Clinical trial NCT03576066
Conditions: Chronic Hepatitis B
Keywords: Chronic hepatitis B HBV HBeAg-positive hepatitis B HBeAg-negative vebicorvir VBR
Sponsor: Assembly Biosciences
Start date: 2018-06-11; Completion date: 2019-07-05
Enrollment: 73 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study is to determine if ABI-H0731 given in combination with a standard of care (SOC) hepatitis B virus (HBV) nucleos(t)ide reverse transcriptase inhibitor (NUC) medication is safe and effective in participants with chronic hepatitis B virus infection (cHBV).

Detailed description:
This is a Phase 2a, Multi-center, Double-blind, Placebo-controlled Study Evaluating ABI-H0731 as Adjunctive Therapy in Virally-suppressed Participants with cHBV.

Arms: arm 1: Virologically suppressed participants will receive ABI-H0731 along with SOC NUC (ETV, TDF or TAF) tablets orally for 24 weeks. Eligible participants may enter a separate extension study after Week 24 to continue open-label ABI-H0731 for up to an additional year if necessary. arm 2: Virologically suppressed participants will receive matching placebo tablets and continue their SOC NUC (ETV, TDF or TAF) for 24 weeks. Eligible participants may enter a separate extension study after Week 24 to start treatment on open-label ABI-H0731 for up to a year if necessary.
Interventions: intervention 1: ABI-H0731 intervention 2: SOC NUC intervention 3: Placebo Oral Tablet
Intervention descriptions: intervention 1: Participants will receive ABI-H0731 300 mg tablets orally once daily (QD). intervention 2: Participants will continue on their SOC NUC (ETV, TDF or TAF) tablet orally as per approved package insert. intervention 3: Participants will receive placebo matching ABI-0731 tablets orally QD.

Protocol documents:
Prot_000.pdf: 
 
Title:  A Phase 2a, Multi-center, Double-blind, Placebo-
controlled Study Evaluating ABI-H0731 as Adjunctive Therapy 
in Virally-suppressed Patients with Chronic Hepatitis B  
  
NCT number:  NCT03576066 
 
Date:  09 Nov 2018 


Protocol ABI-H0731-201 
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CLINICAL RESEARCH PROTOCOL 
PROTOCOL TITLE: 
A Phase 2a, Multi-center, Double-blind, 
Placebo-controlled Study Evaluating ABI-H0731 
as Adjunctive Therapy in Virally-suppressed 
Patients with Chronic Hepatitis B 
 
 
STUDY NUMBER: 
ABI-H0731-201 
 
 
DRUG: 
ABI-H0731 
 
 
REFERENCE NUMBERS: 
 
US IND 136780 
 
 
 
SPONSOR: 
Assembly Biosciences 
 
PROTOCOL: 
Amendment 3, V4.0, 09 November 2018 
 
 
Amendment 2, V3.0, 09 September 2018 
Amendment 1, V2.0, 18 June 2018 
 
 
Original, V1.0, 10 May 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. 


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CLINICAL PROTOCOL APPROVAL FORM 
 
Protocol Title: A Phase 2a, Multi-center, Double-blind, Placebo-controlled Study Evaluating ABI-H0731 
as Adjunctive Therapy in Virally-Suppressed Patients with Chronic Hepatitis B 
 
Study No: ABI-H0731-201 
Protocol Date: 09 November 2018 
This study protocol was subject to critical review and has been approved by the appropriate 
protocol review personnel of the Sponsor. The information contained in this protocol is consistent 
with: 
• The current risk-benefit evaluation of the investigational product. 
• The ethical and scientific standards governing clinical research that are set out in the current 
International Council for Harmonisation (ICH) guideline (E6) on Good Clinical Practice 
(GCP), US Title 21 of the Code of Federal Regulations (CFR) parts 50, 54, 56, and 312, 
and other applicable local requirements. 
The Investigator will be supplied with details of any significant or new findings, including adverse 
events, relating to treatment with the investigational product. 
 
 
 


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Summary of Changes Included in the Full Protocol Amendment of: 
ABI-H0731-201  
A Phase 2a, Multi-center, Double-blind, Placebo-controlled Study Evaluating ABI-H0731 as 
Adjunctive Therapy in Virally-suppressed Patients with Chronic Hepatitis B 
The amended Protocol is identified as: 
Amendment 3, Dated 09 November 2018 
 
The primary purposes of this full version amendment are to: 
1. Include change to Inclusion Criterion #7 which was implemented in a  Clarification Letter 
#1, dated 14 September 2018. 
2. Revise Inclusion Criterion #10 for HBeAg-positive subjects to allow for a lower HBsAg 
value of 400 IU/mL. 
3. Modify the re-screening language in Section 5.5 (Screen Failures) 
4. Clarify in Section 4.1 (Study Design) that safety data intervals are outlined in DMC charter. 
5. Clarify a daily multivitamin is allowed in Section 5.4 (Lifestyle Considerations) 
6. Administrative changes to protocol headers, Table 2 (Schedule of Assessments), Appendix 
II (Adverse Event Intensity Grading), and Appendix III (Cytochrome P450 2B6, 2C8, 2C9, 
and 2D6 Substrates) that have no effect on the way the study is to be conducted. 
 
Additions to protocol text are indicated in bold; deletions are indicated by strikethrough. Unless 
otherwise stated, headers, section and page numbers reflect the current version of the protocol. 
 
1. AMENDED INCLUSION CRITERION #7 AS PER CLARIFICATION LETTER #1 
• Added clarification to Inclusion Criterion #7 
7. 
Virologically suppressed (defined as HBV DNA ≤LOQ) for at least 6 months 
before screening on SOC NUC therapy  
a. Subjects with a low but quantifiable viral load (for example <60 IU/mL) 
within 6 months prior to screening which was shown to be an exception in 
a subject who has previously been well suppressed, may be eligible for 
study if the subject is virologically suppressed at screening 
 
2. MODIFIED INCLUSION CRITERION # 10 
• The allowable HBsAg value for HBeAg-positive subjects has been lowered from 1000 
IU/mL to 400 IU/mL. Clinically, there is no difference in risk factors or worse disease 
between subjects with HBsAg levels of 400 to 1000 IU/mL than subjects with HBsAg 
values greater than 1000 IU/mL. Additionally, the power to detect clinically 
meaningful declines of 0.5 log or more is retained. HBeAg-positive subjects who 
screen failed previously will be permitted to rescreen due to this criterion’s revision. 
10. Hepatitis B surface antigen (HBsAg) levels: 
• HBeAg positive subjects must have >1000 400 IU/mL HBsAg at screening;  
• HBeAg negative subjects must have >100 IU/mL HBsAg at screening  


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3. MODIFIED THE RESCREEN CRITERIA IN SECTION 5.5 (SCREEN FAILURES)  
• 
Revised to allow for medical monitor input 
 
Screen failures are defined as subjects who consent to participate in the clinical trial, 
but are not subsequently randomly assigned to the study intervention or entered in the 
study. Individuals who do not meet the criteria for participation in this trial (screen 
failure) because of an abnormal screening laboratory value may be rescreened one 
time. It will be at the discretion of the medical monitor on a case-by-case basis 
whether rescreening will be permitted under other circumstances.  Rescreened 
subjects should be assigned the same subject number the initial screening.  
 
4. CLARIFIED IN SECTION 4.1 (STUDY DESIGN) THAT SAFETY DATA REVIEW 
INTERVALS ARE SPECIFIED IN DMC CHARTER 
• 
Updated DMC text in section 4.1 Study Design to be consistent with Section 12.2 Data 
Monitoring Committee 
Safety will be monitored by a Data Monitoring Committee (DMC), including a 
safety analysis after all subjects have completed Week 12 (or discontinued study 
without completing Week 12) laboratory data and adverse events, at intervals 
outlined in the DMC charter.  
5. CLARIFIED A DAILY MULTIVITAMIN IS ALLOWED IN SECTION 5.4 
(LIFESTYLE CONSIDERTIONS)  
• Abstain from the use of herbal or other supplements (a multivitamin is permitted) 
6. ADMINISTRATIVE CHANGES TO HEADERS, TABLE 2 SCHEDULE OF 
ASSESSMENTS, APPENDIX II ADVERSE EVENT INTENSITY GRADING, AND 
APPENDIX III CYTOCHROME P450 2B6, 2C8, 2C9 AND 2D6 SUBSTRATES 
• 
Modified protocol document headers to reflect Amendment 3 version date 
• 
Table 2 Schedule of Assessments: Updated Week 24 physical exam from symptom-
directed to full physical exam. 
• 
Appendix II Adverse Event Intensity Grading: Corrected typos to Grade 4 high 
calcium and Grade 4 low sodium  
• 
Appendix III Cytochrome P450 2B6, 2C8, 2C9, and 2D6 Substrates: Updated for 
clarification 
 


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ABI-H0731-201 
A Phase 2a, Multi-center, Double-blind, Placebo-controlled Study Evaluating 
ABI-H0731 as Adjunctive Therapy in Virally-suppressed Patients with 
Chronic Hepatitis B 
 
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 SYNOPSIS 
Protocol 
Number: 
ABI-H0731-201 
Title:  
A Phase 2a, Multi-center, Double-blind, Placebo-controlled Study Evaluating 
ABI-H0731 as Adjunctive Therapy in Virally-suppressed Patients with 
Chronic Hepatitis B 
Phase: 
2a 
Number of 
Subjects: 
Approximately 70 
Study 
Duration: 
Approximately 2-3 months enrollment, 6 months treatment, and 3 months 
safety follow-up only for subjects who do not opt for the separate open-label, 
extension study 
Rationale:  
Chronic hepatitis B infection (CHB) is a major global cause of severe liver 
morbidity and liver-related mortality. ABI-H0731 is a direct-acting antiviral 
targeting the hepatitis B virus (HBV) core protein. It is anticipated that 
addition of ABI-H0731 to a standard of care (SOC) nucleos(t)ide analogue 
(NUC) therapy will be safe and potentially increase the functional cure rate 
for CHB patients. This study will explore the safety of this combination 
therapy and its efficacy on serum biomarkers of functional cure: quantitative 
and qualitative reduction in the viral antigens hepatitis B “e” antigen (HBeAg, 
in HBeAg positive subjects), hepatitis B surface antigen (HBsAg), and 
reduction in circulating HBV RNA. 
Target 
Population: 
Male or female subjects with CHB, age 18 to 70 years, with no evidence of 
cirrhosis or end-stage liver disease, on stable SOC NUC therapy whose viral 
load has been below the limit of quantitation (LOQ) for at least 6 months. 
Test 
Product: 
Active-treatment subjects will receive 300mg of ABI-H0731, administered 
orally, once daily, as three 100mg tablets in addition to their SOC NUC 
therapy (which must be either entecavir [ETV], tenofovir alafenamide 
fumarate [TAF], or tenofovir disoproxil fumarate [TDF]). 
Reference 
Product: 
Placebo subjects will receive placebo (matching placebo to ABI-H0731 
100mg tablets), administered orally, once daily, as three tablets in addition to 
their SOC NUC therapy. 
Study 
Design: 
This is a Phase 2a, multi-center, randomized, double-blind, placebo-controlled 
study evaluating the safety, efficacy, pharmacokinetics (PK), and 
pharmacodynamics of ABI-H0731 in combination with a SOC NUC in 
subjects with CHB virus infection who are virally-suppressed on SOC NUC 
therapy. Subjects will be randomized in a ratio of 3:2 (HBeAg Positive 
subjects: 27 subjects will receive ABI-H0731 + NUC: 18 subjects will receive 
matching placebo + NUC; HBeAg Negative subjects: 15 subjects will receive 
ABI-H0731 + NUC: 10 subjects will receive matching placebo + NUC) to 
receive investigational agent as add-on therapy to their current SOC NUC for 
up to 6 months. Efficacy, safety, and PK will be assessed during the 6-month 


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treatment period. At the end of the 6-month treatment period, subjects can opt 
to roll over to an optional, open-label, extension study of ABI-H0731 + SOC 
NUC (protocol ABI-H0731-211) or continue receiving their SOC NUC 
therapy and stop treatment with ABI-H0731/placebo. Subjects who opt not to 
roll over to the extension study must complete a 3-month, safety follow-up 
period after the 6-month treatment period. 
Study 
Objectives:  
Primary: 
• To evaluate the potential for ABI-H0731 to increase clinical cure rates in 
CHB subjects whose viral replication is stably suppressed on a SOC NUC 
therapy, as measured by changes from Baseline in serum biomarkers (ie, 
HBsAg or HBeAg) of transcriptionally active covalently closed circular 
DNA (cccDNA) 
Secondary: 
• To evaluate the safety and tolerability of ABI-H0731 when added to SOC 
NUC therapy in subjects already virally suppressed on SOC therapy 
• To confirm a lack of drug-drug interactions between SOC NUC and 
ABI-H0731 
Exploratory: 
• To evaluate the kinetics of and absolute changes from Baseline in 
biomarkers of transcriptionally active cccDNA (HBeAg and HBsAg) 
• To evaluate the kinetics of and absolute changes from Baseline in 
circulating HBV RNA 
• To assess the relationship between changes in exploratory viral biomarkers 
such as changes in viral RNA and hepatitis B core-related antigen 
(HBCrAg) with clinical outcomes 
• To monitor for emergence of resistance, if any, for ABI-H0731 in 
combination with SOC NUC 
• To explore the PK of ABI-H0731 
• For subjects who provide an optional pharmacogenomic sample, to 
evaluate the potential contribution of host genomics to outcomes 
Primary 
Endpoint:  
The primary efficacy endpoint will be: 
• Change in mean log10 serum viral antigen (HBsAg or HBeAg) from 
Baseline (Day 1) to Week 24 on ABI-H0731 + NUC as compared to 
placebo + NUC 
Secondary 
Endpoints: 
The secondary endpoints will be: 
• Number of subjects with adverse events, premature discontinuations, 
abnormal safety laboratory results, electrocardiogram (ECG), or vital signs 
• Subjects with abnormal alanine aminotransferase (ALT) at Baseline who 
have normal ALT at Week 24 on ABI-H0731 + NUC therapy as compared 
with placebo + NUC therapy 
• Drug concentrations: 


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o Trough levels and (in subjects where optional samples are available) 
trough to peak ratios of ABI-H0731 on ABI-H0731 + NUC therapy 
o Trough levels and (in subjects where optional samples are available) 
trough to peak ratios of NUC on ABI-H0731 + NUC therapy as 
compared with placebo + NUC therapy 
Exploratory 
Endpoints: 
Exploratory endpoints include: 
• Quantitative changes in serum HBV RNA and HBCrAg levels on ABI-
H0731 + NUC as compared with placebo + NUC, at each time point 
• Subjects with loss (defined as below LOQ) or decline in HBsAg or HBeAg 
(<0.5 log10, ≥0.5 to 1.0 log10, or >1.0 log10 decrease in viral antigen) on 
ABI-H0731 + NUC as compared with placebo + NUC at end of treatment 
and end of follow-up 
• Subjects with HBsAg seroconversion (loss of HBsAg and appearance of 
HBs antibody) or HBeAg seroconversion (loss of HBeAg and appearance 
of HBe antibody) on ABI-H0731 + NUC as compared with placebo + 
NUC 
• Subjects with HBV DNA “detectable” at Baseline whose HBV DNA 
becomes “non-detectable” on ABI-H0731 + NUC as compared with 
placebo + NUC 
• Emergence of resistant HBV variants, if any 
• For subjects who do NOT rollover onto the optional extension study, ABI-
H0731-211: 
o Subjects with suppression of detectable serum HBV RNA on treatment 
whose HBV RNA rebounds after discontinuing treatment with ABI-
H0731 + SOC NUC as compared with placebo + SOC NUC 
o Subjects with changes from baseline in HBsAg or HBeAg whose viral 
antigen rebounds after discontinuing treatment with ABI-H0731 + 
SOC NUC as compared with placebo + SOC NUC 
• Subjects with HBsAg or HBeAg loss at Week 24 that is maintained 
through end of follow-up (Week 36) after discontinuing treatment with 
ABI-H0731 + SOC NUC as compared with placebo + SOC NUC 
• If differences are seen in outcomes/adverse events between racial or ethnic 
groups: Pharmacogenomics correlation with clinical outcomes subjects 
who provide optional informed consent 
Statistical 
Methods: 
As a proof-of-concept trial, statistical hypotheses to compare the treatment 
effects in this study will be explored descriptively, graphically and 
inferentially. Unless stated otherwise, the statistical null hypothesis for all 
assessments is that the effects of ABI-H0731 + SOC NUC and placebo + SOC 
NUC are not different. The alternative hypothesis is that effects of the two 
treatments are different. 


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A two-sample test of difference with a two-sided 0.05 significance level will 
be used to assess differences between the treatment groups in change in mean 
log10 serum antigen (HBsAg or HBeAg) from Baseline to Week 24. 
Secondary and exploratory endpoints will be analyzed descriptively. All 
secondary and exploratory efficacy endpoints will be summarized. 
For continuous variables, such as observed and change from Baseline HBsAg 
values at each timepoint, descriptive statistics will be used and will include the 
number, mean, standard deviation, median, minimum, maximum, and 
interquartile range and, where appropriate, a 95% confidence interval. 
For categorical variables, such as subjects with a 1 log10 drop in serum antigen 
(HBsAg or HBeAg) titers from Baseline and subjects with HBeAg (and 
HBsAg) loss and seroconversion, descriptive statistics will include number 
and percent who meet the endpoint criteria. 
Kaplan-Meier methods will be used to evaluate time to event variables (eg, 
time to HBsAg levels less than LOQ), and the treatment groups will be 
compared using log-rank tests. 
Cox proportional hazards regression models will be used to identify baseline 
factors associated with HBsAg loss rates, as defined in the statistical analysis 
plan. 
Key 
Eligibility: 
Inclusion Criteria 
Subjects must meet inclusion criteria in order to be eligible for enrollment. 
1. Male or female between ages 18 and 70 years (inclusive) 
2. Female subjects must agree to use dual effective birth control methods for 
the duration of the study and follow-up or be surgically sterile for at least 
6 months or at least 2 years post-menopausal, with serum follicle-
stimulating hormone (FSH) levels consistent with a post-menopausal 
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) – inclusive of IUDs with hormonal components), 
diaphragm, or cervical cap. Systemic (oral/injectable) hormonal birth 
control are prohibited. Female subjects must have a negative serum 
pregnancy test at screening 
3. All heterosexually active male subjects must agree to use dual effective 
birth control methods for the duration of the study and follow-up. Effective 
birth control methods include male or female condom (may not be used 
together due to increased risk of breakage), vasectomy, hormone-based 
contraception, IUD, diaphragm, or cervical cap 
4. Body mass index (BMI) 18 to 36 kg/m2 and a minimum body weight of 45 
kg (inclusive) 
5. Agreement to adhere to Lifestyle Considerations (including abstaining 
from alcohol abuse [defined as alcohol consumption exceeding 2 standard 


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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 Protocol Section 5.4) throughout study 
duration 
6. In good general health except for chronic HBV infection (defined as HBV 
infection for at least 6 months documented by – for example – history of 
two repeated HBsAg positivity and/or detectable viral load documented at 
least two times ≥6 months apart – inclusive of screening) 
7. Virologically suppressed (defined as HBV DNA ≤LOQ) for at least 6 
months before screening on SOC NUC therapy  
a. Subjects with a low but quantifiable viral load (for example <60 
IU/mL)within 6 months prior to screening which was shown to be an 
exception in a subject who has previously been well suppressed, may 
be eligible for study if the subject is virologically suppressed at 
screening 
8. Subjects will be stratified 9:5 HBeAg positive to HBeAg negative.  
Subjects in the HBeAg-positive cohort must be HBeAg positive at 
screening 
9. HBsAg: HBeAg positive subjects must have >400 IU/mL HBsAg at 
screening; HBeAg negative subjects must have >100 IU/mL HBsAg at 
screening 
10. Liver biopsy results of 
o Metavir F0-F2 (absence of bridging fibrosis or cirrhosis) within 1 year 
of screening 
OR 
o Fasting FibroScan ≤8 kPa within 3 months of screening (including 
screening visit) or other Sponsor-approved hepatic imaging study 
(hepatic magnetic resonance imaging [MRI], or hepatic ultrasound by 
a ultrasonographer with expertise in evaluation of liver fibrosis) within 
6 months of screening indicating lack of cirrhosis or advanced liver 
disease (F0-F2 or equivalent).  
 
Subjects with an ambiguous non-invasive result, eg, a fasting 
FibroScan >8 kPa and ≤10 kPa are excluded unless a biopsy within 
the 12 months before first visit confirms the absence of bridging 
fibrosis and cirrhosis. Subjects with a FibroScan >10 kPa are excluded 
11. Have the ability to take oral medication and be willing to adhere to the 
ABI-H0731-201 regimen in the opinion of the Investigator 
12. Willing and able to provide informed consent 
 
 


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Exclusion Criteria 
 
Subjects who meet the exclusion criteria will not be eligible for enrollment. 
1. Co-infection with human immunodeficiency virus (HIV), hepatitis C virus 
(HCV), hepatitis E virus (HEV), or hepatitis D virus (HDV) 
2. History or evidence of hepatic decompensation (including gastrointestinal 
bleeding or esophageal varices) at any time prior to or at time of screening 
3. Subject is febrile (temperature >37.5°C) at screening 
4. 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 
5. Previous treatment with an investigational agent for HBV other than ABI-
H0731 in the last 6 months before screening 
6. Previous treatment with an HBV capsid targeting agent other than ABI-
H0731 at any time 
7. Participation in another clinical trial of a drug or device whereby the last 
investigational drug/device administration is within 60 days or five half-
lives prior to the first study drug administration, whichever is longer 
8. History of persistent ethanol abuse (alcohol consumption exceeding 2 
standard drinks per day on average [1 standard drink = 10 grams of 
alcohol]) or illicit drug abuse within 3 years before screening 
9. Females who are lactating or pregnant or wish to become pregnant are 
excluded from the study 
10. History of hepatocellular carcinoma (HCC) 
11. A history of malignancy other than HCC unless the subject’s malignancy 
has been in complete remission off chemotherapy and without additional 
medical or surgical interventions during the 3 years before screening 
12. Exclusionary laboratory results 
a. Platelet count <100,000/mm3 
b. Albumin <lower limit of normal (LLN) 
c. Total bilirubin >1.2×upper limit of normal (ULN) unless known Gilbert 
syndrome; subjects with Gilbert syndrome are eligible if direct bilirubin 
is within normal limits 
d. Direct bilirubin >1.2×ULN 


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e. ALT >5×ULN at screening 
f. Serum alpha fetoprotein (AFP) ≥100 ng/mL. If AFP at Screening is 
>ULN but <100 ng/mL, subject is eligible if a hepatic imaging study 
prior to the initiation of study drug reveals no lesions suspicious of 
possible HCC 
g. Prothrombin time: International Normalized Ratio (INR) >1.5×ULN 
h. Glomerular filtration rate (GFR) <60 mL/min/1.73 m2 by Chronic 
Kidney Disease Epidemiology Collaboration (CKD-EPI) equation 
(Levey 2009) 
i. Serum hemoglobin A1c (HbA1c) >8% 
j. Any other laboratory abnormality deemed clinically significant by the 
Sponsor or the Investigator 


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TABLE OF CONTENTS 
1 
SYNOPSIS ...............................................................................................................................6 
2 
INTRODUCTION AND RATIONALE .............................................................................20 
2.1 
Study Rationale ................................................................................................................20 
2.2 
Background ......................................................................................................................20 
2.2.1 
Chronic Hepatitis B Virus .........................................................................................20 
2.2.2 
Hepatitis B Virus Biology and Rationale for Hepatitis B Virus Core Protein 
Allosteric Modifiers (CpAMs) ..................................................................................22 
2.2.3 
Summary of Nonclinical Pharmacology and Toxicology .......................................24 
2.2.4 
Summary of Clinical Studies with ABI-H0731 .......................................................24 
2.3 
Risk/Benefit Assessment ..................................................................................................26 
2.3.1 
Known and Potential Risks .......................................................................................26 
2.3.2 
Known and Potential Benefits...................................................................................26 
2.3.3 
Assessment of Potential Risks and Benefits .............................................................27 
3 
STUDY OBJECTIVES AND ENDPOINTS ......................................................................29 
3.1 
Objectives..........................................................................................................................29 
3.1.1 
Primary Objective ......................................................................................................29 
3.1.2 
Secondary Objectives.................................................................................................29 
3.1.3 
Exploratory Objectives ..............................................................................................29 
3.2 
Study Endpoints ...............................................................................................................29 
3.2.1 
Primary Endpoint ......................................................................................................29 
3.2.2 
Secondary Endpoints .................................................................................................30 
3.2.3 
Exploratory Endpoint ................................................................................................30 
4 
STUDY PLAN .......................................................................................................................32 
4.1 
Study Design .....................................................................................................................32 
4.2 
Scientific Rationale ..........................................................................................................33 
4.3 
Dose Justification .............................................................................................................33 
4.4 
Study Drug Resistance Monitoring ................................................................................33 
4.5 
End of Study Definition ...................................................................................................33 
4.6 
Management of Toxicities ...............................................................................................34 
4.6.1 
Subjects with Alanine Aminotransferase Elevations ..............................................34 
4.6.2 
Subjects with Rash .....................................................................................................36 
4.7 
Study Schematic ...............................................................................................................37 
4.8 
Schedule of Assessments ..................................................................................................37 
5 
POPULATION ......................................................................................................................41 
5.1 
Number of Subjects..........................................................................................................41 
5.2 
Inclusion Criteria .............................................................................................................41 
5.3 
Exclusion Criteria ............................................................................................................42 
5.4 
Lifestyle Considerations ..................................................................................................44 
5.5 
Screen Failures .................................................................................................................44 
5.6 
Strategies for Recruitment and Retention .....................................................................44 
6 
STUDY DRUG ......................................................................................................................45 
6.1 
Description ........................................................................................................................45 


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6.2 
Formulation ......................................................................................................................45 
6.3 
Storage ..............................................................................................................................45 
6.4 
Packaging and Shipment .................................................................................................46 
6.5 
Dose and Administration .................................................................................................46 
6.5.1 
Dosing in the Study ....................................................................................................46 
6.5.2 
Preparation .................................................................................................................46 
6.5.3 
Blinding .......................................................................................................................46 
6.6 
Accountability ..................................................................................................................46 
6.7 
Compliance .......................................................................................................................47 
6.8 
Concomitant Therapy ......................................................................................................47 
6.8.1 
Prohibited Concomitant Therapy ............................................................................47 
6.8.2 
Other Medications and Treatments .........................................................................47 
7 
STUDY CONDUCT ..............................................................................................................48 
7.1 
Study Procedures by Time Point ....................................................................................48 
7.2 
Discontinuation ................................................................................................................48 
7.2.1 
Discontinuation from Treatment ..............................................................................48 
7.2.2 
Discontinuation from Study ......................................................................................48 
8 
DESCRIPTION OF STUDY PROCEDURES ...................................................................49 
8.1 
Efficacy Assessments .......................................................................................................49 
8.1.1 
Primary Efficacy Assessment ....................................................................................49 
8.1.2 
Secondary and Exploratory Efficacy Assessments .................................................49 
8.1.3 
Additional Efficacy Assessments and Pharmacogenomic Assessments ................49 
8.2 
Safety Assessments ...........................................................................................................50 
8.2.1 
Clinical Laboratory Tests..........................................................................................50 
8.2.2 
Other Safety Assessments..........................................................................................51 
8.3 
Pharmacokinetic Assessments ........................................................................................51 
8.4 
Other Assessments ...........................................................................................................51 
8.5 
Protocol Deviations ..........................................................................................................52 
9 
ADVERSE EVENTS ............................................................................................................52 
9.1 
Documenting Adverse Events .........................................................................................52 
9.2 
Assessment of Intensity....................................................................................................53 
9.3 
Assessment of Causality ..................................................................................................53 
9.4 
Expectedness .....................................................................................................................54 
9.5 
Adverse Events of Special Interest .................................................................................54 
9.6 
Clinical Laboratory Changes ..........................................................................................54 
9.7 
Adverse Event Follow-up ................................................................................................54 
9.8 
Pregnancy .........................................................................................................................54 
10 SERIOUS ADVERSE EVENT ............................................................................................56 
10.1 
Definition of Serious Adverse Event ..............................................................................56 
10.2 
Reporting Serious Adverse Events .................................................................................57 
10.3 
Overdose ...........................................................................................................................57 
11 STATISTICS .........................................................................................................................58 
11.1 
Statistical Hypotheses ......................................................................................................58 
11.2 
Sample Size .......................................................................................................................58 
11.3 
Analysis Populations ........................................................................................................59 


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11.4 
Statistical Methods ...........................................................................................................60 
11.4.1 
General Considerations .............................................................................................60 
11.4.2 
Primary Endpoint(s) ..................................................................................................60 
11.4.3 
Secondary and Exploratory Endpoint(s) .................................................................60 
11.4.4 
Pharmacokinetic Endpoints and Analyses ..............................................................61 
11.4.5 
Analysis of Safety .......................................................................................................61 
11.4.6 
Demographic and Baseline Characteristics .............................................................62 
11.5 
Interim Analysis ...............................................................................................................62 
11.6 
Exploratory Analyses.......................................................................................................62 
12 ETHICS AND RESPONSIBILITIES .................................................................................63 
12.1 
Good Clinical Practice .....................................................................................................63 
12.2 
Data Monitoring Committee ...........................................................................................63 
12.3 
Institutional Review Board/Independent Ethics Committee .......................................64 
12.4 
Informed Consent ............................................................................................................64 
12.5 
Records Management ......................................................................................................64 
12.5.1 
Source Documentation...............................................................................................64 
12.5.2 
Study Files and Record Retention ............................................................................65 
12.6 
Conflicts of Interest ..........................................................................................................65 
13 DATA MANAGEMENT, AUDITING, AND MONITORING ........................................65 
13.1 
Data Management ............................................................................................................65 
13.2 
Auditing ............................................................................................................................66 
13.3 
Monitoring ........................................................................................................................66 
14 AMENDMENTS ...................................................................................................................67 
15 STUDY REPORT AND PUBLICATIONS ........................................................................67 
16 STUDY DISCONTINUATION ...........................................................................................67 
17 CONFIDENTIALITY ..........................................................................................................67 
18 REFERENCES .....................................................................................................................68 
19 APPENDICES .......................................................................................................................70 
19.1 
APPENDIX I – Names of Study Personnel....................................................................70 
19.2 
APPENDIX II – Adverse Event Intensity Grading ......................................................71 
19.3 
APPENDIX III – Cytochrome P450 2B6, 2C8, 2C9, and 2D6 Substrates ..................92 
LIST OF TABLES 
Table 1 
Subject Allocation by HBeAg status ..................................................................32 
Table 2 
Schedule of Assessments ......................................................................................38 
Table 3 
Clinical Laboratory Tests....................................................................................50 
Table 4 
Pharmacokinetic Sample Collection ..................................................................51 
Table 5 
Power Calculations under Various Mean Differences in the Change from 
Baseline in HBsAg (or HBeAg) levels at Week 24 between Treatment 
Groups ...................................................................................................................59 
Table 6 
Power Calculations under Various Mean Differences in the Change from 
Baseline in HBsAg levels at Week 24 between Treatment Groups .................59 


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LIST OF FIGURES 
Figure 1 
Study Schematic ...................................................................................................37 


