Clinical trial NCT04454567
Conditions: Chronic Hepatitis B
Sponsor: Assembly Biosciences
Start date: 2020-11-11; Completion date: 2021-04-08
Enrollment: 2 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This study will explore the safety and antiviral activity of ABI-H0731 when added to a nucleos(t)ide reverse transcriptase inhibitor (NrtI) in participants who are partially virologically suppressed.

Detailed description:

Arms: arm 1: Participants with chronic hepatitis B virus (HBV) infection with partial virologic suppression on NrtI alone will receive ABI-H0731 300 mg once daily plus standard of care (SOC) NrtI for 96 weeks, followed by SOC NrtI alone for an additional 24 weeks (120 weeks total). arm 2: Participants with chronic HBV infection with partial virologic suppression on NrtI alone will receive placebo to ABI-H0731 once daily plus SOC NrtI for 48 weeks, followed by ABI-H0731 300 mg once daily plus SOC NrtI for Weeks 48 to 96, followed by SOC NrtI alone for Weeks 96 to 120.
Interventions: intervention 1: ABI-H0731 intervention 2: Placebo intervention 3: NrtI
Intervention descriptions: intervention 1: Participants will receive ABI-H0731 tablets orally once daily intervention 2: Participants will receive placebo to ABI-H0731 tablets orally once daily intervention 3: Entecavir (ETV), tenofovir alafenamide (TAF), or tenofovir disoproxil fumarate (TDF) SOC according to the respective package insert

Protocol documents:
Prot_SAP_000.pdf: 
Study Title: A Phase 2a, Multicenter, Single-Blind, Placebo-Controlled Study Evaluating Treatment 
Intensification with ABI-H0731 in Subjects with Chronic Hepatitis B Infection on Nucleos(t)ide Reverse 
Transcriptase Inhibitors 
 
NCT Number: NCT04454567 
 
Date of Document: 08 September 2020  


 CLINICAL RESEARCH PROTOCOL 
PROTOCOL TITLE: 
A Phase 2a, Multicenter, Single-Blind, Placebo-Controlled Study 
Evaluating Treatment Intensification with ABI-H0731 in Subjects 
with Chronic Hepatitis B Infection on Nucleos(t)ide Reverse 
Transcriptase Inhibitors 
 
STUDY NUMBER: 
ABI-H0731-205 
 
DRUG: 
ABI-H0731 
 
REFERENCE NUMBERS: 
US IND 136780 
 
SPONSOR: 
Assembly Biosciences 
331 Oyster Point Boulevard, 4th Floor 
South San Francisco, California 94080, USA 
(833) 509-4583 
 
PROTOCOL: 
Amendment 1 – 08 September 2020  
 
PROTOCOL HISTORY:  
Original – 29 April 2020  
 
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 Phase 2a, Multi-Center, Single-Blind, Placebo-Controlled Study 
Evaluating Treatment Intensification with ABI-H0731 in Subjects 
with Chronic Hepatitis B Infection on Nucleos(t)ide Reverse 
Transcriptase Inhibitors 
Protocol Number: 
ABI-H0731-205 
Protocol Date: 
Amendment 1 – 08 September 2020 
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) guideline (E6) on 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. 
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  
 
Chief Medical Officer 
Assembly Biosciences 
 
 
 
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INVESTIGATOR STATEMENT 
Protocol Title: 
A Phase 2a, Multi-Center, Single-Blind, Placebo-Controlled Study 
Evaluating Treatment Intensification with ABI-H0731 in Subjects 
with Chronic Hepatitis B Infection on Nucleos(t)ide Reverse 
Transcriptase Inhibitors 
Protocol Number: 
ABI-H0731-205 
Protocol: 
Amendment 1 – 08 September 2020 
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) 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 signature page in your records and email a 
copy to your site monitor for archival in the Trial Master File. 
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1. 
SYNOPSIS 
Protocol 
Number: 
ABI-H0731-205 
Title:  
A Phase 2a, Multi-Center, Single-Blind, Placebo-Controlled Study Evaluating Treatment 
Intensification with ABI-H0731 in Subjects with Chronic Hepatitis B Infection on 
Nucleos(t)ide Reverse Transcriptase Inhibitors 
Phase: 
2a 
Number of 
Subjects: 
Approximately 40 
Study Duration:  
Up to 45 days for Screening, 96 weeks treatment, and 24 weeks of follow-up 
Rationale:  
Chronic hepatitis B infection (CHB) is a major cause of liver-related morbidity and 
mortality worldwide. While standard-of-care nucleos(t)ide reverse transcriptase inhibitors 
(NrtI) targeting the hepatitis b virus (HBV) polymerase are able to suppress viral 
replication (ie, HBV DNA below the limitation of quantification [LLOQ]), around 30% of 
hepatitis B ‘e’ antigen (HBeAg) positive patients and 10% of HBeAg negative patients 
have only a partial virologic response and are not able to reach this goal by treatment Week 
48. Combination approaches are needed to provide adequate viral suppression in these 
patients. ABI-H0731 is a direct-acting antiviral agent targeting the HBV core protein. 
Through this mechanism, ABI-H0731 interferes with multiple steps in the viral lifecycle 
including capsid disassembly and HBV DNA delivery to the nucleus, HBV pregenomic 
RNA (pgRNA) encapsidation, capsid assembly and HBV DNA recirculation preventing de 
novo cccDNA establishment. It is anticipated that ABI-H0731 administered in combination 
with NrtI will be safe and result in complete viral suppression in subjects unable to attain 
this status on NrtI alone. This Phase 2a study will explore the safety of ABI-H0731 when 
added to NrtI and evaluate the antiviral activity of the ABI-H0731+NrtI combination as 
measured by the proportions of partially virologically suppressed subjects achieving HBV 
DNA <LLOQ at Week 48. 
Target 
Population: 
Male or female, aged 18 to 65 years (inclusive), with HBeAg positive or HBeAg negative 
CHB and no evidence of cirrhosis or end-stage liver disease who are not adequately 
suppressed on NrtI therapy. 
Test Product: 
300 mg ABI-H0731 as three 100 mg tablets and NrtI, oral administration  
Reference 
Product: 
ABI-H0731-matching placebo (PBO) (as 3 tablets) and NrtI, oral administration   
Study Design: 
This is a Phase 2a, multi-center, randomized, single-blind, PBO-controlled study, 
evaluating the safety, antiviral activity, and pharmacokinetics (PK) of ABI-H0731 
administered in addition to standard of care NrtI in subjects with CHB who have not 
achieved adequate virologic suppression of HBV DNA <LLOQ on NrtI alone. For this 
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study, HBV DNA is analyzed by COBAS® TaqMan Version 2.0 at the central laboratory 
(lower limit of quantification [LLOQ]=20 IU/mL). 
Approximately 40 eligible subjects will be randomized in a 1:1 ratio to the treatment groups 
described below. 
 
Abbreviations: NrtI=nucleos(t)ide reverse transcriptase inhibitor; PBO=placebo; QD=once daily; Wk=week. 
Treatment with ABI-H0731 or PBO and NrtI will be administered orally, once daily  
• 
Group 1 will receive ABI-H0731+NrtI for 96 weeks 
• 
Group 2 will receive PBO+NrtI for 48 weeks, and then ABI-H0731+NrtI until 
Week 96 
All subjects will continue to receive NrtI alone from Week 96 through Week 120 (during 
the 24-week follow-up period). 
The study will enroll up to 75% subjects on entecavir (ETV). Treatment assignments will 
be stratified by the concurrent NrtI administered (ie, ETV) versus tenofovir (alafenamide 
versus [TAF] or disoproxil fumarate [TDF]) and HBV DNA (HBV DNA ≥500 IU/mL 
versus <500 IU/mL) during the Screening visits. 
Objectives:  
Primary Objectives: 
• 
To evaluate the safety and tolerability of ABI-H0731 when administered in 
combination with NrtI in subjects with CHB 
• 
To evaluate the effect of the addition of ABI-H0731 to NrtI in fully suppressing 
HBV DNA in subjects with CHB 
Secondary Objectives: 
• 
To evaluate the effect of the addition of ABI-H0731 to NrtI in reducing HBV 
pgRNA levels in subjects with CHB 
• 
To evaluate the effect of the addition of ABI-H0731 to NrtI in reducing HBV 
antigens (ie, HBeAg, hepatitis B core-related antigen [HBcrAg], and hepatitis B 
surface antigen [HBsAg]) in subjects with CHB 
• 
To evaluate the effect of the addition of ABI-H0731 to NrtI on normalization of 
alanine aminotransferase (ALT) in subjects with abnormal ALT 
• 
To evaluate the PK of ABI-H0731 and NrtI in subjects with CHB 
• 
To evaluate the emergence of resistance to ABI-H0731 when administered in 
combination with NrtI 
Exploratory Objectives:  
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• 
To assess the relationship between immunological and/or viral biomarkers with 
virologic and/or clinical outcomes 
• 
For subjects who provide an optional pharmacogenomic sample, to evaluate the 
potential contribution of host genomics to clinical or virologic outcomes and/or 
drug disposition 
Primary 
Endpoint:  
Primary Endpoints: 
• 
Proportion of subjects with adverse events, premature treatment discontinuation, 
and abnormal laboratory results 
• 
Proportion of subjects with HBV DNA <LLOQ at Week 48 for PBO+NrtI and 
ABI-H0731+NrtI 
Secondary 
Endpoints: 
Secondary Endpoints: 
• 
Mean change in log10 HBV DNA from Baseline at each timepoint 
• 
Proportion of subjects with HBV DNA is <LLOQ at each timepoint 
• 
Proportion of subjects with HBV DNA is <level of detection (target not detected) 
at each timepoint 
• 
Mean change in log10 HBV pgRNA from Baseline at each timepoint 
• 
Proportion of subjects with HBV pgRNA <LLOQ at each timepoint 
• 
Mean change in log10 serum viral antigens (ie, HBeAg, HBcrAg, and HBsAg) from 
Baseline at each timepoint 
• 
Proportion of subjects with abnormal ALT at Baseline who have normal ALT at 
each timepoint 
• 
Analysis of ABI-H0731 and NrtI drug concentrations: 
o PK on study visit days of ABI-H0731 on ABI-H0731+NrtI 
o PK on study visit days of NrtI on PBO+NrtI and ABI-H0731+NrtI 
• 
The incidence of HBV variants with reduced susceptibility to ABI-H0731 
Exploratory  
Endpoints: 
Exploratory Endpoints: 
• 
Proportion of subjects with loss of serum viral antigens (defined as <LLOQ) in 
HBeAg, HBcrAg, and HBsAg 
• 
Proportion of subjects with HBeAg seroconversion (defined as loss of HBeAg and 
appearance of HBeAg antibody [HBeAb]) or HBsAg seroconversion (defined as 
loss of HBsAg and appearance of HBsAg antibody [HBsAb]) at each timepoint 
• 
Immunologic outcomes, including changes in humoral and cellular immunity to 
PBO+NrtI and ABI-H0731+NrtI 
• 
Pharmacogenomic correlations may be performed with clinical or virologic 
outcomes for subjects who provide optional informed consent 
• 
For subjects who provide an optional pharmacogenomic sample, to evaluate 
known gene variants and ABI-H0731, its metabolites, and PK and/or safety 
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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 dose groups within cohorts. 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 compared 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 of child-bearing potential (Appendix 4) must be non-pregnant and 
have a negative serum pregnancy test at Screening and a negative urine pregnancy 
test predose on Day 1 
5. HBeAg positive or HBeAg negative CHB, defined as HBV infection documented 
for ≥12 months 
6. HBV DNA >LLOQ (using a commercially available assay with LLOQ=20 IU/mL) 
from 2 samples drawn on 2 separate occasions during the Screening period 
approximately 10-14 days apart. If the results from these 2 samples indicate a 
numeric decline in HBV DNA, then a third sample will be collected at least a week 
later for Sponsor review and approval prior to randomization 
7. On a stable NrtI regimen (ETV, TDF or TAF) for more than 12 months, without 
evidence of resistance and while known to be adherent to therapy 
8. Lack of cirrhosis or advanced liver disease as documented by the following: 
• 
Liver biopsy results of METAVIR F0-F3 (absence of cirrhosis) within 
1 year of Screening 
OR 
• 
Fasting FibroScan® ≤14 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 (F0 to 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 
9. Agreement to comply with protocol-specified contraceptive requirements (Refer 
to Appendix 4) 
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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 for the duration of the trial 
11. In good general health, except for CHB (in the opinion of the Investigator). 
12. Have the ability to take oral medication and, in the opinion of the Investigator, be 
willing to adhere to trial treatment 
 
Exclusion Criteria: 
Subjects who meet any of the following exclusion criteria will not be eligible for the trial. 
1. Current or prior treatment for CHB with 
• 
Lamivudine, telbivudine or adefovir (any duration) 
• 
HBV core inhibitor (any duration) 
• 
Previous treatment with an investigational agent for HBV infection 
2. Presence of substitutions in the HBV polymerase coding region which may confer 
reduced susceptibility to NrtIs (Appendix 2) 
3. Co-infection with human immunodeficiency virus, 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 
trial 
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 diseases or conditions such as 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 trial participation 
8. History of hepatocellular carcinoma (HCC) 
9. A 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 
10. History or presence at Screening of electrocardiogram abnormalities deemed 
clinically significant, in the opinion of the Investigator 
11. History of hypersensitivity or idiosyncratic reaction to any components or 
excipients of the investigational drug or PBO formulation 
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12. History of any significant food or drug-related allergic reactions such as, 
anaphylaxis or Stevens-Johnson syndrome 
13. The following are exclusionary laboratory results at the Screening visit: 
• 
Platelet count <100,000/mm3 
• 
Albumin <lower limit of normal  
• 
Total bilirubin >1.2 × upper limit of normal (ULN) unless known 
Gilbert’s syndrome; subjects with Gilbert’s syndrome are eligible for 
trial participation if the direct bilirubin is within the normal range 
• 
Direct bilirubin >1.2 × ULN 
• 
ALT >10 × ULN 
• 
Serum alpha fetoprotein (AFP) ≥100 ng/mL. If AFP at Screening is 
>ULN but <100 ng/mL, the subject is eligible if a hepatic imaging 
trial prior to initiation of study drug reveals no lesions indicative of 
possible HCC. 
• 
International Normalized Ratio >1.5 × ULN 
• 
Glomerular filtration rate <50 mL/min/1.73 m2 by Chronic Kidney 
Disease Epidemiology Collaboration equation  
• 
Any other laboratory abnormality deemed clinically significant by 
the Sponsor or the Investigator 
14. Subjects receiving prohibited concomitant medications, as defined in Section 6.4.1 
of the protocol, grapefruit juice, or prohibited herbal/over-the-counter medications 
within 7 days or 5 half-lives (if known), whichever is longer, prior to 
administration of the first dose of study drug and for the duration of the trial period 
15. Participation in another clinical trial of a 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, whichever is longer. However, subjects 
receiving any prior investigational therapy for HBV, will be excluded 
16. Subjects who have received, in the previous 4 weeks, a treatment likely to alter the 
immune response (intravenous immunoglobulins, blood-derived products, or 
high-dose steroids, or other immunosuppressants) 
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TABLE OF CONTENTS 
1. 
SYNOPSIS ............................................................................................................................ 4 
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 .......................................................................... 16 
2.3. 
Study Rationale ............................................................................................................. 23 
3. 
STUDY OBJECTIVES AND ENDPOINTS ................................................................... 25 
3.1. 
Study Objectives ........................................................................................................... 25 
3.1.1. 
Primary Objective .................................................................................................. 25 
3.1.2. 
Secondary Objectives ............................................................................................. 25 
3.1.3. 
Exploratory Objectives: ......................................................................................... 25 
3.2. 
Study Endpoints ............................................................................................................ 25 
3.2.1. 
Primary Endpoint ................................................................................................... 25 
3.2.2. 
Secondary Endpoints .............................................................................................. 25 
3.2.3. 
Exploratory Endpoints ........................................................................................... 26 
4. 
STUDY PLAN .................................................................................................................... 27 
4.1. 
Study Design .................................................................................................................. 27 
4.2. 
Dose Justification .......................................................................................................... 27 
4.3. 
Study Treatments .......................................................................................................... 28 
4.4. 
Duration of Treatment ................................................................................................. 28 
5. 
POPULATION .................................................................................................................. 29 
5.1. 
Number of Subjects ...................................................................................................... 29 
5.2. 
Inclusion Criteria .......................................................................................................... 29 
5.3. 
Exclusion Criteria ......................................................................................................... 30 
6. 
INVESTIGATIONAL MEDICAL PRODUCTS............................................................ 32 
6.1. 
Randomization, Blinding and Treatment Codes ....................................................... 32 
6.1.1. 
Randomization ........................................................................................................ 32 
6.1.2. 
Blinding .................................................................................................................... 32 
6.1.3. 
Unblinding in Emergency Situations .................................................................... 32 
6.2. 
Description and Handling of ABI-H0731 and Matching Placebo (Investigational 
Medicinal Product) ....................................................................................................... 33 
6.2.1. 
Formulation ............................................................................................................. 33 
6.2.2. 
Packaging and Labeling ......................................................................................... 33 
6.2.3. 
Storage and Handling ............................................................................................. 33 
6.3. 
Description and Handling of NrtI (Non-Investigational Medicinal Product) ......... 33 
6.4. 
Prior and Concomitant Medications ........................................................................... 34 
6.4.1. 
Prohibited Concomitant Therapy ......................................................................... 34 
6.5. 
Drug Accountability ..................................................................................................... 34 
6.6. 
Study Drug Administration and Compliance ............................................................ 35 
6.7. 
Return or Disposal of Study Drug ............................................................................... 35 
7. 
STUDY PROCEDURES ................................................................................................... 36 
7.1. 
Subject Enrollment and Treatment Assignment ....................................................... 36 
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7.1.1. 
Screen Failures ........................................................................................................ 36 
7.2. 
Screening Assessments (Day -45 to Day -1) ................................................................ 36 
7.3. 
Day 1 .............................................................................................................................. 37 
7.4. 
Study Weeks 2 Through 48 .......................................................................................... 38 
7.5. 
Study Weeks 52 to 96 .................................................................................................... 39 
7.6. 
Follow-up Assessments ................................................................................................. 39 
7.7. 
Unscheduled Visit ......................................................................................................... 40 
7.8. 
Premature Termination Visit ...................................................................................... 41 
7.9. 
Discontinuation ............................................................................................................. 41 
7.9.1. 
Discontinuation from Treatment........................................................................... 42 
7.9.2. 
Discontinuation from Study ................................................................................... 42 
7.9.3. 
Subjects Lost to Follow-up ..................................................................................... 42 
7.10. PK Assessments ............................................................................................................. 43 
7.11. End of Study Definition ................................................................................................ 43 
7.12. Resistance Monitoring .................................................................................................. 43 
8. 
ADVERSE EVENTS ......................................................................................................... 44 
8.1. 
Documenting Adverse Events ...................................................................................... 44 
8.2. 
Assessment of Intensity ................................................................................................ 44 
8.3. 
Assessment of Causality ............................................................................................... 44 
8.4. 
Expectedness ................................................................................................................. 45 
8.5. 
Abnormal Laboratory Test Values ............................................................................. 45 
8.6. 
Adverse Event Follow-up ............................................................................................. 45 
8.7. 
Pregnancy ...................................................................................................................... 45 
8.7.1. 
Female subjects who become pregnant ................................................................. 45 
8.7.2. 
Male subjects with partners who become pregnant ............................................ 46 
9. 
SERIOUS ADVERSE EVENTS ...................................................................................... 47 
9.1. 
Definition of SAE .......................................................................................................... 47 
9.2. 
Reporting Serious Adverse Events .............................................................................. 47 
9.3. 
Overdose ........................................................................................................................ 48 
9.4. 
Management of On-treatment and Post-treatment ALT Elevations ....................... 48 
10. STATISTICAL CONSIDERATIONS ............................................................................. 51 
10.1. Determination of Sample Size ...................................................................................... 51 
10.2. Analysis Populations ..................................................................................................... 51 
10.3. Planned Analyses .......................................................................................................... 51 
10.3.1. 
Disposition of the Study Subjects .......................................................................... 51 
10.3.2. 
Demographic and Baseline Characteristics.......................................................... 52 
10.3.3. 
Exposure to Study Treatment and Compliance ................................................... 52 
10.3.4. 
Analysis of Primary Efficacy Endpoints............................................................... 52 
10.3.5. 
Analysis of Secondary Efficacy Endpoints ........................................................... 52 
10.3.6. 
PK Analysis ............................................................................................................. 52 
10.3.7. 
Safety Analysis ........................................................................................................ 53 
10.4. Interim Analysis ............................................................................................................ 53 
10.5. Independent Data Monitoring Committee ................................................................. 53 
10.6. Handling of Missing Data ............................................................................................ 54 
10.7. Multiplicity Adjustment ............................................................................................... 54 
11. RESPONSIBILITIES ........................................................................................................ 55 
11.1. Investigator Responsibilities ........................................................................................ 55 
11.1.1. 
Good Clinical Practice ............................................................................................ 55 
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11.1.2. 
Institutional Review Board (IRB)/Independent Ethics Committee (IEC) ........ 55 
11.1.3. 
Informed Consent ................................................................................................... 55 
11.1.4. 
Confidentiality......................................................................................................... 55 
11.1.5. 
Study Files and Retention of Records ................................................................... 56 
11.1.6. 
Audits and Inspections ........................................................................................... 56 
11.1.7. 
Protocol Compliance .............................................................................................. 56 
11.2. Sponsor Responsibilities ............................................................................................... 57 
11.2.1. 
Protocol Amendments and Modifications ............................................................ 57 
11.2.2. 
Data Management ................................................................................................... 57 
11.2.3. 
Study Report and Publications .............................................................................. 57 
12. REFERENCES .................................................................................................................. 58 
13. APPENDICES .................................................................................................................... 60 
APPENDIX 1 
SCHEDULE OF ASSESSMENTS TABLE.............................................. 61 
APPENDIX 2 
CLINICAL AND LABORATORY ASSESSMENTS ............................. 65 
APPENDIX 3 
TOXICITY GRADING SCALE FOR ADVERSE EVENTS AND 
LABORATORY ABNORMALITIES ............................................................................. 68 
APPENDIX 4 
PREGNANCY PRECAUTIONS AND THE DEFINITION OF 
CHILDBEARING POTENTIAL AND CONTRACEPTIVE REQUIREMENTS ..... 89 
APPENDIX 5 
CYTOCHROME P450 3A4 INHIBITORS AND INDUCERS AND 
CYP2C9 SUBSTRATES ................................................................................................... 91 
APPENDIX 6 
SUMMARY OF CHANGES ...................................................................... 92 
 
