Clinical trial NCT03780543
Conditions: Chronic Hepatitis B
Keywords: CHB (chronic hepatitis B infection) HBV (hepatitis B virus) HBeAg positive (hepatitis B "e" antigen - positive) HBeAg negative (hepatitis B "e" antigen - negative) Hepatitis B (hepatitis B virus) Hepatitis B virus (HBV) SVR (sustained viral response)
Sponsor: Assembly Biosciences
Start date: 2018-12-20; Completion date: 2021-04-26
Enrollment: 92 participants; Allocation: NON_RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Open-label, extension study to evaluate the safety and efficacy of combination therapy and its effect on sustained viral response biomarkers.

Detailed description:
This is an open-label extension of parent studies ABI-H0731-201 (NCT03576066) and ABI-H0731-202 (NCT03577171). The extension study will assess the safety of long-term (up to 100 weeks of treatment in extension study ABI-H0731-211) combination therapy and its effect on biomarkers of sustained viral response (SVR) (NCT03780543).

Arms: arm 1: Subjects who on Day 1 of parent study ABI-H0731-201 (NCT03576066) were standard of care (SOC) nucleos(t)ide (NrtI)-suppressed and HBeAg-negative will receive both ABI-H0731 + SOC NrtI for at least 52 weeks, after which time they will discontinue both ABI-H0731 and SOC NrtI and enter long-term off-treatment follow-up (FU) for up to 3 years. arm 2: Subjects who on Day 1 of parent study ABI-H0731-201 (NCT03576066) were SOC NrtI-suppressed and HBeAg-positive will receive ABI-H0731 + SOC NrtI for at least 52 weeks, after which time their viral response will be evaluated.

1. Subjects who meet the virologic response criteria will discontinue both ABI-H0731 and SOC NrtI and enter long-term off-treatment follow-up (FU) for up to 3 years.
2. Subjects with insufficient virologic response will discontinue ABI-H0731 only and continue on SOC NrtI alone and followed-up for 12 weeks. arm 3: Subjects who on Day 1 of parent study ABI-H0731-202 (NCT03577171) were treatment-naive and HBeAg-positive will receive ABI-H0731 + SOC NrtI for at least 52 weeks, after which time their viral response will be evaluated.

1. Subjects who meet the virologic response criteria at Week 52 will continue to receive ABI-H0731 + SOC NrtI for an additional 96 weeks, after which time their viral response will be evaluated at Week 148.

   Subjects who meet the virologic response criteria at Week 148 will discontinue both ABI-H0731 and SOC NrtI and enter long-term off-treatment follow-up for up to 3 years. Subjects with insufficient virologic response at Week 148, will discontinue ABI-H0731 only and continue on SOC NrtI alone for up to 12 weeks.
2. Subjects with insufficient virologic response at Week 52 will discontinue from ABI-H0731only and continue on SOC NrtI alone and enter follow-up for up to 12 weeks.
Interventions: intervention 1: standard of care (SOC) Nucleoside reverse transcriptase inhibitor (NrtI)
Intervention descriptions: intervention 1: Participants will continue on their SOC NrtI, Entecavir (ETV), Tenofovir Disoproxil Fumarate (TDF) or Tenofovir Alafenamide (TAF) tablet QD (once daily) orally as per approved package insert.

Protocol documents:
Prot_000.pdf: 
 
CLINICAL RESEARCH PROTOCOL 
PROTOCOL TITLE: 
A Multi-center, Open-label, Long-term Extension 
Study of ABI-H0731+Nucleos(t)ide as Finite 
Treatment for Chronic Hepatitis B Patients 
STUDY NUMBER: 
ABI-H0731-211 
DRUG: 
ABI-H0731 
REFERENCE NUMBERS: 
 
 
SPONSOR: 
Assembly Biosciences 
331 Oyster Point Blvd., Fourth Floor 
South San Francisco, CA 94080 USA 
(833) 509-4583 
AMENDMENT 4, VERSION 5.0 
14 October 2020 
AMENDMENT 3, VERSION 4.2 DATE: 
(UK only; Category C, Non-Substantial 
Amendment)  
 
22 May 2020 
 
AMENDMENT 3, VERSION 4.1 DATE: 
10 April 2020 
AMENDMENT 3, VERSION 4.0 DATE: 
10 March 2020 
AMENDMENT 2, VERSION 3.0 DATE: 
14 November 2019 
AMENDMENT 1, VERSION 2.0 DATE: 
12 July 2019 
PROTOCOL VERSION 1.2 DATE 
(UK Only): 
6 February 2019 
PROTOCOL VERSION 1.1 DATE: 
2 November 2018 
PROTOCOL VERSION 1.0 DATE: 
9 September 2018 
CONFIDENTIAL 
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. 




Protocol ABI-H0731-211 
ABI-H0731+NrtI for CHB Patients 
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ABI-H0731-211 
A MULTI-CENTER, OPEN-LABEL, LONG-TERM EXTENSION STUDY 
OF ABI-H0731+NUCLEOS(T)IDE AS FINITE TREATMENT FOR 
CHRONIC HEPATITIS B PATIENTS 
 
INVESTIGATOR STATEMENT 
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 Name (printed) 
Signature 
 
______________________________ 
____________________________________ 
Date 
 
 
 
 
 
Site Number 
 
Please keep the original, signed copy of this Investigator signature page in your records and 
email a copy to your Clinical Research Associate. 
 
 
 


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1.0 
SYNOPSIS 
Protocol 
Number: 
ABI-H0731-211 
Title:  
A Multi-center, Open-label, Long-term Extension Study of 
ABI-H0731+Nucleos(t)ide as Finite Treatment for Chronic Hepatitis B Patients 
Phase: 
2a open-label extension 
Number of 
Subjects: 
Up to 100 anticipated  
Rationale:  
Chronic hepatitis B infection (CHB) is a major global cause of severe liver morbidity 
and liver-related mortality. ABI-H0731 (also known as vebicorvir) is a direct-acting 
antiviral targeting the hepatitis B virus (HBV) core protein. It is anticipated that the 
addition of ABI-H0731 to standard of care (SOC) nucleos(t)ide reverse transcriptase 
inhibitor (NrtI) therapy will be safe and result in an increase in the sustained viral 
response (SVR) rate for patients with CHB. ABI-H0731-211 is an open-label 
extension study that will assess the safety of extended treatment with ABI-H0731 
(i.e., up to 148 weeks in ABI-H0731-211) when administered in combination with 
SOC NrtI in subjects previously participating in Studies ABI-H0731-201 and ABI-
H0731-202. The study will also evaluate off-treatment virologic response rates 
following cessation of treatment in subjects meeting prespecified criteria.  
Additionally, the study will assess the effect of the combination regimen on serum 
biomarkers such as HBV deoxyribonucleic acid (DNA), quantitative and qualitative 
reduction in the viral antigens, hepatitis B “e” antigen (HBeAg), hepatitis B 
core-related antigen (HBcrAg) and hepatitis B surface antigen (HBsAg), as well as 
exploratory biomarkers such as reduction in circulating HBV pre-genomic RNA 
(pgRNA). 
Target 
Population: 
Male or female subjects with CHB who have completed 24 weeks of treatment in 
Study ABI-H0731-201 or ABI-H0731-202. 
Duration of 
Participation: 
Up to 148 weeks of treatment in ABI-H0731-211 (ie, cumulative duration of up to 
172 weeks including treatment in ABI-H0731-201 or ABI-H0731-202). Following 
completion of treatment in ABI-H0731-211, subjects may be followed for up to 
3 years. 
Test Product: 
ABI-H0731 300 mg, administered orally, once daily, as three 100 mg tablets in 
addition to SOC NrtI therapy. 
Reference 
Product: 
Not Applicable. 
Study Design: 
This is an open-label, multi-center, long-term extension study evaluating the safety 
and efficacy of ABI-H0731 in combination with a SOC NrtI in subjects with CHB 
who have completed 24 weeks of treatment in one of two parent studies, 
ABI-H0731-201 (Study 201) or ABI-H0731-202 (Study 202). 
In ABI-H0731-211 (Study 211), subjects may receive up to 148 weeks of treatment 
with ABI-H0731+NrtI. The actual duration of treatment received by each individual 
subject will be based on their HBV treatment history (ie, NrtI suppressed or treatment 
naïve) and HBeAg status (ie, HBeAg positive or HBeAg negative) at Baseline in the 
parent study, and the individual subject’s virologic response in Study 211. Based on 




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achieve pgRNA 
<LLOQ  
Week 
148  
If subject has 
total HBV 
nucleic acids 
(DNA+pgRNA) 
<20 IU/mL and 
HBeAg 
≤5 IU/mL for 
≥7 consecutive 
visits¥ 
Discontinue both 
ABI-H0731+NrtI. 
Enter long-term off-
treatment follow-up 
for up to 3 years 
If subject does 
not have total 
HBV nucleic 
acids 
(DNA+pgRNA) 
<20 IU/mL and 
HBeAg 
≤5 IU/mL for 
≥7 consecutive 
visits¥ 
Discontinue 
ABI-H0731 only 
and continue on 
SOC NrtI alone 
Enter follow-up on 
SOC NrtI alone for 
up to 12 weeks  
†Treatment History and HBeAg-status at Baseline in the parent studies (Study 201 or Study 202) 
*Subjects without virologic assessment at Week 52 will be evaluated at the next study visit. 
¥Consecutive visits are determined from the last timepoint at which values are available for all 
parameters. 
As described above, based on the respective treatment action, additional follow-up 
visits may be undertaken. These visits are briefly summarized below and described 
in further detail in later sections of the protocol. 
3-Year Off-treatment Follow-up 
All subjects who discontinue both ABI-H0731+NrtI will be followed for up to 3 years 
from the date of treatment discontinuation to assess the durability of virologic 
response.   Subjects will have an Unscheduled Visit to notify them of the Treatment 
Action to be implemented, at which point, each individual subject’s visit schedule is 
then reset after the Unscheduled Visit, and subjects will return to the clinic for follow-
up every 4 weeks for visits at 4, 8, 12, 16, 20, and 24 weeks post-treatment 
discontinuation, then every 8 weeks for visits at 32, 40 and 48 weeks post-treatment 
discontinuation, and then every 12 weeks until completion of the 3-year follow-up. 
Additional unscheduled visits may be performed at the Investigator’s discretion. 
Following completion of the visit 3 years after ABI-H0731+NrtI discontinuation, 
subjects will exit the study and be under the routine care of their physician. 
12-Week Follow-up on NrtI Alone 
All subjects who discontinue ABI-H0731 only and continue SOC NrtI alone will be 
followed for 12 weeks from the date of ABI-H0731 discontinuation. Subjects will 
have an Unscheduled Visit to notify them of the Treatment Action to be implemented, 
at which point, each individual subject’s visit schedule is then reset after the 
Unscheduled Visit, and subjects will return to the clinic for follow-up visits at 4, 8, 
and 12 weeks after discontinuation of ABI-H0731. Additional unscheduled visits may 
be performed at the Investigator’s discretion. Following completion of the follow-up 
visit 12 weeks after discontinuation of ABI-H0731, subjects will exit the study and 
be under the routine care of their physician. 


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Continuation of Treatment with ABI-H0731+NrtI 
All subjects who continue ABI-H0731+NrtI beyond Week 52 will return to the clinic 
for visits every 4 weeks until Week 148. Subjects may be notified of their Treatment 
Action by phone and continue on their current study visit schedule. At Week 148, 
subjects will be evaluated for virologic response as described in the table above, and 
will either discontinue both ABI-H0731 and NrtI and be followed for up to 3 years 
(as described in Section 3-Year Off-treatment Follow-up above) or discontinue ABI-
H0731 only and continue on SOC NrtI alone and be followed for 12 weeks (as 
described in Section 12-Week Follow-up on NrtI Alone above). 
Criteria to Restart SOC NrtI Following Discontinuation of Both ABI-H0731 
and NrtI 
Subjects who discontinue both ABI-H0731+NrtI will be followed to assess the 
durability of virologic response. The Investigator will use clinical judgment as to 
when restarting SOC NrtI is indicated. However, SOC NrtI therapy will be 
reintroduced if any of the following criteria listed below are met. 
• 
Alanine aminotransferase (ALT) >10 × upper limit of normal (ULN) 
• 
Direct bilirubin >2.0 × ULN 
• 
International Normalized Ratio >1.5 
• 
ALT >3 × ULN and HBV DNA >100,000 IU/mL 
• 
ALT >ULN and HBV DNA >2,000 IU/mL on 3 consecutive visits at least 
one month apart 
• 
Any clinical decompensation, regardless of HBV DNA level 
• 
Physician or subject’s decision 
Should any of these criteria be met, then subjects may have an Unscheduled Visit to 
notify them to restart SOC NrtI. Subjects’ visit schedules are then reset upon 
restarting SOC NrtI, and subjects who restart SOC NrtI will return for follow-up 
visits at 4, 8 and 12 weeks after starting SOC NrtI and will then complete 
participation in the study. 
Study 
Objectives:  
Primary Objective: 
• 
To evaluate the potential for combination therapy with ABI-H0731+ NrtI to 
increase SVR rates in subjects who have CHB 
Secondary Objectives: 
• 
To evaluate the longer-term safety and tolerability of ABI-H0731 added to 
SOC NrtI therapy 
• 
To evaluate improvement in transaminases in subjects on treatment and 
post-treatment 


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• 
To evaluate the durability of changes in viral antigen and viral DNA after 
discontinuation of combination therapy 
Exploratory objectives: 
• 
To evaluate the kinetics of and absolute changes from Baseline in 
biomarkers of transcriptionally active covalently closed circular DNA 
(cccDNA; HBeAg and HBsAg) 
• 
To assess the relationship between exploratory viral biomarkers, such as 
changes in viral pgRNA and HBcrAg, and outcome 
• 
To evaluate potential emergence of HBV resistance associated variants 
(RAVs), if any, to ABI-H0731 in combination with an SOC NrtI 
• 
To evaluate the durability of virologic response between 24 weeks 
post-treatment discontinuation and 36 months post-treatment 
discontinuation 
• 
For subjects who have provided an optional pharmacogenomic sample in 
parent studies (eg, ABI-H0731-201 or ABI-H0731-202), to evaluate the 
potential contribution of host genomics to outcomes 
• 
To assess steady state plasma levels of ABI-H0731 and SOC NrtI for 
possible correlation with markers of safety and efficacy 
Primary 
Endpoint:  
The primary efficacy endpoint will be: 
• 
Proportion of subjects with SVR at 24 weeks off treatment. 
 
Secondary 
Endpoints: 
Secondary endpoints include: 
• 
Incidence of adverse events (AEs), premature discontinuations due to AE, 
abnormal safety laboratory results, electrocardiogram, or vital signs 
• 
Incidence of subjects with abnormal ALT at Baseline who have normal 
ALT at end of treatment (EOT) and end of study. 
• 
Incidence of subjects with suppression/loss of viral antigen/DNA on 
combination treatment whose viral antigens rebound off therapy 
Exploratory 
Endpoints: 
Exploratory endpoints include: 
• 
Mean change from Baseline in log10 serum HBeAg 
• 
Mean change from Baseline in log10 serum HBsAg 
• 
Incidence of subjects with loss or change in log10 HBsAg or log10 HBeAg 
(<0.5, ≥0.5 to 1.0, or >1.0 in viral antigens) at EOT and end of follow-up 


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• 
Incidence of subjects with HBsAg seroconversion (loss of HBsAg and 
appearance of HBsAg antibody) or HBeAg seroconversion (loss of HBeAg 
and appearance of HBeAg antibody) 
• 
Incidence of subjects with “detectable” HBV DNA by polymerase chain 
reaction at Baseline whose HBV DNA becomes “target not detected” 
• 
Quantitative changes from Baselines in viral RNA on treatment and through 
end of follow-up 
• 
Quantitative changes in serum HBcrAg levels on treatment and through end 
of follow-up 
• 
Incidence of HBsAg or HBeAg seroreversion in subjects up to 3 years off 
therapy 
• 
Incidence of subjects requiring retreatment following SVR through 3 years 
off therapy 
• 
Incidence of subjects with emergence of HBV RAVs 
• 
If differences are seen in outcomes/AEs between racial or ethnic groups: 
Pharmacogenomics correlation will be performed with clinical outcomes in 
subjects who have provided an optional informed consent and sample in 
Study ABI-H0731-201 or Study ABI-H0731-202 
• 
Quantitative levels of ABI-H0731 and NrtI in plasma 
Statistical 
Methods: 
The primary objective will be evaluated based on the proportion of subjects who meet 
the definition of SVR at 24 weeks off treatment. The SVR rate and corresponding 
95% confidence interval will be presented for the overall population while on 
combination therapy. 
Secondary and exploratory endpoints will be analyzed descriptively. For continuous 
variables, such as change from Baseline in mean log10 serum HBeAg or HBsAg 
values at each timepoint, descriptive statistics will be used and will include the 
number, mean, standard deviation, median, minimum, and maximum and, where 
appropriate, a 95% CI. 
For categorical variables, such as subjects with loss or decline in HBsAg or HBeAg 
(<0.5 log10, ≥0.5 to 1.0 log10, or >1.0 log10 decrease in viral antigen), summary 
statistics will include number and percent who meet the endpoint criteria. 
Inclusion 
Criteria: 
Subjects must meet the following inclusion criteria in order to be eligible for 
enrollment: 
1. Willing and able to provide informed consent. 
2. Previously enrolled in a study of ABI-H0731 and completed the treatment 
period, with demonstrated compliance in the opinion of the Investigator. 


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3. Female subjects must agree to use an effective birth control method for the 
duration of the study and follow-up, or be surgically sterile for at least 6 months, 
or at least 2 years postmenopausal with serum follicle-stimulating hormone 
levels consistent with a postmenopausal status. Effective birth control methods 
include male or female condom (may not be used together due to increased risk 
of breakage), vasectomy, intrauterine device (IUD), diaphragm, or cervical cap. 
Female subjects of childbearing potential must have a negative pregnancy test. 
4. All heterosexually active male subjects must agree to use an effective birth 
control method 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, hormone-based contraception (only 
female partner of a male subject), IUD, diaphragm, or cervical cap. 
5. Agreement to adhere to lifestyle considerations including abstaining from 
alcohol abuse (defined as alcohol consumption exceeding 2 standard drinks per 
day on average [1 standard drink = 10 g of alcohol]) and the use of illicit 
substances, herbal or other substances, or unnecessary over-the-counter 
medications; see  Section 5.4) throughout study duration. 
6. In good general health except for chronic HBV infection. 
7. Have the ability to take oral medication and be willing to adhere to the 
ABI-H0731-211 regimen in the opinion of the Investigator. 
Exclusion 
Criteria: 
Subjects who meet the following exclusion criteria will not be eligible for enrollment: 
1. Must not have had evidence of RAVs or lack of compliance on a previous study 
of ABI-H0731. 
2. Must not have had a treatment-emergent AE or laboratory abnormalities deemed 
clinically significant and possibly or probably related to drug while on a 
previous study of ABI-H0731, that in the opinion of the Investigator or the 
Sponsor makes the subject unsuitable for this study. 
3. Current clinically significant cardiac or pulmonary disease; chronic or recurrent 
renal or urinary tract disease; liver disease other than HBV; endocrine disorder; 
autoimmune disorder; diabetes mellitus requiring treatment with insulin or 
hypoglycemic agents; neuromuscular, musculoskeletal, or mucocutaneous 
conditions requiring frequent treatment; seizure disorders requiring treatment; 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 the study. 
4. Females who are lactating or pregnant or wish to become pregnant within the 
duration of the ABI-H0731-211 study.  


