Conditions: Hepatitis B, Chronic
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 48
Healthy volunteers: no

Brief summary:
The purpose of this study is to evaluate the efficacy in terms of hepatitis B surface antigen (HBsAg) levels of the study intervention (that is, JNJ-73763989 + JNJ-56136379 + nucleos\[t\]ide analog \[NA\] and pegylated interferon alpha-2a \[PegIFN-alpha2a\]).

Detailed description:
This study is an intervention specific appendix to the Hepatitis B wings platform trial (PLATFORMPAHPB2001). The study title reflects the original study design and JNJ-56136379 (JNJ-6379) was initially part of the study intervention but has been removed as part of amendment 3 of the study.

Arms:
arm 1: Participants will receive combination treatment with JNJ-73763989+ nucleos(t)ide analog (NA) for 12 weeks during Treatment Period 1 and the participants who meet the eligibility criteria for PegIFN-alpha2a at Week 12 will receive combination treatment with JNJ-73763989 + NA plus PegIFN-α2a for 12 weeks during Treatment Period 2.

Interventions: intervention 1: JNJ-73763989 intervention 2: Tenofovir disoproxil intervention 3: Tenofovir alafenamide (TAF) intervention 4: Entecavir (ETV) monohydrate intervention 5: PegIFN-alpha2a
Intervention descriptions: intervention 1: JNJ-73763989 injection will be administered subcutaneously once every 4 weeks. intervention 2: Tenofovir disoproxil film-coated tablet will be administered orally once daily. intervention 3: TAF film-coated tablet will be administered orally once daily. intervention 4: ETV monohydrate film-coated tablet will be administered orally once daily. intervention 5: PegIFN-alpha2a injection will be administered subcutaneously once weekly.

Protocol document:
Prot_000.pdf: 
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
1
Status: Approved,  Date: 01 December 2021
Janssen Research & Development *
Clinical Protocol
Intervention-specific Appendix 4 to Clinical Protocol PLATFORMPAHPB2001
A Phase 2, Open-label, Single-arm, Multicenter Study to Assess Efficacy, Safety, 
Tolerability, and Pharmacokinetics of Treatment With JNJ-73763989, JNJ-56136379, 
Nucleos(t)ide Analogs, and Pegylated Interferon Alpha-2a in Virologically Suppressed 
Patients With Chronic Hepatitis B Virus Infection
The PENGUIN Study
Protocol 73763989PAHPB2006; Phase 2
Amendment 4
JNJ-73763989 and JNJ-56136379
*Janssen Research & Development is a global organization that operates through different legal entities in
various countries. Therefore, the legal entity acting as the sponsor for Janssen Research & Development
studies may vary, such as, but not limited to Janssen Biotech, Inc.; Janssen Products, LP; Janssen
Biologics, BV; Janssen-Cilag International NV; Janssen, Inc; Janssen Pharmaceutica NV; Janssen
Sciences Ireland UC; Janssen Biopharma Inc.; or Janssen Research & Development, LLC. The term
“sponsor” is used throughout the protocol to represent these various legal entities; the sponsor is
identified on the Contact Information page that accompanies the protocol.
EudraCT NUMBER: 2020-003956-34
Status:
Approved
Date:
01 December 2021
Prepared by:
Janssen Research & Development, a division of Janssen Pharmaceutica NV
EDMS number:
EDMS-RIM-144194, 8.0
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 and JNJ-56136379
Clinical Protocol 73763989PAHPB2006
Amendment 4
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
2
Status: Approved,  Date: 01 December 2021
PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE
DOCUMENT HISTORY
Document
Date
Amendment 4
This document
Amendment 3
04 October 2021
Amendment 2
07 May 2021
Amendment 1
10 March 2021
Original Protocol
02 October 2020
Amendment 4 (This document)
Overall Rationale for the Amendment: The primary reason for this amendment is to update the criteria 
for post-treatment monitoring and for nucleos(t)ide analog (NA) re-treatment for participants who 
discontinued NA treatment at follow-up Week 2.
With Amendment 3, changes were introduced to the criteria for post-treatment monitoring and NA 
re-treatment for patients who discontinued NA treatment. These changes were triggered by a case of 
hepatitis B reactivation with subacute hepatic failure (initially reported as severe clinical ALT flare) 
following NA treatment cessation as per protocol in the REEF-2 (73763989PAHPB2002) study which led 
to listing of the patient for high urgency liver transplantation. The patient received a donor liver at Week 14 
post-stopping NA and has since then shown an uneventful post-operative recovery.
To further protect the safety of study participants, the current amendment includes additional changes to 
the criteria for post-treatment monitoring and for NA re-treatment for participants who discontinued NA 
treatment. 
These changes are based on additional follow-up information from participants in the REEF-2 study who 
stopped all treatment including NA per protocol and is incorporating recommendations from Health 
Authorities and the independent data monitoring committee.
Description of Change
Brief Rationale 
Section Number and Name
Update of criteria for post-
treatment monitoring and for 
NA re-treatment.
In further off-treatment analysis 
of REEF-2 with all participants 
having reached at least 
12 weeks of follow-up post 
stopping NA, some participants 
show a pattern of fast increase 
of HBV DNA followed by 
significant elevations of ALT 
that improved after re-starting 
of NA treatment. Based on these 
observations it was decided to 
implement more conservative 
rules for post-treatment 
monitoring and re-treatment 
criteria for all participants who 
met NA treatment completion 
criteria and stopped NA 
treatment.
1.1 Synopsis
1.3 Schedule of Activities
2.3.3 Benefit-Risk Assessment for Study 
Participation
4.2 Scientific Rationale for Study Design
6.7.1 NA Re-treatment Criteria and Monitoring 
After Stopping of NA
10.12 Appendix 12: NA Re-treatment and 
Monitoring After Stopping of NA
Minor errors were corrected.
Correction
1.1 Synopsis
1.3 Schedule of Activities
2.1 Study Rationale
6.8 Continued Access to Study Intervention
After the End of the Study
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JNJ-73763989 and JNJ-56136379
Clinical Protocol 73763989PAHPB2006
Amendment 4
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
3
Status: Approved,  Date: 01 December 2021
TABLE OF CONTENTS
PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE ............................................................... 2
TABLE OF CONTENTS ............................................................................................................................... 3
LIST OF IN-TEXT TABLES AND FIGURES................................................................................................ 6
1.
PROTOCOL SUMMARY ..................................................................................................................... 7
1.1.
Synopsis........................................................................................................................................... 7
1.2.
Schema .......................................................................................................................................... 19
1.3.
Schedule of Activities..................................................................................................................... 21
2.
INTRODUCTION................................................................................................................................ 28
2.1.
Study Rationale.............................................................................................................................. 29
2.2.
Background .................................................................................................................................... 29
2.2.1.
Primary Pharmacology ............................................................................................................... 29
2.2.2.
Nonclinical Studies ..................................................................................................................... 31
2.2.2.1.
JNJ-3989 and JNJ-6379.......................................................................................................... 31
2.2.2.2.
Combination of JNJ-3989 or JNJ-6379 With Entecavir, Tenofovir Disoproxil, or 
Tenofovir Alafenamide............................................................................................................. 38
2.2.2.3.
Combination of JNJ-3989 or JNJ-6379 With PegIFN-α2a ...................................................... 39
2.2.2.3.1.
Combination of JNJ-6379 With PegIFN-α2a........................................................................ 39
2.2.2.3.2.
Combination of JNJ-3989 with PegIFN-α2a ........................................................................ 40
2.2.3.
Clinical Studies ........................................................................................................................... 41
2.2.3.1.
JNJ-3989 and JNJ-6379.......................................................................................................... 41
2.2.3.2.
Combination of JNJ-3989 and JNJ-6379 with Entecavir, Tenofovir Disoproxil, or 
Tenofovir Alafenamide............................................................................................................. 47
2.2.3.3.
Combination of JNJ-3989 and JNJ-6379 with PegIFN-α2a .................................................... 48
2.3.
Benefit-Risk Assessment ............................................................................................................... 49
2.3.1.
Benefits for Study Participation .................................................................................................. 50
2.3.1.1.
Known Benefits........................................................................................................................ 50
2.3.1.2.
Potential Benefits..................................................................................................................... 50
2.3.2.
Risks for Study Participation....................................................................................................... 50
2.3.2.1.
Known Risks............................................................................................................................ 50
2.3.2.2.
Potential Risks......................................................................................................................... 51
2.3.2.2.1.
Potential Risks for JNJ-3989................................................................................................ 51
2.3.2.2.2.
Potential Risks for JNJ-6379................................................................................................ 51
2.3.2.2.3.
Potential Risks for Entecavir, Tenofovir Disoproxil, Tenofovir Alafenamide, and 
PegIFN-α2a.......................................................................................................................... 53
2.3.3.
Benefit-Risk Assessment for Study Participation ....................................................................... 53
3.
OBJECTIVES AND ENDPOINTS ..................................................................................................... 55
4.
STUDY DESIGN ................................................................................................................................ 57
4.1.
Overall Design................................................................................................................................ 57
4.2.
Scientific Rationale for Study Design............................................................................................. 59
4.2.1.
Study-Specific Ethical Design Considerations ........................................................................... 62
4.3.
Justification for Dose and Treatment Duration .............................................................................. 62
4.3.1.
JNJ-3989 .................................................................................................................................... 62
4.3.2.
JNJ-6379 .................................................................................................................................... 63
4.4.
End of Study Definition................................................................................................................... 63
5.
STUDY POPULATION ...................................................................................................................... 64
5.1.
Inclusion Criteria ............................................................................................................................ 64
5.2.
Exclusion Criteria ........................................................................................................................... 67
5.3.
Lifestyle Considerations................................................................................................................. 72
5.4.
Screen Failures .............................................................................................................................. 72
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JNJ-73763989 and JNJ-56136379
Clinical Protocol 73763989PAHPB2006
Amendment 4
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
4
Status: Approved,  Date: 01 December 2021
6.
STUDY INTERVENTION AND CONCOMITANT THERAPY............................................................ 73
6.1.
Study Intervention(s) Administered................................................................................................ 73
6.2.
Preparation/Handling/Storage/Accountability ................................................................................ 76
6.3.
Measures to Minimize Bias: Randomization and Blinding............................................................. 77
6.4.
Study Intervention Compliance...................................................................................................... 78
6.5.
Concomitant Therapy..................................................................................................................... 78
6.6.
Study Intervention Completion at Week 24.................................................................................... 80
6.7.
Dose Modification........................................................................................................................... 80
6.7.1.
NA Re-treatment Criteria and Monitoring After Stopping of NA ................................................. 81
6.8.
Continued Access to Study Intervention After the End of the Study ............................................. 82
7.
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL ............................................................................................... 82
7.1.
Discontinuation of Study Intervention ............................................................................................ 82
7.2.
Participant Discontinuation/Withdrawal From the Study................................................................ 84
7.2.1.
Withdrawal From the Use of Research Samples ....................................................................... 84
7.3.
Lost to Follow-up............................................................................................................................ 85
8.
STUDY ASSESSMENTS AND PROCEDURES ............................................................................... 85
8.1.
Efficacy Assessments .................................................................................................................... 85
8.1.1.
Sequencing................................................................................................................................. 86
8.2.
Safety Assessments....................................................................................................................... 86
8.2.1.
Physical Examinations................................................................................................................ 87
8.2.2.
Vital Signs................................................................................................................................... 87
8.2.3.
Electrocardiograms..................................................................................................................... 87
8.2.4.
Clinical Safety Laboratory Assessments .................................................................................... 87
8.2.5.
Ophthalmic Examinations........................................................................................................... 87
8.3.
Adverse Events, Serious Adverse Events, and Other Safety Reporting ....................................... 87
8.3.1.
Time Period and Frequency for Collecting Adverse Event and Serious Adverse Event 
Information.................................................................................................................................. 87
8.3.2.
Method of Detecting Adverse Events and Serious Adverse Events .......................................... 87
8.3.3.
Follow-up of Adverse Events and Serious Adverse Events ....................................................... 88
8.3.4.
Regulatory Reporting Requirements for Serious Adverse Events ............................................. 88
8.3.5.
Pregnancy................................................................................................................................... 88
8.3.6.
Adverse Events of Special Interest............................................................................................. 88
8.3.6.1.
Rash ........................................................................................................................................ 88
8.3.6.2.
Injection Site Reactions ........................................................................................................... 89
8.3.6.3.
Acute Systemic Allergic Reactions.......................................................................................... 89
8.3.6.4.
Intervention-emergent ALT/AST Elevations ............................................................................ 90
8.3.6.5.
Renal Complications................................................................................................................ 91
8.3.6.6.
Hematologic Abnormalities...................................................................................................... 91
8.4.
Treatment of Overdose .................................................................................................................. 92
8.5.
Pharmacokinetics........................................................................................................................... 92
8.5.1.
Evaluations ................................................................................................................................. 92
8.5.2.
Analytical Procedures................................................................................................................. 93
8.5.3.
Pharmacokinetic Parameters and Evaluations........................................................................... 93
8.6.
Pharmacokinetic/Pharmacodynamic Evaluations.......................................................................... 93
8.7.
Immune Assessments.................................................................................................................... 93
8.8.
Host Genetics................................................................................................................................. 94
8.9.
Exploratory Host Biomarkers ......................................................................................................... 94
9.
STATISTICAL CONSIDERATIONS.................................................................................................. 95
9.1.
Statistical Hypotheses.................................................................................................................... 95
9.2.
Sample Size Determination ........................................................................................................... 95
9.3.
Populations for Analysis Sets ........................................................................................................ 96
9.4.
Statistical Analyses ........................................................................................................................ 96
9.4.1.
General Considerations.............................................................................................................. 96
9.4.2.
Efficacy Analyses........................................................................................................................ 96
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JNJ-73763989 and JNJ-56136379
Clinical Protocol 73763989PAHPB2006
Amendment 4
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
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Status: Approved,  Date: 01 December 2021
9.4.2.1.
Primary Efficacy Endpoint ....................................................................................................... 97
9.4.2.2.
Secondary Efficacy Endpoints................................................................................................. 97
9.4.2.3.
Resistance Analyses ............................................................................................................... 97
9.4.3.
Safety Analyses .......................................................................................................................... 97
9.4.4.
Other Analyses ........................................................................................................................... 97
9.5.
Interim Analyses............................................................................................................................. 99
9.6.
Data Review Committee ................................................................................................................ 99
9.7.
Independent Flare Expert Panel .................................................................................................. 100
10.
SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS .......................... 101
10.1.
Appendix 1: Abbreviations and Definitions of Terms................................................................... 101
10.2.
Appendix 2: Clinical Laboratory Tests ......................................................................................... 104
10.3.
Appendix 3: Regulatory, Ethical, and Study Oversight Considerations....................................... 106
10.3.1.
Regulatory and Ethical Considerations .................................................................................... 106
10.3.2.
Financial Disclosure.................................................................................................................. 106
10.3.3.
Informed Consent Process ....................................................................................................... 106
10.3.4.
Data Protection ......................................................................................................................... 106
10.3.5.
Long-Term Retention of Samples for Additional Future Research .......................................... 106
10.3.6.
Committees Structure............................................................................................................... 106
10.3.7.
Publication Policy/Dissemination of Clinical Study Data .......................................................... 106
10.3.8.
Data Quality Assurance............................................................................................................ 106
10.3.9.
Case Report Form Completion................................................................................................. 106
10.3.10.
Source Documents ................................................................................................................... 107
10.3.11.
Monitoring ................................................................................................................................. 107
10.3.12.
On-Site Audits........................................................................................................................... 107
10.3.13.
Record Retention...................................................................................................................... 107
10.3.14.
Study and Site Start and Closure ............................................................................................. 107
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............................................................................................................................... 108
10.4.1.
Adverse Event Definitions and Classifications ......................................................................... 108
10.4.2.
Attribution Definitions................................................................................................................ 108
10.4.3.
Severity Criteria ........................................................................................................................ 108
10.4.4.
Special Reporting Situations .................................................................................................... 108
10.4.5.
Procedures ............................................................................................................................... 108
10.4.6.
Product Quality Complaint Handling......................................................................................... 108
10.4.7.
Contacting Sponsor Regarding Safety, Including Product Quality........................................... 108
10.5.
Appendix 5: Contraceptive and Barrier Guidance ....................................................................... 109
10.6.
Appendix 6: Rash Management................................................................................................... 111
10.7.
Appendix 7: Intervention-emergent ALT/AST Elevations ............................................................ 114
10.8.
Appendix 8: Cardiovascular Safety – Abnormalities.................................................................... 115
10.9.
Appendix 9: DAIDS Table ............................................................................................................ 116
10.10.
Appendix 10: Study Conduct During a Natural Disaster.............................................................. 138
10.11.
Appendix 11: Protocol Amendment History ................................................................................. 143
10.12.
Appendix 12: NA Re-treatment and Monitoring After Stopping of NA ......................................... 150
11.
REFERENCES................................................................................................................................. 151
INVESTIGATOR AGREEMENT ............................................................................................................... 153
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JNJ-73763989 and JNJ-56136379
Clinical Protocol 73763989PAHPB2006
Amendment 4
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
6
Status: Approved,  Date: 01 December 2021
LIST OF IN-TEXT TABLES AND FIGURES
TABLES
Table 1:
Animal/Human Exposure Ratios at NOAEL for JNJ-3989........................................................ 33
Table 2:
Animal/Human Ratios at the NOAEL in Rat and Dog (Human Exposure at 250 mg 
JNJ-6379 Once Daily for 28 Days [Study 56136379HPB1001]) .............................................. 34
Table 3:
Disallowed Medication .............................................................................................................. 79
Table 4:
Sample Size Determination ...................................................................................................... 95
Table 5:
Management of Rash Events by Severity Grade ................................................................... 111
FIGURES
Figure 1:
Schematic Overview of the Study – Prior to Protocol Amendment 3 ....................................... 19
Figure 2:
Schematic Overview of the Study – As of Protocol Amendment 3........................................... 20
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JNJ-73763989 and JNJ-56136379
Clinical Protocol 73763989PAHPB2006
Amendment 4
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
7
Status: Approved,  Date: 01 December 2021
1.
PROTOCOL SUMMARY
1.1.
Synopsis
Clinical Protocol 73763989PAHPB2006: A Phase 2, Open-label, Single-arm, Multicenter Study to Assess 
Efficacy, Safety, Tolerability, and Pharmacokinetics of Treatment With JNJ-73763989, JNJ-56136379, 
Nucleos(t)ide Analogs, and Pegylated Interferon Alpha-2a in Virologically Suppressed Patients With 
Chronic Hepatitis B Virus Infection.
Protocol 73763989PAHPB2006 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 treatment with nucleos(t)ide analogs (NAs), the current 
standard of care (Wooddell 2017).
JNJ-56136379 (JNJ-6379) is an orally administered Class N capsid assembly modulator (CAM-N) 
interfering with the capsid assembly and disassembly during HBV replication. JNJ-6379 binds to hepatitis 
B core protein (HBc) and interferes with the viral capsid assembly process, thereby preventing the 
polymerase-bound pgRNA encapsidation. This results in the formation of HBV capsids with normal shape 
but which are devoid of HBV DNA or RNA (non-functional capsids; Class N), and ultimately in the 
inhibition of HBV replication. In addition, JNJ-6379 also acts at an early stage of the viral life cycle by 
inhibiting the de novo formation of cccDNA potentially by interfering with the capsid disassembly process.
JNJ-6379 was initially part of the study intervention for participants enrolled before Protocol Amendment 3 
was in effect, but has been removed as study intervention with the implementation of an urgent safety 
measure, as described in Protocol Amendment 3.
As of Protocol Amendment 3: The term “study intervention” throughout the protocol, refers to JNJ-3989, 
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 
levels of the study intervention (ie, JNJ-3989 
+ JNJ-6379d + NA and PegIFN-α2a).

Proportion of participants with a reduction of at 
least 2 log10 IU/mL in HBsAg levels from 
baseline to 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 (serious) 
adverse events ([S]AEs) and abnormalities in 
clinical laboratory tests (including hematology, 
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JNJ-73763989 and JNJ-56136379
Clinical Protocol 73763989PAHPB2006
Amendment 4
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
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Status: Approved,  Date: 01 December 2021
This open-label study will be conducted in 4 periods:

Screening Period (4 weeks [if necessary, can be extended to a maximum of 8 weeks decided on a 
case-by-case basis and in agreement with the sponsor]).

Treatment Period 1 (12 weeks) consisting of combination treatment with JNJ-3989 + NA.

Treatment Period 2 (12 weeks) adding PegIFN-α2a to the combination treatment regimen of Treatment 
Period 1.

Follow-up (FU) Period (48 weeks).
The total duration of individual participation will be up to 76 weeks (including 4 weeks of screening).
Enrolled participants will start Treatment Period 1 with the following combination treatment regimen for a 
duration of 12 weeks:
200 mg JNJ-3989 (subcutaneous injection every 4 weeks [Q4W]) +
NA (tablets QD): tenofovir disoproxil (245 mg), or tenofovir alafenamide (TAF; 25 mg), or entecavir 
(ETV; 0.5 mg).
At Week 12, participants who still meet the eligibility criteria for PegIFN-α2a (see Section 5.2, Exclusion 
Criteria) will start Treatment Period 2 for a duration of 12 weeks:
200 mg JNJ-3989 (subcutaneous injection Q4W) +
NA (tablets QD): tenofovir disoproxil (245 mg), or TAF (25 mg), or ETV (0.5 mg) +
180 µg PegIFN-α2a (subcutaneous injection once weekly).Participants no longer meeting the PegIFN-α2a 
eligibility criteria at Week 12 will continue with the Period 1 treatment until Week 24.
At Week 24, all participants will stop treatment with JNJ-3989 + PegIFN-α2a and start the FU Period. If 
the protocol-defined NA treatment completion criteria (HBsAg <10 IU/mL, and HBeAg-negative, and 
HBV DNA <LLOQ, and ALT <3x upper limit of normal [ULN]) have been met at Week 24, NA will be 
stopped at the next scheduled visit (ie, FU Week 2), otherwise NA treatment will continue during the 
complete FU Period. Participants who meet the protocol-defined NA treatment completion criteria will be 
monitored closely during the 48-week FU Period and should re-start NA treatment immediately if NA 
re-treatment criteria are met, as specified below.
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 at Week 24, 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.
All participants will have sparse PK sampling during the treatment periods. Participants who consent to 
participate in the intensive PK substudy (optional) will also undergo intensive PK sampling.
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 and Monitoring After Stopping of NA
Participants who meet the protocol-defined NA treatment completion criteria will be monitored closely 
during the FU Period.
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JNJ-73763989 and JNJ-56136379
Clinical Protocol 73763989PAHPB2006
Amendment 4
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Status: Approved,  Date: 01 December 2021
After stopping NA treatment, participants should be monitored as follows: 

Regular monitoring visits will be every 4 weeks during the follow-up phase in accordance with the 
Schedule of Activities.

A post-treatment HBV DNA value of >20,000 IU/mL should trigger re-testing of ALT/AST, HBV 
DNA, and total and direct bilirubin within a maximum of 7 days from receipt of the data and further 
repeats as necessary (ie, weekly until HBV DNA returns to <20,000 IU/mL).

A post-treatment HBV DNA value of >2,000 IU/mL (but <20,000 IU/mL) should trigger a re-test 
within 14 days from receipt of the data and further repeats as necessary (ie, every other week until HBV 
DNA returns to <2,000 IU/mL).

A post-treatment ALT value of >5x ULN should trigger re-testing of ALT, AST, ALP, total and direct 
bilirubin, International Normalized Ratio (INR), albumin, and HBV DNA on a weekly basis until ALT 
and AST levels have returned to <5x ULN.
After stopping NA treatment, participants should re-start NA treatment:

Immediately with signs of decreasing liver function based on laboratory findings (eg, INR, direct 
bilirubin) or clinical assessment (eg, ascites, hepatic encephalopathy).

Immediately with an HBV DNA value of >100,000 IU/mL (irrespective of confirmation and/or ALT 
increase).

With confirmed post-treatment HBeAg seroreversion (HBeAg positive after it was negative at NA 
completion).

With confirmed* post-treatment increases in HBV DNA >2,000 IU/mL and ALT >5x ULN.

With confirmed* post-treatment increases in HBV DNA >20,000 IU/mL.
* At least 4 weeks apart – frequency of visits as described above
Note: Additional re-testing and/or earlier restarting of NA treatment is at the investigator’s discretion, even 
if the above cut-offs are not yet met.
To avoid delays in decision making, sites are encouraged to run local re-testing in parallel with central re-
testing in the situations described above that require more frequent re-testing. Local test results are to be 
recorded in the CRF and/or source documents, including information on the HBV DNA assay used. In 
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.
NUMBER OF PARTICIPANTS
Approximately 50 virologically suppressed CHB-infected participants, 18-65 years (inclusive) of age, will 
be enrolled in this study. Approximately 40% HBeAg-positive participants will be enrolled.
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JNJ-73763989 and JNJ-56136379
Clinical Protocol 73763989PAHPB2006
Amendment 4
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
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Status: Approved,  Date: 01 December 2021
Description of Interventions
Intervention Name
JNJ-3989
JNJ-6379***
PegIFN-α2a
Tenofovir disoproxil 
Tenofovir 
alafenamide (TAF)*
Entecavir (ETV) 
monohydrate
Type
Drug
Drug
Drug
Drug
Drug
Drug
Dose Formulation
Solution for injection
Tablets
Solution for injection
Film-coated tablets
Film-coated tablets
Film-coated tablets
Unit Dose Strength(s)
200 mg/mL
25 and 100 mg
180 µg/0.5 mL
245 mg
25 mg
0.5 mg
Dosage Level(s)
200 mg once every 4 
weeks (Q4W)
250 mg once daily 
(QD)
180 µg once weekly 
(QW)
245 mg QD
25 mg QD
Lamivudine-
refractory patients: 
1 mg** QD (but 
should preferably be 
treated with 
tenofovir disoproxil
or TAF* instead)
Other indications:
1 mg** QD (must be 
agreed upon by the 
sponsor)
Route of Administration
Subcutaneous 
injection (in the 
abdomen)
Oral
Subcutaneous 
injection (in the thigh 
or abdomen)
Oral
Oral
Oral
Use
Investigational 
intervention
Investigational 
intervention
Investigational 
intervention
Background 
intervention
Background 
intervention
Background 
intervention
Investigational Medicinal 
Product (IMP)
Yes
Yes
Yes
Yes
Yes
Yes
Non-investigational 
Medicinal Product/ 
Auxiliary Medicinal 
Product (NIMP/AxMP)
No
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
Provided centrally by 
the sponsor
NCT04667104


JNJ-73763989 and JNJ-56136379
Clinical Protocol 73763989PAHPB2006
Amendment 4
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
13
Status: Approved,  Date: 01 December 2021
Intervention Name
JNJ-3989
JNJ-6379***
PegIFN-α2a
Tenofovir disoproxil 
Tenofovir 
alafenamide (TAF)*
Entecavir (ETV) 
monohydrate
Packaging and Labeling
Each unit will be 
labeled with unique 
medication ID 
number
Each unit will be 
labeled with unique 
medication ID 
number.
Commercial supplies 
will be sourced. 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
In child-resistant 
packaging
Labels will contain information to meet the applicable regulatory requirements.
Food/Fasting Instructions
Regardless of food 
intake
Regardless of food 
intake
Per the prescribing 
information
Per the prescribing 
information
Per the prescribing 
information
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.
** 2 tablets of 0.5 mg.
*** Participants enrolled before Protocol Amendment 3 was in effect, may have received JNJ-6379 as part of their study intervention. As of Protocol Amendment 3: 
Study intervention includes JNJ-3989, NA and PegIFN-α2a
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JNJ-73763989 and JNJ-56136379
Clinical Protocol 73763989PAHPB2006
Amendment 4
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
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Status: Approved,  Date: 01 December 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 an on-site Fibroscan device, Fibroscan assessments will be performed 
at different time points to determine changes in fibrosis levels.
Samples may be used by the sponsor for additional exploratory assessments analyzing the serologic and 
virologic characteristics of HBV infection and efficacy or safety of the study intervention.
Sequencing
Viral genome sequence analysis will be performed to evaluate mutations associated with the study 
intervention.
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, ophthalmic examinations will be performed and urine samples for urine chemistry and renal 
biomarkers will be collected.
Specific toxicity management plans are in place for follow-up of rash, injection site reactions (ISRs), acute 
systemic allergic reactions, ALT/aspartate aminotransferase (AST) elevations, renal complications, and 
hematologic abnormalities.
PHARMACOKINETIC EVALUATIONS
Plasma or serum samples, as applicable, will be used to evaluate the PK of the study intervention. Samples 
collected for PK may additionally be used to evaluate safety or efficacy aspects.
Venous blood samples will be collected for measurement of plasma or serum (as applicable) concentrations 
of JNJ-3989 (ie, JNJ-3976 and JNJ-3924) and, optionally, NA and/or 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. 
Bioanalysis of JNJ-6379 may also be done on samples collected from participants who received JNJ-6379 
prior to Protocol Amendment 3.
All participants will have sparse PK sampling during the treatment periods. Participants who consent to 
participate in the intensive PK substudy (optional) will also undergo intensive PK sampling at time points 
specified in the Schedule of Activities.
Concentration-time data for JNJ-3989 (ie, JNJ-3976 and JNJ-3924), and optionally JNJ-6379, NA and/or 
PegIFN-α2a will be analyzed via noncompartmental methods for all participants who underwent intensive 
PK sampling. The PK parameters will be maximum plasma concentration (Cmax), plasma concentration 
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JNJ-73763989 and JNJ-56136379
Clinical Protocol 73763989PAHPB2006
Amendment 4
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Status: Approved,  Date: 01 December 2021
24 hours after administration (C24h), and area under the plasma concentration-time curve from 
administration to 24 hours (AUC24h). Additional PK parameters may be calculated if applicable. To assess 
the effect of PegIFN-α2a on JNJ-6379 (as applicable) and JNJ-3989, the PK parameters of JNJ-6379 (as 
applicable), JNJ-3976, and JNJ-3924 coadministered with PegIFN-α2a at Week 20 (or 16) will be compared 
to those of JNJ-6379 (as applicable), JNJ-3976, and JNJ-3924 at Week 4 (or 8) as reference (time points as 
specified in the Schedule of Activities).
Data from this study may be combined with other studies via population PK modeling to enable the 
calculation of the above PK parameters also in participants who only underwent sparse PK sampling.
PHARMACOKINETIC/PHARMACODYNAMIC EVALUATIONS
Relationships of individual PK parameters for JNJ-3976, JNJ-3924, and optionally JNJ-6379, NA and/or 
PegIFN-α2a, with selected efficacy and/or safety endpoints may be evaluated, if applicable.
IMMUNE ASSESSMENTS
At selected sites, peripheral blood mononuclear cell (PBMC) samples for immune analyses will be collected 
during study intervention and follow-up and will be analyzed centrally for HBV-specific responses by 
enzyme-linked immunospot (ELISpot) and/or intracellular cytokine staining (ICS) after stimulation with 
HBV-specific antigens.
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, 
myeloid-derived suppressor cells [MDSCs], dendritic cells [DCs], and B-cells) related to HBV infection or 
study intervention (safety/efficacy).
Additional PBMC samples may be taken in case of ALT flares, upon discussion with the sponsor, which 
may require an unscheduled visit.
HOST GENETICS
A mandatory sample for human leukocyte antigen (HLA) haplotyping will be collected from all 
participants.
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 MDSCs. These samples will only be collected from 
participants who consent separately to this component of the study.
In addition, other samples may be used for exploratory genetic or epigenetic research in participants 
consenting separately to this part of the study. No genetic research will be performed on any sample in 
participants who have not provided the additional separate consent for host genetic research. These samples 
can only be used to investigate the potential association of genetic or epigenetic factors with efficacy, safety, 
or PK of the study intervention, or HBV infection, or may be used to develop tests/assays related to the 
study intervention or HBV infection.
EXPLORATORY HOST BIOMARKERS
The study includes collection of blood samples for exploratory analysis of host blood biomarkers at the 
host RNA, protein, and cell level.
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JNJ-73763989 and JNJ-56136379
Clinical Protocol 73763989PAHPB2006
Amendment 4
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Status: Approved,  Date: 01 December 2021
The analyses may include gene expression and cytokine analyses assessing markers such as 
interferon-stimulated genes (ISGs), alpha interferon (IFN-α), and interferon γ-induced protein 10 (IP-10).
Samples can only be used for research related to study intervention or HBV infection or may be used to 
develop tests/assays related to study intervention or HBV infection.
Blood samples will be taken at the time points indicated in the Schedule of Activities which can be used to 
explore immunogenicity of JNJ-3989 and optionally PegIFN-α2a. The emergence of antidrug antibodies to 
JNJ-3989 and optionally to PegIFN-α2a might be analyzed using assays such as an enzyme-linked 
immunosorbent assay or functional assays.
STATISTICAL METHODS
The primary efficacy analysis will be performed when all participants have completed Week 24 (EOSI) or 
discontinued earlier. The final analysis will be performed when all participants have completed the last 
study visit (FU Week 48) or discontinued earlier.
Sample Size Determination
No formal sample size calculation was performed, as this is a single-arm study for exploratory and proof 
of concept (PoC) purposes. However, with a sample size of 50 participants having data for the primary 
efficacy endpoint at Week 24, if at least 25 (50%) participants are responders, it can be concluded with 90% 
confidence that the true response rate is at least 0.38, with a confidence interval (CI) width of 0.248
(90% CI: 0.376-0.624). With a sample size of 20 participants (for one of the interim analyses [IAs]) the 
precision of the estimate of the primary efficacy endpoint decreases, as the two-sided 90% CI width 
increases. For the same assumed proportion of responders of 50% (10 out of 20 participants), the 90% CI 
width becomes 0.396. The table below shows the 90% CI and the corresponding width for proportion of 
responders of 0.30, 0.50, 0.70, and 0.90.
N=20
N=50
Proportion of 
responders
90% CI*
Width of CI
90% CI*
Width of CI
0.30
0.140-0.508
0.368
0.195-0.424
0.229
0.50
0.302-0.698
0.396
0.376-0.624
0.248
0.70
0.492-0.860
0.368
0.576-0.805
0.229
0.90
0.717-0.982
0.265
0.801-0.960
0.159
CI: confidence interval.
* Clopper-Pearson exact method is used.
Efficacy Analyses
To evaluate the efficacy, the primary analysis set will be the intent-to-treat (ITT) population (ie, all 
participants who were enrolled and who received at least 1 dose of study intervention within this ISA).
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.
Primary Efficacy Endpoint
The primary endpoint is the proportion of participants with a reduction in HBsAg levels of at least 
2 log10 IU/mL from baseline to Week 24. Participants who do not have HBsAg data in the analysis window 
of Week 24 will be defined as non‑responders.
The primary efficacy endpoint will be summarized with the point estimate paired with its 90% CI using the 
Clopper-Pearson exact method. The same method will apply in a secondary analysis of the primary endpoint 
to the IFN-ITT analysis set comprising the ITT participants who have received at least 1 dose of 
PegIFN-α2a.
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JNJ-73763989 and JNJ-56136379
Clinical Protocol 73763989PAHPB2006
Amendment 4
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Status: Approved,  Date: 01 December 2021
Secondary Efficacy Endpoints
Descriptive statistics and 90% CIs will be used to summarize all efficacy endpoints. 
Specific key selected endpoints may be analyzed using suitable categorical data approaches (eg, 
Clopper-Pearson interval 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.
Resistance Analyses
The results of HBV viral sequencing will be evaluated by the sponsor virologist. Relevant changes of amino 
acid and/or nucleic acid variations (eg, substitutions) in the HBV genome will be tabulated and described.
Additional exploratory characterization of the HBV viral sequence and phenotype may be performed and 
reported separately.
Safety Analyses
Safety analyses are specified in Section 9.4.3 of the Master protocol PLATFORMPAHPB2001. 
Safety will be evaluated by means of descriptive summaries of (S)AEs including AEs of special interest to 
any of the study interventions, clinical laboratory tests, ECGs, vital signs, and physical examinations. The 
safety analysis will be done by study period. Results will be presented in tabular format and/or graphically 
over time, as appropriate.
Other Analyses
Pharmacokinetic Analyses
Descriptive statistics (n, mean, standard deviation [SD], coefficient of variation [CV], geometric mean, 
median, minimum, and maximum) will be calculated for the plasma concentrations of JNJ-3989 (JNJ-3976, 
and JNJ-3924) and, optionally, of NA, PegIFN-α2a and/or JNJ-6379, and for the derived plasma PK 
parameters for noncompartmental PK analyses.
For each participant with intensive PK sampling, plasma concentration-time data of JNJ-3976 and JNJ-
3924, and, optionally, of NA, PegIFN-α2a and/or JNJ-6379, will be graphically presented. Similarly, graphs 
of the mean plasma concentration-time profiles and overlay graphs with combined individual plasma 
concentration-time profiles will be produced. Plasma PK parameters in participants undergoing intensive 
PK sampling will be calculated via noncompartmental methods for JNJ-3976 and JNJ-3924, and, 
optionally, NA, PegIFN-α2a and/or JNJ-6379. The PK parameters will be Cmax, C24h, and AUC24h; other PK 
parameters may also be calculated. The PK parameters will be subjected to an exploratory graphical 
analysis, including various transformations, to get a general overview.
To assess the effect of PegIFN-α2a on JNJ-3989, the PK parameters of JNJ-3989 coadministered with 
PegIFN-α2a at Week 20 (or 16) will be compared to those of JNJ-3989 at Week 4 (or 8) as reference. The 
primary PK parameters are Cmax and AUC24h on the logarithmic scale. A mixed effects model will be fitted 
to log-transformed PK parameters with treatment period as a fixed effect and participant as a random effect.
Special attention will be paid to the plasma concentrations and PK parameters of those participants who 
discontinued the study for an AE, or who experienced an AE ≥grade 3, or an SAE.
Population PK analysis of plasma concentration-time data of JNJ-3976 and JNJ-3924 may be performed 
using non-linear mixed effects modeling. Data may be combined with those from Phase 1 and/or 2 studies 
to support a relevant structural model. Available baseline characteristics (eg, 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.
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JNJ-73763989 and JNJ-56136379
Clinical Protocol 73763989PAHPB2006
Amendment 4
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
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Status: Approved,  Date: 01 December 2021
Pharmacokinetic/Pharmacodynamic Analyses 
Relationships of PK parameters for JNJ-3976 and JNJ-3924, and, optionally, of NA, PegIFN-α2a and/or 
JNJ-6379 with selected efficacy and/or safety endpoints may be evaluated and graphically displayed. 
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 conducted, the results will 
be presented in a separate report.
Immune Analyses
Descriptive statistics (n, mean, SD, CV, geometric mean, median, minimum, and maximum) will be used 
to describe the magnitude of the gamma interferon (IFN-γ) T-cell response or the CD4+ and CD8+ T-cell 
responses (expressing at least 1 cytokine such as interleukin [IL]-2, tumor necrosis factor [TNF]-α or IFN-γ 
specific to any HBV antigen) as defined by ELISpot and/or ICS, respectively. Changes from baseline (if
present) will also be tabulated for PBMCs during study intervention and follow-up. The proportion (%) of 
CHB patients with positive responses based on the magnitude of the IFN-γ T-cell response or the CD4+ or 
CD8+ T-cells expressing at least 1 of the cytokines amongst IL-2, TNF-α or IFN-γ for 1 of the HBV 
antigens as defined by ELISpot and/or ICS, respectively, will be determined. Other immune cells, such as 
NK-cells, MDSCs, DCs, and B-cells, may be evaluated/explored.
Pharmacogenomic Analyses
The statistical approach for analyzing the exploratory host DNA research, 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.
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 internal decisions about additional studies and/or investigation 
of other treatment combinations. The IAs are planned when:

Approximately 20 participants have completed Week 24 (EOSI) or discontinued earlier.