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LIST OF ABBREVIATIONS AND TERMS 
AFP 
alpha fetoprotein 
ALT 
alanine aminotransferase 
API 
active pharmaceutical ingredient 
AST 
aspartate aminotransferase 
AUC 
area under the concentration-time curve 
BMI 
body mass index 
CC50 
50% cytotoxic concentration 
cccDNA 
covalently closed circular DNA 
CFR 
Code of Federal Regulations 
CHB 
chronic hepatitis B infection 
CKD-EPI 
Chronic Kidney Disease Epidemiology Collaboration  
CI 
confidence interval 
Cmax 
maximum plasma concentration 
CNS 
central nervous system 
CpAM 
CRO 
core protein allosteric modifier 
Clinical Research Organization (PRA Health Sciences) 
CYP 
cytochrome P450 
DAA 
direct acting antivirals 
DAIDS 
Division of AIDS  
DMC 
Data Monitoring Committee 
dsDNA 
double-stranded DNA 
EC50 
50% effective concentration 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
EDC 
electronic data capture 
ETV 
entecavir 
FSH 
follicle-stimulating hormone 
GCP 
Good Clinical Practice 
GFR 
glomerular filtration rate 
GLP 
Good Laboratory Practices 
GMP 
Good Manufacturing Practices 
HAV 
hepatitis A virus 
HbA1c 
hemoglobin A1c 
HBCrAb 
antibody to the HBV core protein  
HBCrAg 
hepatitis B core-related antigen 
HBeAb 
HBeAg antibody 
HBeAg 
hepatitis B “e” antigen 
HBsAb 
HBsAg antibody 


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HBsAg 
hepatitis B surface antigen 
HBV 
hepatitis B virus 
HCC 
hepatocellular carcinoma 
HCV 
hepatitis C virus 
HDV 
hepatitis D virus 
HEV 
hepatitis E virus 
HIV 
human immunodeficiency virus  
IB 
Investigator’s Brochure 
ICF 
Informed Consent Form 
ICH 
International Council for Harmonisation 
IEC 
Independent Ethics Committee 
IFN 
interferon 
IgM 
immunoglobulin M 
INR 
International Normalized Ratio 
IRB 
Institutional Review Board 
ISG 
IFN-stimulated gene 
ITT 
intent-to-treat 
IUD 
intrauterine device 
LLN 
lower limit of normal 
LOQ 
limit of quantitation 
MedDRA 
Medical Dictionary for Regulatory Activities 
MRI 
magnetic resonance imaging  
NOAEL 
no-observed-adverse effect level 
NUC 
nucleos(t)ide inhibitors of the HBV polymerase; also called nucleos(t)ide 
analogues or nucleos(t)ides 
PBMC 
peripheral blood mononuclear cell 
pgRNA 
pre-genomic RNA 
PK 
pharmacokinetic(s) 
PK1 
Pharmacokinetic Population 1 
PK2 
Pharmacokinetic Population 2 
Pol/RT 
polymerase/reverse transcriptase 
PP 
per-protocol 
rcDNA 
relaxed circular DNA 
SAP 
statistical analysis plan 
SOC 
standard of care 
Sponsor 
Assembly Biosciences 
TAF 
tenofovir alafenamide  
TDF 
tenofovir disoproxil fumarate  
Tmax 
time to Cmax 


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ULN 
upper limit of normal 
WHO 
World Health Organization 
 


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2 INTRODUCTION AND RATIONALE 
2.1 
Study Rationale 
Worldwide >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 two 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 inhibitors [NUCs] 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 
[Papatheodoris 2016]. New therapies are required which can increase clinical cures, either alone 
or in combination with existing standard of care (SOC) for CHB. 
ABI-H0731 is a novel HBV core protein allosteric modifier (CpAM), 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 NUC analogues or IFN-α. In pre-clinical models, ABI-H0731 binds to the HBV 
core protein and induces altered, non-functional core protein assembly. Experience in patients with 
hepatitis C virus (HCV), another viral hepatitis, has shown that combination of multiple direct 
acting antivirals (DAAs) can increase rates of cures compared to monotherapy with a potent NUC 
inhibitor alone [Gane 2013]. Thus, 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 durable clinical cures in a 
finite treatment period. 
This Phase 2a study will be the first study to explore the potential to increase rates of clinical cure 
by addition of ABI-H0731 (a Core inhibitor) to SOC NUC therapy (entecavir [ETV], tenofovir 
alafenamide [TAF], or tenofovir disoproxil fumarate [TDF]) in patients who are chronically 
suppressed to the limit of quantitation (LOQ) on SOC NUC therapy alone, but who have ongoing 
expression of the viral antigens hepatitis B surface antigen (HBsAg) and hepatitis B “e” antigen 
(HBeAg) – biomarkers of active cccDNA transcription. 
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 
serologic markers of HBV infection include: HBV DNA, HBsAg, antibody to HBsAg (HBsAb), 
HBeAg, antibody to HBeAg (HBeAb), and, in almost all patients, antibody to the HBV core 


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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 four 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% people in highly endemic regions (eg, 
East Asia and equatorial Africa), 2% to 7% people in moderately endemic regions (eg, the Middle 
East and the Indian subcontinent), and <2% in locales of low endemicity (eg, North America and 
Europe) [ Schweitzer et al 2015; WHO 2015]. 
Some HBV carriers will lose detectable serum HBsAg and HBV viremia will drop to non-
detectable 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 two clinically accepted options for the treatment of CHB: IFNs and oral NUCs, 
which act as inhibitors of the viral polymerase. Of these, oral NUCs 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 NUC antivirals, with slightly higher rates of HBsAg loss recently reported 
in combination studies of tenofovir disoproxil fumarate (TDF) together with pegylated IFN-alfa 
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 durable post-treatment. Specifically, 
improved rates of two types of durable outcomes are desirable for new HBV therapies: durable 
HBeAg loss/seroconversion (in HBeAg-positive patients), and HBsAg loss/seroconversion (in all 
patients), in addition to sustained off-treatment viral load suppression and normalization of 
transaminases. Such “clinical cures” are predicted to afford improved long-term patient outcomes, 
ie, reduced HBV-associated morbidity and mortality from end-stage liver disease and HCC. 


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2.2.2 
Hepatitis B Virus Biology and Rationale for Hepatitis B Virus Core Protein 
Allosteric Modifiers (CpAMs) 
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 (Pol/RT), 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 pore 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 
CpAMs 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 (ISGs). 
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 
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2.2.2.3 
Hepatitis B Virus Core Protein Allosteric Modifiers and ABI-H0731 
2.2.2.3.1 
In Vitro Activity of ABI-H0731 
ABI-H0731 is a small molecule inhibitor of HBV replication that induces non-functional assembly 
of the HBV core protein and exhibits potent inhibition of HBV replication in vitro via a different 
mechanism than NUC or IFN-α therapy. ABI-H0731 binds to the HBV core protein and induces 
altered, non-functional core protein assembly in vitro. The antiviral activity of ABI-H0731 against 
HBV replication in vitro was evaluated using a standard HepAD38 cell line, which stably 
expresses infectious genotype D HBV. Analysis of intracellular HBV DNA showed a dose-
dependent reduction of viral DNA in the presence of ABI-H0731. In an inducible cell line model 
of HBV, the mean 50% effective concentration (EC50) for ABI-H0731 against HBV DNA 
replication was 173 nM, with no cellular toxicity observed at the highest concentration tested (50% 
cytotoxic concentration [CC50] >10 µM). Similar or better antiviral activity (EC50 of 86-142 nM) 
was observed in HBV DNA transfection-based assays against representative HBV strains of 
genotypes A, B, C, and D. ABI-H0731 therefore showed broad inhibition across genotypes. 
Specificity of ABI-H0731 for HBV was confirmed by the absence of antiviral activity when tested 
against other DNA and RNA viruses (HSV-1, HRV-16, and influenza A) at the highest 
concentrations tested (10 μM). ABI-H0731 was also evaluated for selectivity by determining the 
CC50 levels in seven human cell types/lines (Huh7, HepG2, HeLa H1A, HEK 293, NCI H226, and 
MOLT-4) and freshly isolated peripheral blood mononuclear cell (PBMC) cultures representing 
various human tissues following 4 days of incubation. ABI-H0731 showed no significant effects 
at a concentration of 3.3 μM (<7% reduction in cell viability) and up to 16% reduction in cell 
viability in some cell types/lines at 10 μM. These results demonstrate that ABI-H0731 is a highly 
selective and specific HBV inhibitor, consistent with specificity in targeting the HBV core protein 
target of ABI-H0731. 
See the Investigator’s Brochure (IB) for further information. 
2.2.2.3.2 
Combination Therapy 
Combining drugs from different classes provides numerous advantages compared with 
monotherapy, including the potential for additive or synergistic antiviral effects and establishment 
of higher resistance barriers, reducing the likelihood of adverse mutations. Combination studies of 
ABI-H0731 with a representative NUC polymerase inhibitor, ETV (Baraclude®), showed additive 
to synergistic effects over a wide range of concentrations, with no evidence of antagonism, 
indicating that ABI-H0731 has the capacity to be successfully combined with NUCs in the 
treatment of HBV. Please see the IB for further information. 
2.2.2.3.3 
Study Drug Resistance 
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 the 
Phase 1b monotherapy study, ABI-H0731-101(b), CHB subjects treated with ABI-H0731 for 28 
days were monitored closely for evidence of resistance emergence. To date, a single subject was 


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observed to enter study ABI-H0731-101(b) harboring a resistance variant at baseline (T109M). 
While this subject had a blunted response to therapy, they still exhibited a 1 log10 IU/mL decline 
in viral load over 28 days, suggesting that ABI-H0731 may achieve sufficient intrahepatic 
concentrations to inhibit replication of at least some naturally occurring resistant mutants. 
Importantly, the T109M mutant is not known to have a reduced susceptibility to SOC NUCs or 
pre-exist as a polymorphic substitution in HBV database sequences at any significant frequency. 
To date, no de novo mutations were noted to arise on treatment in any other subjects. 
2.2.3 
Summary of Nonclinical Pharmacology and Toxicology 
The nonclinical pharmacokinetics (PK), absorption, distribution, metabolism, and excretion of 
ABI-H0731 were characterized in vitro and in vivo in mice, rats, dogs, rabbits, and monkeys. 
Results are summarized in the IB. 
A standard battery of nonclinical safety studies, including safety pharmacology, genotoxicity, and 
repeat dose toxicity studies has been conducted. In safety pharmacology studies, there were no 
adverse central nervous system, cardiovascular, or respiratory system effects in rats or monkeys 
following single oral doses of ABI-H0731 up to 500 mg/kg. ABI-H0731 was not genotoxic in the 
in vitro bacterial or mammalian cell assays or in the in vivo rat micronucleus study. 
In chronic toxicity studies, ABI-H0731 was well-tolerated at the highest tested dose levels of 
250 mg/kg/day for 6 months in rats and 500 mg/kg/day for 9 months in monkeys, with no 
drug-attributed animal deaths and no patterns of adverse effects or changes in clinical pathology. 
There were no clear target organ findings in these studies. Histopathology observations in rats 
consisted of increased adrenal gland weight for males given ≥100 mg/kg/day and females given 
≥200 mg/kg/day, with correlating microscopic findings of minimal or mild diffuse hypertrophy of 
the zona fasciculata and/or minimal to moderate multifocal cortical vacuolation in some animals 
given ≥100 mg/kg/day. These findings were considered non-adverse, based on the absence of any 
apparent detrimental effect on the overall health of the animals and the partial or complete 
reversibility of the effects during the 28-day recovery period. In monkeys, there were no 
measurable effects beyond normal morphologic variations. Therefore, the no-observed-adverse 
effect levels (NOAELs) are the highest doses tested, 250 mg/kg/day for 6 months in rats and 500 
mg/kg/day for 9 months in monkeys. These dosing levels resulted in rat and monkey maximum 
plasma concentrations (Cmax) levels of 10.0 µg/mL and 8.47 µg/mL, respectively, and area under 
the concentration-time curve from time 0 to 24 hours post-dose values of 147 hr*µg/mL and 122 
hr*µg/mL, respectively. For more information, please refer to the IB. 
2.2.4 
Summary of Clinical Studies with ABI-H0731 
Clinical experience with ABI-H0731 consists primarily of three early-phase clinical studies: (1) 
the recently completed Phase 1a/1b dose-ranging study in healthy volunteers and treatment-naïve 
CHB subjects, ABI-H0731-101; (2) an essentially identical sister Phase 1b study 
ABI-H0731-101(B) (in treatment-naïve subjects with CHB); and (3) the second recently 
completed Phase 1a study ABI-H0731-102. These studies are summarized briefly below. For more 
complete information, please refer to the IB. 


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2.2.4.1 
Clinical Safety Data of ABI-H0731 
Clinical experience with ABI-H0731 consists primarily of Phase 1 dose-ranging studies conducted 
to assess the safety, tolerability, PK, and initial efficacy of ABI-H0731 monotherapy: 
• The first-in-human study Phase 1a conducted in healthy volunteers in New Zealand 
(ABI-H0731-101, Part 1). Intensive PK was assessed following single ascending doses (100, 
300, 600, and 1,000 mg) under fasted (100 and 300 mg) and fed (300, 600, and 1,000 mg) 
conditions, as well as 800 mg once daily and 800 mg twice daily (under fed conditions) for 
7 days. Overall, the results suggested that these single and multiple oral doses of ABI-H0731 
were well-tolerated with dose-related increases in plasma exposures. During the off-treatment 
follow-up period, one patient in the 800 mg once daily cohort and two patients in the 800 mg 
twice daily cohort developed transient rashes that were considered mild (Grade 1). 
• A Phase 1b study conducted at multiple sites in Australia, New Zealand, Hong Kong, England, 
South Korea, and Taiwan (ABI-H0731-101, Part 2, and ABI-H0731-101B) in which HBV 
patients received ABI-H0731 at doses of 100, 200, 300, or 400 mg once daily for 28 days. 
ABI-H0731 was well-tolerated in CHB patient cohorts at 100, 200, and 300 mg once daily 
through the 28-day dosing period and two weeks of follow-up (follow-up out to 4 weeks post-
treatment is ongoing at the time of this IB update). One subject in the 300 mg cohort developed 
a transient localized (Grade 1) rash approximately two days following the end of therapy. The 
rash was considered unrelated to drug both by the Investigator and a consulting dermatologist. 
One of two patients dosed in the 400 mg once daily cohort developed a Grade 3 rash following 
10 days of dosing. The rash was deemed related to study drug, and the subject was discontinued 
from treatment. The rash rapidly resolved off treatment with no other intervention required. 
Other than the individual patient with the Grade 3 rash, all other treatment-emergent adverse 
events were considered mild (Grade 1), and all Phase 1b subjects completed their study dosing 
and follow-up evaluations. There were no other premature treatment discontinuations, nor 
treatment dose modifications. There were no serious adverse events, or treatment 
emergent- laboratory abnormalities that were deemed drug related and clinically significant. 
• A Phase 1a study conducted in healthy volunteers in the US to obtain additional safety and PK 
data for a longer dosing period (ABI-H0731-102). Three cohorts received ABI-H0731 at 100 
mg, 200 mg or 300 mg once daily for 14 days. Treatment-emergent adverse events were 
infrequent (six in total), mild, and deemed unrelated to study drug. Laboratory abnormalities 
were generally minor, not related to dose, duration or target organ, and considered not 
clinically significant. PK data were consistent with the previous Phase 1a study. 
For more complete information, please refer to the IB. 
2.2.4.2 
Preliminary Pharmacokinetic Data for ABI-H0731 
PK parameters from studies ABI-H0731-101 and ABI-H0731-102 were calculated from plasma 
concentration over time, using WinNonlin™ software. In general, ABI-H0731 was rapidly and 
well absorbed following oral administration, with a median time to maximum plasma 
concentration (Tmax) ranging from 3 to 4.5 hours. ABI-H0731 demonstrated increasing exposures 


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as doses increased, which were approximately dose proportional with modest variability through 
600 mg, and it exhibited a terminal half-life of approximately 24 hours. Clinical activity was seen 
with the lowest doses explored (100 mg). 
Based on the pre-dose trough assessments in ABI-H0731-101, ABI-H0731-101(B), and ABI-
H0731-102 protocols, it appears that PK steady-state may be achieved by or prior to Day 8. 
Detailed information can be found in the IB. 
2.3 
Risk/Benefit Assessment 
2.3.1 
Known and Potential Risks 
ABI-H0731 is a novel direct acting HBV inhibitor that will be among the first HBV CpAMs to be 
investigated in CHB patients for >28 days. At this stage of development, the risk considerations 
for ABI-H0731 are primarily based on the nonclinical and Phase 1 data summarized in the IB. 
No evidence was found for genotoxicity or clastogenicity. 
In the Good Laboratory Practices (GLP) chronic toxicology studies in rats and monkeys, ABI-
H0731 was generally well-tolerated, with no animal deaths or severe in-life effects attributed to 
ABI-H0731 treatment at any exposure level (refer to the IB). There were no clear target organ 
findings in these studies, and the NOAELs were the highest doses tested, 250 mg/kg/day for 
6 months in rats and 500 mg/kg/day for 9 months in monkeys. Specialized safety pharmacology 
studies were conducted to the same maximal dosing intensities as the 28-day GLP toxicology 
studies, 500 mg/kg/day in rats and 300 mg/kg/day in monkeys, with the results indicating no 
appreciable adverse effects on cardiac, respiratory, or central nervous system (CNS) functions at 
any ABI-H0731 dose level. 
Human exposure data for ABI H0731 was obtained from the three Phase 1 clinical studies 
described above, in which a total of 84 healthy volunteers, and 38 CHB patients were treated with 
ABI-H0731 or matching placebo (refer to the IB). The single- and multiple-dose exposures were 
closely monitored with clinical and laboratory assessments at each study visit. ABI-H0731 was 
well-tolerated with no serious adverse events, no clinically significant vital sign or ECG changes, 
and no drug related clinically significant laboratory findings. One CHB patient was discontinued 
from treatment because of a Grade 3 rash, which resolved with no further intervention required 
other than drug discontinuation. Across all studies, with the possible exception of rash, no pattern 
of adverse events nor of laboratory abnormalities was seen with associated with either dose or 
duration of ABI-H0731 exposure suggesting any potential target organ pathology. 
Refer to the IB for additional information. 
2.3.2 
Known and Potential Benefits 
There is a need for improved HBV antiviral therapies that can offer a “clinical cure” for patients 
with CHB. Such therapy should produce durable post-treatment suppression of viral load and 
normalization of transaminases, and, ideally, a loss of detectable viral antigens in a higher 


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proportion of CHB patients than achieved with current therapies. The HBV core protein is involved 
in multiple aspects of the HBV life cycle. Therapy with CpAMs may disrupt multiple core protein 
functions (including cccDNA replenishment and possibly core-mediated interactions with HBV-
specific immune responses) and thus is a highly attractive class of novel DAAs that may increase 
clinical cure rates for CHB. 
In Phase 1a and 1b studies, ABI-H0731 has been able to achieve liver and blood levels sufficient 
to demonstrate significant antiviral activity. In the phase 1b studies, the resultant decrease in 
detectable HBV DNA and RNA in serum or plasma supports inhibition of RNA packaging and is 
consistent with the mechanism of action – inappropriate polymerization of HBV core protein. It is 
anticipated that this pleotropic mechanism of action may lead to more complete inhibition of the 
viral replicative cycle than inhibition of the viral polymerase alone, resulting in more rapid loss of 
active cccDNA and higher rates of clinical cures for CHB patients. 
This study will specifically evaluate a 6-month course of therapy that may provide a lasting 
therapeutic benefit. Subjects who complete this study will be offered the opportunity to enroll in 
an open-label extension study of ABI-H0731. In the extension study, all subjects will receive up 
to 12 months active treatment. 
2.3.3 
Assessment of Potential Risks and Benefits 
In this study, chronically HBV-infected adults who have previously been found to be viremic but 
are currently suppressed to the limits of quantitation on an approved SOC NUC therapy for HBV 
will be enrolled. These subjects are expected to have normal alanine aminotransferase (ALT) and 
have reduced, if any, liver inflammation. They will, however, have detectable circulating 
biomarkers of ongoing active cccDNA transcription – HBsAg, HBeAg (in HBeAg positive 
subjects), hepatitis B core-related antigen (HBCrAg), and encapsidated viral RNA. The 24-week 
treatment period in this Phase 2a trial is expected to be sufficient to assess the safety and 
tolerability of ABI-H0731 + SOC NUC therapy as well as the potential for increased rates of 
clinical cure via increased loss of active cccDNA as compared to subjects on SOC NUC therapy 
alone. 
As compared to monotherapy with a NUC, addition of ABI-H0731 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 is thus anticipated to demonstrate 
clinical antiviral effects not seen with NUC monotherapy (eg, serum HBV RNA, HBsAg, and 
HBeAg reductions). The degree of reduction or duration of effect with 24 weeks of therapy, 
however, may be insufficient to establish any lasting clinical benefit for any of the subjects enrolled. 
The predictable benefits of this study are thus primarily 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. 
The nonclinical profile and Phase 1a and Phase 1b clinical data for ABI-H0731 predicts adequate 
safety margins for assessing ABI-H0731 dosing in CHB subjects at the 300-mg dose in this 
protocol, with a likelihood for demonstrable antiviral efficacy for ABI-H0731 on biomarkers of 
active cccDNA transcription (HBeAg, HBsAg) in the proposed Phase 2a evaluation. The kinetics 


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of viral antigen declines observed in this study will help define the length of treatment required for 
more definitive “HBV cure studies” to follow. These considerations support the advancement of 
ABI-H0731 into Phase 2a clinical investigation. 


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3 STUDY OBJECTIVES AND ENDPOINTS 
3.1 
Objectives 
3.1.1 
Primary Objective 
• To evaluate the potential for ABI-H0731 to increase clinical cure rates in CHB subjects whose 
viral replication is stably suppressed on SOC NUC therapy, as measured by changes from 
Baseline in serum biomarkers (i.e., HBsAg or HBeAg) of transcriptionally active cccDNA 
3.1.2 
Secondary Objectives 
• To evaluate the safety and tolerability of ABI-H0731 when added to SOC NUC therapy in 
subjects already virally suppressed on SOC therapy 
• To confirm a lack of drug-drug interaction between SOC NUC therapies and ABI-H0731 
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 evaluate the kinetics of and absolute changes from Baseline in circulating HBV RNA 
• To assess the relationship between changes in exploratory viral biomarkers such as changes in 
viral RNA and HBCrAg with clinical outcomes 
• To monitor for emergence of resistance, if any, for ABI-H0731 in combination with SOC NUC 
• To explore the PK of ABI-H0731 
• For subjects who provide an optional pharmacogenomic sample, to evaluate the potential 
contribution of host genomics to outcomes 
3.2 
Study Endpoints 
3.2.1 
Primary Endpoint 
The primary efficacy endpoint will be: 
• Change in mean log10 serum viral antigen (HBsAg or HBeAg) from Baseline (Day 1) to Week 
24 on ABI-H0731 + NUC as compared to placebo + NUC 


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3.2.2 
Secondary Endpoints 
The secondary endpoints will be: 
• Number of subjects with adverse events, premature discontinuations, abnormal safety 
laboratory results, electrocardiogram (ECG), or vital signs 
• Subjects with abnormal ALT at Baseline who have normal ALT at Week 24 on ABI-H0731 + 
NUC therapy as compared with placebo + NUC therapy 
• Drug concentrations: 
o Trough levels and (in subjects where optional samples are available) trough to peak ratios 
of ABI-H0731 on ABI-H0731 + NUC therapy 
o Trough levels and (in subjects where optional samples are available) trough to peak ratios 
of NUC on ABI-H0731 + NUC therapy as compared with placebo + NUC therapy 
3.2.3 
Exploratory Endpoint 
Exploratory endpoints include: 
• Quantitative changes in serum HBV RNA and HBCrAg levels on ABI-H0731 + NUC as 
compared with placebo + NUC, at each time point 
• Subjects with loss (defined as below LOQ) or decline in HBsAg or HBeAg (<0.5 log10, ≥0.5 
to 1.0 log10, or >1.0 log10 decrease in viral antigen) on ABI-H0731 + NUC as compared with 
placebo + NUC at end of treatment and end of follow-up 
• Subjects with HBsAg seroconversion (loss of HBsAg and appearance of HBs antibody) or 
HBeAg seroconversion (loss of HBeAg and appearance of HBe antibody) on ABI-H0731 + 
NUC as compared with placebo + NUC 
• Subjects with HBV DNA “detectable” at Baseline whose HBV DNA becomes “non-detectable” 
on ABI-H0731 + NUC as compared with placebo + NUC 
• Emergence of resistant HBV variants, if any 
• For subjects who do NOT rollover onto the optional extension study, ABI-H0731-211: 
o Subjects with suppression of detectable serum HBV RNA on treatment whose HBV RNA 
rebounds after discontinuing treatment with ABI-H0731 + SOC NUC as compared with 
placebo + SOC NUC 


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o Subjects with changes in HBsAg or HBeAg whose viral antigen rebounds after 
discontinuing treatment with ABI-H0731 + SOC NUC as compared with placebo + SOC 
NUC 
o Subjects with HBsAg or HBeAg loss at Week 24 that is maintained through end of follow-
up (Week 36) after discontinuing treatment with ABI-H0731 + SOC NUC as compared 
with placebo + SOC NUC 
• If differences are seen in outcomes/adverse events between racial or ethnic groups: 
Pharmacogenomics correlation with clinical outcomes subjects who provide optional informed 
consent 


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4 STUDY PLAN 
4.1 
Study Design 
This Phase 2a, multi-center, randomized, double-blind, placebo-controlled study will assess the 
safety, efficacy, PK, and pharmacodynamics of 300 mg ABI-H0731 daily in combination with 
SOC NUC therapy in subjects with CHB who are already virally suppressed on SOC NUC therapy 
at entry to study. Subjects will be stratified 9:5 (HBeAg positive:HBeAg negative) and randomized 
3:2 to receive investigational agent as add-on therapy to their current SOC NUC therapy for up to 
6 months (HBeAg positive subjects: 27 subjects will receive ABI-H0731 + NUC therapy: 18 
subjects will receive matching placebo + NUC therapy; HBeAg negative subjects: 15 subjects will 
receive ABI-H0731 + NUC therapy: 10 subjects will receive matching placebo + NUC therapy). 
NUC treatment will continue uninterrupted for the duration of the study as well as during follow-
up. 
Table 1 
Subject Allocation by HBeAg status 
 
Total 
Patients receiving  
ABI-H0731 
Patients receiving  
placebo 
HBeAg positive 
45 
27 
18 
HBeAg negative 
25 
15 
10 
 
Safety will be monitored by a Data Monitoring Committee (DMC), including laboratory data and 
adverse events, at intervals outlined in the DMC Charter. There will be an assessment of PK data 
after all subjects have completed Week 4 (or discontinued study without completing Week 4) to 
confirm a lack of an important impact of ABI-H0731 on the steady-state PK of SOC NUC therapy. 
At the end of the treatment period in this study, subjects will either continue their SOC NUC 
therapy and stop treatment with ABI-H0731/placebo, or they may elect to roll over onto the 
optional, open-label, extension study ABI-H0731-211. 
• Subjects who do not roll into optional open-label study ABI-H0731-211 will continue on SOC 
NUC therapy alone and be monitored for an additional 12 weeks to determine if any changes 
in either viral antigens or viral RNA which may have been noted on treatment will persist 
through end of follow-up. 
• Subjects who do elect to roll over to the optional, open-label, extension study of ABI-H0731 
+ SOC NUC (protocol ABI-H0731-211) will continue on open-label combination therapy as 
per that study. The objective of the extension study, ABI-H0731-211, will be to evaluate the 
safety and potential for benefits of up to one additional year of therapy with ABI-H0731. 
Subjects will be required to sign a separate informed consent form for the ABI-H0731-211 
study. 


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4.2 
Scientific Rationale 
It is anticipated that the addition of ABI-H0731, a DAA targeting the HBV core protein, to SOC 
NUC therapy will be safe and may potentially result in an increase in the functional cure rate for 
subjects with CHB by preventing the establishment and possible maintenance of cccDNA more 
completely than SOC NUC therapy alone. Loss of cccDNA is expected to result in a decrease in 
serum viral RNA as well as serum viral antigens which reflect the activity of cccDNA (eg, HBsAg 
and HBeAg). This study will explore both the safety of combination therapy in subjects whose 
viral load has already been suppressed to the LOQ on a SOC NUC, as well as reduction in 
circulating viral RNA and potential serum biomarkers of functional cures:  quantitative and 
qualitative reduction in the viral antigens HBeAg (in HBeAg positive subjects) and HBsAg. 
4.3 
Dose Justification 
In the Phase 1 clinical studies, ABI-H0731 was well-tolerated in healthy subjects at single doses 
of up to 1000 mg daily, at twice daily doses of 800 mg for 7 days, and at single daily doses of up 
to 300 mg for 14 days. All treatment-emergent adverse events (TEAE) 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. 
Preliminary data indicated that there is a dose-dependent decrease in viral load at doses of 100 mg, 
200 mg, and 300 mg daily in subjects with CHB. It is expected that 300 mg daily will be safe and 
provide sufficient exposure to ABI-H0731 to produce the desired antiviral effect in CHB subjects 
in this study, and within the dose range that was well-tolerated in previously treated healthy 
subjects and subjects with CHB. 
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 study are expected to have a Baseline viral load below LOQ. As such, 
no sequencing of the Cp region is possible. As all subjects will remain on their SOC NUC therapy 
throughout the study including the follow-up period, the potential for emergence of resistance to 
combination therapy is minimal. However, all subjects will have viral load monitored throughout 
the study, and any subject who develops persistent (i.e., 2 consecutive visits) HBV DNA viremia 
on study to a quantifiable level sufficient for DNA sequencing, will have the RT and Cp regions 
sequenced and evaluated for potential resistance mutations. 
4.5 
End of Study Definition 
The study will be completed when the last subject completes the 12-week post-treatment follow-up 
period or when the last subject transitions to protocol ABI-H0731-211 (or when the last subject 
discontinues the study before completing the follow-up period or transitioning to the extension 
study), whichever is later. 


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4.6 
Management of Toxicities 
4.6.1 
Subjects with Alanine Aminotransferase Elevations 
Subjects experiencing ALT elevations ≥2×Baseline or on-treatment nadir and >2×upper limit of 
normal (ULN) during study treatment or during post-treatment follow-up will be closely monitored. 
The following guidance is offered for management of study subjects with ALT elevations or 
biochemical evidence of declining hepatic function: 
• ALT flare on treatment 
o All subjects with an ALT flare on treatment, defined as ALT > 2×Baseline or on-treatment 
nadir and ≥10×ULN, should have the ALT findings confirmed within 3 days of receipt of 
the original results. All subjects should return for an unscheduled visit and 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, International Normalized Ratio (INR), and serum 
albumin. 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), HCV RNA, hepatitis D virus (HDV) RNA, and hepatitis E virus 
(HEV) IgM should also be drawn.  
 If an intercurrent cause is determined to be causal, the intercurrent cause should be 
treated as deemed medically appropriate by the treating physician.  
 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 2-5 days until the ALT elevation has stabilized.  
Subjects whose ALT has stabilized should continue to be monitored weekly (or 
more frequently - as deemed necessary by the treating physician) until ALT 
values return to normal or baseline levels.  
 Subjects with ALT “flares” or ALT elevations without declining hepatic function 
or contraindications should stop study drug if the ALT remains persistently elevated 
for > two weeks in the absence of decreasing HBV DNA (if detectable), and/or 
HBV RNA, and/or viral antigen (HBeAg or HBsAg). 
 
