A Platform Study Evaluating the Efficacy and Safety of Investigational Therapies in Participants With Chronic Hepatitis B Infection (PREVAIL)
Phase: PHASE1
Conditions: Hepatitis B, Chronic
Sponsor: Vir Biotechnology, Inc.

Official Title: A Platform Study Evaluating the Efficacy and Safety of Investigational Therapies in Participants with 
Chronic Hepatitis B Infection (PREVAIL) 
NCT Number: NCT05612581
Document Date: 11 October 2022, Version 3.0

PREVAIL PLATFORM CLINICAL STUDY 
MASTER PROTOCOL 
PROTOCOL AMENDMENT 2 
Study Title 
A Platform Study Evaluating the Efficacy and Safety of 
Investigational Therapies in Participants with Chronic Hepatitis B 
Infection (PREVAIL) 
Brief Title 
A Platform Study to Evaluate Investigational Therapies in Chronic 
Hepatitis B Infection 
Study Number 
VIR-MHB1-V200 
Indication 
Chronic Hepatitis B Infection 
Study Phase 
1b/2 
Study Sponsor 
Vir Biotechnology, Inc. 
499 Illinois Street, Suite 500 
San Francisco, CA 94158, USA 
Regulatory Agency 
Identifying Numbers 
EudraCT: TBD 
NCT: TBD 
Protocol Date 
11 October 2022, Version 3.0 
This study will be conducted in compliance with International Council for Harmonisation (ICH) Good Clinical 
Practice (GCP), including the archiving of essential documents 
CONFIDENTIALITY STATEMENT  
This document contains confidential information that is the property of Vir Biotechnology, Inc. This confidential 
information is being provided to you, your staff, the applicable Institutional Review Board/Independent Ethics 
Committee, and applicable regulatory authorities solely for the purpose of evaluating or conducting this clinical 
study. This confidential information will be protected by you and your staff against disclosure to or use by third 
parties, except as necessary for the evaluation or conduct of the study. 

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INVESTIGATOR SIGNATURE PAGE 
VIR BIOTECHNOLOGY, INC 
499 ILLINOIS STREET SUITE 500 
SAN FRANCISCO, CA 94158 
STUDY ACKNOWLEDGMENT 
A Platform Study Evaluating the Efficacy and Safety of Investigational Therapies in 
Participants with Chronic Hepatitis B Infection (PREVAIL) 
This Master Protocol has been approved by Vir Biotechnology, Inc. The following signature 
documents this approval.  
Printed Name 
Signature and Date 
INVESTIGATOR STATEMENT 
I have read the protocol, including all appendices, and I agree that it contains all necessary 
details for me and my staff to conduct this study as described. I will conduct this study as 
outlined herein and will make a reasonable effort to complete the study within the time 
designated.  
I will provide all study personnel under my supervision copies of the protocol and access to all 
information provided by Vir Biotechnology, Inc. I will discuss this material with them to ensure 
they are fully informed about the drugs and the study.  
Principal Investigator Printed Name 
Signature 
Date 
PPD

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PROTOCOL AMENDMENT 2 (11 OCTOBER 2022) SUMMARY OF CHANGES TABLE 
Table 1: 
Protocol Document History 
Summaries of changes for Amendment 1 are provided in Section 10.5. 
Table 2: 
Protocol Amendment 2 Summary of Changes 
Section # and Name 
Description of Change 
Brief Rationale 
1.1. Synopsis 
3. Objectives and Endpoints
9.1. Statistical Hypotheses
9.4.2. Primary Endpoint(s)
Analysis
9.4.2.3. Population Level
Summary
Added new potential primary endpoint to 
evaluate the proportion of participants achieving 
hepatitis B virus (HBV) DNA suppression of 
HBV DNA (< LLOQ [lower limit of 
quantitation]) with hepatitis B surface antigen 
(HBsAg) loss (< 0.05 IU/mL) at the end of 
treatment. 
Added for better understanding of the effect of the study 
interventions on both viral parameters and to better align 
with the FDA HBV clinical guidance (FDA 2022). 
The statistical analysis and hypotheses sections were 
updated to incorporate this change. 
4.1.1. Brief Summary 
In Table 3, added Protocol Population VII: 
HBeAg negative, HBV DNA > LLOQ, alanine 
aminotransferase (ALT) ≤ upper limit of normal 
(ULN). 
This study population was added to allow evaluation of 
study interventions in participants that have low levels of 
HBV DNA but elevated ALT.  
7.1. Study Stopping Rules 
Added new subsection to refer to sub-protocols 
for specific details regarding study stopping rules. 
To allow sub-protocols to describe the criteria to 
discontinue, modify or continue the study(ies). 
7.4. Replacement of 
Participants 
Modified to not replace any participants that have 
received any dose of study intervention(s). 
To allow analyses using data from all participants enrolled 
in study that receive study intervention(s). 
8.1. Screening Period 
Allowed screening laboratory tests to be repeated 
with Sponsor medical monitor approval. 
To allow repeat laboratory tests when, in the opinion of 
the medical monitor and investigator, there may be 
erroneous results. 
Document 
Date 
Amendment 2 
11 October 2022 
Amendment 1 
16 May 2022 
Original Protocol 
01 April 2022 

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Section # and Name 
Description of Change 
Brief Rationale 
8.3.1. Physical Examinations 
Clarified that any abnormal findings at screening 
will be recorded as medical history.  
To distinguish medical history from adverse events. 
8.3.4. Pregnancy Testing 
10.6. Appendix 6: 
Contraceptive and Barrier 
Guidance 
Clarified that an elevated follicle stimulating 
hormone (FSH) in the post-menopausal range 
should be used to confirm a post-menopausal 
state in women not using hormonal contraception 
or hormone replacement therapy. 
To correct FSH criteria used to confirm a post-menopausal 
state. 
9.3. Analysis Sets 
Definition of the Full Analysis Set modified to 
include all participants who received at least one 
dose of study intervention(s) irrespective of post-
dose assessments. 
To allow inclusion of all participants enrolled in the study 
and receiving at least 1 dose of study intervention(s) in the 
full analysis population. 
9.4.2.2. Missing Data (new 
section title; previously 
Possible Intercurrent Events) 
Removed possible intercurrent events. 
Added additional procedures for handling of 
missing data.  
To reflect the removal of estimands from the protocol and 
to clarify handling of missing data. 
10.2. Appendix 2: Clinical 
Laboratory Tests 
Added proteins, red blood cells (RBCs), and 
urobilinogen under urinalysis lab test. 
To align with urinalysis lab tests listed in the 
sub-protocols. 
10.3.4. Definition of Adverse 
Event of Interest (AEI) 
10.3.5. Recording and 
Follow-Up of AEs, SAEs, 
SSRs (including Pregnancies) 
and/or AEIs 
Updated definitions and procedures for recording, 
evaluating, and reporting for adverse event of 
interest (AEI) and AE assessment of causality. 
The term adverse event of special interest (AESI) 
was changed to AEI. 
To provide updated information regarding Sponsor's 
current safety reporting procedures. 
10.7. Appendix 7: Schedule of 
Activities 
In footnote “f”, removed specific guidance for 
liver scans and replaced with cross-reference to 
sub-protocols for additional details regarding 
liver scans. 
To make liver scan guidance broader in the master 
protocol, allowing the use of different methods of liver 
scanning. 
Entire document 
Other administrative, formatting, and other minor 
changes 
These changes were made to clarify, ensure consistency, 
provide up-to-date information, or rectify typographical 
errors. 

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TABLE OF CONTENTS 
INVESTIGATOR SIGNATURE PAGE .........................................................................................2 
1.
PROTOCOL SUMMARY ............................................................................................9 
1.1. 
Synopsis ........................................................................................................................9 
1.2. 
Study Schema .............................................................................................................12 
1.3. 
Schedule of Activities .................................................................................................13 
2.
INTRODUCTION ......................................................................................................14 
2.1. 
Background .................................................................................................................14 
2.2. 
Study Rationale ...........................................................................................................16 
2.3. 
Benefit/Risk Assessment ............................................................................................17 
3.
OBJECTIVES AND ENDPOINTS ............................................................................18 
4.
STUDY DESIGN .......................................................................................................20 
4.1. 
Overall Study Design ..................................................................................................20 
4.1.1. 
Brief Summary ............................................................................................................20 
4.1.2. 
Number of Participants ...............................................................................................21 
4.1.3. 
Intervention Groups and Duration ..............................................................................21 
4.1.4. 
Study Committees .......................................................................................................21 
4.2. 
Scientific Rationale for Study Design ........................................................................21 
4.3. 
End of Study Definition ..............................................................................................22 
5.
STUDY POPULATION .............................................................................................22 
5.1. 
Inclusion Criteria ........................................................................................................22 
5.2. 
Exclusion Criteria .......................................................................................................23 
5.3. 
Lifestyle Considerations .............................................................................................24 
5.4. 
Screen Failures ............................................................................................................24 
6.
STUDY INTERVENTION(S) AND CONCOMITANT THERAPY ........................24 
7.
DISCONTINUATION OF STUDY, STUDY INTERVENTION AND
PARTICIPANT DISCONTINUATION/WITHDRAWAL .......................................24 
7.1. 
Study Stopping Rules .................................................................................................24 
7.2. 
Discontinuation of Study Intervention........................................................................24 
7.3. 
Participant Discontinuation/Withdrawal from the Study ...........................................25 
7.4. 
Replacement of Participants .......................................................................................25 
7.5. 
Lost to Follow-up .......................................................................................................25 
8.
STUDY ASSESSMENTS AND PROCEDURES ......................................................26 

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8.1. 
Screening Period .........................................................................................................26 
8.1.1. 
Screening Confirmation of Chronic HBV Infection ...................................................26 
8.1.2. 
Screening Viral Serology Parameters .........................................................................26 
8.1.3. 
Screening for Drugs of Abuse ....................................................................................26 
8.2. 
Efficacy Assessments .................................................................................................27 
8.3. 
Safety Assessments .....................................................................................................27 
8.3.1. 
Physical Examinations ................................................................................................27 
8.3.2. 
Vital Signs ..................................................................................................................27 
8.3.3. 
Clinical Safety Laboratory Tests ................................................................................27 
8.3.4. 
Pregnancy Testing ......................................................................................................27 
8.3.5. 
Other Safety Assessments ...........................................................................................28 
8.4. 
Assessment of Viral Parameters, Antiviral Activity, and Resistance 
Surveillance ................................................................................................................28 
8.5. 
28 
8.6. 
Exploratory Assessments ............................................................................................28 
8.6.1. 
Exploratory Analysis Samples ....................................................................................28 
8.6.2. 
29 
8.6.2.1. 
29 
8.6.2.2. 
29 
8.6.2.3. 
29 
8.7. 
Adverse Events (AEs), Serious Adverse Events (SAEs), and Other Safety 
Reporting ....................................................................................................................29 
8.7.1. 
Time Period and Frequency for Collecting AE and SAE Information .......................30 
8.7.2. 
Follow-up of AEs and SAEs .......................................................................................30 
8.7.3. 
Regulatory Reporting Requirements for SAEs ...........................................................30 
8.7.4. 
Adverse Events of Interest ..........................................................................................31 
8.7.5. 
Clinical Laboratory Abnormalities and Other Abnormal Assessments as AEs 
or SAEs .......................................................................................................................31 
8.7.6. 
Laboratory Events of Clinical Interest ........................................................................31 
8.7.7. 
Special Situation Reports ............................................................................................31 
8.7.7.1. 
Pregnancy ...................................................................................................................32 
8.7.8. 
Other Safety Reporting ...............................................................................................33 
8.8. 
Other Assessments ......................................................................................................33 
CCI
CCI
CCI
CCI
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9.
STATISTICAL CONSIDERATIONS .......................................................................33 
9.1. 
Statistical Hypotheses .................................................................................................33 
9.1.1. 
Multiplicity Adjustment..............................................................................................33 
9.2. 
Sample Size Determination ........................................................................................33 
9.3. 
Analysis Sets ...............................................................................................................35 
9.4. 
Statistical Analyses .....................................................................................................35 
9.4.1. 
General Considerations ...............................................................................................35 
9.4.2. 
Primary Endpoint(s) Analysis .....................................................................................36 
9.4.2.1. 
Population ...................................................................................................................36 
9.4.2.2. 
Missing Data ...............................................................................................................36 
9.4.2.3. 
Population Level Summary ........................................................................................36 
9.4.3. 
Secondary Endpoint(s) Analysis.................................................................................37 
9.4.4. 
Exploratory Endpoint(s) Analysis ..............................................................................37 
9.4.5. 
Missing Data ...............................................................................................................37 
9.4.6. 
Other Safety Analyses ................................................................................................37 
9.5. 
Interim Analysis ..........................................................................................................37 
9.6. 
Other Analyses ............................................................................................................37 
10.
SUPPORTING DOCUMENTATION AND OPERATIONAL
CONSIDERATIONS ..................................................................................................38 
10.1. 
Appendix 1: Regulatory, Ethical, and Study Oversight Considerations ....................38 
10.1.1. 
Regulatory and Ethical Considerations ......................................................................38 
10.1.2. 
Financial Disclosure ...................................................................................................39 
10.1.3. 
Informed Consent Process ..........................................................................................39 
10.1.4. 
Data Protection ...........................................................................................................39 
10.1.5. 
Confidentiality ............................................................................................................39 
10.1.6. 
Committees Structure .................................................................................................40 
10.1.6.1. 
Liver Flare Adjudication Committee (LFAC) ............................................................40 
10.1.7. 
Dissemination of Clinical Study Data ........................................................................40 
10.1.8. 
Data Quality Assurance ..............................................................................................40 
10.1.9. 
Source Documents ......................................................................................................40 
10.1.10. 
Electronic Case Report Forms (eCRF) .......................................................................40 
10.1.11. 
Study and Site Start and Closure ................................................................................41 
10.1.12. 
Publication Policy .......................................................................................................42 