All participants have completed Week 36 (FU Week 12) or discontinued earlier.

All participants have completed Week 48 (FU Week 24) or discontinued earlier.
An optional IA may be conducted when all participants have completed Week 60 (FU Week 36) or 
discontinued earlier.
The study is open-label, and the sponsor will conduct the pre-planned IAs. Hence, the study team and the 
DRC will have access to the IA results, while the investigators and participants will not.
Both primary and interim analyses will be based on all data available at the pre-defined cut-off time points, 
and may include data at later time points for those participants who have reached subsequent visits.
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JNJ-73763989 and JNJ-56136379
Clinical Protocol 73763989PAHPB2006
Amendment 4
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Status: Approved,  Date: 01 December 2021
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.
1.2.
Schema
Figure 1:
Schematic Overview of the Study – Prior to Protocol Amendment 3
ALT: alanine aminotransferase ; DNA: deoxyribonucleic acid; EOS: end of study; EOSI: end of study intervention; 
FU: follow-up; HBeAg: hepatitis B e antigen; HBsAg: hepatitis B surface antigen; HBV: hepatitis B virus; 
JNJ-3989: JNJ-73763989; JNJ-6379: JNJ-56136379; LLOQ: lower limit of quantification; n: number of 
participants; NA: nucleos(t)ide analog; PegIFN-α2a: pegylated interferon alpha-2a; ULN: upper limit of normal; 
Q4W: every 4 weeks; QD: once daily; QW: once weekly.
a If NA treatment completion criteria (HBsAg <10 IU/mL, and HBeAg-negative, and HBV DNA <LLOQ, and ALT 
<3x ULN) have been met at Week 24, NA will be stopped at the next scheduled visit (ie, FU Week 2), otherwise 
NA treatment will continue during the complete FU period.
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JNJ-73763989 and JNJ-56136379
Clinical Protocol 73763989PAHPB2006
Amendment 4
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
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Status: Approved,  Date: 01 December 2021
Figure 2:
Schematic Overview of the Study – As of Protocol Amendment 3
ALT: alanine aminotransferase ; DNA: deoxyribonucleic acid; EOS: end of study; EOSI: end of study intervention; 
FU: follow-up; HBeAg: hepatitis B e antigen; HBsAg: hepatitis B surface antigen; HBV: hepatitis B virus; 
JNJ-3989: JNJ-73763989; LLOQ: lower limit of quantification; n: number of participants; NA: nucleos(t)ide analog; 
PegIFN-α2a: pegylated interferon alpha-2a; ULN: upper limit of normal; Q4W: every 4 weeks; QD: once daily; 
QW: once weekly.
a If NA treatment completion criteria (HBsAg <10 IU/mL, and HBeAg-negative, and HBV DNA <LLOQ, and ALT 
<3x ULN) have been met at Week 24, NA will be stopped at the next scheduled visit (ie, FU Week 2), otherwise 
NA treatment will continue during the complete FU period.
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JNJ-73763989 and JNJ-56136379
Clinical Protocol 73763989PAHPB2006
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Status: Approved,  Date: 01 December 2021
2.
INTRODUCTION
This intervention-specific appendix (ISA) describes a Phase 2a study of JNJ-73763989 (JNJ-3989) 
in combination with a nucleos(t)ide analog (NA) and pegylated interferon alpha-2a (PegIFN-α2a). 
Prior to Protocol Amendment 3, the study intervention also included JNJ-56136379 (JNJ-6379). 
It is a companion document to the Master Protocol PLATFORMPAHPB2001, which describes the 
sponsor’s Platform study in participants with chronic hepatitis B (CHB). This ISA describes 
specific and/or additional protocol elements applicable to this intervention cohort, in which 
participants will be treated with the study intervention, JNJ-3989 in combination with an NA and
PegIFN-α2a (see Section 2.2, Background).
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 treatment with NAs, the current standard of care (Wooddell 2017).
JNJ-6379 is an orally administered Class N capsid assembly modulator (CAM-N) interfering with 
the capsid assembly and disassembly during HBV replication. JNJ-6379 binds to hepatitis B core 
protein (HBc) and interferes with the viral capsid assembly process, thereby preventing the 
polymerase-bound pgRNA encapsidation. This results in the formation of HBV capsids with 
normal shape but which are devoid of HBV DNA or RNA (non-functional capsids; Class N), and 
ultimately in the inhibition of HBV replication. In addition, JNJ-6379 also acts at an early stage of 
the viral life cycle by inhibiting the de novo formation of cccDNA potentially by interfering with 
the capsid disassembly process. JNJ-6379 was initially part of the study intervention, but has been 
removed as study intervention with the implementation of an urgent safety measure, as described 
in Protocol Amendment 3.
Select NAs and PegIFN-α2a are approved treatments of chronic HBV infection. 
For the most comprehensive nonclinical and clinical information regarding JNJ-3989 and 
JNJ-6379, refer to the latest version of the Investigator’s Brochures (IBs) (IB JNJ-3989 2020; IB 
JNJ-6379 2021). 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.
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JNJ-73763989 and JNJ-56136379
Clinical Protocol 73763989PAHPB2006
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Status: Approved,  Date: 01 December 2021
As of Protocol Amendment 3, 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.
The term “participant” throughout the protocol refers to the common term “subject”.
2.1.
Study Rationale
At the time of protocol writing, combination treatment with JNJ-3989, JNJ-6379, and NA was 
believed to have 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. 
This study is designed to assess efficacy and safety of a treatment regimen of JNJ-3989 and NA 
for 24 weeks with the addition of PegIFN-α2a during the last 12 weeks. Prior to Protocol 
Amendment 3, the study intervention also included JNJ-56136379 (JNJ-6379).The combination 
of the treatment regimen of JNJ-3989 + NA with PegIFN-α2a is based on 2 different properties of 
alpha interferon (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). In addition, IFN-α is expected to act as immune 
booster with potential to reactivate natural killer (NK)-cells (Gill 2016).
Virologically suppressed CHB-infected patients will be enrolled with the target to include both 
HBeAg-positive and negative patients.
The primary objective of the study will be to assess the effect on HBsAg levels at EOSI. In 
addition, off-treatment efficacy will be explored to evaluate if a treatment duration of 24 weeks, 
including 12 weeks of combined treatment with PegIFN-α2a, can induce functional cure in patients 
with CHB.
2.2.
Background
JNJ-6379 was initially part of the study intervention, but has been removed as study intervention 
with the implementation of an urgent safety measure, as described in Protocol Amendment 3. For 
completeness, background information on JNJ-6379 is still included in this section.
2.2.1.
Primary Pharmacology
JNJ-3989
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 
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JNJ-73763989 and JNJ-56136379
Clinical Protocol 73763989PAHPB2006
Amendment 4
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
30
Status: Approved,  Date: 01 December 2021
fact that all HBV transcripts expressed from cccDNA, including the RNA transcript (pgRNA) that 
is used as a template for replication of HBV DNA, are terminated by the same polyadenylation 
site and share a common sequence region upstream of this site. One RNAi trigger (JNJ-3924) in 
JNJ-3989 has its target within this common sequence region and thus has the potential to knock 
down expression of all viral proteins as well as the pgRNA expressed from cccDNA. The second 
RNAi trigger (JNJ-3976), which targets the HBsAg-encoding region, was designed to knock down 
expression of HBsAg derived from integrated HBV DNA as well as all viral proteins derived from 
cccDNA with the exception of HBV x protein. Silencing viral RNA will reduce HBV DNA and 
viral proteins, including HBsAg.
In mice transiently harboring the human HBV genome, treatment with JNJ-3989 led to 
dose-dependent reductions of serum HBsAg, HBeAg, and HBV DNA. Multiple doses of JNJ-3989 
resulted in additional and prolonged antigen and HBV DNA reductions in a stepwise fashion when 
compared to a single dose. This was consistent with prolonged liver persistence of antisense 
strands, which, when loaded into the RNA-induced silencing complex (RISC), exert the 
pharmacologic RNAi activity. The ability of JNJ-3989 to reduce serum HBV DNA was additive 
to synergistic with entecavir (ETV). ETV alone had no effect on serum HBsAg levels, and no 
negative effect on the ability of JNJ-3989 to reduce serum HBsAg was observed when given in 
combination.
JNJ-6379
JNJ-6379 is an HBV capsid assembly modulator (CAM) with dual mode of action; (1) interfering 
with capsid assembly, preventing encapsidation of pgRNA and blocking HBV replication, 
(2) inhibition of the de novo formation of cccDNA. JNJ-6379 binds to the core protein dimer and 
disrupts the normal viral capsid assembly process, thereby preventing the Pol-pgRNA 
encapsidation. This results in the formation of HBV capsids, devoid of HBV DNA (non-functional 
capsids), and ultimately in the inhibition of HBV replication in vitro. In addition, JNJ-6379 also 
acts at an early stage of the viral life cycle by inhibiting the de novo formation of cccDNA 
potentially by interfering with the capsid disassembly process. 
In a stable HBV-replicating HepG2.117 cell line, JNJ-6379 displayed median 50% and 90% 
effective concentration (EC50 and EC90) values of 54 nM (22.6 ng/mL) and 226 nM (94.6 ng/mL), 
respectively. Addition of human serum proteins had limited effect on JNJ-6379 anti-HBV activity 
with an approximately 4-fold shift for 40% human serum. Antiviral activity of JNJ-6379 was also 
assessed in primary human hepatocytes with an EC90 of 376 nM for HBV DNA, representing the 
"primary" mechanism of action of JNJ-6379, ie, interfering with HBV capsid assembly. In 
addition, JNJ-6379 inhibited the de novo formation of cccDNA with an EC90 of 4,019 nM, based 
on HBV RNA) when compound was added together with viral inoculum ("secondary" mechanism 
of action).
In cytotoxicity assays, the 50% cytotoxic concentrations (CC50) of JNJ-6379 were ≥29.9 μM across 
the cell lines tested resulting in selectivity indices of ≥554 (based on the antiviral activity in the 
stable HBV-replicating HepG2.117 cell line).
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JNJ-73763989 and JNJ-56136379
Clinical Protocol 73763989PAHPB2006
Amendment 4
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
31
Status: Approved,  Date: 01 December 2021
In vitro combination studies of JNJ-6379 with either ETV or tenofovir resulted in additive to 
synergistic anti-HBV activity. 
JNJ-6379 remained active against a diverse panel of genotype A to H clinical isolates. Analysis of 
site-directed mutant (SDMs) identified amino acid substitutions in the CAM-binding pocket at 
positions 23 (F23Y), 25 (P25G), 30 (L30F), 33 (T33N, T33P), 37 (L37Q), 106 (S106T), 
110 (F110I), 118 (Y118F), 124 (V124G), 127 (R127H) and 128 (T128I) reduced anti-HBV 
activity of JNJ-6379 ranging from 3.0- (S106T) to 85-fold (T33N). All substitutions were rare in 
a public database of >7,600 HBV core sequences (frequencies 0.01–0.3%). NAs retained full 
activity against these core SDMs.
2.2.2.
Nonclinical Studies
2.2.2.1.
JNJ-3989 and JNJ-6379
Nonclinical assessments to support clinical development have been performed for the single agents 
JNJ-3989 and JNJ-6379, and also for their combination (up to 3-month studies).
JNJ-3989
Little potential for off-target inhibition of human gene expression in participants is expected, based 
on in silico human genome database screening. 
The nonclinical safety profile of JNJ-3989 has been evaluated through a series of in vitro and in 
vivo studies. Repeat-dose subcutaneous toxicity studies of 2 weeks up to 24 or 37 weeks were 
conducted in rat and monkey, respectively. In the 2-week studies, JNJ-3989 was administered once 
weekly via subcutaneous injection at 30 up to 300 mg/kg. In the 24- or 37-week studies, JNJ-3989 
was administered once weekly for the first month, followed by once monthly thereafter at 30 up 
to 180 mg/kg. JNJ-3989 was well tolerated in these studies.
In the 2-week and the 24-week studies in rat, JNJ-3989-related target organs were the liver, the 
kidney, and the injection site. The mandibular and mesenteric lymph nodes were identified as 
target organ in the 24-week study only. In the liver, hepatocyte alteration and hepatocyte mitosis, 
accompanied by an increase in hepatocellular vacuoles, oval cell hyperplasia, Kupffer cell 
vacuolation and/or increased liver weights were observed. The hepatocyte findings correlated to 
increased alkaline phosphatase (ALP) activity levels seen in the 24-week study. Kidney findings 
were characterized by cytoplasmic alteration of the cortical tubule epithelium. At the injection site, 
mononuclear cell or vacuolated macrophage infiltrates, epidermal exudate, hemorrhages and/or 
interstitial granules were observed. Macrophage vacuolation was observed in the sinus spaces of 
the mandibular and mesenteric lymph nodes.
Liver findings persisted throughout the recovery period. Partial recovery was observed in the 
kidney. No findings were present anymore at the injection sites and the lymph nodes at the end of 
the recovery period.
All these changes likely represented the distribution, accumulation, and clearance of JNJ-3989 and 
were considered not to be adverse due to the nature of the findings and the low severity. These are 
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JNJ-73763989 and JNJ-56136379
Clinical Protocol 73763989PAHPB2006
Amendment 4
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
32
Status: Approved,  Date: 01 December 2021
commonly described findings for N-acetylgalactosamine-conjugated RNAi (Janas 2018). The no 
observed adverse effect level (NOAEL) was therefore considered to be the highest dose tested, ie, 
mg/kg in the 24-week study. 
In the 2-week study in monkey, apart from a minimally increased ALP activity which was 
considered not adverse, no JNJ-3989-related effects were observed. In the 37-week study, 
JNJ-3989-related target organs were the liver, mandibular and/or mesenteric lymph nodes, and the 
subcutaneous injection site. Findings included Kupffer cell basophilia/hypertrophy in the liver, 
vacuolated macrophages in the lymph nodes, and macrophage infiltrates in the injection site.
Partial reversibility was observed for these findings. This likely represented the distribution, 
accumulation, and clearance of JNJ-3989 and was considered not to be adverse due to the low 
severity and/or nature of the findings. These are commonly described findings for 
N-acetylgalactosamine conjugated RNAi (Janas 2018). A non-adverse, minimally increased ALP 
activity was observed at 180 mg/kg without a microscopic correlate. The NOAEL in the monkey 
was considered to be the highest dose tested, ie, 
mg/kg in the 37-week study.
In the embryofetal development (EFD) studies, JNJ-3989 was not teratogenic in rats and rabbits.
The fertility study showed no effects on parental and reproductive parameters in male and female 
rats given JNJ-3989 up to a dose of 180 mg/kg/week.
JNJ-3989 was shown to be non-genotoxic when tested in the bacterial reverse mutation assay, and 
in vitro and in vivo micronucleus test. 
Results of the non-Good Laboratory Practice (GLP) in vitro studies demonstrated there is no 
potential for induction of the innate immune system (cytokine and complement activation), 
mitochondrial toxicity/cytotoxicity, or platelet aggregation associated with JNJ-3989 exposure at 
concentrations up to 250 µg/mL. 
The animal-to-human exposure ratios were calculated using rat and monkey exposures at NOAEL 
from the 24-week and 37-week studies, respectively, and human exposures after a single 
subcutaneous injection of 200 mg JNJ-3989 in human volunteers (Study AROHBV1001) 
(Table 1).
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NCT04667104


JNJ-73763989 and JNJ-56136379
Clinical Protocol 73763989PAHPB2006
Amendment 4
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
33
Status: Approved,  Date: 01 December 2021
Table 1:
Animal/Human Exposure Ratios at NOAEL for JNJ-3989
Ratio Total Concentration
Sex
NOAEL 
(mg/kg)
Cmax
(ng/mL)
AUCa
(ng∙h/mL)
Cmax
A/H Ratio
AUCa
A/H Ratio
JNJ-73763976
Human exposureb
1,315
20,136
-
-
24-week ratc
M
41,100
437,000
31.3
21.7
F
43,100
270,000
32.8
13.4
37-week monkeyd
M
73,200
1,230,000
55.7
61.1
F
65,800
988,000
50.0
49.1
JNJ-73763924
Human exposureb
363
4,605
-
-
24-week ratc
M
25,200
271,000
69.4
58.8
F
26,200
163,000
72.2
35.4
37-week monkeyd
M
21,600
383,000
59.5
83.2
F
23,000
392,000
63.4
85.1
AUC: area under the plasma concentration-time curve; AUC0-24h = area under the plasma concentration-time curve from 
administration to 24 h; AUC0-last = area under the plasma concentration-time curve from administration to last quantifiable 
sampling point; A/H ratio = animal/human ratio; Cmax: maximum plasma concentration; F = female; M = male; NOAEL: no 
observed adverse effect level.
a
AUC0-last for human exposure; AUC0-24h for animal exposures.
b
Single dose of 200 mg JNJ-73763989 in healthy participants via subcutaneous injection (Study AROHBV1001; based on recent 
clean dataset with data cut-off date 29 October 2019).
c
Once weekly dosing for 5 weeks, followed by once monthly dosing up to a total of 24 weeks.
d
Once weekly dosing for 5 weeks, followed by once monthly dosing, up to a total of 37 weeks.
JNJ-6379
Following 6 months of treatment in rats, the kidney and female reproductive tract (irregular estrous 
cycle) were identified as target organs. However, after further assessment of the kidney findings 
and their clinical relevance, it is deemed unlikely that the retrograde nephropathy seen in 1 out of 
20 male rats following 6 months of dosing with JNJ-6379 at 100 mg eq./kg/day are relevant for 
the clinical studies. The retrograde nephropathy was partially recovered after a 9-week recovery 
period. In the 6-month rat study, female rats (at 200 mg eq./kg/day) showed an irregular estrous 
cycle, from which they recovered at the end of the 9-week treatment free period. These irregular 
estrous cycles were also apparent in the female fertility studies (main and mechanistic). These 
changes were related to lowered hormone levels (luteinizing hormone, progesterone, estradiol). 
JNJ-6379, however, did not affect female fertility. The fetal loss seen during the early stages of 
pregnancy was considered to result from low hormone levels. In the dog study, no changes were 
observed in the reproductive tract at higher exposures in dogs. 
In the 9-month dog study, the target organs identified were the adrenal glands and bone marrow. 
The adrenal glands did not show degenerative changes or loss of function and were therefore 
considered as non-adverse target organs. One female dog out of 4 dosed at 25 mg eq./kg/day (the 
highest dose) was sacrificed on Day 61, after showing poor health condition. A JNJ-6379 plasma 
level of 42,000 ng/mL was observed for this animal on Day 61, at approximately 24 hours after 
last dosing. Pronounced clinical pathologic changes including pancytopenia were noted. Marked 
increase in plasma cell-like cells was seen in the bone marrow during histopathologic examination, 
resulting in a marked reduction of hematopoietic tissue and extramedullary hematopoiesis in liver 
and spleen. The cause of the deteriorating condition was likely related to changes in the bone 
marrow. A second dog in the same dose group with pancytopenia recovered after a drug holiday 
and was re-exposed uneventfully.
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JNJ-73763989 and JNJ-56136379
Clinical Protocol 73763989PAHPB2006
Amendment 4
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
34
Status: Approved,  Date: 01 December 2021
In the EFD studies, JNJ-6379 was not teratogenic in rats and rabbits.
JNJ-6379 was not genotoxic in the in vitro micronucleus and Ames tests, and in the in vivo 
micronucleus tests in rats.
Animal/human ratios at the NOAEL in rat and dog for human exposure at 250 mg JNJ-6379 once 
daily (QD) for 28 days are displayed in Table 2.
Table 2:
Animal/Human Ratios at the NOAEL in Rat and Dog (Human Exposure at 250 mg JNJ-6379 
Once Daily for 28 Days [Study 56136379HPB1001])
Sex
NOAEL
(mg eq./kg/day)
Cmax
(ng/mL)
AUC0-24h
(ng.h/mL)
Ratio Total 
Concentration
Ratio 
Concentration 
Corrected for 
Plasma Protein 
Bindingb
Cmax
A/H 
Ratio
AUC0-24h
A/H 
Ratio
Cmax
A/H 
Ratio
AUC0-24h
A/H 
Ratio
Human exposurea
13,798
267,180
-
-
6M rat
M
7,540
93,100
0.6
0.3
0.9
0.6
M
13,600d
180,000d
1.0
0.7
1.7
1.1
F
19,900
233,000
1.4
0.9
2.4
1.5
9M dog
M
30,000
606,000
2.2
2.3
3.3
3.4
F
22,500
383,000
1.6
1.4
2.5
2.2
AUC: area under the plasma concentration-time curve; AUC0-24h: area under the plasma concentration-time curve from 
administration to 24 h; A/H: animal/human ratio; Cmax: maximum plasma concentration; F: female; M: male; NOAEL: no 
observed adverse effect level; QD: once daily.
a
250 mg JNJ-6379 QD for 28 days (Study 56136379HPB1001).
b
Ratio of the total Cmax or AUC corrected for species difference in plasma unbound fraction. Calculation: [animal Cmax or 
AUC0-24h x animal free fraction] / [human Cmax or AUC0-24h x human free fraction].
c
A dose of 
mg eq./kg/day in male rats is considered to be above the NOAEL due to kidney findings in male rats, which 
are likely not relevant for human. 
d
The plasma Cmax of 13,600 ng/mL and AUC0-24h of 180,000 ng.h/mL in male rats at 100 mg eq./kg/day corresponds to an 
unbound Cmax of 1,754 ng/mL and AUC0-24h of 23,220 ng h/mL (fraction unbound rat plasma=12.9%). This unbound plasma 
exposure will be achieved in humans at a total plasma Cmax of 22,784 ng/ml and AUC0-24h of 301,558 ng h/mL (fraction 
unbound in human plasma=7.7%).
Combination of JNJ-3989 and JNJ-6379
A 1-month repeat-dose combination toxicity study of JNJ-6379 and JNJ-3989 was conducted in 
male and female Sprague-Dawley rats (Study TOX13609). JNJ-6379 (in polyethylene glycol 400 
+ 10% polyvinylpyrrolidone-vinyl acetate) was administered daily via oral gavage at 100 mg/kg, 
alone or in combination with JNJ-3989 (in 
 saline) which was administered 
weekly via subcutaneous injections at 30 and 180 mg/kg. In addition, 180 mg/kg JNJ-3989 
(subcutaneous, weekly) was dosed as well in a monotherapy group. Control animals received both 
vehicles via the respective routes.
No treatment-related mortality occurred during the study and no relevant clinical signs were noted. 
Body weights and body weight gain were slightly decreased during the last weeks of treatment in 
males at ≥100/30 mg/kg JNJ-6379/JNJ-3989 and in females at 100/180 mg/kg 
JNJ‑6379/JNJ-3989, with correlating lower food intake at the high dose.
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NCT04667104


JNJ-73763989 and JNJ-56136379
Clinical Protocol 73763989PAHPB2006
Amendment 4
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
35
Status: Approved,  Date: 01 December 2021
JNJ-6379 and/or JNJ-3989 elicited minimal to mild changes in white (WBC) and red blood cell 
(RBC) parameters, as well as minimal decreases in platelets, fibrinogen and a minimal increase in 
activated partial thromboplastin time at ≥100/30 mg/kg JNJ-6379/JNJ-3989. Minimal to mild 
increases in alanine aminotransferase (ALT), ALP, gamma-glutamyl transferase, urea, cholesterol 
(up to moderate), phospholipids, and triglycerides were observed from the same dose onwards. At 
100/180 mg/kg JNJ-6379/JNJ-3989, minimal to mild increases in glutamate dehydrogenase 
(GLDH) and bilirubin concentrations in females were observed, and a minimal decrease in glucose 
concentrations in males. The above changes in clinical pathology were considered non‑adverse 
based on the minimal severity observed and were of a similar nature and magnitude as when 
animals were dosed with the test items alone.
Drug-containing sediment was observed in the urine of animals dosed with JNJ-6379 at 100 mg/kg, 
either alone or in combination, with mainly males being affected. In the group given JNJ‑6379 
alone, the drug-containing sediment was studied and correlated with significant amounts of 
drug-related material in the urine (predominantly M7 but also unchanged drug).
JNJ-6379-related morphological findings at 100 mg/kg/day in males and/or females were 
considered non-adverse, and were seen in the liver (centrilobular hypertrophy, weight increase), 
thymus (decreased lymphoid cellularity, weight decrease, small size), spleen (infiltration 
mononuclear cells in capsule, correlating with pale white focus/irregular surface), adrenal gland 
(hypertrophy of zona fasciculata correlating with enlargement, weight increase), and thyroid gland 
(follicular cell hypertrophy).
JNJ-3989-related morphological findings at 30 mg/kg in males and/or females were considered 
non-adverse and were seen in the liver (increased vacuolation and increased mitosis) and 
administration site (mixed cell infiltrate, infiltration of vacuolated macrophages with basophilic 
stippling). Non-adverse findings at 180 mg/kg were seen in the liver (increased vacuolation of 
hepatocytes and/or Kupffer cells correlating with pale discoloration, prominent lobular pattern; 
single cell necrosis, increased mitosis, karyomegaly, hypertrophy/hyperplasia of bile ducts), 
kidney (vacuolation and basophilic granules in tubular epithelium), mesenteric, axillary and/or 
popliteal lymph nodes (macrophage vacuolation, sinus histiocytosis), and the administration site 
(mixed cell infiltrate, infiltration of vacuolated macrophages with basophilic stippling).
Differences in morphologic alterations between rats dosed with the single compounds, compared 
to the groups dosed with the combination of the 2 compounds included a minor increase in 
incidence and severity of decreased lymphoid cellularity in the thymus with lower thymus weights 
in females of the 100/180 mg/kg JNJ-6379/JNJ-3989 group. All remaining findings in the groups 
dosed with the combination of test articles were in line with the findings recorded for the groups 
dosed with the single compounds. There were no additional target organs or findings identified 
following the treatment with the combination of JNJ-6379 with JNJ-3989.
No relevant drug-drug interaction (DDI) was seen.
In conclusion, weekly subcutaneous injections with JNJ-3989 at 30 or 180 mg/kg in combination 
with daily administration of JNJ‑6379 at 100 mg/kg (oral) for 1 month were well tolerated with no 
NCT04667104


JNJ-73763989 and JNJ-56136379
Clinical Protocol 73763989PAHPB2006
Amendment 4
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
36
Status: Approved,  Date: 01 December 2021
clinical signs or treatment-related mortality. Changes in clinical pathology and histopathology 
were mostly similar to the findings for the monotherapy groups dosed with JNJ‑6379 at 100 mg/kg 
(oral) alone or with JNJ‑3989 at 180 mg/kg (subcutaneous) alone. The only synergistic changes 
included a slight decrease in body weight (gain) at ≥100/30 mg/kg JNJ-6379/JNJ-3989, in food 
consumption at 100/180 mg/kg JNJ-6379/JNJ-3989, and a further decrease in lymphoid cellularity 
in the thymus of females at 100/180 mg/kg JNJ-6379/JNJ-3989. These alterations were minor and 
non-adverse in nature. Based on these results, the NOAEL was considered to be 
mg/kg 
JNJ-6379/JNJ-73989. Maximum plasma concentration (Cmax) and area under the plasma 
concentration-time curve from administration to 24 hours (AUC0-24h) for JNJ-6379 in males were 
13,200 ng/mL and 181,000 ng.h/mL, and for females 15,500 ng/mL and 206,000 ng.h/mL, 
respectively, after 1 month of treatment. The mean Cmax and AUC0-24h for analyte JNJ-3924 in 
males were 20,900 ng/mL and 160,000 ng.h/mL, and for females 21,300 ng/mL and 
125,000 ng.h/mL, respectively. For analyte JNJ‑3976, the mean Cmax and AUC0-24h in males were 
35,200 ng/mL and 258,000 ng.h/mL, and for females 35,300 ng/mL and 201,000 ng.h/mL, 
respectively.
A 3-month combination toxicity study of JNJ-3989 and JNJ-6379 was conducted 
(Study TOX13608). In this study, JNJ‑3989 was initially administered weekly (ie, a total of 
6 doses) and monthly thereafter, via subcutaneous injections at dose levels of 60 and 180 mg/kg 
when given in combination with JNJ-6379, and at 180 mg/kg for the monotherapy group. JNJ-6379 
was administered daily via oral gavage at a dose level of 100 mg/kg in the monotherapy and 
combination groups. Control animals received both vehicles via the respective routes.
No test article-related mortalities were noted among animals dosed with JNJ-6379 alone, JNJ‑3989
alone, or JNJ-6379/JNJ-3989 at 100/180 mg/kg. One male receiving JNJ‑3989 alone at 180 mg/kg 
died on Day 45, after a rapid change in its clinical condition. The death of this animal was 
considered to reflect an acute stress response without a relationship to the test article. 
One accidental death due to a possible gavage error was noted among the toxicokinetic animals in 
the 100/60 mg/kg JNJ-6379/JNJ-3989 group.
One male rat (No. 48) dosed at 100/60 mg/kg JNJ-6379/JNJ-989 was euthanized on Day 24 after 
showing severe clinical signs in the morning (decreased activity, erected fur, pallor and cold to 
touch). No clinical signs were noted for this animal until Day 23, and body weight and weight gain 
were unaffected during the first 3 weeks of the study. The cause of moribundity was considered to 
be a markedly decreased hematopoietic cellularity of the bone marrow with pancytopenia 
including markedly reduced platelet counts and consequent hemorrhages (in a variety of organs 
and tissues) and blood loss. A relation to the treatment with JNJ-6379 and/or JNJ‑3989 cannot be 
excluded. None of the remaining animals of this study showed decreased cellularity of the bone 
marrow.
Body weight and weight gain were slightly decreased in the JNJ-6379 monotherapy group, and in 
both combination groups, with correlating lower food intake. Given the magnitude of the changes 
and the absence of clinical signs, these findings were considered non-adverse.
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JNJ-73763989 and JNJ-56136379
Clinical Protocol 73763989PAHPB2006
Amendment 4
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
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Status: Approved,  Date: 01 December 2021
JNJ-6379-related changes included increases in lymphocytes, total WBCs, hepatobiliary enzyme 
activities (ALT, GLDH and/or ALP), cholesterol, and triglycerides. In addition, females showed 
decreases in glucose, and males had an increased urea concentration. JNJ-3989-related changes 
included increases in ALP, ALT, GLDH, cholesterol and triglycerides in males and/or females. In 
one or both combination groups, decreased platelet counts (females), RBC parameters (males), 
glucose, albumin, globulin and (occasionally) total protein concentrations and increased ALP, 
ALT, gamma-glutamyl transferase and GLDH activities, and cholesterol levels were observed in 
one or both sexes. Both sexes showed an increased plasma urea concentration. Based on the 
magnitude of changes, these were concluded to be non-adverse for either monotherapy or 
combination therapy groups.
No changes were observed for the urinary biomarkers albumin, β2-microglobulin, Kidney Injury 
Molecule-1 [KIM-1], Neutrophil Gelatinase Associated Lipocalin [NGAL], cystatin-C, and 
clusterin in the JNJ-6379 monotherapy group. Precipitate was observed in the urine of animals 
dosed with JNJ-6379.
JNJ-6379-related morphological findings were observed in the female reproductive tract (included 
a decreased number of corpora lutea, prominent atretic follicles in the ovary), which was 
considered adverse. Other findings were observed in the liver (centrilobular hepatocellular 
hypertrophy), kidney (diffuse dilatation in females), spleen (infiltration of mononuclear cells 
and/or fibrosis in the capsule), adrenal gland (hypertrophy of the zona fasciculata in females), and 
thyroid gland (follicular cell hypertrophy in males). All findings were considered non-adverse due 
to the nature of the findings and the low severity.
JNJ-3989-related morphological findings were observed in the liver (increased vacuolation of 
hepatocytes and/or Kupffer cells, single cell necrosis, oval cell hyperplasia, basophilic granules, 
increased mitosis and/or karyocytomegaly), kidney (basophilic granules and vacuolation in tubular 
epithelium), lymph nodes (macrophage vacuolation and/or sinus histiocytosis), and injection site 
(infiltration of macrophages with basophilic stippling, mononuclear cell infiltrate, multinucleate 
giant cells and/or increased incidence and severity of hemorrhage). The findings were usually 
dose-related in incidence and/or severity, and were considered non-adverse due to the nature of 
the findings and the low severity.
In the combination groups, differences in morphological alterations versus the monotherapy 
groups consisted of a minor increase and severity of decreased lymphoid cellularity in the thymus, 
possibly partly explained by the reduce body weight gain seen in these groups. There were no 
additional target organs or findings identified.
No DDI was observed.
In conclusion, administration of JNJ-6379 (daily, orally) and JNJ-3989 (intermittent, 
subcutaneous) in monotherapy groups and in the JNJ-6379/JNJ-3989 100/180 mg/kg group was 
well tolerated. In the 100/60 mg/kg group, one male rat was euthanized. The cause of moribundity 
was considered to be a markedly decreased hematopoietic cellularity of the bone marrow with 
pancytopenia including markedly reduced platelet counts and consequent hemorrhages and blood 
NCT04667104


JNJ-73763989 and JNJ-56136379
Clinical Protocol 73763989PAHPB2006
Amendment 4
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
38
Status: Approved,  Date: 01 December 2021
loss. A relation to the treatment with JNJ-6379 and/or JNJ‑3989 cannot be excluded. In the 
surviving rats, changes in clinical pathology and histopathology were similar in the monotherapy 
and combination groups. Synergistic changes at ≥100/60 mg/kg included a dose-related decrease 
in body weight (gain) and food intake, a moderate decrease in platelet counts in females and a 
minimal decrease in RBC parameters in males. Microscopically a further decrease in lymphoid 
cellularly in the thymus was observed. These alterations were mild in nature and considered 
non-adverse. A NOAEL could not be defined.
Based on the observation of pancytopenia in 1 rat and a mild platelet decrease in the combination 
groups in the 3-month combination toxicity study, the sponsor is implementing additional 
monitoring of significant on-treatment hematologic changes in clinical studies with dosing longer 
than 4 weeks (see Section 8.3.6.6, Hematologic Abnormalities). However, no significant 
abnormalities of hematologic parameters have been observed in clinical studies to date.
For further information, refer to the latest version of the IBs for JNJ-3989 and JNJ-6379 (IB 
JNJ-3989 2020; IB JNJ-6379 2021).
2.2.2.2.
Combination of JNJ-3989 or JNJ-6379 With Entecavir, Tenofovir 
Disoproxil, or Tenofovir Alafenamide
There is no common target organ between JNJ-6379 or JNJ-3989 and ETV (Memorandum 2005). 
The single common toxicity target organ between JNJ-6379, 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 
renal function (Henry 2012; Janas 2018). These kidney findings have been observed in both the 
2-week and 6-month studies and did not worsen over time. No kidney findings were observed in 
monkeys.
In the chronic rat study (6 months) with JNJ-6379, retrograde nephropathy, secondary to papillary 
or pelvic calculi/precipitates, was noted in male rats but not in dogs or female rats. This finding is 
mainly due to precipitation or calculi formation in distal parts of the kidney/lower urinary tract and 
is of limited relevance to man, due to differences in urinary composition and functional anatomy 
between (male) rats and humans. In general, compounds or metabolites of low solubility and high 
renal clearance may cause concretions in the kidneys/urinary tract, especially at high doses, as the 
urine concentrates in the distal nephron and supersaturation of the compound can occur. Urinary 
pH, proteins and osmolality can also influence the formation of urinary concretions. Male rat urine 
normally has a high concentration of protein and high osmolality. In addition, rats may be 
predisposed to retrograde nephropathy because they are known to experience spontaneous urine 
reflux during micturition or urinary bladder contraction, and this reflux phenomenon can be 
increased or exacerbated by treatment-induced obstructions. The retrograde nephropathy in male 
NCT04667104


