Clinical trial NCT02224456
Conditions: Hepatitis B, Chronic
Keywords: Tenofovir disoproxil fumarate hepatocellular carcinoma chronic hepatitis B Cirrhosis
Sponsor: GlaxoSmithKline
Start date: 2015-03-25; Completion date: 2020-12-04
Enrollment: 197 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
Chronic Hepatitis B infection (CHB) is known as the most frequently identified cause of liver disease that predisposes patients to the development of hepatocellular carcinoma (HCC). Active hepatitis B virus (HBV) replication is the key driver of liver injury and disease progression. Majority of Chinese patients are infected with genotype B and C HBV, which is different from Caucasian counterparts. This prospective multi-center cohort open-label study is designed to investigate the long-term effect of TDF on prevention of HCC and disease progression as well as to evaluate the efficacy and safety of long-term TDF in Chinese CHB subjects with advanced liver diseases. The study will enrol 240 subjects.

Detailed description:

Arms: arm 1: Subjects will receive TDF 300 milligrams (mg) tablet once daily for 240 weeks in the study. Subjects who receive add-on rescue treatment may take LAM 100 mg, ETV 0.5 mg or LdT 600 mg per day upon investigator's decision in addition to TDF tablet.
Interventions: intervention 1: Tenofovir disoproxil fumarate
Intervention descriptions: intervention 1: White, almond-shaped, film-coated tablet containing 300 mg of TDF, debossed with "GILEAD" and "4331" on one side of the tablet.

Protocol documents:
Prot_000.pdf: 
0 
Protocol Amendment 02 (Version:3.0) 
Study ID:  201213 
Official Title of Study:  A prospective, multi-center, cohort study to evaluate the efficacy and safety of 
Tenofovir Disoproxil Fumarate (TDF) therapy in Chinese chronic hepatitis B (CHB) subjects with advanced 
fibrosis & compensated cirrhosis 
Version Date: 27-Mar-2016
Sponsor Signature Date (Effective Date): 09-Sep-2016 (This date is redacted on page 2 as it was 
handwritten) 


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INVESTIGATOR PROTOCOL AGREEMENT PAGE 
 
I confirm agreement to conduct the study in compliance with the protocol. 
 
I acknowledge that I am responsible for overall study conduct. I agree to 
personally conduct or supervise the described clinical study. 
 
I agree to ensure that all associates, colleagues and employees assisting in the 
conduct of the study are informed about their obligations. Mechanisms are in 
place to ensure that site staff receives the appropriate information throughout the 
study. 
Investigator Name:  _____________________________ 
 
 
 
 
Investigator Signature 
 
Date 
 


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TABLE OF CONTENTS 
PAGE 
LIST OF ABBREVIATIONS ............................................................................................. 8 
PROTOCOL SUMMARY ............................................................................................... 10 
Primary Objective ................................................................................................... 10 
Secondary Objective .............................................................................................. 10 
Primary Endpoint .................................................................................................... 12 
Secondary Endpoints ............................................................................................. 12 
Other Endpoints ..................................................................................................... 13 
1. 
INTRODUCTION .................................................................................................... 14 
1.1. 
Background ................................................................................................ 14 
1.2. 
Rationale .................................................................................................... 15 
1.3. 
Benefit:Risk Assessment ............................................................................ 15 
1.3.1. 
Risk Assessment ......................................................................... 15 
1.3.2. 
Benefit Assessment ..................................................................... 17 
1.3.3. 
Overall Benefit:Risk Conclusion ................................................... 18 
2. 
OBJECTIVE(S) ...................................................................................................... 18 
2.1. 
Primary Objective ....................................................................................... 18 
2.2. 
Secondary Objectives ................................................................................. 18 
3. 
INVESTIGATIONAL PLAN ..................................................................................... 18 
3.1. 
Study Design .............................................................................................. 18 
3.2. 
Discussion of Design .................................................................................. 19 
4. 
SUBJECT SELECTION AND WITHDRAWAL CRITERIA ....................................... 20 
4.1. 
Number of Subjects .................................................................................... 20 
4.2. 
Inclusion Criteria ......................................................................................... 20 
4.3. 
Exclusion Criteria ........................................................................................ 21 
4.4. 
Withdrawal Criteria ..................................................................................... 22 
4.5. 
Screening/Run-in Failures .......................................................................... 23 
5. 
STUDY TREATMENTS .......................................................................................... 23 
5.1. 
Investigational Product and Other Study Treatment .................................... 23 
5.1.1. 
Handling and Storage of Investigational Product .......................... 24 
5.1.2. 
Dosage and Administration .......................................................... 24 
5.2. 
Treatment Assignment ................................................................................ 25 
5.3. 
Blinding ....................................................................................................... 25 
5.4. 
Product Accountability ................................................................................ 25 
5.5. 
Treatment Compliance ................................................................................ 26 
5.6. 
Concomitant Medications and Non-Drug Therapies .................................... 26 
5.6.1. 
Permitted Medications and Non-Drug Therapies .......................... 26 
5.6.2. 
Prohibited Medications and Non-Drug Therapies ......................... 26 
5.7. 
Treatment after the End of the Study .......................................................... 27 
5.8. 
Treatment of Study Treatment Overdose .................................................... 27 
6. 
STUDY ASSESSMENTS AND PROCEDURES ..................................................... 28 
6.1. 
Critical Baseline Assessments .................................................................... 31 


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6.2. 
Efficacy ....................................................................................................... 31 
6.2.1. 
Serum/Plasma Storage ................................................................ 31 
6.2.2. 
Primary Endpoint ......................................................................... 31 
6.2.3. 
Clinical Endpoint .......................................................................... 31 
6.2.4. 
Virological Endpoint ..................................................................... 32 
6.2.5. 
Biochemical Endpoint .................................................................. 32 
6.2.6. 
Serological Endpoint .................................................................... 32 
6.2.7. 
Liver fibrosis endpoint .................................................................. 32 
6.2.8. 
Resistance Surveillance ............................................................... 33 
6.3. 
Safety ......................................................................................................... 33 
6.3.1. 
On-Treatment ALT Flare, ALT Elevation With or Without 
Hepatic Dysfunction, and Post-Treatment Exacerbation of 
Hepatitis Management ................................................................. 33 
6.3.1.1. 
Management of ALT Flare or ALT Elevation 
With Hepatic Dysfunction in Subjects 
Receiving Study Medication ....................................... 33 
6.3.1.2. 
Increased monitoring for On-Treatment ALT 
Elevation Alone .......................................................... 34 
6.3.1.3. 
Management of Exacerbation of Hepatitis in 
Subjects who have Discontinued Study 
Medication .................................................................. 35 
6.3.2. 
Serum Creatinine Elevation ......................................................... 35 
6.3.3. 
Adverse Events............................................................................ 35 
6.3.3.1. 
Definition of an AE ...................................................... 36 
6.3.3.2. 
Definition of an SAE ................................................... 37 
6.3.3.3. 
Sentinel Events .......................................................... 38 
6.3.4. 
Cardiovascular Events ................................................................. 38 
6.3.5. 
Death Events ............................................................................... 38 
6.3.6. 
Laboratory and Other Safety Assessment Abnormalities 
Reported as AEs and SAEs ......................................................... 39 
6.3.7. 
Pregnancy ................................................................................... 39 
6.3.8. 
Time Period and Frequency of Detecting AEs and SAEs ............. 39 
6.3.9. 
Method of Detecting AEs and SAEs ............................................. 40 
6.3.10. 
Prompt Reporting of Serious Adverse Events and Other 
Events to GSK ............................................................................. 40 
6.3.10.1. Regulatory Reporting Requirements for SAEs ............ 40 
6.3.11. 
Other Safety Outcome ................................................................. 41 
6.4. 
Viral Genotyping and Phenotyping .............................................................. 41 
7. 
DATA MANAGEMENT ........................................................................................... 41 
8. 
DATA ANALYSIS AND STATISTICAL CONSIDERATIONS ................................... 42 
8.1. 
Hypotheses ................................................................................................. 42 
8.2. 
Study Design Considerations ...................................................................... 42 
8.2.1. 
Sample Size Assumptions ........................................................... 42 
8.2.2. 
Sample Size Sensitivity ................................................................ 42 
8.2.3. 
Sample Size Re-estimation .......................................................... 43 
8.3. 
Data Analysis Considerations ..................................................................... 43 
8.3.1. 
Analysis Populations .................................................................... 43 
8.3.2. 
Analysis Data Sets ....................................................................... 43 
8.3.3. 
Treatment Comparisons .............................................................. 43 
8.3.3.1. 
Primary Comparisons of Interest ................................ 43 


