml may be achieved prior to the week of interest but must 
be observed at the given week of interest.
5.4.1.1.13.
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.
5.4.1.1.14.
Flares
The criteria based on blood markers/lab tests for each of the flare types are defined as below.
1. Virologic flare is defined as follows:
Virologic flare will be assessed only for those participants who are off-treatment.
The start of a confirmed virologic flare is defined as the first date of two consecutive visits with 
HBV DNA >200 IU/mL. The end date of the same confirmed virologic flare is defined as the first 
date when HBV DNA value returns to ≤200 IU/mL or the date of NA treatment restart, whichever 
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comes first. Each virologic flare will be categorized based on the confirmed (i.e. two consecutive 
values) peak HBV DNA above any of the three thresholds within the start and end date of that 
flare as follows: 20,000 IU/mL 2,000 IU/mL and 200 IU/mL.

1 (Yes) = confirmed** HBV DNA > peak threshold.   

0 (No) = at least one off-treatment HBV DNA measurement available and not meeting the 
criteria of confirmed HBV DNA > peak threshold.

2 (Not applicable) = no off-treatment HBV DNA quantitative measurements available.
2. Off-treatment Biochemical flare is defined as follows:
The start date of a confirmed off-treatment biochemical flare is defined as the first date of two 
consecutive visits with ALT and/or AST≥3x ULN and ≥3x off-treatment nadir (i.e. lowest value 
observed during off-treatment period up to the time point of meeting the biochemical flare criteria) 
while the participant does not receive any of the study interventions. The end date of the same off-
treatment biochemical flare is defined as the first date when there is a 50% reduction from the peak 
ALT and/or AST level & <3x ULN.

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
3. 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 on-treatment nadir (i.e. lowest value 
observed on-treatment period up to the time point of meeting the biochemical flare criteria) 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
4. Clinical flare is defined as follows:
A clinical flare occurs either when a virologic flare and biochemical flare overlap in time or when 
a biochemical flare starts within 4 weeks following the end of a virologic flare. The start date of a 
clinical flare is defined as the minimum start date of the virologic flare and the biochemical flare. 
The end date of a clinical flare is defined as the maximum end date of the virologic flare and 
biochemical flare, i.e., the later date of HBV DNA returns to ≤200 IU/mL and 50% reduction from 
the peak ALT and/or AST level.

1 (Yes) = confirmed** HBV DNA > peak threshold and confirmed** ALT and/or AST ≥3x 
ULN and confirmed** ≥3x nadir (i.e. lowest value during study participation).
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
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.
The virologic and clinical flares will be assessed only off-treatment, while biochemical flares will 
be identified on-treatment and off-treatment. On-treatment virologic flares are described as 
virologic breakthrough in Section 5.4.1.1.13. On-treatment will be defined as the time period in 
which the participant receives any of the study interventions. Off-treatment will be defined as the 
period after stopping all study interventions (including NA). 
5.4.1.2.
Continuous Endpoints
5.4.1.2.1.
HBsAg, HBeAg, HBV DNA and ALT
Actual values (original unit and log10 transformed values), changes from baseline (log10
transformed values) and change from RTs over time in HBsAg, HBeAg, HBV DNA and ALT 
(actual values only) 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, HBeAg, and HBV DNA will be evaluated at 3 intervals: on-treatment nadir (first 24 
weeks), during follow-up nadir, and entire study nadir.
5.4.1.3.
Time to Event Endpoints
5.4.1.3.1.
Time to First HBsAg Seroclearance
Time to HBsAg seroclearance is defined as the number of days between the date of first study 
intervention intake and the date of the first occurrence of HBsAg seroclearance (i.e. the date of the 
first HBsAg seroclearance – the date of first study intervention intake + 1). The participants who 
withdrew early from the study before achieving HBsAg seroclearance or who did not achieve 
HBsAg seroclearance will be censored at the last available HBsAg assessment.
Time to HBsAg seroclearance will be also analyzed considering the participants who were 
retreated with NA before achieving HBsAg seroclearance as censored at the date of NA 
retreatment.
In addition, time to the first occurrence of the following events (i.e. the date of the first occurrence 
of the event – the date of first study intervention intake + 1) will be analyzed:

HBsAg <100 IU/mL 

HBsAg decline ≥1.0 log10 IU/mL

HBsAg decline ≥2.0 log10 IU/mL

HBsAg decline ≥3.0 log10 IU/mL
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Time to the first occurrence of the events above will be also analyzed considering the participants 
who were retreated with NA before achieving the event as censored at the date of NA retreatment.
5.4.1.3.2.
Time to First HBsAg Seroconversion
Time to first HBsAg seroconversion is defined as the number of days between the date of first 
study intervention intake and the date of the first occurrence of HBsAg seroclearance and 
appearance of anti-HBs antibodies (i.e. the date of the first HBsAg seroclearance and anti-HBs 
antibodies – the date of first study intervention intake + 1). The participants who withdrew early 
from the study before achieving HBsAg seroclearance and anti-HBs antibodies or who did not 
achieve HBsAg seroclearance and anti-HBs antibodies will be censored at the last available anti-
HBs antibodies assessment.
Time to first HBsAg seroconversion will be the participants who were retreated with NA before 
achieving HBsAg seroclearance and anti-HBs antibodies will be censored at the date of NA 
retreatment.
5.4.1.3.3.
Time to HBV DNA < LLOQ
Time to HBV DNA < LLOQ is defined as the number of days between HBV DNA >LLOQ for 
participants who re-treated with NA and the date of the first occurrence of HBV DNA < LLOQ
after NA re-treatment (i.e. the date of the HBV DNA < LLOQ after being re-treated with NA – the 
date of first occurrence of HBV DNA>LLOQ + 1). Time to first HBV DNA < LLOQ will be 
analyzed only for participants who met the NA treatment completion criteria and re-treated with 
NA during FU.
5.4.1.3.4.
Time to First Virologic Breakthrough
Time to first HBV virologic breakthrough will be defined as the number of days between the date 
of first study intervention intake and the date of the first occurrence of virologic breakthrough (i.e. 
the date of the first virologic breakthrough [the first of the two confirmation visits] - the date of 
first study intervention intake +1). The participants who withdrew early from the study before 
experiencing virologic breakthrough or who did not experience virologic breakthrough will be 
censored at the last available HBV DNA assessment at or before EOT.
5.4.1.3.5.
Time to First Flare
Time to first biochemical flare (on- and off-treatment), clinical flare off-treatment, and virologic 
flare off-treatment will be evaluated.
Time to first on-treatment flare will be defined as the number of days between the date of first 
study intervention intake and the date of the first occurrence of on-treatment flare (i.e. the date of 
the first on-treatment flare [the first of the two confirmation visits] of each type- the date of first 
study intervention intake+1). The participants who withdrew early from the study before 
experiencing on-treatment flare or who did not experience on-treatment flare will be censored at 
the last available blood markers or liver enzymes assessment at or before EOT.
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Time to the first off-treatment flare will be defined as the number of days between the date of last 
study intervention intake and the date of the first occurrence of off-treatment flare (i.e. the date of 
experiencing the first off-treatment flare [the first of the two confirmation visits] of each type- the 
date of last study intervention intake). The participants who withdrew early from the study before 
experiencing off-treatment flare or who did not experience off-treatment flare will be censored at 
the last available blood markers or liver enzymes assessment.
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 will 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.
5.4.2.1.
Binary Endpoints
All binary endpoints defined using HBsAg values/changes from baseline (HBsAg cut-offs, HBsAg 
seroclearance/seroconversion, Functional Cure) will be analyzed also using the virtual control 
approach described in Section 5.3.6. 
For single arm point and 90% CI estimates, the Clopper Pearson method will be used. For the 
difference between paired matched case-control binomial proportions, the McNemar test at 0.05 
one-sided Type 1 error rate will be used.
Graphical displays using bar charts and/or radar plots will show the binary endpoints over time, 
by subgroups of interest, or combining multiple binary endpoints together. 
Potential association between treatment outcome and baseline factors will be explored by 
multivariate logistic regression model in a similar fashion as described in Section 5.3.5.
5.4.2.1.1.
LOCF Imputation Method

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 
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/later than 12 weeks from the actual time point of interest (FU 
Week 12 and FU Week 36, respectively) will be imputed.

If the lab value at FU Week 36 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 36 which is no earlier/later than 12 weeks from the actual time point of interest (FU 
Week 24 and FU Week 48, respectively) will be imputed.