JNJ-73763989 and JNJ-56136379
Clinical Protocol 73763989PAHPB2006
Amendment 4
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
39
Status: Approved,  Date: 01 December 2021
rats correlated with increased urea and creatinine in plasma and with urinary changes (red/brown 
discolored urine, increased volume, decreased pH, presence of blood and WBCs and RBCs in 
sediment) (Cohen 2002; Tannehill-Gregg 2009). No kidney findings were observed in dogs.
Although both compounds (JNJ-3989 and JNJ-6379) showed histological kidney findings in the 
rat, the primary anatomical location, mechanism and severity are different. For JNJ-3989, the renal 
findings are without anticipated clinical or clinicopathological consequences and located in the 
proximal part of the nephron (outer cortex) and intracellular (not in the tubular lumen). For 
JNJ-6379, the main findings are restricted to male rats and initiate in distal parts of the kidney 
(renal pelvis/ papilla) and/or in the lumen of the lower urinary tract with secondary more proximal 
changes due to reflux.
For 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 2016).
Based on the available toxicology data, there are no specific concerns about additive or synergistic 
toxicities in the kidney when JNJ-6379 or JNJ-3989 are combined with ETV, tenofovir disoproxil 
or TAF. In addition, no clinically relevant DDIs are expected when JNJ‑6379 or JNJ-3989 are 
combined with ETV, or tenofovir disoproxil, or TAF.
2.2.2.3.
Combination of JNJ-3989 or JNJ-6379 With PegIFN-α2a
2.2.2.3.1.
Combination of JNJ-6379 With PegIFN-α2a
As there is no appropriate species for studying the combination of JNJ-6379 with PegIFN-α2a, an 
in vitro study on human bone marrow derived erythroid and myeloid progenitors using colony 
forming assays was conducted. JNJ-6379 (5-100 μM) and PegIFN-α2a (Pegasys®, 0.00005-
0.1 μM) were tested in combination in order to evaluate their potential additive or synergistic 
effects (study TOX14629).
The half maximal inhibitory concentration (IC50) values of the combination treatment were 
markedly lower compared to JNJ-6379 alone for all tested concentrations but similar to the values 
with PegIFN-α2a alone. When the higher concentrations of PegIFN-α2a were tested in 
NCT04667104


JNJ-73763989 and JNJ-56136379
Clinical Protocol 73763989PAHPB2006
Amendment 4
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
40
Status: Approved,  Date: 01 December 2021
combination with JNJ-6379, the reduction in colonies was mainly due to the strong toxicity of 
PegIFN-α2a at these concentrations.
Comparing the predicted (adding the percent of reduction of JNJ-6379 and PegIFN-α2a alone) and 
the actual percent reduction in colonies relative to the solvent control, it became clear that there 
were only minimal differences, pointing more to an additive effect and not a synergistic effect 
when JNJ-6379 and PegIFN-α2a were combined.
2.2.2.3.2.
Combination of JNJ-3989 with PegIFN-α2a 
The objective of study TOX14273 was to determine the potential additive or synergistic effects 
when combining JNJ-3989 (60 or 180 mg/kg, once monthly) with PegIFN-α2a (Pegasys®
0.015 mg/kg twice weekly) given subcutaneously for 3 months to the Cynomolgus monkey (study 
TOX14273).
There were no JNJ-3989 related mortalities. JNJ-3989 (alone or combined with PegIFN-α2a) was 
well tolerated and did not induce relevant effects on clinical signs, body weight, food consumption, 
ophthalmoscopic examination, electrocardiology evaluation, coagulation, clinical chemistry or 
urinalysis parameters, cytokines IP-10 and IFNα, as well as organ weight and macroscopic 
examination.
JNJ-3989 induced minimal to mild hematological changes starting at 60 mg/kg. These clinical 
pathology changes were limited to transient, non-dose-related increases in neutrophils and total 
white blood cells in males and females administered 180 mg/kg JNJ-3989 alone or in combination 
≥60/0.015 mg/kg JNJ-3989/PegIFN-α2a on Day 30 only. In addition, comparable transient 
increases in neutrophils and total white blood cells were also observed in both males and females 
administered 0.015 mg/kg PegIFN-α2a alone.
PegIFN-α2a induced increases in IFNα and IP-10 after the first injection. Levels were at baseline 
values prior to dosing on Day 30 and no increases were observed after dosing as well as after 
dosing on Day 90. Combination of JNJ-3989 at 60 or 180 mg/kg with PegIFN-α2a did not induce 
any further effects than the increases observed with PegIFN-α2a given alone.
JNJ-3989 induced microscopic findings in the lymph nodes and liver. In the mesenteric, axillary, 
popliteal and/or other lymph nodes, minimal to mild vacuolation of macrophages were observed 
in both sexes administered ≥60 mg/kg/0.015 mg/kg JNJ-3989/PegIFN-α2a or 180 mg/kg JNJ-3989 
alone. In the liver, minimal hypertrophy of Kupffer cells was observed in 1 female administered 
180 mg/kg/0.015 mg/kg JNJ-3989/PegIFN-α2a and 2 females administered 180 mg/kg JNJ-3989 
alone. The microscopic changes were comparable between the animals administered with 
JNJ-3989 alone or in combination with PegIFN-α2a indicating an absence of additive or 
synergistic effect.
In conclusion, the intermittent subcutaneous administration of JNJ-3989 given alone or combined 
with PegIFN-α2a for 3 months was well tolerated in Cynomolgus monkeys at levels of 60 and 
180 mg/kg. Treatment only induced transient hematological changes and microscopic findings in 
liver and lymph nodes, all considered as non-adverse. The administration of JNJ-3989 in 
NCT04667104


JNJ-73763989 and JNJ-56136379
Clinical Protocol 73763989PAHPB2006
Amendment 4
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
41
Status: Approved,  Date: 01 December 2021
combination with PegIFN-α2a did not amplify any toxicological effect. Based on these results, 
there are no additive or synergistic effects on the toxicological profile and no DDI when the test 
item is combined with the reference item. The NOAEL of the test item was considered to be 
mg/kg per administration, whether given alone or in combination with the reference item.
2.2.3.
Clinical Studies
2.2.3.1.
JNJ-3989 and JNJ-6379
JNJ-3989
At the time of protocol writing, JNJ-3989 is being evaluated in 5 clinical studies. One Phase 1 
study (Study 73763989HPB1001) in healthy adult Japanese participants is completed. 
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 CHB is completed with 
final analysis and report writing ongoing. One Phase 1 study (Study 73763989HPB1002) in adult 
participants with or without hepatic impairment, and 2 Phase 2 studies (Study 73763989HPB2001 
[REEF-1] and Study 73763989PAHPB2002 [REEF-2]) in adult CHB participants are ongoing. In 
total, 58 healthy, 435 CHB participants, and 6 participants with moderately impaired hepatic 
function have been dosed in the aforementioned 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 (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 treatment. 
Efficacy was assessed using snapshot data through 26 March 2020. Antiviral activity data were 
available for 56 CHB participants 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.
JNJ-6379
At the time of protocol writing, 148 healthy and 242 CHB-infected participants have been dosed 
with JNJ-6379 in 7 completed Phase 1 studies (56136379HPB1001, 56136379HPB1002, 
CCI
NCT04667104


JNJ-73763989 and JNJ-56136379
Clinical Protocol 73763989PAHPB2006
Amendment 4
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
42
Status: Approved,  Date: 01 December 2021
56136379HPB1003, 
56136379HPB1004, 
56136379HPB1005, 
56136379HPB1007, 
and 
56136379HPB1008), 1 completed Phase 2 study (56136379HPB2001, also referred to as JADE; 
final analysis and report writing are currently ongoing), and 1 ongoing Phase 1 study
(56136379HPB1006).
Human Pharmacokinetics and Product Metabolism
Single-dose Studies in Healthy Participants
In Study 56136379HPB1001, single ascending doses (25, 50, 150, 300, and 600 mg) of JNJ-6379 
(or placebo) were administered under fasting conditions to healthy participants. No major 
differences were observed in the shape of the mean JNJ-6379 plasma concentration-time curves 
for the different dose levels. Mean and individual pharmacokinetic (PK) profiles showed minimal 
lag-time. A single rather flat concentration peak was observed in the PK profiles of most 
participants. Plasma concentrations in the terminal phase declined generally in parallel for all dose 
levels. The Cmax and AUC0-24h increased proportionally with dose after single-dose administration 
of JNJ-6379 doses of 25 mg to 300 mg and less than dose-proportionally at the dose of 600 mg. 
The AUC from administration to last quantifiable sampling point (AUC0-last) and the AUC to last 
sampling point from time zero extrapolated to infinity (AUC∞) increased proportionally between 
the JNJ-6379 25-mg and 600-mg dose levels. Mean values for terminal half-life (t1/2term) were 
comparable for the 25-mg to 300-mg dose levels, and averaged between 93.3 hours and 
110.5 hours. For the 600-mg dose group, the average t1/2term was 141.3 hours. Mean values for the 
total apparent oral clearance (CL/F) were comparable for the 25-mg, 50-mg and 150-mg dose 
level, and appeared to decrease at higher dose levels. Mean values of the apparent volume of 
distribution were generally comparable for the different dose groups.
In Study 56136379HPB1002, study drug exposure levels using a novel tablet formulation, 
containing hydroxypropylmethylcellulose E5-based spray-dried powder, were similar to exposure 
levels observed in Study 56136379HPB1001 using the original formulation, both in fed conditions. 
The relative bioavailability of new 25-mg oral tablets of JNJ-6379 administered as a 150-mg dose 
under fasting and fed conditions, and of new 100-mg oral tablets of JNJ-6379 administered as a 
300-mg dose under fasting conditions, was assessed in healthy adult participants. Assuming 
proportionality, based on the geometric mean ratios between the 3x 100-mg dose, fasting (test) 
and the 6x 25-mg dose, fasting (reference) of the dose-normalized PK parameters, Cmax was 
21.56% lower for the 100-mg tablet strength compared to the 25-mg tablet strength, and AUC0-last 
and AUC∞were similar. The median time to reach Cmax (tmax) was around 1.75 hours when 150 mg 
JNJ-6379 was dosed as 6x 25-mg oral tablets, and around 3.00 hours when 300 mg JNJ-6379 was 
dosed as 3x 100-mg oral tablets.
In Study 56136379HPB1005, the oral bioavailability of a single 300-mg dose of JNJ-6379 
administered 
as 
a 
100-mg 
tablet 
containing 
hydroxypropylmethylcellulose-acetate 
succinate-based spray-dried powder (test tablet) was assessed. All 14 healthy adult participants 
received a 300-mg dose of JNJ-6379 under fasted conditions. Preliminary PK analysis was 
performed and mean Cmax was 3,105 ng/mL, mean AUC0-72h was 111,286 ng.h/mL and mean 
AUC∞was 280,926 ng.h/mL. The median tmax was around 3.00 hours. These preliminary PK 
NCT04667104


JNJ-73763989 and JNJ-56136379
Clinical Protocol 73763989PAHPB2006
Amendment 4
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
43
Status: Approved,  Date: 01 December 2021
parameter values are comparable to the PK parameters obtained after administration of JNJ-6379 
formulated as hydroxypropylmethylcellulose E5-based spray-dried powder tablet.
Multiple-dose Studies in Healthy Participants
In Session 7 of Study 56136379HPB1001, participants received 150 mg JNJ-6379 twice daily 
under fed conditions for the first 2 days of treatment, followed by 100 mg JNJ-6379 QD until 
Day 12. JNJ-6379 plasma concentrations accumulated during the study (accumulation ratio of 
approximately 6). The CL/F at steady-state and the t1/2term were similar to values observed after 
single-dose administration, suggesting time-linear PK.
In Study 56136379HPB1004, participants received 250 mg of JNJ-6379 twice daily on Days 6 and 
7 (fed conditions), followed by 170 mg QD on Day 8 to 25 in fed conditions (with exception of 
Day 21). On Day 21, a single dose of JNJ-6379 170 mg and a single dose of 
drospirenone/ethinylestradiol 3 mg/0.02 mg and a single dose of midazolam 2 mg were 
administered under fasted conditions. Mean JNJ-6379 Cmax and area under the plasma 
concentration-time curve over the dosing interval (AUCτ) increased between Day 6 (first dose of 
JNJ-6379) and Day 20 as JNJ-6379 plasma concentrations accumulated due to the multiple-dose 
regimen administered in this study. Steady-state was reached before Day 20. Plasma 
concentration-time 
profiles 
of 
JNJ-6379 
were 
similar 
to 
those 
observed 
in 
Study 56136379HPB1001.
Multiple-dose Studies in Chronic HBV-infected Participants
In Sessions 8, 9, 10, 11, and A of Study 56136379HPB1001, treatment-naïve chronic 
HBV-infected participants were administered multiple-dose regimens (25, 75, 150, and 250 mg) 
of JNJ-6379 for 28 days. Pharmacokinetics of JNJ-6379 were not markedly different between 
healthy participants and chronic HBV-infected participants. Mean JNJ-6379 exposures in chronic 
HBV-infected participants could be predicted from data in healthy participants. The PK data show 
that exposure of JNJ-6379 in chronic HBV-infected participants is dose proportional and CL/F is 
constant over time.
Food Interaction 
Although Study 56136379HPB1001 suggested slightly higher exposure of JNJ-6379 in fed 
conditions, data from Study 56136379HBP1002 with a higher number of participants showed that 
there is no food effect on JNJ-6379 exposure, and a preliminary PK analysis from Study 
56136379HBP1005 suggests the same.
Drug-drug Interaction
Oral contraceptives: When administered simultaneously with 3 mg drospirenone/0.02 mg 
ethinylestradiol in Study 56136379HPB1004, JNJ-6379 increases the extent of exposure and 
decreases the CL/F of ethinylestradiol while the peak plasma concentration decreased. In contrast, 
JNJ-6379 has no clear effect on the extent of exposure and CL/F of drospirenone, a cytochrome 
P450 (CYP)3A4-sensitive progestin: peak plasma concentration decreased while no change in 
exposure and apparent clearance was observed. Consequently, oral contraceptives are still 
NCT04667104


JNJ-73763989 and JNJ-56136379
Clinical Protocol 73763989PAHPB2006
Amendment 4
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
44
Status: Approved,  Date: 01 December 2021
considered to be effective when administered simultaneously with JNJ-6379. However, as a 
precaution to avoid high exposure to ethinylestradiol, ethinylestradiol-containing contraceptives 
are only allowed if the ethinylestradiol content is ≤20 µg.
Midazolam: In Study 56136379HPB1004, coadministration of 170 mg JNJ-6379 QD with oral 
midazolam as a CYP3A4 probe substrate showed a reduction of 41.7% in Cmax and 53.9% in AUC 
of midazolam, implying that JNJ-6379 may induce the metabolism of CYP3A4-sensitive 
substrates. 
Itraconazole: In Study 56136379HPB1008, coadministration of a single 250-mg dose of JNJ-6379 
with multiple-dose itraconazole 200 mg QD, a strong inhibitor of CYP3A, CYP2C19, P-gp, and 
BCRP, showed a 1.38-fold increase in the AUC0-408h of JNJ-6379 compared to when JNJ-6379 
was given alone. Oral administration of JNJ-6379 as a single dose and in combination with 
itraconazole under fed conditions was generally safe and well tolerated in this study.
Efficacy Studies
Antiviral activity data are available from Part II of Study 56136379HPB1001 (final analysis, 
57 treatment-naïve participants treated with multiple-dose regimens of 25 to 250 mg JNJ-6379 QD
for 28 days, unblinded). Available antiviral activity data for 4 weeks of treatment with JNJ-6379 
in this study showed potent HBV DNA and RNA reductions but no changes in HBsAg, indicating 
that longer treatments are needed.
Interim efficacy data (unblinded Week 24 data) are available from the Phase 2a JADE study. In 
this study, 232 chronic HBV-infected participants were randomized to receive JNJ-6379 QD (75 or 
250 mg) or placebo in combination with an NA (tenofovir disoproxil/ETV) or JNJ-6379 (75 or 
250 mg) alone. Of these, 172 participants were enrolled in the combination treatment arms: 
88 chronic HBV-infected participants not treated at screening and 84 virologically suppressed 
chronic HBV-infected participants. Of the 88 participants not treated at screening, 33 received 
75 mg QD JNJ-6379 in addition to an NA, 33 received 250 mg QD JNJ-6379 in addition to an 
NA, and 22 received placebo in addition to an NA. Of the 84 virologically suppressed participants, 
33 received 75 mg QD JNJ-6379 in addition to an NA, 30 received 250 mg QD JNJ-6379 in 
addition to an NA, and 21 received placebo in addition to an NA.
In currently not treated HBeAg-positive participants (mean baseline HBV DNA levels 7.65 to 
8.24 log10 IU/mL), there were pronounced declines in mean (standard error [SE]) HBV DNA from 
baseline of 5.53 (0.23) and 5.88 (0.34) log10 IU/mL for JNJ-6379 75 mg and 250 mg + NA, 
respectively, and 5.21 (0.42) log10 IU/mL for placebo + NA. In currently not treated 
HBeAg-negative participants (mean baseline HBV DNA levels 4.89 to 5.40 log10 IU/mL), 
interpretation of mean (SE) HBV DNA decline was confounded since many participants had HBV 
DNA < lower limit of quantification (LLOQ) from Week 4 onwards.
In currently not treated participants, JNJ-6379 75 mg and 250 mg + NA showed a clear mean (SE) 
HBV RNA decline from baseline (2.82 [0.25] and 3.13 [0.35] log10 copies/mL, respectively) 
compared with placebo + NA (1.43 [0.32] log10 copies/mL), thereby differentiating JNJ-6379 from 
NCT04667104


JNJ-73763989 and JNJ-56136379
Clinical Protocol 73763989PAHPB2006
Amendment 4
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
45
Status: Approved,  Date: 01 December 2021
NAs. HBV RNA was target not detected (TND) at Week 24 in 16/27 (59%), 19/25 (76%) and 
9/20 (45%) participants, respectively.
The 24-week interim efficacy data in virologically suppressed participants showed that most 
participants had HBV DNA levels below the limit of quantification at baseline. All virologically 
suppressed participants on JNJ-6379 + NA who had detectable HBV RNA at baseline achieved 
HBV RNA TND at Week 24 (13/13 participants on 75 mg JNJ-6379 and 8/8 participants on
250 mg JNJ-6379) vs 1/7 (14%) participants on placebo + NA.
In currently not treated HBeAg-positive participants, JNJ-6379 75 mg and 250 mg + NA resulted 
in a mean (SE) HBsAg decline of 0.13 (0.10) and 0.40 (0.15) log10 IU/mL, respectively, compared 
with 0.22 (0.11) for placebo + NA at Week 24. Participants with HBsAg declines also had HBeAg 
declines and frequently had early on-treatment isolated ALT flares. In both JNJ-6379 + NA arms:

Maximal individual HBsAg and HBeAg reductions were 1.28 and 1.8 log10 IU/mL,
respectively, at Week 24;

The proportion of currently not treated HBeAg-positive participants with >0.3 log10 IU/mL 
reductions from baseline in:

HBsAg was 8/23 (35%) vs 1/8 (13%) for placebo + NA;

HBeAg was 19/23 (83%) vs 4/8 (50%) for placebo + NA;

The 
proportion 
of 
virologically 
suppressed 
HBeAg-positive 
participants 
with 
>0.3 log10 IU/mL reductions in HBeAg was 7/19 (37%) vs 1/5 (20%) for placebo + NA.
No cases of virologic breakthrough were observed in any of the arms combining JNJ-6379/placebo 
with NA treatment. Confirmed viral breakthrough (defined as confirmed on-treatment HBV DNA 
increase by >1 log10 IU/mL from nadir) occurred in 5/28 participants on JNJ-6379 75 mg 
monotherapy. All 5 participants with virologic breakthrough had an emerging core amino acid 
mutation T33N (JNJ-6379 fold change of 85), which is known to confer reduced JNJ-6379 activity 
in vitro. All 5 participants discontinued JNJ-6379 and started NA treatment. An urgent safety 
measure was implemented to discontinue JNJ-6379 treatment in all participants in this arm and 
offer NA treatment. A futility rule was implemented in the 250-mg JNJ-6379 monotherapy arm (if 
≥1 participant in the 250-mg monotherapy arm experienced virologic breakthrough during the first 
24 weeks of treatment, NA treatment was to be added to JNJ-6379 treatment as soon as possible 
for all remaining participants).
In the monotherapy arm with 250 mg JNJ-6379, 1 participant with non-response (<1 log10 IU/mL 
decline from baseline at Week 4) had subsequent virologic breakthrough. This participant 
(genotype E) carried I105T baseline polymorphism (fold change of 2.7) and had no emerging 
mutations at HBV core protein positions of interest. The participant discontinued JNJ-6379 
treatment and started NA treatment at the withdrawal visit, due to meeting non-response criteria. 
NA treatment was added for all remaining participants in the JNJ-6379 250-mg monotherapy arm 
in accordance with the futility rule mentioned above.
NCT04667104


JNJ-73763989 and JNJ-56136379
Clinical Protocol 73763989PAHPB2006
Amendment 4
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
46
Status: Approved,  Date: 01 December 2021
Safety Studies
Data from 5 completed Phase 1 studies (56136379HPB1001, 56136379HPB1002, 
56136379HPB1003, 56136379HPB1004, and 56136379HPB1005) in healthy and chronic 
HBV-infected participants (N=126 and 41, respectively), indicate that orally administered 
JNJ-6379 as single doses up to 600 mg or as multiple doses (250 mg twice daily for 2 days followed 
by 170 mg QD for 18 days or 150 mg twice daily for 2 days followed by 100 mg QD for 10 days) 
in healthy participants and as multiple doses up to 250 mg for 28 days in chronic HBV-infected 
participants was safe and well tolerated. No SAEs considered at least possibly related to the study 
intervention were reported. Most AEs were mild and not considered treatment-related, with no 
dose-related trends. 
Safety data are also available from the Week 24 interim analysis (IA) conducted for the Phase 2a 
JADE study, which was mentioned above. There were no deaths or SAEs considered at least 
possibly related to the study intervention. Most AEs were grade 1 or 2 in severity. The majority of 
reported AEs were considered unrelated to JNJ-6379 by the investigator. Adverse events leading 
to treatment discontinuation were reported in 1 participant on placebo + NA (abdominal 
discomfort/gastrointestinal upset) and 1 participant on JNJ-6379 75 mg + NA (streptococcal toxic 
shock syndrome, acute cardiac failure, myocarditis and muscle necrosis). Most frequent grade 3 
or 4 AEs were gastrointestinal disorders (colitis and dyspepsia in the placebo + NA arm) and 
investigations (ALT and ALT elevations in the JNJ-6379 75 mg + NA and JNJ-6379 250 mg + NA 
arms).
Increased cholesterol is considered a laboratory abnormality of interest for JNJ-6379, based on 
safety review from nonclinical and clinical studies. Cholesterol increased was reported as an AE 
in 4 (4.1%) participants on JNJ-6379 for the pooled Phase 1 studies, in 1 (2.4%) participant on 
JNJ-6379 for the Phase 1 study 56136379HPB1005, and in none of the participants in the Phase 2a 
JADE study.
Combination of JNJ-3989 and JNJ-6379
Clinical data of triple combination treatment of JNJ-3989, JNJ-6379, and NA are available from 
the Phase 1/2a AROHBV1001 study (Cohort 12). Twelve adult chronic HBV mono-infected 
participants have received 3 subcutaneous injections of JNJ-3989 (200 mg Q4W) in combination 
with oral JNJ-6379 (250 mg QD) and oral NA treatment (ETV or tenofovir disoproxil). 
Up to the IA cut-off date of 29 October 2019, no deaths, SAEs, or treatment-emergent adverse 
events (TEAEs) leading to study drug discontinuation were reported. Two (16.7%) participants 
reported at least 1 TEAE during the treatment phase. The TEAEs (upper respiratory tract infection 
and hypertension) were of mild severity and considered not related to the study drug by the 
investigator.
The triple combination treatment of JNJ-3989, JNJ-6379, and NA is currently being investigated 
in chronic HBV mono-infected participants in the ongoing Phase 2 clinical studies 
73763989HPB2001 
(REEF-1, 
90 
participants 
in 
triple 
combination 
Arm 
1)
and
73763989PAHPB2002 (REEF-2, 80 participants in triple combination Arm 1). 
NCT04667104


JNJ-73763989 and JNJ-56136379
Clinical Protocol 73763989PAHPB2006
Amendment 4
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
47
Status: Approved,  Date: 01 December 2021
Since the initial protocol writing, interim results of the REEF-1 and REEF-2 studies had become 
available. In the primary REEF-1 analysis (Week 48, end of treatment) the mean reduction of 
HBsAg levels in the triple arm (JNJ-6379+JNJ-3989 100mg+NA) appeared to be less than in the 
dual arm (JNJ-3989 100mg+NA). More recent interim results of the REEF-2 study (Week 48, end 
of treatment) confirmed this observation when the effect of JNJ-6379+JNJ-3989 200mg+NA on 
mean HBsAg level reduction in REEF-2 study is compared to JNJ-3989 200mg+NA in the 
REEF-1 study. To match with the REEF-2 population, this cross-study comparison focused on the 
REEF-1 subpopulation of HBeAg negative, virologically suppressed participants with chronic 
hepatitis B. PK-PD modelling analyses accounting for variability in baseline characteristics further 
support this observation. Therefore, a negative effect of JNJ-6379 on the HBsAg lowering effect 
of JNJ-3989+NA is suspected.
2.2.3.2.
Combination of JNJ-3989 and JNJ-6379 with Entecavir, Tenofovir 
Disoproxil, or Tenofovir Alafenamide
Entecavir monohydrate is an HBV NA reverse transcriptase inhibitor indicated for the treatment 
of chronic HBV infection in adults and children at least 2 years of age with evidence of active viral 
replication and either evidence of persistent elevations in serum aminotransferases (ALT or 
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 between JNJ-6379 or JNJ-3989 and ETV (Memorandum 2005).
Tenofovir disoproxil (available in several salt forms including tenofovir disoproxil fumarate and 
tenofovir disoproxil maleate) is a first-generation oral prodrug of the NA tenofovir that is indicated 
for the treatment of chronic HBV infection in adult and pediatric patients at least 12 years of age. 
In addition, tenofovir disoproxil in combination with other antiretrovirals is indicated for the 
treatment of human immunodeficiency virus type 1 (HIV-1) infection in adult and pediatric 
patients at least 2 years of age. The most common adverse reactions (≥10% of participants) are 
abdominal pain, nausea, insomnia, pruritus, vomiting, dizziness, and pyrexia. 
Tenofovir alafenamide is an ester prodrug of the NA tenofovir that is indicated for the treatment 
of chronic HBV infection in adults and that is characterized by a better safety profile than tenofovir 
disoproxil. The most common adverse reaction (≥10% of participants) is headache. 
The single common toxicity target organ between JNJ-6379, JNJ-3989, and tenofovir disoproxil 
or TAF is the kidney (see Section 2.2.2.2, Combination of JNJ-3989 or JNJ-6379 With Entecavir, 
Tenofovir Disoproxil, or Tenofovir Alafenamide). 
Clinical data on dual combination treatment of JNJ-6379 and NA are available from the ongoing 
Phase 2a 56136379HPB2001 study (IB JNJ-6379 2021). In participants treated with tenofovir 
disoproxil, Ctrough concentrations of tenofovir at Week 12 were higher in participants receiving 
tenofovir disoproxil in combination with JNJ-6379 than in participants receiving tenofovir 
disoproxil as monotherapy (94.2 [30.0] and 115 [66.0] ng/mL for 75- and 250-mg JNJ-6379, 
respectively in combination with tenofovir disoproxil, vs 66.8 [37.0] ng/mL as tenofovir disoproxil 
monotherapy).
NCT04667104


JNJ-73763989 and JNJ-56136379
Clinical Protocol 73763989PAHPB2006
Amendment 4
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
48
Status: Approved,  Date: 01 December 2021
Clinical data of triple combination treatment of JNJ-3989, JNJ-6379, and NA are available from 
the Phase 1/2a AROHBV1001 study (see Section 2.2.3.1, JNJ-3989 and JNJ-6379). Dosing 
JNJ-6379 with NA for 12 weeks did not show 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-6379 or JNJ-3989 are 
combined with ETV, or tenofovir disoproxil, or TAF:

Available toxicology data, described in Section 2.2.2.2, Combination of JNJ-3989 or 
JNJ-6379 With Entecavir, Tenofovir Disoproxil, or Tenofovir Alafenamide.

In vitro drug transporters.

Metabolic interaction data.

Absence of relevant DDIs in the combination toxicity studies up to 3 months with JNJ-6379 
and JNJ-3989.

Absence of synergistic or additive histology findings in the kidney observed in the 
combination toxicity studies up to 3 months with JNJ-6379 and JNJ-3989.

Available clinical data with JNJ-6379 (JADE study [56136379HPB2001]) up to 24 weeks 
treatment on the absence of changes in kidney parameters/glomerular function.

Available clinical data of triple combination treatment of JNJ-3989, JNJ-6379, and NA 
described in Section 2.2.3.1, JNJ-3989 and JNJ-6379.
In addition, pancytopenia in 1 rat and a mild platelet decrease were seen in the combination groups 
in the 3-month combination toxicity study (preliminary data, Section 2.2.2.1, JNJ-3989 and 
JNJ-6379). No significant abnormalities of hematologic parameters have been observed in clinical 
studies to date. The sponsor is implementing additional monitoring of significant on-treatment 
hematologic changes in clinical studies with dosing longer than 4 weeks (see Section 8.3.6.6, 
Hematologic Abnormalities). For further information, refer to the latest version of the IBs for 
JNJ-3989 and JNJ-6379 (IB JNJ-3989 2020; IB JNJ-6379 2021).
2.2.3.3.
Combination of JNJ-3989 and JNJ-6379 with PegIFN-α2a
PegIFN-α2a is a covalent conjugate of recombinant alfa-2a interferon that is indicated for the 
treatment of CHB 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.
NCT04667104


JNJ-73763989 and JNJ-56136379
Clinical Protocol 73763989PAHPB2006
Amendment 4
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
49
Status: Approved,  Date: 01 December 2021
Treatment with PegIFN-α2a has been associated with decreases in platelet count (common adverse 
reaction). In the Phase 1/2a AROHBV1001 study (see Section 2.2.3.1, JNJ-3989 and JNJ-6379), 
no effect on platelet count has been observed in the triple combination treatment cohort 12 
(JNJ-3989, JNJ-6379, and NA). Of the 84 adult chronic HBV-infected participants that received 
3 subcutaneous injections of JNJ-3989, 6 participants developed grade 1 platelet reduction with no 
general trend towards a continuous decline. For JNJ-6379, no effect on platelet count has been 
observed in ongoing Phase 2a 56136379HPB2001 study (JADE) for the 189 adult chronic 
HBV-infected participants that were dosed with JNJ-6379.
Based on pre-clinical data, a potential common toxicity target organ between JNJ-6379, JNJ-3989, 
and PegIFN-α2a is the bone marrow (see Section 2.2.2, Nonclinical Studies). Bone marrow 
suppression is a known side effect of PegIFN-α2a (rare).
No PK interaction is expected between JNJ-3989 or JNJ-6379 and PegIFN-α2a based on the
known pharmacologic profile of the compounds (IB JNJ-3989 2020; IB JNJ-6379 2021; Yeh 
2019).
Since initial 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 2.2.2.3, Combination of 
JNJ-3989 or JNJ-6379 With PegIFN-α2a. 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 and 
JNJ-6379 may be found in the respective IBs (IB JNJ-3989 2020; IB JNJ-6379 2021).
For the benefit-risk evaluation of ETV, tenofovir disoproxil, TAF, and PegIFN-α2a, refer to the 
respective prescribing information and Summary of Product Characteristics.
JNJ-6379 was initially part of the study intervention but has been removed as study intervention 
with the implementation of an urgent safety measure, as described in Protocol Amendment 3. 
Emerging data from the REEF-1 and REEF-2 studies resulted in an unfavorable benefit-risk 
balance of JNJ-6379 in combination with JNJ-3989+NA, compared to JNJ-3989+NA alone. 
Therefore, the Sponsor decided to discontinue treatment with JNJ-6379 in all ongoing clinical 
studies effective immediately and as an urgent safety measure. Participants who were on treatment 
with JNJ-6379 were contacted and requested to stop taking JNJ-6379, while continuing treatment 
with NA, JNJ-3989 and PegIFN-α2a. For newly enrolled participants, JNJ-6379 was taken out of 
the treatment regimen. For completeness, the benefit-risk assessment for JNJ-6379 is still included 
in this section.
NCT04667104


JNJ-73763989 and JNJ-56136379
Clinical Protocol 73763989PAHPB2006
Amendment 4
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
50
Status: Approved,  Date: 01 December 2021
2.3.1.
Benefits for Study Participation
2.3.1.1.
Known Benefits
The clinical benefit of JNJ-3989 and JNJ-6379 remains to be established.
2.3.1.2.
Potential Benefits
Results from clinical studies with JNJ-3989, JNJ-6379, NAs, and PegIFN-α2a may be useful for 
the development of a novel therapeutic approach for chronic HBV infection.
The combination of JNJ-6379 and JNJ-3989 on a background of NAs would target different stages 
of the viral life cycle. While NA treatment reduces HBV DNA to levels close to or below the 
LLOQ of the HBV DNA assay, HBV replication is not completely inhibited, resulting in 
replenishment of the cccDNA pool. The addition of JNJ-6379, which targets the HBV capsid 
assembly (“primary” mode of action [MoA]) and the de novo cccDNA formation (“secondary” 
MoA), is expected to block HBV replication more profoundly by inhibiting formation of HBV 
RNA and DNA containing particles, and to inhibit de novo cccDNA formation, ultimately leading 
to reduction in cccDNA levels/transcriptional activity and HBsAg seroclearance (“intensified viral 
suppression”). The addition of JNJ-3989 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 short-term PegIFN-α2a (12 weeks) 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 
short-term 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
No known risks associated with JNJ-3989 or JNJ-6379 have been identified from clinical 
observations so far in the Phase 1 and 2 studies. Injection site reactions were identified as adverse 
drug reactions for JNJ-3989.
Side effect profile of PegIFN-α2a is well established and includes, but is not limited to, 
neuropsychiatric, autoimmune, ischemic, ophthalmologic, hematological, and infectious 
disorders. 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.
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JNJ-73763989 and JNJ-56136379
Clinical Protocol 73763989PAHPB2006
Amendment 4
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
51
Status: Approved,  Date: 01 December 2021
2.3.2.2.
Potential Risks
All therapies have the potential to cause adverse experiences. In addition, the discontinuation of 
NA treatment bares a risk of hepatitis B flares.
Patients with positive HBV DNA and positive HBsAg can always experience increases in liver 
transaminases which may indicate immune activation and may result in the reduction of viral 
parameters such as HBV DNA and/or HBsAg/HBeAg. Whether this occurs at higher frequency 
during or after treatment with JNJ-6379 and JNJ-3989 is not known.
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
Reproductive Risks and Pregnancy
In the EFD studies, JNJ-3989 was not teratogenic in rats and rabbits. The fertility in male and 
female rats is not impacted with JNJ-3989 up to a dose of 180 mg/kg/week.
Based on the difference in metabolic pathways and in vitro data indicating absence of impact of 
JNJ-3989 on CYP enzymes and transporters, no clinically relevant interactions are anticipated 
between JNJ-3989 and oral contraceptives. 
Potential Genotoxicity
JNJ-3989 is considered to be devoid of genotoxic activity. Nonclinical carcinogenicity studies 
have not been conducted. 
Other Potential Toxicity/Events of Special Interest
JNJ-3989 is considered non-cytotoxic, did not activate human platelet aggregation, did not activate 
the innate immune system to a significant degree in vitro, and did not activate complement in vitro. 
Viral Resistance
Treatment with JNJ-3989 may lead to viral resistance, but resistance to JNJ-3989 is not anticipated 
to impact treatment with other siRNAs. 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 JNJ-6379
Since the initial protocol writing, interim results of the REEF-1 and REEF-2 studies had become 
available. The data suggested that JNJ-6379 has a negative impact on the HBsAg lowering effect 
of JNJ-3989+NA (see Section 2.2.3.1). In addition, there were new insights in the adverse renal 
profile of JNJ-6379, resulting from increase in biomarkers of proximal renal tubular injury 
observed in REEF-2. Taken together, it was concluded that JNJ-6379 had an unfavorable benefit-
risk balance in combination with JNJ-3989+NA, compared to JNJ-3989+NA alone. Therefore, the 
NCT04667104


JNJ-73763989 and JNJ-56136379
Clinical Protocol 73763989PAHPB2006
Amendment 4
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
52
Status: Approved,  Date: 01 December 2021
Sponsor decided to discontinue treatment with JNJ-6379 in all ongoing clinical studies effective 
immediately. For completeness, the potential risks for JNJ-6379 are still described in this section.
Reproductive Risks and Pregnancy
In the fertility study in females, early embryonic development was affected: an increase in pre- and 
post-implantation loss, reduction in implantation and live fetuses at 300 mg eq./kg/day. The fetal 
loss seen during the early stages of pregnancy was considered the result of low hormone levels 
(decreased luteinizing hormone, progesterone, estradiol) induced by treatment with JNJ-6379. 
In the EFD studies, JNJ-6379 was not teratogenic in rats and rabbits. 
In the EFD study in rats, fetal weights at 300 mg eq./kg/day were lowered, and there was retarded 
ossification from 100 mg eq./kg/day onwards. The NOAEL for EFD was considered to be 
mg eq./kg/day. At this dose, the AUC0-24h was 84,000 ng.h/mL and the Cmax was 5,190 ng/mL.
In the EFD study in rabbits, the NOAEL for EFD was considered to be the highest dose tested, ie, 
mg eq./kg/day. At this dose, the AUC0-24h was 99,200 ng.h/mL and the Cmax was 6,880 ng/mL.
Potential Genotoxicity
JNJ-6379 was not genotoxic in the in vitro and in vivo tests.
JNJ-6379 did not affect male or female fertility. Carcinogenicity studies are not yet conducted.
Other Potential Toxicity/Events of Special Interest
Based on nonclinical findings in rats and dogs and based on clinical findings, increased cholesterol 
was identified as a laboratory abnormality of interest. 
Viral Resistance
Treatment with JNJ-6379 may lead to emergence of viral variants with reduced susceptibility or 
resistance to JNJ-6379. Based on nonclinical data, these variants remain susceptible to tenofovir 
disoproxil and ETV but might affect treatment options with CAMs in the future. All 5 participants 
with virologic breakthrough in the JADE study who received 75 mg JNJ-6379 monotherapy, had 
an emerging core amino acid mutation T33N, which is known to confer reduced JNJ-6379 activity 
in vitro (see Section 2.2.3.1, JNJ-3989 and JNJ-6379, for the results of the IA). 
Drug-drug Interactions
Based on results from DDI study 56136379HPB1004 investigating the potential effect of 
coadministration of JNJ-6379 with oral contraceptives, it is not anticipated that the efficacy of oral 
contraceptives will be impacted during coadministration with JNJ-6379 since the exposure of a 
progestin sensitive to CYP3A4 induction was not significantly affected by coadministration of 
JNJ-6379. In contrast, it is anticipated that coadministration with ethinylestradiol-containing 
contraceptives will result in an increased exposure to ethinylestradiol. Therefore, specific 
requirements on the use of ethinylestradiol-containing contraceptives are included in Section 6.5, 
Concomitant Therapy.
CC
I
CC
I
NCT04667104


JNJ-73763989 and JNJ-56136379
Clinical Protocol 73763989PAHPB2006
Amendment 4
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
53
Status: Approved,  Date: 01 December 2021
2.3.2.2.3.
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 with JNJ-3989 and JNJ-6379 might increase the risk of 
hematologic abnormalities and/or of bone marrow suppression.