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10.2. 
Appendix 2: Clinical Laboratory Tests .......................................................................43 
10.3. 
Appendix 3: AEs, SAEs, SSRs and AEIs: Definitions and Procedures for 
Recording, Evaluating, Follow-up, and Reporting .....................................................44 
10.3.1. 
Definition of AE .........................................................................................................44 
10.3.2. 
Definition of SAE .......................................................................................................45 
10.3.3. 
Definitions of Special Situations (SSR) .....................................................................46 
10.3.4. 
Definition of Adverse Event of Interest (AEI) ...........................................................47 
10.3.5. 
Recording and Follow-Up of AEs, SAEs, SSRs (including Pregnancies) 
and/or AEIs .................................................................................................................47 
10.3.6. 
Reporting of SAEs, SSRs (including Pregnancies) and/or AEIs ................................51 
10.4. 
Appendix 4: List of Abbreviations and Definitions of Terms ....................................52 
10.5. 
Appendix 5: Summaries of Changes for Previous Protocol Amendments .................54 
10.6. 
Appendix 6: Contraceptive and Barrier Guidance ......................................................56 
10.7. 
58 
11.
REFERENCES ...........................................................................................................63 
LIST OF TABLES 
Table 1: 
Protocol Document History ..........................................................................................3 
Table 2: 
Protocol Amendment 2 Summary of Changes .............................................................3 
Table 3: 
Populations Included in This Platform Protocol .........................................................21 
Table 4: 
Power and Sample Size Calculation for Single Arm Efficacy Evaluation .................34 
Table 5: 
Power and Sample Size Calculation for Efficacy Evaluation with Concurrent 
Controls.......................................................................................................................34 
Table 6: 
Protocol-Required Safety Laboratory Tests ...............................................................43 
Table 7: 
CTCAE (v5.0) Definitions of Severity .......................................................................49 
Table 8: 
Schedule of Activities: Screening and Treatment Periods .........................................58 
Table 9: 
Schedule of Activities: Follow-Up Period ..................................................................61 
LIST OF FIGURES 
Figure 1: 
Study Schema .............................................................................................................13 
Figure 2: 
Stages of Chronic HBV Infection ...............................................................................15 
CCI

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1.
PROTOCOL SUMMARY
1.1. 
Synopsis
Study Title 
A Platform Study Evaluating the Efficacy and Safety of Investigational Therapies in Participants 
with Chronic Hepatitis B Infection (PREVAIL) 
Brief Title  
A Platform Study to Evaluate Investigational Therapies in Chronic Hepatitis B Infection 
Background and Rationale 
Chronic HBV infection remains an important global public health problem with significant 
morbidity and mortality (Trepo 2014). It is estimated that approximately 300 million people are 
living with chronic HBV infection worldwide (Polaris Observatory Collaborators 2018). Over 
time, chronic HBV infection leads to serious sequelae, including cirrhosis, liver failure, 
hepatocellular carcinoma (HCC), and death. Almost 800,000 people worldwide are estimated to 
die annually due to chronic HBV infection (Stanaway 2016). Chronic HBV infection is a 
dynamic process characterized by the interplay of viral replication and the host immune 
response. Patients can be divided into different stages of the disease based on the levels of 
Hepatitis B e antigen (HBeAg), HBV DNA, ALT, and liver inflammation (EASL 2017; 
Sarin 2015; Terrault 2018). 
Current treatment options for chronic HBV infection are limited to nucleos(t)ide reverse 
transcriptase inhibitors (NRTIs) and peginterferon-alfa-2a (PEG-IFNα) (Liang 2015). Long-term 
NRTI therapy can suppress HBV replication and viremia but do not eliminate the cccDNA or 
integrated DNA. In contrast to NRTIs, PEG-IFNα can induce long-term viral control, but only in 
a small percentage of patients (< 10%) and after 48 weeks of therapy (Konerman 2016). 
Moreover, treatment indication is restricted to patients with certain disease characteristics such 
as elevated ALT in addition to having high HBV DNA (EASL 2017; Sarin 2015; Terrault 2018). 
This highlights an unmet need for patients with chronic HBV infection in all stages of the 
disease. The goal of this platform study is to evaluate safety and efficacy of investigational 
therapies aimed to achieve functional cure in patients at different stages of chronic HBV 
infection. 

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Primary and Secondary Objectives and Endpoints 
The general primary and secondary objectives and endpoints for this platform study are outlined 
below. Depending on the phase of the development in the sub-protocol, the primary and 
secondary endpoints will vary as described. Each sub-protocol will describe specific objectives 
and endpoints relevant to the investigational therapy(ies) being evaluated. 
Objectives 
Endpoints 
Primary 
Depending on the development phase, the primary 
endpoint(s) associated analysis methods and 
power calculations will be from those listed 
below. The time point at which it will be assessed 
will be specified within the sub-protocol. 
•
To evaluate the efficacy of the investigational
regimen(s)
•
Proportion of participants achieving sustained
suppression of HBV DNA (< LLOQ) with
HBsAg loss (< 0.05 IU/mL) at 24 weeks after
discontinuation of all treatmenta
•
Proportion of participants achieving sustained
suppression of HBV DNA (< LLOQ) at
24 weeks after discontinuation of all
treatmenta
•
Proportion of participants with HBsAg loss
(< 0.05 IU/mL) at 24 weeks post-end of
treatmentb
•
Proportion of participants achieving
suppression of HBV DNA (< LLOQ [lower
limit of quantitation]) with HBsAg loss
(< 0.05 IU/mL) at the end of treatmentb
•
Proportion of participants with HBsAg loss
(< 0.05 IU/mL) at the end of treatmentb
•
Mean change in serum HBsAg from baseline
across timepoints in the study
Secondary 
•
To evaluate the safety and tolerability of the
investigational regimens
•
To assess the effect of the investigational
regimens on serum hepatitis B surface antigen
(HBsAg)
•
To assess the effect of the investigational
regimens on anti-HBs
1.
Proportion of participants with
treatment-emergent adverse events (TEAEs)
and serious adverse events (SAEs)
2.
Proportion of participants with serum HBsAg
< 10 IU/mL at the end of treatmentb 
3.
Proportion of participants with serum HBsAg
< 10 IU/mL at 24 weeks post-end of
treatmentb

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Objectives 
Endpoints 
4.
Serum HBsAg levels and change from
baseline across timepoints in the study
5.
Serum HBsAg level at nadir during the study
6.
Time to achieve nadir of serum HBsAg
during the study
7.
Time to achieve serum HBsAg loss
(< 0.05 IU/mL)
8.
Proportion of participants with HBsAg loss
and anti-HBs seroconversion at end of
treatment and at 24 weeks post-end of
treatmentb
a Discontinuation of all therapies as defined in the sub-protocols (including investigational therapies and background 
NRTI, if applicable) 
b End of treatment as defined in the sub-protocols 
Overall Study Design 
The intention of the PREVAIL Master Protocol is to provide a standard Phase 1b/2 platform 
study framework to evaluate the safety and efficacy of investigational candidate(s) and their 
combinations as potential treatments for adults with chronic HBV infection. The Master Protocol 
describes the overall study outline, study populations, common objectives and endpoints, 
common inclusion and exclusion criteria, common elements of randomization scheme, statistical 
methodology, general study assessments (which include efficacy and safety assessments), and 
the planned analyses that are common to all sub-protocols. The Master Protocol should be read 
in conjunction with each sub-protocol. The sub-protocols will identify specific investigational 
therapy(ies), the population(s) in which they will be tested, the study-specific design, and any 
additional information pertinent to the investigational intervention(s) included.  
The safety and efficacy of investigational therapies may be evaluated simultaneously, in parallel 
or sequentially in cohorts as described in the specific sub-protocol. The exact duration of the 
study and the individual study periods will be described in the sub-protocols. Overall, the study 
duration will be as follows: 
•
Screening period – up to 56 days (8 weeks).
•
Treatment period – Minimum of 8 weeks, maximum duration as defined in respective
sub-protocol based on the investigational candidate(s).
•
Follow-Up Period – Minimum of 24 weeks after the end of Treatment Period,
maximum duration as defined in respective sub-protocol based on the investigational
candidate(s).
At the end of the Follow-Up Period, the participants may either end the study or be provided 
with an option to enroll into another cohort within the sub-protocol, another sub-protocol, or 
another study, if available and all eligibility criteria are met. 

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Brief Summary 
This platform study will evaluate the safety and efficacy of investigational therapies in one or 
more of the populations of adult participants with chronic HBV infection as follows:  
Protocol Population 
HBeAg Status 
HBV DNA Level 
ALT Level 
I 
Positive 
Higha
≤ ULN 
II 
Positive 
Higha 
> ULN
III 
Negative 
> LLOQa
> ULN
IV 
Negative 
≤ 2,000 IU/mL 
≤ ULN 
V 
Positive 
≤ LLOQ or low (on NRTI therapy) a 
Variablea 
VI 
Negative 
≤ LLOQ or low (on NRTI therapy) a 
Variablea 
VII 
Negative 
> LLOQ a
≤ ULN 
HBeAg: Hepatitis B e Antigen; LLOQ: Lower limit of quantitation; ALT: Alanine Aminotransferase; ULN: Upper 
limit of normal; NRTI: Nucleos(t)ide Reverse Transcriptase Inhibitor 
a As defined in the respective sub-protocol 
Specific details of the population(s) included and investigational therapies will be included in the 
respective sub-protocol(s).  
Number of Participants  
Refer to specific sub-protocol. 
Intervention Groups and Duration 
Refer to specific sub-protocol. 
Study Committees 
The committees in the sub-protocols may include but not be limited to a Liver Flare 
Adjudication Committee (LFAC), Safety Review Committee (SRC), and/or Independent Data 
Monitoring Committee (IDMC). 
1.2. 
Study Schema 
Patients will be screened for eligibility and enrolled into active sub-protocols. Eligible 
participants may be assigned or randomized to treatment groups as specified in the sub-protocols. 
Once enrolled in a sub-protocol, participants will follow the schedule of activities for the 
respective sub-protocol/cohort Treatment and Follow-Up Periods. After the participants 
complete the Follow-Up Period, they may be enrolled into another cohort, sub-protocol, or study, 
if eligible. If not, participants will exit the study (Figure 1). 

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Figure 1: 
Study Schema 
1.3. 
Schedule of Activities  
Schedules of activities are provided in Section 10.7. 

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2.
INTRODUCTION
2.1. 
Background 
Chronic hepatitis B virus (HBV) infection remains an important global public health problem 
with significant morbidity and mortality (Trepo 2014). It is estimated that approximately 
300 million people are living with chronic HBV infection worldwide 
(Polaris Observatory Collaborators 2018). Chronic HBV infection leads to serious sequelae, 
including cirrhosis, liver failure, hepatocellular carcinoma (HCC), and death. Almost 
800,000 people worldwide are estimated to die annually due to chronic HBV infection 
(Stanaway 2016).  
HBV is a double stranded DNA virus belonging to the Hepadnaviridae family that infects, 
replicates, and establishes persistent infection in human hepatocytes (Protzer 2012). The small 
viral genome (3.2 kb) consists of partially double-stranded, relaxed-circular DNA (rcDNA) and 
has 4 open reading frames encoding 7 proteins: HBcAg (HBV core antigen, viral capsid protein), 
HBeAg (Hepatitis B e antigen), HBV polymerase, PreS1/PreS2/HBsAg (large, medium, and 
small surface envelope glycoproteins), and HBx (a regulator of transcription required for the 
initiation of infection) (Seeger 2015; Tong 2016).  
There are 10 major genotypes of HBV (A-J) that have been identified with 35 sub-genotypes. 
The prevalence of the different genotypes is usually associated with geographic locations. In 
North America and Africa, genotype A, B and genotype C are most commonly observed. In east 
Asia, genotypes B and C are most predominant, with genotype D being most common in Europe 
and India (Castaneda 2021; EASL 2017; Tang 2018; Terrault 2018). The response to therapy 
may also differ based on the genotype. For example, in comparison to genotypes B and D, 
genotype A has been associated with higher rates of HBeAg and Hepatitis B surface antigen 
(HBsAg) loss after interferon therapy. 
Chronic HBV infection is a dynamic process based on the relationship between viral replication 
and the host immune response. Based on the levels of biomarkers such as HBV antigens, HBV 
DNA, and HBsAg, patients may oscillate between different phases of the disease (Figure 2). 
Serial monitoring of these biomarkers is essential in determining the stage of infection and 
disease and thereby the clinical management of these patients. Patients that are HBeAg positive 
and have high levels of serum HBV DNA (> 2,000 IU/mL) but normal alanine aminotransferase 
(ALT) are often referred to as “immune tolerant” and are not currently indicated for treatment. 
Patients that are HBeAg positive, have high HBV DNA (usually > 2,000 or > 20,000 IU/mL) and 
have elevated ALT levels are referred to as “immune active” and are currently indicated for 
treatment. Patients with high levels of HBV DNA (> 2,000 IU/mL) and elevated ALT but that 
are HBeAg negative are also grouped as “immune active” and are indicated for treatment. 
However, patients that are HBeAg negative, with normal ALT and HBV DNA < 2,000 IU/mL 
persistent for at least 1 year are considered “inactive carriers” or “immune inactive” and are not 
indicated for treatment (EASL 2017; Sarin 2015; Terrault 2018).  

