Clinical trial NCT04781647
Conditions: Chronic Hepatitis B
Keywords: cHBV HBV vebicorvir VBR
Sponsor: Assembly Biosciences
Start date: 2021-02-18; Completion date: 2022-12-02
Enrollment: 54 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study is to evaluate the safety, antiviral activity, and pharmacokinetics of ABI-H0731 in combination with entecavir (ETV) and with ETV plus pegylated-interferon alpha (Peg-IFNα) in Chinese participants with chronic hepatitis B virus infection (cHBV)

Detailed description:

Arms: arm 1: Participants with cHBV will receive ABI-H0731 with ETV for 48 weeks, followed by ETV alone for 12 weeks arm 2: Participants with cHBV will receive ABI-H0731 with ETV and Peg-IFNα for 24 weeks, followed by ABI-H0731 with ETV for 24 weeks, followed by ETV alone for 12 weeks arm 3: Participants with cHBV will receive ETV and Peg-IFNα for 24 weeks, followed by ABI-H0731 with ETV for 24 weeks, followed by ETV alone for 12 weeks
Interventions: intervention 1: ABI-H0731 intervention 2: ETV intervention 3: Peg-IFNα
Intervention descriptions: intervention 1: Participants will receive ABI-H0731 300 mg tablets orally once daily intervention 2: Participants will receive ETV 0.5 mg tablets orally once daily intervention 3: Participants will receive Peg-IFNα with a starting dose of 180 µg solution by subcutaneous injection once weekly

Protocol documents:
Prot_SAP_000.pdf: 
Study Title: A Randomized Phase 2a, Multicenter, Open-label Study Evaluating ABI-H0731-
Containing Regimens in Patients with Chronic Hepatitis B 
 
NCT Number: 04781647 
 
Date of Document: 29 July 2021 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


CLINICAL RESEARCH PROTOCOL 
PROTOCOL TITLE: 
A Randomized Phase 2a, Multicenter, Open-Label Study 
Evaluating ABI-H0731-Containing Regimens in Patients with 
Chronic Hepatitis B 
 
STUDY NUMBER: 
ABI-H0731-203 
 
DRUG: 
ABI-H0731 
 
SPONSOR: 
Assembly Biosciences 
331 Oyster Point Boulevard, 4th Floor 
South San Francisco, California 94080, USA 
(833) 509-4583 
 
AMENDMENT 3.0, DATE: 
AMENDMENT 2.0, DATE:  
AMENDMENT 1.0, DATE: 
ORIGINAL PROTOCOL 
DATE: 
 
29 July 2021 
09 December 2020  
20 July 2020 
07 December 2018 
CONFIDENTIALITY STATEMENT 
The information contained in this protocol and all other information relevant to Assembly Biosciences 
are the confidential and proprietary information of Assembly Biosciences and, except as may be 
required by federal, state, or local laws or regulation, may not be disclosed to others without prior 
written permission of Assembly Biosciences.  


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CLINICAL PROTOCOL APPROVAL FORM 
Protocol Title: 
A Randomized Phase 2a, Multicenter, Open-Label Study Evaluating 
ABI-H0731-Containing Regimens in Patients with Chronic 
Hepatitis B 
Protocol Number: 
ABI-H0731-203 
Protocol Date: 
Amendment 3.0, 29 July 2021 
This study protocol was subject to critical review and has been approved by the appropriate protocol 
review personnel of the Sponsor. The information contained in this protocol is consistent with: 

The current risk-benefit evaluation of the investigational product.

The ethical and scientific standards governing clinical research that are set out in the current
International Council for Harmonisation (ICH) harmonised tripartite guideline E6(R2)
Good Clinical Practice (GCP), United States (US) Title 21 of the Code of Federal
Regulations (CFR) Parts 50, 54, 56, and 312, and other applicable local requirements.

China GCP (2020)
The Investigator will be supplied with details of any significant or new findings, including adverse 
events (AEs), relating to treatment with the investigational product. 
Name and Title 
Approval Signature and Date 
Luisa M. Stamm, MD, PhD 
 
Assembly Biosciences 
DocuSign Envelope ID: C63F0AC4-EBEE-4B1E-B0D9-189EE810212F
30-Jul-2021 | 03:51:50 PDT


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INVESTIGATOR STATEMENT 
Protocol Title: 
A Randomized Phase 2a, Multicenter, Open-Label Study Evaluating 
ABI-H0731-Containing Regimens in Patients with Chronic 
Hepatitis B 
Protocol Number: 
ABI-H0731-203 
Protocol: 
Amendment 3.0, 29 July 2021 
I have read the protocol, including all appendices, and I agree that it contains all of the necessary 
information for me and my staff to conduct this study as described. I will conduct this study as 
described herein, in accordance with Good Clinical Practice (GCP) as set out in the current 
International Council for Harmonisation (ICH) guidelines (E6[R2]) and other applicable national or 
local requirements, 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 any amendments, 
and access to all information provided by Assembly Biosciences or specified designees. I will discuss 
the material with them to ensure that they are fully informed about Assembly Biosciences and the 
study. 
Principal Investigator Signature:  
Print Name:  
Date:  
Please keep the original, signed copy of this Investigator Statement page in your records and provide a 
copy to your site monitor for archival in the Trial Master File. 
 
 


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1. 
SYNOPSIS 
Protocol 
Number: 
ABI-H0731-203 
Title:  
A Randomized Phase 2a, Multicenter, Open-label Study Evaluating 
ABI-H0731-Containing Regimens in Patients with Chronic Hepatitis B 
Phase: 
2a 
Number of 
Subjects: 
Approximately 60 
Study Duration:  
Up to 45 days for Screening, 48 weeks of treatment and 12 weeks of follow-up 
Rationale:  
Chronic hepatitis B (CHB) is a major cause of liver-related morbidity and mortality 
worldwide. ABI-H0731 (731) is an orally administered, direct-acting antiviral agent 
targeting the hepatitis B virus (HBV) core protein. Through its interaction with core 
protein, 731 interferes with multiple steps in the viral lifecycle including early events 
(capsid disassembly and DNA delivery to the nucleus for formation of covalently closed 
circular [cccDNA]) and late events (assembly of pregenomic (pg) RNA-containing capsids 
which are required for HBV replication). ABI-H0731 may also prevent newly formed 
DNA-containing nucleocapsids from delivering HBV DNA to the nucleus to amplify the 
pool of cccDNA in infected cells. Entecavir (ETV) is an approved, orally administered 
direct-acting antiviral that inhibits the reverse transcription of HBV pgRNA to DNA. 
Pegylated (Peg)-interferon alpha (IFNα) is an approved, subcutaneously administered 
biologic which has both antiviral and immunomodulatory activities. While the specific 
mechanisms by which Peg-IFNα exerts its antiviral activity against HBV are not fully 
understood, it is thought to inhibit multiple steps in the viral lifecycle and to augment the 
host immune response. The combination of 731 with ETV and Peg-IFNα will provide 
multiple complementary antiviral mechanisms that may act synergistically to increase 
CHB cure rates. It is anticipated that the combination of 731 and ETV with or without 
Peg-IFNα will be safe, reduce viral nucleic acids (ie, HBV pgRNA and HBV DNA) and 
reduce viral antigens (ie, hepatitis B “e” antigen [HBeAg], hepatitis B core-related antigen 
[HBcrAg], and hepatitis B surface antigen [HBsAg]) in subjects with CHB. This Phase 2a 
study will explore the safety of the 731+ETV+Peg-IFNα combination, its antiviral activity, 
as measured by effects on serum HBV pgRNA, HBV DNA, and HBV antigens, and 
pharmacokinetics (PK). 
Target 
Population: 
Male or female, 18 to 65 years (inclusive) of age, treatment naïve with HBeAg positive 
CHB and no evidence of cirrhosis or end-stage liver disease. Eligible subjects must be 
candidates to receive Peg-IFNα according to approved prescribing information. 
Test Product(s): 
731 100 mg tablets + ETV 0.5 mg tablets + Peg-IFNα 180 µg solution 
Reference 
Product(s): 
• 
731 100 mg tablets + ETV 0.5 mg tablets 


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• 
ETV 0.5 mg tablets + Peg-IFNα 180 µg solution 
Study Design: 
This is a randomized Phase 2a, multicenter, open-label study evaluating the safety, antiviral 
activity, and PK of 731 administered in addition to ETV with or without Peg-IFNα in 
treatment-naïve Chinese subjects with CHB. 
Approximately 60 eligible subjects with HBeAg positive CHB will be randomly assigned 
in a 1:1:1 ratio to the treatment groups described in the following figure. 
Abbreviations: BL = Baseline; ETV = entecavir; Peg-IFNα = pegylated-interferon alpha; Wk = week. 
Treatment with 731 (where applicable) and ETV will be administered orally, once daily; 
treatment with Peg-IFNα (where applicable) will be administered subcutaneously, once 
weekly. 
• 
Group 1 will receive 731+ETV for 24 weeks 
• 
Group 2 will receive 731+ETV+Peg-IFNα for 24 weeks 
• 
Group 3 will receive ETV+Peg-IFNα for 24 weeks 
All subjects will receive 731+ETV from Week 24 through Week 48 and then ETV alone 
from Week 48 through Week 60 during the 12-week follow-up period. 
Treatment assignments will be stratified by the HBV genotype (GT; ie, HBV GT A or B 
vs GT C or D vs other GTs) and baseline alanine aminotransferase (ALT; ie, ALT 
<5 × upper limit of normal [ULN] vs ALT ≥5 × ULN) during the Screening visits. 
Objectives:  
Primary Objective: 
• 
To evaluate the safety and tolerability of 731 when administered in combination with 
ETV with or without Peg-IFNα in subjects with CHB 
Secondary Objectives: 
• 
To evaluate the effect of 731 when administered in combination with ETV with or 
without Peg-IFNα in reducing HBV pgRNA levels in subjects with CHB 
• 
To evaluate the effect of 731 when administered in combination with ETV with or 
without Peg-IFNα in reducing HBV DNA levels in subjects with CHB 
• 
To evaluate the effect of 731 when administered in combination with ETV with or 
without Peg-IFNα in reducing HBV antigens (ie, HBeAg, HBcrAg, and HBsAg) in 
subjects with CHB 
• 
To evaluate the effect of 731 when administered in combination with ETV with or 
without Peg-IFNα on normalization of ALT 


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• 
To evaluate the PK of 731 and future PK evaluation of Peg-IFNα and ETV in subjects 
with CHB 
• 
To evaluate the emergence of resistance to 731 when administered with ETV with or 
without Peg-IFNα 
Primary 
Endpoint:  
Primary Endpoint: 
• 
Proportion of subjects with adverse events, premature treatment discontinuation, and 
abnormal laboratory results 
Secondary 
Endpoints: 
Secondary Endpoints: 
• 
Mean change in log10 HBV pgRNA from Baseline at each timepoint 
• 
Mean change in log10 HBV DNA from Baseline at each timepoint 
• 
Mean change in log10 serum viral antigens (ie, HBeAg, HBcrAg, and HBsAg) from 
Baseline at each timepoint 
• 
Proportion of subjects with normal ALT at each timepoint 
• 
Analysis of 731 and ad hoc analysis of Peg-IFNα and ETV drug concentrations 
• 
The incidence of HBV variants with reduced susceptibility to 731 
Statistical 
Methods: 
This is a proof-of-concept study. The sample size is similar to that previously utilized for 
this type of study and is not based upon statistical considerations. 
All safety, antiviral activity, and PK endpoints will be summarized using descriptive 
statistics by treatment groups. Continuous endpoints will be described using the mean, 
standard deviation, median, minimum, and maximum. Categorical endpoints will be 
described using the number and percent of subjects who meet the endpoint criterion. 
Due to sample size limitations, no formal statistical inference is planned. Assessment of 
antiviral activity will be evaluated by treatment groups using 95% confidence intervals 
where appropriate. 
Key Eligibility 
Criteria: 
Inclusion Criteria: 
Subjects must meet all the following inclusion criteria in order to be eligible for the study: 
1. Willing and able to provide informed consent 
2. Male or female between the ages 18 and 65 years (inclusive) 
3. Body mass index (BMI) 18 to 36 kg/m2 and a minimum body weight of 45 kg 
(inclusive) 
4. Female subjects must be non-pregnant and have a negative serum pregnancy test 
at Screening and a negative urine pregnancy test predose on Day 1 
5. Chronic hepatitis B infection, defined as HBV infection for ≥6 months 
documented, for example, by at least 2 measurements of HBsAg positivity and/or 
detectable HBV DNA ≥6 months apart (inclusive of Screening). For subjects 
without clear documentation of CHB, serum immunoglobulin M (IgM) antibody 
to the HBV core antigen (HBcAb) must be negative at Screening to exclude acute 
HBV infection.  


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6. HBeAg positive with HBV DNA ≥2 × 104 IU/mL at Screening 
7. Lack of cirrhosis or advanced liver disease as documented by the following: 
• 
Liver biopsy results demonstrating absence of cirrhosis (eg, METAVIR 
F0-F3 or equivalent) within 1 year of Screening 
OR 
• 
Fasting FibroScan® ≤12 kPa within 3 months of Screening (including the 
Screening visit) or other Sponsor-approved hepatic imaging method 
within 6 months of Screening indicating lack of cirrhosis (eg, F0-F3 or 
equivalent) 
If results from both liver biopsy and FibroScan are available, then the 
diagnostic method reporting the most advanced liver disease will be used 
to determine eligibility for the study 
8. A candidate for interferon-based therapy  
9. Agreement to comply with protocol-specified contraceptive requirements 
(Appendix 4) 
10. Agreement to abstain from alcohol abuse (defined as alcohol consumption 
exceeding 2 standard drinks per day on average [1 standard drink = 14 grams of 
alcohol]) and the use of illicit substances from Screening through the duration of 
the study 
11. In good general health, except for CHB, in the opinion of the Investigator 
12. Have the ability to take oral medication, be willing to receive subcutaneous 
injections of Peg-IFNα (if applicable), and in the opinion of the Investigator, be 
willing to adhere to study treatment and procedures 
 
Exclusion Criteria: 
Subjects who meet any of the following exclusion criteria will not be eligible for the study. 
1. Current or prior treatment for CHB with 
• 
A nucleos(t)ide reverse transcriptase inhibitor of the HBV polymerase 
(NrtI) (ETV, tenofovir disoproxil fumarate or tenofovir alafenamide) for 
>4 weeks at any time. Note, NrtI treatment of ≤4 weeks duration cannot 
be within 6 months prior to Screening 
• 
Interferon-based therapy within 6 months prior to Screening  
• 
Liver-protecting and/or ALT-lowering treatment including traditional 
Chinese medicine within 1 month of Screening 
• 
Lamivudine, telbivudine or adefovir (of any duration) 
• 
Previous treatment with siRNA within 9 months prior to Screening 
• 
HBV core inhibitors (any duration) 
• 
Previous treatment with any other investigational agent for HBV infection 
within 6 months prior to Screening  
2. Deleted per protocol amendment 3 


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3. Co-infection with HIV, hepatitis A virus, hepatitis C virus, hepatitis E virus, or 
hepatitis D virus 
4. Females who are lactating or wish to become pregnant during the course of the 
study 
5. History or evidence of advanced liver disease or hepatic decompensation 
(including jaundice, ascites, portal hypertension, gastrointestinal bleeding 
esophageal varices, hepatic encephalopathy,) at any time prior to, or at the time of 
Screening 
6. History of persistent alcohol abuse (alcohol consumption exceeding 2 standard 
drinks per day on average [1 standard drink = 14 grams of alcohol]) or illicit drug 
abuse within 3 years prior to Screening 
7. Clinically significant psychiatric disease, including severe depression, history of 
suicidal ideation or suicide attempt 
8. Clinically significant cardiac disease, including poorly-controlled or unstable 
hypertension; pulmonary disease; chronic or recurrent renal or urinary tract 
disease; liver disease other than CHB; endocrine disorder; autoimmune disorder; 
poorly controlled diabetes mellitus; neuromuscular, musculoskeletal, or 
mucocutaneous conditions requiring frequent treatment, seizure disorders 
requiring treatment; ongoing infection or other medical conditions requiring 
frequent medical management or pharmacologic or surgical treatment that, in the 
opinion of the Investigator or the Sponsor, makes the subject unsuitable for study 
participation 
9. History of hepatocellular carcinoma (HCC) 
10. History of malignancy other than HCC unless the subject’s malignancy has been 
in complete remission off chemotherapy and without additional medical or surgical 
interventions during the 3 years before Screening 
11. History or presence at Screening of electrocardiogram abnormalities deemed 
clinically significant, in the opinion of the Investigator 
12. History of hypersensitivity or idiosyncratic reaction to any components or 
excipients of the investigational drug 
13. History of any significant food or drug-related allergic reactions such as, 
anaphylaxis or Stevens-Johnson syndrome 
14. The following are exclusionary laboratory results at Screening: 
• 
Hemoglobin <12g/dL for males or <11g/dL for females 
• 
Platelet count <100,000/mm3 
• 
White blood cell count <2,500/mm3 
• 
Absolute neutrophil count <1,500/mm3 
• 
Albumin <lower limit of normal  
• 
History of thyroid disease poorly controlled on prescribed medications, 
with thyroid-stimulating hormone, free triiodothyronine or free thyroxine 
outside the normal limits 


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• 
Total bilirubin >1.2 × ULN unless known Gilbert’s syndrome; subjects 
with Gilbert’s syndrome are eligible for study participation if the direct 
bilirubin is within the normal range 
• 
Direct bilirubin >1.2 × ULN 
• 
ALT ≤1 × ULN or ≥10 × ULN 
• 
Serum alpha fetoprotein (AFP) ≥100 ng/mL. If AFP at Screening is > ULN 
but <100 ng/mL, the subject is eligible if hepatic imaging prior to initiation 
of study drug reveals no lesions indicative of possible HCC 
• 
International Normalized Ratio >1.5 × ULN (unless on a stable 
anticoagulant regimen) 
• 
Glomerular filtration rate <60 mL/min/1.73 m2 by Chronic Kidney 
Disease Epidemiology Collaboration equation 
• 
Serum creatinine >1.5 × ULN 
• 
Any other laboratory abnormality deemed clinically significant by the 
Sponsor or the Investigator 
15. Subjects receiving prohibited concomitant medications or medications that 
should be avoided (as outlined in Section 6.6 and Appendix 5) within 7 days or 
5 half-lives (if known), whichever is longer, prior to administration of the first 
dose of study drug (Day 1) and for the duration of the study period.  Please refer 
to Exclusion Criterion #1 for criteria regarding liver protecting and/or ALT 
lowering agents 
16. Participation in another clinical study of any non-HBV-related drug or device 
whereby the last investigational drug/device administration is within 60 days or 5 
half-lives prior to the first study drug administration (Day 1), whichever is longer.  
17. Subjects who have received, in the previous 4 weeks, a treatment likely to alter the 
immune response (ie, intravenous immunoglobulins, blood-derived products, or 
high-dose steroids, or other immunosuppressants) 


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TABLE OF CONTENTS 
1. 
SYNOPSIS ............................................................................................................................ 4 
TABLE OF CONTENTS ......................................................................................................... 10 
LIST OF ABBREVIATIONS AND TERMS ......................................................................... 13 
2. 
INTRODUCTION ............................................................................................................. 15 
2.1. 
Background ................................................................................................................... 15 
2.2. 
ABI-H0731 ..................................................................................................................... 16 
2.2.1. 
General Information ............................................................................................... 16 
2.2.2. 
Preclinical Pharmacology and Toxicology ........................................................... 16 
2.2.3. 
Clinical Studies with ABI-H0731 .......................................................................... 17 
2.3. 
Study Rationale ............................................................................................................. 17 
3. 
STUDY OBJECTIVES AND ENDPOINTS ................................................................... 17 
3.1. 
Study Objectives ........................................................................................................... 17 
3.1.1. 
Primary Objective .................................................................................................. 17 
3.1.2. 
Secondary Objectives ............................................................................................. 17 
3.2. 
Study Endpoints ............................................................................................................ 18 
3.2.1. 
Primary Endpoint ................................................................................................... 18 
3.2.2. 
Secondary Endpoints .............................................................................................. 18 
4. 
STUDY PLAN .................................................................................................................... 18 
4.1. 
Study Design .................................................................................................................. 18 
4.2. 
Dose Justification .......................................................................................................... 19 
4.3. 
Duration of Treatment ................................................................................................. 19 
5. 
POPULATION .................................................................................................................. 19 
5.1. 
Number of Subjects ...................................................................................................... 19 
5.2. 
Inclusion Criteria .......................................................................................................... 20 
5.3. 
Exclusion Criteria ......................................................................................................... 21 
6. 
INVESTIGATIONAL MEDICAL PRODUCTS ............................................................ 23 
6.1. 
Randomization, Blinding, and Treatment Codes ...................................................... 23 
6.1.1. 
Randomization ........................................................................................................ 23 
6.1.2. 
Blinding .................................................................................................................... 23 
6.2. 
Study Treatments .......................................................................................................... 23 
6.2.1. 
ABI-H0731 ............................................................................................................... 23 
6.2.2. 
Entecavir .................................................................................................................. 23 
6.2.3. 
Pegylated-Interferon Alpha ................................................................................... 23 
6.2.4. 
Study Drug Administration ................................................................................... 24 
6.3. 
Description and Handling of Study Drugs ................................................................. 24 
6.3.1. 
ABI-H0731 ............................................................................................................... 24 
6.3.2. 
Entecavir .................................................................................................................. 24 
6.3.3. 
Pegylated-Interferon Alpha ................................................................................... 25 
6.4. 
Study Drug Accountability .......................................................................................... 25 
6.5. 
Return or Disposal of Study Drug ............................................................................... 26 
6.6. 
Prior and Concomitant Medications ........................................................................... 26 
6.6.1. 
Prohibited Concomitant Therapy ......................................................................... 26 
7. 
STUDY PROCEDURES ................................................................................................... 27 
7.1. 
Subject Enrollment and Treatment Assignment ....................................................... 27 
7.1.1. 
Screen Failures ........................................................................................................ 27 


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7.2. 
Screening Assessments (Day -45 to Day -1) ................................................................ 27 
7.3. 
Day 1 .............................................................................................................................. 28 
7.4. 
Study Week 1 ................................................................................................................. 29 
7.5. 
Study Weeks 2 Through 24 .......................................................................................... 29 
7.6. 
Study Weeks 28 Through 48 ........................................................................................ 30 
7.7. 
Study Weeks 52 Through 60 (Follow-up Assessments) ............................................. 31 
7.8. 
Unscheduled Visit ......................................................................................................... 31 
7.9. 
Premature Termination Visit ...................................................................................... 32 
7.10. Discontinuation ............................................................................................................. 32 
7.10.1. 
Discontinuation from Treatment ........................................................................... 33 
7.10.2. 
Subjects Lost to Follow-up ..................................................................................... 33 
7.11. Pharmacokinetic Assessments ..................................................................................... 33 
7.12. End of Study Definition ................................................................................................ 34 
7.13. Resistance Monitoring .................................................................................................. 34 
8. 
ADVERSE EVENTS ......................................................................................................... 34 
8.1. 
Documenting Adverse Events ...................................................................................... 34 
8.2. 
Assessment of Intensity ................................................................................................ 35 
8.3. 
Assessment of Causality ............................................................................................... 35 
8.4. 
Expectedness ................................................................................................................. 35 
8.5. 
Abnormal Laboratory Test Values ............................................................................. 35 
8.6. 
Dose Modification due to Adverse Events .................................................................. 36 
8.7. 
Adverse Event Follow-up ............................................................................................. 36 
8.8. 
Pregnancy ...................................................................................................................... 36 
8.8.1. 
Female subjects who become pregnant ................................................................. 36 
8.8.2. 
Male subjects with partners who become pregnant ............................................ 37 
9. 
SERIOUS ADVERSE EVENTS ...................................................................................... 37 
9.1. 
Definition of Serious Adverse Event ........................................................................... 37 
9.2. 
Reporting Serious Adverse Events .............................................................................. 38 
9.3. 
Overdose ........................................................................................................................ 38 
9.4. 
Management of ALT Elevations .................................................................................. 38 
10. STATISTICAL CONSIDERATIONS ............................................................................. 40 
10.1. Determination of Sample Size ...................................................................................... 41 
10.2. Analysis Populations ..................................................................................................... 41 
10.3. Planned Analyses .......................................................................................................... 41 
10.3.1. 
Disposition of the Study Subjects .......................................................................... 41 
10.3.2. 
Demographic and Baseline Characteristics .......................................................... 42 
10.3.3. 
Exposure to Study Treatment and Compliance ................................................... 42 
10.3.4. 
Analysis of Efficacy Endpoints .............................................................................. 42 
10.3.5. 
Pharmacokinetic Analysis ...................................................................................... 42 
10.3.6. 
Safety Analysis ........................................................................................................ 43 
10.4. Interim Analysis ............................................................................................................ 43 
10.5. Independent Data Monitoring Committee ................................................................. 43 
10.6. Handling of Missing Data ............................................................................................ 44 
10.7. Multiplicity Adjustment ............................................................................................... 44 
11. RESPONSIBILITIES ........................................................................................................ 44 
11.1. Investigator Responsibilities ........................................................................................ 44 
11.1.1. 
Good Clinical Practice ............................................................................................ 44 
11.1.2. 
Institutional Review Board/Independent Ethics Committee .............................. 44 


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11.1.3. 
Informed Consent ................................................................................................... 44 
11.1.4. 
Confidentiality ......................................................................................................... 45 
11.1.5. 
Study Files and Retention of Records ................................................................... 45 
11.1.6. 
Audits and Inspections ........................................................................................... 45 
11.1.7. 
Protocol Compliance .............................................................................................. 46 
11.2. Sponsor Responsibilities ............................................................................................... 46 
11.2.1. 
Protocol Amendments and Modifications ............................................................ 46 
11.2.2. 
Data Management ................................................................................................... 46 
11.2.3. 
Study Report and Publications .............................................................................. 46 
12. REFERENCES .................................................................................................................. 47 
13. APPENDICES .................................................................................................................... 49 
APPENDIX 1 
SCHEDULE OF ASSESSMENTS TABLE.............................................. 50 
APPENDIX 2 
CLINICAL AND LABORATORY ASSESSMENTS ............................. 53 
APPENDIX 3 
TOXICITY GRADING SCALE FOR ADVERSE EVENTS AND 
LABORATORY ABNORMALITIES ............................................................................. 56 
APPENDIX 4 
PREGNANCY PRECAUTIONS AND THE DEFINITION OF 
CHILDBEARING POTENTIAL AND CONTRACEPTIVE REQUIREMENTS ..... 76 
APPENDIX 5 
CYTOCHROME P450 3A4 INHIBITORS AND INDUCERS AND 
CYP2C9 SUBSTRATES ................................................................................................... 78 
 
LIST OF TABLES 
Table 1:  
Pharmacokinetic Sample Collection ........................................................................... 34 
Table 2:  
Clinical Laboratory Tests ............................................................................................ 53 
 
LIST OF FIGURES 
Figure 1:  
Study Overview ............................................................................................................. 19 


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LIST OF ABBREVIATIONS AND TERMS 
Abbreviation 
Term or Definition 
ABI-H0731 
731 
AE 
adverse event 
AFP 
alpha fetoprotein 
ALT 
alanine aminotransferase 
AST 
aspartate aminotransferase 
BMI 
body mass index 
cccDNA 
covalently closed circular DNA 
CFR 
Code of Federal Regulations 
CHB 
chronic hepatitis B  
cHBV 
chronic hepatitis B virus infection 
CRO 
Clinical Research Organization 
CSR 
clinical study report 
CYP 
cytochrome P450 
DAIDS 
Division of AIDS 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
ETV 
entecavir 
FDA 
Food and Drug Administration 
FSH 
follicle-stimulating hormone 
GCP 
Good Clinical Practice 
GT 
genotype 
HAV 
hepatitis A virus 
HBcAb 
antibody to the HBV core protein  
HBcrAg 
hepatitis B core-related antigen 
HBeAb 
antibody to HBeAg  
HBeAg 
hepatitis B “e” antigen 
HBsAb 
antibody to HBsAg  
HBsAg 
hepatitis B surface antigen 
HBV 
hepatitis B virus 
HCC 
hepatocellular carcinoma 
HCV 
hepatitis C virus 
HDV 
hepatitis D virus 
HEV 
hepatitis E virus 
HRT 
hormonal replacement therapy 
IB 
Investigator’s Brochure 
ICF 
Informed Consent Form 
ICH 
International Council for Harmonisation  
ICMJE 
International Committee of Medical Journal Editors 
IEC 
Independent Ethics Committee 
IFNα 
interferon alpha 


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Abbreviation 
Term or Definition 
IgM(s) 
immunoglobulin M(s) 
INR 
international normalized ratio 
IRB 
Institutional Review Board 
IRT 
Interactive Response Technology 
IUD 
intrauterine device 
LLOQ 
lower limit of quantification 
MedDRA 
Medical Dictionary for Regulatory Activities 
NrtI 
nucleos(t)ide reverse transcriptase inhibitor of the HBV polymerase 
Peg 
pegylated 
pgRNA 
[HBV] pregenomic RNA 
PK 
pharmacokinetic(s) 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SVR 
sustained virologic response 
T4 
thyroxine 
TEAE 
treatment-emergent adverse event 
TSH 
thyroid-stimulating hormone 
ULN 
upper limit of normal 
US 
United States 
WHO 
World Health Organization 
 
 


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2. 
INTRODUCTION 
2.1. 
Background 
Worldwide >240 million people are chronically infected with the hepatitis B virus (HBV), and chronic 
hepatitis B infection (CHB) is a major cause of severe liver morbidity and liver-related mortality 
(WHO 2019). An estimated 600,000 to 1 million people die each year due to cirrhosis and 
hepatocellular carcinoma (HCC), the end-stage complications of CHB (Colvin & Mitchell 2010; 
EASL 2017; El-Serag 2012). There are 4 major HBV genotypes (A, B, C, and D). Genotype A is 
regarded as pandemic and is predominantly found in North America, Northern/Western Europe, and 
Central Africa. HBV genotype B is most common in Asia including China, Vietnam, Japan, Taiwan, 
and Indonesia. Genotype C is predominant in East Asia and Oceania. Genotype D (also pandemic) is 
most highly prevalent in North America, Asia (including India), the Mediterranean, India, and the 
Middle East (Guettouche & Hnatyszyn 2005). The global prevalence of chronic HBV infection shows 
wide geographic variation, with a prevalence of >6% of the population in highly endemic regions such 
as the Western Pacific and African Regions, 1.6% to 3.3% of people in moderately endemic regions 
(eg, Eastern Mediterranean, South-East Asia, and European Regions), and <1% in locales of low 
endemicity such as the Region of the Americas (WHO 2019). 
In China, the pooled estimated prevalence of HBV infection in the general population from 2013 to 
2017 was close to 7% (Wang et al 2019). Despite the implementation of HBV vaccination programs in 
China, new cases of HBV infection are still common; it is estimated that in 2018, 84 million people 
were HBsAg positive (Wang et al 2019). A recent report estimates that 97 million people in China are 
HBV carriers and, of these, at least 20 million suffer from active cHBV with or without cirrhosis 
and/or HCC (Cui et al 2013). Although significant improvements in liver disease prevention, 
diagnosis, management, and treatment have been made, HCC is the second most common cancer in 
China. This translates to death due to liver cancer in approximately 383,000 people every year in 
China, which accounts for more than half of the deaths from liver cancer worldwide (Wang et al 2014). 
The clinical stages of HBV infection represent different risks for ongoing liver injury depending on the 
degree of HBV replication and individuals’ concurrent immune responses to HBV infection 
(EASL 2012; Gish et al 2015; Hoofnagle et al 2007; Lok & McMahon 2009; Pungpapong & 
Kim 2013; Sorrell et al 2009; Yim & Lok 2006; WHO 2019). The standard virologic and serologic 
markers for HBV infection include HBV DNA, hepatitis B surface antigen (HBsAg), antibody to 
HBsAg (HBsAb), hepatitis B “e” antigen (HBeAg), antibody to HBeAg (HBeAb), and in almost all 
patients, antibody to the HBV core protein (HBcAb). More recently, HBV pregenomic RNA (pgRNA) 
and HBV core-related antigen (b 
) have also been used as markers of infection. Historically, treatment goals included prevention of 
HBV-related liver injury through suppression of HBV replication to low levels, achievement of 
HBeAg loss and seroconversion. A transition to an HBsAg negative, minimally replicative state is rare 
but usually durable and, if it precedes the development of cirrhosis and HCC, is associated with 
improved long-term clinical outcomes (EASL 2012). As such, HBsAg seroconversion has been 
considered a “functional cure” and a potential endpoint for HBV therapy. However, as HBsAg is 
derived from both covalently closed circular DNA (cccDNA) as well as integrated HBV DNA 
(Podlaha et al 2019), sustained undetectable HBV DNA without HBsAg loss after stopping treatment 
(“sustained virologic responses [SVR]”) may be considered as an intermediate goal (Cornberg et 
al 2020). 