• Declining hepatic function during treatment 


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o Subjects with confirmed biochemical evidence of declining hepatic function, should be 
discontinued from study treatment. Declining hepatic function is 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 2-5 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 treating physician) until the relevant laboratory values return to 
normal or baseline.  
• Post-treatment ALT “flare” or ALT elevation with declining hepatic function 
o For subjects who elect not to enroll in the open-label, extension study ABI-H0731-211, 
risk of post-treatment flare is mitigated by advising subject to continue with their previous 
SOC NUC therapy for CHB. Any subject with a post-treatment ALT elevation meeting the 
ALT “flare” definition or a lesser post-treatment ALT elevation with biochemical evidence 
of declining hepatic function (described above), while on treatment with a regulatory-
approved HBV antiviral agent should return for an unscheduled visit every 2-5 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 
treating physician) until the relevant laboratory values return to normal or baseline. 
Subsequently, subjects should continue to be followed on their regular study visit schedule, 
with the addition of any unscheduled visits the Principal Investigator believes are merited 
for the safety and well-being of the subject. 
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 return to clinic as deemed medically appropriate by 
the Principal Investigator, in consultation with the Sponsor, and the unscheduled visit module in 
the case report form should be utilized as needed to gather additional clinical and laboratory data 
until the ALT flare is documented to be either resolved or resolving (defined as consistent ALT 
declines of 10% or more or normalization of ALT) on at least two successive visits. 
If 2 or more subjects meet these LFT flare management criteria, the US FDA and other relevant 
regulatory agencies will be notified. 
It is important to note that ALT elevations early on in treatment tend to resolve with continued 
treatment and are more common in patients with greater early antiviral efficacy responses, e.g. 


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rapid serum HBV DNA reductions that may be associated with higher rates of HBeAg or HBsAg 
clearance. In contrast, ALT flares occurring following immunosuppression or cessation of 
treatment with a NUC can be severe and can be associated with biochemical signs of hepatic 
insufficiency [Chang and Liaw 2014, EASL 2012, Perrillo 2009, Perrillo, 2001]. Therefore, 
subjects on study will not be discontinued from treatment unless they meet discontinuation criteria 
listed above (see Section 4.6.1). For subjects remaining on the study, it is anticipated that the close 
laboratory and clinical monitoring, as well as the provision for all subjects to continue on SOC 
NUC therapy during the treatment period of this study is appropriate to minimize excess risk for 
study participants. 
4.6.2 
Subjects with Rash 
In the event of any rash, subjects should return to clinic for evaluation for an unscheduled visit 
(Day 0 of rash). Digital photographs of the rash should be taken, and blood samples should be 
taken and evaluated at the site’s local laboratory as well as the central laboratory. 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 and electronic case report form (eCRF). A copy of the dermatologist report will be 
de-identified and collected by the 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 prerogative 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, collected 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 even if treatment 
is discontinued, with additional unscheduled visits as deemed medically appropriate by the 
Investigator. 
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 
two successive visits. 
4.7 
Study Schematic 
The study schematic is presented in Figure 1. 
Figure 1 
Study Schematic 
 
I/E = inclusion/exclusion 
4.8 
Schedule of Assessments 
The Schedule of Assessments is presented in Table 2. 


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Table 2 
Schedule of Assessments 
Period or Visit 
Screening 
On Treatment 
Follow-Up a 
Premature 
Termination b 
Unscheduled c 
Study Day or Week 
Day (-45) 
to Day (-1) 
Day  
1 
Week 
2 
Week 
4 
Week 
8 
Week 
12 
Week 
16 
Week 
20 
Week 
24 a 
Week 
28 
Week 
36 
Varies 
Varies 
Visit Window (days) 
0 
+/- 2 
+/- 2 
+/- 3 
+/- 3 
+/- 3 
+/- 3 
- 3 
+/- 3 
+/- 3 
N/A 
N/A 
Informed Consent(s) d 
X 
 
 
 
 
 
 
 
X j 
 
 
 
 
Demographic data 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Medication history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Liver screening e 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Full physical examination 
X 
 
 
 
 
 
 
 
X 
 
X 
X 
 
12 Lead ECG  
X 
X 
 
 
 
X 
 
 
X 
 
X 
X 
if indicated 
Height and weight 
X 
X 
 
X 
 
 
 
 
X 
 
X 
 
 
Vital signs 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant medications / 
Adverse events 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Confirm eligibility 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Randomization (IRT) 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Symptom directed physical 
exam 
 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
 
X 
Paper diary 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
Study drug accountability 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
if applicable 
 
Study drug dispensation 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
In-clinic dosing: study drug  
 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
Dosing: SOC NUC k 
 
Xk 
Xk 
Xk 
X 
X 
X 
X 
X 
X 
 
 
 
Digital photography c 
 
 
 
 
 
 
 
 
 
 
 
 
if indicated 
Virology/Immunology 
HBV genotype 
X 
 
 
 
 
 
 
 
 
 
 
 
 
HBV DNA viral load 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Quant HBsAg, quant HBeAg 
f 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
HBsAb, HBeAb 
X 
X 
 
 
 
X 
 
 
X 
 
X 
X 
 
HBV RNA 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 


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Table 2 
Schedule of Assessments (continued) 
Period or Visit 
Screening 
On Treatment 
Follow-Up a 
Premature 
Termination b 
Unscheduled c 
Study Day or Week 
Day (-45) to 
Day (-1) 
Day  
1 
Week 
2 
Week 
4 
Week 
8 
Week 
12 
Week 
16 
Week 
20 
Week 
24 a 
Week 
28 
Week 
36 
Varies 
Varies 
HIV Ab 
X 
 
 
 
 
 
 
 
 
 
 
 
 
HCV Ab; HDV Ab; HAV 
(IgM); HEV (IgM) 
X 
 
 
 
 
 
 
 
 
 
 
 
Xc 
Laboratory Assessment 
Chemistryb 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Hematology 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Coagulation 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Serum AFP  
X 
 
 
 
 
 
 
 
 
 
 
 
 
FSH (females only) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Urinalysis 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Urine drug test 
X 
X 
 
 
 
 
 
 
 
 
 
X 
X 
Pregnancy Test g 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
PK Sample Collection  
Pre-dose h 
ABI-H0731 
 
X 
X 
X 
 
X 
 
 
X 
X 
 
X 
X 
Nucleos(t)ide 
analogue 
 
X 
X 
X 
 
X 
 
 
X 
X 
 
X 
X 
Optional post-dose i 
4 (±2) hours after ABI-
H0731 and NUC 
administration 
 
X 
X 
X 
 
 
 
 
 
 
 
 
 
Exploratory 
Optional PG sample c 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Core protein (HBCrAg) 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Viral nucleic acid 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
a 
Subjects who elect NOT to enter rollover study ABI-H0731-211 at Week 24 will enter into the 12-week follow-up period (inclusive of Weeks 28 and 36). 
b 
Subjects who discontinue treatment before Week 24 should immediately undergo the assessments listed for the Premature Termination visit and then continue scheduled assessments, 
except that these subjects need only two further PK collections (at the Premature Termination visit and the next scheduled time point). Subjects who discontinue study assessments 
before completing the 12-week follow-up period should undergo the assessments listed for the Premature Termination visit. 
c 
Any subjects with rash or ALT flare (defined in Section 4.6) should return to the clinic for an unscheduled visit as soon as possible, ideally within 3 days.  
Unscheduled visit for ALT flare: All subjects should have the laboratory findings confirmed within 3 days of receipt of the original results. All subjects should undergo a symptom 
directed physical examination and the following laboratory tests: ALT, AST, total bilirubin, INR, and serum albumin. If the ALT flare is confirmed, perform the following tests: HBV 


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DNA, quantitative HBV serologies (HBeAg [reflex qualitative HBeAg if quantitative HBeAg is negative] and HBsAg [reflex qualitative HBsAg if quantitative HBsAg is negative], 
HAV IgM, HCV RNA, HDV RNA, and HEV IgM 
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 and eCRF. 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 two successive visits. 
d 
Study specific including optional PG consent. PG sample collection requires documentation of completed PG consent. 
e 
Liver evaluation to be done by any protocol approved method (Biopsy, fasting FibroScan, MRI, liver ultrasound), unless a liver biopsy demonstrating lack of cirrhosis or bridging 
fibrosis has been conducted in the last 6 months. 
f 
If quant HBsAg or HBeAg are negative at any visit subsequent to Screening, reflex to qualitative. 
g 
A serum pregnancy test is required at screening, and on Day 1 both urine and serum should be performed (subjects may begin treatment based on urine results; any subjects negative 
by urine subsequently found to be positive on serum should immediately discontinue treatment and may be replaced). All post-Day 1 pregnancy tests may be conducted by urine 
dipstick. If positive on dipstick, please reflex to serum. 
h 
If the subject inadvertently administers study drug prior to collection, a PK sample should still be drawn. Refer to the protocol PK Assessments Section 8.3. 
i 
Optional post-dose PK samples for ABI-H0731 and NUC targeted collection is 4 (±2) hours after in-clinic study drug + NUC administration at Day 1 and either Week 2 or Week 4.  
j 
Subjects who elect to roll over onto the open-label extension study will be required to sign a separate consent at Week 24. 
k 
It is recommended that subjects take SOC NUC in-clinic on Day 1, Week 2 and Week 4, if subjects opt to provide the optional post-dose PK samples. 
 
 
Ab=antibody; AFP=alfa fetoprotein; ALT=alanine aminotransferase; AST=aspartate aminotransferase; ECG=electrocardiogram; eCRF=electronic case report form; FSH=follicle-
stimulating hormone; HAV=hepatitis A virus; HBCrAg =hepatitis B core-related antigen; HBeAb=HBeAg antibody; HBeAg=hepatitis B “e” antigen; HBsAb=HBsAg antibody; 
HBsAg=hepatitis B surface antigen; HBV=hepatitis B virus; HCV=hepatitis C virus; HDV=hepatitis D virus; HEV=hepatitis E virus; HIV=human immunodeficiency virus; 
IgM=immunoglobulin M; MRI=magnetic resonance imaging; N/A=not applicable; PG=pharmacogenomic; PK=pharmacokinetic; Quant=quantitative; ULN =upper limit of normal. 
 


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5 POPULATION 
5.1 
Number of Subjects 
Globally, approximately 70 male or female subjects with CHB, between the ages of 18 and 70, 
with no evidence of cirrhosis or end-stage liver disease, and on stable SOC NUC therapy, whose 
HBV DNA viral load has been below the LOQ for at least 6 months, will be randomized. 
5.2 
Inclusion Criteria 
Subjects must meet ALL of the following inclusion criteria in order to be eligible for enrollment: 
1. Male or female between ages 18 and 70 years (inclusive) 
2. Female subjects must agree to use dual effective birth control methods for the duration of the 
study and follow-up or be surgically sterile for at least 6 months or at least 2 years 
post-menopausal, with serum follicle-stimulating hormone (FSH) levels consistent with a post-
menopausal 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 – 
inclusive of IUDs with hormonal components), diaphragm, or cervical cap. Systemic 
(oral/injectable) hormonal birth control are prohibited. Female subjects must have a negative 
serum pregnancy test at screening 
3. All heterosexually active male subjects must agree to use dual effective birth control methods 
for the duration of the study and follow-up. Effective birth control methods include male or 
female condom (may not be used together due to increased risk of breakage), vasectomy, 
hormone-based contraception, IUD, diaphragm, or cervical cap 
4. Body mass index (BMI) 18 to 36 kg/m2 and a minimum body weight of 45 kg (inclusive) 
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 (defined as HBV infection for at least 
6 months documented by – for example – history of two repeated HBsAg positivity and/or 
detectable viral loads documented at least two times ≥6 months apart – inclusive of screening),  
7. Virologically suppressed (defined as HBV DNA ≤LOQ) for at least 6 months before screening 
on NUC therapy  
a. Subjects with a low but quantifiable viral load (for example <60 IU/mL) within 6 months 
prior to screening which was shown to be an exception in a subject who has previously 
been well suppressed, may be eligible for study if the subject is virologically suppressed at 
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8. Subjects will be stratified 9:5 (HBeAg Positive:HBeAg negative). HBeAg-positive cohort 
must be HBeAg positive at screening  
9. Hepatitis B surface antigen (HBsAg) levels: 
• HBeAg positive subjects must have >400 IU/mL HBsAg at screening;  
• HBeAg negative subjects must have >100 IU/mL HBsAg at screening  
10. Liver biopsy results of 
o Metavir F0-F2 (absence of bridging fibrosis or cirrhosis) within 1 year of screening 
OR 
o Fasting FibroScan ≤8 kPa within 3 months of screening (including screening visit) or other 
Sponsor-approved hepatic imaging study (hepatic magnetic resonance imaging [MRI], or 
hepatic ultrasound by an ultrasonographer with expertise in evaluation of liver fibrosis) 
within 6 months of screening indicating lack of cirrhosis or advanced liver disease (F0-F2 
or equivalent). 
Subjects with an ambiguous non-invasive result, eg, fasting FibroScan >8 kPa and ≤10 kPa 
are excluded unless a biopsy within the 12 months before first visit confirms the absence of 
bridging fibrosis and cirrhosis. Subjects with a FibroScan >10 kPa are excluded 
11. Have the ability to take oral medication and be willing to adhere to the study regimen in the 
opinion of the Investigator 
12. Willing and able to provide informed consent 
5.3 
Exclusion Criteria 
Subjects who meet ANY of the following exclusion criteria will not be eligible for enrollment: 
1. Co-infection with human immunodeficiency virus (HIV), HCV, HEV, or HDV 
2. History or evidence of hepatic decompensation (including gastrointestinal bleeding or 
esophageal varices) at any time prior to or at time of screening 
3. Subject is febrile (temperature >37.5°C) at screening 
4. 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 


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5. Previous treatment with an investigational agent for HBV other than ABI-H0731 in the last 
6 months before screening 
6. Previous treatment with an HBV capsid targeting agent other than ABI-H0731 at any time 
7. Participation in another clinical trial of a drug or device whereby the last investigational 
drug/device administration is within 60 days or five half-lives prior to the first study drug 
administration, whichever is longer 
8. History of persistent ethanol abuse (alcohol consumption exceeding 2 standard drinks per day 
on average [1 standard drink = 10 grams of alcohol]) or illicit drug abuse within 3 years before 
screening 
9. Females who are lactating or pregnant or wish to become pregnant are excluded from the study 
10. History of HCC 
11. A history of malignancy other than HCC unless the subject’s malignancy has been in complete 
remission off chemotherapy and without additional medical or surgical interventions during 
the 3 years before screening 
12. Exclusionary laboratory results 
a. Platelet count <100,000/mm3 
b. Albumin <lower limit of normal (LLN) 
c. Total bilirubin >1.2×ULN of unless known Gilbert syndrome; subjects with Gilbert 
syndrome are eligible if direct bilirubin is within normal limits 
d. Direct bilirubin >1.2×ULN 
e. ALT >5×ULN at screening 
f. Serum alpha fetoprotein (AFP) ≥100 ng/mL. If AFP at Screening is >ULN but <100 ng/mL, 
subject is eligible if a hepatic imaging study prior to the initiation of study drug reveals no 
lesions suspicious of possible HCC 
g. Prothrombin time: INR >1.5×ULN 
h. Glomerular filtration rate (GFR) <60 mL/min/1.73 m2 by Chronic Kidney Disease 
Epidemiology Collaboration (CKD-EPI) equation (Levey 2009) 
i. Serum hemoglobin A1c (HbA1c) >8% 
j. Any other laboratory abnormality deemed clinically significant by the Sponsor or the 
Investigator 


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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 supplements (other than over the counter multivitamins) 
• 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 
Screen Failures 
Screen failures are defined as subjects who consent to participate in the clinical trial, but are not 
subsequently randomly assigned to the study intervention or entered in the study. Individuals who 
do not meet the criteria for participation in this trial (screen failure) because of an abnormal 
screening laboratory value may be rescreened one time.  It will be at the discretion of the medical 
monitor on a case-by-case basis whether rescreening will be permitted under other circumstances. 
5.6 
Strategies for Recruitment and Retention 
Approximately 70 subjects will be enrolled globally. 
Outpatient subjects will be enrolled by their treating physician or referred to an enrolling 
Investigator by their treating physician. Subject recruitment will be performed by the study sites 
in accordance with local standards and regulations and will be detailed in a separate plan. 
Subjects who complete the treatment phase of the study will be eligible to receive continued 
treatment in an extension protocol. Subjects randomized to active drug and subjects randomized 
to placebo will all receive active treatment in an open-label fashion in the extension study. 


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6 STUDY DRUG 
6.1 
Description 
ABI-H0731 active pharmaceutical ingredient (API) is manufactured under current Good 
Manufacturing Practices (GMP) via standard synthetic chemistry methods. 
Drug Substance 
Code name 
ABI-H0731 
US Adopted Name 
Not yet assigned 
International Nonproprietary Name 
Not yet assigned 
Relative molecular mass 
467.44 amu 
Physicochemical Properties 
Appearance 
White to off-white powder 
Physical form 
Crystalline  
Melting point 
301°C 
Solubility 
0.1 N HCl (pH 1.1) 
4 µg/mL 
FaSSIF (pH 6.5) 
35 µg/mL 
Acetone 
17 mg/mL 
Dimethyl acetamide 
>625 mg/mL 
Ethanol 
Insoluble 
FaSSIF=fasted state simulated intestinal fluid; HCl = 
hydrochloride 
6.2 
Formulation 
The drug product is a tablet containing ABI-H0731 in a solid dispersion produced by spray drying 
a solution of ABI-H0731 with an inert polymer. This spray-dried dispersion has been mixed with 
standard pharmaceutical excipients, such as microcrystalline cellulose, mannitol, croscarmellose 
sodium, and magnesium stearate, and compressed into a tablet containing approximately 100 mg 
ABI-H0731, manufactured according to GMP. Matching placebo tablets contain the same 
excipients and are also manufactured according to GMP. 
6.3 
Storage 
Bottled drug product at the study site should be stored at controlled room temperature [15 °C to 
30 °C (59 °F to 86 °F)] in a secure, locked location at the sites, accessible only to study personnel. 


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6.4 
Packaging and Shipment 
ABI-H0731 tablets and placebo tablets are packaged in high density polyethylene bottles fitted 
with child-resistant screw caps containing a desiccant (silica gel) and stored at controlled room 
temperature. 
6.5 
Dose and Administration 
6.5.1 
Dosing in the Study 
All subjects will take study drug (ABI-H0731 or matching placebo) as three 100-mg tablets once 
daily, after a meal, at approximately the same time each day. SOC NUC should be taken as per 
package insert. 
On study treatment visit days, study drug will be administered in the clinic; subjects will 
self-administer study drug on all other treatment days. Subjects will be required to record the dates 
and times of each dose they self-administer in a patient diary. If possible, study personnel will 
document time of study drug and SOC NUC administration in subject’s medical record.  
Refer to the Site Operations Manual for detailed instructions on managing missed or incorrect 
doses. 
6.5.2 
Preparation 
Not applicable. 
6.5.3 
Blinding 
Study subjects and site personnel administering the study drug and performing the clinical 
assessments on the subjects, will be blinded to individual subjects’ treatments assignments 
(ABI-H0731 + NUC therapy or placebo + NUC therapy). The DMC, as well as select individuals 
at the Sponsor and the CRO will not be blinded to subjects’ treatment assignments to facilitate 
randomization, prompt analysis of any arising safety/tolerance issues, and the DMC safety data 
review. As this is an exploratory Phase 2a study, certain individuals may also be unblinded to the 
efficacy results before the final analysis. 
6.6 
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 


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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 or vials 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 containers. The clinical 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 dosing period. 
6.7 
Compliance 
To monitor compliance and to facilitate drug accountability at the study site, subjects will be 
required to record each dose they take in a diary. 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. 
6.8 
Concomitant Therapy 
A concomitant medication is defined as any prescription or over-the-counter preparation, including 
vitamins, over-the-counter medications, and supplements. For all randomized subjects, all 
concomitant medications are discouraged, and 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). 
All subjects on this study will continue to take their SOC NUC therapy for the duration of the 
study. Subjects will provide a log of their ongoing SOC NUC therapy together with that of 
ABI-H0731/placebo at each clinic visit. 
6.8.1 
Prohibited Concomitant Therapy 
As the potential for drug-drug interactions between ABI-H0731 and other compounds has not yet 
been fully evaluated, consumption of grapefruit/grapefruit juice is forbidden. 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. 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. In 
particular, medications metabolized by cytochrome P450 (CYP) isoenzymes 2B6, 2C8, 2C9, or 
2D6 should be avoided (see  APPENDIX III). Concomitant prescription medications, 
over-the-counter medications, and supplements will be reported in the eCRF. 
6.8.2 
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 


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be recorded in the eCRF, including name of the medication or treatment, the start and stop dates, 
and the indication. 
7 STUDY CONDUCT 
7.1 
Study Procedures by Time Point 
Refer to the Schedule of Assessments (Table 2). 
7.2 
Discontinuation 
7.2.1 
Discontinuation from Treatment 
If an individual subject is not satisfactorily tolerating study drug treatment in the judgment of the 
clinical investigator, then -in consultation with the sponsor- that participant may be discontinued 
from treatment. Discontinuation from treatment does not mean discontinuation from the study. 
Subjects who discontinue treatment before Week 24 should immediately undergo the assessments 
listed for the Premature Termination visit (Table 2) and then continue scheduled assessments, 
except that these subjects need only two further PK collections (at the Premature Termination and 
the next scheduled time point). 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 finding will 
be reported as an adverse event. 
In this study, subjects will be closely monitored for any evidence of worsening hepatic function or 
evidence of dermatologic adverse events. Subjects with post-Baseline ALT elevations of 2-fold or 
higher will be closely monitored. Study treatment will be discontinued in subjects with confirmed 
evidence of declining hepatic function during treatment (Section 4.6.1). 
Specific guidance on management and the data to be collected at the time of study intervention 
discontinuation are described below. 
Any subjects negative by urine pregnancy test on Day 1 who are subsequently found to be positive 
on serum pregnancy test should immediately discontinue treatment and may be replaced. 
7.2.2 
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 DESCRIPTION OF STUDY PROCEDURES 
8.1 
Efficacy Assessments 
To provide an assessment of the antiviral efficacy of ABI-H0731 in NUC-suppressed HBV 
subjects, this study will evaluate treatment-related changes in serum HBsAg, serum HBeAg, 
HBCrAg, and serum HBV RNA levels. Additionally, in CHB subjects where HBV DNA is 
detectable in serum, an evaluation will be made to determine if HBV has become undetectable. 
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 RNA 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 viral antigen decline (serum HBsAg or HBeAg). Samples for quantitative 
HBsAg and HBeAg levels will be collected at screening, Day 1, and Weeks 4, 8, 12, 16, 20, and 
24 (or at the time of discontinuation). Follow-up samples will be collected Weeks 28 and 36 for 
subjects who do not continue treatment in the extension protocol. Subjects who enter the 
continuation protocol will have samples collected according to the extension protocol. 
8.1.2 
Secondary and Exploratory Efficacy Assessments 
Blood samples for the assessment of secondary and exploratory efficacy endpoints will be 
collected as described below. For all analytes, the follow-up samples will only be collected for 
subjects who do not continue treatment in the extension protocol. Subjects will have the following 
samples collected according to the Schedule of Assessments (Table 2): 
• Quantitative/qualitative HBsAg and HBeAg levels 
• HBsAb and HBeAb 
• HBV DNA 
• HBV RNA 
• HBCrAg (HBV Core related Antigen) 
• Samples for exploratory viral research  
 
HBV resistance testing, using exploratory research samples, will only be performed on subjects 
whose HBV DNA viral load becomes persistently (≥ 2 consecutive visits) detectable at a sufficient 
viral quantity for sequence analysis. 
8.1.3 
Additional Efficacy Assessments and Pharmacogenomic Assessments 
Pharmacogenomic samples will be collected at Day 1 for subjects who consent to this procedure. 
These samples may be saved for future research. 


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8.2 
Safety Assessments 
For adverse events, see Section 9. 
For serious adverse events, see Section 10. 
8.2.1 
Clinical Laboratory Tests 
Clinical laboratory tests will be performed at the timepoints indicated in the Schedule of 
Assessments (Table 2). The clinical laboratory assessments are listed in Table 3. 
Table 3 
Clinical Laboratory Tests 
Panel 
Tests 
Clinical chemistries 
Blood glucose levels, serum or plasma electrolytes (sodium, potassium, 
chloride, bicarbonate), calcium, blood urea nitrogen, creatinine, uric acid, total 
and direct bilirubin a, ALT, AST, GGT, alkaline phosphatase, LDH, amylase, 
triglycerides, total cholesterol, inorganic phosphate or total phosphate, total 
protein, albumin, lipase, and total serum or plasma globulins 
In case of ALT 
flares 
ALT, AST, total bilirubin, serum albumin, and INR 
Hematology 
Complete blood counts: hemoglobin, hematocrit, RBC indices (MCV, MCHC), 
reticulocyte counts, leukocyte counts (total and differential), and platelet counts 
Coagulation 
Prothrombin time/INR and aPTT 
Urinalysis 
pH, specific gravity, protein, glucose, ketones, and occult blood 
Rash Panel 
Erythrocyte sedimentation rate, complete blood count (with differential), 
creatinine, ALT, AST, and total bilirubin. 
Other 
AFP, HbA1c, and FSH 
Pregnancy tests 
For females only; a serum or plasma pregnancy test must be performed at 
screening, and both serum/plasma and urine are required Day 1; urine 
pregnancy test may be performed at all subsequent visits.  
A positive result disqualifies the subject for study treatment 
Urine drug 
screening 
Amphetamine/methamphetamine, barbiturates, benzodiazepines, cannabinoids, 
cocaine metabolite, ecstasy, ethanol, opiates, phencyclidine, and propoxyphene.  
Note: If cannabinoids are not illegal in the subject’s local, cannabinoids are not 
exclusionary 
Antibodies 
HCV, HDV, HAV IgM, HEV IgM, and HIV 
AFP=alpha fetoprotein; ALT=alanine aminotransferase; aPTT=activated partial thromboplastin time; AST=aspartate 
aminotransferase; FSH=follicle-stimulating hormone; GGT=gamma-glutamyl transpeptidase; HAV=hepatitis A 
virus; HbA1c=hemoglobin A1c; HCV=hepatitis C virus; HDV=hepatitis D virus; HEV=hepatitis E virus; 
HIV=human immunodeficiency virus; IgM=immunoglobulin M; INR=International Normalized Ratio; LDH=lactate 
dehydrogenase; MCHC=mean corpuscular hemoglobin concentration; MCV=mean corpuscular volume; RBC=red 
blood cell; ULN=upper limit of normal 
a 
Perform fractionated bilirubin, if total bilirubin >ULN. 


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During the study, any clinically significant laboratory abnormality or clinically significant change 
from Baseline should be recorded as an adverse event (Section 9). 
8.2.2 
Other Safety Assessments 
Other safety assessments include the following: 
• Vital signs. 
• Twelve-lead ECG. During the study, any clinically significant ECG result or change from 
Baseline should be confirmed, and if confirmed, should be recorded as an adverse event 
(Section 9). 
• Concomitant medications, including supplements and over-the-counter medications, will 
be recorded. 
8.3 
Pharmacokinetic Assessments 
Pre-dose samples will be collected to determine trough concentrations of ABI-H0731 and the SOC 
NUC therapy. Post-dose samples for both ABI-H0731 and SOC NUC will be collected from 
subjects willing and able to provide the sample 4 ± 2 hours after in-clinic dosing. Sample timing 
is outlined in Table 4. 
Table 4 
Pharmacokinetic Sample Collection 
Time Period 
Timepoint a 
Time Relative to Study Drug 
Administration b 
Double-Blind 
Treatment 
 
Study Day 1 pre-dose 
Before  
Study Weeks 2, 4, 12, 24 pre-dose Before 
OPTIONAL c 
Day 1, Week 2, and/or Week 4, 
post-dose (see laboratory manual) 
4 (±2) hours post-dose 
Follow-Up 
Study Week 28 pre-dose 
Collect at same time with other central 
labs 
a 
A PK sample should be collected if an unscheduled or premature termination visit is performed. 
b 
Sample collection times are targeted times. Samples collected outside of these targeted times will not be 
considered protocol deviations as long as the actual collection time of the sample is accurately recorded on 
source documentation and the case report form. 
c 
If a subject can only provide optional samples on Weeks 2 or 4, those may be collected from subjects that 
were not able to provide optional PK samples on Day 1. 
 
8.4 
Other Assessments 
Other assessments include the following: 
• Liver assessment at screening: To be eligible, subjects must have liver biopsy results of 


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o Metavir F0-F2 (absence of bridging fibrosis or cirrhosis) within 1 year of screening  
 
OR 
o Fasting FibroScan <8 kPa within 3 months of screening (including screening visit) or 
other approved hepatic imaging study (hepatic MRI, or hepatic ultrasound by an 
ultrasonographer with expertise in evaluation of liver fibrosis) within 6 months of 
screening indicating lack of cirrhosis or advanced liver disease (F0-F2 or equivalent). 
FibroScan should be conducted after an overnight fast. 
 
Subjects with an ambiguous non-invasive result, eg, a FibroScan >8 kPa and ≤10 kPa are 
excluded unless a biopsy within the 12 months before first visit confirms the absence of 
bridging fibrosis and cirrhosis. Subjects with a FibroScan >10 kPa are excluded. 
• Demography, medical history, and full physical examination will be performed at screening. 
8.5 
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 blinded review of data. 
9 ADVERSE EVENTS 
An adverse event is any untoward medical occurrence in a study subject administered an 
investigational product(s) regardless of the causal relationship with treatment. 
An adverse event, 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 adverse event. This includes any side effect, injury, toxicity, 
or sensitivity reaction. 
9.1 
Documenting Adverse Events 
Adverse events will be monitored throughout the entire study. Investigators will ask the subject at 
each visit if they have experienced any untoward effects since the last study visit. All adverse 
events 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. 
Adverse events will be recorded from the time written informed consent is signed until completion 
of the Week 36 follow-up visit or until 30 days following cessation of the last dose of treatment 
with the study drug for subjects who discontinue from follow-up. 


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9.2 
Assessment of Intensity 
The severity of each adverse event and laboratory abnormality is to be assessed by the Investigator 
according to the modified Division of AIDS (DAIDS) Table for Grading the Severity of Adult and 
Pediatric Adverse Events (APPENDIX II), which grades the severity of clinical adverse events 
and laboratory abnormalities in a four-category system. 
For adverse events 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 
Note that an adverse event or laboratory abnormality that is life-threatening as it exists constitutes 
a serious adverse event. 
9.3 
Assessment of Causality 
All adverse events 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 adverse event 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 adverse event 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 adverse event, 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 
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• Possibly related: An adverse event 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 adverse event 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 (dechallenge) was clinically reasonable. 
9.4 
Expectedness 
An adverse event is considered “unexpected” if it is not listed in the IB or is not listed at the 
specificity or severity that has been observed. The CRO and Sponsor medical monitors will be 
responsible for determining whether an adverse event is expected or unexpected. 
9.5 
Adverse Events of Special Interest 
Adverse events 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 adverse 
events 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 
adverse event and followed up until it returns to the normal range and/or an adequate explanation 
of the abnormality is found. 
9.7 
Adverse Event Follow-up 
After the initial adverse event or serious adverse event 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 adverse events or serious adverse events 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. 
9.8 
Pregnancy 
Pregnancy in itself is not regarded as an adverse event 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 serious adverse events (see Section 10.2). 
All reports of congenital abnormalities/birth defects are serious adverse events. Spontaneous 
miscarriages should also be reported and handled as serious adverse events. Elective abortions 


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without complications should not be handled as adverse events. All outcomes of pregnancy must 
be reported to the CRO. 
Pregnancies among female partners of male subjects will also be reported and followed for 
outcome. 