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TABLE OF CONTENTS 
1.0 
SYNOPSIS ..........................................................................................................................4 
2.0 
INTRODUCTION AND RATIONALE .........................................................................18 
2.1 
Study Rationale ......................................................................................................18 
2.2 
Background ............................................................................................................18 
2.2.1 
Chronic Hepatitis B Virus .....................................................................18 
2.2.2 
Hepatitis B Virus Biology and Rationale for Hepatitis B Virus Core 
Inhibitors ...............................................................................................20 
2.3 
Summary of Additional Clinical Data with ABI-H0731 .......................................21 
2.3.1 
Phase 2a Studies ....................................................................................21 
2.3.2 
Recently Completed Clinical Pharmacology Studies ...........................21 
2.4 
Overall Risk/Benefit Assessment ..........................................................................21 
3.0 
STUDY OBJECTIVES AND ENDPOINTS ..................................................................24 
3.1 
Objectives ..............................................................................................................24 
3.1.1 
Primary Objective .................................................................................24 
3.1.2 
Secondary Objectives ............................................................................24 
3.1.3 
Exploratory Objectives..........................................................................24 
3.2 
Study Endpoints .....................................................................................................24 
3.2.1 
Primary Endpoint ..................................................................................24 
3.2.2 
Secondary Endpoints .............................................................................25 
3.2.3 
Exploratory Endpoints ..........................................................................25 
4.0 
STUDY PLAN ..................................................................................................................27 
4.1 
Study Design ..........................................................................................................27 
4.1.1 
3-Year Off-treatment Follow-up ...........................................................29 
4.1.2 
12-Week Follow-up on NrtI Alone .......................................................29 
4.1.3 
Continuation of Treatment with ABI-H0731+NrtI ...............................29 
4.1.4 
Criteria to Restart SOC NrtI Following Discontinuation of Both 
ABI-H0731 and NrtI .............................................................................29 
4.2 
Scientific Rationale ................................................................................................30 
4.3 
Dose Justification ...................................................................................................30 
4.4 
Study Drug Resistance Monitoring ........................................................................31 
4.5 
HCC Surveillance ..................................................................................................31 
4.6 
End of Study (EOS) Definition ..............................................................................31 
4.7 
Management of Toxicities .....................................................................................31 
4.7.1 
General Stopping Rules.........................................................................31 


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4.7.2 
Subjects with Alanine Aminotransferase (ALT) Elevations .................32 
4.7.3 
Subjects with Rash ................................................................................34 
4.8 
Schedule of Assessments .......................................................................................36 
5.0 
POPULATION .................................................................................................................41 
5.1 
Number of Subjects................................................................................................41 
5.2 
Inclusion Criteria ...................................................................................................41 
5.3 
Exclusion Criteria ..................................................................................................41 
5.4 
Lifestyle Considerations ........................................................................................42 
5.5 
Strategies for Recruitment and Retention ..............................................................42 
6.0 
STUDY DRUG .................................................................................................................43 
6.1 
Description .............................................................................................................43 
6.1.1 
Formulation ...........................................................................................43 
6.1.2 
Storage...................................................................................................43 
6.2 
Packaging and Shipment ........................................................................................43 
6.3 
Dose and Administration .......................................................................................43 
6.3.1 
Dosing in the Study ...............................................................................43 
6.4 
Accountability ........................................................................................................44 
6.5 
Compliance ............................................................................................................44 
6.6 
Concomitant Therapy.............................................................................................44 
6.6.1 
Prohibited Concomitant Therapy ..........................................................45 
6.6.2 
Other Medications and Treatments .......................................................45 
7.0 
STUDY CONDUCT .........................................................................................................46 
7.1 
Study Procedures by Time Point............................................................................46 
7.1.1 
Premature Discontinuation from Treatment..........................................46 
7.1.2 
Discontinuation from Study ..................................................................46 
8.0 
DESCRIPTION OF STUDY PROCEDURES ..............................................................47 
8.1 
Efficacy Assessments.............................................................................................47 
8.1.1 
Primary Efficacy Assessment ...............................................................47 
8.1.2 
Secondary and Exploratory Efficacy Assessments ...............................47 
8.2 
Safety Assessments ................................................................................................47 
8.2.1 
Clinical Laboratory Tests ......................................................................48 
8.2.2 
Other Safety Assessments .....................................................................48 
8.3 
Protocol Deviations ................................................................................................49 
9.0 
ADVERSE EVENTS .......................................................................................................50 
9.1 
Documenting Adverse Events................................................................................50 


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9.2 
Assessment of Intensity .........................................................................................50 
9.3 
Assessment of Causality ........................................................................................51 
9.4 
Expectedness ..........................................................................................................51 
9.5 
Adverse Events of Special Interest ........................................................................51 
9.6 
Clinical Laboratory Changes .................................................................................51 
9.7 
Adverse Event Follow-up ......................................................................................52 
9.8 
Pregnancy ...............................................................................................................52 
10.0 
SERIOUS ADVERSE EVENT .......................................................................................53 
10.1 
Definition of Serious Adverse Event .....................................................................53 
10.2 
Reporting Serious Adverse Events ........................................................................54 
10.3 
Overdose ................................................................................................................54 
11.0 
STATISTICS ....................................................................................................................55 
11.1 
Statistical Hypotheses ............................................................................................55 
11.2 
Sample Size ............................................................................................................55 
11.3 
Analysis Populations ..............................................................................................55 
11.4 
Statistical Methods .................................................................................................55 
11.4.1 
General Considerations .........................................................................55 
11.4.2 
Efficacy Endpoints ................................................................................56 
11.4.3 
Analysis of Safety .................................................................................56 
11.5 
Interim Analysis .....................................................................................................57 
11.6 
Final Study Report .................................................................................................57 
12.0 
ETHICS AND RESPONSIBILITIES ............................................................................58 
12.1 
Good Clinical Practice ...........................................................................................58 
12.2 
Data Monitoring Committee and Ongoing Safety Reviews ..................................58 
12.3 
Institutional Review Board/Independent Ethics Committee..................................58 
12.4 
Informed Consent...................................................................................................58 
12.5 
Records Management.............................................................................................59 
12.5.1 
Source Documentation ..........................................................................59 
12.5.2 
Study Files and Record Retention .........................................................59 
12.6 
Conflicts of Interest................................................................................................59 
13.0 
DATA MANAGEMENT, AUDITING, AND MONITORING ...................................60 
13.1 
Data Management ..................................................................................................60 
13.2 
Auditing .................................................................................................................60 
13.3 
Monitoring .............................................................................................................60 
14.0 
AMENDMENTS ..............................................................................................................62 


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15.0 
STUDY REPORT AND PUBLICATIONS ...................................................................63 
16.0 
STUDY DISCONTINUATION ......................................................................................64 
17.0 
CONFIDENTIALITY .....................................................................................................65 
18.0 
REFERENCES .................................................................................................................66 
19.0 
APPENDICES ..................................................................................................................67 
19.1 
APPENDIX I – Names of Study Personnel ...........................................................67 
19.2 
APPENDIX II – Adverse Event Intensity Grading ...............................................68 
 


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LIST OF TABLES 
Table 1-1  
Decision Criteria and Treatment Actions ....................................................5 
Table 4-1  
Decision Criteria and Treatment Actions ..................................................28 
Table 4-2 
Schedule of Assessments: On-treatment (ABI-H0731+NrtI) through 
Week 100 ...................................................................................................36 
Table 4-3 
Schedule of Assessments: Long-term Off-treatment Follow-up for 
Subjects Who Discontinue Both ABI-H0731+NrtI ...................................38 
Table 4-4 
Schedule of Assessments: Follow-up for Subjects Who 1) Prematurely 
Discontinue the Study, 2) Stop ABI-H0731 only and Continue NrtI 
alone, or 3) Start SOC NrtI after Discontinuation of both ABI-
H0731+NrtI ................................................................................................39 
Table 8-1 
Clinical Laboratory Tests ...........................................................................48 
LIST OF FIGURES 
Figure 4-1  
ABI-H0731-211 Study Overview ..............................................................27 


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LIST OF ABBREVIATIONS AND TERMS 
AE 
adverse event 
ALT 
alanine aminotransferase 
AST 
aspartate aminotransferase 
cccDNA 
covalently closed circular DNA 
CFR 
Code of Federal Regulations 
CHB 
chronic hepatitis B infection 
CI 
confidence interval 
CpAM 
core protein allosteric modifier 
CRO 
Clinical Research Organization (PRA Health Sciences) 
CSR 
Clinical Study Report 
CYP 
cytochrome P450 
DAIDS 
Division of AIDS  
DNA 
deoxyribonucleic acid 
dsDNA 
double-stranded DNA 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
EDC 
electronic data capture 
EOS 
end of study 
EOT 
end of treatment 
FAS 
Full Analysis Set 
FDA 
US Food and Drug Administration 
GCP 
Good Clinical Practice 
GMP 
Good Manufacturing Practices 
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 
HCC 
hepatocellular carcinoma 
HCV 
hepatitis C virus 
HDV 
hepatitis D virus 
HEV 
hepatitis E virus 
IB 
Investigator’s Brochure 
ICF 
Informed Consent Form 
ICH 
International Council for Harmonisation 
IEC 
Independent Ethics Committee 


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IFN 
interferon 
IgM 
immunoglobulin M 
INR 
International Normalized Ratio 
IRB 
Institutional Review Board 
IUD 
intrauterine device 
LTFU 
Long-term Follow-up 
MedDRA 
Medical Dictionary for Regulatory Activities 
NrtI 
Nucleos(t)ide reverse transcriptase inhibitor 
OLE 
open-label extension 
pgRNA 
pre-genomic RNA 
PK 
pharmacokinetic 
PP 
per-protocol 
RAV 
HBV resistance associated variant 
rcDNA 
relaxed circular DNA 
SAE 
serious adverse event 
SAP 
Statistical Analysis Plan 
SOC 
standard of care 
SVR 
sustained viral response 
ULN 
upper limit of normal 
WHO 
World Health Organization 
 


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2.0 
INTRODUCTION AND RATIONALE 
2.1 
Study Rationale 
Worldwide more than 240 million people are chronically infected with the hepatitis B virus (HBV), 
and chronic hepatitis B infection (CHB) is a major global cause of severe liver morbidity and 
liver-related mortality [WHO 2015]. Moreover, the burden of global mortality attributable to 
chronic viral hepatitis (B and C combined) has increased over the last 2 decades; it was the seventh 
leading cause of death worldwide in 2013, compared with the tenth in 1990 [Stanaway 2016]. 
Current therapies (comprising interferon [IFN] products and nucleos(t)ide reverse transcriptase 
inhibitors [NrtIs] of the HBV polymerase) are highly effective at suppressing serum viremia but 
rarely lead to loss of viral antigenemia – a biomarker of persistent covalently closed circular DNA 
(cccDNA) activity. Additionally, in a surprising number of patients, ongoing low-level viremia 
remains detectable, as does cccDNA and intrahepatic viral intermediates [Boyd 2016; Marcellin 
2014]. As a result of the persistence of active cccDNA, durable antiviral response is rare after 
cessation of treatment [Papatheodoridis 2016]. New therapies are required which can increase 
sustained off-treatment viral response, either alone or in combination with existing standard of 
care (SOC) for CHB. 
ABI-H0731 (also known as vebicorvir) is a novel HBV core protein inhibitor (or “Core inhibitor”) 
discovered by Assembly Biosciences (“the Sponsor”), and it is being developed as a potential 
therapeutic advance for CHB patients. ABI-H0731 inhibits HBV replication by interfering with 
essential functions of the HBV core protein, and it therefore inhibits HBV replication by different 
mechanisms than NrtI analogues or IFN-α. In pre-clinical models, ABI-H0731 binds to the HBV 
core protein and induces altered, nonfunctional core protein assembly. Inhibition of HBV core 
protein functions by ABI-H0731, when used in combination with currently approved HBV 
antivirals, may offer the potential to improve therapy for chronic HBV and provide patients with 
enhanced rates of “sustained viral response” (SVR) – defined as sustained off-treatment loss or 
suppression of viral antigens, and lack of DNA rebound, after a finite treatment period. 
This study will assess the safety of extended treatment with ABI-H0731 (i.e., up to 148 weeks in 
ABI-H0731-211) when administered in combination therapy with a SOC NrtI in subjects 
previously participating in Studies ABI-H0731-201 and ABI-H0731-202. The study will also 
evaluate off-treatment virologic response rates following cessation of treatment in subjects 
meeting prespecified criteria. 
Additionally, the study will assess the effect of the combination regimen on serum biomarkers 
such as HBV deoxyribonucleic acid (DNA), quantitative and qualitative reduction in the viral 
antigens hepatitis B “e” antigen (HBeAg), hepatitis B core-related antigen (HBcrAg) and hepatitis 
B surface antigen (HBsAg), as well as exploratory biomarkers such as reduction in circulating 
HBV pre-genomic RNA (pgRNA). 
2.2 
Background 
2.2.1 
Chronic Hepatitis B Virus 
HBV remains a major public health burden. HBV contributes to as much as 30% of cases of 
cirrhosis and 45% of cases of hepatocellular carcinoma (HCC) [WHO 2015]. The standard 


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serologic markers of 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. Chronic HBV infection is clinically 
defined as the persistence of HBsAg in a subject for 6 to 12 months or more [Terrault 2018]. 
There are 4 major HBV genotypes (A, B, C, and D). Genotype A is regarded as pandemic and is 
predominantly found in North America, Northern/Western Europe, and Central Africa. HBV 
genotype B is most common in Asia including China, Vietnam, Japan, Taiwan, and Indonesia. 
Genotype C is predominant in East Asia and Oceania. Genotype D (also pandemic) is most highly 
prevalent in North America, Asia (including India), the Mediterranean, India, and the Middle East 
[Guettouche and Hnatyszyn 2005]. 
Despite broad implementation of HBV vaccination programs, new cases of HBV infection are still 
common. The World Health Organization (WHO) estimates that there are >4 million acute HBV 
infections worldwide each year [WHO 2015]. The global prevalence of chronic HBV infection 
shows wide geographic variation, with a prevalence of >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 <2% of people in locales of low endemicity 
(eg, North America and Europe) [Schweitzer 2015; WHO 2015]. 
Some HBV carriers will lose detectable serum HBsAg and HBV viremia will drop to 
nondetectable levels. Such a transition to an HBsAg-negative, minimally replicative state (termed 
“HBsAg seroconversion”) is 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. 
Currently there are 2 clinically accepted options for the treatment of CHB: IFNs and oral NrtIs, 
which act as inhibitors of the viral polymerase. Of these, oral NrtIs are much more broadly used, 
and have shown remarkable success in achieving maintained viral suppression in CHB patients, 
with associated decreases in long-term clinical complications [Lampertico and Liaw 2012]. 
Despite suppression of viremia for extended periods of time, however, HBsAg loss and/or 
seroconversion is rarely achieved in a practical timeframe with current therapies. HBsAg loss is 
achieved by <10% of CHB patients within 5 years after a year of treatment with IFN products 
and/or after 5 years of NrtI antivirals, with slightly higher rates of HBsAg loss recently reported 
in combination studies of tenofovir disoproxil fumarate together with pegylated IFN-α for one year 
[Marcellin 2014]. 
There is clearly a need for improved HBV therapies that are of finite duration and can produce a 
substantially higher rate of therapeutic responses that will be sustained post-treatment. Specifically, 
improved rates of 2 types of outcomes are desirable for new HBV therapies: durable viral antigen 
loss/seroconversion (HBeAg in HBeAg-positive patients and HBsAg loss/seroconversion in all 
patients), in addition to sustained off-treatment viral load suppression. Such “SVRs” are predicted 
to afford improved long-term patient outcomes, (ie, reduced HBV-associated morbidity and 
mortality from virus induced inflammation resulting in end-stage liver disease and HCC). 


