A Multinational, Multicenter, Open-label, Randomized Controlled Trial to Investigate the Effectiveness of Tenofovir Alafenamide in Reducing Clinical Events in Chronic Hepatitis B Patients Beyond Treatment Indications by Current Guidelines
Phase: PHASE4
Conditions: Chronic Hepatitis b
Sponsor: Young-Suk Lim

ClinicalTrials.gov ID (NCT Number): NCT03753074   
 (https://clinicaltrials.gov/study/NCT03753074)  
Unique Protocol Id: IN-KR-320-5358 
 
 
 
 
================================================================= 
A Multinational, Multicenter, Open-label, Randomized Controlled Trial to Investigate the 
Effectiveness of TENofovir Alafenamide in Reducing Clinical Events in Chronic Hepatitis B 
Patients beyond Treatment IndicaTIONs by Current Guidelines (ATTENTION) 
================================================================= 
 
Protocol Version 
Master Version Number 5.0 (Ver. Date: 26/SEP/2023) 
Local Version for Taiwan, Number 5.0(Ver. Date: 26/SEP/2023) 
Clinical Study Type 
Investigator Initiated Trial 
Chief Investigator 
Young-Suk Lim 
Department of Gastroenterology, Liver Center, Asan Medical 
Center, University of Ulsan College of Medicine, South Korea 
Clinical Phase 
Phase Ⅳ 
 
Confidentiality 
 
The information contained in this document is provided to you in confidence as an 
investigator, potential investigator, or consultant, for review by you, your staff, and an 
applicable Institutional Review Board or Independent Ethics Committee. The information 
is only to be used by you in connection with authorized clinical studies of the 
investigational drug described in the protocol. You should not disclose any of the 
information to others without written authorization from the investigator, except to the 
extent necessary to obtain informed consent from those persons to whom the drug may be 
administered. 
Clinical Trial Protocol 

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Synopsis 
Protocol Title 
A Multinational, Multicenter, Open-label, Randomized Controlled Trial to 
Investigate the Effectiveness of Tenofovir Alafenamide in Reducing Clinical 
Events in Chronic Hepatitis B Patients beyond Treatment Indications by 
Current Guidelines (ATTENTION) 
Chief 
Investigator 
Professor Young-Suk Lim, 
Department of Gastroenterology, Asan Medical Center,  
University of Ulsan College of Medicine 
Investigators 
International and Multicenter 
Study Sites 
10 sites in Korea + 12 sites in Taiwan 
Clinical Phase 
Phase IV 
Study Design 
Multinational, Multicenter, Open-label, Randomized Controlled Trial 
Number of 
Subjects to be 
Enrolled 
780 subjects 
• 
Treatment Arm: TAF 25 mg QD 
• 
Observation Arm: Best Supportive Care 
Number of 
Subjects Planned 
780 subjects 
• 
Treatment Arm: 390 subjects 
• 
Observation Arm: 390 subjects 
Group-Sequential Two-Sided Log-rank Tests(O'Brien-Fleming) Maximum follow-up 
= 12 years (1st interim = 4 years, 2nd interim = 8 years, final analysis = 12 
years) 
-Proportional hazards assumption model, assumed survival rates (12 years)  
= 0.889/0.801 (Treatment Arm/Observation Arm) 
-Hazard ratio Treatment Arm/Observation Arm) = 0.53 
-Required number of events: 115 (assuming hazard ratio of 0.53) 
-Power: 0.85 
-Type I error rate: 0.025 
Study Population 
Chronic hepatitis B male and female adults, without cirrhosis who are not 
currently receiving treatment for hepatitis B and are beyond treatment 
indications by current guidelines 
Objectives 
To assess the efficacy of Tenofovir Alafenamide (TAF) in reducing liver-related 
events 
(hepatocellular 
carcinoma 
[HCC], 
liver-related 
death, 
liver 
transplantation, and decompensated liver disease) in chronic hepatitis B 
patients beyond treatment indications by current guidelines, compared with 
best supportive care 
Duration of 
Study Planned 
Until December 31, 2031., from the date of IRB approval. 
 
The study’s end is defined as the last date of information collection 
for the primary and secondary outcome variable analyses for the first 
subject 
Investigational 
Products 
Tenofovir Alafenamide 25 mg (Vemlidy®) 
Methodology 
Approximately 780 subjects meeting eligibility criteria will be enrolled.  
Subjects will be randomized (1:1) to Treatment Arm or Observation Arm, 
below: 
• 
Treatment Arm (n=390): TAF 25 mg once daily with food  
• 
Observation Arm (n=390): Best supportive care  
 Participants will be randomly allocated to each study arm in order to prevent 
bias and ensure comparability between the Treatment arm and Observation 
arm. Centralized stratified block randomization will be utilized in which 
participants will be stratified by HBeAg status (positive or negative) and, in 

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each stratum, randomly allocated to either Treatment or Observation arm in 
1:1 ratio as HBeAg status is expected to affect the primary outcome based on 
the clinical evidence stating that HBeAg status may influence the primary 
outcome.  
This study will be followed up for 12 years. Observation arm (treatment arm 
B) will initiate TAF treatment if the participants in the observation arm 
satisfy the criteria of TAF treatment issued by American Association for the 
Study of Liver Disease 2018. The criteria of TAF treatment in the 
observation arm is as follows: 
 
 ALT level ≥70 IU/L (males) or ≥50 IU/L (females) by local 
laboratory test 
 40≤ALT levels<70 IU/L (males) or 40≤ ALT levels<50 IU/L 
(females) with evidence of significant fibrosis  (F2 ≥7.2 kPa) as 
measured by either liver biopsy, Fibroscan, or MR elastography 
performed within 3 months 
 If they were clinically judged to have cirrhosis by investigators and 
confirmed with Fibroscan (≥ 12.0 kPa). 
 
* Study Design 
 Efficacy 
Evaluation 
Primary Efficacy Endpoint:  
The primary efficacy endpoint of this study is the occurrence of composite 
events during follow-up observation. including death, liver transplantation, or 
decompensated liver diseases [Child-Pugh score≥7], complications of portal 
hypertension [ascites, gastroesophageal varices] or HCC in the full analysis set. 
 
Secondary Efficacy Endpoints: 
The secondary endpoints of this study include: 
 Cumulative incidence of composite clinical events (Composite 
endpoint: death, liver transplantation, decompensated cirrhosis 
[Child-Pugh score≥7], portal hypertension complications [ascites, 
esophageal varices], HCC)  
 Cumulative incidence of HCC  
 Cumulative incidence of death  
 Cumulative incidence of liver transplantation 
 Cumulative incidence of decompensated liver diseases[Child-Pugh 
score ≥7] 
  Cumulative incidence of complications of portal hypertension 
[ascites, gastroesophageal varices]  
 Proportion of subjects who start treatment with TAF in Observation 
Arm 
 Cumulative Proportion with viral response (HBV < 15 IU/mL) 
 Cumulative Proportion with normal ALT  
 Cumulative Proportion with HBeAg seroclearance (only for subjects 

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who are HBeAg-positive at baseline) 
 Serial changes of Fibroscan 
 Serial changes of APRI index  
 Serial changes of FIB-4 index  
 Serial changes in the quality of life of the study patients according to 
treatment, treatment response, treatment duration, outcomes 
(hepatitis, cirrhosis, HCC) 
 
*Subgroup analysis for HBeAg(+) or HBeAg(-) 
-Cumulative incidence of HCC 
-Cumulative incidence of mortality 
-Cumulative incidence of liver transplantation 
-Cumulative incidence of decompensated liver diseases [Child-Pugh score≥7] 
-Cumulative incidence of portal hypertension complications [ascites, 
gastroesophageal varices] 
-Cumulative Proportion with viral response (HBV < 15 IU/mL) 
-Cumulative Proportion with normal ALT  
 
 
*Subgroup analysis of subjects according to baseline ALT level (normal ALT 
and elevated ALT)  
-Cumulative incidence of HCC 
-Cumulative incidence of mortality 
-Cumulative incidence of liver transplantation 
-Cumulative incidence of decompensated liver diseases [Child-Pugh score≥7] 
-Cumulative incidence of portal hypertension complications [ascites, 
gastroesophageal varices] 
-Cumulative Proportion with viral response (HBV < 15 IU/mL) 
 
 Cumulative and annual rate of patients with clinical events (death, 
liver transplantation, liver decompensation, portal hypertensive 
complications, and HCC) after excluding patients who occurs clinical 
events within 6 months of enrollment 
 
 Cumulative and annual rate of patients with clinical events (death, 
liver transplantation, liver decompensation, portal hypertensive 
complications, and HCC) after excluding patients who occurs clinical 
events within 12 months of enrollment 
 