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 36 may be carried forward.
5.4.2.1.2.
NA Treatment Completion Criteria at Week 24 and During FU
The count and proportion of participants (and associated 90% CI) who met the NA treatment
completion criteria at Week 24, will be summarized by intervention arm.
Starting at the end of treatment period, the incidence of participants who did not meet the NA
treatment completion criteria will be summarized at each timepoint during the study by 
intervention arm, accompanied by the distribution of each of the 4 criteria that is not met. The NA 
treatment completion criteria are based on a threshold for the laboratory tests of ALT, HBV DNA, 
HBeAg and HBsAg.
The count and proportion of participants (and associated 90% confidence interval) who met the
NA treatment completion criteria (Section 5.4.1.1.1) at any time during the FU phase will be
summarized by intervention arm. All the NA treatment completion criteria will be checked based 
on clinical laboratory tests in FU phase.
5.4.2.1.3.
NA Re-Treatment Criteria During FU
The count and proportion of participants (and associated 90% CI) who meet the criteria for NA re-
treatment at any time during FU will be summarized descriptively by intervention arm. In addition, 
the count and proportion of participants (and associated 90% CI) who met the criteria according 
to the flag on the CRF page of ‘NA Re-treatment Criteria Assessment’ during the follow-up phase 
will be summarized over time by intervention arm. The proportion of participants who met each 
sub-criteria will also be summarized by intervention arm.
The count and proportion of participants (and associated 90% CI) who actually re-started NA 
treatment during the follow-up phase on the basis of the ‘Study Drug Administration for NA’ CRF 
page will be summarized separately over time by intervention arm.
A cross-tabulation of participants who actually re-started NA treatment (re-started/not restarted) 
versus participants who met the above criteria (met/not met) will be presented over time by 
intervention arm.
5.4.2.1.4.
HBsAg Cut-offs
The cut-offs for HBsAg values and decreases from baseline will be used in separate summaries 
over time by intervention arm. The count and proportion of participants who meet those HBsAg 
thresholds during the study will be summarized descriptively by intervention arm, and analysis 
phase over time and displayed in graphs like bar charts and/or radar plots.
Cross-tabulations overtime of quantitative HBsAg (<LLOQ, ≥LLOQ) versus qualitative HBsAg 
(positive, negative), respectively, will also be presented by intervention arm.
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5.4.2.1.5.
HBsAg Seroclearance
5.4.2.1.5.1. On Treatment
The count and proportion of participants (and associated 90% CI) who achieve HBsAg 
seroclearance over time during the study intervention phase will be summarized by intervention 
arm.
5.4.2.1.5.2. Off Treatment 
The count and proportion of participants (and associated 90% CI) who achieve HBsAg 
seroclearance over time during FU will be summarized by intervention arm. 
The count and proportion of participants who achieve HBsAg seroclearance will be evaluated by 
intervention arm at each of the following off-treatment time points: 12, 24, 36 and 48 weeks, 
respectively, after stopping all study interventions and without restarting NA treatment. In an 
additional summary, these proportions will be calculated with the denominator including only 
those participants who have reached the off-treatment timepoint (week 12, 24, 36 or 48), and have 
stopped all interventions including NA and have not restarted NA prior to the timepoint of interest.
For all time points, HBsAg seroclearance will be analyzed using the observed case data. LOCF 
will be used for selected time points (Section  5.4.2.1.1).
5.4.2.1.5.3. Functional Cure
The count and proportion of participants (and associated 90% CI) who achieve FC at each of the 
selected FU time points will be summarized descriptively by intervention arm.
The main analysis will be on observed cases data with no imputation of missing values. 
Two sensitivity analyses will be performed.
1. Missing as non-response: If participants withdrew from the study prior to the selected FU time 
point or had missing HBsAg values at the selected FU time point, they will be considered as 
non-responders. 
2. LOCF: If participants withdrew from the study prior to the selected FU time point, they will 
be considered as non-responders. The LOCF rules to handle missing data will be applied to 
selected time points as explained in Section 5.4.2.1.1.
5.4.2.1.6.
Treatment Failure
The count and proportion of on-treatment failure participants (and associated 90% CI) will be 
summarized by intervention arm.
5.4.2.1.7.
HBsAg Seroconversion
The count and proportion of participants (and associated 90% CI) who achieve HBsAg 
seroconversion will be summarized descriptively by intervention arm and analysis phase.
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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.
5.4.2.1.8.
HBeAg Cut-offs
The cut-offs for HBeAg values will be used in separate summaries over time by intervention arm. 
The count and proportion of participants who meet those HBeAg thresholds during the study will 
be summarized descriptively by intervention arm and analysis phase over time and displayed in 
graphs like bar charts and/or radar plots.
Cross-tabulations overtime of quantitative HBeAg (<LLOQ, ≥LLOQ) versus qualitative HBeAg 
(positive, negative), respectively, will also be presented by intervention arm.
5.4.2.1.9.
HBV DNA Cut-offs
The cut-offs for HBV DNA values will be used in separate summaries over time by intervention 
arm. The count and proportion of participants who meet those HBV DNA thresholds during the 
study will be summarized descriptively by intervention arm and analysis phase over time.
5.4.2.1.10.
Suppressed HBV DNA
The count and proportion of participants (and associated 90% CI) with HBV DNA <LLOQ 
(overall and separately for HBV DNA detectable and HBV DNA TND) will be evaluated by
intervention arm and analysis phase over time.
The count and proportion of participants (and associated 90% CI) with HBV DNA <LLOQ 
(overall and separately for HBV DNA detectable and HBV DNA TND) will be evaluated by 
intervention arm at each of the FU Weeks 12, 24, 36, and 48, respectively, after stopping all study 
interventions at Week 24 and without restarting NA treatment. 
In an additional summary, these proportions will be calculated with the denominator including 
only those participants who have reached the off-treatment timepoint (week 12, 24, 36 or 48), and 
have stopped all interventions including NA and have not restarted NA prior to the timepoint of 
interest.
The count and proportion of participants (and associated 90% CI) with HBV DNA <LLOQ 
(overall and separately for HBV DNA detectable and HBV DNA TND) after restart of NA 
treatment during follow-up will also be presented by intervention arm. 
The number of occurrences each subject has HBV DNA <LLOQ (overall and separately for HBV 
DNA detectable and HBV DNA TND) will be determined and summarized by intervention arm 
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using frequency distributions and descriptive statistics. Additionally, the number of occurrences 
will be displayed graphically.
For all time points, HBV DNA <LLOQ will be analyzed using the observed case data. LOCF will 
be used for selected time points (Section  5.4.2.1.1).
The same analyses will also be performed for HBV DNA < 60 IU/mL.
5.4.2.1.11.
ALT Normalization
The count and proportion of participants (and associated 90% CI) who achieve ALT normalization 
on treatment and off treatment but without restarting NA treatment will be summarized 
descriptively over time by intervention arm, only for the subjects who had ALT elevation 
(ALT≥ULN) at baseline. 
The count and proportion of participants (and associated 90% CI) who have ALT ≥ULN before 
NA re-treatment and reach ALT normalization after NA re-treatment during follow-up will be 
summarized by intervention arm.
5.4.2.1.12.
Partial Cure
The count and proportion of participants (and associated 90% CI) who achieve partial cure during 
the study will be summarized descriptively by intervention arm at the selected FU time points. 
The main analysis will be on observed cases data with no imputation of missing values. 
Two sensitivity analyses will be performed.
1. Missing as non-response: If participants withdrew from the study prior to the selected FU time 
point or had missing HBsAg or HBV DNA values at the selected FU time point, they will be 
considered as non-responders. 
2. LOCF: If participants withdrew from the study prior to the selected FU time point, they will 
be considered as non-responders. The LOCF rules to handle missing data for HBsAg and HBV 
DNA will be applied to selected time points as explained in Section 5.4.2.1.1.
5.4.2.1.13.
Virologic Breakthrough
The count and proportion of participants (and associated 90% CI) who experience a virologic 
breakthrough and those who experience virologic breakthrough followed by on-treatment 
biochemical flare will be summarized, respectively, by intervention arm and analysis phase.
5.4.2.1.14.
Flares
The incidence rate will be calculated and summarized for each type of on-treatment or off-
treatment flares (virologic, biochemical and clinical) separately, as well as the overall incidence 
of participants experiencing at least one flare, regardless of type, by intervention arm. Additionally, 
for each participant the total number of flares the participant experienced will be counted by type. 
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Such counts will be used to summarize the distribution of the total number of flares by type and 
intervention arm.
For on-treatment biochemical flares, the incidence of flares causing treatment discontinuation will 
be summarized by intervention arm. Further, for off-treatment flares, the count and percentage of 
participants who experienced a flare followed by NA re-treatment will be summarized by flare 
type and 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.
Additional analysis for off-treatment flares will be performed for those who met the NA treatment 
completion criteria and stopped NA.
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 log10 transformed values) and changes 
from baseline (log10 transformed values) over time in HBsAg, HBeAg, HBV DNA, and ALT 
(original unit) will be summarized by intervention arm. Mean (+/- SE) plots of the actual values,
change from baseline (log10 transformed) and change from RTs will be presented over time per 
endpoint by intervention arm and analysis phase. The change from baseline value to the nadirs (i.e. 
maximum decrease for each participant) in HBsAg, HBeAg and HBV DNA will be summarized 
descriptively by intervention arm. Box plots of the changes to nadirs in HBsAg and HBV DNA
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), their interaction, and 2 randomization stratification 
factors (ie, country grouping as proxy for HBV genotype (GT) at enrollment [Poland 
(predominantly GT-A) vs Russia (predominantly GT-D) vs all other countries (other or mixed GT 
prevalence)] and absolute HBsAg value at baseline [<1,000 IU/mL versus >1,000 IU/mL]) and 
baseline blood marker categorical variable 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 and the intervention arm-by-
baseline interaction term. 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) and changes 
from baseline (log10 transformed values) at end of treatment in HBsAg, HBeAg and HBV DNA 
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will be summarized by study intervention arm by outcome response (i.e. by reduction of at least 2 
log10 IU/mL in HBsAg levels from baseline at Week 24, by HBsAg seroclearance at Week 24, FU 
Week 24 and FU Week 48, and by partial cure status at Week 24, and for participants who achieved 
functional cure at FU Week 24 and FU Week 48).
Spaghetti plots for both absolute values and changes from baseline of HBsAg and HBV DNA will 
be presented over time per blood marker by intervention arm and by selected subgroups 
(Section 5.7.7.1).
Waterfall plots for changes from baseline and RTs of HBsAg, HBeAg, and HBV DNA will also 
be presented.
Descriptive statistics of the absolute values, changes from baseline and RTs 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.
5.4.2.3.
Time to Event Endpoints
The Kaplan-Meier method will be used to estimate and plot the cumulative incidence by each 
intervention arm. The log-rank test will be performed to compare between the intervention arms. 
The median time with 90% CI will be estimated using Kaplan-Meier method. To explore the 
impact of selected baseline factors in addition of study intervention, the survival probabilities will 
be estimated based on a stratified Cox regression model including study intervention arm, and each 
baseline factor at a time with the intervention arm-by-baseline factor interaction term. The strata
in the stratified Cox model are the 2 randomization stratification factors to allow for a separate 
baseline hazard for each level of those factors. The interaction between study intervention arm and 
baseline/disease characteristic will be explored graphically. 
5.5.
Exploratory Endpoints
5.5.1.
Definitions
5.5.1.1.
Binary Endpoints
5.5.1.1.1.
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

≥ 6 kPa
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Only participants from sites with available VCTE (Fibroscan) will be included in the analysis. 
Within these participants, missing LSM (in kPa) at a specific timepoint will be considered as non-
responders for that timepoint. No imputation rule will be used in case of missing data.
5.5.1.1.2.
HBV RNA Cut-offs
The cut-offs for HBV RNA are as follows:

< LOD

< LLOQ

<1000 copies/mL
The cut-offs for HBV RNA change from baseline and RTs are as follows:

decrease by ≥ 1.0 log copies/mL

decrease by ≥ 2.0 log copies/mL

decrease by ≥ 3.0 log copies/mL
5.5.1.1.3.
HBcrAg Cut-offs
The cut-offs for HBcrAg are as follows:

< 3.0 log U/mL

< 4.0 log U/mL
The cut-offs for HBcrAg change from baseline and RTs are as follows:

decrease by ≥ 1.0 log U/mL

decrease by ≥ 2.0 log U/mL

decrease by ≥ 3.0 log U/mL
5.5.1.1.4.
Anti-HBe Antibodies 
Participants who have positive and negative Anti-HBe values will be evaluated over time.
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) and changes from RTs over time in 
HBV RNA and HBcrAg will be evaluated.
Change from baseline is defined as the value at a given time point minus baseline value.
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The change from baseline value to nadir (i.e. maximum decrease for each participant) in HBV 
RNA and HBcrAg will be evaluated at 3 intervals: on-treatment nadir (first 24 weeks), during 
follow-up nadir, and entire study nadir.
5.5.1.2.3.
Anti-HBs Antibodies
Actual values and change from baseline will be evaluated over time when anti-HBs antibodies are 
assessed.
Change from baseline is defined as the value at a given time point minus baseline value.
5.5.1.3.
Time to Event Endpoints
5.5.1.3.1.
Time to First HBV RNA<LOD
Time to first HBV RNA<LOD is defined as the duration from the date of first study intervention 
intake to the date of the first occurrence of HBV RNA<LOD (i.e. the date of the first occurrence 
of HBV RNA<LOD – the date of first study intervention intake + 1). The participants who did not 
achieve undetectability or who early withdrew from the study before achieving HBV RNA<LOD 
will be censored at the last HBV RNA assessment before the date of withdrawal. 
Time to first HBV RNA<LOD will be also analyzed considering the participants who were 
retreated with NA before achieving HBV RNA<LOD as censored at the date of NA retreatment.
Only the participants with HBV RNA values ≥LOD+ 0.5 log10 cp/mL (i.e. ≥1.898 log10 cp/mL) at 
baseline will be included in this analysis. Similarly, additional analyses for participants with HBV 
RNA values ≥LOD+ 1.0 log10 cp/mL and ≥LOD+ 2.0 log10 cp/mL, respectively, will be 
summarized.
5.5.1.3.2.
Time to First HBcrAg Undetectability
Time to first undetectability of HBcrAg is defined as the duration from the date of first study 
intervention intake to the date of the first occurrence of undetectability of HBcrAg (i.e. the date of 
the first occurrence of HBcrAg<LLOQ – the date of first study intervention intake + 1). The 
participants who did not achieve undetectability or who early withdrew from the study before 
achieving undetectability of HBcrAg will be censored at the last HBcrAg assessment before the 
date of withdrawal. 
Time to first undetectability of HBcrAg will be also analyzed considering the participants who 
were retreated with NA before achieving HBcrAg<LLOQ as censored at the date of NA 
retreatment.
Only the participants with HBcrAg values ≥LLOQ+ 0.5 log10 U/mL (i.e. ≥3.5 log10 U/mL) at 
baseline will be included in this analysis.
5.5.1.3.3.
Time to Appearance of Anti-HBs Antibodies
Appearance of anti-HBs antibodies is defined as a baseline anti-HBs (quantitative) <LLOQ and a 
post-baseline assessment ≥LLOQ. 
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Time to appearance of anti-HBs antibodies is defined as the time (days) from the date of first study 
intervention intake to the date of the first occurrence of anti-HBs antibodies appearance + 1.  The 
participants who did not experience emergence of antibodies or who early withdrew from the study 
before showing emergence of anti-HBs antibodies will be censored at the last anti-HBs antibodies
assessment before the date of withdrawal. 
Time to appearance of anti-HBs antibodies will be also analyzed considering the participants who 
were retreated with NA before achieving appearance of anti-HBs antibodies as censored at the date 
of NA retreatment.
5.5.1.3.4.
Time to Appearance of Anti-HBe Antibodies
Appearance of anti-HBe antibodies is defined as a baseline anti-HBe antibodies (qualitative) with 
a "NEGATIVE" result and a post-baseline assessment with “POSITIVE” result. 
Time to appearance of anti-HBe antibodies is defined as the time (days) from the date of first study 
intervention intake to the date of the first occurrence of anti-HBe antibodies appearance + 1. The 
participants who did not experience emergence of antibodies or who early withdrew from the study 
before showing emergence of anti-HBe antibodies will be censored at the last anti-HBe antibodies
assessment before the date of withdrawal. 
Time to appearance of anti-HBe antibodies will be also analyzed considering the participants who 
were retreated with NA before achieving appearance of anti-HBe antibodies as censored at the 
date of NA retreatment.
5.5.1.4.
Endpoints for Correlation
5.5.1.4.1.
Association Between Baseline Characteristics/Viral Blood Markers 
and Selected Efficacy Variables 
Correlations between baseline characteristics and on-treatment HBV blood markers with off-
treatment endpoints will be evaluated. The list of HBV blood markers, including but not limited 
to, are defined in Table 6. 
Table 6:
Pairs of off treatment endpoints and baseline characteristics/on treatment HBV markers
Off treatment HBV marker
Baseline Characteristics/On treatment HBV marker
HBsAg change from baseline at FU Week 24