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8.3.3.2. 
Other Comparisons of Interest .................................... 44 
8.3.4. 
Interim Analysis ........................................................................... 44 
8.3.5. 
Key Elements of Analysis Plan .................................................... 44 
8.3.5.1. 
Efficacy Analyses ....................................................... 44 
8.3.5.2. 
Safety Analyses .......................................................... 44 
8.3.5.3. 
Viral Genotyping/Phenotyping Analyses ..................... 45 
9. 
STUDY CONDUCT CONSIDERATIONS ............................................................... 45 
9.1. 
Posting of Information on Publicly Available Clinical Trial Registers ............ 45 
9.2. 
Regulatory and Ethical Considerations, Including the Informed 
Consent Process ........................................................................................ 45 
9.3. 
Quality Control (Study Monitoring) .............................................................. 46 
9.4. 
Quality Assurance ....................................................................................... 46 
9.5. 
Study and Site Closure ............................................................................... 46 
9.6. 
Records Retention ...................................................................................... 47 
9.7. 
Provision of Study Results to Investigators, Posting of Information 
on Publicly Available Clinical Trials Registers and Publication .................... 47 
10. REFERENCES ....................................................................................................... 49 
11. APPENDICES ........................................................................................................ 51 
11.1. 
Appendix 1: CHILDS-PUGH SCORE .......................................................... 51 
11.2. 
Appendix 2: Estimated creatinine clearance rate (CLcr) Cockcroft-
Gault formula and Estimated Glomerular Filtration Rate (GFR) 
Equation ..................................................................................................... 52 
11.3. 
Appendix 3: Histological Score ................................................................... 53 
11.4. 
Appendix 4: Lactic Acidosis Guidelines ....................................................... 55 
 


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LIST OF ABBREVIATIONS 
ADV 
Adefovir dippivoxil  
 
AE 
Adverse event 
 
 
ALT 
Alanine aminotransferase 
 
 
ANA 
Anti-nuclear antibody 
 
 
AST 
Aspartate aminotransferase 
 
 
BP 
Blood pressure 
 
 
CFDA 
China Food and Drug Administration 
 
CHB 
Chronic hepatitis B 
 
 
CRF 
Case report form(s) 
 
 
DAPD 
(2R,4R)-4-(2,6-Diaminopurin-9-yl)-1,3-dioxolan-2-yl]methanol 
 
DNA 
Deoxyribonucleic acid 
 
 
EC 
Ethics committee 
 
 
ETV 
Entecavir 
 
 
FTC 
Emtricitabine 
 
 
GCP 
Good Clinical Practice (Guidelines) 
 
GFR 
glomerular filtration rate 
 
 
HAV 
Hepatitis A virus 
 
 
HBeAg 
Hepatitis B e antigen 
 
 
HBsAg 
Hepatitis B s antigen 
 
 
HBV 
Hepatitis B virus 
 
 
HCV 
Hepatitis C virus 
 
 
HCC 
Hepatocellular carcinoma 
 
 
HDV 
Hepatitis delta virus 
 
 
HIV 
Human immunodeficiency virus 
 
IB 
Investigator brochure 
 
 
IFN 
Interferon 
 
 
INR 
International normalised ratio 
 
 
IP 
Investigational product 
 
 
IUD 
Inter uterine device 
 
 
IUS 
Inter uterine system 
 
 
L-FMAU 
1-(2-fluoro-5-methyl-beta, L-arabinofuranosyl) uracil 
 
LAM 
Lamivudine 
 
 
LdT 
Telbivudine 
 
 
LFT 
Liver function test 
 
 
LLD 
Lower limit of detection 
 
 
LSLV 
Last subject last visit 
 
 
LSM 
Liver stiffness measure 
 
 
mITT 
Modified Intent-to-treat (population) 
 
MedDRA 
Medical dictionary for regulatory activities 
 
NA 
PP 
Nucleos(t)ide analogues 
Per protocol population 
 
 
PT 
Prothrombin time 
 
 
PTA 
Prothrombin time activity 
 
 
QD 
quaque die (Once daily) 
 
 
RAP 
Reporting and analysis plan 
 
 
SA 
Safety analysis population 
 
 


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SAE 
Serious adverse event 
 
 
SOP 
Standard operating procedure  
 
SPM 
Study procedures manual 
 
 
TDF 
TE 
Tenofovir disoproxil fumarate 
Transient elastography  
 
 
ULN 
Upper limit of the normal range 
 
 
Trademark Information 
Trademarks of the GlaxoSmithKline 
group of companies 
 
Trademarks not owned by the 
GlaxoSmithKline group of companies 
Heptodin 
 
Viread 
 
 
Sebivo 
 
 
Baraclude 
 


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PROTOCOL SUMMARY 
Rationale 
Chronic hepatitis B infection affects over 240 million people worldwide, of whom about 
93 million live in China. Chronic hepatitis B infection is known as the most frequently 
identified cause of liver disease that predisposes patients to the development of 
hepatocellular carcinoma (HCC). It is now clear that active HBV replication is the key 
driver of liver injury and disease progression.  
Over the past decades, four oral nucleos(t)ide analogues (NA) have been approved for 
antiviral treatment of CHB in China. They have been shown to be effective in decreasing 
serum HBV DNA and alanine aminotransferase (ALT) levels, improving hepatic reserve 
and liver histology. Seven years of tenofovir DF (TDF) therapy in treatment naïve 
patients results in sustained viral suppression with no development of resistance and was 
associated with either the halting or regression of fibrosis in 96%, and reversal of 
cirrhosis in 74% of previously cirrhotic patients(Marcellin et al., 2013). 
Only a few long-term studies of patients with advanced liver diseases undergoing 
antiviral treatment are available, mostly using LAM. However, LAM is associated with a 
high rate of resistance, which may cause disease progression and reduce benefit of 
antiviral therapy. Newer NAs with low resistance rates, such as entecavir (ETV) and TDF, 
show good efficacy in suppressing HBV DNA, but the long-term effects on the 
prevention of decompensation and HCC are not well characterised.  
 This prospective multi-center cohort study is designed (1) to investigate the long-term 
effect of TDF on prevention of HCC and disease progression in Chinese CHB subjects 
with compensated cirrhosis; (2) to evaluate the efficacy and safety of long-term TDF in 
Chinese CHB subjects with compensated cirrhosis; (3) to explore baseline and on-
treatment risk factors associated with disease progression and development of HCC in 
Chinese CHB subjects with compensated cirrhosis 
Objective(s) 
Primary Objective 
 
To evaluate the incidence of hepatocellular carcinoma (HCC) during 240-weeks of  TDF 
300mg QD treatment in Chinese CHB subjects with advanced fibrosis and compensated 
cirrhosis. 
 
To evaluate the rate of disease progression during 240-weeks of TDF 300mg QD 
treatment in Chinese CHB subjects with advanced fibrosis and compensated cirrhosis. 
Secondary Objective 
 
To evaluate the efficacy and safety of 240 weeks of TDF 300mg QD treatment  in 
Chinese CHB subjects with advanced fibrosis and compensated cirrhosis  