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Figure 2: 
Stages of Chronic HBV Infection 
HBV DNA: Hepatitis B viral DNA; ALT: Alanine Aminotransferase 
Currently, there are 2 standard-of-care treatment options for patients with chronic HBV 
infection: nucleos(t)ide reverse transcriptase inhibitors (NRTIs) and peginterferon-alfa-2a 
(PEG-IFNα) (Liang 2015). NRTIs inhibit HBV replication by interfering with 
polymerase/reverse transcriptase (pol/RT) activity, leading to DNA chain termination, thus 
preventing the production of HBV DNA containing virions. Although HBV DNA suppression 
can be achieved with NRTIs alone, NRTIs do not directly eliminate cccDNA or integrated DNA, 
and, therefore, transcription and translation of viral proteins continues. Thus, continued HBV 
DNA suppression requires lifelong treatment and rarely results in HBsAg loss. Consequently, 
expression of viral proteins on hepatocytes, secretion of subviral particles, and immune 
dysfunction remain largely unaffected by NRTI therapy. Additionally, while NRTI therapy 
reduces the incidence of HCC, it does not eliminate the increased risk of HCC due to the 
reservoir of cccDNA and integrated HBV forms. Patients that are on NRTIs and have sustained 
low to undetectable levels of HBV DNA, irrespective of HBeAg status or ALT levels are 
“virally-suppressed.” 
In contrast to NRTIs, PEG-IFNα can induce long-term viral control, but only in a small 
percentage of patients (< 10%) and after 48 weeks of therapy (Konerman 2016). While the exact 
mechanism of action of PEG-IFNα treatment is unknown, interferon induces multiple innate 
immune mechanisms and exerts antiproliferative and antiviral effects at various points of the 
HBV lifecycle in vitro (PEGASYS® Prescribing Information; Rijckborst 2010). The low 
response rate coupled with limited tolerability and a long treatment course preclude the treatment 
of most patients with PEG-IFNα monotherapy (PEGASYS® Prescribing Information). The 
limitations of NRTI and PEG-IFNα therapy highlight the need for novel HBV therapies that are 
well tolerated and have a finite duration of administration.  
Several investigational agents are currently under development for the treatment of chronic HBV 
infection. These include HBsAg targeting monoclonal antibodies, small interfering RNA, viral 
entry inhibitors, capsid assembly modulators, innate immune stimulators, therapeutic vaccines, 
checkpoint inhibitors, and nucleic acid polymers. Early clinical data suggests that a combination 
Immune 
Tolerant
Immune 
active
Inactive 
carrier
Reactivation
HBV DNA
ALT

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of multiple therapeutic modalities may be necessary to achieve functional cure in the majority of 
chronic HBV patients and that lowering HBsAg is a critical component of any combination 
regimen (Revill 2019; Zoulim 2015).  
2.2. 
Study Rationale 
This study is intended to evaluate multiple study intervention(s) and their combinations in 
different populations of chronic HBV infected participants. A platform design has been chosen to 
implement this study. The platform design will allow for a modular approach with a Master 
Protocol that contains common elements shared across all sub-protocols and interventions. The 
sub-protocols may contain additional interventions, patient populations, or study-specific 
elements. A platform study design will allow for evaluation of safety and efficacy of study 
interventions across the sub-protocols among the different patient populations. Platform study 
designs are routinely used in oncology and Coronavirus disease 2019 (COVID-19) clinical trials 
and are also being currently utilized to evaluate interventions in chronic HBV infection 
(clinicaltrials.gov identifiers: NCT04225715, NCT04667104, NCT04129554, NCT04746183, 
NCT04518410, NCT03697304, NCT01042379).  
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2.3. 
Benefit/Risk Assessment 
This platform design study is intended to evaluate different regimens of investigational therapies 
in participants with chronic HBV infection. Compared to the current standard of care, the 
regimens to be evaluated will offer the potential benefits of finite duration, pan-genotypic 
activity, and the potential to achieve a functional cure, which may be associated with a reduction 
in HBV-associated severe sequelae such as cirrhosis, liver failure, HCC, or death. Given the 
nature of chronic HBV infection, all the sub-protocols are designed with an emphasis on hepatic 
safety. These include but are not limited to specific participant selection criteria, regular 
monitoring of laboratory evaluations, and procedures for timely reporting and oversight of any 
safety-related events. The sub-protocols describe the intervention-specific benefit/risk 
assessments.  
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3.
OBJECTIVES AND ENDPOINTS
Objectives 
Endpoints 
Primary 
Depending on the development phase, the primary 
endpoint(s) associated analysis methods and 
power calculations will be from those listed 
below. The time point at which it will be assessed 
will be specified within the sub-protocol. 
•
To evaluate the efficacy of the investigational
regimen(s)
•
Proportion of participants achieving sustained
suppression of HBV DNA (< LLOQ) with
HBsAg loss (< 0.05 IU/mL) at 24 weeks after
discontinuation of all treatmenta
•
Proportion of participants achieving sustained
suppression of HBV DNA (< LLOQ) at
24 weeks after discontinuation of all
treatmenta
•
Proportion of participants with HBsAg loss
(< 0.05 IU/mL) at 24 weeks post-end of
treatmentb
•
Proportion of participants achieving
suppression of HBV DNA (< LLOQ [lower
limit of quantitation]) with HBsAg loss
(< 0.05 IU/mL) at the end of treatmentb
•
Proportion of participants with HBsAg loss
(< 0.05 IU/mL) at the end of treatmentb
•
Mean change in serum HBsAg from baseline
across timepoints in the study
Secondary 
•
To evaluate the safety and tolerability of the
investigational regimens
•
To assess the effect of the investigational
regimens on serum hepatitis B surface antigen
(HBsAg)
•
To assess the effect of the investigational
regimens on anti-HBs
1.
Proportion of participants with treatment-
emergent adverse events (TEAEs) and serious
adverse events (SAEs)
2.
Proportion of participants with serum HBsAg
≤ 10 IU/mL at end of treatmentb
3.
Proportion of participants with serum HBsAg
≤ 10 IU/mL at 24 weeks post-end of
treatmentb
4.
Serum HBsAg levels and change from
baseline across timepoints in the study
5.
Serum HBsAg level at nadir during the study

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Objectives 
Endpoints 
6.
Time to achieve nadir of serum HBsAg
during the study
7.
Time to achieve serum HBsAg loss (< 0.05
IU/mL)
8.
Proportion of participants with HBsAg loss
with anti-HBs seroconversion at end of
treatment and at 24 weeks post-end of
treatmentb
Exploratory 
•
To evaluate additional viral parameters
associated with HBV and/or study
intervention(s)
•
To evaluate the emergence of viral resistance
to study intervention(s)
1.
Additional viral parameters associated with
HBV and/or study intervention(s), including
but not limited to HBV RNA and Hepatitis B
core-related antigen (HBcrAg)
4.
Emergence of viral resistance to study
intervention(s)
a Discontinuation of all therapies as defined in the sub-protocols (including investigational therapies and background 
NRTI, if applicable) 
b End of treatment as defined in the sub-protocols 
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4.
STUDY DESIGN
4.1. 
Overall Study Design 
The intention of the PREVAIL Master Protocol is to provide a standardized platform study 
design to evaluate the safety and efficacy of investigational candidate(s) and their combinations 
as potential treatments for adults with chronic HBV infection. The Master Protocol describes the 
overall study outline, study populations, common objectives and endpoints, common inclusion 
exclusion criteria, common elements of randomization scheme, statistical methodology, general 
study assessments which include efficacy and safety assessments, and the planned analyses that 
are common to all sub-protocols. The Master Protocol should be read in conjunction with each 
sub-protocol. The sub-protocols will identify specific investigational therapy(ies), the 
population(s) in which they will be tested, the study-specific design and any additional 
information pertinent to the regimen(s). Additional sub-protocols may be added to this Master 
Protocol to evaluate novel study intervention(s) and combinations in populations defined herein.  
The safety and efficacy of investigational therapies may be evaluated in parallel or sequentially 
in cohorts as described in the specific sub-protocol. Participants will consent to the Master 
Informed Consent Form (ICF) and the sub-protocol ICF prior to enrollment into a cohort. All 
protocol-related activities will be conducted only after the participant has signed the ICFs. After 
the participant has consented to participating in the study, they will be screened. Based on the 
screening data and the eligibility for sub-protocol(s), the participants will be enrolled into a 
cohort by the Interactive Response Technology (IRT). The exact duration of the study and the 
individual study periods will be described in the sub-protocols.  
At the end of the Follow-Up Period, the participants may either end the study or be provided 
with an option to enroll into another cohort, sub-protocol, or study, if available. Participants who 
have provided informed consent will undergo evaluation for eligibility for optional enrollment 
into another study cohort. Data collection will be carried out per cohort or sub-protocol in which 
the participant is enrolled. If a participant is not eligible, data collection will stop which will 
conclude study participation. 
4.1.1. 
Brief Summary 
This platform study will evaluate the safety and efficacy of investigational interventions in one 
or more of the following populations of adult participants with chronic HBV infection as 
described in Table 3. 

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Table 3: 
Populations Included in This Platform Protocol 
Protocol Population 
HBeAg status 
HBV DNA level 
ALT level 
I 
Positive 
Higha 
≤ ULN 
II 
Positive 
Higha 
> ULN
III 
Negative 
> LLOQa
> ULN
IV 
Negative 
≤ 2,000 IU/mL 
≤ ULN 
V 
Positive 
≤ LLOQ or low (on NRTI therapy)a 
Variable a 
VI 
Negative 
≤ LLOQ or low (on NRTI therapy)a 
Variable a 
VII 
Negative 
> LLOQa
≤ ULN 
HBeAg: Hepatitis B e Antigen; LLOQ: Lower limit of quantitation; ALT: Alanine Aminotransferase; ULN: Upper 
limit of normal; NRTI: Nucleos(t)ide Reverse Transcriptase Inhibitor 
a As defined in the respective sub-protocol 
Specific details of the population(s) included and investigational therapies will be included in the 
respective sub-protocol(s).  
4.1.2. 
Number of Participants  
The number of participants will be specified in each sub-protocol.  
In Phase 1b evaluations, each cohort will include up to approximately 10 participants. 
For a single-arm Phase 2 sub-protocol, approximately 10-25 participants will be enrolled. For a 
Phase 2 sub-protocol with a concurrent control, approximately 75-120 total participants will be 
enrolled to be randomized to active and control in a 2:1 ratio. 
4.1.3. 
Intervention Groups and Duration 
Refer to specific sub-protocol. 
4.1.4. 
Study Committees 
The committees in the sub-protocols may include but not be limited to a Liver Flare 
Adjudication Committee (LFAC), Safety Review Committee (SRC), and/or Independent Data 
Monitoring Committee (IDMC). 
4.2. 
Scientific Rationale for Study Design 
Chronic HBV infection is a dynamic process based on the relationship between viral replication 
and the host immune response. Currently available treatment options for treatment of chronic 
HBV include NRTIs and/or PEG-IFNα. NRTIs provide suppression of viral replication but have 
low rates of functional cure, do not eliminate cccDNA or integrated DNA, and require life-long 
treatment. PEG-IFNα is associated with low rates (<10%) of functional cure on average and 
tolerability concerns. In addition, given the dynamic nature of the disease, not all patients qualify 
for the currently available treatment options. Therefore, there exists an unmet need for 
alternative treatment options with finite treatment regimens, better tolerability, and higher rates 
of efficacy.  

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This study is intended to evaluate multiple study intervention(s) and their combinations in 
different populations of participants with chronic HBV infection. Participants co-infected with 
HAV, HCV, HDV, HEV or HIV have been excluded in this study to allow better 
characterization of the investigational therapies in the absence of other clinically significant co-
infections. A platform design has been chosen to implement this study and the advantages of 
utilizing a platform design are described in Section 2.2.  
4.3. 
End of Study Definition 
The end of study for this Master Protocol is defined as the date of the last scheduled visit 
(or scheduled contact) of the last participant in the last open sub-protocol. 
5.
STUDY POPULATION
Participants that fulfil the following inclusion/exclusion criteria in addition to those outlined in 
the sub-protocols may be included in the study. 
5.1. 
Inclusion Criteria 
Participants must meet the following inclusion criteria to be eligible for this Master Protocol. 
Additional clarifications and sub-protocol-specific criteria as described in respective 
sub-protocol(s) will be applicable: 
1.
Adult ≥ 18 years of age (or age of legal consent, whichever is older)
2.
Chronic HBV infection defined as a positive serum HBsAg, HBV DNA, or HBeAg on
2 occasions at least 6 months apart based on previous or current laboratory
documentation (any combination of these tests performed 6 months apart is acceptable)
Additional characteristics of the chronic HBV infection (eg: HBeAg status, HBV DNA
level, ALT level) will be required based on the patient population (Table 3) included in
respective sub-protocols
3.
Besides chronic infection with HBV, must be in good health, determined from medical
history, and no clinically significant findings from physical examination other than
those expected in persons with cirrhosis, vital signs, and laboratory values
4.
Female participants must have a negative pregnancy test or confirmation of
postmenopausal status. Post-menopausal status is defined as 12 months with no menses
without an alternative medical cause (see Section 10.6 for additional details). Women
of child-bearing potential (WOCBP) must have a negative blood pregnancy test at
screening and a negative urine pregnancy test on Day 1, cannot be breast feeding, and
must be willing to use highly effective methods of contraception (Section 10.6) 14 days
before study intervention administration through period defined in sub-protocol.
Female participants must also agree to refrain from egg donation and in vitro
fertilization from the time of study intervention administration through period defined
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5.
Male participants with female partners of child-bearing potential must agree to meet
1 of the following contraception requirements from the time of study intervention
administration through period defined in sub-protocol: documentation of vasectomy or
azoospermia, or male condom use plus partner use of 1 of the contraceptive options
listed for contraception for WOCBP (Section 10.6). Male participants must also agree
to not donate sperm from the time of first study intervention administration through
period defined in sub-protocol
6.
Able to understand and comply with the study requirements and able to provide written
informed consent
5.2. 
Exclusion Criteria 
Participants are excluded from the study if any of the following criteria apply. Additional 
exclusion criteria may be described in respective sub-protocol(s): 
1.
History of clinically significant liver disease from non-HBV etiology
2.
History or current evidence of hepatic decompensation, including ascites, hepatic
encephalopathy, and/or esophageal or gastric varices
3.
History or current suspicion of malignancy diagnosed or treated within 5 years
(localized treatment of squamous or non-invasive basal cell skin cancers is permitted;
cervical carcinoma in situ is allowed if appropriately treated prior to screening);
participants under evaluation for malignancy are not eligible.
4.
History of bone marrow or solid organ transplant
5.
Known active infection other than chronic HBV infection or any clinically significant
acute condition such as fever (> 38° C) or acute respiratory or GI illness within 7 days
prior to Day 1
6.
Co-infection with human immunodeficiency virus (HIV), hepatitis A virus (HAV),
hepatitis C virus (HCV), hepatitis D virus (HDV) or hepatitis E virus (HEV).
Participants who are HCV antibody or HDV antibody positive, but have a documented
negative HCV RNA or HDV RNA, respectively, are eligible. Participants with positive
HAV immunoglobulin M (IgM) or HEV IgM but asymptomatic and with a positive
HAV IgG or HEV immunoglobulin G (IgG) are eligible.
7.
History or clinical evidence of alcohol or drug abuse within the 12 months before
screening or a positive drug screen at screening unless it can be explained by a
prescribed medication (the diagnosis and prescription must be approved by the
investigator). Note: cannabis use is permitted
8.
Received an investigational agent within 90 days or 5 half-lives (if known), whichever
is longer, before study intervention administration or are active in the follow-up phase
of another clinical study involving interventional treatment. Participants must also
agree not to take part in any other interventional study at any time during their
participation in this study, inclusive of the Follow-Up Period.