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2.2.2 
Hepatitis B Virus Biology and Rationale for Hepatitis B Virus Core Inhibitors 
2.2.2.1 
Overview of Hepatitis B Virus Biology 
HBV is a member of the Hepadnaviridae family. The HBV genome consists of a partially 
double-stranded DNA (dsDNA) (~3.2 kb) that is synthesized through reverse transcription of its 
pre-genomic RNA (pgRNA) precursor. The infectious HBV virion, called the Dane particle, 
comprises an enveloped nucleocapsid, which contains a single copy of the HBV genome as 
partially double-stranded, relaxed circular DNA (rcDNA) and viral reverse transcriptase, enclosed 
in a polymeric capsid, assembled from HBV core protein subunits. The life cycle of HBV can be 
conceptualized as occurring in several steps. Circulating HBV must enter cells. Following entry, 
virus must enter the nucleus where rcDNA is converted to a stable chromosome-like moiety (the 
cccDNA). The cccDNA functions as the template for full length pgRNA and the mRNAs for viral 
proteins. These proteins include polymerase/reverse transcriptase, HBV X protein, core protein, 
and HBsAg. RNA produced from the cccDNA is transported from the nucleus into the hepatocyte 
cytoplasm, where it is bound by HBV polymerase and encapsidated by 120 viral core protein 
dimers. Within the capsid, pgRNA is reverse transcribed into viral dsDNA. This dsDNA filled 
particle can then either acquire an S antigen envelope and be secreted as new infectious virus or 
recycle rcDNA back to the nucleus where it can amplify the cccDNA pool. Details of the HBV 
replication cycle have recently been reviewed in detail by Seeger et al [Seeger 2013]. 
2.2.2.2 
Hepatitis B Virus Core (Capsid) Protein and Core Protein Functions 
HBV core protein has several essential roles in the life cycle of HBV infection, including the 
formation of capsids. The appropriate kinetics of HBV core protein assembly is critical in enabling 
functional capsid formation and encapsidation of pgRNA. These steps are essential for the 
formation of new infectious virions. The HBV capsid is also essential for the process of nuclear 
import of the HBV rcDNA through a regulated interaction with nuclear core proteins. In the 
nucleus, the rcDNA is converted to cccDNA. cccDNA is a long-lived circular, episomal DNA 
from which all HBV RNAs are derived. Core protein contributes to replenishing nuclear cccDNA 
pools by mediating nuclear import of genomic DNA from newly formed capsids in the cytoplasm 
of infected cells. Nuclear forms of HBV core protein can also affect the expression of viral and 
host genes and contribute to regulated splicing and nuclear export of HBV RNAs, and HBV core 
protein allosteric modifiers (CpAMs) - or “core inhibitors” - have been reported to be able to 
interfere with cccDNA function [Gruffaz 2013, Belloni 2013]. HBV core protein is therefore a 
critical component of the HBV life cycle. Additionally, some data suggest that HBV core protein 
induces an HBV-specific dysfunction of the innate immune response in HBV-infected hepatocytes 
[Gruffaz 2013], including a suppression of expression of IFN-stimulated genes. 
These findings suggest that allosteric modulation of core protein may allow targeting of multiple 
aspects of the viral life cycle: assembly into virion capsids, trafficking of HBV DNA into cell 
nuclei, cccDNA replenishment, and potentially interference with the innate immune response in 
infected cells. 
2.2.2.3 
Hepatitis B Virus Core Protein Inhibitors and ABI-H0731 
Please refer to the Investigator’s Brochure (IB) for additional information describing: 


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• in vitro activity of ABI-H0731 
• combination therapy 
• study drug resistance 
• nonclinical pharmacokinetics 
• nonclinical pharmacology and toxicology 
• clinical experience 
2.3 
Summary of Additional Clinical Data with ABI-H0731 
2.3.1 
Phase 2a Studies 
Study ABI-H0731-211 is an open-label extension (OLE) of Phase 2a double-blinded, 
placebo-controlled proof-of-concept studies (ABI-H0731-201 and ABI-H0731-202). No new 
on-treatment safety signals have been identified during the course of these studies following 
2 independent pre-scheduled Data Monitoring Committee reviews. Refer to the IB for additional 
details. 
2.3.2 
Recently Completed Clinical Pharmacology Studies 
2.3.2.1 
Drug-Drug Interaction (DDI) Study 
Clinical Study ABI-H0731-103 was conducted with sensitive index substrates of cytochrome P450 
(CYP) 3A4, 2B6, 2C8, 2C9, 2C19, and 2D6 to test the inhibition potential of ABI-H0731 300 mg. 
This study also investigated the effect of ABI-H0731 300 mg on the induction of CYP2B6 and 
CYP3A4. ABI-H0731-103 was conducted in a total of 58 healthy volunteers. Results from this 
clinical study indicate that ABI-H0731, when given along with a cocktail of index substrates, is 
not an inhibitor of CYP2C19 or CYP2D6. In addition, ABI-H0731 is not an inhibitor of CYP2C8, 
CYP3A4, or CYP2B6. ABI-H0731 is a weak inhibitor of CYP2C9, increasing the concentration 
of the index substrate tolbutamide by ~30%. ABI-H0731 300 mg is not an inducer of CYP2B6. 
Midazolam levels were reduced by approximately 30% after 7 days of daily administration and 
remained at the same lower level after 14 days of administration of ABI-H0731 300 mg. The 
CYP3A4 mediated metabolite of midazolam, 1-hydroxymidazolam, was not increased on either 
Day 7 or 15. These results suggest ABI-H0731 is not an inducer of CYP3A4; however, the 
mechanism of midazolam exposure reduction remains unclear. 
2.4 
Overall Risk/Benefit Assessment 
ABI-H0731 is a novel, potent, direct-acting, once daily, HBV core inhibitor that is among the first 
HBV core inhibitors to be investigated in CHB patients for more than 28 days. The combination 
of ABI-H0731 with a SOC NrtI has the potential to be a once-daily regimen for the treatment of 
HBV infection. This extension study will enroll chronically HBV-infected subjects who have 
completed Study ABI-H0731-201 or Study ABI-H0731-202. This study will specifically evaluate 


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whether extending a course of combination therapy (ABI-H0731+ SOC NrtI) for at least 52 weeks 
may provide a lasting therapeutic benefit. 
As compared with monotherapy, the potential benefits of an ABI-H0731 + SOC NrtI combination 
for the treatment of HBV include: 
• A potential novel therapeutic option for those with ongoing low-level viremia on existing 
SOC NrtI 
• Greater on-treatment antiviral efficacy (more rapid and greater extent of suppression of 
HBV replication with resultant reduction of viral replication induced inflammation) 
compared to current SOC alone 
• Greater inhibition of cccDNA establishment - and thus greater loss of cccDNA - as 
compared to current SOC alone 
• Potential for finite therapy as compared to SOC NrtIs which are often lifelong therapies. 
The safety database currently includes approximately 250 healthy subjects and CHB subjects who 
have been administered ABI-H0731. No new clinical safety issues specifically related to 
ABI-H0731 have been identified to date beyond those described in the IB. 
Based on the available data from completed Phase 1 studies and preliminary data from the Phase 
2 studies, ABI-H0731-201 and ABI-H0731-202, ABI-H0731+NrtI combination treatment is 
generally well-tolerated, and there is no expectation of significant overlapping or new, unexpected 
toxicities upon continued administration of ABI-H0731 together with SOC NrtI therapies. 
During the conduct of this OLE study, the Sponsor will perform ongoing safety data reviews of 
the clinical and laboratory assessments at each study visit. To provide consistency for the intensity 
assessments of clinical adverse events (AEs) and lab abnormalities for the interim safety reviews 
and for the eventual study report, any observed AEs and laboratory abnormalities during this study 
will be graded according to the table in APPENDIX II , “Toxicity Grading of Clinical Adverse 
Events and Laboratory Abnormalities,” which has been adapted by the Sponsor from the July 2017 
(Version 2.1) Division of AIDS (DAIDS)/NIAID grading table. Additional specific guidance has 
been provided for evaluation of potential hepatic or dermatologic abnormalities (Section 4.7.1 and 
Section 4.7.3) should they arise. 
In summary, there is no approved all-oral, direct-acting antiviral therapy for HBV-infected patients 
that provides a high rate of off-treatment cure. As compared to monotherapy with a NrtI, it is 
anticipated that addition of ABI-H0731 to SOC NrtI therapy may result in more complete 
suppression of cccDNA metabolism and pleotropic effects on the viral core protein, potentially 
resulting in accelerated loss of cccDNA. It is thus anticipated that over the course of therapy in 
this study, ABI-H0731+NrtI may demonstrate greater clinical antiviral effects than seen with NrtI 
monotherapy alone (eg, serum HBV DNA, HBV pgRNA, HBsAg, and HBeAg reductions). 
However, it is unknown whether the degree of reduction or duration of effect of ABI-H0731+NrtI 
therapy will be sufficient to establish any lasting clinical benefit for any of the subjects enrolled. 


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The predictable benefits of this study are thus limited to the clinical care provided as a part of this 
clinical study, with the potential for additional benefits if ABI-H0731 does increase rates of 
cccDNA loss. If high rates of “SVR” can be obtained with a finite regimen for HBV, then the 
anticipated reduction in burden of disease would offer a favorable risk-benefit determination for 
treatment-experienced individuals with chronic HBV infection, and would potentially support 
further registrational clinical studies for ABI-H0731. 
 
 


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3.0 
STUDY OBJECTIVES AND ENDPOINTS 
3.1 
Objectives 
3.1.1 
Primary Objective 
• To evaluate the potential for combination therapy with ABI-H0731+ NrtI to increase 
SVR rates in subjects who have CHB 
3.1.2 
Secondary Objectives 
• To evaluate the longer-term safety and tolerability of ABI-H0731 added to SOC NrtI 
therapy 
• To evaluate improvement in transaminases in subjects on treatment and post-treatment 
• To evaluate the durability of changes in viral antigen and viral DNA after discontinuation 
of combination therapy 
3.1.3 
Exploratory Objectives 
• To evaluate the kinetics of and absolute changes from Baseline in biomarkers of 
transcriptionally active cccDNA (HBeAg and HBsAg) 
• To assess the relationship between exploratory viral biomarkers, such as changes in viral 
pgRNA and hepatitis B core-related antigen (HBcrAg), and outcome 
• To evaluate potential emergence of HBV resistance associated variants (RAVs), if any, to 
ABI-H0731 in combination with an SOC NrtI 
• To evaluate the durability of virologic response between 24 weeks post-treatment 
discontinuation and 36 months post-treatment discontinuation 
• For subjects who have provided an optional pharmacogenomic sample in parent studies 
(eg, ABI-H0731-201 or ABI-H0731-202), to evaluate the potential contribution of host 
genomics to outcomes 
• To assess steady state plasma levels of ABI-H0731 and SOC NrtI for possible correlation 
with markers of safety and efficacy 
3.2 
Study Endpoints 
3.2.1 
Primary Endpoint 
The primary efficacy endpoint will be: 
• Proportion of subjects with SVR at 24 weeks off treatment. 


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3.2.2 
Secondary Endpoints 
The secondary endpoints include: 
• Incidence of AEs, premature discontinuations due to AEs, abnormal safety laboratory 
results, electrocardiogram, or vital signs 
• Incidence of subjects with abnormal ALT at Baseline who have normal ALT at end of 
treatment (EOT) and end of study (EOS) 
• Incidence of subjects with suppression/loss of viral antigen/DNA on combination treatment 
whose viral antigens rebound off therapy 
3.2.3 
Exploratory Endpoints 
Exploratory endpoints include: 
• Mean change from Baseline in log10 serum HBeAg 
• Mean change from Baseline in log10 serum HBsAg 
• Incidence of subjects with loss or change in log10 HBsAg or log10 HBeAg (<0.5, ≥0.5 to 
1.0, or >1.0 in viral antigens) at EOT and end of follow-up 
• Incidence of subjects with HBsAg seroconversion (loss of HBsAg and appearance of 
HBsAg antibody) or HBeAg seroconversion (loss of HBeAg and appearance of HBeAg 
antibody) 
• Incidence of subjects with “detectable” HBV DNA by polymerase chain reaction at 
Baseline whose HBV DNA becomes “target not detected” 
• Quantitative changes from Baselines in viral RNA on treatment and through end of 
follow-up 
• Quantitative changes in serum HBcrAg levels on treatment and through end of follow-up 
• Incidence of HBsAg or HBeAg seroreversion in subjects up to 3 years off therapy 
• Incidence of subjects requiring retreatment following SVR through 3 years off therapy 
• Incidence of subjects with emergence of HBV RAVs 
• If differences are seen in outcomes/AEs between racial or ethnic groups: 
Pharmacogenomics correlation will be performed with clinical outcomes in subjects who 
have provided an optional informed consent and sample in Study ABI-H0731-201 or 
Study ABI-H0731-202 


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• Quantitative levels of ABI-H0731 and NrtI in plasma 
 
 


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4.0 
STUDY PLAN 
4.1 
Study Design 
This is an open-label, multi-center, long-term extension study evaluating the safety and efficacy 
of ABI-H0731 in combination with a SOC NrtI in CHB subjects who have completed 24 weeks 
of treatment in either of the parent Studies ABI-H0731-201 (Study 201) or ABI-H0731-202 
(Study 202). Figure 4-1 presents an overview of the study design. 
Figure 4-1  
ABI-H0731-211 Study Overview 
To participate in ABI-H0731-211 (Study 211), in addition to completing 24 weeks of treatment in 
ABI-H0731-201 or ABI-H0731-202, subjects must also meet the eligibility criteria described in 
Section 5.2 and Section 5.3. 
In ABI-H0731-211, subjects may receive up to 148 weeks of treatment with ABI-H0731+NrtI. 
The actual duration of treatment received by each individual subject will be based on their HBV 
treatment history (ie, NrtI suppressed or treatment naïve) and HBeAg status (ie, HBeAg positive 
or HBeAg negative) at Baseline in the parent study, and the individual subject’s virologic response 
in ABI-H0731-211. Based on assessment of these factors at specific study visits, each subject will 
be evaluated for virologic response and assigned one of the following three treatment actions: 
1) Discontinue both ABI-H0731+NrtI 
2) Discontinue ABI-H0731 only and continue SOC NrtI alone 
3) Continue both ABI-H0731+NrtI for up to 148 weeks 




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As described in Table 4-1, based on the respective treatment action, additional follow-up visits 
may be undertaken. These visits are briefly summarized below with further details provided in 
Table 4-2, Table 4-3, and Table 4-4. 
4.1.1 
3-Year Off-treatment Follow-up 
All subjects who discontinue both ABI-H0731+NrtI will be followed for up to 3 years from the 
date of treatment discontinuation to assess the durability of virologic response. Subjects will have 
an Unscheduled Visit to notify them of the Treatment Action to be implemented, at which point, 
each individual subject’s visit schedule is then reset after the Unscheduled Visit, and subjects  will 
return to the clinic for follow-up every 4 weeks for visits at 4, 8, 12, 16, 20, and 24 weeks post-
treatment discontinuation, then every 8 weeks for visits at 32, 40 and 48 weeks post-treatment 
discontinuation, and then every 12 weeks until completion of the 3-year follow-up (Table 4-3). 
Additional unscheduled visits may be performed at the Investigator’s discretion. Following 
completion of the visit 3 years after ABI-H0731+NrtI discontinuation, subjects will exit the study 
and be under the routine care of their physician. 
4.1.2 
12-Week Follow-up on NrtI Alone 
All subjects who discontinue ABI-H0731 only and continue SOC NrtI alone will be followed for 
12 weeks from the date of ABI-H0731 discontinuation. Subjects will have an Unscheduled Visit 
to notify them of the Treatment Action to be implemented, at which point, each individual subject’s 
visit schedule is then reset after the Unscheduled Visit, and subjects will return to the clinic for 
follow-up visits at 4, 8, and 12 weeks after discontinuation of ABI-H0731. Additional unscheduled 
visits may be performed at the Investigator’s discretion. Following completion of the follow-up 
visit 12 weeks after discontinuation of ABI H0731, subjects will exit the study and be under the 
routine care of their physician. 
4.1.3 
Continuation of Treatment with ABI-H0731+NrtI 
All subjects who continue ABI-H0731+NrtI beyond Week 52 will return to the clinic for visits 
every 4 weeks until Week 148. Subjects may be notified of their Treatment Action by phone and 
continue on their current study visit schedule. At Week 148, subjects will be evaluated for virologic 
response as described in Table 4-1, and will either discontinue both ABI H0731 and NrtI and be 
followed for up to 3 years (as described in Section 4.1.1) or discontinue ABI-H0731 only and 
continue on SOC NrtI alone and be followed for 12 weeks (as described in Section 4.1.2). 
4.1.4 
Criteria to Restart SOC NrtI Following Discontinuation of Both ABI-H0731 and 
NrtI 
Subjects who discontinue both ABI-H0731+NrtI will be followed to assess the durability of 
virologic response. The Investigator will use clinical judgment as to when restarting SOC NrtI is 
indicated. However, SOC NrtI therapy will be reintroduced if any of the following criteria listed 
below are met. 
• 
Alanine aminotransferase (ALT) >10 × upper limit of normal (ULN) 
• 
Direct bilirubin >2.0 × ULN 


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• 
International Normalized Ratio >1.5 
• 
ALT >3 × ULN and HBV DNA >100,000 IU/mL 
• 
ALT >ULN and HBV DNA >2,000 IU/mL on 3 consecutive visits at least one month 
apart 
• 
Any clinical decompensation, regardless of HBV DNA level 
• 
Physician or subject’s decision 
Should any of these criteria be met, then subjects may have an Unscheduled Visit to notify them 
to restart SOC NrtI. Subjects’ visit schedules are then reset upon restarting SOC NrtI, and subjects 
will return for follow-up visits at 4, 8, and 12 weeks after restarting SOC NrtI and will then 
complete participation in the study (Table 4-4). 
4.2 
Scientific Rationale 
There is a significant unmet medical need for HBV therapies that can provide durable clinical 
responses off therapy. The HBV core protein is a pleotropic molecule involved in multiple parts 
of the HBV life cycle. Non-clinical and clinical work has shown that core inhibitors are potent 
DAAs which can prevent establishment of cccDNA and have the potential to be additive to or 
synergistic with SOC NrtIs in the inhibition of viral replication. This study will explore the 
long-term safety of the ABI-H0731+NrtI combination in subjects completing participation in the 
ABI-H0731-201 and ABI-H0731-202 Phase 2 studies. Additionally, the study will evaluate the 
effect of the combination regimen on serum biomarkers of functional cures, specifically, serum 
HBV DNA, quantitative and qualitative reduction in the viral antigens HBeAg, HBcrAg, HBsAg, 
and reduction in circulating HBV pgRNA. As compared to monotherapy with a NrtI, the 
ABI-H0731+NrtI combination is expected to result in more complete suppression of cccDNA 
metabolism and pleotropic effects on the viral core protein, potentially resulting in accelerated loss 
of cccDNA. ABI-H0731 thus may demonstrate greater clinical antiviral effects not seen with NrtI 
monotherapy (eg, serum HBV DNA, RNA, HBsAg, and HBeAg reductions), and potentially 
higher rates of off-treatment SVRs. 
4.3 
Dose Justification 
The ABI-H0731 dose selected for continued evaluation in this study is 300 mg PO QD. 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 treatment-emergent AEs 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. 
One subject with CHB developed a Grade 3 rash after approximately 10 days of repeated doses of 
400 mg daily, the rash resolved off treatment with no intervention other than dose discontinuation 
required. 
ABI-H0731 monotherapy in CHB subjects resulted in dose-dependent decreases in viral load at 
doses of 100, 200, and 300 mg daily in subjects with CHB. It is anticipated that 300 mg daily will 