 
LIST OF TABLES 
Table 1: 
Duration of ABI-H0731+NrtI Treatment (Weeks) in Study 211 by Parent Study . 17 
Table 2: 
Overall Summary of TEAEs Through Week 24 (Study 211) ................................... 18 
Table 3: 
HBV DNA and pgRNA for Treatment-Naïve Subjects with CHB by Week of 
Treatment with ABI-H0731+ETV (Study 202/211) ................................................... 20 
Table 4: 
HBV Antigens for Treatment-Naïve Subjects with CHB by Week of Treatment with 
ABI-H0731+ETV (Study 202/211) .............................................................................. 21 
Table 5: 
HBV DNA for Virologically-Suppressed Subjects with CHB by Week of Treatment 
with ABI-H0731+NrtI (Study 201/211) ....................................................................... 22 
Table 6: 
HBV pgRNA for Virologically-Suppressed Subjects with CHB by Week of 
Treatment with ABI-H0731+NrtI (Study 201/211) ................................................... 23 
Table 7:  
Pharmacokinetic Sample Collection ........................................................................... 43 
Table 8:  
Clinical Laboratory Tests ............................................................................................ 65 
 
LIST OF FIGURES 
Figure 1: 
Study Design for Open-Label Extension (Study 211) ................................................ 17 
Figure 2: 
Mean Change from Baseline in HBV DNA for Treatment-Naïve Subjects with CHB 
(Study 202/211).............................................................................................................. 19 
Figure 3: 
Mean Change from Baseline in HBV pgRNA for Treatment-Naïve Subjects with 
CHB (Study 202/211) .................................................................................................... 20 
Figure 4:  
Study Overview ............................................................................................................. 27 
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LIST OF ABBREVIATIONS AND TERMS 
Abbreviation 
Term or Definition 
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 infection 
CI 
core inhibitor 
CKD-EPI 
Chronic Kidney Disease Epidemiology Collaboration 
CRO 
Contract Research Organization 
CSR 
clinical study report 
CYP 
cytochrome P450 
DAIDS 
Division of AIDS 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
FDA 
Food and Drug Administration 
ETV 
entecavir 
FSH 
follicle-stimulating hormone 
GCP 
Good Clinical Practice 
GFR 
glomerular filtration rate 
GMP 
Good Manufacturing Practices 
HAV 
hepatitis A virus 
HBcAb 
antibody to the HBV core protein  
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 
HCC 
hepatocellular carcinoma 
HCV 
hepatitis C virus 
HDV 
hepatitis D virus 
HEV 
hepatitis E virus 
HIV 
human immunodeficiency 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 
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Abbreviation 
Term or Definition 
IFNα 
Interferon alpha 
IgM 
immunoglobulin M 
INR 
international normalized ratio 
IRB 
Institutional Review Board 
IRT 
Interactive Response Technology 
IUD 
intrauterine device 
LLOQ 
lower limit of quantification 
LOD 
level of detection 
MedDRA 
Medical Dictionary for Regulatory Activities 
NrtI 
nucleos(t)ide reverse transcriptase inhibitor of the HBV polymerase; also called 
nucleos(t)ide analogues or nucleos(t)ides 
PBMC 
peripheral blood mononuclear cell 
pgRNA 
[HBV] pre-genomic RNA 
PK 
pharmacokinetic(s) 
PBO 
placebo 
QD 
once daily 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SVR 
sustained virologic response 
TEAE 
Treatment-emergent adverse event 
TAF 
tenofovir alafenamide 
TD 
target detected 
TDF 
tenofovir disoproxil fumarate 
TND 
target not detected 
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 (EASL 2017, WHO 2016, El-
Serag 2012, Colvin 2010). The global prevalence of chronic HBV infection shows wide geographic 
variation, with a prevalence of more than 8% of people in highly endemic regions (eg, East Asia and 
equatorial Africa), 2% to 7% of people in moderately endemic regions (eg, the Middle East and the 
Indian subcontinent), and less than 2% in locales of low endemicity (eg, North America and Europe) 
(Schweitzer 2015, WHO 2015). Despite broad implementation of HBV vaccination programs, new 
cases of HBV infection are still common. The World Health Organization (WHO) estimates that there 
are more than 4 million acute HBV infections worldwide each year (WHO 2015). 
The clinical stages of HBV 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 2015, Hoofnagle 2007, Lok 2009, Pungpapong 2013, Sorrell 2009, Yim 2006). 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 
pre-genomic RNA (pgRNA) and HBV core-related antigen (HBcrAg) have also been used as markers 
of infection. Historically, treatment goals include prevention of HBV-related liver injury through 
suppression of HBV DNA to low levels, achievement of HBeAg loss and seroconversion, and loss of 
HBsAg 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 is 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, sustained undetectable HBV DNA 
without HBsAg loss after stopping treatment (“sustained virologic responses [SVR]”) may be 
considered as an intermediate goal (Cornberg 2020). 
Currently, there are 2 clinically accepted treatment options for CHB: interferon alfa (IFNα) and 
nucleos(t)ide reverse transcriptase inhibitors of the HBV polymerase (NrtI). Of these agents, oral NrtIs 
are more broadly used and have demonstrated success in achieving and maintaining viral suppression 
in most patients (Lampertico 2012). However, there is a sizable number of individuals who do not 
achieve complete viral suppression to levels below quantification on commercially available assays 
following an adequate course of NrtI therapy. In the Phase 3 studies with entecavir (ETV), 33% of 
HBeAg positive subjects and 10% of HBeAg negative subjects did not achieve HBV DNA <lower 
limit of quantification (LLOQ) (300 copies/mL) after 48 weeks of treatment (Chang 2006; Lai 2006). 
Similarly, in a Phase 3 trial in HBeAg positive subjects, 36% of tenofovir alafenamide (TAF) 
recipients and 33% of subjects receiving tenofovir disoproxil fumarate (TDF) had HBV DNA >LLOQ 
(29 IU/mL) at Week 48 (Chan 2016). In the complementary Phase 3 trial in HBeAg negative subjects, 
6% of TAF recipients and 7% of those receiving TDF had HBV DNA >LLOQ (29 IU/mL) at Week 48 
(Buti 2016). Importantly, the level of HBV replication as measured by HBV DNA in those treated with 
and without complete virologic response (ie, achieving/not achieving HBV DNA <LLOQ) has been 
predictive of progression of liver disease and risk of hepatocellular carcinoma (EASL 2017, 
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Paptheodoridis 2015, Yip 2020). Further, despite suppression of HBV DNA for extended periods of 
time, the template for ongoing viral replication, cccDNA, is not eliminated in most patients. As a 
result, off-treatment SVR with currently approved agents is rare, necessitating long-term chronic 
suppressive treatment approaches. There is a need for improved, novel HBV therapies that further 
reduce HBV replication and result in a higher proportion of patients achieving virologic response (ie, 
HBV DNA <LLOQ) with a subsequent improvement in long-term patient outcomes, (ie, reduction of 
HBV-associated hepatic inflammation leading to reduced morbidity and mortality from end-stage liver 
disease and HCC). Additionally, such deeper virologic responses may enable patients to achieve 
durable virologic and clinical outcomes following finite treatment duration. 
ABI-H0731 is a novel, HBV core inhibitor (CI) 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, and therefore inhibits HBV replication by 
different mechanisms than NrtIs. Thus, inhibition of HBV core protein functions by ABI-H0731, when 
used in combination with currently approved HBV antivirals, has the potential to immediately improve 
current therapy for chronic HBV infection 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 ABI-H0731 is described in the Investigator’s Brochure (IB). 
2.2.2. 
Preclinical Pharmacology and Toxicology 
Refer to the ABI-H0731 IB for a complete summary of the preclinical and toxicology studies 
performed to date. 
2.2.3. 
Clinical Studies with ABI-H0731 
Summaries of the clinical studies completed to date and the Phase 2a studies, Study ABI-H0731-201 
(Study 201) and Study ABI-H0731-202 (Study 202), are provided in the ABI-H0731 IB. In addition, 
the ongoing Phase 2a trial, ABI-H0731-211 is summarized below in Section 2.2.3.1. 
2.2.3.1. 
Ongoing Study ABI-H0731-211 (Open-label Treatment Extension) 
Following completion of treatment in Study 202 and Study 201, eligible subjects were able to 
participate in Study ABI-H0731-211 (Study 211), a long-term extension trial and receive open-label, 
300 mg ABI-H0731+NrtI for up to an additional 76 weeks (Figure 1). 
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Figure 1: 
Study Design for Open-Label Extension (Study 211) 
 
Abbreviations: ETV=entecavir; NrtI= nucleos(t)ide reverse transcriptase inhibitor of the HBV polymerase; also called nucleos(t)ide 
analogues or nucleos(t)ides; PBO=placebo.  
2.2.3.2. 
Summary of Exposure  
Overall, 92 subjects have been enrolled in ongoing open-label treatment extension Study 211. The 
overall summary of exposure based on a data cut date of 12 March 2020 is summarized in Table 1. For 
the purposes of this summary (unless otherwise noted), preliminary safety and efficacy data through 
Week 24 in Study 211 are presented. Through the first 24 weeks of Study 211, 90 (98%) of subjects 
who enrolled continued on study treatment, 1 subject discontinued study drug due to a Grade 1 AE or 
rash and 1 subject discontinued study drug due to virologic resistance in the setting of non-compliance 
with study drug. 
Table 1: 
Duration of ABI-H0731+NrtI Treatment (Weeks) in Study 211 by Parent Study  
Treatment duration in weeks 
Study 202 
Study 201 
HBeAg 
HBeAg 
Positive 
(N=23) 
Positive 
(N=43) 
Negative 
(N=26) 
Mean (SD) 
50.6 (7.40) 
45.1 (7.65) 
40.3 (10.26) 
Median 
50.1 
45.3 
43.2 
Minimum, maximum 
36.4, 64.1 
27.7, 61.6 
1.1, 48.4 
Source: Data on file.  
Abbreviations: HBeAg=hepatitis B “e” antigen; N=Number of subjects in the Intent-to-Treat population; N=number of subjects in the 
Intent-to-Treat population; NrtI=nucleos(t)ide reverse transcriptase inhibitor of the HBV polymerase; SD=standard deviation 
Duration of Treatment=(Date of Last Reported Exposure – Date of First Exposure in Study 211)/7 
2.2.3.2.1. Summary of Safety  
In Study 211, preliminary safety data are available for all subjects through 24 weeks of treatment with 
ABI-H0731+NrtI and demonstrate that ABI-H0731 300 mg daily continues to be generally 
well-tolerated in the open-label treatment extension trial (Table 2). No subjects discontinued treatment 
due to TEAEs in Study 211. One subject discontinued treatment due to a Grade 1 AE of rash which 
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began in Study 201. Overall, 42 of 92 subjects (46%) have experienced TEAEs, the majority of which 
were Grade 1. The only AEs reported by >5% of subjects in the first 24 weeks of Study 211 are rash 
(5/92, 5%) and upper respiratory tract infection (5/92, 5%). All the AEs of rash were Grade 1 and 2 
were considered not related to study drug. Two subjects reported Grade 3 AEs. One subject 
experienced Grade 3 elevations in alanine aminotransferase (ALT) and aspartate aminotransferase 
(AST) which were not considered related to study drug and resolved on continued treatment. Another 
subject experienced a Grade 3 elevation in ALT which was reported as a Grade 3 AE and considered 
possibly related to study drug; this was associated with a Grade 2 elevation in AST and improved to 
Grade 2 on continued treatment. No Grade 4 AEs or serious AEs (SAEs) were reported and no deaths 
occurred. Most treatment-emergent laboratory abnormalities were Grade 1. In addition to the Grade 3 
elevations in ALT and AST reported as AEs, 1 subject had a Grade 3 prolonged prothrombin time and 
another subject had a Grade 3 elevation in AST (not reported as an AE). There were no Grade 4 
laboratory abnormalities. 
Table 2: 
Overall Summary of TEAEs Through Week 24 (Study 211) 
Characteristic [n, (%)] 
ABI-H0731+NrtI 
(N=92) 
Any treatment-emergent AEa 
44 (48) 
Grade 1 
27 (29) 
Grade 2 
15 (16) 
Grade 3 or 4 
2 (2) 
Serious adverse events 
0 
TEAEs leading to study drug discontinuationb 
0 
Source: Data on file.  
Abbreviations: AE=adverse event; DAIDS=Division of Aids; N=number of subjects in the Safety population; 
NrtI=nucleos(t)ide analog reverse transcriptase inhibitor; TEAE=treatment-emergent adverse event. 
Adverse events were graded according to DAIDS criteria. 
a Subjects with more than 1 TEAE were reported in the highest TEAE grade 
b One non-TEAE (which began in Study 201) led to study drug discontinuation in Study 211. 
2.2.3.2.2. Summary of Efficacy  
This section summarizes the antiviral activity for subjects continuing treatment from Study 202 or 
Study 201 into Study 211 through 24 weeks of treatment. The preliminary analyses for Study 211 
reported below are based on subject characteristics and the initial study into which they enrolled, with 
treatment-naïve subjects with HBeAg positive CHB originating from Study 202 and virologically-
suppressed subjects with HBeAg positive or HBeAg negative CHB originating from Study 201. 
Treatment-Naïve Subjects with HBeAg Positive CHB in ABI-H0731-211 (Originating from 
Study 202) 
The changes in HBV DNA and HBV pgRNA from the beginning of Study 202 through Week 24 in 
Study 211 are presented in graphical form in Figure 2 and Figure 3. In both figures, each line 
represents a treatment group originating in Study 202 (either ABI-H0731+ETV or PBO+ETV) with 
green representing ABI-H0731+ETV and blue representing PBO+ETV. The numbers of subjects 
contributing data at each timepoint are presented below the x-axes. These figures demonstrate the 
different declines in HBV nucleic acids over time in the treatment groups. At Week 24 in Study 202, 
the ABI-H0731+ETV group had statistically significant lower levels of HBV DNA and pgRNA 
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compared to group receiving PBO+ETV (p=0.048 and p=0.002, respectively). In addition, there was a 
change in trajectory of HBV DNA and HBV pgRNA following the addition of ABI-H0731 to ETV at 
the end of Study 202 in the group who were initially assigned to PBO+ETV. Of note, there is a clear 2-
phase decline in pgRNA observed in both treatment groups observed upon initiation of ABI-H0731 
treatment. The initial rapid phase decline of pgRNA is thought to be primary mechanism-based 
inhibition (ie, core inhibition preventing encapsidation of pgRNA and secretion into serum), while the 
second slower phase decline of pgRNA is believed to reflect reduction in the cccDNA pool over time. 
Although all subjects received ABI-H0731+ETV in Study 211, pooling data of data in this study is not 
appropriate given the differing treatments received during Study 202. The Study 202 treatment 
assignments (ABI-H0731+ETV and PBO+ETV) led to different starting points for markers of HBV 
infection at the beginning of Study 211. Consequently, the remainder of this section will focus on the 
subjects who received 48 weeks of ABI-H0731+ETV from the beginning of Study 202 through Week 
24 in Study 211. 
Figure 2: 
Mean Change from Baseline in HBV DNA for Treatment-Naïve Subjects with 
CHB (Study 202/211) 
 
