Clinical trial NCT03577171
Conditions: Chronic Hepatitis B
Keywords: cHBV HBV HBeAg-positive hepatitis B vebicorvir VBR
Sponsor: Assembly Biosciences
Start date: 2018-06-19; Completion date: 2019-06-21
Enrollment: 25 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) entecavir (ETV) is safe and effective in participants with chronic hepatitis B infection (cHBV)

Detailed description:
This is a Phase 2a, multi-center, double-blind, placebo-controlled study evaluating ABI-H0731+ ETV vs ETV alone for the treatment of viremic hepatitis B "e" antigen (HBeAg)-positive participants with cHBV.

Arms: arm 1: Participants with cHBV who are currently not being treated will receive ABI-H0731 along with SOC ETV 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: Participants with cHBV who are currently not being treated will receive matching placebo along with SOC ETV tablets orally 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 ETV intervention 3: Placebo Oral Tablet
Intervention descriptions: intervention 1: Participants will receive 300mg QD of ABI-H0731 tablets orally. intervention 2: Participants will receive SOC ETV (0.5 mg QD) orally as per approved package insert. intervention 3: Participants will receive matching QD placebo tablets orally.

Protocol documents:
Prot_000.pdf: 
 
Title: A Phase 2a, Multi-center, Double-blind, Placebo-controlled Study 
Evaluating ABI-H0731 + Entecavir vs Entecavir Alone for the 
Treatment of Viremic, HBeAg-positive Patients with Chronic Hepatitis 
B 
 
NCT number:  NCT03577171 
 
Date:  18 June 2018 


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CLINICAL RESEARCH PROTOCOL 
PROTOCOL TITLE: 
A Phase 2a, Multi-center, Double-blind, Placebo-
controlled Study Evaluating ABI-H0731 + Entecavir vs 
Entecavir Alone for the Treatment of Viremic, HBeAg-
positive Patients with Chronic Hepatitis B 
 
STUDY NUMBER: 
ABI-H0731-202 
 
DRUG: 
ABI-H0731 
 
REFERENCE NUMBERS: 
US IND 136780 
 
SPONSOR: 
Assembly Biosciences 
 
PROTOCOL: 
Amendment 1.0, V2.0, 18 June 2018 
Original, V1.0, 15 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 + 
Entecavir vs Entecavir Alone for the Treatment of Viremic, HBeAg-positive Patients with Chronic Hepatitis B 
Study No: ABI-H0731-202 
Protocol Date: 18 June 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. 
Name and Title 
Approval Signature 
Date 
19Jun2018 
19June2018


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ABI-H0731-202 PROTOCOL AMENDMENT 1:  
SUMMARY OF CHANGES 
 
Amendment 1 Dated: 18 June 2018 
 
This document represents the primary changes to Protocol Amendment 1. Changes are either in bold or 
strikethrough text to note additions or omissions, respectively.  For a comprehensive list of the detailed 
changes made from the Original Protocol to Protocol Amendment 1, refer to the separate redlined 
(tracked changes) document. 
1. CLARIFIED INCLUSION CRITERIA #2 and 6: 
Clarified that systemic hormonal birth control (such as oral contraceptive pills or injectable 
contraceptive depots) are prohibited, whereas, IUDs, including IUDs with hormonal components are 
allowed.  Therefore, Inclusion Criteria #2 has been modified as follows: 
• 
 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 – 
including 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. 
 
Clarified that the Screening laboratory HBV results may be used for the ≥6 month evaluation for the 
determination of chronic HBV infection as defined in Inclusion #6: 
 
• 6.  In good general health except for chronic HBV infection (defined as HBV infection for at 
least 2 times >6 months documented by – for example – at least two repeated HBsAg 
positivity and/or history of detectable viral load documented at least two times ≥6 months 
apart (inclusive of screening), and serum IgM anti-HBV core-related antibody negative at 
screening 
 
The following sections were updated to reflect these changes: 
• Synopsis/Key Eligibility 
• Section 5.2/Inclusion Criteria 
 
 
2. REVISED SECTION 6.6.1/PROHIBITED CONCOMITANT THERAPY 
Revised Section 6.6.1/Prohibited Concomitant Therapy to be consistent with the updated Inclusion 
Criteria #2. 
6.6.1 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 


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(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…. 
 
 
3. REVISED SECTION 4.6.1: SUBJECTS WITH ALANINE AMINOTRANSFERASE 
ELEVATIONS 
Revised Section 4.6.1/Subjects with Alanine Aminotransferase Elevations per the request of a 
regulatory agency: 
 
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 deteriorating declining hepatic function (“possible 
decompensation”): 
 
• 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….   
▪ If an intercurrent cause is determined to be causal, the intercurrent cause 
should be treated as deemed medically appropriate by the Study 
Investigatortreating physician.  
▪ In the absence of evidence of possible decompensationdeclining hepatic 
function, and in the absence of contraindications, subjects with an ALT flare 
may continue on study under close observation, with unscheduled visits as 
deemed necessary by the Study Investigator. 
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. 
Subsequently, sSubjects whose ALT has stabilized should continue 
to be monitored at least 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 
o Subjects with confirmed biochemical evidence of deterioratingdeclining hepatic 
function, ie, a direct bilirubin increase to ≥2×Baseline and ≥2×ULN, an albumin 


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decline ≥0.5 g/dL, INR >2×Baseline and >2×ULN, with an associated ALT elevation 
≥2×Baseline and >2×ULN, 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 - if deemed necessary by the treating physician) until 
the relevant laboratory values return to normal or baseline.  
 
• Post-treatment ALT “flare” or ALT elevation with possible decompensationdeclining 
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 on ETV 
for CHB. Any subject with a post-treatment ALT elevation meeting the ALT “flare” 
definition (described above)(ALT ≥2×Baseline and ≥10×ULN 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 levels.  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 abovedeemed warranted by the Principal Investigator. If the post-
treatment ALT flare has not substantially resolved by the last study follow-up visit, subjects 
should continue to return to clinic…. 
 
If 2 or more subjects meet these LFT flare management criteria, the US FDA and other 
relevant regulatory agencies will be notified. 
 
 
4. REVISED SECTIONS TO BE CONSISTENT WITH SECTION 4.6.1/ SUBJECTS WITH 
ALANINE AMINOTRANSFERASE ELEVATIONS 
Various sections of the protocol were revised to be consistent with the definitions of ALT flare and 
declining hepatic function per section 4.6.1/Subjects with Alanine Aminotransferase Elevations. 
• 7.2.1 Discontinuation from Treatment 


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… 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 any subjects with confirmed evidence of declining hepatic function during 
treatment, ie, bilirubin elevations to >2×ULN or confirmed 0.5 g/dL declines in albumin, 
with an associated ALT elevation, or increase in INR >2×Baseline and >2×ULN (Section 
4.6.1)… 
 
• Appendix II/Adverse Event Intensity Grading was modified as follows: 
o The following Laboratory Values: Chemistries were added: 
 
Parameter 
Grade 1 Mild 
Grade 2 Moderate 
Grade 3 Severe 
Grade 4 
Potentially Life- 
Threatening 
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 
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) 
 
 
5. CORRECTED AND REVISED THE SCHEDULE OF ASSESSMENTS (TABLE 1) 
The following corrections and revisions were made to the Schedule of Assessments/Table 1: 
• Informed Consent(s) 
o Footnote d was revised for clarity as follows: 
▪ d.  Study specific including optional PG consent. PG sample collection 
requires documentation of completed PG consent. Subjects who elect to roll 
over onto the open-label extension study will be required to sign a separate 
consent at Week 24. 
o Added to the Table that this assessment is to be performed at Week 24 and added 
Footnote l.  To clarify, subjects are to sign a separate consent form specific to open-
label extension study (ABI-H0731-211) if they choose to participate in that study.  
Footnote l has been added to the Schedule of Assessments as follows: 


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▪ l. Subjects who elect to roll over onto the open-label extension study will 
be required to sign a separate consent at Week 24.  
• Study Drug Accountability was revised to Study Drug accountability to clarify reference 
to combination therapy of ETV ± ABI-H0731 
• Study Drug Dispensation was revised to Study Drug dispensation to clarify reference to 
combination therapy of ETV ± ABI-H0731 
• In-clinic dosing: study drug  
o The line was revised to In-clinic dosing: study drug ABI-H0731/placebo 
o Footnote k was revised for clarity:  
▪ k. At non-PK collection visits, ETV may be taken outside of the clinic visit 
pPer package insert instructions for dosing. Of note, ETV is recommended 
to be dosed 2 hours before or after eating.  If subjects are not able to 
remain in clinic for ETV dosing, then ETV may be dosed following their 
clinic visits and subjects should be reminded to record the dosing time 
within their dosing diary.  Subjects should not time of dosing and provide 
this information to the site at the earliest opportunity. 
• Footnote c was revised to be consistent with the definition of ALT flare: 
o c. Any subjects with rash or ALT flare (defined in section 4.6 as ALT≥2×Baseline 
[or 2× on-treatment nadir] and ≥10×ULN) should return to the clinic for an 
unscheduled visit as soon as possible, ideally within 3 days 
 
 
6. ADMINISTRATIVE CHANGES 
The following changes were made throughout the protocol: 
• Table 3/Pharmacokinetic Sample Collection was revised for clarity. 
o The Time Relative to Study Drug Administration for the Day 1 pre-dose and the Study 
Weeks 2, 4, 12, 24 pre-dose samples were changed from “Immediately Before” to 
“Immediately Before”. 
• The Protocol Synopsis was updated to be consistent with the revisions made to the body of 
the protocol per Amendment 1 
• Minor changes have been throughout the document made to improve clarity and consistency 
between sections. Misspellings and typographical errors were corrected and the document 
was formatted so that section numbering would be consistent.   
 