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be well-tolerated and provides sufficient ABI-H0731 exposure to produce the desired antiviral 
effect in CHB subjects in this study. 
4.4 
Study Drug Resistance Monitoring 
There are no established methods for the selection of drug resistance against HBV in vitro because 
there are no in vitro cell culture systems that allow multiple cycles of HBV replication. In this 
study, all subjects who enter the study are expected to have a Baseline viral load near or below the 
lower limit of quantification. As such, no sequencing of the Cp region may be possible. As all 
subjects will remain on their SOC NrtI therapy with demonstrated high barriers to resistance 
throughout this OLE study, the potential for emergence of RAVs to combination therapy is 
considered minimal. However, all subjects will have samples collected for viral load monitoring 
throughout the study. 
To assess potential HBV core gene sequences associated with viral resistance or blunted treatment 
response, serum samples from subjects with evidence of nonresponse to treatment, including on-
treatment viral DNA rebound (≥1 log10 HBV DNA rebound from on-treatment nadir) or viral load 
plateauing (≥2 consecutive samples with viral load remaining within 0.5 log10 of nadir) will be 
selected for HBV core gene sequencing, with sequence comparisons to Baseline sequences, as well 
as comparisons to core gene sequences from placebo recipients and HBV database sequences. 
Subjects with persistent viral rebound found to have developed resistance to treatment, or in whom 
no resistance is found and are identified as significantly noncompliant, or who have <0.5 HBV 
DNA log10 reduction from Baseline for ≥3 consecutive visits at least 4 weeks apart will be 
discontinued from ABI-H0731 treatment. 
4.5 
HCC Surveillance 
All subjects entering Study ABI-H0731-211 will undergo regular HCC surveillance per SOC for 
the duration of time they are on study. HCC surveillance will consist of an abdominal ultrasound, 
unless another modality is specifically clinically indicated and discussed with the Sponsor. 
Subjects who enter long-term follow-up (off treatment), will continue to have HCC surveillance 
conducted approximately every 6 months for the duration of study. 
4.6 
End of Study (EOS) Definition 
The study will be completed when the last subject completes the last post-treatment follow-up visit 
(see Section 4.8, Schedule of Assessments) or when the last subject discontinues the study before 
completing the last follow-up visit. 
4.7 
Management of Toxicities 
4.7.1 
General Stopping Rules 
Any individual subject who meets either of the criteria below will be requested to stop treatment 
with study drug, in consultation with the Sponsor: 
• Any serious adverse events (SAE) deemed at least possibly related to the study drug 


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• Any Grade 3 or 4 AE deemed related to the study drug 
4.7.2 
Subjects with Alanine Aminotransferase (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 will 
be closely monitored with regular Unscheduled visits every 1 to 2 weeks at the discretion of the 
Investigator. If analysis of blood samples collected at these visits cannot be performed at the central 
laboratory, then a local laboratory may be used. In which case, local laboratory reports will be de-
identified, collected by the Site Monitor, securely stored by the Sponsor and will not entered in the 
study database. The following guidance is offered for management of study subjects with ALT 
elevations or biochemical evidence of declining hepatic function. 
• ALT Flare: 
o An ALT flare is defined as: 
▪ ALT >2 × Baseline and ≥10 × ULN, or 
▪ ALT >2 × on-treatment nadir and ≥10 × ULN 
o Subjects with an ALT flare should have the ALT findings confirmed within 3 days of 
receipt of the original results. All such subjects should return for an Unscheduled Visit 
and undergo a symptom-directed physical examination, review of concomitant 
medications (including herbal medications or supplements), and the following 
laboratory tests: ALT, aspartate aminotransferase (AST), total bilirubin (if total 
bilirubin is elevated, reflex to direct bilirubin), International Normalized Ratio (INR), 
serum albumin, and creatine kinase. If the ALT flare is confirmed, HBV DNA, 
quantitative HBV serologies (HBeAg [reflex qualitative HBeAg if quantitative HBeAg 
is negative] and HBsAg [reflex qualitative HBsAg if quantitative HBsAg is negative]), 
hepatitis A virus (HAV) immunoglobulin M (IgM), hepatitis C virus (HCV) RNA, 
hepatitis D virus (HDV) RNA, and hepatitis E virus (HEV) IgM should also be drawn. 
▪ If an intercurrent illness is determined to be causal, subjects with an ALT elevation 
without declining hepatic function and without contraindications may continue 
treatment and the intercurrent illness should be treated as deemed medically 
appropriate by the Investigator. 
▪ In the absence of evidence of declining hepatic function, and in the absence of 
contraindications, subjects with an ALT flare may continue on study under close 
observation. 
o 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, subjects will undergo a symptom-directed physical 
examination, review of concomitant medications (including herbal 


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medications or supplements) and the following laboratory tests should be 
performed: ALT, AST, total bilirubin (if total bilirubin is elevated, reflex to 
direct bilirubin), INR, serum albumin, creatine kinase, HBV DNA, 
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 Investigator) until ALT values return to normal or Baseline 
levels. 
▪ In the absence of declining hepatic function or contraindications, extension of the 
monitoring period to 4 weeks is considered clinically appropriate to safely monitor 
subjects during the period of increased ALT. 
• Declining hepatic function during treatment 
o Subjects with confirmed ALT elevation and biochemical evidence of declining hepatic 
function should be discontinued from study treatment, defined as: 
▪ ALT elevation ≥2 × (Baseline or nadir) and >2 × ULN AND 
o Direct bilirubin increase to ≥2 × Baseline and ≥2 × ULN, OR 
o An albumin decline ≥0.5 g/dL or INR >2 × Baseline, OR 
o Symptoms of liver inflammation (fatigue, weakness, lack of appetite, 
nausea, vomiting, jaundice, or discolored feces). 
o Subjects with evidence of declining hepatic function should return for an Unscheduled 
Visit 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 “flare” or ALT elevation with declining hepatic function 
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 declining hepatic function or ALT flare (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 flare has not 
substantially resolved by the last study follow-up visit, subjects should continue to 


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return to clinic as deemed medically appropriate by the Investigator, in consultation 
with the Sponsor, until the ALT flare is documented to be either resolved or 
stabilized/resolving (defined as consistent ALT declines of 10% or more or 
normalization of ALT) on at least 2 successive visits. 
If 2 or more subjects meet these flare management criteria, the US Food and Drug Administration 
(FDA) and other relevant regulatory agencies will be notified, and subsequent steps will be 
determined after consultation with these agencies. 
4.7.3 
Subjects with Rash 
In the event of any rash, subjects should return to clinic for evaluation for an unscheduled visit 
(Day 1 of rash). Digital photographs of the rash should be taken, and blood samples should be 
collected for central laboratory evaluation. At the Investigator’s discretion, a site’s local laboratory 
may be used in addition to the central laboratory, but such laboratory data will not be entered into 
the study database. Laboratory tests should include: erythrocyte sedimentation rate, complete 
blood count (with differential), creatinine, ALT, AST, and total bilirubin. Local laboratory reports 
and digital photographs will be de-identified, collected by the Site Monitor, and securely stored by 
the Sponsor. 
If the rash diagnosis is uncertain, or if a rash is Grade 2, a referral to a dermatologist should be 
made and a skin biopsy should be conducted if recommended by the dermatologist. For a rash that 
is Grade 3 or higher, a referral to a dermatologist should be made and a skin biopsy should be 
requested of the dermatologist. All dermatologist reports and skin biopsy results will be included 
in the source documents. A copy of the dermatologist report will be de-identified and collected by 
the Site Monitor on behalf of the Sponsor. 
If the rash is considered by the Investigator to be likely related to a non-study exposure (drug, food, 
or concomitant illness), then subjects should be treated symptomatically and as deemed 
appropriate by the Investigator (or consulting dermatologist) until the rash has resolved. Additional 
unscheduled visits should be performed during the study at the Investigator’s discretion until 
resolution of the rash. Digital photographs of lesions should be obtained at each visit to document 
any change in condition. If required for patient management, local and central laboratory samples 
should also be drawn at additional unscheduled visits. Any local laboratory test results and digital 
photographs will be de-identified, copied by the Site Monitor, and securely provided to 
PRA Health Sciences (“the Clinical Research Organization [CRO]”) for provision to the Sponsor. 
If rash is considered possibly or probably related to study drug, then: 
• For Grade 1 rashes, subjects can continue to take study drug at the Investigator’s discretion. 
• For Grade 2 rashes, subjects may continue to take study drug in consultation with Sponsor 
and at the Investigator’s discretion. If the rash progresses or worsens, subjects must 
discontinue study drug. Subjects should be advised to contact the study site staff 
immediately if the rash worsens, if systemic signs develop, or if mucosal lesions develop. 


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• For Grade 3 and higher rashes, study drug will be discontinued, and the subjects will 
continue on study as described below. 
Subjects with rashes should continue to be followed on their study visit schedule, with additional 
unscheduled visits as deemed medically appropriate by the Investigator. Subjects who discontinue 
treatment should be followed on the appropriate follow-up schedule after treatment is discontinued. 
If the rash has not substantially resolved by the last study visit, subjects should return for an 
unscheduled visit at least every other week or as deemed medically appropriate by the Investigator. 
Unscheduled visits should continue until the rash has resolved or declined to Grade 1 or less for 
2 successive visits. 
 
 










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Schedule of Assessments Footnotes and Acronyms – Applies to All Tables 
a 
Any subjects with rash or ALT flare (defined in Sections 4.7.1 and 4.7.2) should return to the clinic for an unscheduled visit as soon as possible, ideally within 3 days for assessments described in 
Section 4.7.2. 
Unscheduled visit for rash: Digital photographs of the rash should be taken and blood samples should be taken (for erythrocyte sedimentation rate, complete blood count [with differential], 
creatinine, ALT, AST, and total bilirubin). If the rash diagnosis is uncertain, or if a rash is Grade 2, a referral to a dermatologist should be made and a biopsy should be conducted if 
recommended by the dermatologist. For a rash that is Grade 3 or higher, a referral to a dermatologist should be made and a biopsy should be requested of the dermatologist. All dermatologist 
reports and biopsy results will be included in the source documents. Digital photographs of the rash should be obtained at each visit to document any change in condition. Unscheduled visits 
should continue until the rash has resolved or declined to Grade 1 or less for 2 successive visits. 
b 
OLE Day 1 is the final in-clinic treatment visit of the parent study. 
c 
Timepoints of assessment of SVR. 
d 
Written informed consent must be obtained prior to enrolling in OLE study and receiving open-label study drug. This can be done up to and including OLE Day 1 (the last on-treatment visit of 
the parent study). Subjects who complete the parent study’s treatment period will be eligible to enter the OLE study. 
e 
The criteria for evaluating each subject’s virologic response and the corresponding course of action for each individual subject are listed in Table 4-1. 
f 
Study drug is dispensed only for subjects who continue ABI-H0731+NrtI treatment. If the subject continues taking SOC NrtI, then NrtI should continue to be dispensed as normal. If the subject 
discontinues ABI-H0731+NrtI, then no study drug should be dispensed to the subject. 
g 
The HCC surveillance window is ±4 weeks from the scheduled visit, or approximately every 6 months for the duration of the study. Refer to Section 4.5 for additional details. 
h 
If quantitative HBeAg and/or HBsAg is <LLOQ at any visit, reflex qualitative HBeAg and/or HBsAg testing will be done. If HBeAg and/or HBsAg are <LLOQ at any visit, reflex qualitative 
HBeAb and/or HBsAb testing will be done to assess for seroconversion.  
i 
HBV resistance testing, using exploratory research samples (i.e., viral nucleic acid), will be performed on subjects whose on-treatment HBV DNA viral load increases by ≥1 log10 IU/mL from 
on-treatment nadir. Resistance testing may also be performed on subjects who do not respond to treatment (≥2 consecutive samples with viral load remaining within 0.5 log10 of nadir). 
j 
WOCP: women of child-bearing potential only. 
k 
Subjects with a post-treatment ALT elevation >2x ULN or HBV DNA >2000 IU/mL will be asked to return to clinic every 2 weeks for an unscheduled visit to monitor liver function and viral 
load until subject’s lab values resolve or the subject requires restart of NrtI therapy. Refer to Section 4.1.4 for criteria to restart NrtI after discontinuing ABI-H0731+NrtI. 
l 
Any concomitant medications must be recorded in the designated eCRF from the date informed consent is obtained to 30 days following the last dose of all study drug(s), with the exception of 
concomitant medications used for treatment of HBV in subjects who are restarted on HBV therapy, which should be collected through end of follow-up. 
m 
The Follow-up 1, 2, and 3 Visits will occur 4, 8, and 12 weeks (respectively) after the subject discontinues ABI-H0731 and continues NrtI, or re-starts SOC NrtI, or prematurely terminates from 
the study. Additional Follow-up (Unscheduled) visits may occur as clinically indicated, eg, AE/AESI, ALT flare (see Section 4.7.2). 
n 
A trough PK sample is to be taken prior to ABI-H0731 administration at Week 48 ± 8 weeks. 
Abbreviations: AE=adverse event; AESI=adverse event of special interest; ALT=alanine aminotransferase; AST=aspartate aminotransferase; d=days; ECG=electrocardiogram; eCRF=electronic case 
report form; EOS=end of study; 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; HCC=hepatocellular carcinoma; HCV=hepatitis C virus; HDV=hepatitis D virus; HEV=hepatitis E virus; IgM=immunoglobulin M; 
INR=International Normalized Ratio; LTFU=Long-term Follow-up; N/A=not applicable; NrtI= nucleos(t)ide inhibitors of the HBV polymerase; OLE=open-label extension; PK=pharmacokinetic; 
Q3=every 3 months; Q6=every 6 months; SOC=standard of care; SVR=sustained viral response; Wk=week; WOCP=women of childbearing potential. 


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5.0 
POPULATION 
5.1 
Number of Subjects 
Globally, it is anticipated that less than 100 male or female subjects with CHB, who completed 
24 weeks of treatment in ABI-H0731-201 or ABI-H0731-202 will be enrolled. 
5.2 
Inclusion Criteria 
Subjects must meet the following inclusion criteria in order to be eligible for enrollment: 
1. Willing and able to provide informed consent. 
2. Previously enrolled on a study of ABI-H0731 and completed the treatment period, with 
demonstrated compliance in the opinion of the Investigator. 
3. Female subjects must agree to use an effective birth control method for the duration of the 
study and follow-up, or be surgically sterile for at least 6 months, or at least 2 years 
postmenopausal with serum follicle-stimulating hormone levels consistent with a 
postmenopausal status. Effective birth control methods include male or female condom 
(may not be used together due to increased risk of breakage), vasectomy, intrauterine 
device (IUD), diaphragm, or cervical cap. Female subjects of childbearing potential must 
have a negative pregnancy test. 
4. All heterosexually active male subjects must agree to use an effective birth control method 
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, 
hormone-based contraception (only female partner of a male subject), IUD, diaphragm, or 
cervical cap. 
5. Agreement to adhere to lifestyle considerations including abstaining from alcohol abuse 
(defined as alcohol consumption exceeding 2 standard drinks per day on average 
[1 standard drink = 10 grams of alcohol] and the use of illicit substances, herbal or other 
substances, or unnecessary over-the-counter medications; see Section 5.4) throughout 
study duration. 
6. In good general health except for chronic HBV infection. 
7. Have the ability to take oral medication and be willing to adhere to the ABI-H0731-211 
regimen in the opinion of the Investigator. 
5.3 
Exclusion Criteria 
Subjects who meet the exclusion criteria will not be eligible for enrollment: 
1. Must not have had evidence of RAVs or lack of compliance on a previous study of 
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2. Must not have had a treatment-emergent AE or laboratory abnormalities deemed clinically 
significant and possibly or probably related to drug while on a previous study of 
ABI-H0731, that in the opinion of the Investigator or the Sponsor makes the subject 
unsuitable for this study. 
3. Current clinically significant cardiac or pulmonary disease, chronic or recurrent renal or 
urinary tract disease, liver disease other than HBV, endocrine disorder, autoimmune 
disorder, diabetes mellitus requiring treatment with insulin or hypoglycemic agents, 
neuromuscular, musculoskeletal, or mucocutaneous conditions requiring frequent 
treatment, seizure disorders requiring treatment, 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 the study. 
4. Females who are lactating or pregnant or wish to become pregnant within the duration of 
the ABI-H0731-211 study. 
5.4 
Lifestyle Considerations 
During this study, subjects are asked to: 
• Abstain from abuse of alcohol (defined as alcohol consumption exceeding 2 standard drinks 
per day on average [1 standard drink = 10 grams of alcohol]) and from any use of illicit 
substances for the duration of the study 
• Abstain from the use of herbal or other supplements 
• Abstain from use of over-the-counter concomitant medications unless they are medically 
indicated for the health and well-being of the subject in the opinion of the Investigator 
5.5 
Strategies for Recruitment and Retention 
Subjects will be enrolled globally from ongoing studies of ABI-H0731. 
Subjects will be enrolled by their treating physician while in process of completing a parent study. 
No subjects who are not already participating in a study of ABI-H0731 will be allowed to enroll 
in the study. 
To reduce the risk of potential exposure to COVID-19, study visits may be conducted by home 
health personnel in the home of the subject and study drug may be shipped by courier directly from 
the study site to the subject or provided via other alternative mechanisms of provision. Subjects 
must provide prior consent (verbal or written) for home visits and direct shipment of study drug to 
their home. Telemedicine visits may be allowed if the clinical site or subject is directly affected 
by local COVID restrictions. Blood sampling for telemedicine visits may be drawn by home health 
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6.0 
STUDY DRUG 
6.1 
Description 
ABI-H0731 active pharmaceutical ingredient is a white to off-white crystalline powder 
manufactured under current Good Manufacturing Practices (GMP) via standard synthetic 
chemistry methods. 
6.1.1 
Formulation 
 
 
 
 
 
6.1.2 
Storage 
 
 
6.2 
Packaging and Shipment 
 
 
 
 
6.3 
Dose and Administration 
6.3.1 
Dosing in the Study 
All subjects will take study drug (ABI-H0731) as three 100 mg tablets once daily, after a meal, at 
approximately the same time each day. SOC NrtI should be taken as per package insert. 
Subjects will self-administer study drug during this study. If possible, study personnel will 
document time of study drug and SOC NrtI administration in subject’s medical record. 
Refer to the Site Operations Manual for detailed instructions on managing missed or incorrect 
doses. In general, if a subject remembers within 8 hours of having missed their scheduled dose, 
they should take that day’s dose. Subjects who miss a dose should not “catch up” and take twice 
the dose on the following day. If a subject reports having missed 2 or more consecutive doses, or 
multiple missed single doses, then the Medical Monitor should be contacted before taking any 
further action. These missed doses should be recorded in the source documents. If a subject 
demonstrates continued noncompliance with study drug dosing, despite educational efforts, the 
Investigator should contact the Medical Monitor to discuss discontinuation of the subject from the 
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6.4 
Accountability 
Regulatory requirements stipulate accounting of all investigational drug received by the study site. 
Records of drug disposition must include the date received by the site, date administered, quantity 
administered, and the subject to whom study drug was administered. The Investigator is 
responsible for the accountability of all used and unused study drug containers and unused study 
drug. 
The study site is to use a study drug accountability record to document study drug disposition. All 
items on this form are to be fully completed. The Sponsor or the CRO will confirm if the method 
of recording study drug accountability by the clinical site and the location of study drug records at 
the site is appropriate. 
Each time study personnel dispense study drug for a subject, he or she is to record the date 
dispensed, the number of tablets and bottles of study drug dispensed, and his or her initials. Study 
site personnel are to monitor the inventory of clinical supplies and maintain a count of all used and 
unused tablets and bottles. The Site Monitor will review study drug accountability records during 
monitoring visits. The Site Pharmacist or designated staff member will keep accurate records of 
drug dispensation routinely during the study. Study drug dispensation is planned for Day 1 and 
each scheduled visit thereafter during the treatment period. 
6.5 
Compliance 
To monitor compliance, tablet counts will be conducted on returned bottles. Subjects will also be 
asked to return used bottles and any unused study drug at study visits. Subjects who forget to return 
bottles will be asked to return them at the next study visit. 
At every study visit, the Investigator should reinforce to his/her subject(s) the importance of 
consistently maintaining compliance with the study drug regimen (ABI-H0731+NrtI). Subjects 
should be reminded of the importance of taking both drugs daily as prescribed. The treatment only 
works as a combination and missing one or both of the study drugs is a study deviation that should 
be avoided. 
6.6 
Concomitant Therapy 
ABI-H0731 300 mg is a weak inhibitor of CYP2C9. ABI-H0731 300 mg has been shown to 
decrease the concentration of midazolam by ~30% after daily administration for 7 days. The 
mechanism of midazolam decrease doesn’t appear to be CYP3A4 mediated induction, however, 
the mechanism remains unknown. 
A concomitant medication is defined as any prescription or over-the-counter preparation, including 
vitamins over-the-counter medications, and supplements. Concomitant medications are 
discouraged. Systemic (oral, injectable or implanted) hormonal birth control is not permitted as an 
acceptable means of birth control for female subjects of child-bearing potential. To the extent 
possible, medications with narrow therapeutic indices should be avoided. Since ABI-H0731 is a 
weak inhibitor of CYP2C9, concomitant use with warfarin and other CYP2C9 substrates should 
be avoided. Concomitant prescription medications, over-the-counter medications, and 
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following the last dose of all study drug(s), with the exception of medications used to manage 
HBV in subjects who restarted on HBV therapy. Medications for management of HBV, including 
NrtI therapy, should be captured until the last follow-up visit. 
6.6.1 
Prohibited Concomitant Therapy 
As the potential for DDIs between ABI-H0731 and other compounds has not yet been fully 
evaluated, additional prescription medication use is discouraged, unless required for an emergent 
medical need occurring during the course of the study. To the extent possible, medications with 
narrow therapeutic indices should be avoided. 
6.6.2 
Other Medications and Treatments 
Within the suggested guidelines above, subjects may receive any other medication or treatment 
that is deemed medically necessary by the treating physician. All medication and treatments should 
be recorded in the eCRF. 
 