JNJ-6379 might increase tenofovir plasma concentrations.
2.3.3.
Benefit-Risk Assessment for Study Participation
Based on the available data and proposed safety measures, the overall risk/benefit assessment for 
JNJ-3989 and JNJ-6379 clinical studies is deemed acceptable for the following reasons:

At the time of protocol writing, JNJ-3989 was generally safe and well tolerated during the 
Phase 1/2a Study AROHBV1001 (see Section 2.2.3, Clinical Studies). All but one AE were 
mild or moderate in severity. All ISRs, identified as adverse drug reactions for JNJ-3989, were 
mild in intensity. 

No clinically significant safety concerns had been raised for JNJ-6379 at the time of initial 
protocol writing, based on the safety information from studies in healthy adult participants 
and adult participants with chronic HBV infection. Most observed AEs at that time were mild 
in severity and considered not related to JNJ-6379 by the investigator (see Section 2.2.3, 
Clinical Studies). At the time of Protocol Amendment 3 writing, it was concluded that JNJ-
6379 has an unfavorable benefit-risk balance in combination with JNJ-3989+NA, compared 
to JNJ-3989+NA alone (see Section 2.3.2.2.2). Therefore, the Sponsor decided to discontinue 
treatment with JNJ-6379 in all ongoing clinical studies effective immediately, as a measure to 
minimize risk to participants of this and other study.

Events of Special Interest are significant AEs that are judged to be of special interest because 
of clinical importance, known class effects or based on nonclinical signals. Events of Special 
Interest that will be carefully monitored during the study include ISRs, ALT/AST elevations, 
renal complications, hematologic abnormalities, and events related to cholesterol increase (see 
Section 8.3.6, Adverse Events of Special Interest, and Section 8.2.4, Clinical Safety 
Laboratory Assessments). In addition, the following toxicities will also be carefully 
monitored: rash and acute systemic allergic reactions (Section 8.3.6, Adverse Events of 
Special Interest). 

Continued careful assessment of the safety, efficacy, and PK during treatment is included in 
this study. 

To minimize potential risk and stress to participants, the following measures are in place:

Utilization of selection criteria which exclude participants who may potentially be at 
higher risk of an AE (see Section 5, Study Population).
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JNJ-73763989 and JNJ-56136379
Clinical Protocol 73763989PAHPB2006
Amendment 4
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Status: Approved,  Date: 01 December 2021

Utilization of withdrawal criteria (see Section 7, Discontinuation of Study Intervention 
and Participant Discontinuation/Withdrawal). If a participant drops out due to withdrawal 
of consent, he/she retains the option to participate in the safety follow-up procedures.

At regular time points throughout the study (see Schedule of Activities), blood samples 
for biochemistry, blood coagulation, and hematology and urine samples for urinalysis, 
urine chemistry, and renal biomarkers will be collected. Vital signs (systolic and diastolic 
blood pressure, pulse rate, and body temperature), height (only at screening), body 
weight, and electrocardiograms (ECGs) will be recorded throughout the study. Physical 
examinations will be performed and AEs will be assessed (see Section 8.2, Safety 
Assessments). Events of Special Interest will be closely monitored (Section 8.3.6, 
Adverse Events of Special Interest).

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 or 
JNJ-6379 With 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 of treatment 
and combination of PegIFN-α2a with JNJ-6379 induces minimal additive effect in in vitro 
study. Forty-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.

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 (see Section 9.6, Data Review 
Committee). In addition, an Independent Flare Expert Panel (IFLEP) will be appointed 
to characterize and adjudicate each ALT flare (see Section 9.7, Independent Flare Expert 
Panel).

After stopping treatment with JNJ-3989, JNJ-6379, PegIFN-α2a, and NA, if NA 
completion criteria are met at Week 24 (EOSI), participants will be monitored closely 
during the FU Period, with frequent follow-up visits and pre-defined NA re-treatment 
criteria in case of flares (Section 6.7.1, NA Re-treatment Criteria and Monitoring After 
Stopping of NA).

The post-treatment monitoring and NA re-treatment criteria were further updated based 
on findings from a case of post-treatment HBV reactivation with subacute hepatic failure 
and assessment of additional REEF-2 study data (Section 6.7.1, NA Re-treatment Criteria 
and Monitoring After Stopping of NA)

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).
NCT04667104


NCT04667104


NCT04667104


JNJ-73763989 and JNJ-56136379
Clinical Protocol 73763989PAHPB2006
Amendment 4
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
57
Status: Approved,  Date: 01 December 2021
HYPOTHESIS
As this is an exploratory single-arm study, no formal statistical hypothesis has been formulated.
4.
STUDY DESIGN
4.1.
Overall Design
This ISA describes a Phase 2a study of the combination regimen of JNJ-3989 with NA and 
PegIFN-α2a. Prior to Protocol Amendment 3, the study intervention also included JNJ-6379. This 
ISA is a companion document to the Master Protocol PLATFORMPAHPB2001, which describes 
the common design elements of the Platform study in participants with CHB. This ISA describes 
specific and/or additional protocol elements applicable to this open-label, single-arm, multicenter,
interventional study to evaluate the efficacy, safety, tolerability, and PK of the combination of 
JNJ-3989, NAs, and PegIFN-α2a in approximately 50 patients with CHB. 
Note that as of Protocol Amendment 3, JNJ-6379 has been removed as study intervention and the 
study will continue with JNJ-3989, NA and PegIFN-α2a only. Participants had to stop JNJ-6379 
treatment immediately. 
Approximately 50 virologically suppressed CHB-infected participants, 18-65 years (inclusive) of 
age, will be enrolled in this study. Approximately 40% HBeAg-positive participants will be 
enrolled.
This open-label study will be conducted in 4 periods:

Screening Period (4 weeks [if necessary, can be extended to a maximum of 8 weeks decided 
on a case-by-case basis and in agreement with the sponsor]).

Treatment Period 1 (12 weeks) consisting of combination treatment with JNJ-3989 + NA.

Treatment Period 2 (12 weeks) adding PegIFN-α2a to the combination treatment regimen of 
Treatment Period 1.

Follow-up (FU) Period (48 weeks).
The total duration of individual participation will be up to 76 weeks (including 4 weeks of 
screening).
Enrolled participants will start Treatment Period 1 with the following combination treatment 
regimen for a duration of 12 weeks:
200 mg JNJ-3989 (subcutaneous injection Q4W) +
NA (tablets QD): tenofovir disoproxil (245 mg), or TAF (25 mg), or ETV (0.5 mg).At Week 12, 
participants who still meet the eligibility criteria for PegIFN-α2a (see Section 5.2, Exclusion 
Criteria) will start Treatment Period 2 for a duration of 12 weeks:
200 mg JNJ-3989 (subcutaneous injection Q4W) +
NA (tablets QD): tenofovir disoproxil (245 mg), or TAF (25 mg), or ETV (0.5 mg) +
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JNJ-73763989 and JNJ-56136379
Clinical Protocol 73763989PAHPB2006
Amendment 4
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Status: Approved,  Date: 01 December 2021
180 µg PegIFN-α2a (subcutaneous injection once weekly).Participants no longer meeting the 
PegIFN-α2a eligibility criteria at Week 12 will continue with the Period 1 treatment until Week 
24.
At Week 24, all participants will stop treatment with JNJ-3989 + PegIFN-α2a and start the FU 
Period. If the protocol-defined NA treatment completion criteria (HBsAg <10 IU/mL, and HBeAg-
negative, and HBV DNA <LLOQ, and ALT <3x ULN) have been met at Week 24, NA will be 
stopped at the next scheduled visit (ie, FU Week 2), otherwise NA treatment will continue during 
the complete FU Period. Participants who meet the protocol-defined NA treatment completion 
criteria will be monitored closely during the 48-week FU Period and should re-start NA treatment 
immediately if NA re-treatment criteria are met (see Section 6.7.1, NA Re-treatment Criteria and 
Monitoring After Stopping of NA, for more details).
Both the Platform Master informed consent form (ICF) and the ISA ICF must be signed before the 
first study-related activity.
Participants may optionally participate in a PK substudy. Participants in the PK substudy will have 
intensive blood sampling for PK of JNJ-3989, and optionally for PK of NA and PegIFN-α2a, over 
24 hours at Week 4 (or 8) during Treatment Period 1 and at Week 20 (or 16) during Treatment 
Period 2.
Safety and tolerability, including AEs, laboratory assessments, ECGs, vital signs, and physical 
examination, will be assessed throughout the study from the time that the ISA ICF is signed until 
the completion of the last study-related activity (see Section 8.2, Safety Assessments, and 
Section 8.3, Adverse Events and Serious Adverse Events).
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). Sequencing of samples obtained may be triggered by 
the sponsor’s virologist based on changes in HBV DNA levels observed in each individual 
participant and the limits of the sequencing assay.
The study includes collection of blood samples for exploratory analysis of viral markers (see 
Section 8.1, Efficacy Assessments) and host blood biomarkers at the host RNA, protein, and cell 
level (see Section 8.9, Exploratory Host Biomarkers).
A population PK analysis may be performed based on the available data for JNJ-3989 (ie, 
JNJ-3976 and JNJ-3924), potentially in combination with data from a selection of Phase 1 and/or 
2 studies. PK parameters in participants undergoing intensive PK sampling will be calculated via 
noncompartmental methods (see Section 8.5, Pharmacokinetics). To assess the effect of PegIFN-
α2a on JNJ-6379 (as applicable) and JNJ-3989, the PK parameters of JNJ-6379  (as applicable), 
JNJ-3976, and JNJ-3924 coadministered with PegIFN-α2a at Week 20 (or 16) will be compared 
to those of JNJ-6379  (as applicable), JNJ-3976 and JNJ-3924 at Week 4 (or 8) as reference.
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Status: Approved,  Date: 01 December 2021
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).
A pharmacogenomic blood sample and samples for epigenetic testing will be collected from 
participants who consent separately to this component of the study (see Section 8.8, Host 
Genetics).
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 the investigational intervention (before Week 24/EOSI),
the participant will have an early withdrawal visit and will enter the 48-week FU Period as per the 
Schedule of Activities, unless the participant withdraws consent.
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.
The Schedule of Activities summarizes the frequency and timing of efficacy, safety, and other 
assessments applicable to the Master Protocol PLATFORMPAHPB2001 and this ISA.
An internal DRC will be commissioned for monitoring safety of participants enrolled in this study
(Section 9.6, Data Review Committee). In addition, an IFLEP will be appointed (Section 9.7, 
Independent Flare Expert Panel).
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.
4.2.
Scientific Rationale for Study Design
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). In addition, IFN-α is expected to act as immune 
booster with potential to reactivate NK-cells (Gill 2016). Addition of short-term PegIFN-α2a 
(12 weeks) 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.
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JNJ-73763989 and JNJ-56136379
Clinical Protocol 73763989PAHPB2006
Amendment 4
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60
Status: Approved,  Date: 01 December 2021
Study Design Change – Protocol Amendment 3
Based 
on 
emerging 
data 
from 
the 
REEF-1 
(73763989HPB2001) 
and 
REEF-2 
(73763989PAHPB2002) studies, the study design has been adapted in Protocol Amendment 3.
In summary, the data from the REEF-1 and REEF-2 studies suggested that JNJ-6379 has a negative 
impact on the HBsAg lowering effect of JNJ-3989+NA (see details in Section 2.2.3.1) and that 
JNJ-6379 in combination with TDF may further contribute to renal tubulo-toxicity (see details in 
Section 2.3.2.2.2). Together, this led to a conclusion of an unfavorable benefit-risk balance of 
JNJ-6379 in combination with JNJ-3989+NA, compared to JNJ-3989+NA alone. Therefore, the 
Sponsor decided to discontinue treatment with JNJ-6379 in all ongoing clinical studies effective 
immediately and as an urgent safety measure. Participants currently on treatment with JNJ-6379 
were contacted and requested to stop taking JNJ-6379, while continuing treatment with NA, JNJ-
3989, and PegIFN-α2a. For newly enrolled participants, JNJ-6379 was taken out of the treatment 
regimen.  
Furthermore, the sponsor decided to make additional changes to the study design because of a 
severe clinical ALT flare that was reported following discontinuation of NA treatment in a 
participant who was randomized to the control arm (placebo + placebo + NA) in the REEF-2 study. 
Discontinuation of NA treatment was following the protocol-defined criteria and in line with recent 
EASL treatment guidelines (EASL 2017). Flares following NA discontinuation are not 
unexpected, but the rapid evolution and clinical deterioration seen in this participant who had no 
history or evidence of liver cirrhosis was unforseeable. Therefore, to protect the safety of 
participants, the protocol was amended: more frequent monitoring of participants who 
discontinued NA treatment during follow-up was included and the NA re-treatment criteria for all 
participants who discontinued NA treatment were revised.
Criteria for Completion of NA Treatment
At the end of Treatment Period 2 (Week 24/EOSI), all participants will enter the FU Period and 
stop treatment with JNJ-3989 and PegIFN-α2a. If the protocol-defined NA treatment completion 
criteria (described in Section 6.6, Study Intervention Completion at Week 24) have been met at 
Week 24, NA will also be stopped at the next scheduled visit (ie, at FU Week 2), otherwise NA 
treatment will continue during the complete FU duration. 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 chance of sustained off-treatment response are allowed to 
stop all study intervention. Across a range of studies, HBsAg levels below 100 IU/mL are 
consistently associated with favorable off-treatment response (Jeng 2018; Papatheodoridis 2018). 
The stringent HBsAg cut-off of 10 IU/mL for NA treatment completion was chosen to account for 
the direct effect of JNJ-3989 on HBsAg levels.
After stopping all study interventions, participants will be monitored closely during the 48-week 
FU Period and should re-start NA treatment in accordance with the NA re-treatment criteria (see 
Section 6.7.1, NA Re-treatment Criteria and Monitoring After Stopping of NA, for more details).
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JNJ-73763989 and JNJ-56136379
Clinical Protocol 73763989PAHPB2006
Amendment 4
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Status: Approved,  Date: 01 December 2021
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 ≥3xULN 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 decompensated liver disease at the time of NA discontinuation. These 
patients are not eligible to participate in the study. Still, a vigilant follow-up of patients during this 
phase of the study is critical to ensure patient safety. Signs of decreased liver function, or an HBV 
DNA value of >100,000 IU/mL (irrespective of confirmation and/or ALT increase), will trigger 
immediate re-initiation of NA treatment based on protocol-defined NA re-treatment criteria (see 
Section 6.7.1, NA Re-treatment Criteria and Monitoring After Stopping of NA). 
Re-initiation of NA treatment is also required in case of confirmed HBeAg seroreversion (HBeAg 
positive after it was negative at NA completion), in case of confirmed* ALT increase (>5x ULN) 
in combination with increased HBV DNA replication (>2,000 IU/mL), and in case of confirmed*
increased HBV DNA replication at higher levels (>20,000 IU/mL).
* At least 4 weeks apart
A post-treatment HBV DNA value of >20,000 IU/mL should trigger re-testing of ALT/AST, HBV 
DNA, and total and direct bilirubin within a maximum of 7 days from receipt of the data and 
further repeats as necessary (ie, weekly until HBV DNA returns to <20,000 IU/mL). A post-
treatment HBV DNA value of >2,000 IU/mL (but <20,000 IU/mL) should trigger a re-test within 
14 days from receipt of the data and further repeats as necessary (ie, every other week until HBV 
DNA returns to <2,000 IU/mL). A post-treatment ALT value of >5x ULN should trigger re-testing 
of ALT, AST, ALP, total and direct bilirubin, INR, albumin, and HBV DNA on a weekly basis 
until ALT and AST levels have returned to <5x ULN. Additional re-testing and/or earlier restarting 
of NA treatment is at the investigator’s discretion, even if the above cut-offs are not yet met.
To avoid delays in decision making, sites are encouraged to run local re-testing in parallel with 
central re-testing in the situations described above that require more frequent re-testing. Local test 
results are to be recorded in the CRF and/or source documents, including information on the HBV 
DNA assay used. In addition, to avoid delays in NA re-treatment, it should be considered to 
dispense NA to participants who potentially met the NA re-treatment criteria (eg, pending 
confirmation) and who will not be available to come to the study site immediately at the time the 
confirmatory test results will become available. This should ensure that the participant can 
immediately restart NA treatment if indicated, upon direct confirmation by the investigator.
NA re-treatment criteria during follow-up are presented graphically in Section 10.12 Appendix 12: 
NA Re-treatment and Monitoring After Stopping of NA.
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JNJ-73763989 and JNJ-56136379
Clinical Protocol 73763989PAHPB2006
Amendment 4
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Status: Approved,  Date: 01 December 2021
Host DNA and Exploratory Host Biomarker Collection
Refer to Section 4.2 of the Master Protocol PLATFORMPAHPB2001.
4.2.1.
Study-Specific Ethical Design Considerations
Refer to Section 4.2.1 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 are selected to maximize the chance for patients to 
achieve functional cure and are supported by scientific understanding of available data. For both 
compounds, doses are selected that are currently being tested in ongoing Phase 2b studies REEF-1
(73763989HPB2001) and REEF-2 (73763989PAHPB2002) (ie, 200 mg for JNJ-3989). Addition 
of short-term PegIFN-α2a (12 weeks) 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.
Note: JNJ-6379 was initially part of the study intervention, but has been removed as study 
intervention with the implementation of an urgent safety measure, as described in Protocol 
Amendment 3. 
4.3.1.
JNJ-3989
Clinical data on PK and safety of JNJ-3989 are available from the Phase 1/2a AROHBV1001 study 
with a data cut-off date of 29 October 2019. In addition, snapshot efficacy and PD data are 
available with a data cut-off date of 26 March 2020. The study has been completed and final 
analysis and report writing are ongoing. 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 
2020). 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 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 
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Status: Approved,  Date: 01 December 2021
at doses between 100 mg and 400 mg JNJ-3989, a numerically smaller mean decline was observed 
at the lower doses of 25 mg and 50 mg, mainly apparent after end of JNJ-3989 dosing.
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. 
The Phase 2b study REEF-1 is designed to establish the optimal dose of JNJ-3989. Based on data 
from the Phase 1/2a study AROHBV1001 with limited treatment duration, 200 mg was selected 
as the highest dose of JNJ-3989 tested in REEF-1. Until lower doses are proven equivalently 
effective in REEF-1, additional combination studies with JNJ-3989 and JNJ-6379 are conducted 
with 200 mg of JNJ-3989.
4.3.2.
JNJ-6379
Note: JNJ-6379 was initially part of the study intervention but has been removed as study 
intervention with the implementation of an urgent safety measure, as described in Protocol 
Amendment 3.
At the time of initial protocol writing, a dose of 250 mg JNJ-6379 QD was chosen for this study. 
A dose of 250 mg of JNJ-6379 was considered to ensure maximal viral inhibition via “primary” 
MoA (ie, interfering with the capsid assembly process). In addition, it ensured sufficiently high 
exposures to engage the “secondary” MoA (ie, inhibition of de novo cccDNA formation). This 
dose selection was supported by translational PK/PD analyses and viral kinetic modeling. Analyses 
of the HBV DNA data from the 4-week 56136379HPB1001 study showed a profound but slightly 
less substantial reduction of plasma HBV DNA, as a measure of the “primary” MoA, in the 25-mg 
dose group compared to the 75-mg and higher dose groups, suggesting that for JNJ-6379 maximum 
effect (Emax) in terms of HBV DNA inhibition via primary MoA was approached starting from a 
dose of 75 mg onwards. Since it was not possible to derive the engagement of the “secondary” 
MoA from the available short term data, the in vitro primary human hepatocyte 90% effective 
concentration values in the presence of serum proteins obtained for both MoAs were used to 
translate from the “primary” to the “secondary” MoA.
Interim analysis data are available from the ongoing Phase 2a JADE study in which the 250-mg 
dose is being tested for 48 weeks. Unblinded Week 24 data from 63 chronic HBV-infected 
participants who received 250 mg QD JNJ-6379 in addition to an NA showed that there were no 
deaths or AEs leading to discontinuation. Most AEs were mild or moderate in severity. Grade 3 or 
4 AEs were reported in 6 (10%) participants in this treatment arm (most frequently ALT and AST 
elevations).
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) 
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JNJ-73763989 and JNJ-56136379
Clinical Protocol 73763989PAHPB2006
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Status: Approved,  Date: 01 December 2021
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 
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)
Male or female participants ≥18 years of age (or older if the legal age of consent in 
the jurisdiction in which the study is taking place is >18) to ≤65 years of age.
M02
Participants must be medically stable based on physical examination, medical 
history, vital signs, and 12-lead ECG performed at screening. If there are 
abnormalities, they must be consistent with the underlying illness in the study 
population. This determination must be recorded in the participant’s source 
documents and initialed by the investigator.
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Clinical Protocol 73763989PAHPB2006
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Status: Approved,  Date: 01 December 2021
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 on stable HBV treatment, defined as currently receiving NA treatment for 
at least 6 months prior to screening and having been on the same NA treatment 
regimen (at the same dose) as used in this study for at least 3 months at the 
time of screening, AND

have serum HBV DNA <60 IU/mL on 2 sequential measurements at least 
6 months apart (one of which is at screening), AND

have documented ALT values <2.0x ULN on 2 sequential measurements at 
least 6 months apart (one of which is at screening).
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.
A05 
(adapted 
from M05)
Participants must sign a Master ICF (specific for the Master Protocol 
PLATFORMPAHPB2001) and must sign an ICF specific for this intervention 
cohort, indicating that he or she understands the purpose of, and procedures 
required for, the study and is willing to participate in the study.
M06
Participants must sign a separate ICF if he or she agrees to provide an additional 
optional DNA sample for research (where local regulations permit). Refusal to give 
consent for the optional DNA research sample does not exclude a participant from 
participation in the study.
Note: a mandatory sample for human leukocyte antigen (HLA) haplotyping will be 
collected from all participants.
A07 
(adapted 
from M07)
Criterion modified per Amendment 3
A07.1 Female participants must be (as defined in Section 10.5 Appendix 5: 
Contraceptive and Barrier Guidance):
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 
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JNJ-73763989 and JNJ-56136379
Clinical Protocol 73763989PAHPB2006
Amendment 4
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Status: Approved,  Date: 01 December 2021

Participants with a positive IgM antibody test for HEV infection may be 
enrolled after discussion with the sponsor if an active HEV infection can be 
ruled out by documentation of negative anti-HEV IgG.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 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 has been ruled 
out by a more specific imaging procedure (contrast-enhanced ultrasound, CT or 
MRI).
A06 
(adapted 
from M06)
Criterion modified per Amendment 3
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 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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Clinical Protocol 73763989PAHPB2006
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Status: Approved,  Date: 01 December 2021
a.
Estimated glomerular filtration rate (eGFR) <80 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. 
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, 
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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 6.5, 
Concomitant Therapy, before screening or baseline.
M17
Participants having used any invasive investigational medical device within 
3 months, or having received an investigational intervention or a biological 
product, immunoglobulin or other blood product not intended for the treatment of 
HBV within 6 months or 5 half-lives (whichever is longer), before the planned first 
dose of study intervention, or is currently enrolled in an interventional clinical 
study with an investigational product.
A18 
(adapted 
from M18)
Female participants who are pregnant, or breast-feeding, or planning to become 
pregnant while enrolled in this study or within 90 days after the last dose of study 
intervention.
A19 
(adapted 
from M19)
Male participants who plan to father a child while enrolled in this study or within 
90 days after the last dose of study intervention.
M20
Participants who had major surgery (eg, requiring general anesthesia), excluding 
diagnostic surgery, within 12 weeks before screening; or will not have fully 
recovered from surgery; or have surgery planned during the time of expected 
participation in the study.
Note: Participants with planned surgical procedures to be conducted under local 
anesthesia may participate.
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NOTE: Investigators should ensure that all study enrollment criteria have been met at screening. 
If a participant’s clinical status changes (including any available laboratory results or receipt of 
additional medical records) after screening but before the first dose of study intervention is given 
such that he or she no longer meets all eligibility criteria, then the participant should be excluded 
from participation in the study. The required source documentation to support meeting the 
enrollment criteria are noted in Attachment 3 of the Master Protocol PLATFORMPAHPB2001.
5.3.
Lifestyle Considerations
Potential participants must be willing and able to adhere to the following lifestyle restrictions 
during the course of the study to be eligible for participation:
1.
Agree to follow all requirements outlined in Section 6.5, Concomitant Therapy, 
regarding prohibited and restricted therapy during the study.
2.
Agree to follow all requirements that must be met during the study as noted in the 
Inclusion and Exclusion Criteria (eg, contraceptive requirements).
5.4.
Screen Failures
Refer to Section 5.4 of the Master Protocol PLATFORMPAHPB2001 for handling of screen 
failures and use of participant identification, enrollment, and screening logs.
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6.
STUDY INTERVENTION AND CONCOMITANT THERAPY
6.1.
Study Intervention(s) Administered
Description of Interventions
Intervention Name
JNJ-3989
JNJ-6379***
PegIFN-α2a
Tenofovir disoproxil 
Tenofovir 
alafenamide (TAF)*
Entecavir (ETV) 
monohydrate
Type
Drug
Drug
Drug
Drug
Drug
Drug
Dose Formulation
Solution for injection
Tablets
Solution for injection
Film-coated tablets
Film-coated tablets
Film-coated tablets
Unit Dose Strength(s)
200 mg/mL
25 and 100 mg
180 µg/0.5 mL
245 mg
25 mg
0.5 mg
Dosage Level(s)
200 mg once every 4 
weeks (Q4W)
250 mg once daily 
(QD)
180 µg once weekly 
(QW)
245 mg QD
25 mg QD
Lamivudine-
refractory patients: 
1 mg** QD (but 
should preferably be 
treated with 
tenofovir disoproxil
or TAF* instead)
Other indications:
1 mg** QD (must be 
agreed upon by the 
sponsor)
Route of Administration
Subcutaneous 
injection (in the 
abdomen)
Oral
Subcutaneous 
injection (in the thigh 
or abdomen)
Oral
Oral
Oral
Use
Investigational 
intervention
Investigational 
intervention
Investigational 
intervention
Background 
intervention
Background 
intervention
Background 
intervention
Investigational Medicinal 
Product (IMP)
Yes
Yes
Yes
Yes
Yes
Yes
Non-investigational 
Medicinal Product/ 
Auxiliary Medicinal 
Product (NIMP/AxMP)
No
No
No
No
No
No
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Status: Approved,  Date: 01 December 2021
Intervention Name
JNJ-3989
JNJ-6379***
PegIFN-α2a
Tenofovir disoproxil 
Tenofovir 
alafenamide (TAF)*
Entecavir (ETV) 
monohydrate
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
Provided centrally by 
the sponsor
Packaging and Labeling
Each unit will be 
labeled with unique 
medication ID 
number
Each unit will be 
labeled with unique 
medication ID 
number.
Commercial supplies 
will be sourced. 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
In child-resistant 
packaging
Labels will contain information to meet the applicable regulatory requirements.
Food/Fasting Instructions
Regardless of food 
intake
Regardless of food 
intake
Per the prescribing 
information
Per the prescribing 
information
Per the prescribing 
information
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.
** 2 tablets of 0.5 mg.
*** Participants enrolled before Protocol Amendment 3 was in effect, may have received JNJ-6379 as part of their study intervention. As of Protocol Amendment 3: 
Study intervention includes JNJ-3989, NA and PegIFN-α2a
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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, 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 Treatment Period 2 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 8.4, Treatment of Overdose.
6.2.
Preparation/Handling/Storage/Accountability
Preparation/Handling/Storage
All study intervention must be stored as specified on the product-specific labeling.
Study site personnel will instruct participants on how to store 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 
intervention. The JNJ-3989 and PegIFN-α2a injections administered to the participant at the study 
                                                
a For participants in Japan, weekly administration of PegIFN-α2a must be performed at the study site by the 
investigator or his/her designee.
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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.
Participants who stopped JNJ-6379 per Protocol Amendment 3, must return their JNJ-6379 supply 
at the next scheduled visit. The return of JNJ-6379 from the participant must be documented on 
the intervention accountability form.
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
As this is a single-arm study, randomization procedures are not applicable.
Blinding
As this is an open-label study, blinding procedures are not applicable.
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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.
Concomitant Therapy
Note: With the removal of JNJ-6379 as study intervention in Protocol Amendment 3, 
JNJ-6379-specific disallowed medications and concomitant medications to be used with caution 
are no longer applicable and have been removed.
An overviews 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 
                                                
a Not applicable for participants in Japan, where weekly administration of PegIFN-α2a must be performed at the study 
site by the investigator or his/her designee.
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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 Treatment Period 2: 

COVID-19 vaccine and PegIFN-α2a should not be administered on the same day.

If required, PegIFN-α2a injection can be delayed with 2 days. The next PegIFN-α2a injection 
should be performed 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.
Table 3:
Disallowed Medication
Disallowed at any time prior to screening until end of follow-up:

Any CAM, oligonucleotide-based treatment (eg, siRNA, nucleic acid polymers, and antisense 
oligonucleotides), and IFN, other than the study intervention taken in the context of this study.
Note: Prior hepatic treatment with herbal or nutritional products is also allowed but should be stopped at 
screening.
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: Approved COVID-19 vaccines or COVID-19 vaccines with conditional marketing authorization, 
emergency use authorization or special approval for emergency are allowed.
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. 
Note: NA standard of care treatment is allowed between screening and baseline.

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.
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Status: Approved,  Date: 01 December 2021
Note: The list of disallowed concomitant medication is not exhaustive; for products falling in one 
of the categories and not mentioned by name, the sponsor should be contacted to determine 
whether the product can be allowed.
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, 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 away from the JNJ-3989 and PegIFN-α2a injection sites.
6.6.
Study Intervention Completion at Week 24
With the implementation of Protocol Amendment 3, all participants had to stop JNJ-6379 
treatment immediately.
Participants will stop treatment with JNJ-3989 and PegIFN-α2a at Week 24 (EOSI). If all of the 
following NA treatment completion criteria are met at Week 24, treatment with NA will also be 
stopped at the next scheduled visit (ie, FU Week 2):

The participant has ALT <3x ULN, AND

The participant has HBV DNA <LLOQ, AND

The participant is HBeAg-negative, AND

The participant has HBsAg <10 IU/mL.
Note: In case of ALT elevation ≥3x ULN at Week 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 at Week 24 should continue NA treatment during 
the 48-week FU Period. 
If a participant prematurely discontinues investigational intervention before Week 24, follow-up 
assessments should be obtained as per the Schedule of Activities until 48 weeks after the end of 
investigational intervention unless the participant withdraws consent. In this case, NA treatment 
may be continued or, in consultation with the sponsor, discontinued, based on the above-mentioned 
NA treatment completion criteria.
6.7.
Dose Modification
Dose modifications of JNJ-3989 and NA (increase or decrease of dose level) are not allowed 
during the study.
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Status: Approved,  Date: 01 December 2021
For PegIFN-α2a, dose adjustment guidelines are applicable for participants who develop 
laboratory abnormalities during PegIFN-α2a treatment, as recommended in the locally approved 
prescribing information for PegIFN-α2a and upon investigator’s assessment. 
In exceptional circumstances (ie, laboratory abnormalities during PegIFN-α2a treatment) the use 
of a local laboratory may be considered in parallel to the central laboratory testing, at the study 
investigator’s discretion, to obtain rapid results to ensure patient safety. If applicable, a copy of 
the local laboratory report should be reviewed by the investigator and filed with the source 
documents, along with reference ranges.
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.
6.7.1.
NA Re-treatment Criteria and Monitoring After Stopping of NA
Participants who meet the protocol-defined NA treatment completion criteria outlined in 
Section 6.6, Study Intervention Completion at Week 24, will be monitored closely during the FU 
Period.
After stopping NA treatment, participants should be monitored as follows:

Regular monitoring visits will be every 4 weeks during the follow-up phase in accordance 
with the Schedule of Activities.

A post-treatment HBV DNA value of >20,000 IU/mL should trigger re-testing of ALT/AST, 
HBV DNA, and total and direct bilirubin within a maximum of 7 days from receipt of the data 
and further repeats as necessary (ie, weekly until HBV DNA returns to <20,000 IU/mL).

A post-treatment HBV DNA value of >2,000 IU/mL (but <20,000 IU/mL) should trigger a 
re-test within 14 days from receipt of the data and further repeats as necessary (ie, every other 
week until HBV DNA returns to <2,000 IU/mL).

A post-treatment ALT value of >5x ULN should trigger re-testing of ALT, AST, ALP, total 
and direct bilirubin, INR, albumin, and HBV DNA on a weekly basis until ALT and AST 
levels have returned to <5x ULN.
After stopping NA treatment, participants should re-start NA treatment:

Immediately with signs of decreasing liver function based on laboratory findings (eg, INR, 
direct bilirubin) or clinical assessment (eg, ascites, hepatic encephalopathy).

Immediately with an HBV DNA value of >100,000 IU/mL (irrespective of confirmation 
and/or ALT increase).

With confirmed post-treatment HBeAg seroreversion (HBeAg positive after it was negative 
at NA completion).

With confirmed* post-treatment increases in HBV DNA >2,000 IU/mL and ALT >5x ULN.
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
With confirmed* post-treatment increases in HBV DNA >20,000 IU/mL.
* At least 4 weeks apart – frequency of visits as described above
Note: Additional re-testing and/or earlier restarting of NA treatment is at the investigator’s 
discretion, even if the above cut-offs are not yet met.
To avoid delays in decision making, sites are encouraged to run local re-testing in parallel with 
central re-testing in the situations described above that require more frequent re-testing. Local test 
results are to be recorded in the CRF and/or source documents, including information on the HBV 
DNA assay used. In addition, to avoid delays in NA re-treatment, it should be considered to 
dispense NA to participants who potentially met the NA re-treatment criteria (eg, pending 
confirmation) and who will not be available to come to the study site immediately at the time the 
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 EOS or until clinical 
stabilization, whichever comes later.
Management of intervention-emergent ALT/AST elevations is discussed in Section 8.3.6.4, 
Intervention-emergent ALT/AST Elevations.
NA re-treatment criteria during follow-up are presented graphically in Section 10.12 Appendix 12: 
NA Re-treatment and Monitoring After Stopping of NA.
6.8.
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 at 
Week 24, who did not re-start NA treatment during the follow-up phase, and who did not achieve 
and maintain HBsAg seroclearance. NA will not be provided by the sponsor after the final study 
visit.
7.
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL
If a participant discontinues study intervention for any reason before Week 24/EOSI, the 
participant will have an early withdrawal visit and will enter follow-up unless he/she withdraws 
consent. If the reason for withdrawal from the study is withdrawal of consent, then the participant 
will be offered an optional safety follow-up visit. Study intervention assigned to the participant 
who discontinued study intervention may not be assigned to another participant.
7.1.
Discontinuation of Study Intervention
With the implementation of Protocol Amendment 3, all participants had to stop JNJ-6379 
treatment immediately.
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Status: Approved,  Date: 01 December 2021
Treatment with JNJ-3989 (and PegIFN-α2a during Treatment Period 2) must be discontinued 
before Week24/EOSI if any of the discontinuation criteria listed below are met. Criteria specific 
for this ISA are highlighted (colored fill). For the few criteria from the Master Protocol that are 
specified or more restricted in this ISA, the changes compared to the Master Protocol are also 
highlighted (colored fill). If JNJ-3989 is discontinued, PegIFN-α2a (only applicable in Treatment 
Period 2) should also be discontinued. NA treatment may be continued or, in consultation with the 
sponsor, discontinued based on investigator judgement.
The discontinuation criteria are:

The participant withdraws consent to receive study intervention.

The investigator believes that for safety or tolerability reasons (eg, AE) it is in the best interest 
of the participant to discontinue JNJ-3989 (and PegIFN-α2a, if applicable).

The participant becomes pregnant. 