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ABI-H0731-202 
A PHASE 2A, MULTI-CENTER, DOUBLE-BLIND, PLACEBO-CONTROLLED 
STUDY EVALUATING ABI-H0731+ ENTECAVIR VERSUS ENTECAVIR 
ALONE FOR THE TREATMENT OF VIREMIC, HBEAG-POSITIVE 
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-H0731-202 
Title:  
A Phase 2a, Multi-center, Double-blind, Placebo-controlled Study Evaluating ABI-
H0731 + Entecavir versus Entecavir Alone for the Treatment of Viremic, HBeAg-
positive Patients with Chronic Hepatitis B 
Phase: 
2a 
Number of 
Subjects: 
Approximately 24 
Study Duration:  
Up to 45 days for screening, 6 months treatment, and 3 months follow-up 
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 ABI-H0731 in combination with entecavir (ETV), 
a standard of care (SOC) nucleos(t)ide analogue (NUC) therapy, will be safe and increase 
the functional cure rate for treatment-naïve patients with CHB. This study will explore the 
safety of combination therapy, as well as its potential for enhanced anti-viral efficacy as 
measured by the improvement in serum viral DNA reductions, effect on serum biomarkers 
of functional cures: quantitative and qualitative reduction in the viral antigens hepatitis B 
“e” antigen (HBeAg) and hepatitis B surface antigen (HBsAg), and reduction in circulating 
HBV RNA. 
Target 
Population: 
Male or female HBeAg-positive treatment-naïve subjects with CHB, age 18 to 70 years, 
with no evidence of cirrhosis or end-stage liver disease. 
Test Product: 
Active treatment subjects will receive ABI-H0731 300 mg, administered orally, once daily, 
as three 100-mg tablets in addition to ETV therapy. 
Reference 
Product: 
Placebo subjects will receive placebo (matching ABI-H0731 100-mg tablets), administered 
orally, once daily, as three tablets in addition to ETV 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 ETV in treatment-naïve subjects with HBeAg-positive CHB 
virus infection. Subjects will be randomized 1:1 to receive investigational agent (ABI-
H0731 or matching placebo) as add-on therapy to ETV for up to 6 months. Efficacy, safety, 
and PK will be assessed during the 6-month treatment period. At the end of the study 
treatment period, subjects will have the option to roll over into an optional, open-label, 
extension study of ABI-H0731 + SOC NUC (protocol ABI-H0731-211) or continue 
receiving ETV therapy and stop treatment with ABI-H0731/placebo.  


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Objectives:  
Primary: 
• 
To evaluate the potential for ABI-H0731 to increase the rapidity of HBV DNA 
loss in HBeAg-positive CHB subjects by initiating treatment with ABI-H0731 + 
ETV in subjects who are not yet on treatment for CHB, as measured by timing and 
magnitude of change in serum HBV DNA from Baseline 
Secondary: 
• 
To evaluate the safety and tolerability of ABI-H0731 when added to ETV therapy 
as initial therapy for HBeAg-positive CHB subjects 
• 
To confirm a lack of drug-drug interactions between ETV and ABI-H0731 
• 
To evaluate the potential for emergence of resistance, if any, to ABI-H0731 in 
combination with ETV therapy 
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 viral 
RNA 
• 
To assess the relationship between exploratory viral biomarkers such as changes 
in viral RNA and hepatitis B core-related antigen (HBCrAg) and outcome 
• 
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 HBV DNA from Baseline (Day 1) to Week 12 or Week 24 
on ABI-H0731 + ETV as compared to placebo + ETV 
Secondary 
Endpoints: 
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 + ETV as compared to placebo + ETV 
• 
Percent of subjects with a decline in viral DNA to below limit of quantitation 
(LOQ; on ABI-H0731 + ETV as compared to placebo + ETV) at end of treatment 
• 
Median time to viral suppression, defined as HBV DNA <20 IU/mL, on ABI-
H0731 + ETV as compared to placebo + ETV 
• 
Emergence of resistant HBV variants, if any 
• 
Drug concentrations: 
o Trough levels and (in subjects where optional post-dose samples are 
available) trough to peak ratios of ABI-H0731 on ABI-H0731 + ETV 
therapy 
o Trough levels and (in subjects where optional post-dose samples are 
available) trough to peak ratios of ETV on ABI-H0731 + ETV therapy as 
compared with placebo + ETV therapy 


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Exploratory 
Endpoints: 
Exploratory endpoints will include: 
• 
Quantitative changes in serum viral antigen (HBsAg or HBeAg, and HBCrAg) on 
ABI-H0731 + ETV as compared with placebo + ETV, 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 + ETV as compared with placebo + ETV 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 + ETV as compared with placebo + ETV 
• 
Quantitative changes from Baseline in mean log10 viral RNA, on ABI-H0731 + 
ETV, as compared with placebo + ETV, at each time point 
• 
Subjects whose HBV DNA achieves “target not detected” on ABI-H0731 + ETV 
as compared with placebo + ETV 
• 
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 RNA rebounds after discontinuing treatment with ABI-H0731 + 
ETV as compared with placebo + ETV therapy 
o Subjects with changes in HBsAg or HBeAg from Baseline whose viral 
antigen rebounds after discontinuing investigational treatment with ABI-
H0731 + ETV as compared with placebo + ETV 
o Subjects with HBsAg or HBeAg loss at Week 24 that is maintained 
through end of Follow-up (Week 36) after discontinuing investigational 
treatment with ABI-H0731 + ETV as compared with placebo + ETV 
• 
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, 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, as noted below. 
The primary comparison for the primary variable will be made using a two-sided, two-
sample t-test for mean differences with alpha=0.05. 
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 HBV DNA 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 (CI). 
For categorical variables, such as subjects with a 1 log10 drop in serum HBsAg titers from 
Baseline and subjects with HBeAg (or HBsAg) loss and seroconversion, descriptive 
statistics will include number and percent who meet the endpoint criteria. 


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Kaplan-Meier methods will be used to evaluate time to HBsAg and HBeAg loss (ie, antigen 
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 and HBeAg 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), 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, 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 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 - by  two repeated HBsAg positivity 
and/or detectable viral load documented at least two times ≥6 months apart (inclusive 
of screening), and serum IgM anti-HBV core-related antibody negative at screening 
7. HBV viral load ≥2×105 IU/mL 
8. HBeAg-positive at screening 
9. HBsAg >1000 IU/mL 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 ultrasongrapher with expertise in 


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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-
202 regimen in the opinion of the Investigator 
12. Willing and able to provide informed consent 
 
Exclusion Criteria 
 
Subjects who meet 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. Any prior treatment with lamivudine or telbivudine, previous treatment with an 
investigational agent for HBV other than ABI-H0731; or any other SOC treatment for 
>4 weeks 
6. 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 
7. 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 
8. Females who are lactating or pregnant or wish to become pregnant 
9. History of hepatocellular carcinoma (HCC) 
10. 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 
11. Exclusionary laboratory results 
a. Platelet count <100,000/mm3 
b. Albumin < lower limit of normal (LLN) 


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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 
e. ALT >10×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 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 ............................................................................................................................ 9 
2 
INTRODUCTION AND RATIONALE .......................................................................... 21 
2.1 
Study Rationale ............................................................................................................. 21 
2.2 
Background ................................................................................................................... 21 
2.2.1 
Chronic Hepatitis B Virus...................................................................................... 21 
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 .................................................... 25 
2.3 
Risk/Benefit Assessment ............................................................................................... 26 
2.3.1 
Known and Potential Risks of ABI-H0731 ........................................................... 26 
2.3.2 
Known and Potential Benefits of ABI-H0731 ...................................................... 27 
2.3.3 
Assessment of Potential Risks and Benefits .......................................................... 28 
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 Endpoints ........................................................................................... 30 
4 
STUDY PLAN .................................................................................................................... 32 
4.1 
Study Design .................................................................................................................. 32 
4.2 
Scientific Rationale ....................................................................................................... 32 
4.3 
Dose Justification .......................................................................................................... 33 
4.4 
Study Drug Resistance Monitoring ............................................................................. 33 
4.5 
End of Study Definition ................................................................................................ 33 
4.6 
Management of Toxicities ............................................................................................ 33 
4.6.1 
Subjects with Alanine Aminotransferase Elevations........................................... 33 
4.6.2 
Subjects with Rash .................................................................................................. 35 
4.7 
Study Schematic ............................................................................................................ 36 
4.8 
Schedule of Assessments............................................................................................... 36 
5 
POPULATION .................................................................................................................. 40 
5.1 
Number of Subjects ...................................................................................................... 40 
5.2 
Inclusion Criteria .......................................................................................................... 40 
5.3 
Exclusion Criteria ......................................................................................................... 41 
5.4 
Lifestyle Considerations ............................................................................................... 42 
5.5 
Screen Failures .............................................................................................................. 43 
5.6 
Strategies for Recruitment and Retention .................................................................. 43 
6 
STUDY DRUG ................................................................................................................... 44 
6.1 
Description ..................................................................................................................... 44 


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6.1.1 
Formulation ............................................................................................................. 44 
6.1.2 
Storage ..................................................................................................................... 44 
6.2 
Packaging and Shipment .............................................................................................. 45 
6.3 
Dose and Administration ............................................................................................. 45 
6.3.1 
Dosing in the Study ................................................................................................. 45 
6.3.2 
Preparation .............................................................................................................. 45 
6.3.3 
Blinding .................................................................................................................... 45 
6.4 
Accountability ............................................................................................................... 45 
6.5 
Compliance .................................................................................................................... 46 
6.6 
Concomitant Therapy .................................................................................................. 46 
6.6.1 
Prohibited Concomitant Therapy ......................................................................... 46 
6.6.2 
Other Medications and Treatments ...................................................................... 46 
7 
STUDY CONDUCT .......................................................................................................... 47 
7.1 
Study Procedures by Time Point ................................................................................. 47 
7.2 
Discontinuation ............................................................................................................. 47 
7.2.1 
Discontinuation from Treatment........................................................................... 47 
7.2.2 
Discontinuation from Study ................................................................................... 47 
8 
DESCRIPTION OF STUDY PROCEDURES ................................................................ 48 
8.1 
Efficacy Assessments .................................................................................................... 48 
8.1.1 
Primary Efficacy Assessment ................................................................................ 48 
8.1.2 
Secondary and Exploratory Efficacy Assessments .............................................. 48 
8.2 
Safety Assessments ........................................................................................................ 48 
8.2.1 
Clinical Laboratory Tests ...................................................................................... 49 
8.2.2 
Other Safety Assessments ...................................................................................... 49 
8.3 
Pharmacokinetic Assessments ..................................................................................... 50 
8.4 
Other Assessments ........................................................................................................ 50 
8.5 
Protocol Deviations ....................................................................................................... 51 
9 
ADVERSE EVENTS ......................................................................................................... 52 
9.1 
Documenting Adverse Events ...................................................................................... 52 
9.2 
Assessment of Intensity ................................................................................................ 52 
9.3 
Assessment of Causality ............................................................................................... 53 
9.4 
Expectedness ................................................................................................................. 53 
9.5 
Adverse Events of Special Interest .............................................................................. 53 
9.6 
Clinical Laboratory Changes....................................................................................... 53 
9.7 
Adverse Event Follow-up ............................................................................................. 54 
9.8 
Pregnancy ...................................................................................................................... 54 
10 SERIOUS ADVERSE EVENT ......................................................................................... 55 
10.1 
Definition of Serious Adverse Event ........................................................................... 55 
10.2 
Reporting Serious Adverse Events .............................................................................. 56 
10.3 
Overdose ........................................................................................................................ 57 
11 STATISTICS ...................................................................................................................... 58 
11.1 
Statistical Hypotheses ................................................................................................... 58 
11.2 
Sample Size .................................................................................................................... 58 
11.3 
Analysis Populations ..................................................................................................... 58 
11.4 
Statistical Methods ........................................................................................................ 59 