Age

HBsAg value at baseline

HBsAg change from baseline at Week 12

HBsAg change from baseline at Week 24

Treatment failure (Yes; No)
HBsAg change from baseline at FU Week 48

Age

HBsAg value at baseline

HBsAg change from baseline at Week 12

HBsAg change from baseline at Week 24

Treatment failure (Yes; No)
HBsAg seroclearance at FU Week 24 (Yes; No)

Age

HBsAg value at baseline

HBsAg change from baseline at Week 12
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Off treatment HBV marker
Baseline Characteristics/On treatment HBV marker

HBsAg change from baseline at Week 24

Treatment failure (Yes; No)
HBsAg seroclearance at FU Week 48 (Yes; No)

Age

HBsAg value at baseline

HBsAg change from baseline at Week 12

HBsAg change from baseline at Week 24

Treatment failure (Yes; No)
NA re-treatment at FU Week 24 (Yes; No)

Age

HBsAg value at baseline

HBsAg change from baseline at Week 12

HBsAg change from baseline at Week 24

Treatment failure (Yes; No)
NA re-treatment at FU Week 48 (Yes; No)

Age

HBsAg value at baseline

HBsAg change from baseline at Week 12

HBsAg change from baseline at Week 24

Treatment failure (Yes; No)
Partial cure at FU Week 24 (Yes; No)

Age

HBsAg value at baseline

HBsAg change from baseline at Week 12

HBsAg change from baseline at Week 24 

Treatment failure (Yes; No)
Partial cure at FU Week 48 (Yes; No)

Age

HBsAg value at baseline

HBsAg change from baseline at Week 12

HBsAg change from baseline at Week 24

Treatment failure (Yes; No)
Functional cure at FU Week 24 (Yes; No)

Age

HBsAg value at baseline

HBsAg change from baseline at Week 12

HBsAg change from baseline at Week 24

Treatment failure (Yes; No)
Functional cure at FU Week 48 (Yes; No)

Age

HBsAg value at baseline

HBsAg change from baseline at Week 12

HBsAg change from baseline at Week 24

Treatment failure (Yes; No)
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.
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5.5.2.1.
Binary Endpoints
5.5.2.1.1.
Liver Stiffness Measurement
The count and proportion of participants who meet those change from baseline thresholds for LSM 
during the study will be summarized by intervention arm at Week 24, FU Week 24 and FU 
Week 48.
At each assessment time point, a frequency distribution of severity scores will be produced.
5.5.2.1.2.
HBV RNA Cut-offs
The cut-offs for HBV RNA values and decreases from baseline will be used in separate summaries 
over time. The count and proportion of participants who meet those HBV RNA thresholds during 
the study will be summarized descriptively by intervention arm and analysis phase over time, and 
displayed in graphs like bar charts and/or radar plots.
5.5.2.1.3.
HBcrAg Cut-offs
The cut-offs for HBcrAg values and decreases from baseline will be used in separate summaries 
over time. The count and proportion of participants who meet those HBcrAg thresholds during the 
study will be summarized descriptively by intervention arm and analysis phase over time, and 
displayed in graphs like bar charts and/or radar plots.
5.5.2.1.4.
Anti-HBe Antibodies
The count and proportion of participants with positive and negative anti-HBe values will be 
summarized descriptively by intervention arm and analysis phase over time.
Shift tables in Anti-HBe positive/negative values from baseline will also be provided at each time 
point.
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.
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, SE, 90% CI, median, minimum, maximum) by intervention arm.
The comparison among intervention arms will be done using ANCOVA with intervention arm, 
randomization stratification factors as main effects and baseline score as covariate.
Plots of mean (+/- SE) values and changes from baseline over time will be presented. In addition, 
a waterfall plot will be produced to display the individual changes from baseline in LSM for each 
participant at a given timepoint.
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5.5.2.2.2.
HBV RNA and HBcrAg
The actual values, changes from baseline and changes from RTs in HBV RNA and HBcrAg, 
respectively, will be summarized only descriptively over time in a similar manner as for values
and changes from baseline over time in HBsAg, HBeAg, and HBV DNA as described in
Section 5.4.2.2.1, including the change from baseline value to nadir (i.e. maximum decrease for 
each participant) and the various graphical displays. 
Waterfall plots for changes from baseline of HBV RNA and HBcrAg will also be presented.
5.5.2.2.3.
Anti-HBs Antibodies
The actual values of and changes from baseline in anti-HBs antibodies will be summarized only 
descriptively in a similar manner as described for values and changes from baseline over time in 
other blood disease markers in Section 5.4.2.2.1.
For all participants with positive anti-HBs antibodies at baseline who will reach HBsAg 
seroclearance (as defined in Section 5.4.1.1.4), descriptive statistics will be calculated for the 
change of anti-HBs antibodies level from baseline at the timepoint when achieving the HBsAg 
seroclearance.  In an additional summary, the change of anti-HBs antibodies level from baseline 
at the specific timepoint will be summarized descriptively for the subset of the participants 
achieving HBsAg seroclearance at any time before or at that given timepoint.
Cross-tabulations overtime of quantitative versus qualitative anti-HBs values, respectively, will 
also be presented.
5.5.2.3.
Time to Event Endpoints
The time-to-event endpoints will be analyzed in a similar manner as for the time-to-event 
endpoints described in Section 5.4.2.3.
5.5.2.4.
Endpoints for Correlation
5.5.2.4.1.
Association Between Baseline Characteristics/Viral Blood Markers 
and Selected Efficacy Variables
Correlations will be evaluated graphically using scatter plots, and heat maps displaying such 
potential associations.
The following correlation coefficients will be calculated by intervention arm for the different 
correlation scenarios:

Pearson’s correlation coefficient for two continuous variables.

Phi correlation coefficient for two binary variables.

Point biserial correlation coefficient for one binary variable and one continuous variable.
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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), 
physical examinations, ophthalmic examinations, vital signs measurements, clinical laboratory 
tests (including hematology, blood biochemistry, blood coagulation, and urinalysis), and ECGs.
For all continuous safety variables, descriptive statistics by intervention group will include the N, 
mean, standard deviation, 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, 
median, and range (minimum, maximum)) during the treatment period will be summarized. The 
duration of treatment with NA will be also summarized for the follow-up phase by intervention 
arm. 
Because of the different route and frequency of treatment administration across the 3 agents (for 
JNJ-3989 one subcutaneous injection once every 4 weeks, for PegIFN-α2a one subcutaneous 
injection weekly and for NA once daily tablet) the total duration for each study treatment as 
follows:

JNJ-3989: [Min ((Date of last JNJ-3989 injection in the given phase+27 days), Date of 
discontinuation from JNJ-3989, Date of trial disposition, cut-off date) – Date of first JNJ-3989 
injection in the given phase + 1] / 7  

PegIFN-α2a: [Min (Date of the last PegIFN-α2a injection+6 days, Date of discontinuation 
from PegIFN-α2a, Date of trial disposition, cut-off date) – Date of first PegIFN-α2a injection
+ 1] /7

NA: [Min (Date of the last NA administration in the given phase, Date of discontinuation from 
NA, Date of trial disposition, Date of clinical cut-off) – Date of first NA administration date 
in the given phase + 1] / 7
For NA treatment, the total duration of exposure will be calculated separately for treatment period 
and FU phases. For FU, the total duration will add up the weeks of NA treatment post-treatment 
period for those participants during the NA re-treatment weeks. Those participants who never 
restarted NA treatment after Week 24 will be counted as having zero weeks of NA exposure during 
the FU.
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 PegIFN-α2a or 
NA will be summarized separately for each study intervention by intervention arm during the 
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treatment period. Additionally, the number and percentage of participants who missed 2 or more 
JNJ-3989 injections, or who missed more than 5 doses of NA within a four-week period or who 
missed 2 or more PegIFN-α2a injections will be presented.
Study intervention compliance will be summarized descriptively. See Appendix 7 for further 
details.
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 21.1 or higher). 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 including NA

AEs by relationship to each study agent within a study intervention including NA

AEs leading to dose interruption/dose modification of each study agent within a study 
intervention.
In addition to the summary tables, listings will be provided for participants who:

Had SAEs

Had AEs leading to discontinuation of each study agent withing a study intervention including 
NA
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:

ALT/AST elevations

Injection Site Reactions Related to JNJ-3989 and/or PegIFN-α2a
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
Renal Complications

Hematologic Abnormalities (platelet count, hemoglobin, reticulocytes, neutrophil count)
The list of all preferred terms belonging to ALT/AST elevation, renal complications, and 
hematologic abnormalities is provided in Appendix 8. Injection site reactions will be identified 
using the eCRF Injection Site Reaction form.
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 7.
Table 7:
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
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)
Alanine aminotransferase (ALT)
Gamma-glutamyltransferase (GGT)
α1-acid glycoprotein
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
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 
amylase or lipase increase from 
screening onwards)
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Laboratory 
Assessments
Parameters
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 proteina
Beta-2-microglobulina
Note: Other biomarkers might be measured.
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 DAIDS Toxicity Grade Scale (see 
Clinical Protocol Appendix 9, DAIDS table)) 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.