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Currently, there are 2 clinically accepted, first-line treatment options for CHB: nucleos(t)ide reverse 
transcriptase inhibitors of the HBV polymerase (NrtIs) and interferon alfa (IFNα). The NrtIs are orally 
administered, potent, direct-acting antivirals targeting the reverse transcription of HBV pgRNA to 
DNA. They are broadly used, generally safe and well-tolerated and have demonstrated success in 
achieving and maintaining viral suppression in most patients (Lampertico & Liaw 2012). However, 
despite suppression of HBV DNA for extended periods of time with NrtI treatment, HBeAg and 
HBsAg loss is uncommon and the template for ongoing viral replication, cccDNA, is not eliminated in 
most patients. As a result, off-treatment SVR with NrtIs is rare, necessitating long-term chronic 
suppressive treatment. In contrast, IFNα is an approved, subcutaneously administered protein which 
directly and indirectly targets HBV. While the specific mechanism of action is not fully understood, it 
is thought that IFNα inhibits multiple steps in the viral lifecycle resulting in modest antiviral activity 
(Konerman & Lok 2016). In addition, IFNα augments innate immunity and triggers HBV-specific 
T cell responses. Pegylated (Peg)-IFNα is the preferred formulation due to increased pharmacokinetic 
(PK) and pharmacodynamic half-life supporting weekly dosing. The recommended treatment duration 
is 48 weeks. Compared with NrtIs, IFNα is poorly tolerated due to common side effects, including 
flu-like symptoms, mood disturbances, and cytopenias. With a finite treatment duration, IFNα results 
in a higher rate of durable virologic response and modest HBeAg and HBsAg loss. However, even 
with the incremental improvements in virologic response of Peg-IFNα monotherapy, this regimen 
remains suboptimal and is offset by its safety and tolerability profile. 
There is a need for improved, novel HBV therapies, including combination regimens that result in a 
higher proportion of patients achieving durable virologic response and clinical outcomes following 
finite treatment duration. Ideally, components of a combination regimen for cHBV should have 
additive or synergistic antiviral activity, promote restoration of the immune response and have no 
added toxicity. Combination therapy with NrtIs and IFNα or Peg-IFNα has been shown to be safe in 
multiple small studies with potential therapeutic value in select patient subgroups (Brouwer et al 2016; 
Viganò et al 2018); however, none of these combination approaches have been approved for use or 
recommended by guidelines due to limited evidence that the combination is superior to either 
monotherapy (Xie et al 2014). 
ABI-H0731 (731) is a novel, HBV core inhibitor discovered by Assembly Biosciences, which is being 
developed as a therapeutic agent for the treatment of CHB. ABI-H0731 inhibits HBV replication by 
interfering with essential functions of the HBV core protein. Thus, inhibition of HBV core protein 
functions by 731, when used in combination with currently approved HBV antivirals, has the potential 
to immediately improve current therapy for cHBV and ultimately provide patients with enhanced rates 
of SVR following a finite treatment period. 
2.2. 
ABI-H0731 
2.2.1. 
General Information 
General information concerning 731 is described in the Investigator’s Brochure (IB). 
2.2.2. 
Preclinical Pharmacology and Toxicology 
Refer to the 731 IB for a complete summary of the preclinical and toxicology studies performed to 
date. 


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2.2.3. 
Clinical Studies with ABI-H0731 
Summaries of the clinical studies completed to date, including the Phase 2a studies, 
Study ABI-H0731-201 (Study 201) and Study ABI-H0731-202 (Study 202), and preliminary data from 
the ongoing Phase 2a Study ABI-H0731-211 are provided in the 731 IB.  
2.3. 
Study Rationale 
In the treatment of chronic viral infections, combinations of antiviral agents that inhibit viral 
replication by different and complementary mechanisms can afford improved efficacy. There are 
2 first-line recommended therapies for CHB: NrtIs, which directly target reverse transcription of 
HBV pgRNA to HBV DNA, and IFNα, which has both antiviral and immunomodulatory activities. 
Despite distinct and complementary mechanisms of action, combination therapies of NrtIs and IFNα 
has not been adopted by HBV treatment guideline committees. A number of studies have demonstrated 
the potential benefit for interferon combination regimens in selected patient subgroups (Brouwer et al 
2016; Viganò et al 2018) while other studies indicate limited evidence that combination regimens are 
superior to monotherapy (Xie et al 2014). 
The HBV core protein is involved in multiple steps in the HBV life cycle, including early events 
(capsid disassembly and DNA delivery to the nucleus for formation of cccDNA) and late events 
(assembly of pgRNA-containing capsids which are required for HBV replication); 731 may also 
prevent newly formed DNA-containing nucleocapsids from delivering HBV DNA to the nucleus to 
amplify the pool of cccDNA in infected cells (Belloni et al 2013; Levrero et al 2009). Inhibition of 
HBV core protein represents a novel therapeutic strategy for the treatment of CHB (Yang et al 2019). 
Analyses of Phase 2a studies, including ongoing open-label study, Study 211, demonstrate that 
treatment-naïve and virologically suppressed subjects treated with 731+NrtI, compared to those treated 
with NrtI alone, achieve deeper declines in HBV DNA (Section 2.2.3). Based on these data, the 
addition of 731 to ETV and Peg-IFNα therapy may increase suppression of HBV DNA, HBV pgRNA, 
and viral antigens. The present Phase 2a study (ABI-H0731-203) will explore the safety of 
combination therapy with 731, ETV and Peg-IFNα and evaluate the antiviral activity as measured by 
viral nucleic acids (ie, HBV pregenomic pgRNA and HBV DNA) and viral antigens (ie, HBeAg, 
HBcrAg, and HBsAg). 
3. 
STUDY OBJECTIVES AND ENDPOINTS 
3.1. 
Study Objectives 
3.1.1. 
Primary Objective 
• To evaluate the safety and tolerability of 731 when administered in combination with ETV 
with or without Peg-IFNα in subjects with CHB 
3.1.2. 
Secondary Objectives 
• To evaluate the effect of 731 when administered in combination with ETV with or without 
Peg-IFNα in reducing HBV pgRNA levels in subjects with CHB 
• To evaluate the effect of 731 when administered in combination with ETV with or without 
Peg-IFNα in reducing HBV DNA levels in subjects with CHB 


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• To evaluate the effect of 731 when administered in combination with ETV with or without 
Peg-IFNα in reducing HBV antigens (ie, HBeAg, HBcrAg, and HBsAg) in subjects with 
CHB 
• To evaluate the effect of 731 when administered in combination with ETV with or without 
Peg-IFNα on normalization of alanine aminotransferase (ALT)  
• To evaluate the PK of 731 and future PK evaluation of Peg-IFNα and ETV in subjects with 
CHB 
• 
To evaluate the emergence of resistance to 731 when administered with ETV with or 
without Peg-IFNα 
3.2. 
Study Endpoints 
3.2.1. 
Primary Endpoint 
• Proportion of subjects with adverse events (AEs), premature treatment discontinuation, and 
abnormal laboratory results 
3.2.2. 
Secondary Endpoints 
• Mean change in log10 HBV pgRNA from Baseline at each timepoint 
• Mean change in log10 HBV DNA from Baseline at each timepoint 
• Mean change in log10 serum viral antigens (ie, HBeAg, HBcrAg, and HBsAg) from 
Baseline at each timepoint 
• Proportion of subjects with normal ALT at each timepoint 
• Analysis of 731 and ad hoc analysis of Peg-IFNα and ETV drug concentrations 
• The incidence of HBV variants with reduced susceptibility to 731 
4. 
STUDY PLAN 
4.1. 
Study Design 
This is a randomized Phase 2a, multicenter, open-label study evaluating the safety, antiviral activity, 
and PK of 731 administered in addition to ETV with or without Peg-IFNα in treatment-naïve, Chinese 
subjects with CHB. The study will be conducted at approximately 5 to 10 study sites in China.  
Approximately 60 eligible subjects with HBeAg positive CHB will be randomly assigned in a 1:1:1 
ratio to the treatment groups shown in the study overview presented in Figure 1. 
Treatment with 731 and/or ETV will be administered orally, once daily; treatment with Peg-IFNα will 
be administered subcutaneously, once weekly. Group 1 will receive 731+ETV for 24 weeks, Group 2 
will receive 731+ETV+Peg-IFNα for 24 weeks. Group 3 will receive ETV+Peg-IFNα for 24 weeks. 
All subjects will receive 731+ETV from Week 24 through Week 48 and then ETV alone from 
Week 48 through Week 60 during the 12-week follow-up period. 


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Treatment assignments will be stratified by the HBV genotype (GT; ie, GT A or B vs GT C or D, vs 
other GTs) and baseline ALT (ie, ALT <5 × upper limit of normal [ULN] vs ALT ≥5 × ULN) during 
the Screening visits. 
Figure 1:  
Study Overview 
 
 
Abbreviations: BL = Baseline; ETV = entecavir; Peg-IFNα = pegylated-interferon alpha; Wk = week. 
The schedule of study procedures is described in Section 7 and presented in tabular form in  
Appendix 1. A detailed review of the planned PK analyses is provided in Section 7.11. 
4.2. 
Dose Justification 
In the Phase 1 clinical studies, 731 was well-tolerated in healthy subjects at single doses of up to 
1000 mg daily, at twice-daily doses of 800 mg for 7 days, and at once-daily doses of up to 300 mg for 
14 days. All treatment-emergent adverse events (TEAEs) were considered mild (Grade 1) and 
reversible. In subjects with CHB, 731 was well-tolerated at doses of up to 300 mg daily for 28 days. 
Final data indicate that there is a dose-dependent decrease in viral load at doses of 100, 200, and 
300 mg daily in subjects with CHB. Phase 2 studies (Studies 201, 202, and 211) demonstrate that 
300 mg 731 administered once daily in combination with NrtI for 48 weeks is well-tolerated and leads 
to continued reductions in HBV DNA and HBV pgRNA. It is expected that 731 300 mg administered 
in addition to ETV with or without Peg-IFNα will be safe, well tolerated and demonstrate improved 
antiviral activity in subjects with CHB. The cumulative safety, tolerability, and antiviral activity data 
generated to date support the conduct of the proposed study. In this study, ETV and Peg-IFNα will be 
administered in accordance with the approved product labeling. 
4.3. 
Duration of Treatment 
All subjects will receive their randomized treatment for 24 weeks. After completion of the assigned 
treatment, all subjects will receive 731+ETV for an additional 24 weeks and then ETV only during the 
12-week follow-up period. After completion of the 12-week follow-up period, subjects will exit the 
study and resume standard of care oversight by their physicians. 
5. 
POPULATION 
5.1. 
Number of Subjects 
Approximately 60 male or female subjects between the ages of 18 and 65 years inclusive will be 
enrolled in the study. Subjects will be treatment-naïve, have HBeAg positive CHB, and no evidence of 
cirrhosis or end-stage liver disease. 


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5.2. 
Inclusion Criteria 
Subjects must meet all of the following inclusion criteria in order to be eligible for enrollment: 
1. Willing and able to provide informed consent 
2. Male or female between the ages 18 and 65 years (inclusive) 
3. Body mass index (BMI) 18 to 36 kg/m2 and a minimum body weight of 45 kg (inclusive) 
4. Female subjects must be non-pregnant and have a negative serum pregnancy test at 
Screening and a negative urine pregnancy test predose on Day 1 
5. Chronic hepatitis B infection, defined as HBV infection for ≥6 months documented, for 
example, by at least 2 measurements of HBsAg positivity and/or detectable HBV DNA ≥6 
months apart (inclusive of Screening). For subjects without clear documentation of CHB, 
serum immunoglobulin M (IgM) antibody to the HBV core antigen (HBcAb) must be 
negative at Screening to exclude acute HBV infection.  
6. HBeAg positive with HBV DNA ≥2 × 104 IU/mL at Screening 
7. Lack of cirrhosis or advanced liver disease as documented by the following: 
• Liver biopsy results demonstrating absence of cirrhosis (eg, METAVIR F0-F3 or 
equivalent) within 1 year of Screening 
OR 
• Fasting FibroScan® ≤12 kPa within 3 months of Screening (including the Screening 
visit) or other Sponsor-approved hepatic imaging method within 6 months of 
Screening indicating lack of cirrhosis (eg, F0-F3 or equivalent) 
If the results from both liver biopsy and FibroScan are available, then the diagnostic 
method reporting the most advanced liver disease will be used to determine 
eligibility for the study 
8. A candidate for interferon-based therapy 
9. Agreement to comply with protocol-specified contraceptive requirements (Appendix 4) 
10. Agreement to abstain from alcohol abuse (defined as alcohol consumption exceeding 
2 standard drinks per day on average [1 standard drink = 14 grams of alcohol]) and the use 
of illicit substances from Screening through the duration of the study 
11. In good general health, except for CHB, in the opinion of the Investigator 
12. Have the ability to take oral medication, be willing to receive subcutaneous injections of 
Peg-IFNα (if applicable), and in the opinion of the Investigator, be willing to adhere to 
study treatment and procedures 


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5.3. 
Exclusion Criteria 
Subjects who meet any of the following exclusion criteria will not be eligible for the study: 
1. Current or prior treatment for CHB with 
• NrtI class (ETV, tenofovir disoproxil fumarate or tenofovir alafenamide) for 
>4 weeks at any time. Note, NrtI treatment of ≤4 weeks duration cannot be within 6 
months prior to Screening 
• Interferon-based therapy within 6 months prior to Screening  
• Liver-protecting and/or ALT-lowering treatment, including traditional Chinese 
medicine, within 1 month of Screening 
• Lamivudine, telbivudine or adefovir (of any duration) 
• Previous treatment with siRNA within 9 months prior to Screening 
• HBV core inhibitors (any duration) 
• Previous treatment with any other investigational agent for HBV infection within 6 
months prior to Screening  
2. Deleted per protocol amendment 3 
3. Co-infection with HIV, hepatitis A virus (HAV) hepatitis C virus (HCV), hepatitis E virus 
(HEV), or hepatitis D virus (HDV) 
4. Females who are lactating, or wish to become pregnant during the course of the study 
5. History or evidence of advanced liver disease or hepatic decompensation (including 
jaundice, ascites, portal hypertension, gastrointestinal bleeding esophageal varices, hepatic 
encephalopathy) at any time prior to, or at the time of Screening 
6. History of persistent alcohol abuse (alcohol consumption exceeding 2 standard drinks per 
day on average [1 standard drink = 14 grams of alcohol]) or illicit drug abuse within 3 years 
prior to Screening 
7. Clinically significant psychiatric disease, including severe depression, history of suicidal 
ideation or suicide attempt 
8. Clinically significant cardiac disease including poorly controlled or unstable hypertension; 
pulmonary disease; chronic or recurrent renal or urinary tract disease; liver disease other 
than CHB; endocrine disorder; autoimmune disorder; poorly controlled diabetes mellitus; 
neuromuscular, musculoskeletal, or mucocutaneous conditions requiring frequent 
treatment; seizure disorders requiring treatment; ongoing infection or other medical 
conditions requiring frequent medical management; or pharmacologic or surgical treatment 
that, in the opinion of the Investigator or the Sponsor, makes the subject unsuitable for 
study participation 
9. History of HCC 
10. History of malignancy other than HCC unless the subject’s malignancy has been in 
complete remission off chemotherapy and without additional medical or surgical 
interventions during the 3 years before Screening 


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11. History or presence at Screening of electrocardiogram (ECG) abnormalities deemed 
clinically significant, in the opinion of the Investigator 
12. History of hypersensitivity or idiosyncratic reaction to any components or excipients of the 
investigational drug 
13. History of any significant food or drug-related allergic reactions such as, anaphylaxis or 
Stevens-Johnson syndrome 
14. The following exclusionary laboratory results at Screening: 
• Hemoglobin <12g/dL for males or <11g/dL for females 
• Platelet count <100,000/mm3 
• White blood cell count <2,500/mm3 
• Absolute neutrophil count <1,500/mm3 
• Albumin <lower limit of normal 
• History of thyroid disease poorly controlled on prescribed medications, with 
thyroid-stimulating hormone (TSH), free triiodothyronine or free thyroxine (T4) 
outside the normal limits 
• Total bilirubin >1.2 × ULN unless known Gilbert’s syndrome; subjects with 
Gilbert’s syndrome are eligible for study participation if the direct bilirubin is within 
the normal range 
• Direct bilirubin >1.2 × ULN 
• ALT ≤1 × ULN or ≥10 × ULN 
• Serum alpha fetoprotein (AFP) ≥100 ng/mL. If AFP at Screening is > ULN but 
<100 ng/mL, the subject is eligible if hepatic imaging prior to initiation of study 
drug reveals no lesions indicative of possible HCC 
• International Normalized Ratio (INR) >1.5 × ULN (unless on a stable anticoagulant 
regimen) 
• Glomerular filtration rate <60 mL/min/1.73 m2 by Chronic Kidney Disease 
Epidemiology Collaboration equation (Levey et al 2009) 
• Serum creatinine >1.5 × ULN 
• Any other laboratory abnormality deemed clinically significant by the Sponsor or 
the Investigator 
15. Subjects receiving prohibited concomitant medications or medications that should be 
avoided (as outlined in Section 6.6 and Appendix 5) within 7 days or 5 half-lives (if 
known), whichever is longer, prior to administration of the first dose of study drug (Day 1) 
and for the duration of the study period. Please refer to Exclusion Criterion #1 for criteria 
regarding liver protecting and/or ALT lowering agents 


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16. Participation in another clinical study of any non-HBV-related drug or device whereby the 
last investigational drug/device administration is within 60 days or 5 half-lives prior to the 
first study drug administration (Day 1), whichever is longer.  
17. Subjects who have received, in the previous 4 weeks, a treatment likely to alter the immune 
response (intravenous immunoglobulins [IgMs], blood-derived products, or high-dose 
steroids, or other immunosuppressants) 
6. 
INVESTIGATIONAL MEDICAL PRODUCTS 
6.1. 
Randomization, Blinding, and Treatment Codes 
6.1.1. 
Randomization 
Randomization of eligible subjects to their respective treatment assignments will be performed 
centrally using an Interactive Response Technology (IRT) system. The IRT system will assign eligible 
subjects in a 1:1:1 ratio to receive either 731+ETV, 731+ ETV+Peg-IFNα or ETV+Peg-IFNα for 
24 weeks. Treatment assignments will be stratified by the HBV GT (ie, GT A or B vs GT C or D, vs 
other GTs) and baseline ALT (ie, ALT <5 × ULN vs ≥5 × ULN) collected at Screening. Additional 
information on the use of the IRT is provided in the IRT User Manual. 
6.1.2. 
Blinding 
Not applicable as this is an open-label study. 
6.2. 
Study Treatments  
Details concerning dose and administration of the study drugs (731, ETV and Peg-IFNα) are provided 
in the following sections. 
6.2.1. 
ABI-H0731 
ABI-H0731 will be administered orally, once daily as three 100-mg tablets (ie, 300 mg/day).  
ABI-H0731 will be taken at the same time as ETV and consequently will be administered on an empty 
stomach (Section 6.2.2). 
6.2.2. 
Entecavir  
Entecavir will be administered as a single oral 0.5-mg tablet once daily. Entecavir should be 
administered on an empty stomach (ie, at least 2 hours after a meal and 2 hours before the next meal). 
Further dosing information for ETV is provided in the package insert for the commercially available 
product used in this study. 
6.2.3. 
Pegylated-Interferon Alpha 
The starting dose of Peg-IFNα will be 180 µg administered once weekly as a subcutaneous injection. 
Dose adjustment to lower doses (135 µg, 90 µg, or 45 µg) for adverse reactions is described in 
Section 8.6. Further dosing information for Peg-IFNα is provided in the package insert for the 
commercially available product used in this study. 


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6.2.4. 
Study Drug Administration 
ABI-H0731 (where applicable) and ETV tablets will be administered orally as a single dose, once 
daily, and Peg-IFNα (where applicable) will be administered as a subcutaneous injection, once weekly. 
Subjects should be instructed to take 731 and ETV at the same time of the day with the possible 
exception of in-clinic visit days (Appendix 1). Pegylated-interferon alpha should be administered at 
approximately the same time each week; while not required, Peg-IFNα may be administered in the 
evening prior to sleeping to help manage AEs. 
The study staff will administer 731 (if applicable) and ETV (if possible) to the subject at each study 
visit and the subject will take 731 (if applicable) on all other days as per the Schedule of Assessments 
(Appendix 1). 
Subjects receiving Peg-IFNα as part of their assigned regimen must be trained in the proper injection 
technique for self-administration. The first dose of Peg-IFNα may be administered in the clinic for 
training purposes; however, in-clinic administration is not required at subsequent visits in order to 
support nighttime administration for AE management. If a subject prefers to have a caregiver to 
administer Peg-IFNα, the caregiver will need to present at the clinic on Day 1 for injection training. 
6.3. 
Description and Handling of Study Drugs 
Details concerning formulation, dose strength, packaging, storage, and handling of study drugs (731, 
ETV, and Peg-IFNα) are presented in the following sections. Further details for ETV and Peg-IFNα are 
provided in the respective package inserts. 
6.3.1. 
ABI-H0731 
Formulation 
 
 
 
 
Packaging and Labeling 
 
 
 
Storage and Handling 
 
 
6.3.2. 
Entecavir 
Formulation 
Commercially available ETV will be supplied by Assembly Biosciences for this study. Entecavir is a 
guanosine nucleoside analogue with selective activity against HBV. Film-coated tablets are available 
for oral administration at 0.5 mg strength and contain the following inactive ingredients: lactose 


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monohydrate, microcrystalline cellulose, crospovidone, povidone, and magnesium stearate. The tablet 
coating contains titanium dioxide, hypromellose, polyethylene glycol 400, and polysorbate 80.  
Packaging and Labeling 
Tablets are packaged in film/foil blister strips or plastic bottles with closures. Entecavir supplied will 
be commercial product labeled for the China market. 
Storage and Handling 
Tablets should be stored in a tightly closed container at 25°C; excursions permitted between 
15°C-30°C. Further details for packaging, labeling, storage, and handling of ETV are described in the 
package insert. 
6.3.3. 
Pegylated-Interferon Alpha 
Formulation 
Commercially available Peg-IFNα will be supplied by Assembly Biosciences for this study. The active 
ingredient is prepared by modifying recombinant human IFNα expressed in yeast system with 
polyethylene glycol (40kD Y-type). Excipients include sodium chloride, sodium acetate, mannitol, 
aspartic acid, water for injection, sodium hydroxide for adjusting pH. Injectable solution is available in 
prefilled syringes of different strengths. For this study, Peg-IFNα will be supplied as 180 µg prefilled 
syringes. 
Packaging and Labeling 
The product is packaged in prefilled syringes. Pegylated-interferon alpha supplied will be commercial 
product labeled for the China market. 
Storage and Handling 
Syringes should be refrigerated between 2°C-8°C. Further details for packaging, labeling, storage, and 
handling of Peg-IFNα are described in the package insert. 
6.4. 
Study Drug Accountability 
Regulatory requirements stipulate accounting of all investigational drug received by the study site. 
Records of drug disposition must include the date received by the site, date administered, quantity 
administered, and the subject to whom study drug was administered. The Investigator is responsible for 
the accountability of all study drugs at his or her site. This includes all used and unused study drug 
containers (ie, syringes for Peg-IFNα and bottles for 731 and ETV) and unused study drug (ie, 731, 
ETV, or Peg-IFNα). 
Each study site is to use a study drug accountability record to document study drug disposition. All 
items on this form are to be fully completed. The Sponsor or the Clinical Research Organization 
(CRO) will confirm if the method of recording study drug accountability by the site and the location of 
study drug records at the site is appropriate. 
Each time designated site personnel dispense study drug for a subject, he or she is to record the date 
dispensed, the quantity of study drug dispensed, and his or her initials. Study site personnel are to 
monitor the inventory of clinical supplies and maintain a count of all used and unused study drug. The 
site monitor will review the study drug accountability records during monitoring visits. The site 
pharmacist or designated staff member will keep accurate records of drug dispensation routinely 