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11.4.1 
General Considerations .......................................................................................... 59 
11.4.2 
Primary Endpoint(s) ............................................................................................... 59 
11.4.3 
Secondary and Exploratory Endpoint(s) .............................................................. 59 
11.4.4 
Pharmacokinetic Endpoints and Analyses ........................................................... 60 
11.4.5 
Analysis of Safety .................................................................................................... 60 
11.4.6 
Demographic and Baseline Characteristics.......................................................... 61 
11.5 
Interim Analysis ............................................................................................................ 61 
11.6 
Exploratory Analyses ................................................................................................... 61 
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 .................................... 63 
12.4 
Informed Consent ......................................................................................................... 63 
12.5 
Records Management ................................................................................................... 64 
12.5.1 
Source Documentation ........................................................................................... 64 
12.5.2 
Study Files and Record Retention ......................................................................... 64 
12.6 
Conflicts of Interest ...................................................................................................... 65 
13 DATA MANAGEMENT, AUDITING, AND MONITORING ..................................... 66 
13.1 
Data Management ......................................................................................................... 66 
13.2 
Auditing ......................................................................................................................... 66 
13.3 
Monitoring ..................................................................................................................... 66 
14 AMENDMENTS ................................................................................................................ 68 
15 STUDY REPORT AND PUBLICATIONS ..................................................................... 69 
16 STUDY DISCONTINUATION ........................................................................................ 70 
17 CONFIDENTIALITY ....................................................................................................... 71 
18 REFERENCES .................................................................................................................. 72 
19 APPENDICES .................................................................................................................... 73 
19.1 
APPENDIX I – Names of Study Personnel ................................................................ 73 
19.2 
APPENDIX II – Adverse Event Intensity Grading ................................................... 74 
19.3 
APPENDIX III – Cytochrome P450 2B6, 2C8, 2C9, and 2D6 Substrates ............... 95 
LIST OF TABLES 
Table 1 
Schedule of Assessments............................................................................................... 37 
Table 2 
Clinical Laboratory Tests ............................................................................................ 49 
Table 3 
Pharmacokinetic Sample Collection ........................................................................... 50 
Table 4 
Power Calculations under Various Mean Differences in the Change from Baseline 
in HBV DNA levels at Week 12 or 24 between Treatment Groups ......................... 58 
 LIST OF FIGURES  
Figure 1 
Study Schematic ............................................................................................................ 36 


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LIST OF ABBREVIATIONS AND TERMS 
AFP 
alpha fetoprotein 
ALT 
alanine aminotransferase 
API 
active pharmaceutical ingredient 
AST 
aspartate aminotransferase 
BMI 
body mass index 
CC50 
50% cytotoxic concentration 
cccDNA 
covalently closed circular DNA 
CFR 
Code of Federal Regulations 
CHB 
chronic hepatitis B infection 
CI 
confidence interval 
CKD-EPI 
Chronic Kidney Disease Epidemiology Collaboration 
Cmax 
maximum plasma concentration 
CNS 
central nervous system 
CpAM 
core protein allosteric modifier 
CRO 
Contract 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 
HBcAb 
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 
RBC 
red blood cell 
rcDNA 
relaxed circular DNA 
SAP 
statistical analysis plan 
SOC 
standard of care 
Sponsor 
Assembly Biosciences 
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 
functional 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) 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 functional 
cures in a finite treatment period. 
This Phase 2a study will be the first study to explore the potential to increase rates of functional cure by 
addition of ABI-H0731 (a CpAM) to SOC NUC therapy, entecavir (ETV), in treatment-naïve, hepatitis 
B “e” antigen positive (HBeAg) positive CHB patients. 
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 protein (HBcAb). Chronic HBV infection 
is clinically defined as the persistence of HBsAg in a subject for 6 to 12 months or more [Heimbach 
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 


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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) [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 [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 
‘functional cures’ are predicted to afford improved long-term patient outcomes, ie, reduced HBV-
associated morbidity and mortality from end-stage liver disease and HCC. 
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 


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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 infected cells. 
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). 


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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 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. 


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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 (CNS), 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-H0731-101B (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. 
2.2.4.1 
Clinical Safety Data of ABI-H0731 
Clinical experience with ABI-H0731 consists of two 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 subject in the 800 mg 
once daily cohort and two subjects 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 


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ABI-H0731 at doses of 100, 200, 300, or 400 mg once daily for 28 days. ABI-H0731 was well-
tolerated in CHB subjects 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 subjects 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 subject 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 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 5. Detailed information 
can be found in the IB. 
2.3 
Risk/Benefit Assessment 
2.3.1 
Known and Potential Risks of ABI-H0731 
ABI-H0731 is a novel direct acting HBV inhibitor that will be among the first HBV CpAMs to be 
investigated in CHB subjects for > 28 days. At this stage of development, the risk considerations for 
ABI-H0731 are primarily based on the non-clinical and Phase 1 data summarized in the IB. 


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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 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 subjects 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 electrocardiogram (ECG) changes, and no 
treatment-emergent drug related clinically significant laboratory findings. One CHB subject 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, there 
was no pattern of adverse events nor of laboratory abnormalities that suggested any potential target organ 
pathology was associated with either dose or duration of ABI H0731 exposure. 
Refer to the IB for additional information. 
2.3.2 
Known and Potential Benefits of ABI-H0731 
There is a need for improved HBV antiviral therapies that can offer a “functional 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 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 functional cure rates for CHB. 
In Phase 1a and 1b studies, ABI-H0731 has been able to safely achieve liver and blood levels sufficient 
to demonstrate significant antiviral activity. 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 functional 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 into an open-label, 
extension study of ABI-H0731 treatment with SOC NUC therapy. In the extension study, all subjects 
will receive up to 12 additional months of ABI-H0731. 


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2.3.3 
Assessment of Potential Risks and Benefits 
In this study, chronically HBV-infected adults who have not previously been treated for HBV >4 weeks 
with a NUC or with any CpAM other than ABI-H0731 will be enrolled. These subjects will have 
detectable viremia as well as circulating biomarkers of ongoing viral replication and active cccDNA 
transcription – HBsAg, HBeAg, 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 + ETV combination therapy as well as the potential for increased rate of 
functional cure via more rapid reduction in viral load and increased loss of active cccDNA as compared 
to subjects on ETV therapy alone. 
As compared to monotherapy with ETV alone, 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 with ETV therapy is thus anticipated to 
demonstrate clinical antiviral effects not seen with ETV 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, the potential benefit derived from the ETV therapy provided as part of this study, as well as the 
potential for additional benefit if ABI-H031 with ETV therapy does increase rates of cccDNA loss.   
Eligible subjects will also be provided the opportunity to enroll into a long-term, open-label, extension 
study (ABI-H0731-211) to evaluate if longer courses of combination therapy (with ETV and ABI-H0731) 
increase the potential for functional cure. Subjects who choose not to enroll in the long-term extension 
study will continue to be followed for up to 12 more weeks on ETV alone as part of this study (ABI-
H0731-202).  After the 12-week follow-up period, subjects may elect to continue on ETV or other SOC 
therapy in consultation with their Study Investigator or external treating physician. Subjects who choose 
not to continue on SOC therapy after completion of 3-month follow-up should be monitored closely for 
the potential for viral rebound and possible “flare” with associated decompensation.  Risk of such a flare 
is mitigated by the recommendation for SOC therapy and careful patient selection for inclusion into this 
protocol. Additionally, any follow-on treatment required for management of a post-treatment ALT flare, 
as defined in this protocol, will be reimbursable by the Sponsor for up to one-year post-study.   


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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 the rapidity of HBV DNA loss in HBeAg-
positive CHB subjects by initiating treatment with ABI-H0731 + ETV in subjects who are not yet 
on treatment for CHB, as measured by timing and magnitude of change in serum HBV DNA from 
Baseline 
3.1.2 
Secondary Objectives 
• To evaluate the safety and tolerability of ABI-H0731 in combination with ETV therapy as initial 
therapy for HBeAg-positive CHB subjects 
• To confirm a lack of drug-drug interactions between ETV and ABI-H0731 
• To evaluate the potential for emergence of resistance, if any, for ABI-H0731 in combination with 
ETV therapy 
3.1.3 
Exploratory Objectives 
• To evaluate the kinetics of and absolute changes from Baseline in biomarkers of transcriptionally 
active cccDNA (HBeAg and HBsAg) 
• To evaluate the kinetics of and absolute changes from Baseline in circulating viral RNA 
• To assess the relationship between exploratory viral biomarkers such as changes in viral RNA and 
HBCrAg and outcome 
• 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 HBV DNA from Baseline (Day 1) to Week 12 or Week 24 on ABI-H0731 + 
ETV as compared to placebo + ETV 


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3.2.2 
Secondary Endpoints 
Secondary endpoints will be: 
• Number of subjects with adverse events, premature discontinuations, abnormal safety laboratory 
results, ECG, or vital signs 
• Subjects with abnormal alanine aminotransferase (ALT) at Baseline who have normal ALT at Week 
24 on ABI-H0731 + ETV as compared to placebo + ETV 
• Percent of subjects with a decline in viral DNA to below limit of quantitation (LOQ; on ABI-H0731 
+ ETV as compared to placebo + ETV) at end of treatment 
• Median time to viral suppression, defined as HBV DNA <20 IU/mL, on ABI-H0731 + ETV as 
compared to placebo + ETV 
• Emergence of resistant HBV variants, if any 
• 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 
3.2.3 
Exploratory Endpoints 
Exploratory endpoints will include: 
• Quantitative changes in serum viral antigen (HBsAg or HBeAg, and HBCrAg) on ABI-H0731 + 
ETV as compared with placebo + ETV, at each time point 
• Subjects with loss (defined as below LOQ) or decline in HBsAg and or HBeAg (<0.5 log10, ≥0.5 to 
1.0 log10, or >1.0 log10 decrease in viral antigen) on ABI-H0731 + ETV as compared with placebo + 
ETV at end of treatment and end of follow-up 
• Subjects with HBsAg or HBeAg seroconversion (loss of HBsAg and appearance of HBs antibody) 
or HBeAg seroconversion (loss of HBeAg and appearance of HBe antibody) on ABI-H0731 + ETV 
as compared with placebo + ETV 
• Quantitative changes from Baselines in mean log10 viral RNA, on ABI-H0731 + ETV, as compared 
with placebo + ETV, at each time point 
• Subjects whose HBV DNA achieves “target not detected” on ABI-H0731 + ETV as compared with 
placebo + ETV 