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 
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(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. The incidence table of worst toxicity grade abnormality in laboratory parameters will 
be also presented stratified by the subgroups of interest identified in Section 5.7.7.2.
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. 
5.6.3.2.
Renal Safety
Renal safety parameters include the urine creatinine, serum creatinine, urine glucose total urine 
protein, 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).
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Descriptive statistics (n, mean, SD, 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. Descriptive statistics will also be calculated by subgroups 
(eGFRcr Grade ≥3 [at least once during the treatment period] vs Grade <3, confirmed eGFRcr
Grade ≥3, Type of NA at Baseline).
Plots of mean (+/- SE) values and changes from baseline over time for the renal safety parameters 
will be presented overall, and by subgroups (eGFRcr Grade ≥3 [at least once during the treatment 
period] vs Grade <3, confirmed eGFRcr Grade ≥3, Type of NA at Baseline).
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.
The analyses will be also performed using subgroups based on eGFRcys.
5.6.3.2.1.
eGFR
Stages of eGFR at baseline versus the minimum post-baseline eGFR value and the last available 
value will be summarized by count and percent of participants. 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. The following analyses will be done for both eGFRcr and eGFRcys
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)

Supine systolic blood pressure (mmHg)

Supine diastolic blood pressure (mmHg)
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
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 8).
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 8, 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 baseline 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 either in the clinical study report or 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 PegIFN-
α2a with 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.
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) will 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. Changes 
from baseline (or positivity threshold) in HBV-specific peripheral blood T-cell responses will be 
summarized and tabulated.
Graphs showing the individual subject 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 will 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 will 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 (IFNγ and/or TNFα and/or
IL-2), pie charts will 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 will be presented to reflect the mean magnitude of each combination.
5.7.4.
Viral Genome Sequence Analysis
The sequencing of samples from participants in this study may be triggered by the sponsor 
virologist based on changes in HBV DNA levels observed in each individual subject and the limits 
of the sequencing assay.
Viral genome sequence analysis will be performed to evaluate the presence of genetic variations 
(including substitutions) associated with JNJ-3989, and/or ETV or TDF/TAF treatment on both 
nucleotide and/or amino acid level.
Sequencing of the HBV genome will be performed to monitor HBV variants present at the time 
points indicated in Section 5.7.4.1. 
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
Wild type: If at certain position the amino acid/nucleotide in the subject sequence matches the 
reference sequence, that is no genetic variation is present at that position, the virus is 
considered to be wild type at that position.
5.7.4.3.
Parameters to Analyze
At specified time points and for each list specified in the section below, the following parameters 
will be analyzed:

Number (%) of subjects with a substitution at a specific position.

Number (%) of subjects with a specific substitution.

Number (%) of subjects with a specific substitution profile

Number (%) of subjects with substitutions on amino acid level (overall and by HBV genotype 
(A, B, C, D, E, F, G, H, I and Unknown))

at positions of interest in the RT-domain of the polymerase, 

at positions of interest in the major hydrophilic loop of HBsAg.

Number (%) of subjects with substitutions on nucleotide level 

at the binding site positions of JNJ-3989 (i.e. JNJ-3976 and JNJ-3924) (overall and by 
HBV genotype (A, B, C, D, E, F, G, H, I and Unknown)). 

in the precore (genome position 1896) and basal core promotor (genome positions 
1762/1764) region (overall, by HBV genotype (A, B, C, D, E, F, G, H, I and Unknown)) 
The focus will be on substitutions at a time point, and reversion to wild type state. The above 
summaries will be repeated for genetic variations (not needed for CSR). 
In the sequence analysis, sequences will be mapped to the respective genotype specific reference 
sequences after which nucleotide (nt) changes and amino acid (aa) substitutions will be annotated 
compared to the respective genotype specific reference (see Table in Section 5.7.4.2). In addition, 
the X02763 (HBV genotype A), which is the master reference sequence of the HBV database (db), 
will be used as universal reference sequence.
All NGS data will be collected using a nt and aa read frequency cut-off of ≥0.01. For the analysis 
of nt changes and/or aa substitutions in terms of frequency of variant, a read frequency cut-off of 
≥0.15 will be used. The persistence of nt changes and aa substitutions will be evaluated using a 
cut-off of ≥0.15 and ≥0.01. 
The applicability of the sequencing approach described here (e.g. the 0.01 sensitivity limit) will be 
assessed during the development program and might be adapted if needed.
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5.7.4.4.
Positions & Genetic Variations of Interest
On the nucleotide level:
In the basal core promotor region:

1762 and 1764 (ECo numbering will be used)
In the precore region:

1896 (ECo numbering will be used)
In the basel core/precure region

Combination of basal core promotor and/or precore region
In the JNJ-3989 binding pocket positions:

JNJ-3976  
Positions of Interest in the S gene: 261, 262, 263, 264, 265, 266, 267, 268, 269, 270, 271, 
272, 273, 274, 275, 276, 277, 278, 279, 280.

JNJ-3924
Positions of Interest in the X gene: 1781, 1782, 1783, 1784, 1785, 1786, 1787, 1788, 1789, 
1790, 1791, 1792, 1793, 1794, 1795, 1796, 1797, 1798, 1799, 1800.

In the JNJ-3976/JNJ-3924
Combination of JNJ-3989 binding site positions JNJ-3976 and/or JNJ-3924
Amino acid level:
In the pol/RT protein:

169, 173, 180, 181, 184, 194, 202, 204, 236, 250
See below breakdown of relative amino acid position of the 10 POI in the RT-domain of 
polymerase by HBV genotype. 
HBV GT-A
HBV-GT-B/C/F/H/I
HBV GT-D
HBV-GT-E/G
POL 
number
RT 
number
POL 
number
RT 
number
POL 
number
RT 
number
POL 
number
RT 
number
517
169
515
169
504
169
514
169
521
173
519
173
508
173
518
173
528
180
526
180
515
180
525
180
529
181
527
181
516
181
526
181
532
184
530
184
519
184
529
184
542
194
540
194
529
194
539
194
550
202
548
202
537
202
547
202
552
204
550
204
539
204
549
204
584
236
582
236
571
236
581
236
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HBV GT-A
HBV-GT-B/C/F/H/I
HBV GT-D
HBV-GT-E/G
598
250
596
250
585
250
595
250
In the major hydrophilic loop of the S-protein region (linked to vaccine escape):

Amino acids 99 to 169

Positions of interest: 116, 118, 120, 126, 129, 130, 131, 133, 134, 141, 142, 143, 144, 145, 
164, 195, and 196.
5.7.4.5.
Analysis Methods
Frequencies and percentages will be presented at the time points specified above for the specified 
parameters. The denominator is the number of subjects with sequencing data at the selected time 
point. 
A frequency output and/or figure will only be generated if number of participants with respective 
sequence information available (i.e. baseline sequence info for baseline outputs and paired 
baseline/post-baseline sequence info for post-baseline outputs) for that respective output or figure 
is greater or equal to 5 (N≥5).
For comparison of amino acid or nucleotide levels to universal or genotype specific HBV reference 
sequences descriptive summaries may be performed by subgroups.  
5.7.4.5.1.
Post-Baseline

Time of Virologic Breakthrough (if applicable)
For virologically suppressed participants who experience virologic breakthrough but who don't 
have baseline sequence information available, the frequency of genetic variations (with a primary 
focus on substitutions) at time of viral breakthrough will be tabulated in frequency outputs (n, %), 
based on NGS data (1% and 15% cut-off), for participants with viral sequence info available at 
time of viral breakthrough.
The return to wild type for subjects with virologic breakthrough and genetic variations at time of 
virologic breakthrough will be tabulated in frequency outputs based on NGS data, as well as the 
genetic variations in subjects who did not return to wild type.

Time of Virologic /Clinical Flare (if applicable)
For virologically suppressed participants who experience virologic/clinical flare but who don't 
have baseline sequence information available, the frequency of genetic variations (with a primary 
focus on substitutions) at time of virological/clinical flare will be tabulated in frequency outputs 
(n, %), based on NGS data (1% and 15% cut-off), for participants with viral sequence information 
available at time of flare.
The return to wild type for subjects with virologic/clinical flare and genetic variations at time of 
virologic/clinical flare will be tabulated in frequency outputs based on NGS data, as well as the 
genetic variations in subjects who did not return to wild type.
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
Time of Re-treatment during Post-treatment Follow-up  
For virologically suppressed participants who meet NA re-treatment criteria but who don't have 
baseline sequence information available, the frequency of genetic variations (with a primary focus 
on substitutions) at time of meeting NA re-treatment criteria will be tabulated in frequency outputs 
(n, %), based on NGS data (1% and 15% cut-off), for participants with viral sequencing 
information available at time of meeting NA retreatment criteria.
The return to wild type for subjects who meet re-treatment criteria during follow-up and genetic 
variations at time of meeting the re-treatment criteria will be tabulated in frequency outputs based 
on NGS data, as well as the genetic variations in subjects who did not return to wild type.

Other Post-Baseline
The frequency of variant of genetic variations at other time points will be tabulated in frequency 
outputs (n, %), based on NGS data (1% and 15% cut-off), and the genetic variations will be listed 
for all subjects. Time points of specific interest are end-of-treatment, time point of re-treatment, 
and end-of-study. 
5.7.4.5.2.
  Over the Study Period
For all subjects, listings with relevant baseline disease and demographic characteristics, session 
info, all genetic variations at baseline (if available), at time of virologic breakthrough (if 
applicable), at end of study treatment, and at end of study will be generated. 
For all subjects, listings with relevant baseline disease and demographic characteristics, session 
info, and aggregate post-baseline sequence data over the whole treatment period, and aggregate 
post-baseline sequence data over the whole study period will be generated.
5.7.5.
HBV genotype
For all subjects for whom viral sequencing is performed, also an HBV genotype will be reported 
using the HBV full genome sequence and phylogenetic analysis. The number and percentage of 
subjects by HBV genotype for study analysis will be tabulated. 
Exploratory HBV genotyping may be performed based on HBV RNA.
5.7.6.
Health Economics
Medical resource utilization will be descriptively summarized by treatment group and analysis 
phase.
5.7.7.
Definition of Subgroups
5.7.7.1.
Subgroups for Efficacy Analyses
Table 8:
Subgroups for efficacy analyses
Subgroup
Definition
Sex
Male, Female
Age
≤45 years, >45 years
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Subgroup
Definition
Race
Asian, Non-Asian
Geographical Region
Europe (Spain, UK, Poland, Russia), Asia (South Korea, Japan, 
Taiwan, Hong Kong, Thailand), North America (US, Canada)
Type of NA at Baseline
TeD, TAF, ETV
HBsAg level at baseline
<100 IU/mL; ≥100 IU/mL-<1,000 IU/mL; ≥1,000 IU/mL-<10,000 
IU/mL; ≥10,000 IU/mL
HBV RNA level at baseline
<1,000 copies/mL; ≥1,000 copies/mL
HBcrAg level at baseline
<3 log U/mL; ≥3 log U/mL-<4 log U/mL; ≥4 log U/mL
Anti-HBs level at baseline
<10 mIU/mL; ≥10 mIU/mL
Alanine Transferase (ALT) 
at baseline 
≤1.0 ULN; >1.0 ULN
HBV Genotype
Genotype A, B, C, D, E, F, G, H, I, J and Unknown
5.7.7.2.
Subgroups for Safety Analyses
Table 9:
Subgroups for safety analyses
Subgroup
Definition
Sex
Male, Female
Age
≤45 years, >45 years
Race
Asian, Non-Asian
BMI
Underweight: <18.5 kg/m2
Normal: ≥18.5-<25 kg/m2
Overweight: ≥25-<30 kg/m2
Obese: ≥30 kg/m2
Type of NA at Baseline
TeD, TAF, ETV
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 will be included in the IFLEP charter.
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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: approximately 50% of the randomized participants have completed Week 4 or 
discontinued earlier

Thereafter, data reviews will occur approximately every 8 weeks.
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.
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) will 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 IAs are planned when:

Approximately 50% of the randomized participants have completed Week 12 or discontinued 
earlier.

Approximately 50% of the randomized participants have completed Week 24 or discontinued 
earlier.

All randomized participants have completed Week 36 (FU Week 12) or discontinued earlier.

All randomized participants have completed Week 48 (FU Week 24) or discontinued earlier.