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9.
Any clinically significant medical or psychiatric condition that may interfere with
study intervention, assessment, or compliance with the protocol or otherwise makes the
participant unsuitable for participation in the study, as determined by the investigator.
5.3. 
Lifestyle Considerations 
Lifestyle considerations (eg, restrictions regarding diet, caffeine, alcohol, tobacco, etc.), if 
applicable, will be included in the respective sub-protocol. 
5.4. 
Screen Failures  
Screen failed participants may be re-screened after discussion with Sponsor. 
6.
STUDY INTERVENTION(S) AND CONCOMITANT THERAPY
This platform study is intended to evaluate multiple study interventions alone or in combinations 
for the treatment of chronic HBV infection in different patient populations. Study interventions 
and the details of their dosage, route of administration, frequency and duration of dosing, 
preparation, compliance, dose modification, and any other applicable information will be defined 
in respective sub-protocols. Permitted and non-permitted concomitant medications will also be 
defined in the sub-protocol. 
7.
DISCONTINUATION OF STUDY, STUDY INTERVENTION AND
PARTICIPANT DISCONTINUATION/WITHDRAWAL
7.1. 
Study Stopping Rules 
Refer to respective sub-protocols for specific details regarding study stopping rules. 
7.2. 
Discontinuation of Study Intervention 
Refer to respective sub-protocol for specific details. Participants that have received at least 
1 dose of the study intervention(s) will not receive additional doses if any one of the criteria 
described are met:  
1.
Any clinical manifestations of hepatic decompensation
2.
Grade 3 or higher study intervention-related AE of anaphylaxis, cytokine release
syndrome, or immune complex disease
3.
Additional criteria will be defined in sub-protocols as applicable
The investigator should notify the medical monitor immediately in the event that any of the 
above criteria are met. Upon documented agreement with the investigator, Sponsor medical 
monitor, and other safety review committees as applicable per sub-protocol, the participant may 
be considered to continue receiving study intervention.  
Participants who become pregnant during the Treatment Period will not receive additional doses 
of study intervention. See Section 8.7.7.1 for additional details.  

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Participants who discontinue study intervention(s) prematurely (eg, due to meeting a stopping 
rule) will undergo assessments for the EOT visit at the time of discontinuation. These 
participants will continue to the Follow-Up Period visit schedule in accordance with the 
Schedule of Activities (SOA) of their sub-protocol.  
7.3. 
Participant Discontinuation/Withdrawal from the Study 
If a participant discontinues from the study (eg, due to withdrawal of consent) after initiation of 
study intervention(s) but before the final dose of study intervention, assessments for the EOT 
visit should be performed.  
If a participant discontinues from the study after the EOT visit, assessments for the final visit of 
the Follow-Up Period (EOFU) should be performed.  
7.4. 
Replacement of Participants  
Participants who receive any dose of the planned regimen will not be replaced. 
7.5. 
Lost to Follow-up 
A participant will be considered lost to follow-up if he/she repeatedly fails to return for 
scheduled visits and is unable to be contacted by the study site. 
The following actions must be taken if a participant fails to return to the clinic for a required 
study visit: 
•
The site must attempt to contact the participant and reschedule the missed visit as
soon as possible, counsel the participant on the importance of maintaining the
assigned visit schedule and ascertain whether the participant wishes to and/or should
continue in the study.
•
Before a participant is deemed lost to follow-up, the investigator or designee must
make every effort to regain contact with the participant (where possible, 3 telephone
calls, and if necessary, a certified letter to the participant’s last known mailing
address or local equivalent methods). These contact attempts should be documented
in the participant’s medical record.
•
Should the participant continue to be unreachable, or the vital status be determined as
deceased, he/she will be considered to have withdrawn from the study. If the
investigator becomes aware of an AE/SAE, the information must be recorded per
Section 8.7 or Section 10.3.

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8.
STUDY ASSESSMENTS AND PROCEDURES
•
Study procedures and their timing are summarized in SOA (Section 10.7).
•
Protocol waivers or exemptions are not allowed.
•
Immediate safety concerns should be discussed with the Sponsor immediately upon
occurrence or awareness.
•
Adherence to the study design requirements, including those specified in the SOA, is
essential and required for study conduct.
•
All screening evaluations must be completed and reviewed by the investigator(s) to confirm
that potential participants meet all eligibility criteria. The site will maintain a screening log to
record details of all participants screened and to confirm eligibility or record reasons for
screening failure, as applicable.
•
Procedures conducted as part of the participant’s routine clinical management (eg, blood
count) and obtained before signing of the ICF as allowable by ICH/GCP and/or CFRs may be
utilized for screening or baseline purposes provided the procedure met the protocol-specified
criteria and was performed within the time frame defined in the SOA.
•
Repeat or unscheduled laboratory samples may be taken for safety reasons or for technical
issues with the samples.
8.1. 
Screening Period 
Informed consent must be obtained before conducting any study procedures. Screening will be 
performed within 56 days (8 weeks) prior to dosing and include the assessments (such as medical 
history and demographics) outlined in the sub-protocol specific SOA. Screening laboratory tests 
may be repeated (eg, for values thought to be erroneous) with Sponsor medical monitor approval. 
8.1.1. 
Screening Confirmation of Chronic HBV Infection  
Chronic HBV infection will be determined at screening and is defined as the following: 
•
Positive serum HBsAg, HBV DNA, or HBeAg on 2 occasions at least 6 months apart
based on previous or current laboratory documentation (any combination of these
tests performed 6 months apart is acceptable)
8.1.2. 
Screening Viral Serology Parameters
Screening viral serology parameters are as follows: active infection with HIV, HAV, HCV, 
HDV, and HEV. Participants who have positive HCV or HDV serology result must have 
HCV-RT PCR or HDV-RT PCR reflex testing respectively to determine eligibility. Participants 
with positive HAV or HEV IgM must have reflex HAV or HEV IgG, respectively. 
8.1.3. 
Screening for Drugs of Abuse 
Urine will be collected at the screening visit for drugs of abuse screening, per the SOA. The 
panel will include amphetamines, cocaine, methadone, and opiates.  

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8.2. 
Efficacy Assessments 
Efficacy in this study will be assessed based on the changes to viral parameters as listed in 
endpoints. Primarily, but not limited to the following will be recorded and evaluated as the 
efficacy endpoints: HBsAg, HBeAg, HBV DNA, anti-HBs, and anti-HBe levels.  
8.3. 
Safety Assessments 
8.3.1. 
Physical Examinations 
A full physical examination will be conducted to determine the overall physical health of the 
participant, and any abnormal findings at screening will be recorded as medical history. The 
physical examination may include but is not limited to general appearance, head, neck, 
chest/respiratory, heart/cardiovascular, gastrointestinal/liver, extremities, skin, and screening 
neurological assessment 
8.3.2. 
Vital Signs 
Vital sign measurements include blood pressure, pulse rate, temperature (oral preferred), and 
respiratory rate. Vital signs should be measured after the participant has rested comfortably for 
approximately 10 minutes. When scheduled at the same timepoints, the assessments of vital 
signs must be performed before blood sample collections and study intervention 
administration(s). 
8.3.3. 
Clinical Safety Laboratory Tests 
Clinical laboratory tests (such as serum chemistry, hematology, urinalysis, etc.) that will be 
performed are presented in Section 10.2. The respective sub-protocols will list additional 
assessments required depending on the study population and study interventions being evaluated. 
Screening laboratory tests may be repeated once (eg, for values thought to be erroneous) with 
Sponsor approval. 
8.3.4. 
Pregnancy Testing 
A pregnancy test or confirmation of post-menopausal status must be confirmed for all female 
participants. Post-menopausal status is defined as no menses for 12 months without an 
alternative medical cause. An elevated follicle stimulating hormone (FSH) level in the post-
menopausal range should be used to confirm a post-menopausal state in women not using 
hormonal contraception or hormone replacement therapy (HRT). In the absence of 12 months of 
amenorrhea, confirmation with more than one FSH measurement is required. Females on HRT 
and whose menopausal status is in doubt must discontinue HRT to allow confirmation of 
postmenopausal status before study enrollment. Pregnancy tests will be performed for WOCBP 
only. Pregnancy testing will be performed per the SOA and any time pregnancy is suspected. A 
WOCBP who is known to be pregnant or who does not have a negative pregnancy test at 
screening is not eligible for study participation. A blood pregnancy test will be performed at 
screening and urine pregnancy tests will be performed at subsequent visits. During the study, the 
results of these pregnancy tests must be known prior to study intervention administration. A 
WOCBP determined to be pregnant while on study will be followed until the pregnancy outcome 
is known, as described in Section 8.7.7.1. 

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8.3.5. 
Other Safety Assessments 
Other safety assessments relevant to the study intervention will be described in the respective 
sub-protocol. 
8.4. 
Assessment of Viral Parameters, Antiviral Activity, and Resistance 
Surveillance  
Assessment of screening viral parameters will include: HBsAg (quantitative), anti-HBs 
(qualitative), HBeAg (qualitative), anti-HBe (qualitative), and HBV DNA (quantitative). 
Any additional viral parameters, anti-viral activity, and resistance surveillance, if applicable, will 
be described in the sub-protocol.  
8.5. 
Patient Reported Outcomes (PROs) may be collected, see sub-protocol SOA for detail. 
8.6. 
Exploratory Assessments 
Exploratory assessments will be conducted as part of this study. Additional exploratory 
assessments will be described in respective sub-protocols. 
8.6.1. 
Exploratory Analysis Samples  
Exploratory samples may include but are not limited to the following: 
•
Virologic biomarkers, including but not limited to HBV RNA and HBcrAg. This may
also include viral sequencing.
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Details will be described in the respective sub-protocol and/or sub-protocol specific laboratory 
manual. Samples already collected for other tests from the same study visit may be used to run 
additional exploratory tests that are included in this sub-protocol. If a participant is negative for a 
given virologic biomarker, additional samples may not be tested. 
8.6.2. 
Details regarding the processing, shipping, and analysis of these samples are provided in the 
Laboratory Manual. Refer to respective sub-protocol for details as appropriate.  
8.6.2.1. 
In the event of DNA extraction failure, a replacement genetic blood sample may be requested 
from the participant. Signed informed consent will be required to obtain a replacement sample 
unless it was included in the original consent. 
8.6.2.2. 
8.6.2.3. 
 a replacement genetic blood sample may be requested 
from the participant. Signed informed consent will be required to obtain a replacement sample 
unless it was included in the original consent. 
8.7. 
Adverse Events (AEs), Serious Adverse Events (SAEs), and Other 
Safety Reporting  
The definitions of AEs, SAEs, and other safety events are provided in Section 10.3. 
AEs will be reported by the participant (or, when appropriate, by a caregiver, surrogate, or the 
participant’s legally authorized representative). 
The investigator and any qualified designees are responsible for detecting, documenting, and 
recording events that meet the definition of an AE or SAE and remain responsible for following 
up all AEs. 
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The method of recording, evaluating, and assessing causality of AEs and SAEs and the 
procedures for completing and transmitting SAE reports are provided in Section 10.3. 
8.7.1. 
Time Period and Frequency for Collecting AE and SAE Information 
After signing of the ICF, but prior to initiation of study intervention, AEs/SAEs related to 
protocol-mandated procedures should be reported. Following initiation of study intervention, all 
AEs/SAEs, regardless of cause or relationship, will be recorded for the entire duration of the 
study. 
Medical occurrences that begin before the start of study intervention but after obtaining informed 
consent, and are not considered related to protocol mandated procedures, will be recorded as 
medical history/current medical conditions, not as AEs. 
All SAEs, regardless of causal relationship, will be collected from signing of ICF until the end of 
study. 
All SAEs must be recorded and reported to the Sponsor or designee immediately and under no 
circumstance should this exceed 24 hours from the investigator or designee awareness of the 
event, as indicated in Section 10.3. The investigator will submit any updated SAE data to the 
Sponsor or designee within 24 hours of it being available. 
Investigators are not obligated to actively seek information on AEs or SAEs after conclusion of 
the study participation. However, if the investigator learns of any SAE, including a death, at any 
time after a participant has been discharged from the study, and he/she considers the event to be 
reasonably related to the study intervention or study participation, the investigator must promptly 
notify the Sponsor. 
8.7.2. 
Follow-up of AEs and SAEs 
After the initial AE/SAE report, the investigator is required to proactively follow each participant 
at subsequent visits/contacts. All AEs, SAEs, pregnancy, and special situation reports (SSRs) 
(as defined in Section 10.3) will be followed until resolution, stabilization, the event is otherwise 
explained, or the participant is lost to follow-up (as defined in Section 7.5). Further information 
on follow-up procedures is provided in Section 10.3. 
8.7.3. 
Regulatory Reporting Requirements for SAEs 
Prompt notification by the investigator to the Sponsor of an SAE is essential to meet legal 
obligations and ethical responsibilities towards the safety of participants and the safety of a study 
intervention under clinical investigation. The investigator will record the SAE information on the 
appropriate form and submit it to Sponsor or designee within 24 hours of awareness of the event. 
The Sponsor has a legal responsibility to notify both the local regulatory authority and other 
regulatory agencies about the safety of a study intervention under clinical investigation. The 
Sponsor will comply with country-specific regulatory requirements relating to safety reporting to 
the regulatory authority, institutional review boards (IRBs)/independent ethics committees 
(IECs), and investigators. 
An investigator who receives an investigator safety report describing an SAE or other specific 
safety information (eg, summary or listing of SAEs) from the Sponsor will review the 