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• 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 RNA rebounds 
after discontinuing investigational treatment with ABI-H0731 + ETV as compared with placebo 
+ ETV therapy 
o Subjects with changes in HBsAg or HBeAg whose viral antigen rebounds off therapy after 
discontinuing investigational treatment with ABI-H0731 + ETV as compared with placebo + 
ETV therapy 
o Subjects with HBsAg or HBeAg loss at Week 24 that is maintained through end of follow-up 
(Week 36) after discontinuing investigational treatment with ABI-H0731 + ETV therapy as 
compared with placebo + ETV therapy 
• 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 ETV in 
treatment-naïve subjects with HBeAg-positive CHB. Subjects will be randomized 1:1 to receive 
investigational agent (ABI-H0731 + ETV or matching placebo + ETV) for up to 6 months. ETV will 
continue uninterrupted for the duration of the study as well as during follow-up. 
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). 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 
ETV. 
At the end of the treatment period in this study, subjects will either continue ETV 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 over into the optional, open-label, extension study ABI-H0731-211 will be 
treated under the direction of their Study Investigator and 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. Refer to Section 2.3.3 of this protocol for additional 
post-study follow-on guidance. 
• 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 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 in combination with SOC NUC therapy. 
Subjects will be required to sign a separate consent prior to entering the ABI-H0731-211 study. 
4.2 
Scientific Rationale 
It is anticipated that addition of ABI-H0731, a DAA targeting the HBV core protein to ETV, a SOC 
NUC therapy, will be safe and may 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 ETV 
therapy alone. Combination therapy with two potent DAAs is expected to result in a more rapid decrease 
of viral DNA as compared to monotherapy, as well as a decrease of serum viral RNA. Additionally, 
combination therapy is expected to result in a greater loss of cccDNA with a corresponding decline in 
serum viral antigens which reflect the presence and activity of cccDNA (eg, HBsAg and HBeAg). This 
study will explore both the safety of combination therapy in HBeAg-positive, treatment-naïve subjects, 
as well as evaluate measures of antiviral efficacy such as reduction in serum viral DNA, reduction in 
circulating viral RNA, and potential serum biomarkers of functional cures: quantitative and qualitative 
reduction in the viral antigens HBeAg and HBsAg. 


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4.3 
Dose Justification 
In the Phase 1 clinical studies, ABI-H0731 was well-tolerated in healthy subjects at daily doses up to 
1000 mg, twice daily doses of 800 mg for 7 days, and at daily doses up to 300 mg for 14 days. All 
treatment-emergent adverse events were considered mild (Grade 1) and reversible. Similarly, in subjects 
with CHB, at doses up to 300 mg daily for 28 days, ABI-H0731 was well-tolerated and all drug related 
treatment-emergent adverse events were mild (Grade 1) and reversible. 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 required other than dose discontinuation. 
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 i within the dose range that was 
well-tolerated in healthy subjects and subjects with CHB. 
4.4 
Study Drug Resistance Monitoring 
To assess potential HBV core gene sequences associated with viral resistance or blunted treatment 
response, serum samples from subjects with evidence of nonresponse to treatment, viral DNA rebound 
(>1 log10 HBV DNA rebound from on treatment nadir) or viral load plateauing (≥2 consecutive samples 
with viral load remaining within 0.5 log10 of nadir) will be selected for HBV core gene sequencing, with 
sequence comparisons to baseline sequences, as well as comparisons to core gene sequences from 
placebo recipients and HBV database sequences. 
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 study before completing the follow-up period or transitioning to the extension study, 
whichever is later. 
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 


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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 
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 on ETV for their CHB. Any 


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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. 
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 subject 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, 


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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 
• 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 1. 


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Table 1 
Schedule of Assessments 
Period or Visit 
Screenin
g 
On Treatment 
Post-Treatment 
Follow-Up a 
Premature 
Termination 
b 
Unscheduled c 
Study Day or Week 
Day (-45) 
to Day (-
1) 
Day 
1 
Wee
k 
2 
Wee
k 
4 
Wee
k 
8 
Wee
k 12 
Wee
k 16 
Wee
k 20 
Wee
k 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 
 
 
 
 
 
 
 
Xl 
 
 
 
 
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 
 
 
 
 
Drug accountability 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X  j 
if applicable 
 
Drug dispensation 
 
X 
X 
X 
X 
X 
X 
X 
X 
X  j 
 
 
 
In-clinic dosing:  
ABI-H0731/placebo 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
ETV dosingk  
 
X k 
X k 
X k 
X 
X 
X 
X 
X 
X 
 
 
 
Digital photography c 
 
 
 
 
 
 
 
 
 
 
 
 
if indicated 
Virology/Immunology 
HBV genotype 
X 
 
 
 
 
 
 
 
 
 
 
 
 
HBV viral load 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Quantitative HBsAg, quant 
HBeAg f 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 


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HBsAb, HBeAb 
X 
X 
 
 
 
X 
 
 
X 
 
X 
X 
 
HBV RNA 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Table 1 
Schedule of Assessments (continued) 
Period or Visit 
Screening 
On Treatment 
Post-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 
HBV DNA serum resistance  
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
HIV Ab 
X 
 
 
 
 
 
 
 
 
 
 
 
 
HCV Ab; HDV Ab; HAV 
(IgM); HEV (IgM) 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
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 
ETV 
 
X 
X 
X 
 
X 
 
 
X 
X 
 
X 
X 
Optional post-dose i  
4 (±2) hours after ABI-H0731 
and ETV 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 discontinue ABI-H0731 and continue to take ETV during 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. 


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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 
DNA, HBV serologies (quantitative HBeAg [reflex qualitative HBeAg if quantitative HBeAg is negative] and HBsAg [reflex qualitative HBsAg if quantitative HBsAg is negative]), 
HAV IgM, HCV RNA, HDV RNA, and HEV IgM. 
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 quantitative 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 protocol’s PK Assessments section. 
i 
Optional post-dose PK samples for ABI-H0731 and ETV may be collected 4 (±2) hours after in-clinic study drug + ETV administration at Day 1 and either Week 2 or Week 4. 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. 
j 
Week 28 drug dispensation and Week 36 drug accountability only applies to ETV, not to ABI-H0731/placebo. 
k 
If subjects are not able to remain in clinic for ETV dosing, then ETV may be dosed following their clinic visit and subjects should be reminded to record the dosing time within their 
dosing diary.   
1 
Subjects who elect to roll over onto the open-label extension study will be required to sign a separate consent at Week 24. 
 
 
Ab=antibody; AFP=alfa fetoprotein; ALT=alanine aminotransferase; AST=aspartate aminotransferase; ECG=electrocardiogram; eCRF=electronic case report form; ETV = entecavir; 
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 24 male or female HBeAg-positive treatment-naïve subjects with CHB, 
between the ages of 18 and 70, with no evidence of cirrhosis or end-stage liver disease 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- including 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 (only applicable to female partners of male subjects), 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 – for example - by two repeated HBsAg positivity and/or history of detectable 
viral load documented at least two times ≥6 months apart (inclusive of screening), and serum IgM 
anti-HBV core-related antibody negative at screening 
7. HBV viral load ≥2×105 IU/mL 
8. HBeAg-positive at screening 
9. HBsAg >1000 IU/mL at screening 


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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 ultrasongrapher 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-H0731-202 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 
5. Any prior treatment with lamivudine or telbivudine, previous treatment with an investigational agent 
for HBV other than ABI-H0731; or any other SOC treatment for > 4 weeks 
6. 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 
7. 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 


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8. Females who are lactating or pregnant or wish to become pregnant 
9. History of HCC 
10. 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 
11. Previous treatment with or contraindication to use of ETV per local prescribing information 
12. Exclusionary laboratory results 
a. Platelet count <100,000/mm3 
b. Albumin < LLN 
c. Total bilirubin >1.2×ULN 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 >10×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 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 
5.4 
Lifestyle Considerations 
During this study, subjects are asked to: 
• Abstain from abuse of alcohol (in the opinion of the Investigator; abuse is considered alcohol 
consumption exceeding 2 standard drinks per day on average [1 standard drink = 10 grams of alcohol]) 
and from any use of illicit substances for the duration of the study 
• Abstain from the use of herbal or other supplements 


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• 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 Principal 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. Rescreened subjects should be assigned the same subject 
number as for the initial screening. 
5.6 
Strategies for Recruitment and Retention 
Approximately 24 subjects will be enrolled globally. 
Subject recruitment will be performed by the study sites in accordance with local standards and 
regulations and be detailed in a separate plan. 
Subjects who complete the treatment phase of this study will be eligible to receive open-label ABI-
H0731 and ETV in an 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 
6.1.1 
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. 
6.1.2 
Storage 
Bottled drug product at the study site should be stored at controlled room temperature (15°C to 30°C 
[59°F to 89°F]) in a secure, locked location at the sites, accessible only to study personnel. 


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6.2 
Packaging and Shipment 
ABI-H0731 tablets and matching placebo tablets are packaged in high density polyethylene bottles fitted 
with child-resistant screw caps containing a desiccant (silica gel) and shipped to sites under at ambient 
conditions (15°C to 30°C [59°F to 89°F]). 
6.3 
Dose and Administration 
6.3.1 
Dosing in the Study 
All subjects will take ABI-H0731 or matching placebo as three 100-mg tablets once daily. Dosing should 
be after a meal, and at approximately the same time each day. ETV should be taken as recommended per 
package insert. 
On study treatment visit days, ABI-H0731/placebo will be administered in the clinic; subjects will self-
administer on all other treatment days. On study treatment visit days which include PK collection, 
subjects will administer ABI-H0731/placebo in clinic, and if possible, also the ETV in the clinic. Study 
personnel will document time of study drug administration in subject’s medical record. Subjects will be 
required to record the dates and times of each dose they self-administer in a diary. 
Refer to the Site Operations Manual for detailed instructions on managing missed or incorrect doses. 
6.3.2 
Preparation 
Not applicable. 
6.3.3 
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 + ETV 
therapy or placebo + ETV 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 Week 12 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. 
6.4 
Accountability 
Regulatory requirements stipulate accounting of all investigational drug received by the study site. 
Records of drug disposition must include the date received by the site, date administered, quantity 
administered, and the subject to whom study drug was administered. The Investigator is responsible for 
the accountability of all used and unused study drug containers and unused study drug. 
The study site is to use a study drug accountability record to document study drug disposition. All items 
on this form are to be fully completed. The Sponsor or the CRO will confirm if the method of recording 
study drug accountability by the clinical site and the location of study drug records at the site is 
appropriate. 