 Cumulative and annual rate of patients with clinical events (death, 
liver transplantation, liver decompensation, portal hypertensive 
complications, and HCC) in patients with normal ALT (<40 U/L) at 
the time of enrollment, after excluding patients who occurs clinical  
events within 6 months of enrollment 
 
 Cumulative and annual rate of patients with clinical events (death, 
liver transplantation, liver decompensation, portal hypertensive 
complications, and HCC) in patients with normal ALT (<40 U/L) at 
the time of enrollment, after excluding patients who occurs clinical 
events within 12 months of enrollment 

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Eligibility 
Criteria 
(Inclusion/Exclus
ion) 
Inclusion Criteria 
1) Willing and able to provide written informed consent prior to study entry. 
2) Age ≥40 years and ≤80 years at the time of screening. 
3) Chronic hepatitis B infection defined as HBsAg (+) or HBV DNA (+) for at 
least 6 months prior to the Screening visit, or the subject is not regarded to have 
acute hepatitis B according to the clinical assessment of the investigator. 
4) Either HBeAg (+) or HBeAg (-) 
5) Subject must be documented as non-cirrhotic (Platelet ≥ 100,000/ mm3) 
6) Serum HBV DNA levels ≥1.0 x 104 IU/mL and ≤1.0 x 108 IU/mL (4.00 log10 
IU/mL ≤ Serum HBV DNA levels ≤ 8.00 log10 IU/mL) 
7) Serum ALT levels<70 IU/L (males) or <50 IU/L (females) 
8) Estimated creatinine clearance ≥ 30 ml/min (CrCl or CKD-EPI)  
9) Ability to comply with all study requirements 
 
Exclusion Criteria 
1) Confirmed known co-infection with HCV, HIV, or HDV 
2) Current alcohol (60g/day) or substance abuse judged by the investigator 
that will potentially interfere with subject compliance 
3) History or current evidence of clinically hepatic decompensation (e.g., 
ascites, encephalopathy, variceal hemorrhage) 1 year prior to Screening, or a 
Child-Pugh grade 7 (with the exception of Gilbert syndrome) at the time of 
Screening. 
4-1) Evidence of liver cirrhosis defined as meeting any of the following 
criteria: 
a) Platelet count <100,000/mm3 
b) Clinically significant portal hypertension 
c) Presence of esophageal or gastric varices by endoscopy in 2 years 
before the time of screening 
d) Fibroscan ≥ 12.0 kPa (If the test was done in 3 months before the 
time of screening.) and confirmed to have liver cirrhosis by an investigator 
4-2) 40≤ALT levels<70 IU/L (males) or 40≤ ALT levels<50 IU/L (females) 
with evidence of significant fibrosis  (F2 ≥7.2 kPa) as measured by either 
liver biopsy, Fibroscan, or MR elastography performed within 3 months 
5) Currently on or have received therapy with Interferon or 
immunosuppressant (including systemic chemotherapy) within 12 months 
prior to the screening 
6) Requirement for chronic use of systemic immunosuppressant including, 
but not limited to, corticosteroid (prednisone equivalent of >40 mg/day for >2 
weeks), azathioprine, or monoclonal antibodies 
7) Received solid organ or bone marrow transplant 
8) History of severe, life-threatening or other significant sensitivity to any 
excipients of the study drugs 
9) Any other clinical conditions (cardiovascular, respiratory, neurologic, or 
renal conditions) or prior therapy that, in the opinion of the investigator, 
would make the subject unsuitable for the study or unable to comply with 
dosing requirements. 
10) Currently on or have received antiviral treatment for ≥ 2 weeks within 6 
months prior to the screening 
11) History or current evidence of HCC, or high α-fetoprotein (AFP) > 20 
ng/mL. (Patients with AFP>20ng/mL can be enrolled, however if imaging 
investigations, such as dynamic CT or MRI, provide no evidence of HCC 
within 4 months prior to Screening) 
12) Malignancy other than HCC within 5 years prior to the screening, with 
the exception of specific cancers that are cured by surgical resection (within 2 

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years prior to screening with confirmation of no evidence of disease). 
Subjects under evaluation for possible malignancy are not eligible. 
13) Concurrent enrollment in another clinical study for other type of antiviral 
treatment for CHB or immune modulatory drug within 3 months prior to 
randomization,, Participation to an observational (non-interventional) clinical 
studies or interventional studies not using anti-HBV or immune modulatory 
drugs, or during the follow-up period of an interventional study are not 
exclusion criteria. 
14) Pregnant women, women who are breastfeeding or who believe they may 
wish to become pregnant during the course of the study 
Statistical 
Analysis 
The primary analysis set for efficacy analysis is the full analysis set (FAS), 
defined as all subjects who were randomized to Treatment Arm or Observation 
Arm (intention-to-treat analysis). Subjects will be analyzed according to the 
randomized or enrolled treatment assignment. 
Demographic and baseline characteristics will be summarized by Treatment 
Arm and Observation Arm using standard descriptive methods. Continuous 
endpoints will be summarized using conventional descriptive statistics by the 
initially assigned group. Categorical endpoints will be summarized by number 
and percentage of subjects that meet the endpoint by the initially assigned 
group.  
Exploratory analyses will be also performed to evaluate the effect of TAF 
treatment in the rate of HCC development using Cox proportional hazard 
model by adjusting potential confounders including age, sex, HBeAg 
positivity, serum HBV DNA level at baseline, ALT level, and platelet counts. 
Exploratory analyses for secondary endpoints will be performed by on-
treatment analysis.  
P<0.05 considers statistically significant. SPSS (SPSS, Chicago, IL, USA) 
and R program (https://cran.r-project.org/) will be used for statistical analyses. 
Serial changes in the quality of life (EQ-5D and EQ-VAS) of the study patients 
according to treatment, treatment response, treatment duration, outcomes 
(hepatitis, cirrhosis, HCC) will be analyzed by Generalized Estimation 
Equation (GEE) adjusted by age, gender, and baseline clinical characteristics 
of the patients. 
Interim analyses will be conducted at 4 and 8 years after the start of the study, 
including all randomly assigned patients. If the null hypothesis is not rejected, 
a final analysis will be performed at the 12-year mark to demonstrate 
statistical significance.  

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Signature Page 
 
 
Protocol Agreement  
 
 
Clinical Study Title 
A Multinational, Multicenter, Open-label, Randomized Controlled Trial to Investigate the 
Effectiveness of Tenofovir Alafenamide in Reducing Clinical Events in Chronic Hepatitis B 
Patients beyond Treatment Indications by Current Guidelines (ATTENTION) 
 
 
 
I have read the protocol, including all appendices, and I agree that it contains all necessary 
details for me and my staff to conduct this study as described. I will conduct this study as 
outlined herein 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 access to all 
information provided by primary site of this study. I will discuss this material with them to 
ensure that they are fully informed about the drugs and the study 
 
 
 
Investigator 
 
 
 
____________________   _____________________     ______________________ 
Printed Name                      Signature                        Date (DD/MM/YYYY) 
 
 

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Table of Contents 
Synopsis ......................................................................................................................................................... 2 
Signature Page ............................................................................................................................................... 7 
 
Study Title and Phase ................................................................................................................... 10 
1.1 Study Title .................................................................................................................................................................. 10 
1.2 Study Phase ................................................................................................................................................................ 10 
 
Study Sites and Investigators ....................................................................................................... 10 
 
Purpose and Background ............................................................................................................. 11 
 
Study Design ................................................................................................................................. 13 
 
Projected Duration of the Study .................................................................................................. 13 
 
Study Population .......................................................................................................................... 13 
 
Study Subjects Criteria (Inclusion/Exclusion) ............................................................................. 14 
7.1 Inclusion Criteria ...................................................................................................................................................... 14 
7.2 Exclusion Criteria ..................................................................................................................................................... 14 
 
Study Procedures and Methods ................................................................................................... 16 
8.1 Treatment Allocation ............................................................................................................................................... 16 
8.2 Evaluation Assessments .......................................................................................................................................... 16 
8.2.1 
Timetable of the study............................................................................................................................ 17 
8.2.2 
Study Procedures ..................................................................................................................................... 18 
8.3 Assessments for Premature Discontinuation from Study ............................................................................... 20 
 
Study Drug ................................................................................................................................... 20 
9.1 Storage and Handling of the Study Drug ............................................................................................................ 21 
9.2 Assessment of Adverse Effects ............................................................................................................................. 21 
9.3 Concomitant Drugs .................................................................................................................................................. 21 
9.4 Drugs Prohibited ....................................................................................................................................................... 21 
 
Adverse Events ............................................................................................................................. 22 
10.1 Definition of Adverse Events ................................................................................................................................ 22 
10.2 Assessment of AEs................................................................................................................................................... 22 