Source: Data on file.  
Abbreviations: 731=ABI-H0731, CHB=chronic hepatitis B infection; ETV=entecavir; HBV=hepatitis B virus; 
IU=international units; PBO=placebo. 
Includes subjects in the Intent-to-Treat population. HBV DNA LLOQ=20 IU/mL (1.20 log10 IU/mL).  
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Figure 3: 
Mean Change from Baseline in HBV pgRNA for Treatment-Naïve Subjects with 
CHB (Study 202/211) 
 
Source: Data on file. 
Abbreviations: 731=ABI-H0731, CHB=chronic hepatitis B infection; ETV=entecavir; HBV=hepatitis B virus; 
LLOQ=lower limit of quantification; PBO=placebo; pgRNA=pregenomic RNA; U=units. 
Includes subjects in the Intent-to-Treat population.  HBV pgRNA LLOQ 135 U/mL (1.54 log10 U/mL).  
For subjects who have received 48 cumulative weeks of ABI-H0731+ETV in Study 202/211, Table 3 
summarizes the mean (minimum, maximum) absolute value and change from Baseline in HBV DNA 
(COBAS® TaqMan; LLOQ=20 IU/mL) and HBV pgRNA (Assembly RT-qPCR; LLOQ=135 U/mL) 
by week of treatment. In these subjects, the mean (minimum, maximum) Baseline HBV DNA was 7.9 
(5.5, 8.7) log10 IU/mL which declined to 1.6 (1.0, 2.7) log10 IU/mL after 48 weeks of treatment with 
ABI-H0731+ETV, representing a mean (minimum, maximum) change of -6.3 (-7.2, -4.2) log10 IU/mL. 
Further, the proportion of subjects in this group who had HBV DNA < LLOQ increased from 0% at 
Baseline to 42% (5/12) at Week 48. The mean (minimum, maximum) HBV pgRNA at Baseline was 
7.1 (4.8, 8.6) log10 IU/mL which declined to 4.3 (2.1, 5.8) log10 IU/mL after 48 weeks of treatment 
with ABI-H0731+ETV, representing a mean (minimum, maximum) change 
of -2.8 (-4.9, -1.9) log10 IU/mL. The proportion of subjects in this group who had HBV 
pgRNA <LLOQ was 0% at Baseline to 8% (1/12) at Week 48. 
Table 3: 
HBV DNA and pgRNA for Treatment-Naïve Subjects with CHB by Week of 
Treatment with ABI-H0731+ETV (Study 202/211) 
Week of treatment 
HBV DNAa 
log10 IU/mL 
(N=12) 
HBV pgRNAa 
log10 U/mL 
(N=12) 
Baseline 
 
 
n 
12 
12 
Mean (min, max) 
7.9 (5.5, 8.7) 
7.1 (4.8, 8.6) 
Week 12 
 
 
n 
12 
12 
Mean (min, max) 
3.4 (1.3, 5.3) 
4.7 (2.5, 6.3) 
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Mean change from Baseline (min, max) 
-4.5 (-6.2, -3.2) 
-2.4 (-4.2, -1.6) 
Week 24 
 
 
n 
12 
12 
Mean (min, max) 
2.2 (1.3, 3.4) 
4.6 (2.6, 6.2) 
Mean change from Baseline (min, max) 
-5.7 (-6.8, -4.2) 
-2.5 (-4.3, -1.6) 
Week 36 
 
 
n 
11 
11 
Mean (min, max) 
1.8 (1.3, 3.4) 
4.3 (2.1, 5.8) 
Mean change from Baseline (min, max) 
-6.1 (-7.3, -4.2) 
-2.7 (-4.5, -1.8) 
Week 48 
 
 
n 
12 
12 
Mean (min, max) 
1.6 (1.0, 2.7) 
4.3 (2.1, 5.8) 
Mean change from Baseline (min, max) 
-6.3 (-7.2, -4.2) 
-2.8 (-4.9, -1.9) 
Source: Study 211 Trends Analysis Table 4.1.1, 4.2. 
N = Number of subjects in the Intent-to-Treat population. HBV DNA LLOQ = 20 IU/mL (1.30 log10 IU/mL); HBV pgRNA LLOQ 
135 U/mL (2.13 log10 U/mL). 
Abbreviations: ETV = entecavir; H; HBV = hepatitis B virus; IU = international units; Min = minimum; Max = maximum; pgRNA = 
pregenomic RNA; U = units. 
aSubjects who received ABI-H0731+ETV in Study 202 
As HBV DNA and HBV pgRNA decline over time, it is anticipated that reductions in HBV antigens 
may be observed reflective of a lower viral replicative state. Table 4 summarizes the absolute and 
change from Baseline in HBeAg, HBcrAg and HBsAg by week of treatment. The Baseline values for 
HBeAg, HBcrAg and HBsAg were 2.5 log10 IU/mL, 5.5  log10 kU/mL and 4.5 log10 IU/mL, 
respectively. The change from Baseline at Week 48 was -0.4 Log10 IU/mL, -0.8 log10 kU/mL and -0.2 
log10 IU/mL for HBeAg, HBcrAg and HBsAg, respectively. 
Table 4: 
HBV Antigens for Treatment-Naïve Subjects with CHB by Week of Treatment 
with ABI-H0731+ETV (Study 202/211) 
Week of Treatment 
HBeAga 
log10 IU/mL 
(N=12) 
HBcrAga 
log10 kU/mL 
(N=12) 
HBsAga 
log10 IU/mL 
(N=12) 
Baseline 
 
 
 
n 
12 
12 
12 
Mean (min, max) 
2.5 (0.6, 3.1) 
5.5 (3.6, 6.2) 
4.5 (3.3, 4.9) 
Week 12 
 
 
 
n 
12 
12 
12 
Mean (min, max) 
2.2 (0.2, 3.1) 
5.1 (3.1, 5.9) 
4.3 (3.4, 4.9) 
Change from Baseline (min, max) 
-0.3 (-1.5, 0.1) 
-0.4 (-2.0, 0.0) 
-0.1 (-1.5, 0.5) 
Week 24 
 
 
 
n 
12 
11 
12 
Mean (min, max) 
2.1 (0.1, 3.1) 
4.9 (3.0, 6.0) 
4.3 (3.3, 4.8) 
Change from Baseline (min, max) 
-0.4 (-1.1, 0.0) 
-0.50 (-2.1, -0.1) 
-0.2 (-1.6, 0.7) 
Week 36 
 
 
 
n 
11 
11 
11 
Mean (min, max) 
2.0 (0.1, 3.1) 
4.6 (2.6, 5.7) 
4.2 (3.4, 4.8) 
Change from Baseline (min, max) 
-0.4 (-1.1, 0.1) 
-0.8 (-2.5, -0.1) 
-0.20 (-1.5, 0.7) 
Week 48 
 
 
 
n 
12 
12 
12 
Mean (min, max) 
2.1 (0.0, 3.1) 
4.7 (2.5, 5.8) 
4.2 (3.3, 4.8) 
Change from Baseline (min, max) 
-0.4 (-1.2, 0.1) 
-0.8 (-2.6, 0.0) 
-0.2 (-1.5, 0.7) 
Source: Study 211 Trends Analysis Tables 4.3, 4.4, 4.5  
HBeAg LLOQ = 0.11 IU/mL (-0.96 log10 IU/mL); HBcrAg LLOQ = 1 kU/mL (0 log10 kU/mL); HBsAg LLOQ = 0.05 IU/mL (-1.30 
log10 IU/mL). 
Abbreviations: CHB=chronic hepatitis infection; ETV=entecavir; HBcrAg = hepatitis B core-related antigen; HBeAg = hepatitis B 
e antigen; HBsAg = hepatitis B surface antigen; HBV = hepatitis B virus; IU = international units; kU = kilounits; Min = minimum; 
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Max = maximum; N=number of subjects in the Intent-to-Treat population. 
aSubjects who received ABI-H0731+ETV in Study 202 
Virologically-suppressed Subjects with HBeAg Positive or HBeAg Negative CHB in ABI-H0731-211 
(Originating from Study 201) 
Virologically-suppressed subjects with CHB who enrolled in Study 201 had low HBV DNA at 
Baseline, thus HBV DNA in this population is reported in Study 201 and Study 211 by a high 
sensitivity Assembly semi-quantitative polymerase chain reaction assay with a LOD=5 IU/mL. Table 5 
summarizes the proportions of HBeAg positive and HBeAg negative subjects with undetectable HBV 
DNA (target not detected; TND) at Baseline, Week 24 and Week 48 of treatment with ABI-
H0731+NrtI in Study 201/211. 
To be eligible for participation in the Study 201, subjects must have had HBV DNA ≤ LLOQ 
(20 IU/mL) on NrtI treatment for at least 6 months before screening. As shown in Table 5, despite this 
eligibility criterion, only 7% (2/27) HBeAg positive and 63% (10/16) HBeAg negative subjects had 
HBV DNA TND (LOD=5 IU/mL) at Baseline by the high sensitivity Assembly assay. This is 
consistent with prior reports in which virologically-suppressed individuals with CHB on standard of 
care NrtI treatment who had HBV DNA <20 IU/mL still harbored low levels of infectious virus 
(Burdette 2019). Following 48 weeks of treatment with ABI-H0731+NrtI, 81% (21/26) HBeAg 
positive subjects and 93% (13/14) of HBeAg negative subjects had achieved HBV DNA TND by the 
high sensitivity Assembly assay. These data provide evidence that the addition of ABI-H0731 to NrtI 
results in deeper virologic suppression in virologically-suppressed subjects with HBeAg positive or 
HBeAg negative CHB who have received chronic NrtI therapy for some time. 
Table 5: 
HBV DNA for Virologically-Suppressed Subjects with CHB by Week of Treatment 
with ABI-H0731+NrtI (Study 201/211) 
Week of Treatment 
HBV DNA  
Subjects with TND 
[n/N, (%)] 
HBeAg Positivea 
(N=27) 
HBeAg Negativea 
(N=16) 
Baseline 
2/27 (7) 
10/16 (63) 
Week 24 
22/27 (81) 
15/16 (94) 
Week 48 
21/26 (81) 
13/14 (93) 
Source: Study 211 Table 7 
HBV DNA LOD=5 IU/mL.  
Abbreviations: HBeAg = hepatitis B e antigen; HBV = hepatitis B virus; N=number of subjects in Intent-to-Treat population; 
NrTI=nucleos(t)ide reverse transcriptase inhibitor of the HBV polymerase; TD=target detected; TND = target not detected. 
a Subjects who received ABI-H0731+NrtI in Study 201 
The virologically-suppressed subjects with CHB who enrolled in Study 201 had low HBV pgRNA at 
Baseline and so HBV pgRNA in this population is reported in Study 201 and Study 211 by a high 
sensitivity Assembly RT-qPCR assay with LLOQ <35 U/mL. Table 6 summarizes the absolute value, 
change from Baseline in HBV pgRNA and proportion of subjects with HBV pgRNA <LLOQ by week 
of treatment. In HBeAg positive subjects, the mean (minimum, maximum) Baseline HBV pgRNA was 
3.6 (1.5, 6.1) log10 IU/mL which decreased to 1.9 (1.5, 4.6) log10 IU/mL after 48 weeks, representing a 
mean (minimum, maximum) change of -1.7 (-3.7, 0) log10 IU/mL. Compared to HBeAg positive 
subjects, HBV pgRNA was lower in HBeAg negative subjects and showed less change over 48 weeks 
of treatment with ABI-H0731+NrtI. In HBeAg negative subjects, the mean (minimum, maximum) 
Baseline HBV pgRNA was 1.7 (1.5, 2.6) log10 IU/mL which decreased to 1.5 (1.5, 1.6) log10 IU/mL at 
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Week 48. In both HBeAg positive and negative subjects, the proportion of subjects <LLOQ generally 
increased over time during treatment with ABI-H0731+NrtI. 
Table 6: 
HBV pgRNA for Virologically-Suppressed Subjects with CHB by Week of 
Treatment with ABI-H0731+NrtI (Study 201/211) 
Week of treatment 
HBV pgRNA 
log10 U/mL 
HBeAg Positivea 
(N=27) 
HBeAg Negativea 
(N=16) 
Baseline 
 
 
n 
27 
16 
Mean (min, max) 
3.6 (1.5, 6.1) 
1.7 (1.5, 2.6) 
<LLOQ, n (%) 
4 (15) 
13 (81) 
Week 12 
 
 
n 
27 
16 
Mean (min, max) 
1.9 (1.5, 3.7) 
1.5 (1.5, 1.5) 
Change from Baseline (min, max) 
-1.7 (-3.5, 0) 
-0.1 (-1.0, 0) 
<LLOQ, n (%) 
15 (56) 
16 (100) 
Week 24 
 
 
n 
27 
16 
Mean (min, max) 
1.9 (1.5, 3.4) 
1.5 (1.5, 1.7) 
Change from Baseline (min, max) 
-1.7 (-3.1, 0) 
-0.1 (-1.0, 0) 
<LLOQ, n (%) 
16 (59) 
15 (94) 
Week 36 
 
 
n 
27 
14 
Mean (min, max) 
1.9 (1.5, 3.6) 
1.6 (1.5, 1.9) 
Change from Baseline (min, max) 
-1.7 (-3.6, 0) 
-0.1 (-1.0, 0.3) 
<LLOQ, n (%) 
16 (59) 
11 (79) 
Week 48 
 