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Study Design 
This is a prospective, multi-centre, open-label, cohort study to investigate efficacy and 
safety of TDF treatment in Chinese chronic hepatitis B (CHB subjects with advanced 
fibrosis and compensated cirrhosis. The study will enrol 186 subjects. 
Screen phase (≤4 weeks): Subjects considered eligible to enroll into the 
study will be assessed at a screening visit as described in Table 1 to decide if 
they meet the study criteria (see section 4.2 and 4.3). Between Screen 
visit and baseline visit, subjects will not receive investigational 
product. 
Treatment phase (0 Day ~Week 240): 186 subjects will be administered TDF 300 mg 
QD and undergo regular safety and efficacy assessments every 12 weeks for a total of up 
to 240 weeks(see Table 1). Subjects will be questioned about adverse events, concurrent 
medications, and study drug accountability; blood will be taken for hematology and 
biochemistry profiles; serum samples well be tested for HBV markers, and the 
prothrombin time will be measured. Serum samples will be collected at Week 12, 24, 
36,48, 60, 72, 84, and 96 and every 24 weeks thereafter and analyzed for HBV DNA 
levels at a central laboratory. Abdominal ultrasound and serum alpha-fetoprotein test will 
be performed every 12 weeks for HCC surveillance. If abdominal ultrasound reports a 
liver mass or nodule, CT of MRI will be performed. At baseline and W216, a subset of 
100 subjects will undergo liver biopsy to evaluate liver histological changes pre- and 
post- TDF treatment. All subjects will be followed up to Week 240.  
Rescue treatment could be optionally initiated, at the discretion of the investigator if   
 subjects have confirmed virological breakthrough as defined as a  ≥ 1 log10 IU/mL 
increase in HBV DNA from nadir determined by two sequential HBV DNA 
measurements at least 1 month apart, OR 
 subjects have HBV DNA ≥200IU/ml at week 48 and afterwards have ≤ one log 
decrease in HBV DNA at two consecutive tests, confirmed by a third visit at least 
one month apart.   
Confirmation of HBV DNA test will require an additional visit to collect serum sample. 
To receive rescue treatment subjects must have investigational product (IP) compliance > 
80% in the last regular visits period (usually 12 weeks). Add-on combination with a 
second nucleoside agent (LAM, ETV or telbivudine (LdT)) is acceptable rescue treatment 
in this study, to be decided by the investigator. Before rescue treatment, serum sample 
should be collected for resistance testing. 
Subjects who reach primary endpoint (i.e. develop liver complications or HCC) may 
withdraw from study. Investigator and subjects can decide whether to continue study 
drug. Subjects who continue to take study drug will be followed as per the original 
schedule until Week 240. During the follow-up period, AEs, concomitant medication, 
vital signs, hepatitis B virus DNA, haematology, chemistry and prothrombin will be 
evaluated. Serum/plasma storage also will be conducted. 


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Supplementary study conduct information not mandated to be present in this protocol is 
provided in the accompanying Study Procedures Manual (SPM). The SPM will provide 
the site personnel with administrative and detailed technical information that does not 
affect subject safety. 
Study Endpoints/Assessments 
Primary Endpoint 
 
Incidence of hepatocellular carcinoma at Week 240. 
 
Incidence of disease progression at Week 240, defined as the first occurrence of any 
one of the following criteria: 
 
An increase in Childs-Pugh score (as defined in Appendix 1) of 2 or more points 
from baseline. an increase in Childs-Pugh score of 2 or more points, solely 
based on laboratory parameters (i.e. bilirubin, prothrombin time and/or 
albumin),  confirmed between two consecutive visits at least one month apart; 
 
spontaneous bacterial peritonitis (with proven sepsis); 
 
renal insufficiency defined as a decrease in creatinine clearance rate to ≤50 
mL/minute confirmed on two occasions at least one week apart (calculated from 
serum creatinine concentration, see section 11.2 Appendix 2); 
 
bleeding gastric/oesophageal varices; 
 
hepatocellular carcinoma; 
 
liver-related death 
Secondary Endpoints 
 
Incidence of HCC at Week 48, Week 96 Week 144, and Week 192 
 
Cumulative incidence of HCC at Week 48, Week 96, Week 144, Week 192 and 
Week 240 
 
Cumulative incidence of disease progression at Week 48, Week 96, Week 144 and 
Week 192, and Week 240 
 
The mean changes of liver stiffness measurement (LSM) at Week 48, Week 96, 
Week 144, Week 192 and Week 240 
 
Proportion of subjects with serum HBV DNA <20 IU/mL (Roche COBAS Taqman 
HBV Test) at Week 48, Week 96, Week 144, Week 192 and Week 240. 
 
The mean log10 reduction in serum HBV DNA at Week 48, Week 96, Week 144, 
Week 192 and Week 240 compared with baseline. 
 
The proportion of subjects with ALT normalization at Week 48, Week 96, 
Week 144, Week 192 and Week 240 in subjects who have abnormal ALT at 
baseline. 


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 
For HBeAg positive subjects: the proportion of subjects achieving HBeAg loss, 
HBeAg seroconversion or HBsAg loss and HBsAg seroconversion at Week 24, 
Week 48, Week 96, Week 144, Week 192 and Week 240. 
 
For HBeAg negative subjects: the proportion of subjects achieving HBsAg loss and 
HBsAg seroconversion at Week 48, Week 96, Week 144, Week 192 and Week 240. 
 
Incidence of virological breakthrough as defined by  1 log10 increase in HBV DNA 
from nadir (as determined by two sequential HBV DNA measurements at least 1 
month apart, or the last on-treatment measurement) up to Week 48, Week 96, Week 
144, Week 192 and Week 240 
 
The proportion of subjects with histological improvement (a reduction of two or 
more points in the Knodell necroinflammatory score with no increase in fibrosis) at 
Week 216 in the subset of subjects with paired baseline and W216 liver biopsies.  
 
The proportion of subjects with cirrhosis reversal (a reduction of one or more points 
in the Ishak score and no evidence of cirrhosis) at Week 216 in the subset of subjects 
with paired baseline and W216 liver biopsies and with a baseline Ishak score higher 
than or equal to five. 
 
Subject safety as determined by adverse events and laboratory assessments. 
Other Endpoints 
 
Incidence of TDF resistance substitutions (if identified) at Week 48, Week 96, Week 
144, Week 192 and Week 240.  
 
Baseline or on-treatment risk factors for HCC/disease progression (e.g. gender, age, 
HBV DNA, genotype, HBeAg sero-status, ALT, treatment response etc) 
 


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1. 
INTRODUCTION 
1.1. 
Background 
Chronic hepatitis B infection affects over 240 million people worldwide, of whom about 
93 million live in China(Chinese Society of Hepatology & Chinese Society of Infectious 
Diseases, 2011). And It has been reported that 15–20% of CHB patients progress to 
cirrhosis within 5 years. Over 70% of Chinese patients with cirrhosis are HBsAg 
positive(Zhang, Zhang, Elizabeth, & Liu, 2012). CHB infection is also known as the most 
frequently identified cause of liver disease that predisposes patients to the development of 
hepatocellular carcinoma (HCC), accounting for approximately 70%-80% of cases(Lai & 
Yuen, 2013). HCC is the second most common type of malignancy in China, developing 
at an annual incidence of 3–6 % in patients with cirrhosis and far less frequently in non-
cirrhotic patients(Nguyen, Law, & Dore, 2009), (Chen, Chu, Yeh, & Liaw, 2007). It is 
now clear that active HBV replication is the key driver of liver injury and disease 
progression.  
Over the past decades, four oral nucleos(t)ide analogues (NA) have been approved for 
antiviral treatment of CHB in China(Chinese Society of Hepatology & Chinese Society 
of Infectious Diseases, 2011). They have been shown to be effective in decreasing serum 
HBV DNA and alanine aminotransferase (ALT) levels, improving hepatic reserve and 
liver histology. The goal of antiviral therapy in cirrhotic patients is to prevent hepatic 
decompensation, reduce or prevent progression and/or HCC, and prolong 
survival(Chinese Society of Hepatology & Chinese Society of Infectious Diseases, 
2011),(Liaw et al., 2012). 
Only a few long-term studies of patients with advanced liver diseases undergoing 
antiviral treatment are available. A randomized placebo-controlled study in 651 patients 
showed that LAM therapy for a median of 32.4 months could reduce the incidence of 
HCC (hazard ratio 0.49, P = 0.047) and the incidence of liver complications (hazard ratio 
0.45, P=0.02) in patients with advanced fibrosis or compensated cirrhosis (Liaw et al., 
2004). A large Korean cohort of lamivudine-treated patients was compared with 
historical controls and reported that long-term viral suppression reduced the rate of HCC 
compared with those with viral breakthrough or untreated controls in patients with 
cirrhosis at baseline (Eun, Lee, Kim, & Lee, 2010). However, LAM is associated with a 
high rate of resistance, especially with long-term therapy. Clinical studies have shown 
that the greatest benefit in preventing disease progression was observed in patients 
without drug resistance, and the benefit decreased after emergence of drug resistance 
(Liaw et al., 2004),(Di Marco et al., 2004). Newer NAs with low resistance rates, such as 
entecavir (ETV), show good efficacy in suppressing HBV DNA, but the long-term effects 
of ETV treatment are not well characterised. In one report the 5-year cumulative 
incidence of HCC in a retrospective-prospective cohort  undergoing ETV treatment were 
2.1% and 12.9% in the non-cirrhosis and cirrhosis subgroups, respectively (Wong et al., 
2013). Hosaka et al reported that long-term ETV treatment may reduce the incidence of 
HCC (versus historical control, hazard ratio: 0.37, P = 0.030) (Hosaka et al., 2013). 
However, Papatheodoridis et al reported that risk of HCC continued to  increase in their 
large mutlicenter study of predominantly Caucasian patients treated with ETV or TDF 
(Papatheodoridis, Dalekos, & Yurday-, 2013). 