The participant has a ≥grade 3 rash (see Section 10.6, Appendix 6: Rash Management) or 
allergic reaction (see Section 8.3.6.3, Acute Systemic Allergic Reactions).

The participant has signs of hepatic decompensation (ie, clinical evidence of ascites, bleeding 
varices, or hepatic encephalopathy) or an increase in direct bilirubin >1.5x ULN in 
combination with INR ≥1.5x ULN or albumin <3.0 g/dL, treatment with JNJ-3989 should be 
discontinued and alternative treatment options (outside the study) should be considered in 
discussion with the sponsor.

The participant has a confirmed ≥grade 3 eGFR abnormality, considered at least possibly 
related to JNJ-3989 (or PegIFN-α2a, if applicable) that persists despite change of tenofovir 
disoproxil to ETV or TAF (if the patient was receiving tenofovir disoproxil). Change of NA 
treatment should be considered according to the prescribing information (see Section 8.3.6.5, 
Renal Complications).

The participant has a QTcF prolongation (defined as a QTcF value of >500 ms, or an increase 
from baseline of >60 ms) at any given time point.

The participant requires ≥7 days of treatment with any of the disallowed medications listed in 
Section 6.5, Concomitant Therapy, and does not intend to discontinue treatment with the 
disallowed medication.

The participant has confirmed HBV virologic breakthrough (ie, confirmed on-treatment HBV 
DNA increase by >1 log10 IU/mL from nadir or confirmed on-treatment HBV DNA level 
>200 IU/mL in participants who had HBV DNA level <LLOQ of the HBV DNA assay).
In case of virologic breakthrough, the same assessments will be done at an unscheduled visit 
as will be done in case of an ALT flare, but no PBMC sample will be taken (see 
Section 8.3.6.4, Intervention emergent ALT/AST Elevations, and Schedule of Activities).

The 
participant 
has 
ALT/AST 
elevations, 
as 
described 
in 
Section 
8.3.6.4, 
Intervention-emergent ALT/AST Elevations.
Note: The grades are based on the DAIDS Toxicity Grading Scale (see Section 10.9, Appendix 9: 
DAIDS Table).
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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 6.7, 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 (e.g., 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.
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.
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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 approximately 945 mL.a  In addition, PBMC samples (at selected sites only; 
approximately 450 mL), optional exploratory host genotyping and epigenetic research samples 
(approximately 20 mL) and optional intensive PK samples (approximately 200 mL) may be 
collected.
Note: The total blood volume to be collected from each participant may vary, depending on several 
factors (eg, unscheduled re-tests, 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).
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 
                                                
a For participants in Japan only, the total blood volume to be collected during planned assessments for the entire study 
will be approximately 985 mL due to additional hematology assessments.
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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 ensure that JNJ-3989 (and PegIFN-α2a in Treatment Period 
2) 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 6.6, 
Study Intervention Completion at Week 24).

To assess whether re-start of NA treatment during follow-up is needed (see Section 6.7.1, NA 
Re-treatment Criteria and Monitoring After Stopping of NA).
In participants enrolled at a site with an on-site Fibroscan device, Fibroscan assessments will be 
performed at different time points to determine changes in fibrosis levels.
Samples may be used by the sponsor for additional exploratory assessments analyzing the 
serologic and virologic characteristics of HBV infection and efficacy or safety of the study 
intervention.
8.1.1.
Sequencing
Viral genome sequence analysis will be performed to evaluate mutations associated with the study 
intervention.
Sequencing of the HBV genome will be performed to monitor HBV variants present at the time 
points indicated in the Schedule of Activities. The sequencing of samples may be triggered by the 
sponsor virologist based on changes in HBV DNA levels observed in each individual participant 
and the limits of the sequencing assay.
Samples may be used by the sponsor for additional assessments analyzing the serologic and 
virologic characteristics of the HBV infection and efficacy of the study intervention, including 
viral genotypic and phenotypic assessments.
8.2.
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, ophthalmic 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.
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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.
For this study, the laboratory abnormality of cholesterol increase is identified as laboratory 
abnormality of interest.
8.2.5.
Ophthalmic Examinations
Ophthalmic 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 ophthalmic 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.
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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 
that will be carefully monitored during the study include ISRs, ALT/AST elevations, renal 
complications,
hematologic abnormalities, and events related to cholesterol increase 
(Section 8.2.4, Clinical Safety Laboratory Assessments). In addition, the following toxicities will 
also be carefully monitored: rash and acute systemic allergic reactions. 
For participants reporting rash, ISRs, acute systemic allergic reactions, ALT/AST elevations, renal 
complications, and hematologic abnormalities as specified in the DAIDS Toxicity Grading Scale 
(see Section 10.9, Appendix 9: DAIDS Table), the following should be done.
Note: renal complications and cholesterol increase are AESIs specific for JNJ-6379, which was 
part of the study intervention prior to Protocol Amendment 3 and has been removed with the 
implementation of Protocol Amendment 3. Because most participants who were enrolled before 
Protocol Amendment 3 was in effect, also received JNJ-6379 as part of their study intervention, 
the AESIs have not been revised with the removal of JNJ-6379.
8.3.6.1.
Rash
Participants should be informed that they should contact their doctor immediately when they 
notice any generalized skin reaction. This skin reaction should be evaluated in the clinic the 
same day (if possible) or the next 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 5 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.
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The participant may be treated symptomatically until the rash resolves. Oral antihistamines (eg, 
cetirizine, levocetirizine) and/or topical corticosteroids may provide symptomatic relief but 
effectiveness of these measures has not been established. If systemic corticosteroids exceeding 
5 mg of prednisolone equivalent/day are required for treatment of rash, JNJ-3989 (and PegIFN-
α2a in Treatment Period 2) needs 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.
8.3.6.2.
Injection Site Reactions
At the time points specified in the Schedule of Activities or at an unscheduled visit if needed, an 
evaluation of the injection site will be performed based on participant’s description and/or physical 
examination. Evaluations will be recorded in the source documents and will include at a minimum 
the time of occurrence, time of resolution and a description of the abnormality including its 
maximal diameter. For each ISR, information on pain, erythema, induration and pruritus should 
be obtained as specified in the DAIDS scale (see Section 10.9, Appendix 9: DAIDS Table).
All ISRs (including ISRs below grade 1) will need to be recorded in the special events section of 
the CRF. 
Digital pictures will be taken when considered appropriate; all efforts should be made to collect 
images in case of grade 3 and 4 ISRs. Digital pictures will only be taken and collected from 
participants who consent separately to this component of the study. If digital pictures are required, 
they should be de-identified and provided to the sponsor.
8.3.6.3.
Acute Systemic Allergic Reactions
Grade 1 (Localized Urticaria [Wheals] With no Medical Intervention Indicated)
Participants may continue the intake of study interventions.
Cetirizine, levocetirizine, topical corticosteroids or antipruritic agents may be prescribed.
Participants should be advised to contact the investigator immediately if there is any worsening of 
the acute systemic allergic reaction.
Grade 2 (Localized Urticaria With Intervention Indicated, or Mild Angioedema With no 
Intervention Indicated)
Participants may continue the intake of study interventions.
Cetirizine, levocetirizine, topical corticosteroids or antipruritic agents may be prescribed.
Participants should be advised to contact the investigator immediately if there is any worsening of 
the acute systemic allergic reaction, in which case the participant will permanently discontinue the 
intake of JNJ-3989 (and PegIFN-α2a in Treatment Period 2). Rechallenge is not allowed. The 
participant’s NA treatment may be discontinued based on investigator judgement in consultation 
with the sponsor.
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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 in Treatment 
Period 2). Rechallenge is not allowed. The participant’s NA treatment may be discontinued based 
on investigator judgement in consultation with the sponsor. 
Participants will be treated as clinically appropriate. Participants should be followed until 
resolution of the AE and standard management should be undertaken.
8.3.6.4.
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 in 
Treatment Period 2) 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/or 
AST levels have returned to <5x ULN and HBV DNA is <20,000 IU/mL.
If the ALT and/or AST level is ≥3x ULN and ≥3x nadir and is associated with any of the following 
laboratory results or clinical symptoms:

INR ≥1.5, OR 

direct bilirubin >1.5x ULN, OR

serum albumin <3.0 g/dL, OR

ascites, hepatic encephalopathy, or liver-related symptoms (eg, severe fatigue, nausea, 
vomiting, right upper quadrant pain in the absence of an alternative medical explanation), OR

other indication of reduced liver function,
the participant should discontinue JNJ-3989 (and PegIFN-α2a in Treatment Period 2) and should 
be monitored on a weekly basis or more frequently, or as per good clinical practice, until ALT and 
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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).
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).
The NA re-treatment criteria during follow-up are presented in Section 6.7.1, NA Re-treatment 
Criteria and Monitoring After Stopping of NA.
8.3.6.5.
Renal Complications
If renal complications develop, participants should be closely monitored for disturbances in 
creatinine clearance. Additional investigations can be performed at the investigator’s discretion. 
Participants must be treated as clinically appropriate.
Participants who develop confirmed grade 3 or 4 eGFR abnormalities will change their NA from 
tenofovir disoproxil to ETV or TAF (if the patient was receiving tenofovir disoproxil). 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 in Treatment 
Period 2) if considered at least possibly related to JNJ-3989 (or PegIFN-α2a in Treatment Period 2) 
and should be followed appropriately until resolution of the AE or toxicity. Rechallenge is not 
allowed. Change of NA treatment should be considered according to the prescribing information.
For all participants having received at least one dose of JNJ-6379, renal safety monitoring will be 
continued.
8.3.6.6.
Hematologic Abnormalities
Mild thrombocytopenia was observed in recently conducted non-clinical toxicology studies with 
the combination of JNJ-3989 and JNJ-6379. In addition, in a 3-month combination study with 
80 rats, 1 rat developed pancytopenia related to bone marrow depletion after 23 days of dosing. 
Previously, in a 9-month dog study in 24 dogs treated with JNJ-6379 alone, pancytopenia which 
correlated with a marked increase in plasma cell-like cells in the bone marrow was observed in 
1 dog after 60 days of dosing. 
No thrombocytopenia or pancytopenia has been observed in the ongoing JADE study 
(56136379HPB2001) investigating JNJ-6379/Placebo with or without NA treatment. All 
232 participants have completed at least 24 weeks of study intervention. 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 and JNJ-6379 were given in combination over a 12-week period.
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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).

Reticulocytes: Reduction to <0.5% of the RBC count.

Neutrophil count: Treatment-emergent reduction to at least grade 2 (DAIDS).
In case any of the above criteria are met, a confirmatory visit should be scheduled as soon as 
possible, preferably within 7 days of the receipt of the initial results. Confirmation of the results 
will trigger weekly or biweekly (every other week) unscheduled visits until improvement or 
stabilization of the respective parameter(s). Stabilization is defined as no further significant 
reduction over two consecutive visits. 
In case of confirmed grade 3 or grade 4 hematologic abnormalities, discontinuation of 
investigational study treatment (JNJ-3989 [and PegIFN-α2a in Treatment Period 2]) should be 
considered. In case of discontinuation, NA treatment should be continued.
8.4.
Treatment of Overdose
For this study, any dose of JNJ-3989 greater than the protocol-specified dose (refer to Section 6.1, 
Study Intervention(s) Administered) will be considered an overdose; any dose of NA (ETV, 
tenofovir disoproxil, or TAF) and 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.

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.
8.5.
Pharmacokinetics
Plasma or serum samples, as applicable, will be used to evaluate the PK of the study intervention.
Samples collected for PK may additionally be used to evaluate safety or efficacy aspects.
8.5.1.
Evaluations
Venous blood samples will be collected for measurement of plasma or serum (as applicable)
concentrations of JNJ-3989 (ie, JNJ-3976 and JNJ-3924) and, optionally, NA and/or PegIFN-α2a, 
at time points specified in the Schedule of Activities. Bioanalysis of NA and/or PegIFN-α2a is 
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optional at the discretion of the sponsor. Bioanalysis of JNJ-6379 may also be done on samples 
collected from participants who received JNJ-6379 prior to Protocol Amendment 3.
All participants will have sparse PK sampling during the treatment periods. Participants who 
consent to participate in the intensive PK substudy (optional) will also undergo intensive PK 
sampling at time points specified in the Schedule of Activities.
8.5.2.
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, JNJ-6379, 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.
8.5.3.
Pharmacokinetic Parameters and Evaluations
Parameters
Concentration-time data for JNJ-3989 (ie, JNJ-3976 and JNJ-3924) and optionally JNJ-6379, NA 
and/or PegIFN-α2a will be analyzed via noncompartmental methods for all participants who 
underwent intensive PK sampling. The PK parameters will be Cmax, plasma concentration 24 hours 
after administration (C24h), and AUC24h. Additional PK parameters may be calculated if applicable. 
To assess the effect of PegIFN-α2a on JNJ-3989, the PK parameters of JNJ-3976 and JNJ-3924 
coadministered with PegIFN-α2a at Week 20 (or 16) will be compared to those of JNJ-3976 and 
JNJ-3924 at Week 4 (or 8) as reference (time points as specified in the Schedule of Activities).
Data from this study may be combined with other studies via population PK modeling to enable 
the calculation of the above PK parameters also in participants who only underwent sparse PK 
sampling.
8.6.
Pharmacokinetic/Pharmacodynamic Evaluations
Relationships of individual PK parameters for JNJ-3976 and JNJ-3924, and optionally JNJ-6379, 
NA and/or PegIFN-α2a, with selected efficacy and/or safety endpoints may be evaluated, if 
applicable.
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 
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to a specific antigenic stimulation, whereas ICS determines the frequency of CD4+ and CD8+ 
T-cells secreting cytokines such as IFN-γ, interleukin (IL)-2 and tumor necrosis factor (TNF)-α in 
response to a specific antigenic stimulation.
Additional experiments may be performed to further phenotypically and functionally characterize 
PBMCs using proliferation or cytotoxic assays or other methods such as cytometry by time of 
flight to evaluate innate and adaptive immune responses. Leftover PBMC samples may be used at 
the sponsor’s discretion for additional exploratory research (eg, assessment of other immune cells 
such as NK-cells, myeloid-derived suppressor cells [MDSCs], dendritic cells [DCs], and B-cells) 
related to HBV infection or study intervention (safety/efficacy).
Additional PBMC samples may be taken in case of ALT flares, upon discussion with the sponsor, 
which may require an unscheduled visit.
8.8.
Host Genetics
A mandatory sample for HLA haplotyping will be collected from all participants. 
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 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 (see Section 7.2.1 of the 
Master Protocol PLATFORMPAHPB2001).
In addition, other samples may be used for exploratory genetic or epigenetic research in 
participants consenting separately to this part of the study. No genetic research will be performed 
on any sample in participants who have not provided the additional separate consent for host 
genetic research. These samples can only be used to investigate the potential association of genetic 
or epigenetic factors with efficacy, safety, or PK of the study intervention, or HBV infection, or 
may be used to develop tests/assays related to the study intervention or HBV infection.
These analyses will be performed at the sponsor’s discretion, will always be under the sponsor’s 
supervision, and may be reported separately.
8.9.
Exploratory Host Biomarkers
The study includes collection of blood samples for exploratory analysis of host blood biomarkers 
at the host RNA, protein, and cell level. Sampling will be performed at the time points indicated 
in the Schedule of Activities. Leftovers of other samples might also be used for exploratory 
research of host and viral markers.
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The analyses may include gene expression and cytokine analyses assessing markers such as 
interferon-stimulated genes (ISGs), IFN-α, and interferon γ-induced protein 10 (IP-10).
Samples can only be used for research related to study intervention or HBV infection or may be 
used to develop tests/assays related to study intervention or HBV infection.
Blood samples will be taken at the time points indicated in the Schedule of Activities which can 
be used to explore immunogenicity of JNJ-3989 and optionally PegIFN-α2a. The emergence of 
antidrug antibodies to JNJ-3989 and optionally to PegIFN-α2a might be analyzed using assays 
such as an enzyme-linked immunosorbent assay or functional assays.
These analyses will be performed at the sponsor’s discretion, will always be under the sponsor’s 
supervision, and may be reported separately.
More information is provided in Section 8.8 of the Master Protocol PLATFORMPAHPB2001.
9.
STATISTICAL CONSIDERATIONS
Statistical analysis will be done by the sponsor or under the authority of the sponsor. A general 
description of the statistical methods to be used to analyze the efficacy and safety data is outlined 
below. Specific details will be provided in the Statistical Analysis Plan (SAP).
9.1.
Statistical Hypotheses
As this is an exploratory single-arm study, no formal statistical hypothesis has been formulated.
9.2.
Sample Size Determination
No formal sample size calculation was performed, as this is a single-arm study for exploratory and 
proof of concept (PoC) purposes. However, with a sample size of 50 participants having data for 
the primary efficacy endpoint at Week 24, if at least 25 (50%) participants are responders, it can 
be concluded with 90% confidence that the true response rate is at least 0.38, with a confidence 
interval (CI) width of 0.248 (90% CI: 0.376-0.624). With a sample size of 20 participants (for one 
of the IAs), the precision of the estimate of the primary efficacy endpoint decreases, as the two-
sided 90% CI width increases. For the same assumed proportion of responders of 50% (10 out of 
20 participants), the 90% CI width becomes 0.396. Table 4 shows the 90% CI and the 
corresponding width for proportion of responders of 0.30, 0.50, 0.70, and 0.90.
Table 4:
Sample Size Determination
N=20
N=50
Proportion of
responders
90% CI*
Width of CI
90% CI*
Width of CI
0.30
0.140-0.508
0.368
0.195-0.424
0.229
0.50
0.302-0.698
0.396
0.376-0.624
0.248
0.70
0.492-0.860
0.368
0.576-0.805
0.229
0.90
0.717-0.982
0.265
0.801-0.960
0.159
CI: confidence interval.
* Clopper-Pearson exact method is used.
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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 an ICF specific for this ISA.
Enrolled
All participants who were enrolled in this ISA.
Intent-to-treat 
(ITT)
All participants who were enrolled and who received at least 1 dose of study intervention 
within this ISA.
IFN-ITT
All participants who were enrolled and who received at least 1 dose of PegIFN-α2a within this 
ISA.
9.4.
Statistical Analyses
The SAP will include a more technical and detailed description of the statistical analyses described 
in this section. This section is a summary of the planned statistical analyses of the most important 
endpoints including primary and key secondary endpoints.
9.4.1.
General Considerations
Refer to Section 9.4.1 of the Master Protocol PLATFORMPAHPB2001.
9.4.2.
Efficacy Analyses
The primary efficacy analysis will be performed when all participants have completed Week 24 
(EOSI) or discontinued earlier. The final analysis will be performed when all participants have 
completed the last study visit (FU Week 48) or discontinued earlier.
To evaluate the efficacy, the primary analysis set will be the ITT population (defined in 
Section 9.3, Populations for Analysis Sets). Selected efficacy analyses will be repeated for the 
IFN-ITT analysis set and described in the SAP.
All efficacy summaries will be presented with descriptive statistics and 90% CIs. If the endpoint 
is continuous, the descriptive statistics will include the number of participants, mean, standard 
deviation (SD), median, and range. If the endpoint is binary or categorical, the frequency 
distribution with the number and percentage of participants in each category will be calculated. 
For time-to-event variables, a summary table including number of participants included in the 
analysis, number of participants censored, 25th and 75th percentiles and median time-to-event will 
be shown. Graphic displays will also be used to summarize the data. 
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.
Additional analyses of efficacy to generate new hypotheses and guide the design of new studies 
may be performed on the primary efficacy endpoint and/or selected secondary endpoints using, for 
example, the Bayesian methodology or other methodologies to leverage the Platform Study 
framework. Such analyses may incorporate external data and/or data from other ISAs which are 
currently in the platform study or may enter in the future. Details on these analyses will be provided 
in a separate document (SAP or Modeling and Simulation Report, as applicable).
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9.4.2.1.
Primary Efficacy Endpoint
The primary endpoint is the proportion of participants with a reduction of at least 2 log10 IU/mL 
in HBsAg levels from baseline to Week 24. Participants who do not have HBsAg data in the 
analysis window of Week 24 will be defined as non‑responders.
The primary efficacy endpoint will be summarized with the point estimate paired with its 90% CI 
using the Clopper-Pearson exact method. The same method will apply in a secondary analysis of 
the primary endpoint to the IFN-ITT analysis set comprising the ITT participants who have 
received at least 1 dose of PegIFN-α2a (see Section 9.3, Populations for Analysis Sets).
9.4.2.2.
Secondary Efficacy Endpoints
Descriptive statistics and 90% CIs will be used to summarize all efficacy endpoints. 
Specific key selected endpoints may be analyzed using suitable categorical data approaches (eg, 
Clopper-Pearson interval 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.
9.4.2.3.
Resistance Analyses
The results of HBV viral sequencing will be evaluated by the sponsor virologist. Relevant changes 
of amino acid and/or nucleic acid variations (eg, substitutions) in the HBV genome will be 
tabulated and described.
Additional exploratory characterization of the HBV viral sequence and phenotype may be 
performed and reported separately.
9.4.3.
Safety Analyses
Safety analyses are specified in Section 9.4.3 of the Master protocol PLATFORMPAHPB2001. 
Safety will be evaluated by means of descriptive summaries of (S)AEs including AEs of special 
interest to any of the study interventions, clinical laboratory tests, ECGs, vital signs, and physical 
examinations. The safety analysis will be done by study period. Results will be presented in tabular 
format and/or graphically over time, as appropriate.
9.4.4.
Other Analyses
Pharmacokinetic Analyses
Descriptive statistics (n, mean, SD, coefficient of variation [CV], geometric mean, median, 
minimum, and maximum) will be calculated for the plasma concentrations of JNJ-3989 (JNJ-3976, 
and JNJ-3924) and, optionally, of NA, PegIFN-α2a and/or JNJ-6379, and for the derived plasma 
PK parameters for noncompartmental PK analyses.
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For each participant with intensive PK sampling, plasma concentration-time data of JNJ-3976 and 
JNJ-3924, and, optionally, of NA, PegIFN-α2a and/or JNJ-6379, will be graphically presented. 
Similarly, graphs of the mean plasma concentration-time profiles and overlay graphs with 
combined individual plasma concentration-time profiles will be produced. Plasma PK parameters 
in participants undergoing intensive PK sampling will be calculated via noncompartmental 
methods for JNJ-3976 and JNJ-3924, and, optionally, NA, PegIFN-α2a and/or JNJ-6379. The PK 
parameters will be Cmax, C24h, and AUC24h; other PK parameters may also be calculated. The PK 
parameters will be subjected to an exploratory graphical analysis, including various 
transformations, to get a general overview.
To assess the effect of PegIFN-α2a on JNJ-6379 (as applicable) and JNJ-3989, the PK parameters 
of JNJ-6379 (as applicable) and JNJ-3989 coadministered with PegIFN-α2a at Week 20 (or 16)
will be compared to those of JNJ-6379 (as applicable) and JNJ-3989 at Week 4 (or 8) as reference. 
The primary PK parameters are Cmax and AUC24h on the logarithmic scale. A mixed effects model 
will be fitted to log-transformed PK parameters with treatment period as a fixed effect and 
participant as a random effect.
Special attention will be paid to the plasma concentrations and PK parameters of those participants 
who discontinued the study for an AE, or who experienced an AE ≥grade 3, or an SAE.
Population PK analysis of plasma concentration-time data of JNJ-3976 and JNJ-3924 may be 
performed using non-linear mixed effects modeling. Data may be combined with those from Phase 
1 and/or 2 studies to support a relevant structural model. Available baseline characteristics (eg, 
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.
Pharmacokinetic/Pharmacodynamic Analyses 
Relationships of PK parameters for JNJ-3976 and JNJ-3924, and, optionally, of NA, PegIFN-α2a 
and/or JNJ-6379 with selected efficacy and/or safety endpoints may be evaluated and graphically 
displayed. 
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 
conducted, the results will be presented in a separate report.
Immune Analyses
Descriptive statistics (n, mean, SD, CV, geometric mean, median, minimum, and maximum) will 
be used to describe the magnitude of the IFN-γ T-cell response or the CD4+ and CD8+ T-cell 
responses (expressing at least 1 cytokine such as IL-2, TNF-α or IFN-γ specific to any HBV 
antigen) as defined by ELISpot and/or ICS, respectively. Changes from baseline (if present) will 
also be tabulated for PBMCs during study intervention and follow-up. The proportion (%) of CHB 
patients with positive responses based on the magnitude of the IFN-γ T-cell response or the CD4+ 
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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. Other immune 
cells, such as NK-cells, MDSCs, DCs, and B-cells, may be evaluated/explored.
Pharmacogenomic Analyses
The statistical approach for analyzing the exploratory host DNA research, 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.
9.5.
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 internal decisions about additional studies 
and/or investigation of other treatment combinations. The IAs are planned when:

Approximately 20 participants have completed Week 24 (EOSI) or discontinued earlier

All participants have completed Week 36 (FU Week 12) or discontinued earlier

All participants have completed Week 48 (FU Week 24) or discontinued earlier.
An optional IA may be conducted when all participants have completed Week 60 (FU Week 36) 
or discontinued earlier.
The study is open-label, and the sponsor will conduct the pre-planned IAs. Hence, the study team 
and the DRC will have access to the IA results, while the investigators and participants will not.
Both primary and interim analyses will be based on all data available at the pre-defined cut-off 
time points, and may include data at later time points for those participants who have reached 
subsequent visits.
More details are provided in Section 9.5 of the Master Protocol PLATFORMPAHPB2001.
9.6.
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.
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9.7.
Independent Flare Expert Panel
An IFLEP will be appointed. The IFLEP is composed of 3 independent medical experts with 
experience and expertise in HBV and its treatment. The 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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10.
SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS
10.1.
Appendix 1: Abbreviations and Definitions of Terms
Abbreviations
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
CHB
chronic hepatitis B
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
eGFR
estimated glomerular filtration rate
ELISpot
enzyme-linked immunospot
EOS
end of study
EOSI
end of study intervention
ETV
entecavir
FOIA
Freedom of Information Act
FU
follow-up
GLDH
glutamate dehydrogenase
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
HEV
hepatitis E virus
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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 
IgG
immunoglobulin G
IgM
immunoglobulin M
IL
interleukin
INR
International Normalized Ratio
ISA
intervention-specific appendix
ISR
injection site reaction
ITT
intent-to-treat
LLN
lower limit of normal
LLOQ
lower limit of quantification
MDSC
myeloid-derived suppressor cell
MoA
mode of action
MRI
magnetic resonance imaging
NA
nucleos(t)ide analog
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
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
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
As of Protocol Amendment 3: JNJ-73763989 (JNJ-3989), NA (either ETV, tenofovir 
disoproxil, or TAF), and PegIFN-α2a (in Treatment Period 2)
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 method provided that the partner is the 
sole sexual partner of the woman of childbearing potential and the absence of sperm has been 
confirmed. If not, additional highly effective method of contraception should be used. 
Spermatogenesis cycle is approximately 74 days.)
USER DEPENDENT
Highly Effective Methods That Are User Dependent Failure rate of <1% per year when used 
consistently and correctly.

Combined (estrogen- and progestogen-containing) hormonal contraception associated with 
inhibition of ovulation
oral
intravaginal
transdermal
injectable

Progestogen-only hormone contraception associated with inhibition of ovulation
oral
injectable

Sexual abstinence
(Sexual abstinence is considered a highly effective method only if defined as refraining from 
heterosexual intercourse during the entire period of risk associated with the study intervention. 
The reliability of sexual abstinence needs to be evaluated in relation to the duration of the study 
and the preferred and usual lifestyle of the participant.)
a) Typical use failure rates may differ from those when used consistently and correctly. Use should be 
consistent with local regulations regarding the use of contraceptive methods for participants in 
clinical studies.
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10.6.
Appendix 6: Rash Management
Table 5:
Management of Rash Events by Severity Grade
Definition
Study 
Intervention 
Action
Activities by Daya
Referral to 
Dermatologist and 
Dermatology 
Activities
Grade 1 rash 
(with or 
without 
pruritus)b
Erythema
Study 
intervention 
intake may be 
continued at the 
investigator’s 
discretion
Day 0: optional on-site visit for initial rash evaluation may be performed 
at the investigator’s discretion.
Safety laboratory assessments may be performed at the investigator’s 
discretion (recommended if visit occurs).
Digital picturesc of skin lesions may be taken at the investigator’s 
discretion. 
Determine if participant was adhering to the recommended sun-
protective measures. If appropriate, provide sun protection counseling.
Day 1 and thereafter: appropriate follow-up visits at the investigator’s 
discretion until resolution of rash.
Safety laboratory assessments and photography (digital picturesc of skin 
lesions) may be performed at the investigator’s discretion.
Not required
Grade 2 rash 
(with or without 
pruritus)b
Diffuse, maculopapular 
rash, or dry 
desquamation
Study 
intervention 
intake may be 
continued at the 
investigator’s 
discretion
Day 0: required on-site visit (if a visit is not possible, telephone contact 
with the participant should take place to collect information and give 
advice on the necessary measures to be taken).
Safety laboratory assessments may be performed at the investigator’s 
discretion (recommended).
Digital picturesc of skin lesions may be taken at the investigator’s 
discretion. Digital picturesc of skin lesions are recommended in case 
consultation of a dermatologist is required. Determine if participant was 
adhering to the recommended sun-protective measures. If appropriate, 
provide sun protection counseling.
Day 1 and thereafter: appropriate follow-up visits at the investigator’s 
discretion until resolution of rash or until clinical stability is reached. 
Safety laboratory assessments are required on Day 1 and are required 
thereafter only if the previous values were abnormal (but may be 
performed at the investigator’s discretion). If the rash progresses to a 
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 5:
Management of Rash Events by Severity Grade
Definition
Study 
Intervention 
Action
Activities by Daya
Referral to 
Dermatologist and 
Dermatology 
Activities
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 
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.
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Table 5:
Management of Rash Events by Severity Grade
Definition
Study 
Intervention 
Action
Activities by Daya
Referral to 
Dermatologist and 
Dermatology 
Activities
Grade 4 rash
Exfoliative dermatitis 
OR
Mucous membrane 
involvement in at least 
2 distinct sites OR
Erythema multiforme 
major OR
Stevens-Johnson 
syndrome OR
Toxic epidermal 
necrolysis OR
Necrosis requiring 
surgery
Must permanently 
discontinue 
JNJ-3989 and 
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 required and 
to be performed as 
soon as possible 
after the onset of 
the rash.
AE: adverse event; ALT: alanine aminotransferase; AST: aspartate aminotransferase; NA: nucleos(t)ide analog.
a
Day 0 of the rash is the first day of investigator assessment and not the first day of rash as reported by the participant. The initial visit should be conducted as 
soon as possible after the participant contacts the investigator to report the AE (ie, preferably on Day 0). The initial visit and subsequent visits to manage the rash 
may require unscheduled visit(s).
b
The participant should be advised to contact the investigator immediately if there is any worsening of the rash, if any systemic signs or symptoms appear, or if 
mucosal involvement develops. In case the rash evolves to a higher grade than that first observed, management of the rash should follow the guidelines indicated 
for the higher grade.
c
Digital pictures to be taken at the clinical site upon consent of the participant.
d
If applicable, dermatologist visit should occur preferably within 24 hours after onset of rash.
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 provided to the sponsor.
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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. 
In alignment with recent health authority guidance, the sponsor is providing options for study 
related participant management in the event of disruption to the conduct of the study. This guidance 
does not supersede any local or government requirements or the clinical judgement of the 
investigator to protect the health and well-being of participants and site staff. If, at any time, a 
participant’s safety is considered to be at risk, study intervention will be discontinued, and study 
follow-up will be conducted.
Scheduled visits that cannot be conducted in person at the study site will be performed to the extent 
possible remotely/virtually or delayed until such time that on-site visits can be resumed. At each 
contact, participants will be interviewed to collect safety data. Key efficacy endpoint assessments 
should be performed if required and as feasible. Participants will also be questioned regarding 
general health status to fulfill any physical examination requirement. 
Every effort should be made to adhere to protocol-specified assessments for participants on study 
intervention, including follow up. Modifications to protocol-required assessments may be 
permitted via COVID-19 Appendix after consultation with the participant, investigator, 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 caregiver or delegate of oral study intervention may be implemented, where allowed per local 
regulations 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 
                                                
a Providing additional PegIFN-α2a to study participants is not applicable for sites in Japan, where weekly 
administration of PegIFN-α2a must be performed at the study site by the investigator or his/her designee.
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to study intervention, study intervention will be temporarily or permanently discontinued, 
while every effort should be made to maintain follow-up on study. The benefit of continuing 
study intervention should be assessed by the investigator for each individual participant, 
considering the potential impact of reduced direct clinical supervision on participant safety.

If a participant develops a SARS-CoV-2 infection, the investigator should contact the sponsor 
to discuss plans for study intervention and follow-up. A decision to continue study intervention 
should be made by the investigator depending on symptoms and concomitant medication(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 Treatment Period 2: 

COVID-19 vaccine and PegIFN-α2a should not be administered on the same day.

If required, PegIFN-α2a injection can be delayed with 2 days. The next PegIFN-α2a 
injection should be performed 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 
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allowed for study evaluations. A copy of the local laboratory report should be reviewed by the 
investigator and filed with the source documents, along with reference ranges.

To safely maintain participants on study intervention while site capabilities are compromised 
by COVID-19-related restrictions, study visits may be performed by a nurse (who received 
study-specific training) at the patient’s home (home health nurse) until such time that on-site 
visits can be resumed. The following activities may be completed as required per the Schedule 
of Activities and as feasible: 

Sampling, processing and shipping of laboratory samples (as described above).

Checking study compliance: medication diary (if available), intake of oral study 
intervention, storage of oral study intervention.