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10.3 Severe Adverse Events (SAEs) ............................................................................................................................. 22 
10.4 Reporting Procedures .............................................................................................................................................. 23 
10.5 Intensity of AE .......................................................................................................................................................... 23 
10.6 Causal Relationship of AE ..................................................................................................................................... 23 
 
Statistical Considerations ............................................................................................................. 24 
11.1 Sample Size Justification ........................................................................................................................................ 24 
11.2 Statistical Analyses .................................................................................................................................................. 25 
 
Compliance and modification of the clinical trial protocol ......................................................... 26 
 
Discontinuation and Withdrawal ................................................................................................. 26 
 
Efficacy Evaluation ...................................................................................................................... 27 
14.1 Primary endpoint ...................................................................................................................................................... 27 
14.2 Secondary endpoint .................................................................................................................................................. 27 
 
Safety Protection for the subjects ................................................................................................ 29 
 
Informed Consent, Agreement of Compensation, Post-Study Treatment ................................... 29 
16.1 Patient Information and Informed Consent ........................................................................................................ 29 
16.2 Compensation Available to the Patients in the Event of Trial Related Injury ........................................... 30 
16.3 Treatment of the Subjects after the End of the Clinical Trial ........................................................................ 30 
 
Expected study results and development direction ...................................................................... 30 
 
Additional Ethical Considerations for the Study ......................................................................... 30 
18.1 Compliance and Modification of the Clinical Trial Protocol ........................................................................ 30 
18.2 Monitoring ................................................................................................................................................................. 30 
18.3 Storage of the Documents and Data ..................................................................................................................... 31 
18.4 Confidentiality of the Data and Records of the Subjects ................................................................................ 31 
18.5 Provision of Personal Information to Third Parties and Secondary Use..................................................... 31 
 
Methods for Human Derived Material storage and disposal ...................................................... 32 
 
References .................................................................................................................................... 33 
 

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Study Title and Phase 
1.1 
Study Title 
A Multinational, Multicenter, open-label, Randomized Controlled Trial to Investigate the 
Effectiveness of Tenofovir Alafenamide in Reducing Clinical Events in Chronic Hepatitis B 
Patients beyond Treatment Indications by Current Guidelines (ATTENTION) 
 
1.2 
Study Phase 
Phase IV (Investigator Initiated Trial) 
 
 
Study Sites and Investigators 
Korea Sites 
Study Sites 
Investigators 
Asan Medical Center 
Young-Suk Lim 
Samsung Medical Center 
Wonseok Kang 
Kyung-Hee University Hospital 
Gi-Ae Kim 
Chung-Ang University Hospital 
Hyung Joon Kim 
Seoul National University Hospital 
Ulsan University Hospital 
Yun Bin Lee 
Neung-Hwa Park 
Konkuk University Medical Center 
So Young Kwon 
Kyungpook National University Hospital 
Soo Young Park 
Korea University Guro Hospital 
Ji Hoon Kim 
Seoul National University Bundang Hospital 
Gwang Hyeon Choi 
 
Taiwan Sites 
Study Sites 
Investigators 
Kaohsiung Medical University Hospital  
Ming-Lung Yu  
Kaohsiung Chang Gung Memorial Hospital OF THE G.G.M.F  
Chien-Hung Chen  
E-Da Hospital  
Yao-Chun Hsu  
Taitung Mackay Memorial Hospital  
Ming-Jong Bair  
National Cheng Kung University Hospital  
Pin-Nan Cheng  
Chi Mei Hospital, Liouying  
Hung-Da Tung  

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Chang Gung Memorial Hospital, Chia-Yi  
Te-Sheng Chang  
Ditmanson Medical Foundation Chia-Yi Christian Hospital  
Chi-Yi Chen  
St. Martin De Porres Hospital  
Ching-Chu Lo  
Dalin Tzu Chi General Hospital  
Kuo-Chih Tseng  
Taichung Veterans General Hospital  
Sheng‐Shun Yang  
China Medical University Hospital  
Cheng-Yuan Peng  
 
 
Purpose and Background 
3.1 Purpose 
To determine whether or not TAF treatment in the patients beyond treatment indications by 
current guidelines who have high risk of HCC, deaths and events associated with hepatic 
diseases reduces the incidence of HCC, deaths and events associated with hepatic diseases. 
 
3.2 Background 
The goal of treatment for patients with chronic hepatitis B (CHB) is to improve survival by 
preventing disease progression and HCC.1,2 Ideally, for hepatitis B therapies to be approved, 
they should demonstrate efficacy in preventing HCC and liver-related deaths. However, these 
clinical endpoints evolve over years or decades. Therefore, intermediate surrogate endpoints 
that are easy to assess, occur frequently, and are considered to correlate with clinical outcomes 
have been used for the evaluation of treatment efﬁcacy. Those surrogate endpoints include 
virological, biochemical, and serological biomarkers.1,2 
The natural course of CHB is typically divided into several phases based on hepatitis B e 
antigen (HBeAg) status, serum hepatitis B virus (HBV) DNA levels, and alanine 
aminotransferase (ALT) activity. The first, which is the immune-tolerant (IT) phase, is 
characterized by high circulating HBV DNA and normal ALT level. Antiviral treatment is 
generally not recommended for these patients by most practice guidelines because of the notion 
that the histological activity is dormant and the risk of disease progression is low in the IT 
phase.3-5However, recent studies have claimed that the histological activity and HBV-specific 
immune response do occur in the IT phase and are comparable with those occurring in the 
immune active (IA) phase. 6,7 Moreover, a high level of chromosomal HBV DNA integration 
and clonal hepatocyte expansion was found in patients considered to be in the IT phase, 
indicating that hepatocarcinogenesis could be under way in these patients.8  These findings 
suggest that therapeutic interventions to minimize further damage to the hepatocytes should be 

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considered for IT-phase patients. However, virtually no clinical evidence exists regarding 
whether long-term antiviral treatment of IT-phase patients reduces the risk of HCC and 
mortality. A recently large-scale historical cohort study revealed that untreated IT-phase 
patients were associated with significantly higher risk of HCC and death/transplantation than 
the IA-phase patients treated with nucloes(t)ide analogues.9 Moreover, the risks of HCC and 
death/transplantation were further increased among patients in the mildly active phase (ALT 
levels, 1-2 x upper limit of normal).9 This historical cohort study also found out that older age, 
male, lower HBV DNA levels (but above 20,000 IU/mL) and low platelet counts were 
independently associated with a significantly higher risk of clinical events.9 
 
Most HBeAg‐negative CHB patients remain in an inactive hepatitis phase with low HBV DNA 
levels (<2000 IU/ mL) and persistently normal ALT. Approximately 10%–20% of patients 
progress to “HBeAg‐negative active hepatitis phase”  characterized by high levels of serum 
HBV DNA (≥2000 IU/mL), elevated ALT levels (≥2 upper limits of normal [ULN]), and 
continued necroinflammation, and are indicated for antiviral treatment.10However, 
approximately 30%–35% of HBeAg‐negative CHB patients are in the “grey zone” having 
persistently normal or only mildly elevated ALT (<2ULN) despite high HBV DNA levels 
(≥2000 IU/mL).8,11Antiviral treatment for these patients is generally not recommended by most 
practice guidelines unless the liver biopsy show significant disease activity.InHBeAg‐negative 
CHB patients with persistently normal ALT, high HBV DNA levels were independently 
associated with histologically significant hepatic inflammation and fibrosis. Furthermore, in a 
prospective cohort study that mostly included HBeAg‐negative CHB patients (REVEAL‐HBV 
cohort), high levels of HBV DNA (>2000 IU/mL) were associated with a high risk of 
hepatocellular carcinoma (HCC) and disease progression, irrespective of serum ALT levels.12,13 
However, little clinical evidence exists for whether antiviral treatment would reduce the risks 
of HCC and death/transplantation in the patients with high HBV DNA levels and persistently 
normal ALT levels or mildly elevated ALT levels.In a recently conducted large observational 
cohort study of 5,414 HBeAg-negative CHB patients, compared with the treated group, the 
untreated patients with high HBV DNA levels showed a significantly higher risk of HCC and 
death/transplantation by propensity score-matched analysis.14 
 
In the aforementioned two large observational studies, older age (≥40 years old) and serum 
HBV DNA levels between 1.0x104 IU/mL and 1.0x108 IU/mL were predictive factors of 

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development of HCC and death/transplantation. With these two predictive factors, the 
cumulative rate of clinical events including HCC or death/transplantation) were 2.77/100 
person-years in untreated group, whereas 1.45/100 person-years in antiviral treatment groups. 
(Hazard ratio = 0.53) 
Collectively, patients beyond treatment indication by current practice guidelines of CHB are 
not thoroughly researched. Few study exists whether long-term antiviral treatment for CHB in 
patients with above characterization can improve the long-term clinical outcomes. In particular, 
older age (≥40 years old) with intermediate range of serum HBV DNA (104-108 IU/mL) should 
be further evaluated. 
 