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Until now, liver biopsy (LB) remains the gold standard for assessing the degree of liver 
fibrosis. But recently many non-invasive methodologies have been developed. Among 
them, transient elastography (FibroScan, Echosens, France) has been widely accepted for 
the measure of liver stiffness and helping to stage liver fibrosis. Some researchers have 
proposed diagnostic algorithms that use dual TE cut-offs, for positive and negative 
prediction of significant fibrosis. And based on their results, China’s Review Panel for 
Liver Stiffness Measurement offered recommendations for the clinical application of 
transient elastography in liver fibrosis assessment(Review Panel for Liver Stiffness 
Measurement, 2013). 
1.2. 
Rationale 
Two Phase III studies (GS-US-174-0103, GS-US-174-0102) have shown that 
seven years of tenofovir disoproxil fumarate (TDF) therapy in treatment naïve patients 
results in sustained viral suppression with no development of resistance and was 
associated with either the halting or regression of fibrosis in 96%, and reversal of 
cirrhosis in 74% of previously cirrhotic patients (Marcellin et al., 2008) ,(Marcellin et al., 
2013), (Kitrinos et al., 2013). However, the long-term effect of TDF on the prevention of 
decompensation and HCC has not been well established. 
Additionally, the characteristics of Chinese CHB population differ from those enrolled in 
studies referred to above in which the majority of cirrhotic subjects were NAs treatment 
naïve and genotype A/D, while in China the majority of cirrhotic patients are NAs 
treatment experienced and genotype B/C (Liaw et al., 2012). Due to these differences the 
efficacy and safety of TDF on CHB patients with compensated cirrhosis in China may 
differ from those seen in the cirrhosis subgroup analysis above. 
Despite the success of nucleot(s)ide (NA) treatment of CHB infection, antiviral treatment 
has failed to reduce the risk of subsequent HCC. Established risk factors for the 
development of HCC in untreated chronic HBV patients include subject age, male 
gender, presence of cirrhosis, hepatitis B e antigen (HBeAg) positive serostatus, and high 
levels of serum HBV-DNA.  Thus it is important to identify those at higher risk of HCC 
even with potent NAs treatment. 
 This prospective multi-center cohort study is designed (1) to investigate the long-term 
effect of TDF on prevention of HCC and disease progression in Chinese CHB subjects 
with compensated cirrhosis; (2) to evaluate the efficacy and safety of long-term TDF in 
Chinese CHB subjects with compensated cirrhosis; (3) to explore baseline and on-
treatment risk factors associated with disease progression and development of HCC in 
Chinese CHB subjects with compensated cirrhosis 
1.3. 
Benefit:Risk Assessment 
Summaries of findings from both clinical and non-clinical studies conducted with 
Tenofovir can be found in the Investigator’s Brochure and China-specific prescribing 
information for TDF in CHB.  The following section outlines the risk assessment and 
mitigation strategy for this protocol:  
1.3.1. 
Risk Assessment 


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Potential Risk of Clinical 
Significance 
Data/Rationale for Risk 
 
 
Mitigation Strategy 
 
 
Investigational Product (IP)  
Renal toxicity 
Tenofovir is principally 
eliminated by the kidney. Renal 
impairment, including cases of 
acute renal failure and Fanconi 
syndrome (renal tubular injury 
with severe hypophosphatemia), 
has been reported with the use of 
VIREAD. 
 
Exclusion of  CHB 
patients with creatinine 
clearance <70 mL/min 
 
Monitor renal function 
every 12 weeks 
 
Dosing interval 
adjustment of VIREAD is 
recommended in all 
patients with creatinine 
clearance below 50 
mL/min. 
 
Stopping criteria based 
on renal function with 
serum creatinine 
confirms >2.5 mg/dL 
have been clearly 
defined.(see section 
6.3.2) 
Bone events  
 
Decreases in Bone mineral 
density (BMD) has been reported 
in adults and pediatric patients. 
The effects of VIREAD-
associated changes in BMD and 
biochemical markers on long-
termbone health and future 
fracture risk are unknown. 
 
Monitoring the serum 
calcium and phosphate 
every 12 weeks 
 
In every regular visits, the 
information of bone 
related symptoms will be 
collected. 
 
Assessment of BMD and 
related treatment should 
be considered by the 
investigator’s judgement. 
Lactic acidosis/severe 
hepatomegaly with 
steatosis and 
lipodystrophy 
Lactic acidosis/ severe 
hepatomegaly with steatosis, 
including fatal cases, havebeen 
reported with the use of 
nucleoside analogs, including 
VIREAD, in combination with 
other antiretrovirals. 
 
Guidelines for 
management of lactic 
acidosis are outlined in 
Appendix 4. 
Drug-Drug Interaction 
Potential 
Since tenofovir is primarily 
eliminated by the kidneys, 
coadministration of VIREAD 
with drugs that reduce renal 
function or compete for active 
tubular secretion may increase 
 
Estimated creatinine 
clearance will be 
assessed in all patients 
every 12 weeks during 
treatment with TDF 
 
TDF should be avoided 


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serum concentrations of 
tenofovir and/or increase the 
concentrations of other renally 
eliminated drugs. Some 
examples include, but are not 
limited to cidofovir, acyclovir, 
valacyclovir, ganciclovir, 
valganciclovir,aminoglycosides 
(e.g., gentamicin), and high-
dose or multiple NSAIDs 
with concurrent or 
recent use of a 
nephrotoxic agent 
according to the 
protocol(See 
section5.6.2) 
Post-treatment hepatic 
flares 
Discontinuation of anti-HBV 
therapy, including VIREAD, may 
be associated with severe acute 
exacerbations of hepatitis and 
must only take place under 
careful supervision. 
 
Patients who withdraw 
from the investigational 
product during treatment 
period will be followed as 
per the original schedule. 
 
No post-study 
medication is provided; 
the investigator is 
responsible for ensuring 
that consideration has 
been given to the post-
study care of the 
patient’s medical 
condition. 
 
1.3.2. 
Benefit Assessment 
The benefits and risks of TDF have now been characterized in a large range of subject 
populations with HIV-1 and HBV infection enrolled in clinical studies and a large 
number of patients who have received TDF in clinical practice. 
Chronic Hepatitis B Infection 
The effectiveness of TDF has been characterized in a large range of adult populations, 
cirrhotic population included, and in pediatric patients ≥ 12 years of age, with HBV 
infection. 
TDF demonstrates potent and selective inhibition of HBV replication in vitro and in vivo. 
No mutations associated with TDF resistance have been identified in viremic subjects 
(HBV DNA > 400 copies/mL) treated with TDF. 
TDF has been studied in an extensive clinical development program. The strength of 
evidence supporting the overall efficacy of TDF is provided by large-scale long term 
phase III clinical studies, which demonstrate effective reduction of HBV viral load and 
histologic improvement both in general and cirrhotic population. No significant data 
weakness or uncertainties remain. 


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1.3.3. 
Overall Benefit:Risk Conclusion 
Taking into account the measures taken to minimize risk to subjects participating in this 
study, the potential risks identified in association with TDF are justified by the 
anticipated benefits that may be afforded to patients with CHB. 
2. 
OBJECTIVE(S) 
2.1. 
Primary Objective 
 
To evaluate the incidence of hepatocellular carcinoma (HCC) during 240-weeks of 
TDF 300mg QD treatment in Chinese CHB subjects with advanced fibrosis and 
compensated cirrhosis. 
 