 


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7.0 
STUDY CONDUCT 
7.1 
Study Procedures by Time Point 
Refer to the Schedule of Assessments in Section 4.8. 
7.1.1 
Premature Discontinuation from Treatment 
If an individual subject is not satisfactorily tolerating study drug treatment in the judgment of the 
Investigator, then, in consultation with the Sponsor, that subject may be discontinued from 
treatment. Subjects may also be discontinued from treatment if they are significantly noncompliant 
with study drug, develop resistance to treatment, or show evidence of virologic nonresponse to the 
treatment (refer to Section 4.4). 
Discontinuation from treatment does not mean discontinuation from the study. Subjects who 
discontinue treatment prematurely, should immediately undergo the assessments listed for the 
Premature Termination Visit (Table 4-4) and then continue with scheduled follow-up assessments 
as per Premature Termination Visits (Visit Numbers F-U 1, F-U 2, and F-U 3) listed in Table 4-4. 
If a clinically significant finding is identified (including, but not limited to changes from Baseline) 
after enrollment, the Investigator or qualified designee will determine if any change in subject 
management is needed. Any new clinically relevant adverse finding will be reported as an AE. 
In this study, subjects will be closely monitored for any evidence of worsening hepatic function or 
evidence of dermatologic AEs. See Section 4.7.1 for specific management of confirmed toxicities 
that may require early discontinuation. Specific guidance on management and the data to be 
collected at the time of study intervention discontinuation are described below. 
7.1.2 
Discontinuation from Study 
Discontinuation from study (withdrawal of consent) means that the subject does not wish to receive 
further protocol-required therapies or undergo protocol-required procedures, and the subject does 
not wish to or is unable to continue further study participation. Subjects who discontinue during 
follow-up should undergo the assessments listed for the Premature Termination Visit unless they 
withdraw consent to do so. 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. The Investigator is to discuss with the subject appropriate procedures for withdrawal from 
the study. 
 
 


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8.0 
DESCRIPTION OF STUDY PROCEDURES 
8.1 
Efficacy Assessments 
To provide an assessment of the rate of SVR and other evidence of the effect of ABI-H0731, this 
study will evaluate treatment-related changes in serum HBsAg, serum HBeAg, and serum ALT 
levels. Additionally, antibodies to HBeAg and HBsAg, HBV DNA, pgRNA, HBcrAg, and the 
genetic assessment of HBV variants may be assessed. 
To assure standardization of the virologic methods in this study, HBV DNA-related and HBV 
antigen-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. 
8.1.1 
Primary Efficacy Assessment 
• The primary endpoint is the proportion of subjects with SVR at 24 weeks off treatment. 
Samples will be collected as outlined in Section 4.8. 
8.1.2 
Secondary and Exploratory Efficacy Assessments 
Blood samples for the assessment of secondary and exploratory efficacy endpoints will be 
collected as described in Section 4.8. Subjects will have the following samples collected: 
• Quantitative/qualitative HBsAg and HBeAg levels (qualitative to be performed if 
quantitative Ag is below the limit of quantification 
• HBsAb and HBeAb 
• HBV DNA 
• HBV pgRNA 
• HBcrAg 
• Samples for exploratory viral research 
• Pharmacokinetic (PK) sample for ABI-H0731 and SOC NrtI 
HBV resistance testing, using exploratory research samples, will be performed on subjects whose 
on-treatment HBV DNA increases by≥1 log10 IU/ml from on-treatment nadir. Resistance testing 
may also be performed on subjects who do not respond to treatment (<0.5 log10 HBV DNA for ≥3 
consecutive study visits at least 4 weeks apart). 
8.2 
Safety Assessments 
For AEs, see Section 9.0. 
For SAEs, see Section10.0. 




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• Concomitant medications, including supplements and over-the-counter medications, will 
be recorded 
8.3 
Protocol Deviations 
Any deviations from the protocol will be identified by the Site Monitor, Medical Monitor, site 
staff, or statistician, based on the protocol and criteria defined in the Medical Monitoring Plan. 
Identified deviations will be confirmed and documented by the Site Monitor. Prior to database 
lock, protocol deviations will be reviewed and a list of important protocol deviations, and subjects 
who will be excluded from the per-protocol (PP) dataset will be determined based on review of 
data. 
 
 


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9.0 
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 Informed Consent Form (ICF) for 
participation is considered an AE. This includes any side effect, injury, toxicity, or sensitivity 
reaction. 
9.1 
Documenting Adverse Events 
AEs/SAEs 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 
recorded on 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. 
With the exception of “liver flares” or toxicity associated with potential viral rebound, AEs will 
be recorded from the time written informed consent is signed until 4 weeks following cessation of 
the last dose of treatment with the study drug (ABI-H0731). Any “flare” or viral rebound related 
toxicity should be recorded as an AE until the end of follow-up. For SAE documentation see 
Section 10.2. 
9.2 
Assessment of Intensity 
The severity of each AE and laboratory abnormality is to be assessed by the Investigator according 
to the DAIDS Toxicity Grading of Laboratory Abnormalities and Clinical Adverse 
Events(APPENDIX II ), which grades the severity of clinical AEs and laboratory abnormalities in 
a four-category system. 
For AEs not included in APPENDIX II , the following guidelines will be used to describe severity: 
• Mild (Grade 1): Mild symptoms causing no or minimal interference with usual social & 
functional activities with intervention not indicated 
• Moderate (Grade 2): Moderate symptoms causing greater than minimal interference with 
usual social & functional activities with intervention indicated 
• Severe (Grade 3): Severe symptoms causing inability to perform usual social & 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 


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Note that an AE or laboratory abnormality that is life-threatening as it exists constitutes an SAE. 
9.3 
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 and eCRF, whether serious or not serious. For the purposes of this 
study each event is to be assessed with regard to the following causality categorizations, in the 
Investigator’s considered judgment: 
• Not related: An AE with sufficient evidence to accept that there was no causal relationship 
to administration of study medication (eg, no temporal relationship because the study 
medication was administered after the onset of the event, an investigation showed that 
study medication was not administered, another cause was proven). 
• Unlikely related: An AE, including a clinical laboratory test abnormality, with a temporal 
relationship to administration of study medication that made a causal relationship 
improbable and in which other drugs, events, or underlying disease provided plausible 
explanations. 
• Possibly related: An AE with a reasonable time sequence to administration of study 
medication but that could also be explained by concurrent disease or other drugs or events. 
Information on drug withdrawal may have been lacking or unclear. 
• Related: An AE occurred in a plausible time relationship to administration of study 
medication and that could not be explained by a concurrent disease or other drugs or events. 
The response to withdrawal of the drug (de-challenge) was clinically reasonable. 
9.4 
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’s Medical Monitors will be responsible for 
determining whether an AE is expected or unexpected. 
9.5 
Adverse Events of Special Interest 
AEs of Special Interest include rash and ALT flare and should be reported using the Adverse 
Events form of the eCRF. There are no expedited reporting requirements for AEs of Special 
Interest (other than those that meet other reporting requirements). 
9.6 
Clinical Laboratory Changes 
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 
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9.7 
Adverse Event Follow-up 
After the initial AE or SAE report, the Investigator will follow-up proactively on each subject and 
provide further information to the CRO on the subject’s condition. During the study, all AEs and 
SAEs should be followed up 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. 
Subjects who have an ongoing AE or SAE at the end of the trial will be followed until resolution 
or stabilization of the AE or SAE. 
9.8 
Pregnancy 
Pregnancy in itself is not regarded as an AE unless there is a suspicion that an investigational 
product may have interfered with the effectiveness of a contraceptive medication. However, the 
outcome of all pregnancies (spontaneous miscarriage, elective termination, normal birth, or 
congenital abnormality) must be followed up and documented even if the subject was discontinued 
from the study. All pregnancies must be reported using the Pregnancy Report Form within 
24 hours of learning of the pregnancy following the same procedures as for reporting SAEs 
(Section 10.2). Female subjects should report any pregnancies that occur during the study 
treatment period and up to 4 weeks after the last dose of study drug. 
All reports of congenital abnormalities/birth defects are SAEs. Spontaneous miscarriages should 
also be reported and handled as SAEs. Elective abortions without complications should not be 
handled as AEs. All outcomes of pregnancy must be reported to the CRO. 
Pregnancies among female partners of male subjects that occur during the study treatment period 
and up to 4 weeks after the last dose of study drug will also be reported and be requested for 
consent to be followed for outcome. 
 
 


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10.0 
SERIOUS ADVERSE EVENT 
10.1 
Definition of Serious Adverse Event 
An SAE is any event that meets any of the following criteria: 
• Death 
• Life-threatening 
• Inpatient hospitalization or prolongation of existing hospitalization 
• Persistent or significant disability/incapacity 
• Congenital anomaly/birth defect in the offspring of a subject who received 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: 
o Intensive treatment in an emergency room or at home for allergic bronchospasm 
o Blood dyscrasias or convulsions that do not result in inpatient hospitalization 
o Development of drug dependency or drug abuse 
Definition of Terms 
Life-threatening: An AE is life-threatening if the subject was at immediate risk of death from the 
event as it occurred, ie, it does not include a reaction that if it had occurred in a more serious form 
might have caused death. For example, drug induced hepatitis that resolved without evidence of 
hepatic failure would not be considered life-threatening even though drug induced hepatitis can be 
fatal. 
Hospitalization: AEs requiring hospitalization should be considered SAEs. Hospitalization for 
elective surgery or routine clinical procedures that are not the result of an AE (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 “nonserious” 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. 




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11.0 
STATISTICS 
11.1 
Statistical Hypotheses 
Efficacy and safety data will be presented descriptively. No formal hypotheses will be tested 
although inferential statistics such as p-values and confidence intervals may be used descriptively 
to assess magnitude of effect. 
11.2 
Sample Size 
It is anticipated that approximately 100 subjects will enroll in this trial and receive study 
medication. The sample size for this study is not based on statistical considerations and will be 
determined by optional enrollment from other ABI-H0731 studies. All subjects who complete a 
prior study of ABI-H0731 and have not discontinued treatment (such as subjects in 
Study ABI-H0731-201, Study ABI-H0731-202) will have the opportunity to enroll in this study. 
All subjects will receive open-label ABI-H0731 and continue their same SOC NrtI that was 
administered in the prior study. 
11.3 
Analysis Populations 
The following populations for analysis will be used in this study: 
• Full Analysis Set (FAS) Population: The FAS population will be defined as all subjects 
who received any amount of study medication and who had at least one post-dose 
assessment for the endpoint of interest. 
• Per-Protocol Population: The PP population will include subjects who are at least 80% 
compliant with scheduled study drug dosing, and who have no major protocol violations. 
• Safety Population: The safety population will include all subjects who received at least one 
dose of study drug. 
• Pharmacokinetic Population 1 (PK1): The PK1 population will include all subjects in the 
safety population who have ABI-H0731 PK data assessments available. 
• Pharmacokinetic Population 2 (PK2): The PK2 population will include all subjects in the 
safety population who have SOC NrtI PK data assessments available. 
Additional populations may be defined in the Statistical Analysis Plan (SAP). 
11.4 
Statistical Methods 
11.4.1 
General Considerations 
Information regarding the safety and efficacy analyses is given below. An SAP containing the 
detailed planned statistical methods will be finalized prior to locking of the study database for the 
analyses, and it will form the basis for the programming of the displays and analyses of the final 
study data. The plan will define populations to be used for each analysis endpoint, outline all data 
handling conventions including missing data methods, and specify statistical methodology to be 
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Subgroup analyses will be conducted to assess virologic efficacy endpoints in subjects infected 
with different HBV genotypes and for subject subgroups with different Baseline characteristics 
which could potentially influence the efficacy or safety observations in this study 
(eg, pre-treatment ALT level, HBsAg level, HBeAg level, ethnicity, gender). These and other 
subgroup analyses will be further defined in the SAP. 
11.4.2 
Efficacy Endpoints 
Unless otherwise is stated, the evaluation of all efficacy endpoints will be based on the FAS 
population. 
11.4.2.1 
Primary Endpoint 
The primary efficacy endpoint is the proportion of subjects who meet the definition of “SVR” at 
24 weeks off treatment. The SVR rate will be computed as the number of subjects who achieved 
SVR divided by the total number of subjects in the FAS eligible to stop treatment. The SVR rate 
and corresponding 95% confidence interval (CI) will be presented. 
11.4.2.2 
Secondary and Exploratory Endpoints 
Secondary and exploratory endpoints will be analyzed descriptively. All efficacy endpoints will 
be summarized (Section 3.2.2 and Section 3.2.3). 
For continuous variables, such as change from Baseline in log10 serum HBeAg and HBsAg values 
at each timepoint, descriptive statistics will be used and will include the number, mean, standard 
deviation, median, minimum, and maximum and, where appropriate, a 95% CI. 
For categorical variables, such as subjects with decline in HBsAg or HBeAg (<0.5 log10, ≥0.5 to 
1.0 log10, or >1.0 log10 decrease in viral antigen), summary statistics will include number and 
percent who meet the endpoint criteria. 
Trough PK levels of ABI-H0731 and trough PK levels of NrtI will be analyzed descriptively. 
11.4.3 
Analysis of Safety 
The safety parameters to be assessed are described in Section 8.2, Section 9.0, and Section 10.0. 
Displays for safety results will utilize descriptive statistics. No formal hypothesis testing of safety 
data is planned. 
AEs summaries will be tabulated by Medical Dictionary for Regulatory Activities (MedDRA) 
body system and preferred term, for each treatment group. Summaries will include all AEs, AEs 
considered possibly or probably related to treatment, Grade ≥3 (or severe) AEs, and SAEs. All 
AEs will be listed by subject. Any AEs leading to premature discontinuation from the study 
intervention and serious treatment-emergent AEs will be presented as a separate table or a listing. 
Clinical laboratory results will be summarized descriptively by treatment group including values, 
changes from Baseline, and incidence of laboratory abnormalities. Laboratory results will be listed 
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Exposure to study treatment will be summarized descriptively and will include data from the 
double-blinded parent studies in order to evaluate the effects of total time on combination therapy 
with efficacy endpoints. Compliance on study treatment from the time of study enrollment in the 
long-term extension study will be evaluated. 
Vital signs data reported at each visit will be displayed by treatment, using descriptive statistics 
for observed and change from Baseline values. 
Exposure to treatment will be summarized descriptively by treatment group. 
Any changes in physical examination findings noted after Day 1 of the OLE study will be 
summarized in tabular form, by treatment group. 
11.5 
Interim Analysis 
Data will be monitored in an ongoing, unblinded fashion in this open-label study. Descriptive 
statistics and graphical displays may be provided at various times during the study to ensure patient 
safety and acceptable risk-benefit. No formal hypothesis testing will be done. As such, no 
type I error rate is specified for this study and no adjustment will be made to any type I error rate 
to account for multiple comparisons, endpoints or subgroups. 
11.6 
Final Study Report 
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.  
 
 


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12.0 
ETHICS AND RESPONSIBILITIES 
12.1 
Good Clinical Practice 
This study will be conducted in compliance with IRB/IEC and current ICH and GCP (E6) 
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 regulations 
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. 
12.2 
Data Monitoring Committee and Ongoing Safety Reviews 
No data monitoring committee is planned. The Sponsor will oversee safety in this open-label study. 
Individual AEs and aggregated safety will be reviewed in ongoing fashion for this open-label study 
to assess safety of the study medications. No formal stopping rules are provided for the trial; 
however, the Sponsor reserves the right to terminate the study at any time if potential safety or 
futility concerns arise during the study. 
12.3 
Institutional Review Board/Independent Ethics Committee 
Before initiating a trial/study, the Investigator/institution must have written and dated 
approval/favorable opinion from the IRB/IEC for the study protocol/amendment(s), written ICF, 
any consent form updates, subject recruitment procedures (eg, advertisements), and any written 
information to be provided to subjects and a statement from the IRB/IEC that they comply with 
GCP requirements. The IRB/IEC approval must identify the protocol version as well as the 
documents reviewed. 
12.4 
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 to the IRB/IEC. 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 consent form 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, 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 physician about their 
participation in the clinical study. 


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12.5 
Records Management 
12.5.1 
Source Documentation 
Source documents contain the results of original observations and activities of a clinical 
investigation. Source documents include, but are not limited to, medical records (progress notes), 
computer printouts, subject logs, and recorded data from automated instruments. 
All source documents from this study will be maintained by the Investigator and made available 
for inspection by authorized persons. The original signed informed consent for each subject shall 
be filed with records kept by the Investigator and a copy shall be given to the subject. 
12.5.2 
Study Files and Record Retention 
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. 
12.6 
Conflicts of Interest 
Any conflict of interest of persons who have a role in the design, conduct, analysis, publication, 
or any aspect of this trial will be disclosed and managed. Furthermore, persons who have a 
perceived conflict of interest will be required to have such conflicts managed in a way that is 
appropriate to their participation in the design and conduct of this trial. 
 