 
n 
26 
14 
Mean (min, max) 
1.9 (1.5, 4.6) 
1.5 (1.5, 1.6) 
Change from Baseline (min, max) 
-1.7 (-3.7, 0) 
-0.1 (-1.0, 0.1) 
<LLOQ, n (%) 
20 (77) 
13 (93) 
Source: Trends Analysis Study 211 Table 4.2 
HBV pgRNA LLOQ = 35 U/mL.  
Abbreviations: CHB=chronic hepatitis B infection; HBeAg = hepatitis B e antigen; HBV=hepatitis B virus; LL0Q=lower limit of 
quantification; Max=maximum; Min = minimum; N=number of subjects in Intent-to-Treat population; NrtI= nucleos(t)ide reverse 
transcriptase inhibitor of the HBV polymerase; pgRNA = pregenomic RNA; U=units. 
aSubjects who received ABI-H0731+NrtI in Study 201 
The initial results from the ongoing Phase 2a, open-label, treatment extension study, Study 211  
demonstrate that ABI-H0731 administered in combination with NrtI has an efficacy benefit over NrtI 
therapy alone, leading to more complete viral inhibition as measured most directly by HBV DNA and 
HBV pgRNA, and are consistent with results of Study 201 and Study 202 presented in the IB. 
2.3. 
Study Rationale 
While standard of care NrtIs targeting the HBV, polymerase are able to suppress HBV DNA in most 
patients, around 30% of HBeAg positive patients and up to 10% of HBeAg negative patients are not 
able to reach HBV DNA <LLOQ by treatment Week 48. Treatment intensification approaches are 
needed to increase the proportion of patients able to achieve complete viral suppression (ie, proportion 
of subjects achieving HBV DNA <LLOQ at Week 48). The HBV core protein is involved in multiple 
steps in the HBV life cycle, including both viral replication and the establishment of new cccDNA 
(Belloni 2013; Levrero 2009). Inhibition of HBV core protein represents a novel therapeutic strategy 
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for the treatment of CHB (Yang 2019). Analyses of Phase 2a studies, including ongoing open-label 
study, Study 211, demonstrate that treatment-naïve and virologically suppressed subjects treated with 
ABI-H0731 + 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 ABI-H0731 to NrtI therapy may increase the proportions of 
subjects with partial virologic suppression able to achieve complete viral suppression, a status that has 
been shown to correlate with long-term clinical outcomes (EASL 2017, Paptheodoridis 2015, 
Yip 2020). The present Phase 2a study (ABI-H0731-205) will explore the safety of ABI-H0731 when 
added to NrtI and evaluate the antiviral activity of the combination as measured by the proportions of 
subjects achieving HBV DNA <LLOQ at Week 48. At Week 48 all subjects will receive 
ABI-H0731+NrtI through Week 96. Following completion of treatment with ABI-H0731 in this study, 
eligible subjects will undergo follow-up evaluation while continuing standard of care therapy with NrtI 
until Week 120. 
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3. 
STUDY OBJECTIVES AND ENDPOINTS 
3.1. 
Study Objectives 
3.1.1. 
Primary Objective 
• To evaluate the safety and tolerability of ABI-H0731 when administered in combination 
with NrtI in subjects with CHB 
• To evaluate the effect of the addition of ABI-H0731 to NrtI in fully suppressing HBV DNA 
in subjects with CHB 
3.1.2. 
Secondary Objectives 
• To evaluate the effect of the addition of ABI-H0731 to NrtI in reducing HBV pgRNA 
levels in subjects with CHB 
• To evaluate the effect of the addition of ABI-H0731 to NrtI in reducing HBV antigens (ie, 
HBeAg, HBcrAg, and HBsAg) in subjects with CHB 
• To evaluate the effect of the addition of ABI-H0731 to NrtI on normalization of ALT in 
subjects with abnormal ALT 
• To evaluate the pharmacokinetics (PK) of ABI-H0731 and NrtI in subjects with CHB 
• To evaluate the emergence of resistance to ABI-H0731 when administered in combination 
with NrtI 
3.1.3. 
Exploratory Objectives: 
• To assess the relationship between immunological and/or viral biomarkers with virologic 
and/or clinical outcomes 
• For subjects who provide an optional pharmacogenomic sample, to evaluate the potential 
contribution of host genomics to clinical or virologic outcomes and/or drug disposition 
3.2. 
Study Endpoints 
3.2.1. 
Primary Endpoint 
• Proportion of subjects with AEs, premature treatment discontinuation, and abnormal 
laboratory results 
• Proportion of subjects with HBV DNA <LLOQ at Week 48 for PBO+NrtI and 
ABI-H0731+NrtI 
3.2.2. 
Secondary Endpoints 
• Mean change in log10 HBV DNA from Baseline at each timepoint 
• Proportion of subjects with HBV DNA is <LOQ at each timepoint 
• Proportion of subjects with HBV DNA is <LOD (TND) at each timepoint 
• Mean change in log10 HBV pgRNA from Baseline at each timepoint 
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• Proportion of subjects with HBV pgRNA <LLOQ at each timepoint 
• Mean change in log10 serum viral antigens (ie, HBeAg, HBcrAg, and HBsAg) from 
Baseline at each timepoint 
• Proportion of subjects with abnormal ALT at Baseline who have normal ALT at each 
timepoint 
• Analysis of ABI-H0731 and NrtI drug concentrations: 
• PK on study visit days of ABI-H0731 on ABI-H0731+NrtI 
• PK on study visit days of NrtI on PBO+NrtI and ABI-H0731+NrtI 
• The incidence of HBV variants with reduced susceptibility to ABI-H0731 
3.2.3. 
Exploratory Endpoints 
• Proportion of subjects with loss of serum viral antigens (defined < LLOQ) in HBeAg, 
HBcrAg, and HBsAg 
• Proportion of subjects with HBeAg seroconversion (defined as loss of HBeAg and 
appearance of HBeAb) or HBsAg seroconversion (defined as loss of HBsAg and 
appearance of HBsAb) at each timepoint 
• Immunologic outcomes, including changes in humoral and cellular immunity to PBO+NrtI 
and ABI-H0731+NrtI 
• Pharmacogenomic correlations may be performed with clinical or virologic outcomes for 
subjects who provide optional informed consent 
• For subjects who provide an optional pharmacogenomic sample, to evaluate known gene 
variants and ABI-H0731, its metabolites, and PK and/or safety 
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4. 
STUDY PLAN 
4.1. 
Study Design 
This is a Phase 2a, multi-center, randomized, single-blind, PBO-controlled study, evaluating the safety, 
antiviral activity, and PK of ABI-H0731 administered in addition to standard of care NrtI in subjects 
with CHB who have not achieved adequate virologic suppression of HBV DNA <LLOQ on NrtI alone. 
For this study, HBV DNA is analyzed by COBAS TaqMan® Version 2.0 at the central laboratory 
(LLOQ=20 IU/mL). 
The study will be conducted at approximately 10 study centers worldwide. Approximately 40 eligible 
subjects will be randomized in a 1:1 ratio to the treatment groups shown in the study overview 
presented in Figure 4.  
Study investigational drugs, ie, 300 mg (3×100 mg tablets) ABI-H0731 or matching PBO (3 tablets) 
and subjects’ background NrtI therapy will be administered orally, once daily (QD). Group 1 will 
receive ABI-H0731+NrtI for 96 weeks, Group 2 will receive PBO+NrtI for 48 weeks followed by 
ABI-H0731+NrtI for 48 weeks until Week 96. All subjects will continue to receive NrtI alone during 
the 24-week follow-up period from Week 96 through Week 120. 
Treatment assignments will be stratified by the concurrent NrtI administered (ie, ETV) versus 
tenofovir (alafenamide versus [TAF] or disoproxil fumarate [TDF]) and HBV DNA (HBV DNA 
≥500 IU/mL versus <500 IU/mL) during the Screening visits. The study will enroll up to 75% subjects 
on ETV. Safety, antiviral activity, and PK will be assessed during treatment and the 24-week follow-up 
period. 
Figure 4:  
Study Overview 
 