To evaluate the rate of disease progression during 240-week of TDF 300mg QD 
treatment in Chinese CHB subjects with advanced fibrosis and compensated cirrhosis. 
2.2. 
Secondary Objectives 
 
To evaluate the efficacy and safety of 240 weeks of TDF 300mg QD treatment  in 
Chinese CHB subjects with advanced fibrosis and compensated cirrhosis  
 
3. 
INVESTIGATIONAL PLAN 
3.1. 
Study Design 
This is a prospective, multi-centre, open-label, cohort study to investigate efficacy and 
safety of Tenofovir Disoproxil Fumarate (TDF) treatment in Chinese CHB subjects with 
advanced fibrosis and compensated cirrhosis. The study will enrol 186 subjects with a 
diagnosis of CHB and advanced fibrosis or compensated cirrhosis. 
Screen phase (≤4 weeks): Written informed consent must be obtained from each subject 
prior to participation in the study. Subjects considered eligible to enroll in 
the study will be assessed at a screening visit as described in Table 1 to 
decide if they meet the study criteria (see that in 4.2 and 4.3). Between 
Screen visit and baseline visit, subjects will not receive 
investigational product. 
Treatment phase: 186 subjects will be administered TDF 300 mg QD and undergo 
regular safety and efficacy assessments every 12 weeks for a total of up to 240 weeks 
(see Table 1). Subjects will be questioned about adverse events, concurrent medications, 
and study drug accountability; blood will be taken for hematology and biochemistry 
profiles; serum samples well be tested for HBV markers, and the prothrombin time will 
be measured. Serum samples will be collected at Week 12, 24,36, 48, 60, 72, 84, and 96 
and every 24 weeks thereafter and analyzed for HBV DNA levels at a central laboratory. 
Abdominal ultrasound, the prothrombin time and serum alpha-fetoprotein test will be 
performed every visits. If abdominal ultrasound reports a liver mass or nodule, CT or 
MRI will be performed. At baseline and W216, 100 of subjects will take liver biopsy to 


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evaluate liver histological changes pre and post TDF treatment. All subjects will be 
followed through to Week 240. 
Rescue treatment could be optionally initiated in subjects with unsatisfied response to 
TDF, at the discretion of the investigator if  
 subjects have confirmed virological breakthrough as defined by ≥ one log 
increase in HBV DNA from nadir determined by two sequential HBV DNA 
measurements at least 1 month apart, or  
 subjects have HBV DNA ≥200IU/ml at week 48 and afterwards have ≤ one log 
decrease in HBV DNA at two consecutive visits, confirmed by a third visit at 
least one month apart.  
Confirmation of HBV DNA test will require an additional visit to collect serum sample. 
To receive rescue treatment subjects must have investigational product (IP) compliance > 
80% in the last regular visits period (usually 12 weeks). Add-on combination with a 
nucleoside agent (LAM, ETV or LdT) is acceptable rescue treatment in this study, as to 
investigator’s decision. Before rescue treatment, serum sample should be collected for 
resistance testing. 
Subjects who reach primary endpoint (i.e. develop liver complications or HCC) may 
withdraw from study. Investigator and subjects can decide whether to continue study 
drug. Subjects who continue to take study drug will be followed as per the original 
schedule until Week 240. During the follow-up period, AEs, concomitant medication, 
vital signs, hepatitis B virus DNA, haematology, chemistry and prothrombin will be 
evaluated. Serum/plasma storage also will be conducted. 
Supplementary study conduct information not mandated to be present in this protocol is 
provided in the accompanying Study Procedures Manual (SPM). The SPM will provide 
the site personnel with administrative and detailed technical information that does not 
affect subject safety. 
3.2. 
Discussion of Design 
This study is designed to evaluate the cumulative incidence of newly diagnosed HCC in 
patients with advanced fibrosis and compensated cirrhosis during 240 weeks of TDF 
treatment. It will also provide long-term efficacy and safety data (up to 240 weeks) of 
TDF 300 mg QD. 
It is accepted that long-term antiviral therapy benefits cirrhotic patients as will be 
investigated in this study with TDF. As HCC develops at an annual incidence of 
approximately 3–6 % in patients with cirrhosis it will take some time to observe an effect 
of TDF on prevention of HCC, and on histological improvement. 
CHB patients with advanced fibrosis and cirrhosis have severe liver disease and reducing 
viral replication and acheiving HBV DNA undetectability is particularly important in this 
group. In this study subjects with poor response or virological breakthrough after Week 
48 (See Section3.1) may receive rescue treatment, with add-on treatment of additional 
NAs. Before rescue treatment, serum sample should be collected for resistance testing. 


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4. 
SUBJECT SELECTION AND WITHDRAWAL CRITERIA 
4.1. 
Number of Subjects 
186 Chinese CHB subjects with advanced fibrosis & compensated cirrhosis will be 
administered to TDF 300 mg QD.  
Screened 
260 
Enrolled 
186 
Completed/evaluable   
158 
4.2. 
Inclusion Criteria 
Specific information regarding warnings, precautions, contraindications, adverse events, 
and other pertinent information on the GSK investigational product or other study 
treatment that may impact subject eligibility is provided in the IB/IB supplement(s) and 
product label. 
Deviations from inclusion criteria are not allowed because they can potentially jeopardise 
the scientific integrity of the study, regulatory acceptability or subject safety. Therefore, 
adherence to the criteria as specified in the protocol is essential.    
Subjects eligible for enrolment in the study must meet all of the following criteria: 
1. Age 18-60 years(inclusive); 
2. Presence of HBsAg in serum at screening and for at least 6 months before screening 
assessment; 
3. Serum HBV DNA≥ 2000 IU/mL if HBeAg positive at screening (with or without  
ALT elevation); or serum HBV DNA≥ 200IU/mL if HBeAg negative at screening 
(with or without ALT elevation); 
4. Pathologically or clinically diagnosed as advanced fibrosis or compensated cirrhosis 
defined as one  of following(a or b) : 
a. Liver biopsy showing advanced fibrosis or cirrhosis (Ishak score ≥4 or 
Fibrosis stage≥S3 by Scheuer Score, or within the previous 6 months before 
baseline and provided that no treatment likely to improve liver histology has 
been taken since). The slides must be available for review by an independent 
histopathologist.  
b. Clinical diagnosis: liver stiffness measure (LSM) >12.4 kpa (ALT> ULN) or 
LSM>9.0 kpa (ALT≤ULN), (See section 6.2.7)  plus one of the following: 
i. Endoscopy-proven gastroesophageal or gastric varices, non-cirrhotic 
portal hypertension excluded; 
ii. Abdominal ultrasound or CT found changes indicating cirrhosis, 
irregular liver surface or nodularity,  with/without splenomegaly(depth 
of spleen>4.0cm or spleen length>13cm); 
iii. Blood platelets <100 x109/L (and other causes of thrombocytopenia 
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5. Ability to give written informed consent; 
6. A female is eligible to enter and participate in this study if she is of: 
a. non-childbearing potential (i.e., physiologically incapable of becoming 
pregnant, including any female who is post-menopausal), or 
b. Child-bearing potential, has a negative urine pregnancy test at screening, and 
agrees to one of the following methods for avoidance of pregnancy during the 
period of the study and until 30 days after last dose of study medication: 
i. Oral contraceptive, either combined or progestogen alone. 
ii.  Injectable progestogen. 
iii.  Implants of levonorgestrel. 
iv.  Oestrogenic vaginal ring. 
v.  Percutaneous contraceptive patches. 
vi. 
Intrauterine device (IUD) or intrauterine system (IUS) showing that 
the expected failure rate is less than 1% per year as stated in the IUD 
or IUS product label. 
vii.  Has a male partner who is sterilised. 
viii.  Double barrier method: condom and an occlusive cap (diaphragm 
orcervical/vault caps) with a vaginal spermicidal agent (foam/gel/film 
/cream/suppository). 
7. Agreement not to participate in any other investigational trials or to undertake other 
HBV systemic antiviral or IFN regimens during participation in this study. 
4.3. 
Exclusion Criteria 
Deviations from exclusion criteria are not allowed because they can potentially 
jeopardise the scientific integrity of the study, regulatory acceptability or subject safety. 
Therefore, adherence to the criteria as specified in the protocol is essential.  
Subjects meeting any of the following criteria must not be enrolled in the study: 
1. Hepatocellular carcinoma as evidenced by one of the following: 
 
Suspicious foci on ultrasound or radiological examination. 
 