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during the study. Study drug dispensation is planned for Day 1 and at each scheduled visit thereafter 
during the treatment and follow-up periods (Section 7; Appendix 1). 
On days when study drugs are administered in the clinic, study personnel will document the date and 
time of study drug administration in the subject’s medical record. When study drugs are administered 
outside the clinic, subjects will be required to record the dates and times of each dose of study drug (ie, 
731 and Peg-IFNα [if applicable], and ETV) in the dosing diary, which will be provided as indicated in 
the Schedule of Assessments (Appendix 1). 
Subjects will also be asked to return used packaging (syringes for Peg-IFNα) and any unused study 
drug along with the dosing diary for accountability and compliance assessment at each study visit 
(except Day 1). Returned 731, ETV, and Peg-IFNα will be counted and reconciled against the diary 
entries by study site personnel, preferably in the presence of the subject. Subjects who forget to return 
study drugs at a given visit will be asked to return them at the next study visit.  
6.5. 
Return or Disposal of Study Drug 
Procedures for the return of study drug or provisions for onsite destruction (where approved 
prospectively by the Sponsor) are described separately in the Study Pharmacy Manual. 
6.6. 
Prior and Concomitant Medications 
A concomitant medication is defined as any prescription or over-the-counter preparation, including 
vitamins, medications, vaccinations, herbal preparations, and supplements, that is administered to a 
study subject during the conduct of the clinical trial. For subjects randomized to the study, concomitant 
medications are discouraged, unless they are prescribed by the Investigator for treatment of an 
emergent medical event occurring during the course of the study. No concomitant procedures will be 
performed during the study unless approved by the Investigator. 
All concomitant medications taken from the date the Informed Consent Form (ICF) is signed, through 
end of study (completion of follow-up period or the Premature Termination Visit [in the event of 
discontinuation from treatment or study]) must be recorded in the subject’s source documentation. This 
information should include the name of the medication or treatment, the dose and regimen, the start 
and stop dates, and the indication for which the concomitant medication was administered. 
6.6.1. 
Prohibited Concomitant Therapy 
Systemic (oral, injectable, or implanted) hormonal birth control is not considered as an acceptable 
means of contraception for female subjects of child-bearing potential. Additional details on acceptable 
means of contraception are provided in Appendix 4. 
Other treatments for CHB as defined in Exclusion Criterion #1, Section 5.3 are prohibited.  
Since 731 is a weak inhibitor of cytochrome P450 (CYP) 2C9, concomitant use with narrow index 
CYP2C9 substrates such as warfarin and phenytoin are prohibited. Use of other CYP2C9 substrates 
should be avoided. Those taking sulfonylureas for controlled diabetes mellitus should monitor blood 
sugar levels and adjust dosage as appropriate. To the extent possible, other medications with narrow 
therapeutic indices should be avoided. The route of elimination of 731 in humans is not fully 
understood so inhibitors and inducers of CYP3A4 should be avoided. Examples of representative 
medications that should be avoided due to drug-drug interaction potential with 731 is provided in 
Appendix 5. The designated Medical Monitor may be consulted for any questions regarding acceptable 


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or prohibited concomitant medication use during the study. As previously described, concomitant 
medications, over-the-counter medications, and supplements must be recorded in the subject’s source 
documentation. 
The details of permitted concomitant medications and prohibited medications for ETV and Peg-IFNα 
are provided in the respective package inserts for the commercially available products used in this 
study. 
7. 
STUDY PROCEDURES 
The schedule of assessments to be conducted in the study is provided in tabular form in Appendix 1. 
7.1. 
Subject Enrollment and Treatment Assignment 
Following provision of informed consent and completion of all Screening and Day 1 predose 
assessments, if a subject meets all protocol eligibility requirements the Investigator or designee will 
randomize the subject using the IRT system described in Section 6.1.1. Protocol waivers will not be 
granted. 
7.1.1. 
Screen Failures 
Screen failures are defined as subjects who consent to participate in the clinical study but are not 
subsequently randomized to study treatment. Minimal information should be retained on all screen 
failures including demography, screen failure details, eligibility criteria, and any serious adverse event 
(SAE) information. 
Individuals who do not meet the protocol eligibility criteria for participation in this study (ie, screen 
failures) may not be rescreened; however, retest for some laboratory parameter(s) is permitted if there 
is considered to be a specific issue related to the collection, shipping, processing, or analysis of a 
sample (eg, receipt of a hemolyzed sample at the testing laboratory, or samples received by the testing 
laboratory outside of the acceptable temperature range). Subjects who meet all study eligibility 
requirements but are not able to complete the Day 1 visit within the prespecified 45-day window may 
be rescreened for the study. 
7.2. 
Screening Assessments (Day -45 to Day -1) 
It is recommended, though not mandated, that invasive procedures, such as a liver biopsy (if required) 
are not conducted until it has been determined that the subject is broadly eligible for study 
participation. 
The following Screening assessments must be completed within 45 days of the scheduled Day 1 visit: 
• Obtain written informed consent 
• Record demographics and medical history, including HBV history and HBV treatment 
history 
• Liver staging (as required per inclusion criteria, ie, fasting FibroScan) 
• Measure height and body weight 
• Vital signs (temperature, heart rate, respiration rate, and blood pressure) 


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• Complete physical examination (excluding breast and genitalia, unless indicated) 
• 12-lead ECG 
• Review of concomitant medications 
• Review of AEs occurring after provision of informed consent 
• Laboratory analyses (additional details are provided in the Laboratory Manual): 
o Safety labs: chemistry, hematology, coagulation, serum AFP, follicle-stimulating 
hormone (FSH) (females only), TSH and T4, serum pregnancy test, urinalysis, urine 
drug test (Appendix 2) 
o Virology: HBV genotype, HBV DNA, HBsAg, HBeAg, HBsAb, HBeAb, sample 
for HBV nucleic acids, HIV Ab, HCV Ab, HDV Ab, HAV (IgM), HEV (IgM), 
HBcAb (IgM; see Inclusion Criterion #5, Section 5.2) (Appendix 2) 
o HBV sequencing: a blood sample for sequencing of the HBV polymerase coding 
region will be collected and stored for analysis only in the event of any observed 
viral breakthrough or blunted response (Appendix 2) 
7.3. 
Day 1 
The following assessments must be completed predose on Day 1: 
• Update medical history, including HBV history and HBV treatment history 
• Measure body weight 
• Vital signs (temperature, heart rate, respiration rate and blood pressure) 
• Complete physical examination (excluding breast and genitalia, unless indicated) 
• 12-lead ECG 
• Review concomitant medications 
• Review AEs 
• Confirm subject eligibility 
• Complete randomization 
• Laboratory analyses (additional details are provided in the Laboratory Manual): 
o Safety labs: chemistry, hematology, coagulation, urine and serum pregnancy tests, 
urinalysis, urine drug test (Appendix 2) 
o Virology: HBV DNA, HBV pgRNA, HBsAg, HBeAg, HBcrAg, HBsAb, HBeAb, 
sample for HBV sequencing and HBV nucleic acids (Appendix 2)  
• PK samples: predose samples for 731, Peg-IFNα, and ETV 
Dosing: 
• Study drug administration (731, ETV and Peg-IFNα [as applicable])  
The following assessments must be completed postdose on Day 1: 


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• Provide dosing diary to subjects 
• Study drug dispensation (731, ETV, and Peg-IFNα [as applicable]) 
• PK samples: postdose samples for 731, Peg-IFNα, and ETV between 2 and 4 hours 
following study drug administration (Section 7.11) 
7.4. 
Study Week 1 
The following assessments are performed at Study Week 1: 
• Symptom-directed physical examination 
• Review concomitant medications 
• Review AEs 
• Laboratory analyses (additional details are provided in the Laboratory Manual): 
o Virology: HBV DNA, HBV pgRNA, sample for HBV sequencing and HBV nucleic 
acids (Appendix 2) 
• Review dosing diary and assess drug accountability 
7.5. 
Study Weeks 2 Through 24 
The following assessments are performed at Study Weeks 2, 4, 6, 8, 12, 16, 20, and 24 (inclusive) 
unless otherwise indicated. Subjects who discontinue treatment before Week 24 should immediately 
undergo the assessments listed for the Premature Termination Visit and then continue the scheduled 
follow-up assessments. A visit window of ±3 days is applied to each visit through Week 20. A visit 
window of -3 days is applied to Week 24 (Appendix 1). 
• Liver staging (Week 24 only) 
• Measure body weight (Week 24 only) 
• Vital signs (temperature, heart rate, respiration rate, and blood pressure; not at Week 6) 
• Complete physical examination (excluding breast and genitalia, unless indicated; Week 24 
only) 
• Symptom-directed physical examination (not at Week 24) 
• 12-lead ECG (Weeks 12 and 24 only) 
• Review concomitant medications 
• Review AEs 
• Laboratory analyses (additional details are provided in the Laboratory Manual): 
o Safety labs: chemistry (not at Week 6), hematology (not at Week 6), coagulation 
(not at Week 2 or 6), TSH (only at Weeks 12 and 24), urinalysis (not at Week 2 or 
6), urine pregnancy test (not at Week 6) (Appendix 2) 
o Virology: HBV DNA, HBV pgRNA, HBsAg (not at Week 2 or 6), HBeAg (not at 
Week 2 or 6), HBcrAg (not at Week 2 or 6), HBsAb and HBeAb (Weeks 12 and 24 
only), sample for HBV sequencing and HBV nucleic acids (Appendix 2) 


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• PK samples: samples for 731, Peg-IFNα, and ETV between 30 min and 2 hours postdose at 
Weeks 2, 8, 12, and 24, and between 4 and 6 hours postdose at Weeks 16 and 20. Predose 
samples for 731, Peg-IFNα, and ETV will be collected at Week 4 and Week 24 only 
(Section 7.11)  
• Review dosing diary and assess drug accountability 
• Study drug dispensation (not at Weeks 2 and 6; Peg-IFNα will not be dispensed at 
Week 24) 
• Study drug administration (731 and ETV in-clinic [except at Weeks 2 and 6]; Peg-IFNα 
may be administered at home)  
7.6. 
Study Weeks 28 Through 48 
The following assessments are performed at Study Weeks 28, 32, 36, 40, 44, and 48 (inclusive) unless 
otherwise indicated. Subjects who discontinue treatment before Week 48 should immediately undergo 
the assessments listed for the Premature Termination Visit and then continue the scheduled follow-up 
assessment. A visit window of ±3 days is applied to each visit through Week 44. A visit window 
of -3 days is applied to Week 48 (Appendix 1). 
• Liver staging (Week 48 only) 
• Measure body weight (Week 48 only) 
• Vital signs (temperature, heart rate, respiration rate, and blood pressure) 
• Complete physical examination (excluding breast and genitalia, unless indicated; Week 48 
only) 
• Symptom-directed physical examination (not at Week 48) 
• 12-lead ECG (Week 48 only) 
• Review concomitant medications 
• Review AEs 
• Laboratory analyses (additional details are provided in the Laboratory Manual): 
o Safety labs: chemistry, hematology, coagulation, urinalysis (Week 48 only), urine 
pregnancy test (Appendix 2) 
o Virology: HBV DNA, HBV pgRNA, HBsAg, HBeAg, HBcrAg, HBsAb and 
HBeAb (Week 48 only), sample for HBV sequencing and HBV nucleic acids 
(Appendix 2) 
• PK samples: samples for ETV may be collected predose at Week 44 (Section 7.11)  
• Study drug administration (731 and ETV) 
• Review dosing diary and assess drug accountability 
• Study drug dispensation (only ETV will be dispensed at Week 48, not 731) 


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7.7. 
Study Weeks 52 Through 60 (Follow-up Assessments) 
All subjects, including those who prematurely discontinue treatment or complete treatment per 
protocol will enter a 12-week follow-up period. Subjects will remain on ETV during the follow-up 
period. The following assessments are performed every 4 weeks unless otherwise indicated. A visit 
window of ±5 days is applied from Weeks 52 through 60. 
• Measure body weight (Week 60 only) 
• Vital signs (temperature, heart rate, respiration rate and blood pressure) 
• Complete physical examination (excluding breast and genitalia, unless indicated; Week 60 
only) 
• Symptom-directed physical examination (not at Week 60) 
• 12-lead ECG (Week 60 only) 
• Review concomitant medications 
• Review AEs 
• Laboratory analyses (additional details are provided in the Laboratory Manual): 
o Safety labs: chemistry, hematology, coagulation, urinalysis, urine pregnancy test 
(Appendix 2) 
o Virology: HBV DNA, HBV pgRNA, HBsAg, HBeAg, HBcrAg, HBsAb and 
HBeAb (Week 60 only), sample for HBV sequencing and HBV nucleic acids 
(Appendix 2)  
• Review dosing diary 
• Assess drug accountability (final drug accountability performed at Week 60) 
• Study drug dispensation (final study drug dispensation performed at Week 56) 
• Study drug administration (ETV)  
7.8. 
Unscheduled Visit 
An Unscheduled Visit may be performed at any time at the discretion of Investigator in order to further 
evaluate a subject. The specific assessments to be performed at these visits would be determined by the 
Investigator according to nature of the subject specific follow-up required, however at a minimum the 
assessments would include the following: 
• Vital signs (temperature, heart rate, respiration rate and blood pressure) 
• Symptom-directed physical examination 
• Review concomitant medications 
• Review AEs 
• Laboratory analyses (additional details are provided in the Laboratory Manual): 
o Safety labs: chemistry, hematology, coagulation, urinalysis, urine drug test, urine 
pregnancy test (Appendix 2) 


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o Virology: HBV DNA, HBV pgRNA, HBsAg, HBeAg, HBcrAg, sample for HBV 
sequencing, and HBV nucleic acids (Appendix 2) 
o PK samples: samples for 731 and Peg-IFNα (if appropriate), and ETV 
(Section 7.11) 
Assessments performed should be documented in the subject’s source documentation. Clinical 
laboratory assessments should be conducted through the central laboratory. The minimum assessments 
to be completed when managing ALT elevations at an Unscheduled Visit are noted in Section 9.4. 
7.9. 
Premature Termination Visit 
Should a subject prematurely discontinue treatment (Section 7.10.1) or discontinue from the study 
(Section 7.10), a Premature Termination Visit should be scheduled. While the Investigator may include 
additional assessments and evaluations determined by the status of the individual subject, at the 
minimum, the following assessments should be performed as soon as feasibly possible: 
• Measure body weight 
• Vital signs (temperature, heart rate, respiration rate, and blood pressure) 
• Complete physical examination (excluding breast and genitalia unless indicated) 
• 12-lead ECG 
• Review concomitant medications 
• Review AEs 
• Laboratory analyses (additional details are provided in the Laboratory Manual): 
o Safety labs: chemistry, hematology, coagulation, urinalysis, urine drug test, urine 
pregnancy test (Appendix 2) 
o Virology: HBV DNA, HBV pgRNA, HBsAg, HBeAg, HBcrAg, HBsAb, and 
HBeAb, sample for HBV sequencing and HBV nucleic acids (Appendix 2) 
o PK samples: samples for 731and Peg-IFNα (if appropriate), and ETV 
(Section  7.11) 
• Review dosing diary and assess drug accountability (if applicable) 
7.10. 
Discontinuation 
A subject may withdraw from the study at any time at his/her own request or may be withdrawn at any 
time at the discretion of the Investigator or Sponsor for safety, behavioral, compliance, or 
administrative reasons. This is expected to be uncommon. At the time of discontinuation from the 
study, a Premature Termination Visit should be conducted (Section 7.9). If the subject withdraws 
consent for disclosure of future information, the Sponsor may retain and continue to use any data 
collected before such withdrawal of consent. If a subject withdraws from the study, he/she may request 
destruction of any samples taken and not tested, and the Investigator must document this in the site 
study records. 


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7.10.1. 
Discontinuation from Treatment 
If an individual subject is, in the judgement of the Investigator, not satisfactorily tolerating study 
drug treatment due to AEs, then – in consultation with the Sponsor – the subject may discontinue 
treatment with 731 or Peg-IFNα (if applicable). Entecavir may be continued at the discretion of the 
Investigator. Subjects who prematurely discontinue treatment (731 or Peg-IFNα as applicable) 
should immediately undergo the assessments listed for the Premature Termination Visit 
(Section 7.9) and then continue scheduled follow-up assessments (Section 7.7). 
In this study, subjects will be closely monitored for ALT elevations and declining hepatic function. 
Procedures to be followed for these subjects are described in Section 9.4. Study treatment (731 or 
Peg-IFNα as applicable) will be discontinued in subjects with confirmed evidence of declining hepatic 
function during treatment, a Premature Termination Visit (Section 7.9) will be completed, and subjects 
will subsequently undergo the follow-up assessments described in Section 7.7. Entecavir may be 
continued at the discretion of the Investigator in accordance with local practice. 
Any female subject with a negative urine pregnancy test at Baseline (Day 1) who is subsequently 
found to be positive on the Baseline (Day 1) serum pregnancy test should immediately discontinue 
treatment with 731 and Peg-IFNα, as applicable. At future visits, any positive urine pregnancy text will 
require confirmation by a serum pregnancy test. Female subjects with a positive serum pregnancy test 
should immediately discontinue treatment with 731 and Peg-IFNα, as applicable. In these instances, 
entecavir may be continued at the discretion of the Investigator in accordance with local practice and 
the approved ETV package insert. These subjects may be replaced at the discretion of the Sponsor. 
7.10.2. 
Subjects Lost to Follow-up 
A subject 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 subject fails to 
return to the clinic for a required study visit:  
• The site must attempt to contact the subject, reschedule the missed visit as soon as possible, 
and counsel the subject on the importance of maintaining the assigned visit schedule and 
ascertain whether or not the subject wishes to and/or should continue in the study. 
• Before a subject is deemed lost to follow-up, the Investigator or designee must make every 
effort to regain contact with the subject (where possible, 3 telephone calls and, if necessary, 
a certified letter to the subject’s last known mailing address or local equivalent methods). 
These contact attempts should be documented in the subject’s medical record. 
Should the subject continue to be unreachable, he/she will be considered lost to follow-up. 
7.11. 
Pharmacokinetic Assessments 
During the study, predose plasma samples will be collected from all subjects to explore the PK profile 
of 731, Peg-IFNα, and ETV after combination treatment with or without Peg-IFNα in subjects with 
CHB. Additionally, postdose samples will be collected at the timepoints outlined in Table 1. 
Additional details regarding the collection, processing, storage, and shipment of PK samples is 
described in the Laboratory Manual. Plasma samples of Peg-IFNα and ETV will be collected and 
stored for future PK analyses if deemed necessary. 


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Table 1:  
Pharmacokinetic Sample Collection 
Time period 
Time relative to study drug administration a 
Time relative to study drug administration b 
Treatment 
Predose c 
Day 1, Weeks 4 and 24 
30 min to 2 hours postdose 
Weeks 2, 8, 12, and 24 
2 to 4 hours postdose 
Day 1 
4 to 6 hours postdose 
Weeks 16 and 20 
Collect at same time with other central labs 
At Unscheduled and Premature Termination Visits d 
and predose at the Week 44 visit 
a. If the subject administers study drug at home, a pharmacokinetic sample should be collected during the in clinic visit 
with documentation of date and time of the dose in the subject’s source documents. 
b. Sample collection times are targeted times. Samples collected outside of these targeted times will not be considered 
protocol deviations. The actual sample collection date/time should be accurately recorded in the source documentation. 
c. The predose sample may be collected up to 2 hours prior to study drug administration. 
d. A pharmacokinetic sample should also be collected if an Unscheduled or Premature Termination Visit is performed. 
7.12. 
End of Study Definition 
The study will be completed when the last subject completes the 12-week follow-up period, or is 
considered “lost to follow-up” (Section 7.10.2), whichever is later. 
7.13. 
Resistance Monitoring 
To assess for viral resistance during the study, serum samples from subjects at each visit will be 
collected (Section 7). Samples from those subjects with evidence of nonresponse to treatment, such as 
viral breakthrough (ie, ≥1 log10 increase in on-treatment HBV DNA from on-treatment nadir) will be 
selected for HBV gene sequencing, with sequence comparisons to Baseline sequences, as well as 
comparisons to HBV gene sequences from subjects in other treatment groups and HBV database 
sequences. 
8. 
ADVERSE EVENTS 
An AE is any untoward medical occurrence in a study subject administered an investigational 
product(s) regardless of the causal relationship with treatment. 
An AE, therefore, can be any unfavorable and unintended sign (including laboratory finding), 
symptom, or disease temporally associated with participation in an investigational study, whether or 
not considered drug related. In addition to new events, any increase in the severity or frequency of a 
pre-existing condition that occurs after the subject signs the ICF for participation is considered an AE. 
This includes any side effect, injury, toxicity, or sensitivity reaction. 
8.1. 
Documenting Adverse Events 
Adverse events will be monitored throughout the entire study. Investigators will ask the subject at each 
visit if they have experienced any untoward effects since the last study visit. All AEs (for all 
randomized subjects and excluding screen failures) will be entered in the electronic case report form 
(eCRF) provided: a description of the event, severity, time of occurrence, duration, any action (eg, 
treatment and follow-up tests), and the outcome should be provided along with the Investigator’s 
assessment of the relationship to the study treatment. 
Adverse events will be recorded from the date informed consent is signed through the end of study 
(completion of follow-up period or if the subject is lost to follow-up). 


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8.2. 
Assessment of Intensity 
The severity of each AE and laboratory abnormality is to be assessed by the Investigator according to 
the modified Division of AIDS (DAIDS) Table for Grading the Severity of Adult and Pediatric AEs 
(Appendix 3), which grades the severity of clinical AEs and laboratory abnormalities in a 4-category 
system. 
For AEs not included in Appendix 3, the following guidelines will be used to describe severity: 
• Mild (Grade 1): Mild symptoms causing no or minimal interference with usual social and 
functional activities with intervention not indicated 
• Moderate (Grade 2): Moderate symptoms causing greater than minimal interference with 
usual social and functional activities with intervention indicated 
• Severe (Grade 3): Severe symptoms causing inability to perform usual social and 
functional activities with intervention or hospitalization indicated (Of note, the term 
“severe” does not necessarily equate to “serious”) 
• Life-threatening (Grade 4): Potentially life-threatening symptoms causing inability to 
perform basic self-care functions with intervention indicated to prevent permanent 
impairment, persistent disability, or death 
Note that an AE or laboratory abnormality that is life-threatening as it exists constitutes an SAE. 
8.3. 
Assessment of Causality 
All AEs must have their relationship to study drug (731, ETV, or Peg-IFNα) assessed by the clinician 
who examines and evaluates the subject based on temporal relationship and his/her clinical judgment. 
Each AE must be recorded in the source documentation, whether serious or not serious. For the 
purposes of this study each event is to be assessed with regard to the following causality 
categorizations, in the Investigator’s considered judgment: 
• Not related: An AE with sufficient evidence to accept that there was no causal relationship 
to administration of study drug (eg, no temporal relationship because the study drug was 
administered after the onset of the event, an investigation showed that study drug was not 
administered, another cause was proven). 
• Related: An AE occurred in a plausible time relationship to administration of study drug 
and that could not be explained by a concurrent disease or other drugs or events. The 
response to withdrawal of the drug (dechallenge) was clinically reasonable. 
8.4. 
Expectedness 
An AE is considered “unexpected” if it is not listed in the IB or is not listed at the specificity or 
severity that has been observed. The CRO and Sponsor Medical Monitors will be responsible for 
determining whether an AE is expected or unexpected. 
8.5. 
Abnormal Laboratory Test Values 
In the event of abnormal laboratory test values, the tests should be repeated immediately. If the 
Investigator considers the abnormality to be clinically significant, it should be reported as an AE and 


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followed up until it returns to the normal range and/or an adequate explanation of the abnormality is 
found. 
8.6. 
Dose Modification due to Adverse Events 
The dose of Peg-IFNα may be adjusted due to AEs. Where dose adjustment is required for moderate to 
severe adverse reactions (clinical and/or laboratory) initial dose reduction to 135 μg is generally 
adequate for patients. In some cases, dose reduction to 90 μg or 45 μg is necessary. Dose increases to 
or towards the original dose may be considered when the adverse reaction abates. Details of 
recommended dose reductions of Peg-IFNα are provided in the package insert for the commercially 
available product used in this study. 
There is no dose modification allowed for 731 or ETV. 
8.7. 
Adverse Event Follow-up 
After the initial AE or SAE report, the Investigator will follow-up proactively on each subject and 
provide further information to the CRO/Sponsor on the subject’s condition. During the study, all AEs 
or SAEs should be followed to resolution unless the event is considered by the Investigator to be 
unlikely to resolve due to the subject’s underlying disease, or the subject is lost to follow-up. 
8.8. 
Pregnancy 
8.8.1. 
Female subjects who become pregnant 
Any female subject who becomes pregnant while participating in the study will discontinue the study 
drug(s) immediately (Section 7.10). 
The Investigator will collect pregnancy information on any female subject who becomes pregnant 
while participating in this study, including the 12-week follow-up period. The initial information will 
be recorded on the Pregnancy Reporting form and submitted to the CRO Pharmacovigilance group 
within 24 hours of learning of a subject’s pregnancy. Refer to the Study Operations Manual for contact 
information for reporting a pregnancy. 
The subject will be followed to determine the outcome of the pregnancy. The Investigator will collect 
follow-up information on the subject and the neonate and the information will be forwarded to the 
Sponsor. Generally, follow-up will not be required for longer than 6 to 8 weeks beyond the estimated 
delivery date. Any termination of pregnancy will be reported, regardless of fetal status (presence or 
absence of anomalies) or indication for the procedure. 
While pregnancy itself is not considered to be an AE or SAE, any pregnancy complication or elective 
termination of a pregnancy for medical reasons will be reported as an AE or SAE. A spontaneous 
abortion (occurring at <22 weeks gestational ag e) or still birth (occurring at >22 weeks gestational 
age) is always considered to be an SAE and will be reported as such. 
Any post-study pregnancy related SAE considered reasonably related to the study drug(s) by the 
Investigator will be reported to the Sponsor. While the Investigator is not obligated to actively seek 
this information in former study subjects, he or she may learn of an SAE through spontaneous 
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8.8.2. 
Male subjects with partners who become pregnant 
The Investigator will conduct due diligence to collect pregnancy information on any male subject’s 
female partner who becomes pregnant while the male subject is participating in this study. This applies 
only to male subjects who receive at least 1 dose of study drug (731, ETV, or Peg-IFNα). 
After obtaining the necessary signed informed consent from the pregnant female partner directly, the 
Investigator will record pregnancy information on the Pregnancy Reporting form and submit it to the 
CRO Pharmacovigilance group within 24 hours of learning of the partner’s pregnancy. The female 
partner will also be followed to determine the outcome of the pregnancy. Information on the status of 
the mother and child will be forwarded to the Sponsor. Generally, the follow-up will be no longer than 
6 to 8 weeks following the estimated delivery date. Any termination of the pregnancy will be reported 
regardless of fetal status (presence or absence of anomalies) or indication for the procedure. Refer to 
the Study Operations Manual for contact information for reporting a pregnancy. 
9. 
SERIOUS ADVERSE EVENTS 
9.1. 
Definition of Serious Adverse Event  
An SAE is any event that meets any of the following criteria: 
• Death 
• Life-threatening 
• Inpatient hospitalization or prolongation of existing hospitalization 
• Persistent or significant disability/incapacity 
• Congenital anomaly/birth defect in the offspring of a subject who received 731 
• Other: Important medical events that may not result in death, be life-threatening, or require 
hospitalization, may be considered an SAE when, based upon appropriate medical 
judgment, they may jeopardize the subject and may require medical or surgical intervention 
to prevent one of the outcomes listed in this definition. Examples of such events are: 
o Intensive treatment in an emergency room or at home for allergic bronchospasm 
o Blood dyscrasias or convulsions that do not result in inpatient hospitalization 
o Development of drug dependency or drug abuse 
Definition of Terms 
Life-threatening: An AE is life-threatening if the subject was at immediate risk of death from the event 
as it occurred; ie, it does not include a reaction that if it had occurred in a more serious form might 
have caused death. For example, drug induced hepatitis that resolved without evidence of hepatic 
failure would not be considered life-threatening even though drug induced hepatitis can be fatal. 
Hospitalization: AEs requiring hospitalization should be considered SAEs. Hospitalization for elective 
surgery or routine clinical procedures that are not the result of AEs (eg, elective surgery for a 
pre-existing condition that has not worsened) need not be considered AEs or SAEs. If anything 
untoward is reported during the procedure, that occurrence must be reported as an AE, either “serious” 
or “non-serious” according to the usual criteria. 