NrtI=nucleos(t)ide reverse transcriptase inhibitor; PBO=placebo; QD=once daily [administration] 
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 7.10. 
4.2. 
Dose Justification 
In the Phase 1 clinical studies, ABI-H0731 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 single daily doses of up to 300 mg 
for 14 days. All TEAEs were considered mild (Grade 1) and reversible. In subjects with CHB, 
ABI-H0731 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 mg, 200 mg, and 300 mg daily in subjects 
with CHB. Phase 2 studies, Study 201, Study 202 and Study 211, demonstrate that 300 mg ABI-H0731 
administered QD 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 this regimen will be safe, well tolerated 
and demonstrate improved HBV suppression in subjects with CHB compared to standard of care NrtI 
therapy. The cumulative safety, tolerability, and antiviral activity data generated to date support the 
conduct of the proposed study. 
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4.3. 
Study Treatments 
This is a Phase 2a, multicenter, randomized, single-blind, PBO-controlled study, evaluating the safety, 
antiviral activity, and PK of ABI-H0731+NrtI in subjects with CHB who are not suppressed to HBV 
DNA <LLOQ on NrtI alone. See Section 4.1 for a detailed summary of the study design. 
Subjects will be randomized in a 1:1 ratio to 1 of 2 treatment groups. Group 1 will receive ABI-
H0731+NrtI for 96 weeks, Group 2 will receive PBO+NrtI for 48 weeks followed by ABI-H0731+NrtI 
for 48 weeks until Week 96. All subjects will continue to receive NrtI alone during the 24-week 
follow-up period from Week 96 through Week 120.  
Both ABI-H0731 (3×100 mg tablets) or matching PBO (3 tablets) should be taken together at 
approximately the same time each day as the NrtI. ABI-H0731 and matching PBO may be 
administered with or without food, depending on the NrtI with which they are administered. Entecavir 
should be administered on an empty stomach (ie, at least 2 hours after a meal and 2 hours before the 
next meal), whereas TDF or TAF may be administered either with or without food. Further 
information is provided in the respective package insert. 
On study visit days, ABI-H0731 or matching PBO will be administered in the clinic; subjects will 
self-administer assigned treatment on all other days. On study visit days which include PK sample 
collection (Table 7), subjects will administer ABI-H0731 or PBO in the clinic, and if possible, also 
administer NrtI in the clinic and study personnel will document the time of study drug administration 
in subject’s medical record. Subjects will be required to record the dates and times of each dose of 
ABI-H0731 or PBO and NrtI they self-administer in the dosing diary provided to them. Additional 
information concerning study treatments and the management of missed or incorrect doses is provided 
in the Study Pharmacy Manual. 
4.4. 
Duration of Treatment 
All subjects will receive their randomized treatment in a blinded manner for up to 96 weeks. Following 
completion of the assigned treatment, all subjects will continue to receive NrtI during the 24-week 
follow-up period. Following completion of the 24-week follow-up period, subjects will exit the study 
and resume standard of care oversight by their physicians. 
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5. 
POPULATION 
5.1. 
Number of Subjects 
Approximately 40 male or female subjects between the ages of 18 and 65 will be enrolled in the study. 
Subjects will have HBeAg positive or negative CHB, no evidence of cirrhosis or end-stage liver 
disease and will not be adequately suppressed on NrtI therapy. 
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 of child-bearing potential (Appendix 4) must be non-pregnant and have a 
negative serum pregnancy test at Screening and a negative urine pregnancy test predose on 
Day 1. 
5. HBeAg positive or HBeAg negative CHB Chronic hepatitis B infection, defined as HBV 
infection documented for ≥12 months. 
6. HBV DNA >LLOQ (using a commercially available assay with LLOQ=20 IU/mL) from 2 
samples drawn on 2 separate occasions during the Screening period approximately 10-14 
days apart. If the results from these 2 samples indicate a decline in HBV DNA then a third 
sample will be collected at least a week later for Sponsor review and approval prior to 
randomization. 
7. On a stable NrtI regimen (ETV, TDF, or TAF) for more than 12 months, without evidence 
of resistance and while known to be adherent to therapy 
8. Lack of cirrhosis or advanced liver disease as documented by the following: 
• Liver biopsy results of METAVIR F0-F3 (absence of cirrhosis) within 1 year of 
Screening 
OR 
• Fasting FibroScan® ≤14 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 (F0 to 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. 
9. Agreement to comply with protocol-specified contraceptive requirements (Refer to 
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 
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11. In good general health, except for CHB (in the opinion of the Investigator) 
12. Have the ability to take oral medication and, in the opinion of the Investigator, be willing to 
adhere to study treatment 
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 
• Lamivudine, telbivudine or adefovir (any duration) 
• HBV core inhibitor (any duration) 
• Previous treatment with an investigational agent for HBV infection 
2. Presence of substitutions in the HBV polymerase coding region which may confer reduced 
susceptibility to NrtIs (Appendix 2) 
3. Co-infection with human immunodeficiency virus (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 diseases or conditions, such as 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 
8. History of HCC  
9. A 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  
10. History or presence at Screening of electrocardiogram (ECG) abnormalities deemed 
clinically significant in the opinion of the Investigator.  
11. History of hypersensitivity or idiosyncratic reaction to any components or excipients of the 
investigational drug or PBO formulation 
12. History of any significant food or drug-related allergic reactions such as, anaphylaxis or 
Stevens-Johnson syndrome 
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13. The following exclusionary laboratory results at the Screening and Baseline visit: 
• Platelet count <100,000/mm3 
• Albumin <lower limit of normal  
• Total bilirubin >1.2 × upper limit of normal (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 >10 × ULN 
• Serum alpha fetoprotein (AFP) ≥100 ng/mL. If AFP at Screening is >ULN but <100 
ng/mL, the subject is eligible if a hepatic imaging study prior to initiation of study 
drug reveals no lesions indicative of possible HCC. 
• International Normalized Ratio >1.5 × ULN 
• GFR <50 mL/min/1.73 m2 by CKD-EPI equation (Levey 2009) 
• Any other laboratory abnormality deemed clinically significant by the Sponsor or 
the Investigator 
14. Subjects receiving prohibited concomitant medications , grapefruit juice, or prohibited 
herbal/over-the-counter medications (Section 6.4.1) within 7 days or 5 half-lives (if 
known), whichever is longer, prior to administration of the first dose of study drug and for 
the duration of the study period. 
15. Participation in another clinical study of a 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, whichever is longer. However, subjects receiving any prior investigational 
therapy for HBV, will be excluded. 
16. Subjects who have received, in the previous 4 weeks, a treatment likely to alter the immune 
response (intravenous immunoglobulins, blood-derived products, or high -dose steroids, or 
other immunosuppressants). 
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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. Following successful completion of 
Screening assessments and confirmation of subject eligibility, site personnel will enter the subject 
specific information in the IRT system and receive a subject number at the Screening visit. Upon 
confirmation of subject eligibility on Day 1, the IRT system will assign eligible subjects in a 1:1 ratio 
to receive either 300 mg ABI-H0731+NrtI for 96 weeks (n=20) or PBO+NrtI for 48 weeks followed by 
300 mg ABI-H0731+NrtI for 48 weeks (n=20). Individual treatment assignments will be stratified by 
the concurrent NrtI administered (ie, ETV versus TDF or TAF) and HBV DNA (HBV DNA ≥500 
IU/mL versus <500 IU/mL). The study will enroll approximately 75% subjects receiving ETV. 
Additional information on the use of the IRT is provided in the IRT user manual. 
6.1.2. 
Blinding 
Study subjects, Investigators and other site personnel administering the study drug, performing the 
clinical assessments and handling data on the study subjects, will be blinded to individual subject 
treatments assignments (ie, PBO+NrtI or ABI-H0731+NrtI) throughout the duration of the study. To 
support maintenance of the study blind, HBV pgRNA results will not be provided to the study subjects, 
Investigators or other site personnel until completion of the study. 
A limited internal Sponsor team will be unblinded to individual subjects’ treatment assignments 
throughout the study to ensure timely analysis of any emergent safety/tolerability issues, and 
completion of the prespecified safety data reviews. The unblinded individuals will be identified in the 
Statistical Analysis Plan (SAP) along with their specific roles and responsibilities. All other Sponsor 
personnel will remain blinded until completion of the study. The contract research organization’s 
(CRO’s) Medical Monitor may be unblinded to individual subjects’ treatment assignments where 
required for assessment of emergent safety/tolerability issues. 
6.1.3. 
Unblinding in Emergency Situations 
Requests can be made to unblind an individual study subject for emergencies or urgent situations. Prior 
to unblinding, and if the situation permits, the Investigator should first contact the Sponsor and/or 
authorized Medical Monitor to discuss the case. However, the final decision whether to unblind a 
subject will be the Investigator’s decision, and the Investigator need not wait for the unblinding 
permission to be granted by the Sponsor/CRO Medical Monitor in emergency situations where 
identification of the individual treatment assignment is required for the immediate medical 
management of the subject. Access to the unblinded treatment assignment should be limited to the 
minimum number of people required for emergent management of the subject. The actual treatment 
assignment must not be disclosed to the subject and/or other study personnel, including site monitors 
and office staff; nor should there be any written or verbal disclosure of the code in the subject’s study 
documents. 
The request for unblinding should include the protocol number, site number, subject number, treating 
Investigator’s contact info, a detailed reason for the unblinding, and date the information is needed. All 
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key correspondence between the requestor and Sponsor or CRO Medical Monitor should be saved in 
the Trial Master File. 
The IRT system will be used as the unblinding tool. In the event that an individual subject’s treatment 
assignment is unblinded, the date and reason that the blind was broken must be recorded in the source 
documentation. Any treatment assignments that are unblinded must be immediately reported to the 
CRO Medical Monitor and the Sponsor. Code-break IRT access is given to the Investigator/designated 
person at the site and to the designated Medical Monitor(s) for the study. 
Following unblinding, the subject will discontinue ABI-H0731 or matching PBO and continue with the 
study follow-up assessments.  
6.2. 
Description and Handling of ABI-H0731 and Matching Placebo 
(Investigational Medicinal Product) 
The investigational medicinal products (IMPs) to be used in this study are ABI-H0731 and matching 
PBO.  
6.2.1. 
Formulation 
The drug product is a tablet containing ABI-H0731 formulated in a solid dispersion which is produced 
by spray drying a solution of ABI-H0731 with an inert polymer HPMCP HP-55. This spray-dried 
dispersion has been mixed with standard pharmaceutical excipients, such as microcrystalline cellulose, 
calcium phosphate, croscarmellose sodium, and magnesium stearate, and compressed into a tablet 
containing approximately 100 mg of ABI-H0731, manufactured according to Good Manufacturing 
Practices (GMP). 
6.2.2. 
Packaging and Labeling 
ABI-H0731 tablets and matching PBO tablets are packaged in high density polyethylene bottles fitted 
with child-resistant screw caps, induction sealed and shipped to sites under ambient conditions. 
The IMP will be labelled in accordance with US Food and Drug Administration (FDA) requirements 
and European Union GMP Annex 13, Investigational Medicinal Products. Additional local labelling 
requirements in countries of study conduct will be incorporated in the IMP label(s). 
6.2.3. 
Storage and Handling 
Bottled drug product at the study site should be stored at controlled room temperature (15 °C to 30 °C 
[59 °F to 86 °F]) in a secure, locked location at the sites, accessible only to study personnel. 
6.3. 
Description and Handling of NrtI (Non-Investigational Medicinal 
Product) 
All subjects will enter the study receiving standard-of-care NrtI monotherapy of either ETV, TDF or 
TAF. The NrtIs used by subjects in this study are designated as non-investigational medicinal products 
(NIMP) (background therapy). Subjects taking a NrtI other than ETV, TDF, or TAF are excluded from 
study participation. Subjects will continue to administer their same standard-of-care NrtI used prior to 
and during Screening and continue for the entire duration of the study including follow-up. If a 
subject’s access to concurrent standard of care NrtI therapy should change while on-study, then the 
Investigator should first contact the Sponsor and/or authorized Medical Monitor to discuss the case. 
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Details describing the packaging, labelling, storage and handling of the NrtI are described in the 
respective package insert. 
6.4. 
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 randomized subjects, 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 the study (completion of the follow-up period) 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. 
6.4.1. 
Prohibited Concomitant Therapy 
Systemic (oral, injectable, or implanted) hormonal birth control is not permitted as an acceptable 
means of contraception for female subjects of child-bearing potential. Additional details on acceptable 
means of contraception are provided in Appendix 5.  
Since ABI-H0731 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 in humans is not fully understood so inhibitors and inducers of CYP3A4 
should be avoided. Refer to Appendix 5 for details on prohibited CYP2C9 substrates as well as 
inhibitors and inducers of CYP3A4.  
Provisions regarding concomitant medications described in the respective NrtI product labeling must 
also be followed during the study through the end of the follow up period.  
The designated Medical Monitor may be consulted for any questions regarding acceptable 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. 
6.5. 
Drug Accountability 
Regulatory requirements stipulate accounting of all IMP (ie, ABI-H0731 and matching PBO) received 
by the study site. Records of IMP disposition must include the date received by the site, date 
administered, quantity administered, and the subject to whom the IMP was administered. The 
Investigator is responsible for the accountability of all IMP at his or her site. This includes all used and 
unused IMP bottles and unused IMP.  
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Each study site is to use an IMP accountability record to document IMP disposition. All items on this 
form are to be fully completed. The Sponsor or the CRO will confirm if the method of recording IMP 
accountability by the site and the location of IMP records at the site is appropriate. 
Each time designated site personnel dispense IMP for a subject, he or she is to record the date 
dispensed, the quantity of IMP 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 IMP. The site monitor 
will review the IMP accountability records during monitoring visits. The site pharmacist or designated 
staff member will keep accurate records of IMP dispensation routinely during the study (Section 7; 
Appendix 1).  
NrtI accountability will be captured by the subjects in dosing diaries. 
6.6. 
Study Drug Administration and Compliance 
Subjects participating in this study will receive ABI-H0731 or PBO in addition to standard-of-care 
treatment with a NrtI. ABI-H0731 (3 × 100 mg tablets) or PBO tablets should be administered as a 
single dose, once daily. Subjects will self-administer assigned treatment and should be instructed to 
take ABI-H0731 or PBO at the same time of the day with the possible exception of in-clinic visit days. 
To monitor IMP compliance and to facilitate IMP accountability at the study site, subjects will be 
required to record each dose/quantity of tablets taken of ABI-H0731 or matching PBO in a dosing 
diary provided to the subject at visits shown in the Schedule of Assessments (Appendix 1). Subjects 
will also be asked to return used bottles and any unused IMP at study visits for accountability and 
compliance assessment at each visit. Returned IMP 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 
IMPs at a given visit will be asked to return them at the next study visit. The IMP dosing dates and 
time for doses given at the PK collection study visits will be entered in the subject’s eCRF.   
For assessment of compliance to the NrtI (NIMP) regimen, subjects will be provided dosing diaries at 
each study visit and will be asked to record the dosing dates, times, and quantity for NrtI 
administration. The dosing dates and time of NrtI at the PK collection study visits will be entered in 
the subject’s eCRF by study site personnel.  
Additional information concerning study treatments and the management of missed or incorrect doses 
is provided in the Study Pharmacy Manual. 
6.7. 
Return or Disposal of Study Drug 
Procedures for the return of IMP or provisions for onsite destruction (where approved prospectively by 
the Sponsor) are described separately in the Study Pharmacy Manual. 
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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 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 to be retained on all screen failures 
includes demography, screen failure details, eligibility criteria, and any SAE information (if 
applicable). 
Individuals who do not meet the protocol eligibility criteria for participation in this study (ie, screen 
failures) may not be rescreened, however, a single retest for a 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, or resolved intercurrent illness). 
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 
• A separate consent is required for the subject to provide an optional pharmacogenomic 
sample 
• Record demographics and medical history, including HBV history 
• Measure height and 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 of concomitant medications 
• Review of AEs occurring after provision of informed consent 
• Liver staging (as required per inclusion criteria, ie, fasting FibroScan) 
• Laboratory analyses (additional details are provided in the Laboratory Manual): 
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• Safety labs: chemistry, hematology, coagulation, serum AFP, follicle-stimulating-hormone 
(FSH) (females only), HbA1c, serum pregnancy test for females of child-bearing potential 
only, urinalysis, urine drug test (Appendix 2) 
• Virology: HBV DNA, HBV pgRNA, HBsAg, HBeAg, HBsAb, HBeAb, sample for HBV 
sequencing and HBV nucleic acids, HIV Ab, HCV Ab, HDV Ab, HAV (immunoglobulin 
M [IgM]), HEV (IgM) (see Appendix 2) 
▪ A second HBV DNA sample will be drawn approximately 10 to 14 days 
after the initial Screening Visit. If the results from the 2 HBV DNA samples 
indicate a numeric decline in HBV DNA during the Screening assessment 
period, then a third sample at least a week later will be collected for Sponsor 
review and approval prior to randomization. 
• HBV sequencing: a blood sample for sequencing of the HBV polymerase coding region 
will be collected and analyzed. The presence of specific base substitutions which may 
confer reduced susceptibility to NrtIs would exclude subjects from participating in the study 
(see Appendix 2) 
• HBV immunology: whole blood sample for collection of peripheral blood mononuclear 
cells (PBMCs) followed by serum cytokine sample collection for immunologic testing at 
selected sites only (Appendix 2) 
7.3. 
Day 1 
The following assessments must be completed at Day 1: 
• Update medical history, including HBV 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): 
• Safety labs: chemistry, hematology, coagulation, urine pregnancy test for females of child-
bearing potential only, urinalysis, urine drug test (see Appendix 2) 
• Virology: HBV genotype, HBV DNA, HBV pgRNA, HBsAg, HBeAg, HBcrAg, HBsAb, 
HBeAb, sample for HBV sequencing and HBV nucleic acids (see Appendix 2) 
• Immunology (For subjects who provided PBMCs at Screening at selected sites ONLY): 
PBMCs collection followed by serum cytokine sample and PaxGene® DNA and 
PaxGene® RNA sample collection (see Appendix 2). 
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• PK samples: predose samples for ABI-H0731 or PBO and NrtI. Postdose samples for ABI-
H0731 and NrtI between 2 and 4 hours following study drug administration (see Section 
7.10) 
• Pharmacogenomic Sample: Optional and only collected in subjects who provide additional 
informed consent. 
• Dispense dosing diary 
• ABI-H0731 or PBO dispensation 
• ABI-H0731 or PBO administration  
• NrtI administration  
7.4. 
Study Weeks 2 Through 48 
The following assessments are performed at Study Weeks 2, 4, 8, 12, 16, 20, 24 and then every 4 
weeks thereafter through Week 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) 
• 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 (Weeks 12, 24, 36, and 48 only) 
• Review concomitant medications 
• Review AEs 
• Laboratory analyses (additional details are provided in the Laboratory Manual): 
• Safety labs: chemistry, hematology, coagulation (not at Week 2), urinalysis (not at week 2), 
urine pregnancy test for females of child-bearing potential only (see Appendix 2) 
• Virology: HBV DNA, HBV pgRNA, HBsAg (not at Week 2), HBeAg (not at Week 2), 
HBcrAg (not at Week 2), HBsAb and HBeAb (Weeks 12, 24, and 48 only), sample for 
HBV sequencing and HBV nucleic acids (Weeks 20 to 44 and Week 48) (see Appendix 2)  
• Immunology (For subjects who provided PBMCs at Screening at selected sites ONLY): 
PBMCs collection followed by serum cytokine sample collection at Weeks 2, 4, 12, 24, 36, 
and 48 (see Appendix 2)  
• PK samples: samples for ABI-H0731 or PBO and NrtI may be collected from 2 to 4 hours 
postdose on Day 1, between 30 min to 2 hours postdose at Weeks 2, 8, 12, 24, and 28, and 
between 4 and 6 hours postdose at Weeks 16 and 20. Predose samples for ABI-H0731 or 
PBO and NrtI will be collected at Week 4, and Week 48 only (see Section 7.10)  
• Review dosing diary and assess ABI-H0731 or PBO accountability 
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• ABI-H0731 or PBO dispensation 
• ABI-H0731 or PBO administration  
• NrtI administration  
• Dispense dosing diary 
7.5. 
Study Weeks 52 to 96 
The following assessments are performed every 4 weeks unless otherwise indicated. A visit window of 
±5 days is applied from Weeks 52 through 96. 
•  Measure body weight (Week 96 only) 
• Vital signs (temperature, heart rate, respiration rate and blood pressure) 
• Complete physical examination (excluding breast and genitalia, unless indicated; Week 96 
only) 
• Symptom-directed physical examination (Weeks 52 to 92only) 
• 12-lead ECG (Week 96 only) 
• Review concomitant medications 
• Review AEs 
• Laboratory analyses (additional details are provided in the Laboratory Manual): 
• Safety labs: chemistry, hematology, coagulation, urinalysis, urine pregnancy test for 
females of child-bearing potential only (see Appendix 2) 
• Virology: HBV DNA, HBV pgRNA, HBsAg, HBeAg, HBcrAg, HBsAb, and HBeAb 
(Weeks 72 and 96 only), sample for HBV sequencing and HBV nucleic acids (see 
Appendix 2)  
• Immunology (For subjects who provided PBMCs at Screening at selected sites ONLY): 
PBMCs collection followed by serum cytokine sample collection at Weeks 60, 72, 84, and 
96 (see Appendix 2). Additionally, these subjects will provide PaxGene® RNA sample at 
Week 96 only.  
• Review dosing diary 
• Assess ABI-H0731 accountability (final ABI-H0731 accountability performed at Week 96) 
• ABI-H0731 dispensation (final ABI-H0731 dispensation performed at Week 92) 
• ABI-H0731 administration 
• NrtI administration  
• Dispense dosing diary 
7.6. 
Follow-up Assessments 
All subjects who prematurely discontinue treatment or complete treatment per protocol will enter a 
24-week follow-up period during which they will have the following assessments performed between 
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4 weeks and 20 weeks and at 24 weeks (±5 days) after the last dose of study drug unless otherwise 
stated. Subjects will remain on standard of care NrtI during the follow-up period: 
• Measure body weight (24 Weeks post only) 
• Vital signs (temperature, heart rate, respiration rate and blood pressure) 
• Complete physical examination (24 Weeks post only) 
• Symptom-directed physical examination (not at 24 Weeks post) 
• 12-lead ECG (24 Weeks post only) 
• Review concomitant medications 
• Review AEs 
• Laboratory analyses (additional details are provided in the Laboratory Manual): 
• Safety labs: chemistry, hematology, coagulation, urinalysis (4 Weeks post and 24 Weeks 
post only), urine pregnancy test (only at 4 Weeks post and for female of child-bearing 
potential) (see Appendix 2) 
• Virology: HBV DNA, HBV pgRNA, HBsAg, HBeAg, HBcrAg, HBsAb, and HBeAb 
(24 Weeks post only), sample for HBV sequencing and HBV nucleic acids (see Appendix 
2) 
• Immunology (For subjects who provided PBMCs at Screening at selected sites ONLY): 
PBMCs collection followed by serum cytokine sample collection at 4-, 12-, and 24-Weeks 
post (see Appendix 2). Additionally, these subjects will also provide a PaxGene® RNA 
sample at 24 Weeks post only.  
• PK sample: samples for ABI-H0731 or PBO and NrtI collected at 4 Weeks post. See 
Section 7.10 for additional information on PK sampling. 
• Review dosing diary for NrtI ONLY 
• NrtI administration at 4 Weeks post ONLY  
• Dispense dosing diary (EXCEPT at 24 Weeks Post) 
7.7. 
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): 
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• Safety labs: chemistry, hematology, coagulation, urinalysis, urine drug test, urine 
pregnancy test for females of child-bearing potential only (see Appendix 2) 
• Virology: HBV DNA, HBV pgRNA, HBsAg, HBeAg, HBcrAg, sample for HBV 
sequencing, and HBV nucleic acids (see Appendix 2) 
• PK samples: samples for ABI-H0731 or PBO and NrtI. See Section 7.10 for additional 
information on PK sampling. 
Assessments performed should be documented in the subject’s source documentation. Clinical 
laboratory assessments should be conducted through the central laboratory. 
7.8. 
Premature Termination Visit 
Should a subject prematurely discontinue treatment (Section 7.9.1) or discontinue from the study 
(Section 7.9.2), 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: 
• 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): 
• Safety labs: chemistry, hematology, coagulation, urinalysis, urine drug test, urine 
pregnancy test for females of child-bearing potential only (see Appendix 2) 
• Virology: HBV DNA, HBV pgRNA, HBsAg, HBeAg, HBcrAg, HBsAb, and HBeAb, 
sample for HBV sequencing and HBV nucleic acids (see Appendix 2) 
• PK samples: samples for ABI-H0731 or PBO and NrtI. See Section 7.10 for additional 
information. 
• Immunology (For subjects who provided PBMCs at Screening at selected sites ONLY): 
PBMCs collection followed by serum cytokine and PaxGene® RNA sample collection (see 
Appendix 2).  
• Review dosing diary and assess IMP accountability (if applicable) 
7.9. 
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, if possible, a Premature Termination visit should be conducted (Section 7.8). If the subject 
withdraws consent for disclosure of future information, the Sponsor may retain and continue to use any 
data collected before such a withdrawal of consent. If a subject withdraws from the study, he/she may 
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request destruction of any samples taken and not tested, and the Investigator must document this in the 
site study records. 
7.9.1. 
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 ABI-H0731 or PBO. NrtI may be continued at the discretion of the Investigator. Discontinuation 
from treatment does not mean discontinuation from the study. Subjects who prematurely discontinue 
treatment should immediately undergo the assessments listed for the Premature Termination visit 
(Section 7.8) and then continue scheduled follow-up assessments (Section 7.6). 
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 will be 
discontinued in subjects with confirmed evidence of declining hepatic function during treatment, a 
Premature Termination visit (Section 7.8) will be completed, and subjects will subsequently undergo 
the follow-up assessments described in Section 7.6. 
Any subjects negative by urine pregnancy test at Baseline (Day 1) who are subsequently found to be 
positive on serum pregnancy test should immediately discontinue treatment with ABI-H0731 or PBO. 
NrtI may be continued if indicated based on Investigator judgment in accordance with local practice 
and the approved NrtI package insert. These subjects may be replaced at the discretion of the Sponsor. 
7.9.2. 
Discontinuation from Study 
Discontinuation from study (ie, withdrawal of consent) means that the subject does not wish to receive 
further protocol-required treatments or undergo protocol-required procedures, and the subject does not 
wish to, or is unable to, continue further study participation. Subjects who discontinue from the study 
during follow-up should undergo the assessments listed for the Premature Termination visit 
(Section 7.8). It is recommended, though not mandated, that the additional follow-up assessments 
described in Section 7.6 be conducted, with the consent of the subject. Subject data up to withdrawal of 
consent will be included in the analysis of the study, and where permitted, publicly available data can 
be included after withdrawal of consent. 
7.9.3. 
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 to have withdrawn from the 
study. 
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7.10. 
PK Assessments 
During the study, predose plasma samples will be collected from all subjects to explore the PK profile 
of ABI-H0731 and NrtI following combination treatment in subjects with CHB. Additionally, postdose 
and post-treatment samples will be collected. The timing of PK sample collection is outlined in Table 
7. Additional details regarding the collection, processing, storage, and shipment of PK samples is 
described in the Laboratory Manual. 
Table 7:  
Pharmacokinetic Sample Collection 
Time period 
Time relative to study drug administration a 
Time relative to study drug administration b 
Treatment 
Predose 
Day 1, Weeks 4, and 48 
30 min to 2 hours postdose 
Weeks 2, 8, 12, 24, and 28 
2 to 4 hours postdose 
Day 1 
4 to 6 hours postdose 
Weeks 16 and 20 
Follow-up 
Collect at same time with other central labs 
At Unscheduled and Premature Termination c 
Visits and the Week 4 Post Treatment Follow-up 
visit 
a If the subject self-administers the study drug outside the study clinic, a pharmacokinetic sample should be collected during 
the next 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 on source documentation. 
c A pharmacokinetic sample should also be collected if an unscheduled or premature termination visit is performed. 
7.11. 
End of Study Definition 
The study will be completed when the last subject completes the 24-week, post-treatment follow-up 
period, or is considered “lost to follow-up,” (Section 7.9.3) whichever is later. 
7.12. 
Resistance Monitoring 
During the Screening procedures, all subjects will be evaluated for HBV polymerase mutations as 
described in Appendix 2. Subjects having any of these mutations will be excluded from study 
participation. 
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 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 who received PBO and HBV database sequences. 
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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 
adverse event. 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 will be entered in 
the eCRFs 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 (refer to the eCRF completion guidelines). 
Adverse events will be recorded from the date informed consent is signed through end of study 
(completion of follow-up period). 
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 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 intervention 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: 
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• 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 
followed up until it returns to the normal range and/or an adequate explanation of the abnormality is 
found. 
8.6. 
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. 
8.7. 
Pregnancy 
8.7.1. 
Female subjects who become pregnant 
Any female subject who becomes pregnant while participating in the study will discontinue the study 
drug(s) immediately.  
The Investigator will collect pregnancy information on any female subject who becomes pregnant 
while participating in this study, including the 24-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 Reference 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 
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abortion (occurring at <22 weeks gestational age) 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 
reporting. 
8.7.2. 
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 the study drug. 
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 Pharmacy Manual for contact information for reporting a pregnancy. 
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9. 
SERIOUS ADVERSE EVENTS 
9.1. 
Definition of SAE 
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 ABI-H0731 
• 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: 
• Intensive treatment in an emergency room or at home for allergic bronchospasm 
• Blood dyscrasias or convulsions that do not result in inpatient hospitalization 
• 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. 
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 Reference Manual for contact information for 
reporting SAEs. 
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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. 
The CRO will be responsible for informing all central Institutional Review Boards (IRBs)/ 
Independent Ethics Committees (IECs) of SAEs as required. It will be the responsibility of the 
individual Investigators to inform any local IRBs/IECs of SAEs as required. Correspondence with the 
IRB(s)/IEC(s) relating to the reporting of SAEs will be retained in the study file. 
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 On-treatment and Post-treatment 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. For these subjects, at each timepoint, an Unscheduled Visit should be conducted with 
completion of assessments as described in Section 7.7. Additionally, the following guidance is 
provided for management of subjects with ALT elevations: 
• 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. To confirm the ALT finding, the subject should return to 
the clinic for an Unscheduled Visit and undergo all assessments as noted in Section 7.7 
(Unscheduled Visit). 
• If the ALT elevation is confirmed, then an additional Unscheduled Visit will be performed 
to further evaluate the subject. At this visit, the following laboratory tests will be 
performed: ALT, AST, total bilirubin (if total bilirubin is elevated, reflex to Direct 
Bilirubin), serum albumin, HBV DNA, and quantitative HBV serologies (HBeAg [reflex 
qualitative HBeAg if quantitative HBeAg is negative] and HBsAg [reflex qualitative 
HBsAg if quantitative HBsAg is negative]), HAV IgM, HCV RNA, HDV RNA, and HEV 
IgM. 
o If an intercurrent illness is determined to be causal, subjects with an ALT elevation 
without declining hepatic function and without contraindications may continue 
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treatment and the intercurrent illness should be treated as deemed medically appropriate 
by the Investigator. 
o Subjects with an ALT elevation without declining hepatic function and without 
contraindications may continue treatment with study drug under close observation. 
• If ALT is rising at the confirmatory visit, subjects should return for an Unscheduled Visit 
every 2 to 5 days until the ALT elevation has stabilized.  At these visits the following 
laboratory tests will be performed: ALT, AST, total bilirubin (if total bilirubin is elevated, 
reflex to Direct Bilirubin), serum albumin, INR, HBV DNA, and quantitative HBV 
serologies (HBeAg [reflex qualitative HBeAg if quantitative HBeAg is negative] and 
HBsAg [reflex qualitative HBsAg if quantitative HBsAg is negative]). 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. 
o Subjects with an ALT elevation without declining hepatic function and without 
contraindications should discontinue study drug if the ALT remains persistently 
elevated for >4 weeks  
• Subjects with confirmed ALT elevation with evidence of declining hepatic function should 
be discontinued from study treatment. This is defined as:  
o 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) 
• Subjects with evidence of declining hepatic function should return for an Unscheduled Visit 
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.  
• Post-treatment ALT Elevation  
Following cessation of study drug treatment under this protocol all subjects will be closely 
followed for ALT elevations and/or signs of potential decline in hepatic function. This 
applies to all subjects whether they prematurely discontinue study drug or complete the 
study per protocol. Any subject with a post-treatment ALT elevation without evidence of 
declining hepatic function or a post-treatment ALT elevation with evidence of declining 
hepatic function as defined above, will be evaluated as noted above. 
All subjects with ALT elevation without or with declining hepatic function (on or off-
treatment) should continue to be followed on their regular study visit schedule, with the 
addition of unscheduled visits as described above. If the post-treatment 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 Principal Investigator, in 
consultation with the Sponsor, and the unscheduled visit module in the case report form 
should be utilized as needed to gather additional clinical and laboratory data until the ALT 
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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. 
If 5 or more subjects meet these ALT elevation management criteria, the US FDA and other 
relevant regulatory agencies will be notified, and subsequent steps will be determined after 
consultation with these agencies. 
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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 
complete SAP describing all planned analyses will be finalized prior to database lock. 
10.1. 
Determination of Sample Size 
Approximately, 40 subjects with CHB will be enrolled in the study. Subjects will be randomized to 
receive either 300 mg ABI-H0731 or matching PBO in a 1:1 ratio in addition to standard of care NrtI. 
Since this is a proof-of-concept study, 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 Set: It includes all randomized subjects who satisfied the inclusion and exclusion criteria 
described in this protocol. 
Full Analysis Set: It is the main analysis population for the efficacy analysis. It includes all randomized 
subjects, classified according to the treatment arm into which they were randomized regardless of the 
actual treatment received, who used any amount of study drug and have at least 1 post-baseline 
efficacy assessment. 
Safety Set: It includes all subjects, classified according to the actual treatment received regardless of 
random assignment, who used any amount of study drug and have at least 1 post-baseline safety 
evaluation. This is the main analysis population for all safety analyses. 
PK-Evaluable Set: It consists of all subjects, classified according to the actual treatment received 
regardless of random assignment, who receive at least 1 dose of study drug. A Baseline and at least 1 
PK blood sample following a dose of study treatment is required for inclusion in this analysis. This is 
the main analysis population for all PK analyses. 
Based on the actual deviations, the criteria for exclusion of subjects from the different data sets will be 
specified and updated, if necessary, prior to database lock. 
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 
The primary analysis of the study will be performed when all subjects complete Week 48 evaluations. 
10.3.1. 
Disposition of the Study Subjects 
The disposition of subjects will be described with summaries by treatment group of the number of 
subjects in each analysis set described above, the number of subjects who completed the study, and the 
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number of subjects for whom study drug was permanently discontinued (including the reasons for 
discontinuation). Randomized set will be used to produce this analysis. 
10.3.2. 
Demographic and Baseline Characteristics 
Demographic and Baseline characteristics will be summarized and compared by treatment group. 
Results will be reported using subjects in the randomized, full analysis, per protocol and PK analysis 
sets. 
Prior and concomitant medications will be classified according to the anatomical therapeutic chemical 
codes in the WHO Drug dictionary. The incidence rate of each coded medication will be tabulated by 
treatment group. The table will be sorted by the incidence use of the entire sample. 
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 all randomized subjects will also be described by 
treatment group. 
10.3.4. 
Analysis of Primary Efficacy Endpoints 
The primary efficacy endpoint is the proportion of subjects with HBV DNA <LLOQ at Week 48. 
The proportion of subjects achieving the primary efficacy endpoint will be reported along with the 
corresponding 95% asymptotic confidence interval by treatment group. The proportion of responders 
will be compared between the 2 treatment groups using a Cochran-Mantel-Haenszel test accounting 
for stratification factors. 
10.3.5. 
Analysis of Secondary Efficacy Endpoints 
A similar approach will be used to describe and compare the proportion of subjects with reduction in 
HBV DNA < LLOQ, HBV DNA <LOD, HBV pgRNA <LLOQ and subjects with abnormal ALT at 
Baseline who have normal ALT for ABI-H0731+NrtI and PBO+NrtI. 
Change in mean log10 HBV DNA and in mean log10 HBV pgRNA from Baseline for ABI-H0731+NrtI 
and PBO+NrtI will be compared using a linear model with Baseline values and stratification as 
covariates. 
10.3.6. 
PK Analysis 
Drug concentrations of ABI-H0731 or PBO and NrtI will be listed at end of study: 
• ABI-H0731 on ABI-H0731+NrtI therapy stratified by collection time window and 
collection day. 
• NrtI on ABI-H0731+NrtI therapy as compared with PBO+NrtI therapy stratified by 
collection time window and study day. 
Application to a population PK model may be applied, details of which will be provided in the 
pharmacometrics analysis plan. Results from of the population PK work will be reported outside of the 
clinical study report (CSR). 
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10.3.7. 
Safety Analysis 
All safety endpoints will be summarized using data from the Safety 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. 
10.3.7.1. TEAEs 
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 subsets: 
• All adverse events 
• Serious adverse events 
• Drug-related adverse events 
For tables reporting adverse events by severity, if a subject has multiple occurrences of an adverse 
event with the same organ class and preferred term, the most severe event will be presented. 
10.3.7.2. 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. Shift tables from 
Baseline will be presented for laboratory values in the chemistry and hematology panels. 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. 
10.3.7.3. 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. 
10.5. 
Independent Data Monitoring Committee 
An independent Data Monitoring Committee is not planned for this study. 
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10.6. 
Handling of Missing Data 
For the analysis of primary efficacy endpoint, missing HBV DNA data will be imputed using a 
multiple imputation method appropriate to the pattern of missingness. Details of the considered 
patterns and associated sensitivity analyses will be described in the SAP. 
10.7. 
Multiplicity Adjustment 
No formal inference is planned in this study. Hence no multiplicity adjustment is required. 
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11. 
RESPONSIBILITIES 
11.1. 
Investigator Responsibilities 
11.1.1. 
Good Clinical Practice 
This study will be conducted in compliance with IRB/IEC and International Council for Harmonisation 
(ICH) Good Clinical Practice (GCP) Guidelines; Title 21 Part 56 of the US Code of Federal 
Regulations (CFR) relating to IRBs/IECs and GCP as described in the US 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 (IRB)/Independent Ethics Committee (IEC) 
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. 
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. 
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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. 
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. 
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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 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 2018, Battisti 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. Annals Internal Medicine. 2015 Sep 15;163(6)L: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.  
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; Hepatology: 2019 Apr;70(1):e95. 
Buti M, Gane E, Seto WK, et al. Tenofovir alafenamide versus tenofovir disoproxil fumarate for the 
treatment of patients with HBeAg-negative chronic hepatitis B virus infection: a randomised, 
double-blind, phase 3, non-inferiority trial. Lancet Gastroenterol Hepatol. 2016 Nov;1(3):196-206. 
Chan HL, Fung S, Seto WK, et al. Tenofovir alafenamide versus tenofovir disoproxil fumarate for the 
treatment of HBeAg-positive chronic hepatitis B virus infection: a randomised, double-blind, phase 3, 
non-inferiority trial. Lancet Gastroenterol Hepatol. 2016 Nov;1(3):185-95. 
Chang TT, Gish RG, de Man R et al.A Comparison of Entecavir and Lamivudine for HBeAg-Positive 
Chronic Hepatitis B. N Engl J Med. 2006 Mar 9;354(10):1001-10. 
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, and Zoulim F. Guidance for design and endpoints of clinical 
trials in chronic hepatitis B – Report from the 2019 EASL-AASLD HBV Treatment Endpoints 
Conference. Hepatology. 2020 Mar;71(3):1070-92.  
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 Jul;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. 
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 Apr;45(4):1056-75.  
Recommendations for the Conduct, Reporting, Editing, and Publication of Scholarly Work in Medical 
Journals (ICMJE). http://www.icmje.org/recommendations/ Accessed: January 2019. 
Lai CL, Shouval D, Lok AS, Chang TT, Cheinquer H, Goodman Zet, al. Entecavir versus lamivudine 
for patients with HBeAg-negative chronic hepatitis B. N Engl J Med. 2006 Mar 9;354(10):1011-20. 
Lampertico P and Liaw YF. New Perspectives in the Therapy of Chronic Hepatitis B. Gut. 2012 
May;61 Suppl 1:i18-24. 
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Levey AS1, 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 Sep;51(3):581-92. 
Lok ASF, McMahon BJ. Chronic hepatitis B: update 2009. Hepatology. 2009 Sep;50(3):661-2. 
Paptheodoridis GV, Chan H L-Y, Hansen BE, Janssen HLA, Lampertico P. Risk of hepatocellular 
carcinoma in chronic hepatitis B: assessment and modification with current antiviral therapy. J 
Hepatol. 2015 Apr;62(4):956-67. 
Pungpapong S, Kim WR. In the Eye of the B-holder: natural history of chronic hepatitis B. 
Hepatology. 2013 Jul;58(1):6-8.  
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 Oct;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 Jan 20;150(2):104-10.  
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). Guidelines for the prevention, care, and treatment of persons with 
chronic hepatitis B infection. Geneva Switzerland: World Health Organization; 2015. 
World Health Organization (WHO). Hepatitis B: fact sheet. Geneva Switzerland: World Health 
Organization; 2016.  
World Health Organization (WHO). Hepatitis B: fact sheet. Geneva Switzerland: World Health 
Organization; 2019.  
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 May 10;5(5):713-724. 
Yim HJ, Lok ASF. Natural history of chronic hepatitis B virus infection: what we knew in 1981 and 
what we know in 2005. Hepatology. 2006 Feb;43(2 Suppl 1):S173-81. 
Yip TC, Wong WW, Chan HL, Tse YK, Lui GC, Wong GL. Tenofovir is associated with lower risk of 
hepatocellular carcinoma than entecavir in patients with chronic HBV infection in China. 
Gastroenterology. 2020 Jan;158(1):215-225.e6. 
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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 
Termination2  
Unscheduled 
Visit 3 
Study Day or Week 
Day -45 to Day -1 
Day 
1 
Wk 
2 
Wk 
4 
Wk 
8 
Wk 
12 
Wk 
16 
Wks 20-
44 1 
Wk 
48 
Wks  
52-96 1 
4-20 Wks  
Post 1 
24 
Wks  
Post 
 