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10 SERIOUS ADVERSE EVENT 
10.1 
Definition of Serious Adverse Event 
A serious adverse event 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 a serious adverse event 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 adverse event 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: adverse events requiring hospitalization should be considered serious adverse 
events. Hospitalization for elective surgery or routine clinical procedures that are not the result of 
adverse event (eg, elective surgery for a pre-existing condition that has not worsened) need not be 
considered adverse events or serious adverse events. If anything untoward is reported during the 
procedure, that occurrence must be reported as an adverse event, either “serious” or “non-serious” 
according to the usual criteria. 
In general, hospitalization signifies that the subject has been detained (usually involving at least 
an overnight stay) at the hospital or emergency ward for observation and/or treatment that would 
not have been appropriate in the physician's office or outpatient setting. When in doubt as to 


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whether “hospitalization” occurred or was necessary, the adverse event should be considered 
serious. 
Disability/incapacitating: An adverse event 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. 
10.2 
Reporting Serious Adverse Events 
All serious adverse events must be reported within 24 hours of learning about the event. This can 
be done by emailing or faxing a completed Safety Report Form or by direct telephone 
communication to the numbers below. A Safety Report Form must follow all telephone reports 
within 24 hours. 
Fax, phone, or email SAE information to the CRO: 
The initial report should be promptly followed by detailed, written reports, which will include 
copies of relevant hospital case reports, autopsy reports, and other documents when requested and 
applicable. This additional information will be requested, if necessary, by the responsible monitor 
within 5 days of receipt of the alert report. This is to ensure that the initial reporting of serious 
adverse events is made to the Health Authorities within the required time period. 
For a follow-up report to the authorities, the monitor may be required to collect further information 
for a final evaluation of the case. Reporting to the respective country Health Authorities will be 
the responsibility of the Sponsor and the CRO. 
The CRO will be responsible for informing all central Institutional Review Boards (IRBs)/ 
Independent Ethics Committees (IECs) of serious adverse events as required. It will be the 
responsibility of the individual Investigators to inform any local IRBs/IECs of serious adverse 
events as required. Correspondence with the IRB(s)/IEC(s) relating to the reporting of serious 
adverse events will be retained in the study file. 
10.3 
Overdose 
An overdose is defined as the accidental or intentional administration of any dose of a product that 
is considered both excessive and medically important. An overdose is not in and of itself 
considered to be an adverse event unless it results in untoward medical effects. Any adverse event 


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associated with an overdose or incorrect administration of study drug should be recorded on the 
Adverse Event eCRF. If the associated adverse event fulfills the criteria of a serious adverse event, 
then the event should be reported to the Sponsor or CRO within 24 hours after the site learns of 
the event. 
11 STATISTICS 
11.1 
Statistical Hypotheses 
As a proof-of-concept trial, statistical hypotheses to compare the treatment effects in this study 
will be explored descriptively, graphically and inferentially. Unless stated otherwise, the statistical 
null hypothesis for all assessments is that the effects of ABI-H0731 + SOC NUC and placebo + 
SOC NUC are not different. The alternative hypothesis is that effects of the two treatments are 
different. 
11.2 
Sample Size 
The primary objective of the study will be measured by changes from Baseline in serum 
biomarkers (ie, HBsAg or HBeAg). As the results for this study will be used to collect information 
for future studies, both biomarkers will be reviewed independently with no control of the type I 
error (α) level. 
Subjects will be stratified 9:5 (HBeAg positive:HBeAg Negative). HBeAg positive subjects and 
HBeAg negative subjects will be evaluated both together and independently. With a sample size 
of 45 HBeAg positive subjects, randomized in a 3:2 ratio (27 active:18 placebo), a 2-sample t-test 
with a 2-sided α=0.05 significance level has 89.5% power to detect a difference of at least 0.5 log10 
(IU/mL) in the mean change from Baseline in serum HBsAg or HBeAg at Week 24. A similar test 
has 80% power to detect power to detect a treatment difference of at least 0.6 log10 (IU/mL) in the 
change from Baseline in serum HBsAg at Week 24 in HBeAg Negative Subjects. An equal 
standard deviation of 0.5 is assumed for both treatment group (Table 5 and Table 6). 


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Table 5 
Power Calculations under Various Mean Differences in the Change from 
Baseline in HBsAg (or HBeAg) levels at Week 24 between Treatment Groups 
 
Power for N=45 HBeAg Positive subjects  
(27 ABI-H0731: 18 Placebo) 
Estimated mean difference at Week 24 
between placebo + NUC and ABI-
H0731 + NUC groups Change from 
Baseline HBsAg (or HBeAg) levels 
SD = 0.25 
SD = 0.30 
SD = 0.50 
SD = 0.60 
0.25 log10 IU/mL 
0.895 
0.763 
0.362 
0.268 
0.30 log10 IU/mL 
0.971 
0.895 
0.487 
0.362 
0.40 log10 IU/mL 
0.999 
0.990 
0.729 
0.572 
0.50 log10 IU/mL 
>0.999 
>0.999 
0.895 
0.763 
0.60 log10 IU/mL 
>0.999 
>0.999 
0.971 
0.895 
Calculated using SAS, based on a two-sided, two-sample t-test for mean differences, and alpha=0.05. 
HBeAg=hepatitis B “e” antigen; HBsAg=hepatitis B surface antigen; NUC=nucleos(t)ide analogue; SD=standard 
deviation 
 
Table 6 
Power Calculations under Various Mean Differences in the Change from 
Baseline in HBsAg levels at Week 24 between Treatment Groups 
 
Power for N= 25 HBeAg Negative subjects  
(15 ABI-H0731: 10 Placebo) 
Estimated mean difference at Week 24 
between placebo + NUC and ABI-
H0731 + NUC groups Change from 
Baseline HBsAg levels 
SD = 0.25 
SD = 0.30 
SD = 0.50 
SD = 0.60 
0.25 log10 IU/mL 
0.650 
0.498 
0.217 
0.165 
0.30 log10 IU/mL 
0.804 
0.650 
0.291 
0.217 
0.40 log10 IU/mL 
0.963 
0.878 
0.467 
0.347 
0.50 log10 IU/mL 
0.997 
0.974 
0.650 
0.498 
0.60 log10 IU/mL 
>0.999 
0.997 
0.804 
0.650 
Calculated using SAS, based on a two-sided, two-sample t-test for mean differences, and alpha=0.05. 
HBeAg=hepatitis B “e” antigen; HBsAg=hepatitis B surface antigen; NUC=nucleos(t)ide analogue; SD=standard 
deviation 
 
11.3 
Analysis Populations 
The following populations for analysis will be used in this study: 
• Intent-to-treat (ITT) Population: The ITT population will be defined as all randomized 
subjects. Subjects in this population will be analyzed according to their randomized 
treatment assignment, regardless of the actual treatment received. 


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• Per-Protocol (PP) Population: The PP population will include subjects who are at least 80% 
compliant with scheduled study drug dosing in the 24-week treatment period, and who 
have no major protocol violations. 
• Safety Population: The safety population will include all randomized subjects who received 
at least one dose of study drug. Subjects in this population will be analyzed according to 
the actual treatment received. 
• Pharmacokinetic (PK1) Population 1: The PK1 population will include all subjects in the 
safety population who have ABI-H0731 PK data assessments available. 
• Pharmacokinetic (PK2) Population 2: The PK2 population will include all subjects in the 
safety population who have SOC NUC 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, PK, and efficacy analyses is given below. A 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 
used for analysis of safety and efficacy. 
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, safety, or PK observations in this study (eg, pre-
treatment ALT level, HBsAg level, HBeAg level, ethnicity, gender, etc.). These and other 
subgroup analyses will be further defined in the SAP. 
11.4.2 
Primary Endpoint(s) 
The primary efficacy parameter is the change in mean log10 serum HBsAg or HBeAg from 
Baseline to Week 24. A two-sample test of difference with a two-sided 0.05 significance level will 
be used to assess differences between the treatment groups. 
11.4.3 
Secondary and Exploratory Endpoint(s) 
Secondary and exploratory endpoints will be analyzed descriptively. All secondary and 
exploratory efficacy endpoints will be summarized (Section 3.2.2 and Section 3.2.3). 
For continuous variables, such as observed and change from Baseline HBsAg values at each 
timepoint, descriptive statistics will be used, and will include the number, mean, standard deviation, 
median, minimum, maximum, and interquartile range and, where appropriate, a 95% CI. Missing 


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data methods and imputation rules will be defined in the SAP. Additional sensitivity analysis may 
also be performed and will be described in the study SAP. 
For categorical variables, such as subjects with a 1 log10 drop in serum HBsAg or HBeAg titers 
from Baseline and subjects with HBeAg (and HBsAg) loss and seroconversion, descriptive 
statistics will include number and percent who meet the endpoint criteria. 
Kaplan-Meier methods will be used to evaluate time to event variables (eg, time to HBsAg loss), 
and the treatment groups will be compared using log-rank tests. 
Cox proportional hazards regression models will be used to identify baseline factors associated 
with HBsAg loss rates, as defined in the SAP. 
Descriptive p-values may be defined in the SAP. 
11.4.4 
Pharmacokinetic Endpoints and Analyses 
The following will be analyzed descriptively: 
• Trough levels and (for subjects who provide optional post dose samples) trough to peak 
ratios of ABI-H0731 on ABI-H0731 + SOC NUC therapy 
• Trough levels and (for subjects who provide optional post dose samples) trough to peak 
ratios of NUC on ABI-H0731 + SOC NUC therapy as compared with placebo + SOC NUC 
therapy 
After all subjects have completed Week 4 (or discontinued before completing Week 4), PK data 
will be reviewed by an unblinded pharmacology reviewer to ensure NUC steady-state PK levels 
are not being affected by combination treatment with ABI-H0731. All PK time points will be 
included in the final analysis. 
11.4.5 
Analysis of Safety 
The safety parameters to be assessed are described in Section 8.2, Section 9, and Section 10. 
Displays for safety results will utilize descriptive statistics. No formal hypothesis testing of safety 
data is planned; however, exploratory p-values to assess any potential treatment-related differences 
in the incidence of clinical adverse events, laboratory abnormalities, and treatment-emergent 
abnormal ECGs may be defined in the SAP. 
Adverse events summaries will be tabulated by Medical Dictionary for Regulatory Activities 
(MedDRA) body system and preferred term, for each treatment group. Summaries will include all 
adverse events, adverse events considered possibly or probably related to treatment, Grade ≥3 (or 
severe) adverse events, and serious adverse events. All adverse events will be listed by subject. 
Any adverse events leading to premature discontinuation from the study intervention and serious 
treatment-emergent adverse events will be presented as a separate table or a listing. 


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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 
for each subject. 
Exposure to treatment will be summarized descriptively, and compliance on treatments for both 
active and placebo (matching ABI-H0731 100-mg tablets) 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. 
Any post-screening changes in physical examination findings will be summarized in tabular form, 
by treatment group. 
11.4.6 
Demographic and Baseline Characteristics 
Other variables, including subject disposition and demographic and baseline characteristics will 
be summarized descriptively by treatment group. The demographics and baseline characteristics 
include age (in years, at time of signing informed consent), race, ethnicity, height, weight, BMI, 
HBV genotype, pre-treatment ALT levels, and prior SOC NUC therapy. 
11.5 
Interim Analysis 
No formal interim analyses will be conducted to modify or stop the study. As such, there is no 
adjustment to the type I error rate for this trial. As this is an early development trial, patient safety 
is of primary importance.  Data summaries will be provided to a DMC to evaluate safety and to an 
unblinded Pharmacologist to evaluate study drug exposure levels and potential drug-drug 
interactions. See Section 12.2 for the DMC evaluation and Section 11.4.4 for the Week 4 PK 
analysis. 
11.6 
Exploratory Analyses 
Multiple exploratory endpoints may be assessed in this study. NUCs of the HBV Pol/RT inhibit 
HBV DNA synthesis from encapsidated pre-genomic HBV RNA, resulting in reductions in serum 
HBV DNA levels. In NUC-treated subjects, while circulating HBV DNA declines due to inhibition 
of HBV Pol/RT activity, encapsidated HBV RNA remains detectable in circulating virus particles. 
This is not seen with CpAMs such as ABI-H0731 because the mechanisms of action by which 
viral load is reduced with ABI-H0731 differs from that of NUCs. As an HBV CpAM, ABI-H0731 
specifically induces accelerated mis-assembly of HBV core protein into oligomers, with reduced 
incorporation of pre-genomic HBV RNA into functional nucleocapsids. In contrast to HBV NUC 
therapies, ABI-H0731 treatment may reduce circulating levels of HBV RNA [Wang 2016]. By 
altering the encapsidation and tertiary structure of HBV capsid, ABI-H0731 may potentially 
reduce circulating HBCrAg. When NUCs are used in conjunction with a CpAM, inhibition of 
multiple aspects of the viral life cycle may also lead to accelerated loss of viral cccDNA. 
Analysis of changes in serum HBV antigen kinetics, viral RNA, and HBCrAg levels in this study 
may thus provide additional assessments of antiviral efficacy and unique mechanisms of 
ABI-H0731 in HBV subjects. 


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Data collected for this study will be analyzed and stored by the CRO. After the study is completed, 
the de-identified, archived data will be stored by the Sponsor or their designee. 
With the participant’s approval and as approved by local IRBs/IECs, de-identified biological 
samples will be stored by the Sponsor or their designee. These samples could be used to research 
CHB, its complications and other conditions for which individuals with CHB are at increased risk, 
and to improve treatment. The Sponsor will also have a code-link that will allow linking the 
biological specimens with the phenotypic data from each participant, maintaining the blinding of 
the identity of the participant. 
12 ETHICS AND RESPONSIBILITIES 
12.1 
Good Clinical Practice 
This study will be conducted in compliance with IRB/IEC and current International Council for 
Harmonisation (ICH) Good Clinical Practice (GCP) Guidelines (E6); 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 
A DMC external to the Sponsor and the CRO will be formed with members consisting of 
individuals chosen for their expertise in treatment of HBV. Members of the DMC will include, at 
a minimum, physicians external to the Sponsor and the CRO and appropriate statistical 
representation. The primary role of this independent DMC will be to monitor safety data. 
The DMC will review unblinded safety data at specified intervals, including the Week 12 safety 
data (clinical adverse events and laboratory abnormalities), as outlined in the DMC charter. 
In addition, an ad hoc meeting of the DMC may be called at any time by the DMC Chairperson or 
Sponsor if there is an imminent participant safety issue or a significant safety concern to review 
safety and any other aspect of the studies.  Significant safety events may include, but are not limited 
to: 
• A death or life-threatening condition sustained by a participant, regardless of causality 
• An unexpected serious safety issue newly identified during the development program that 
could expose participants to unnecessary risks 
• Any other concern regarding participant safety raised by any DMC member, investigator, 
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The DMC will communicate major safety concerns and recommendations regarding study 
modification or termination to the Sponsor’s senior management at any time during the conduct 
of the study. 
Records of all DMC decisions will be archived by the CRO. Selected Sponsor or CRO staff may 
serve as liaisons with the external DMC, but will not be voting members, and will not be unblinded 
to the results. Details regarding the DMC will be provided in the DMC charter. 
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. 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. 
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, screening logs, and recorded data from automated instruments. 


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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. 
13 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. 


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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 adverse events 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 the CRO may conduct audits at the investigative sites including, but not limited to, 
drug supply, presence of required documents, the informed consent process, and comparison of 
eCRFs with source documents. All medical records (progress notes) must be available for audit. 
The Investigator agrees to participate with audits conducted at a convenient time in a reasonable 
manner. 
Government regulatory authorities may also inspect the site during or after the study. The 
Investigator or designee should contact the Sponsor 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 CRO 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 the CRO 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. 
The site must complete the eCRFs in a timely manner and on an ongoing basis to allow regular 
review by the study 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 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 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. 
15 STUDY REPORT AND PUBLICATIONS 
The Sponsor or its designee is responsible for preparing and providing the appropriate regulatory 
authorities with clinical study reports according to the applicable regulatory requirements. 
The publication policy of the Sponsor is discussed in the Investigator's Clinical Research 
Agreement. 
16 STUDY DISCONTINUATION 
Both the Sponsor and the Investigator reserve the right to terminate the study at the 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. 
17 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 initials and screening and treatment 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 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 F, 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. 
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. 
Chang ML, Liaw YF. Hepatitis B flares in chronic hepatitis B: Pathogenesis, natural course, and 
management. J Hepatol. 2014;61:1407–1417. 
Gane EJ, Stedman CA, Hyland RH, et al. Nucleotide polymerase Inhibitor Sofosbuvir plus 
ribavirin for hepatitis C. N Engl J Med 2013;368:34–44. 
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. 
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, Krastev Z, 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, Naghavi M, et al. The global burden of viral hepatitis from 1990 to 
2013. Lancet. 2016 Sep 10;388(10049):1081–1088. 


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Terrault NA, Lok ASF, McMahon BJ, et al. Update on prevention, diagnosis, and treatment of 
chronic hepatitis B: AASLD 2018 hepatitis B guidance. Hepatology, 2018 Apr;67(4):1560-1599. 
Wang Q, Luan W, Warren L, et al. Serum hepatitis B surface antigen correlates with tissue 
covalently closed circular DNA in patients with hepatitis B-associated hepatocellular carcinoma. 
J Med Virol. 2016 Feb;88(2):244–251. 
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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19 APPENDICES 
19.1 
 APPENDIX I – Names of Study Personnel 
 
Sponsor: 
CRO Medical Monitor: 
 
 
 
 
 


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19.2 
APPENDIX II – Adverse Event Intensity Grading 
TOXICITY GRADING OF LABORATORY ABNORMALITIES AND CLINICAL ADVERSE 
EVENTS. PUBLISH DATE: JULY 2017 
Adapted from the U.S. National Institutes of Health (Division of AIDS) Table for Grading Severity 
of Adult Adverse Experiences (2017). Parameters within the table that have been modified for this 
study are designated by an asterisk (*). 
MAJOR CLINICAL CONDITIONS 
Cardiovascular 
Parameter 
Grade 1 Mild 
Grade 2 Moderate 
Grade 3 Severe 
Grade 4 Potentially 
Life- Threatening 
Arrhythmia 
(by ECG or 
physical 
examination) 
Specify type, if 
applicable 
No symptoms AND 
No intervention 
indicated 
No symptoms AND 
Non-urgent 
intervention indicated 
Non-life-
threatening 
symptoms AND 
Non-urgent 
intervention 
indicated 
Life-threatening 
arrhythmia OR Urgent 
intervention indicated 
Blood Pressure 
Abnormalities  
 
 
 
 
Hypertension (with 
the lowest reading 
taken after repeat 
testing during a visit) 
 
140 to < 160 mmHg 
systolic 
OR 
90 to < 100 mmHg 
diastolic 
≥ 160 to < 180 
mmHg 
systolic OR 
≥ 100 to < 110 
mmHg diastolic 
≥ 180 mmHg 
systolic OR 
≥ 110 mmHg 
diastolic 
Life-threatening 
consequences in a 
participant not 
previously diagnosed 
with hypertension 
(e.g., malignant 
hypertension) OR 
Hospitalization 
indicated 
Hypotension 
No symptoms 
Symptoms corrected 
with oral fluid 
replacement 
Symptoms AND IV 
fluids indicated 
Shock requiring use 
of vasopressors or 
mechanical assistance 
to maintain blood 
pressure 
Cardiac Ischemia or 
Infarction 
Report only one 
NA 
NA 
New symptoms with 
ischemia (stable 
angina) OR New 
testing consistent with 
ischemia 
Unstable angina OR 
Acute myocardial 
infarction 
Heart Failure 
 
 
 
No symptoms AND 
Laboratory or cardiac 
imaging 
abnormalities 
Symptoms with mild 
to moderate activity 
or exertion 
Symptoms at rest or 
with minimal activity 
or exertion (e.g., 
hypoxemia) OR 
Intervention indicated 
(e.g., oxygen) 
Life-threatening 
consequences OR 
Urgent intervention 
indicated (e.g., 
vasoactive 
medications, 
ventricular assist 
device, heart 
transplant) 
Hemorrhage 
(with significant acute 
blood loss) 
NA 
Symptoms AND 
No transfusion 
indicated 
Symptoms AND 
Transfusion of ≤ 2 
units packed RBCs 
indicated 
Life-threatening 
hypotension OR 
Transfusion of > 2 
units packed RBCs 
indicated 


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Cardiovascular 
Parameter 
Grade 1 Mild 
Grade 2 Moderate 
Grade 3 Severe 
Grade 4 Potentially 
Life- Threatening 
Prolonged QTc 
Interval1 
0.45 to 0.47 seconds 
> 0.47 to 0.50 
seconds 
> 0.50 seconds OR 
≥ 0.06 seconds above 
baseline 
Life-threatening 
consequences (e.g., 
Torsade de pointes, 
other associated 
serious ventricular 
dysrhythmia) 
Thrombosis 
or Embolism 
Report only one 
NA 
Symptoms AND No 
intervention indicated 
Symptoms AND 
Intervention indicated 
Life-threatening 
embolic event (e.g., 
pulmonary embolism, 
thrombus) 
1 As per Bazett’s formula. 


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Dermatologic 
Parameter 
Grade 1 Mild 
Grade 2 Moderate 
Grade 3 Severe 
Grade 4 Potentially 
Life- Threatening 
Alopecia (scalp only) 
Detectable by study 
participant, caregiver, 
or physician AND 
Causing no or 
minimal interference 
with usual social & 
functional activities 
Obvious on visual 
inspection AND 
Causing greater than 
minimal interference 
with usual social & 
functional activities 
NA 
NA 
Bruising 
Localized to one area 
Localized to more 
than one area 
Generalized 
NA 
Cellulitis 
NA 
Non-parenteral 
treatment indicated 
(e.g., oral antibiotics, 
antifungals, 
antivirals) 
IV treatment 
indicated (e.g., IV 
antibiotics, 
antifungals, 
antivirals) 
Life-threatening 
consequences (e.g., 
sepsis, tissue necrosis) 
Hyperpigmentation 
Slight or localized 
causing no or 
minimal interference 
with usual social & 
functional activities 
Marked or 
generalized causing 
greater than minimal 
interference with 
usual social & 
functional activities 
NA 
NA 
Hypopigmentation 
Slight or localized 
causing no or 
minimal interference 
with usual social & 
functional activities 
Marked or 
generalized causing 
greater than minimal 
interference with 
usual social & 
functional activities 
NA 
NA 
Petechiae 
Localized to one area 
Localized to more 
than one area 
Generalized 
NA 
Pruritus 3  
(without skin lesions) 
Itching causing no or 
minimal interference 
with usual social & 
functional activities 
Itching causing 
greater than minimal 
interference with 
usual social & 
functional activities 
Itching causing 
inability to perform 
usual social & 
functional activities 
NA 
Rash 
Specify type, if 
applicable 
Localized rash 
Diffuse rash OR 
Target lesions 
Diffuse rash AND 
Vesicles or limited 
number of bullae or 
superficial ulcerations 
of mucous membrane 
limited to one site 
Extensive or 
generalized bullous 
lesions OR Ulceration 
of mucous membrane 
involving 2 or more 
distinct mucosal sites 
OR Stevens-Johnson 
syndrome OR Toxic 
epidermal necrolysis 
3 For pruritus associated with injections or infusions, see the Site Reactions to Injections and Infusions section. 
 


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Endocrine and Metabolic 
Parameter 
Grade 1 Mild 
Grade 2 Moderate 
Grade 3 Severe 
Grade 4 Potentially 
Life- Threatening 
Diabetes Mellitus 
Controlled without 
medication 
Controlled with 
medication OR 
Modification of 
current medication 
regimen 
Uncontrolled despite 
treatment 
modification OR 
Hospitalization for 
immediate glucose 
control indicated 
Life-threatening 
consequences (e.g., 
ketoacidosis, 
hyperosmolar non- 
ketotic coma, end organ 
failure) 
Gynecomastia 
Detectable by study 
participant, 
caregiver, or 
physician AND 
Causing no or 
minimal interference 
with usual social & 
functional activities 
Obvious on visual 
inspection AND 
Causing pain with 
greater than minimal 
interference with 
usual social & 
functional activities 
Disfiguring changes 
AND Symptoms 
requiring intervention 
or causing inability to 
perform usual social 
& functional 
activities 
NA 
Hyperthyroidism 
No symptoms AND 
Abnormal laboratory 
value 
Symptoms causing 
greater than minimal 
interference with 
usual social & 
functional activities 
OR Thyroid 
suppression therapy 
indicated 
Symptoms causing 
inability to perform 
usual social & 
functional activities 
OR Uncontrolled 
despite treatment 
modification 
Life-threatening 
consequences (e.g., 
thyroid storm) 
Hypothyroidism 
No symptoms AND 
Abnormal laboratory 
value 
Symptoms causing 
greater than minimal 
interference with 
usual social & 
functional activities 
OR Thyroid 
replacement therapy 
indicated 
Symptoms causing 
inability to perform 
usual social & 
functional activities 
OR Uncontrolled 
despite treatment 
modification 
Life-threatening 
consequences (e.g., 
myxedema coma) 
Lipoatrophy4 
Detectable by study 
participant, 
caregiver, or 
physician AND 
Causing no or 
minimal interference 
with usual social & 
functional activities 
Obvious on visual 
inspection AND 
Causing greater than 
minimal interference 
with usual social & 
functional activities 
Disfiguring changes 
NA 
Lipohypertrophy5 
Detectable by study 
participant, 
caregiver, or 
physician AND 
Causing no or 
minimal interference 
with usual social & 
functional activities 
Obvious on visual 
inspection AND 
Causing greater than 
minimal interference 
with usual social & 
functional activities 
Disfiguring changes 
NA 
4 Definition: A disorder characterized by fat loss in the face, extremities, and buttocks. 
5 Definition: A disorder characterized by abnormal fat accumulation on the back of the neck, breasts, and abdomen. 


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Gastrointestinal 
Parameter 
Grade 1 Mild 
Grade 2 Moderate 
Grade 3 Severe 
Grade 4 
Potentially Life- 
Threatening 
Anorexia 
Loss of appetite 
without decreased 
oral intake 
Loss of appetite 
associated with 
decreased oral intake 
without significant 
weight loss 
Loss of appetite 
associated with 
significant weight loss 
Life-threatening 
consequences OR 
Aggressive 
intervention 
indicated (e.g., tube 
feeding, total 
parenteral nutrition)  
Ascites 
No symptoms 
Symptoms AND 
Intervention indicated 
(e.g., diuretics, 
therapeutic 
paracentesis) 
Symptoms recur or 
persist despite 
intervention 
Life-threatening 
consequences 
Bloating or Distension 
Report only one 
Symptoms causing 
no or minimal 
interference with 
usual social & 
functional activities 
Symptoms causing 
greater than minimal 
interference with usual 
social & functional 
activities 
Symptoms causing 
inability to perform 
usual social & 
functional activities 
NA 
Cholecystitis 
NA 
Symptoms AND 
Medical intervention 
indicated 
Radiologic, endoscopic, 
or operative 
intervention indicated  
Life-threatening 
consequences (e.g., 
sepsis, perforation) 
Constipation 
NA 
Persistent constipation 
requiring regular use of 
dietary modifications, 
laxatives, or enemas 
Obstipation with 
manual evacuation 
indicated 
Life-threatening 
consequences (e.g., 
obstruction) 
Diarrhea 
Transient or 
intermittent episodes 
of unformed stools 
OR Increase of ≤3 
stools over baseline 
per 24-hour period  
Persistent episodes of 
unformed to watery 
stools OR Increase of 4 
to 6 stools over baseline 
per 24-hour period 
Increase of ≥7 stools 
per 24-hour period OR 
IV fluid replacement 
indicated 
Life-threatening 
consequences (e.g., 
hypotensive shock) 
Dysphagia or 
Odynophagia 
Report only one and 
specify location 
Symptoms but able 
to eat usual diet 
Symptoms causing 
altered dietary intake 
with no intervention 
indicated 
Symptoms causing 
severely altered dietary 
intake with intervention 
indicated 
Life-threatening 
reduction in oral 
intake 


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Gastrointestinal 
Parameter 
Grade 1 Mild 
Grade 2 Moderate 
Grade 3 Severe 
Grade 4 
Potentially Life- 
Threatening 
Gastrointestinal 
Bleeding 
Not requiring 
intervention other 
than iron supplement 
Endoscopic intervention 
indicated 
Transfusion indicated 
Life-threatening 
consequences (e.g., 
hypotensive shock) 
Mucositis or 
Stomatitis 
Report only one and 
specify location 
Mucosal erythema 
Patchy 
pseudomembranes or 
ulcerations 
Confluent 
pseudomembranes or 
ulcerations OR Mucosal 
bleeding with minor 
trauma 
Life-threatening 
consequences (e.g., 
aspiration, choking) 
OR Tissue necrosis 
OR Diffuse 
spontaneous 
mucosal bleeding 
Nausea 
Transient (<24 
hours) or 
intermittent AND 
No or minimal 
interference with 
oral intake 
Persistent nausea 
resulting in decreased 
oral intake for 24 to 48 
hours 
Persistent nausea 
resulting in minimal 
oral intake for >48 
hours OR Rehydration 
indicated (e.g., IV 
fluids) 
Life-threatening 
consequences (e.g., 
hypotensive shock) 
Pancreatitis 
NA 
Symptoms with 
hospitalization not 
indicated 
Symptoms with 
hospitalization indicated 
Life-threatening 
consequences (e.g., 
circulatory failure, 
hemorrhage, sepsis) 
Perforation 
(colon or rectum) 
NA 
NA 
Intervention indicated 
Life-threatening 
consequences 
Proctitis 
Rectal discomfort 
with no intervention 
indicated 
Symptoms causing 
greater than minimal 
interference with usual 
social & functional 
activities OR Medical 
intervention indicated 
Symptoms causing 
inability to perform 
usual social & 
functional activities OR 
Operative intervention 
indicated 
Life-threatening 
consequences (e.g., 
perforation) 
Rectal Discharge 
Visible discharge 
Discharge requiring the 
use of pads 
NA 
NA 
Vomiting 
Transient or 
intermittent AND 
No or minimal 
interference with 
oral intake 
Frequent episodes with 
no or mild dehydration 
Persistent vomiting 
resulting in orthostatic 
hypotension OR 
Aggressive rehydration 
indicated (e.g., IV 
fluids) 
Life-threatening 
consequences (e.g., 
hypotensive shock) 
 


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Musculoskeletal 
Parameter 
Grade 1 Mild 
Grade 2 Moderate 
Grade 3 Severe 
Grade 4 Potentially 
Life- Threatening 
Arthralgia 
Joint pain causing no 
or minimal 
interference with 
usual social & 
functional activities 
Joint pain causing 
greater than minimal 
interference with 
usual social & 
functional activities 
Joint pain causing 
inability to perform 
usual social & 
functional activities 
Disabling joint pain 
causing inability to 
perform basic self-care 
functions 
Arthritis 
Stiffness or joint 
swelling causing no or 
minimal interference 
with usual social & 
functional activities 
Stiffness or joint 
swelling causing 
greater than minimal 
interference with 
usual social & 
functional activities 
Stiffness or joint 
swelling causing 
inability to perform 
usual social & 
functional activities 
Disabling joint 
stiffness or swelling 
causing inability to 
perform basic self-care 
functions 
Myalgia (generalized) 
Muscle pain causing 
no or minimal 
interference with 
usual social & 
functional activities 
Muscle pain causing 
greater than minimal 
interference with 
usual social & 
functional activities 
Muscle pain causing 
inability to perform 
usual social & 
functional activities 
Disabling muscle pain 
causing inability to 
perform basic self-care 
functions 
Osteonecrosis 
NA 
No symptoms but with 
radiographic findings 
AND No operative 
intervention indicated 
Bone pain with 
radiographic findings 
OR Operative 
intervention indicated 
Disabling bone pain 
with radiographic 
findings causing 
inability to perform 
basic self-care 
functions 
Osteopenia 6 
 ≥30 years of age 
BMD t-score -2.5 to -
1 
NA 
NA 
NA 
<30 years of age 
BMD z-score -2 to -1 
NA 
NA 
NA 
Osteoporosis 6 
≥30 years of age 
NA 
 BMD t-score <-2.5 
Pathologic fracture 
(e.g., compression 
fracture causing loss 
of vertebral height) 
 Pathologic fracture 
causing life-
threatening 
consequences 
<30 years of age 
NA 
BMD z-score <-2 
Pathologic fracture 
(e.g., compression 
fracture causing loss 
of vertebral height) 
Pathologic fracture 
causing life-
threatening 
consequences 
6 BMD t and z scores can be found in: Kanis JA on behalf of the WHO Scientific Group (2007). Assessment of osteoporosis at 
the primary health-care level. Technical Report. WHO Collaborating Centre for Metabolic Bone Diseases, University of 
Sheffield, UK. 2007: Printed by the University of Sheffield. 