Normal ultrasound serum alpha-fetoprotein >50 ng/mL at screening.  
2. Serum ALT >10 times ULN at screening or history of acute exacerbation leading to 
transient decompensation; 
3. Documented co-infection with hepatitis A (HAV), hepatitis C (HCV), hepatitis delta 
virus (HDV), hepatitis E virus (HEV) or HIV.  For HCV co-infection, subjects who 
are anti-HCV positive and in whom HCV RNA is undetectable are considered to be 
not eligible for enrolment. 
4. Evidence of active liver disease due to autoimmune hepatitis (antinuclear antibody 
(ANA) titre >1:160)   
5. Decompensated liver disease as indicated by any of the following: 
a. serum bilirubin >1.5 xULN  
b. prothrombin time activity <60% or INR>1.5 
c. serum albumin <32 g/L 
d. history of  previous clinical hepatic decompensation (e.g., 


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ascites, variceal bleeding, or encephalopathy); 
6. Planned for liver transplantation or previous liver transplantation; 
7. Creatinine clearance less than 70 mL/min; 
8. Haemoglobin <10 g/dL, white blood cell (WBC) count <1.5 x 109/L, platelets ≤50 x 
109/L; 
9. Any serious or active medical or psychiatric illnesses other than hepatitis B which, in 
the opinion of the Investigator, would interfere with subject treatment, assessment or 
compliance with the protocol. This would include any uncontrolled clinically 
significant renal, cardiac, pulmonary, vascular, neurogenic, digestive, metabolic 
(diabetes, thyroid disorders, adrenal disease), immunodeficiency disorders, 
pathological fractures or cancer; 
10. Active alcohol or drug abuse or history of alcohol or drug abuse considered by the 
Investigator to be sufficient to hinder compliance with treatment, participation in the 
study or interpretation of results; 
11. A female who is breastfeeding or plan to breastfeed; 
12. Use 
of 
immunosuppressive 
therapy, 
immunomodulatory 
therapy 
(including IFN or thymosin ,), systemic cytotoxic agents, chronic 
antiviral agents including Chinese herbal medicines known to have 
activity against HBV (e.g., LAM, adefovir, ETV LdT or hepatitis B 
immunoglobulin (HBIg)) within the previous 6 months prior to 
screening into this study; 
13. Have ever received TDF or any medicinal products containing the 
above mentioned antiviral agents or any investigative anti-HBV 
treatments (e.g., emtricitabine (FTC), (2R,4R)-4-(2,6-Diaminopurin-
9-yl)-1,3-dioxolan-2-yl]methanol (DAPD) and 1-(2-fluoro-5-methyl-
beta, Larabinofuranosyl) uracil (L-FMAU)); 
14. History of hypersensitivity to nucleoside and/or nucleotide analogues and/or any 
component of study medication; 
15. Therapy with nephrotoxic drugs (e.g., aminoglycosides, amphotercin B, vancomycin, 
cidofovir, foscarnet, cis-platinum, pentamidine etc.) or competitors of renal excretion 
(e.g., probenecid) within 2 months prior to study screening or the expectation that 
subject will receive any of these during the course of the study; 
16. Inability to comply with study requirements as determined by the study Investigator. 
4.4. 
Withdrawal Criteria 
Should a subject fail to attend the clinic for a required study visit, the site should attempt 
to contact the subject and re-schedule the missed visit as soon as possible. The site should 
also counsel the subject on the importance of maintaining the assigned visit schedule and 
ascertain whether or not the subject wishes to and/or should continue in the study based 
on previous non-compliance. In cases where the subject does not return for the 
rescheduled visit or cannot be reached to reschedule the missed visit, the site should 
make every effort to regain contact with the subject (3 telephone calls and if necessary a 
certified letter to the subject’s last known mailing address) so that they can appropriately 
be withdrawn from the study. These contact attempts should be documented in the 
subject’s medical record. Should the subject continue to be unreachable, then and only 


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then will he/she be considered to have withdrawn from the study with a primary reason of 
“Lost to Follow-up”. For all other subjects withdrawing from the study, an alternative 
reason for discontinuation should be recorded in the eCRF. 
Subjects who temporarily interrupted treatment for <28 consecutive days 
were allowed to continue in the study. Subjects with treatment 
interruptions of  28 consecutive days were required to withdraw from the 
study. 
A subject may voluntarily discontinue participation in this study at any time. The 
investigator also have the right to withdraw patients from treatment or the study in the 
event of intercurrent illness, adverse events, protocol violations, administrative reasons or 
other reasons at any time. Any female subject who becomes pregnant while participating 
should withdraw from the study. The reason for withdrawal from the study must be 
recorded in the case report form (CRF).  
Subjects will also be withdrawn from the study if they reached primary 
end-point. These subjects will be eligible for study drugs and 
originally scheduled follow-up.  
Subjects who have received at least one dose of study drug and permanently 
discontinued the study drug should be followed up by the investigator as 
described in Table 1. 
4.5. 
Screening/Run-in Failures 
If a blood sample has been collected and it is determined that the subject does not meet 
the inclusion and exclusion criteria for participation in the study, then the investigator 
must withdraw those subjects and complete the appropriate documentation to request 
sample destruction within the timeframe specified by GSK. 
5. 
STUDY TREATMENTS 
5.1. 
Investigational Product and Other Study Treatment 
Tenofovir disoproxil fumarate (9-[(R)-2-[[bis[[(isopropoxy-carbonyl) oxy] methoxy] 
phosphinyl] methoxy] propyl] adenine fumarate (1:1)); GS4331-05) is an oral pro-drug 
(bisPOC-PMPA) of tenofovir (PMPA), an acyclic nucleoside phosphonate (nucleotide) 
analogue of adenosine 5’-monophosphate. Tenofovir disoproxil fumarate has 
demonstrated antiviral activity against HBV and HIV and is indicated for use in 
combination with other antiretroviral agents in the treatment of HIV infection.  
Tenofovir disoproxil fumarate tablets are white, almond-shaped, film-coated tablets 
containing 300 mg of TDF, debossed with “GSK” and “300” on one side of the tablet. 
Each tablet contains the following inactive ingredients: microcrystalline cellulose, lactose 
monohydrate, pregelatinised starch, croscarmellose sodium, and magnesium stearate. The 
tablets are film coated with Opadry II White 32K18425.  


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Study drugs (TDF) are packaged in white, high-density polyethylene bottles with a white 
child resistant cap. There are 30 tablets per bottle. Each bottle also contains silica gel 
canister(s) to protect the product from humidity and fibre packing to protect the product 
during handling and shipping. 
For subjects who experienced virological breakthrough or partial virological response 
will add another drug without cross resistant to Tenofovir including LAM (Heptodin, 
GlaxoSmithKline, 100mg QD), ETV (Baraclude, Bristol-Myers Squibb, 0.5mg QD) and 
LdT(Sebivo,Novartis,600mg QD).Investigator will make the decision for the drug 
selection. 
5.1.1. 
Handling and Storage of Investigational Product 
No preparation of investigational product is required at site. 
The contents of the label will be in accordance with all applicable regulatory 
requirements. 
Under normal conditions of handling and administration, investigational product is not 
expected to pose significant safety risks to site staff.    A Material Safety Data Sheet 
(MSDS) describing the occupational hazards and recommended handling precautions will 
be provided to site staff if required by local laws or will otherwise be available from GSK 
upon request. 
Investigational product must be stored in a secure area under the appropriate physical 
conditions for the product at lower than 25 C.  Access to and administration of the 
investigational product will be limited to the investigator and authorised site staff.  
Investigational product must be dispensed or administered only to subjects enrolled in the 
study and in accordance with the protocol. 
5.1.2. 
Dosage and Administration 
Subjects will be assigned to receive open-label TDF 300 mg treatments for 240 weeks in 
the study. Subjects will be instructed to take one pill once daily. Investigational product 
absorption is not affected by food intake so the tablets do not have to be taken with a 
meal. 
Subjects who receive add-on rescue treatment may take LAM 100 mg, ETV 0.5 mg or 
LdT 600 mg per day upon investigator’s decision in addition to TDF tablet. 
Subjects will be dispensed study drug at all visits except for the Week 240 or early study 
drug discontinuation visit. Subjects will be instructed to return unused study medication 
in the original container at each post-baseline study visit. The Investigator will be 
responsible for maintaining accurate records for all study drug and study drug bottles 
dispensed and returned. The inventory must be available for inspection by the study 
monitor. Study medication supplies, including partially used or empty bottles, must be 
accounted for and the dispensing logs must be verified by the study monitor prior to 
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If subjects develop renal insufficiency (defined by serum creatinine clearance) during 
study treatment, the following dose reduction criteria should be used when subjects have 
a serum creatinine clearance of <50 mL/minute: 
Calculated Creatinine Clearance (mL/minute)a 
Requiring 
Haemodialysis 
 50 
30–49 
10–29 
Tenofovir disoproxil 
fumarate 300 mg 
every 24 h 
Tenofovir disoproxil 
fumarate 300 mg 
every 48 h 
Tenofovir disoproxil 
fumarate 300 mg 
every 72 h 
Tenofovir disoproxil 
fumarate 300 mg 
every 7 days or after 
a total of 
approximately 12 h 
of dialysisb 
Lamivudine 100 mg 
every 24 h 
Lamivudine is prohibited in such patients. 
Entecavir 0.5 mg 
every 24 h 
Entecavir 0.5 mg 
every 48 h 
Entecavir 0.5 mg 
every 72 h 
Entecavir 0.5 mg 
every 5-7 days post-
haemodialysisc 
Telbivudine 600mg 
every 24 h 
Telbivudine 600mg 
every 48 h 
Telbivudine 600mg 
every 72 h 
Telbivudine 600mg 
every 96 h or after 
dialysisc 
a. Calculated using ideal (lean) body weight.  
b. Generally once weekly assuming three haemodialysis sessions a week of approximately 4 h duration. 
Medication should be administered following completion of dialysis. 
c. Medication should be administered following completion of dialysis. 
5.2. 
Treatment Assignment 
This is an open label, single arm study.  
5.3. 
Blinding 
N/A 
5.4. 
Product Accountability 
In accordance with local regulatory requirements, the investigator, designated site staff, 
or head of the medical institution (where applicable) must document the amount of 
investigational product dispensed and/or administered to study subjects, the amount 
returned by study subjects, and the amount received from and returned to GSK, when 
applicable.  Product accountability records must be maintained throughout the course of 
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5.5. 
Treatment Compliance 
The importance of compliance with the treatment regimen will be emphasised at each 
visit. 
The subject must be reminded to return all unused medication (including empty 
containers). The Investigator or designated study site personnel should count the number 
of tablets returned by the subject to establish the number of tablets used, and compare this 
to the number of tablets expected to be used for the period. A record of this reconciliation 
must be maintained using the accountability forms provided, and any issues of non-
compliance discussed with the subject. 
5.6. 
Concomitant Medications and Non-Drug Therapies 
 