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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 and ETV 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 and ETV dispensation is planned for Day 1 and each scheduled visit 
thereafter during the dosing period. 
6.5 
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. 
6.6 
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 initiate and continue ETV for the duration of the study. Subjects will 
provide a log of their ETV therapy together with that of ABI-H0731/placebo at each clinic visit. 
6.6.1 
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. 
6.6.2 
Other Medications and Treatments 
Within the suggested guidelines above, subjects may receive any other medication or treatment that is 
deemed medically necessary by the Study Investigator. All medication and treatments should be recorded 
in the eCRF, including name of the medication or treatment, the start and stop dates, and the indication. 


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7 STUDY CONDUCT 
7.1 
Study Procedures by Time Point 
Refer to the Schedule of Assessments (Table 1). 
7.2 
Discontinuation 
7.2.1 
Discontinuation from Treatment 
If an individual study participant 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 1) 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 treatment-naïve HBV subjects, this 
study will evaluate treatment-related changes in serum viral DNA, serum HBsAg, serum HBeAg, 
HBCrAg, and serum HBV RNA levels. Additionally, in CHB subjects where HBV DNA is detectable 
is 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 change in mean log10 HBV DNA from Baseline (Day 1) to Week 12 or Week 
24 on ABI-H0731 + ETV as compared to placebo + ETV. Samples for quantitative HBV DNA levels 
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 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 1). 
 
• Quantitative/qualitative HBsAg and HBeAg levels 
• HBsAb and HBeAb 
• HBV RNA 
• HBCrAg (HBV Core related Antigen) 
• HBV resistance samples 
• Samples for exploratory viral research 
8.2 
Safety Assessments 
For adverse events, see Section 9. 
For serious adverse events, see Section 10. 


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8.2.1 
Clinical Laboratory Tests 
Clinical laboratory tests will be performed at the timepoints indicated in the Schedule of Assessments 
(Table 1). The clinical laboratory assessments are listed in Table 2. 
Table 2 
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 
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; a serum, plasma, 
or urine pregnancy test must be performed at all subsequent visits.  
A positive result disqualifies the subject for study treatment 
Urine drug 
screening 
Amphetamine/methamphetamine, barbiturates, benzodiazepines, 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. 
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. 


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• 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 ETV. Post-
dose samples for both ABI-H0731 and ETV will be collected from subjects willing and able to provide 
the optional sample 4 ± 2 hours after dosing. Sample timing is outlined in Table 3. 
Table 3 
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 pharmacokinetic sample should be collected if an unscheduled or early 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 
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 pharmacokinetic 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 
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 MRI, or hepatic ultrasound by a 
ultrasongrapher with expertise in evaluation of liver fibrosis) within 6 months of screening 


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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 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. 
Demography, medical history, and full physical examination will be performed at screening. 
Pharmacogenomic samples will be collected at Day 1 for subjects who consent to this procedure. These 
samples may be saved for future research. 
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. 


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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. 
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 


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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 explanations. 
• 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. 


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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 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 whether 
“hospitalization” occurred or was necessary, the adverse event should be considered serious. 


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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 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. 
During this trial, an SAE with onset during follow-on treatment with regulatory-approved HBV products, 
that is considered by the clinical investigator to be related to the use of these products, and the nature 
and severity of which is clearly “expected” on the basis of the regulatory-approved labels for the 
implicated product, will not be reported to regulatory authorities in an expedited manner, but will be 
included in the periodic safety reviews by the Sponsor and DMC for this study. Such SAEs will also be 
included in all data summaries submitted to national regulatory bodies and ECs/IRBs, and will be 
included in the eventual clinical study report. 


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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 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. 


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11 STATISTICS 
11.1 
Statistical Hypotheses 
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, as noted below. 
11.2 
Sample Size 
The primary objective of the study will be measured by changes from Baseline to Week 12 or Week 24 
in mean log10 HBV DNA. As the results for this study will be used to collect information for future 
studies, both timepoints will be reviewed independently, with no control of the alpha level. 
With a sample size of 24 subjects, randomized in a 1:1 ratio (12 active:12 placebo), a 2-sample t-test test 
for mean difference with a 2-sided 0.05 significance level has 87.7% power to detect a difference of at 
least 0.4 log10 (IU/mL) in the change from Baseline in serum HBV DNA level at Week 12 or Week 24 
between the placebo + ETV and ABI-H0731 + ETV groups, where an equal standard deviation of 0.3 is 
assumed for both groups (Table 4). 
Table 4 
Power Calculations under Various Mean Differences in the Change from Baseline 
in HBV DNA levels at Week 12 or 24 between Treatment Groups 
 
Power for N=24 subjects  
(12 ABI-H0731 + ETV: 12 Placebo + ETV) 
Estimated mean difference at Week 12 
or Week 24 between placebo + ETV 
and ABI-H0731 + ETV groups change 
from Baseline HBV DNA levels 
SD = 0.25 
SD = 0.30 
SD = 0.50 
SD = 0.60 
0.25 log10 IU/mL 
0.649 
0.497 
0.216 
0.164 
0.30 log10 IU/mL 
0.802 
0.649 
0.290 
0.216 
0.40 log10 IU/mL 
0.963 
0.877 
0.466 
0.346 
0.50 log10 IU/mL 
0.997 
0.974 
0.649 
0.497 
0.60 log10 IU/mL 
>0.999 
0.997 
0.802 
0.649 
Calculated using SAS, based on a two-sided, two-sample t-test for mean differences, assuming equal weight of treatment 
groups, and alpha=0.05. 
ETV=entecavir; HBV=hepatitis B virus; 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 ETV 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. An SAP containing the 
detailed planned statistical methods will be finalized prior to locking of the study database for the 
analyses, and it will form the basis for the programming of the displays and analyses of the final study 
data. The plan will define populations to be used for each analysis endpoint, outline all data handling 
conventions including missing data methods, and specify statistical methodology to be 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 endpoint is change in mean log10 HBV DNA from Baseline (Day 1) to Week 12 or Week 
24 on ABI-H0731 + ETV as compared to placebo + ETV. The primary comparison will be made using 
a two-sided, two-sample t-test for mean differences with alpha=0.05. 
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 HBV DNA 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 data 


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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 + ETV therapy 
• Trough levels and (for subjects who provide optional post-dose samples) trough to peak ratios of 
ETV on ABI-H0731 + ETV therapy as compared with placebo + ETV 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 ETV 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 sign 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, 
and pre-treatment ALT levels. 
11.5 
Interim Analysis 
No formal interim analyses are planned. See Section 12.2 for the Week 12 safety analysis and Section 8.3 
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 ETV is 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 DNA, 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. 
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. 


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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. 


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12 ETHICS AND RESPONSIBILITIES 
12.1 
Good Clinical Practice 
This study will be conducted in compliance with IRB/IEC and International Council for Harmonisation 
(ICH) Good Clinical Practice (GCP) Guidelines; Title 21 Part 56 of the US Code of Federal Regulations 
(CFR) relating to IRBs/IECs and GCP as described in the US FDA CFR (21 CFR § 50, 56, 312; 
applicable ICH guidelines regarding clinical safety data management (E2A, E2B(R3)); European 
Community directives 2001/20, 2001/83, 2003/94 and 2005/28 as enacted into local law, and with ICH 
guidelines regarding scientific integrity (E4, E8, E9, and E10). In addition, this study will adhere to all 
local regulatory requirements, and requirements for data protection. 
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 
(Section 11.5), as outlined in the DMC charter. 
In addition, the DMC will communicate major safety concerns and recommendations regarding study 
modification or termination to the Sponsor 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 their designees 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). 


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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. The original, signed ICF will be retained by the Investigator. The 
Investigator will supply all enrolled subjects with a copy of their signed ICF. 
The ICF may need to be revised during the study should important new information become available 
that may be relevant to the safety of the subject. In this instance approval should always be given by the 
IRB/IEC and existing subjects informed of the changes and reconsented. This is documented in the same 
way as previously described. 
The Investigator should encourage subjects to inform their primary 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. 
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. 


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If an Investigator moves, withdraws from an investigation, or retires, responsibility for maintaining the 
records may be transferred to another person who will accept responsibility. Notice of transfer must be 
made to and agreed by the Sponsor. 
12.6 
Conflicts of Interest 
Any conflict of interest of persons who have a role in the design, conduct, analysis, publication, or any 
aspect of this trial will be disclosed and managed. Furthermore, persons who have a perceived conflict 
of interest will be required to have such conflicts managed in a way that is appropriate to their 
participation in the design and conduct of this trial. 


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13 DATA MANAGEMENT, AUDITING, AND MONITORING 
13.1 
Data Management 
An eCRF will be used for the current study, and a data management plan will be prepared by the CRO. 
The data will be collected via electronic data capture (EDC) using the eCRFs. The site will be responsible 
for data entry into the EDC system. In the event of discrepant data, the CRO will request data clarification 
from the sites, which the sites will resolve electronically in the EDC system. The CRO will be 
responsible for the data management of this trial, including quality checking of the data. 
The data management methodology will be consistent with the CRO’s standard operating procedures 
and applicable regulatory guidelines. The data management plan will specify methods to ensure the 
accuracy and quality of the study data. 
Previous and concomitant medications will be coded using the latest available WHO Drug Reference 
Dictionary. Coexistent diseases and 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 their designed, 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 their designee, the 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. 


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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, the currently approved written ICF will require 
similar modification. In such cases, subjects will be required for to sign the amended informed consent 
prior to continued participation in the study. 


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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. 


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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. 