 
Visit 1 
Visit 2 
Visit Window (days) 
0 
±3 
±3 
±3 
±3 
±3 
±3 
-3 
±5 
±5 
±5 
NA 
NA 
Informed Consent(s) 4 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics, medical history, and 
HBV history 
X 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Liver staging 5 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Height and weight 6 
X 
 
X 
 
 
 
 
 
 
X 
X 8 
 
X 
 
 
Vital signs 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Complete physical examination 7 
X 
 
X 
 
 
 
 
 
 
X 
X 8 
 
X 
X 
 
Symptom-directed physical 
 
 
 
X 
X 
X 
X 
X 
X 
 
X 9 
X 
 
 
X 
12-lead ECG 10 
X 
 
X 
 
 
 
X 
 
X 10 
X 
X 10 
 
X 
X 
 
Concomitant medications and AEs22 
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 
Hematology 
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 
HbA1c 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Serum AFP  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
FSH (females only) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy Test 11 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
Urinalysis 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 12 
X 
X 
X 
Urine drug test 
X 
 
X 
 
 
 
 
 
 
 
 
 
 
X 
X 
HBV genotype 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
HBV DNA 
X 
X 13 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
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Period or Visit 
Screening 
On Treatment 
Follow-up 
Premature 
Termination2  
Unscheduled 
Visit 3 
Study Day or Week 
Day -45 to Day -1 
Day 
1 
Wk 
2 
Wk 
4 
Wk 
8 
Wk 
12 
Wk 
16 
Wks 20-
44 1 
Wk 
48 
Wks  
52-96 1 
4-20 Wks  
Post 1 
24 
Wks  
Post 
 
 
Visit 1 
Visit 2 
Visit Window (days) 
0 
±3 
±3 
±3 
±3 
±3 
±3 
-3 
±5 
±5 
±5 
NA 
NA 
HBV pgRNA 
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 
HBcrAg 
 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
HBsAb, HBeAb 
X 
 
X 
 
 
 
X 
 
X15 
X 
X 15 
 
X 
X 
 
Sample for HBV DNA sequencing 
and HBV nucleic acids 
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 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
IMP (ABI-H0731/PBO) 
accountability 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X16 
 
 
X 
 
IMP (ABI-H0731/PBO) 
dispensation 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X16 
 
 
 
 
In-clinic IMP (ABI-H0731/PBO) 
dosing  
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X  
 
 
 
 
In-clinic NrtI dosing  
 
 
X  
X  
X  
X 
X 
X 
X  
X  
X  
X23  
 
 
 
PK Sample 
Collections 17, 18 
ABI-H0731 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 19 
 
X 
X 
NrtI 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 19 
 
X 
X 
Immunology (PBMC followed by 
serum cytokine sample collection) 24 
X 
 
X 
X 
X 
 
X 
 
X 20 
X 
X 20 
X 20 
X 
X 
 
PaxGene® DNA and PaxGene® 
RNA samples 24 
 
 
X 
 
 
 
 
 
 
 