5.6.1. 
Permitted Medications and Non-Drug Therapies 
All concomitant medication and the reason(s) for their use must be entered into the CRF. 
Effort should be made to give only medications which are clearly indicated for a specific 
medical reason. 
5.6.2. 
Prohibited Medications and Non-Drug Therapies 
No other investigational drugs, immunosuppressive therapy, immunomodulatory therapy 
(including IFN or thymosin ), systemic cytotoxic agents, chronic antiviral agents(e.g., 
LAM, adefovir, ETV, LdT, other medicinal products containing tenofovir, ganciclovir, 
famciclovir, FTC, DAPD, LFMAU, HBIg), agents containing glycyrrhizic acid(e.g., 
compound glycyrrhizin, compound ammonium glycyrhetate, diammonium 
glycyrrihizinate), agents containing bicyclol or bifendate will be permitted, unless 
defined in protocol . 
TDF should be avoided with concurrent or recent use of a nephrotoxic agent including 
but are not limited to cidofovir, acyclovir, valacyclovir, ganciclovir, valganciclovir, 
aminoglycosides (e.g., gentamicin), high-dose or multiple NSAIDs,,and herbal 
medications (e.g., tripterygium wilfordii,  leonuri and plant medicine containing 
aristolochic acid).  
Traditional Chinese medicines and other herbal medicines intended to improve/protect 
liver function are prohibited during the study and must be discontinued at the time of 
screening. Such medicines include, but are not restricted to, oxymatrine and agents 
containing schisandra. Medicines intended to improve liver fibrosis are prohibited during 
the study and must be discontinued at the time of screening. Such medicines include, but 
are not restricted to,Fuzheng Huayu Capsule. 
In the events mentioned in Section 6.3.1, medicines intended to improve/protect liver 
function will be allowed based on the Investigator’s judgement after consulting with the 
GlaxoSmithKline medical monitor. All concomitant medication and reasons for their use 


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must be entered into the CRF. However, agents containing bicyclol, bifendate or 
schisandra will not be permitted in any situation. 
5.7. 
Treatment after the End of the Study 
No post-study medication is provided as part of this protocol.  
Discontinuation of anti-HBV therapy, including VIREAD, may be associated with severe 
acute exacerbations of hepatitis and must only take place under careful supervision.  
The investigator is responsible for ensuring that consideration has been given to the post-
study care of the patient’s medical condition whether or not GSK is providing specific 
post study treatment. TDF study medication is commercially available in China. 
5.8. 
Treatment of Study Treatment Overdose 
If a subject in the study takes an overdose, whether intentional or otherwise, the subject 
will be referred to a hospital at the Investigator’s discretion. Management of such a 
subject should be symptomatic and supportive. In these circumstances it is the 
responsibility of the Investigator to obtain as much clinical data as possible, including 
blood samples for TDF or LAM/LdT/ETV assay, and to communicate this to 
GlaxoSmithKline. An SAE form must be completed if the overdose is associated with 
any signs or symptoms. For the purposes of this study, an overdose will be defined as any 
dose administration exceeded the recommended dose of TDF 300 mg, LAM 100mg, LdT 
600mg or ETV 0.5mg per day. 


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6. 
STUDY ASSESSMENTS AND PROCEDURES 
Table 1 
Time and Events Table 
Procedures 
Screening1 
( ≤ 4 weeks 
prior to 
dosing) 
Visit 1 
Baseline 
(Day 0) 
Visit 2 
First Year (Week)2 
Visit 3~6 
Second year 
(Week)2 
Visit 7~10 
third Year to Fourth year 
(Week)2 
Visit 11~18 
Last Year 
(Week) 2 
Visit 19-22 
Withdraw3 
(Week off 
treatment) 
12
±6
d 
24
±6
d 
36
±6
d 
4
8
±
6
d 
60
±6
d 
72
±6
d 
84
±6
d 
96
±6
d 
108
±6d 
120
±6d 
132
±6d 
144
±6d 
204
±6d 
216
±6d 
228
±6d 
240
±6d 
12 
156
±6d 
168
±6d 
180
±6d 
192
±6d 
Written informed consent 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Subject demography14 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history 
4 
5 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion criteria 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Concomitant medication6 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical examination7 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vital signs8 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Adverse events 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Serious adverse events 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Laboratory assessments 
 
 
 
Haematology 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Chemistry(Liver & Renal function, 
electrolyte(phosphate and calcium 
inclusive))  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy test9 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
HAV/HCV/HDVHEV/HIV / ANA 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
B-ultrasound15 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Fibroscan 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
AFP 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urinalysis16 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Prothrombin time and INR 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
HBV DNA10, 13 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
HBeAg/Anti-HBe 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
HBsAg/Anti-HBs 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Genotyping13,18 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Genotypic analysis13,17  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Investigational product 
 
 
 
Study drug dispensed and 
reconciliation of drug dupply11 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Liver biopsy12 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Serum and plasma storage 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
1 
All results to be obtained before baseline visit. 
2 
No more than 6 days before or 6 days after the date scheduled based on the time from baseline visit not from the previous visit. 
3 
In the event of early study drug discontinuation, the evaluation should be performed in 12 weeks after discontinuation of study treatment. 
4 
Medical history will include any acute and chronic medical conditions including prior surgery, information related to hepatitis B history, any current and prior HBV medications, and 
previous HBV-related procedures. 
5 
Update any new medical conditions and/or concomitant medications that have occurred since study screening. 
6 
Concomitant medications including traditional Chinese medicines and/or herbal remedies. 
7 
At screening, a complete physical examination will be performed. For all following indicated visits, a brief physical examination will be performed. 
8 
Including blood pressure, pulse, respiratory rate and temperature.  
9 
Urine pregnancy test will be performed at screening, baseline and every 3 months after dosing.  
10 HBV DNA will be tested using Roche COBAS Taqman HBV test(LLD 20 IU/mL). 
11 Each study visit: All study medication to be collected and reconciled. 