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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 (except in the United Kingdom) and screening 
and randomization 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, 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.European Medicines Agency. Guideline 
on Strategies to Identify and Mitigate Risks for First-In-Human Clinical Trials with Investigational 
Medicinal Products. London; 19 July 2007. 
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. 
Heimbach JK, Kulik LM, Finn RS, et al. AASLD Guidelines for the Treatment of Hepatocellular 
Carcinoma. Hepatology. 2018;67(1):358–380. 
Levey AS1, Stevens LA, et al. A new equation to estimate glomerular filtration rate. Ann Intern Med. 
2009 May 5;150(9):604–612. 
Liaw YF1, Leung N, Kao JH, et al. Asian-Pacific consensus statement on the management of chronic 
hepatitis B: a 2008 update. Hepatol Int. 2008 Sep;2(3):263–283. 
Marcellin, P, Buti, M, et al. Kinetics of hepatitis B surface antigen loss in patients with HBeAg-positive 
chronic hepatitis B treated with tenofovir disoproxil fumarate. J Hepatology. 2014;61(6):1228–1237. 
Ott JJ, Stevens GA, Groeger J, Wiersma ST. Global epidemiology of hepatitis B virus infection: New 
estimates of age-specific HBsAg seroprevalence and endemicity. Vaccine. 2012;30:2212–2219. 
Seeger C, Zoulim F and Mason W, Hepadnaviruses, in Knipe DM and Howley PM eds. Fields Virology, 
6th edition, Volume 2, chapter 68, 2013, Lippincott Williams & Wilkins, Philadelphia. 
Stanaway JD, Flaxman AD, et al. The global burden of viral hepatitis from 1990 to 2013. Lancet. 2016 
Sep 10;388(10049):1081–1088. 
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: 
Assembly Biosciences 
Medical Monitor: 
Clinical Research Organizations: 
PRA Health Sciences 
4130 Parklake Avenue 
Raleigh, NC 27612 USA 
 


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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 (July 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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Entecavir ± ABI-H0731 for Viremic HBeAg+ CHB Patients  
Confidential
Protocol Amendment 1.0 – 18 Jun 2018 
Page 81 of 95
 
 
 
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 
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 


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Entecavir ± ABI-H0731 for Viremic HBeAg+ CHB Patients  
Confidential
Protocol Amendment 1.0 – 18 Jun 2018 
Page 82 of 95
 
 
 
Neurologic 
Parameter 
Grade 1 Mild 
Grade 2 Moderate 
Grade 3 Severe 
Grade 4 Potentially 
Life- Threatening 
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-H0731-202 
Entecavir ± ABI-H0731 for Viremic HBeAg+ CHB Patients  
Confidential
Protocol Amendment 1.0 – 18 Jun 2018 
Page 83 of 95
 
 
 
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-H0731-202 
Entecavir ± ABI-H0731 for Viremic HBeAg+ CHB Patients  
Confidential
Protocol Amendment 1.0 – 18 Jun 2018 
Page 84 of 95
 
 
 
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-H0731-202 
Entecavir ± ABI-H0731 for Viremic HBeAg+ CHB Patients  
Confidential
Protocol Amendment 1.0 – 18 Jun 2018 
Page 85 of 95
 
 
 
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-H0731-202 
Entecavir ± ABI-H0731 for Viremic HBeAg+ CHB Patients  
Confidential
Protocol Amendment 1.0 – 18 Jun 2018 
Page 86 of 95
 
 
 
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-H0731-202 
Entecavir ± ABI-H0731 for Viremic HBeAg+ CHB Patients  
Confidential
Protocol Amendment 1.0 – 18 Jun 2018 
Page 87 of 95
 
 
 
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. 
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-H0731-202 
Entecavir ± ABI-H0731 for Viremic HBeAg+ CHB Patients  
Confidential
Protocol Amendment 1.0 – 18 Jun 2018 
Page 88 of 95
 
 
 
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-H0731-202 
Entecavir ± ABI-H0731 for Viremic HBeAg+ CHB Patients  
Confidential
Protocol Amendment 1.0 – 18 Jun 2018 
Page 89 of 95
 
 
 
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-H0731-202 
Entecavir ± ABI-H0731 for Viremic HBeAg+ CHB Patients  
Confidential
Protocol Amendment 1.0 – 18 Jun 2018 
Page 90 of 95
 
 
 
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 
≥3.5  
≥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 
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 
*Reminder: Choose the method that selects for the higher grade. 


Protocol ABI-H0731-202 
Entecavir ± ABI-H0731 for Viremic HBeAg+ CHB Patients  
Confidential
Protocol Amendment 1.0 – 18 Jun 2018 
Page 91 of 95
 
 
 
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 
≥3.5  
≥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 
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 


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Laboratory Values*: Chemistries 
Parameter 
Grade 1 Mild 
Grade 2 Moderate 
Grade 3 Severe 
Grade 4 Potentially 
Life- Threatening 
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 
≤120  
≤120 
Uric Acid, High (mg/dL; 
mmol/L) 
7.5 to <10.0  
0.45 to <0.59 
10.0 to <12.0  
0.59 to <0.71 
12.0 to <15.0 
0.71 to <0.89 
≥15.0 
≥0.89 
*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. 


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Protocol Amendment 1.0 – 18 Jun 2018 
Page 93 of 95
 
 
 
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. 
 
 


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Confidential
Protocol Amendment 1.0 – 18 Jun 2018 
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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 
 
 
 


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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 be avoided while 
on treatment: 
• 2B6:  Artemisinin, bupropion, cyclophosphamide, efavirenz, ifosphamide, ketamine,  
 
meperidine, methadone, nevirapine, propafol 
• 2C8:  Amodiaquine, cerivastatin, paclitaxel, repaglinide, sorafenib, torsemide 
• 2C9:  NSAIDs: Diclofenac, ibuprofen, lornoxicam, meloxicam, naproxen,  
 
 
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,  
 
 
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 + Entecavir vs Entecavir Alone for the 
Treatment of Viremic, HBeAg-positive Patients with Chronic Hepatitis 
B 
 
NCT number:  NCT03577171 
 
Date:  6 August 2019 




 
 
 
Sponsor: Assembly Biosciences  
Statistical Analysis Plan 
Protocol no: ABI-H0731-202  
Version Date: Final v1.0 06Aug2019 
PRS 005 T 17 G 
Page 1 of 36 
Strictly Confidential.  © 2017, PRA Health Sciences.  All rights reserved. 
Statistical Analysis Plan 
Sponsor: 
Assembly Biosciences 
Protocol No: 
ABI-H0731-202 
PRA Project Id: 
ASM31202-731202 
Protocol Version: 
Amendment 1 v2.1 / 30 July 2018 (UK only) 
Amendment 1 v2.0 / 18 June 2018 (USA, Canada, NZ, HKG) 
Original v1.0 / 15 May 2018 
 
Title: 
A Phase 2a, Multi-center, Double-blind, Placebo-controlled Study Evaluating ABI-
H0731+Entecavir vs Entecavir Alone for the Treatment of Viremic, HBeAg-positive 
Patients with Chronic Hepatitis B 
CRF Version Date: 
25 September 2018 
SAP No./Date 
Final v1.0 / 06 Aug 2019 
 
 Approvals 
Sponsor: Assembly Biosciences 
Signature /Date: 
 
 
Signature /Date: 
 
 
PRA 
Signature /Date: 
 
 
Signature /Date: 
 
 
 
 
 


 
 
 
Sponsor: Assembly Biosciences  
Statistical Analysis Plan 
Protocol no: ABI-H0731-202  
Version Date: Final v1.0 06Aug2019 
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Strictly Confidential.  © 2017, PRA Health Sciences.  All rights reserved. 
Table of Contents 
 
 Approvals ............................................................................................................................................................................ 1 
Table of Contents ..................................................................................................................................................................... 2 
 Purpose ................................................................................................................................................................................ 4 
 Scope ..................................................................................................................................................................................... 4 
 Introduction ....................................................................................................................................................................... 4 
4.1 Changes from Protocol .............................................................................................................................................. 4 
 Study Objectives ............................................................................................................................................................... 4 
5.1 Primary Objectives ..................................................................................................................................................... 4 
5.2 Secondary Objectives ................................................................................................................................................. 5 
5.3 Exploratory Objectives .............................................................................................................................................. 5 
 Study Design ....................................................................................................................................................................... 5 
6.1 Sample Size Considerations .................................................................................................................................... 6 
6.2 Randomization ............................................................................................................................................................. 6 
6.3 Schedule of Assessments .......................................................................................................................................... 6 
 Study Endpoints, Variables and Covariates ........................................................................................................ 10 
7.1 Efficacy Endpoints and Variables ....................................................................................................................... 10 
7.1.1 Primary Efficacy Endpoints .......................................................................................................................... 10 
7.1.2 Secondary Endpoints....................................................................................................................................... 10 
7.1.3 Exploratory Efficacy Endpoints .................................................................................................................. 10 
7.2 Safety Endpoints and Variables ........................................................................................................................... 11 
7.2.1 Adverse Events .................................................................................................................................................. 11 
7.2.2 Clinical Laboratory Tests ............................................................................................................................... 12 
7.2.3 Vital Signs ............................................................................................................................................................. 13 
7.2.4 12-Lead ECG ........................................................................................................................................................ 13 
7.3 Pharmacokinetic Endpoints and Variables..................................................................................................... 14 
7.4 Other Variables........................................................................................................................................................... 14 
7.5 Predetermined Covariates and Prognostic Factors .................................................................................... 15 
 Definitions ......................................................................................................................................................................... 15 
 Analysis Sets ..................................................................................................................................................................... 15 
9.1 Intent-to-Treat............................................................................................................................................................ 15 
9.2 Safety .............................................................................................................................................................................. 15 
9.3 Pharmacokinetic ........................................................................................................................................................ 16 
9.4 Pharmacogenomic .................................................................................................................................................... 16 
 Interim Analyses .......................................................................................................................................................... 16 
10.1 Week 4 Pharmacokinetic Analysis .................................................................................................................. 16 
10.2 Week 12 Safety Analysis ...................................................................................................................................... 17 
 Data Review ................................................................................................................................................................... 17 
11.1 Data Handling and Transfer ............................................................................................................................... 17 
11.2 Data Screening ......................................................................................................................................................... 17 
 Statistical Methods ...................................................................................................................................................... 17 
12.1 General Considerations ........................................................................................................................................ 17 
12.2 Handling of Missing Data / Imputation Methods ...................................................................................... 18 
12.3 Subject Disposition ................................................................................................................................................ 20 
12.4 Protocol Deviations................................................................................................................................................ 21 
12.5 Demographic and Baseline Characteristics ................................................................................................. 21 
12.6 Treatments ................................................................................................................................................................ 21 


 
 