All randomized participants have completed Week 60 (FU Week 36) or discontinued earlier.
The primary analysis will be conducted at the time when all participants have completed 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.
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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 10. Details on the type of summaries and analyses of both efficacy 
and safety variables are described in the following sections.
Table 10: 
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=51)
DR 
approx. 
every 8 
weeks
IA1/ 
Week 
12 
(approx. 
N=51)
IA2/ 
Week 24 
(N=51)
Primary/ 
Week 24 
(approx. 
N=102)
IA3/ 
Week 
36 
(N=102)
IA4/ 
Week 
48
(N=102)
IA5/ 
Week 
60 
(N=102)
Final 
analysis/ 
Week 
72 
(N=102)
Subject 
information
Baseline & 
Demographic 
characteristics
X
X
X
X
X
X
X
X
X
Disposition 
and Study 
Populations
X
X
X
X
X
X
X
X
X
Extend of 
Exposure
X
X
X
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
X
X
X
Laboratory 
tests
X
X
X
X
X
X
X
X
X
ECG
X
X
X
X
X
X
X
X
X
Vital signs
X
X
X
X
X
X
X
X
X
Efficacy
Values and 
Changes over 
time in 
HBsAg, 
HBeAg, HBV 
DNA and ALT
X
X
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
X
X
Other 
secondary 
efficacy 
endpoints
X
X
X
X
X
X
X
Exploratory 
endpoints
X
X
X
X
X
X
X
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DR1/ 
Week 4 
(approx. 
N=51)
DR 
approx. 
every 8 
weeks
IA1/ 
Week 
12 
(approx. 
N=51)
IA2/ 
Week 24 
(N=51)
Primary/ 
Week 24 
(approx. 
N=102)
IA3/ 
Week 
36 
(N=102)
IA4/ 
Week 
48
(N=102)
IA5/ 
Week 
60 
(N=102)
Final 
analysis/ 
Week 
72 
(N=102)
Virologic 
breakthrough
X
X
X
X
X
X
X
X
X
Flares: Viral, 
Biochemical, 
Clinical
X
X
X
X
X
X
X
X
X
PK*
X
X
X
X
X
X
X
*If there are available data, it will be analyze.
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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
EOT
end of treatment
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
interferon
IFN-FAS
PegIFN-α2a full analysis set
IQR
interquartile range
IRT
item response theory
ISR
injection site reaction
IU/mL
international units per milliliter
IWRS
interactive website response system
LiPA
line probe assay
LLOQ
lower limit of quantification
LOCF
last observation carried forward
LSM
liver stiffness measurement
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MCS
mental component summary
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)
PegIFN-α2a
pegylated interferon alpha-2a 
PGIC
Patient Global Impression of Change
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
RGT
response-guided treatment
RR
Interval between R wave of one heartbeat and R wave of preceding heartbeat 
RTs
reference timepoints
SAE
serious adverse event
SAP
statistical analysis plan
SCr
serum creatinine
SD
standard deviation
SF-36v2
Short Form 36 version 2
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
urine protein to creatinine ratio
VAS
Visual Analog Scale
WBC
white blood cell
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6.2.
Appendix 2 Changes to Protocol-Planned Analyses
There are no changes to the protocol-planned analyses.
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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 above ULN 
without another cause than HBV 
infection
-documented transmission event
If none of the above are available, 
the following ways of 
documenting chronicity are 
acceptable at the time of 
screening: 
-liver biopsy with changes 
consistent with chronic HBV, or 
absence of marker for acute HBV 
infection such as positive 
immunoglobulin M (IgM) anti-
hepatitis B surface (HBs) and 
anti-HBc antibodies
- Participants should:

be HBeAg-negative, AND

be anti-HBe antibody-
positive, AND

be on stable HBV 
treatment, defined as 
currently receiving NA 
treatment for at least 2 
years prior to screening, 
and having been on the 
same NA treatment
regimen (at the same dose) 
as used in this study for at 
least 3 months at the time 
of screening, AND

have documented 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)
4
Participants must have a body mass index 
(BMI; weight in kg divided by the square
of height in meters) between 18 0 and 35 0 
kg/m2, extremes included
Inclusion criteria M04 not met 
Participants must have a body 
mass index (BMI; weight in kg 
divided by the square
of height in meters) between 18 0 
and 35 0 kg/m2, extremes 
included
Entered but did not satisfy 
criteria
Yes
No
5
Participants must sign a Master ICF (specific 
for the Master Protocol
PLATFORMPAHPB2001) and must sign the 
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
Inclusion criteria A05 (adapted 
from M05) not met
Participants must sign a Master 
ICF (specific for the Master 
Protocol
PLATFORMPAHPB2001) and 
must sign the 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
Entered but did not satisfy 
criteria
Yes
No
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6
Participants must sign a separate ICF if he or 
she agrees to provide additional optional DNA 
samples for research (where local regulations 
permit)  
Inclusion criteria M06 not met
Participants must sign a separate 
ICF if he or she agrees to provide 
additional optional DNA samples 
for research (where local 
regulations permit)  Refusal to
give consent for the optional 
DNA research samples does not 
exclude a participant from 
participation in the study
Entered but did not satisfy 
criteria
Yes
No
7
Female participants must be (as defined in 
Attachment 5 of the Master Protocol
PLATFORMPAHPB2001):
a  Not of childbearing potential, OR
b  Of childbearing potential and practicing a 
highly effective, preferably user-independent 
method of contraception (failure rate of <1% 
per year when used consistently and correctly) 
for at least 30 days prior to screening and 
agrees to remain on a highly effective method 
while receiving study intervention and
until 90 days after last dose of study 
intervention
Inclusion criteria A07
(adapted from M07) not met
Female participants must be (as 
defined in Attachment 5 of the 
Master Protocol
PLATFORMPAHPB2001):
a  Not of childbearing potential, 
OR
b  Of childbearing potential and 
practicing a highly effective, 
preferably user-independent 
method of contraception (failure 
rate of <1% per year when
used consistently and correctly) 
for at least 30 days prior to 
screening and agrees to remain on 
a highly effective method while 
receiving study intervention and
until 90 days after last dose of 
study intervention  Examples of 
highly effective methods of 
contraception are provided in 
Attachment 5 of the Master 
Protocol
PLATFORMPAHPB2001
Note: Typical use failure rates 
may differ from those when used 
consistently and correctly  Use 
should be consistent with local 
regulations regarding the use of
contraceptive methods for 
participants in clinical studies
Entered but did not satisfy 
criteria
Yes
No
8
Female participants of childbearing potential 
must have a negative highly sensitive serum 
pregnancy test (β-human chorionic 
gonadotropin) at screening and a negative 
urine pregnancy test on Day 1 before the first 
dose of study intervention
Inclusion criteria M08 not met
Female participants of 
childbearing potential must have 
a negative highly sensitive
serum pregnancy test (β-human 
chorionic gonadotropin) at 
screening and a negative urine 
pregnancy test on Day 1 before 
the first dose of study 
intervention
Entered but did not satisfy 
criteria
Yes
No
9
In the investigator’s opinion, the participant is 
able to understand and comply with protocol 
requirements, instructions, and study 
restrictions and is likely to complete the study 
as planned per ISA (including the procedures 
outlined in the Master
Protocol PLATFORMPAHPB2001)
Inclusion criteria M09 not met
In the investigator’s opinion, the 
participant is able to understand 
and comply with protocol 
requirements, instructions, and 
study restrictions and is likely to 
complete the study as planned per 
ISA (including the procedures 
outlined in the Master
Protocol 
PLATFORMPAHPB2001)
Entered but did not satisfy 
criteria
Yes
No
10
Male participants must agree to wear a 
condom when engaging in any activity that
allows for passage of ejaculate to another 
person during the study intervention period 
and until 90 days after last dose of study 
intervention
Inclusion criteria A10(adapted 
from M10) not met
Male participants must agree to 
wear a condom when engaging in 
any activity that allows for 
passage of ejaculate to another 
person during the study 
Entered but did not satisfy 
criteria
Yes
No
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intervention period and until 90 
days after last dose of study 
intervention
11
Female participants must agree not to donate 
eggs (ova, oocytes) for the purposes of 
assisted reproduction during the study 
intervention period and until 90 days after
last dose of study intervention
Inclusion criteria A11 not met
Female participants must agree 
not to donate eggs (ova, oocytes) 
for the purposes of assisted 
reproduction during the study 
intervention period and until 90 
days after last dose of study 
intervention
Entered but did not satisfy 
criteria
Yes
No
12
Male participants must agree not to donate 
sperm for the purpose of reproduction during 
the study intervention period and until 90 days 
after last dose of study intervention
Inclusion criteria A12 not met
Male participants must agree not 
to donate sperm for the purpose 
of reproduction during the study 
intervention period and until 90 
days after last dose of study
intervention
Entered but did not satisfy 
criteria
Yes
No
13
Participants must have serum HBsAg >100 
IU/mL at screening, as assessed by
quantitative HBsAg assay
Inclusion criteria A13 not met
Participants must have serum 
HBsAg >100 IU/mL at screening, 
as assessed by quantitative 
HBsAg assay
Entered but did not satisfy 
criteria
Yes
No
14
Participants must have:
a  Fibroscan liver stiffness measurement ≤9 0 
kPa within 6 months prior to screening or at 
the time of screening, OR
b  If a Fibroscan result is not available: a liver 
biopsy result classified as Metavir F0-F2 
within 1 year prior to screening
Inclusion criteria A14 not met
Participants must have:
a  Fibroscan liver stiffness 
measurement ≤9 0 kPa within 6 
months prior to screening or at 
the time of screening, OR
b  If a Fibroscan result is not 
available: a liver biopsy result 
classified as Metavir F0-F2 
within 1 year prior to screening
Note: Other radiologic liver 
staging modalities (e g acoustic 
radiation force impulse) might be 
used if standard practice at the 
site or if otherwise validated and
agreed with the Sponsor  Results 
should be equivalent to Metavir 
F0-F2
Note: Conventional imaging 
procedures (e g conventional 
liver ultrasound, computed 
tomography [CT] or magnetic 
resonance imaging [MRI]) and 
serum marker panels are not 
allowed to rule out severe fibrosis 
or cirrhosis
Entered but did not satisfy 
criteria
Yes
No
15
Participants with evidence of hepatitis A virus 
infection (hepatitis A antibody
IgM), HCV infection (HCV antibody), 
hepatitis D virus (HDV) infection (HDV
antibody), hepatitis E virus (HEV) infection 
(hepatitis E antibody IgM), or HIV-1
or HIV-2 infection (laboratory confirmed) at 
screening
Exclusion criterion A01 (adapted 
from M01) met: 
Subject has <history/condition> 
<enter details>
Participants with evidence of 
hepatitis A virus infection 
(hepatitis A antibody
IgM), HCV infection (HCV 
antibody), hepatitis D virus 
(HDV) infection (HDV
antibody), hepatitis E virus 
(HEV) infection (hepatitis E 
antibody IgM), or HIV-1
or HIV-2 infection (laboratory 
confirmed) at screening
Entered but did not satisfy 
criteria
Yes
No
NCT05005507


JNJ-73763989
Statistical Analysis Plan 73763989PAHPB2007
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
79
Status: Approved, Date: 06 January 2022

Participants with a positive 
HCV antibody test can be 
enrolled if they have
negative HCV RNA at 
screening and documented 
negative HCV RNA at 
least
6 months prior to 
screening

Participants with a positive 
HDV antibody test may be 
enrolled after discussion 
with the Sponsor if an 
active HDV co-infection 
can be ruled out by
documentation of negative 
HDV RNA

Participants with a positive 
IgM antibody test for HEV 
infection may be enrolled 
after discussion with the 
Sponsor if an active HEV 
infection can be ruled out 
by documentation of 
negative anti-HEV 
immunoglobulin G (IgG)

Participants with a positive 
HIV-1 or HIV-2 
antibody/antigen test at 
screening can be enrolled if 
they have a negative HIV 
RNA test at screening
16
Participants with evidence of hepatic 
decompensation at any time point prior to or
at the time of screening:
a  Total bilirubin >1 5x ULN, OR
Direct bilirubin >1 2x ULN , OR
c  Prothrombin time >1 3x ULN (unless 
caused by anticoagulation therapy or
vitamin K deficiency)
, OR
d  Serum albumin <3 2 g/dL 
Exclusion criterion A02 (adapted 
from M02) met: 
Participants with evidence of 
hepatic decompensation at any 
time point prior to or at the time 
of screening:
a  Total bilirubin >1 5x ULN, OR
Direct bilirubin >1 2x ULN , OR
b  Prothrombin time >1 3x ULN 
(unless caused by anticoagulation 
therapy or vitamin K deficiency), 
OR
c  Serum albumin <3 2 g/dL
Entered but did not satisfy 
criteria
Yes
No
17
History or evidence of clinical signs or 
symptoms of hepatic decompensation,
including but not limited to: 
-portal hypertension
-ascites
-hepatic encephalopathy
-esophageal varices
Exclusion criterion M03 met: 
History or evidence of clinical 
signs or symptoms of hepatic 
decompensation,
including but not limited to: 
-portal hypertension
-ascites
-hepatic encephalopathy
-esophageal varices
Entered but did not satisfy 
criteria
Yes
No
18
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
Exclusion criterion M04 met: 
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
Entered but did not satisfy 
criteria
Yes
No
NCT05005507