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). 
                                                
a Delivering PegIFN-α2a is not applicable for sites in Japan, where weekly administration of PegIFN-α2a must be 
performed at the study site by the investigator or his/her designee.
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Additional on-site monitoring visits may be needed in the future to catch up on source data 
verification. 
Site Audits:

During the COVID-19 pandemic and at the impacted sites, study site Good Clinical Practice 
(GCP) audits with direct impact/engagement from the investigator and study site personnel 
would not be conducted in order to comply with national, local, and/or organizational social 
distancing restrictions. Additional quality assurance activities such as remote audits or focused 
review of study-related documents may take place with limited impact/engagement if possible.
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Status: Approved,  Date: 01 December 2021
10.11. Appendix 11: Protocol Amendment History
The Protocol Amendment Summary of Changes Table for the current amendment is located 
directly before the Table of Contents (TOC).
Amendment 3 (04 October 2021)
Overall Rationale for the Amendment:
The primary reason for this amendment is to remove JNJ-56136379 as study intervention, to add a new
nucleos(t)ide analog (NA) re-treatment criterion for participants who discontinued NA treatment during 
follow-up, and to include more frequent monitoring for participants who discontinued NA treatment during 
follow-up.
Based on emerging data from recent interim analyses of the REEF-1 (73763989HPB2001) and REEF-2 
(73763989PAHPB2002) studies, the benefit-risk profile of JNJ-6379 in combination with JNJ-3989+NA 
is unfavorable compared to JNJ-3989+NA. 
In the primary REEF-1 analysis (Week 48, end of treatment) the mean reduction of hepatitis B surface 
antigen (HBsAg) levels in the triple arm (JNJ-6379+JNJ-3989 100mg+NA) appeared to be less than in the 
dual arm (JNJ-3989 100mg+NA). More recent interim results of the REEF-2 study (Week 48, end of 
treatment) confirmed this observation when the effect of JNJ-6379+JNJ-3989 200mg+NA on mean HBsAg 
level reduction in the REEF-2 study is compared to JNJ-3989 200mg+NA in the REEF-1 study. To match 
with the REEF-2 population, this cross-study comparison focused on the REEF-1 subpopulation of hepatitis 
B e antigen (HBeAg) negative, virologically suppressed participants with chronic hepatitis B. 
Pharmacokinetic-pharmacodynamic modelling analyses accounting for variability in baseline 
characteristics further support this observation. Therefore, a negative impact of JNJ-6379 on the HBsAg 
lowering effect of JNJ-3989+NA is suspected. 
From a safety perspective, transient reductions of estimated glomerular filtration rate based on creatinine 
(eGFRcr) in JNJ-6379 containing treatment arms with fast recovery after end of treatment had been 
described in the Jade study (56136379HPB2001) and confirmed in the REEF-1 study. In absence of a 
pattern of increased biomarkers of proximal tubulo-toxicity (the beta-2microglobulin/creatinine and the 
retinol binding protein/creatinine ratios), the eGFRcr reduction during treatment was interpreted as 
transporter inhibition at the level of creatinine excretion from the proximal tubule rather than renal toxicity.
Recent data from REEF-2 confirm the transient pattern of eGFRcr declines but, in addition, show an 
increase of the beta-2microglobulin/creatinine and the retinol binding protein/creatinine ratios in some 
participants when tenofovir disoproxil fumarate (TDF) treatment was continued and combined with JNJ-
6379+JNJ-3989. These new data are suggesting that JNJ-6379 in combination with TDF may contribute to 
renal tubulo-toxicity. There was no apparent increase in the beta-2-microglobulin/creatinine or retinol 
binding protein/creatinine ratios in participants receiving entecavir (ETV; active or control arm), nor in 
participants receiving TDF+placebo.
The negative impact of JNJ-6379, when combined with JNJ-3989+NA, on HBsAg reduction taken together 
with the adverse renal profile leads to conclusion of an unfavorable benefit-risk balance of JNJ-6379 in 
combination with JNJ-3989+NA, compared to JNJ-3989+NA alone. Therefore, the Sponsor has decided to 
discontinue treatment with JNJ-6379 in all ongoing clinical studies effective immediately. Participants 
currently on treatment with JNJ-6379 will be contacted and requested to stop taking JNJ-6379, while 
continuing treatment with NA, JNJ-3989 and pegylated interferon alpha-2a (PegIFN-α2a; as applicable). 
For newly enrolled participants, JNJ-6379 will no longer be included in the treatment regimen.  
In addition, a new NA re-treatment criterion and more frequent monitoring for participants who 
discontinued NA treatment during follow-up were included. The reason for these changes is a severe 
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Status: Approved,  Date: 01 December 2021
clinical alanine aminotransferase (ALT) flare that was reported following discontinuation of NA treatment 
in a virologically suppressed HBeAg negative participant on long-term TDF treatment who was randomized 
to the control arm (placebo + placebo + NA) in the REEF-2 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 was following 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 unforseeable. Therefore, to protect safety of participants, the protocol was amended as 
detailed below.
Furthermore, the 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
JNJ-6379 has been removed as 
study intervention. Participants 
enrolled before Protocol 
Amendment 3 had to stop 
JNJ-6379 treatment 
immediately. They will 
continue with JNJ-3989+NA 
treatment up to the end of 
Treatment Period 1 (12 weeks) 
and will then enter Treatment 
Period 2 (12 weeks) during 
which they will have 
PegIFN-α2a added to their 
treatment regimen. Throughout 
the protocol, elements specific 
for JNJ-6379 have been 
modified.   
Based on emerging data from 
recent interim analyses of the 
REEF-1 and REEF-2 studies, 
showing that the benefit-risk 
profile of JNJ-6379 in 
combination with JNJ-3989+NA 
is unfavorable compared to 
JNJ-3989+NA.
1.1 Synopsis
1.2 Schema
1.3 Schedule of Activities
2 INTRODUCTION
2.1 Study Rationale
2.2 Background
2.2.3.1 JNJ-3989 and JNJ 6379
2.3 Benefit-Risk Assessment
2.3.2.2.2 Potential Risks for JNJ-6379
2.3.3 Benefit-Risk Assessment for Study 
Participation
3 OBJECTIVES AND ENDPOINTS 
4.1 Overall Design
4.2 Scientific Rationale for Study Design
4.3 Justification for Dose and Treatment 
Duration
4.3.2 JNJ-6379
5.2 Exclusion Criteria
6.1 Study Intervention(s) Administered
6.2 
Preparation/Handling/Storage/Accountability
6.4 Study Intervention Compliance
6.5 Concomitant Therapy
6.6 Study Intervention Completion at Week 24
7.1 Discontinuation of Study Intervention
8.1 Efficacy Assessments
8.3.6 Adverse Events of Special Interest
8.3.6.1 Rash
8.3.6.3 Acute Systemic Allergic Reactions
8.3.6.4 Intervention emergent ALT/AST 
Elevations
8.3.6.5 Renal Complications
8.3.6.6 Hematologic Abnormalities
8.4 Treatment of Overdose
8.5 Pharmacokinetics
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Status: Approved,  Date: 01 December 2021
Description of Change
Brief Rationale
Section number
and Name
8.6 Pharmacokinetic/Pharmacodynamic 
Evaluations
9.4.4 Other Analyses
10.1 Appendix 1: Abbreviations and Definitions 
of Terms
10.6 Appendix 6: Rash Management
10.7 Appendix 7: Intervention-emergent 
ALT/AST Elevations
10.10 Appendix 10: Study Conduct During a 
Natural Disaster
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 at least weekly 
and/or immediately re-start NA 
treatment irrespective of ALT 
levels.
1.1 Synopsis
1.3 Schedule of Activities
4.2 Scientific Rationale for Study Design
6.7.1 NA Re-treatment Criteria During Follow-
up
6.8 Continued Access to Study Intervention 
After the End of the Study
8.3.6.4 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
1.3 Schedule of Activities
4.2 Scientific Rationale for Study Design
6.7.1 NA Re-treatment Criteria During Follow-
up
8 STUDY ASSESSMENTS AND 
PROCEDURES
REFERENCES
The PegIFN-α2a 
discontinuation criteria were 
updated to clarify that 
participants with moderate or 
severe depression or other 
psychiatric symptoms should 
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 
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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Amendment 4
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Status: Approved,  Date: 01 December 2021
Description of Change
Brief Rationale
Section number
and Name
neuropsychiatric adverse event 
resolves, by frequent (at least 
weekly) follow-up phone calls. 
Furthermore, exclusion 
criterion A25 was amended to 
exclude participants with a 
history of a severe psychiatric 
disorder.
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
10.5 Appendix 5: Contraceptive and Barrier 
Guidance
It was clarified that NA will not 
be dispensed at the end of study 
visit, and that NA will not be 
administered during an early 
withdrawal visit.
Correction.
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.
6.5 Concomitant Therapy
10.10 Appendix 10: Study Conduct During a 
Natural Disaster
It was clarified that venous 
blood samples will be collected 
for measurement of JNJ-3989, 
NA, and PegIFN-α2a. 
Bioanalysis of JNJ-6379 may 
also be done on samples 
collected from participants who 
received JNJ-6379 prior to 
Protocol Amendment 3.
Clarification.
1.1 Synopsis
1.3 Schedule of Activities
3 OBJECTIVES AND ENDPOINTS 
8.5.1 Evaluations
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 
Clarification upon Health 
Authority request.
5.2 Exclusion Criteria
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Status: Approved,  Date: 01 December 2021
Description of Change
Brief Rationale
Section number
and Name
evidence of HIV-1 or HIV-2 
infection who are on 
antiretroviral treatment are 
excluded.
Text was added on dose
modifications for PegIFN-α2a.
For completeness.
6.7 Dose Modification
7.1 Discontinuation of Study Intervention
The footnote for Japan only in 
the Schedule of Activities 
(SOA) was adapted to clarify 
that weekly visits are to be 
scheduled up to Week 23 for 
assessments of safety, 
concomitant therapy, and 
adverse events.
Correction.
1.3 Schedule of Activities
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
Text was updated with 48-week 
hematology data from study 
REEF-1.
Update based on the availability 
of new data.
2.2.3.3 Combination of JNJ-3989 and JNJ-6379 
with PegIFN-α2a
2.3.3 Benefit-Risk Assessment for Study 
Participation
Minor errors were corrected, 
and minor clarifications were 
made.
Correction and clarification.
Throughout the protocol.
Amendment 2 (07 May 2021)
Overall Rationale for the Amendment: The primary reason for this amendment is to add guidance on the 
concomitant use of COVID-19 vaccines and PegIFN-α2a.
Description of Change
Brief Rationale
Section number
and Name
Guidance was added on the 
concomitant use of COVID-19 
vaccines and PegIFN-α2a
Due to overlapping safety 
profiles of PegIFN-α2a and 
COVID-19 vaccines
6.5 Concomitant Therapy
10.10 Appendix 10: Study Conduct During a 
Natural Disaster
Language on urine pregnancy 
testing for at-home use was 
updated
To provide additional guidance 
on urine pregnancy testing at 
home
1.3 Schedule of Activities
Minor formatting change was
made
Minor error was noted
5.2 Exclusion Criteria
Amendment 1 (10 March 2021)
Overall Rationale for the Amendment: The primary reason for this amendment is to increase the sample 
size from 20 to approximately 50 participants. In addition, other changes and minor clarifications and 
corrections were made as detailed below.
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JNJ-73763989 and JNJ-56136379
Clinical Protocol 73763989PAHPB2006
Amendment 4
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148
Status: Approved,  Date: 01 December 2021
Description of Change
Brief Rationale 
Section Number and Name
The overall sample size was 
increased from 20 to 
approximately 50 participants.
Update of the sample size 
determination and interim 
analyses (IAs) sections, 
respectively.
This change will allow to 
increase the value of data 
collected from this study to 
support strategic and informed 
decision-making for the 
upcoming JNJ-3989 Phase 3 
program.
To align the sample size 
justification to the increased 
size of approximately 50. To 
adjust the timing of the planned 
IAs to the larger sample size.
1.1 Synopsis
4.1 Overall Design
9.4.2 Efficacy Analyses
9.2 Sample Size Determination
9.5 Interim Analyses
Exclusion criterion A25 was 
updated to include a separate, 
lower absolute neutrophil count 
(ANC) cut off for black or 
African American participants.
The black or African American 
population generally has lower 
ANC values compared with 
other populations.
5.2 Exclusion Criteria
If JNJ-6379 is discontinued, 
participants may continue 
JNJ-3989 (and PegIFN-α2a if 
applicable) after a consultation 
with the sponsor.
Assessing a continued treatment 
with JNJ-3989 and NA (and 
PegIFN-α2a if applicable) is of 
value even if JNJ-6379 needs to 
be discontinued.
1.3 Schedule of Activities
7.1 Discontinuation of Study Intervention
Anticoagulants were moved 
from the list of disallowed 
medications to the list of 
concomitant medications to be 
used with caution.
Preclinical and clinical data for 
JNJ-3989 and JNJ-6379 do not 
show evidence of coagulopathy. 
6.5 Concomitant Therapy
Nonclinical data on the 
combination of JNJ-3989 or 
JNJ-6379 with PegIFN-α2a 
were added.
These data confirm that:

Combination of PegIFN-α2a 
with JNJ-3989 did not 
induce any synergistic or 
additive effect in monkeys 
up to 3 months of treatment.

Combination of PegIFN-α2a 
with JNJ-6379 induces 
minimal additive effect in in 
vitro study.
2.2.2.3 Combination of JNJ-3989 or JNJ-6379 
With PegIFN-α2a
2.2.2.3.1 Combination of JNJ-6379 With 
PegIFN-α2a
2.2.2.3.2 Combination of JNJ-3989 with 
PegIFN-α2a
2.3.3 Benefit-Risk Assessment for Study 
Participation
Additional renal monitoring by 
eGFR calculation based on 
Cystatin C was added to the 
blood chemistry panel.
PK information on the 
combination of tenofovir 
disoproxil with JNJ-6379 was 
added.
To assess whether eGFR based 
on creatinine vs Cystatin C 
differs in participants receiving 
JNJ-6379. 
Clinical data suggest increased 
tenofovir disoproxil plasma 
concentrations when given in 
combination with JNJ-6379.
10.2 Appendix 2: Clinical Laboratory Tests
2.2.3.2 Combination of JNJ-3989 and JNJ-6379 
with Entecavir, Tenofovir Disoproxil, or 
Tenofovir Alafenamide
2.3.2.2.3 Potential Risks for Entecavir, Tenofovir 
Disoproxil, Tenofovir Alafenamide, and 
PegIFN-α2a
The footnote for Japan only in 
the Schedule of Activities 
(SOA) was adapted to clarify 
that in case of twice weekly 
scheduled visits, the same visit 
window should be applied for 
both visits.
Clarification
1.3 Schedule of Activities
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JNJ-73763989 and JNJ-56136379
Clinical Protocol 73763989PAHPB2006
Amendment 4
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
149
Status: Approved,  Date: 01 December 2021
Description of Change
Brief Rationale 
Section Number and Name
A footnote was added to 
exclusion criteria A02 (a, b, c 
and d) to clarify that bilirubin, 
prothrombin time and serum 
albumin above or below the cut 
off are exclusionary unless they 
can be explained by anything 
other than hepatic 
decompensation.
Clarification
5.2 Exclusion Criteria
A footnote was added to 
exclusion criterion A01 to 
allow for the use of HEV RNA 
results to rule out active HEV 
infection.
Clarification
5.2 Exclusion Criteria
A footnote was added to the 
disallowed medication table, 
allowing the use of approved or 
conditionally authorized 
COVID-19 vaccines, as an 
exception.
Clarification
6.5 Concomitant Therapy
Minor grammatical, formatting, 
or spelling changes were made.
Minor errors were noted
Throughout the protocol
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Status: Approved,  Date: 01 December 2021
10.12. Appendix 12: NA Re-treatment and Monitoring After Stopping of NA
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Status: Approved,  Date: 01 December 2021
11.
REFERENCES
Belloni L, Allweiss L, Guerrieri F, et al. IFN-α inhibits HBV transcription and replication in cell culture and in 
humanized mice by targeting the epigenetic regulation of the nuclear cccDNA minichromosome. J Clin Invest. 
2012;122(2):529-537.
Cohen SM, Johansson SL, Arnold LL, Lawson TA. Urinary tract calculi and thresholds in carcinogenesis. Food and 
Chem Toxicol. 2002;40;793-799.
European Medicines Agency (EMA). Assessment report Vemlidy (Tenofovir alafenamide). 
https://www.ema.europa.eu/documents/assessment-report/vemlidy-epar-public-assessment-report_en.pdf. 
10 November 2016. Accessed 18 August 2020.
European Association for the Study of the Liver. EASL clinical practice guidelines on the Management of chronic 
hepatitis B virus infection. J Hepatol. 2017;67(2):370-398.
Fang Z, Li J, Yu X, et al. Polarization of monocytic myeloid-derived suppressor cells by hepatitis B surface antigen 
is mediated via ERK/IL-6/STAT3 signaling feedback and restrains the activation of T cells in chronic hepatitis B 
virus infection. J Immunol. 2015;195(10):4873-4483.
Gane E, 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, 
Boston November 2019, Poster 0696. Available at: http://ir.arrowheadpharma.com/static-files/66178cc7-10ce-4db2-
8400-1c0495271e35. Accessed 18 August 2020.
Gill US, Peppa D, Micco L, et al. Interferon Alpha Induces Sustained Changes in NK Cell Responsiveness to 
Hepatitis B Viral Load Suppression In Vivo. PLoS Pathog. 2016;12(8):e1005788.
Henry SP, Johnson M, Zanardi TA, et al. Renal uptake and tolerability of a 2’-O-methoxyethyl modified antisense 
oligonucleotide (ISIS 113715) in monkey. Toxicology. 2012;301(1-3):13-20.
Investigator’s Brochure: JNJ-56136379 Edition 6. Janssen Research & Development (Feb 2021).
Investigator’s Brochure: JNJ-73763989 Edition 4. Janssen Research & Development (Apr 2020).
Investigator’s Brochure: JNJ-73763989 Edition 4 Addendum 1. Janssen Research & Development (Oct 2020).
Janas MM, Harbison CE, Perry VK, et al. The nonclinical safety profile of GalNac-conjugated RNAi therapeutics in 
subacute studies. Toxicologic Pathology. 2018;46(7):735-745.
Jeng WJ, Chen YC, Chien RN, Sheen IS, Liaw YF. Incidence and predictors of hepatitis B surface antigen 
seroclearance after cessation of nucleos(t)ide analogue therapy in hepatitis B e antigen-negative chronic hepatitis B. 
Hepatology. 2018;68(2):425-434.
Li H, Zhai N, Wang Z, et al. Regulatory NK cells mediated between immunosuppressive monocytes and 
dysfunctional T cells in chronic HBV infection. Gut. 2018;67(11):2035-2044
Memorandum to Advisory Committee Members and Guests from Entecavir Review Team. Briefing document for 
NDA 21-797, entecavir 0.5 and 1 mg tablets and NDA 21-798, entecavir oral solution 0.05 mg/mL, 
10 February 2005.
Memorandum to Advisory Committee Members and Guests from Tenofovir Review Team. Background Package for 
NDA 21-356: VIREAD (tenofovir disoproxil fumarate), 6 September 2001.
Papatheodoridis GV, Rigopoulou EI, Papatheodoridi M, et al. DARING-B: discontinuation of effective entecavir or 
tenofovir disoproxil fumarate long-term therapy before HBsAg loss in non-cirrhotic HBeAg negative chronic 
hepatitis B. Antivir Ther. 2018;23(8):677-685.
PEGASYS Summary of Product Characteristics. Roche Registration GmbH. Revised July 2020. Available at 
https://www.ema.europa.eu/en/documents/product-information/pegasys-epar-product-information_en.pdf. Accessed 
4 September 2020.
PEGASYS United States Prescribing Information. Hoffmann-La Roche, Inc. Revised October 2017. Available at 
https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/103964s5270lbl.pdf. Accessed 4 September 2020.
Tannehill-Gregg SH, Dominick MA, Reisinger AJ, et al. Strain-related Differences in Urine Composition of Male 
Rats of Potential Relevance to Urolithiasis. Toxicol Pathol. 2009;37:293-305.
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JNJ-73763989 and JNJ-56136379
Clinical Protocol 73763989PAHPB2006
Amendment 4
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Status: Approved,  Date: 01 December 2021
Wang S, Chen Z, Hu C, et al. Hepatitis B virus surface antigen selectively inhibits TLR2 ligand-induced IL-12 
production in monocytes/macrophages by interfering with JNK activation. J Immunol. 2013;190(10):5142-5151.
Wooddell CI, Yuen 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).
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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JNJ-73763989 and JNJ-56136379
Clinical Protocol 73763989PAHPB2006
Amendment 4
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153
Status: Approved,  Date: 01 December 2021
INVESTIGATOR AGREEMENT
I have read this protocol and agree that it contains all necessary details for carrying out this study. I will 
conduct the study as outlined herein and will complete the study within the time designated.
I will provide copies of the protocol and all pertinent information to all individuals responsible to me who 
assist in the conduct of this study. I will discuss this material with them to ensure that they are fully informed 
regarding the study intervention, the conduct of the study, and the obligations of confidentiality.
Coordinating Investigator (where required):
Name (typed or printed):
Institution and Address:
Signature:
Date:
(Day Month Year)
Principal (Site) Investigator:
Name (typed or printed):
Institution and Address:
Telephone Number:
Signature:
Date:
(Day Month Year)
Sponsor's Responsible Medical Officer:
Name (typed or printed):
Institution:
Janssen Research & Development
Signature:
[electronic signature appended at the end of the protocol]
Date:
(Day Month Year)
Note: If the address or telephone number of the investigator changes during the course of the study, written 
notification will be provided by the investigator to the sponsor, and a protocol amendment will not be required.
PPD
NCT04667104


Signature
User 
Date 
Reason
 
01-Dec-2021 
22:20:38
(GMT)
Document Approval
PPD
NCT04667104

SAP_001.pdf: 
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
1
Status: Approved, Date: 18 May 2023
Janssen Research & Development
Statistical Analysis Plan
A Phase 2, Open-label, Single-arm, Multicenter Study to Assess Efficacy, Safety, 
Tolerability, and Pharmacokinetics of Treatment With JNJ-73763989, JNJ-56136379, 
Nucleos(t)ide Analogs, and Pegylated Interferon Alpha-2a in Virologically Suppressed 
Patients With Chronic Hepatitis B Virus Infection
The PENGUIN Study
Protocol 73763989PAHPB2006; Phase 2
JNJ-73763989 and JNJ-56136379  
Status:
Approved
Date:
18 May 2023
Prepared by:
Janssen Research & Development, a division of Janssen Pharmaceutica NV
Document No.:
EDMS-RIM-285536, 3.0
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.
NCT04667104


JNJ-73763989 and JNJ-56136379
Statistical Analysis Plan 73763989PAHPB2006
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
2
Status: Approved, Date: 18 May 2023
TABLE OF CONTENTS
TABLE OF CONTENTS ............................................................................................................................... 2
VERSION HISTORY..................................................................................................................................... 6
1.
INTRODUCTION................................................................................................................................ 11
1.1.
Objectives and Endpoints .............................................................................................................. 11
1.2.
Study Design.................................................................................................................................. 13
2.
STATISTICAL HYPOTHESES.......................................................................................................... 16
3.
SAMPLE SIZE DETERMINATION.................................................................................................... 16
4.
POPULATIONS (ANALYSIS SETS) FOR ANALYSIS..................................................................... 16
5.
STATISTICAL ANALYSES............................................................................................................... 17
5.1.
General Considerations ................................................................................................................. 17
5.1.1.
Analysis Phase ........................................................................................................................... 18
5.1.2.
Relative Day by Study Phase ..................................................................................................... 19
5.1.2.1.
Treatment Period 1 Relative Day ............................................................................................ 19
5.1.2.2.
Treatment Period 2 Relative Day ............................................................................................ 19
5.1.2.3.
Follow Up Relative Day ........................................................................................................... 19
5.1.3.
Visit Windows ............................................................................................................................. 19
5.1.4.
Baseline ...................................................................................................................................... 21
5.1.5.
Additional Reference Timepoint ................................................................................................. 21
5.1.6.
Analysis Specifications ............................................................................................................... 21
5.1.7.
Level of Significance................................................................................................................... 22
5.1.8.
Missing and Partial Dates Imputation Rules............................................................................... 22
5.1.8.1.
Adverse Event Onset Date and Resolution Date .................................................................... 22
5.1.8.2.
HBV Diagnosis and Infection Dates ........................................................................................ 23
5.1.8.3.
Concomitant Medication Dates................................................................................................ 23
5.1.8.4.
Dates of Alcohol Consumptions .............................................................................................. 23
5.1.9.
Data Handling Rules................................................................................................................... 24
5.1.10.
Main Groups for Analysis............................................................................................................ 24
5.1.11.
On-treatment and off-treatment periods ..................................................................................... 25
5.2.
Participant Dispositions.................................................................................................................. 25
5.3.
Primary Efficacy Endpoint.............................................................................................................. 26
5.3.1.
Definition..................................................................................................................................... 26
5.3.2.
Analysis Methods........................................................................................................................ 26
5.3.2.1.
Missing Data Handling Rule .................................................................................................... 26
5.3.2.1.1.
Missing as Non-Responder.................................................................................................. 26
5.3.2.1.2.
Observed Case Analysis...................................................................................................... 26
5.3.2.1.3.
Last Observation Carried Forward (LOCF).......................................................................... 26
5.4.
Secondary Efficacy Endpoints ....................................................................................................... 27
5.4.1.
Definitions ................................................................................................................................... 27
5.4.1.1.
Binary Endpoints ..................................................................................................................... 27
5.4.1.1.1.
NA Treatment Completion Criteria at Week 24 and During FU........................................... 27
5.4.1.1.2.
NA Re-Treatment Criteria During FU................................................................................... 27
5.4.1.1.3.
HBsAg Cut-offs..................................................................................................................... 27
5.4.1.1.4.
HBsAg Seroclearance.......................................................................................................... 28
5.4.1.1.4.1.
On Treatment.................................................................................................................... 28
5.4.1.1.4.2.
Off Treatment.................................................................................................................... 28
5.4.1.1.5.
Functional Cure.................................................................................................................... 28
5.4.1.1.6.
Treatment Failure................................................................................................................. 28
5.4.1.1.7.
HBsAg Seroconversion........................................................................................................ 29
5.4.1.1.8.
HBeAg Cut-offs .................................................................................................................... 29
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Statistical Analysis Plan 73763989PAHPB2006
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
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Status: Approved, Date: 18 May 2023
5.4.1.1.9.
HBeAg Seroconversion........................................................................................................ 29
5.4.1.1.10.
HBV DNA Cut-offs................................................................................................................ 29
5.4.1.1.11.
Suppressed HBV DNA ......................................................................................................... 30
5.4.1.1.12.
Thresholds on HBV DNA and HBsAg ................................................................................... 30
5.4.1.1.13.
ALT Normalization................................................................................................................ 30
5.4.1.1.14.
Partial Cure .......................................................................................................................... 30
5.4.1.1.15.
Virologic Breakthrough......................................................................................................... 31
5.4.1.1.16.
Flares ................................................................................................................................... 31
5.4.1.2.
Continuous Endpoints ............................................................................................................. 33
5.4.1.2.1.
HBsAg, HBeAg, HBV DNA and ALT.................................................................................... 33
5.4.1.3.
Time to Event Endpoints ......................................................................................................... 33
5.4.1.3.1.
Time to First HBsAg Seroclearance..................................................................................... 33
5.4.1.3.2.
Time to First HBsAg Seroconversion................................................................................... 33
5.4.1.3.3.
Time to First HBeAg Seroclearance .................................................................................... 34
5.4.1.3.4.
Time to First HBeAg Seroconversion................................................................................... 34
5.4.1.3.5.
Time to First HBV DNA < LLOQ .......................................................................................... 34
5.4.1.3.6.
Time to First Virologic Breakthrough.................................................................................... 35
5.4.1.3.7.
Time to First Flare ................................................................................................................ 35
5.4.2.
Analysis Methods........................................................................................................................ 35
5.4.2.1.
Binary Endpoints ..................................................................................................................... 35
5.4.2.1.1.
LOCF Imputation Method..................................................................................................... 36
5.4.2.1.2.
NA Treatment Completion Criteria at Week 24 and During FU........................................... 36
5.4.2.1.2.1.
NA Re-Treatment Criteria During FU................................................................................ 36
5.4.2.1.2.2.
HBsAg Cut-offs ................................................................................................................. 37
5.4.2.1.3.
HBsAg Seroclearance.......................................................................................................... 37
5.4.2.1.3.1.
On Treatment.................................................................................................................... 37
5.4.2.1.3.2.
Off Treatment.................................................................................................................... 37
5.4.2.1.4.
Functional Cure.................................................................................................................... 37
5.4.2.1.5.
Treatment Failure................................................................................................................. 38
5.4.2.1.6.
HBsAg Seroconversion........................................................................................................ 38
5.4.2.1.7.
HBeAg Cut-offs .................................................................................................................... 38
5.4.2.1.8.
HBeAg Seroconversion........................................................................................................ 38
5.4.2.1.9.
HBV DNA Cut-offs................................................................................................................ 39
5.4.2.1.10.
Suppressed HBV DNA ......................................................................................................... 39
5.4.2.1.11.
Thresholds on HBV DNA and HBsAg .................................................................................. 39
5.4.2.1.12.
ALT Normalization................................................................................................................ 40
5.4.2.1.13.
Partial Cure .......................................................................................................................... 40
5.4.2.1.14.
Virologic Breakthrough......................................................................................................... 40
5.4.2.1.15.
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 ......................................................................................................... 41
5.5.
Exploratory Endpoints.................................................................................................................... 42
5.5.1.
Definitions ................................................................................................................................... 42
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................................................................................................................ 42
5.5.1.1.3.
HBcrAg Cut-offs ................................................................................................................... 42
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 ............................................................................................................. 43
5.5.1.3.
Time to Event Endpoints ......................................................................................................... 43
5.5.1.3.1.
Time to First HBV RNA<LOD............................................................................................... 43
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 ....................................................................... 44
NCT04667104


JNJ-73763989 and JNJ-56136379
Statistical Analysis Plan 73763989PAHPB2006
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
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Status: Approved, Date: 18 May 2023
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
5.5.1.5.
Sustained HBsAg Response ................................................................................................... 46
5.5.2.
Analysis Methods........................................................................................................................ 47
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 ................................................................................................................... 48
5.5.2.1.4.
Anti-HBe Antibodies ............................................................................................................. 48
5.5.2.2.
Continuous Endpoints ............................................................................................................. 48
5.5.2.2.1.
Liver Stiffness Measurement................................................................................................ 48
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 ......................................................................................................... 49
5.5.2.4.
Endpoints for Correlation......................................................................................................... 49
5.5.2.4.1.
Association Between Baseline Characteristics/Viral Blood Markers and Selected 
Efficacy Variables................................................................................................................. 49
5.5.2.5.
Sustained HBsAg Response ................................................................................................... 49
5.6.
Safety Analyses ............................................................................................................................. 49
5.6.1.
Extent of Exposure ..................................................................................................................... 50
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 ............................................................................................................................ 54
5.6.3.2.1.
eGFR.................................................................................................................................... 55
5.6.3.2.2.
Proximal Renal Tubular Function......................................................................................... 56
5.6.3.3.
Electrocardiogram ................................................................................................................... 57
5.6.3.4.
Vital Signs and Body Temperature.......................................................................................... 59
5.6.3.5.
Physical and Ophthalmic Examinations .................................................................................. 60
5.7.
Other Analyses............................................................................................................................... 60
5.7.1.
Pharmacokinetics ....................................................................................................................... 60
5.7.2.
Pharmacokinetic/Pharmacodynamic Relationships ................................................................... 61
5.7.3.
Immune Analyses ....................................................................................................................... 61
5.7.4.
Viral Genome Sequence Analysis .............................................................................................. 62
5.7.5.
Definition of Subgroups .............................................................................................................. 62
5.7.5.1.
Subgroups for Efficacy Analyses............................................................................................. 62
5.7.5.2.
Subgroups for Safety Analyses ............................................................................................... 62
5.8.
Interim Analyses and Data Review Committee ............................................................................. 62
5.8.1.
Data Review Committee............................................................................................................. 62
5.8.2.
Independent Flare Expert Panel................................................................................................. 63
5.8.3.
Data Reviews and Interim Analyses........................................................................................... 63
5.8.3.1.
Data Reviews........................................................................................................................... 63
5.8.3.2.
Interim Analyses ...................................................................................................................... 63
5.8.3.3.
Analysis Overview of Data Reviews, Interim, Primary and Final Analyses............................. 64
6.
SUPPORTING DOCUMENTATION .................................................................................................. 66
6.1.
Appendix 1 List of Abbreviations.................................................................................................... 66
6.2.
Appendix 2 Changes to Protocol-Planned Analyses ..................................................................... 68
6.3.
Appendix 3 Demographics and Baseline Characteristics.............................................................. 69
6.3.1.
Demographics............................................................................................................................. 69
6.3.2.
Baseline Characteristics ............................................................................................................. 69
6.4.
Appendix 4 Protocol Deviations ..................................................................................................... 71
6.5.
Appendix 5 Prior and Concomitant Medications............................................................................ 72
6.6.
Appendix 6 Medical History ........................................................................................................... 73
6.7.
Appendix 7 Intervention Compliance ............................................................................................. 74
6.8.
Appendix 8 Adverse Events of Special Interest............................................................................. 75
6.9.
Appendix 10 Laboratory Toxicity Grading...................................................................................... 80
NCT04667104


JNJ-73763989 and JNJ-56136379
Statistical Analysis Plan 73763989PAHPB2006
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
5
Status: Approved, Date: 18 May 2023
7.
REFERENCES................................................................................................................................... 81
NCT04667104


JNJ-73763989 and JNJ-56136379
Statistical Analysis Plan 73763989PAHPB2006
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
6
Status: Approved, Date: 18 May 2023
VERSION HISTORY
Document History
Document
Date
Original SAP
30 June 2021
Amendment 1
15 October 2021
Amendment 2
18 May 2023
Amendment 2 (this document)
Overall rationale of this Amendment: 
This is an administrative amendment that incorporates additional clarifications on endpoints, data 
handling rules, and updates to descriptive analyses that were previously documented in the Data 
Presentation Specifications.
Clarifications, Additions, Corrections
Section Number and 
Name
Description of Change
Rationale
Section 5.1.9. Data 
Handling Rules
Revised ULOQ and Imputed Values 
data cutpoints for HBsAg, HBeAg and 
HBcrAg.
Updated guidelines for the imputation 
of HBV DNA.
Improved language for clarity and 
precision.
Section 5.1.10. Main 
Groups for Analysis
Section 5.3.2. Analysis 
Methods
Section 5.4.2. Analysis 
Methods
Section 5.5.2. Analysis 
Methods
Section 5.6. Safety Analyses
Analyses will be focused on all 
subjects, and some analyses will be 
performed by group. 
Change in the scope of the analysis.
Section 5.4.1.1.2 NA Re-
Treatment Criteria During 
FU
Section 5.4.2.1.2.1. NA Re-
Treatment Criteria During 
FU
Removed NA re-treatment sub-criteria 
analysis.
NA re-treatment sub-criteria was not 
collected in CRF. 
NCT04667104


JNJ-73763989 and JNJ-56136379
Statistical Analysis Plan 73763989PAHPB2006
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
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Status: Approved, Date: 18 May 2023
Clarifications, Additions, Corrections
Section Number and 
Name
Description of Change
Rationale
Section 5.4.1.1.12. ALT 
Normalization
Section 5.4.2.1.8. HBeAg 
Seroconversion
Section 5.5.2.2.3. Anti-HBs 
Antibodies
Removed an analysis.
Majority of participants had ALT values 
within normal range at baseline.
HBeAg seroclearance is defined only for 
participants who were HBeAg positive 
at baseline.
Qualitative anti-HBs results are not 
collected. 
Section 5.4.1.1.15. Flares
For on and off treatment biochemical 
flare definitions, nadir definition is 
updated to the lowest value observed 
up to the start of the flare.
The nadir definition was updated to 
include screening visit.
Section 5.4.2.1.10. 
Suppressed HBV DNA
Added two thresholds HBsAg and 
HBV DNA thresholds.
Additional analyses for HBsAg and 
HBV DNA thresholds were decided to 
be performed
Section 5.4.2.1.10. 
Suppressed HBV DNA
Section 5.4.2.2.1. HBsAg, 
HBeAg, HBV DNA and 
ALT
Section 5.5.1.4.1. 
Association Between 
Baseline 
Characteristics/Viral Blood 
Markers and Selected 
Efficacy Variables
Section 5.5.2.2.3. Anti-HBs 
Antibodies
Added to text to avoid analyses in 
case of insufficient data.
Improved language for clarity.
Section 5.4.2.2.1. HBsAg, 
HBeAg, HBV DNA and 
ALT
Clarification of text.
Typographical corrections. 
Section 5.4.2.2.1. HBsAg, 
HBeAg, HBV DNA and 
ALT
Section 5.5.2.2.1. Liver 
Stiffness Measurement
Specified time points for the analysis 
and removed HBV DNA from the 
scope.
Clarification of text.
NCT04667104


JNJ-73763989 and JNJ-56136379
Statistical Analysis Plan 73763989PAHPB2006
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
8
Status: Approved, Date: 18 May 2023
Clarifications, Additions, Corrections
Section Number and 
Name
Description of Change
Rationale
Section 5.5.2.2.2. HBV 
RNA and HBcrAg
Section 5.5.1.3.4. Time to 
Appearance of Anti-HBe 
Antibodies
Updated text for time to appearance of 
anti-HBe antibodies analysis which 
will be performed only for anti-HBe 
negative participants at study entry.
Improved language for clarity and 
precision.
Section 5.5.1.5. Sustained 
HBsAg Response
Section 5.5.2.5. Sustained 
HBsAg Response
Added section with definitions of 
HBsAg sustained response and their 
analyses.
Additional analysis for HBsAg was 
included to better characterize off-
treatment HBsAg response.
Section 5.5.2.2.3. Anti-HBs 
Antibodies
Removed cross-tabulation evaluation 
for anti-HBs.
Qualitative results for anti-HBs 
antibodies were not collected. 
Section 5.7.3. Immune 
Analyses
Removed some analyses.
Change in the scope of the analysis.
Section 5.7.4. Viral Genome 
Sequence Analysis 
Removed subsections.
Subsections were removed to simplify 
the analysis.
Section 5.7.5.1. Subgroups 
for Efficacy Analyses
Removed some subgroups.
Remaining subgroups are sufficient for 
the scope.
Appendix 8 Adverse Events 
of Special Interest
Updated preferred terms. 
MedDRA was updated from v23.0 to 
v25.1.
Appendix 9 Medications of 
Interest
Removed the medications of special 
interest section.
Removal due to discontinuation of JNJ-
6379.
Amendment 1 
Overall rationale for the Amendment: 
Based on emerging data from recent interim analyses of the REEF-1 (73763989HPB2001) and 
REEF-2 (73763989PAHPB2002) studies, the benefit-risk profile of JNJ-56136379 (JNJ-6379) in 
combination with JNJ-73763989 (JNJ-3989)+NA is unfavorable compared to JNJ-3989+NA.  
Therefore, the primary reason for this amendment is to align with Protocol Amendment 3 which 
removed JNJ-56136379 as study intervention, added a new nucleos(t)ide analog (NA) re-treatment 
criterion for participants who discontinued NA treatment during follow-up, and included more 
frequent monitoring for participants who discontinued NA treatment during follow-up. 
NCT04667104


JNJ-73763989 and JNJ-56136379
Statistical Analysis Plan 73763989PAHPB2006
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
9
Status: Approved, Date: 18 May 2023
Furthermore, clarifications, additions and corrections were made throughout the SAP detailed 
below.
Main Changes
Section Number and Name
Description of Change
Rationale
Throughout the document
JNJ-6379 has been removed as study 
intervention. 
Participants 
enrolled 
before Protocol Amendment 3 (issued 
on 04 October 2021) had to stop JNJ-
6379 treatment immediately. They will 
continue with JNJ-3989+NA treatment 
up to the end of Treatment Period 1 (12 
weeks) and will then enter Treatment 
Period 2 (12 weeks) during which they 
will have PegIFN-α2a added to their 
treatment regimen. Patients that were 
already in Treatment Period 2 prior to 
Protocol Amendment 3, will stop JNJ-
6379 immediately and continue with 
JNJ-3989+NA+PegIFN-α2a. 
Throughout the protocol, elements 
specific for JNJ-6379 have been 
modified.   
Based on emerging data from recent 
interim analyses of the REEF-1 and 
REEF-2 studies, showing that the 
benefit-risk profile of JNJ-6379 in 
combination with JNJ-3989+NA is 
unfavorable compared to JNJ-3989+NA.
Clarifications, Additions, Corrections
Section Number and Name
Description of Change
Rationale
Section 1.1 Objectives and 
Endpoints
Updated objectives and endpoints 
table and footnote regarding JNJ-6379
To be in line with Protocol Amendment 
3
Section 1.2 Study Design
Updated the study design using the 
Protocol Amendment 3
Added Figure 2 Schematic Overview 
of the Study – As of Protocol 
Amendment 3
To be in line with Protocol Amendment 
3
Section 5.1 General 
Considerations
Updated study intervention based on 
Protocol Amendment 3
To be in line with Protocol Amendment 
3
Section 5.1.3 Visit Windows
Updated Table 4
To account for additional follow-up 
visits for participants who continue NA 
treatment and for participants who have 
restarted NA treatment during the 
follow-up period, provided that their 
HBV DNA and ALT values are stable.
NCT04667104


JNJ-73763989 and JNJ-56136379
Statistical Analysis Plan 73763989PAHPB2006
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
10
Status: Approved, Date: 18 May 2023
Clarifications, Additions, Corrections
Section Number and Name
Description of Change
Rationale
Section 5.1.10 Main Groups 
for Analysis
Added to state the main groups for 
analysis
To refer to it in later sections
Section 5.6.1 Extent of 
Exposure
Modified the formula for the 
calculation of total duration of 
exposure to JNJ-6379
To reflect the change in Protocol 
Amendment 3
Section 6.7 Intervention 
Compliance
Treatment compliance for JNJ-6379 
was updated.
Due to change in study design regarding 
JNJ-6379 
Throughout the document
Clarification of text
Typographical corrections or improved 
language for clarity and precision
NCT04667104


JNJ-73763989 and JNJ-56136379
Statistical Analysis Plan 73763989PAHPB2006
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
11
Status: Approved, Date: 18 May 2023
1.
INTRODUCTION
The statistical analysis plan (SAP) for the 7376763989PAHPB2006 phase 2 trial describes the 
statistical analyses and definitions to assess the efficacy, and safety of the study intervention 
including JNJ-73763989, JNJ-56136379, Nucleos(t)ide analogs (NA), and pegylated interferon 
alpha-2a (PegIFN-α2a) in virologically suppressed participants with chronic hepatitis B (CHB) 
virus infection. In the rest of the document the abbreviations JNJ-3989 and JNJ-6379 are used to 
refer to the treatments JNJ-73763989 and JNJ-56136379, respectively. Prior to Protocol 
Amendment 3, the study intervention also included JNJ-6379. Note that as of Protocol Amendment 
3, JNJ-6379 has been removed as study intervention and the study will continue with JNJ-3989, 
NA and PegIFN-α2a only. Participants had to stop JNJ-6379 treatment immediately after the 
implementation of Urgent Safety Measure (USM) and approval of the protocol amendment 3.
This study is part of the platform trial PLATFORMPAHPB2001 in participants with CHB.  The 
protocol for 73763989PAHPB2006 constitutes the Intervention Specific Appendix that describes 
all the specific and/or additional features of this study complementing the common design 
elements of the platform trial described in the Master Protocol. 
This SAP is to be interpreted in conjunction with the clinical protocol Amendment-3 finalized on 
04 October 2021, and with the Master Protocol Amendment-3 for PLATFORMPAHPB2001 
finalized on 21 January 2021.
Details of the pharmacokinetic (PK) and pharmacokinetic/pharmacodynamics (PK/PD) analyses 
will be described in a separate analysis and modeling plan.
1.1.
Objectives and Endpoints
Objectives
Endpoints
Primary

To evaluate the efficacy in terms of HBsAg levels 
of the study intervention (i.e. JNJ-3989 + JNJ-
6379d + NA and PegIFN-α2a).