 
Study Design 
This is a Phase 4, randomized, open-label, international, multicenter study to evaluate the 
efficacy of Tenofovir Alafenamide in reducing clinical events (HCC, death, liver 
transplantation or decompensated liver diseases) in CHB patients beyond treatment indication 
by current practice guidelines for CHB, compared with patients who receive best supportive 
care. 
 
 
 
Projected Duration of the Study 
Until December 31,, 2031., from the date of IRB approval. 
The study’s end is defined as the last date of information collection for the primary and 
secondary outcome variable analyses for the first subject 
 
 
Study Population 
The study population consists of chronic hepatitis B male and female adults, without cirrhosis 

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who are not currently receiving treatment for hepatitis B and are beyond treatment indications 
by current guidelines 
 
 
Study Subjects Criteria (Inclusion/Exclusion) 
7.1 
Inclusion Criteria 
1) Willing and able to provide written informed consent prior to study entry. 
2) Age ≥40 years and ≤80 years at the time of screening. 
3) Chronic hepatitis B infection defined as HBsAg (+) or HBV DNA (+) for at least 6 months 
prior to the Screening visit, or the subject is not regarded to have acute hepatitis B according 
to the clinical assessment of the investigator. 
4) Either HBeAg (+) or HBeAg (-) 
5) Subject must be documented as non-cirrhotic (Platelet ≥ 100,000/ mm3) 
6) Serum HBV DNA levels ≥1.0 x 104 IU/mL and ≤1.0 x 108 IU/mL (4.00 log10 IU/mL ≤ Serum 
HBV DNA levels ≤ 8.00 log10 IU/mL) 
7) Serum ALT levels<70 IU/L (males) or <50 IU/L (females) 
8) Estimated creatinine clearance ≥ 30 ml/min (CrCl or CKD-EPI) 
9) Ability to comply with all study requirements 
 
7.2 
Exclusion Criteria 
1) Confirmed known co-infection with HCV, HIV, or HDV 
2) Current alcohol (60g/day) or substance abuse judged by the investigator that will 
potentially interfere with subject compliance 
3) History or current evidence of clinically hepatic decompensation (e.g., ascites, 
encephalopathy, variceal hemorrhage) 1 year prior to Screening, or a Child-Pugh grade 7 
(with the exception of Gilbert syndrome) at the time of Screening. 
4-1) Evidence of liver cirrhosis defined as meeting any of the following criteria: 
a) Platelet count <100,000/mm3 
b) Clinically significant portal hypertension 
c) Presence of esophageal or gastric varices by endoscopy in 2 years before the time 
of screening 
d) Fibroscan ≥ 12.0 kPa (If the test was done in 3 months before the time of 
screening.) and confirmed to have liver cirrhosis by an investigator 
4-2) 40≤ALT levels<70 IU/L (males) or 40≤ ALT levels<50 IU/L (females) with evidence of 

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significant fibrosis(F2; ≥7.2 kPa) as measured by either liver biopsy, Fibroscan or MR 
Elastography performed within 3 months. 
5) Currently on or have received therapy with Interferon or immunosuppressant (including 
systemic chemotherapy) within 12 months prior to the screening 
6) Requirement for chronic use of systemic immunosuppressant including, but not limited to, 
corticosteroid (prednisone equivalent of >40 mg/day for >2 weeks), azathioprine, or 
monoclonal antibodies 
7) Received solid organ or bone marrow transplant 
8) History of severe, life-threatening or other significant sensitivity to any excipients of the 
study drugs 
9) Any other clinical conditions (cardiovascular, respiratory, neurologic, or renal conditions) 
or prior therapy that, in the opinion of the investigator, would make the subject unsuitable for 
the study or unable to comply with dosing requirements. 
10) Currently on or have received antiviral treatment for ≥ 2 weeks within 6 months prior to 
the screening 
11) History or current evidence of HCC, or high α-fetoprotein (AFP) > 20 ng/mL. (Patients 
with AFP>20ng/mL can be enrolled, however if imaging investigations, such as dynamic CT 
or MRI, provide no evidence of HCC within 4 months prior to Screening)  
12) Malignancy other than HCC within 5 years prior to the screening, with the exception of 
specific cancers that are cured by surgical resection (within 2 years prior to screening with 
confirmation of no evidence of disease). Subjects under evaluation for possible malignancy 
are not eligible. 
13) Concurrent enrollment in another clinical study for other type of antiviral treatment for 
CHB or immune modulatory drug within 3 months prior to randomization,, Participation to 
an observational (non-interventional) clinical studies or interventional studies not using anti-
HBV or immune modulatory drugs, or during the follow-up period of an interventional study 
are not exclusion criteria. 
14) Pregnant women, women who are breastfeeding or who believe they may wish to become 
pregnant during the course of the study 
 

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Study Procedures and Methods 
8.1 
 Treatment Allocation 
(1) Treatment Arm (Treatment Arm A): Tenofovir Alafenamide (25mg/day) 
(2) Observation Arm (Treatment Arm B): Best supportive care 
(3) Allocation Method: An independent statistician will generate the code to randomly 
allocate participants to either Treatment Arm or Observation Arm in 1:1 ratio by stratified 
block randomization. Centralized stratified block randomization will be utilized in which 
participants will be stratified by HBeAg status (positive or negative) and, in each stratum, 
randomly allocated to either Treatment or Observation arm in 1:1 ratio. The ratio of 
HBeAg(+) to HBeAg(-) in each arm may be variable. Study sites will then randomly 
allocate the eligible patients who provide the informed consent to each study arm. 
Interactive Web Response System (IWRS) will be utilized to randomly allocate the 
participants to either Treatment Arm or Observation Arm in 1:1 ratio. Both investigators 
and patients will be aware of the allocation as this study is the open-label trial.  
(4) Allocated patients: A total number of patients in the study – 780 (Treatment Arm: 390, 
Observation Arm: 390)  
 
(5) Treatment Method: Investigational Product, Administration Method and Dosage 
Group 
Number of subjects 
Treatment 
Treatment Arm 
390 
Tenofovir Alafenamide 25 mg oral once daily 
Observation Arm 
390 
Best supportive care 
 
Observation arm (Treatment Arm B) will initiate TAF treatment if the participants in the 
Observation arm satisfy the criteria of TAF treatment issued by American Association for the 
Study of Liver Disease 2018. The criteria of TAF treatment in the Observation arm is as 
follows: 
 ALT level ≥70 U/L (males) or ≥50 U/L (females) by local laboratory test 
 40≤ALT levels<70 IU/L (males) or 40≤ ALT levels<50 IU/L (females) with evidence of 
significant fibrosis(F2; ≥7.2 kPa) as measured either liver biopsy, Fibroscan or MR 
Elastography performed within 3 months.  
 If they were clinically judged to have cirrhosis by investigators and confirmed with 
Fibroscan (≥ 12.0 kPa). 
 
8.2 
Evaluation Assessments

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8.2.1 Timetable of the study 
Assessment / 
 Procedure 
Screening1 
Baseline 
On-Treatment2 
EOT 
Baseline 
≤ 28days 
M0 
M6/M18/
M30/M42 
M12/M
24/M36 
M48 
M54/M66/
M78/M90/ 
M102/M11
4/M126/M1
38 
M60/M
72/M84 
/M96/M
108/M1
20/M13
2 
M144 
Informed consent 
X 
 
 
 
 
 
 
 
Re-consent for extension 
 
 
 
 
X 
 
 
 
Medical History 
X 
 
 
 
 
 
 
 
Inclusion/Exclusion Criteria 
X 
X 
 
 
 
 
 
 
Physical Examination3 
X 
X 
X 
X 
X 
X 
X 
X 
Randomization 
 
X 
 
 
 
 
 
 
Vital signs4 
X 
X 
X 
X 
X 
X 
X 
X 
EQ-5D questionnaire15 
 
X 
 
X 
X 
 
X 
X 
Hematology5 
X 
X 
X 
X 
X 
X 
X 
X 
Chemistry6 
X7 
X7 
X 
X 
X 
X 
X 
X 
Lipid profile7 
 
X 
X 
X 
X 
X 
X 
X 
Prothrombin Time 
X 
X 
X 
X 
X 
X 
X 
X 
HBV DNA 
X 
X 
X 
X 
X 
X 
X 
X 
HBsAg8 
X10 
X10 
 
X 
X 
 
X 
X 
HBsAb 
X11 
 
 
 
 
 
 
 
HBeAg/HBeAb 
X 
X 
X 
X 
X 
X 
X 
X 
Alpha-fetoprotein 
X 
X 
X 
X 
X 
X 
X 
X 
US or CT or MRI 
X9 
X 
X 
X 
X 
X 
X 
X 
Bone densitometry 
 