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information, document the review, file the safety report along with the relevant study documents, 
and will notify the IRB/IEC, if appropriate, according to local requirements. 
Assessment of expectedness for SAEs will be determined by the Sponsor using the reference 
safety information (RSI) as specified in the Investigator’s Brochure (IB). Assessment of 
expectedness for marketed products will be determined by the Sponsor using the product label. 
Investigator safety reports must be prepared for suspected unexpected serious adverse reactions 
(SUSARs) according to local regulatory requirements and Sponsor policy and forwarded to 
investigators as necessary. 
8.7.4. 
Adverse Events of Interest 
Refer to respective sub-protocol. 
8.7.5. 
Clinical Laboratory Abnormalities and Other Abnormal Assessments as AEs or 
SAEs  
Laboratory abnormalities without an associated AE (signs or symptoms) and/or which do not 
require medical intervention, are not themselves recorded as AEs or SAEs. However, laboratory 
abnormalities (eg, clinical chemistry, hematology, and urinalysis) that require medical or surgical 
intervention or lead to study intervention interruption, modification, or discontinuation must be 
recorded as an AE or as an SAE, if applicable. In addition, laboratory or other abnormal 
assessments (eg, vital signs) that are associated with signs and/or symptoms must be recorded as 
an AE or SAE if they meet the definition of an AE or SAE as described in Section 10.3. If the 
laboratory abnormality is part of a clinical syndrome, record the syndrome or diagnosis 
(eg, anemia), not the laboratory result (ie, decreased hemoglobin). 
Severity should be recorded and graded according to the Common Terminology Criteria for 
Adverse Events (CTCAE) v5.0 or later, as specified in the respective sub-protocol (presented in 
Section 10.3).  
Additional laboratory abnormalities and other abnormal assessment considerations, if applicable, 
will be included in the respective sub-protocol. 
8.7.6. 
Laboratory Events of Clinical Interest 
Laboratory Events of Clinical Interest (ECIs) will be defined in the sub-protocols, as applicable. 
An ECI is a laboratory value of scientific and medical interest specific to understanding of an 
investigational product and may require additional follow-up testing, close monitoring, and rapid 
communication by the investigator to the Sponsor. The rapid reporting of ECIs allows ongoing 
surveillance of these events to characterize and understand them in association with the use of an 
investigational product. The signs, symptoms, and/or clinical sequelae resulting from an ECI will 
be reported as AE or SAE if they fulfill the definition of an AE or SAE. The LFAC may oversee 
and monitor the status of the liver-related ECIs as defined in sub-protocols.  
8.7.7. 
Special Situation Reports 
All special situation reports (SSR) will be collected from the start of intervention until the end of 
follow-up period and include all reports of medication error, abuse, misuse, overdose, pregnancy, 
drug interactions, exposure via breastfeeding, unexpected benefit, occupational exposure, 

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transmission of infectious agents via the product, counterfeit or falsified medicine, and product 
complaints (definitions presented in Section 10.3).  
The investigator will record the special situation information on the appropriate form and submit 
it to the Sponsor or designee within 24 hours of learning of the situation. These reports must 
consist of situations that involve study intervention and/or protocol required concomitant 
medications but do not apply to non-required concomitant medications.  
Any inappropriate use of concomitant medications prohibited by this protocol should not be 
reported as “misuse” but may be more appropriately documented as a protocol deviation. 
All clinical sequelae in relation to these special situation reports (from required and non-required 
medication) will also be reported as AEs or SAEs. Details of the symptoms and signs, clinical 
management, and outcome will be reported, when available.  
8.7.7.1. 
Pregnancy 
Details of all pregnancies in female participants and, if indicated, female partners of male 
participants will be collected after the start of study intervention and until the end of study. 
•
If a pregnancy is reported, the investigator will record pregnancy information on the
appropriate form and submit it to the Sponsor or designee within 24 hours of learning
of the female participant or female partner of male participant pregnancy.
•
While pregnancy itself is not considered to be an AE or SAE, any pregnancy
complication or termination of a pregnancy for any reasons will be reported as an AE
or SAE.
•
Abnormal pregnancy outcomes (eg, spontaneous abortion, fetal death, stillbirth,
congenital anomalies, ectopic pregnancy) are considered SAEs and will be reported
as such.
•
The participant/pregnant female partner (after obtaining the necessary signed
informed consent from the female partner) will be followed to determine the outcome
of the pregnancy. The investigator will collect follow-up information on the
participant/pregnant female partner and the neonate and the information will be
forwarded to the Sponsor.
•
Any post-study pregnancy-related SAE considered reasonably related to the study
intervention by the investigator will be reported to the Sponsor as described in
Section 8.7.3. While the investigator is not obligated to actively seek this information
in former study participants/pregnant female partner, if he/she learns of any SAE and
considers the event to be reasonably related to the study intervention or study
participation, the investigator must promptly notify the Sponsor.
Any female participant who becomes pregnant while participating in the study will discontinue 
study intervention. 
The study participant and/or pregnant female partner, as applicable, should receive any necessary 
counseling regarding the risk of continuing the pregnancy and the possible effects on the fetus. 

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8.7.8. 
Other Safety Reporting 
Other sub-protocol-specific safety reporting requirements eg: cardiovascular events, 
disease-related events and/or disease related outcomes not qualifying as AEs or SAEs will be 
specified in the respective sub-protocol, as applicable. 
8.8. 
Other Assessments 
Other safety, efficacy, and exploratory assessments such as immunogenicity and 
pharmacokinetic assessments may be included as defined in respective sub-protocols 
9.
STATISTICAL CONSIDERATIONS
9.1. 
Statistical Hypotheses 
Phase 1b sub-protocols will be exploratory, and no formal hypothesis testing will be conducted. 
In Phase 2 sub-protocols, if we evaluate response rate, defined as the proportion of participants 
achieving HBV DNA suppression (< LLOQ) with HBsAg loss (< 0.05 IU/mL) at end of 
treatment or at 24 weeks after discontinuation of all treatment, or HBsAg loss at end of treatment 
or 24 weeks post-end of treatment, or HBV DNA suppression 24 weeks after discontinuation of 
all treatment, as the primary endpoint(s), the null hypothesis is that response rate is the same as 
in NRTI-suppressed patients. It is assumed the response rate is ≤ 2% in NRTI-suppressed 
patients. The null hypotheses are described in Table 4 for a single arm study and Table 5 for a 
randomized controlled study with concurrent controls. The alternative hypothesis will be 
described in the sub-protocol. 
9.1.1. 
Multiplicity Adjustment  
The study is exploratory in nature. No multiplicity adjustment will be made. 
9.2. 
Sample Size Determination 
In a phase 1b sub-protocol, the sample size is not based on any statistical hypothesis testing. For 
the purposes of safety evaluation, each cohort will include up to approximately 10 participants. 
For a single-arm Phase 2 sub-protocol, approximately 10-25 participants will be enrolled. For a 
Phase 2 sub-protocol with a concurrent control, approximately 75-120 total participants will be 
enrolled to be randomized to active and control in a 2:1 ratio. 
Since the primary endpoints of HBsAg loss rate at EOT or 24 weeks post-EOT are good 
predictors for achieving the sustained HBV DNA at 24 weeks after discontinuation of all 
treatments, sample size calculation for the initial assessment of an investigational regimen is 
based on HBsAg loss rate as described below (FDA 2018; Terrault 2018). 

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•
An investigational regimen will initially be evaluated in an open label single arm
study, without a concurrent control arm. If the true HBsAg loss rate ranges from
25% to 40%, at least 10 participants will be required to provide > 70% statistical
power to detect a 23% difference in HBsAg loss rate, using a 1-sided exact binomial
test with a significance level of 0.025 (Table 4).
•
An investigational regimen may also be evaluated in a randomized placebo-controlled
study. Assuming a 2:1 active-to-placebo randomization ratio, at least 75 participants
will be required to provide > 70% statistical power to detect a 23% difference in
HBsAg loss rate, using a 1-sided Fisher’s exact test with a significance level of 0.025
(Table 5).
Table 4: 
Power and Sample Size Calculation for Single Arm Efficacy Evaluation 
Null Hypothesis: Response rate is ≤2%, which is the assumed rate in NRTI-suppressed patients. 
Assumptions: Use exact binomial test with 1-sided significance level of 0.025. 
Sample Size 
Power to detect 23% difference in HBsAg 
loss rate, if the true HBsAg loss rate is 
25%  
Power to detect 38% difference in 
HBsAg rate, if the true HBsAg loss rate 
is 40% 
10 
75.6% 
95.4% 
15 
76.4% 
97.3% 
25 
96.8% 
> 99%
30 
98.9% 
> 99%
Table 5: 
Power and Sample Size Calculation for Efficacy Evaluation with Concurrent 
Controls  
Null Hypothesis: Response rate in the study intervention arm is not greater than that in the concurrent 
control. 
Assumptions: (1) Randomization ratio of 2:1 to active and control arms; (2) ≤ 2% of the controls will 
achieve HBsAg loss; (3) Use Fisher’s exact test with 1-sided significance level of 0.025. 
Sample Size 
(Active: Control) 
Power to detect 23% difference 
in response rate, if the true 
response rate is 25%  
Power to detect 38% difference 
in response rate, if the true 
response rate is 40% 
50:25 
71.2% 
98.5% 
60:30 
83.6% 
> 99%
70:35 
91.2% 
> 99%
The larger sample size may be considered to assess efficacies in participant subgroups according 
to their baseline disease characteristics, eg, HBsAg levels, HBeAg status, HBV DNA levels, 
HBV genotypes, or based on other factors such as site or country.  
Refer to the sub-protocols for additional information regarding sample size determination, 
including considerations for cohort expansion will be based on interim analysis of response rate 
for the primary endpoint. 

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9.3. 
Analysis Sets  
For the purposes of analysis, the following analysis sets are defined: 
Analysis Sets 
Description 
All Screened Set 
The All Screened Set includes all participants who signed the 
informed consent form.  
The listing of Eligibility Criteria will be based on All Screened Set. 
All Enrolled Set 
The All Enrolled Set includes all participants in the All Screened Set 
who were assigned to study intervention. 
Summaries for disposition, demographics and baseline characteristics 
will be reported based on the All Enrolled Set. 
Full Analysis Set (FAS) 
The FAS includes all participants in the All Enrolled Set who received 
at least one dose of study intervention(s).  
This is the primary analysis set for efficacy and antiviral analyses. 
Safety Analysis Set 
Safety Analysis Set includes all participants who received any amount 
of study intervention. 
All safety analyses will be based on the Safety Analysis Set. 
9.4. 
Statistical Analyses 
9.4.1. 
General Considerations 
All disposition, demographics and baseline characteristics will be reported based on the All 
Enrolled Set. All safety analyses will be on the Safety Analysis Set. All efficacy and antiviral 
activity analyses will be based on the FAS. 
The Statistical Analysis Plan (SAP) will be finalized prior to Database Lock (DBL) and will 
include technical details and description of the statistical analyses including sensitivity analyses 
that will be performed.  
Unless otherwise stated, the following rules will apply: 
•
Summaries and displays will be presented by treatment cohort.
•
Categorical endpoints will be summarized by number and percentage of participants
who meet the endpoint by treatment cohort.
•
Continuous endpoints will be summarized using conventional descriptive statistics
(n, mean, standard deviation [SD], median, 1st quartile [Q1], 3rd quartile [Q3],
minimum, and maximum) by treatment cohort.
•
TEAE definition: An AE that is reported with an onset date on or after the start of
study intervention(s) until the duration specified in the subprotocol after the last dose
of study intervention(s).
•
Missing value will not be imputed
Only scheduled visits will be presented in summaries. Unscheduled visits will be listed but will 
not be summarized. 