X 21 
 
X 21 
X 
 
Optional pharmacogenomic sample 
collection 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Abbreviations: Ab=antibody; 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; HIV=human immunodeficiency virus; 
IgM=immunoglobulin M; INR=international normalized ratio; IRT=Interactive Response Technology; NA=not applicable; PBO=placebo; PBMC=peripheral blood mononuclear 
cell; PK=pharmacokinetic; pgRNA= pre-genomic RNA; ULN=upper limit of normal; Wk=week; Wks=weeks. 
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1 Study visits occur every 4 weeks between Weeks 20 and 96 on treatment and between Weeks 4 and 20 Post Treatment. 
2 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 assessments. 
3 Any subjects with alanine aminotransferase (ALT) elevation (defined as ALT≥2 × Baseline and ≥10 × ULN) should return to the clinic for an Unscheduled Visit to confirm the 
findings within 3 days of receipt of the original results. At the Unscheduled Visit, subjects should undergo the assessments described in Section 7.7. If the ALT elevation is 
confirmed, the subject will return for an additional Unscheduled Visit at which the following tests: HBV DNA, HBV serologies (quantitative HBeAg [reflex qualitative HBeAg if 
quantitative HBeAg is negative] and HBsAg [reflex qualitative HBsAg if quantitative HBsAg is negative]), HAV IgM, HCV RNA, HDV RNA, and HEV IgM, will be performed. If 
the ALT is rising, the subject will return for additional Unscheduled Visits every 2-5 days until the ALT has stabilized. At these visits the following tests will be performed: HBV 
DNA, HBV serologies (quantitative HBeAg [reflex qualitative HBeAg if quantitative HBeAg is negative] and HBsAg [reflex qualitative HBsAg if quantitative HBsAg is negative]). 
4 In addition to the study specific Informed Consent Form, a separate consent is required for the subject to provide an optional pharmacogenomic sampling. 
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 in a fasted state by FibroScan or 
other Sponsor-approved hepatic imaging method within 3 months of Screening. 
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 Weeks 48 and 96 visits, and at 24 Week post-treatment visit (if applicable). 
9 A Symptom-directed physical exam is performed only at the visits when a complete physical exam is not performed. 
10 During the study, any clinically significant ECG result or change from Baseline (Day 1) should be confirmed, and if confirmed, should be recorded as an AE. 12-lead ECG to be also 
performed at Weeks 24, 36, 48, and 96. 
11 A serum pregnancy test for females of child-bearing potential is required at Screening. On Day 1 both urine and serum 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 and may be replaced). All post-Day 1 pregnancy 
tests may be conducted by urine dipstick. If positive on dipstick, reflex to serum. 
12 Urinalysis will be conducted 4 and 24-Weeks Post Treatment 
13 A second, confirmatory HBV DNA should be drawn 10 to14 days after the initial Screening visit during the Screening assessment period. If the results from these 2 samples indicate 
a decline in HBV DNA then a third sample will be collected to ensure virologic plateau prior to randomization. 
14 If quantitative HBsAg or HBeAg are negative at any visit subsequent to Screening, reflex to qualitative. 
15 HBsAb and HBeAb tests are performed at Weeks 24, 48, 72, and 96. 
16 Final study drug dispensation is performed at Week 92, and final study drug accountability is performed at Week 96. NrtI will be continued throughout the 24-week follow-up 
period.  
17 If the subject inadvertently administers study drug prior to collection, a PK sample should still be drawn. Refer to Section 10.3.6. 
18 Predose PK samples for ABI-H0731 or PBO and NrtI on Day 1 and Weeks 4 and 48. Postdose PK samples for ABI-H0731 and NrtI may be collected from 2 to 4 hours postdose on 
Day 1, and between 30 min and 2 hours after in-clinic study drug + NrtI administration at Weeks 2, 8, 12, 24, and 28. Postdose samples on Weeks 16 and 20 may be collected 
between 4 and 6 hours after in-clinic study drug + NrtI administration.  
19 Collect a PK sample with other central labs at week 4 Post-treatment follow-up visit.  
20 Immunology (PBMCs and serum cytokine sample) collections occur every 12 weeks at Weeks 24, 36, 48, 60, 72, 84, and 96 visits, at selected sites only. At follow-up, collect at 4 
Weeks Post-treatment, 12 Weeks Post-treatment, and 24 Weeks Post-treatment visits, and at the premature termination visit. 
21 PaxGene® RNA only at Week 96, 24-Weeks post treatment visit, and on premature termination visit.  
22 Concomitant medications must be recorded in the subjects’ source documentation until the end of study (completion of follow-up period); NrtIs should be followed through to the 
end of the follow-up period.  
23 In-clinic NrtI administration only required at 4 weeks post visit.  
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24 Only the subjects that provide PBMCs at Screening at selected sites will undergo additional PBMCs, serum cytokine, PaxGene® DNA and PaxGene® RNA sample collection at the 
specified timepoints. Note that PaxGene® DNA sample will only be collected on Day 1. 
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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 8. 
Table 8:  
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, and INR 
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 of child-bearing potential 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/methamphetamine, barbiturates, benzodiazepines, cocaine metabolite, ecstasy, 
ethanol, opiates, phencyclidine, and propoxyphene.  
Antibodies 
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; 
HIV=human immunodeficiency 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 ABI-H0731 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 assure 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 and HBV pgRNA 
testing will be shipped frozen to the Sponsor or 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. HBV pgRNA results could unblind individual subject’s treatment 
assignments and therefore will not be reported to investigative sites or other blinded personnel until 
completion of the study, the database has been locked and the study has been unblinded. 
Additional details concerning the collection and processing of HBV virology samples are described in 
the Laboratory Manual. 
HBV Resistance Testing: 
Specific base substitutions in the HBV polymerase coding region may confer reduced susceptibility to 
NrtIs. During the Screening period HBV sequencing will be performed for all subjects. Subjects with 
base substitutions commonly associated with decreased susceptibility to treatment with NrtI will be 
excluded from participation in the study. 
HBV Immunology 
Subjects will provide whole blood PBMCs samples at Screening at selected sites only. These subjects 
will provide additional whole blood PBMCs samples followed by serum cytokine samples for 
immunologic testing at timepoints specified in Appendix 1. Additionally, these subjects will also 
provide PaxGene® RNA and PaxGene® DNA samples at timepoints specified in Appendix 1.  
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 Uwave 
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:  
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• 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 
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 (Corrected Version 2.1, July 
2017).  
https://rsc.niaid.nih.gov/sites/default/files/daidsgradingcorrectedv21.pdf 
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) 
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 
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 Intervala 
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: 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) 
Lipoatrophyc 
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 
Lipohypertrophyd 
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 
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  
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 
Abbreviations: 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  
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: 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 
 
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. 
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j WHO reference tables may be accessed by clicking the desired age range or by accessing the following URL: http://www.who.int/growthref/who2007_bmi_for_age/en/ for subjects >5 to 19 years of 
age 
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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 
Abbreviations: NA=not applicable. 
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Laboratory Valuesk: 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 x ULN 
2.5 to <5.0 x ULN 
5.0 to <10.0 x ULN 
≥10.0 x 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 x ULN 
2.5 to <5.0 x ULN 
5.0 to <10.0 x ULN 
≥10.0 x 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 x ULN 
2.5 to <5.0 x ULN 
5.0 to <10.0 x ULN 
≥10.0 x 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 lReport only one 
1.1 to 1.3×ULN 
>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 Valuesk: Chemistries* 
Parameter 
Grade 1 Mild 
Grade 2 Moderate 
Grade 3 Severe 
Grade 4 Potentially Life- 
threatening 
Creatinine Clearance m 
or eGFR, Low 
lReport 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  
200 to <240 
 
5.18 to <6.19 
240 to <300 
 
6.19 to <7.77 
≥300 
 
≥7.77 
NA 
LDL, Fasting, High  
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; 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 AE should not be reported to DAIDS in an expedited time frame unless it meets protocol-specific reporting 
requirements. 
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l Reminder: Choose the method that selects for the higher grade. 
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)n  
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)n  
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 
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 ABI-H0731 have not been conducted in animals, therefore 
effects of ABI-H0731 on pregnancy are unknown. Contraceptive requirements for female subjects of 
childbearing potential are required as described below. 
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 
The drug-drug interaction (DDI) study with ABI-H0731 and oral contraceptive has not been 
completed, and therefore, oral contraceptives are not acceptable as a form of effective birth control. 
Female subjects of childbearing potential (defined above) must agree to use dual effective birth control 
methods for the duration of the study and follow-up. Effective birth control methods include male or 
female condom (may not be used together due to increased risk of breakage), vasectomy, tubal 
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sterilization, intrauterine device (IUD), diaphragm, or cervical cap. Note that the DDI of ABI-H0731, 
and systemic (oral/injectable) hormonal birth control has not been assessed and so systemic hormonal 
birth control is not considered effective birth control method for female subjects for the purposes of 
this study. 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 and follow-up. In this case, effective 
birth control methods include systemic (oral/injectable) 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 CYP2C9 substrates and should be avoided 
when taking ABI-H0731: 
CYP3A4 Inhibitors 
HIV antivirals 
indinavir, nelfinavir, ritonavir, saquinavir 
Other 
clarithromycin, itraconazole, ketoconazole, nefazodone, saquinavir, idelalisib, 
ribociclib, telithromycin, aprepitant, erythromycin, fluconazole, 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: 
CYP2C9 Substrates 
Narrow therapeutic index 
substrates that are prohibited 
while taking ABI-H0731 
Warfarin, phenytoin 
Substrates that should be 
avoided while taking 
ABI-H0731 
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 ABI-H0731: 
CYP3A4 Inducers 
 
Barbiturates, brigatinib, carbamazepine, efavirenz, enzalutamide, glucocorticoids, 
modafinil, nevirapine, oxcarbazepine, phenobarbital, phenytoin, pioglitazone, rifabutin, 
rifampin, st. john’s wort, troglitazone 
Source: The Flockhart Table. http://medicine.iupui.edu/clinpharm/ddis/main-table# (Accessed 6 March 2020). 
Abbreviations: CYP=cytochrome P450. 
 
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APPENDIX 6 
SUMMARY OF CHANGES 
The primary purpose of Amendment 1 is to clarify the distinction between the investigational 
medicinal products (IMPs) to be used in this study, ie, ABI-H0731 and matching placebo (PBO), and 
the subjects’ background NrtI therapy (non-IMP [NIMP]). This has implications for the procedures for 
IMP accountability and compliance activities to be performed by site personnel. Further clarifications 
and minor corrections have been applied. A table of summary of major changes included in 
Amendment 1 is provided below.  
Amendment 1 Summary of Changes 
Section Number 
and Name 
Description of Change 
Brief Rationale 
Section 2.3 
Reference Yang 2009 has been corrected to 
Yang 2019.  
Minor correction.  
Sections 4.1, 4.3 
Synopsis 
The number of study centers has been updated 
from approximately 5 to 10.  
ABI-H0731 and matching placebo have been 
defined as IMPs to make the distinction from 
NrtIs, which are defined as NIMP (background 
therapy) in this study.  
To update planned sites for the study. 
To clarify that the use of NrtI therapy in this 
study is considered background therapy.  
Section 5.2, 
Synopsis  
Inclusion #4: “of child-bearing potential” has 
been added. 
Inclusion #6: “at least 2 weeks apart” has been 
updated to “approximately 10-14 days apart.” 
 
 
 
Inclusion #7: Phrase “but <5 years” has been 
deleted.  
 
Inclusion #4 has been modified to clarify that 
only female subjects of child-bearing potential 
will have to undergo a serum pregnancy test at 
Screening and a urine pregnancy test predose 
on Day 1 to qualify for the study participation.  
Inclusion #6 has been modified to clarify that 2 
samples from the Screening period have been 
to be collected approximately 10-14 days apart. 
Inclusion #7 has been modified to expand 
enrollment criteria.  
Section 5.3, 
Synopsis  
Exclusion #7: “diseases or conditions, such as,” 
has been added. 
Exclusion #14: “prohibited” has been added.  
Exclusion #7 has been modified to clarify that 
“clinically significant” applies to all items 
listed in the criterion (minor modification).  
Exclusion #14 has been modified to clarify that 
subjects receiving prohibited herbal/over-the-
counter-medications will not be eligible for 
study participation.  
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Section Number 
and Name 
Description of Change 
Brief Rationale 
Section 6.1.1 
Phrases “at the Screening visit” and “upon 
confirmation of subject eligibility on Day 1,” 
have been added. 
To clarify the sequence of events with respect 
to randomization and treatment assignment.  
Sections 6.2, 6.3, 
6.5, 6.6 
This section has been modified with several 
edits that clarify the distinction between IMP 
(ABI-H0731 and PBO) and NIMP background 
therapy (NrtIs).  
The designation of NrtIs as NIMP (background 
therapy) has been added to clarify how NrtIs 
should be handled.  
Section 6.4.1 
The phrase “concomitant prescription 
medications, over-the-counter medications, and 
supplements will be reported in the electronic 
case report form (eCRF) from the date informed 
consent is obtained to 30 days following the last 
dose of all study drug(s) – with the exception of 
NrtI medications used to manage CHB. 
Medications for management of CHB should be 
captured until the last study visit,” has been 
deleted.  
The deletion has been made to clarify that 
concomitant medications must be recorded in 
the subjects’ source documentation until the 
end of study (completion of follow-up period), 
and that administration of NrtIs should continue 
to the end of the follow-up period. 
Sections 7.2-7.8 
The following modifications have been made:  
Serum and urine pregnancy testing will be 
conducted only for females of child-bearing 
potential.  
Immunology testing will include collection of 
PBMCs at Screening for subjects at selected 
sites only.  PBMCs, serum cytokine samples, 
and PaxGene® DNA and RNA samples will be 
collected from subjects at the selected sites.  
Immunology samples will be collected from 
these subjects at premature termination visits as 
well.  
A dosing diary will be provided at all scheduled 
study visits.  
Only the IMPs will be dispensed at scheduled 
visits. 
Specified accountability by site for the IMPs. 
A pharmacogenomic sample will not be 
collected at Week 96 visit. 
The modifications have been made to clarify 
tests and sample collections from subjects, and 
to clarify the distinction between handling of 
IMPs from that of NrtIs.  
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Section Number 
and Name 
Description of Change 
Brief Rationale 
Section 9.4 
Text has been updated to indicate the laboratory 
tests to be performed during an Unscheduled 
Visit in the event of an ALT elevation.  
To clarify the laboratory tests to be performed.  
Appendix 1 
The ‘x’ for complete randomization has been 
deleted from Screening.  
A row for HbA1c at Screening has been added.  
‘x’s’ have been added for dosing diary for 4-20- 
and 24-Weeks post.  
 
 
 
“Study drug” has been updated to “IMP (ABI-
H0731/PBO)”. 
 
Footnotes 3, 11, 20, 21 have been updated.  
 
Footnotes 22, 23, and 24 have been added.  
 
 
 
‘x’ has been deleted from Week 96 for 
pharmacogenomic sampling.  
To clarify that randomization will be completed 
on Day 1.  
To correct for an omission.  
To reflect that diaries will be provided for 
subjects during this follow-up period to record 
NrtI dosing.  
 
To clarify the distinction between IMPs and 
NrtIs (NIMPs). 
 
To align with updates in Section 9.4 and 
Section 7.1-7.7.  
To clarify the follow up period of concomitant 
medications and NrtIs; to clarify that in-clinic 
NrtI during the follow-up period will be 
conducted only at the 4-Weeks Post visit; and 
to clarify the timepoints and conditions for 
immunologic testing.  
Week 96 pharmacogenomic sampling will not 
be conducted.  
Appendix 2 
Sentences “Subjects will provide whole blood 
PBMCs samples at Screening at selected sites 
only. These subjects will provide additional 
whole blood PBMCs samples followed by 
serum cytokine samples for immunologic testing 
at timepoints specified in Appendix 1. 
Additionally, these subjects will also provide 
PaxGene® RNA and PaxGene® DNA samples 
at timepoints specified in Appendix 1” have 
been added.  
HbcrAb has been deleted from “HBV 
Virology.” 
To clarify the conditions for immunologic 
testing.  
 
 
 
 
 
 
Correction.  
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Section Number 
and Name 
Description of Change 
Brief Rationale 
Appendix 3 
A row for “Prolonged PR Interval or AV Block” 
has been added to align with standard DAIDS 
table.  
Minor corrections have been made to acidosis, 
calcium high, and sodium low.  
Corrections were made to align with the 
DAIDS 2017 Corrected Version 2.1.  
Appendix 4 
Tubal sterilization has been added as an 
effective birth control method.  
Statement “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,” has been added.  
Text has been added for comprehensive 
instructions.   
 
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Study Title: A Phase 2a, Multicenter, Single-Blind, Placebo-Controlled Study Evaluating Treatment 
Intensification with ABI-H0731 in Subjects with Chronic Hepatitis B Infection on Nucleos(t)ide Reverse 
Transcriptase Inhibitors 
 
NCT Number: NCT04454567 
 
Date of Document: 06 May 2021   


ABI-H0731-205 
 
Statistical Analysis Plan 
Version 1.0 
CONFIDENTIAL 
Page 1 
06 May 2021 
 
 
 
 
STATISTICAL ANALYSIS PLAN 
 
Sponsor:  
Assembly Biosciences, Inc  
331 Oyster Point Blvd 
South San Francisco, CA 94030  
 
 
Protocol Number: 
ABI-H0731-205 
 
 
Protocol Title: 
A Phase 2a, Multicenter, Single-Blind, Placebo-Controlled 
Study Evaluating Treatment Intensification with ABI-H0731 
in Subjects with Chronic Hepatitis B Infection on 
Nucleos(t)ide Reverse Transcriptase Inhibitors 
 
Product: 
Vebicorvir (formerly ABI-H0731) 
 
 
 
 
Protocol Version (Date): 
Amendment 1 (08 September 2020) 
 
Indication: 
Chronic Hepatitis B Virus Infection  
Analysis Type: 
Final Analysis for Early Termination  
 
 
 
Analysis Plan Version (Date): 
Version 1.0 (06 May 2021) 
 
 
 
Analysis Plan Author(s): 
 
Contractor, Biostatistics 
 
 
 
CONFIDENTIAL AND PROPRIETARY INFORMATION 
 


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STATISTICAL ANALYSIS PLAN APPROVAL FORM 
Protocol Title: 
A Phase 2a, Multicenter, Single-Blind, Placebo-Controlled Study 
Evaluating Treatment Intensification with ABI-H0731 in Subjects 
with Chronic Hepatitis B Infection on Nucleos(t)ide Reverse 
Transcriptase Inhibitors 
Protocol Number: 
ABI-H0731-205 
SAP Version (Date): 
Version 1.0 (06 May 2021) 
The SAP was subject to critical review and has been approved by the participating members. 
Name and Title 
Approval Signature 
Date 
 
Vice President, Biometrics 
Assembly Biosciences 
 
 
 
See e-signature page 
 
 
 
 
Chief Medical Officer 
Assembly Biosciences 
 
 
See e-signature page 
 
 
 
 
 
 
 