X10 
 
X11 
X11 
 
X11 
X11 
Fibroscan 
X12 
 
 
X11 
X11 
X11 
X11 
X11 
HbA1C 
 
X11 
 
X 
X 
 
X 
X 
Serum for storage13 
 
X 
X 
X 
X 
X 
X 
X 
Buffy coat 
 
X14 
 
 
 
 
 
 
Dispense study drug 
 
X 
X 
X 
X 
X 
X 
 
Adverse Events 
 
 
X 
X 
X 
X 
X 
X 
Compliance check 
 
 
X 
X 
X 
X 
X 
X 
Concomitant 
Medications 
X 
X 
X 
X 
X 
X 
X 
X 
 
1. Screening and baseline evaluation can be done once on the same day. Laboratory tests can be replaced if the tests were 
done within 2 months prior to the screening. 
2. Window period of 2 months from the designated visit date is allowed for each follow-up visit during the study period. 
3. A complete physical examination will be taken at screening, and a symptom based physical examination will be performed 
at each visit  
4. Vital Signs: Blood pressure, pulse rate, weight. Height will be measured at the screening visit only. And waist 
circumference will be measured at Baseline, M12, M24, M36, M48 visit only. 
5. Hematology: Hemoglobin, WBC, platelet count, ANC 
6. Chemistry: Sodium, potassium, BUN, creatinine, total protein, albumin, AST, ALT, ALP, Total/direct bilirubin, phosphorus, 
calcium. Just sodium, potassium, BUN, calcium, direct bilirubin, phosphorus could be optional. 
7. Lipid profile: Triglyceride, Total Cholesterol, HDL, LDL, it will be done accordance with the decision of the investigator. 
8. HBsAg can be measured by either quantitative or qualitative methods at each study site. Study sites can measure HBsAg 
with stored serum by quantitative methods after the end of this study. 

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9. Can be replaced if relevant imaging tests (abdominal USG, CT, or MRI) were done within 4 months prior to the screening 
10. Can be replaced if the Bone mineral density was done within 12 months prior to the baseline, not mandatory 
11. Not mandatory 
12. Can be replaced if the Fibroscan was done within 3 months prior to the Screening 
13. At every visit serum samples are collected and distributed 0.3-0.5 mL to each cryo tubes (aliquot into at least 4 tubes). 
These samples will be stored under -70 Celsius degree. 
14. If the sample is not collected at screening, it may be collected at any other visit during the study. 
15. The questionnaire is optional in Taiwan sites. 
 
8.2.2 Study Procedures 
  1) Screening visit (Baseline ≤28 days) 
- 
Obtain written informed consent 
- 
Basic information and medical history 
- 
Review of inclusion/exclusion criteria 
- 
Complete physical examination and vital signs 
 Physical examination: Lower leg edema, Ascites 
 Vital signs: blood pressure, pulse rate, body weight, height (height can be 
measured only one time at screening visit) 
- 
Laboratory assessments(Can be replaced if tests were done within 2 months prior to 
the screening) 
 Blood: Hematology, Chemistry, Prothrombin Time, HBV DNA, HBsAg, HBsAb, 
HBeAg/HBeAb, AFP 
 HBsAg assessment can be replaced by HBV DNA (+) test results. 
 HBsAb assessment is recommended to be performed at the screening 
visit, but it can be still completed during baseline or M6. 
 Sodium, potassium, BUN, calcium, direct bilirubin and phosphorus are 
not mandatory Chemistry assessments. 
- 
Evaluate last clinical imaging (Abdominal US, CT, or MRI, which can be replaced if 
relevant imaging tests were done within 4 months prior to the screening) 
- 
Fibroscan (Can be replaced if the test was done within 3 months prior to the Screening) 
- 
Review concomitant drugs 
 
2) Baseline (Month 0) 
- 
Review of inclusion/exclusion 
- 
Complete physical examination and vital signs 
 Physical examination: Lower leg edema, Ascites 

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 Vital signs: blood pressure, pulse rate, body weight, waist circumference 
- 
Randomization 
- 
Dispense study drug for patients assigned to “Treatment Arm” 
- 
EQ-5D questionnaire 
- 
Laboratory assessments (Can be replaced if tests were done within 2 months prior to 
the baseline) 
 Blood: Hematology, Chemistry, Lipid profile, Prothrombin Time, HBV DNA, 
HBsAg, HBeAg/HBeAb, AFP, HbA1C, Buffy coat &Serum for storage 
 HBsAg assessment can be replaced by HBV DNA (+) test results. 
 HbA1c measurement is not mandatory. 
 Sodium, potassium, BUN, calcium, direct bilirubin and phosphorus are not 
mandatory Chemistry assessments.  
- 
Bone mineral density (Can be replaced if the test was done within 12 months prior to 
the baseline, not mandatory) 
- 
Evaluate last clinical imaging (Abdominal US, CT, or MRI, which can be replaced if 
relevant imaging tests were done within 4 months prior to the baseline) 
- 
Review concomitant drugs 
 
3) Follow-up visits (Month 6, 12, 18, 24, 30, 36, 42, 48, 54, 60, 66, 72, 78, 84, 90, 96, 102, 
108, 120, 126, 132 and 138) 
- 
Physical examination: Lower leg edema, Ascites 
- 
Vital signs: blood pressure, pulse rate, body weight 
(Waist circumference at Baseline, M12, M24, M36 and M48 visit only) 
- 
EQ-5D questionnaire (Month 12, 24, 36, 48, 60, 72, 84, 96, 108, 120 and 132 only) 
- 
Laboratory assessments 
 Blood: Hematology, Chemistry, Lipid profile, Prothrombin Time, HBV DNA, 
HBeAg/HBeAb,AFP, Serum for storage,  
 Blood: HBsAg and HbA1c (Month 12, 24, 36, 48, 60, 72 and 84 only) 
- 
Image tests (Abdominal US, CT, or MRI) 
- 
Bone mineral density (Month 12, 24, 36, 48, 60, 72 and 84 only / Not mandatory) 
- 
Fibroscan (Month 12, 24, 36, 48, 54, 60, 66, 72, 78, 84, 90, 96, 102, 108, 114, 120, 
126,132 and 138 only / Not mandatory) 
- 
Review adverse events 

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- 
Dispense study drug for patients assigned to “Treatment Arm” 
- 
Perform study drug compliance  
- 
Review concomitant drugs 
 
4) Month 144 
- 
Physical examination: Lower leg edema, Ascites 
- 
Vital signs: blood pressure, pulse rate, body weight 
- 
EQ-5D questionnaire 
- 
Laboratory assessments 
 Blood: Hematology, Chemistry, Lipid profile, Prothrombin Time, HBV DNA, 
HBsAg, HBeAg/HBeAb, AFP, Serum for storage, HbA1C  
- 
Image tests (Abdominal US, CT, or MRI) 
- 
Bone mineral density (Not mandatory) 
- 
Fibroscan (Not mandatory) 
- 
Review adverse events 
- 
Return study drug 
- 
Perform study drug compliance  
- 
Review concomitant drugs 
 
8.3 
Assessments for Premature Discontinuation from Study 
If a subject in the Treatment Arm discontinues study drug, every attempt should be made to 
keep the subject taking study drug in the study and continue to perform the required study-
related follow-up and procedures. If this is not possible or acceptable to the subject or 
investigator, the subject may be withdrawn from the study. However, the information regarding 
the primary outcomes (e.g. survival, HCC occurrence) can be collected for the primary and 
secondary analyses, even after the withdrawal of the subject from the study. 
In case of diagnosis of HCC during the study period, based on the current practice guidelines, 
TAF should be continued. The study drug (TAF) would be continuously provided to the subject, 
as long as the subject is willing to do so. 
 
 
Study Drug 
During the study period, principal investigators (PI) and pharmacists of study sites are 
responsible for storage and handling of the study drug. 

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9.1 
Storage and Handling of the Study Drug 
TAF tablets should be stored at controlled room temperature of 25°C. Storage conditions are 
specified on the label. Until dispensed to the subjects, all bottles of study drugs should be stored 
in a securely locked area, accessible only to authorized site personnel. 
To ensure the stability and proper identification, study drug(s) should not be stored in a 
container other than the container in which they were supplied. 
Consideration should be given to handling, preparation, and disposal through measures that 
minimize drug contact with the body. Appropriate precautions should be followed to avoid 
direct eye contact or exposure when handling. 
At the beginning of the study, the study monitor will evaluate the study center’s study drug 
disposal procedures and provide appropriate instruction for return or destruction of unused 
study drug supplies. If the site has an appropriate Standard Operating Procedures (SOP) for 
drug destruction, the site may destroy used and unused study drug supplies performed in 
accordance with the site’s SOP. If the site does not have acceptable procedures in place for drug 
destruction, arrangements will be made from the primary site of the present study. 
 