 
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12.6.1 Prior and Concomitant Medications ....................................................................................................... 21 
12.6.2 Procedures ........................................................................................................................................................ 22 
12.6.3 Compliance and Exposure to Study Drug ............................................................................................. 22 
12.7 Efficacy Analyses ..................................................................................................................................................... 22 
12.7.1 Primary Endpoint Assessment: HBV DNA Change from Baseline ............................................. 22 
12.7.2 Secondary and Exploratory Assessments ............................................................................................ 23 
12.8 Safety Analyses ..................................................................................................................................................... 25 
12.8.1 Adverse Events ................................................................................................................................................ 25 
12.8.2 Deaths and Serious Adverse Events ....................................................................................................... 26 
12.8.3 Central Laboratory Data .............................................................................................................................. 26 
12.8.4 Vital Signs .......................................................................................................................................................... 27 
12.8.5 Physical Examinations, ECGs, and Other Observations Related to Safety .............................. 27 
12.9 Pharmacokinetics ................................................................................................................................................... 27 
 Validation ........................................................................................................................................................................ 28 
 References ...................................................................................................................................................................... 28 
Appendix 1 Glossary of Abbreviations ......................................................................................................................... 29 
Appendix 2 Tables, Figures, Listings, and Supportive SAS Output Appendices .......................................... 31 
Appendix 3 Grading of Laboratory Values .................................................................................................................. 32 
Laboratory Values*: Chemistries ............................................................................................................................... 33 
Hematology ......................................................................................................................................................................... 35 
Urinalysis ............................................................................................................................................................................. 36 
 


 
 
 
Sponsor: Assembly Biosciences  
Statistical Analysis Plan 
Protocol no: ABI-H0731-202  
Version Date: Final v1.0 06Aug2019 
PRS 005 T 17 G 
Page 4 of 36 
Strictly Confidential.  © 2017, PRA Health Sciences.  All rights reserved. 
 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-H0731-202, “A Phase 2a, Multi-
center, Double-blind, Placebo-controlled Study Evaluating ABI-H0731 + Entecavir vs Entecavir Alone for 
the Treatment of Viremic, HBeAg-positive 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 representatives 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 Protocol Amendment 1.0, v2.1 dated 30 July 2018 and CRF 
dated 30 August 2018. 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. If necessary, changes following 
final approval of the SAP will be tracked in a 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  
Following an increase in the number of subjects in the sister protocol ABI-H0731-201 (Study 201), 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 25% of subjects across BOTH studies 
completing a Week 12 visit and 75% of all subjects completing a Week 12 visit. 
 
PK sampling 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. 
 Study Objectives 
5.1 Primary Objectives 
The primary objective of the study is to evaluate the potential for ABI-H0731 to increase the rapidity of HBV 
DNA decline in hepatitis B “e” antigen (HBeAg) positive chronic hepatitis B infection (CHB) subjects by 
initiating treatment with ABI-H0731 + ETV in subjects who are not yet on treatment for CHB, as measured 
by timing and magnitude of change in serum HBV DNA from Baseline. 


 
 
 
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5.2 Secondary Objectives 
The following secondary objectives are defined for this study: 
• 
To evaluate the safety and tolerability of ABI-H0731 in combination with ETV therapy as initial 
therapy for HBeAg-positive CHB subjects. 
• 
To confirm a lack of drug-drug interactions between ETV and ABI H0731. 
• 
To evaluate the potential for emergence of resistance, if any, for ABI-H0731 in combination with 
ETV therapy. 
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 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 ETV in treatment-
naïve subjects with HBeAg-positive CHB. Twenty-four subjects will be randomized in a 1:1 ratio to receive 
investigational agent (ABI-H0731 or matching placebo) as add-on therapy to ETV for up to 6 months. ETV 
will continue uninterrupted for the duration of the study as well as during follow-up. 
Safety will be monitored by a Data Monitoring Committee (DMC) when approximately 25% and 75% 
subjects (across ASM31201-731201 Amendment 3 v4.0 / 09 November 2018 and ASM31202-731202 
studies 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 discontinued study without completing Week 12). This timing 
differs from that defined in the protocol, to allow for earlier identification of potential safety concerns. 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 ETV. 
At the end of the 24-week treatment period in this study, subjects will either continue ETV 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 ETV alone and will 
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 in combination with SOC NUC therapy. Subjects will be required 
to sign a separate informed consent form prior to entering the ABI H0731-211 study. 


 
 
 
Sponsor: Assembly Biosciences  
Statistical Analysis Plan 
Protocol no: ABI-H0731-202  
Version Date: Final v1.0 06Aug2019 
PRS 005 T 17 G 
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Strictly Confidential.  © 2017, PRA Health Sciences.  All rights reserved. 
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 to Week 12 or Week 24 in 
mean log10 HBV DNA. As the results for this study will be used to collect information for future studies, both 
timepoints will be reviewed independently, with no control of the alpha level. 
With a sample size of 24 subjects, randomized in a 1:1 ratio (12 ABI-H0731:12 placebo), a 2-sample t-test 
for mean difference with a 2-sided 0.05 significance level has 87.7% power to detect a difference of at least 
0.4 log10 (IU/mL) in the change from Baseline in serum HBV DNA level at Week 12 or Week 24 between 
the placebo + ETV and ABI-H0731 + ETV groups, where an equal standard deviation of 0.3 is assumed for 
both groups (Table 1). 
Table 1 
Power Calculations under Various Mean Differences in the Change from Baseline in HBV 
DNA levels at Week 12 or 24 between Treatment Groups 
Estimated mean difference at Week 12 or 
Week 24 between placebo + ETV and 
ABI-H0731 + ETV groups Change from 
Baseline HBV DNA levels 
Power for N=24 subjects  
(12 ABI-H0731 + ETV: 12 Placebo + ETV) 
SD = 0.25 
SD = 0.30 
SD = 0.50 
SD = 0.60 
0.25 log10 IU/mL 
0.649 
0.497 
0.216 
0.164 
0.30 log10 IU/mL 
0.802 
0.649 
0.290 
0.216 
0.40 log10 IU/mL 
0.963 
0.877 
0.466 
0.346 
0.50 log10 IU/mL 
0.997 
0.974 
0.649 
0.497 
0.60 log10 IU/mL 
>0.999 
0.997 
0.802 
0.649 
Calculated using SAS, based on a two-sided, two-sample t-test for mean differences, assuming equal weight of 
treatment groups, and alpha=0.05. ETV=entecavir; HBV=hepatitis B virus; SD=standard deviation. 
 
6.2 Randomization 
Approximately twenty-four subjects will be randomized in a 1:1 ratio (12 ABI-H0731:12 placebo) by an 
independent Interactive Web Response System (IWRS) vendor.  
6.3 Schedule of Assessments 
The study schedule of assessments per Amendment 1 v2.1 dated 30-July-2018 is noted 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 l 
 
 
 
 
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 
examm 
 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
 
X 
Paper diary 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
Drug accountability 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
Xj 
if applicable 
 
Drug dispensation 
 
X 
X 
X 
X 
X 
X 
X 
X 
Xj 
 
 
 
In-clinic dosing:  
ABI-H0731/placebo 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
ETV dosingk 
 
Xk 
Xk 
Xk 
X 
X 
X 
X 
X 
X 
 
 
 
Digital photography c 
 
 
 
 
 
 
 
 
 
 
 
 
if indicated 
Virology/Immunology 
HBV genotype 
X 
 
 
 
 
 
 
 
 
 
 
 
 
HBV 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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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 
  HBV DNA serum resistance 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
HIV Ab 
X 
 
 
 
 
 
 
 
 
 
 
 
 
HCV Ab; HDV Ab; HAV 
(IgM); HEV (IgM) 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
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 
ETV 
 
X 
X 
X 
 
X 
 
 
X 
X 
 
X 
X 
Optional post-dose i 
4 (±2) hours after ABI-
H0731 and ETV 
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 discontinue ABI-H0731 and continue to take ETV during 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 (quantitative HBeAg [reflex qualitative HBeAg if quantitative HBeAg is negative] and HBsAg [reflex qualitative HBsAg if quantitative HBsAg is negative]), HAV IgM, HCV 
RNA, HDV RNA, and HEV IgM 


 
 
 
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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 quantitative 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 ETV may be collected 4 (±2) hours after in-clinic study drug + ETV administration at Day 1 and either Week 2 or Week 4. If a subject can only 
provide optional samples on Weeks 2 or 4, then those may be collected from subjects that were not able to provide optional PK samples on Day 1. 
j 
Week 28 drug dispensation and Week 36 drug accountability only applies to ETV, not to ABI-H0731/placebo. 
k 
If subjects are not able to remain in clinic for ETV dosing, then ETV may be dosed following their clinic visit and subjects should be reminded to record the dosing time within their dosing diary. 
l 
Subjects who elect to roll over onto the open-label extension study will be required to sign a separate consent at Week 24. 
m 
Dermatology assessments were added based on protocol v2.1 for UK only. 
 
Ab=antibody; AFP=alfa fetoprotein; ALT=alanine aminotransferase; AST=aspartate aminotransferase; ECG=electrocardiogram; eCRF=electronic case report form; ETV=entecavir; 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 efficacy endpoint is two co-primary endpoints: 
1) the mean change from baseline in log10 HBV DNA at Week 12  
2) the mean change from baseline in log10 HBV DNA at Week 24 
using a HBV DNA transfection-based assays against representative HBV strains of genotypes A, B, C, and 
D. 
7.1.2 Secondary Endpoints 
The primary efficacy variable, HBV DNA, 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 Weeks 28 and 36 for subjects who do not continue treatment in the 
extension protocol (ABI-H0731-211). Subjects who enter the ABI-H0731-211 protocol will have samples 
collected according to that protocol. 
 
The following secondary endpoints will be evaluated using these variables:  
• 
Percent of subjects with a decline in viral DNA to below limit of quantitation (LOQ) at end of treatment 
• 
Median time to viral suppression, defined as HBV DNA <20 IU/mL 
• 
Incidence of Emergence of resistant HBV variants, if any 
Other Secondary Endpoints include: 
• 
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 Efficacy Endpoints 
Blood samples for the assessment of secondary and exploratory efficacy endpoints are collected according 
to the Schedule of Assessments (Table 2). These assessments include HBV DNA, quantitative/qualitative 
HBsAg and HBeAg levels, HBsAg antibody (HBsAb) and HBeAg antibody (HBeAb), HBV RNA, HBCrAg, 
and HBV resistance samples.  
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. 