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In general, hospitalization signifies that the subject has been detained (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. When in doubt as to whether 
“hospitalization” occurred or was necessary, the AE should be considered serious. 
Disability/incapacitating: An AE is incapacitating or disabling if the experience results in a substantial 
and/or permanent disruption of the subject's ability to carry out normal life functions. 
9.2. 
Reporting Serious Adverse Events 
All SAEs must be reported within 24 hours of learning about the event using the SAE Report form to 
the CRO Pharmacovigilance group. Refer to the Study Operations Manual for contact information for 
reporting SAEs. 
The initial report should be promptly followed by detailed, written reports, which will include copies 
of relevant hospital case reports, autopsy reports, and other documents when requested and applicable. 
This additional information will be requested, if necessary, by the responsible monitor within 5 days of 
receipt of the alert report. This is to ensure that the initial reporting of SAEs is made to regulatory 
authorities within the required time period. 
For a follow-up report to the authorities, the monitor may be required to collect further information for 
a final evaluation of the case. Reporting to the respective country regulatory authorities will be the 
responsibility of the Sponsor and the CRO. 
It will be the responsibility of the individual Investigators to inform any local Independent Ethics 
Committees (IECs) of SAEs as required. Correspondence with the IEC(s) relating to the reporting of 
SAEs will be retained in the study file. 
Serious adverse events will be recorded from the date informed consent is signed through the end of 
study (completion of follow-up period or if the subject is lost to follow-up). 
9.3. 
Overdose 
An overdose is defined as the accidental or intentional administration of any dose of a product that is 
considered both excessive and medically important. The Medical Monitor may be contacted for 
questions concerning potential cases of overdose. An overdose is not in and of itself considered to be 
an AE unless it results in untoward medical effects. Any AE associated with an overdose or incorrect 
administration of study drug should be entered in the subject’s source documentation and Adverse 
Event eCRF. If the associated AE fulfills the criteria of an SAE, then the event should be reported to 
the Sponsor or CRO within 24 hours after the site learns of the event. 
9.4. 
Management of ALT Elevations 
All subjects participating in the study will be closely monitored for ALT elevations and/or signs of 
potential decline in hepatic function. Subjects experiencing ALT elevations ≥2 × Baseline or 
on-treatment nadir and >2 × ULN during study treatment or during post-treatment follow-up should be 
closely monitored with regular Unscheduled Visits every 1 to 2 weeks at the discretion of the 
Investigator. At these visits, the following laboratory tests will be performed: ALT, aspartate 
aminotransferase (AST), total bilirubin (if total bilirubin is elevated, reflex to direct bilirubin), serum 
albumin, INR and creatine kinase. The Investigator will determine if other Unscheduled Visit 


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assessments (Section 7.8) should be performed. Additionally, the following guidance is provided for 
management of subjects with ALT elevations: 
• ALT elevation without declining hepatic function 
o All subjects with an ALT elevation on treatment, defined as ALT >2 × Baseline or 
on-treatment nadir and ≥10 × ULN, should have the ALT findings confirmed within 
3 days of receipt of the original results. All subjects should return for an 
Unscheduled Visit and complete all Unscheduled Visit procedures (Section 7.8).  
o If the ALT elevation is confirmed, then an additional Unscheduled Visit will be 
performed to further evaluate the subject. At this visit, the following tests will be 
performed: ALT, AST, total bilirubin (if total bilirubin is elevated, reflex to direct 
bilirubin), serum albumin, INR, creatine kinase, HBV DNA, quantitative HBV 
serologies (HBeAg [reflex qualitative HBeAg if quantitative HBeAg is less than the 
lower limit of quantification (LLOQ)] and HBsAg [reflex qualitative HBsAg if 
quantitative HBsAg is <LLOQ]), HAV IgM, HCV RNA, HDV RNA, and HEV 
IgM. The Investigator will determine if other assessments specified in Section 7.8 
should be performed. 
▪ If an intercurrent illness is determined to be causal, subjects with an ALT 
elevation without declining hepatic function and without contraindications 
may continue assigned treatment (ie, 731, ETV and Peg-IFNα as applicable) 
and the intercurrent illness should be treated as deemed medically 
appropriate by the Investigator. 
▪ In the absence of an intercurrent illness that is determined to be causal, 
subjects with an ALT elevation without declining hepatic function and 
without contraindications may continue assigned treatment (ie, 731, ETV 
and Peg-IFNα as applicable) under close observation. 
o If ALT is rising at the confirmatory visit, subjects should return for an Unscheduled 
Visit (Section 7.8) every 2 to 5 days until the ALT elevation has stabilized. At these 
visits only the following laboratory tests will be performed: ALT, AST, total 
bilirubin (if total bilirubin is elevated, reflex to direct bilirubin), serum albumin, 
INR, creatine kinase, HBV DNA, and quantitative HBV serologies (HBeAg [reflex 
qualitative HBeAg if quantitative HBeAg is <LLOQ] and HBsAg [reflex qualitative 
HBsAg if quantitative HBsAg is <LLOQ]). The Investigator will determine if other 
assessments specified in Section 7.8 should be performed. Subjects whose ALT has 
stabilized should continue to be monitored weekly (or more frequently, as deemed 
necessary by the treating physician) until ALT values return to normal or Baseline 
levels. 
▪ Subjects with an ALT elevation without declining hepatic function and 
without contraindications may continue on 731 and ETV as applicable and 
have the dose of Peg-IFNα adjusted, if applicable (Section 8.6). There are no 
dose adjustments for 731 or ETV. 
▪ Subjects with an ALT elevation without declining hepatic function and 
without contraindications should discontinue Peg-IFNα (if applicable) and 
731 (if applicable) if the ALT remains persistently >2 × ULN elevated for 


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>8 weeks and there is no decline in viral parameters. Entecavir may be 
continued at the discretion of the Investigator in accordance with local 
practice. For information specific to dose modification or interruption, see 
Section 7.10.1 “Discontinuation from Treatment.” 
▪ Subjects with an ALT elevation >10 × ULN should consider dose 
interruption of Peg-IFNα (if applicable). After 8 weeks of interruption, if 
ALT has not returned to <2 × ULN, subject should discontinue Peg-IFNα (if 
applicable) and 731 (if applicable). If ALT returns to <2 × ULN, 
re-introduction of Peg-IFNα (if applicable) should be considered at the 
Investigator’s discretion. Entecavir may be continued at the discretion of the 
Investigator in accordance with local practice.  
• ALT elevation with declining hepatic function 
o Subjects with confirmed ALT elevation with evidence of declining hepatic function 
should discontinue Peg-IFNα (if applicable) and 731 (if applicable). Entecavir may 
be continued at the discretion of the Investigator in accordance with local practice. 
Elevation of ALT with declining hepatic function is defined as:  
▪ ALT elevation ≥2 × Baseline or nadir and >2 × ULN AND 
• Direct bilirubin increase to ≥2 × Baseline and ≥2 × ULN OR  
• Albumin decline ≥0.5 g/dL OR INR >2 × Baseline OR  
• Symptoms of liver inflammation (eg, fatigue, weakness, lack of 
appetite, nausea, vomiting, jaundice, or discolored feces) 
o Subjects with evidence of declining hepatic function should return for an 
Unscheduled Visit (Section 7.8) every 2 to 5 days until the relevant laboratory 
values stabilize. Subjects whose hepatic function has stabilized should continue to 
be monitored weekly (or more frequently as deemed necessary by the Investigator) 
until the relevant laboratory values return to normal or Baseline.  
All subjects with ALT elevation without or with declining hepatic function should continue to be 
followed on their regular study visit schedule, with the addition of Unscheduled Visits (Section 7.8) as 
described previously. If the ALT elevation has not substantially resolved by the last study follow-up 
visit, subjects should continue to return to clinic as deemed medically appropriate by the Investigator 
and in consultation with the Sponsor. The Unscheduled Visit module in the case report form should be 
utilized as needed to gather additional clinical and laboratory data until the ALT elevation is 
documented to be either resolved or resolving (defined as consistent ALT declines of 10% or more or 
normalization of ALT) on at least 2 successive visits. 
10. 
STATISTICAL CONSIDERATIONS 
This section provides the key details of the statistical analyses for a final analysis to be performed 
using data captured according to this protocol. No interim analysis is planned for this study.  
A description of analysis methods and detailed definitions for efficacy and safety endpoints will be 
provided in the statistical analysis plan (SAP), which will be finalized prior to database lock. 


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10.1. 
Determination of Sample Size 
Approximately 60 eligible subjects with HBeAg positive CHB will be enrolled in the study. Subjects 
will be randomized to receive 1 of the following 3 treatments, 731+ETV, ETV+Peg IFNα, or 
731+ETV+Peg IFNα in a 1:1:1 ratio. 
This is a proof-of-concept study. The sample size is similar to that previously utilized for this type of 
study and is not based upon statistical considerations. 
10.2. 
Analysis Populations 
The following populations will be considered for analysis of various endpoints: 
• Randomized Analysis Set: This analysis set includes all randomized subjects, classified 
according to the treatment group into which they were randomized regardless of the actual 
treatment received. 
• Full Analysis Set: This analysis set includes all randomized subjects, classified according to 
the treatment group into which they were randomized regardless of the actual treatment 
received, who receive at least 1 dose of study drug. This is the main analysis population for 
the efficacy analysis. 
• Safety Analysis Set: This analysis set includes all subjects, classified according to the actual 
treatment received regardless of random assignment, who receive at least 1 dose of study 
drug. This is the main analysis population for all safety analyses. 
• Pharmacokinetic Evaluable Set: This analysis set consists of all subjects, classified 
according to the actual treatment received regardless of random assignment, who receive at 
least 1 dose of study drug. At least 1 PK blood sample following a dose of study drug (731) 
is required for inclusion in this analysis. This is the main analysis population for all PK 
analyses. 
10.3. 
Planned Analyses 
As a general strategy, continuous efficacy and safety endpoints will be summarized using the 
five-number summary (mean, standard deviation, median, minimum, and maximum). Frequency 
distributions (counts and percentages) will be used to summarize categorical endpoints. 
Analyses by treatment group will be presented as follows: 
• Efficacy analyses: according to the treatment to which subjects were randomized 
• Safety and PK analyses: according to the treatment received 
10.3.1. 
Disposition of the Study Subjects 
The disposition of subjects will be described with summaries by treatment group for the number of 
subjects in each analysis set described above, the number of subjects who completed the study drugs, 
and the number of subjects for whom study drug was permanently discontinued (including the reasons 
for discontinuation).  


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10.3.2. 
Demographic and Baseline Characteristics 
Demographic and Baseline characteristics will be summarized using standard descriptive methods by 
treatment group and overall. Demographic summaries will include age, sex, race, ethnicity, body 
weight, and BMI. Baseline disease characteristics data will include, but are not limited to, years 
positive for HBV, HBV genotype, HBV DNA, HBV RNA, HBeAg, HBsAg, HBcrAg, and ALT levels 
at Baseline.  
10.3.3. 
Exposure to Study Treatment and Compliance 
Frequency distributions of the number of doses received will be presented by treatment group. 
Treatment duration and treatment compliance for the Safety Analysis Set will also be described by 
treatment group. 
10.3.4. 
Analysis of Efficacy Endpoints 
The key efficacy endpoints include: 
• Mean change in log10 HBV pgRNA from Baseline at each timepoint 
• Mean change in log10 HBV DNA from Baseline at each timepoint 
• Mean change in log10 serum viral antigens (ie, HBeAg, HBcrAg, and HBsAg) from Baseline at 
each timepoint 
• Proportion of subjects with normal ALT at each timepoint 
• The incidence of HBV variants with reduced susceptibility to 731 
For the continuous variables, such as mean change from baseline, in addition to the descriptive 
statistics at each time point, they will be evaluated using a regression model with Baseline values and 
stratification as covariates.  
The binary variables, such as the proportion of subjects with abnormal ALT at baseline who have 
normal ALT and incidence of HBV variants with reduced susceptibility will be evaluated pairwise 
among treatment groups using a Cochran-Mantel-Haenszel test accounting for stratification factors. 
10.3.5. 
Pharmacokinetic Analysis 
Drug concentrations of 731, Peg-IFNα, and ETV will be listed at end of study as follows: 
• 731 on 731+ETV or on 731+ETV+Peg-IFNα therapy stratified by collection time window 
and collection day. 
• Ad hoc analysis of ETV on 731+ETV therapy and ETV+Peg-IFNα therapy stratified by 
collection time window and study day. 
• Ad hoc analysis of Peg-IFNα on 731+ETV+Peg-IFNα therapy stratified by collection time 
window and collection day. 
Application to a population PK model may be applied, details of which will be provided in the 
pharmacometrics analysis plan. 


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10.3.6. 
Safety Analysis 
All safety endpoints will be summarized using data from the Safety Analysis Set. Safety analyses will 
involve examination of the incidence, severity and type of TEAEs reported, changes from Baseline 
(the assessment prior to first dose) in laboratory test results and in vital signs to specified time points 
throughout the study, and concomitant medications use. 
10.3.6.1. Treatment-emergent Adverse Events 
Treatment-emergent adverse events reported during the study will be coded using the Medical 
Dictionary for Regulatory Activities (MedDRA) dictionary. Incidence of TEAEs will be summarized 
by treatment group and the following: 
• Preferred term 
• System organ class and preferred term 
• System organ class, preferred term, and severity 
These summaries will be presented for the following TEAE categories: 
• All AEs 
• SAEs 
• Drug-related AEs 
For tables reporting adverse events by severity, if a subject has multiple occurrences of an AE with the 
same system organ class and preferred term, the most severe event will be presented. 
All AEs will be recorded from the first dose of study drug (731, ETV, or Peg-IFNα) until the last study 
visit. 
10.3.6.2. Clinical Laboratory Evaluation 
Laboratory parameters will be summarized by treatment group at each visit. Each summary will 
include the values of the laboratory parameters and their change from Baseline. Parameters will be 
classified according to the laboratory reference normal ranges. A listing will be provided for out of 
normal range as well as clinically significant abnormal laboratory values. 
10.3.6.3. Vital Signs 
Vital signs, including heart rate, blood pressure, temperature, height, and body weight will be 
summarized by treatment group and time point. For each assessment of vital signs, change and percent 
change in vital signs from Baseline will be summarized by treatment group. 
10.4. 
Interim Analysis 
No formal interim analysis is planned. As an open-label study, the data will be reviewed periodically.  
10.5. 
Independent Data Monitoring Committee 
No Data Monitoring Committee is planned for this study. 


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10.6. 
Handling of Missing Data 
Statistical considerations and methodology for handling missing data will be detailed in the SAP. 
10.7. 
Multiplicity Adjustment 
No formal inference is planned in this study. Hence no multiplicity adjustment is required. 
11. 
RESPONSIBILITIES 
11.1. 
Investigator Responsibilities 
11.1.1. 
Good Clinical Practice 
This study will be conducted in compliance with Institutional Review Board (IRB)/IEC and 
International Council for Harmonisation (ICH) Good Clinical Practice (GCP) Guidelines (E6[R2]); 
Title 21 Part 56 of the United States (US) Code of Federal Regulations (CFR) relating to IRBs/IECs 
and GCP as described in the US Food and Drug Administration (FDA) CFR (21 CFR § 50, 56, 312); 
applicable ICH guidelines regarding clinical safety data management (E2A, E2B[R3]); European 
Community directives 2001/20, 2001/83, 2003/94, and 2005/28 as enacted into local law, and with 
ICH guidelines regarding scientific integrity (E4, E8, E9, and E10). In addition, this study will adhere 
to all local regulatory requirements, and requirements for data protection. 
11.1.2. 
Institutional Review Board/Independent Ethics Committee 
Before initiating a clinical study, the Investigator/institution must have written and dated 
approval/favorable opinion from the IRB/IEC, as well as for study protocol amendment(s), written 
ICF, any ICF updates, subject recruitment procedures (eg, advertisements), and any written 
information to be provided to subjects and a statement from the IRB/IEC that complies with GCP 
requirements. The IRB/IEC approval must identify the protocol version as well as the documents 
reviewed. 
11.1.3. 
Informed Consent 
The Investigator will explain the benefits and risks of participation in the study to each subject or the 
subject’s legally acceptable representative and obtain written informed consent. Written informed 
consent must be obtained prior to the subject entering the study and before initiation of any 
study-related procedure (including administration of investigational product). 
The Sponsor or its designee will provide a sample ICF. The final, version dated, ICF must be agreed to 
by the Sponsor and the IRB/IEC and will contain all elements in the sample form, in language readily 
understood by the subject. Each subject’s original ICF must be personally signed and dated by the 
subject or by the subject’s legally acceptable representative, and by the person who conducted the 
informed consent discussion. The original, signed ICF will be retained by the Investigator. The 
Investigator will supply all enrolled subjects with a copy of their signed ICF. 
The ICF may need to be revised during the study should important new information become available 
that may be relevant to the safety of the subject. In this instance approval should always be given by 
the IRB/IEC and existing subjects informed of the changes and reconsented. This is documented in the 
same way as previously described. 


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The Investigator should encourage subjects to inform their primary physicians about their participation 
in the clinical study. 
11.1.4. 
Confidentiality 
All information generated in this study is considered confidential and must not be disclosed to any 
person or entity not directly involved with the study unless prior written consent is gained from the 
Sponsor. However, authorized regulatory officials, IRB/IEC personnel, and the Sponsor and the 
Sponsor’s authorized representatives are allowed full access to the records. 
Identification of subjects and eCRFs shall be by subject number only. If required, the subject's full 
name may be made known to an authorized regulatory agency or other authorized official. 
11.1.5. 
Study Files and Retention of Records 
Records must be retained in accordance with the current ICH guidelines on GCP. All essential study 
documents including records of subjects, source documents, eCRFs, and investigational product 
inventory must be kept on file. 
Essential documents should be retained until at least 2 years after the last approval of a marketing 
application in an ICH region and until there are no pending or contemplated marketing applications in 
an ICH region, or until at least 2 years have elapsed since the formal discontinuation of clinical 
development of the investigational products. However, essential documents may be retained for a 
longer period if required by the applicable regulatory requirements or by agreement with the Sponsor. 
The Sponsor is responsible for informing the Investigator when these documents need no longer be 
retained. 
The Investigator will not dispose of any records relevant to this study without written permission from 
the Sponsor and will give the Sponsor the opportunity to collect such records. The Investigator shall 
take responsibility for maintaining adequate and accurate hard copy source documents of all 
observations and data generated during this study. Such documentation is subject to inspection by the 
Sponsor, its representatives, and regulatory authorities. 
If an Investigator moves, withdraws from an investigation, or retires, responsibility for maintaining the 
records may be transferred to another person who will accept responsibility. Notice of transfer must be 
made to and agreed by the Sponsor. 
11.1.6. 
Audits and Inspections 
The Sponsor or their designee, the CRO, may conduct audits at the investigative sites including, but 
not limited to, drug supply, presence of required documents, the informed consent process, and 
comparison of eCRFs with source documents. All medical records (progress notes) must be available 
for audit. The Investigator agrees to participate with audits conducted at a convenient time in a 
reasonable manner. 
Government regulatory authorities may also inspect the site during or after the study. The Investigator 
or designee should contact the Sponsor and/or the CRO, immediately if this occurs. The site must 
cooperate fully with regulatory authorities or other audits conducted at a convenient time in a 
reasonable manner. 
The purpose of an audit is to assess whether ethical, regulatory, and quality requirements are fulfilled. 


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11.1.7. 
Protocol Compliance 
It is the responsibility of the Investigator to ensure that the study is conducted at his/her respective site 
in accordance with this protocol. Protocol compliance assessments will be conducted during routine 
site monitoring visits and ongoing data review by the Sponsor and CRO. 
11.2. 
Sponsor Responsibilities 
11.2.1. 
Protocol Amendments and Modifications 
Protocol modifications, except those intended to reduce immediate risk to study subjects, may be made 
only by the Sponsor. A protocol change intended to eliminate an apparent immediate hazard to subjects 
may be implemented immediately, provided the IRB/IEC is notified within 5 days. 
Any permanent, significant change to the protocol must be handled as a protocol amendment. The 
written amendment must be submitted to the IRB/IEC and the Investigator must await approval before 
implementing the changes. The Sponsor will submit protocol amendments to the appropriate 
regulatory authorities for approval. 
If, in the judgment of the IRB/IEC, the Investigator, and/or the Sponsor, the amendment to the protocol 
substantially changes the study design and/or increases the potential risk to the subject and/or has an 
impact on the subject's involvement as a study subject, the currently approved written ICF will require 
similar modification. In such cases, subjects will be required to sign the amended informed consent 
prior to continued participation in the study. 
11.2.2. 
Data Management 
A set of data management documents will be created under the responsibility of the Sponsor, or 
designated CRO, to describe the processes being used to ensure data quality. 
The data management plan and other associated documentations will specify data capture methods, 
who is authorized to enter data, decisions about ownership of data, source data storage, which data will 
be transferred (including timing of transfers), and the origin/destination of data. 
11.2.3. 
Study Report and Publications 
The Sponsor or its designee is responsible for preparing and providing the appropriate regulatory 
authorities with clinical study reports (CSRs) according to the applicable regulatory requirements. 
CSRs will be developed in accordance with the ICH E3 Guideline on the ‘Structure and Content of 
Clinical Study Reports’. Local country requirements will be considered during CSR preparation. 
The results of this study may be published or presented at scientific meetings. If this is foreseen, the 
Investigator agrees to submit all proposed manuscripts or abstracts to the Sponsor before submission. 
This allows the Sponsor to protect proprietary information and to provide comments. The Sponsor will 
comply with the requirements for publication of study results. In accordance with standard editorial 
and ethical practice, the Sponsor will generally support publication of multicenter studies only in their 
entirety and not as individual site data. In this case, a coordinating Investigator will be designated by 
mutual agreement. 
Assembly Biosciences follows the guidelines and recommendations of the International Committee of 
Medical Journal Editors (ICMJE) and the International Society for Medical Publication Professionals 
when preparing publications associated with clinical studies (ICMJE 2019; Battisti et al 2015). 


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12. 
REFERENCES 
Battisti WP, Wager E, Baltzer L, et al. Good publication practice for communicating 
company-sponsored medical research: GPP3. Ann Intern Med. 2015;163(6):461-4. 
Belloni L, Li L, Palumbo GA, et al. HAPs hepatitis B virus (HBV) capsid inhibitors block core protein 
interaction with the viral minichromosome and host cell genes and affect cccDNA transcription and 
stability. Hepatology. 2013;58(4 suppl 1):277A.  
Brouwer WP, Sonneveld MJ, Xie Q, et al. Peginterferon add‐on results in more HBsAg decline 
compared to monotherapy in HBeAg‐positive chronic hepatitis B patients. J Viral Hepat. 
2016;23(6):419-26. DOI: 10.1111/jvh.12468. 
Burdette D, Cathcart A, Shauf A, et al. Evidence for the presence of infectious virus in the serum from 
chronic hepatitis B patients suppressed on nucleos (t)ide therapy with detectable but not quantifiable 
HBV DNA. J Hepatol. 2019;70(1):e95. 
Colvin HM, Mitchell AE. Hepatitis and liver cancer: A National Strategy for Prevention and Control 
of Hepatitis B and C. Washington DC: The National Academies Press; 2010. 
Cornberg M, Lok AS-F, Terrault NA, Zoulim F. Guidance for design and endpoints of clinical trials in 
chronic hepatitis B – Report from the 2019 EASL-AASLD HBV Treatment Endpoints Conference. J 
Hepatol. 2020;72(3):539-57. 
Cui Y, Jia J. Update on epidemiology of hepatitis B and C in China. J Gastroenterol Hepatol. 
2013;28(Suppl 1):7-10. 
El-Serag HB. Epidemiology of viral hepatitis and hepatocellular carcinoma. Gastroenterology. 
2012;142(6):1264-73. 
European Association for the Study of the Liver (EASL) Clinical Practice Guidelines: Management of 
chronic hepatitis B virus infection. J Hepatol. 2012;57(1):167-85. 
European Association for the Study of the Liver (EASL) Clinical Practice Guidelines on the 
management of hepatitis B virus infection. J Hepatol. 2017 Aug;67(2):370-98. 
Guettouche T, Hnatyszyn HJ. Chronic hepatitis B and viral genotype: the clinical significance of 
determining HBV genotypes. Antivir Ther. 2005;10(5):593-604. 
Gish RG, Given BD, Lai CL, et al. Chronic hepatitis B: Virology, natural history, current management 
and a glimpse at future opportunities. Antiviral Res. 2015 Sep;121:47-58. 
Hoofnagle JH, Doo E, Liang TJ, Fleischer R, Lok AS. Management of hepatitis B: summary of a 
clinical research workshop. Hepatology. 2007;45(4):1056-75. 
Konerman MA, Lok AS. Interferon treatment for hepatitis B. Clin Liver Dis. 2016;20(4):645-65. 
Lampertico P, Liaw YF. New Perspectives in the Therapy of Chronic Hepatitis B. Gut. 
2012;61(Suppl 1):i18-24. 
Levey AS, Stevens LA, Schmide CH, et al. A new equation to estimate glomerular filtration rate. Ann 
Intern Med. 2009 May 5;150(9):604-12. 
Levrero M, Pollicino T, Petersen J, Belloni L, Raimondo G, Dandri M. Control of cccDNA function in 
hepatitis B virus infection. J Hepatol. 2009;51(3):581-92. 
Lok ASF, McMahon BJ. Chronic hepatitis B: update 2009. Hepatology. 2009 Sep;50(3):661-2. 


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Podlaha O, Wu G, Downlo B, et al. Host genome integration of hepatitis B is prolific and is the 
primary contributor to viral hepatitis B surface antigen gene expression. Poster presented at EASL: 
The International Liver Congress; April 10-14, 2019; Vienna, Austria. 
Pungpapong S, Kim WR. In the Eye of the B-holder: natural history of chronic hepatitis B. 
Hepatology. 2013;58(1):6-8. 
Recommendations for the Conduct, Reporting, Editing, and Publication of Scholarly Work in Medical 
Journals (ICMJE). http://www.icmje.org/recommendations/ Accessed: January 2019. 
Schweitzer A, Horn J, Mikolajczyk RT, Krause G, Ott JJ. Estimations of worldwide prevalence of 
chronic hepatitis B virus infection: a systematic review of data published between 1965 and 2013. 
Lancet. 2015;386(10003):1546-55.  
Sorrell MF, Belongia EA, Costa J, et al. National Institutes of Health consensus development 
conference statement: management of hepatitis B. Ann Intern Med. 2009;150(2):104-10.  
Viganò M, Grossi G, Loglio A, Lampertico P. Treatment of hepatitis B: Is there still a role for 
interferon? Liver Int. 2018;38(Suppl 1):79-83. https://doi.org/10.1111/liv.13635. 
Wang FS, Fan JG, Zhang Z, et al. The global burden of liver disease: The major impact of China. 
Hepatology. 2014;60(6):2099-108. 
Wang H, Men P, Xiao Y, et al. Hepatitis B infection in the general population of China: a systematic 
review and meta-analysis. BMC Infect Dis. 2019;19(1):811. 
World Health Organization (WHO) Scientific Group Technical Report. Assessment of osteoporosis at 
the primary health-care level. University of Sheffield, United Kingdom: World Health Organization; 
2007. 
World Health Organization (WHO). Hepatitis B: fact sheet. Geneva Switzerland: World Health 
Organization; 2019. 
Xie Q, Zhou H, Bai X, et al. A randomized, open-label clinical study of combined pegylated interferon 
alfa-2a (40KD) and entecavir treatment for hepatitis B "e" antigen-positive chronic hepatitis B. Clin 
Infect Dis. 2014;59(12):1714-23. 
Yang L, Liu F, Tong X, Hoffman D, Zuo J, Lu M. Treatment of chronic hepatitis B virus infection 
using small molecule modulators of nucleocapsid assembly: recent advances and perspectives. ACS 
Infect Dis. 2019;5(5):713-24. 
Yim HJ, Lok AS-F. Natural history of chronic hepatitis B virus infection: what we knew in 1981 and 
what we know in 2005. Hepatology. 2006;43(2 Suppl 1):S173-81. 