9.2 
Assessment of Adverse Effects 
The investigator or qualified sub-investigator is responsible for assessing the adverse effects 
using clinical judgment. 
The principal sources of safety for TAF consist of 2 Phase 3 studies in subjects with CHB, 
Study GS-US-320-0108 and GS-US-320-0110. Subjects included in the Safety Analysis Set 
received at least 1 dose of study drug.15,16 
A list of expected adverse events associated with Vemlidy treatment is presented in 
[Appendix 4]. 
 
9.3 
Concomitant Drugs 
Concomitant medications taken at the time of screening, up to and including the date of the 
last study visit, need to be recorded in the source documents and eCRFs. 
 
9.4 
Drugs Prohibited  
The antiviral agents which can affect the CHB treatment such as medications containing 

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Tenofovir (Atripla, Complera and Truvada), Adefovir (Hepsera) and Entecavir (Baraclude) 
cannot be taken during the clinical trial. 
Precautionary and prohibited medications while treating with Vemlidy is listed in [Appendix 
4]. 
 Adverse Events 
10.1 Definition of Adverse Events 
All adverse events will be assessed and recorded on the AE CRF page by the investigator. An 
adverse event (AE) is any untoward medical occurrence in a patient or clinical investigation 
after randomization and which does not necessarily have a causal relationship with this 
treatment. An adverse event (AE) can therefore be any unfavorable and unintended sign 
(including an abnormal laboratory finding), symptom, or disease temporally associated with 
the use of an investigational product, whether or not related to the investigational product.  
 
10.2 Assessment of AEs 
All AEs and SAEs occurring after randomization and until the end of follow-up/final visit 
should be recorded in the CRF.  
 
10.3 Severe Adverse Events (SAEs) 
A serious adverse event is any untoward medical occurrence after randomization: 
 
Death or life-threatening events 
   Hospitalization or prolongation of existing hospitalization 
 
Persistent or significant disability/incapacity 
 
Development of fetal anomalies  
 
Cases in which other medically important situations, such as drug dependence or abuse, 
or blood diseases other than the above cases 
 
* Hospitalizations which were already planned prior to the participation in the clinical trial is 
not considered a SAE. 
* Hospitalization for elective treatment of a pre-existing condition that did not worsen from 
baseline is not considered a SAE. 
 

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10.4 Reporting Procedures 
The principal investigator and sub-investigators have to notify IRB all SAEs during the study 
regardless of causal relationship. They must fax or e-mail the SAE form to Asan medical center 
within 48 hours of the investigator’s acknowledgement of the event. 
All the information about serious adverse events should be reported to the principal investigator 
and IRB until they are completely resolved. 
 
10.5 Intensity of AE 
Grade 
Description 
Mild 
Asymptomatic or mild symptoms; clinical or diagnostic observations only; 
intervention not indicated; no disruption of normal daily activity. 
Moderate 
Minimal, local or noninvasive intervention indicated; discomfort sufficient 
to reduce or affect daily activity. 
Severe 
Severe or medically significant, but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; inability to 
work or perform normal daily activity. 
Life-threatening 
Represents an immediate threat to life. 
 
10.6 Causal Relationship of AE 
The following categories and definitions of causal relationship to the study drug should be used 
for any AE: 
1) Definitely related 
 Event or laboratory test abnormality, with plausible temporal relationship to the 
drug intake 
 Cannot be explained by the disease or other drugs 
 Response by the withdrawal of the study drug (pharmacologically, pathologically) 
 Event definitive pharmacologically or clinically (i.e. an objective and specific 
medical disorder or a recognized pharmacological phenomenon)  
2) Probably related 
 Event or laboratory test abnormality, with reasonable time relationship to drug 
intake 
 Unlikely to be attributed by the disease or other drugs 
 Response to withdrawal clinically reasonable  

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3) Possibly related 
 Event or laboratory test abnormality, with reasonable time relationship to drug 
intake 
 Could also be explained by disease or other drugs  
 Response to withdrawal clinically reasonable 
4) Probably not related 
 Event or laboratory test abnormality, could be explained by the disease or other 
drugs than the study drug intake 
 Response to withdrawal unsatisfactory or vague  
5) Definitely not related 
 Event or laboratory test abnormality, with a temporal relationship to the drug 
intake unlikely 
 The disease or other drugs provide plausible explanations  
6) Unknown 
 Cannot be judged because information is insufficient or contradictory  
 Data cannot be supplemented or verified 
 
 Statistical Considerations 
11.1 Sample Size Justification 
The primary outcome variable is the ratio of hazard rates based on the cumulative incidence of 
liver-related events, including death, liver transplantation, or decompensated liver diseases [Child-
Pugh score≥7], complications of portal hypertension [ascites, gastroesophageal varices] or HCC among 
randomly assigned and treated patients.  
The null hypothesis (H0) states that 'the hazard rate ratio in the treatment group compared to 
the control group is equal to 1,' and the alternative hypothesis suggests that 'the hazard rate 
ratio in the treatment group compared to the control group is not equal to 1.' Sample size was 
calculated using the O'Brien-Fleming adjusted Group-Sequential Two-Sided Log-rank Test to 
plan for a maximum of 3 statistical analyses over a period of 12 years. 
Assuming a proportional hazards model, the estimated 12-year survival rates for the treatment 
and observation groups are 0.889 and 0.801, respectively (hazard rate ratio = 0.53). With a 
power of 85% and a Type I error rate of 2.5%, a minimum of 115 cases of composite events is 
needed. Assuming initial interim analysis at 4 years, a second analysis at 8 years, and the final 

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analysis at 12 years, and considering a 4.8% drop-out rate, the required number of participants 
is 390 in each group, with a total of 780 participants. 
 
11.2 Statistical Analyses 
 
The primary analysis for assessing treatment efficacy and safety will be conducted using the 
Full Analysis Set, including all randomly assigned patients (Modified Intention-to-Treat 
analysis). Secondary analyses will involve on-treatment analysis, which includes patients 
participating in the study at the analysis points. Patients who discontinue the clinical trial during 
the 12-year study period will be considered as having early termination for all endpoints from 
the discontinuation point onwards. 
The cumulative incidence of primary outcome events in the two groups will be estimated using 
the Kaplan-Meier method, and comparison will be made using the log-rank test statistics (Zk), 
where k represents the analysis time point. The first interim analysis will be conducted at 4-
year from the study initiation. If the null hypothesis is not rejected, the second interim analysis 
will be performed at 8-year from the study initiation. If the null hypothesis is not also rejected 
in the second interim analysis, the final analysis will be conducted at the end of the study. The 
stopping boundaries for the log-rank test statistics, determined using the O'Brien-Fleming 
method, are as follows: if the absolute value of the test statistics is less than 4.17084 (first 
interim analysis) or 2.8458 (second interim analysis), the trial will be continued. However, if 
the absolute value of the test statistics exceeds 4.17084 (first interim analysis) or 2.8458 
(second interim analysis), the null hypothesis is rejected, and the efficacy of the treatment group 
is declared, leading to the termination of the study. 
Additionally, a Cox proportional hazard model adjusted for baseline variables will be 
performed. Adjustments will be made for variables such as age, gender, HBeAg positivity, 
HBV DNA level, ALT level, platelet count, and more. Continuous or categorical variables 
between the two groups will be compared using appropriate tests such as Student’s t-test, Chi-
square test, or Fisher’s exact test. The statistical significance level will be set at 5%. 
During the interim analysis, changes in secondary outcome variables such as viral response, 
changes in liver function, and degree of liver fibrosis will also be observed. These changes will 
be utilized as data for developing indicators for predicting long-term clinical outcomes. 

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Additionally, for economic evaluations, differences in health-related quality of life utility 
weights (EQ-5D and EQ-VAS) based on treatment, treatment response, disease status (hepatitis, 
liver cirrhosis, HCC), and duration of illness will be analyzed using Generalized Estimation 
Equation (GEE). Adjustments will be made for age, gender, and clinical baseline variables. 
Before performing the GEE analysis, exploratory analyses will compare trends in utility weight 
changes for each variable using paired t-tests.  
All statistical analyses will be performed using SPSS (SPSS, Chicago, IL, USA) and R 
(http://cran.r-project.org/). 
 
 Compliance and modification of the clinical trial protocol 
Subjects should bring all the study drug to the study drug compliance at every follow-up visits 
including premature discontinuation. The site will record the number of tablets returned at these 
visits and determine compliance to the medication 
 
Compliance (%) = 
 
The amount of drug ingested 
X 100 
The amount the subject should have ingested 
 
 Discontinuation and Withdrawal 
Subjects may be withdrawn from the study at the investigator’s discretion in any of the 
following instances: 
 Development of a toxicity or adverse event which warrants drug discontinuation 
 The lack of efficacy of the medication or the exacerbation of signs or symptoms 
determined by the investigators, which warrant drug discontinuation 
 The subjects are revealed to be ineligible to participate in the clinical trial regarding  
the safety of the participants 
 The investigators determine that it is inappropriate to continue the clinical trial 
 Unexpected pregnancy during the trial 

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 The subjects withdraw the consent to participate in the clinical trial   
 
Treatment after discontinuation or withdrawal will be determined by the investigator. In case 
of discontinuation or withdrawal due to adverse events or safety issue, subjects should be 
followed until full recovery and the events should be recorded in CRFs. 
 