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Neurologic 
Parameter 
Grade 1 Mild 
Grade 2 Moderate 
Grade 3 Severe 
Grade 4 Potentially 
Life- Threatening 
Acute CNS Ischemia 
NA 
NA 
Transient ischemic 
attack 
Cerebral vascular 
accident (e.g., stroke 
with neurological 
deficit) 
Altered Mental 
Status 
(for Dementia, see 
Cognitive, Behavioral, 
or Attentional 
Disturbance below) 
Changes causing no 
or minimal 
interference with 
usual social & 
functional activities 
Mild lethargy or 
somnolence causing 
greater than minimal 
interference with 
usual social & 
functional activities 
Confusion, memory 
impairment, lethargy, 
or somnolence 
causing inability to 
perform usual social 
& functional activities 
Delirium OR 
Obtundation OR Coma 
Ataxia 
Symptoms causing no 
or minimal 
interference with 
usual social & 
functional activities 
OR No symptoms 
with ataxia detected 
on examination 
Symptoms causing 
greater than minimal 
interference with 
usual social & 
functional activities 
Symptoms causing 
inability to perform 
usual social & 
functional activities 
Disabling symptoms 
causing inability to 
perform basic self-care 
functions 
Cognitive, 
Behavioral, or 
Attentional 
Disturbance 
(includes dementia and 
attention deficit 
disorder) 
Specify type, if 
applicable 
Disability causing no 
or minimal 
interference with 
usual social & 
functional activities 
OR Specialized 
resources not 
indicated 
Disability causing 
greater than minimal 
interference with 
usual social & 
functional activities 
OR Specialized 
resources on part- 
time basis indicated 
Disability causing 
inability to perform 
usual social & 
functional activities 
OR Specialized 
resources on a full- 
time basis indicated 
Disability causing 
inability to perform 
basic self-care 
functions OR 
Institutionalization 
indicated 
Headache 
Symptoms causing no 
or minimal 
interference with 
usual social & 
functional activities 
Symptoms causing 
greater than minimal 
interference with 
usual social & 
functional activities 
Symptoms causing 
inability to perform 
usual social & 
functional activities 
Symptoms causing 
inability to perform 
basic self-care 
functions OR 
Hospitalization 
indicated OR Headache 
with significant 
impairment of alertness 
or other neurologic 
function 
Neuromuscular 
Weakness (includes 
myopathy and 
neuropathy) Specify 
type, if applicable 
Minimal muscle 
weakness causing no 
or minimal 
interference with 
usual social & 
functional activities 
OR No symptoms 
with decreased 
strength on 
examination 
Muscle weakness 
causing greater than 
minimal interference 
with usual social & 
functional activities 
Muscle weakness 
causing inability to 
perform usual social 
& functional activities 
Disabling muscle 
weakness causing 
inability to perform 
basic self-care 
functions OR 
Respiratory muscle 
weakness impairing 
ventilation 


Protocol ABI-H0731-201 
ABI-H0731 + NUC for Virally-Suppressed CHB Patients 
Confidential
Protocol Amendment 3.0 – 09 Nov 2018 
Page 79 of 92
 
 
 
Neurologic 
Parameter 
Grade 1 Mild 
Grade 2 Moderate 
Grade 3 Severe 
Grade 4 Potentially 
Life- Threatening 
Neurosensory 
Alteration 
(includes paresthesia 
and painful 
neuropathy) 
Specify type, if 
applicable 
Minimal paresthesia 
causing no or minimal 
interference with 
usual social & 
functional activities 
OR No symptoms 
with sensory 
alteration on 
examination 
Sensory alteration or 
paresthesia causing 
greater than minimal 
interference with 
usual social & 
functional activities 
Sensory alteration or 
paresthesia causing 
inability to perform 
usual social & 
functional activities 
Disabling sensory 
alteration or paresthesia 
causing inability to 
perform basic self-care 
functions 
Seizures 
New Onset Seizure  
NA 
NA 
 1 to 3 seizures 
 Prolonged and 
repetitive seizures (e.g., 
status epilepticus) OR 
Difficult to control 
(e.g., refractory 
epilepsy) 
Pre-existing Seizure 
NA 
Increased frequency 
from previous level of 
control without 
change in seizure 
character 
Change in seizure 
character either in 
duration or quality 
(e.g., severity or 
focality) 
Prolonged and 
repetitive seizures (e.g., 
status epilepticus) OR 
Difficult to control 
(e.g., refractory 
epilepsy) 
Syncope 
Near syncope without 
loss of consciousness 
(e.g., presyncope) 
Loss of consciousness 
with no intervention 
indicated 
Loss of consciousness 
AND Hospitalization 
or intervention 
required 
NA 
 


Protocol ABI-H0731-201 
ABI-H0731 + NUC for Virally-Suppressed CHB Patients 
Confidential
Protocol Amendment 3.0 – 09 Nov 2018 
Page 80 of 92
 
 
 
Pregnancy, Puerperium, and Perinatal 
Parameter 
Grade 1 Mild 
Grade 2 Moderate 
Grade 3 Severe 
Grade 4 Potentially 
Life- Threatening 
Stillbirth (report 
using mother’s 
participant ID) 
Report only one 
NA 
NA 
Fetal death occurring 
at ≥20 weeks 
gestation 
NA 
Preterm Birth (report 
using mother’s 
participant ID) 
Live birth at 34 to 
<37 weeks gestational 
age 
Live birth at 28 to 
<34 weeks gestational 
age 
Live birth at 24 to 
<28 weeks gestational 
age 
Live birth at <24 
weeks gestational age 
Spontaneous 
Abortion or 
Miscarriage 7 (report 
using mother’s 
participant ID) 
Report only one 
Chemical pregnancy 
Uncomplicated 
spontaneous abortion 
or miscarriage 
Complicated 
spontaneous abortion 
or miscarriage 
NA 
7 Definition: A pregnancy loss occurring at <20 weeks gestational age. 
 


Protocol ABI-H0731-201 
ABI-H0731 + NUC for Virally-Suppressed CHB Patients 
Confidential
Protocol Amendment 3.0 – 09 Nov 2018 
Page 81 of 92
 
 
 
Psychiatric 
Parameter 
Grade 1 Mild 
Grade 2 Moderate 
Grade 3 Severe 
Grade 4 Potentially 
Life- Threatening 
Insomnia 
Mild difficulty falling 
asleep, staying asleep, 
or waking up early 
causing no or minimal 
interference with usual 
social & functional 
activities 
Moderate difficulty 
falling asleep, staying 
asleep, or waking up 
early causing more 
than minimal 
interference with usual 
social & functional 
activities 
Severe difficulty 
falling asleep, staying 
asleep, or waking up 
early causing inability 
to perform usual social 
& functional activities 
requiring intervention 
or hospitalization 
NA 
Psychiatric Disorders 
(includes anxiety, 
depression, mania, and 
psychosis) 
Specify disorder 
Symptoms with 
intervention not 
indicated OR 
Behavior causing no 
or minimal 
interference with usual 
social & functional 
activities 
Symptoms with 
intervention indicated 
OR Behavior causing 
greater than minimal 
interference with usual 
social & functional 
activities 
Symptoms with 
hospitalization 
indicated OR 
Behavior causing 
inability to perform 
usual social & 
functional activities 
Threatens harm to self 
or others OR Acute 
psychosis OR 
Behavior causing 
inability to perform 
basic self-care 
functions 
Suicidal Ideation or 
Attempt 
Report only one 
Preoccupied with 
thoughts of death 
AND No wish to kill 
oneself 
Preoccupied with 
thoughts of death 
AND Wish to kill 
oneself with no 
specific plan or intent 
Thoughts of killing 
oneself with partial or 
complete plans but no 
attempt to do so OR 
Hospitalization 
indicated 
Suicide attempted 
 


Protocol ABI-H0731-201 
ABI-H0731 + NUC for Virally-Suppressed CHB Patients 
Confidential
Protocol Amendment 3.0 – 09 Nov 2018 
Page 82 of 92
 
 
 
Respiratory 
Parameter 
Grade 1 Mild 
Grade 2 Moderate 
Grade 3 Severe 
Grade 4 Potentially 
Life- Threatening 
Acute Bronchospasm 
Forced expiratory 
volume in 1 second or 
peak flow reduced to 
≥70 to <80% OR 
Mild symptoms with 
intervention not 
indicated 
Forced expiratory 
volume in 1 second or 
peak flow 50 to <70% 
OR Symptoms with 
intervention indicated 
OR Symptoms 
causing greater than 
minimal interference 
with usual social & 
functional activities 
Forced expiratory 
volume in 1 second or 
peak flow 25 to <50% 
OR Symptoms 
causing inability to 
perform usual social 
& functional activities 
Forced expiratory 
volume in 1 second or 
peak flow <25% OR 
Life-threatening 
respiratory or 
hemodynamic 
compromise OR 
Intubation 
Dyspnea or 
Respiratory Distress 
Report only one 
Dyspnea on exertion 
with no or minimal 
interference with 
usual social & 
functional activities 
OR Wheezing OR 
Minimal increase in 
respiratory rate for 
age 
Dyspnea on exertion 
causing greater than 
minimal interference 
with usual social & 
functional activities 
OR Nasal flaring OR 
Intercostal retractions 
OR Pulse oximetry 90 
to <95% 
Dyspnea at rest 
causing inability to 
perform usual social 
& functional activities 
OR Pulse oximetry 
<90% 
Respiratory failure 
with ventilator support 
indicated (e.g., CPAP, 
BPAP, intubation) 
 


Protocol ABI-H0731-201 
ABI-H0731 + NUC for Virally-Suppressed CHB Patients 
Confidential
Protocol Amendment 3.0 – 09 Nov 2018 
Page 83 of 92
 
 
 
Sensory 
Parameter 
Grade 1 Mild 
Grade 2 Moderate 
Grade 3 Severe 
Grade 4 Potentially 
Life- Threatening 
Hearing Loss  
NA 
Hearing aid or 
intervention not 
indicated 
Hearing aid or 
intervention indicated 
Profound bilateral 
hearing loss (>80 dB at 
2 kHz and above) OR 
Non-serviceable 
hearing (i.e., >50 dB 
audiogram and <50% 
speech discrimination) 
Tinnitus 
Symptoms causing no 
or minimal 
interference with usual 
social & functional 
activities with 
intervention not 
indicated 
Symptoms causing 
greater than minimal 
interference with 
usual social & 
functional activities 
with intervention 
indicated 
Symptoms causing 
inability to perform 
usual social & 
functional activities 
NA 
Uveitis 
No symptoms AND 
Detectable on 
examination 
Anterior uveitis with 
symptoms OR 
Medical intervention 
indicated 
Posterior or pan-
uveitis OR Operative 
intervention indicated 
Disabling visual loss in 
affected eye(s) 
Vertigo 
Vertigo causing no or 
minimal interference 
with usual social & 
functional activities 
Vertigo causing 
greater than minimal 
interference with 
usual social & 
functional activities 
Vertigo causing 
inability to perform 
usual social & 
functional activities 
Disabling vertigo 
causing inability to 
perform basic self-care 
functions 
Visual Changes 
(assessed from 
baseline) 
Visual changes 
causing no or minimal 
interference with usual 
social & functional 
activities 
Visual changes 
causing greater than 
minimal interference 
with usual social & 
functional activities 
Visual changes 
causing inability to 
perform usual social 
& functional activities 
Disabling visual loss in 
affected eye(s) 
 


Protocol ABI-H0731-201 
ABI-H0731 + NUC for Virally-Suppressed CHB Patients 
Confidential
Protocol Amendment 3.0 – 09 Nov 2018 
Page 84 of 92
 
 
 
Systemic 
Parameter 
Grade 1 Mild 
Grade 2 Moderate 
Grade 3 Severe 
Grade 4 Potentially 
Life- Threatening 
Acute Allergic 
Reaction 
Localized urticaria 
(wheals) with no 
medical intervention 
indicated 
Localized urticaria 
with intervention 
indicated OR Mild 
angioedema with no 
intervention indicated 
Generalized urticaria 
OR Angioedema with 
intervention indicated 
OR Symptoms of mild 
bronchospasm 
Acute anaphylaxis OR 
Life-threatening 
bronchospasm OR 
Laryngeal edema 
Chills 
Symptoms causing no 
or minimal 
interference with 
usual social & 
functional activities 
Symptoms causing 
greater than minimal 
interference with usual 
social & functional 
activities 
Symptoms causing 
inability to perform 
usual social & 
functional activities 
NA 
Cytokine Release 
Syndrome 8 
Mild signs and 
symptoms AND 
Therapy (i.e., 
antibody infusion) 
interruption not 
indicated 
Therapy (i.e., antibody 
infusion) interruption 
indicated AND 
Responds promptly to 
symptomatic treatment 
OR Prophylactic 
medications indicated 
for ≤24 hours 
Prolonged severe 
signs and symptoms 
OR Recurrence of 
symptoms following 
initial improvement 
Life-threatening 
consequences (e.g., 
requiring pressor or 
ventilator support) 
Fatigue or Malaise 
Report only one 
Symptoms causing no 
or minimal 
interference with 
usual social & 
functional activities 
Symptoms causing 
greater than minimal 
interference with usual 
social & functional 
activities 
Symptoms causing 
inability to perform 
usual social & 
functional activities 
Incapacitating 
symptoms of fatigue or 
malaise causing 
inability to perform 
basic self-care 
functions 
Fever (non-axillary 
temperatures only) 
38.0 to <38.6°C or 
100.4 to <101.5°F 
≥38.6 to <39.3°C or ≥
101.5 to <102.7°F 
≥39.3 to <40.0°C or ≥
102.7 to <104.0°F 
≥40.0°C or  
≥104.0°F 
Pain 9 (not associated 
with study agent 
injections and not 
specified elsewhere) 
Specify location 
Pain causing no or 
minimal interference 
with usual social & 
functional activities 
Pain causing greater 
than minimal 
interference with usual 
social & functional 
activities 
Pain causing inability 
to perform usual social 
& functional activities 
Disabling pain causing 
inability to perform 
basic self-care 
functions OR 
Hospitalization 
indicated 
Serum Sickness 10 
Mild signs and 
symptoms 
Moderate signs and 
symptoms AND 
Intervention indicated 
(e.g., antihistamines) 
Severe signs and 
symptoms AND 
Higher level 
intervention indicated 
(e.g., steroids or IV 
fluids) 
Life-threatening 
consequences (e.g., 
requiring pressor or 
ventilator support) 
Underweight 11 
 
WHO BMI z-score  
<-1 to -2 
WHO BMI z-score 
 <-2 to -3 
WHO BMI z-score <-
3 
WHO BMI z-score <-
3 with life-threatening 
consequences 
Unintentional 
Weight Loss  
(excludes postpartum 
weight loss) 
NA 
5 to <9% loss in body 
weight from baseline 
≥9 to <20% loss in 
body weight from 
baseline 
≥20% loss in body 
weight from baseline 
OR Aggressive 
intervention indicated 
(e.g., tube feeding, 
total parenteral 
nutrition) 
8 Definition: A disorder characterized by nausea, headache, tachycardia, hypotension, rash, and/or shortness of breath. 
9 For pain associated with injections or infusions, see the Site Reactions to Injections and Infusions section. 
10 Definition: A disorder characterized by fever, arthralgia, myalgia, skin eruptions, lymphadenopathy, marked discomfort, 
and/or dyspnea. 


Protocol ABI-H0731-201 
ABI-H0731 + NUC for Virally-Suppressed CHB Patients 
Confidential
Protocol Amendment 3.0 – 09 Nov 2018 
Page 85 of 92
 
 
 
 11 WHO reference tables may be accessed by clicking the desired age range or by accessing the following URL: 
http://www.who.int/growthref/who2007_bmi_for_age/en/ for participants >5 to 19 years of age 


Protocol ABI-H0731-201 
ABI-H0731 + NUC for Virally-Suppressed CHB Patients 
Confidential
Protocol Amendment 3.0 – 09 Nov 2018 
Page 86 of 92
 
 
 
Urinary 
Parameter 
Grade 1 Mild 
Grade 2 Moderate 
Grade 3 Severe 
Grade 4 Potentially 
Life- Threatening 
Urinary Tract 
Obstruction 
NA 
Signs or symptoms of 
urinary tract 
obstruction without 
hydronephrosis or 
renal dysfunction 
Signs or symptoms of 
urinary tract 
obstruction with 
hydronephrosis or 
renal dysfunction 
Obstruction causing 
life-threatening 
consequences 
 
 


Protocol ABI-H0731-201 
ABI-H0731 + NUC for Virally-Suppressed CHB Patients 
Confidential
Protocol Amendment 3.0 – 09 Nov 2018 
Page 87 of 92
 
 
 
Site Reactions to Injections and Infusions 
Parameter 
Grade 1 Mild 
Grade 2 Moderate 
Grade 3 Severe 
Grade 4 Potentially 
Life- Threatening 
Injection Site Pain or 
Tenderness  
Report only one 
Pain or tenderness 
causing no or minimal 
limitation of use of 
limb 
Pain or tenderness 
causing greater than 
minimal limitation of 
use of limb 
Pain or tenderness 
causing inability to 
perform usual social 
& functional activities 
Pain or tenderness 
causing inability to 
perform basic self-care 
function OR 
Hospitalization 
indicated 
Injection Site 
Erythema or 
Redness 12 
Report only one 
2.5 to <5 cm in 
diameter OR 6.25 to 
<25 cm2 surface area 
AND Symptoms 
causing no or minimal 
interference with usual 
social & functional 
activities 
≥5 to <10 cm in 
diameter OR ≥25 to 
<100 cm2 surface area 
OR Symptoms 
causing greater than 
minimal interference 
with usual social & 
functional activities 
≥10 cm in diameter 
OR ≥100 cm2 surface 
area OR Ulceration 
OR Secondary 
infection OR Phlebitis 
OR Sterile abscess 
OR Drainage OR 
Symptoms causing 
inability to perform 
usual social & 
functional activities 
Potentially life- 
threatening 
consequences (e.g., 
abscess, exfoliative 
dermatitis, necrosis 
involving dermis or 
deeper tissue) 
Injection Site 
Induration or 
Swelling 
Report only one  
Same as for Injection 
Site Erythema or 
Redness, >15 years of 
age 
Same as for Injection 
Site Erythema or 
Redness, >15 years of 
age 
Same as for Injection 
Site Erythema or 
Redness, >15 years of 
age 
Same as for Injection 
Site Erythema or 
Redness, >15 years of 
age 
Injection Site 
Pruritus 
Itching localized to the 
injection site that is 
relieved spontaneously 
or in <48 hours of 
treatment 
Itching beyond the 
injection site that is 
not generalized OR 
Itching localized to 
the injection site 
requiring ≥48 hours 
treatment 
Generalized itching 
causing inability to 
perform usual social 
& functional activities 
NA 
12 Injection Site Erythema or Redness should be evaluated and graded using the greatest single diameter or measured surface 
area. 
 


Protocol ABI-H0731-201 
ABI-H0731 + NUC for Virally-Suppressed CHB Patients 
Confidential
Protocol Amendment 3.0 – 09 Nov 2018 
Page 88 of 92
 
 
 
Laboratory Values*: Chemistries 
Parameter 
Grade 1 Mild 
Grade 2 Moderate 
Grade 3 Severe 
Grade 4 Potentially 
Life- Threatening 
Acidosis 
NA 
pH≤7.3 to <LLN 
pH<7.3 without life- 
threatening 
consequences 
pH<7.3 with life- 
threatening 
consequences 
Albumin, Low 
(g/dL; g/L) 
3.0 to < LLN 
30  to < LLN 
≥ 2.0 to < 3.0 
≥ 20  to < 30 
< 2.0 
< 20 
NA 
Alkaline Phosphatase, 
High 
1.25 to < 2.5 x 
ULN 
2.5 to < 5.0 x ULN 
5.0 to < 10.0 x ULN 
≥ 10.0 x ULN 
Alkalosis 
NA 
pH > ULN to ≤ 7.5 
pH > 7.5 without life- 
threatening 
consequences 
pH > 7.5 with life- 
threatening 
consequences 
ALT or SGPT, High 
Report only one 
1.25 to < 2.5 x 
ULN 
2.5 to < 5.0 x ULN 
5.0 to < 10.0 x ULN 
≥ 10.0 x ULN 
Amylase (Pancreatic) or 
Amylase (Total), High 
Report only one 
1.1 to 
<1.5×ULN 
1.5 to <3.0×ULN 
3.0 to <5.0×ULN 
≥5.0×ULN 
AST or SGOT, High 
Report only one 
1.25 to < 2.5 x 
ULN 
2.5 to < 5.0 x ULN 
5.0 to < 10.0 x ULN 
≥ 10.0 x ULN 
Bicarbonate, Low  
(mEq/L; mmol/L) 
16.0 to <LLN 
16.0 to <LLN 
11.0 to <16.0 11.0 to 
<16.0 
8.0 to <11.0 
8.0 to <11.0 
<8.0  
<8.0 
Bilirubin 
Direct Bilirubin, 
High 
 
 
NA 
 
NA 
 
> ULN with other signs 
and symptoms of 
hepatotoxicity 
 
> ULN with life- 
threatening 
consequences (e.g., 
signs and symptoms of 
liver failure) 
Total Bilirubin, 
High  
1.1 to 
<1.6×ULN 
 1.6 to <2.6×ULN 
2.6 to <5.0×ULN 
≥5.0×ULN 
Calcium, High (mg/dL; 
mmol/L)  
10.6 to <11.5  
2.65 to <2.88 
11.5 to <12.5  
2.88 to <3.13 
12.5 to <13.5  
3.13 to <3.38 
≥ 13.5  
≥3.38 
Calcium (Ionized), High 
(mg/dL; mmol/L) 
>ULN to <6.0 
>ULN to <1.5 
6.0 to <6.4 
1.5 to <1.6 
6.4 to <7.2  
1.6 to <1.8 
≥7.2  
≥1.8 
Calcium, Low (mg/dL; 
mmol/L)  
7.8 to <8.4 
1.95 to <2.10 
7.0 to <7.8  
1.75 to <1.95 
6.1 to <7.0  
1.53 to <1.75 
 <6.1  
<1.53 
Calcium (Ionized), Low 
(mg/dL; mmol/L) 
<LLN to 4.0  
<LLN to 1.0 
3.6 to <4.0  
0.9 to <1.0 
3.2 to <3.6  
0.8 to <0.9 
<3.2  
<0.8 
Cardiac Troponin I, High 
NA 
NA 
NA 
Levels consistent with 
myocardial infarction 
or unstable angina as 
defined by the local 
laboratory 
Creatine Kinase, High 
3 to <6×ULN 
6 to <10×ULN 
10 to <20×ULN 
≥20×ULN 
Creatinine, High *Report 
only one 
1.1 to 1.3×ULN 
>1.3 to 1.8×ULN OR 
Increase to 1.3 to 
<1.5×participant’s 
baseline 
>1.8 to <3.5×ULN OR 
Increase to 1.5 to 
<2.0×participant’s 
baseline 
≥3.5×ULN OR 
Increase of ≥2.0×
participant’s baseline 


Protocol ABI-H0731-201 
ABI-H0731 + NUC for Virally-Suppressed CHB Patients 
Confidential
Protocol Amendment 3.0 – 09 Nov 2018 
Page 89 of 92
 
 
 
Laboratory Values*: Chemistries 
Parameter 
Grade 1 Mild 
Grade 2 Moderate 
Grade 3 Severe 
Grade 4 Potentially 
Life- Threatening 
Creatinine Clearance 13 
or eGFR, Low 
*Report only one 
NA 
<90 to 60 ml/min or 
ml/min/1.73 m2 OR 
10 to <30% decrease 
from participant’s 
baseline 
<60 to 30 ml/min or 
ml/min/1.73 m2 OR 30 
to <50% decrease from 
participant’s baseline 
<30 ml/min or 
ml/min/1.73 m2 OR ≥
50% decrease from 
participant’s baseline 
or dialysis needed 
Glucose (mg/dL; mmol/L) 
Fasting, High 
110 to 125  
6.11 to <6.95 
>125 to 250 
6.95 to <13.89 
>250 to 500 
 13.89 to <27.75 
≥500 
≥27.75 
Nonfasting, High 
116 to 160 
6.44 to <8.89 
>160 to 250  
8.89 to <13.89 
>250 to 500 
13.89 to <27.75 
≥500 
≥27.75 
Glucose, Low (mg/dL; 
mmol/L)  
 55 to 64 
3.05 to <3.55 
40 to <55 
2.22 to <3.05 
30 to <40 
1.67 to <2.22 
 <30 
<1.67 
Lactate, High 
ULN to 
<2.0×ULN 
without acidosis 
≥2.0×ULN without 
acidosis 
Increased lactate with 
pH <7.3 without life- 
threatening 
consequences 
Increased lactate with 
pH <7.3 with life- 
threatening 
consequences 
Lipase, High 
1.1 to 
<1.5×ULN 
1.5 to <3.0×ULN 
3.0 to <5.0×ULN 
≥5.0×ULN 
Lipid Disorders (mg/dL; 
mmol/L) 
Cholesterol, Fasting, High  
200 to <240 
 
5.18 to <6.19 
240 to <300 
 
6.19 to <7.77 
≥300 
 
≥7.77 
NA 
LDL, Fasting, High  
130 to <160 
3.37 to <4.12 
160 to <190  
4.12 to <4.90 
≥190 
≥4.90 
NA 
Triglycerides, Fasting, 
High 
150 to 300 
1.71 to 3.42 
>300 to 500  
>3.42 to 5.7 
>500 to <1,000 
>5.7 to 11.4 
>1,000 
>11.4 
Magnesium 14, Low 
(mEq/L; mmol/L) 
1.2 to <1.4  
0.60 to <0.70 
0.9 to <1.2  
0.45 to <0.60 
0.6 to <0.9  
0.30 to <0.45 
<0.6 
<0.30 
Phosphate, Low (mg/dL; 
mmol/L)  
2.0 to <LLN 
0.65 to <LLN 
1.4 to <2.0  
0.45 to <0.65 
1.0 to <1.4  
0.32 to <0.45 
 <1.0 
<0.32 
Potassium, High (mEq/L; 
mmol/L) 
5.6 to <6.0  
5.6 to <6.0 
6.0 to <6.5  
6.0 to <6.5 
6.5 to <7.0  
6.5 to <7.0 
≥7.0  
≥7.0 
Potassium, Low (mEq/L; 
mmol/L) 
3.0 to <3.4  
3.0 to <3.4 
2.5 to <3.0 
2.5 to <3.0 
2.0 to <2.5  
2.0 to <2.5 
<2.0 
<2.0 
Sodium, High (mEq/L; 
mmol/L) 
146 to <150 
146 to <150 
150 to <154  
150 to <154 
154 to <160  
154 to <160 
≥160  
≥160 
Sodium, Low (mEq/L; 
mmol/L) 
130 to <135  
130 to <135 
125 to <130  
125 to <130 
121 to <125  
121 to <125 
<121  
<121 
Uric Acid, High (mg/dL; 
mmol/L) 
7.5 to <10.0  
0.45 to <0.59 
10.0 to <12.0  
0.59 to <0.71 
12.0 to <15.0 
0.71 to <0.89 
≥15.0 
≥0.89 
*Reminder: Choose the method that selects for the higher grade. 
*Reminder: An asymptomatic abnormal laboratory finding without an accompanying adverse event should not be reported to 
DAIDS in an expedited time frame unless it meets protocol-specific reporting requirements. 
13 Use the applicable formula (i.e., Cockcroft-Gault in mL/min or Schwartz, MDRD, CKD-Epi in mL/min/1.73m2). Sites should 
choose the method defined in their study and when not specified, use the method most relevant to the study population. 
14 To convert a magnesium value from mg/dL to mmol/L, laboratories should multiply by 0.4114. 


Protocol ABI-H0731-201 
ABI-H0731 + NUC for Virally-Suppressed CHB Patients 
Confidential
Protocol Amendment 3.0 – 09 Nov 2018 
Page 90 of 92
 
 
 
Hematology 
Parameter 
Grade 1 Mild 
Grade 2 Moderate 
Grade 3 Severe 
Grade 4 Potentially 
Life- Threatening 
Absolute CD4+ 
Count, Low 
(cell/mm3; cells/L) (not 
HIV infected) 
300 to <400 
300 to <400 
200 to <300 
200 to <300 
100 to <200 
100 to <200 
<100 
<100 
Absolute Lymphocyte 
Count, Low 
(cell/mm3; cells/L) 
(not HIV infected) 
600 to <650 
0.600×109 to 
<0.650×109 
500 to <600 
0.500×109 to 
<0.600×109 
350 to <500 
0.350×109 to 
<0.500×109 
<350  
<0.350×109 
Absolute Neutrophil 
Count (ANC), Low 
(cells/mm3; cells/L) 
800 to 1,000  
0.800×109 to 
1.000×109 
600 to 799 
0.600×109 to 
0.799×109 
400 to 599 
0.400×109 to 
0.599×109 
<400 
<0.400×109 
Fibrinogen, 
Decreased (mg/dL; 
g/L) 
100 to <200 
1.00 to <2.00 OR 0.75 
to <1.00×LLN 
75 to <100 
0.75 to <1.00 OR ≥
0.50 to <0.75×LLN 
50 to <75 
0.50 to <0.75 OR 
0.25 to <0.50×LLN 
<50 
<0.50 OR 
<0.25×LLN OR 
Associated with gross 
bleeding 
Hemoglobin 15, Low 
(g/dL; mmol/L) 16  
Male only 
10.0 to 10.9 
6.19 to 6.76 
9.0 to <10.0 
5.57 to <6.19 
7.0 to <9.0 
4.34 to <5.57 
<7.0 
<4.34 
Hemoglobin 15, Low 
(g/dL; mmol/L) 16  
female only 
9.5 to 10.4 
5.88 to 6.48 
8.5 to <9.5 
5.25 to <5.88 
6.5 to <8.5 
4.03 to <5.25 
<6.5 
<4.03 
INR, High (not on 
anticoagulation 
therapy) 
1.1 to <1.5×ULN 
1.5 to <2.0×ULN 
2.0 to <3.0×ULN 
≥3.0×ULN 
Methemoglobin 
(% hemoglobin) 
5.0 to <10.0% 
10.0 to <15.0% 
15.0 to <20.0% 
≥20.0% 
PTT, High 
(not on anticoagulation 
therapy) 
1.1 to <1.66×ULN 
1.66 to <2.33×ULN 
2.33 to <3.00×ULN 
≥3.00×ULN 
Platelets, Decreased 
(cells/mm3; cells/L) 
100,000 to <125,000 
100.000×109 to 
<125.000×109 
50,000 to <100,000 
50.000×109 to 
<100.000×109 
25,000 to <50,000 
25.000×109 to 
<50.000×109 
<25,000  
<25.000×109 
PT, High 
(not on anticoagulation 
therapy) 
1.1 to <1.25×ULN 
1.25 to <1.50×ULN 
1.50 to <3.00×ULN 
≥3.00×ULN 
WBC, Decreased 
(cells/mm3; cells/L)  
2,000 to 2,499  
2.000×109 to 
2.499×109 
1,500 to 1,999  
1.500×109 to 
1.999×109 
1,000 to 1,499  
1.000×109 to 
1.499×109 
<1,000 
<1.000×109 
15 Male and female sex are defined as sex at birth. For transgender participants who have been on hormone therapy for more 
than 6 consecutive months, grade hemoglobin based on the gender with which they identify (i.e., a transgender female should be 
graded using the female sex at birth hemoglobin laboratory values). 
16 The most commonly used conversion factor to convert g/dL to mmol/L is 0.6206. For grading hemoglobin results obtained by 
an analytic method with a conversion factor other than 0.6206, the result must be converted to g/dL using appropriate conversion 
factor for the particular laboratory. 
 