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13. 
APPENDICES 


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APPENDIX 1 
SCHEDULE OF ASSESSMENTS TABLE 
Period or Visit 
Screening 
On Treatment 
Follow-up 
Premature 
Termination3  
Unscheduled 
Visit 4 
Study Day or Week 
Day -45  
to Day -1 
Day 
1 1 
Wk 
1 
Wk 
2 
Wk 
4 
Wk 
6 
Wk 
8 
Wk  
12 
Wk 
16 
Wk  
20 
Wk  
24 2 
Wk  
28 2 
Wk  
48 
Wks 
52, 56 2 
Wk 
60  
 
 
Visit Window (days) 
 
0 
±1 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
-3 
±3 
-3 
±5 
±5 
NA 
NA 
Informed Consent(s)  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics, medical history, 
and HBV history 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Liver staging 5 
X 
 
 
 
 
 
 
 
 
 
X 
 
X 
 
 
 
 
Height and weight 6 
X 
X 
 
 
 
 
 
 
 
 
X 
 
X 
  
X 
X 
 
Vital signs 
X 
X 
 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Complete physical examination7 
X 
X 
 
 
 
 
 
 
 
 
X 8 
 
X 8 
 
X 8 
X 
 
Symptom-directed physical 9 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
X 
 
 
X 
12-lead ECG 10 
X 
X 
 
 
 
 
 
X 10 
 
 
X 10 
 
X 10 
. 
X 10 
X 
 
Concomitant medications and 
AEs 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Confirm subject eligibility 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Complete randomization (IRT) 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Chemistry 
X 
X 
 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Hematology 
X 
X 
 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Coagulation 
X 
X 
 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Serum AFP  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
FSH (females only) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
TSH and T4 11 
X 
 
 
 
 
 
 
X 11 
 
 
X 11 
 
 
 
 
 
 
Pregnancy Test 12 
X 
X 
 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Urinalysis 
X 
X 
 
 
X 
 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
Urine drug test 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
HBV genotype 
X 13 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Period or Visit 
Screening 
On Treatment 
Follow-up 
Premature 
Termination3  
Unscheduled 
Visit 4 
Study Day or Week 
Day -45  
to Day -1 
Day 
1 1 
Wk 
1 
Wk 
2 
Wk 
4 
Wk 
6 
Wk 
8 
Wk  
12 
Wk 
16 
Wk  
20 
Wk  
24 2 
Wk  
28 2 
Wk  
48 
Wks 
52, 56 2 
Wk 
60  
 
 
Visit Window (days) 
 
0 
±1 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
-3 
±3 
-3 
±5 
±5 
NA 
NA 
HBV DNA 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
HBV pgRNA 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
HBsAg, HBeAg 14 
X 
X 
 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
HBcrAg 
 
X 
 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
HBsAb, HBeAb  
X 
X 
 
 
 
 
 
X  
 
 
X  
 
X  
  
X  
X 
 
Sample for HBV DNA 
sequencing and HBV nucleic 
acids 15 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
HIV Ab, HCV Ab, HDV Ab, 
HAV (IgM), HEV (IgM) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Dosing diary 16 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Study drug accountability 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 17 
X 
X 17 
X 17 
X 
X 
 
Study drug dispensation 17 
 
X 
 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 17 
 
 
 
In-clinic dosing 731 18 
 
X 
 
 
X 
 
X 
X 
X 
X 
X 
X 
X 19 
 
 
 
 
In-clinic ETV dosing 18 
 
X  
 
 
X  
 
X 
X 
X 
X 
X  
X 
X 
X  
X 19 
 
 
In-clinic Peg-IFNα dosing 18, 19 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
PK sample 
collection 20, 21 
731,  
Peg-IFNα 
 
X 
 
X 
X 
 
X 
X 
X 
X 
X 
 
 
 
 
X 
X 
ETV 
 
X 
 
X 
X 
 
X 
X 
X 
X 
X 
X 21 
 
 
 
X 
X 
HBcAb (IgM) 22 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Abbreviations: Ab = antibody; 731 = ABI-H0731; AE = adverse event; AFP = alpha fetoprotein; ALT = alanine aminotransferase; AST = aspartate aminotransferase;  
ECG = electrocardiogram; FSH = follicle-stimulating hormone; HAV = hepatitis A virus; HBcrAg = hepatitis B core-related antigen; HBeAb = HBeAg antibody; HBeAg = hepatitis B 
“e” antigen; HBsAb = HBsAg antibody; HBsAg = hepatitis B surface antigen; HBV = hepatitis B virus; HCV = hepatitis C virus; HDV = hepatitis D virus; HEV = hepatitis E virus; 
IgM = immunoglobulin M; INR = international normalized ratio; IRT = Interactive Response Technology; NA = not applicable; PK = pharmacokinetic; pgRNA = pregenomic RNA; 
T4=thyroxine; TSH = thyroid-stimulating hormone; ULN = upper limit of normal; Wk(s) = week(s). 
 
 
 


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1  The assessments that need to be performed prior to the first dose of study drugs on Day 1 are listed in Section 7.3. 
2 
Study visits occur every 4 weeks between Weeks 24 and 60. 
3  Subjects who discontinue treatment before Week 24 (731 or Peg-IFNα) or Week 48 (731) should immediately undergo the assessments listed for the Premature Termination Visit 
and then continue the scheduled follow-up assessments. ETV administration may be continued at the discretion of the Investigator. 
4  Any subjects with alanine aminotransferase (ALT) elevation should return to the clinic for an Unscheduled Visit. The minimum assessments to be completed when managing ALT 
elevations are noted in Section 9.4. 
5  Liver staging is to be performed to determine lack of cirrhosis or advanced liver disease as required by inclusion criteria and should be performed by liver biopsy (within 1 year of 
Screening), by fasting FibroScan (within 3 months of Screening) or other Sponsor-approved hepatic imaging method within 6 months of Screening, and again at Weeks 24 and 48. 
6  Height is measured at the Screening visit only. 
7  For the complete physical examination, assessment of the breasts and genitalia are not required unless indicated. 
8  Complete physical exam and weight measurement are performed only at Screening, Day 1, and Weeks 24, 48, and 60. 
9  Symptom-directed physical exam is performed only at the visits when a complete physical exam is not performed. 
10  Any clinically significant ECG result or change from Baseline (Day 1) should be confirmed, and if confirmed, should be recorded as an AE. A 12-lead ECG will be performed at 
Weeks 12, 24, 48, and 60. 
11  T4 and TSH are measured only at Screening. TSH is measured at Weeks 12 and 24 (only for Peg-IFNα-containing treatment groups).  
12 A serum pregnancy test is required at Screening. On Day 1 both urine and serum tests should be performed (subjects may begin treatment based on urine results; any subjects 
negative by urine subsequently found to be positive on serum should immediately discontinue treatment). All post-Day 1 pregnancy tests may be performed on urine. If the result 
from a urine pregnancy test is positive, then a serum pregnancy test should be performed. 
13  HBV genotype results should be received prior to Day 1 as this is required for treatment stratification. 
14  If quantitative HBsAg and/or HBeAg is less than the lower limit of quantification (LLOQ) at any visit subsequent to Screening, reflex qualitative HBsAg and/or HBeAg testing will 
be done. If HBsAg and/or HBeAg are <LLOQ at any visit, reflex qualitative HBsAb and/or HBeAb testing will be done to assess for seroconversion.  
15  HBV DNA sequencing will not be performed routinely at Screening and subsequent study visits. Samples will be collected, stored, and analyzed only in the event of an observed 
viral breakthrough or blunted response. If HBV DNA sequencing is not required, then these samples may be used for additional HBV DNA or HBV pgRNA testing as required. 
16  A dosing diary is provided to all subjects on Day 1. At subsequent in-clinic visits, the diary is reviewed and a new diary card is provided. At Week 60, only review of dosing diary 
is performed. 
17  Final study drug dispensation of Peg-IFNα will occur at Week 20, 731 at Week 44, and ETV at Week 56. Final study drug accountability of Peg-IFNα is performed at Week 24, 731 
at Week 48, and ETV at Week 60.  
18  731 and ETV administration are in-clinic at the study visits and self-administered once daily at home on all other days. Day 1 Peg-IFNα administration is in-clinic for injection 
training purposes; subsequently, subjects will administer Peg-IFNα once weekly at home. 
19  Dosing with Peg-IFNα (if applicable) will stop at Week 24. Dosing with 731 (if applicable) will stop at Week 48. Dosing with ETV will continue until Week 60.  
20  If the subject inadvertently administers study drug prior to collection, a PK sample should still be drawn. Refer to Section 7.11. 
21  Predose PK samples for 731, ETV, and Peg-IFNα on Day 1 and Weeks 4 and 24. Postdose PK samples for 731, ETV, and Peg-IFNα may be collected from 2 to 4 hours postdose on 
Day 1, and between 30 min and 2 hours after in-clinic study drug administration at Weeks 2, 8, 12, and 24. Postdose samples at Weeks 16 and 20 may be collected between 4 and 
6 hours after in-clinic study drug administration. Predose samples for ETV may be collected at Week 44. 
22  HBcAb IgM testing may be performed for some subjects at Screening, see Inclusion Criterion #5, Section 5.2.  
 


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APPENDIX 2 
CLINICAL AND LABORATORY ASSESSMENTS 
Clinical Laboratory Tests 
Clinical laboratory tests will be performed at the designated central laboratories at the timepoints 
indicated in Section 7 and the Schedule of Assessments table in Appendix 1. Should any laboratory 
parameter require urgent testing to support immediate medical care of a subject, samples should be 
collected for both local and central laboratory assessment. The local result may be used to manage the 
emergent medical situation; however, only the results from the central laboratory will be reported in 
the study database for analysis purposes. Urgent local laboratory testing results conflicting with the 
central laboratory results should be discussed between the Investigator and the study Medical Monitor. 
The specific components of the clinical laboratory tests are listed below in Table 2. 
Table 2:  
Clinical Laboratory Tests 
Panel 
Tests 
Clinical chemistry 
Blood glucose levels, serum or plasma electrolytes (sodium, potassium, chloride, bicarbonate), 
calcium, blood urea nitrogen, serum creatinine, creatine kinase, GFR, uric acid, total and direct 
bilirubin a, ALT, AST, GGT, alkaline phosphatase, LDH, amylase, triglycerides, total 
cholesterol, inorganic phosphate or total phosphate, total protein, albumin, lipase, and total 
serum or plasma globulins 
In case of elevated 
ALT  
ALT, AST, total bilirubin, serum albumin, creatine kinase, and INR; Refer to Section 9.4 for 
virology and serology 
Hematology 
Complete blood counts: hemoglobin, hematocrit, RBC indices (MCV, MCHC), reticulocyte 
counts, leukocyte counts (total and differential), and platelet counts 
Coagulation 
Prothrombin time/INR and aPTT 
Urinalysis 
pH, specific gravity, protein, glucose, ketones, and occult blood 
Other 
AFP, HbA1c, and FSH 
Pregnancy tests 
For females only; a serum or plasma pregnancy test must be performed at Screening, and both 
serum/plasma and urine are required at Day 1; a serum, plasma, or urine pregnancy test must 
be performed at all subsequent visits.  
A positive result disqualifies the subject for study treatment 
Urine drug screening 
Amphetamine, barbiturates, benzodiazepines, cocaine metabolite, ethanol, opiates, and 
phencyclidine 
Antibodies 
HBcAb IgM (see Inclusion Criterion #5, Section 5.2), HCV, HDV, HAV IgM, HEV IgM, and 
HIV 
Abbreviations: AFP = alpha fetoprotein; ALT = alanine aminotransferase; aPTT = activated partial thromboplastin time; AST = aspartate 
aminotransferase; FSH = follicle-stimulating hormone; GGT = gamma-glutamyl transpeptidase; GFR = glomerular filtration rate;  
HAV = hepatitis A virus; HbA1c = hemoglobin A1c; HCV = hepatitis C virus; HDV = hepatitis D virus; HEV = hepatitis E virus;  
IgM = immunoglobulin M; INR = International Normalized Ratio; LDH = lactate dehydrogenase; MCHC = mean corpuscular 
hemoglobin concentration; MCV = mean corpuscular volume; RBC = red blood cell; ULN = upper limit of normal. 
a.  Perform fractionated bilirubin, if total bilirubin > ULN. 
HBV Virology 
To provide an assessment of the antiviral efficacy of 731 in subjects with CHB, this study will evaluate 
treatment effects on the following parameters: 
• HBV genotyping 
• HBV DNA 
• HBV pgRNA 


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• HBsAg 
• HBeAg 
• HBcrAg 
• HBsAb, HBeAb 
• HBV sequence analysis for assessment of resistance 
To ensure standardization of the virologic methodologies utilized in this study, HBV DNA-related, 
HBV antigen-related and HBV antibody-related virologic assessments will be conducted at a central 
reference laboratory. Subject serum samples for resistance-related sequencing (to be performed in the 
event of observing a viral breakthrough or blunted response) and HBV pgRNA testing will be shipped 
frozen to a designated third-party laboratory for testing. The HBV virology tests will be performed at 
the timepoints indicated in Section 7 and the Schedule of Assessments table in Appendix 1. 
Additional details concerning the collection and processing of HBV virology samples are described in 
the Laboratory Manual. 
Other Safety Assessments 
12-lead ECG: 
Prior to the conduct of 12-lead ECGs, subjects should rest in a supine position for 10 minutes. ECGs 
should be conducted in accordance with local practice and equipment. The ECG assessment will 
include interpretation of the tracings (eg, rhythm, presence of arrhythmia or conduction defects, 
morphology, any evidence of myocardial infarction, or ST segment, T-wave, and U-wave 
abnormalities). The Investigator or a physician sub-investigator is responsible for reviewing and 
overreading the ECG interpretation, for assessing whether the ECG machine interpretation findings are 
accurate, appropriate, normal or abnormal, and for providing corrected interpretations as appropriate. 
In addition, any abnormal ECGs will be assessed for clinical significance. 
Additional ECGs may be obtained if clinically indicated and will be obtained if abnormal and 
clinically significant or thought to be an error (eg, lead placement error, movement artifact, etc.). Any 
additional relevant data obtained by the Investigator during the course of this study will be recorded in 
the subject’s source documentation. The Investigator or a physician sub-investigator will review all 
ECGs, evaluate the results, and sign/date the tracing or report. For any ECG abnormality that the 
Investigator considers clinically significant, the Investigator will:  
• Repeat the ECG; 
• Obtain follow-up ECG(s) if any significant abnormalities are detected after study drug 
administration to document resolution and as clinically indicated; 
• Record as an AE any ECG abnormality that: (1) is confirmed and the Investigator considers 
clinically significant; (2) requires a subject to be discontinued from the study; or (3) the 
abnormality requires a subject to receive treatment. (Section 8). 
Complete Physical Examination: 
Complete physical examinations will be performed by the Investigator or qualified sub-investigator at 
the time points indicated in the Study Procedures section (Section 7, Appendix 1). The complete 
physical examination will consist of the following body systems: head, eyes, ears, nose, and throat; 
cardiovascular; respiratory; gastrointestinal; dermatologic; musculoskeletal; nervous; extremities; and 


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lymph nodes. Additional body systems may be evaluated at the Investigator’s discretion. Examination 
of the breast and genitalia are not required unless clinically indicated. 
Additional symptom-directed physical examinations will be performed at the time points indicated in 
the Study Procedures section (Section 7; Appendix 1). Additional symptom-directed of complete 
physical examinations made be performed at the Investigator’s discretion throughout the course of the 
study. If the subject reports feeling unwell or has ongoing AEs, the Investigator or qualified 
sub-investigator will examine the appropriate body system(s). 
 


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APPENDIX 3 
TOXICITY GRADING SCALE FOR ADVERSE EVENTS AND LABORATORY ABNORMALITIES 
Adapted from the US National Institutes of Health (DAIDS) Table for Grading Severity of Adult Adverse Experiences (July 2017).  
MAJOR CLINICAL CONDITIONS 
Cardiovascular 
Parameter 
Grade 1 Mild 
Grade 2 Moderate 
Grade 3 Severe 
Grade 4 Potentially 
Life-threatening 
Arrhythmia 
(by ECG or physical examination) 
Specify type, if applicable 
No symptoms AND no intervention 
indicated 
No symptoms AND non-urgent 
intervention indicated 
Non-life-threatening symptoms AND 
Non-urgent intervention indicated 
Life-threatening arrhythmia OR 
urgent intervention indicated 
Blood Pressure Abnormalities  
 
 
 
 
Hypertension (with the lowest 
reading taken after repeat testing 
during a visit) 
≥18 years of age 
140 to <160 mmHg systolic 
OR 
90 to <100 mmHg diastolic 
≥160 to <180 mmHg systolic OR 
≥100 to <110 mmHg diastolic 
≥180 mmHg systolic OR 
≥110 mmHg diastolic 
Life-threatening consequences in a 
subject not previously diagnosed with 
hypertension (eg, malignant 
hypertension) OR hospitalization 
indicated 
Hypotension 
No symptoms 
Symptoms corrected with oral fluid 
replacement 
Symptoms AND IV fluids indicated 
Shock requiring use of vasopressors 
or mechanical assistance to maintain 
blood pressure 
Cardiac Ischemia or Infarction 
Report only one 
NA 
NA 
New symptoms with ischemia (stable 
angina) OR New testing consistent 
with ischemia 
Unstable angina OR Acute 
myocardial infarction 
Heart Failure 
No symptoms AND Laboratory or 
cardiac imaging abnormalities 
Symptoms with mild to moderate 
activity or exertion 
Symptoms at rest or with minimal 
activity or exertion (eg, hypoxemia) 
OR Intervention indicated (eg, 
oxygen) 
Life-threatening consequences OR 
Urgent intervention indicated (eg, 
vasoactive medications, ventricular 
assist device, heart transplant) 
Hemorrhage 
(with significant acute blood loss) 
NA 
Symptoms AND No transfusion 
indicated 
Symptoms AND Transfusion of 
≤2 units packed RBCs indicated 
Life-threatening hypotension OR 
Transfusion of >2 units packed RBCs 
indicated 


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Cardiovascular 
Parameter 
Grade 1 Mild 
Grade 2 Moderate 
Grade 3 Severe 
Grade 4 Potentially 
Life-threatening 
Prolonged PR Interval 
or AV Block 
Report only one 
≥16 years of age 
PR interval 0.21 to 
<0.25 seconds 
PR interval ≥0.25 
seconds OR Type I 
2nd degree AV block 
Type II 2nd degree 
AV block OR 
Ventricular pause ≥3.0 seconds 
Complete AV block 
Prolonged QTc Interval a 
0.45 to 0.47 seconds 
>0.47 to 0.50 seconds 
>0.50 seconds OR 
≥0.06 seconds above Baseline 
Life-threatening consequences (eg, 
Torsade de pointes, other associated 
serious ventricular dysrhythmia) 
Thrombosis or Embolism 
Report only one 
NA 
Symptoms AND No intervention 
indicated 
Symptoms AND Intervention 
indicated 
Life-threatening embolic event (eg, 
pulmonary embolism, thrombus) 
Abbreviations: AV = atrioventricular; ECG = electrocardiogram; IV = intravenous; NA = not applicable; QTc = corrected QT interval; RBC = red blood cell. 
a.  As per Bazett’s formula. 


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Dermatologic 
Parameter 
Grade 1 Mild 
Grade 2 Moderate 
Grade 3 Severe 
Grade 4 Potentially Life-threatening 
Alopecia (scalp only) 
Detectable by study subject, 
caregiver, or physician AND 
Causing no or minimal interference 
with usual social and functional 
activities 
Obvious on visual inspection AND 
Causing greater than minimal 
interference with usual social and 
functional activities 
NA 
NA 
Bruising 
Localized to 1 area 
Localized to more than 1 area 
Generalized 
NA 
Cellulitis 
NA 
Non-parenteral treatment indicated 
(eg, oral antibiotics, antifungals, 
antivirals) 
IV treatment indicated (eg, IV 
antibiotics, antifungals, antivirals) 
Life-threatening consequences (eg, 
sepsis, tissue necrosis) 
Hyperpigmentation 
Slight or localized causing no or 
minimal interference with usual 
social and functional activities 
Marked or generalized causing 
greater than minimal interference 
with usual social and functional 
activities 
NA 
NA 
Hypopigmentation 
Slight or localized causing no or 
minimal interference with usual 
social and functional activities 
Marked or generalized causing 
greater than minimal interference 
with usual social and functional 
activities 
NA 
NA 
Petechiae 
Localized to 1 area 
Localized to more than 1 area 
Generalized 
NA 
Pruritus b  
(without skin lesions) 
Itching causing no or minimal 
interference with usual social and 
functional activities 
Itching causing greater than minimal 
interference with usual social and 
functional activities 
Itching causing inability to 
perform usual social and 
functional activities 
NA 
Rash 
Specify type, if applicable 
Localized rash 
Diffuse rash OR Target lesions 
Diffuse rash AND Vesicles or 
limited number of bullae or 
superficial ulcerations of mucous 
membrane limited to 1 site 
Extensive or generalized bullous lesions 
OR Ulceration of mucous membrane 
involving 2 or more distinct mucosal 
sites OR Stevens-Johnson syndrome 
OR Toxic epidermal necrolysis 
Abbreviations: IV = intravenous; NA = not applicable. 
b.  For pruritus associated with injections or infusions, see the Site Reactions to Injections and Infusions section. 


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Endocrine and Metabolic 
Parameter 
Grade 1 Mild 
Grade 2 Moderate 
Grade 3 Severe 
Grade 4 Potentially Life-Threatening 
Diabetes Mellitus 
Controlled without medication 
Controlled with medication OR 
Modification of current medication 
regimen 
Uncontrolled despite treatment 
modification OR Hospitalization 
for immediate glucose control 
indicated 
Life-threatening consequences (eg, 
ketoacidosis, hyperosmolar non-ketotic 
coma, end organ failure) 
Gynecomastia 
Detectable by study subject, 
caregiver, or physician AND 
Causing no or minimal interference 
with usual social and functional 
activities 
Obvious on visual inspection AND 
Causing pain with greater than 
minimal interference with usual 
social and functional activities 
Disfiguring changes AND 
Symptoms requiring intervention 
or causing inability to perform 
usual social and functional 
activities 
NA 
Hyperthyroidism 
No symptoms AND Abnormal 
laboratory value 
Symptoms causing greater than 
minimal interference with usual 
social and functional activities OR 
Thyroid suppression therapy 
indicated 
Symptoms causing inability to 
perform usual social and functional 
activities OR Uncontrolled despite 
treatment modification 
Life-threatening consequences (eg, thyroid 
storm) 
Hypothyroidism 
No symptoms AND Abnormal 
laboratory value 
Symptoms causing greater than 
minimal interference with usual 
social and functional activities OR 
Thyroid replacement therapy 
indicated 
Symptoms causing inability to 
perform usual social and functional 
activities OR Uncontrolled despite 
treatment modification 
Life-threatening consequences (eg, 
myxedema coma) 
Lipoatrophy c 
Detectable by study subject, 
caregiver, or physician AND 
Causing no or minimal interference 
with usual social and functional 
activities 
Obvious on visual inspection AND 
Causing greater than minimal 
interference with usual social and 
functional activities 
Disfiguring changes 
NA 
Lipohypertrophy d 
Detectable by study subject, 
caregiver, or physician AND 
Causing no or minimal interference 
with usual social and functional 
activities 
Obvious on visual inspection AND 
Causing greater than minimal 
interference with usual social and 
functional activities 
Disfiguring changes 
NA 
Abbreviation: NA = not applicable. 
c. Definition: A disorder characterized by fat loss in the face, extremities, and buttocks. 
d.  Definition: A disorder characterized by abnormal fat accumulation on the back of the neck, breasts, and abdomen. 


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Gastrointestinal 
Parameter 
Grade 1 Mild 
Grade 2 Moderate 
Grade 3 Severe 
Grade 4 Potentially Life-threatening 
Anorexia 
Loss of appetite without decreased 
oral intake 
Loss of appetite associated with 
decreased oral intake without 
significant weight loss 
Loss of appetite associated with 
significant weight loss 
Life-threatening consequences OR 
Aggressive intervention indicated (eg, 
tube feeding, total parenteral nutrition)  
Ascites 
No symptoms 
Symptoms AND Intervention indicated 
(eg, diuretics, therapeutic paracentesis) 
Symptoms recur or persist 
despite intervention 
Life-threatening consequences 
Bloating or Distension 
Report only one 
Symptoms causing no or minimal 
interference with usual social and 
functional activities 
Symptoms causing greater than 
minimal interference with usual social 
and functional activities 
Symptoms causing inability to 
perform usual social and 
functional activities 
NA 
Cholecystitis 
NA 
Symptoms AND Medical intervention 
indicated 
Radiologic, endoscopic, or 
operative intervention indicated  
Life-threatening consequences (eg, 
sepsis, perforation) 
Constipation 
NA 
Persistent constipation requiring 
regular use of dietary modifications, 
laxatives, or enemas 
Obstipation with manual 
evacuation indicated 
Life-threatening consequences (eg, 
obstruction) 
Diarrhea 
≥1 year of age 
Transient or intermittent episodes of 
unformed stools OR Increase of ≤3 
stools over Baseline per 24-hour 
period  
Persistent episodes of unformed to 
watery stools OR Increase of 4 to 6 
stools over Baseline per 24-hour period 
Increase of ≥7 stools per 24-hour 
period OR IV fluid replacement 
indicated 
Life-threatening consequences (eg, 
hypotensive shock) 
Dysphagia or Odynophagia 
Report only 1 and specify location 
Symptoms but able to eat usual diet 
Symptoms causing altered dietary 
intake with no intervention indicated 
Symptoms causing severely 
altered dietary intake with 
intervention indicated 
Life-threatening reduction in oral intake 
Gastrointestinal Bleeding 
Not requiring intervention other 
than iron supplement 
Endoscopic intervention indicated 
Transfusion indicated 
Life-threatening consequences (eg, 
hypotensive shock) 
Mucositis or Stomatitis 
Report only 1 and specify location 
Mucosal erythema 
Patchy pseudomembranes or 
ulcerations 
Confluent pseudomembranes or 
ulcerations OR Mucosal 
bleeding with minor trauma 
Life-threatening consequences (eg, 
aspiration, choking) OR Tissue necrosis 
OR Diffuse spontaneous mucosal 
bleeding 
Nausea 
Transient (<24 hours) or intermittent 
AND No or minimal interference 
with oral intake 
Persistent nausea resulting in decreased 
oral intake for 24 to 48 hours 
Persistent nausea resulting in 
minimal oral intake for >48 
hours OR Rehydration indicated 
(eg, IV fluids) 
Life-threatening consequences (eg, 
hypotensive shock) 
Pancreatitis 
NA 
Symptoms with hospitalization not 
indicated 
Symptoms with hospitalization 
indicated 
Life-threatening consequences (eg, 
circulatory failure, hemorrhage, sepsis) 
Perforation 
(colon or rectum) 
NA 
NA 
Intervention indicated 
Life-threatening consequences 


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Gastrointestinal 
Parameter 
Grade 1 Mild 
Grade 2 Moderate 
Grade 3 Severe 
Grade 4 Potentially Life-threatening 
Proctitis 
Rectal discomfort with no 
intervention indicated 
Symptoms causing greater than 
minimal interference with usual social 
and functional activities OR Medical 
intervention indicated 
Symptoms causing inability to 
perform usual social and 
functional activities OR 
Operative intervention indicated 
Life-threatening consequences (eg, 
perforation) 
Rectal Discharge 
Visible discharge 
Discharge requiring the use of pads 
NA 
NA 
Vomiting 
Transient or intermittent AND No or 
minimal interference with oral 
intake 
Frequent episodes with no or mild 
dehydration 
Persistent vomiting resulting in 
orthostatic hypotension OR 
Aggressive rehydration indicated 
(eg, IV fluids) 
Life-threatening consequences (eg, 
hypotensive shock) 
Abbreviations: IV = intravenous; NA = not applicable. 


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Musculoskeletal 
Parameter 
Grade 1 Mild 
Grade 2 Moderate 
Grade 3 Severe 
Grade 4 Potentially Life-threatening 
Arthralgia 
Joint pain causing no or minimal 
interference with usual social and 
functional activities 
Joint pain causing greater than 
minimal interference with usual 
social and functional activities 
Joint pain causing inability to 
perform usual social and 
functional activities 
Disabling joint pain causing inability to 
perform basic self-care functions 
Arthritis 
Stiffness or joint swelling causing no 
or minimal interference with usual 
social and functional activities 
Stiffness or joint swelling causing 
greater than minimal interference 
with usual social and functional 
activities 
Stiffness or joint swelling causing 
inability to perform usual social 
and functional activities 
Disabling joint stiffness or swelling 
causing inability to perform basic 
self-care functions 
Myalgia (generalized) 
Muscle pain causing no or minimal 
interference with usual social and 
functional activities 
Muscle pain causing greater than 
minimal interference with usual 
social and functional activities 
Muscle pain causing inability to 
perform usual social and 
functional activities 
Disabling muscle pain causing inability 
to perform basic self-care functions 
Osteonecrosis 
NA 
No symptoms but with radiographic 
findings AND No operative 
intervention indicated 
Bone pain with radiographic 
findings OR Operative 
intervention indicated 
Disabling bone pain with radiographic 
findings causing inability to perform 
basic self-care functions 
Osteopenia e 
 ≥30 years of age 
BMD t-score -2.5 to -1 
NA 
NA 
NA 
<30 years of age 
BMD z-score -2 to -1 
NA 
NA 
NA 
Osteoporosis e 
≥30 years of age 
NA 
 BMD t-score <-2.5 
Pathologic fracture (eg, 
compression fracture causing loss 
of vertebral height) 
 Pathologic fracture causing 
life-threatening consequences 
<30 years of age 
NA 
BMD z-score <-2 
Pathologic fracture (eg, 
compression fracture causing loss 
of vertebral height) 
Pathologic fracture causing 
life-threatening consequences 
Abbreviations: BMD = bone mineral density; NA = not applicable; WHO = World Health Organization. 
e.  Bone mineral density t and z scores can be found in WHO 2007. 