 


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13.0 
DATA MANAGEMENT, AUDITING, AND MONITORING 
13.1 
Data Management 
An eCRF will be used for the current study, and a data management plan will be prepared by the 
CRO. The data will be collected via electronic data capture (EDC) using the eCRFs. The site will 
be responsible for data entry into the EDC system. In the event of discrepant data, the CRO will 
request data clarification from the sites, which the sites will resolve electronically in the EDC 
system. The CRO will be responsible for the data management of this trial, including quality 
checking of the data. 
The data management methodology will be consistent with the CRO’s standard operating 
procedures and applicable regulatory guidelines. The data management plan will specify methods 
to ensure the accuracy and quality of the study data. 
Previous and concomitant medications will be coded using the latest available WHO Drug 
Reference Dictionary. Coexistent diseases and AEs will be coded using MedDRA. 
When the database has been declared to be complete and accurate, the database will be locked. 
Any changes to the database after that time can only be made by written agreement between the 
Sponsor (or designee) and the CRO project team. 
13.2 
Auditing 
The Sponsor or its designee 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 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. 
13.3 
Monitoring 
The Sponsor or their designee will assign site monitors to conduct regular site visits to the 
investigational facilities for the purpose of monitoring various aspects of the study. The 
Investigator must agree to allow personnel authorized by the Sponsor or their designee direct 
access to the clinical (or associated) files and clinical study supplies (dispensing and storage areas) 
for all study subjects considered for study entry for the purpose of verifying entries made in the 
eCRF, and assist with their activities, if requested. Adequate time and space for monitoring visits 
should be made available by the Investigator. 


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The site must complete the eCRFs in a timely manner and on an ongoing basis to allow regular 
review by the Site Monitor. 
Whenever a subject name is revealed on a document that is to be collected for the Sponsor, the 
name must be blacked out permanently by the site personnel, leaving the initials visible (or other 
appropriate de-identifying information), and annotated with the subject number as identification. 
 
 


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14.0 
AMENDMENTS 
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 business 
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, then the currently approved 
written ICF will require similar modification. In such cases, the amended ICF will be required for 
subjects to sign prior to continued participation into the study. 
 
 


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15.0 
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. 
The publication policy of the Sponsor is discussed in the Investigator's Clinical Research 
Agreement. 
 
 


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16.0 
STUDY DISCONTINUATION 
Both the Sponsor and the Investigator reserve the right to terminate the study overall and at any 
Investigator’s site at any time. Should this be necessary, the Sponsor or a specified designee will 
inform the appropriate regulatory authorities of the termination of the study and the reasons for its 
termination, and the Investigator will inform the IRB/IEC of the same. In terminating the study, 
the Sponsor and the Investigator will assure that adequate consideration is given to the protection 
of the subjects’ interests. 
 
 


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17.0 
CONFIDENTIALITY 
All information generated in this study is considered highly confidential and must not be disclosed 
to any person or entity not directly involved with the study unless prior written consent is gained 
from the Sponsor. However, authorized regulatory officials, IRB/IEC personnel, and the Sponsor, 
and the Sponsor’s authorized representatives are allowed full access to the records. 
Identification of subjects and eCRFs shall be by the subject’s enrollment numbers only. If required, 
the subject's full name may be made known to an authorized regulatory agency or other authorized 
official. 
 
 


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18.0 
REFERENCES 
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. 
Boyd, A, Lacombe, K, Lavocat, et al. Decay of ccc-DNA is slow and marks persistence of 
intrahepatic viral DNA synthesis under tenofovir in HIV-HBV co-infected patients. J Hepatol. 
2016;65:683–691. 
Chang ML, Liaw YF. Hepatitis B flares in chronic hepatitis B: Pathogenesis, natural course, and 
management. J Hepatol. 2014;61:1407–1417. 
European Association for the Study of the Liver (EASL) Clinical Practice Guidelines: 
Management of chronic hepatitis B virus infection. J Hepatol. 2012;57:167-185. 
Gruffaz M et al. The nuclear function of hepatitis B capsid (HBc) protein is to inhibit IFN response 
very early after infection of hepatocytes. American Association for the Study of Liver Diseases 
(AASLD), The Liver Meeting 2013, November 01 - 05, 2013; Washington, DC. Abstract #136. 
Guettouche T, Hnatyszyn HJ. Chronic hepatitis B and viral genotype: the clinical significance of 
determining HBV genotypes. Antivir Ther. 2005;10(5):593–604. 
Terrault N, Lok A, McMahon B, et al. Update on Prevention, Diagnosis, and Treatment of Chronic 
Hepatitis B: AASLD 2018 Hepatitis B Guidance. Hepatology. 2018;67(4):1560-1599. 
Lampertico P, Liaw YF. New perspectives in the therapy of chronic hepatitis B. Gut. 2012 May;61 
Suppl 1:i18-24. 
Marcellin, P, Buti, M, et al. Kinetics of hepatitis B surface antigen loss in patients with HBeAg-
positive chronic hepatitis B treated with tenofovir disoproxil fumarate. J Hepatology. 
2014;61(6):1228–1237. 
Papatheodoridis G, Vlachogiannakos I, Cholongitas E, et al. Discontinuation of oral antivirals in 
chronic hepatitis B: a systematic review. Hepatology. 2016;May;63(5):1481-92. 
Perrillo R. Benefits and risks of interferon therapy for hepatitis B. Hepatology. 2009;49:S103-
S111. 
Perrillo, RP. Acute flares in chronic hepatitis B: the natural and unnatural history of an 
immunologically mediated liver disease. Gastroenterology. 2001;120(4):1009–1022. 
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 [Internet]. 2015;386(10003):1546–55. 
Seeger C, Zoulim F, and Mason W. Hepadnaviruses, in Knipe DM and Howley PM eds. Fields 
Virology, 6th edition, Volume 2, chapter 68, 2013, Lippincott Williams & Wilkins, Philadelphia. 
Stanaway JD, Flaxman AD, et al. The global burden of viral hepatitis from 1990 to 2013. Lancet. 
2016;388(10049):1081–1088. 
World Health Organization. Hepatitis B: fact sheet. Updated July 2015. 
http://www.who.int/mediacentre/factsheets/fs204/en/. Accessed 22 March 2018. 
 
 


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Amendment 4, Version 5.0 14 October 2020 
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19.0 
APPENDICES 
19.1 
APPENDIX I – Names of Study Personnel 
 
Sponsor: 
Assembly Biosciences 
331 Oyster Point Blvd., Fourth Floor 
South San Francisco, CA 94080 USA 
Phone: +1-833-509-4583 
Sponsor Medical Monitor: 
 
 
 
Sponsor Clinical Research Lead: 
 
 
 
 
 
 
 
 
 
CRO Medical Monitors: 
 
 
 
 
 
 
 
 
 
 























































SAP_001.pdf: 
ABI-H0731-211 
Statistical Analysis Plan 
Version 1.0 
Assembly Biosciences 
Proprietary and Confidential 
Page 1 of 35 
 
 
 
 
 
STATISTICAL ANALYSIS PLAN 
 
Sponsor 
Assembly Biosciences, Inc  
331 Oyster Point Blvd 
South San Francisco, CA 94030 
 
 
Protocol Number: 
ABI-H0731-211 
 
 
Protocol Title: 
A Multi-center, Open-label, Long-term Extension 
Study of ABI-H0731+Nucleos(t)ide as Finite 
Treatment for Chronic Hepatitis B Patients 
 
 
Product: 
Vebicorvir (VBR; formerly ABI-H0731) 
 
 
Protocol Version (Date): 
Amendment 4 (14 October 2020) 
 
 
Indication: 
Chronic Hepatitis B Virus Infection 
 
 
Analysis Type: 
Final Analysis for Early Termination 
 
 
Analysis Plan Version (Date): 
Version 1.0 (30 June 2021) 
 
 
Analysis Plan Author: 
 
 
 
 
 
 
 
CONFIDENTIALITY STATEMENT  
  
The information contained in this document 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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STATISTICAL ANALYSIS PLAN (SAP) APPROVAL FORM 
Protocol Title: 
A Multi-center, Open-label, Long-term Extension Study of ABI-
H0731+Nucleos(t)ide as Finite Treatment for Chronic Hepatitis 
B Patients 
Protocol Number: 
ABI-H0731-211 
SAP Version (Date): 
Version 1.0 (30 June 2021) 
The SAP was subject to critical review and has been approved by the participating members. 
Name and Title 
Approval Signature/Date 
 
 
 
 
 
See e-signature page 
 
 
 
 
 
 
See e-signature page 
 
 


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TABLE OF CONTENTS 
TABLE OF CONTENTS .............................................................................................................................................. 3 
LIST OF ABBREVIATIONS ........................................................................................................................................ 5 
1. 
INTRODUCTION ................................................................................................................................................ 7 
1.1. 
Study Objectives ...................................................................................................................................... 7 
1.2. 
Study Design ............................................................................................................................................ 8 
1.3. 
Sample Size and Power .......................................................................................................................... 10 
1.4. 
Methods of Assigning Subjects to Treatment ........................................................................................ 11 
1.4.1. 
Randomization ..................................................................................................................... 11 
1.4.2. 
Blinding ................................................................................................................................ 11 
2. 
TYPE OF PLANNED ANALYSES ................................................................................................................... 12 
2.1. 
Interim Analysis ..................................................................................................................................... 12 
2.2. 
Final Analysis ........................................................................................................................................ 12 
3. 
GENERAL CONSIDERATIONS FOR DATA ANALYSES ............................................................................ 13 
3.1. 
Analysis Sets .......................................................................................................................................... 13 
3.1.1. 
All Enrolled Analysis Set ..................................................................................................... 13 
3.1.2. 
Full Analysis Set .................................................................................................................. 13 
3.1.3. 
Per-Protocol Population ....................................................................................................... 13 
3.1.4. 
Safety Population ................................................................................................................. 13 
3.1.5. 
Pharmacokinetic Population 1 .............................................................................................. 13 
3.1.6. 
Pharmacokinetic Population 2 .............................................................................................. 14 
3.2. 
Data Handling Conventions and Transformations ................................................................................. 14 
3.2.1. 
General ................................................................................................................................. 14 
3.2.2. 
Non-PK Data ........................................................................................................................ 14 
3.2.3. 
PK Data ................................................................................................................................ 14 
3.3. 
Missing Data and Outliers ...................................................................................................................... 15 
3.3.1. 
Missing Data ........................................................................................................................ 15 
3.3.2. 
Outliers ................................................................................................................................. 15 
3.4. 
Analysis Phases and Visits ..................................................................................................................... 15 
3.4.1. 
Definition of Phases ............................................................................................................. 15 
3.4.2. 
Definition of Study Day ....................................................................................................... 15 
3.4.3. 
Analysis Visits...................................................................................................................... 16 
3.4.4. 
Analysis by Phase ................................................................................................................. 16 
4. 
SUBJECT DISPOSITION .................................................................................................................................. 17 
4.1. 
Subject Enrollment and Disposition ....................................................................................................... 17 
4.2. 
Extent of Study Drug Exposure ............................................................................................................. 18 
4.2.1. 
Duration of Exposure to Study Drug .................................................................................... 18 
4.3. 
Protocol Deviations ................................................................................................................................ 18 
5. 
BASELINE CHARACTERISTICS .................................................................................................................... 19 
5.1. 
Demographics and Baseline Characteristics .......................................................................................... 19 
5.2. 
Baseline Disease Characteristics ............................................................................................................ 19 
6. 
EFFICACY ANALYSES ................................................................................................................................... 21 
6.1. 
Primary Efficacy Endpoint ..................................................................................................................... 21 
6.1.1. 
Definition of Primary Efficacy Endpoint ............................................................................. 21 
6.1.2. 
Analysis of Primary Efficacy Endpoint ................................................................................ 21 
6.2. 
Secondary Efficacy Endpoints ............................................................................................................... 21 


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6.2.1. 
Definition of Secondary Efficacy Endpoints ........................................................................ 21 
6.2.2. 
Analysis of Secondary Efficacy Endpoints .......................................................................... 21 
6.3. 
Exploratory Efficacy Endpoints ............................................................................................................. 22 
6.3.1. 
Definition of Exploratory Efficacy Endpoints ...................................................................... 22 
6.3.2. 
Analysis of Exploratory Efficacy Endpoints ........................................................................ 22 
6.4. 
Multiple Comparisons ............................................................................................................................ 23 
6.5. 
Changes From Protocol-Specified Efficacy Analyses............................................................................ 23 
7. 
SAFETY ANALYSES ........................................................................................................................................ 24 
7.1. 
Adverse Events and Deaths .................................................................................................................... 24 
7.1.1. 
Adverse Event Dictionary .................................................................................................... 24 
7.1.2. 
Adverse Event Severity ........................................................................................................ 24 
7.1.3. 
Relationship of Adverse Events to Study Drug .................................................................... 24 
7.1.4. 
Serious Adverse Events ........................................................................................................ 24 
7.1.5. 
Treatment-Emergent Adverse Events ................................................................................... 24 
7.1.5.1. 
Definition of Treatment-Emergent Adverse Events ....................................... 24 
7.1.5.2. 
Incomplete Dates ............................................................................................ 24 
7.1.6. 
Summaries of Adverse Events and Deaths ........................................................................... 25 
7.1.7. 
Additional Analysis of Adverse Events ............................................................................... 26 
7.2. 
Laboratory Evaluations .......................................................................................................................... 26 
7.2.1. 
Summaries of Numeric Laboratory Results ......................................................................... 27 
7.2.2. 
Summaries of Categorical Laboratory Results ..................................................................... 27 
7.2.3. 
Graded Laboratory Values ................................................................................................... 27 
7.2.3.1. 
Treatment-Emergent Laboratory Abnormalities ............................................. 27 
7.2.3.2. 
Summaries of Laboratory Abnormalities ........................................................ 27 
7.2.4. 
ALT Flare and Elevation ...................................................................................................... 28 
7.3. 
Body Weight and Vital Signs ................................................................................................................. 29 
7.4. 
Concomitant Medications ...................................................................................................................... 29 
7.5. 
Electrocardiogram Results ..................................................................................................................... 30 
7.6. 
Other Safety Measures ........................................................................................................................... 30 
7.7. 
Changes From Protocol-Specified Safety Analyses ............................................................................... 30 
8. 
PHARMACOKINETIC (PK) ANALYSES ........................................................................................................ 32 
9. 
REFERENCES ................................................................................................................................................... 33 
10. SOFTWARE ....................................................................................................................................................... 34 
11. DOCUMENT HISTORY .................................................................................................................................... 35 
 


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LIST OF ABBREVIATIONS 
AASLD 
american association for the study of liver diseases  
AE 
adverse event 
ALT 
alanine aminotransferase 
AST 
aspartate aminotransferase 
ATC 
anatomical therapeutic chemical 
BLOQ 
below the limit of quantitation 
BMI 
body mass index 
cHBV 
chronic hepatitis B virus infection  
CI 
confidence interval 
CSR 
clinical study report 
DAIDS  
Division of AIDS  
DNA 
deoxyribonucleic acid  
ECG 
electrocardiogram 
eCRF 
case report form 
EDC 
electronic data capture  
ET 
early termination 
ETV 
entecavir 
FAS 
full Analysis Set 
HBcAb 
antibody to the HBV core antigen  
HBcrAg  
hepatitis B core-related antigen 
HBeAb 
HBeAg antibody  
HBeAg  
hepatitis B “e” antigen 
HBsAb 
HBsAg antibody  
HBsAg 
hepatitis B surface antigen  
HBV 
hepatitis B virus  
HLGT 
high-level group term 
HLT 
high-level term 
ID 
identification 
INR 
international normalized ratio  
IPD 
important protocol deviation(s) 
IRT 
interactive response technology 
LLOQ 
lower limit of quantitation  
LLT 
lower-level term 
LOQ 
limit of quantitation 
MedDRA 
medical dictionary for regulatory activities 
MMRM 
mixed model for repeated measures  
NrtI 
Nucleos(t)ide reverse transcriptase inhibitor 
PD 
protocol deviation(s) 
pgRNA  
pregenomic ribonucleic acid  


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PT 
preferred term 
PK 
pharmacokinetics 
Q1, Q3 
first quartile, third quartile 
QD 
once daily  
RAV 
resistance associated variants 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SD 
standard deviation 
SE 
standard error 
SOC 
system organ class 
TEAE 
treatment-emergent adverse event 
TFLs 
tables, figures, and listings 
ULN 
upper limit of normal 
VBR 
vebicorvir 
WHO 
world health organization 
 
 
 


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1. 
INTRODUCTION 
This statistical analysis plan (SAP) describes the statistical analysis methods and data 
presentations to be used in tables, figures, and listings (TFLs) in the clinical study report (CSR) 
for Study ABI-H0731-211. This SAP is based on the Study Protocol Amendment 4 dated 
October 14, 2020 and the electronic case report form (eCRF). On December 8, 2020, Assembly 
made the decision to close the study early since the goals and objectives had been met based 
upon the predetermined study endpoints and available data generated by that date. The decision 
for early termination of the study was not related to any safety concern, but rather because there 
was no meaningful durable off-treatment virologic response despite a demonstrated deeper level 
of on-treatment viral suppression. Therefore, some efficacy analyses specified in the protocol 
will not be performed (Section 6.5). 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 objective of this study is as follows: 
• To evaluate the potential for combination therapy with vebicorvir (VBR; formerly ABI-
H0731)+NrtI to increase sustained viral response (SVR) rates in subjects who have chronic 
hepatitis B virus infection (cHBV) 
The secondary objectives of this study are as follows: 
• To evaluate the longer-term safety and tolerability of VBR added to standard of care 
nucleos(t)ide reverse transcriptase inhibitor (NrtI) therapy 
• To evaluate improvement in transaminases in subjects on treatment and post-treatment 
• To evaluate the durability of changes in viral antigen and viral DNA after discontinuation of 
combination therapy 
The exploratory objectives of this study are as follows: 
• To evaluate the kinetics of and absolute changes from Baseline in biomarkers of 
transcriptionally active covalently closed circular DNA (cccDNA; HBeAg and HBsAg) 
• To assess the relationship between exploratory viral biomarkers, such as changes in viral 
pgRNA and hepatitis B core-related antigen (HBcrAg), and outcome 
• To evaluate potential emergence of HBV resistance associated variants (RAVs), if any, to 
VBR in combination with NrtI 
• To evaluate the durability of virologic response between 24 weeks post-treatment 
discontinuation and 36 months post-treatment discontinuation 
• For subjects who have provided an optional pharmacogenomic sample in parent studies (eg, 
ABI-H0731-201 or ABI-H0731-202), to evaluate the potential contribution of host genomics 
to outcomes 


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• To assess steady state plasma levels of VBR and NrtI for possible correlation with markers of 
safety and efficacy 
1.2. 
Study Design 
This is an open-label, multi-center, long-term extension study evaluating the safety and efficacy 
of VBR in combination with NrtI in subjects with cHBV who have completed 24 weeks of 
treatment in one of two parent studies, ABI-H0731-201 (Study 201) or ABI-H0731-202 (Study 
202) (Figure 1). 
Figure 1.  
ABI-H0731-211 Study Overview 
 
In ABI-H0731-211 (Study 211), subjects may receive up to 148 weeks of treatment with 
VBR+NrtI. The actual duration of treatment received by each individual subject will be based on 
their HBV treatment history (ie, NrtI suppressed or treatment naïve) and HBeAg status (ie, 
HBeAg positive or HBeAg negative) at Baseline in the parent study, and the individual subject’s 
virologic response in Study 211. Based on assessment of these factors at specific study visits, 
each subject will be evaluated for virologic response and assigned to one of the following three 
treatment actions:  
1) Discontinue both VBR+NrtI  
2) Discontinue VBR only and continue NrtI alone 
3) Continue both VBR+NrtI for up to 148 weeks 
 
Table 1 below summarizes, the population subgroups, the study visits at which virologic 
response is assessed, the decision criteria applied, and the subsequent treatment action. 