 


Protocol ABI-H0731-201 
ABI-H0731 + NUC for Virally-Suppressed CHB Patients 
Confidential
Protocol Amendment 3.0 – 09 Nov 2018 
Page 91 of 92
 
 
 
Urinalysis 
Parameter 
Grade 1 Mild 
Grade 2 Moderate 
Grade 3 Severe 
Grade 4 Potentially 
Life- Threatening 
Glycosuria (random 
collection tested by 
dipstick) 
Trace to 1+ or ≤250 
mg 
2+ or ˃250 to ≤500 
mg 
>2+ or >500 mg 
NA 
Hematuria (not to be 
reported based on 
dipstick findings or on 
blood believed to be 
of menstrual origin) 
6 to <10 RBCs per 
high power field 
≥10 RBCs per high 
power field 
Gross, with or without 
clots OR With RBC 
casts OR Intervention 
indicated 
Life-threatening 
consequences 
Proteinuria (random 
collection tested by 
dipstick) 
1+ 
2+ 
3+ or higher 
NA 


Protocol ABI-H0731-201 
ABI-H0731 + NUC for Virally-Suppressed CHB Patients 
Confidential
Protocol Amendment 3.0 – 09 Nov 2018 
Page 92 of 92
 
 
 
 
19.3 
 APPENDIX III – Cytochrome P450 2B6, 2C8, 2C9, and 2D6 Substrates 
The following drugs are known substrates of CYP 2B6, 2C8, 2C9, and 2D6 and should only be 
used with caution while receiving ABI-H0731. Drugs with a low therapeutic index should be 
avoided. 
• 2B6:  Artemisinin, bupropion, cyclophosphamide, efavirenz, ifosphamide, ketamine,  
 
meperidine, methadone, nevirapine, propafol 
• 2C8:  Amodiaquine, cerivastatin, paclitaxel, repaglinide, sorafenib, torsemide 
• 2C9:  NSAIDs: Diclofenac, ibuprofen, lornoxicam, meloxicam, S-naproxen→Nor,  
 
 
piroxicam, suprofen 
 
Oral Hypoglycemic Agents: Tolbutamide, glipizide 
 
Angiotensin II Blockers: Losartan, Irbesartan 
 
Sulfonylureas: Glyburide, glibenclamide, glipizide, glimepiride, tolbutamide 
 
Other: Amitriptyline, celecoxib, fluoxetine, fluvastatin, glyburide, nateglinide,  
 
 
phenytoin-4-OH2, rosiglitazone, tamoxifen 
• 2D6: Tamoxifen 
 
Beta Blockers: Carvedilol, S-metoprolol, propafenone, timolol 
 
Antidepressants: Amitriptyline, clomipramine, desipramine, fluoxetine,  
 
 
imipramine, paroxetine, venlafaxine 
 
Antipsychotics: Haloperidol, perphenazine, risperidone→9-OH, thioridazine,  
 
 
zuclopenthixol 
 
Other: Alprenolol, amphetamine, aripiprazole, atomoxetine, bufuralol,  
 
 
chlorpheniramine, chlorpromazine, clonidine, codeine (→O-desMe),  
 
 
debrisoquine, dexfenfluramine, dextromethorphan, donepezil, duloxetine,  
 
 
encainide, flecainide, fluvoxamine, lidocaine, metoclopramide,  
 
 
methoxyamphetamine, mexiletine, minaprine, nebivolol, nortriptyline,  
 
 
ondansetron, oxycodone, perhexiline, phenacetin, phenformin, promethazine,  
 
 
propafenone, propranolol, risperidone, sparteine, tramadol 
 
Source: 
The Flockhart Table. http://medicine.iupui.edu/clinpharm/ddis/main-table# [Accessed 
26 Apr 2018] 
 

SAP_001.pdf: 
 
Title:  A Phase 2a, Multi-center, Double-blind, Placebo-
controlled Study Evaluating ABI-H0731 as Adjunctive Therapy 
in Virally-suppressed Patients with Chronic Hepatitis B  
  
NCT number:  NCT03576066 
 
Date:  06 Aug 2019 




 
 
 
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Protocol no: ABI-H0731-201  
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Strictly Confidential.  © 2017, PRA Health Sciences.  All rights reserved. 
Statistical Analysis Plan 
Sponsor: 
Assembly Biosciences 
Protocol No: 
ABI-H0731-201 
PRA Project Id: 
ASM31201-731201 
Protocol Version: 
Amendment 3 v4.0 / 09 November 2018 
Amendment 2 v3.0 / 09 September 2018 
Amendment 1 v2.0 / 18 June 2018 
Original v1.0 / 10 May 2018 
 
Title: 
A Phase 2a, Multi-center, Double-blind, Placebo-controlled Study Evaluating ABI-
H0731 as Adjunctive Therapy in Virally-suppressed Patients with Chronic Hepatitis B 
CRF Version Date: 
15 Jan 2019 
SAP No./Date 
Final v1.0 / 06 Aug 2019 
 
 Approvals 
Sponsor: Assembly Biosciences 
Representative/ Title: 
Signature /Date: 
 
 
Representative/ Title: 
Signature /Date: 
 
 
PRA 
Project Manager/Title: 
Signature /Date: 
 
 
Biostatistician / Title 
(Owner): 
Signature /Date: 
 
 
 
 
 


 
 
 
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Table of Contents 
 Approvals ............................................................................................................................................................................ 1 
Table of Contents ..................................................................................................................................................................... 2 
 Purpose ................................................................................................................................................................................ 4 
 Scope ..................................................................................................................................................................................... 4 
 Introduction ....................................................................................................................................................................... 4 
4.1 Changes from Protocol .............................................................................................................................................. 4 
 Study Objectives ............................................................................................................................................................... 5 
5.1 Primary Objectives ..................................................................................................................................................... 5 
5.2 Secondary Objectives ................................................................................................................................................. 5 
5.3 Exploratory Objectives .............................................................................................................................................. 5 
 Study Design ....................................................................................................................................................................... 5 
6.1 Sample Size Considerations .................................................................................................................................... 6 
6.2 Randomization ............................................................................................................................................................. 7 
6.3 Schedule of Assessments .......................................................................................................................................... 7 
 Study Endpoints, Variables and Covariates ........................................................................................................ 11 
7.1 Efficacy Endpoints and Variables ....................................................................................................................... 11 
7.1.1 Primary Efficacy Endpoints .......................................................................................................................... 11 
7.1.2 Secondary Endpoints....................................................................................................................................... 11 
7.1.3 Exploratory Endpoints ................................................................................................................................... 11 
7.2 Safety Endpoints and Variables ........................................................................................................................... 12 
7.2.1 Adverse Events .................................................................................................................................................. 12 
7.2.2 Clinical Laboratory Tests ............................................................................................................................... 13 
7.2.3 Vital Signs ............................................................................................................................................................. 14 
7.2.4 12-Lead ECG ........................................................................................................................................................ 14 
7.3 Pharmacokinetic Endpoints and Variables..................................................................................................... 14 
7.4 Other Variables........................................................................................................................................................... 15 
7.5 Predetermined Covariates and Prognostic Factors .................................................................................... 15 
 Definitions ......................................................................................................................................................................... 16 
 Analysis Sets ..................................................................................................................................................................... 16 
9.1 Intention-to-Treat ..................................................................................................................................................... 16 
9.2 Safety .............................................................................................................................................................................. 16 
9.3 Pharmacokinetic ........................................................................................................................................................ 16 
9.4 Pharmacogenomic .................................................................................................................................................... 17 
 Interim Analyses .......................................................................................................................................................... 17 
10.1 Week 4 Pharmacokinetic Analysis .................................................................................................................. 17 
10.2 Week 12 Safety Analysis ...................................................................................................................................... 17 
 Data Review ................................................................................................................................................................... 18 
11.1 Data Handling and Transfer ............................................................................................................................... 18 
11.2 Data Screening ......................................................................................................................................................... 18 
 Statistical Methods ...................................................................................................................................................... 18 
12.1 General Considerations ........................................................................................................................................ 18 
12.2 Handling of Missing Data / Imputation Methods ...................................................................................... 18 
12.3 Subject Disposition ................................................................................................................................................ 21 
12.4 Protocol Deviations................................................................................................................................................ 22 
12.5 Demographic and Baseline Characteristics ................................................................................................. 22 
12.6 Treatments ................................................................................................................................................................ 22 


 
 
 
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12.6.1 HBV Treatment History ............................................................................................................................... 22 
12.6.2 Prior and Concomitant Medications ....................................................................................................... 22 
12.6.3 Procedures ........................................................................................................................................................ 23 
12.6.4 Compliance and Exposure to Study Drug ............................................................................................. 23 
12.7 Efficacy Analyses ..................................................................................................................................................... 23 
12.7.1 Primary Endpoint Assessments ............................................................................................................... 23 
12.7.2 Exploratory Efficacy Assessments .......................................................................................................... 24 
12.8 Safety Analyses ........................................................................................................................................................ 26 
12.8.1 Adverse Events ................................................................................................................................................ 26 
12.8.2 Deaths and Serious Adverse Events ....................................................................................................... 27 
12.8.3 Central Laboratory Data .............................................................................................................................. 27 
12.8.4 Vital Signs .......................................................................................................................................................... 28 
12.8.5 Physical Examinations, ECGs, and Other Observations Related to Safety .............................. 28 
12.9 Pharmacokinetics ................................................................................................................................................... 28 
 Validation ........................................................................................................................................................................ 29 
 References ...................................................................................................................................................................... 29 
Appendix 1 Glossary of Abbreviations ......................................................................................................................... 30 
Appendix 2 Tables, Figures, Listings, and Supportive SAS Output Appendices .......................................... 32 
Appendix 3 Grading of Laboratory Values .................................................................................................................. 33 
 


 
 
 
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 Purpose 
The statistical analysis plan (SAP) describes the statistical methods to be used during the reporting and 
analyses of data collected under Assembly Biosciences Protocol ABI-H0731-201, “A Phase 2a, Multi-
center, Double-blind, Placebo-controlled Study Evaluating ABI-H0731 as Adjunctive Therapy in Virally-
suppressed Patients with Chronic Hepatitis B”. 
 Scope 
This plan is a living document that will be created during the trial start-up. The Statistical Analysis Plan will 
be drafted within three months of final CRF and maintained throughout the lifecycle of the trial. Each version 
of the SAP will require sign off from the Project Manager and the sponsor prior to programming starting or 
being updated as a result of an amended version of the SAP.   
The SAP outlines the following: 
• 
Study objectives 
• 
Study design 
• 
Variables analyzed and analysis sets 
• 
Applicable study definitions 
• 
Statistical methods regarding important protocol deviations, study drug exposure, efficacy 
analysis, concomitant medications, adverse events handling, laboratory data and physical 
examinations  
 Introduction 
This SAP should be read in conjunction with the study protocol and case report form (CRF). This version 
of the plan has been developed using the amended protocol v3.0 dated 09NOV2018 and CRF dated 
15JAN2019. Any further changes to the protocol or CRF may necessitate updates to the SAP. 
Versions of the SAP up to sponsor approval will be known as a draft SAP. Programming activities will 
commence upon finalization and approval of the SAP. If necessary, changes following final approval of the 
SAP will be tracked in the SAP Change Log. The final sponsor approval of any amended version of the 
SAP will occur prior to database lock.  
4.1 Changes from Protocol 
Subjects entered study with additional NUCs not originally noted in the protocol. These NUCs are recorded 
as ongoing concomitant medications in the CRF. 
Protocol Specified NUCs 
Additional NUCs 
entecavir (ETV) 
Descovy (emtricitabine and tenofovir alafenamide) 
tenofovir alafenamide fumarate (TAF) 
Truvada (emtricitabine and tenofovir disoproxil fumarate) 
tenofovir disoproxil fumarate (TDF) 
Tenofovir (Tenofovir disoproxil fumarate) and entecavir 
 
Following an increase in the number of subjects in the sister protocol (ABI-H0731-202), the timing of DMC 
meetings was changed to accommodate the two protocols in a single programmatic overview.  As a 
result, instead of requiring all subjects in study 202 (and separately in study 201) to have completed 
Week 12 prior to triggering a DMC, the DMC trigger was based on 25% of subjects across BOTH studies 
completing a week 12 visit and 75% of all subjects completing a Week 12 visit. 
PK sample collection for subjects to provide optional samples on Weeks 2 or 4, that were not able to 
provide optional PK samples on Day 1 was changed to: Optional sample collection on Day 1, Week 2, or 
Week 4 are not dependent on collection at any prior or subsequent sample collection time. 
 


 
 
 
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 Study Objectives 
5.1 Primary Objectives 
The primary objective of the study is to evaluate the potential for ABI-H0731 to increase clinical cure rates 
in subjects with chronic hepatitis B infection (CHB) whose viral replication is stably suppressed on a 
standard of care (SOC) nucleos(t)ide (NUC) therapy, as measured by changes from Baseline in serum 
biomarkers (i.e. hepatitis B surface antigen [HBsAg] or hepatitis B e antigen [HBeAg]) of transcriptionally 
active covalently closed circular DNA (cccDNA). 
5.2 Secondary Objectives 
The following secondary objectives are defined for this study: 
• 
To evaluate the safety and tolerability of ABI-H0731 when added to SOC NUC therapy in subjects 
already virally suppressed on SOC therapy 
• 
To confirm a lack of drug-drug interactions between SOC NUC and ABI H0731 
5.3 Exploratory Objectives 
The following exploratory objectives are defined for this study: 
• 
To evaluate the kinetics of and absolute changes from Baseline in biomarkers of transcriptionally 
active cccDNA (HBeAg and HBsAg) 
• 
To evaluate the kinetics of and absolute changes from Baseline in circulating hepatitis B virus 
(HBV) RNA 
• 
To assess the relationship between changes in exploratory viral biomarkers such as changes in 
viral RNA and hepatitis B core-related antigen (HBCrAg) with clinical outcomes 
• 
To monitor for emergence of resistance, if any, for ABI-H0731 in combination with SOC NUC 
• 
To explore the pharmacokinetics (PK) of ABI-H0731 
• 
For subjects who provide an optional pharmacogenomic (PG) sample, to evaluate the potential 
contribution of host genomics to outcomes 
 Study Design 
This Phase 2a, multi-center, randomized, double-blind, placebo-controlled study will assess the safety, 
efficacy, PK, and pharmacodynamics of 300 mg ABI-H0731 daily in combination with SOC NUC therapy in 
subjects with CHB virus infection who are already virally suppressed on SOC NUC therapy at entry to study. 
Seventy subjects will be stratified in a ratio of 9:5 (i.e. 45 HBeAg positive subjects: 25 HBeAg negative 
subjects) and randomized to treatment groups in a 3:2 ratio to receive investigational agent as add-on 
therapy to their current SOC NUC therapy for up to 6 months (24 weeks).  
HBeAg Positive (N=45):  
• 
27 subjects will receive ABI-H0731 + NUC therapy 
• 
18 subjects will receive matching placebo + NUC therapy.  
HBeAg Negative (N=25): 
• 
15 subjects will receive ABI-H0731 + NUC therapy 
• 
10 subjects will receive matching placebo + NUC therapy.  
NUC treatment will continue uninterrupted for the duration of the study as well as during follow-up. 


 
 
 
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Safety will be monitored by a Data Monitoring Committee (DMC), including a safety analysis when 
approximately 25% and 75% subjects (across ABI-H0731-201 Amendment 3 v4.0 / 09 November 2018 and 
ABI-H0731-202 Amendment 1 v2.1 / 30 July 2018 [UK only] Amendment 1 v2.0 / 18 June 2018 [USA, 
Canada, NZ, HKG] studies) complete their Week 12 visit (or discontinues before completing Week 12). This 
timing differs from that defined in the protocol, following an amendment adding of 25 additional subjects to 
the ABI-H0731-201 protocol, to allow for earlier identification of potential safety events that may arise. There 
will be an assessment of PK data after all subjects have completed Week 4 (or discontinued study without 
completing Week 4) to confirm a lack of an important impact of ABI-H0731 on the steady-state PK of SOC 
NUC therapy. 
At the end of the 24-week treatment period in this study, subjects will either continue their SOC NUC therapy 
and stop treatment with ABI-H0731/placebo, or they may elect to roll over onto the optional, open-label, 
extension study ABI-H0731-211. 
Subjects who do not roll into optional open-label study ABI-H0731-211 will continue on SOC NUC therapy 
alone and be monitored for an additional 12 weeks to determine if any changes in either viral antigens or 
viral RNA which may have been noted on treatment will persist through end of follow-up. 
Subjects who do elect to roll over to the optional, open-label, extension study of ABI-H0731 + SOC NUC 
(protocol ABI-H0731-211) will continue on open-label combination therapy as per that study. The objective 
of the extension study, ABI-H0731-211, will be to evaluate the safety and potential for benefits of up to one 
additional year of therapy with ABI-H0731. Subjects will be required to sign a separate informed consent 
form for the ABI-H0731-211 study. 
6.1 Sample Size Considerations 
As a proof-of-concept trial, there are no statistical hypotheses, per se, regarding treatment effects in this 
study. Rather, displays and comparisons of study results, regarding dose-related safety, efficacy, and PK 
profiles among the treatment groups, will primarily utilize descriptive statistics. 
The primary objective of the study will be measured by changes from Baseline in serum biomarkers (i.e. 
HBsAg or HBeAg). As the results for this study will be used to collect information for future studies, both 
biomarkers will be reviewed independently, with no control of the alpha level. 
Subjects will be stratified 9:5 (HBeAg positive: HBeAg Negative). HBeAg positive subjects and HBeAg 
negative subjects will be evaluated both together and independently. With a sample size of 45 HBeAg 
positive subjects, randomized in a 3:2 ratio (27 active:18 placebo), a 2-sample t-test with a 2-sided α=0.05 
significance level has 89.5% power to detect a difference of at least 0.5 log10 (IU/mL) in the mean change 
from Baseline in serum HBsAg or HBeAg at Week 24 (Table 1). A similar test has 80% power to detect a 
treatment difference of at least 0.6 log10 (IU/mL) in the change from Baseline in serum HBsAg at Week 24 
in HBeAg negative subjects (Table 2). An equal standard deviation of 0.5 is assumed for both treatment 
groups. 
 
 


 
 
 
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Table 1  HBeAg Positive Subjects: Power Calculations under Various Mean Differences in the 
Change from Baseline in HBsAg (or HBeAg) levels at Week 24 between Treatment Groups 
Estimated mean difference at Week 24 
between placebo + NUC and ABI-H0731 + 
NUC groups Change from Baseline 
HBsAg (or HBeAg) levels 
Power for N=45 HBeAg Positive subjects  
(27 ABI-H0731: 18 Placebo) 
SD = 0.25 
SD = 0.30 
SD = 0.50 
SD = 0.60 
0.25 log10 IU/mL 
0.895 
0.763 
0.362 
0.268 
0.30 log10 IU/mL 
0.971 
0.895 
0.487 
0.362 
0.40 log10 IU/mL 
0.999 
0.990 
0.729 
0.572 
0.50 log10 IU/mL 
>0.999 
>0.999 
0.895 
0.763 
0.60 log10 IU/mL 
>0.999 
>0.999 
0.971 
0.895 
Calculated using SAS, based on a two-sided, two-sample t-test for mean differences, and alpha=0.05. HBeAg=hepatitis 
B “e” antigen; HBsAg=hepatitis B surface antigen; NUC=nucleos(t)ide analogue; SD=standard deviation. 
Table 2 HBeAg Negative Subjects: Power Calculations under Various Mean Differences in the 
Change from Baseline in HBsAg levels at Week 24 between Treatment Groups 
Estimated mean difference at Week 24 
between placebo + NUC and ABI-H0731 + 
NUC groups Change from Baseline 
HBsAg levels 
Power for N=25 HBeAg Negative subjects  
(15 ABI-H0731: 10 Placebo) 
SD = 0.25 
SD = 0.30 
SD = 0.50 
SD = 0.60 
0.25 log10 IU/mL 
0.650 
0.498 
0.217 
0.165 
0.30 log10 IU/mL 
0.804 
0.650 
0.291 
0.217 
0.40 log10 IU/mL 
0.963 
0.878 
0.467 
0.347 
0.50 log10 IU/mL 
0.997 
0.974 
0.650 
0.498 
0.60 log10 IU/mL 
>0.999 
0.997 
0.804 
0.650 
Calculated using SAS, based on a two-sided, two-sample t-test for mean differences, and alpha=0.05. HBeAg=hepatitis 
B “e” antigen; HBsAg=hepatitis B surface antigen; NUC=nucleos(t)ide analogue; SD=standard deviation. 
6.2 Randomization 
Approximately 70 subjects will be stratified 9:5 HBeAg positive to HBeAg negative and randomized in a 3:2 
ratio by an independent Interactive Web Response System (IWRS) vendor to receive investigational agent 
as add-on therapy to their current SOC NUC therapy for up to 6 months (24 weeks).  
HBeAg positive subjects (N=45):  
27 subjects will receive ABI-H0731 + NUC therapy: 18 subjects will receive matching placebo + NUC 
therapy.  
HBeAg negative subjects (N=25):  
15 subjects will receive ABI-H0731 + NUC therapy: 10 subjects will receive matching placebo + NUC 
therapy.  
6.3 Schedule of Assessments 
The study schedule of assessments per Amendment 3 v4.0 dated 09 November 2018 is noted in Table 3. 


 
 
 
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Table 3. Schedule of Assessments 
Period or Visit 
Screening 
On Treatment 
Follow-Up a 
Premature 
Termination b 
Unscheduled c 
Study Day or Week 
Day (-45) to 
Day (-1) 
Day 1 
Week 
2 
Week 
4 
Week 
8 
Week 
12 
Week 
16 
Week 
20 
Week 
24 a 
Week 
28 
Week 
36 
Varies 
Varies 
Visit Window (days) 
0 
+/- 2 
+/- 2 
+/- 3 
+/- 3 
+/- 3 
+/- 3 
- 3 
+/- 3 
+/- 3 
N/A 
N/A 
Informed Consent(s) d 
X 
 
 
 
 
 
 
 
X j 
 
 
 
 
Demographic data 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Medication history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Liver screening e 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Full physical examination 
X 
 
 
 
 
 
 
 
X 
 
X 
X 
 
12 Lead ECG  
X 
X 
 
 
 
X 
 
 
X 
 
X 
X 
if indicated 
Height and weight 
X 
X 
 
X 
 
 
 
 
X 
 
X 
 
 
Vital signs 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant medications / 
Adverse events 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Confirm eligibility 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Randomization (IRT) 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Symptom directed physical 
exam 
 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
 
X 
Paper diary 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
Study drug accountability 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
if applicable 
 
Study drug dispensation 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
In-clinic dosing: study drug  
 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
Dosing: SOC NUC k 
 
X k 
X k 
X k 
X 
X 
X 
X 
X 
X 
 
 
 
Digital photography c 
 
 
 
 
 
 
 
 
 
 
 
 
if indicated 
Virology/Immunology 
HBV genotype 
X 
 
 
 
 
 
 
 
 
 
 
 
 
HBV DNA viral load 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Quant HBsAg, quant 
HBeAg f 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
HBsAb, HBeAb 
X 
X 
 
 
 
X 
 
 
X 
 
X 
X 
 
HBV RNA 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
HIV Ab 
X 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
 
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Period or Visit 
Screening 
On Treatment 
Follow-Up a 
Premature 
Termination b 
Unscheduled c 
Study Day or Week 
Day (-45) to 
Day (-1) 
Day 1 
Week 
2 
Week 
4 
Week 
8 
Week 
12 
Week 
16 
Week 
20 
Week 
24 a 
Week 
28 
Week 
36 
Varies 
Varies 
HCV Ab; HDV Ab; HAV 
(IgM); HEV (IgM) 
X 
 
 
 
 
 
 
 
 
 
 
 
Xc 
Laboratory Assessment 
Chemistryb 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Hematology 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Coagulation 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Serum AFP  
X 
 
 
 
 
 
 
 
 
 
 
 
 
FSH (females only) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Urinalysis 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Urine drug test 
X 
X 
 
 
 
 
 
 
 
 
 
X 
X 
Pregnancy Test g 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
PK Sample Collection  
Pre-dose h 
ABI-H0731 
 
X 
X 
X 
 
X 
 
 
X 
X 
 
X 
X 
Nucleos(t)ide 
analogue 
 
X 
X 
X 
 
X 
 
 
X 
X 
 
X 
X 
Optional post-dose i 
4 (±2) hours after ABI-
H0731 and NUC 
administration 
 
X 
X 
X 
 
 
 
 
 
 
 
 
 
Exploratory 
Optional PG sample c 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Core protein (HBCrAg) 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Viral nucleic acid 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
a 
Subjects who elect NOT to enter rollover study ABI-H0731-211 at Week 24 will enter into the 12-week follow-up period (inclusive of Weeks 28 and 36). 
b 
Subjects who discontinue treatment before Week 24 should immediately undergo the assessments listed for the Premature Termination visit and then continue scheduled assessments, except that 
these subjects need only two further PK collections (at the Premature Termination visit and the next scheduled time point). Subjects who discontinue study assessments before completing the 12-
week follow-up period should undergo the assessments listed for the Premature Termination visit. 
c 
Any subjects with rash or ALT flare (defined as ALT≥2×Baseline and ≥10×ULN) should return to the clinic for an unscheduled visit as soon as possible, ideally within 3 days. 
Unscheduled visit for ALT flare: All subjects should have the laboratory findings confirmed within 3 days of receipt of the original results. All subjects should undergo a symptom directed 
physical examination and the following laboratory tests: ALT, AST, total bilirubin, INR, and serum albumin. If the ALT flare is confirmed, perform the following tests: HBV DNA, quantitative 
HBV serologies (HBeAg [reflex qualitative HBeAg if quantitative HBeAg is negative] and HBsAg [reflex qualitative HBsAg if quantitative HBsAg is negative], HAV IgM, HCV RNA, HDV 
RNA, and HEV IgM 
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 


 
 
 
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dermatologist. All dermatologist reports and biopsy results will be included in the source and eCRF. 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 two successive visits. 
d 
Study specific including optional PG consent. PG sample collection requires documentation of completed PG consent. 
e 
Liver evaluation to be done by any protocol approved method (Biopsy, fasting FibroScan, MRI, liver ultrasound), unless a liver biopsy demonstrating lack of cirrhosis or bridging fibrosis has been 
conducted in the last 6 months. 
f 
If quant HBsAg or HBeAg are negative at any visit subsequent to Screening, reflex to qualitative. 
g 
A serum pregnancy test is required at screening, and on Day 1 both urine and serum should be performed (subjects may begin treatment based on urine results; any subjects negative by urine 
subsequently found to be positive on serum should immediately discontinue treatment and may be replaced). All post-Day 1 pregnancy tests may be conducted by urine dipstick. If positive on 
dipstick, please reflex to serum. 
h 
If the subject inadvertently administers study drug prior to collection, a PK sample should still be drawn. Refer to the protocol PK Assessments section. 
i 
Optional post-dose PK samples for ABI-H0731 and NUC targeted collection is 4 (±2) hours after in-clinic study drug + NUC administration at Day 1 and either Week 2 or Week 4. 
j 
Subjects who elect to roll over onto the open-label extension study will be required to sign a separate consent at Week 24. 
k 
It is recommended that subjects take SOC NUC in-clinic on Day 1, Week 2 and Week 4, if subjects opt to provide the optional post-dose PK samples. 
 
Ab=antibody; AFP=alfa fetoprotein; ALT=alanine aminotransferase; AST=aspartate aminotransferase; ECG=electrocardiogram; eCRF=electronic case report form; FSH=follicle-stimulating hormone; 
HAV=hepatitis A virus; HBCrAg =hepatitis B core-related antigen; HBeAb=HBeAg antibody; HBeAg=hepatitis B “e” antigen; HBsAb=HBsAg antibody; HBsAg=hepatitis B surface antigen; 
HBV=hepatitis B virus; HCV=hepatitis C virus; HDV=hepatitis D virus; HEV=hepatitis E virus; HIV=human immunodeficiency virus; IgM=immunoglobulin M; MRI=magnetic resonance imaging; 
N/A=not applicable; PG=pharmacogenomic; PK=pharmacokinetic; Quant=quantitative; ULN =upper limit of normal. 
 