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Neurologic 
Parameter 
Grade 1 Mild 
Grade 2 Moderate 
Grade 3 Severe 
Grade 4 Potentially Life-
threatening 
Acute CNS Ischemia 
NA 
NA 
Transient ischemic attack 
Cerebral vascular accident (eg, stroke 
with neurological deficit) 
Altered Mental Status 
(for Dementia, see Cognitive, 
Behavioral, or Attentional 
Disturbance below) 
Changes causing no or minimal 
interference with usual social and 
functional activities 
Mild lethargy or somnolence causing 
greater than minimal interference 
with usual social and functional 
activities 
Confusion, memory impairment, 
lethargy, or somnolence causing 
inability to perform usual social 
and functional activities 
Delirium OR Obtundation OR Coma 
Ataxia 
Symptoms causing no or minimal 
interference with usual social and 
functional activities OR No 
symptoms with ataxia detected on 
examination 
Symptoms causing greater than 
minimal interference with usual 
social and functional activities 
Symptoms causing inability to 
perform usual social and 
functional activities 
Disabling symptoms causing inability to 
perform basic self-care functions 
Cognitive, Behavioral, or 
Attentional Disturbance 
(includes dementia and attention 
deficit disorder) 
Specify type, if applicable 
Disability causing no or minimal 
interference with usual social and 
functional activities OR Specialized 
resources not indicated 
Disability causing greater than 
minimal interference with usual 
social and functional activities OR 
Specialized resources on part-time 
basis indicated 
Disability causing inability to 
perform usual social and 
functional activities OR 
Specialized resources on a 
full-time basis indicated 
Disability causing inability to perform 
basic self-care functions OR 
Institutionalization indicated 
Headache 
Symptoms causing no or minimal 
interference with usual social and 
functional activities 
Symptoms causing greater than 
minimal interference with usual 
social and functional activities 
Symptoms causing inability to 
perform usual social and 
functional activities 
Symptoms causing inability to perform 
basic self-care functions OR 
Hospitalization indicated OR Headache 
with significant impairment of alertness 
or other neurologic function 
Neuromuscular Weakness 
(includes myopathy and neuropathy)  
Specify type, if applicable 
Minimal muscle weakness causing no 
or minimal interference with usual 
social and functional activities OR 
No symptoms with decreased 
strength on examination 
Muscle weakness causing greater 
than minimal interference with usual 
social and functional activities 
Muscle weakness causing inability 
to perform usual social and 
functional activities 
Disabling muscle weakness causing 
inability to perform basic self-care 
functions OR Respiratory muscle 
weakness impairing ventilation 
Neurosensory Alteration 
(includes paresthesia and painful 
neuropathy) 
Specify type, if applicable 
Minimal paresthesia causing no or 
minimal interference with usual 
social and functional activities OR 
No symptoms with sensory alteration 
on examination 
Sensory alteration or paresthesia 
causing greater than minimal 
interference with usual social and 
functional activities 
Sensory alteration or paresthesia 
causing inability to perform usual 
social and functional activities 
Disabling sensory alteration or 
paresthesia causing inability to perform 
basic self-care functions 
Seizures 
New Onset Seizure 
≥18 years of age 
NA 
NA 
 1 to 3 seizures 
 Prolonged and repetitive seizures (eg, 
status epilepticus) OR Difficult to 
control (eg, refractory epilepsy) 


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Neurologic 
Parameter 
Grade 1 Mild 
Grade 2 Moderate 
Grade 3 Severe 
Grade 4 Potentially Life-
threatening 
Pre-existing Seizure 
NA 
Increased frequency from previous 
level of control without change in 
seizure character 
Change in seizure character either 
in duration or quality (eg, severity 
or focality) 
Prolonged and repetitive seizures (eg, 
status epilepticus) OR Difficult to 
control (eg, refractory epilepsy) 
Syncope 
Near syncope without loss of 
consciousness (eg, presyncope) 
Loss of consciousness with no 
intervention indicated 
Loss of consciousness AND 
Hospitalization or intervention 
required 
NA 
Abbreviations: CNS = central nervous system; NA = not applicable. 


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Pregnancy, Puerperium, and Perinatal 
Parameter 
Grade 1 Mild 
Grade 2 Moderate 
Grade 3 Severe 
Grade 4 Potentially Life-
threatening 
Stillbirth (report using mother’s 
subject ID) 
Report only one 
NA 
NA 
Fetal death occurring at ≥20 weeks 
gestation 
NA 
Preterm Birth (report using 
mother’s subject ID) 
Live birth at 34 to <37 weeks 
gestational age 
Live birth at 28 to <34 weeks 
gestational age 
Live birth at 24 to <28 weeks 
gestational age 
Live birth at <24 weeks gestational 
age 
Spontaneous Abortion or 
Miscarriage f (report using mother’s 
subject ID) 
Report only one 
Chemical pregnancy 
Uncomplicated spontaneous abortion 
or miscarriage 
Complicated spontaneous abortion or 
miscarriage 
NA 
Abbreviations: ID = identification; NA = not applicable. 
f.  Definition: A pregnancy loss occurring at <20 weeks gestational age. 


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Psychiatric 
Parameter 
Grade 1 Mild 
Grade 2 Moderate 
Grade 3 Severe 
Grade 4 Potentially Life-
threatening 
Insomnia 
Mild difficulty falling asleep, staying 
asleep, or waking up early causing no 
or minimal interference with usual 
social and functional activities 
Moderate difficulty falling asleep, 
staying asleep, or waking up early 
causing more than minimal 
interference with usual social and 
functional activities 
Severe difficulty falling asleep, 
staying asleep, or waking up early 
causing inability to perform usual 
social and functional activities 
requiring intervention or 
hospitalization 
NA 
Psychiatric Disorders 
(includes anxiety, depression, mania, 
and psychosis) 
Specify disorder 
Symptoms with intervention not 
indicated OR Behavior causing no or 
minimal interference with usual 
social and functional activities 
Symptoms with intervention 
indicated OR Behavior causing 
greater than minimal interference 
with usual social and functional 
activities 
Symptoms with hospitalization 
indicated OR Behavior causing 
inability to perform usual social and 
functional activities 
Threatens harm to self or others OR 
Acute psychosis OR Behavior 
causing inability to perform basic 
self-care functions 
Suicidal Ideation or Attempt 
Report only one 
Preoccupied with thoughts of death 
AND No wish to kill oneself 
Preoccupied with thoughts of death 
AND Wish to kill oneself with no 
specific plan or intent 
Thoughts of killing oneself with 
partial or complete plans but no 
attempt to do so OR Hospitalization 
indicated 
Suicide attempted 
Abbreviation: NA = not applicable. 


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Respiratory 
Parameter 
Grade 1 Mild 
Grade 2 Moderate 
Grade 3 Severe 
Grade 4 Potentially Life-
threatening 
Acute Bronchospasm 
Forced expiratory volume in 1 
second or peak flow reduced to ≥70 
to <80% OR Mild symptoms with 
intervention not indicated 
Forced expiratory volume in 1 
second or peak flow 50 to <70% OR 
Symptoms with intervention 
indicated OR Symptoms causing 
greater than minimal interference 
with usual social and functional 
activities 
Forced expiratory volume in 1 
second or peak flow 25 to <50% OR 
Symptoms causing inability to 
perform usual social and functional 
activities 
Forced expiratory volume in 1 
second or peak flow <25% OR 
Life-threatening respiratory or 
hemodynamic compromise OR 
Intubation 
Dyspnea or Respiratory Distress 
Report only one 
Dyspnea on exertion with no or 
minimal interference with usual 
social and functional activities OR 
Wheezing OR Minimal increase in 
respiratory rate for age 
Dyspnea on exertion causing greater 
than minimal interference with usual 
social and functional activities OR 
Nasal flaring OR Intercostal 
retractions OR Pulse oximetry 90 to 
<95% 
Dyspnea at rest causing inability to 
perform usual social and functional 
activities OR Pulse oximetry <90% 
Respiratory failure with ventilator 
support indicated (eg, CPAP, BPAP, 
intubation) 
Abbreviations: CPAP = continuous positive airway pressure, BPAP = bilevel positive airway pressure. 


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Sensory 
Parameter 
Grade 1 Mild 
Grade 2 Moderate 
Grade 3 Severe 
Grade 4 Potentially Life-
threatening 
Hearing Loss 
≥12 years of age 
NA 
Hearing aid or intervention not 
indicated 
Hearing aid or intervention indicated 
Profound bilateral hearing loss (>80 
dB at 2 kHz and above) OR 
Non-serviceable hearing (ie, >50 dB 
audiogram and <50% speech 
discrimination) 
Tinnitus 
Symptoms causing no or minimal 
interference with usual social and 
functional activities with intervention 
not indicated 
Symptoms causing greater than 
minimal interference with usual 
social and functional activities with 
intervention indicated 
Symptoms causing inability to 
perform usual social and functional 
activities 
NA 
Uveitis 
No symptoms AND Detectable on 
examination 
Anterior uveitis with symptoms OR 
Medical intervention indicated 
Posterior or pan-uveitis OR 
Operative intervention indicated 
Disabling visual loss in affected 
eye(s) 
Vertigo 
Vertigo causing no or minimal 
interference with usual social and 
functional activities 
Vertigo causing greater than minimal 
interference with usual social and 
functional activities 
Vertigo causing inability to perform 
usual social and functional activities 
Disabling vertigo causing inability to 
perform basic self-care functions 
Visual Changes 
(assessed from Baseline) 
Visual changes causing no or 
minimal interference with usual 
social and functional activities 
Visual changes causing greater than 
minimal interference with usual 
social and functional activities 
Visual changes causing inability to 
perform usual social and functional 
activities 
Disabling visual loss in affected 
eye(s) 
Abbreviations: dB = decibel; kHz = kilohertz; NA = not applicable. 


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Systemic 
Parameter 
Grade 1 Mild 
Grade 2 Moderate 
Grade 3 Severe 
Grade 4 Potentially Life-
threatening 
Acute Allergic Reaction 
Localized urticaria (wheals) with no 
medical intervention indicated 
Localized urticaria with intervention 
indicated OR Mild angioedema with 
no intervention indicated 
Generalized urticaria OR 
Angioedema with intervention 
indicated OR Symptoms of mild 
bronchospasm 
Acute anaphylaxis OR Life-
threatening bronchospasm OR 
Laryngeal edema 
Chills 
Symptoms causing no or minimal 
interference with usual social and 
functional activities 
Symptoms causing greater than 
minimal interference with usual 
social and functional activities 
Symptoms causing inability to 
perform usual social and functional 
activities 
NA 
Cytokine Release Syndrome g 
Mild signs and symptoms AND 
Therapy (ie, antibody infusion) 
interruption not indicated 
Therapy (ie, antibody infusion) 
interruption indicated AND 
Responds promptly to symptomatic 
treatment OR Prophylactic 
medications indicated for ≤24 hours 
Prolonged severe signs and 
symptoms OR Recurrence of 
symptoms following initial 
improvement 
Life-threatening consequences (eg, 
requiring pressor or ventilator 
support) 
Fatigue or Malaise 
Report only one 
Symptoms causing no or minimal 
interference with usual social and 
functional activities 
Symptoms causing greater than 
minimal interference with usual 
social and functional activities 
Symptoms causing inability to 
perform usual social and functional 
activities 
Incapacitating symptoms of fatigue 
or malaise causing inability to 
perform basic self-care functions 
Fever (non-axillary temperatures 
only) 
38.0 to <38.6°C or 100.4 to <101.5°F 
≥38.6 to <39.3°C or ≥101.5 to 
<102.7°F 
≥39.3 to <40.0°C or ≥102.7 to 
<104.0°F 
≥40.0°C or ≥104.0°F 
Pain h (not associated with study 
agent injections and not specified 
elsewhere) 
Specify location 
Pain causing no or minimal 
interference with usual social and 
functional activities 
Pain causing greater than minimal 
interference with usual social and 
functional activities 
Pain causing inability to perform 
usual social and functional activities 
Disabling pain causing inability to 
perform basic self-care functions OR 
Hospitalization indicated 
Serum Sickness i 
Mild signs and symptoms 
Moderate signs and symptoms AND 
Intervention indicated (eg, 
antihistamines) 
Severe signs and symptoms AND 
Higher level intervention indicated 
(eg, steroids or IV fluids) 
Life-threatening consequences (eg, 
requiring pressor or ventilator 
support) 
Underweight j 
>5 to 19 years of age 
WHO BMI z-score  
<-1 to -2 
WHO BMI z-score 
 <-2 to -3 
WHO BMI z-score <-3 
WHO BMI z-score <-3 with life-
threatening consequences 
Unintentional Weight Loss  
(excludes postpartum weight loss) 
NA 
5 to <9% loss in body weight from 
Baseline 
≥9 to <20% loss in body weight from 
Baseline 
≥20% loss in body weight from 
Baseline OR Aggressive intervention 
indicated (eg, tube feeding, total 
parenteral nutrition) 
Abbreviations: BMI = body mass index; IV = intravenous; NA = not applicable; WHO = World Health Organization. 
g.  Definition: A disorder characterized by nausea, headache, tachycardia, hypotension, rash, and/or shortness of breath. 
h.  For pain associated with injections or infusions, see the Site Reactions to Injections and Infusions section. 
i.  Definition: A disorder characterized by fever, arthralgia, myalgia, skin eruptions, lymphadenopathy, marked discomfort, and/or dyspnea. 
j. WHO reference tables for subjects >5 to 19 years of age may be accessed at the following URL: http://www.who.int/growthref/who2007_bmi_for_age/en/. 


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Urinary 
Parameter 
Grade 1 Mild 
Grade 2 Moderate 
Grade 3 Severe 
Grade 4 Potentially Life-
threatening 
Urinary Tract Obstruction 
NA 
Signs or symptoms of urinary tract 
obstruction without hydronephrosis 
or renal dysfunction 
Signs or symptoms of urinary tract 
obstruction with hydronephrosis or 
renal dysfunction 
Obstruction causing life-threatening 
consequences 
Abbreviation: NA = not applicable. 


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Laboratory Values k: Chemistries 
Parameter 
Grade 1 Mild 
Grade 2 Moderate 
Grade 3 Severe 
Grade 4 Potentially Life-threatening 
Acidosis 
NA 
pH ≥7.3 to <LLN 
pH <7.3 without life-threatening 
consequences 
pH <7.3 with life-threatening 
consequences 
Albumin, Low 
(g/dL; g/L) 
3.0 to <LLN 
30 to <LLN 
≥2.0 to <3.0 
≥20 to <30 
<2.0 
<20 
NA 
Alkaline Phosphatase, High 
1.25 to <2.5 × ULN 
2.5 to <5.0 × ULN 
5.0 to <10.0 × ULN 
≥10.0 × ULN 
Alkalosis 
NA 
pH >ULN to ≤7.5 
pH >7.5 without life-threatening 
consequences 
pH >7.5 with life-threatening 
consequences 
ALT or SGPT, High 
Report only one 
1.25 to <2.5 × ULN 
2.5 to <5.0 × ULN 
5.0 to <10.0 × ULN 
≥10.0 × ULN 
Amylase (Pancreatic) or Amylase (Total), 
High 
Report only one 
1.1 to <1.5 × ULN 
1.5 to <3.0 × ULN 
3.0 to <5.0 × ULN 
≥5.0 × ULN 
AST or SGOT, High 
Report only one 
1.25 to <2.5 × ULN 
2.5 to <5.0 × ULN 
5.0 to <10.0 × ULN 
≥10.0 × ULN 
Bicarbonate, Low  
(mEq/L; mmol/L) 
16.0 to <LLN 
16.0 to <LLN 
11.0 to <16.0 
11.0 to <16.0 
8.0 to <11.0 
8.0 to <11.0 
<8.0  
<8.0 
Bilirubin 
Direct Bilirubin, High 
 
NA 
 
NA 
 
>ULN with other signs and symptoms 
of hepatotoxicity 
 
>ULN with life-threatening 
consequences (eg, signs and symptoms 
of liver failure) 
Total Bilirubin, High  
1.1 to <1.6 × ULN 
 1.6 to <2.6 × ULN 
2.6 to <5.0 × ULN 
≥5.0 × ULN 
Calcium, High 
(mg/dL; mmol/L)  
10.6 to <11.5  
2.65 to <2.88 
11.5 to <12.5  
2.88 to <3.13 
12.5 to <13.5  
3.13 to <3.38 
≥13.5  
≥3.38 
Calcium (Ionized), High 
(mg/dL; mmol/L) 
>ULN to <6.0 
>ULN to <1.5 
6.0 to <6.4 
1.5 to <1.6 
6.4 to <7.2  
1.6 to <1.8 
≥7.2  
≥1.8 
Calcium, Low 
(mg/dL; mmol/L)  
7.8 to <8.4 
1.95 to <2.10 
7.0 to <7.8  
1.75 to <1.95 
6.1 to <7.0  
1.53 to <1.75 
 <6.1  
<1.53 
Calcium (Ionized), Low 
(mg/dL; mmol/L) 
<LLN to 4.0  
<LLN to 1.0 
3.6 to <4.0  
0.9 to <1.0 
3.2 to <3.6  
0.8 to <0.9 
<3.2  
<0.8 
Cardiac Troponin I, High 
NA 
NA 
NA 
Levels consistent with myocardial 
infarction or unstable angina as 
defined by the local laboratory 
Creatine Kinase, High 
3 to <6 × ULN 
6 to <10 × ULN 
10 to <20 × ULN 
≥20 × ULN 
Creatinine, High l 
Report only one 
1.1 to 1.3× U LN 
>1.3 to 1.8 × ULN OR Increase to 
1.3 to <1.5 × subject’s Baseline 
>1.8 to <3.5 × ULN OR Increase to 
1.5 to <2.0×subject’s Baseline 
≥3.5 × ULN OR Increase of ≥2.0 × 
subject’s Baseline 


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Laboratory Values k: Chemistries 
Parameter 
Grade 1 Mild 
Grade 2 Moderate 
Grade 3 Severe 
Grade 4 Potentially Life-threatening 
Creatinine Clearance l,m 
or eGFR, Low 
Report only one 
NA 
<90 to 60 mL/min or mL/min/1.73 
m2 OR 10 to <30% decrease from 
subject’s Baseline 
<60 to 30 mL/min or mL/min/1.73 m2 
OR 30 to <50% decrease from 
subject’s Baseline 
<30 mL/min or mL/min/1.73 m2 OR 
≥50% decrease from subject’s 
Baseline or dialysis needed 
Glucose (mg/dL; mmol/L) 
Fasting, High 
110 to 125  
6.11 to <6.95 
>125 to 250 
6.95 to <13.89 
>250 to 500 
 13.89 to <27.75 
≥500 
≥27.75 
Nonfasting, High 
116 to 160 
6.44 to <8.89 
>160 to 250  
8.89 to <13.89 
>250 to 500 
13.89 to <27.75 
≥500 
≥27.75 
Glucose, Low (mg/dL; mmol/L)  
 55 to 64 
3.05 to <3.55 
40 to <55 
2.22 to <3.05 
30 to <40 
1.67 to <2.22 
 <30 
<1.67 
Lactate, High 
ULN to <2.0 × ULN 
without acidosis 
≥2.0 × ULN without acidosis 
Increased lactate with pH <7.3 without 
life-threatening consequences 
Increased lactate with pH <7.3 with 
life-threatening consequences 
Lipase, High 
1.1 to <1.5 × ULN 
1.5 to <3.0 × ULN 
3.0 to <5.0 × ULN 
≥5.0 × ULN 
Lipid Disorders (mg/dL; mmol/L) 
Cholesterol, Fasting, High 
≥18 years of age 
 
200 to <240 
5.18 to <6.19 
 
240 to <300 
6.19 to <7.77 
 
≥300 
≥7.77 
 
NA 
LDL, Fasting, High 
≥18 years of age 
130 to <160 
3.37 to <4.12 
160 to <190  
4.12 to <4.90 
≥190 
≥4.90 
NA 
Triglycerides, Fasting, High 
150 to 300 
1.71 to 3.42 
>300 to 500  
>3.42 to 5.7 
>500 to <1,000 
>5.7 to 11.4 
>1,000 
>11.4 
Magnesium n, Low 
(mEq/L; mmol/L) 
1.2 to <1.4  
0.60 to <0.70 
0.9 to <1.2  
0.45 to <0.60 
0.6 to <0.9  
0.30 to <0.45 
<0.6 
<0.30 
Phosphate, Low 
(mg/dL; mmol/L)  
2.0 to <LLN 
0.65 to <LLN 
1.4 to <2.0  
0.45 to <0.65 
1.0 to <1.4  
0.32 to <0.45 
 <1.0 
<0.32 
Potassium, High 
(mEq/L; mmol/L) 
5.6 to <6.0  
5.6 to <6.0 
6.0 to <6.5  
6.0 to <6.5 
6.5 to <7.0  
6.5 to <7.0 
≥7.0  
≥7.0 
Potassium, Low 
(mEq/L; mmol/L) 
3.0 to <3.4  
3.0 to <3.4 
2.5 to <3.0 
2.5 to <3.0 
2.0 to <2.5  
2.0 to <2.5 
<2.0 
<2.0 
Sodium, High 
(mEq/L; mmol/L) 
146 to <150 
146 to <150 
150 to <154  
150 to <154 
154 to <160  
154 to <160 
≥160  
≥160 
Sodium, Low  
mEq/L; mmol/L) 
130 to <135  
130 to <135 
125 to <130  
125 to <130 
121 to <125  
121 to <125 
≤120 
≤120 
Uric Acid, High 
(mg/dL; mmol/L) 
7.5 to <10.0  
0.45 to <0.59 
10.0 to <12.0  
0.59 to <0.71 
12.0 to <15.0 
0.71 to <0.89 
≥15.0 
≥0.89 
Abbreviations; ALT = alanine aminotransferase; AST = aspartate aminotransferase; eGFR = estimated glomerular filtration rate; LDL = low-density lipoprotein; LLN = lower limit of normal; NA = not 
applicable; SGOT = serum glutamic oxaloacetic transaminase; SGPT = serum glutamic pyruvic transaminase; ULN = upper limit of normal.  
k.  Reminder: An asymptomatic abnormal laboratory finding without an accompanying adverse event should not be reported to DAIDS in an expedited time frame unless it meets protocol-specific 
reporting requirements. 
l.  Reminder: Choose the method that selects for the higher grade. 


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m. Use the applicable formula (ie, Cockcroft-Gault in mL/min or Schwartz, MDRD, CKD-Epi in mL/min/1.73m2). Sites should choose the method defined in their study and when not specified, use the 
method most relevant to the study population. 
n.  To convert a magnesium value from mg/dL to mmol/L, laboratories should multiply by 0.4114. 
 


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Laboratory Values: Hematology 
Parameter 
Grade 1 Mild 
Grade 2 Moderate 
Grade 3 Severe 
Grade 4 Potentially Life-
Threatening 
Absolute CD4+ Count, Low 
(cell/mm3; cells/L) (not HIV infected) 
300 to <400 
300 to <400 
200 to <300 
200 to <300 
100 to <200 
100 to <200 
<100 
<100 
Absolute Lymphocyte Count, Low 
(cell/mm3; cells/L) (not HIV infected) 
600 to <650 
0.600 × 109 to <0.650×109 
500 to <600 
0.500 × 109 to <0.600×109 
350 to <500 
0.350 × 109 to <0.500 × 109 
<350  
<0.350 × 109 
Absolute Neutrophil Count (ANC), 
Low (cells/mm3; cells/L) 
800 to 1,000  
0.800 × 109 to 1.000 × 109 
600 to 799 
0.600 × 109 to 0.799 × 109 
400 to 599 
0.400 × 109 to 0.599 × 109 
<400 
<0.400 × 109 
Fibrinogen, Decreased 
(mg/dL; g/L) 
100 to <200 
1.00 to <2.00 OR 0.75 to <1.00 × 
LLN 
75 to <100 
0.75 to <1.00 OR ≥0.50 to <0.75 × 
LLN 
50 to <75 
0.50 to <0.75 OR 0.25 to <0.50 × 
LLN 
<50 
<0.50 OR <0.25 × LLN OR 
Associated with gross bleeding 
Hemoglobin o, Low (g/dL; mmol/L) p  
≥13 years of age; male only 
10.0 to 10.9 
6.19 to 6.76 
9.0 to <10.0 
5.57 to <6.19 
7.0 to <9.0 
4.34 to <5.57 
<7.0 
<4.34 
Hemoglobin p, Low (g/dL; mmol/L) p  
≥13 years of age; female only 
9.5 to 10.4 
5.88 to 6.48 
8.5 to <9.5 
5.25 to <5.88 
6.5 to <8.5 
4.03 to <5.25 
<6.5 
<4.03 
INR, High 
(not on anticoagulation therapy) 
1.1 to <1.5 × ULN 
1.5 to <2.0 × ULN 
2.0 to <3.0 × ULN 
≥3.0 × ULN 
Methemoglobin 
(% hemoglobin) 
5.0 to <10.0% 
10.0 to <15.0% 
15.0 to <20.0% 
≥20.0% 
PTT, High 
(not on anticoagulation therapy) 
1.1 to <1.66 × ULN 
1.66 to <2.33 × ULN 
2.33 to <3.00 × ULN 
≥3.00 × ULN 
Platelets, Decreased 
(cells/mm3; cells/L) 
100,000 to <125,000 
100.000 × 109 to <125.000 × 109 
50,000 to <100,000 
50.000 × 109 to <100.000 × 109 
25,000 to <50,000 
25.000 × 109 to <50.000 × 109 
<25,000  
<25.000 × 109 
PT, High 
(not on anticoagulation therapy) 
1.1 to <1.25 × ULN 
1.25 to <1.50 × ULN 
1.50 to <3.00 × ULN 
≥3.00 × ULN 
WBC, Decreased 
(cells/mm3; cells/L)  
2,000 to 2,499  
2.000 × 109 to 2.499 × 109 
1,500 to 1,999  
1.500 × 109 to 1.999 × 109 
1,000 to 1,499  
1.000 × 109 to 1.499 × 109 
<1,000 
<1.000 × 109 
Abbreviations: HIV = human immunodeficiency virus; INR = international normalized ratio; LLN = lower limit of normal; PT = prothrombin time; PTT = partial thromboplastin time; WBC = white blood 
cell; ULN = upper limit of normal. 
o.  Male and female sex are defined as sex at birth. For transgender subjects who have been on hormone therapy for more than 6 consecutive months, grade hemoglobin based on the gender with which 
they identify (ie, a transgender female should be graded using the female sex at birth hemoglobin laboratory values). 
p.  The most commonly used conversion factor to convert g/dL to mmol/L is 0.6206. For grading hemoglobin results obtained by an analytic method with a conversion factor other than 0.6206, the result 
must be converted to g/dL using appropriate conversion factor for the particular laboratory. 


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Laboratory Values: Urinalysis 
Parameter 
Grade 1 Mild 
Grade 2 Moderate 
Grade 3 Severe 
Grade 4 Potentially Life-
Threatening 
Glycosuria (random collection tested 
by dipstick) 
Trace to 1+ or ≤250 mg 
2+ or ˃250 to ≤500 mg 
>2+ or >500 mg 
NA 
Hematuria (not to be reported based 
on dipstick findings or on blood 
believed to be of menstrual origin) 
6 to <10 RBCs per high power field 
≥10 RBCs per high power field 
Gross, with or without clots OR with 
RBC casts OR Intervention indicated 
Life-threatening consequences 
Proteinuria (random collection 
tested by dipstick) 
1+ 
2+ 
3+ or higher 
NA 
 
Abbreviations: NA = not applicable; RBC = red blood cells. 
 


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APPENDIX 4 
PREGNANCY PRECAUTIONS AND THE DEFINITION OF 
CHILDBEARING POTENTIAL AND CONTRACEPTIVE 
REQUIREMENTS 
Pregnancy Precautions 
Embryofetal development studies with 731 have not been conducted in animals, therefore effects of 
731 on pregnancy are unknown. Contraceptive requirements for female subjects of childbearing 
potential are required as described below. Contraceptive requirements for ETV and Peg-IFNα are 
described in the respective package inserts. 
Definition of Female Subjects of Childbearing Potential  
A female subject is considered of childbearing potential following menarche and until becoming 
postmenopausal unless permanently sterile (see below). 
If fertility is unclear (eg, amenorrhea in adolescents or athletes) and a menstrual cycle cannot be 
confirmed before first dose of study drug, additional evaluation should be considered. 
Female subjects in the following categories are not considered of childbearing potential  
Premenopausal with one of the following: 
• Documented hysterectomy 
• Documented bilateral salpingectomy 
• Documented bilateral oophorectomy 
Postmenopausal: A postmenopausal state is defined as no menses for 12 months without an alternative 
medical cause. 
A high FSH level in the postmenopausal range may be used to confirm a postmenopausal state in 
women not using hormonal contraception or hormonal replacement therapy (HRT). However, in the 
absence of 12 months of amenorrhea, confirmation with more than 1 FSH measurement is required. 
Females on HRT and whose menopausal status is in doubt will be required to use one of the non-
estrogen hormonal highly effective contraception methods if they wish to continue their HRT during 
the study. Otherwise, they must discontinue HRT to allow confirmation of postmenopausal status 
before study enrollment. 
For individuals with permanent infertility due to an alternate medical cause other than the above, (eg, 
Müllerian agenesis, androgen insensitivity), Investigator discretion should be applied to determining 
study entry. 
Documentation to determine childbearing potential can come from the site personnel’s review of the 
subject’s medical records, medical examination, or medical history interview. 
Contraceptive Requirements 
Note that the drug-drug interaction of 731 and systemic (oral/injectable/implantable) hormonal birth 
control has not been assessed; therefore, systemic hormonal birth control is not considered an effective 
birth control method for female subjects for the purposes of this study.  