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TABLE OF CONTENTS 
TABLE OF CONTENTS .............................................................................................................................................. 3 
LIST OF ABBREVIATIONS ........................................................................................................................................ 5 
1. 
INTRODUCTION ................................................................................................................................................ 6 
1.1. 
Study Objectives ...................................................................................................................................... 6 
1.2. 
Study Design ............................................................................................................................................ 7 
1.3. 
Sample Size and Power ............................................................................................................................ 7 
1.4. 
Methods of Assigning Subjects to Treatment .......................................................................................... 7 
1.4.1. 
Randomization ....................................................................................................................... 7 
1.4.2. 
Blinding .................................................................................................................................. 8 
2. 
TYPE OF PLANNED ANALYSIS ...................................................................................................................... 9 
2.1. 
Final Analysis .......................................................................................................................................... 9 
3. 
GENERAL CONSIDERATIONS FOR DATA ANALYSES ............................................................................ 10 
3.1. 
Analysis Sets .......................................................................................................................................... 10 
3.1.1. 
All Randomized Analysis Set ............................................................................................... 10 
3.2. 
Data Handling Conventions and Transformations ................................................................................. 10 
3.2.1. 
General ................................................................................................................................. 10 
3.2.2. 
Non-PK Data ........................................................................................................................ 10 
4. 
SUBJECT DISPOSITION .................................................................................................................................. 11 
4.1. 
Subject Enrollment and Disposition ....................................................................................................... 11 
4.2. 
Extent of Study Drug Administration .................................................................................................... 11 
5. 
BASELINE CHARACTERISTICS .................................................................................................................... 12 
5.1. 
Demographics and Baseline Characteristics .......................................................................................... 12 
5.2. 
Baseline Disease Characteristics ............................................................................................................ 12 
6. 
EFFICACY ANALYSES ................................................................................................................................... 13 
7. 
SAFETY ANALYSES ........................................................................................................................................ 14 
7.1. 
Adverse Events....................................................................................................................................... 14 
7.1.1. 
Adverse Event Dictionary .................................................................................................... 14 
7.1.2. 
Adverse Event Severity ........................................................................................................ 14 
7.1.3. 
Relationship of Adverse Events to Study Drug .................................................................... 14 
7.1.4. 
Serious Adverse Events ........................................................................................................ 14 
7.1.5. 
Treatment-Emergent Adverse Events ................................................................................... 14 
7.1.5.1. 
Definition of Treatment-Emergent Adverse Events ....................................... 14 
7.1.6. 
Adverse Events Results ........................................................................................................ 14 
7.2. 
Laboratory Evaluations .......................................................................................................................... 14 
7.2.1. 
Graded Laboratory Values ................................................................................................... 15 
7.3. 
Body Weight and Vital Signs ................................................................................................................. 15 
7.4. 
Prior and Concomitant Medications ....................................................................................................... 15 
7.4.1. 
Prior Medications ................................................................................................................. 15 
7.4.2. 
Concomitant Medications ..................................................................................................... 15 
7.5. 
Electrocardiogram Results ..................................................................................................................... 16 
7.6. 
Other Safety Measures ........................................................................................................................... 16 
8. 
PHARMACOKINETIC (PK) ANALYSES ........................................................................................................ 17 
9. 
REFERENCES ................................................................................................................................................... 18 
10. SOFTWARE ....................................................................................................................................................... 19 


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11. SAP REVISION .................................................................................................................................................. 20 
12. APPENDICES .................................................................................................................................................... 21 
 


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LIST OF ABBREVIATIONS 
AE 
adverse event 
ALT 
alanine aminotransferase 
AST 
aspartate aminotransferase 
BLQ 
below the limit of quantitation 
BMI 
body mass index 
cHBV 
chronic hepatitis B virus infection  
CK 
creatine kinase 
CRF 
case report form 
CSR 
clinical study report 
ECG 
Electrocardiogram 
ET 
early termination 
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 infection  
HLT 
high-level term 
LOQ 
limit of quantitation 
LLOQ 
lower limit of quantitation  
MedDRA 
Medical Dictionary for Regulatory Activities 
NrtI 
nucleos(t)ide reverse transciptase inhinitors 
pgRNA 
pergenomic RNA 
PK 
pharmacokinetic 
PT 
preferred term 
QT 
electrocardiographic interval between the beginning of the Q wave and termination of the 
T wave representing the time for both ventricular depolarization and repolarization to occur 
QTc 
QT interval corrected for heart rate 
QTcF 
QT interval corrected for heart rate using Fridericia’s formula 
RR 
electrocardiographic interval representing the time measurement between the R wave of one 
heartbeat and the R wave of the preceding heartbeat 
SAP 
statistical analysis plan 
SI (units) 
international system of units 
SOC 
system organ class 
TEAE 
treatment-emergent adverse event 
TFLs 
tables, figures, and listings 
ULN 
upper limit of normal 
WHO 
World Health Organization 
 
 


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1. 
INTRODUCTION 
Study ABI-H0731-205 is a Phase 2a, multi-center, randomized, single-blind, placebo (PBO)-
controlled study to assess the safety, antiviral activity, and pharmacokinetics (PK) of once daily 
dose of 300 mg vebicorvir (VBR, formerly ABI-H0731) (3 × 100 mg tablets) administered in 
addition to standard of care nucleos(t)ide reverse transciptase inhibitors (NrtI) in subjects with 
chronic hepatitis B virus infection (cHBV) who have not achieved adequate virologic 
suppression of hepatitis B virus (HBV) DNA less than the limit of quantitation (<LLOQ) on NrtI 
alone. Due to a change in the Sponsor’s development strategy, Study ABI-H0731-205 has been 
terminated early. At the time of early termination,  a total of 2 subjects were randomized in the 
entire study. 
 
This statistical analysis plan (SAP) describes the statistical analysis methods and data 
presentations to be used in tables, figures, and listings (TFLs) in the synoptic clinical study 
report (CSR) for Study ABI-H0731-205. This SAP is based on the study protocol Amendment 1 
dated 08 September 2020 and the electronic case report form (eCRF). The SAP will be finalized 
before database lock. Any changes made after the finalization of the SAP will be documented in 
the CSR. 
 
1.1. 
Study Objectives 
The primary objectives of this study are as follows: 
• To evaluate the safety and tolerability of VBR when administered in combination with NrtI 
in subjects with cHBV  
• To evaluate the effect of the addition of VBR to NrtI in fully suppressing HBV DNA in 
subjects with cHBV  
The secondary objectives of this study are as follows: 
• To evaluate the effect of the addition of VBR to NrtI in reducing HBV pregenomic RNA 
(pgRNA) levels in subjects with cHBV  
• To evaluate the effect of the addition of VBR to NrtI in reducing HBV antigens (ie, hepatitis 
B “e” antigen [HBeAg], hepatitis B core-related antigen [HBcrAg], and hepatitis B surface 
antigen [HBsAg]) in subjects with cHBV  
• To evaluate the effect of the addition of VBR to NrtI on normalization of alanine 
aminotransferase (ALT) in subjects with abnormal ALT  
• To evaluate the PK of VBR and NrtI in subjects with cHBV  
• To evaluate the emergence of resistance to VBR when administered in combination with NrtI  
The exploratory objectives of this study are as follows: 


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• To assess the relationship between immunological and/or viral biomarkers with virologic 
and/or clinical outcomes  
• For subjects who provide an optional pharmacogenomic sample, to evaluate the potential 
contribution of host genomics to clinical or virologic outcomes and/or drug disposition  
1.2. 
Study Design 
This is a Phase 2a, multi-center, randomized, single-blind, PBO-controlled study. This study will 
assess the safety, antiviral activity, and PK of VBR administered in addition to standard of care 
NrtI in subjects with cHBV who have not achieved adequate virologic suppression of HBV DNA 
<LLOQ on NrtI alone.  
Approximately 40 eligible subjects will be randomized in a 1:1 ratio to the two treatment groups 
as below.  
Treatment with VBR or PBO and NrtI will be administered orally, once daily:  
• Group 1 will receive VBR+NrtI for 96 weeks 
• Group 2 will receive PBO+NrtI for 48 weeks, and then VBR+NrtI until Week 96  
All subjects will continue to receive NrtI alone during the 24-week follow-up period from Week 
96 through Week 120. Treatment assignments will be stratified by the concurrent NrtI 
administered (ie, entecavir, ETV) versus tenofovir (alafenamide versus [TAF] or disoproxil 
fumarate [TDF]) and HBV DNA (HBV DNA ≥500 IU/mL versus <500 IU/mL) during the 
Screening visits. The study will enroll up to 75% subjects on ETV.  
The schedule of study procedures is presented in tabular form in Appendix 1 of the study 
protocol.   
 
1.3. 
Sample Size and Power 
Approximately 40 subjects with cHBV will be enrolled in the study. Subjects will be randomized 
to receive either 300 mg VBR (3×100 mg tablets) or matching PBO in a 1:1 ratio in addition to 
standard of care NrtI. Since 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. 
 
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. Following successful 
completion of Screening assessments and confirmation of subject eligibility, site personnel will 
enter the subject specific information in the IRT system and receive a subject number and 


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treatment assignment. The IRT system will assign eligible subjects in a 1:1 ratio to receive either 
300 mg VBR+NrtI for 96 weeks (n=20) or PBO+NrtI for 48 weeks followed by 300 mg 
VBR+NrtI for 48 weeks (n=20). Individual treatment assignments will be stratified by the 
concurrent NrtI administered (ie, ETV versus TDF or TAF) and HBV DNA (HBV DNA ≥500 
IU/mL versus <500 IU/mL) during the Screening visits. The study will enroll approximately 
75% subjects receiving ETV. Additional information on the use of the IRT is provided in the 
IRT user manual. 
 
1.4.2. 
Blinding 
Study subjects, Investigators, and other site personnel administering the study drug, performing 
the clinical assessments and handling data on the study subjects, will be blinded to individual 
subject treatments assignments (ie, PBO+NrtI or VBR+NrtI) throughout the duration of the 
study. To support maintenance of the study blind, HBV pgRNA results will not be provided to 
the study subjects, Investigators, or other site personnel until completion of the study.  
Except for the personnels with standard unblinded roles, all other study team members remain 
blinded prior to the database lock.  
 


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2. 
TYPE OF PLANNED ANALYSIS 
2.1. 
Final Analysis 
The study is being terminated early. The final analysis will be performed after the enrolled 
subjects have been terminiated from the study, outstanding data queries have been resolved or 
adjudicated as unresolvable, and the data has been cleaned and finalized.   


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3. 
GENERAL CONSIDERATIONS FOR DATA ANALYSES 
Statistical analysis will not be performed for this study. Only listings will be provided.  
By-subject listings will be presented for all subjects in the All Randomized Analysis Set and 
sorted by subject ID number, visit date, and time (if applicable) in chronological order within the 
subject. The treatment group to which subjects were randomized will be used in the listings. 
3.1. 
Analysis Sets 
Analysis set defines the subjects to be included in an analysis. Analysis set and its definition is 
provided in this section. The analysis set will be identified and included as a subtitle of each 
listing.  
3.1.1. 
All Randomized Analysis Set 
All Randomized Analysis Set includes all subjects who were randomized in the study. 
3.2. 
Data Handling Conventions and Transformations 
3.2.1. 
General 
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, imputed month 
and day (January 1st), and informed consent date. 
3.2.2. 
Non-PK Data 
The laboratory data that are below the LLOQ or above the upper limit of quantitation (LOQ) will 
be listed as such. 


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4. 
SUBJECT DISPOSITION 
4.1. 
Subject Enrollment and Disposition 
A subject disposition listing will be provided by subject identification (ID) number in ascending 
order based on All Randomized Analysis Set. The treatment group, date of randomiazation, date 
of first and last dose, the status of study drug and study completion, and reasons for premature 
discontinuation will be presented in the by-subject listing.  
4.2. 
Extent of Study Drug Administration 
A study drug administration listing will be provided by subject ID number in ascending order 
based on All Randomized Analysis Set. The planned treatment group and actual drug received, 
dose amount and unit, dose frequency, route, dose start date, dose end date, and discontinuation 
from the study drug will be included in the listing.  
 


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5. 
BASELINE CHARACTERISTICS 
5.1. 
Demographics and Baseline Characteristics 
Subject demographic variables (ie, age, sex, race, and ethnicity), baseline characteristics (body 
weight [in kg], height [in cm], body mass index [BMI; in kg/m2]) will be provided for all 
subjects in the All Randomized Analysis Set. 
The by-subject demographic listing, including the informed consent date, will be provided by 
subject ID number in ascending order. 
5.2. 
Baseline Disease Characteristics 
A by-subject listing of baseline disease characteristics based on the All Randomized Analysis Set 
will be provided by subject ID number in ascending order. The following baseline disease 
characteristics will be included in the listing: 
• Years positive for HBV 
• HBV Genotype  
• Type of nucleoside/nucleotide treatment at Baseline 
• Years on current HBV treatment (years) 
• Baseline HBeAg status (positive, negative) 
• Baseline HBV DNA (log10 IU/mL) and HBV DNA group (< LLOQ) 
• Baseline HBV pgRNA (log10 U/mL) and HBV pgRNA group (< LLOQ) 
• Baseline HBeAg (log10 IU/mL) and HBV HBeAg group (< LLOQ) 
• Baseline HBcrAg (log10 kU/mL) and HBV HBcrAg group (< LLOQ) 
• Baseline HBsAg (log10 IU/mL) and HBV HBsAg group (< LLOQ) 
• Baseline ALT (U/L) and ALT group (>ULN [Covance], >ULN [AASLD]) 
• Baseline HBeAg antibody (HBeAb)  
• Baseline HBsAg antibody (HBsAb)  
• Liver biopsy staging   
• Fibroscan result 


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6. 
EFFICACY ANALYSES 
No formal efficacy analysis will be performed. A listing of virology parameters will be provided 
by subject ID number and visit in ascending order based on the All Randomized Analysis Set. 
The following virology parameters will be included in the listing: 
• HBV DNA  
• HBV pgRNA  
• HBsAg  
• HBeAg  
• HBcrAg 
• HBeAb  
• HBsAb  


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7. 
SAFETY ANALYSES 
7.1. 
Adverse Events  
7.1.1. 
Adverse Event Dictionary 
Clinical and laboratory adverse events (AEs) will be coded using the current version of Medical 
Dictionary for Regulatory Activities (MedDRA). 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 the data listing. 
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 ABI-H0731/Placebo” based on the Investigator’s choice. Events for 
which the Investigator did not record relationship will show the relationship as missing in the by-
subject data listing. 
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 on or 
after the study drug start date and no later than 28 days after permanent discontinuation of study 
drug. 
7.1.6. 
Adverse Events Results  
All AEs will be provided in a by-subject listing based on the All Randomized Analysis Set. 
7.2. 
Laboratory Evaluations 
Laboratory data collected during the study will be presented based on the All Randomized 
Analysis Set. The lab values that are below LLOQ or above the upper LOQ will be listed as 
such. A by-subject listing for all laboratory test results (including hematology, serum chemistry, 
and urinalysis) will be provided by subject ID number and time visit in chronological order.  


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7.2.1. 
Graded Laboratory Values 
The criteria specified in the study protocol will be used to grade laboratory results as normal 
(Grade 0), mild (Grade 1), moderate (Grade 2), severe (Grade 3) or potentially life threatening 
(Grade 4). See Appendix 3 of the study protocol for detailed DAIDS grading criteria on the 
relevant laboratory tests. Grade 0 includes all values that do not meet the criteria for an 
abnormality of at least Grade 1. 
The relevant reference range and DAIDS severity grade will also be provided in the laboratory 
test listing. 
7.3. 
Body Weight and Vital Signs 
A by-subject listing of vital signs (systolic and diastolic blood pressure [mmHg], pulse 
[beats/min], respiration [breaths/min], and body temperature [oC]), body weight, height, and BMI 
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. 
7.4.1. 
Prior Medications 
Prior medications are defined as any medications taken before a subject took the first study drug. 
A medication will be considered a prior medication if it meets one of the following criteria: 
• A medication with a start date prior to the first dosing 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 dosing date.  
• A medication with a completely missing start date will be included in the prior medication 
summary, unless otherwise specified. 
7.4.2. 
Concomitant Medications 
Concomitant medications are defined as medications taken while a subject took study drug.  
A medication will be considered as a concomitant medication if it meets one of the following 
criteria: 
• A medication with a start date prior to or on the first dosing date of study drug, that is  
continued to be taken after the first dosing date.  


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• A medication started after the first dosing date but prior to or on the last dosing 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 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 dosing date or the last dosing 
date of study drug    
• Medications with completely missing start and stop dates, unless otherwise specified. 
All prior and concomitant medications will be provided based on All Randomized Analysis Set 
in a by-subject listing sorted by subject ID number and administration date in chronological 
order. The Anatomical Therapeutic Chemical (ATC) drug class Level 2, preferred name of 
medications will be included in the listing.  
7.5. 
 Electrocardiogram Results 
A by-subject listing for overall ECG assessment results will be provided by subject ID number 
and visit in chronological order. The ECG date, overall interpretation of the ECG, significance of 
abnormality will be presented. 
7.6. 
Other Safety Measures  
For female subjects in the All Randomized Analysis Set, results from urine pregnancy tests will 
be presented in a data listing. 
 


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8. 
PHARMACOKINETIC (PK) ANALYSES 
PK analysis will not be performed for this study.  
 


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9. 
REFERENCES 
None. 


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10. 
SOFTWARE 
SAS® Software Version 9.4. SAS Institute Inc., Cary, NC, USA. 


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11. 
SAP REVISION 
Revision Date 
(DD MMM YYYY) 
Section 
Summary of Revision 
Reason for Revision 
 
 
 
 
 
 
 
 


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12. 
APPENDICES 
None. 


Signature Page for VV-TMF-04911 v1.0
Signature Page for VV-TMF-04911 v1.0
Reason for signing: Approved
Date of signature: 07-May-2021 04:24:37 GMT+0000
Reason for signing: Approved
Date of signature: 07-May-2021 12:12:43 GMT+0000