JNJ-73763989
Statistical Analysis Plan 73763989PAHPB2007
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
80
Status: Approved, Date: 06 January 2022
liver disease considered clinically 
significant by the investigator
19
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 hepatocellular 
carcinoma (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)
Exclusion criterion A05 (adapted 
from M05) met: 
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
hepatocellular carcinoma (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)
Entered but did not satisfy
criteria
Yes
No
20
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 Clinical 
Protocol Section 10 9, Appendix 9: DAIDS
Table):
a Estimated glomerular filtration rate (eGFR) 
≥Grade 3 (ie, <60 mL/min/1 73 m2) at 
screening, calculated by the Chronic Kidney
Disease Epidemiology Collaboration (CKD-
EPI) formula;
b  Pancreatic lipase elevation ≥Grade 3;
c  Pancreatic amylase elevation ≥Grade 3;
d  Hemoglobin ≤10 9 g/dL (males), ≤10 4 
g/dL (females);
e  Platelet count ≤lower limit of normal 
(LLN);
f  Alpha-fetoprotein (AFP) >100 ng/mL;
Note: Participants with AFP >ULN but ≤100 
ng/mL may be eligible if HCC
can be ruled out based on a sensitive imaging 
study (e g contrast-enhanced ultrasound, CT 
or MRI) during screening
g  Any other laboratory abnormality 
considered to be clinically significant by
the investigator (also see exclusion criterion 
A02)
Exclusion criterion A06 (adapted 
from M06) met: 
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 Clinical Protocol Section
10 9, Appendix 9: DAIDS 
Table):
a  Estimated glomerular filtration 
rate (eGFR) ≥Grade 3 (ie,
<60 mL/min/1 73 m2) at 
screening, calculated by the 
Chronic Kidney
Disease Epidemiology 
Collaboration (CKD-EPI) 
formula;
b  Pancreatic lipase elevation 
≥Grade 3;
c  Pancreatic amylase elevation 
≥Grade 3;
d  Hemoglobin ≤10 9 g/dL 
(males), ≤10 4 g/dL (females);
e  Platelet count ≤lower limit of 
normal (LLN);
f  Alpha-fetoprotein (AFP) >100 
ng/mL;
Note: Participants with AFP 
>ULN but ≤100 ng/mL may be 
eligible if HCC
can be ruled out based on a 
sensitive imaging study (e g
contrast-enhanced
ultrasound, CT or MRI) during 
screening
g  Any other laboratory 
abnormality considered to be 
clinically significant by
the investigator (also see 
exclusion criterion A02)
Entered but did not satisfy 
criteria
Yes
No
21
Participants with hemoglobin A1c >8% at 
screening
Exclusion criterion M07 met: 
Participants with hemoglobin 
A1c >8% at screening
Entered but did not satisfy 
criteria
Yes
No
22
Participants with a history of malignancy 
within 5 years before screening
(exceptions are squamous and basal cell 
carcinomas of the skin and carcinoma in
Exclusion criterion M08 met: 
Participants with a history of 
malignancy within 5 years before 
Entered but did not satisfy 
criteria
Yes
No
NCT05005507


JNJ-73763989
Statistical Analysis Plan 73763989PAHPB2007
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
81
Status: Approved, Date: 06 January 2022
situ of the cervix, or malignancy, which are 
considered cured with minimal risk of
recurrence)
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)
23
Participants with abnormal sinus rhythm 
(heart rate <45 or >100 beats per minute
[bpm]); QT interval corrected for heart rate 
according to Fridericia’s formula (QTcF) 
>450 ms for males and >470 ms for females; 
QRS interval ≥120 ms; PR interval >220 ms; 
abnormal conduction; or any other clinically 
significant abnormalities on a 12-lead ECG at 
screening
Note: Retesting of an abnormal ECG that may 
lead to exclusion will be allowed once without 
prior asking approval from the Sponsor  
Retesting will take place during an 
unscheduled visit in the screening phase  
Participants not meeting the above exclusion 
criterion at retest may be included
Exclusion criterion M09 met
Participants with abnormal sinus 
rhythm (heart rate <45 or >100 
beats per minute [bpm]); QT 
interval corrected for heart rate 
according to Fridericia’s formula 
(QTcF) >450 ms for males and 
>470 ms for females; QRS 
interval ≥120 ms; PR
interval >220 ms; abnormal 
conduction; or any other
clinically significant
abnormalities on a 12-lead ECG 
at screening
Note: Retesting of an abnormal 
ECG that may lead to exclusion 
will be allowed
once without prior asking 
approval from the Sponsor  
Retesting will take place
during an unscheduled visit in the 
screening phase  Participants not 
meeting the above exclusion 
criterion at retest may be 
included
Entered but did not satisfy 
criteria
Yes
No
24
Participants with a history of or current 
cardiac arrhythmias (e g extrasystole,
tachycardia at rest), history of risk factors for 
Torsade de Pointes syndrome (e g  
hypokalemia, family history of long QT 
Syndrome) or history or other clinical
evidence of significant or unstable cardiac 
disease (e g 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
Exclusion criterion M10 met
Entered but did not satisfy 
criteria
Yes
No
25
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 (e g 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 (e g chronic obstructive 
pulmonary disease), gastrointestinal (e g
significant diarrhea, gastric stasis, or 
constipation that in the investigator’s opinion 
could influence drug absorption or 
bioavailability), endocrine (e g thyroid 
disease), neurologic, hematologic, 
rheumatologic, psychiatric, neoplastic, or 
metabolic disturbances  Any condition 
possibly affecting drug absorption (e g
gastrectomy or other significant 
gastrointestinal tract surgery, such as 
gastroenterostomy, small bowel resection, or 
active enterostomy) will also lead to 
exclusion
Exclusion criterion M11 met
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 (e g 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 (e g chronic 
obstructive pulmonary disease),
gastrointestinal (e g significant 
diarrhea, gastric stasis, or 
constipation that in the
investigator’s opinion could 
influence drug absorption or 
bioavailability), endocrine (e g
thyroid disease), neurologic, 
hematologic, rheumatologic,
psychiatric, neoplastic, or 
metabolic disturbances  Any 
condition possibly affecting drug 
absorption (e g gastrectomy or 
other significant gastrointestinal 
tract surgery, such as 
gastroenterostomy, small bowel 
resection, or active enterostomy) 
will also lead to exclusion
Entered but did not satisfy 
criteria
Yes
No
NCT05005507


JNJ-73763989
Statistical Analysis Plan 73763989PAHPB2007
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
82
Status: Approved, Date: 06 January 2022
26
Participants who have received an organ 
transplant (except for skin, hair, or cornea
transplants)
Exclusion criterion M12 met
Participants who have received 
an organ transplant (except for 
skin, hair, or cornea transplants)
Entered but did not satisfy 
criteria
Yes
No
27
Participants with any history of or current 
clinically significant skin disease
requiring regular or periodic treatment
Exclusion criterion M13 met
Participants with any history of or 
current clinically significant skin 
disease requiring regular or 
periodic treatment
Entered but did not satisfy 
criteria
Yes
No
28
Participants with clinically relevant alcohol or 
drug abuse within 12 months of
screening
Exclusion criterion M14 met
Participants with clinically 
relevant alcohol or drug abuse 
within 12 months of screening
Entered but did not satisfy 
criteria
Yes
No
29
Participants with history of clinically relevant 
drug rash
Exclusion criterion M15 met
Participants with history of 
clinically relevant drug rash
Entered but did not satisfy 
criteria
Yes
No
30
Participants who have taken any disallowed 
therapies as noted in Clinical Protocol Section 
6 8, Concomitant Therapy, before screening or 
baseline  Participants who have taken
IFN within the last 3 years prior to screening  
Participants with lamivudine-
refractory chronic hepatitis B
Exclusion criterion A16 (adapted
from M16) met
Participants who have taken any 
disallowed therapies as noted in 
Clinical Protocol Section 6 8, 
Concomitant Therapy, before 
screening or baseline  
Participants who have taken
IFN within the last 3 years prior 
to screening  Participants with 
lamivudine-refractory chronic 
hepatitis B
Entered but did not satisfy 
criteria
Yes (only 
for IFN 
use in last 
3 years 
and 
lamivudine 
refractory)
No
31
Participants with known allergies, 
hypersensitivity, or intolerance to JNJ-3989 or
its excipients (refer to the IB [IB JNJ-3989 
2020]) and/or to NA and/or to PegIFN-α2a or 
their excipients (refer to the respective 
prescribing information)
Exclusion criterion A23 met
Participants with known allergies, 
hypersensitivity, or intolerance to 
JNJ-3989 or its excipients (refer 
to the IB [IB JNJ-3989 2020]) 
and/or to NA and/or to
PegIFN-α2a or their excipients 
(refer to the respective 
prescribing information)
Entered but did not satisfy 
criteria
Yes
No
32
Participants who meet any of the additional 
exclusion criteria for PegIFN-α2a as described 
in local prescribing information (e g refer to 
Pegasys SmPC or Pegasys USPI) per the 
investigator’s discretion  
Key exclusion criteria for PegIFN-α2a
include:
1  Participants with signs or symptoms 
compatible with autoimmune disorders
2  Participants with bone marrow suppression
3  Participants with hypoglycaemia, 
hyperglycaemia, and/or diabetes mellitus, who 
cannot be effectively controlled by 
medication
4  Participants with pre-existing
ophthalmologic disorders
5  Participants with one or more of the 
following laboratory abnormalities:
- Absolute neutrophil count <1,500 cells/mm3 
(<1,000 cells/mm³ for
black or African American participants)
- Serum creatinine >1 5x ULN
- Inadequately controlled thyroid function 
(thyroid stimulating hormone [TSH] and 
thyroxine [T4])
6  Participants with pre-existing severe 
psychiatric conditions or a history of severe 
psychiatric disorders, including severe 
depression, suicidal ideation
and attempted suicide
Exclusion criterion A24 met
Participants who meet any of the 
additional exclusion criteria for 
PegIFN-α2a as described in local 
prescribing information (e g refer 
to Pegasys SmPC or Pegasys
USPI) per the investigator’s 
discretion  
Entered but did not satisfy 
criteria
Yes
No
NCT05005507


JNJ-73763989
Statistical Analysis Plan 73763989PAHPB2007
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
83
Status: Approved, Date: 06 January 2022
Note: Contraindications to the use of PegIFN-
α2a need to be checked at screening
and again at Week 12 for participants in Arm 
2
33
Disallowed from 3 years prior to screening 
until end of follow-up: IFN, other than the 
PegIFN-α2a taken in the context of this study
Received protocol prohibited 
medication <specify medication 
and/or dose>
Received a disallowed 
concomitant treatment 
If 
classified 
as major 
protocol
deviation 
(reviewed 
case by
case), 
excluded 
from PP 
set
Yes
34
Disallowed from 1 year prior to baseline until 
end of follow-up: Any oligonucleotide-based 
treatment (e g siRNA, nucleic acid polymers, 
antisense oligonucleotides), other than the 
study intervention taken in the context of this 
study
Received protocol prohibited 
medication <specify medication 
and/or dose>
Received a disallowed 
concomitant treatment 
If 
classified 
as major 
protocol
deviation 
(reviewed 
case by
case), 
excluded 
from PP 
set
Yes
35
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
Received protocol prohibited 
medication <specify medication 
and/or dose>
Received a disallowed 
concomitant treatment 
If 
classified 
as major 
protocol
deviation 
(reviewed 
case by
case), 
excluded 
from PP 
set
Yes
36
Disallowed from 6 months prior to baseline 
until end of follow-up: Any systemically (e g
intravenously, intramuscularly, orally, 
subcutaneously) administered medication
that directly or indirectly interferes with 
immune responses (e g cyclosporine, 
interleukins, systemic corticosteroids 
exceeding 5 mg of prednisolone 
equivalent/day)
Received protocol prohibited 
medication <specify medication 
and/or dose>
Received a disallowed 
concomitant treatment 
If 
classified 
as major 
protocol
deviation 
(reviewed 
case by
case), 
excluded 
from PP 
set
Yes
37
Disallowed from screening until end of 
follow-up: Any anti-HBV drug (including 
vaccines) other than the study intervention 
taken in the context of this study
Notes:

NA standard of care treatment is 
allowed between screening and 
baseline

Prior hepatic treatment with herbal or 
nutritional products is allowed but 
should be stopped at screening
Received protocol prohibited 
medication <specify medication 
and/or dose>
Received a disallowed 
concomitant treatment 
If 
classified 
as major 
protocol
deviation 
(reviewed 
case by
case), 
excluded 
from PP 
set
Yes
38
Disallowed from screening until end of study 
intervention:
Products containing Hypericum perforatum 
(St  John’s wort)
-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
Received protocol prohibited 
medication <specify medication 
and/or dose>
Received a disallowed 
concomitant treatment 
If 
classified 
as major 
protocol
deviation 
(reviewed 
case by
case), 
excluded 
from PP 
set
Yes
39
Approved COVID-19 vaccines or COVID-19 
vaccines with conditional marketing 
Subjects received approved 
COVID -19 Vaccine or COVID-
Received a disallowed 
concomitant treatment 
If 
classified 
Yes
NCT05005507


JNJ-73763989
Statistical Analysis Plan 73763989PAHPB2007
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
84
Status: Approved, Date: 06 January 2022
authorization, emergency use authorization or 
special approval for emergency are allowed 
during the study and within 2 days prior to 
PegIFN-α2a administration during treatment 
phase 2
19 vaccine with conditional 
marketing authorization on the 
same day as PegIFN-α2a
administration
as major 
protocol
deviation 
(reviewed 
case by
case), 
excluded 
from PP 
set
40
Dose of study medication JNJ-3989, not 
administered within scheduled time window
Subject missed JNJ-3989 dose(s)
If an injection of JNJ-3989 was 
missed, the injection should be 
given as soon as possible but
within 3 weeks after the 
scheduled time  Otherwise, the 
injection should be skipped and 
the next injection should be given 
at the next scheduled time point 
per the initial injection
schedule
Received wrong treatment 
or incorrect dose
If 
classified 
as major 
protocol
deviation 
(reviewed 
case by
case), 
excluded 
from PP 
set
Yes
41
If a dose of NA is missed, the participant 
should follow the guidelines in the prescribing
information
Subject missed NA doses
Received wrong treatment 
or incorrect dose
If 
classified 
as major 
protocol
deviation 
(reviewed 
case by
case), 
excluded 
from PP 
set
Yes
42
Doses of study medication PegIFN-α2a was 
missed
Subject missed 2 or more 
PegIFN-α2a doses 
Received wrong treatment 
or incorrect dose 
If 
classified 
as major 
protocol
deviation 
(reviewed 
case by
case), 
excluded 
from PP 
set
Yes
43
Dose modifications of JNJ-3989 and NA 
(increase or decrease of dose level) are not 
permitted
Subject received modified dose 
of JNJ-3989 or NA
Received wrong treatment 
or incorrect dose
If 
classified 
as major 
protocol
deviation 
(reviewed 
case by
case), 
excluded 
from PP 
set
Yes
44
For PegIFN-α2a, dose adjustment guidelines 
are recommended for participants who 
develop laboratory abnormalities during 
PegIFN-α2a treatment, as recommended in the 
locally approved prescribing information for 
PegIFN-α2a
Subject developed laboratory 
abnormalities but did not receive 
any PegIFN-α2a dose adjustment
Recommended dose adjustments:
-ANC <750 cells/mm³ Reduce to 
135µg
-ANC <500 cells/mm³ 
Discontinue treatment until ANC 
values return to more than 1,000 
cells/mm³  Reinstitute at 90µg 
and monitor ANC
- Platelet <50,000 cells/mm³ 
Reduce to 90µg
- Platelet <25,000 cells/mm³ 
Discontinue treatment
Received wrong treatment 
or incorrect dose
If 
classified 
as major 
protocol
deviation 
(reviewed 
case by
case), 
excluded 
from PP 
set
Yes
45
Subject stopped NA treatment at week 24, 
although some relevant changes in participant 
baseline status with regards to ALT, HBV 
DNA levels and/or HBeAg status were 
observed at Week 20 or any other event that in 
the opinion of the investigator could prevent 
stopping NA, were observed
Subject stopped NA treatment at 
week 24, although some relevant
changes in participant baseline 
status with regards to ALT, HBV 
DNA levels and/or HBeAg status 
were observed at Week 20 or any 
other event that in the opinion of 
the investigator could prevent 
stopping NA, were observed
Received wrong treatment 
or incorrect dose
If 
classified 
as major 
protocol
deviation 
(reviewed 
case by
case), 
excluded 
Yes
NCT05005507


JNJ-73763989
Statistical Analysis Plan 73763989PAHPB2007
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
85
Status: Approved, Date: 06 January 2022
from PP 
set
46
Subject did not stop NA treatment at week 24, 
although no relevant changes in participant 
baseline status with regards to ALT, HBV 
DNA levels and/or HBeAg status or no other 
events that in the opinion of the investigator 
could prevent stopping NA treatment, were 
observed
Subject did not stop NA 
treatment at week 24, although no 
relevant changes in participant 
baseline status with regards to 
ALT, HBV DNA levels and/or 
HBeAg status or no other events  
that in the opinion of the 
investigator could prevent 
stopping NA treatment, were 
observed
Received wrong treatment 
or incorrect dose
If 
classified 
as major 
protocol
deviation 
(reviewed 
case by
case), 
excluded 
from PP 
set
Yes
During the 48-week FU period, subject 
showed signs of decreasing liver function 
based on laboratory findings (e g
International Normalized Ratio [INR], direct 
bilirubin) or clinical assessment (e g ascites, 
hepatic encephalopathy), but did not restart 
NA treatment
Subject has event of signs of
decreasing liver function based 
on laboratory or clinical findings, 
but did not start NA treatment
Received wrong
treatment or
incorrect dose
If 
classified 
as major 
protocol
deviation 
(reviewed 
case by
case), 
excluded 
from PP 
set
Yes
47
During the 48-week FU period, subject has
confirmed HBeAg seroreversion (HBeAg
positive after it was negative at NA 
completion), but subject did not restart NA 
treatment
Subject has confirmed HBeAg
seroreversion, but did not start 
NA treatment
Received wrong
treatment or
incorrect dose
If 
classified 
as major 
protocol
deviation 
(reviewed 
case by
case), 
excluded 
from PP 
set
Yes
48
During the 48-week FU period, subject has
confirmed post-treatment increases in HBV 
DNA >2,000 IU/mL and ALT >5x ULN, over 
a period of at least 4 weeks, but subject did 
not restart NA treatment
Subject has a confirmed post-
treatment increase in HBV DNA 
>2,000 IU/mL and ALT >5 x 
ULN over a period of at least 4 
weeks, but did not start NA
treatment
Received wrong
treatment or
incorrect dose
If 
classified 
as major 
protocol
deviation 
(reviewed 
case by
case), 
excluded 
from PP 
set
Yes
49
During the 48-week FU period, subject has
confirmed has a confirmed post-treatment
increase in HBV DNA >20,000 IU/mL over a
period of at least 4 weeks, but subject did not
restart NA treatment
Subject has a confirmed post-
treatment increase in HBV DNA 
>20,000 IU/mL over a period of 
at least 4 weeks, but did not start 
NA treatment
Received wrong
treatment or
incorrect dose
If 
classified 
as major 
protocol
deviation 
(reviewed 
case by
case), 
excluded 
from PP
set
Yes
50
Subject received incorrect injection treatment
JNJ-3989
Received wrong treatment of 
study drug JNJ-3989: incorrect 
dose or placebo when 
randomized to active (and vice
versa)
Received wrong
treatment or
incorrect dose
If 
classified 
as major 
protocol
deviation 
(reviewed 
case by
case), 
excluded 
from PP 
set
Yes
51
Subject withdrew consent but was not 
discontinued from the study treatment  
Subject withdrew consent to the 
trial but was not discontinued 
from the study treatment
Developed withdrawal 
criteria but not withdrawn 
Yes
No
52
The investigator believes that for safety or 
tolerability reasons (e g AE) it is in the best 
interest of the  participant to discontinue 
investigational intervention, but the patient 
was not discontinued from the study 
treatment  
Subject must discontinue the 
study treatment for safety reasons 
but subject continued study 
treatment  
Developed withdrawal 
criteria but not withdrawn 
Yes
No
53
The participant becomes pregnant but was not 
discontinued from the study treatment  
Subject is pregnant but subject 
continued study treatment  
Developed withdrawal 
criteria but not withdrawn 
Yes
No
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54
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, but subject 
did not discontinue treatment with JNJ-3989 
and the study
Subject 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, but 
continued treatment
Developed withdrawal 
criteria but not withdrawn
Yes
Yes
55
The participant has a confirmed ≥Grade 3 
eGFR abnormality and a drop from baseline of
>10 mL/min/1 73 m2 , considered at least 
possibly related to JNJ-3989 (or PegIFN-α2a, 
if applicable) that persists despite changing 
tenofovir disoproxil to ETV or TAF (if the 
patient was receiving tenofovir disoproxil) but 
was not discontinued from the study
Subjects has a confirmed ≥Grade 
3 eGFR abnormality and a drop 
from baseline of >10mL/min/1 73 
m2, considered at least possibly 
related to JNJ-3989 (or PegIFN-
α2a, if applicable) that persists 
despite changing tenofovir 
disoproxil to ETV or TAF (if the 
patient was receiving tenofovir 
disoproxil) but continued 
treatment
Developed withdrawal 
criteria but not withdrawn
Yes
Yes
56
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 but was not discontinued from the 
study
Subject 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 but continued treatment
Developed withdrawal 
criteria but not withdrawn
Yes
No
57
The participant requires ≥7 days of treatment 
with any of the disallowed medications listed 
in Clinical Protocol Section 6 8, Concomitant 
Therapy, and does not discontinue treatment 
with the disallowed medication
Subject received ≥7 days of
treatment with any of the 
disallowed medications listed in
Clinical Protocol Section 6 8, 
Concomitant Therapy, but 
continued treatment with the
disallowed medication
Developed withdrawal 
criteria but not withdrawn
Yes
No
58
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) but did not discontinue treatment
Subject 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) but 
continued treatment
Note: If virologic breakthrough 
occurs during PegIFN-α2a 
administration, this does not
automatically lead to stop of JNJ-
3989 and/or PegIFN-α2a, but 
should be assessed/discussed
with the Sponsor
In case of virologic breakthrough, 
a viral sequencing sample will be 
collected during an unscheduled 
visit within 7 days of the DNA 
increase
Developed withdrawal 
criteria but not withdrawn
Yes
Yes
59
The participant has ALT/AST elevations, as 
described in Clinical Protocol Section 8 3 6 2,
Intervention-emergent ALT/AST Elevations 
but did not discontinue treatment
Subject has ALT/AST elevations, 
as described in Clinical Protocol
Section 8 3 6 2, Intervention-
emergent ALT/AST Elevations 
but discontinued treatment
Note: The grades are based on the 
DAIDS Toxicity Grading Scale 
(see Clinical Protocol Section 
10 9, Appendix 9: DAIDS Table)
If the ALT and/or AST level is 
≥3x ULN and ≥3x nadir and is 
associated with any of the 
following laboratory results or 
clinical symptoms:
- INR ≥1 5, OR
- direct bilirubin >1 5x ULN, OR
- serum albumin <3 0 g/dL, OR
- ascites, hepatic encephalopathy, 
or liver-related symptoms (e g
severe fatigue, nausea, vomiting, 
right upper quadrant pain in the 
Developed withdrawal 
criteria but not withdrawn
Yes
Yes
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absence of an alternative medical 
explanation), OR
- other indication of reduced liver 
function
60
PegIFN-α2a was not discontinued but the 
subject developed one of the following:
- evidence of hepatic decompensation during 
treatment, or ALT increase
clinically significant or accompanied by direct 
bilirubin increase
-thyroid disorders or diabetes during treatment 
and cannot be controlled with medication
- new or worsening ophthalmologic disorders
- any deterioration of cardiovascular status
- acute hypersensitivity reaction (e g urticaria, 
angioedema, bronchoconstriction, 
anaphylaxis)
- serious infection (bacterial, viral, fungal) and 
sepsis
- persistent or unexplained pulmonary 
infiltrates or pulmonary function
impairment
- onset or worsening of psoriatic lesion
- moderate or severe depression (for mild 
depression, treatment discontinuation may be 
considered)
- develops colitis symptoms (such as but not 
limited to abdominal pain, bloody
diarrhea, and fever)
- symptoms or signs suggestive of pancreatitis
Subject did not discontinued 
PegIFN-α2a but developed one of 
the following:
- evidence of hepatic 
decompensation during treatment, 
or ALT increase clinically 
significant or accompanied by 
direct bilirubin increase
-thyroid disorders or diabetes 
during treatment and cannot be 
controlled with medication
- new or worsening 
ophthalmologic disorders
- any deterioration of 
cardiovascular status
- acute hypersensitivity reaction 
(e g urticaria, angioedema,
bronchoconstriction, 
anaphylaxis)
- serious infection (bacterial, 
viral, fungal) and sepsis
- persistent or unexplained 
pulmonary infiltrates or 
pulmonary function impairment
- onset or worsening of psoriatic 
lesion
- moderate or severe depression 
(for mild depression, treatment
discontinuation may be 
considered)
- develops colitis symptoms (such 
as but not limited to abdominal 
pain, bloody diarrhea, and fever)
- symptoms or signs suggestive of 
pancreatitis
Developed withdrawal 
criteria but not withdrawn
Yes
Yes
61
In case of confirmed Grade 3 or Grade 4
hematologic abnormalities, discontinuation of
investigational study treatment JNJ-3989
(and PegIFN-α2a if applicable) should be
considered  In case of discontinuation, NA
treatment should be continued (see the
description in Clinical Protocol Section 
8 3 6 3)
Subject has confirmed Grade 3 or
Grade 4 hematologic 
abnormalities, but
discontinuation of study 
treatment was
not considered
Developed
withdrawal
criteria but not
withdrawn
Yes
Yes
62
Study procedure not done at scheduled visits, 
such as:
Hematology 
Chemistry 
Blood coagulation
Urine chemistry
Urinalysis 
Pregnancy 
ECG 
Vital signs 
Physical Examination
Liver Staging
Ophthalmologic examination (including
fundoscopy)
Testing for hepatitis A, B, C, D, and E virus,
HIV-1 and -2b
Serum IgM anti-HBc antibody test
AFP test
Hemoglobin A1c test
TSH and T4
<enter study specific 
procedure(s)> <was/were> not 
done at <enter scheduled visit>
Other
If 
classified 
as major 
protocol
deviation 
(reviewed 
case by
case), 
excluded 
from PP 
set
No
63
Efficacy evaluation not done at scheduled 
visits, such as: 
HBV Virology
Qualitative and quantitative HBsAg and 
HBeAg
HBV DNA
anti-HBs
anti HBe antibodies
Fibroscan
Ultrasound
<enter study specific efficacy 
evaluation(s)> <was/were> not 
done at <enter scheduled visit>
Other
If 
classified 
as major 
protocol
deviation 
(reviewed 
case by
case), 
excluded 
from PP 
set
No
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64
Study Visits not performed, or Visit was not 
performed within the allowed window as per 
the protocol
<enter study visit> was not 
performed as per protocol 
schedule
Other
If 
classified 
as major 
protocol
deviation 
(reviewed 
case by
case), 
excluded 
from PP 
set
No
65
Usage of incorrect visit material (lab kits,  
etc )
Incorrect <enter incorrect visit 
material> was used
Other
If 
classified 
as major 
protocol
deviation 
(reviewed 
case by
case), 
excluded 
from PP 
set
No
66
Site reported protocol deviation not specified 
elsewhere 
<enter reported protocol 
deviation not specified 
elsewhere>
Other
If 
classified 
as major 
protocol
deviation 
(reviewed 
case by
case), 
excluded 
from PP 
set
No
67
Blood and urine samples were collected (e g  
PK Samples) erroneously when should have 
not been collected and have not been 
subsequently destroyed (sample collected in 
error should be destroyed)
<enter blood or urine sample> 
sample were collected in error 
however not destroyed
Other
If 
classified 
as major 
protocol
deviation 
(reviewed 
case by
case), 
excluded 
from PP 
set
No
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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/7) * 100%