Proportion of participants with a reduction of at 
least 2 log10 IU/mL in HBsAg levels from baseline 
to 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 (serious) adverse 
events (S)AEs and abnormalities in clinical 
laboratory tests (including hematology, blood 
biochemistry, blood coagulation, urinalysis, urine 
chemistry, 
and 
renal 
biomarkers), 
12-lead 
electrocardiograms (ECGs), vital signs, and 
ophthalmic and physical examinations throughout 
the study.

To evaluate the efficacy of the study intervention 
at the end of the 24-week treatment period.

Proportion of participants meeting the protocol-
defined NA treatment completion criteria at EOSI.

To evaluate the efficacy of the study intervention 
as measured by blood markers (such as HBsAg, 
HBeAga, 
HBV 
DNA, 
and
alanine 
aminotransferase [ALT]) during the study 
intervention and follow-up (FU) period.

Proportion of participants with HBeAga, HBsAg, 
HBV DNA, and ALT levels below/above different 
cut-offs.

Proportion of participants with HBsAg and/or 
HBeAga seroconversion.
NCT04667104


JNJ-73763989 and JNJ-56136379
Statistical Analysis Plan 73763989PAHPB2006
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
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Status: Approved, Date: 18 May 2023
Objectives
Endpoints

Change from baseline over time in HBsAg, 
HBeAga, and/or HBV DNA.

Time 
to 
achieve 
HBsAg 
and/or 
HBeAga
seroclearance/seroconversion, and/or HBV DNA< 
lower limit of quantification (LLOQ).

To 
evaluate 
the 
frequency 
of 
virologic 
breakthroughb during the 24-week treatment 
period, as well as during the FU period for 
participants who continue treatment with NA.

Proportion 
of 
participants 
with 
virologic 
breakthroughb.

To evaluate the efficacy of the study intervention 
during the FU period.

Proportion 
of 
participants 
with 
HBsAg 
seroclearance at Week 48 (ie, 24 weeks after 
completion of all study interventions at Week 24) 
without re-starting NA treatment.

Proportion of participants with HBV DNA <LLOQ 
at Week 48 (ie, 24 weeks after completion of all 
study interventions at Week 24) without re-starting 
NA treatment. 

Frequency of virologic and/or biochemical flares.

Proportion 
of 
participants 
requiring 
NA 
re-treatment.

To evaluate the pharmacokinetics (PK) of 
JNJ-3989 
(JNJ-3924 
and 
JNJ-3976), 
and 
optionally of JNJ-6379, NA and PegIFN-α2a.

PK parameters of JNJ-3989 (JNJ-3924 and JNJ-
3976).

Optionally, PK parameters of JNJ-6379, NA and/or 
PegIFN-α2a compared to historical data.
Exploratory

To explore host and viral baseline and on-
treatment markers associated with end of 
treatment and/or off-treatment response.

Association 
of 
baseline 
characteristics 
and 
baseline/on-treatment host and viral blood markers 
(such as age and HBsAg levels) with selected on or 
off-treatment efficacy variables. 

To explore changes in the severity of liver 
disease.

Changes in fibrosis (accounting to Fibroscan liver 
stiffness measurements) at EOSI and the end of the 
FU period versus baseline.

To explore efficacy of the study intervention in 
terms of changes in HBV RNA and hepatitis B 
core-related antigen (HBcrAg) levels during the 
study intervention and FU period.

Changes from baseline in HBV RNA and HBcrAg 
levels over time.

To explore the relationship of PK with selected 
pharmacodynamic (PD) parameters of efficacy 
and safety. 

Relationship of various PK parameters with 
selected efficacy and safety endpoints.

To 
explore 
the 
effect 
of 
PegIFN-α2a 
coadministration on the PK of JNJ-3989 (JNJ-
3924 and JNJ-3976) and JNJ-6379e, as applicable
(PK substudy).

Effect of PegIFN-α2a coadministration on the PK of 
JNJ-3989 (JNJ-3924 and JNJ-3976) and JNJ-6379, 
as applicable.

To explore the HBV genome sequence during the 
study intervention and FU period.

Assessment of intervention-associated mutations 
over time.

To explore HBV-specific T-cell responses during 
the study intervention and FU period.c

Changes from baseline in HBV-specific peripheral 
blood T-cell responses over time.c
NCT04667104


JNJ-73763989 and JNJ-56136379
Statistical Analysis Plan 73763989PAHPB2006
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
13
Status: Approved, Date: 18 May 2023
Objectives
Endpoints

To explore the efficacy of NA re-treatment in 
participants who meet the criteria for NA re-
treatment.

Proportion of participants who reach HBV DNA 
<LLOQ after re-start of NA treatment during the FU 
period.
a.
In HBeAg-positive participants only.
b.
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.
c.
Peripheral blood mononuclear cell (PBMC) samples for immune analyses will be collected at selected sites only.
d.
As per Protocol Amendment 3, JNJ-6379 has been removed as study intervention and the study will continue with 
JNJ-3989, NA and PegIFN-α2a only. Participants had to stop JNJ-6379 treatment immediately.
e.
Not all participants completed treatment with JNJ-6379, as JNJ-6379 has been removed as study intervention with 
the implementation of Protocol Amendment 3.
1.2.
Study Design
This is a Phase 2a, open-label, single-arm, multicenter study to assess efficacy, safety, tolerability 
and pharmacokinetics of treatment with JNJ-3989, JNJ-6379 (as applicable), NA, and PegIFN-α2a 
in virologically suppressed patients with chronic hepatitis B virus infection. Prior to Protocol 
Amendment 3, the study intervention also included JNJ-6379. Note that as of Protocol Amendment 
3, JNJ-6379 has been removed as study intervention and the study will continue with JNJ-3989, 
NA and PegIFN-α2a only. Participants had to stop JNJ-6379 treatment immediately after the 
implementation of Urgent Safety Measure (USM) and approval of the protocol amendment 3.
Approximately 50 virologically suppressed CHB-infected participants, 18-65 years (inclusive) of 
age, will be enrolled in this study. Approximately 40% HBeAg-positive participants will be 
enrolled.
The study will be conducted in 4 periods: 

Screening period (4 weeks [if necessary, can be extended to a maximum of 8 weeks decided 
on a case-by-case basis and in agreement with the sponsor]).

Treatment Period 1 (12 weeks) consisting of combination treatment with JNJ-3989 +  NA.

Treatment Period 2 (12 weeks) adding PegIFN-α2a to the combination treatment regimen of 
Treatment Period 1.

Follow-up (FU) Period (48 weeks).
The total duration of individual participation will be up to 76 weeks (including 4 weeks of 
screening).
A schematic of the trial prior to Protocol Amendment 3 is presented in Figure 1.
NCT04667104


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Figure 1:
Schematic Overview of the Study – Prior to Protocol Amendment 3
ALT: alanine aminotransferase; DNA: deoxyribonucleic acid; EOS: end of study; EOSI: end of study intervention; 
FU: follow-up; HBeAg: hepatitis B e antigen; HBsAg: hepatitis B surface antigen; HBV: hepatitis B virus; JNJ-3989: 
JNJ-73763989; JNJ-6379: JNJ-56136379; LLOQ: lower limit of quantification; n: number of participants; NA: 
nucleos(t)ide  analog; PegIFN-α2a: pegylated interferon alpha-2a; ULN: upper limit of normal; Q4W: every 4 weeks; 
QD: once daily; QW: once weekly.
a.
If NA treatment completion criteria (HBsAg <10 IU/mL, and HBeAg-negative, and HBV DNA <LLOQ, and 
ALT <3x ULN) have been met at Week 24, NA will be stopped at the next scheduled visit (ie, FU Week 2), 
otherwise NA treatment will continue during the complete FU period.
A schematic of the trial as of Protocol Amendment 3 is presented in Figure 2.
Figure 2: Schematic Overview of the Study – As of Protocol Amendment 3
ALT: alanine aminotransferase ; DNA: deoxyribonucleic acid; EOS: end of study; EOSI: end of study intervention; 
FU: follow-up; HBeAg: hepatitis B e antigen; HBsAg: hepatitis B surface antigen; HBV: hepatitis B virus; 
JNJ-3989: JNJ-73763989; LLOQ: lower limit of quantification; n: number of participants; NA: nucleos(t)ide analog; 
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PegIFN-α2a: pegylated interferon alpha-2a; ULN: upper limit of normal; Q4W: every 4 weeks; QD: once daily; 
QW: once weekly.
a If NA treatment completion criteria (HBsAg <10 IU/mL, and HBeAg-negative, and HBV DNA <LLOQ, and ALT 
<3x ULN) have been met at Week 24, NA will be stopped at the next scheduled visit (ie, FU Week 2), otherwise 
NA treatment will continue during the complete FU period.
Prior to Protocol Amendment 3:
Enrolled participants (approximately n=50) will start Treatment Period 1 with triple combination 
treatment (JNJ-3989 [200 mg once every 4 weeks (Q4W)] + JNJ-6379 [250 mg once daily (QD)] 
+ NA [tenofovir disoproxil (TeD; 245 mg), or tenofovir alafenamide (TAF; 25 mg), or entecavir 
(ETV; 0.5 mg) (QD)]) for a duration of 12 weeks.
At Week 12, participants who still meet the eligibility criteria for PegIFN-α2a will start Treatment 
Period 2 with quadruple combination treatment (JNJ-3989 [200 mg once every 4 weeks (Q4W)] + 
JNJ-6379 [250 mg once daily (QD)] + NA [tenofovir disoproxil (TeD; 245 mg), or tenofovir 
alafenamide (TAF; 25 mg), or entecavir (ETV; 0.5 mg) (QD)] + PegIFN-α2a [180 µg once 
weekly]) for a duration of 12 weeks.
Participants no longer meeting the PegIFN-α2a eligibility criteria at Week 12 will continue with 
the Period 1 treatment until Week 24. 
At Week 24, all participants will stop treatment with JNJ-3989 + JNJ-6379 + PegIFN-α2a and start 
the FU Period. NA treatment will be continued during the FU phase in patients not meeting the 
NA completion criteria.
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.
As of Protocol Amendment 3:
Enrolled participants will start Treatment Period 1 with the following combination treatment 
regimen (JNJ-3989 [200 mg once every 4 weeks (Q4W)] + NA [tenofovir disoproxil (TeD; 245 
mg), or tenofovir alafenamide (TAF; 25 mg), or entecavir (ETV; 0.5 mg) (QD)]) for a duration of 
12 weeks.
At Week 12, participants who still meet the eligibility criteria for PegIFN-α2a will start Treatment 
Period 2 with triple combination treatment (JNJ-3989 [200 mg once every 4 weeks (Q4W)] + NA 
[tenofovir disoproxil (TeD; 245 mg), or tenofovir alafenamide (TAF; 25 mg), or entecavir (ETV; 
0.5 mg) (QD)] + PegIFN-α2a [180 µg once weekly]) for a duration of 12 weeks.
Participants no longer meeting the PegIFN α2a eligibility criteria at Week 12 will continue with 
the Period 1 treatment until Week 24. 
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At Week 24, all participants will stop treatment with JNJ-3989 + PegIFN-α2a and start the FU 
Period. NA treatment will be continued during the FU phase in patients not meeting the NA 
completion criteria.
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.
2.
STATISTICAL HYPOTHESES
As this is an exploratory proof of concept (PoC), single-arm study, no formal hypothesis has been 
formulated.
3.
SAMPLE SIZE DETERMINATION
No formal sample size calculation was performed, as this is a single-arm study for exploratory and 
PoC purposes. However, with a sample size of 50 participants having data for the primary efficacy 
endpoint at Week 24, if at least 25 (50%) participants are responders, it can be concluded with 
90% confidence that the true response rate is at least 0.38, with a confidence interval (CI) width 
of 0.248 (90% CI: 0.376-0.624). With a sample size of 20 participants (for one of the interim 
analyses [IAs]) the precision of the estimate of the primary efficacy endpoint decreases, as the 
two-sided 90% CI width increases. For the same assumed proportion of responders of 50% (10 out 
of 20 participants), the 90% CI width becomes 0.396. Table 1 shows the 90% CI and the 
corresponding width for proportion of responders of 0.30, 0.50, 0.70, and 0.90.
Table 1:
Confidence intervals for a range of proportions
N=20
N=50
Proportion of 
responders
90% CI*
Width of CI
90% CI*
Width of CI
0.30
0.140-0.508
0.368
0.195-0.424
0.229
0.50
0.302-0.698
0.396
0.376-0.624
0.248
0.70
0.492-0.860
0.368
0.576-0.805
0.229
0.90
0.717-0.982
0.265
0.801-0.960
0.159
CI: confidence interval.
* Clopper-Pearson exact method is used.
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 the efficacy analyses will be the FAS set, 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 difference of 
at least 2 participants between analysis sets.
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Table 2:
Analysis Sets for Analysis
Analysis Sets
Description
Screened
All participants who signed the ICF for the Master 
Protocol and an ICF specific for the ISA.
Enrolled
All participants who were enrolled in this ISA.
Full Analysis Set (FAS)
All participants who were enrolled and who received at 
least 1 dose of study intervention within this ISA.
Modified FAS
All participants who were enrolled and who received at 
least 1 dose of study intervention excluding those 
participants who, because of  COVID-19 or similar 
pandemics related reasons, withdrew prematurely from 
the study prior to Week 24 (end of study intervention 
[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. 
IFN-FAS
All participants who were enrolled and who received at 
least 1 dose of PegIFN-α2a within this ISA.
Modified IFN-FAS
All participants who were enrolled and who received at 
least 1 dose of PegIFN-α2a 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.
Safety
All participants who received at least 1 dose of study 
intervention.
Participants will be analyzed according to the study 
intervention they actually received.
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, JNJ-6379, NA, and PegIFN-α2a

Study agent refers to: JNJ-3989, JNJ-6379, and PegIFN-α2a

Study intervention refers to: 

Treatment Period 1: 
o
JNJ-3989 + JNJ-6379 + NA
o
JNJ-3989 + NA

Treatment Period 2: 
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o
JNJ-3989 + JNJ-6379 + NA + PegIFN-α2a
o
JNJ-3989 + NA + PegIFN-α2a
NA can be either ETV, TeD or TAF.
5.1.1.
Analysis Phase
The analysis 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 
(excluding PegIFN-α2a)
Treatment 
Period 1
Date of first study agent intake (excluding 
PegIFN-α2a)
For participants who receive PegIFN-α2a:
Min [Date of first PegIFN-α2a intake - 1 day, 
cut-off dateb]
For participants who do not receive PegIFN-
α2a:
Date of Week 12 study agent intake - 1 day
For participants who discontinue treatment 
before Week 12:
Max [last intake date of any study agent, study 
agent discontinuation date, early study 
withdrawal visit date] + 5 daysa or cut-off dateb, 
whichever occurs first 
Treatment 
Period 2
For participants who receive PegIFN-
α2a:
Date of first PegIFN-α2a intake
For participants who did not withdraw from 
the study prior to the projected/actual Week 
24 visit date:
Max [last intake date of any study agent, study 
agent discontinuation date, projected/actual 
Week 24 visit date] + 5 daysa or cut-off dateb, 
whichever occurs first 
Participants who withdrew from the study 
prior to the projected/actual Week 24 visit 
date:
Max [last intake date of any study agent, study 
agent discontinuation date, early study 
withdrawal visit date] + 5 daysa or cut-off dateb, 
whichever occurs first 
For participants who do not receive 
PegIFN-α2a:
Date of Week 12 study agent intake
Otherwise: missing
Follow-up
Participants who did not withdraw 
informed consent during treatment 
period 1 or 2:
Max [End date of Treatment Period 1, 
End date of the Treatment Period 2] + 1 
day
Otherwise: missing
Max [study discontinuation date, study 
completion date] or cut-off dateb, whichever 
occurs first
Otherwise: missing
a Addition of 5 days is only applicable for Adverse Events and Concomitant Medications. 
b  Cutoff dates will be defined to match the prespecified timepoints for DRC safety monitoring, interim analyses, the primary and 
final analyses, respectively. 
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5.1.2.
Relative Day by Study Phase
An analysis relative day (ADY) will be calculated for all assessments at all visits for each 
participant.
5.1.2.1.
Treatment Period 1 Relative Day
The treatment period 1 start date (TP Day 1) is defined as the date of the first study agent intake 
(excluding PegIFN-α2a). All efficacy and safety assessments during the treatment period 1 will be 
assigned an analysis study day relative to this date.
The study day in the treatment period 1 phase (TP1 ADY) is defined as:
TP1 ADY=visit date – TP1 start date+1
for visits on or after treatment period 1 Day 1, and 
TP1 ADY=visit date – TP1 start date
for visits before TP1 Day 1 (Screening phase).
There is no ‘TP1 Day 0’.
5.1.2.2.
Treatment Period 2 Relative Day
The treatment period 2 start date (TP2 Day 1) is defined as the date of first PegIFN-α2a injection 
for those who receive PegIFN-α2a in treatment period 2, and the date of Week 12 agent intake for 
those who don’t receive PegIFN-α2a. Efficacy and safety assessments during the TP2 will be 
assigned an analysis study day relative to this date, unless otherwise specified.
The study day in the TP2 phase (TP2 ADY) is defined as:
TP2 ADY=visit date – TP2 start date+1
for visits on or after TP2 Day 1. 
5.1.2.3.
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:
FU ADY=visit date – FU start date+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 
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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 1 (EOT1), end of treatment period 2 (EOT2), 
and end of study (EOS) visits. If a participant has 2 or more actual visits in one visit window, the 
visit closest to the target day will be used as the protocol visit for that visit window. The other 
additional visit(s) will not be used in the summaries or analyses, but they can be used for 
determination of clinically important endpoints. If 2 actual visits are equidistant from the target 
day within a visit window, the later visit is used. If there are two or more measurements on the 
same day, then the last measurement in chronological order will be used. If the time of the 
assessment is not available, the highest record/sequence number will be selected.
The listings will include all measurements, also those multiple assessments with the same visit 
window/phase. Spaghetti plots will also display all measurements. 
End of treatment period 1 (i.e. EOT1), end of treatment period 2 (i.e. EOT2) and end of study (i.e. 
EOS) time points will be included in all analyses over time unless stated otherwise.
Table 4 provides the analysis time points and time intervals for each visit per analysis phase.
Table 4:
Visit Windows
a) Screening, Treatment Period 1, and Treatment Period 2
Analysis phase
Target day
Analysis 
time point 
(Week)
Analysis 
time point
(label)
Time 
interval 
(days)
Screening
-∞
-1
Screening
<0
Treatment period 1
1
0
Baseline 
Pre-dose: 1
15
2
Week 2
[2,22]
29
4
Week 4
[23,43]
57
8
Week 8
[44,81]
85a
12.1
Week 12
period 1
[82, 92]a
Last visit in treatment period 1
12.15b
EOT1b
Treatment period 2
85a
12.2
Week 12
period 2
[82, 92]a
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 2
25c
EOT2c
a Day 85 is the target day for the first administration of PegIFN-α2a. Time interval [82-92] was selected to align the 
visit window with the protocol Schedule of Activities for Week 12. Any assessments performed before the 
administration of PegIFN-α2a (date/time) at week 12 will be considered under treatment period 1 (Week 12 period 1) 
and assessments after the administration of PegIFN-α2a (date/time) will be considered as treatment period 2 (Week 
12 period 2). 
b End of treatment period 1 (EOT1) visit will be the last visit of treatment period 1.
c End of treatment period 2 (EOT2) visit will be the last visit of treatment period 2.
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b)
Follow-up
Analysis phase
FU Target 
day
Analysis time point 
(Week)
Analysis time point
(label)
Time interval 
(FU days)
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
999 a
EOS a
a End of study (EOS) visit (last available data during the follow-up phase) 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 
TP1 Day 1 will be used as the baseline measurement. If no observed measurement on Day 1, the 
last observed measurement before Day 1 will be used as the baseline assessment.
5.1.5.
Additional Reference Timepoint 
An additional reference timepoint (RT) will be used for an additional analysis of selected efficacy 
endpoints for treatment period 2 and FU phase. 
The RT for those analyses is defined as the last observed non-missing measurement before the first 
PegIFN-α2a intake.
5.1.6.
Analysis Specifications
In general, continuous variables will be summarized using descriptive statistics including the 
number of participants, mean, 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 single 
sample proportion (Newcombe 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.
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5.1.7.
Level of Significance
Due to exploratory nature of this study, no formal test will be performed. Only two-sided 90% CIs 
will be provided with no adjustment for multiplicity.
5.1.8.
Missing and Partial Dates Imputation Rules
For analysis and reporting purposes, missing or partial dates in adverse event (AE onset date; AE 
end date), HBV diagnosis and infection dates, concomitant therapies (start date; end date) will be 
imputed according to the rules in the following subsections. The original, non-imputed, dates will 
be used only in listings.
5.1.8.1.
Adverse Event Onset Date and Resolution Date
Partial AE onset dates will be imputed as follows:

If the AE onset date is missing the day only, it will be set to:

The first day of the month when the AE occurred, if month/year of the AE onset date is 
different than the month/year of the first administration of study 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.
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5.1.8.2.
HBV Diagnosis and Infection Dates
If the reported date is partially missing, the following imputation rules will be applied:

the 15th of the month, if only the day is missing.

the 30th of June, if only the year is available.

No imputation if completely missing.
5.1.8.3.
Concomitant Medication Dates
In case of partially missing concomitant medication start/end dates, the following imputation rules 
will be applied:

the 15th of the month, if only the day is missing.

the 30th of June, if only the year is available.

If the imputed start date is after the concomitant medication end date, further adjustment of 
the imputed start date is required. It will be imputed as the concomitant medication end date.

No imputation if completely missing.
If the medication was taken prior to study start (TP1 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 (TP1 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 baseline visit date. 
Otherwise, no imputation if completely missing.
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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.
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
249,750.00 IU/mL 
with dilution
0.025 IU/mL (a)
274,725.00IU/mL (b) with 
dilution
HBeAg
0.11 IU/mL
7,000.00 IU/mL 
with dilution
0.055 IU/mL (a)
7,700.00 IU/mL(b) with 
dilution
HBcrAg*
3.0 log10 U/mL
9.0 log10 U/mL 
with dilution
2.7 log10 U/mL
9.9 log10 U/mL (b)
with dilution
HBV DNA
20 IU/mL
170,000,000 
IU/mL w/o 
dilution
If target detected: 
15 IU/mL
If target not 
detected: 5 
IU/mL**
187,000,000(b)(c) IU/mL 
w/o dilution
HBV RNA*
LLOQ = 2.939
log10 cp/mL
(i.e. 869 cp/mL)
LOD = 1.398
log10 cp/mL
(i.e. 25 cp/mL)
NAP
If <LOD or target 
not detected then 
1.114 log10 cp/mL
(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.
** For HBV DNA <LLOQ: Spaghetti plots showing absolute values, the imputed value will be 15 IU/mL for both 
target detected, and target not detected. All other tables, listings, and figures will be produced using 15 IU/mL as an 
imputed value if target is detected and 5 IU/mL if target is not detected. 
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.
5.1.10.
Main Groups for Analysis
While most analyses will be focused on all subjects without separating by study intervention, some
analysis will be performed in three different groups:
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1. Group 1: Participants who received at least one tablet of JNJ-6379 during treatment 
period 2:
o
Treatment Period 1: JNJ-3989 + JNJ-6379 + NA
o
Treatment Period 2: JNJ-3989 + JNJ-6379 + NA + PegIFN-α2a
2. Group 2: Participants who did not receive JNJ-6379 at treatment period 2: 
o
Treatment Period 1: 
JNJ-3989 + JNJ-6379 + NA 
JNJ-3989 + NA
o
Treatment Period 2: JNJ-3989 + NA + PegIFN-α2a
Some analysis will be performed separately by the study intervention of treatment period 1 and 
overall.
3. Group 3: all participants who were enrolled in the trial
Post-hoc analyses may be performed based on duration of exposure to JNJ-6379.
5.1.11.
On-treatment and off-treatment periods
The on-treatment period begins with the first drug intake date and finishes with the maximum 
between:

Last dose of NA + 2 days

Last dose of PegIFN α2a + 10 days,

Last dose of JnJ-3989 + 28 days.
The off-treatment period stops if the NA re-treatment starts.
5.2.
Participant Dispositions
All the summaries will be done on the FAS analysis set. The IFN-FAS and modified FAS/IFN-
FAS analysis sets will be used if there is a difference of at least 2 participants between analysis 
sets.  
Screened participants and reason for screen failures will be summarized overall.
The number of participants in the following disposition categories will be summarized by analysis 
phase.

Participants who received any study intervention (JNJ-3989, JNJ-6379, PegIFN-α2a or NA)

Participants in each study analysis phase

Participants who completed the study
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
Participants who discontinued study interventions

Reasons for discontinuation of study interventions

Participants who terminated study prematurely

Reasons for termination of study
A listing of participants will be provided for the following categories

Participants who discontinued study interventions

Participants who terminated study prematurely
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 to Week 24. 
5.3.2.
Analysis Methods
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 difference of at least 2 participants
between analysis sets.
Some analysis will be performed by group, as defined in Section 5.1.10 above.
The count and proportion of participants with a reduction of at least 2 log10 IU/mL in HBsAg levels 
from baseline to Week 24 and the associated 90% CI using the Clopper-Pearson method will be 
calculated.
5.3.2.1.
Missing Data Handling Rule
The missing as non-responder is the primary rule to handle missing data. Two sensitivity analyses 
will be conducted using the observed case data and LOCF approach, respectively.
5.3.2.1.1.
Missing as Non-Responder
Participants who do not have HBsAg data in the analysis window of Week 24 will be defined as 
non‑responders.
5.3.2.1.2.
Observed Case Analysis
Only participants who have HBsAg data at Week 24 will be used for the analysis.
5.3.2.1.3.
Last Observation Carried Forward (LOCF)
If the HBsAg value at Week 24 is missing, the non-missing value 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 the Week 24 assessment will be defined as non-responders.
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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.
5.4.1.
Definitions
5.4.1.1.
Binary Endpoints
5.4.1.1.1.
NA Treatment Completion Criteria at Week 24 and During FU
NA treatment completion criteria are defined based on laboratory results at Week 24 as follows:

HBsAg <10 IU/mL, and

HBeAg-negative, and

HBV DNA <LLOQ, and

ALT <3x ULN
The NA completion criteria will be assessed based on clinical laboratory tests and summarized at 
Week 24 (EOSI) and during FU phase.
5.4.1.1.2.
NA Re-Treatment Criteria During FU
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’. 
5.4.1.1.3.
HBsAg Cut-offs
The cut-offs for HBsAg level are as follow:

<1000 IU/mL

<100 IU/mL

<10 IU/mL

<1 IU/mL

<LLOQ (0.05 IU/mL)
The cut-offs for HBsAg change from baseline and RT 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 
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
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 12, 24, 36 and 48 weeks after stopping all study interventions at the end of treatment 
period 2 and without restarting NA treatment.
HBsAg seroclearance will be also evaluated when assessed at 12, 24, 36 and 48 weeks after 
stopping all study interventions (regardless when intervention was stopped) 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:

met the criteria for stopping NA treatment at Week 24, and

had HBsAg seroclearance at the given week of interest, and

not required NA re-treatment between FU Week 2 and the given 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 in HBsAg 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:

< 100 IU/mL

< 10 IU/mL

< 1 IU/mL

< LLOQ (0.11 IU/mL) 
Of note, seroclearance of HBeAg is defined as (quantitative) HBeAg<LLOQ. 
The cut-offs for HBeAg change from baseline and RT are as follows:

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 
Only HBeAg positive participants will be used for the analysis of the HBeAg cut-offs.
5.4.1.1.9.
HBeAg Seroconversion
Seroconversion of HBeAg is defined as having achieved HBeAg seroclearance together with 
appearance of anti-HBe antibodies. 
Seroclearance of HBeAg is defined as (quantitative) HBeAg <LLOQ. 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. 
5.4.1.1.10.
HBV DNA Cut-offs
The cut-offs for HBV DNA are as follows:

< LLOQ for target detected and not detected
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
< 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
5.4.1.1.11.
Suppressed HBV DNA
HBV DNA < LLOQ (HBV DNA detectable or HBV DNA TND) will be evaluated over all time 
points when assessed with emphasis at FU Weeks 12, 24, 34 and 48, after stopping all study 
interventions at the end of treatment period 2 and without restarting NA treatment.
HBV DNA < LLOQ (HBV DNA detectable or HBV DNA TND) will also be evaluated at 12, 24, 
36 and 48 weeks after stopping all study interventions (regardless when intervention was stopped) 
and without restarting NA treatment.
5.4.1.1.12.
Thresholds on HBV DNA and HBsAg
The count and proportion of participants who meet HBsAg and HBV DNA thresholds will be 
assessed using the last available measurement. 
5.4.1.1.13.
ALT Normalization
ALT elevation at baseline is defined as ALT≥ULN. A participant with ALT elevation at baseline 
achieves ALT normalization if his/her ALT value post-baseline is <ULN at any given time point.
Participants who achieve ALT normalization on treatment 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.
5.4.1.1.14.
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 week of interest, and

had HBsAg ≥LLOQ at the given week of interest, and

not required NA re-treatment after stopping all study interventions.
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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.
5.4.1.1.15.
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 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.
5.4.1.1.16.
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 and had HBV 
DNA<LLOQ at the last observed point on all study treatments.
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 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 nadir (i.e. lowest value observed 
up to the start of the flare) 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.
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
1 (Yes) = confirmed** ALT and/or AST ≥3x ULN and ≥3x nadir (i.e. lowest value observed
up to the start of 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 nadir (i.e. lowest value observed 
up to the start of the flare) while the participant receives any of the study interventions. The 
end date of the same on-treatment biochemical flare is defined as the first date when there is a 
50% reduction from the peak ALT and/or AST level & <3x ULN, regardless of stopping the 
study interventions.

1 (Yes) = confirmed** ALT and/or AST ≥3x ULN and ≥3x nadir (i.e. lowest value observed
up to the start of 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).