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9.4.2. 
Primary Endpoint(s) Analysis 
The primary efficacy objective evaluation in a sub-protocol will be performed using the FAS. 
Depending on the development phase, each sub-protocol will specify the primary endpoint(s) 
from the list below. 
•
Proportion of participants achieving suppression of HBV DNA (< LLOQ) with
HBsAg loss (< 0.05 IU/mL) at EOT
•
Proportion of participants achieving sustained suppression of HBV DNA (< LLOQ)
at 24 weeks after discontinuation of all treatment
•
Proportion of participants achieving sustained suppression of HBV DNA (< LLOQ)
with HBsAg loss (< 0.05 IU/mL) at 24 weeks after discontinuation of all treatment
•
Proportion of participants with HBsAg loss (< 0.05 IU/mL) at EOT
•
Proportion of participants with HBsAg loss (< 0.05 IU/mL) at 24 weeks post-EOT
•
Mean change in serum HBsAg from baseline across timepoints in the study
9.4.2.1. 
Population 
All eligible participants with chronic HBV infection, as defined in the FAS. 
9.4.2.2. 
Missing Data 
Every effort will be made to reduce missing data. Missing data for the HBV DNA will be 
assumed to be < LLOQ if HBV DNA measures were < LLOQ at both the prior and subsequent 
visits. Missing data for HBsAg loss will be assumed to be < 0.05 IU/mL if HBsAg measures 
were < 0.05 IU/mL at both the prior and subsequent visits. Other than the imputation specified 
above, no other imputation will be done. For all efficacy response variables, the missing equals 
failure (MEF) approach will be used for the primary analysis. As a sensitivity analysis, the 
primary endpoints may be evaluated in participants with a minimum level of incompliance with 
the investigational regimen, defined in the SAP, and without important major protocol deviations 
that could substantially affect the outcome of the treatment. When applicable and sample size 
permits, the primary endpoints may also be evaluated in participants meeting specified threshold 
criteria (eg: NRTI discontinuation criteria). 
Further details will be specified in the SAP of the sub-protocol. 
9.4.2.3. 
Population Level Summary 
Proportion of participants who achieved suppression of HBV DNA [< LLOQ] with HBsAg loss 
(< 0.05 IU/mL) at EOT and the corresponding two-sided 95% confidence interval will be 
calculated for each cohort. 
Proportion of participants who achieved sustained suppression of HBV DNA [< LLOQ] at 
24 weeks after discontinuation of all treatment and the corresponding two-sided 95% confidence 
interval will be calculated for each cohort. 

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Proportion of participants who achieved sustained suppression of HBV DNA [< LLOQ] with 
HBsAg loss (< 0.05 IU/mL) 24 weeks after discontinuation of all treatment and the 
corresponding two-sided 95% confidence interval will be calculated for each cohort. 
Proportion of participants who achieved HBsAg loss (< 0.05 IU/mL) at EOT and the 
corresponding two-sided 95% confidence interval will be calculated for each cohort. 
Proportion of participants who achieved HBsAg loss (< 0.05 IU/mL) at 24 weeks post-EOT and 
the corresponding two-sided 95% confidence interval will be calculated for each cohort. 
The maximum reduction of serum HBsAg from baseline will be summarized using the 
conventional descriptive statistics (n, mean, SD, median, Q1, Q3, minimum, and maximum) for 
each cohort.  
9.4.3. 
Secondary Endpoint(s) Analysis 
The number and percentage of participants with adverse events will be summarized by severity, 
seriousness, relationship to the study drug, MedDRA system organ class, and preferred term 
based on the Safety Analysis Set. 
The key secondary efficacy endpoints including the effect of the study intervention on HBsAg, 
anti-HBs, HBeAg, and HBV DNA in the FAS will be summarized. 
9.4.4. 
Exploratory Endpoint(s) Analysis 
Refer to sub-protocol for details. 
9.4.5. 
Missing Data  
Handling of missing data will be described in the sub-protocols and SAP as applicable. 
9.4.6. 
Other Safety Analyses 
Additional safety will be evaluated by assessment of clinical laboratory tests, physical 
examinations, and vital signs measurements at various time points during the study and by the 
documentation of AEs, when applicable. 
All safety data collected on or after administration of study intervention(s) up to the last 
scheduled visit, unless specified otherwise, will be summarized by treatment cohort. 
9.5. 
Interim Analysis 
Interim analysis may be performed. The timing and adaption rule of the interim analysis will be 
defined in the respective sub-protocols for each experimental regimen. 
9.6. 
Other Analyses 
Other analyses that may be conducted for a sub-protocol include but are not limited 
pharmacokinetics, genetics, biomarkers, etc. These will be defined in the respective 
sub-protocols as applicable. 

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10.
SUPPORTING DOCUMENTATION AND OPERATIONAL
CONSIDERATIONS
10.1. 
Appendix 1: Regulatory, Ethical, and Study Oversight
Considerations
10.1.1. 
Regulatory and Ethical Considerations
•
This study will be conducted in accordance with the Master Protocol and applicable sub-
protocols with the following:
−
Consensus ethical principles derived from international guidelines including the
Declaration of Helsinki and Council for International Organizations of Medical
Sciences (CIOMS) International Ethical Guidelines
−
Applicable ICH GCP guidelines
−
Applicable laws and regulations
•
The Master Protocol, sub-protocols, protocol amendments, ICF, IB, and other relevant
documents (eg, advertisements) must be submitted to an IRB/IEC by the investigator and
reviewed and approved by the IRB/IEC before the study is initiated.
•
Any amendments to the protocol will require IRB/IEC approval before implementation of
changes made to the study design, except for changes necessary to eliminate an immediate
hazard to study participants.
•
Protocols and any substantial amendments to the protocol will require health authority
approval prior to initiation except for changes necessary to eliminate an immediate hazard to
study participants.
•
The investigator will be responsible for the following:
−
Providing written summaries of the status of the study to the IRB/IEC annually or
more frequently in accordance with the requirements, policies, and procedures
established by the IRB/IEC
−
Notifying the IRB/IEC of SAEs or other significant safety findings as required by
IRB/IEC procedures
−
Providing oversight of the conduct of the study at the site and adherence to
requirements of 21 CFR, ICH guidelines, the IRB/IEC, European regulation
536/2014 for clinical studies (if applicable), and all other applicable local
regulations

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10.1.2. 
Financial Disclosure 
Investigators, sub-investigators, and applicable site staff will provide the Sponsor or designee 
with sufficient, accurate financial information as requested to allow the Sponsor/designee to 
submit complete and accurate financial certification or disclosure statements to the appropriate 
regulatory authorities. Investigators, sub-investigators, and applicable site staff are responsible 
for providing information on financial interests during the course of the study and for 1 year after 
site closure. 
10.1.3. 
Informed Consent Process 
The participant’s signed and dated informed consent (either signed by participant or their legally 
authorized representative [LAR]) must be obtained before conducting any study procedures.  
10.1.4. 
Data Protection 
•
Participants will be assigned a unique identifier by the Sponsor. Any participant records or
datasets that are transferred to the Sponsor will be anonymized except for the identifier;
participant names or any information which would make the participant identifiable will not
be transferred.
•
All participants must provide informed consent to the use and disclosure of their information
obtained during the study. This includes informing the participant how their personal study-
related data will be used by the Sponsor and the level of disclosure.
•
The participant must also be informed and consent to the possible examination of their
medical records by Clinical Quality Assurance auditors or other authorized personnel
appointed by the Sponsor, by appropriate IRB/IEC members, and by inspectors from
regulatory authorities.
10.1.5. 
Confidentiality 
The investigator must assure that participant’s anonymity will be strictly maintained and that 
their identities are protected from unauthorized parties. Only participant initials and date of birth 
(where local regulations allow) and an identification code (i.e. not names) should be recorded on 
any form or biological sample submitted to the Sponsor, IRB or IEC, or laboratory. The 
investigator must keep a screening log showing codes, names, and addresses for all participants 
screened and for all participants enrolled in the trial. 
The investigator agrees that all information received from the Sponsor, including but not limited 
to the IB, this Master Protocol, all sub-protocols, eCRFs, the investigational new drug(s), and 
any other study information, remain the sole and exclusive property of the Sponsor during the 
conduct of the study and thereafter. This information is not to be disclosed to any third party 
(except employees or agents directly involved in the conduct of the study or as required by law) 
without prior written consent from the Sponsor. The investigator further agrees to take all 
reasonable precautions to prevent the disclosure by any employee or agent of the clinical 
investigative site to any third party or otherwise into the public domain. 

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10.1.6. 
Committees Structure 
The committees in the sub-protocols may include but not be limited to a LFAC, SRC and/or 
IDMC. 
10.1.6.1. Liver Flare Adjudication Committee (LFAC) 
The LFAC is an independent committee that will provide hepatic safety oversight by performing 
periodic reviews of hepatic safety data as well as adjudicate ECI. Laboratory ECI will be 
pre-defined in each of the respective sub-protocols. The LFAC membership composition and 
data review requirements are described in detail in the LFAC Charter. 
10.1.7. 
Dissemination of Clinical Study Data 
•
A clinical study report for each sub-protocol will be written and may be provided to the
appropriate regulatory authorities.
•
This clinical study may be registered, and its results posted on public registries in compliance
with local and/or regional regulations.
10.1.8. 
Data Quality Assurance 
Periodically, the Sponsor or its authorized representatives audit clinical investigative sites as an 
independent review of core trial process and documents to determine whether these activities 
were conducted, and data were recorded, analyzed, and accurately reported according to the 
protocol, GCP guidelines of ICH, and any applicable regulatory requirements. A regulatory 
authority, an IEC or an IRB may visit the clinical investigative site to perform audits or 
inspections, including source data verification. The investigator should contact the Sponsor, or 
its designee, immediately if contacted by a regulatory agency about an inspection. 
10.1.9. 
Source Documents 
All documentation relating to the study should be retained for the period of time required by 
applicable local law. If it becomes necessary for the Sponsor or designee, applicable IRB/IEC, or 
applicable regulatory authorities to review or audit any documentation relating to the study, the 
investigator must permit direct access to all source documents/data. Records will not be 
destroyed without informing the Sponsor in writing and giving the Sponsor the opportunity to 
store the records for a longer period of time at the Sponsor’s expense.  
10.1.10. 
Electronic Case Report Forms (eCRF) 
•
Data collected during the study (except clinical laboratory results, PK analysis, study disease
testing results, immunogenicity) will be recorded in each participant’s eCRF provided by the
Sponsor or designee.
•
The study site(s) will use an Electronic Data Capture (EDC) system that is compliant with
relevant Food and Drug Administration (FDA) regulatory requirements per 21 CFR Part 11.
•
Data queries and data correction on the eCRF will be handled through the same system.
•
All transactions within the EDC system are fully documented within an electronic audit trail.

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•
Data reported on the eCRF must be transcribed from a source document with consistency and
accuracy.
•
The investigator must maintain accurate documentation (source data) that supports the
information entered in the eCRF.
•
Study monitors will perform ongoing source data verification to confirm the accuracy of data
entered into the eCRF. Each set of completed eCRFs must be reviewed after being source
verified by the monitor and electronically signed and dated by the investigator.
•
Validated and secure electronic access will be granted to qualified Sponsor staff to review the
participants’ electronic records to verify that the information in the records matches the
information entered in the EDC system. If required, in the event of audit, auditor(s) may be
granted access to electronic records.
−
In cases where validated and secure electronic access to the participant’s
electronic records is not available, unredacted source documents (including ICF,
Regulatory Documents and Source data) will be uploaded into a regulatory and
data privacy-compliant cloud environment, generating certified copies of source
documents (as per ICH/GCP guidelines) to be verified by the study monitor
against the information entered in the EDC. As per ICH/GCP guidelines, the
principal investigator and site staff users remain in control of the source
documents, only site personnel can upload or invalidate source data, while only
Clinical Research Associates (or auditors, as required) assigned to a given site can
view the source documents remotely.
10.1.11. 
Study and Site Start and Closure 
First Act of Recruitment  
The first act of recruitment is the first participant enrolled and will be the study start date. 
Study/Site Termination 
The Sponsor or designee reserves the right to close the study site and/or terminate one or more 
individual cohorts, sub-protocols or the overall study at any time for any reason at the sole 
discretion of the Sponsor. Study sites will be closed upon study completion. A study site is 
considered closed when all required documents and study supplies have been collected and a 
study-site closure visit has been performed. 
The investigator may initiate study-site closure at any time, provided there is reasonable cause 
and sufficient notice is given in advance of the intended termination. If the investigator 
terminates or suspends a trial without the prior agreement of the Sponsor, the investigator should 
inform the institution (where applicable) of the suspension or termination at the investigative 
site. The investigator / institution should promptly inform the IRB/EC and the Sponsor of the 
termination/ suspension with a detailed, written explanation of the reason for the suspension or 
termination of the trial. 