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Female subjects of childbearing potential (defined above) must agree to use dual effective birth control 
methods for the duration of the study including the follow-up period. Effective birth control methods 
include male or female condom (may not be used together due to increased risk of breakage), 
vasectomy, tubal sterilization, intrauterine device (IUD), diaphragm, or cervical cap. Female subjects 
must have a negative serum pregnancy test at Screening and a negative urine pregnancy test prior to 
receiving the first dose of study drug at Baseline (Day 1). 
All male subjects must agree to use dual effective birth control methods with their female partners if 
they are of childbearing potential for the duration of the study including the follow-up period. In this 
case, effective birth control methods include systemic (oral/injectable/implantable) hormonal birth 
control, male or female condom (may not be used together due to increased risk of breakage), 
vasectomy, tubal sterilization, IUD, diaphragm, or cervical cap. Male subjects must avoid sperm 
donation from the time of the first dose of study drug and throughout the study period, and for at least 
30 days after administration of the last dose of study drug. 


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APPENDIX 5 
CYTOCHROME P450 3A4 INHIBITORS AND INDUCERS 
AND CYP2C9 SUBSTRATES 
The following drugs are known inhibitors of CYP3A4 and should be avoided when taking 731: 
CYP3A4 Inhibitors 
HIV antivirals 
indinavir, nelfinavir, ritonavir, saquinavir 
Other 
clarithromycin, itraconazole, ketoconazole, nefazodone, saquinavir, idelalisib, 
ribociclib, telithromycin, aprepitant, erythromycin, fluconazole, grapefruit, grapefruit 
juice, netupitant/palonosetrone, verapamil, diltiazem, voriconazole cimetidine, 
amiodarone, NOT azithromycin, chloramphenicol, boceprevir, ciprofloxacin, 
delaviridine, diethyl-dithiocarbamate, fluvoxamine, gestodene, imatinib, mibefradil, 
mifepristone, norfloxacin, norfluoxetine, starfruit, telaprevir, voriconazole 
The following drugs are known substrates of CYP2C9 and are prohibited or should be avoided when 
taking 731: 
CYP2C9 Substrates 
Narrow therapeutic index 
substrates that are prohibited 
while taking 731 
Warfarin, phenytoin 
Substrates that should be 
avoided while taking 731 
Amitriptyline, capecitabine, celecoxib, clopidogrel, diclofenac, doxepin, fluoxetine, 
Fluvastatin, glibenclamide, glimepiride, glipizide, glyburide, ibuprofen, irbesartan, 
lesinurad, lornixicam, losartan, meloxicam, nateglinide, piroxicam, rosiglitazone, 
naproxen, suprofen, tamoxifen, tolbutamide, torsemide, valproic acid, venlafaxine, 
voriconazole, zakirlukast 
The following drugs are known inducers of CYP3A4 and should be avoided when taking 731: 
CYP3A4 Inducers 
Inducers that should be 
avoided while taking 731 
Barbiturates, brigatinib, carbamazepine, efavirenz, enzalutamide, glucocorticoids, 
modafinil, nevirapine, oxcarbazepine, phenobarbital, phenytoin, pioglitazone, rifabutin, 
rifampin, st. john’s wort, troglitazone 
Abbreviations: 731 = ABI-H0731; CYP = cytochrome P450. 
Source: The Flockhart Table. http://medicine.iupui.edu/clinpharm/ddis/main-table# (Accessed 6 March 2020). 
Note: Refer to Exclusion Criterion #1, Section 5.3 of the protocol for prohibited medications. 
Additionally, the list of medications included in this appendix is not exhaustive. The Investigator 
should evaluate the mechanism of other concomitant medications to determine if they should be 
allowed in the study.  
The details of prohibited concomitant medications and medications with a potential for drug-drug 
interactions with ETV and Peg-IFNα are described in the respective package inserts. 


Study Title: A Randomized Phase 2a, Multicenter, Open-label Study Evaluating ABI-H0731-
Containing Regimens in Patients with Chronic Hepatitis B 
 
NCT Number: 04781647 
 
Date of Document: 09 January 2023 
 


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STATISTICAL ANALYSIS PLAN 
 
Sponsor:  
Assembly Biosciences, Inc  
331 Oyster Point Blvd 
South San Francisco, CA 94030  
 
 
Protocol Number: 
ABI-H0731-203 
 
 
Protocol Title: 
A Randomized Phase 2a, Multicenter, Open-Label 
Study Evaluating ABI-H0731-Containing Regimens in 
Patients with Chronic Hepatitis B  
 
Product: 
ABI-H0731 
 
 
 
 
Protocol Version (Date): 
Amendment 3.0 (29 July 2021) 
 
Indication: 
Chronic Hepatitis B Virus Infection 
 
Analysis Type: 
Final Analysis for Synoptic CSR 
 
 
 
Analysis Plan Version (Date): 
Version 2.0 (09 January 2023) 
 
 
 
 
 
Analysis Plan Author: 
Jieming Liu, MS 
 
 
 
 
CONFIDENTIAL AND PROPRIETARY INFORMATION


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STATISTICAL ANALYSIS PLAN APPROVAL FORM 
 
Protocol Title: 
A Randomized Phase 2a, Multicenter, Open-Label Study 
Evaluating ABI-H0731-Containing Regimens in Patients with 
Chronic Hepatitis B  
Protocol Number: 
ABI-H0731-203 
SAP Version (Date): 
Version 2.0 (09 January 2023) 
The SAP was subject to critical review and has been approved. 
Name and Title 
Approval Signature/Date 
Jieming Liu, MS 
 
Assembly Biosciences 
 
 
See e-signature page 
 
 
 
Grace Wang, MD 
 
 
Assembly Biosciences 
 
 
See e-signature page 
 
Michele Anderson 
 
Assembly Biosciences 
 
 
See e-signature page 
 
 
 
 
 
 
 


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1. 
INTRODUCTION ................................................................................................................................................ 7 
1.1. 
Study Objectives ...................................................................................................................................... 7 
1.2. 
Study Design ............................................................................................................................................ 8 
1.3. 
Sample Size and Power ............................................................................................................................ 8 
1.4. 
Methods of Assigning Subjects to Treatment .......................................................................................... 9 
1.4.1. 
Randomization ....................................................................................................................... 9 
1.4.2. 
Blinding .................................................................................................................................. 9 
2. 
TYPE OF PLANNED ANALYSIS .................................................................................................................... 10 
2.1. 
Interim Analyses .................................................................................................................................... 10 
2.2. 
Final Analysis ........................................................................................................................................ 10 
3. 
GENERAL CONSIDERATIONS FOR DATA ANALYSES ............................................................................ 11 
3.1. 
Analysis Sets .......................................................................................................................................... 11 
3.1.1. 
All Randomized Analysis Set ............................................................................................... 11 
3.1.2. 
Full Analysis Set .................................................................................................................. 11 
3.1.3. 
Safety Analysis Set ............................................................................................................... 11 
3.2. 
Subject Grouping ................................................................................................................................... 11 
3.3. 
Strata and Covariates .............................................................................................................................. 12 
3.4. 
Data Handling Conventions and Transformations ................................................................................. 12 
3.5. 
Missing Data and Outliers ...................................................................................................................... 13 
3.5.1. 
Missing Data ........................................................................................................................ 13 
3.5.2. 
Outliers ................................................................................................................................. 13 
3.6. 
Analysis Visit Windows ......................................................................................................................... 13 
3.6.1. 
Definition of Study Drug ...................................................................................................... 13 
3.6.2. 
Definition of Study Phase ..................................................................................................... 13 
3.6.3. 
Definition of Study Day ....................................................................................................... 13 
3.6.4. 
Analysis Visit Windows ....................................................................................................... 14 
3.6.5. 
Selection of Data in the Event of Multiple Records in an Analysis Visit 
Window ................................................................................................................................ 18 
4. 
SUBJECT DISPOSITION .................................................................................................................................. 19 
4.1. 
Subject Enrollment and Disposition ....................................................................................................... 19 
4.2. 
Extent of Study Drug Exposure and Compliance ................................................................................... 20 
4.2.1. 
Duration of Exposure to Study Drug .................................................................................... 20 
4.2.2. 
Study Drug Compliance ....................................................................................................... 21 
4.2.2.1. 
On-Treatment Compliance ............................................................................. 21 
4.3. 
Protocol Deviations ................................................................................................................................ 22 
5. 
BASELINE CHARACTERISTICS .................................................................................................................... 23 
5.1. 
Demographics and Baseline Characteristics .......................................................................................... 23 
5.2. 
Baseline Disease Characteristics ............................................................................................................ 23 
5.3. 
Medical History ...................................................................................................................................... 24 
6. 
EFFICACY ANALYSES ................................................................................................................................... 25 
6.1. 
Efficacy Endpoints ................................................................................................................................. 25 
6.1.1. 
Definition of Primary Efficacy Endpoints ............................................................................ 25 
6.1.2. 
Primary Analysis for Primary Efficacy Endpoints ............................................................... 25 
6.2. 
Changes From Protocol-Specified Efficacy Analyses............................................................................ 25 
7. 
SAFETY ANALYSES ........................................................................................................................................ 26 
7.1. 
Adverse Events and Deaths .................................................................................................................... 26 
7.1.1. 
Adverse Event Dictionary .................................................................................................... 26 
7.1.2. 
Adverse Event Severity ........................................................................................................ 26 


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7.1.3. 
Relationship of Adverse Events to Study Drug .................................................................... 26 
7.1.4. 
Serious Adverse Events ........................................................................................................ 26 
7.1.5. 
Treatment-Emergent Adverse Events ................................................................................... 26 
7.1.5.1. 
Definition of Treatment-Emergent Adverse Events ....................................... 26 
7.1.5.2. 
Incomplete Dates ............................................................................................ 26 
7.1.6. 
Summaries of Adverse Events and Deaths ........................................................................... 27 
7.2. 
Laboratory Evaluations .......................................................................................................................... 28 
7.2.1. 
Graded Laboratory Values ................................................................................................... 28 
7.2.1.1. 
Treatment-Emergent Laboratory Abnormalities ............................................. 28 
7.2.1.2. 
Summaries of Laboratory Abnormalities ........................................................ 29 
7.2.2. 
ALT Elevation ...................................................................................................................... 29 
7.2.2.1. 
ALT Elevation without Declining Hepatic Function ...................................... 29 
7.2.2.2. 
ALT Elevation with Declining Hepatic Function ........................................... 29 
7.3. 
Vital Signs .............................................................................................................................................. 30 
7.4. 
Prior and Concomitant Medications ....................................................................................................... 30 
7.4.1. 
Prior Medications ................................................................................................................. 30 
7.4.2. 
Concomitant Medications ..................................................................................................... 31 
7.5. 
Electrocardiogram Results ..................................................................................................................... 32 
7.6. 
Other Safety Measures ........................................................................................................................... 32 
8. 
REFERENCES ................................................................................................................................................... 33 
9. 
SOFTWARE ....................................................................................................................................................... 34 
10. DOCUMENT HISTORY .................................................................................................................................... 35 
11. APPENDICES .................................................................................................................................................... 36 
 
LIST OF IN-TEXT TABLES 
 
 
Table 3-1 
On-Treatment Analysis Visit Windows for HBV DNA and pgRNA ..................................... 14 
Table 3-2 
On-Treatment Analysis Visit Windows for Vital Signs, Chemistry, and Hematology .......... 15 
Table 3-3 
On-Treatment Analysis Visit Windows for HBsAg, HBeAg, HBcrAg, and 
Coagulation ............................................................................................................................ 16 
Table 3-4 
On-Treatment Analysis Visit Windows for Urinalysis ........................................................... 16 
Table 3-5 
On-Treatment Analysis Visit Windows for ECG ................................................................... 17 
Table 3-6 
Follow-Up Analysis Visit Windows for Efficacy, Vital Signs, and Laboratory 
Assessments............................................................................................................................ 17 
Table 3-7 
Follow-Up Analysis Visit Windows for ECG ........................................................................ 18 
 
LIST OF IN-TEXT FIGURES 
 
Figure 1-1 
 Study Overview ....................................................................................................................... 8 
 
LIST OF ABBREVIATIONS 
 
AASLD 
american association for the study of liver diseases  
AE 
adverse event 


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ALT 
alanine aminotransferase 
ANCOVA 
analysis of covariance  
ATC 
anatomical therapeutic chemical 
BLOQ 
below the limit of quantitation 
BMI 
body mass index 
cHBV 
chronic hepatitis B virus infection  
CI 
confidence interval 
CMH 
Cochran-Mantel-Haenszel 
CSR 
clinical study report 
DAIDS  
Division of AIDS  
DNA 
deoxyribonucleic acid  
DRC 
data review committee 
ECG 
electrocardiogram 
eCRF 
case report form 
EDC 
electronic data capture  
EOS 
end of study 
EOT 
end of treatment 
ET 
early termination 
ETV 
entecavir 
FAS 
full analysis set 
GT 
genotype 
Hb 
hemoglobin 
HBcrAb 
antibody to the HBV core-related antigen  
HBcrAg  
hepatitis B core-related antigen 
HBeAb 
HBeAg antibody  
HBeAg  
hepatitis B “e” antigen 
HBsAb 
HBsAg antibody  
HBsAg 
hepatitis B surface antigen  
HBV 
hepatitis B virus  
HLGT 
high-level group term 
HLT 
high-level term 
ID 
identification 
IFNα 
interferon alpha 
INR 
international normalized ratio 
IPD 
important protocol deviation(s) 
IRT 
interactive response technology 
LLOQ 
lower limit of quantitation  
LLT 
lower-level term 
LOD 
limit of detection 
LOQ 
limit of quantitation 


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MedDRA 
medical dictionary for regulatory activities 
MMRM 
mixed model for repeated measures  
NrtI 
Nucleos(t)ide reverse transcriptase inhibitor 
PD 
protocol deviation(s) 
Peg 
pegylated 
pgRNA 
pregenomic ribonucleic acid 
PK 
pharmacokinetics 
PT 
preferred term 
Q1, Q3 
first quartile, third quartile 
QD 
once daily  
RAV 
resistance associated variants 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SD 
standard deviation 
SE 
standard error 
SOC 
system organ class 
TEAE 
treatment-emergent adverse event 
TFLs 
tables, figures, and listings 
ULN 
upper limit of normal 
VBR 
vebicorvir 
WHO 
world health organization 
 
 
 
 


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1. 
INTRODUCTION 
Study ABI-H0731-203 is a randomized Phase 2a, multicenter, open-label study evaluating 
vebicorvir (VBR; formerly ABI-H0731) -containing regimens in subjects with chronic hepatitis 
B virus (HBV) infection (cHBV). The target population is male or female subjects, 18 to 65 
years of age, inclusive, treatment naïve with hepatitis B virus “e” antigen (HBeAg) positive 
cHBV and no evidence of cirrhosis or end-stage liver disease. 
This statistical analysis plan (SAP) describes the statistical analysis methods and data 
presentations to be used in tables, figures, and listings (TFLs) in the clinical study report (CSR) 
for Study ABI-H0731-203. This SAP is based on the study protocol amendment 3, dated 29 July 
2021 and the electronic case report form (eCRF). In July 2022, Assembly made the decision to 
terminate this study and discontinue the development of VBR after review of interim data 
suggested that none of the study drug regimens were likely to lead to functional cure. 
Subsequently, participants in Study ABI-H0731-203 ended study treatment and entered in 
follow-up period with entecvir (ETV) for 12 weeks..  . Therefore, only key safety and efficacy 
endpoints will be performed for this study. The SAP will be finalized before database lock. Any 
changes made after the finalization of the SAP will be documented in the Synoptic CSR.  
1.1. 
Study Objectives 
The primary objective of this study is as follows: 
• To evaluate the safety and tolerability of VBR) when administered in combination with 
entecavir (ETV) with or without pegylated interferon alpha (Peg-IFNα) in subjects with cHBV 
The secondary objectives of this study are as follows: 
• To evaluate the effect of VBR when administered in combination with ETV with or without 
Peg-IFNα in reducing HBV pgRNA levels in subjects with cHBV 
• To evaluate the effect of VBR when administered in combination with ETV with or without 
Peg-IFNα in reducing HBV deoxyribonucleic acid (DNA) levels in subjects with cHBV 
• To evaluate the effect of VBR when administered in combination with ETV with or without 
Peg-IFNα in reducing HBV antigens (ie, HBeAg, hepatitis B core-related antigen [HBcrAg], 
and hepatitis B surface antigen [HBsAg]) in subjects with cHBV 
• To evaluate the effect of VBR when administered in combination with ETV with or without 
Peg-IFNα on normalization of alanine aminotransferase (ALT) 
• To evaluate the pharmacokinetics (PK) of VBR and future PK evaluation of Peg-IFNα and 
ETV in subjects with cHBV 
• To evaluate the emergence of resistance to VBR when administered with ETV with or 
without Peg-IFNα 


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1.2. 
Study Design 
This study will assess the safety, antiviral activity, and PK of VBR administered in combination 
with ETV with or without Peg-IFNα in treatment-naïve, HBeAg positive Chinese subjects with 
cHBV. The study will be conducted at approximately 5 to 10 study sites in China. 
Approximately 60 eligible subjects with HBeAg positive cHBV will be randomly assigned in a 
1:1:1 ratio to the treatment groups shown in the study overview presented in Figure 1-1 
 Study 
Overview. 
Treatment with VBR and/or ETV will be administered orally, once daily; treatment with Peg-
IFNα will be administered subcutaneously, once weekly. Group 1 will receive VBR+ETV for 24 
weeks, Group 2 will receive VBR+ETV+Peg-IFNα for 24 weeks and Group 3 will receive 
ETV+Peg-IFNα for 24 weeks. All subjects will receive VBR+ETV from Week 24 through Week 
48 and then ETV alone from Week 48 through Week 60 during the 12-week follow-up period. 
Treatment assignments will be stratified by the HBV genotype (GT;ie, GT A or B vs GT C or D, 
vs other GTs) and baseline ALT (ie, ALT <5 × upper limit of normal [ULN] vs ALT ≥5 × ULN) 
during the Screening visits. 
Figure 1-1 
 Study Overview  
 
Abbreviations: BL = Baseline; ETV = entecavir; Peg-IFNα = pegylated-interferon alpha; Wk = 
week. 
Note: ABI-H0731 is the former designation for VBR. 
The schedule of study procedures is presented in tabular form in Appendix 1 of the study 
protocol.  
1.3. 
Sample Size and Power 
Approximately 60 eligible male or female subjects between the ages of 18 and 65 years with 
HBeAg positive cHBV will be enrolled in the study. Subjects will be randomized to receive 1 of 
the following 3 treatments, VBR+ETV, ETV+Peg-IFNα, or VBR+ETV+Peg-IFNα in a 1:1:1 
ratio. 
This is a proof-of-concept study. The sample size is similar to that previously utilized for this 
type of study and is not based upon statistical considerations. 


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1.4. 
Methods of Assigning Subjects to Treatment 
1.4.1. 
Randomization 
Randomization of eligible subjects to their respective treatment assignments will be performed 
centrally using an Interactive Response Technology (IRT) system. The IRT system will assign 
eligible subjects in a 1:1:1 ratio to receive either VBR+ETV, VBR+ ETV+Peg-IFNα or 
ETV+Peg-IFNα for 24 weeks. Treatment assignments will be stratified by the HBV GT (ie, GT 
A or B vs GT C or D, vs other GTs) and baseline ALT (ie, ALT <5 × ULN vs ≥5 × ULN) 
collected at Screening. Additional information on the use of the IRT is provided in the IRT User 
Manual. 
1.4.2. 
Blinding 
Not applicable as this is an open-label study. 


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2. 
TYPE OF PLANNED ANALYSIS 
2.1. 
Interim Analyses 
No formal interim analyses are planned. As an open-label study, the data will be reviewed 
periodically. 
2.2. 
Final Analysis 
As of 25 July 2022, the study was terminated early. The final analysis to support a ‘Synoptic 
Clinical Study Report’ will be performed after all subjects have discontinued or completed the 
12-week follow-up visits, outstanding data queries have been resolved or adjudicated as 
unresolvable, and the data have been cleaned and finalized.   


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3. 
GENERAL CONSIDERATIONS FOR DATA ANALYSES 
Analysis results will be presented using descriptive statistics. For categorical variables, the 
number and percentage of subjects in each category will be presented; for continuous variables, 
the number of subjects (n), mean, standard deviation (SD) or standard error (SE), median, first 
quartile (Q1), third quartile (Q3), minimum, and maximum will be presented. 
No formal inference is planned in this study. Hence no multiplicity adjustment is required.  
3.1. 
Analysis Sets 
Analysis sets define the subjects to be included in an analysis. Analysis sets and their definitions 
are provided in this section. The analysis set will be identified and included as a subtitle of each 
table, figure, and listing. For each analysis set, the number and percentage of subjects eligible for 
inclusion will be summarized by treatment group. A listing of reasons for exclusion from 
analysis sets will be provided by subject. 
3.1.1. 
All Randomized Analysis Set 
All Randomized Analysis Set includes all subjects who were randomized in the study, classified 
according to the treatment group into which they were randomized regardless of the actual 
treatment received.  
3.1.2. 
Full Analysis Set 
The Full Analysis Set (FAS) includes all randomized subjects, classified according to the 
treatment group into which they were randomized regardless of the actual treatment received 
who took at least 1 dose of study drug. This is the primary analysis set for efficacy analyses. 
3.1.3. 
Safety Analysis Set 
The Safety Analysis Set includes all subjects, classified according to the actual treatment 
received regardless of randomization assignment, who took at least 1 dose of study drug. This is 
the primary analysis set for safety analyses. 
3.2. 
Subject Grouping 
For analyses based on the All Randomized Analysis Set and FAS, subjects will be grouped 
according to the treatment to which they were randomized. For analyses based on the Safety 
Analysis Set, subjects will be grouped according to the actual treatment received. The actual 
treatment received will differ from the randomized treatment only when their actual treatment 
differs from randomized treatment for the entire treatment duration. 


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3.3. 
Strata and Covariates 
Subjects will be randomly assigned to treatment groups via an IRT system in a 1:1:1 ratio using a 
stratified randomization schedule. Stratification will be based on the following variables during 
the Screening visits: 
• HBV GT (ie, GT A or B vs GT C or D, vs other GTs) 
• Baseline ALT (ie, ALT <5 × upper limit of normal ULN vs ALT ≥5 × ULN) 
If there are discrepancies in stratification factor values between the IRT and the clinical database, 
the values recorded in the clinical database will be used for analyses. Given that the study is 
terminated early, sensitivity analysis of the primary efficacy endpoint will not be performed for 
the stratification discrepancy. 
3.4. 
Data Handling Conventions and Transformations 
Subject age collected at Screening visit will be used for analyses and presented in listings. The 
age is derived in the electronic data capture (EDC) system based on year of birth and informed 
consent date. 
Laboratory data that are continuous in nature but are less than the lower limit of quantitation 
(LLOQ), less than the limit of detection (LOD), or above the upper limit of quantitation (LOQ) 
will be imputed for the purposes of calculating descriptive statistics. 
A value that is half of the LLOQ will be used to calculate descriptive statistics if the datum is 
reported in the form of <x or <=x (where x is considered the LLOQ or LOD), or is reported as 
not detected. If the LLOQ is reported in log units, the imputed value will be half of the 
equivalent non-log LLOQ value. 
A value that is 1 significant value unit above the upper LOQ will be used to calculate descriptive 
statistics if the datum is reported in the form of “> x” (where x is considered the LOQ). For 
example, if the result of a continuous laboratory test is >20, a value of 21 will be assigned. If the 
result of a continuous laboratory test is >20.1, a value of 20.2 will be assigned.  
The LOQ will be used to calculate descriptive statistics if the datum is reported in the form of “≥ 
x” (where x is considered the LOQ). 
For selected analyses, virology efficacy data will be transformed to the logarithmic (base 10) 
scale. 
Total bilirubin values entered as < 0.2 mg/dL will be analyzed as 0.1 mg/dL; direct bilirubin 
values entered as < 0.1 mg/dL will be analyzed as 0.05 mg/dL (according to the methods of 
Nehls and Akland, 1973).  
 


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3.5. 
Missing Data and Outliers 
3.5.1. 
Missing Data 
In general, missing data will not be imputed unless methods for handling missing data are 
specified. Exceptions are presented in this document. 
For missing last dose date of study drug, imputation rules are described in Section 4.2.1. The 
handling of missing efficacy data is described in Section 6.1.2. The handling of missing or 
incomplete dates for adverse event (AE) onset is described in Section 7.1.5.2, and for prior and 
concomitant medications in Section 7.4. 
3.5.2. 
Outliers 
Outliers will be identified during the data management review process. No sensitivity analyses 
will be conducted. All data will be included in the data analysis. 
3.6. 
Analysis Visit Windows 
3.6.1. 
Definition of Study Drug 
In this study, study drugs are defined as VBR, ETV, and Peg-IFNα. 
3.6.2. 
Definition of Study Phase 
The following phases will be defined: Randomized Treatment Phase and Overall Treatment 
Phase are on treatment; and the Follow-up Phase is off treatment. 
• Randomized Treatment Phase: from first dose date through Week 24 visit (or premature 
termination visit if before Week 24)  
• Overall Treatment Phase: from first dose date through Week 48 visit (or premature 
termination visit if before Week 48) 
• Follow-up Phase: after Week 48 visit (or premature termination visit) through end of study 
End of study will be when the subject completes the last visit of the follow-up period or is 
considered “lost to follow-up,” whichever is later.  
3.6.3. 
Definition of Study Day 
The first dose date of VBR when administered in combination with ETV with or without  Peg-
IFNα will be calculated where applicable. Study Day 1 is defined as the first dose date of study 
drug, which is the earliest/minimum of the first dose dates of VBR, ETV, and Peg-IFNα in a 
treatment group. If the first dose date is missing, the date of randomization will be used. 


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The last dose date of VBR, ETV, and of Peg-IFNα will be calculated where applicable. For the 
Randomized Treatment Phase, the last dose date of study drug VBR will be the Week 24 visit 
date or the end date on study drug administration CRF if a subject discontinued study drug prior 
to Week 24 visit. For study drug ETV, the last dose date will be obtained from End of 
Treatment-ETV eCRF. For study drug Peg-IFNα, the last dose date will be obtained from End of 
Treatment-Peg-IFNα eCRF. For the Overall Treatment Phase, the last dose date for each drug 
will be the end date on the respective End of Treatment  eCRF pages. The last dose date of study 
drug will be defined as the latest/maximum of the last dose dates of VBR, ETV, and  Peg-IFNα 
in a treatment group. 
For the on-treatment phases, Study Day will be calculated from Study Day 1 and derived as 
follows: 
• For days prior to the first dose: Assessment Date – Study Day 1 
• For postdose study days: Assessment Date – Study Day 1 + 1 
For the Follow-up Phase, the follow-up Study Day 1 is defined as the day after Week 48 visit or 
Premature Termination visit. The follow-up study day will be derived as Assessment Date – 
follow-up Study Day 1 +1. 
3.6.4. 
Analysis Visit Windows  
Subject visits might not occur on protocol-specified days. Therefore, for the purpose of analysis, 
observations will be assigned to analysis windows. In general, the baseline value will be the last 
nonmissing value on or prior to the first dose date of study drug. The on-treatment phases 
include Randomized Treatment Phase and Overall Treatment Phase. For the Randomized 
Treatment Phase, the data will be summarized up to the Week 24 visit or premature termination 
visit. For the Overall Treatment Phase, the data will be summarized up to the Week 48 visit or 
premature termination visit. For the Follow-up Phase, the data will be summarized from follow-
up Study Day 1 through the end of study, where Follow-Up Baseline data is from Week 48 visit 
or premature termination visit. 
The analysis windows for the on-treatment HBV DNA and HBV pgRNA assessments are 
provided in Table 3-1.  
Table 3-1 
On-Treatment Analysis Visit Windows for HBV DNA and pgRNA 
Nominal Visit 
On-Treatment 
Nominal Study Day 
Visit Window Study Day 
Lower Limit 
Upper Limit 
Day 1 
1 
(none) 
1 
Week 1 
7 
2 
10 
Week 2 
14 
11 
21 
Week 4 
28 
22 
35 


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Nominal Visit 
On-Treatment 
Nominal Study Day 
Visit Window Study Day 
Lower Limit 
Upper Limit 
Week 6 
42 
36 
49 
Week 8 
56 
50 
70 
Week 12 
84 
71 
98 
Week 16 
112 
99 
126 
Week 20 
140 
127 
154 
Week 24 
168 
155 
182 
Week 28 
196 
183 
210 
Week 32 
224 
211 
238 
Week 36 
252 
239 
266 
Week 40 
280 
267 
294 
Week 44 
308 
295 
322 
Week 48 
336 
323 
≥336 
 
The analysis windows for the on-treatment assessments of vital signs, chemistry, and 
hemotology are provided in Table 3-2.  
Table 3-2 
On-Treatment Analysis Visit Windows for Vital Signs, Chemistry, 
and Hematology 
Nominal Visit 
On-Treatment 
Nominal Study Day 
Visit Window Study Day 
Lower Limit 
Upper Limit 
Day 1 
1 
(none) 
1 
Week 2 
14 
2 
21 
Week 4 
28 
22 
42 
Week 8 
56 
43 
70 
Week 12 
84 
71 
98 
Week 16 
112 
99 
126 
Week 20 
140 
127 
154 
Week 24 
168 
155 
182 
Week 28 
196 
183 
210 
Week 32 
224 
211 
238 
Week 36 
252 
239 
266 
Week 40 
280 
267 
294 


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Nominal Visit 
On-Treatment 
Nominal Study Day 
Visit Window Study Day 
Lower Limit 
Upper Limit 
Week 44 
308 
295 
322 
Week 48 
336 
323 
≥336 
 
The analysis windows for the on-treatment HBsAg, HBeAg, HBcrAg, and coagulation 
assessments are provided in Table 3-3. 
Table 3-3 
On-Treatment Analysis Visit Windows for HBsAg, HBeAg, HBcrAg, 
and Coagulation 
Nominal Visit 
On-Treatment 
Nominal Study Day 
Visit Window Study Day 
Lower Limit 
Upper Limit 
Day 1 
1 
(none) 
1 
Week 4 
28 
2 
42 
Week 8 
56 
43 
70 
Week 12 
84 
71 
98 
Week 16 
112 
99 
126 
Week 20 
140 
127 
154 
Week 24 
168 
155 
182 
Week 28 
196 
183 
210 
Week 32 
224 
211 
238 
Week 36 
252 
239 
266 
Week 40 
280 
267 
294 
Week 44 
308 
295 
322 
Week 48 
336 
323 
≥336 
 
The analysis windows for the on-treatment urinalysis assessments are provided in Table 3-4. 
Table 3-4 
On-Treatment Analysis Visit Windows for Urinalysis 
Nominal Visit 
On-Treatment 
Nominal Study Day 
Visit Window Study Day 
Lower Limit 
Upper Limit 
Day 1 
1 
(none) 
1 
Week 4 
28 
2 
42 
Week 8 
56 
43 
70 


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Nominal Visit 
On-Treatment 
Nominal Study Day 
Visit Window Study Day 
Lower Limit 
Upper Limit 
Week 12 
84 
71 
98 
Week 16 
112 
99 
126 
Week 20 
140 
127 
154 
Week 24 
168 
155 
252 
Week 48 
336 
253 
≥336 
 
The analysis windows for on-treatment electrocardiograms (ECG) measurements are provided in 
Table 3-5. 
Table 3-5 
On-Treatment Analysis Visit Windows for ECG 
Nominal Visit 
On-Treatment 
Nominal Study Day 
Visit Window Study Day 
Lower Limit 
Upper Limit 
Day 1 
1 
(none) 
1 
Week 12 
84 
2 
126 
Week 24 
168 
127 
252 
Week 48 
336 
253 
≥336 
 
The analysis windows for Follow-up Phase study assessments of efficacy (except HBsAb and 
HBeAb), vital signs, and laboratory assessments (chemistry, hematology, coagulation and 
urinalysis) are provided in Table 3-6. 
Table 3-6 
Follow-Up Analysis Visit Windows for Efficacy, Vital Signs, and 
Laboratory Assessments 
Nominal Visit 
Off-Treatment  
Nominal Study Day 
Visit Window Study Day 
Lower Limit 
Upper Limit 
FU-Baseline 
-1 
(none) 
-1 
FU-Week 4  
28 
1 
42 
FU-Week 8  
56 
43 
70 
FU-Week 12 
84 
71 
≥126 
The analysis windows for Follow-Up Phase ECG is provided in. 