 Efficacy Evaluation 
14.1 Primary endpoint 
The primary efficacy endpoint of this study is the occurrence of composite events during follow-
up observation including HCC, death, liver transplantation, or decompensated liver diseases 
(e.g., development of portal hypertensive complications including ascites, gastroesophageal 
varices, or Child-Pugh score ≥7), in the full analysis set. 
If a primary endpoint (HCC, decompensation, etc.) occurs, the provision of the study drug is 
stopped with the end of the study. However, the investigator could decide the compassionate 
use of the study drug (tenofovir alafenamide; TAF) up to 8 years from the date of randomization 
if it is regarded necessary and safe for the subject, as long as there is a sufficient reserve of the 
study drugs. 
 
14.2 Secondary endpoint 
 Cumulative proportion of subjects with undetectable HBV DNA 
 Cumulative proportion of subjects with on-treatment normal ALT 
 Cumulative incidence of composite clinical events (Composite endpoint: death, liver 
transplantation, decompensated cirrhosis [Child-Pugh score≥7], portal hypertension 
complications [ascites, esophageal varices], HCC) 
 Cumulative incidence of HCC  
 Cumulative incidence of death or liver transplantation 
 Cumulative incidence of decompensated liver diseases (e.g., development of portal 
hypertensive complications including ascites, gastroesophageal varices, or Child-Pugh 
score ≥7) 
 Cumulative proportion of subjects with HBeAg seroclearance (only for subjects who 
are HBeAg-positive at baseline) 

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 Proportion of subjects who start treatment with TAF in Observation Arm 
 Cumulative ALT flare >5 x UNL by AASLD criteria 
 Fibroscan ≥ 12.0 kPa (Optional) 
 Serial changes of liver stiffness measured by Fibroscan  
 Serial changes of APRI index17  
 Serial changes of FIB-4 index18  
APRI = 
𝐴𝐴𝐴𝐴𝐴𝐴 (𝐼𝐼𝐼𝐼
𝐿𝐿)
𝐴𝐴𝐴𝐴𝐴𝐴 (𝑢𝑢𝑢𝑢𝑢𝑢𝑢𝑢𝑢𝑢 𝑙𝑙𝑙𝑙𝑙𝑙𝑙𝑙𝑙𝑙 𝑜𝑜𝑜𝑜 𝑛𝑛𝑛𝑛𝑛𝑛𝑛𝑛𝑛𝑛𝑛𝑛,𝐼𝐼𝐼𝐼
𝐿𝐿)
𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃 𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶 (
109
𝐿𝐿)
 𝑥𝑥 100 
 
FIB −4 = 
𝐴𝐴𝐴𝐴𝐴𝐴 (𝑦𝑦𝑦𝑦𝑦𝑦𝑦𝑦𝑦𝑦)𝑥𝑥 𝐴𝐴𝐴𝐴𝐴𝐴 (𝐼𝐼𝐼𝐼/𝐿𝐿)
𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃 𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶 ቀ
109
𝐿𝐿ቁ𝑥𝑥 ට𝐴𝐴𝐴𝐴𝐴𝐴 (
𝐼𝐼𝐼𝐼
𝐿𝐿)
 
 Serial changes in the quality of life of the study patients according to treatment, 
treatment response, treatment duration, outcomes (hepatitis, cirrhosis, HCC) 
 Subgroup analysis for HBeAg(+) or HBeAg(-) 
-Cumulative incidence of HCC 
-Cumulative incidence of mortality 
-Cumulative incidence of liver transplantation 
-Cumulative incidence of decompensated liver diseases [Child-Pugh score≥7] 
-Cumulative incidence of portal hypertension complications [ascites, gastroesophageal 
varices] 
-Cumulative proportion of subjects with undetectable HBV DNA 
-Cumulative proportion of subjects with on-treatment normal ALT 
 
 Subgroup analysis of subjects according to baseline ALT level (normal ALT and 
elevated ALT)  
-Cumulative incidence of HCC 
-Cumulative incidence of mortality 
-Cumulative incidence of liver transplantation 
-Cumulative incidence of decompensated liver diseases [Child-Pugh score≥7] 
-Cumulative incidence of portal hypertension complications [ascites, gastroesophageal 
varices] 
-Cumulative proportion of subjects with undetectable HBV DNA 

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 Cumulative and annual rate of patients with clinical events (death, liver transplantation, liver 
decompensation, portal hypertensive complications, and HCC) after excluding patients who 
occurs clinical events within 6 months of enrollment 
 
 Cumulative  and annual rate of patients with clinical events (death, liver transplantation, liver 
decompensation, portal hypertensive complications, and HCC) after excluding patients who 
occurs clinical events within 12 months of enrollment 
 
 Cumulative and annual rate of patients with clinical events (death, liver transplantation, liver 
decompensation, portal hypertensive complications, and HCC) in patients with normal ALT 
(<40 U/L) at the time of enrollment, after excluding patients who occurs clinical  
events within 6 months of enrollment 
 
 Cumulative and annual rate of patients with clinical events (death, liver transplantation, liver 
decompensation, portal hypertensive complications, and HCC) in patients with normal ALT 
(<40 U/L) at the time of enrollment, after excluding patients who occurs clinical events within 
12 months of enrollment 
 
 Safety Protection for the subjects 
As described in this protocol, the clinical trial institution shall have the facilities and 
professional manpower necessary for the clinical trial so that the clinical trial can proceed 
appropriately in accordance with the relevant regulations, and do everything possible to protect 
the safety of the subjects. The person in charge of the clinical trial should fully understand the 
adverse reactions and precautions specified in this protocol before starting the clinical trial, and 
if a serious adverse drug reaction occurs during the clinical trial, immediately stop the clinical 
trial of the subject and take appropriate measures (e.g., additional concomitant treatment with 
other antiviral drugs). After that, it should be notified to the IRB.  
After stopping the clinical trial and taking appropriate measures (e.g. additional concomitant 
treatment with other antiviral drugs), the Clinical Trial Review Committee should be notified. 
 
 Informed Consent, Agreement of Compensation, Post-Study Treatment 
16.1 Patient Information and Informed Consent 
The investigator is responsible for obtaining written informed consent from each participants 
after adequate explanation of the aims, methods, objectives, and potential hazards of the 
study and before undertaking any study-related procedures. The investigator must use the 
IRB-approved consent form for the written informed consent. Each informed consent will be 
appropriately signed and dated by the subject or the subject’s legally authorized 

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representative and the person obtaining the consent.  
A signed copy of the informed consent and any additional patient information must be given 
to each patient or the patient’s legally accepted representative. If the subject or representative 
cannot read, an impartial witness is needed. 
 
16.2 Compensation Available to the Patients in the Event of Trial Related Injury 
In the event of health injury associated with this trial, the sponsor is responsible for 
compensation based on the contract.  
 
16.3 Treatment of the Subjects after the End of the Clinical Trial 
The subjects who have fulfilled the study would follow the standard treatment of CHB by 
current practice guidelines. The subjects who are terminated in the middle of the study should 
receive routine care corresponding patients with CHB. 
 
 Expected study results and development direction 
By deriving therapeutic efficacy and safety from tenofovir alafenamide treatment in patients 
who do not belong to the treatment criteria in the current chronic hepatitis B treatment 
guidelines through the clinical trial results, it is expected to bring a better prognosis for chronic 
hepatitis B patients. 
 
 Additional Ethical Considerations for the Study 
18.1 Compliance and Modification of the Clinical Trial Protocol 
This study must be conducted according to the clinical trial protocol, including written 
informed consent approved by the IRB. All protocol modifications should be upfront 
discussed between the investigators. All protocol modifications, except those intended to 
reduce immediate risk to subjects, should be submitted to and approved by the IRB. 
Approvals must be obtained before changes can be implemented. In the event that 
modification applied to prevent immediate damage to the subjects before the IRB approval, 
they should be reported to the IRB as soon as possible.    
 
18.2 Monitoring 
Assigning the Clinical Research Associate (CRA) in charge of this trial, the CRA will 
regularly visit and monitor the study sites before starting the study and during the whole 

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study period. The monitor is responsible for routine review of the CRFs at regular intervals 
throughout the study to verify adherence to the protocol and the completeness, consistency, 
and accuracy of the data being entered on them. The monitor should have access to any 
subject records needed to verify the entries on the CRFs. The investigator agrees to cooperate 
with the monitor to ensure that any problems detected in the course of these monitoring visits 
are resolved. 
 