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Reasons for the early closure of a study site by the Sponsor or investigator may include but are 
not limited to: 
For study termination: 
•
Discontinuation of further study intervention development
For site termination: 
•
Failure of the investigator to comply with the protocol, the requirements of the
IRB/IEC or local health authorities, the Sponsor’s procedures, or GCP guidelines
•
Inadequate or no recruitment (evaluated after a reasonable amount of time) of
participants by the investigator
If the study is prematurely terminated or suspended, the Sponsor shall promptly inform the 
investigators, the IECs/IRBs, the regulatory authorities, and any contract research organization(s) 
used in the study of the reason for termination or suspension, as specified by the applicable 
regulatory requirements. The investigator shall promptly inform the participant and should assure 
appropriate participant therapy and/or follow-up. 
10.1.12. 
Publication Policy 
•
Site-specific results of this study may be published or presented at scientific meetings subject
to the terms and requirements of the clinical trial agreement

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10.2. 
Appendix 2: Clinical Laboratory Tests 
Table 6: 
Protocol-Required Safety Laboratory Tests 
Additional tests will be listed in respective sub-protocol 
Chemistry 
Hematology 
Albumin 
Blood urea nitrogen 
Calcium 
Bicarbonate 
Chloride 
Creatine kinasea 
Creatinine 
Creatinine clearance (calculated) 
Gammaglutamyltransferase (GGT) 
Glucose (non-fasting) 
Lactate dehydrogenase (LDH) 
Potassium 
Sodium 
Liver Function Tests: Alkaline phosphatase 
(ALP), alanine aminotransferase (ALT), aspartate 
aminotransferase (AST), bilirubin (total and 
direct)  
Complement (C3, C4, CH50)b 
Platelet count 
Red blood cell (RBC) count 
Hemoglobin 
Hematocrit 
White blood cell (WBC) count with 
differential: neutrophils, lymphocytes, monocytes, 
eosinophils, basophils 
RBC indices: mean corpuscular volume (MCV), 
mean corpuscular hemoglobin (MCH), 
% reticulocytes 
Coagulation Parameters 
Pregnancy Testing 
International normalized ratio (INR) 
Prothrombin time (PT) 
Highly sensitive (serum/plasma or urine) human 
chorionic gonadotropin (hCG) pregnancy test (as 
needed for women of childbearing potential) 
Urinalysis 
Additional Screening Tests 
Bilirubin 
Glucose 
Ketones 
Leukocytes 
Microscopy (if blood or protein is abnormal) 
Nitrite 
pH 
Proteins 
RBCs 
Specific gravity 
Urobilinogen 
Visual inspection for appearance and color 
Urine drug screen (to include at minimum: 
amphetamines, barbiturates, cocaine, opiates, 
cannabinoids and benzodiazepines) 
Serology: 
Hepatitis Ac, B, Cd, De and Ec  
Human immunodeficiency virus I and II 
Lipase 
Amylase  
Follicle stimulating hormone (FSH)f  
a Only required if ALT and/or AST is elevated > 2x the predose Day 1 baseline value 
b As indicated in the sub-protocols Schedule of Activities 
c Participants with positive HAV IgM or HEV IgM but asymptomatic and with a positive HAV IgG or HEV IgG are 
eligible.
d Participants with positive HCV screening serology may have HCV RT-PCR performed to determine eligibility.
e Participants with positive HDV screening serology may have HDV RNA performed to determine eligibility.
f Required for confirmation of menopause only as applicable

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10.3. 
Appendix 3: AEs, SAEs, SSRs and AEIs: Definitions and Procedures 
for Recording, Evaluating, Follow-up, and Reporting  
10.3.1. 
Definition of AE 
AE Definition 
•
An AE is any untoward medical occurrence in a clinical study participant, temporally
associated with the use of study intervention, whether or not considered related to the study
intervention.
•
AEs may also include pre- or post-treatment complications that occur as a result of
protocol specified procedures, lack of efficacy, overdose, drug abuse/misuse reports, or
occupational exposure.
•
NOTE: An AE can therefore be any unfavorable and unintended sign (including an
abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally
associated with the use of study intervention.
Events Meeting the AE Definition 
•
Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) or
other safety assessments (eg, vital signs measurements) that require medical or surgical
intervention or lead to study intervention interruption, modification, discontinuation, or are
considered clinically significant in the medical and scientific judgment of the investigator
•
Exacerbation of a chronic or intermittent pre-existing condition (recorded as medical
history) including either an increase in frequency and/or intensity of the condition
•
New condition detected or diagnosed after study intervention even though it may have
been present before the start of the study
•
Signs, symptoms, or the clinical sequelae of a suspected study intervention interaction,
including drug/drug, drug/food, drug/device and drug/alcohol interactions.
•
Signs, symptoms, or the clinical sequelae of a suspected overdose of either study
intervention or a concomitant medication. Overdose per se will not be reported as an
AE/SAE unless it is an intentional overdose taken with possible suicidal/self-harming
intent. Such overdoses should be reported regardless of sequelae.
•
The signs, symptoms, and/or clinical sequelae resulting from lack of efficacy will be
reported as AE or SAE if they fulfill the definition of an AE or SAE.

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Events NOT Meeting the AE Definition 
•
Any clinically significant abnormal laboratory findings or other abnormal safety
assessments that are associated with the underlying disease, unless judged by the
investigator to be more severe than expected for the participant’s condition
•
The disease/disorder being studied or expected progression, signs, or symptoms of the
disease/disorder being studied, unless more severe than expected for the participant’s
condition
•
Medical or surgical procedure (eg, endoscopy, appendectomy, transfusion, tooth
extraction): the condition that leads to the procedure is the AE
•
Pre-existing diseases, conditions, or laboratory abnormalities present or detected before the
screening visit that do not worsen
•
Situations in which an untoward medical occurrence did not occur (social and/or
convenience admission to a hospital, hospitalization for elective surgery)
•
Overdose of study intervention without clinical sequelae
•
Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present or
detected at the screening visit that do not worsen
10.3.2. 
Definition of SAE 
An SAE is defined as any untoward medical occurrence that, at any dose, meets 1 or more of the 
criteria listed: 
1.
Results in death
2.
Is life threatening
•
The term “life threatening” in the definition of “serious” refers to an event in which the
participant was at risk of death at the time of the event. It does not refer to an event, which
hypothetically might have caused death, if it were more severe.
3.
Requires inpatient hospitalization or prolongation of existing hospitalization
•
In general, hospitalization signifies that the participant has been admitted (usually
involving at least an overnight stay) at the hospital or emergency ward for observation
and/or treatment that would not have been appropriate in the physician’s office or
outpatient setting. Complications that occur during hospitalization are AEs. If a
complication prolongs hospitalization or fulfills any other serious criteria, the event is
serious. When in doubt as to whether hospitalization occurred or was necessary, the AE
should be considered serious.
•
Hospitalization for elective treatment of a pre-existing condition that did not worsen from
baseline is not considered an AE.
4.
Results in persistent or significant disability/incapacity

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An SAE is defined as any untoward medical occurrence that, at any dose, meets 1 or more of the 
criteria listed: 
•
The term disability means a substantial disruption of a person’s ability to conduct normal
life functions.
•
This definition is not intended to include experiences of relatively minor medical
significance such as uncomplicated headache, nausea, vomiting, diarrhea, influenza, and
accidental trauma (eg, sprained ankle) that may interfere with or prevent everyday life
functions but do not constitute a substantial disruption.
5.
Is a congenital anomaly/birth defect
6.
Other medically important events
•
Medical or scientific judgment should be exercised by the investigator in deciding whether
SAE reporting is appropriate in other situations such as significant medical events that may
jeopardize the participant or may require medical or surgical intervention to prevent one of
the other outcomes listed in the above definition. These events should usually be
considered serious.
−
Examples of such events include invasive or malignant cancers, intensive treatment for
allergic bronchospasm, blood dyscrasias, convulsions or development of intervention
dependency or intervention abuse, suspected transmission of any infectious agent via
an authorized medicinal product.
10.3.3. 
Definitions of Special Situations (SSR) 
Situations Defined as Special Situations (SSR) 
•
Medication error is any unintentional error in the prescribing, dispensing, or administration
of a medicinal product while in the control of the health care provider, participant, or
consumer.
•
Abuse is defined as persistent or sporadic intentional excessive use of a medicinal product
by a participant.
•
Misuse is defined as any intentional and inappropriate use of a medicinal product that is
not in accordance with the protocol instructions or the local prescribing information.
•
An overdose is defined as an accidental or intentional administration of a quantity of a
medicinal product given per administration or cumulatively which is above the maximum
recommended dose as per protocol (as it applies to the daily dose of the participant in
question). In cases of a discrepancy in drug accountability, overdose will be established
only when it is clear that the participant has taken the excess dose(s). Overdose cannot be
established when the pharmacist cannot account for the discrepancy except in cases in
which the investigator has reason to suspect that the additional dose(s) were administered
to the participant.

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Situations Defined as Special Situations (SSR) 
•
Occupational exposure is defined as exposure to a study intervention as a result of one’s
professional or nonprofessional occupation.
•
Drug interaction is defined as any drug/drug, drug/food, or drug/device interaction.
•
Unexpected benefit is defined as an unintended therapeutic effect where the results are
judged to be desirable and beneficial.
•
Transmission of infectious agents is defined as any suspected transmission of an infected
agent through Sponsor’s study intervention.
•
Counterfeit or falsified medicine: Any study intervention with a false representation of (a)
its identity, (b) its source, or (c) its history.
•
Product complaint is defined as complaints arising from potential deviations in the
manufacture, packaging, or distribution of the medicinal product.
The signs, symptoms, and/or clinical sequelae resulting from a special situation will be reported as AE 
or SAE if they fulfill the definition of an AE or SAE. 
10.3.4. 
Definition of Adverse Event of Interest (AEI) 
AEI Definition 
•
An AEI is a noteworthy event for the particular product or class of products that the
Sponsor may wish to monitor carefully. It could be serious or non-serious (eg, hair loss,
loss of taste, impotence).
•
Such events will be described in the sub-protocol, if applicable, and instructions provided
for investigators as to how and when they should be reported to the Sponsor.
10.3.5. 
Recording and Follow-Up of AEs, SAEs, SSRs (including Pregnancies) and/or 
AEIs  
AE and SAE Recording 
•
When an AE/SAE occurs, it is the responsibility of the investigator to review all
documentation (eg, hospital progress notes, laboratory reports, and diagnostics reports)
related to the event.
•
The investigator will then record all relevant AE/SAE information into the section of the
participant’s AE eCRF and the event description section of the SAE form.
•
All AEs/SAEs should be followed until resolution, stabilization, the event is otherwise
explained, or the participant is lost to follow-up.
•
It is not acceptable for the investigator to send photocopies of the participant’s medical
records to the Sponsor in lieu of completion of the required forms.

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•
There may be instances when copies of medical records for certain cases are requested by
the Sponsor. In this case, all participant identifiers, with the exception of the participant
number, will be redacted on the copies of the medical records before submission.
•
The investigator will attempt to establish a diagnosis of the event based on signs,
symptoms, and/or other clinical information. Whenever possible, the diagnosis (not the
individual signs/symptoms) will be documented as the AE/SAE.
•
For fatal or life-threatening events, copies of hospital case reports, discharge summaries,
autopsy reports, and other documents should be submitted by email or fax when requested
and applicable. Transmission of such documents should occur without personal participant
identification, maintaining the traceability of a document to the participant identifiers.
•
Additional information may be requested to ensure the timely completion of accurate
safety reports.
•
Any medications necessary for treatment of the AE/SAE must be recorded onto the
concomitant medication section of the participant’s eCRF and the event description section
of the SAE form.
SSR (including Pregnancy) and/or AEI Recording 
•
When an SSR (including Pregnancy)/AEI occurs, it is the responsibility of the investigator
to review all documentation and record the relevant information on the corresponding
report form.
•
If the SSR/AEI is associated with an AE/SAE, the information will also be recorded as per
AE/SAE recording procedures.
Assessment of Severity 
•
The investigator will make an assessment of intensity for each AE and SAE reported
during the study according to the standard toxicity grading in the CTCAE v5.0 (or later, if
specified in the respective sub-protocol). Definitions of severity per CTCAE (v5.0) are
presented in Table 7.
−
For each event, the highest grade attained should be reported.

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Table 7: 
CTCAE (v5.0) Definitions of Severity 
Severity 
Definition 
Grade 1 
Mild; asymptomatic or mild symptoms; clinical or 
diagnostic observations only; intervention not 
indicated. 
Grade 2 
Moderate; minimal, local or noninvasive 
intervention indicated; limiting age- appropriate 
instrumental ADL. Instrumental ADL refer to 
preparing meals, shopping for groceries or clothes, 
using the telephone, managing money, etc. 
Grade 3 
Severe or medically significant but not 
immediately life-threatening; hospitalization or 
prolongation of hospitalization indicated; 
disabling; limiting self-care ADL. 
Self-care ADL refer to bathing, dressing and 
undressing, feeding self, using the toilet, taking 
medications, and not bedridden. 
Grade 4 
Life-threatening consequences; urgent 
intervention indicated. 
Grade 5 
Death related to AE. 
ADL=activities of daily living 
Source: NCI 2017 
Assessment of Causality 
•
The investigator is obligated to assess the relationship between each study intervention and
each occurrence of each AE/SAE. The investigator will use clinical judgment to determine
the relationship (Yes or No).
•
A reasonable possibility of a relationship conveys that there are facts, evidence, and/or
arguments to suggest a causal relationship, rather than a relationship cannot be ruled out.
•
Alternative causes, such as underlying disease(s), concomitant therapy, and other risk
factors, as well as the temporal relationship of the event to study intervention
administration, will be considered and investigated.
•
An answer of Yes should be entered when, in the investigator’s opinion, there is a
reasonable possibility that the AE is associated with study intervention. Otherwise,
relationship to study intervention should be categorized as No.
•
The investigator will also consult the IB and/or product information, for marketed
products, in his/her assessment.
•
For each AE/SAE, the investigator must document in the medical notes that he/she has
reviewed the AE/SAE and has provided an assessment of causality.

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Assessment of Causality 
•
There may be situations in which an SAE has occurred and the investigator has minimal
information to include in the initial report to Sponsor. However, it is very important that
the investigator always make an assessment of causality for every event before the initial
transmission of the SAE data to Sponsor.
•
The investigator may change his/her opinion of causality in light of follow-up information
and send an SAE follow-up report with the updated causality assessment.
•
The causality assessment is one of the criteria used when determining regulatory reporting
requirements.
Follow-up of AEs, SAEs, SSRs (including Pregnancies) and/or AEIs 
•
The investigator is obligated to perform or arrange for the conduct of supplemental
measurements and/or evaluations as medically indicated or as requested by Sponsor to
elucidate the nature and/or causality of the AE, SAE or AEI as fully as possible. This may
include additional laboratory tests or investigations, histopathological examinations, or
consultation with other health care professionals.
•
If a participant dies during participation in the study or during a recognized follow-up
period, the investigator will provide the Sponsor with a copy of any postmortem findings
including histopathology.
•
New or updated information will be recorded in the originally submitted documents.
•
The investigator will submit any updated data to Sponsor within 24 hours of receipt of the
information.