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Table 3-7 
Follow-Up Analysis Visit Windows for ECG 
Nominal Visit 
Off-Treatment  
Nominal Study Day 
Visit Window Study Day 
Lower Limit 
Upper Limit 
FU-Baseline 
-1 
(none) 
-1 
FU-Week 12 
84 
1 
≥126 
 
3.6.5. 
Selection of Data in the Event of Multiple Records in an Analysis Visit 
Window 
Depending on the statistical analysis method, single values may be required for each analysis 
window. If a single value is needed, but multiple valid, nonmissing measurements exist in an 
analysis window, records will be chosen based on the following rules: 
• For Baseline, the last nonmissing value on or prior to the first dose date of study drug will be 
selected, unless specified differently. If there are multiple records with the same time or no 
time recorded on the same day, the record with the lowest accession number will be selected 
as the baseline value.  
• For postbaseline values: 
o The record closest to the nominal day for that visit will be selected with the exception of 
virology parameters in which the latest record will be selected.  
o If there are 2 records that are equidistant from the nominal day, the later record will be 
selected. 
o If there is more than 1 record on the selected day with the same time, the retest record 
will be selected. If there is no clear indication for which record is the retest record, then 
the record with the lowest accession number will be selected. 


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4. 
SUBJECT DISPOSITION 
4.1. 
Subject Enrollment and Disposition 
A summary of subject enrollment will be provided by treatment group for each country, 
investigator within a country, and overall. The summary will present the number and percentage 
of subjects enrolled. For each column, the denominator for the percentage calculation will be the 
total number of subjects analyzed for that column. 
A similar enrollment table will be provided by randomization stratum. The denominator for the 
percentage of subjects in the stratum will be the total number of randomized subjects. If there are 
discrepancies in the value used for stratification assignment between the IRT and the clinical 
database, the value collected in the clinical database will be used for the summary. A listing of 
subjects with discrepancies in the value used for stratification assignment between the IRT and 
the clinical database at the time of data finalization will be provided. The randomization 
schedule used for the study will be provided as an appendix to the CSR.  
A summary of subject disposition will be provided by treatment group. This summary will 
present the number of subjects in each of the categories listed below: 
• All Randomized Analysis Set 
• Full Analysis Set   
• Safety Analysis Set   
The number and percentage of the subjects in the following categories will be summarized using 
the Safety Analysis Set: 
• Continuing study drug VBR 
• Completed study drug VBR 
• Did not complete study drug VBR and reasons for study drug discontinuation  
• Continuing study drug ETV 
• Completed study drug ETV 
• Did not complete study drug ETV and reasons for study drug discontinuation 
• Continuing study drug Peg-IFNα  
• Completed study drug Peg-IFNα 
• Did not complete study drug Peg-IFNα and reasons for study drug discontinuation  


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• Continuing study  
• Completed study  
• Did not complete the study and reasons for study discontinuation  
For the status of study drug and study completion and reasons for discontinuation, the number 
and percentage of subjects in each category will be provided. The denominator for the 
percentage calculation will be the total number of subjects in the Safety Analysis Set 
corresponding to that column.   
The following by-subject listings will be provided by subject number in ascending order: 
• Reasons for premature study drug or study discontinuation 
• Dispensed bottle number and lot number for VBR, lot number for Peg-IFNα and ETV 
4.2. 
Extent of Study Drug Exposure and Compliance 
Extent of exposure to study drug will be examined by assessing the total duration of exposure to 
study drug and the level of compliance relative to the study drug regimen specified in the 
protocol.  
4.2.1. 
Duration of Exposure to Study Drug 
Total duration of exposure to each study drug through Week 24 will be defined as the last dose 
date at Week 24 minus the first dose date plus 1 for VBR and for ETV, plus 7 for Peg-IFNα , 
regardless of any temporary interruptions in study drug administration, and will be expressed in 
weeks using up to 1 decimal place (eg, 4.5 weeks). Duration (weeks) = Duration (days) /7.  Total 
duration of exposure to VBR through Week 48 will also be summarized and defined as the last 
dose date of VBR minus the first dose date plus 1 for VBR, similar calculation will be performed 
for total duration of ETV exposure. The last dose date of individual study drug is defined in 
Section 3.6.3. If the last study drug dose date is missing, the latest date among the study drug end 
date, clinical visit date, laboratory sample collection date, and vital signs assessment date that 
occurred during the on-treatment period will be used for subjects included in the final analyses or 
the last available date in the database snapshot for subjects who were still on treatment at the 
time of an interim analysis.  
The total duration of exposure to study drug will be summarized using descriptive statistics. 
Summaries will be provided by treatment group in each on-treatment phase for the Safety 
Analysis Set. For the Randomized Treatment Phase, the expected total duration of Randomized 
Treatment Phase for all subjects is 24 weeks. The distribution of subjects by the total number of 
weeks on therapy (ie, ≤4 weeks, >4-8 weeks, >8-12 weeks, >12-16 weeks, >16-20 weeks, >20-
24 weeks, and ≥24 weeks) will be presented. After completion of the randomized treatment, all 
subjects will receive VBR+ETV for an additional 24 weeks. For the Overall Treatment Phase, 
the duration of exposure to VBR and ETV will be summarized. The expected total duration of 


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Overall Treatment Phase for all subjects is 48 weeks. The distribution of subjects by the total 
number of weeks on therapy (ie, ≤12 weeks, >12-24 weeks, >24 -<48 weeks, and ≥48 weeks) 
will be presented. 
 
 
4.2.2. 
Study Drug Compliance  
Compliance will be calculated for study drugs VBR, ETV and Peg-IFNα. 
The total number of tablets (VBR and ETV) and injections (Peg-IFNα) administered will be 
summarized by treatment phases using descriptive statistics.  
The presumed total number of tablets (VBR and ETV) administered to a subject will be 
determined by the data collected on the Drug Accountability- ABI-H0731 and ETV CRFs 
respectively using the following formula: 
Total Number of Tablets Administered =  
(∑No. of Tablets Dispensed) −(∑No. of Tablets Returned) 
The presumed total number of injections (Peg-IFNα) administered to a subject will be determined 
by the data collected on the Drug Accountability- Peg-IFNα CRF using the following formula: 
Total Number of Doses Administered = 
(∑No. of Syringes Dispensed) −(∑No. of Syringes Returned) 
4.2.2.1. 
On-Treatment Compliance 
The level of on-treatment compliance to the study drug will be determined by the total amount of 
study drug administered relative to the total amount of study drug expected to be administered 
during a subject’s actual on-treatment period. 
The level of on-treatment compliance for each study drug will be expressed as a percentage 
using the following formula: 
On-Treatment Compliance (%) = (
Total Amount of Study Drug Administered
Total Amount of Study Drug Expected to be Administered On Treatment)  x 100 
Per protocol, each subject completing treatment and receiving VBR is expected to take three 100 
mg tablets of VBR daily during the Randomized Treatment Phase (ie, a total of 504 tablets is 
expected in a 24-week period) and during the Overall Treatment Phase (ie, a total of 1008 tablets 
are expected in a 48-week period). Each subject completing treatment and receiving ETV is 
expected to take a single oral 0.5 mg tablet once daily during the Randomized Treatment Phase 
(ie, a total of 168 tablets is expected in a 24-week period), during the Overall Treatment Phase 


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(ie, a total of 336 tablets are expected in a 48-week period). Each subject completing treatment 
and receiving Peg-IFNα is expected to have a total of 24 syringes of Peg-IFNα administered.  
For subjects who prematurely discontinue, the denominator will be the total amount of study 
drug expected to be administered by the date of premature discontinuation.  
Descriptive statistics for the level of on-treatment compliance with the number and percentage of 
subjects belonging to compliance categories (eg, < =80%, > 80-90%, and ≥ 90%) will be 
provided by treatment group for the Safety Analysis Set.  
A by-subject listing of study drug administration and drug accountability will be provided 
separately by subject ID number in ascending order and visit in chronological order. 
4.3. 
Protocol Deviations  
Subjects who did not meet the eligibility criteria for study entry but enrolled in the study will be 
summarized. The number and percentage of subjects who did not meet at least 1 eligibility 
criterion will be provided for specific criteria by treatment group based on the All Randomized 
Analysis Set. A by-subject listing will be provided for those subjects who did not meet at least 1 
eligibility (inclusion or exclusion) criterion. The listing will present the eligibility criterion (or 
criteria if more than 1 deviation) that subjects did not meet and related comments, if collected. 
Protocol deviations (PDs) occurring after subjects entered the study are documented during 
routine monitoring. The number and percentage of subjects with important PDs (IPDs) by 
deviation category will be summarized by treatment group for All Randomized Analysis Set. A 
by-subject listing will be provided for those subjects with any PDs. 
A table will be provided to summarize any COVID-19 related PDs with the deviation reason by 
treatment groups. Any visits that were not performed will be summarized by reason (ie, adverse 
event, COVID-19 restrictions, and Other). A listing of subjects who had study disruption due to 
COVID-19 will be provided with a description.  


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5. 
BASELINE CHARACTERISTICS 
5.1. 
Demographics and Baseline Characteristics 
Subject demographic variables (i.e., age, age group [<50/ ≥ 50 years], sex, race, and ethnicity), 
baseline characteristics (body weight [in kg], height [in m], body mass index [BMI; in kg/m2]) 
will be summarized by treatment group and overall using descriptive statistics for continuous 
variables and using number and percentage of subjects for categorical variables. The summary of 
demographic data will be provided for the Safety Analysis Set. 
A by-subject demographic listing, including the informed consent date, will be provided by 
subject ID number in ascending order. 
5.2. 
Baseline Disease Characteristics 
Baseline disease characteristics will be summarized by treatment group and overall. Descriptive 
summary statistics will be used for continuous variables and the number and percentage of 
subjects will be used for categorical variables. The following factors will be included, but not 
limited to:  
• Years positive for HBV 
• HBV Genotype  
• Baseline HBV DNA (log10 IU/mL) 
• Baseline HBV pgRNA (log10 U/mL) 
• Baseline HBeAg (log10 IU/mL) 
• Baseline HBcrAg (log10 kU/mL) 
• Baseline HBsAg (log10 IU/mL) 
• Baseline HBeAg antibody (HBeAb)  
• Baseline HBsAg antibody (HBsAb)  
• Baseline antibody to the HBV core-related antigen (HBcrAb) 
• Baseline ALT (U/L)  
• Baseline ALT group (>ULN [Covance], >ULN [American Association for the Study of 
Liver Diseases (AASLD)]) 


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• Baseline ALT group (<5 × ULN, ≥5 × ULN) 
• Liver biopsy staging   
• Fibroscan result 
• Metavir Fibrosis Stage 
 
A by-subject listing of baseline disease characteristics will be provided by subject ID number in 
ascending order. 
5.3. 
Medical History 
Medical history collected at screening will be coded using the Medical Dictionary for Regulatory 
Activities (MedDRA) Version (v) 23.1. 
Medical history will be summarized by preferred term (PT), treatment group and overall. 
Subjects who report 2 or more medical history items that are coded to the same PT will be 
counted only once by the unique coded term in the summary. The summary will be provided for 
the Safety Analysis Set.  
HBV-specific medical history will be summarized by mode of HBV infection, treatment group 
and overall. The summary will be provided for the Safety Analysis Set.  
A by-subject listing of medical history will be provided by subject ID number in ascending 
order. 


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6. 
EFFICACY ANALYSES 
The primary analysis set for efficacy analyses will be the FAS, defined in Section 3.1.2. All the 
efficacy analyses will be performed for each cohort separately.  
6.1. 
Efficacy Endpoints 
6.1.1. 
Definition of Primary Efficacy Endpoints 
The efficacy endpoints include the following:  
• Mean change in log10 HBV DNA from Baseline at each timepoint 
• Mean change in log10 HBV pgRNA from Baseline at each timepoint 
• Mean change in log10 serum viral antigens (ie HBcrAg, HBeAg, and HBsAg) from Baseline 
at each timepoint 
 
6.1.2. 
Primary Analysis for Primary Efficacy Endpoints 
The observed and mean change in log10 HBV DNA, HBV pgRNA, HBcrAg, HBeAg and HBsAg 
from Baseline will be summarized using descriptive statistics (sample size, mean, SD, median, 
Q1, Q3, minimum, and maximum) by treatment group.  
The comparison in change from baseline between treatment groups will be performed using the 
analysis of covariance (ANCOVA) model, including baseline value, the stratification factors, and 
treatment group as covariates. The estimated least square means of treatment effects and 
estimated difference in treatment effects between treatment groups will be presented along with 
the 95% CIs and p-values. The analysis will be based on observed data only. No imputation will 
be done for missing data. 
 
 
6.2. 
Changes From Protocol-Specified Efficacy Analyses  
Since the study is terminated early, the efficacy analyses for the key secondary and other 
secondary endpoints specified in the protocol will not be performed. 


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7. 
SAFETY ANALYSES 
7.1. 
Adverse Events and Deaths 
7.1.1. 
Adverse Event Dictionary 
Clinical and laboratory adverse events (AEs) will be coded using the Medical Dictionary for 
Regulatory Activities (MedDRA) Version (v) 23.1. System organ class (SOC), high-level group 
term (HLGT), high-level term (HLT), preferred term (PT), and lower-level term (LLT) will be 
provided in the AE dataset. 
 
7.1.2. 
Adverse Event Severity 
Adverse events are graded by the investigator as Grade 1, 2, 3, or 4 according to the toxicity 
criteria specified in the protocol. The severity grade of events for which the investigator did not 
record severity will be categorized as “missing” for tabular summaries and data listings. The 
missing category will be listed last in summary presentation. 
7.1.3. 
Relationship of Adverse Events to Study Drug 
Related AEs are those for which the investigator selected “Related” on the AE CRF to the 
question of “Relationship to Study Treatment” based on his/her clinical assessment. Events for 
which the investigator did not record relationship to an applicable study drug will be considered 
related to study drug for summary purposes. However, by-subject data listings will show the 
relationship as missing. 
7.1.4. 
Serious Adverse Events 
Serious adverse events (SAEs) will be identified and captured as SAEs if the AEs met protocol-
specified definitions of a SAE.  
7.1.5. 
Treatment-Emergent Adverse Events  
7.1.5.1. 
Definition of Treatment-Emergent Adverse Events 
Treatment-emergent adverse events (TEAEs) are defined as any AEs with an onset date/time 
equal to or after the date/time of first dose of study drug and no later than 28 days after the last 
dose date of any study drug.  
7.1.5.2. 
Incomplete Dates 
If the onset date of the AE is incomplete and the AE stop date is not prior to the first dose date of 
any study drug, then the month and year (or year alone if month is not recorded) of onset 
determine whether an AE is treatment emergent. The event is considered treatment emergent if 
both of the following 2 criteria are met: 


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• The AE onset is the same as or after the month and year (or year) of the first dose date of 
study drug, and 
• The AE onset date is the same as or before the month and year (or year) of the date 
corresponding to 28 days after the date of the last dose of any study drug  
An AE with completely missing onset and stop dates, or with the onset date missing and a stop 
date later than the first dose date of any study drug, will be considered to be treatment emergent. 
In addition, an AE with the onset date missing and incomplete stop date with the same or later 
month and year (or year alone if month is not recorded) as the first dose date of any study drug 
will be considered treatment emergent. 
7.1.6. 
Summaries of Adverse Events and Deaths 
Treatment-emergent AEs will be summarized based on the Safety Analysis Set for the 
Randomized Treatment Phase (up to the last dose at Week 24) and the Overall Treatment Phase 
(up to the last dose of any study drug plus 28 days). 
A brief, high-level summary of the number and percentage of subjects who experienced at least 1 
TEAE in the categories described below will be provided by treatment group. The brief summary 
will also include treatment-related TEAEs, and treatment-related TE SAEs.In addition, a table 
for each category showing the number and percentage of subjects will be provided by PT and 
treatment group in descending order of total frequency: 
• TEAEs  
• TEAEs by severity grade  
• TEAEs related to VBR  
• TEAEs related to ETV 
• TEAEs related to Peg-IFNα 
• TE SAEs 
• TE SAEs related to VBR 
• TE SAEs related to ETV 
• TE SAEs related to Peg-IFNα 
• TEAEs leading to VBR discontinuation 
• TEAEs leading to ETV discontinuation 
• TEAEs leading to Peg-IFNα discontinuation 


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• TEAEs leading to study discontinuation 
• COVID-19 specific TEAEs 
• COVID-19 specific TE SAEs 
Multiple events will be counted only once per subject in each summary. For summary by 
severity grade, the most severe grade will be used for those AEs that occurred more than once in 
an individual subject during the study.  
For the Follow-up Phase, a summary table will also be provided for all the AEs that occurred 
after the last dose of any study drug + 28 days through the end of study by the above category 
and by PT.  
A data listing containing all AEs will be provided.  
7.2. 
Laboratory Evaluations 
Laboratory data collected during the study will be analyzed and summarized using both 
quantitative and qualitative methods based on the Safety Analysis Set. The lab values that are 
below LLOQ or above the upper LOQ will be listed as such, and the closest imputed value will 
be used for the purpose of calculating summary statistics as specified in Section 3.4.  
 
7.2.1. 
Graded Laboratory Values 
The criteria specified in the study protocol will be used to grade laboratory results as normal (no 
grade), mild (Grade 1), moderate (Grade 2), severe (Grade 3) or potentially life threatening 
(Grade 4). See Appendix 3 of the protocol for detailed DAIDS grading criteria on the relevant 
laboratory tests. For laboratory tests with criteria for both increased and decreased levels, 
analyses for each direction (i.e, increased, decreased) will be presented separately. 
7.2.1.1. 
Treatment-Emergent Laboratory Abnormalities 
Treatment-emergent laboratory abnormalities are defined as values that increase at least 
1 toxicity grade from Baseline at any postbaseline time point, up to and including the date of last 
dose of any study drug plus 28 days for the Overall Treatment Phase. For the Randomized 
Treatment Phase, the treatment-emergent laboratory abnormalities will be summarized up to the 
last dose at Week 24.  
If the relevant baseline laboratory value is missing, any abnormality of at least Grade 1 observed 
within the time frame specified above will be considered treatment emergent. 


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7.2.1.2. 
Summaries of Laboratory Abnormalities 
A summary (number and percentage of subjects) for treatment-emergent laboratory 
abnormalities will be provided by lab test and treatment group; subjects will be categorized 
according to the most severe postbaseline abnormality grade for a given lab test. 
For all summaries of laboratory abnormalities, the denominator is the number of subjects with 
nonmissing postbaseline values up to 28 days after last dose date for the Overall Treatment 
Phase and up to Week 24 dose date for the Randomized Treatment Phase.  
The maximum postbaseline grade observed up to 28 days after last dose date or the Week 24 
dose date will be tabulated for each laboratory test, and percentages will be based on the number 
of subjects with a postbaseline evaluation of the specific laboratory test. The laboratory 
abnormalities during the Follow-up Phase will also be summarized.  
A by-subject listing of graded laboratory abnormalities will be provided by subject number and 
visit in chronological order. This listing will include all test results that were collected 
throughout the study for the lab test of interest, with all applicable severity grades displayed. 
7.2.2. 
ALT Elevation 
7.2.2.1. 
ALT Elevation without Declining Hepatic Function 
All subjects with an ALT elevation on treatment, defined as ALT >2 × Baseline or on-treatment 
nadir and ≥10 × ULN, should have the ALT findings confirmed within 3 days of receipt of the 
original results.   
7.2.2.2. 
ALT Elevation with Declining Hepatic Function  
Subjects with confirmed ALT elevation with evidence of declining hepatic function should be 
discontinued from study treatment. This is defined as:  
• ALT elevation ≥2 × Baseline (Day 1) or nadir and >2 × ULN AND 
o Direct bilirubin increases to ≥2 × Baseline (Day 1) and ≥2 × ULN OR  
o Albumin decline from Baseline ≥0.5 g/dL OR international normalized ratio (INR) 
>2 × Baseline (Day 1) OR  
o Symptoms of liver inflammation (eg, fatigue, weakness, lack of appetite, nausea, 
vomiting, jaundice or discolored feces) 
The number of subjects meeting the above criteria will be summarized by treatment group. 
Clinical signs or symptoms of liver inflammation will not be included in the summary. For 
individual laboratory tests, subjects will be counted once based on the most severe postbaseline 
values. For the composite criteria, subjects will be counted once when the criteria are met at the 
same visit. The denominator is the number of subjects in the Safety Analysis Set who have 
nonmissing postbaseline values. A listing of subjects who met at least 1 of the above criteria will 
be provided. 


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7.3. 
Vital Signs 
Descriptive statistics will be provided by treatment group for vital signs (systolic and diastolic 
blood pressure [mmHg], pulse [beats/min], respiration [breaths/min], and body temperature [oC]) 
as follows: 
• Baseline value 
• Values at each postbaseline visit 
• Change from baseline at each postbaseline visit 
A Baseline value will be defined as the last available value collected on or prior to the date/time 
of first dose of study drug. Change from Baseline to a postbaseline visit will be calculated for 
any postbaseline visit including follow-up visits. 
In the case of multiple values in an analysis window, data will be selected for analysis as 
described in Section 3.6.3.   
A by-subject listing of vital signs will be provided by subject ID number and visit in 
chronological order.  
7.4. 
Prior and Concomitant Medications 
Medications collected at screening and during the study will be coded using the current version 
of the World Health Organization (WHO) Drug dictionary (WHODrug Global 1Sep2020). 
7.4.1. 
Prior Medications 
Prior medications are defined as any medications taken before a subject took the first study drug. 
Prior medications will be summarized by Anatomical Therapeutic Chemical (ATC) drug class 
Level 2 and preferred name using the number and percentage of subjects for each treatment 
group and overall. A subject reporting the same medication more than once will be counted only 
once within each ATC drug class. The summary will be ordered alphabetically by ATC medical 
class and then by preferred term in order of descending overall frequency within each ATC 
medical class. For drugs with the same frequency, sorting will be done alphabetically. 
A medication will be considered as a prior medication if it meets one the following criteria: 
• A medication with a start date prior to the first dose date of study drug will be included in 
the prior medication summary regardless of when the stop date is.  
• If a partial start date is entered, the medication will be considered prior unless the month 
and year (if day is missing) or year (if day and month are missing) of the start date are 
after the first dose date.  


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• A medication with a completely missing start date will be included in the prior 
medication summary, unless otherwise specified. 
Summaries will be based on the Safety Analysis Set.  
7.4.2. 
Concomitant Medications 
Concomitant medications are defined as medications taken while a subject took study drug. Use 
of concomitant medications will be summarized by ATC drug class Level 2 and preferred name 
using the number and percentage of subjects for each treatment group. A subject reporting the 
same medication more than once within each ATC drug class will be counted only once when 
calculating the number and percentage of subjects who received that medication. Medications 
may appear under multiple ATC drug classes. The summary will be ordered alphabetically by 
ATC medical class and then by preferred term in descending overall frequency within each ATC 
medical class. For drugs with the same frequency, sorting will be done alphabetically. 
A medication will be considered as a concomitant medication if it meets one the following 
criteria: 
• A medication with a start date prior to or on the first dose date of study drug, and  
continued to be taken after the first dose date.  
• A medication started after the first dose date but prior to or on the last dose date of study 
drug.  
• If a partial start date is entered, any medication with the month and year (if day is 
missing) or year (if day and month are missing) before the study drug stop date, and with 
the stop date after the first dose date of study drug. If a partial stop date is entered, any 
medication with the month and year (if day is missing) or year (if day and month are 
missing) after the date of first study drug  
• A medication started and stopped on the same day as the first dose date or the last dose 
date of study drug    
• Medications with completely missing start and stop dates, unless otherwise specified. 
A medication with a stop date prior to the date of first dose date of study drug or a start date after 
the last dose date of study drug will be excluded from the summary.  
Summaries of prior and concomitant medications will be based on the Safety Analysis Set.   
All the prior and concomitant medications will be provided in a by-subject listing sorted by 
subject ID number and administration date in chronological order. 


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7.5. 
Electrocardiogram Results 
A shift table of the investigators’ assessment of ECG results at each visit compared with baseline 
values will be presented by treatment group using the following categories:  
• normal 
• abnormal (not clinically significant)  
• abnormal (clinically significant)  
• missing/not done 
The number and percentage of subjects in each cross-classification group of the shift table will 
be presented. Subjects with a missing value at Baseline or postbaseline will not be included in 
the denominator for percentage calculation.  
A by-subject listing for ECG assessment results will be provided by subject ID number and visit 
in chronological order. 
7.6. 
Other Safety Measures 
Since the study is terminated early, no additional safety measures specified in the protocol will 
be performed. 


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8. 
REFERENCES 
Nehls G, Akland G. Procedures for Handling Aerometric Data. Journal of the Air Pollution 
Control Association 1973;23 (3):180-4. 
 


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9. 
SOFTWARE 
SAS® Software Version 9.4. SAS Institute Inc., Cary, NC, USA. 


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10. 
DOCUMENT HISTORY 
Version 
Date 
(DD MMM YYYY) 
Summary of Changes 
1.0 
05 JAN 2023 
Original  
2.0 
09 JAN 2023 
Added changes to imputation rules  
 


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11. 
APPENDICES 
None. 


Signature Page for VV-TMF-57431 v2.0
Signature Page for VV-TMF-57431 v2.0
Reason for signing: Approved
Name: Jieming Liu
Role: Author
Date of signature: 09-Jan-2023 22:46:13 GMT+0000
Reason for signing: Approved
Name: Grace Wang
Role: Approver
Date of signature: 09-Jan-2023 22:48:33 GMT+0000
Reason for signing: Approved
Name: Michele Anderson
Role: Approver
Date of signature: 09-Jan-2023 22:52:45 GMT+0000