 
 


 
 
 
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 Study Endpoints, Variables and Covariates 
7.1 Efficacy Endpoints and Variables 
7.1.1 Primary Efficacy Endpoints 
The primary endpoint is viral antigen decline (serum HBsAg or HBeAg), measured as the change in mean 
log10 serum viral antigen from Baseline to Week 24.  
. 
7.1.2 Secondary Endpoints 
The following secondary endpoints will be evaluated: 
• 
Drug concentrations:  
o Trough levels and (in subjects where optional samples are available) trough to peak ratios of ABI-
H0731 on ABI-H0731 + ETV  
o Trough levels and (in subjects where optional samples are available) trough to peak ratios of ETV 
on ABI-H0731 + ETV therapy as compared with placebo + ETV  
Safety endpoints as outlined in Section 7.2 will be evaluated. 
7.1.3 Exploratory Endpoints 
Blood samples for the assessment of exploratory efficacy endpoints are collected according to the Schedule 
of Assessments (Table 2). These variables include quantitative/qualitative HBsAg and HBeAg levels, 
HBsAg antibody (HBsAb) and HBeAg antibody (HBeAb), HBV DNA viral load, HBV RNA, and HBCrAg.  
The primary efficacy variables, quantitative HBsAg and HBeAg, will be collected at Screening, Day 1, and 
Weeks 4, 8, 12, 16, 20, and 24 (or at the time of discontinuation).  
Follow-up samples will be collected at Weeks 28 and 36 for subjects who do not continue treatment in the 
extension protocol. Subjects who enter the optional extension protocol (ABI-H0731-211) will have samples 
collected according to that protocol. 
Reporting for assessments of HBeAg seroconversion (loss) will include only those subjects with detectable 
(positive) HBeAg viral antigen at baseline. 
Reporting for assessments of HBV RNA will include only those subjects with detectable (positive) HBV RNA 
at baseline. 
The assessments will be reported using Covance labs, or Assembly Labs. The incidence of LOQ values for 
each of these assessments will be reported and for numerical summaries the value at LOQ will be reported.  
The following exploratory efficacy endpoints will be evaluated using these variables:  
• 
The mean change from baseline in serum HBV RNA and HBCrAg levels at each time point where 
collected  
• 
Percent of subjects with loss (defined as below LOQ) or decline in HBsAg or HBeAg (< 0.5 log10, ≥ 0.5 
to 1.0 log10, or > 1.0 log10 decrease in viral antigen) at end of treatment and end of follow-up  
• 
Percent of subjects with HBsAg seroconversion (loss of HBsAg and appearance of HBs antibody) or 
HBeAg seroconversion (loss of HBeAg and appearance of HBe antibody) at each timepoint 
• 
Percent of subjects with HBV DNA “detectable” at Baseline whose HBV DNA becomes “non-detectable” 
at each timepoint 
• 
Incidence of emergence of resistant HBV variants, if any 


 
 
 
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• 
For subjects who do NOT rollover onto the optional extension study, ABI-H0731-211: 
o 
Percent of subjects with suppression of detectable serum HBV RNA on treatment whose HBV 
RNA rebounds after discontinuing treatment during Post-Treatment follow-up with ABI-H0731 
+ SOC NUC as compared with placebo + SOC NUC 
o 
Percent of subjects with changes in HBsAg or HBeAg whose viral antigen rebounds after 
discontinuing treatment during Post-Treatment follow-up with ABI-H0731 + SOC NUC as 
compared with placebo + SOC NUC 
o 
Percent of subjects with HBsAg or HBeAg loss at Week 24 that is maintained through the end 
of Post Treatment follow-up (Week 36) after discontinuing treatment with ABI-H0731 + SOC 
NUC as compared with placebo + SOC NUC 
HBV resistance testing, using exploratory research samples, will only be performed on subjects whose HBV 
DNA viral load becomes persistently (≥ 2 consecutive visits) detectable at a sufficient viral quantity for 
sequence analysis. 
Pharmacogenomic (PG) samples will be collected at Day 1 for subjects who provide separate informed 
consent. These samples may be saved for future research. If differences are noted in outcomes between 
racial or ethnic groups, the correlation between PG variables with clinical outcomes may be evaluated for 
subjects who provide optional informed consent. 
7.2 Safety Endpoints and Variables 
The safety variables noted in this section will be used to evaluate the following set of secondary safety 
endpoints: 
• 
Number of subjects with adverse events (AEs), premature discontinuations, abnormal safety laboratory 
results, electrocardiogram (ECG), or vital signs 
• 
Subjects with abnormal alanine aminotransferase (ALT) at Baseline who have normal ALT (ALT < ULN) 
at Week 24 on ABI-H0731 + NUC therapy as compared with placebo + NUC therapy 
7.2.1 Adverse Events 
Adverse events will be coded using MedDRA 21.0 (March 2018) and graded by Medidata Rave Coding 
tool. 
AEs will be monitored and reported from the time written informed consent is signed until completion of the 
Week 36 follow-up visit or until 30 days following cessation of the last dose of treatment with the study drug 
for subjects who discontinue from follow-up. For subjects who roll over into extension study ABI-H0731-
211, AEs that have not resolved by time of rollover will continue to be followed in study ABI-H0731-211. 
An AE is defined as 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. 
An AE will be considered a treatment-emergent AE (TEAE) if it first occurs or begins previous to and 
worsens on or after the first study drug dose date and before the last dose date + 30 days. 
The following AE details will be recorded on the eCRFs: 
• 
Adverse event (verbatim) 
• 
Whether the AE is an adverse event of special interest (AESI). AESI’s include rash and ALT flare. 


 
 
 
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• 
Start / end date of the AE 
• 
Whether the AE is serious or not, and if yes, which category (AE resulted in death; AE is life-
threatening; AE resulted in persistent or significant disability or incapacity; AE resulted in initial or 
prolonged hospitalization; AE is associated with a congenital anomaly or birth defect; AE is a 
medically important event not covered by other criteria). 
• 
Relationship to Study Treatment (Not related; Unlikely related; Possibly related; Related) 
• 
Action taken with Study Treatment (Dose not changed; Drug interrupted; Drug withdrawn; Not 
applicable; Unknown) 
• 
Intensity (Mild (Grade 1); Moderate (Grade 2); Severe (Grade 3); Life threatening (Grade 4)) 
• 
Outcome (Fatal; Not recovered/not resolved; Recovered/resolved; Recovered/resolved with 
sequelae; Recovered/resolving; Unknown) 
• 
Non-study drug treatment received for the AE 
The intensity of each AE and laboratory abnormality will be assessed by the Investigator according to the 
modified Division of AIDS (DAIDS) Table for Grading the Severity of Adult and Pediatric Adverse Events 
(noted in APPENDIX II of the protocol), which grades the severity of clinical AEs and laboratory 
abnormalities in a four-category system. 
7.2.2 Clinical Laboratory Tests  
Clinical laboratory tests will be performed at the timepoints indicated in the Schedule of Assessments (Table 
3). The clinical laboratory assessments are listed in Table 4. 
Table 4  
Clinical Laboratory Tests 
Panel 
Tests 
Clinical chemistries 
Blood glucose levels, serum or plasma electrolytes (sodium, potassium, chloride, 
bicarbonate), calcium, blood urea nitrogen, creatinine, uric acid, total and direct 
bilirubin a, ALT, aspartate aminotransferase (AST), gamma-glutamyl transferase 
(GGT), alkaline phosphatase, lactate dehydrogenase (LDH), amylase, triglycerides, 
total cholesterol, inorganic phosphate or total phosphate, total protein, albumin, 
lipase, and total serum or plasma globulins 
In case of ALT flares 
ALT, AST, total bilirubin, serum albumin, and INR 
Hematology 
Complete blood counts: hemoglobin, hematocrit, RBC indices (MCV, MCHC), 
reticulocyte counts, leukocyte counts (total and differential), and platelet counts 
Coagulation 
Prothrombin time, INR and aPTT 
Urinalysis 
pH, specific gravity, protein, glucose, ketones, and occult blood 
Rash Panel 
Erythrocyte sedimentation rate, complete blood count (with differential), creatinine, 
ALT, AST, and total bilirubin. 
Other 
AFP, HbA1c, and FSH 
Pregnancy tests 
For females only; a serum or plasma pregnancy test must be performed at screening, 
and both serum/plasma and urine are required Day 1; urine pregnancy test may be 
performed at all subsequent visits.  
A positive result disqualifies the subject for study treatment 
Urine drug screening 
Amphetamine/methamphetamine, barbiturates, benzodiazepines, cannabinoids, 
cocaine metabolite, ecstasy, ethanol, opiates, phencyclidine, and propoxyphene.  
Note: If cannabinoids are not illegal in the subject’s local, cannabinoids are not 
exclusionary 
Antibodies 
HCV, HDV, HAV IgM, HEV IgM, and HIV 


 
 
 
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AFP=alpha fetoprotein; ALT=alanine aminotransferase; aPTT=activated partial thromboplastin time; AST=aspartate 
aminotransferase; FSH=follicle-stimulating hormone; GGT=gamma-glutamyl transpeptidase; HAV=hepatitis A virus; 
HbA1c=hemoglobin A1c; HCV=hepatitis C virus; HDV=hepatitis D virus; HEV=hepatitis E virus; HIV=human 
immunodeficiency virus; IgM=immunoglobulin M; INR=International Normalized Ratio; LDH=lactate dehydrogenase; 
MCHC=mean corpuscular hemoglobin concentration; MCV=mean corpuscular volume; RBC=red blood cell; 
ULN=upper limit of normal 
a 
Perform fractionated bilirubin, if total bilirubin >ULN. 
 
During the study, any clinically significant laboratory abnormality or clinically significant change from 
Baseline will be recorded as an AE. 
7.2.3 Vital Signs 
Vital signs will be collected at screening, Day 1, and Weeks 2, 4, 8, 12, 16, 20, and 24 (or at the time of 
discontinuation). Follow-up samples will be collected at Weeks 28 and 36 for subjects who do not continue 
treatment in the extension protocol.  
Variables will include temperature, systolic blood pressure, diastolic blood pressure, pulse rate, and 
respiratory rate. Additionally, height, weight, and body mass index (BMI) will be collected on the CRF at 
screening, with weight collected again at Day 1, and Weeks 4 and 24, and Week 36 for subjects who remain 
in the follow-up period. 
7.2.4 12-Lead ECG 
Twelve-lead ECGs will be collected at Screening, Day 1, and Weeks 12, 24, and 24 (or at the time of 
discontinuation). Follow-up ECGs will be collected at Week 36 for subjects who do not continue treatment 
in the extension protocol. During the study, any clinically significant ECG result should be confirmed, and if 
confirmed, should be recorded as an AE. 
7.3 Pharmacokinetic Endpoints and Variables 
The pharmacokinetic endpoints for this study are as follows: 
• 
Trough levels and (in subjects where optional samples are available) trough to peak ratios of ABI-
H0731 on ABI-H0731 + NUC therapy 
• 
Trough levels and (in subjects where optional samples are available) trough to peak ratios of NUC 
on ABI-H0731 + NUC therapy as compared with placebo + NUC therapy 
Pre-dose drug concentration samples will be collected to determine trough concentrations of ABI-H0731 
and the SOC NUC therapy. Post-dose samples for both ABI-H0731 and SOC NUC will be collected from 
subjects willing and able to provide the sample at 4 ± 2 hours after in-clinic dosing. Sample collection timing 
is outlined in Table 5. 
 
 


 
 
 
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Table 5  
 
Pharmacokinetic Sample Collection 
Time Period 
Timepointa 
Time 
Relative 
to 
Study 
Drug 
Administrationb 
Double-Blind 
Treatment 
 
Study Day 1 pre-dose 
Immediately before  
Study Weeks 2, 4, 12, 24 pre-dose 
Immediately before 
OPTIONALc 
Day 1, Week 2, and/or Week 4, post-
dose (see laboratory manual) 
4 (±2) hours post-dose 
Follow-Up 
Study Week 28 pre-dose 
Collect at same time with other central labs 
a A PK sample should be collected if an unscheduled or premature termination visit is performed. 
b Sample collection times are targeted times. Samples collected outside of these targeted times will not be 
considered protocol deviations as long as the actual time the sample is collected is accurately recorded on source 
documentation and the case report form. 
c Optional sample collection on day 1, week 2, or week 4 are not dependent on collection at any prior or subsequent 
sample collection time. 
 
7.4 Other Variables 
Other assessments that will be collected and included for analyses include:  
• 
Demographic characteristics, including sex, ethnicity and race 
• 
Liver screening using Fibroscan categorization method of F0 through F2. 
• 
Prior and concomitant medications  
• 
HBV treatment history 
• 
Medical and surgical history 
• 
Procedures 
• 
Complete and symptom-directed physical examinations 
• 
Drugs of Abuse testing 
• 
Pregnancy testing 
• 
Exposure and compliance to study medication 
 
7.5 Predetermined Covariates and Prognostic Factors 
Race, ethnicity, and HBV genotype (A, B, C, D, E-H) will be used as a covariate where indicated within the 
analysis. 
 
 


 
 
 
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 Definitions 
The following table will be used to define variables used within the statistical tables, figures, and listings. 
Table 6 Variables and Definitions 
Variable 
Definition 
Baseline 
 
Baseline is defined as the value closest to but prior to the initiation of study 
drug administration.   
Change from Baseline 
Change from baseline will be defined as the post-baseline value minus the 
baseline value, where applicable (on a subject level). Change from baseline 
will only be calculated for subjects who have both baseline and at least one 
post-baseline value for any parameter.  
Study Day 
Study Day 1 will be based on the date of first dose. Events prior to this day 
will be reported as a negative study day (i.e. there will be no Day 0). The 
study day of an event will be calculated as (event date) – (first dose date) 
when the event occurred prior to first dose, and (event date) – (first dose 
date) + 1 when the event occurred after first dose. 
Duration Variables 
Duration variables (ex. time in study, exposure to study drug treatment, days 
since last visit, duration of AEs, etc.) will be calculated using the general 
formulas below: 
   Duration (days) = (End date - Start date) + 1 
   Duration (weeks) = Duration (days) / 7 
   Duration (months) = Duration (days) / 30.25 
Body Mass Index (BMI) 
Where not collected on the eCRF, BMI will be calculated as: 
   BMI = Weight (kg) / Height (m)2 
 
 Analysis Sets 
9.1 Intention-to-Treat 
The Intent-to-treat (ITT) population will be defined as all randomized subjects. Subjects in this population 
will be analyzed according to their randomized treatment assignment, regardless of the actual treatment 
received. 
9.2 Safety 
The safety population will include all randomized subjects who received any amount of study drug. Subjects 
in this population will be analyzed according to the actual treatment received. 
9.3 Pharmacokinetic 
Pharmacokinetic Population 1 (PK1): The PK1 population will include all subjects in the safety population 
who have ABI-H0731 PK data assessments available. 


 
 
 
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Pharmacokinetic Population 2 (PK2): The PK2 population will include all subjects in the safety population 
who have SOC NUC PK data assessments available. Subpopulations of the PK 2 population will be defined 
by the specific SOC NUCs taken during the study: 1) SOC NUC TDF, 2) SOC NUC TAF, 3) SOC NUC 
ETV, 4) Any other combination. For SOC NUC of TDF + ETV, subjects will be included in both 1) and 3) 
SOC NUC subpopulations for PK2 population. 
9.4 Pharmacogenomic  
The pharmacogenomic population will consist of subjects who have consented to, and have provided, an 
optional PG sample. Subjects in this population will be analyzed according to the actual treatment received. 
 Interim Analyses 
No formal interim analyses are planned. However, there will be a Week 4 PK analysis as well as a Data 
Monitoring Committee safety analysis for all data collected when approximately 25% and 75% subjects 
(across ABI-H0731-201 and ABI-H0731-202 studies) complete their Week 12 visit (or discontinues before 
completing Week 12). An unblinded statistician and programmer will provide these analyses. 
An informal safety and efficacy analysis may be conducted opportunistically for presentation at interim 
medical conference. 
10.1 Week 4 Pharmacokinetic Analysis 
After all subjects have completed Week 4 (or discontinued before completing Week 4), PK data will be 
reviewed by an unblinded pharmacology reviewer from Assembly and/or a representative from PRA to 
verify whether NUC steady-state exposure levels are affected by combination treatment with ABI-H0731. 
Results will be provided once reviewed and will include trough levels and trough to peak ratios (as available) 
for ABI-H0731 and NUC concentrations in tabular and graphical format. The list of statistical outputs to be 
produced for the DMC members and the unblinded Sponsor statistician will be documented in the ABI-
H0731-201 and ABI-H0731-202 DMC Data Transfer Plan and PK Data Transfer Plans as applicable. 
These results will be provided for the PK1 and PK2 Populations in an unblinded manner by treatment group, 
delivered by the unblinded PRA statistician. The unblinded PK results will be posted on a user-restricted 
study portal to ensure that only the intended recipients have access to the results. The unblinded 
recipient(s) specified below will be notified when results are posted to complete their review of the unblinded 
PK data. 
Name 
Title and Company 
Email 
10.2 Week 12 Safety Analysis 
A DMC external to the Sponsor and the CRO will be formed with members consisting of individuals chosen 
for their expertise in treatment of HBV. Members of the DMC will include, at a minimum, physicians external 
to the Sponsor and the CRO and appropriate statistical representation. The primary role of this independent 
DMC will be to monitor unblinded safety data. 
Details of the DMC will be outlined separately in a DMC Charter. The charter will detail data to be analyzed, 
and will identify members of the DMC, responsibility of those members, and frequency of meetings. 
These results will be provided to the DMC members and the Sponsor’s designated unblinded statistician in 
an unblinded manner delivered by the unblinded PRA statistician for posting on a user-restricted study 
portal, to ensure that only the intended recipients have access to the results. The unblinded recipients will 
be notified when results are posted. Details of the distribution of data outputs to the DMC members and 
sponsor’s designated unblinded statistician will be outlined in the DMC Charter. 


 
 
 
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The list of statistical outputs to be produced for the DMC members and the unblinded Sponsor statistician 
will be documented in the ABI-H0731-201 and 202 DMC Data Transfer Plan; including a separate set of 
unblinded TFL shells for unblinded DMC members and the unblinded Sponsor statistician and a separate 
set of blinded TFLs for the blinded Sponsor team members.  
 Data Review 
11.1 Data Handling and Transfer 
Details regarding the data handling, including how data is received by external vendors and which data is 
included in cleaning and transfers of data, are referenced in the ABI-H0731-201 Data Management Plan.  
11.2 Data Screening 
Beyond the data screening built into the PRA Data Management Plan, the PRA programming of analysis 
datasets and TFLs provides additional data screening. Presumed data issues will be output into SAS logs 
identified by the word “Problem” and extracted from the logs by a SAS macro and sent to Data Management. 
The PRA statistician and the Sponsor must approve database lock. 
 Statistical Methods 
12.1 General Considerations 
All analyses will use SAS version 9.4 or higher. Results will be reported by stratification (HBeAg positive or 
HBeAg negative), and treatment group, based on the following test and reference product categories: 
• 
ABI-H0731: This group will include subjects receiving test product ABI-H0731 in addition to their 
standard of care NUC therapy (which must include either entecavir [ETV], tenofovir alafenamide 
fumarate [TAF], or tenofovir disoproxil fumarate [TDF]). 
• 
Placebo: This group will include subjects receiving placebo (matching placebo to ABI-H0731 
tablets) in addition to their SOC NUC therapy 
Data from each participating investigational study site will be pooled together for all analyses. 
Adjustments for multiplicity will not be made since this is a proof-of concept study. Separate inferences will 
be drawn for assessment. 
Unless otherwise noted, categorical variables will be summarized using counts and percentages. 
Percentages will be rounded to one decimal place, except 100% which will be displayed without any decimal 
places. Percentages will not be displayed for zero counts.  
Continuous variables will be summarized using the number of observations (n), mean, standard deviation 
(SD), median, minimum and maximum. The minimum and maximum values will be displayed to the same 
level of precision as the raw data, the mean and median to a further decimal place and the SD to two 
additional decimal places. 
Confidence intervals will be two-sided and use the Clopper-Pearson (exact binomial) method at a 95% 
confidence level. 
12.2 Handling of Missing Data / Imputation Methods 
All attempts will be made to prevent missing data.  
 
To assess robustness of the primary efficacy variables, sensitivity analysis with missing values imputed by 
MMRM Using Multiple imputation (MI) will be performed see Appendix 2 for multiple imputation method. 


 
 
 
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Missing data will only be imputed for the co-primary endpoints. Percent of subjects with missing visits, and 
total missing visits per lab assessment may be summarized for the primary, secondary, and exploratory 
endpoints to assess the effect on repeated measures analysis for these endpoints. 
 
All missing and partial dates for adverse events will be queried for a value. If no value can be obtained, 
substitutions will be made as detailed in Table 7. These substitutions will be used in calculations, however, 
the actual value recorded on the eCRF will be presented in all listings.  
 
 


 
 
 
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Table 7.  
Adverse Event Start/Stop Date Imputation 
Imputation Rules for Partial Dates (D = day, M = month, Y = year) 
Parameter 
Missing 
Additional Conditions 
Imputation 
Start 
date 
for AEs 
 
D 
M and Y same as M and Y of first dose of 
treatment 
Date 
of 
first 
dose 
of 
treatment 
M and/or Y not same as date of first dose of 
treatment 
First day of month 
D and M 
Y same as Y of first dose of treatment 
Date 
of 
first 
dose 
of 
treatment 
Y prior to Y of first dose of treatment but same 
as Y of screening date 
Date of screening date 
D, M, Y 
None - date completely missing 
Date 
of 
first 
dose 
of 
treatment 
Stop 
date 
for AEs 
 
D 
M and Y same as M and Y of last dose of 
treatment 
Date 
of 
last 
dose 
of 
treatment 
M and/or Y not same as date of last dose of 
treatment 
Use last day of month (i.e.. 
D may take on values of 28, 
29, 30, or 31, depending on 
month) 
D and M 
Y same as Y of last dose of treatment 
Date 
of 
last 
dose 
of 
treatment 
Y not same as Y of last dose of treatment 
Use Dec 31 
D, M, Y 
None - date completely missing 
No imputation, but assume 
ongoing 
D=day, M=month, Y=year 
Note:  In all cases, if an estimated start date is after a complete stop date, use the first day of the stop date month. 
Similarly, if the estimated stop date is before a complete or imputed start date, use the last day of the start day 
month. 
In all cases, if it cannot be determined if the AE occurred prior to or after the first dose of treatment, the AE should 
be defined as treatment emergent. 
 
In the event that an AE has missing results for relationship to study treatment or intensity of AE, no 
imputation will be applied. 
 
 


 
 
 
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Table 7.  
Prior and Concomitant Medications Start/Stop Date Imputation 
Imputation Rules for Partial Dates (D = day, M = month, Y = year) 
Parameter 
Missing 
Additional Conditions 
Imputation 
Start date for 
con meds  
D only 
M and Y same as M and Y of first 
dose of study drug 
Date of first dose of study 
drug 
M and/or Y not same as date of first 
dose of study drug 
First day of month 
M and D 
Y same as Y of first dose of study 
drug 
Date of first dose of study 
drug 
Y not same as Y of first dose of 
study drug 
Use Jan 01 of Y 
M, D, and Y 
None - date completely missing 
Day prior to date of first dose 
of study drug 
Stop date for 
con meds  
D only 
M and Y same as M and Y of last 
dose of study drug 
Date of last dose of study 
drug 
M and/or Y not same as date of last 
dose of study drug 
Last day of month 
M and D 
Y same as Y of last dose of study 
drug 
Date of last dose of study 
drug 
Y not same as Y of last dose of 
study drug 
Use Dec 31 of Y 
M, D, and Y 
None - date completely missing and 
NOT ongoing 
Date of last dose of study 
drug 
Note:  In all cases, if an estimated start date is after a complete stop date, use the first day of the 
stop date month. 
Similarly, if the estimated stop date is before a complete or imputed start date, use the last day of 
the start day month. 
For laboratory data, if the reported value of a parameter cannot be used in a statistical summary table (e.g., 
a character string is reported for a parameter of the numerical type), a coded value will be appropriately 
determined and used in the statistical analyses. In general, a value or lower limit of normal range such as 
‘< 10’ or ‘≤ 5’ will be treated as ‘10’ or ‘5’ respectively, and a value or upper limit of normal range such as 
‘> 100’ will be treated as ‘100’. However, the actual values as reported in the database will be presented in 
data listings.   
12.3 Subject Disposition 
The number of screened subjects, subjects randomized, and subjects within each of the analysis 
populations (ITT, Safety, PK1, PK2, and PG) will be summarized by treatment group, and enrollment by 
site will be tabulated for subjects randomized into the study.   
A list of subjects who did not meet all inclusion/exclusion criteria, and which criteria were not met, will be 
presented.   
The number and percentage of subjects completing the study drug treatment period (up to and including 
Week 24), as well as the completion status of the study will be presented for each treatment group in the 
ITT population. Reasons for discontinuation from the study, as recorded on the eCRF, will be summarized 
(number and percentage) by treatment group. A listing of all subjects’ disposition from the Treatment Phase 
and at end of study will be presented, along with the primary reason for discontinuation, as applicable. 
Percent of subjects who entered study 211 will be summarized by treatment group. 
 
The number and percentage of subjects at each study visit will also be presented, and descriptive statistics 
will be used to summarize the total time in study from randomization in weeks. 


 
 
 
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All disposition data will be included within listings. 
12.4 Protocol Deviations 
Per PRA processes, protocol deviations data will be entered into a Clinical Trials Management System 
(CTMS). The study team and the sponsor will conduct on-going reviews of the deviation data from CTMS 
and the resulting set of evaluable subjects.  
Deviations will be categorized into general categories: inclusion/exclusion criteria not met, study drug 
deviation (including storage issues, subject unblinding), prohibited medication received, overdose/misuse, 
study procedures not done (efficacy and safety), out of visit window, etc. The study team will also categorize 
protocol deviations as important or not important Final review of protocol deviations will be conducted and 
finalized prior to unblinding the database.   
The number of subjects with at least one major protocol deviation and the number of subjects with at least 
one minor protocol deviation within each deviation category will be presented by treatment group for the 
ITT population.  Major and minor protocol deviations are defined per the study Protocol Deviation Guidance 
document. 
12.5 Demographic and Baseline Characteristics 
Demographics will be summarized for the ITT, and Safety populations, and will include sex, race, ethnicity, 
age (in years, at time of signing informed consent), categorical age (i.e., < 65 years,  65 years – < 75 
years, ≥ 75 years), weight, height, BMI, HBV genotype (A, B, C, D, E-H), pre-treatment ALT levels, and 
SOC NUC therapy reported at time of randomization, including combination therapies. Percent of subjects 
who entered study 211 will be summarized by treatment group. 
All medical/surgical history, including those ongoing at screening, will be summarized in the ITT population 
based on the number and percentage of subjects reporting each event, as coded per Medical Dictionary 
for Regulatory Activities (MedDRA) v21.0. Current medical history events, denoted as ‘ongoing’ on the 
CRF, will be reported in a separate table. 
All demographic and baseline characteristics, including HBV history (i.e. infection and diagnosis dates), 
and results from the screening liver examination, will be provided within data listings. 
12.6 Treatments 
12.6.1 HBV Treatment History  
For each HBV treatment history reported at Screening (i.e. entecavir (ETV), tenofovir alafenamide fumarate 
(TAF), Tenofovir disoproxil fumarate (TDF), or Other SOC NUC), the outcome to treatment and ongoing 
status will be summarized by treatment group, and daily oral dose (mg), when reported, will be summarized 
using descriptive statistics. If a subject received the same HBV treatment more than once prior to entering 
the study, the most recent record, based on the treatment end date, will be summarized in this table for the 
given HBV treatment. In such cases, if none of the records note the treatment as ongoing, the end date 
month and/or year information will be used to determine most recent record, in the event of partial dates. A 
listing will be provided to include all information collected on the CRF regarding HBV treatment history. 
Data will be presented for the ITT population. 
12.6.2 Prior and Concomitant Medications 
Medications received prior to, or concomitantly with study drug will be categorized by Anatomical 
Therapeutic Classification (ATC) level 4 and preferred medication name, according to the WHODRUG 
dictionary (Version 2018MAR01 DDE B3). The number and percentage of subjects using each medication 
will be displayed by treatment group in the ITT population. Subjects will be counted only once for an ATC 
class and preferred term. 


 
 
 
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If a medication has an end date which occurs prior to the first dose of study drug, then it will be summarized 
as a prior medication. In the case where the medication end date is partially complete (i.e. missing day or 
month), then the month and/or year information will be used to determine if the medication was taken prior 
to study drug dosing, as applicable. 
If a medication has a start date which occurs prior to the first dose of study drug and end date is after the 
first dose of study drug, then it will be summarized as a concomitant medication. All other medications with 
a start date after the first dose of study drug will be summarized as concomitant medications.   
12.6.3 Procedures 
Procedures will be recorded from 7 days prior to the informed consent date through to study completion 
defined as last study follow up visit or enrollment into study ABI-H0731-211. All procedures will be 
summarized in the ITT population based on the number and percentage of subjects reporting each 
procedure, as coded per MedDRA v21.0. 
12.6.4 Compliance and Exposure to Study Drug  
The summaries for compliance and exposure to study drug by treatment group will be presented for the 
Safety population.   
For extent of study drug exposure, the duration will be calculated from Day 1 to the date of last study drug 
administration collected on the End of Treatment CRF. The expected total duration of on-treatment therapy 
for all subjects is 24 weeks. The distribution of subjects by the total number of weeks on therapy (i.e. < 1 
week, 1-< 4 weeks, 4-< 8weeks, 8-< 12weeks, 12-< 16weeks, 16-< 20weeks, and >=20 weeks) will be 
presented as will descriptive statistics for the total duration of days on therapy. This duration will be 
calculated as defined in the Section 8 Definitions. 
In order to assess compliance with scheduled study drug dosing in the 24-week treatment period, the drug 
dispensing and return information collected on the drug accountability Case Report Forms will be used.  
Per protocol, each subject is expected to take three 100mg tabs every day during the treatment phase. In 
a 24-week period, a total of 504 tabs would be expected. 
The percent compliance in 24 weeks will be calculated as: 
% compliance = 100 *  
𝐴𝑐𝑡𝑢𝑎𝑙 𝑛𝑢𝑚𝑏𝑒𝑟 𝑜𝑓 𝑡𝑎𝑏𝑙𝑒𝑠 𝑡𝑎𝑘𝑒𝑛
𝐸𝑥𝑝𝑒𝑐𝑡𝑒𝑑 𝑛𝑢𝑚𝑏𝑒𝑟 𝑜𝑓 𝑡𝑎𝑏𝑙𝑒𝑡𝑠 𝑜𝑣𝑒𝑟 24 𝑤𝑒𝑒𝑘𝑠  
where the actual number of tablets taken will be calculated as the sum of all tablets dispensed minus the 
sum of all tablets returned as reported on the Study Drug Accountability CRF, plus the number of tablets 
taken at each of the in-clinic dosing visits as reported in the Study Drug Administration CRF on Day 1, and 
Weeks 2, 4, 12, and 24. The expected number of tablets over 24 weeks is 504 or (last date subject took 
study drug – start date subject took study drug) + 1 as days exposed multiplied by 3 tablets daily. 
Descriptive statistics for treatment compliance and the number and percentage of subjects at least 80% 
compliant will be presented by treatment group.   
12.7 Efficacy Analyses 
Summary statistics will be presented in the ITT population, unless otherwise noted.  For virology samples, 
a listing will be provided for the Safety population, and will include the following variables: HBsAg (IU/mL), 
HBsAg (qualitative), HBeAg (IU/mL), HBeAg (qualitative), HBV DNA (IU/mL), HBCrAg, and HBV RNA.  
12.7.1 Primary Endpoint Assessments 
The primary endpoint is viral antigen decline (serum HBsAg or HBeAg), measured as the mean change 
from baseline in log10 serum viral antigen from Baseline to Week 24.  