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10.3.6. 
Reporting of SAEs, SSRs (including Pregnancies) and/or AEIs 
Safety (SAE, SSR, Pregnancy and/or AEI) Reporting to Sponsor 
•
Email or Facsimile transmission of the paper data collection tool is the primary method to
transmit this information to Sponsor within 24 hours.
•
The investigator is responsible for assessing SAEs and AEIs for causality and severity, and
for final review and confirmation of accuracy of event information and assessments on the
reporting forms.
•
Sponsor’s designee for receipt of all reports is UBC Pharmacovigilance.
•
Contacts for safety reporting is as follows:
CCI

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10.4. 
Appendix 4: List of Abbreviations and Definitions of Terms 
ADL 
activities of daily living 
AE 
adverse events 
AEI 
adverse events of interest 
ALT 
alanine aminotransferase 
CIOMS 
Council for International Organizations of Medical Sciences 
CTCAE 
Common Terminology Criteria for Adverse Events 
DBL 
database lock 
ECI 
event of clinical interest 
eCRF 
electronic case report form 
EDC 
Electronic Data Capture 
EOFU 
End of Follow-Up 
EOT 
End of Treatment 
FAS 
full analysis set 
FDA 
Food and Drug Administration 
FSH 
follicle stimulating hormone 
GCP 
Good Clinical Practice 
HAV 
hepatitis A virus 
HBcAg 
HBV core antigen 
HBcrAg 
hepatitis B core-related antigen 
HBeAg 
hepatitis B e antigen 
HBsAg 
hepatitis B surface antigen 
HBV 
hepatitis B virus 
HBx 
hepatitis B x antigen 
HCC 
hepatocellular carcinoma 
HCV 
hepatitis C virus 
HDV 
hepatitis D virus 
HEV 
hepatitis E virus 
HIV 
human immunodeficiency virus 
IB 
Investigator’s Brochure 
CCI
CCI
CCI
CCI

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ICF 
Informed Consent Form 
ICH 
International Council for Harmonisation 
IEC 
independent ethics committee 
IgG 
immunoglobulin G 
IgM 
immunoglobulin M 
IRB 
institutional review board 
IDMC 
Independent Data Monitoring Committee 
IRT 
Interactive Response Technology 
LAR 
legally authorized representative 
LFAC 
Liver Flare Adjudication Committee 
LLOQ 
Lower Limit of Quantitation 
MEF 
missing equals failure 
NRTI 
nucleos(t)ide reverse transcriptase inhibitor 
PEG-IFNα 
peginterferon-alfa-2a 
pol/RT  
polymerase/reverse transcriptase  
PreS1/PreS2/HBsAg 
large, medium, and small surface envelope glycoproteins 
Q1 
1st quartile 
Q3 
3rd quartile 
rcDNA 
relaxed-circular DNA 
RNA 
ribonucleic acid 
RSI 
reference safety information 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SD 
standard deviation 
SOA 
schedule of activities 
SRC 
Safety Review Committee 
SSR 
special situation reports 
SUSAR 
suspected unexpected serious adverse reaction 
TEAE 
treatment-emergent adverse event 
ULN 
upper limit of normal 
WOCBP 
women of child-bearing potential  
CCI
CCI
CCI

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10.5. 
Appendix 5: Summaries of Changes for Previous Protocol Amendments 
Protocol Amendment 1 (16 May 2022) Summary of Changes Table 
Section # and Name 
Description of Change 
Brief Rationale 
1.1 Synopsis 
3. Objectives, endpoints
and estimands
9.1 Statistical
Hypotheses
9.2 Sample Size
Determination
9.4.2 Primary Endpoint 
Analysis 
Additional potential primary endpoints 
added 
Proportion of participants achieving 
sustained suppression of HBV DNA 
(< LLOQ) at 24 weeks after 
discontinuation of all treatment 
Proportion of participants achieving 
sustained suppression of HBV DNA 
(< LLOQ) with HBsAg loss (< 0.05 
IU/mL) at 24 weeks after 
discontinuation of all treatment 
Clarified existing primary endpoint’s viral 
marker levels.  
Relevant changes were made to the 
primary estimands, primary endpoint 
analysis sections, sample size 
determination 
Two additional optional primary endpoints were added to conform 
with the FDA HBV guidance (FDA 2022) 
1.1 Synopsis 
Table 3 Populations 
Included in This 
Platform Protocol 
Modified the protocol populations I and IV 
to include participants that are at the limits 
indicated below: 
ALT < ULN modified to ALT ≤ ULN 
and/or HBV DNA < 2,000 IU/mL 
modified to HBV DNA ≤ 2,000 IU/mL 
These modifications were made to include participants that may have 
the limit values and to align with major clinical practice guidelines 
(AASLD and EASL) 
4.2 Scientific Rationale 
for Study Design 
Added rationale for not including co-
infected participants (HAV, HCV, HDV, 
HEV or HIV) in the study 
To allow better characterization of the investigational therapies in the 
absence of other clinically significant co-infections 

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Table 9 Schedule of 
Activities: Follow-Up 
Period 
Removed exploratory assessments from 
additional Follow-Up visits SOA 
Additional Follow-Up visits that added to sub-protocols may not 
require collection of these exploratory assessments. If required, the 
sub-protocols will specify the exploratory assessments needed. This 
will ensure reduction of participant burden in terms of sample 
collection unless necessary for analyses. 
Entire document 
Other administrative, formatting, and other 
minor changes 
These changes were made to clarify, ensure consistency, or rectify 
typographical errors.  

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10.6. 
Appendix 6: Contraceptive and Barrier Guidance 
WOCBP may be included in this study and include any female participant who has experienced 
menarche and who is not post-menopausal or permanently sterilized (eg, bilateral tubal 
occlusion, hysterectomy, bilateral oophorectomy, or bilateral salpingectomy). 
WOCBP must be willing to use highly effective methods of contraception from 14 days before 
the first dose of study intervention through period described in sub-protocol. Highly effective 
methods of birth control are defined as those that result in a low failure rate (ie, less than 1% per 
year). Birth control methods which are considered highly effective include: 
•
Established use of combined (estrogen and progestogen containing) oral, intravaginal,
or transdermal hormonal methods of contraception associated with inhibition of
ovulation OR established use of progestogen-only oral, injectable, or implantable
hormonal methods of contraception associated with inhibition of ovulation. It is not
currently known whether study interventions will impact the effectiveness of
hormonal contraceptive methods; therefore, it is recommended to use an additional
form of contraception (i.e., barrier method) for period defined in sub-protocol.
•
Placement of an intrauterine device
•
Placement of an intrauterine hormone-releasing system
•
Surgical sterilization of male partner (with the appropriate documentation of
vasectomy or the absence of sperm in the ejaculate; for female participants on the
study, the vasectomized male partner should be the sole partner for that participant)
•
True sexual abstinence from heterosexual contact, when in line with the preferred and
usual lifestyle of the participant. Periodic abstinence (eg, calendar, ovulation,
symptothermal, post ovulation methods) and withdrawal are not acceptable methods
of contraception. Abstinent participants must agree to use 1 of the above-mentioned
contraceptive methods for period defined in sub-protocol if they start heterosexual
relationships during the study.
•
Barrier method in combination with hormonal contraceptive, as described above
Post-menopausal status is defined as 12 months with no menses without an alternative medical 
cause. An elevated FSH level in the post-menopausal range should be used to confirm a post-
menopausal state in women not using hormonal contraception or HRT. In the absence of 
12 months of amenorrhea, confirmation with more than one FSH measurement is required. 
Females on HRT and whose menopausal status is in doubt must discontinue HRT to allow 
confirmation of postmenopausal status before study enrollment.  
Female participants must also agree to refrain from egg donation and in vitro fertilization from 
the time of study intervention administration through period defined in sub-protocol. 

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Male participants with female partners of child-bearing potential must agree to meet 1 of the 
following contraception requirements from the time of study intervention administration until 
period defined in sub-protocol. 
•
Documentation of azoospermia or vasectomy
•
Male condom plus partner use of 1 of the contraceptive options listed above for
contraception for WOCBP (hormonal contraceptive, intrauterine device)
Male participants must also agree not to donate sperm from the first dose of study intervention 
through period defined in sub-protocol.

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10.7. 
Appendix 7: Schedule of Activities  
Sub-protocols will define the timing of the visits and any additional assessments in the Treatment Period. 
Table 8: 
Schedule of Activities: Screening and Treatment Periods 
Study Stage 
Screening 
Treatment Perioda
Visit Week 
W1 
On-Treatment Visit Week 
(Week Defined in Sub-Protocol) 
EOTb
Visit Day ± Visit Window 
D -56 to -1 
D1 
D8±2 
On-Treatment Visit Day  
(Day Defined in Sub-Protocol) 
Study Procedures 
Informed consent 
X 
Inclusion/exclusion criteria 
X 
Xc
Demography 
X 
Physical examination 
X 
X 
Medical history 
X 
Vital signsd 
X 
X 
X 
X 
X 
Adverse event review/recorde
X 
X 
X 
X 
X 
Prior and concomitant medication 
X 
X 
X 
X 
X 
Liver scan (eg, Fibroscan)f 
X 
Drug Administrationg 
As defined in sub-protocol 
Laboratory Assessmentsh 
Pregnancy testi 
X 
X 
X 
X 
X 
Screening viral serologyj 
X 
Liver function testsk 
X 
X 
X 
X 
X 
Serum chemistryk 
X 
X 
X 
X 
X 

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Study Stage 
Screening 
Treatment Perioda
Visit Week 
W1 
On-Treatment Visit Week 
(Week Defined in Sub-Protocol) 
EOTb
Visit Day ± Visit Window 
D -56 to -1 
D1 
D8±2 
On-Treatment Visit Day  
(Day Defined in Sub-Protocol) 
Hematology k 
X 
X 
X 
X 
X 
Coagulation parameters k 
X 
X 
X 
X 
X 
Urinalysis k 
X 
X 
X 
X 
X 
Urine for drugs of abuse l 
X 
HBsAg quantitative 
X 
X 
X 
X 
X 
Anti-HBs qualitative 
X 
Anti-HBs quantitative 
X 
X 
X 
HBeAg qualitative 
X 
HBeAg quantitative 
X 
X 
X 
Anti-HBe qualitative 
X 
HBV DNA quantification 
X 
X 
X 
X 
X 
Exploratory Assessments 
Resistance surveillancem 
X 
X 
X 
CCI
CCI
CCI
CCI
CCI
CCI
CCI

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Study Stage 
Screening 
Treatment Perioda
Visit Week 
W1 
On-Treatment Visit Week 
(Week Defined in Sub-Protocol) 
EOTb
Visit Day ± Visit Window 
D -56 to -1 
D1 
D8±2 
On-Treatment Visit Day  
(Day Defined in Sub-Protocol) 
Stabilized whole blood for immune cell assays 
X 
X 
X 
X 
D = day; W = week; EOT= End of Treatment 
a On days in which study intervention is administered, assessments performed predose unless otherwise specified. 
b If a participant discontinues treatment or withdraws prematurely from the study prior to the last visit in the Treatment Period, EOT assessments should be 
performed. 
c Prior to study intervention administration on Day 1, participant eligibility will be confirmed. 
d Vital signs (blood pressure, pulse rate, respiratory rate, and temperature) should be measured after the participant has rested comfortably for approximately 10 
minutes. 
e After signing of the ICF, but prior to initiation of study intervention, AEs/SAEs related to protocol-mandated procedures will be reported. Following initiation 
of study intervention, all AEs/SAEs, regardless of cause or relationship, will be recorded for the entire duration of the study. Further details can be found in 
Section 8.7. 
f As described in respective sub-protocols. 
g Will be defined in sub-protocol as applicable.  
h Screening laboratory tests may be repeated (eg, for values thought to be erroneous) with Sponsor approval. 
i WOCBP are required to have pregnancy tests. A blood pregnancy test will be performed at screening, and a urine pregnancy test will be performed at 
subsequent visits. Negative pregnancy test must be confirmed prior to study intervention administration. 
j See Section 8.4 for viral serology parameters. 
k Clinical laboratory and urinalysis parameters are described in Section 10.2. 
l Drugs of abuse included in the panel are described in Section 8.1.3.
m See Section 8.4 and Section 8.1.2 for more information.
n As this assessment is exploratory, the collection and specific assays used may be changed or removed at the Sponsor’s discretion based on emerging data.
Further details can be found in Section 8.6. 

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Table 9: 
Schedule of Activities: Follow-Up Period  
Sub-protocols will define any additional visits or additional assessments in the Follow-Up Period. 
Study Stage 
Follow-Up Perioda
Follow-Up Week 
F1 
F4 
F8 
F12 
F16 
F20 
F24 
Fxb 
(additional 
F visits) 
EOFUc 
Visit Day ± Visit Window 
D7±2 
D29±7 
D57±7 
D85±7 
D113±7 
D141±7 
D169±7 
Dx 
Dx 
Study Procedures 
Vital signs 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Adverse event review/record 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Laboratory Assessments 
Pregnancy testinge
X 
X 
X 
X 
X 
Liver function testsf 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Serum chemistryf 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Hematologyf 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Coagulation parametersf 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Urinalysisf 
X 
X 
X 
X 
HBsAg quantitative 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Anti-HBs quantitative 
X 
X 
X 
X 
X 
X 
X 
X 
X 
HBeAg quantitative 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Anti-HBe qualitative 
X 
X 
X 
X 
X 
X 
X 
X 
X 
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Study Stage 
Follow-Up Perioda
Follow-Up Week 
F1 
F4 
F8 
F12 
F16 
F20 
F24 
Fxb 
(additional 
F visits) 
EOFUc 
Visit Day ± Visit Window 
D7±2 
D29±7 
D57±7 
D85±7 
D113±7 
D141±7 
D169±7 
Dx 
Dx 
HBV DNA quantitation 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Exploratory Assessments 
D = day; F= Follow-Up visit week; EOFU= End of Follow-Up; WPAI:GH= Work Productivity and Activity Impairment Questionnaire: General Health (v2.0) 
a Certain assessments may be performed remotely. The start of the Follow-Up Period relative to the end of the Treatment Period will be defined in the respective 
sub-protocol. 
b Additional follow up visits as provided in sub-protocol. 
c The assessments will be done at the last visit in the follow up period, if F24 is the last FU visit then EOFU assessments supersede those listed in F24. 
d
e Urine pregnancy test for WOCBP only. 
f Clinical laboratory and urinalysis parameters are described in Section 10.2. 
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11.
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