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 5.4.1.1.15. 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). 
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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 changes from RT (log10 transformed values) 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 five intervals: treatment period 1 nadir (first 
12 weeks of treatment), treatment period 2 nadir (second 12 weeks of treatment), on-treatment 
nadir (first 24 weeks), during follow-up nadir, and entire study nadir.
Only HBeAg positive participants will be used for the analysis of HBeAg values and changes from 
baseline.
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
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 
NCT04667104


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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 sereoconversion 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 First HBeAg Seroclearance
Seroclearance of HBeAg is defined as (quantitative) HBeAg level < LLOQ.
Time to first HBeAg seroclearance is defined as the number of days between the date of first study 
intervention intake and the date of the first occurrence of HBeAg seroclearance (i.e. the date of the 
first HBeAg seroclearance – the date of first study intervention intake + 1). The participants who 
withdrew early from the study before achieving HBeAg < LLOQ or who did not achieve HBeAg
< LLOQ will be censored at the last available HBeAg assessment.
Time to first HBeAg seroclearance will be also analyzed considering the participants who were 
retreated with NA before achieving HBeAg seroclearance as censored at the date of NA 
retreatment.
Time to first HBeAg seroclearance will be calculated only for HBeAg positive participants.
5.4.1.3.4.
Time to First HBeAg Seroconversion
Time to first HBeAg seroconversion is defined as the number of days between the date of first 
study intervention intake and the date of the first occurrence of HBeAg seroclearance and 
appearance of anti-HBe antibodies (i.e. the date of the first HBeAg seroclearance and anti-HBe 
antibodies – the date of first study intervention intake + 1).  who withdrew early from the study 
before achieving HBeAg seroclearance and anti-HBe antibodies or who did not achieve HBeAg 
seroclearance and anti-HBe antibodies will be censored at the last available anti-HBe antibodies 
assessment.
Time to first HBeAg seroconversion will be also analyzed considering the participants who were 
retreated with NA before achieving HBeAg seroclearance and anti-HBe antibodies as censored at 
the date of NA retreatment.
Time to first HBeAg seroconversion will be calculated only for HBeAg positive participants.
5.4.1.3.5.
Time to First HBV DNA < LLOQ
Time to first HBV DNA < LLOQ is defined as the number of days between the date of first study 
intervention intake and the date of the first occurrence of HBV DNA < LLOQ (i.e. the date of the 
first HBV DNA < LLOQ – the date of first study intervention intake + 1). The participants who 
withdrew early from the study before achieving HBV DNA < LLOQ or who did not achieve HBV 
DNA < LLOQ will be censored at the last available HBV DNA assessment.
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Time to first HBV DNA < LLOQ will be also analyzed considering the participants who were 
retreated with NA before achieving HBV DNA < LLOQ as censored at the date of NA retreatment.
5.4.1.3.6.
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.
5.4.1.3.7.
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.
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
All secondary endpoints will be analyzed using the FAS. The analysis may be repeated in the IFN-
FAS and modified FAS/IFN-FAS analysis sets if there is a difference of at least 2 participants 
between analysis sets.
Some analysis will be performed by group, as defined in Section 5.1.10.Summaries and graphs 
will be provided for each analysis phase, unless specified otherwise.
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.
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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 will show the binary endpoints over time, by subgroups of 
interest, or combining multiple binary endpoints together. 
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 
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 the end of treatment period 2, will be summarized.
Starting at end of treatment period 2, the incidence of participants who did not meet the NA 
treatment completion criteria will be summarized at each timepoint during the study, 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. All the NA treatment completion criteria will be checked based on clinical laboratory 
tests in FU phase.
5.4.2.1.2.1.
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. 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. 
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Status: Approved, Date: 18 May 2023
The count and proportion of participants (and associated 90% CI) who 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.
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.
5.4.2.1.2.2.
HBsAg Cut-offs
The cut-offs for HBsAg values, decreases from baseline and RT will be used in separate summaries 
over time. The count and proportion of participants who meet those HBsAg thresholds during the 
study will be summarized descriptively by analysis phase over time and displayed in graphs like 
bar charts.
Cross-tabulations overtime of quantitative HBsAg (<LLOQ, ≥LLOQ) versus qualitative HBsAg
(positive, negative), respectively, will also be presented.
5.4.2.1.3.
HBsAg Seroclearance
5.4.2.1.3.1.
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.
5.4.2.1.3.2.
Off Treatment 
The count and proportion of participants (and associated 90% CI) who achieve HBsAg 
seroclearance over time during FU will be summarized. Separate analyses will be performed for 
participants who completed treatment as planned (at the end of treatment period 2), and regardless 
when treatment was stopped. 
The count and proportion of participants who achieve HBsAg seroclearance will be evaluated at 
each of the following off-treatment time points: 12, 24, 36 and 48 weeks, respectively, after 
stopping all study interventions and without restarting 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).
5.4.2.1.4.
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.
The main analysis will be on observed cases data with no imputation of missing values. 
Two sensitivity analyses will be performed.
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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.
5.4.2.1.5.
Treatment Failure
The count and proportion of on-treatment failure participants (and associated 90% CI) will be 
summarized.
5.4.2.1.6.
HBsAg Seroconversion
The count and proportion of participants (and associated 90% CI) who achieve HBsAg 
seroconversion will be summarized descriptively by analysis phase.
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 analysis 
phase.
5.4.2.1.7.
HBeAg Cut-offs
The cut-offs for HBeAg values, decreases from baseline and RT will be used in separate summaries 
over time. The count and proportion of participants who meet those HBeAg thresholds during the 
study will be summarized descriptively by analysis phase over time and displayed in graphs like 
bar charts.
Cross-tabulations overtime of quantitative HBeAg (<LLOQ, ≥LLOQ) versus qualitative HBeAg
(positive, negative), respectively, will also be presented.
5.4.2.1.8.
HBeAg Seroconversion
The count and proportion of participants (and associated 90% CI) who achieve HBeAg 
seroconversion will be summarized by analysis phase. Separate tabulations will be made for the 
subset of participants who were HBeAg positive at baseline and for the subset of participants who 
were anti-HBe negative at baseline, respectively. The seroconversion will only be assessed at the 
time points when the anti-HBe antibodies assessment is available.
In addition, the count and proportion of participants (and associated 90% CI) with HBeAg 
seroclearance and without appearance of anti-HBe antibodies will also be summarized by analysis 
phase.
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Status: Approved, Date: 18 May 2023
5.4.2.1.9.
HBV DNA Cut-offs
The cut-offs for HBV DNA values will be used in separate summaries over time. The count and 
proportion of participants who meet those HBV DNA thresholds during the study will be 
summarized descriptively by 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 
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 at each 
of the FU Weeks 12, 24, 36, and 48, respectively, after stopping all study interventions at the end 
of treatment period 2 and without restarting NA treatment. 
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 at each 
of the following off-treatment timepoints: 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.
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.
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 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), if there is at least 10% of the
participants with missing HBV DNA results for the selected time points.
5.4.2.1.11.
Thresholds on HBV DNA and HBsAg 
The number and proportion of participants who meet the following HBV DNA reduction and 
seroclearance thresholds at last available timepoint will be summarized descriptively. Only 
participants who stopped all study treatments without restarting NA will be assessed. 
Thresholds based on HBV DNA and HBsAg 

HBV DNA < 2000 IU/mL

HBV DNA < LLOQ

HBsAg<LLOQ and HBV DNA<LLOQ
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Status: Approved, Date: 18 May 2023

HBsAg<100 IU/mL and HBV DNA<LLOQ

HBsAg<100 IU/mL and HBV DNA<2,000 IU/mL
5.4.2.1.12.
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, 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.
5.4.2.1.13.
Partial Cure
The count and proportion of participants (and associated 90% CI) who achieve partial cure during 
the study will be summarized descriptively 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.
5.4.2.1.14.
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 analysis phase.
5.4.2.1.15.
Flares
The incidence rate will be calculated and summarized for each type of on-treatment or 
off-treatment flares (virologic, biochemical and clinical) separately, as well as the overall 
incidence of participants experiencing at least one flare, regardless of type. Additionally, for each 
participant the total number of flares the participant experienced will be counted by type. Such 
counts will be used to summarize the distribution of the total number of flares by type.
For on-treatment biochemical flares, the incidence of flares causing treatment discontinuation will 
be summarized. Further, for off-treatment flares, the count and percentage of participants who 
experienced a flare followed by NA re-treatment will be summarized by flare type. Similarly, the 
incidence of flares followed by the achievement of HBsAg seroclearance (at any time) will be 
summarized by flare type.
NCT04667104


JNJ-73763989 and JNJ-56136379
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Status: Approved, Date: 18 May 2023
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 (except for 
ALT)], changes from baseline and changes from RT over time in HBsAg, HBeAg, HBV DNA and 
ALT will be summarized. Mean (+/- SE) plots of the values, change from baseline and change 
from RT over time will be presented by analysis phase. The change from baseline value to nadir 
(i.e. maximum decrease for each participant) in HBsAg, HBeAg and HBV DNA will be 
summarized descriptively. Box plots of the changes to nadir in HBsAg, HBeAg, and HBV DNA 
will display the distribution. 
Change from baseline based on log10 transform for quantitative HBsAg and HBeAg will be 
analyzed using mixed effects model for repeated measures [MMRM]) including analysis time 
point (week), baseline blood marker variable, and their interaction. 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) will be provided.
Descriptive statistics on actual values (original unit and log10 transformed values) and changes 
from baseline (log10 transformed values) at the end of treatment in HBsAg, HBeAg, HBV DNA 
and ALT (original unit) will be summarized by outcome response (i.e. by achieving a reduction of 
at least 2 log10 IU/mL in HBsAg levels from baseline to Week 24, by NA treatment completion 
criteria status), by HBsAg seroclearance at the end of treatment period 2, FU Week 24 and FU 
Week 48, and by partial cure status at FU Week 24 and FU Week 48, and for participants who 
achieved functional cure at FU Week 24 and FU Week 48 if there is at least 10% response for each
by-group.
Spaghetti plots for both absolute values and changes from baseline of HBsAg and HBV DNA will 
be presented over time per blood marker by selected subgroups (Section 5.7.5.1).
Waterfall plots for changes from baseline of HBsAg and HBeAg will be presented over time.
Descriptive statistics of the absolute values and changes from baseline over time in ALT will be 
summarized by analysis phase for those participants who had ALT elevation at baseline. 
5.4.2.3.
Time to Event Endpoints
The Kaplan-Meier method will be used to estimate and plot the cumulative incidence and estimate 
the median time with 90% CI. In addition, the number and percentage of participants who had an 
event or were censored will be reported.
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Status: Approved, Date: 18 May 2023
5.5.
Exploratory Endpoints
See Section 1.1 for a list of the exploratory endpoints. All exploratory endpoints will be analyzed 
using observed case data. 
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:

≥1 kPa

≥2 kPa

≥4 kPa

≥6 kPa
Only participants from sites with available VCTE (Fibroscan) will be included in the analysis. 
Within these participants, missing LSM (in kPa) at a specific timepoint will be considered as non-
responders for that timepoint. 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 RT 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 RT are as follows:

decrease by ≥ 1.0 log U/mL

decrease by ≥ 2.0 log U/mL
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Status: Approved, Date: 18 May 2023

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 RT 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.
The change from baseline value to nadir (i.e. maximum decrease for each participant) in HBV 
RNA and HBcrAg will be evaluated at five intervals: treatment period 1 nadir (first 12 weeks of 
treatment), treatment period 2 nadir (second 12 weeks of treatment), 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 
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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 ≥LOD+ 0.5 log10 cp/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. 
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.
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Time to appearance of anti-HBe antibodies will be calculated only for anti-HBe negative 
participants.
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. 
A categorical off-treatment HBV marker will be evaluated if there is at least 10% response. 
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

NA treatment completion at Week 24 (Yes; No)

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

NA treatment completion at Week 24 (Yes; No)

Treatment failure (Yes; No)
HBsAg seroclearance 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

NA treatment completion at Week 24 (Yes; No)

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

NA treatment completion at Week 24 (Yes; No)

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
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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 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

NA treatment completion at Week 24 (Yes; No)

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

NA treatment completion at Week 24 (Yes; No)

Treatment failure (Yes; No)
5.5.1.5.
Sustained HBsAg Response
The definitions of sustained HBsAg response are as follows:

Definition #1: 
-
For participants with Follow-up Week 48 data: participants who had a >1 log10 decline 
from baseline in HBsAg at Follow-up Week 48 and HBsAg < 1,000 IU/mL at Follow-up 
Week 48. 
-
For participants without Follow-up Week 48 data: participants who had a >2 log10 decline 
from baseline in HBsAg at Follow-up Week 24 or a >1.5 log10 decline in HBsAg at 
Follow-up Week 36 (most recent value used) and had HBsAg <1,000 IU/mL at the last 
available timepoint. 

Definition #2: 
-
For participants with a >1 log10 decline from baseline in HBsAg at the last Follow-up 
visit: among the 3 most recent visits, the difference between log10 HBsAg at 2 of the 3 
last visits and 1 of the 3 last visits is <0.2 log10 IU/mL and the difference between log10
HBsAg at 3 of the 3 last visits and 1 of the 3 last visits is <0.2 log10 IU/mL. 

Definition #3: 
-
For participants with a >1 log10 decline from baseline in HBsAg at the last Follow-up 
visit: among the 3 most recent visits, the difference between log10 HBsAg at 2 of the 3 
last visits and 1 of the 3 last visits is <0.2 log10 IU/mL and the difference between log10
HBsAg at 3 of the 3 last visits and 1 of the 3 last visits is <0.2 log10 IU/mL and had 
HBsAg <1,000 IU/mL at the last available timepoint. 

Definition #4: 
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
Three categories regarding the difference between HBsAg level at the last Follow-up 
timepoint and Week 24 (EOT): 
o
>0.2 log10 decrease: Decreasing level
o
≤0.2 log10 increase or ≤0.2 log10 decrease: Stable level
o
≤0.2 log10 increase or ≥0.2 log10 decrease: Stable or Decreasing level
o
>0.2 log10 increase: Increasing level 
For all definitions of the sustained HBsAg response, only participants with at least 24 weeks of 
follow-up data after JNJ-3989 stop will be used for the analysis.
The count and proportion (%) of participants achieving sustained HBsAg response will be 
summarized.
Spaghetti plots for HBsAg actual values and change from baseline will be presented by study panel 
over time using color coding by category. 
5.5.2.
Analysis Methods
All exploratory endpoints will be analyzed using the FAS. The analysis may be repeated in the 
IFN-FAS and modified FAS/IFN-FAS analysis sets if there is a difference of at least 2 participants 
between analysis sets.
Some analysis will be performed by group, as defined in Section 5.1.10.
Summaries and graphs will be provided for each analysis phase, unless specified otherwise.
All exploratory endpoints will be analyzed based on the observed case data. No imputation for 
missing data will be used.
5.5.2.1.
Binary Endpoints
The methods of analysis of the binary exploratory endpoints will be the same as those described 
in Section 5.4.2.1.
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 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, decreases from baseline, and RT will be used in separate 
summaries over time. The number and proportion of participants who meet those HBV RNA 
thresholds during the study will be summarized descriptively by analysis phase over time and 
displayed in graphs like bar charts.
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5.5.2.1.3.
HBcrAg Cut-offs
The cut-offs for HBcrAg values, decreases from baseline and RT will be used in separate 
summaries over time. The number and proportion of participants who meet those HBcrAg 
thresholds during the study will be summarized descriptively by analysis phase over time and 
displayed in graphs like bar charts.
5.5.2.1.4.
Anti-HBe Antibodies
The number and proportion of participants with positive and negative anti-HBe values will be 
summarized descriptively by 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). 
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 over time.
5.5.2.2.2.
HBV RNA and HBcrAg
The actual values, changes from baseline and changes from RT in HBV RNA and HBcrAg, 
respectively, will be summarized only descriptively over time in a similar manner as for values,
changes from baseline and changes from RT 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 over 
time.
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 
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Status: Approved, Date: 18 May 2023
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 if there is at least 
10% of the participants for the subset.
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 study intervention arm for the different 
correlation scenarios:

Pearson’s correlation coefficient for two continuous variables.

Phi correlation coefficient for two binary variables.

Point biserial correlation coefficient for one binary variable and one continuous variable.
5.5.2.5.
Sustained HBsAg Response
Summary tables with counts and percentages of participants who meet each of the definition will 
be presented if there is at least 1 participant who meet the criteria.  
Spaghetti plots for both absolute values and changes from baseline of HBsAg will be presented 
over time for each of the definition. 
5.6.
Safety Analyses
All safety analyses will be performed using the safety analysis set. All assessments will be 
presented by analysis phase (for treatment period 1, for treatment period 2 and FU phase) and 
overall.  All summaries will be descriptive.
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.
Continuous parameters will be summarized using the following statistics: number of observations, 
mean, standard deviation (SD), standard error (SE), minimum, median and maximum, unless 
specified otherwise. Frequencies and percentages will be used for summarizing categorical data.
Some analysis will be performed by group, as defined in Section 5.1.10.
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JNJ-73763989 and JNJ-56136379
Statistical Analysis Plan 73763989PAHPB2006
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
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Status: Approved, Date: 18 May 2023
5.6.1.
Extent of Exposure
Because of the different route and frequency of treatment administration across the 4 agents (for 
JNJ-3989 one subcutaneous injection every 4 weeks (Q4W), for JNJ-6379 once daily tablets (QD),
for NA once daily tablet (QD), and for PegIFN-α2a one subcutaneous injection weekly (QW)) the 
total duration of exposure (weeks) will be calculated for each agent as follows: 

JNJ-3989: [Min ((Date of last JNJ-3989 injection in the given phase+27 days), Date of trial 
disposition, cut-off date) – Date of first JNJ-3989 injection in the given phase + 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

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
The total duration of exposure (weeks) to JNJ-6379 will be calculated for participants who 
received JNJ-6379 as follows:

JNJ-6379: [Min (Date of the last JNJ-6379 administration in the given phase, Date of 
treatment disposition for JNJ-6379, Date of trial disposition, Date of clinical cut-off)- Date of 
first JNJ-6379 administration in the given phase+ 1] / 7
Cutoff dates will be defined to match the prespecified timepoints for DRC periodical data reviews, 
interim analyses and the primary analysis, respectively (see Section 5.8).
Descriptive statistics for duration of each study treatment within a study intervention (N, mean, 
SD, median, and range (minimum, maximum)) during the 24 weeks of treatment (treatment period
1 and 2) will be summarized. The duration of treatment with NA will be summarized also for the 
FU phase. Those participants who stopped NA treatment at or before Week 24 and never restarted 
NA treatment thereafter will be counted as having zero weeks of NA exposure during the FU 
phase.
The number and percentage of participants who skipped any dose of JNJ-3989 or JNJ-6379 or NA
or PegIFN-α2a will be summarized separately for each study intervention. Additionally, the 
number and percentage of participants who missed 2 or more JNJ-3989 injections, or who missed 
more than 5 JNJ-6379 doses within a four-week period, 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 
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Statistical Analysis Plan 73763989PAHPB2006
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Status: Approved, Date: 18 May 2023
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.
Summary tables and listings 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
In addition to the summary tables, listings will be provided for participants who experienced any:

SAEs

AEs leading to discontinuation of each study agent within 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

Renal Complications

Cholesterol increase

Hematologic abnormalities (platelet count, hemoglobin, reticulocytes, neutrophil count)
The list of all preferred terms belonging to ALT/AST elevation, renal complication, cholesterol 
increase, 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.
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JNJ-73763989 and JNJ-56136379
Statistical Analysis Plan 73763989PAHPB2006
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
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Status: Approved, Date: 18 May 2023
for the same lab test within the same phase, the participant will be counted in the analysis for both 
toxicity directions (abnormally high and low).
Imputation rules:
In case continuous laboratory results are not numerically expressed, but as a character (e.g. ‘less 
than 2’, ‘>25’), these results will be numerically imputed as follows:

If the analysis result contains '<' then the result will be multiplied by 0.999 (e.g. <6.1 becomes 
6.0939). 

If analysis result contains '>' then the result will be multiplied by 1.001 (e.g. >6.1 becomes 
6.1061).  

If analysis result contains '≤' or '≥' then only the numeric portion of the result will be used.
This also applies to normal limits expressed as such.
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 also 
including 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 5.7.5.2.
Plots of mean (+/- SE) values and changes from baseline over time for selected laboratory 
parameters will be presented. Spaghetti-plots for selected laboratory parameters will be presented 
over time (with Week shown on x-axis).
A listing including all parameters with at least one treatment-emergent toxicity or abnormality per 
participant (exclusion of urinalysis) will be generated. 
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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Status: Approved, Date: 18 May 2023
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 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).
The same analysis will be performed by eGFRcys subgroups.
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.
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. This 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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Status: Approved, Date: 18 May 2023
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 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.
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. 
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 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 visit using descriptive statistics.
FEPO4 will be calculated as follows:

Based on unadjusted serum creatinine:
FEPO4 (%) = (SCr × UPO4) / (SPO4 × UCr) × 100 (%)
Where SCr is serum creatinine concentration, UPO4 is urine phosphate concentration, SPO4 is 
serum phosphate concentration, and UCr is urine creatinine concentration.
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Status: Approved, Date: 18 May 2023
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 visit using 
descriptive statistics. Median (Q1, Q3) change from baseline in FEPO4 over time will be plotted. 
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.
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.
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;
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Status: Approved, Date: 18 May 2023
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).
Only data from the vendor ERT will be analyzed. All other ECG data will be listed.
For the time points on which triplicate ECGs apply, a rounded mean value to the next integer per 
triplet will be calculated per time point before any further handling. This rounded mean value will 
be used through the entire analysis also in case of 1 or 2 missing values.
ECG records with partial dates (any of day/month/year is missing) will not be used in analysis, 
except in the listings. The following imputation rules will be applied.
If heart rate (HR) is missing, it will be calculated using RR (if available) and rounded to the integer 
value (see formula below) before any further handling if applicable. 
60
)
(
)
(
1000
bpm
HR
ms
RR

HR from the vital signs section (i.e. pulse) will not be used in this ECG analysis section. RR values 
(if available) will only be listed. Recalculated HR values will be flagged.
Descriptive statistics will be calculated for observed values and changes from baseline per 
parameter (all parameters except for RR) at each scheduled time point. 
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.
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JNJ-73763989 and JNJ-56136379
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CONFIDENTIAL – FOIA Exemptions Apply in U.S.
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Status: Approved, Date: 18 May 2023
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 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.
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. 
5.6.3.4.
Vital Signs and Body Temperature
The following parameters measurements will be analyzed:

Supine pulse rate (bpm)

Supine systolic blood pressure (mmHg)

Supine diastolic blood pressure (mmHg)

Body temperature (℃)
The abnormalities in vital signs 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.
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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.
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
Descriptive statistics (n, mean, standard deviation [SD], coefficient of variation [CV], geometric 
mean, median, minimum, and maximum) will be calculated for the plasma concentrations of 
JNJ-3989 (JNJ-3976, and JNJ-3924), and, optionally, of NA, PegIFN-α2a and/or JNJ-6379, and 
for the derived plasma PK parameters for noncompartmental PK analyses.
For each participant with intensive PK sampling, plasma concentration-time data of JNJ-3976, and 
JNJ-3924, and, optionally, of NA, PegIFN-α2a and/or JNJ-6379, will be graphically presented. 
Similarly, graphs of the mean plasma concentration-time profiles and overlay graphs with 
combined individual plasma concentration-time profiles will be produced. Plasma PK parameters 
in participants undergoing intensive PK sampling will be calculated via noncompartmental 
methods for JNJ-3976, and JNJ-3924, and, optionally, NA, PegIFN-α2a and/or JNJ-6379. The PK 
parameters will be Cmax, C24h, and AUC24h; other PK parameters may also be calculated. The PK 
parameters will be subjected to an exploratory graphical analysis, including various 
transformations, to get a general overview.
To assess the effect of PegIFN-α2a on JNJ-6379 (as applicable) and JNJ-3989, the PK parameters 
of JNJ-6379 (as applicable) and JNJ-3989 coadministered with PegIFN-α2a at Week 20 (or 16) 
will be compared to those of JNJ-6379 (as applicable) and JNJ-3989 at Week 4 (or 8) as reference. 
The primary PK parameters are Cmax and AUC24h on the logarithmic scale. A mixed effects model 
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will be fitted to log-transformed PK parameters with treatment period as a fixed effect and 
participant as a random effect.
Special attention will be paid to the plasma concentrations and PK parameters of those participants 
who discontinued the study for an AE, or who experienced an AE ≥grade 3, or an SAE.
Population PK analysis of plasma concentration-time data of JNJ-6379 (as applicable), JNJ-3976, 
and 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 (eg, 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, of NA, PegIFN-α2a 
and/or JNJ-6379 with selected efficacy and/or safety endpoints may be evaluated and graphically 
displayed. 
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 
conducted, the results will be presented in a separate report.
5.7.3.
Immune Analyses
Descriptive statistics (n, mean, SD, CV, geometric mean, median, minimum, and maximum) may 
be used to describe the magnitude of the 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 threshold) may also be tabulated for PBMCs 
during study intervention and follow-up. The proportion (%) of CHB patients with positive
detectable responses based on the magnitude of the IFN-γ T-cell response or the CD4+ or CD8+ 
T-cells expressing at least 1 of the cytokines amongst IL-2, TNF-α or IFN-γ for 1 of the HBV 
antigens as defined by ELISpot and/or ICS, respectively, may be determined. Other immune cells, 
such as NK-cells, MDSCs, DCs, and B-cells, may be evaluated/explored.
Changes from baseline (or positivity threshold) in HBV-specific peripheral blood T-cell responses 
may 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 may be 
presented. The spaghetti plots may be used to show the patient profiles per time point for each 
assay. A graph showing the median and IQR over time may be presented. A bar chart may be used 
to show the breadth of response (i.e. HBV-specific immune response rate for combinations of 
peptide pools).
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For intracellular cytokine staining (ICS), for all cytokine combinations (IFNγ and/or TNFα and/or 
IL-2), pie charts may be presented to reflect the distribution of each of the cytokine combinations 
(i.e. the proportion of a specific cytokine combination of the CD4 or CD8 T-cells secreting at least 
one cytokine), and bar charts may be presented to reflect the mean magnitude of each combination.
5.7.4.
Viral Genome Sequence Analysis
Viral genome sequence analysis may be performed to identify pre-existing baseline 
polymorphisms and to evaluate emergence of genetic variations (including substitutions) 
associated with JNJ-56136379, JNJ-3989, and/or ETV or TD treatment on both nucleotide and/or 
amino acid level. 
The sequencing of samples may be triggered by the sponsor virologist based on changes in HBV 
DNA levels observed in each individual participant and the limits of the sequencing assay.
Virology results will be presented by specified timepoints and genetic region and position of 
interest. A separate virology report may be prepared.
5.7.5.
Definition of Subgroups
5.7.5.1.
Subgroups for Efficacy Analyses
Table 8:
Subgroups for efficacy analyses
Subgroup
Definition
Sex
Male, Female
Age Group
≤45 years, > 45 years
Race
Asian, Non-Asian
Geographical region 
Asia, Europe, Oceania
Type of NA at baseline 
TeD, TAF, ETV
HBsAg level at baseline
<1,000 IU/mL; ≥1,000 IU/mL-<10,000 IU/mL; ≥10,000 IU/mL
HBeAg at baseline
Positive, Negative
5.7.5.2.
Subgroups for Safety Analyses
Table 9:
Subgroups for safety analyses
Subgroup
Definition
Sex
Male, Female
Age Group
≤45 years, > 45 years
Race
Asian, Non-Asian
BMI at Baseline
Underweight <18.5, Normal ≥18.5 - <25, Overweight ≥25 - <30, and Obese 
≥30
Type of NA at Baseline 
TeD, TAF, ETV
5.8.
Interim Analyses and Data Review Committee
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 
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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.
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: 20 participants have reached the Week 12 (end of treatment period 1) time point or 
discontinued earlier.

DR2: 20 participants have reached the Week 16 time point or discontinued earlier.

DR3: 20 participants have reached the FU Week 12 time point or discontinued earlier.

DR4: 20 participants have reached the FU Week 48 time point or discontinued earlier.
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 internal decisions about additional studies 
and/or investigation of other treatment combinations. The IAs are planned when all:

Approximately 20 participants have completed Week 24 (EOSI) or discontinued earlier.
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
All participants have completed Week 36 (FU Week 12) or discontinued earlier.

All participants have completed Week 48 (FU Week 24) or discontinued earlier.

An optional IA may be conducted when all 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.
The final analysis will be performed when all participants have completed the last study visit (FU 
Week 48) or discontinued earlier.
5.8.3.3.
Analysis 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.
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Table 10:
Overview of Data Summaries and Analyses to be Provided to the DRC at Data Reviews, 
Interim, Primary and Final Analyses
DR1/
Week 
12
(N=20)
DR2/
Week 16
(N=20)
IA1/
Week 
24
(N=20
)
DR3 / 
FU 
Week 12 
(N=20) 
Prima
ry 
Analy
sis/ 
Week 
24
(N=50
)
IA2/ 
FU 
Week 
12
(N=50
)
IA3 / 
FU 
Week 
24 
(N=50
)
DR4 / 
FU 
Week 
48 
(N=20
)
IA4 / FU 
Week 36 
(N=50) 
(optional
)
Final 
Analysi
s/ FU 
Week 
48
(N=50)
Subject Information
Baseline & 
Demographic 
characteristics
X
X
X
X
X
X
X
X
X
X
Disposition and Study 
Populations
X
X
X
X
X
X
X
X
X
X
Extent of Exposure
X
X
X
X
X
X
X
X
X
X
Safety
TEAEs, SAEs, AE of 
interest, fatal AEs, AEs 
causing treatment 
discontinuation
X
X
X
X
X
X
X
X
X
X
Laboratory Tests
X
X
X
X
X
X
X
X
X
X
ECG
X
X
X
X
X
X
X
X
X
X
Vital signs
X
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
X
X
Proportion of 
participants with a 
reduction of at least 2 
log10 IU/mL in HBsAg 
levels from baseline 
over time
X
X
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
X
X
Other secondary 
efficacy endpoints
X
X
X
X
X
X
X
X
Exploratory endpoints
X
X
X
X
X
X
X
X
Virologic breakthrough
X
X
X
X
X
X
X
X
X
X
Flares: Viral, 
Biochemical, Clinical
X
X
X
X
X
X
X
X
X
X
PK*
X
X
X
X
X
X
X
X
X
X
*If there are available data, it will be analyzed.
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6.
SUPPORTING DOCUMENTATION
6.1.
Appendix 1 List of Abbreviations
AE
adverse event
ALT
alanine aminotransferase
AST
aspartate aminotransferase
ATC
anatomic and therapeutic class
AUC
area under the curve
BMI
body mass index
BUN
blood urea nitrogen
CHB
chronic hepatitis B
CI
confidence interval
Cmax
maximum concentration
CPK
creatine phosphokinase
CRF
case report form
CSR
Clinical Study Report
CV
coefficient of variation
DAIDS
division of acquired immunodeficiency syndrome
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
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 
HBe
hepatitis B envelope
HBs
hepatitis B surface
HBeAg
hepatitis B envelope antigen
HBsAg
hepatitis B surface antigen
HBV
hepatitis B virus
HBV DNA
hepatitis B virus deoxyribonucleic acid
HBV RNA
hepatitis B virus ribonucleic acid
IA
Interim analysis
ICH
International Conference on Harmonisation
ICS
intracellular cytokine staining
IFLEP
Independent Flare Expert Panel
IFN-FAS
Interferon-Full Analysis Set
IQR
Interquartile range
ISR
injection site reaction
IU/mL
international units per milliliter
KPD
kinetic pharmacodynamic model 
LDh
lactic acid dehydrogenase 
LOQ
lower limit of quantification
LOCF
last observation carried forward
LOD
limit of detection
LSM
liver stiffness measurements
MedDRA
Medical Dictionary for Regulatory Activities
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mFAS
modified full analysis set
MH 
Mantel Haenszel
NA
nucleos(t)ide analogs
NGS
next generation sequencing
PBMC
peripheral blood mononuclear cell
PD
pharmacodynamic(s)
PegIFN-α2a
pegylated interferon alpha-2a
PI
principal investigator
PK
pharmacokinetic(s)
PoC
Proof of Concept
QTc
corrected QC interval
QTcF
QT interval corrected for heart rate according to Fridericia
RBP
retinol binding protein
RR
Interval between R wave of one heartbeat and R wave of preceding heartbeat
RT
Reference Timepoint
SAE
serious adverse event
SAP
Statistical Analysis Plan
SCr
serum creatinine
SD
standard deviation
SMQs
standardised MedDRA queries
SPO4
serum phosphate
TAF
tenofovir alafenamide
TEAE
treatment-emergent adverse event
TD
Target detected
TeD
tenofovir disoproxil
Tmax
time to maximum concentration
TND
target not detected
TNF
tumor necrosis factor
TSH
thyroid stimulating hormone
T4
thyroxine
UACR
urine albumin to creatinine ratio
UCr
urine creatinine
ULN
Upper limit of normal
UPCR
urine protein to creatinine ratio
WBC
white blood cell
WHO-DD
World Health Organization Drug Dictionary
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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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6.4.
Appendix 4 Protocol Deviations
In general, the following list of major protocol deviations may have the potential to impact 
participants’ rights, safety or well-being, or the integrity and/or result of the clinical study. 
Participants with major protocol deviations will be identified prior to database lock and the 
participants with major protocol deviations will be summarized by category.

Developed withdrawal criteria but not withdrawn

Entered but did not satisfy criteria

Received a disallowed concomitant treatment

Received wrong treatment or incorrect dose

Other
All major protocol deviations will be tabulated by coded term for the FAS. A listing of the major 
protocol deviations will be also presented.
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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, 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 overall and ATC class 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 and 
overall.
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6.7.
Appendix 7 Intervention Compliance
Compliance will be summarized descriptively for the safety analysis set for each study agent (i.e. 
excluding NA).
Treatment compliance for treatment period 1 and treatment period 2 is defined as follows.
Treatment period 1

For JNJ-3989: (Total number of injections received/3) * 100%

For JNJ-6379: (Total medication intake / 4 *a) * 100%
As the 250 mg daily dose of JNJ-6379 consists of 4 tablets (2 tablets of 100 mg strength 
and 2 tablets of 25 mg strength). The numerator representing the total medication intake 
for JNJ-6379 is calculated as:
Total medication intake=(Total number of tablets dispensed–Total number of 
tablets returned).
a: for each participant, the individual period (days) of receiving JNJ-6379 (end date of 
JNJ-6379 – start date of JNJ-6379)
Treatment period 2
For JNJ-3989 : (Total number of injections received/ 3) * 100%
For PegIFN-α2a: (Total number of injections received/ 12) * 100%
For JNJ-6379: (Total medication intake/ 4 *a) * 100%
As the 250 mg daily dose of JNJ-6379 consists of 4 tablets (2 tablets of 100 mg strength 
and 2 tablets of 25 mg strength). The numerator representing the total medication intake 
for JNJ-6379 is calculated as:
Total medication intake=(Total number of tablets dispensed–Total number of 
tablets returned).
a: for each participant, the individual period (days) of receiving JNJ-6379 (end date of 
JNJ-6379 – start date of JNJ-6379)
Compliance to JNJ-6379 will be calculated only for participants who received JNJ-6379.
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6.8.
Appendix 8 Adverse Events of Special Interest
Adverse events of special interest list of MedDRA preferred terms.
Adverse 
Event of 
Special 
Interest
Source
Preferred Term
ALT/AST 
elevation
(Modified) Liver related investigations, 
signs and symptoms (SMQ) narrow, 
(MedDRA v25.1)
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
(Modified) Acute renal failure (SMQ) 
broad (MedDRAv25.1)
Acute kidney injury
Anuria
Nephropathy toxic
Oliguria
Renal failure
Renal impairment
Subacute kidney injury
Blood creatinine abnormal
Blood creatinine increased
Creatinine renal clearance abnormal
Creatinine renal clearance decreased
Creatinine urine abnormal
Creatinine urine decreased
Crystal nephropathy
Glomerular filtration rate abnormal
Glomerular filtration rate decreased
Nephritis
Proteinuria
Renal function test abnormal
Renal tubular disorder
Renal tubular dysfunction
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Adverse 
Event of 
Special 
Interest
Source
Preferred Term
Renal tubular injury
Renal tubular necrosis
Urine output decreased
Nephropathy
Nephropathy toxic
Glomerulonephropathy
Nephrolithiasis
Cholesterol 
increase
Dyslipidaemia (SMQ), (MedDRA v25.1)
Blood cholesterol abnormal
Blood cholesterol esterase increased
Blood cholesterol increased
Dyslipidaemia
High density lipoprotein abnormal
High density lipoprotein decreased
High density lipoprotein increased
Hypercholesterolaemia
Hyperlipidaemia
Hypo HDL cholesterolaemia
Intermediate density lipoprotein decreased
Intermediate density lipoprotein increased
LDL/HDL ratio decreased
LDL/HDL ratio increased
Lipid metabolism disorder
Lipids abnormal
Lipids increased
Lipoprotein abnormal
Lipoprotein increased
Low density lipoprotein abnormal
Low density lipoprotein decreased
Low density lipoprotein increased
Non-high-density lipoprotein cholesterol decreased
Non-high-density lipoprotein cholesterol increased
Primary hypercholesterolaemia
Remnant hyperlipidaemia
Remnant-like lipoprotein particles increased
Total cholesterol/HDL ratio abnormal
Total cholesterol/HDL ratio decreased
Total cholesterol/HDL ratio increased
Very low density lipoprotein abnormal
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Adverse 
Event of 
Special 
Interest
Source
Preferred Term
Very low density lipoprotein decreased
Very low density lipoprotein increased
Hematologic 
abnormalities
(Modified) Haematopoietic cytopenias 
affecting more than one type of blood cell 
(SMQ), (MedDRA v25.1)
Aplastic anaemia
Autoimmune aplastic anaemia
Bicytopenia
Bone marrow failure
Cytopenia
Febrile bone marrow aplasia
Full blood count decreased
Gelatinous transformation of the bone marrow
Immune-mediated pancytopenia
Pancytopenia
Panmyelopathy
Aspiration bone marrow abnormal
Biopsy bone marrow abnormal
Full blood count abnormal
Blood disorder
Bone marrow disorder
Bone marrow infiltration
Bone marrow myelogram abnormal
Bone marrow necrosis
Haematotoxicity
Myelodysplastic syndrome
Myelodysplastic syndrome transformation
Myelofibrosis
Myeloid metaplasia
Plasmablast count decreased
Scan bone marrow abnormal
(Modified) Haematopoietic erythropenia 
(SMQ), (MedDRA v25.1)
Aplasia pure red cell
Aplastic anaemia
Erythroblast count decreased
Erythroid maturation arrest
Erythropenia
Hypoplastic anaemia
Microcytic anaemia
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Adverse 
Event of 
Special 
Interest
Source
Preferred Term
Proerythroblast count decreased
Red blood cell count decreased
Reticulocyte count decreased
Reticulocytopenia
Anaemia
Erythroblast count abnormal
Erythropoiesis abnormal
Haematocrit abnormal
Haematocrit decreased
Haemoglobin abnormal
Haemoglobin decreased
Leukoerythroblastic anaemia
Normochromic anaemia
Normochromic normocytic anaemia
Normocytic anaemia
Proerythroblast count abnormal
Red blood cell count abnormal
Reticulocyte count abnormal
Reticulocyte percentage decreased
(Modified) Haematopoietic leukopenia 
(SMQ), (MedDRA v25.1)
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
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Adverse 
Event of 
Special 
Interest
Source
Preferred Term
Monocyte count decreased
Monocytopenia
Myeloblast count decreased
Myelocyte count decreased
Neutropenia
Neutropenic infection
Neutropenic sepsis
Neutrophil count decreased
Promyelocyte count decreased
Pure white cell aplasia
T-lymphocyte count decreased
White blood cell count decreased
Basophil count abnormal
Basophil percentage decreased
B-lymphocyte abnormalities
B-lymphocyte count abnormal
Differential white blood cell count abnormal
Eosinophil count abnormal
Eosinophil percentage decreased
Full blood count abnormal
Granulocytes abnormal
Leukopenia neonatal
Lymphocyte count abnormal
Lymphocyte percentage abnormal
Lymphocyte percentage decreased
Monocyte count abnormal
Monocyte percentage decreased
Mononuclear cell count decreased
Myeloblast percentage decreased
Myelocyte percentage decreased
Myeloid maturation arrest
Neutrophil count abnormal
Neutrophil percentage decreased
Plasma cell disorder
Plasma cells absent
White blood cell analysis abnormal
White blood cell count abnormal
White blood cell disorder
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Adverse 
Event of 
Special 
Interest
Source
Preferred Term
(Modified) Haematopoietic 
thrombocytopenia (SMQ), (MedDRA 
v25.1)
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
6.9.
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.
NCT04667104


JNJ-73763989 and JNJ-56136379
Statistical Analysis Plan 73763989PAHPB2006
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81
Status: Approved, Date: 18 May 2023
7.
REFERENCES
Bourne, C. R., Finn, M. G., & Zlotnick, A. (2006). Global structural changes in hepatitis B virus capsids induced by 
the assembly effector HAP1. Journal of virology, 80(22), 11055-11061.
Katen, S. P., Tan, Z., Chirapu, S. R., Finn, M. G., & Zlotnick, A. (2013). Assembly-directed antivirals differentially 
bind quasiequivalent pockets to modify hepatitis B virus capsid tertiary and quaternary structure. Structure, 21(8), 
1406-1416.
Klumpp, K., Lam, A. M., Lukacs, C., Vogel, R., Ren, S., Espiritu, C., ... & Efimov, A. (2015). High-resolution 
crystal structure of a hepatitis B virus replication inhibitor bound to the viral core protein. Proceedings of the 
National Academy of Sciences, 112(49), 15196-15201.
Newcombe RG. Two-sided confidence intervals for the single proportion: comparison of seven methods. Stat Med. 
1998 Apr 30;17(8):857-72.
Qiu, Z., Lin, X., Zhou, M., Liu, Y., Zhu, W., Chen, W., ... & Huang, M. (2016). Design and synthesis of orally 
bioavailable 4-methyl heteroaryldihydropyrimidine based hepatitis B virus (HBV) capsid inhibitors. Journal of 
medicinal chemistry, 59(16), 7651-7666.
Tu, J., Li, J. J., Shan, Z. J., & Zhai, H. L. (2017). Exploring the binding mechanism of 
Heteroaryldihydropyrimidines and Hepatitis B Virus capsid combined 3D-QSAR and molecular dynamics. Antiviral 
research, 137, 151-164.
Zhou, Z., Hu, T., Zhou, X., Wildum, S., Garcia-Alcalde, F., Xu, Z., ... & Shen, F. (2017). 
Heteroaryldihydropyrimidine (HAP) and sulfamoylbenzamide (SBA) inhibit hepatitis B virus replication by 
different molecular mechanisms. Scientific reports, 7, 42374.
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