 
 
 
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For each endpoint variable, summary statistics will be provided by treatment group for the observed and 
change from baseline log10 results at all study visits. Summaries will be provided in the ITT population. 
Mean change from baseline and 95% confidence intervals will be presented. 
A repeated measures analysis using observed data from all scheduled visits for change from baseline in 
HBV DNA will be performed on the ITT population. This analysis will compare treatment groups over time 
using a linear mixed effects repeated measure model which includes fixed effects for treatment, visit, 
treatment-by-visit interaction, baseline value, baseline-by-visit interaction, and baseline covariates 
(baseline ALT, HBV genotype, time on historical HBV treatment).  Unstructured covariance matrix will be 
used. If there are convergence issues, then the use of first-order autoregressive (AR1) and/or the 
compound symmetry (CS) covariance matrices will be considered. The difference in least squares means 
between treatment groups and 95% confidence interval will be presented. 
A similar analysis of the primary endpoints (serum HBsAg and HBeAg) as described above will be 
presented by stratum (HBeAg positive subjects vs HBeAg negative subjects) in the ITT population.  
As this is a proof-of concept study, both primary endpoint parameters will be assessed independently. There 
is no plan to control for alpha for each of the primary variables, however, a significant difference for either 
of the primary variables at the Week 24 timepoint would be considered clinically desirable and may warrant 
further investigation. 
Graphs will be used to illustrate the changes from baseline for all post-baseline results up to Week 24. 
Results from both treatment groups will be presented on the same graph. 
12.7.2 Exploratory Efficacy Assessments 
12.7.2.1 Serum HBV RNA and HBCrAg levels 
For HBV RNA and HBCrAg variables, summary statistics will be provided by treatment group for the 
observed and change from baseline log10 serum results at all study visits. Summaries will be provided in 
the ITT population. 
12.7.2.2 Serum HBsAg and HBeAg loss and seroconversion 
The number and percentage of subjects with antigen loss (defined as below LOQ) or decline in HBsAg or 
HBeAg (< 0.5 log10, ≥ 0.5 to 1.0 log10, or >1.0 log10 decrease in viral antigen) will be tabulated for all 
measured visits in the ITT population. For HBeAg, the analytical measurement range is 0.11 –700.00 IU/mL. 
Samples with HBeAg concentrations greater than 700.00 IU/mL are diluted up to 1:2, extending the upper 
reporting limit to 1400.00 IU/mL. For HBsAg, the reportable range for the HBsAg quantitative assay is 0.05 
– 124925.00 IU/mL. The analytical measurement range is 0.05 – 250.00 IU/mL. Samples with HBsAg 
concentrations greater than 250.00 IU/mL are diluted up to a maximum dilution of 1:500, extending the 
upper reporting limit to 124925.00 IU/mL. 
Time to HBsAg loss and HBeAg loss will be evaluated using Kaplan-Meier estimates for each treatment 
group. The summary will be provided based on results observed up to Week 24.  A subject will be identified 
as having loss if the HBsAg, HBeAg result of < LOQ is observed for the subject, and all subsequent 
measurements of HBsAg, HBeAg are < LOQ. Subjects will be considered censored for the Kaplan-Meier 
analysis if any of the following occur: 1) Subjects who are not observed to have encountered viral 
suppression by Week 24 (HBV DNA of <20 IU/mL) will be censored at their last observed visit up to week 
24, 2) If a subject rebounds within the 24-week period, HBsAg, HBeAg are >= LOQ then the overall status 
for that subject will be considered as censored at the first occurrence of a rebound, 3) if a subject 
discontinues study participation prior to an occurrence of). This rebound censoring technique adequately 
accounts for seroreversions. Patients who are not observed to have encountered loss by Week 24 will be 
censored at their last observed visit up to week 24. The 25th, 50th (median), and 75th percentiles for time to 
loss in weeks will be reported, along with the corresponding 95% confidence interval. An unstratified log-
rank test will be used to assess differences in loss rates between treatment groups. 


 
 
 
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Additionally, a Cox regression analysis will be used to determine association of the following baseline 
covariates on HBsAg and HBeAg loss: gender (male, female), race (Asian vs non-Asian, and Black vs non-
Black), ethnicity (Hispanic/Latino, Non-Hispanic/Latino), and HBV genotype (A, B, C, D, E-H).  Hazard ratios 
and corresponding 95% Wald confidence limits will be provided in a summary table, along with the Wald 
Chi-Square p-value comparing the loss rates between the treatment groups. 
Seroconversion status will be summarized at all post-baseline time points when antibodies for HBsAg and 
HBeAg are collected (i.e. Weeks 12, 24, and 36). For subjects where antibody is present, subjects with 
seroconversion will be presented as the number of subjects who also observed loss (i.e. HBsAg below 
LOQ, or HBeAg below LOQ) at the identified timepoint. Results will be provided by treatment group in the 
ITT population. 
12.7.2.3 HBsAg, HBeAg, HBCrAg, and HBV RNA levels 
For HBsAg, HBeAg, HBCrAg, and HBV RNA variables, summary statistics will be provided by treatment 
group for the observed and change from baseline log10 serum results at each study visit. Summaries will 
be provided in the ITT population. Mean change from baseline and 95% confidence intervals will be 
presented. 
A repeated measures analysis using observed data from all scheduled visits for change from baseline in 
HBsAg, HBeAg, HBCrAg, and HBV RNA will be performed on the ITT population. This analysis will compare 
treatment groups over time using a linear mixed effects repeated measure model which includes fixed 
effects for treatment, visit, treatment-by-visit interaction, baseline value, baseline-by-visit interaction, and 
baseline covariates (baseline ALT, HBV genotype, time on historical HBV treatment). Unstructured 
covariance matrix will be used. If there are convergence issues, then the use of first-order autoregressive 
(AR1) and/or the compound symmetry (CS) covariance matrices will be considered. The difference in least 
squares means between treatment groups and 95% confidence interval will be presented. 
12.7.2.4 HBV DNA  
For subjects reporting detectable HBV DNA at Baseline, the number and percentage of those with loss at 
each post-baseline assessment will be tabulated in the ITT population. The categories for loss will be similar 
as those used in the HBsAg and HBeAg analysis indicated above, including subjects who achieve below 
LOQ results (i.e. reported as < 20 IU/mL, or No HBV DNA detected). 
Additionally, summary statistics will be provided by treatment group for the observed and change from 
baseline log10 serum results at all study visits. Mean change from baseline and 95% confidence intervals 
will be presented. 
A repeated measures analysis using observed data from all scheduled visits for change from baseline in 
HBV DNA will be performed on the ITT population.  This analysis will compare treatment groups over time 
using a linear mixed effects repeated measure model which includes fixed effects for treatment, visit, 
treatment-by-visit interaction, baseline value, baseline-by-visit interaction, and baseline covariates 
(baseline ALT, HBV genotype, time on historical HBV treatment).  Unstructured covariance matrix will be 
used. If there are convergence issues, then the use of first-order autoregressive (AR1) and/or the 
compound symmetry (CS) covariance matrices will be considered. The difference in least squares means 
between treatment groups and 95% confidence interval will be presented. 
12.7.2.5 Follow-up Subject Assessments 
Follow-up efficacy assessments will be performed on ITT subjects who do not rollover onto the optional 
extension study, ABI-H0731-211. 
For subjects with suppression of detectable serum HBV RNA (i.e. HBV RNA below LOQ at Week 24), the 
number of subjects whose HBV RNA rebounds after discontinuing treatment will be presented at Weeks 
28 and 36 in both treatment groups. Similar analyses will be presented for both HBsAg and HBeAg for 
subjects with loss at Week 24, to determine whether results have rebounded following the treatment phase. 


 
 
 
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12.7.2.6 Pharmacogenomic Assessments 
Pharmacogenomic samples will be collected at Day 1 for subjects who consent to this procedure. These 
samples may be saved for future research.  If differences are noted in outcomes between racial or ethnic 
groups from the Cox regression analysis defined in Section 12.7.2.2, the correlation between PG variables 
with clinical outcomes may be evaluated for subjects who provide optional informed consent.   
A listing of PG results will be provided for the Safety population. 
12.8 Safety Analyses 
12.8.1 Adverse Events 
Verbatim descriptions of AEs will be coded using Version 21.0 of MedDRA.  Summary tables will be 
provided for all treatment-emergent adverse events (TEAEs) in the Safety Population.   
A treatment-emergent AE is defined as any AE that newly appeared or worsened in severity on or after the 
first dose of study drug but not more than 30 days after the subject’s last dose. If the start date of the AE is 
partial or missing, Table 6 in Section 12.2 will be used to determine the flag for treatment emergence. 
An overall summary of TEAEs will be presented by treatment group and overall, and will include the 
following tabulations: 
• 
the number of subjects reporting at least one TEAE, and the total the number of events reported 
• 
the number of subjects with an Adverse Event of Special Interest (AESI) (i.e. ALT flare, rash, or other) 
• 
the number of subjects with a treatment-related TEAE (i.e. either Possibly Related or Related) 
• 
the number of subjects with Grade ≥ 3 (severe) TEAE 
• 
the number subjects discontinuing the study due to a TEAE  
• 
the number of subjects with at least one serious TEAE  
• 
the number of subjects with a TEAE resulting in death.  
Additionally, AEs will also be summarized as categorized by body system and preferred term coded 
according to the MedDRA dictionary. Tabulations will be by subject, such that subjects are only counted 
once within each body system or preferred term. These summaries will be provided for the following: 
• 
all TEAEs, and the total number of events reported 
• 
TEAEs of special interest 
• 
TEAEs per SOC NUC at randomization 
• 
TEAEs related to study treatment (i.e. Related or Possibly Related) 
• 
TEAEs with Grade ≥ 3 (severe)  
• 
TEAEs leading to study discontinuation 
• 
Serious TEAE’s 
• 
TEAEs resulting in death 
All adverse events (including non-treatment-emergent events) recorded on the CRF will be listed.   
Rash assessments will be listed separately for subjects with this AESI. 


 
 
 
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12.8.2 Deaths and Serious Adverse Events 
Subjects with treatment-emergent adverse events with an outcome of death will be summarized. A listing 
of all deaths that occurred following the first dose of treatment will be presented in a listing.  Similarly, all 
AEs noted as serious will be displayed in a listing. 
12.8.3 Central Laboratory Data 
Laboratory data will be summarized in the Safety Population using descriptive statistics (based on SI units) 
for the observed and change from baseline results for hematology and clinical chemistry by treatment group 
at each visit. Only the numeric part in laboratory values that contain non-numeric qualifiers, such as less 
than (<) a certain value, or greater than (>) a certain value, will be used in the summary statistics. 
For continuous data, the following hematology tests will be summarized for observed and change from 
baseline values: 
• 
Basophils (% and abs), Blasts (% and abs), Eosinophils (% and abs), Hematocrit, Hemoglobin, 
Lymphocytes (% and abs), mean corpuscular hemoglobin concentration (MCHC), mean corpuscular 
volume (MCV), Monocytes (% and abs), Neutrophils (% and abs), Platelets, red blood cell (RBC) count, 
RBC Morphology, Reticulocyte Count (% and abs), white blood cell (WBC) count    
 
The following chemistry tests will be summarized for observed and change from baseline values: 
• 
Alkaline Phosphatase, Albumin, ALT (SGPT), Amylase, AST (SGOT), Bicarbonate, Bilirubin (direct), 
Bilirubin (indirect), Bilirubin (total), Calcium, Chloride, Cholesterol, Creatinine, estimated GFR (eGFR) 
CKD, GGT, Globulin, lactate dehydrogenase (LDH), Lipase, Phosphorus, Potassium, Serum Glucose, 
Sodium, Total Protein, Triglycerides, Urea Nitrogen (BUN), Uric Acid 
 
The following coagulation factors will be summarized for observed and change from baseline values:  
• 
International normalized ratio (INR), Prothrombin time (PT) and activated partial thromboplastin time 
(aPTT).  
 
The following urinalysis parameters will be summarized for observed and change from baseline values: 
• 
Continuous parameters: pH, Specific gravity 
• 
Categorical parameters: protein, glucose, ketones, blood 
Clinically abnormal laboratory values will be applied based on the modified Division of AIDS (DAIDS) Table 
for Grading Severity of Adult Adverse Experiences (2017), as noted in Appendix 3. In the summary tables, 
values of grading will be displayed as 0, 1, 2, 3, or 4, where a grade of ‘0’ will be assigned if the lab value 
was non-missing but did not meet a grading criterion (i.e. defined as normal). The maximum post-baseline 
grade observed up to end of study will be tabulated for each laboratory test, and percentages will be based 
on the number of subjects with a post-baseline evaluation of the specific laboratory test.  
Additionally, a shift table will be used to tabulate the grading observed at Baseline to the maximum post-
Baseline result up to the end of study for each lab parameter, in order to highlight important grading 
differences noted during the study. 
The DAIDS grades will be applied within the Covance central lab datasets for the following parameters: 
• 
Hematology: Hemoglobin, Lymphocytes (absolute), Neutrophils (absolute), Platelets, and WBC. 
• 
Chemistry: Alkaline Phosphatase, Albumin, ALT (SGPT), Amylase, AST (SGOT), Bicarbonate, Bilirubin 
(total), Calcium, Creatinine, eGFR CKD, GGT, Lipase, Phosphorus, Potassium, Serum Glucose, 
Sodium, Uric Acid 


 
 
 
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• 
Coagulation: PT, aPTT, and INR  
 
For subjects reporting an AESI of ALT Flare, a separate summary lab data associated with the flare will be 
presented for both treatment groups. Data may include results for clinical chemistries (i.e. AST, ALT, GGT, 
alkaline phosphatase, total bilirubin, and albumin). 
For subjects with abnormal ALT at Baseline (defined as modified DAIDS grading of ≥ 1), the number and 
percentage of subjects who have normal ALT at Week 24 (i.e. a grading of 0) will be presented. 
A shift table will be used to tabulate the ALT levels observed at baseline  to post-baseline measurements 
up to end of the study for the following categories: Normal (ALT < ULN), ALT >= 1xULN to < 3xULN, ALT 
>= 3xULN to < 5xULN, ALT >= 5xULN to < 20xULN, ALT >= 20xULN. 
By-patient listings will be provided for hematology, clinical chemistry, coagulation, and urinalysis. 
Laboratory values outside normal limits will be identified in the subject data listings with flags for low (L) 
and high (H). 
Additional listings will be provided for other laboratory assessments, including serum alpha fetoprotein 
(AFP), hemoglobin A1c (HbA1c), and follicle-stimulating hormone (FSH; females only) as collected, as well 
as information collected regarding drug abuse from the urine drug results (i.e. amphetamine, barbiturates, 
benzodiazepines, cannabinoids, cocaine, propoxyphene, ethanol, opiates, and phencyclidine).   
Antibody tests for hepatitis B surface antigen (HBsAb), hepatitis B “e” antigen (HBeAb), hepatitis C virus 
(HCV), hepatitis D virus (HDV), hepatitis A virus immunoglobulin M (HAV IgM), hepatitis E virus 
immunoglobulin M (HEV IgM), HBV core protein (HBCrAb), and human immunodeficiency virus (HIV) will 
be listed by subject as collected. 
12.8.4 Vital Signs 
Blood pressure (systolic and diastolic), respiratory rate (breaths/min), pulse rate (beats/min), and 
temperature (ºC) will be summarized in the Safety Population using descriptive statistics, for both the 
absolute and the change from baseline assessments over time. Timepoints will include screening, Baseline 
(Day 1), and Weeks 2, 4, 8, 12, 16, 20, and 24, and follow-up samples will be collected Weeks 28 and 36 
for subjects who do not continue treatment in the extension protocol. Weight (kg) will also be included in 
the summary table, for the following timepoints: screening, Baseline (Day 1), and Weeks 4, 24, and Week 
36 for subjects who remain in the follow-up period. 
12.8.5  Physical Examinations, ECGs, and Other Observations Related to Safety 
Physical examination results will be summarized in the Safety Population by body system for each timepoint 
based on the frequency and percentage of subjects with interpretations of normal, abnormal – clinically 
significant, abnormal – not clinically significant, or not done.  Results of 12-lead ECG interpretations will be 
presented by timepoint in a similar manner. 
For female subjects in the Safety Population, results from blood (serum β-hCG) and urine pregnancy tests 
will be tabulated.  All results will be presented in a data listing. 
12.9 Pharmacokinetics 
For ABI-H0731-treated subjects with a PK assessment (i.e. subjects in Pharmacokinetic Set 1), summary 
statistics will be presented for trough PK plasma concentrations observed at Baseline, Weeks 2, 4, 12, and 
24, as well as Week 28 for subjects who enter the follow-up phase. If a subject provides consent to optional 
post-dose PK sample collections, then the post-dose (peak) concentration, and the trough to peak ratio will 
be summarized descriptively at Baseline, Week 2 and Week 4. 
For all subjects receiving SOC NUC (either entecavir [ETV], tenofovir alafenamide fumarate [TAF], 
tenofovir disoproxil fumarate [TDF]) with a PK assessment (i.e. subjects in Pharmacokinetic Set 2), a 
similar analysis as described above will be provided, for both treatment groups. Each SOC NUC will be 


 
 
 
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analyzed separately. For SOC NUC Other Combinations, only the TDF, TAF, and ETV components will be 
measured for the PK assessment. 
For subjects in Pharmacokinetic Set 2, the comparisons of SOC NUC trough concentration between 
treatment arms (ABI-H0731 vs Placebo) will be presented in a table. The comparisons will be based on the 
geometric mean ratio (with 90% CI) obtained from a two-sample t-test that compares the natural log-
transformed trough PK measurements between treatment arms.  
Trough plasma concentrations for ABI-H0731 and NUC levels at Baseline, Week 2, Week 4, Week 12, and 
Week 24, as well as Week 28 (for subjects who enter the follow-up phase) will be presented side-by-side 
in a graph. At each timepoint, the following 2 results will be plotted: SOC NUC PK levels in ABI-H0731 
subjects, and SOC NUC PK levels in Placebo subjects. 
Drug-drug interaction effects of SOC NUC at Baseline, Week 2, and Week 4 will be presented in a graph. 
At each time point the geometric mean ratio of trough SOC NUC PK values for [ABI-H0731 + SOC NUC / 
SOC NUC alone] will be plotted. 
 Validation 
PRA's goal is to ensure that each TFL delivery is submitted to the highest level of quality. Our quality control 
procedures will be documented separately.  
 References 
None. 
 
 
 


 
 
 
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Appendix 1 Glossary of Abbreviations 
Glossary of Abbreviations: 
AE 
adverse event 
AESI 
adverse event of special interest 
AFP 
alpha fetoprotein 
ALT 
alanine aminotransferase 
aPTT 
activated partial thromboplastin time 
AST 
aspartate aminotransferase 
ATC 
Anatomic therapeutic classification 
AUC 
area under the concentration-time curve 
BMI 
body mass index 
cccDNA 
covalently closed circular DNA 
CHB 
chronic hepatitis B infection 
CKD-EPI 
Chronic Kidney Disease Epidemiology Collaboration  
CI 
confidence interval 
CRF 
case report form 
CRO 
Clinical Research Organization (PRA Health Sciences) 
CTMS 
Clinical Trials Management System (PRA) 
DAIDS 
Division of AIDS  
DMC 
Data Monitoring Committee 
dsDNA 
double-stranded DNA 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
eGFR 
estimated glomerular filtration rate 
ETV 
entecavir 
FSH 
follicle-stimulating hormone 
GFR 
glomerular filtration rate 
HAV 
hepatitis A virus 
HbA1c 
hemoglobin A1c 
HBCrAb 
antibody to the HBV core protein  
HBCrAg 
hepatitis B core-related antigen 
HBeAb 
HBeAg antibody 
HBeAg 
hepatitis B “e” antigen 
HBsAb 
HBsAg antibody 
HBsAg 
hepatitis B surface antigen 
HBV 
hepatitis B virus 
HCV 
hepatitis C virus 
HDV 
hepatitis D virus 
HEV 
hepatitis E virus 
HIV 
human immunodeficiency virus  
ICF 
Informed Consent Form 
IgM 
immunoglobulin M 
INR 
International Normalized Ratio 
ITT 
intent-to-treat 


 
 
 
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IWRS 
Interactive Web Response System 
LOQ 
limit of quantitation 
MCHC 
mean corpuscular hemoglobin concentration  
MCV 
mean corpuscular volume  
MedDRA 
Medical Dictionary for Regulatory Activities 
MRI 
magnetic resonance imaging  
NUC 
nucleos(t)ide inhibitors of the HBV polymerase; also called nucleos(t)ide analogues 
or nucleos(t)ides 
PG 
pharmacogenomic 
pgRNA 
pre-genomic RNA 
PK 
pharmacokinetic(s) 
PK1 
Pharmacokinetic Population 1 
PK2 
Pharmacokinetic Population 2 
PT 
prothrombin time 
rcDNA 
relaxed circular DNA 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SOC 
standard of care 
TAF 
tenofovir alafenamide  
TDF 
tenofovir disoproxil fumarate  
TEAE 
treatment-emergent adverse event 
TFL 
tables, figures, and listings 
ULN 
upper limit of normal 
WHO 
World Health Organization 


 
 
 
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 Appendix 2 Tables, Figures, Listings, and Supportive SAS Output 
Appendices 
 
Please refer to the Table, Figure and Listing shells to support this SAP, provided in a separate document. 
Isolated missing values will be imputed by Markov Chain Monte Carlo (SAS PROC MI, MCMC) first to make 
the missing pattern monotone and then imputed by monotone linear regression. SAS PROC MI and PROC 
MIXED will be used to obtain MMRM estimates of treatment difference. SAS PROC MIANALYZE will be 
used to combine estimates and to generate the average test statistics for hypothesis testing. The Missing 
at Random method will be used with the following parameters:  MAR – assume missing at random, 
number of imputation=100, seed= SEED11 (for MCMC) and SEED12 (for MONOTONE REG) for 
imputation. 
 
 


 
 
 
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Appendix 3 Grading of Laboratory Values 
TOXICITY GRADING OF LABORATORY ABNORMALITIES AND CLINICAL ADVERSE EVENTS. 
PUBLISH DATE: JULY 2017 
Adapted from the U.S. National Institutes of Health (Division of AIDS) Table for Grading Severity of Adult Adverse 
Experiences (2017). Parameters within the table that have been modified for this study are designated by an asterisk 
(*). 
Laboratory Values*: Chemistries  
Parameter  
Grade 1 Mild  
Grade 2 Moderate  
Grade 3 Severe  
Grade 4 Potentially Life- 
Threatening  
Acidosis  
NA  
pH≤7.3 to <LLN  
pH<7.3 without life- 
threatening 
consequences  
pH<7.3 with life- threatening 
consequences  
Albumin, Low  
(g/dL; g/L)  
3.0 to < LLN  
30 to < LLN  
≥ 2.0 to < 3.0  
≥ 20 to < 30  
< 2.0  
< 20  
NA  
Alkaline 
Phosphatase, High  
1.25 to < 2.5 x 
ULN  
2.5 to < 5.0 x ULN  
5.0 to < 10.0 x ULN  
≥ 10.0 x ULN  
Alkalosis  
NA  
pH > ULN to ≤ 7.5  
pH > 7.5 without life- 
threatening 
consequences  
pH > 7.5 with life- 
threatening consequences  
ALT or SGPT, High  
Report only one  
1.25 to < 2.5 x 
ULN  
2.5 to < 5.0 x ULN  
5.0 to < 10.0 x ULN  
≥ 10.0 x ULN  
Amylase 
(Pancreatic) or 
Amylase (Total), 
High Report only one  
1.1 to 
<1.5×ULN  
1.5 to <3.0×ULN  
3.0 to <5.0×ULN  
≥5.0×ULN  
AST or SGOT, High  
Report only one  
1.25 to < 2.5 x 
ULN  
2.5 to < 5.0 x ULN  
5.0 to < 10.0 x ULN  
≥ 10.0 x ULN  
Bicarbonate, Low 
(mEq/L; mmol/L)  
16.0 to <LLN 
16.0 to <LLN  
11.0 to <16.0 11.0 to <16.0  8.0 to <11.0 8.0 to 
<11.0  
<8.0 <8.0  
Bilirubin  
Direct Bilirubin, 
High  
NA  
NA  
> ULN with other 
signs and symptoms 
of hepatotoxicity  
> ULN with life- threatening 
consequences (e.g., signs and 
symptoms of liver failure)  
Total Bilirubin, High  1.1 to 
<1.6×ULN  
1.6 to <2.6×ULN  
2.6 to <5.0×ULN  
≥5.0×ULN  
Calcium, High 
(mg/dL; mmol/L)  
10.6 to <11.5 
2.65 to <2.88  
11.5 to <12.5 2.88 to <3.13  12.5 to <13.5 3.13 to 
<3.38  
≥ 13.5 ≥3.38  
Calcium (Ionized), 
High (mg/dL; 
mmol/L)  
>ULN to <6.0 
>ULN to <1.5  
6.0 to <6.4 1.5 to <1.6  
6.4 to <7.2 1.6 to 
<1.8  
≥7.2 ≥1.8  
Calcium, Low 
(mg/dL; mmol/L)  
7.8 to <8.4 1.95 
to <2.10  
7.0 to <7.8 1.75 to <1.95  
6.1 to <7.0 1.53 to 
<1.75  
<6.1 <1.53  
Calcium (Ionized), 
Low (mg/dL; 
mmol/L)  
<LLN to 4.0 
<LLN to 1.0  
3.6 to <4.0 0.9 to <1.0  
3.2 to <3.6 0.8 to 
<0.9  
<3.2 <0.8  
Cardiac Troponin I, 
High  
NA  
NA  
NA  
Levels consistent with 
myocardial infarction or 
unstable angina as defined 
by the local laboratory  
Creatine Kinase, 
High  
3 to <6×ULN  
6 to <10×ULN  
10 to <20×ULN  
≥20×ULN  
Creatinine, High 
*Report only one  
1.1 to 1.3×ULN  
>1.3 to 1.8×ULN OR 
Increase to 1.3 to 
<1.5×participant’s baseline  
>1.8 to <3.5×ULN 
OR Increase to 1.5 to 
<2.0×participant’s 
baseline  
≥3.5×ULN OR Increase of 
≥2.0×participant’s baseline  


 
 
 
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Laboratory Values*: Chemistries  
Parameter  
Grade 1 Mild  
Grade 2 Moderate  
Grade 3 Severe  
Grade 4 Potentially Life- 
Threatening  
Creatinine 
Clearance 13  
or eGFR, Low  
*Report only one  
NA  
<90 to 60 ml/min or 
ml/min/1.73 m2 OR 10 to 
<30% decrease from 
participant’s baseline  
<60 to 30 ml/min or 
ml/min/1.73 m2 OR 
30 to <50% decrease 
from participant’s 
baseline  
<30 ml/min or ml/min/1.73 
m2 OR ≥50% decrease from 
participant’s baseline or 
dialysis needed  
Glucose (mg/dL; 
mmol/L) Fasting, 
High  
110 to 125  
6.11 to <6.95  
>125 to 250  
6.95 to <13.89  
>250 to 500  
13.89 to <27.75  
≥500 
≥27.75  
Nonfasting, High  
116 to 160  
6.44 to <8.89  
>160 to 250  
8.89 to <13.89  
>250 to 500  
13.89 to <27.75  
≥500  
≥27.75  
Glucose, Low 
(mg/dL; mmol/L)  
55 to 64  
3.05 to <3.55  
40 to <55  
2.22 to <3.05  
30 to <40  
1.67 to <2.22  
<30  
<1.67  
Lactate, High  
ULN to 
<2.0×ULN 
without acidosis  
≥2.0×ULN without 
acidosis  
Increased lactate with 
pH <7.3 without life- 
threatening 
consequences 3.0 to 
<5.0×ULN  
Increased lactate with pH 
<7.3 with life- threatening 
consequences  
Lipase, High  
1.1 to  
<1.5×ULN  
1.5 to <3.0×ULN  
3.0 to <5.0×ULN  
 
≥5.0×ULN  
Lipid Disorders 
(mg/dL; mmol/L)  
Cholesterol, Fasting, 
High  
200 to <240  
5.18 to <6.19  
240 to <300  
6.19 to <7.77  
≥300  
≥7.77  
NA  
LDL, Fasting, High  
130 to <160 
3.37 to <4.12  
160 to <190  
4.12 to <4.90  
≥190  
≥4.90  
NA  
Triglycerides, 
Fasting, High  
150 to 300  
1.71 to 3.42  
>300 to 500  
>3.42 to 5.7  
>500 to <1,000  
>5.7 to 11.4  
>1,000  
>11.4  
Magnesium 14, Low 
(mEq/L; mmol/L)  
1.2 to <1.4  
0.60 to <0.70  
0.9 to <1.2  
0.45 to <0.60  
0.6 to <0.9  
0.30 to <0.45  
<0.6  
<0.30  
Phosphate, Low 
(mg/dL; mmol/L)  
2.0 to <LLN 
0.65 to <LLN  
1.4 to <2.0  
0.45 to <0.65  
1.0 to <1.4  
0.32 to <0.45  
<1.0  
<0.32  
Potassium, High 
(mEq/L; mmol/L)  
5.6 to <6.0  
5.6 to <6.0  
6.0 to <6.5  
6.0 to <6.5  
6.5 to <7.0  
6.5 to <7.0  
≥7.0  
≥7.0  
Potassium, Low 
(mEq/L; mmol/L)  
3.0 to <3.4  
3.0 to <3.4  
2.5 to <3.0  
2.5 to <3.0  
2.0 to <2.5  
2.0 to <2.5  
<2.0  
<2.0  
Sodium, High 
(mEq/L; mmol/L)  
146 to <150  
146 to <150  
150 to <154  
150 to <154  
154 to <160  
154 to <160  
≥160  
≥160  
Sodium, Low 
(mEq/L; mmol/L)  
130 to <135  
130 to <135  
125 to <130  
125 to <130  
121 to <125  
121 to <125  
<121  
<121  
Uric Acid, High 
(mg/dL; mmol/L)  
7.5 to <10.0 
0.45 to <0.59  
10.0 to <12.0  
0.59 to <0.71  
12.0 to <15.0  
0.71 to <0.89  
≥15.0  
≥0.89  
 
 


 
 
 
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Hematology  
Parameter  
Grade 1 Mild  
Grade 2 Moderate  
Grade 3 Severe  
Grade 4 Potentially 
Life- Threatening  
Absolute CD4+ 
Count, Low 
(cell/mm3; cells/L) 
(not HIV infected)  
300 to <400  
300 to <400  
200 to <300  
200 to <300  
100 to <200  
100 to <200  
<100  
<100  
Absolute 
Lymphocyte Count, 
Low (cell/mm3; 
cells/L)  
(not HIV infected)  
600 to <650 
0.600×109 to 
<0.650×109  
500 to <600 
0.500×109 to 
<0.600×109  
350 to <500 
0.350×109 to 
<0.500×109  
<350  
<0.350×109  
Absolute Neutrophil 
Count (ANC), Low 
(cells/mm3; cells/L)  
800 to 1,000 
0.800×109 to 
1.000×109  
600 to 799  
0.600×109 to 
0.799×109  
400 to 599  
0.400×109 to 
0.599×109  
<400  
<0.400×109  
Fibrinogen, 
Decreased (mg/dL; 
g/L)  
100 to <200  
1.00 to <2.00 OR 
0.75 to <1.00×LLN  
75 to <100  
0.75 to <1.00 OR ≥
0.50 to <0.75×LLN  
50 to <75  
0.50 to <0.75 OR 
0.25 to <0.50×LLN  
<50 <0.50  
OR <0.25×LLN OR 
Associated with gross 
bleeding  
Hemoglobin 15, Low 
(g/dL; mmol/L) 16 
Male only  
10.0 to 10.9  
6.19 to 6.76  
9.0 to <10.0  
5.57 to <6.19  
7.0 to <9.0  
4.34 to <5.57  
<7.0  
<4.34  
Hemoglobin 15, Low 
(g/dL; mmol/L) 16 
female only  
9.5 to 10.4  
5.88 to 6.48  
8.5 to <9.5  
5.25 to <5.88  
6.5 to <8.5  
4.03 to <5.25  
<6.5  
<4.03  
INR, High (not on 
anticoagulation 
therapy)  
1.1 to <1.5×ULN  
1.5 to <2.0×ULN  
2.0 to <3.0×ULN  
≥3.0×ULN  
Methemoglobin  
(% hemoglobin)  
5.0 to <10.0%  
10.0 to <15.0%  
15.0 to <20.0%  
≥20.0%  
PTT, High  
(not on 
anticoagulation 
therapy)  
1.1 to <1.66×ULN  
1.66 to <2.33×ULN  
2.33 to <3.00×ULN  
≥3.00×ULN  
Platelets, Decreased 
(cells/mm3; cells/L)  
100,000 to <125,000 
100.000×109 to 
<125.000×109  
50,000 to <100,000 
50.000×109 to 
<100.000×109  
25,000 to <50,000 
25.000×109 to 
<50.000×109  
<25,000  
<25.000×109  
PT, High  
(not on 
anticoagulation 
therapy)  
1.1 to <1.25×ULN  
1.25 to <1.50×ULN  
1.50 to <3.00×ULN  
≥3.00×ULN  
WBC, Decreased 
(cells/mm3; cells/L)  
2,000 to 2,499 
2.000×109 to 
2.499×109  
1,500 to 1,999 
1.500×109 to 
1.999×109  
1,000 to 1,499 
1.000×109 to 
1.499×109  
<1,000  
<1.000×109  
 
 


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