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the clinic for follow-up every 4 weeks for visits at 4, 8, 12, 16, 20, and 24 weeks post-treatment 
discontinuation, then every 8 weeks for visits at 32, 40, and 48 weeks post-treatment 
discontinuation, and then every 12 weeks until completion of the 3-year follow-up. Additional 
unscheduled visits may be performed at the Investigator’s discretion. Following completion of 
the visit 3 years after VBR+NrtI discontinuation, subjects will exit the study and be under the 
routine care of their physician. 
12-Week Follow-up on NrtI Alone 
All subjects who discontinue VBR only and continue NrtI alone will be followed for 12 weeks 
from the date of VBR discontinuation. Subjects will return to the clinic for follow-up visits at 4, 
8, and 12 weeks after discontinuation of VBR. Additional unscheduled visits may be performed 
at the Investigator’s discretion. Following completion of the visit 12 weeks after discontinuation 
of VBR, subjects will exit the study and be under the routine care of their physician. 
Continuation of Treatment with VBR+NrtI 
All subjects who continue VBR+NrtI beyond Week 52 will return to the clinic for visits every 4 
weeks until Week 148. At Week 148, subjects will be evaluated for virologic response as 
described in the table above and will either discontinue both VBR and NrtI and be followed for 
up to 3 years (as described in the ‘3-Year Off-Treatment Follow-up’) or discontinue VBR only 
and continue on NrtI alone and be followed for 12 weeks (as described in ‘12-Week Follow-up 
on NrtI Alone’). 
Criteria to Restart NrtI Following Discontinuation of Both VBR and NrtI 
Subjects who discontinue VBR+NrtI will be followed to assess the durability of virologic 
response. The Investigator will use clinical judgment as to when restarting NrtI is indicated. 
However, NrtI therapy will be reintroduced if any of the following criteria listed below are met: 
• Alanine aminotransferase (ALT) >10 × upper limit of normal (ULN) 
• Direct bilirubin >2.0 × ULN 
• International Normalized Ratio >1.5 
• ALT >3 × ULN and HBV DNA >100,000 IU/mL 
• ALT >ULN and HBV DNA >2000 IU/mL on 3 consecutive visits at least one month 
apart 
• Any clinical decompensation, regardless of HBV DNA level 
• Physician or subject’s decision 
Subjects who restart NrtI will return for follow-up visits at 4, 8, and 12 weeks after starting NrtI 
and will then complete participation in the study. 
1.3. 
Sample Size and Power 
It is anticipated that approximately 100 subjects will enroll in this trial and receive study 
medication. The sample size for this study is not based on statistical considerations and will be 
determined by optional enrollment from other VBR studies. All subjects who complete a prior 


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study of VBR and have not discontinued treatment in Studies 201 or 202 will have the 
opportunity to enroll in this study.   
1.4. 
Methods of Assigning Subjects to Treatment 
1.4.1. 
Randomization 
This is an open-label, multi-center, long-term extension study with all subjects receiving VBR 
300 mg QD + NrtI QD. There is no randomization performed in this study. 
1.4.2. 
Blinding 
This is an open-label, multi-center, long-term extension study and consequently there is no 
blinding concern.  


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2. 
TYPE OF PLANNED ANALYSES 
2.1. 
Interim Analysis 
Data will be monitored in an ongoing, unblinded fashion in this open-label study. Descriptive 
statistics and graphical displays may be provided at various times during the study to ensure 
patient safety and acceptable risk-benefit. No formal hypothesis testing will be performed. As 
such, no type I error rate is specified for this study and no adjustment will be made to any type I 
error rate to account for multiple comparisons, endpoints, or subgroups. 
2.2. 
Final Analysis 
The study is early terminated. The final analysis will be performed after all subjects have 
discontinued or completed the early termination visits, outstanding data queries have been 
resolved or adjudicated as unresolvable, and the data have been cleaned and finalized.   


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3. 
GENERAL CONSIDERATIONS FOR DATA ANALYSES 
Analysis results will be presented using descriptive statistics. For categorical variables, the 
number and percentage of subjects in each category will be presented; for continuous variables, 
the number of subjects (n), mean, standard deviation (SD), median, first quartile (Q1), third 
quartile (Q3), minimum, and maximum will be presented.  
By-subject listings will be presented for all subjects in the All Enrolled Analysis Set and sorted 
by subject identification (ID) number, visit date, and time (if applicable) in chronological order 
within the subject. The treatment group to which subjects were initially randomized in the parent 
Studies 201 and 202 will be included in the listings. 
3.1. 
Analysis Sets 
Analysis sets define the subjects to be included in an analysis. Analysis sets and their definitions 
are provided in the following sections. The analysis set will be identified and included as a 
subtitle of each table, figure, and listing. For each analysis set, the number and percentage of 
subjects eligible for inclusion will be summarized by treatment group. A by-subject listing of 
reasons for exclusion from analysis sets will be provided. 
3.1.1. 
All Enrolled Analysis Set 
All Enrolled Analysis Set will include all subjects who were enrolled in Study 211. 
3.1.2. 
Full Analysis Set 
The Full Analysis Set (FAS) population will include all subjects who received any amount of 
study drug and who had at least one postdose assessment for the endpoint of interest. 
3.1.3. 
Per-Protocol Population 
The Per-Protocol (PP) Population will include subjects in the FAS subjects who are at least 80% 
compliant with scheduled study drug dosing, and who have no major protocol deviations. Given 
that the study was terminated early, PP analyses will not be performed.  
3.1.4. 
Safety Population 
The Safety Population will include all subjects who received at least 1 dose of study drug. 
3.1.5. 
Pharmacokinetic Population 1 
The Pharmacokinetic population 1 (PK1) will include all subjects in the Safety Population who 
have VBR PK data assessments available. 


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3.1.6. 
Pharmacokinetic Population 2 
The Pharmacokinetic population 2 (PK2) will include all subjects in the Safety Population who 
have NrtI PK data assessments available. 
3.2. 
Data Handling Conventions and Transformations 
3.2.1. 
General 
Subject’s date of birth was collected at the Screening visit in the parent studies. The age is 
derived in the electronic data capture (EDC) based on the year of birth and the informed consent 
date of Study 211. The age will be used for analyses and presented in listings. 
3.2.2. 
Non-PK Data 
In general, laboratory data that are continuous in nature but are less than the lower limit of 
quantitation (LLOQ) or above the upper limit of quantitation (LOQ) will be imputed to the value 
of the lower or upper limit plus or minus 1 significant digit, respectively (eg, if the result of a 
continuous laboratory test is < 20, a value of 19 will be assigned). 
• A value that is 1 unit less than the LLOQ will be used to calculate descriptive statistics if the 
datum is reported in the form of “< x” (where x is considered the LOQ). For example, if the 
values are reported as < 50 and < 5.0, values of 49 and 4.9, respectively, will be used to 
calculate summary statistics. An exception to this rule is any value reported as < 1 or < 0.1, 
etc. For values reported as < 1 or < 0.1, a value of 0.9 or 0.09, respectively, will be used to 
calculate summary statistics. 
• A value that is 1 unit above the upper LOQ will be used to calculate descriptive statistics if 
the datum is reported in the form of “> x” (where x is considered the LOQ). Values with 
decimal points will follow the same logic as above. 
• The LOQ will be used to calculate descriptive statistics if the datum is reported in the form of 
“≤ x” or “≥ x” (where x is considered the LOQ). 
For selected analyses, virology efficacy data will be transformed to the logarithmic (base 10) 
scale (log10 IU/mL).  
Total bilirubin values entered as < 0.2 mg/dL will be analyzed as 0.1 mg/dL; direct bilirubin 
values entered as < 0.1 mg/dL will be analyzed as 0.05 mg/dL (Nehls and Akland, 1973).  
3.2.3. 
PK Data 
Sparse PK concentration values that are below the limit of quantitation (BLOQ) will be 
presented as “BLOQ” in the data listing. 


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3.3. 
Missing Data and Outliers 
3.3.1. 
Missing Data 
In general, missing data will not be imputed unless methods for handling missing data are 
specified.   
For missing last dosing date of study drug, imputation rules are described in Section 4.2.1. The 
handling of missing or incomplete dates for adverse event (AE) onset is described in Section 
7.1.5.2, and for concomitant medications in Section 7.4. 
3.3.2. 
Outliers 
Outliers will be identified during the data management review process. No sensitivity analyses 
will be conducted. All data will be included in the data analysis. 
3.4. 
Analysis Phases and Visits  
3.4.1. 
Definition of Phases 
The analyses will include all the data collected in this study based on three phases defined as 
follows. The duration of each phase will be summarized.  
• On-Treatment Phase: when a subject is undergoing treatment with VBR+NrtI (ie, from 
the first dose of VBR in Study 211 up to the last dose of VBR) 
• Off-Treatment Phase: after a subject has discontinued both VBR+NrtI or discontinued 
VBR alone post treatment action and prior to NrtI restart if applicable (ie, after the last 
dose of VBR through the end of study or before the first dose of NrtI if it was restarted) 
• NrtI-Restart Phase: after a subject has restarted NrtI, following the Off-Treatment Phase 
(ie, from the first dose of NrtI through the end of study) 
3.4.2. 
Definition of Study Day 
The study drug is VBR in Study 211. For On-Treatment Phase, Study Day 1 (or on-treatment 
Baseline) is defined as the first dose date of the study drug in Study 211. The last dose date of 
the study drug will be the end date on study drug administration eCRF. Study day will be 
calculated from Study Day 1 and is derived as follows: 
• For days prior to the first dose: Assessment Date − Study Day 1 
• For postdose study days: Assessment Date − Study Day 1 + 1 
For the Off-Treatment Phase, the Off-Treatment Day 1 (or Off-Treatment Baseline) will be 
defined as the last dose date of VBR. The off-treatment study day will be calculated from the last 
dose date and derived as Assessment Date − Last Dosing Date of VBR. 


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For the NrtI-Restart Phase, the NrtI-Restart Day 1 (or NrtI-Restart Baseline) will be defined as 
the first dose date of NrtI. The NrtI-Restart study day will be calculated from the first dose of 
NrtI and derived as Assessment Date – First Dosing Date of NrtI + 1. 
3.4.3. 
Analysis Visits 
The nominal visit as recorded on the eCRF will be used when data are summarized by visit. Any 
data relating to unscheduled visits will be assigned to a particular visit or time point as follows: 
• An unscheduled visit prior to the first dosing of study drug may be included in the calculation 
of the Baseline value, if applicable. 
• Unscheduled visits after the first dose of study drug will be included in determining the 
maximum postbaseline toxicity grade. 
The follow-up visits after discontinuing VBR will be summarized and labeled as “Off-
Treatment” visits. The follow-up visits after NrtI was restarted will be summarized and labeled 
as “NrtI-Restart” visits. 
3.4.4. 
Analysis by Phase 
For the On-Treatment Phase, the analyses will be summarized by parent study (ie, Studies 201 
and 202), HBV treatment history (ie, virologically suppressed or treatment naïve), HBeAg status 
(ie, HBeAg positive or HBeAg negative), and the randomized treatment group in parent studies 
(ie, VBR+NrtI or Placebo+NrtI). The total number of subjects by study population and parent 
study will be provided and the grand total may be provided where appropriate.  
For the Off-Treatment Phase, the analyses will be summarized by treatment action in addition to 
parent study, HBV treatment history and HBeAg status. The total number of subjects following 
different treatment actions may be provided for safety analyses.  
For the NrtI-Restart Phase, the analyses will be only applicable for subjects who discontinued 
both VBR and NrtI from Study 201. The analyses will be grouped by HBeAg status in parent 
studies.  


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4. 
SUBJECT DISPOSITION 
4.1. 
Subject Enrollment and Disposition 
A summary of subject enrollment will be provided for each country, Investigator within a 
country, and overall. The summary will present the number and percentage of subjects enrolled. 
The denominator for the percentage calculation will be the total number of subjects analyzed for 
each column. A by-subject listing will be provided for the subject enrollment based on All 
Enrolled Analysis Set.  
A summary of subject disposition will be provided. This summary will present the number of 
subjects enrolled, and the number of subjects in each of the categories listed below: 
• Full Analysis Set   
• Safety Population  
• PK1 Population 
• PK2 Population 
The number and percentage of the subjects in the following categories will be summarized using 
the Safety Population: 
• Completed study drug  
• Did not complete study drug with reasons for study drug discontinuation   
• Completed study   
• Did not complete study with reasons for study discontinuation 
For the status of study drug and study completion and reasons for discontinuation, the number 
and percentage of subjects in each category will be provided. The denominator for the 
percentage calculation will be the total number of subjects in the Safety Population 
corresponding to that column.   
The following by-subject listings will be provided by subject ID number in ascending order: 
• Reasons for premature study drug or study discontinuation 
• Dispensed lot number and kit ID for VBR 


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A summary table will be provided with the number and percentage of subjects who completed 52 
weeks of treatment and meet the treatment action criteria based on the virologic response as 
described in Table 1. The corresponding by-subject listing will be provided.  
4.2. 
Extent of Study Drug Exposure  
Extent of exposure to study drug will be examined by assessing the total duration of exposure to 
study drug. 
4.2.1. 
Duration of Exposure to Study Drug 
Total duration of exposure to study drug will be defined as the last dosing date minus the first 
dosing date plus 1, regardless of any temporary interruptions in study drug administration, and 
will be expressed in weeks using up to 1 decimal place (eg, 4.5 weeks). Duration (weeks) = 
Duration (days) /7. If the last study drug dosing date is missing, the latest date among the study 
drug end date, clinical visit date, laboratory sample collection date, and vital signs assessment 
date that occurred during the on-treatment period will be used for subjects included in the final 
analyses. 
The total duration of exposure to study drug will be summarized using descriptive statistics for the 
Safety Population. The distribution of subjects by the total number of weeks on therapy (ie, ≤24 
weeks, >24 -48 weeks, >48 -72 weeks, >72-96 weeks, >96-120 weeks, >120 weeks) will be 
presented. 
4.3. 
Protocol Deviations  
Protocol deviations (PD) occurring after subjects entered the study are documented during 
routine monitoring. The number and percentage of subjects with important protocol deviations 
(IPDs) by deviation reason (eg, non-compliance to study drug, violation of select 
inclusion/exclusion criteria) will be summarized by treatment group for All Enrolled Analysis 
Set. A by-subject listing will be provided for those subjects with IPD.  
A table will be provided to summarize any COVID-19 related PDs with the deviation reason by 
treatment group. A by-subject listing of subjects who had study disruption due to COVID-19 
may be provided with a description.  


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5. 
BASELINE CHARACTERISTICS 
5.1. 
Demographics and Baseline Characteristics 
Subject demographic variables (ie, age, age group [<50/ ≥50 years], sex, race, and ethnicity), 
baseline characteristics (body weight [in kg], height [in m], body mass index [BMI; in kg/m2]) 
will be summarized using descriptive statistics for continuous variables and using number and 
percentage of subjects for categorical variables. The summary will be based on the Safety 
Population. Age, weight, and BMI will be measured at Study 211 Baseline. A by-subject listing 
will be provided by subject ID number in ascending order. 
5.2. 
Baseline Disease Characteristics 
Disease characteristics will be summarized at Stud 211 Baseline. Descriptive statistics will be 
used for continuous variables and the number and percentage of subjects will be used for 
categorical variables. The following factors will be included, but not limited to: 
• Years positive for HBV  
• Baseline NrtI type  
• Years on current NrtI treatment 
• Baseline HBV DNA (log10 IU/mL) (Cobas)  
• Baseline HBV DNA (TD/TND) (Assembly) 
• Baseline HBV pgRNA (log10 U/mL) (Assembly) 
• Baseline Total Nucleic Acid (TNA) (Composite DNA + pgRNA) (Assembly) 
• Baseline HBeAg (log10 IU/mL)   
• Baseline HBeAg Status for subjects with HBeAg <LLOQ 
• Baseline HBcrAg (log10 kU/mL) 
• Baseline HBsAg (log10 IU/mL) 
• HB e antibody (HBeAb) 
• HB s antibody (HBsAb) 
• Baseline ALT (U/L)  
• ALT groups (>ULN [Covance], >ULN [AASLD])  


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A by-subject listing of baseline disease characteristics will be provided by subject ID number in 
ascending order. 