For PegIFN-α2a: (Total number of injections received/ Total number of injections 
supposed to be received a) * 100%
a For participants in Arm 1, a total of 24 injections should be administered. For participants in 
Arm 2 and 3, a total of 12 injections 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 14:
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 v23.1)
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 v23.1)
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 v23.1)
Albuminuria
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Blood creatinine abnormal
Blood creatinine increased
Blood urea abnormal
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 v23.1)
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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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 v23.1)
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
Urinary casts present
Urine phosphorus abnormal
Hematologic 
abnormalities
(Modified)  Haematopoietic cytopenias
affecting more than one type of blood cell 
(SMQ), (MedDRA v23.1)
Aplastic anaemia
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Autoimmune aplastic anaemia
Bicytopenia
Bone marrow failure
Cytopenia
Febrile bone marrow aplasia
Full blood count decreased
Gelatinous transformation of the bone marrow
Immune-mediated pancytopenia
Pancytopenia
Panmyelopathy
Aspiration bone marrow abnormal
Biopsy bone marrow abnormal
Blood count abnormal
Blood disorder
Bone marrow disorder
Bone marrow infiltration
Bone marrow myelogram abnormal
Bone marrow necrosis
Bone marrow toxicity
Haematotoxicity
Myelodysplastic syndrome
Myelodysplastic syndrome transformation
Myelofibrosis
Myeloid metaplasia
Plasmablast count decreased
Scan bone marrow abnormal
(Modified) Haematopoietic erythropenia 
(SMQ), (MedDRA v23.1)
Aplasia pure red cell
Aplastic anaemia
Erythroblast count decreased
Erythroid maturation arrest
Erythropenia
Hypoplastic anaemia
Microcytic anaemia
Proerythroblast count decreased
Red blood cell count decreased
Reticulocyte count decreased
Reticulocytopenia
Anaemia
Erythroblast count abnormal
Erythropoiesis abnormal
Haematocrit abnormal
Haematocrit decreased
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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 v23.1)
Agranulocytosis
Band neutrophil count decreased
Band neutrophil percentage decreased
Basophil count decreased
Basophilopenia
B-lymphocyte count decreased
Cyclic neutropenia
Eosinopenia
Eosinophil count decreased
Febrile neutropenia
Granulocyte count decreased
Granulocytes maturation arrest
Granulocytopenia
Idiopathic neutropenia
Leukopenia
Lymphocyte count decreased
Lymphopenia
Metamyelocyte count decreased
Monoblast count decreased
Monocyte count decreased
Monocytopenia
Myeloblast count decreased
Myelocyte count decreased
Neutropenia
Neutropenic infection
Neutropenic sepsis
Neutrophil count decreased
Promyelocyte count decreased
Pure white cell aplasia
T-lymphocyte count decreased
White blood cell count decreased
Basophil count abnormal
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Basophil percentage decreased
B-lymphocyte abnormalities
B-lymphocyte count abnormal
Differential white blood cell count abnormal
Eosinophil count abnormal
Eosinophil percentage decreased
Full blood count abnormal
Granulocytes abnormal
Leukopenia neonatal
Lymphocyte count abnormal
Lymphocyte percentage abnormal
Lymphocyte percentage decreased
Monocyte count abnormal
Monocyte percentage decreased
Mononuclear cell count decreased
Myeloblast percentage decreased
Myelocyte percentage decreased
Myeloid maturation arrest
Neutrophil count abnormal
Neutrophil percentage decreased
Plasma cell disorder
Plasma cells absent
White blood cell analysis abnormal
White blood cell count abnormal
White blood cell disorder
(Modified) Haematopoietic
thrombocytopenia (SMQ), (MedDRA 
v23.1)
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
The following medications are of interest (not including disallowed medications)
1. Antimicrobial, if not already disallowed, e.g. augmentin, ciprofloxacin, nitrofurantoin,
penicillin, 
sulfonamides, 
sulfamethoxazole/trimethoprim, 
tetracycline, 
rifampin,
pyrazinamide, didanosine, efavirenz, flucloxacillin, minocycline, nevirapine, telithromycin
2. Anticonvulsants, if not already disallowed, e.g. valproic acid
3. Psychotropic medications, e.g.
bupropion, tricyclic antidepressants, chlorpromazine,
risperidone, selective serotonin reuptake inhibitors, trazodone
4. Lipid-lowering agents:

HMG-CoA reductase inhibitors (statins): e.g. atorvastatin, lovastatin, pitavastatin,
pravastatin, rosuvastatin, simvastatin

nicotinic acid (niacin)

inclisiran
5. Antihypertensives, e.g. labetolol, hydralazine, lisinopril, losartan, methyldopa
6. Antiarrhythmics, if not already disallowed, e.g. amiodarone, procainamide
7. Hormonal Medications, e.g. tamoxifen, testosterone, hormone replacement therapy
8. Medications used in Diabetes Mellitus, e.g. acarbose, pioglitazone, sulfonylureas
9. Antiplatelets, e.g. ticlopidine, aspirin
10. Corticosteroids: Low dose (<5 mg/day prednisone or equivalent) for ≥4 weeks, if not already 
disallowed
11. Analgesics: 
ergoloid 
mesylates, 
ergotamine 
tartrate, 
dihydroergotamine, 
and
methylergonovine
12. Acetaminophen or paracetamol >2 g per day
13. NSAIDS, e.g. iboprufen, diclofenac, nimesulide, sulindac
14. Calcium channel blockers, if not disallowed, e.g. amlodipine, bepridil, nicardipine, nifedipine, 
nisoldipine
15. Phosphodiesterase-5 inhibitors, e.g. sildenafil, vardenafil, tadalafil
16. Sedatives/anxiolytics, e.g. midazolam, triazolam
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17. Miscellaneous hepatotoxic medications

halothane

etretinate

HIV protease inhibitors

omeprazole

dantrolene (muscle relaxant)

disulfiram (substance abuse agent)

gold salts

propylthiouracil (antithyroid)
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 9, DAIDS Table) 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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Brooks ST, Whitely E, Egger M, Smith GD, Mulheran PA, Peters TJ. Subgroup analyses in 
randomized trials:risks of subgroup-specific analyses; power and sample size for the 
interaction test. J Clin Epidemiol. 2004;229- 236.
3.
Lui K.J., Kelly C. A Revisit on Tests for Homogeneity of the Risk Difference, Biometrics, 
2000; 56:309-315.
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Mantel N and Haenszel W. Statistical aspects of the analysis of data from retrospective 
studies of disease. J Natl Cancer Inst. 1959; 22:719-748.
5.
Newcombe RG. Two-sided confidence intervals for the single proportion: comparison of 
seven methods. Stat Med. 1998 Apr 30;17(8):857-72.
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