 
 
 
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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 endpoints will be evaluated using these variables:  
• 
The mean change from baseline in serum viral antigen (HBsAg, HBeAg, 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 (Week 24) 
• 
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 
• 
Change from Baseline in mean log10 viral RNA at each timepoint 
• 
Percent of subjects whose HBV DNA achieves “target not detected” at each timepoint 
• 
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 
+ ETV as compared with placebo + ETV 
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 + ETV as compared 
with placebo + ETV 
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 + ETV as 
compared with placebo + ETV 
HBV resistance testing, using exploratory research samples, will be performed on subjects with evidence 
of nonresponse to treatment, to assess potential HBV core gene sequences associated with viral resistance 
or blunted treatment response, viral DNA rebound (>1 log10 HBV DNA rebound from on treatment nadir) 
or viral load plateauing (≥2 consecutive samples with viral load remaining within 0.5 log10 of nadir). 
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, 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 at Week 24 
on ABI-H0731 + ETV therapy as compared with placebo + ETV therapy 
7.2.1 Adverse Events 
Adverse events will be coded using MedDRA 21.0 (March 2018) and graded by Medidata Rave Coding 
tool. Adverse events 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. 


 
 
 
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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. 
• 
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 
2). The clinical laboratory assessments are listed in Table 3. 
 
 


 
 
 
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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 
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; a serum, 
plasma, or urine pregnancy test must be performed at all subsequent visits.  
A positive result disqualifies the subject for study treatment 
Urine drug 
screening 
Amphetamine/methamphetamine, barbiturates, benzodiazepines, 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. 
 
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 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 ECG will be collected at screening, Day 1, and Weeks 12, and 24 (or at the time of 
discontinuation). Follow-up samples 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. 


 
 
 
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7.3 Pharmacokinetic Endpoints and Variables 
The pharmacokinetic endpoints for this study are as follows: 
• 
Trough levels and (in subjects where optional post-dose samples are available) trough to peak 
ratios of ABI-H0731 on ABI-H0731 + ETV therapy 
• 
Trough levels and (in subjects where optional post-dose samples are available) trough to peak 
ratios of ETV on ABI-H0731 + ETV therapy as compared with placebo + ETV therapy 
Pre-dose drug concentration samples will be collected to determine trough concentrations of ABI-H0731 
and ETV. Post-dose samples for both ABI-H0731 and ETV 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-dosee 
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 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. 
 
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 


 
 
 
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• 
Exposure and compliance to study medication 
 
7.5 Predetermined Covariates and Prognostic Factors 
Race, ethnicity, and/or HBV genotype (A, B, C, D, E-H) may be used as a covariate where indicated within 
the analysis. 
 Definitions 
The following table will be used to define variables used within the statistical tables, figures, and listings. 
Table 5 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 Intent-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 used any amount of study drug. Subjects in 
this population will be analyzed according to the actual treatment received. 


 
 
 
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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. 
Pharmacokinetic Population 2 (PK2): The PK2 population will include all subjects in the safety population 
who have ETV PK data assessments available. 
9.4 Pharmacogenomic  
The pharmacogenomic (PG) 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 (DMC) safety analyses for data collected to Week 12.  The unblinded statistician and 
programmer will provide these analyses, as indicated in Section 6.3. 
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 to verify whether ETV steady-state exposure are affected 
by combination treatment with ABI-H0731. 
Results will be provided once and will include trough levels and trough to peak ratios (as available) for ABI-
H0731 and ETV concentrations in tabular and graphical format.  
These results will be provided for the PK1 and PK2 Populations in an unblinded manner by treatment group, 
delivered by the unblinded PRA statistician or by a PRA PK expert. 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 recipients will be notified of when results are posted to complete their review of the unblinded PK 
data. 
 
 


 
 
 
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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 DMC 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. 
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 project’s 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. 
Review of a pre-freeze TFL run on clean subjects and a post-freeze TFL run on the frozen database allow 
for further data screening prior to lock. The post-freeze TFL will be discussed with the sponsor in a data 
review meeting to identify any final data issues and seek corrections prior to database lock. 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 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 
ETV therapy. 


 
 
 
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• 
Placebo: This group will include subjects receiving placebo (matching placebo to ABI-H0731 
tablets) in addition to their ETV therapy 
Sites 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% will be displayed without any decimal 
places and 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. 
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. 
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 6. 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 6.  
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 the AE will be assumed to be 
related. If intensity of AE is missing, then no imputation will be applied. 
 
 


 
 
 
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Table 6.  
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) if available, pre-treatment ALT levels, and 
ETV therapy reported at time of randomization. 
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 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. 
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 .  


 
 
 
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12.6.2 Procedures 
Procedures will be recorded from 7 days prior to the informed consent date through to study completion. 
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. 
12.6.3 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-<1 6weeks, 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 tablets 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 𝑡𝑎𝑏𝑙𝑒𝑡𝑠 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, unless otherwise noted.  For virology samples, a listing will 
be provided for the Safety population, and will include the following variables: HBV DNA (IU/mL),HBsAg 
(IU/mL), HBsAg (qualitative), HBeAg (IU/mL), HBeAg (qualitative), HBCrAg (IU/mL, and HBV RNA 
(copies/mL).  
12.7.1 Primary Endpoint Assessment: HBV DNA Change from Baseline 
The primary endpoint is the mean change from baseline in log10 HBV DNA at Week 12 and at Week 24.  
The primary efficacy variable, HBV DNA, is collected at screening, Day 1, and Weeks 2, 4, 8, 12, 16, 20, 
and 24 (or at the time of discontinuation). Summary statistics will be provided by treatment group for the 
observed and change from baseline log10 serum results at the above study visits. Summaries will be 
provided for subjects 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 


 
 
 
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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. 
As this is a proof-of concept study, both primary timepoints of interest, Week 12 and Week 24 will be 
reviewed independently. There is no plan to control for alpha for reviewed timepoint, however, a significant 
difference at either timepoint would be considered clinically desirable and may warrant further exploratory 
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 Secondary and Exploratory Assessments 
12.7.2.1 ALT 
For ALT Percent of subjects with normal value (within normal ranges as specified by central lab) at baseline 
and percent of subjects who continue to have normal ALT values at Week 24 will be provided by treatment 
group in the ITT population.  
 
12.7.2.2 HBV DNA Loss and Time to Viral Suppression 
At each post-baseline timepoint, the number and percentage of subjects with detectable (>=LOQ) vs 
undetectable (<LLOQ) HBV DNA will be tabulated in the ITT population for each treatment group.  
Time to viral suppression, defined as HBV DNA < 20 IU/mL, 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 viral suppression if a HBV DNA of <20 IU/mL is observed for the subject, 
and all subsequent HBV DNA measurements are <20 IU/mL or below 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, HBV DNA of <20 IU/mL 
occurs prior to Week 24 but a later assessment (HBV DNA of >=20 IU/mL) occurs 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 HBV DNA of <20 IU/mL). . The 25th, 50th (median), 
and 75th percentiles for time to viral suppression in weeks will be reported, along with the corresponding 
95% confidence interval. An unstratified log-rank test will be used to assess differences in viral suppression 
rates between treatment groups.  
12.7.2.3 HBsAg, HBeAg, and HBCrAg levels 
For HBsAg, HBeAg, HBCRAg, 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, AND HBCRAg 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. 
 


 
 
 
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12.7.2.4 HBsAg and HBeAg loss and seroconversion 
The number and percentage 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) 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 a result of <LOQ is noted for the subject, and all later records 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 HBsAg or HBeAg loss indicated by a result of <LOQ by Week 24 will be censored at their 
last observed visit up to week 24, 2) If a subject rebounds within the 24-week period, HBsAg or HBeAg < 
LOQ occurs prior to Week 24 but a later assessment of >=LOQ) occurs 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 HBsAg or HBeAg < LOQ. 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. 
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), ethnicity 
(Hispanic/Latino, Non-Hispanic/Latino), and HBV genotype (A, B, C, D, E-H), as available.  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 time point.  
12.7.2.5 HBV RNA 
Summary statistics will be provided by treatment group for the observed and change from baseline log10 
viral RNA 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 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. 
 
12.7.2.6 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 


 
 
 
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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. 
 
12.7.2.7 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 12.7.2.3, 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 5 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 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 
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. 


 
 
 
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• 
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 
• 
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 


 
 
 
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24, as well as Week 28 for subjects who enter the follow-up phase. If a subject consents 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 ETV with a PK assessment (i.e. subjects in Pharmacokinetic Set 2), a similar 
analysis as described above will be provided, for both treatment groups.  
For subjects in Pharmacokinetic Set 2 (treated with ETV), the comparison of ETV trough concentration 
between treatment arms (ABI-H0731 vs Placebo) will be presented in a table. The comparison 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 ETV levels in subjects randomized to ABI-H0731 vs Placebo 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 results will be plotted: ETV PK 
levels in ABI-H0731 subjects, and ETV PK levels in Placebo subjects. 
Drug-drug interaction effects of ETV at Baseline, Week 2, Week 4, Week 12, Week 24, and Week 28 (for 
subjects who enter the follow-up phase) will be presented in a graph. At each time point the geometric 
mean ratio of trough ETV PK values for [ABI-H0731 + ETV / ETV 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 
IWRS 
Interactive Web Response System 
LOQ 
limit of quantitation 
MCHC 
mean corpuscular hemoglobin concentration  


 
 
 
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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 (*). 
 


 
 
 
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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 Bilirubinm, 
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 
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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 
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 
(Phosphorus), Low 
(mg/dL; mmol/L)  
2.0 to <LLN 
0.65 to <LLN 
1.4 to <2.0  
0.45 to <0.65 
1.0 to <1.4  
0.32 to <0.45 
 <1.0 
<0.32 
Potassium, High 
(mEq/L; mmol/L) 
5.6 to <6.0  
5.6 to <6.0 
6.0 to <6.5  
6.0 to <6.5 
6.5 to <7.0  
6.5 to <7.0 
≥7.0  
≥7.0 
Potassium, Low 
(mEq/L; mmol/L) 
3.0 to <3.4  
3.0 to <3.4 
2.5 to <3.0 
2.5 to <3.0 
2.0 to <2.5  
2.0 to <2.5 
<2.0 
<2.0 
Sodium, High 
(mEq/L; mmol/L) 
146 to <150 
146 to <150 
150 to <154  
150 to <154 
154 to <160  
154 to <160 
≥160  
≥160 
Sodium, Low 
(mEq/L; mmol/L) 
130 to <135  
130 to <135 
125 to <130  
125 to <130 
121 to <125  
121 to <125 
≤120  
≤120 
Uric Acid, High 
(mg/dL; mmol/L) 
7.5 to <10.0  
0.45 to <0.59 
10.0 to <12.0  
0.59 to <0.71 
12.0 to <15.0 
0.71 to <0.89 
≥15.0 
≥0.89 
*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. 
 
 


 
 
 
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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 
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. 
 
 


 
 
 
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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