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6. 
EFFICACY ANALYSES 
The efficacy analyses will be based on the FAS, defined in Section 3.1.2. The efficacy analyses 
will be based on all available data. If not specified, no imputation will be used for the missing 
data. No statistical comparison will be made. For continuous variables, descriptive statistics will 
include mean, SD, median, minimum, and maximum. For categorical variables, summary 
statistics will include the number and percentage of subjects who meet the endpoint criteria. A 
95% confidence interval (CI) will be provided, where appropriate. 
6.1. 
Primary Efficacy Endpoint 
6.1.1. 
Definition of Primary Efficacy Endpoint 
The primary efficacy endpoint is the sustained viral response (SVR) rate at 24 weeks off 
treatment. The viral response is defined as HBV DNA <LLOQ where LLOQ is defined as 20 
IU/mL using the COBAS TaqMan Version 2.0 HBV DNA assay.   
6.1.2. 
Analysis of Primary Efficacy Endpoint 
The number and percentage of subjects reaching SVR at off-treatment Week 24 will be presented 
with 95% CI based on Clopper-Pearson method.  
6.2. 
Secondary Efficacy Endpoints 
6.2.1. 
Definition of Secondary Efficacy Endpoints 
The secondary endpoints include the following: 
• Incidence of subjects with abnormal ALT at Baseline who have normal ALT at end of 
treatment (EOT) and end of study (EOS) 
• Incidence of subjects with suppression/loss of viral antigen/DNA on combination treatment 
whose viral antigens rebound off therapy 
6.2.2. 
Analysis of Secondary Efficacy Endpoints 
The ALT normalization at EOT and EOS will be summarized for subjects who have abnormal 
ALT (ie, >ULN based on Covance lab) at Baseline. The number and proportion of subjects with 
normal ALT will also be summarized over time by phase regardless of Baseline status. The 
normal ranges are specified by both central lab and AASLD criteria. In addition, the change from 
Baseline in ALT will be analyzed descriptively over time by phase using the summary statistics 
and a line plot with mean (SE) will be provided by phase. 
The viral antigen rebound off therapy is defined as a ≥1 log10 increase in viral antigen from the 
off-treatment Baseline or a change in viral antigen from <LLOQ on treatment to ≥LLOQ off 
treatment. A table and listing will be provided for subjects who had reached the suppression or 


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loss of a viral antigen and DNA on combination treatment but had a viral antigen rebound while 
off treatment. 
6.3. 
Exploratory Efficacy Endpoints 
6.3.1. 
Definition of Exploratory Efficacy Endpoints 
Exploratory endpoints include the following: 
• Mean change from Baseline in log10 serum HBeAg. 
• Mean change from Baseline in log10 serum HBsAg. 
• Incidence of subjects with loss or change in log10 HBsAg or log10 HBeAg (<0.5, ≥0.5 to 
1.0, or >1.0 in viral antigens) at EOT and end of follow-up. 
• Incidence of subjects with HBsAg seroconversion (loss of HBsAg and appearance of 
HBsAg antibody) or HBeAg seroconversion (loss of HBeAg and appearance of HBeAg 
antibody). 
• Incidence of subjects with “detectable” HBV DNA by polymerase chain reaction at 
Baseline whose HBV DNA becomes “target not detected”. 
• Quantitative changes from Baselines in viral pgRNA on treatment and through end of 
follow-up. 
• Quantitative changes in serum HBcrAg levels on treatment and through end of follow-up. 
• Incidence of HBsAg or HBeAg seroreversion in “Complete Responders” up to 3 years off 
therapy. 
• Incidence of subjects requiring retreatment following SVR through 3 years off therapy. 
• Incidence of subjects with emergence of HBV RAVs.  
The loss of HBsAg is defined as HBsAg ≥LLOQ at Baseline plus HBsAg <LLOQ at a post-
Baseline visit. The loss of HBeAg is defined as HBeAg ≥LLOQ at Baseline plus HBeAg <LLOQ 
and HBeAg status negative at a post-Baseline visit. 
HBsAg seroconversion is defined as loss of HBsAg and appearance of HBsAg antibody. The 
appearance of HBsAg antibody is defined as negative antibody at Baseline plus positive or 
borderline HBsAg antibody at a post-Baseline visit. HBeAg seroconversion is defined as loss of 
HBeAg and appearance of HBeAg antibody. The appearance of HBeAg antibody is defined as 
negative HBeAg antibody at Baseline plus positive or borderline HBeAg antibody at a post-
Baseline visit. 
6.3.2. 
Analysis of Exploratory Efficacy Endpoints 
The change from Baseline in log10 serum HBV DNA (Cobas), pgRNA, HBeAg, HBsAg, and 
HBcrAg will be analyzed descriptively over time and EOT by phase using the summary 
statistics. Mean ± SE of the change from Baseline values will be plotted using a line plot over 
time by phase. The change from Baseline in log10 TNA (Assembly) will be summarized and 
plotted for the On-Treatment Phase. 


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The number and percentage subject with loss or change in log10 HBsAg and log10 HBeAg (<0.5, 
≥0.5 to 1.0, or >1.0) at EOT and EOS will be summarized.  
The number and percentage of subjects with HBsAg seroconversion and HBeAg seroconversion 
will be summarized at EOT and EOS. 
A summary will be provided for subjects with “detectable” HBV DNA (Cobas) at Baseline and 
becomes “target not detected” at any post-Baseline visit during the On-Treatment Phase.  
The proportion of subjects with ≥1 log10 IU/mL increase in on-treatment HBV DNA from on-
treatment nadir will be summarized and their virology data will be listed. The incidence of HBV 
variants with reduced susceptibility to VBR will be assessed in the virology report. 
In addition, the number and percentage of subjects reaching HBV DNA (Cobas) <LLOQ will be 
summarized by visit and phase. The categories of HBV DNA (Cobas) <LLOQ TD and TND will 
also be summarized. For the HBV DNA measured by Assembly lab, the summary of the number 
and percentage of subjects with TD and TND will be provided.  
Subjects who restarted NrtI will be summarized with the associated reasons as described in 
Section 1.2.  
6.4. 
Multiple Comparisons 
Adjustments for multiplicity will not be made, because no formal statistical testing will be 
performed in this study. 
6.5. 
Changes From Protocol-Specified Efficacy Analyses 
Due to study early termination and limited follow up time, the protocol-specified exploratory 
endpoint of incidence of HBsAg or HBeAg seroreversion in “Complete Responders” up to 3 years 
off therapy, will not be analyzed. In addition, the analysis of subjects with emergence of HBV 
RAVs will be provided separately by a virology report. The pharmacogenomic data will not be 
analyzed in this CSR but may be explored in the future. 
In addition, the per-protocol and subgroup analyses will not be performed for the primary 
endpoint since no subjects reached SVR at off-treatment Week 24. 


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7. 
SAFETY ANALYSES 
7.1. 
Adverse Events and Deaths 
7.1.1. 
Adverse Event Dictionary 
Clinical and laboratory adverse events (AEs) will be coded using the Medical Dictionary for 
Regulatory Activities (MedDRA) Version (v) 21.0. System organ class (SOC), high-level group 
term (HLGT), high-level term (HLT), preferred term (PT), and lower-level term (LLT) will be 
provided in the AE dataset. 
 
7.1.2. 
Adverse Event Severity 
Adverse events are graded by the Investigator as Grade 1, 2, 3, or 4 according to the toxicity 
criteria specified in the protocol. The severity grade of events for which the Investigator did not 
record severity will be categorized as “missing” for tabular summaries and data listings. The 
missing category will be listed last in summary presentation. 
7.1.3. 
Relationship of Adverse Events to Study Drug 
Related AEs are those for which the Investigator selected “Related” on the AE eCRF to the 
question of “Relationship to Study Treatment” based on the his/her clinical assessment. Events 
for which the Investigator misses to record a relationship to study drug will be considered related 
to study drug for summary purposes. However, by-subject data listings will show the relationship 
as missing. 
7.1.4. 
Serious Adverse Events 
Serious adverse events (SAEs) will be identified and captured as SAEs if the AEs met protocol-
specified definitions of a SAE. 
7.1.5. 
Treatment-Emergent Adverse Events  
7.1.5.1. 
Definition of Treatment-Emergent Adverse Events 
Treatment-emergent adverse events (TEAEs) are defined as any AEs with an onset date on or 
after the study drug start date and no later than 28 days after permanent discontinuation of study 
drug. 
7.1.5.2. 
Incomplete Dates 
If the onset date of the AE is incomplete and the AE stop date is not prior to the first dosing date 
of study drug, then the month and year (or year alone if month is not recorded) of onset 
determine whether an AE is treatment emergent. The event is considered treatment emergent if 
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• The AE onset is in the same month or after the month and year (or year) of the first dosing 
date of study drug, and 
• The AE onset date is in the same month or before the month and year (or year) of the date 
corresponding to 28 days after the date of the last dose of study drug  
An AE with completely missing onset and stop dates, or with the onset date missing and a stop 
date later than the first dosing date of study drug, will be considered as treatment emergent. In 
addition, an AE with the onset date missing and incomplete stop date with the same or later 
month and year (or year alone if month is not recorded) as the first dosing date of study drug will 
be considered treatment emergent. 
7.1.6. 
Summaries of Adverse Events and Deaths 
TEAEs will be summarized based on the Safety Population for the On-Treatment Phase.  
A brief, high-level summary of the number and percentage of subjects who experienced at least 1 
TEAE in the categories described below will be provided by treatment group. All deaths 
observed in the study will also be included in this summary. In addition, the number and 
percentage of subjects will be provided by SOC, PT, and treatment group for each AE category 
as well as by PT only in descending order of total frequency: 
• TEAEs  
• TEAEs by severity grade 
• Treatment-related TEAEs 
• TE SAEs 
• Treatment-related TE SAEs  
• TEAEs leading to study drug discontinuation  
• TEAEs leading to study discontinuation 
• TEAEs leading to death (outcome of death) 
• COVID-19 specific TEAEs 
• COVID-19 specific TE SAEs 
Multiple events will be counted only once per subject in each summary. Adverse events will be 
summarized and listed first in alphabetical order by SOC, and then by PT in descending order of 
total frequency within each SOC. For summary by severity grade, the most severe grade will be 
used for those AEs that occurred more than once in an individual subject during the study.  


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A summary table by PT will also be provided for the above relevant AE categories that occurred 
during the Off-Treatment and NrtI-Restart phases. For the Off-Treatment Phase, the AEs are 
counted from the 29 days after the last dose of VBR and before the first dose of NrtI if it was 
restarted. For the NrtI-Restart Phase, the AEs are counted from the first dose of NrtI though the 
end of study. 
Data listings will be provided for the following: 
• All AEs 
• All treatment-related AEs 
• All SAEs 
• All treatment-related SAEs 
• All AEs with severity of Grade 3 or higher 
• All AEs leading to discontinuation of study drug  
• All AEs leading to discontinuation of study   
• All deaths 
7.1.7. 
Additional Analysis of Adverse Events 
Additional analysis will be performed for the rash AEs during each phase. A summary will be 
provided for the number and percentage of subjects with PTs of rash, rash erythematous, rash 
macular, rash papular, ad rash pruritic. A data listing will be provided for subjects with any rash 
AEs.  
7.2. 
Laboratory Evaluations 
Laboratory data collected during the study will be analyzed and summarized using both 
quantitative and qualitative methods based on the Safety Population. The laboratory values that 
are below LLOQ or above the upper LOQ will be listed as such, and the closest imputed value 
will be used for the purpose of calculating summary statistics as specified in Section 3.4.  
A by-subject listing for laboratory test results will be provided by subject ID number and visit in 
chronological order for hematology, serum chemistry, coagulation, and urinalysis separately. 
Values falling outside of the relevant reference range and/or having a United States National 
Institutes of Health Division of AIDS (DAIDS) severity grade of 1 or higher will be flagged in 
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7.2.1. 
Summaries of Numeric Laboratory Results 
Descriptive statistics will be provided by treatment group for each laboratory test specified in the 
study protocol as follows: 
• Baseline values  
• Values at each postbaseline visit 
• Change and percentage change from baseline at each postbaseline visit 
A Baseline laboratory value will be defined as the last measurement obtained on or prior to the 
date/time of first dose of study drug. Change from Baseline to a postbaseline visit will be 
calculated for any postbaseline visit for the On-Treatment Phase. 
7.2.2. 
Summaries of Categorical Laboratory Results 
For categorical urinalysis parameters, the number and percentage of subjects in each category 
will be presented by treatment group at each visit in the On-Treatment Phase. 
7.2.3. 
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 2 of the 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. For laboratory tests with criteria for both increased and decreased levels, analyses 
for each direction (ie, increased, decreased) will be presented separately. 
7.2.3.1. 
Treatment-Emergent Laboratory Abnormalities 
Treatment-emergent laboratory abnormalities are defined as values that increase at least 
1 toxicity grade from Baseline at any postbaseline time point, up to and including the date of last 
dose of study drug plus 28 days for the On-Treatment Phase. If the relevant baseline laboratory 
value is missing, any abnormality of at least Grade 1 observed within the time frame specified 
above will be considered treatment emergent. 
7.2.3.2. 
Summaries of Laboratory Abnormalities 
The summaries (number and percentage of subjects) for treatment-emergent laboratory 
abnormalities will be provided by laboratory test and treatment group; subjects will be 
categorized according to the most severe postbaseline abnormality grade for a given laboratory 
test. For all summaries of laboratory abnormalities, the denominator is the number of subjects 
with nonmissing postbaseline values up to 28 days after last dosing date. 


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The maximum postbaseline grade observed up to 28 days after last dosing date will be tabulated 
for each laboratory test, and percentages will be based on the number of subjects with a 
postbaseline evaluation of the specific laboratory test.  
All the graded lab abnormalities will be summarized for the Off-Treatment and NrtI-Restart 
phases. For the Off-Treatment Phase, the lab abnormalities are included from the 29 days after 
the last dose of VBR and before the first dose of NrtI if it was restarted. For the NrtI-Restart 
Phase, the lab abnormalities are included from the first dose of NrtI though the end of study. 
A by-subject listing of treatment-emergent laboratory abnormalities will be provided by subject 
ID number and visit in chronological order. This listing will include all test results that were 
collected throughout the study for the laboratory test of interest, with all applicable severity 
grades displayed. 
7.2.4. 
ALT Flare and Elevation 
An ALT flare is defined as: 
• ALT >2 × Baseline and ≥10 × ULN, or  
• ALT >2 × on-treatment nadir and ≥10 × ULN  
ALT elevation with declining hepatic function is defined as:  
• ALT ≥2 × (Baseline or nadir) and >2 × ULN AND  
• Direct bilirubin increase to ≥2 × Baseline and ≥2 × ULN, OR  
• An albumin decline ≥0.5 g/dL or international normalized ratio (INR) >2 × Baseline,  
OR  
• Symptoms of liver inflammation (fatigue, weakness, lack of appetite, nausea, 
vomiting, jaundice, or discolored feces).   
The number and subjects meeting the above criteria will be summarized by phase. Clinical signs 
or symptoms of liver inflammation will not be included in the summary. For individual 
laboratory tests, subjects will be counted once based on the most severe postbaseline values. For 
the composite criteria, subjects will be counted once when the criteria are met at the same visit. 
The denominator is the number of subjects in the Safety Population who have nonmissing 
postbaseline values. A listing of subjects who met at least 1 of the above criteria will be 
provided. 


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7.3. 
Body Weight and Vital Signs 
Descriptive statistics will be provided by treatment group during the On-Treatment Phase for 
body weight, BMI, and vital signs (systolic and diastolic blood pressure [mmHg], pulse 
[beats/min], respiration rate [breaths/min], and body temperature [oC]) as follows: 
• Baseline value 
• Values at each postbaseline visit 
• Change from Baseline at each postbaseline visit 
A Baseline value will be defined as the last available value collected on or prior to the date/time 
of first dose of study drug. Change from Baseline to a postbaseline visit will be defined as the 
postbaseline value minus the Baseline value. 
A by-subject listing of vital signs will be provided by subject ID number and visit in 
chronological order. In the same manner, a by-subject listing of body weight, height, and BMI 
will be provided separately. 
7.4. 
Concomitant Medications 
Medications collected during the study will be coded using the World Health Organization 
(WHO) Drug dictionary (WHODrug Global Sep2018). 
Concomitant medications are defined as medications taken while a subject took study drug. Use 
of concomitant medications will be summarized by Anatomical Therapeutic Chemical (ATC) 
drug class Level 2 and preferred name using the number and percentage of subjects for each 
treatment group. A subject reporting the same medication more than once within each ATC drug 
class will be counted only once when calculating the number and percentage of subjects who 
received that medication. Medications may appear under multiple ATC drug classes. The 
summary will be ordered alphabetically by ATC medical class and then by PT in descending 
overall frequency within each ATC medical class. For drugs with the same frequency, sorting 
will be done alphabetically. 
A medication will be considered as a concomitant medication if it meets any one of the following 
criteria: 
• A medication with a start date prior to or on the first dosing date of study drug, and  
continued to be taken after the first dosing date.  
• 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 


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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. 
A medication with a stop date prior to the date of first dosing date of study drug or a start date 
after the last dosing date of study drug will be excluded from the summary.  
Summaries of concomitant medications will be provided based on the Safety Population.  
All the concomitant medications will be provided in a by-subject listing sorted by subject ID 
number and administration date in chronological order. 
7.5. 
Electrocardiogram Results 
A shift table of the Investigators’ assessment of electrocardiogram (ECG) results at each visit 
during the On-Treatment Phase compared with Baseline values will be presented by treatment 
group using the following categories:  
• normal 
• abnormal (not clinically significant)  
• abnormal (clinically significant)  
• missing/not done 
The number and percentage of subjects in each cross-classification group of the shift table will 
be presented. Subjects with a missing value at Baseline or postbaseline will not be included in 
the denominator for percentage calculation.  
A by-subject listing for ECG assessment results will be provided by subject ID number and visit 
in chronological order. 
7.6. 
Other Safety Measures 
No additional safety measures are specified in the protocol. 
7.7. 
Changes From Protocol-Specified Safety Analyses 
In the protocol, the rash and ALT flare were defined as AESIs. However, further review has 
determined these events are appropriately described as TEAEs. These events were monitored 
closely and discussed in detail in this report but are not defined as AESIs. Rash events are 


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recorded in the AE listings and will be summarized in a table. Events of ALT elevation (ALT≥ 
10xULN is one of the requirements of ALT flare) will be provided in a table. 
 
In addition, COVID-19 related safety analyses are added per regulatory guidance.  


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8. 
PHARMACOKINETIC (PK) ANALYSES 
For VBR-treated subjects with a PK assessment (ie, subjects in PK Set 1), summary statistics 
will be presented for trough PK plasma concentrations at Week 48 when predose (trough) 
concentration is available. For all subjects receiving NrtI with a PK assessment (ie, subjects in 
PK Set 2), a similar analysis as described above will be provided for each NrtI.  
Individual subject concentration data for VBR and NrtI will be listed and summarized using 
descriptive statistics. The sample size will be based on the number of subjects with nonmissing 
concentration data at that time point. The number of subjects with concentration BLQ will be 
presented for each time point. For summary statistics, BLQ values will be treated as 0 at predose. 
Summary statistics (n, mean, SD, coefficient of variation [%CV], median, min, max, Q1, and 
Q3) will be presented.  
The listings will be provided for PK sampling details and PK concentrations by subject.  
The correlation between the plasma levels of VBR and NrtI with markers of safety and efficacy 
may be explored in a future population PK-Pharmacodynamic model.  


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9. 
REFERENCES 
Nehls G, Akland G. Procedures for Handling Aerometric Data. Journal of the Air Pollution 
Control Association 1973;23 (3):180-4.  


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


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11. 
DOCUMENT HISTORY 
Version 
Date 
(DD MMM YYYY) 
Summary of Changes