18.3 Storage of the Documents and Data 
The investigator must maintain all the documents and records of this study to be adequate and 
accurate and should subsequently verify them. The investigator is responsible for maintaining 
and providing of the essential documents. The essential documents mean ones that allow 
evaluating conduct of the clinical trial. The clinical trial essential document will contain the 
protocol/amendments, CRF and query forms, IRB approval with correspondence, informed 
consent, and monitoring records and other appropriate documents and correspondence.  
Subject clinical source documents contain all the observed date, the records of clinical trial 
activities and all the reports and records for assessment and reconstruction of the clinical trial. 
Therefore, subject clinical source documents should include the records of all the procedures 
conducted by the clinical trial protocol. 
All clinical study documents must be retained by the investigator in accordance with local rule 
after the end of the study. 
 
18.4 Confidentiality of the Data and Records of the Subjects 
The investigator must assure that subjects’ anonymity will be strictly maintained. The 
subjects should be accessed by only subject initials or an identification code. Their identities 
have to be protected from unauthorized parties. Only the investigators, study coordinators, 
those who conduct inspections, IRB, the director of KFDA can review the data of the subjects 
to verify the reliability and the study process within the range prescribed by the relevant 
provisions and without violating the confidentiality of research subjects. 
 
18.5 Provision of Personal Information to Third Parties and Secondary Use 
After the primary research is done, the follow-up secondary research is set to begin. For the 
secondary research, no new data needs to be collected. Therefore, the personal information 

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given by the research subject can be used for statistical analysis in the secondary research for 
purposes other than those that were originally planned in the primary research. 
1) Subjects to whom personal information is provided: A data management institution 
designated by the Minister of Health and Welfare of Korea 
2) Data recipients’ intended use: Public purpose for public health promotion  
3) Provided information: Personally identifiable information, personal information (medical 
records, etc.)  
4) Period of storage and use of personal information: 5 years after the end of the primary 
research 
Research subjects have the right to refuse consent to the provision of personal information to 
a third party, and there is no disadvantage in refusing. To keep research information safe, it 
will be kept in a locked place (data room, etc.) under the supervision of the data management 
manager. Only authorized administrators will be able to access it.  
In the case of obtaining written consent for the provision of personal information from the 
research subject, the personal information may be provided to a third party in a 
pseudonymized state for research purposes after deliberation by the institutional review 
committee. It will be provided and utilized only for research that is judged to be of public 
interest through deliberation by the institutional review committee, and where the expected 
outcome is considered to be a contribution to the promotion of public health. 
 
 Methods for Human Derived Material storage and disposal 
Human materials will be transferred and stored to the storage facility of the institution or Asan 
Medical Center (South Korea). In case of disposal by the institution, it is discarded after 
obtaining written approval from Asan Medical Center. The identification information of the 
subjects is anonymized throughout the entire process. 
Human materials will be managed under the supervision of Principal Investigator, and each 
human material management number will be managed separately from personally identifiable 
information. The personal identification code sheet should be recorded and managed only by 
the researcher in charge (or the researcher entrusted with it). 
 
 

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 References 
1. 
Terrault NA, Lok ASF, McMahon BJ, et al. Update on prevention, diagnosis, and 
treatment of chronic hepatitis B: AASLD 2018 hepatitis B guidance. Hepatology 
(Baltimore, Md). 2018;67(4):1560-1599. 
2. 
European Association for the Study of the Liver. Electronic address eee, European 
Association for the Study of the L. EASL 2017 Clinical Practice Guidelines on the 
management of hepatitis B virus infection. J Hepatol. 2017;67(2):370-398. 
3. 
Tseng TC, Kao JH. Treating Immune-tolerant Hepatitis B. J Viral Hepat. 
2015;22(2):77-84. 
4. 
Andreani T, Serfaty L, Mohand D, et al. Chronic hepatitis B virus carriers in the 
immunotolerant phase of infection: histologic findings and outcome. Clin 
Gastroenterol Hepatol. 2007;5(5):636-641. 
5. 
Hui CK, Leung N, Yuen ST, et al. Natural history and disease progression in Chinese 
chronic hepatitis B patients in immune-tolerant phase. Hepatology (Baltimore, Md). 
2007;46(2):395-401. 
6. 
Kennedy PTF, Sandalova E, Jo J, et al. Preserved T-cell function in children and 
young adults with immune-tolerant chronic hepatitis B. Gastroenterology. 
2012;143(3):637-645. 
7. 
Lai M, Hyatt BJ, Nasser I, Curry M, Afdhal NH. The clinical significance of 
persistently normal ALT in chronic hepatitis B infection. J Hepatol. 2007;47(6):760-
767. 
8. 
Kumar M, Sarin SK, Hissar S, et al. Virologic and histologic features of chronic 
hepatitis B virus-infected asymptomatic patients with persistently normal ALT. 
Gastroenterology. 2008;134(5):1376-1384. 
9. 
Kim GA, Lim YS, Han S, et al. High risk of hepatocellular carcinoma and death in 
patients with immune-tolerant-phase chronic hepatitis B. Gut. 2018;67(5):945-952. 
10. 
Terrault NA, Bzowej NH, Chang KM, Hwang JP, Jonas MM, Murad MH. AASLD 
guidelines for treatment of chronic hepatitis B. Hepatology. 2016;63(1):261-283. 
11. 
Lin CL, Liao LY, Liu CJ, et al. Hepatitis B viral factors in HBeAg-negative carriers 
with persistently normal serum alanine aminotransferase levels. Hepatology. 
2007;45(5):1193-1198. 
12. 
Chen CJ, Yang HI, Su J, et al. Risk of hepatocellular carcinoma across a biological 
gradient of serum hepatitis B virus DNA level. Jama. 2006;295(1):65-73. 

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13. 
Iloeje UH, Yang HI, Su J, et al. Predicting cirrhosis risk based on the level of 
circulating hepatitis B viral load. Gastroenterology. 2006;130(3):678-686. 
14. 
Choi GH, Kim GA, Choi J, Han S, Lim YS. High risk of clinical events in untreated 
HBeAg-negative chronic hepatitis B patients with high viral load and no significant 
ALT elevation. Aliment Pharmacol Ther. 2019;50(2):215-226. 
15. 
Buti M, Gane E, Seto WK, et al. Tenofovir alafenamide versus tenofovir disoproxil 
fumarate for the treatment of patients with HBeAg-negative chronic hepatitis B virus 
infection: a randomised, double-blind, phase 3, non-inferiority trial. Lancet 
Gastroenterol Hepatol. 2016;1(3):196-206. 
16. 
Chan HL, Fung S, Seto WK, et al. Tenofovir alafenamide versus tenofovir disoproxil 
fumarate for the treatment of HBeAg-positive chronic hepatitis B virus infection: a 
randomised, double-blind, phase 3, non-inferiority trial. The Lancet Gastroenterology 
& Hepatology. 2016;1(3):185-195. 
17. 
Lin ZH, Xin YN, Dong QJ, et al. Performance of the aspartate aminotransferase-to-
platelet ratio index for the staging of hepatitis C-related fibrosis: an updated meta-
analysis. Hepatology (Baltimore, Md). 2011;53(3):726-736. 
18. 
Sterling RK, Lissen E, Clumeck N, et al. Development of a simple noninvasive index 
to predict significant fibrosis in patients with HIV/HCV coinfection. Hepatology 
(Baltimore, Md). 2006;43(6):1317-1325. 
 
 
 

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Appendix1. Management of Clinical and Laboratory Adverse Events 
 
 
 
Appendix2. GSI Grading Scale for Severity of Adverse Events and Laboratory Abnormalities 
 
 

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Appendix 3. Internal Monitoring Committee (IMC) and Scientific Oversight Committee (SOC) 
 
The IMC will perform periodic safety data review to ensure that continuation of the study does not pose a health 
hazard to participants. 
 
IMC meetings will be scheduled following each of the planned interim analyses. 
Additional review meetings may be scheduled as determined by the IMC. Membership of the IMC will include 
representatives from Clinical Science (Translational Medicine), Clinical Safety, Biostatistics. If required, 
additional functional representatives may attend an IMC meeting. 
 
A SOC will act as a consultative body to the Sponsor, providing external expert opinions on the safety data 
collected during the study. This committee will consist of an external group of at least two CHB therapeutic area 
experts who will advise the Sponsor on the interpretation of study data. 
 
Data being evaluated by the SOC will include demographic, adverse event, serious adverse event, and relevant 
laboratory data. SOC may review efficacy data if safety concerns necessitate benefit-risk assessments. The 
Sponsor will retain all decision making authority for this study.