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12 Liver biopsy will be done in 100 subjects in sites at baseline and week 216. Liver biopsy can be done at screening (Visit 1) or at baseline (Visit 2), at the discretion of investigator. 
Liver biopsy slides within 6 months prior to baseline can be accepted as baseline evaluation.  
13 Tests will be performed at central lab  
14 Demographic data includes birth date, gender and race 
15 B ultrasound examination include liver, pancreas, spleen, gall bladder and kidney 
16 Urinalysis: urine glucose, ketones, specific gravity, blood, pH and protein 
17 Serum will be colleted as scheduled for potential resistance surveillance. Genotypic analysis will be performed under the condition defined in protocol (see section 6.2.8) 
18 Genotyping will be performed at central lab at screen


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6.1. 
Critical Baseline Assessments 
Prior to dispensing study medication on Day 1, the procedures listed in Table 1 must be 
performed and documented in the CRF. 
The first dose of study medication will be administered at this visit, after all the study 
procedures have been completed. Subjects can be discharged immediately after dosing. 
6.2. 
Efficacy 
Samples for efficacy analysis will be collected at times outlined in Table 1. Collection 
and processing procedures for each type of sample will be detailed in the SPM. 
6.2.1. 
Serum/Plasma Storage 
Serum and plasma will be stored at the central laboratory and frozen at or below -20°C to 
allow possible evaluation of changes in laboratory markers of HBV infection (including 
resistance testing) observed during the course of the study. 
6.2.2. 
Primary Endpoint 
To determine the incidence of newly diagnosed HCC (from week 24 to week 240), the 
subject must meet one of the following criteria: 
 A histological diagnosis of HCC (i.e. by biopsy or at post-mortem) 
 In patients with nodules >2 cm, identification of typical  HCC 
characteristics (hypervascular in the arterial phase with washout in the 
portal venous or delayed phases) by  4-phase multidetector CT scan or 
dynamic contrast-enhanced MRI 
 In patients with nodules > 1 cm, , identification of typical  HCC 
characteristics by both techniques (4-phase multidetector CT and dynamic 
contrast-enhanced MRI )  
6.2.3. 
Clinical Endpoint 
The cumulative incidence of disease progression during the study timepoints will be 
defined as the first occurrence of any one of the following criteria: 
 
an increase in Childs-Pugh score (as defined in section 11.1 Appendix 1) of 2 or 
more points from baseline.  
 
An increase in Childs-Pugh score of 2 or more points, solely based on laboratory 
parameters (i.e. bilirubin, prothrombin time and/or albumin),  confirmed at two 
consecutive visits at least one month apart; 
 
spontaneous bacterial peritonitis (with proven sepsis); 


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 
renal insufficiency defined as a decrease in creatinine clearance to ≤50 
mL/minute confirmed on two occasions at least one week apart (calculated from 
serum creatinine concentration); 
 
bleeding gastric/oesophageal varices; 
 
hepatocellular carcinoma; 
 
liver-related death 
6.2.4. 
Virological Endpoint 
To evaluate the proportion of subjects with HBV DNA< 20 IU/mL and viral load change 
over time, HBV DNA level will be quantified using the Roche COBAS Taqman HBV 
test(LLD 20IU/mL) at times outlined in Table 1. 
6.2.5. 
Biochemical Endpoint 
To evaluate the biochemical response, ALT will be measured at times outlined in Table 1. 
6.2.6. 
Serological Endpoint 
To evaluate the serological response, HBeAg/anti-HBe and HBsAg/anti-HBs will be 
measured at times outlined in Table 1. 
6.2.7. 
Liver fibrosis endpoint 
Liver fibrosis will be assessed using non-invasive FibroScan in all study subjects, and by 
formal liver biopsy in a subset of study subjects. 
To assess liver fibrosis changes non-invasively a liver stiffness measure (LSM) will be 
obtained for all patients by transient elastography using FibroScan (EchoSens) at times 
outlined in Table 1.  
. The LSM result will be expressed as a median value of the total measurements in 
kiloPascal (kPa). Only subject examinations with at least 10 validated measurements,  a 
success rate of at least 60%, and an interquartile range (IQR) of all validated 
measurements of less than 30% will be considered a reliable LSM measure. Mean 
changes of LSM at Week 48, Week 96, Week 144, Week 192 and Week 240 will be 
reported. 
To evaluate the proportion of subjects who experience an improvement in histology at 
Week 216 a subset of study subjects (approximately 100 subjects) will undergo liver 
biopsies at times outlined in Table 1. 
A single central pathologist will evaluate all baseline and final biopsy slides in a 
pairedfashion and blinded to timing of biopsy. The baseline and end of treatment biopsies 
will be read at the same time. (See Appendix 3) 


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6.2.8. 
Resistance Surveillance 
To evaluate the resistance (if identified) rate,  genotypic analysis of the HBV polymerase 
gene will be performed on storage serum at times outlined in Table 1 using a central 
laboratory in the following situations:  
 
Subjects with HBV DNA ≥20 IU/mL at their last visit. (i.e. week 240 or last 
visit before withdrawl) 
 
Subjects with virological breakthrough, defined as HBV DNA level increase ≥1 
log10 IU/mL above the treatment nadir (confirmed on two consecutive visits at 
least 1 month apart). 
 
Subjects have HBV DNA ≥200IU/ml at week 48 and afterwards have ≤ one log 
decrease in HBV DNA at two consecutive visits, confirmed by a third visit at 
least one month apart. 
6.3. 
Safety 
6.3.1. 
On-Treatment ALT Flare, ALT Elevation With or Without Hepatic 
Dysfunction, and Post-Treatment Exacerbation of Hepatitis 
Management  
DEFINITIONS 
ALT FLARE 
ALT Both >2x baseline 
value and >10x ULN 
See Section 6.3.1.1 
ALT ELEVATION With 
HEPATIC DYSFUNCTION 
ALT Both >2x nadir value 
and >5xULN with evidence 
of worsened hepatic function 
(e.g. Direct 
Bilirubin >1.5mg/dL INR 
≥1.7, or abnormal serum 
albumin ≤2.7) 
See Section 6.3.1.1 
ALT ELEVATION ALONE 
ALT Both >2x nadir value 
and >5x ULN 
See Section 6.3.1.2 
6.3.1.1. 
Management of ALT Flare or ALT Elevation With Hepatic Dysfunction in 
Subjects Receiving Study Medication 
If laboratory results indicate ALT Flare or ALT Elevation With Hepatic Dysfunction 
the following is recommended: 
Schedule the subject to return to the clinic as soon as possible (ideally within 3 days after 
initial laboratory results were drawn). During the visit, a clinical assessment of the 
subject will be performed. The assessment should include a physical examination and 
evaluation of the subject’s mental status. 


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Check the following laboratory parameters: serum ALT and AST, alkaline phosphatase, 
total and direct bilirubin, INR, and serum albumin. 
If the ALT Flare or ALT Elevation With Hepatic Dysfunction is confirmed, request 
the clinical laboratory to conduct reflex testing for plasma HBV DNA, serology for HBV 
(HBsAg, HBeAg, HBeAb, and HBsAb), HDV, HAV IgM, HCV, and HEV 
Based on the results of the confirmatory tests, the following treatment modifications are 
recommended: 
Evidence of worsening HBV infection: 
 If Plasma HBV DNA is increasing (≥1 log increase), the investigator should discuss 
initiation of additional therapy with the medical monitor. 
In the absence of evidence of worsening HBV infection: 
 If ALT levels are elevated (+/- direct bilirubin/INR/albumin) as above, the subject 
may remain on study medication and should be monitored with ALT and AST, 
alkaline phosphatase, total and direct bilirubin, INR, and serum albumin at least 
weekly until laboratory abnormalities return to baseline level. 
 During monitoring, if the ALT values (+/- direct bilirubin/INR/albumin) are 
worsening or remain persistently abnormal or elevated after 4weeks, the Investigator 
should discuss with the Medical Monitor regarding the monitoring schedule and 
whether the study drug should be discontinued. 
For subjects with bridging fibrosis or cirrhosis, study drug discontinuation with 
treatment-free follow-up is to be avoided due to the potential risk of exacerbation of 
hepatitis in the setting of low hepatic reserve which could lead to decompensation. 
Subjects with bridging fibrosis or cirrhosis should be placed on commercially available 
HBV therapy following study drug discontinuation. 
Subjects should be followed until laboratory parameters return to baseline up to a 
maximum of 6 months after the initial occurrence of the event. 
 
6.3.1.2. 
 Increased monitoring for On-Treatment ALT Elevation Alone 
 In patients with confirmed ALT Elevation Alone (both >2x nadir and also >5xULN) 
but have not reached ALT Flare (Both ALT >2x baseline value and >10x ULN) and 
do not have evidence of worsened hepatic function (e.g. Direct Bilirubin >1.5mg/dL 
INR ≥1.7, or abnormal serum albumin <=2.7) the subject may remain on study 
medication and should be monitored weekly until ALT levels return to baseline level. 
During monitoring, if after 4 weeks the ALT values remain stable but persistently 
abnormal, the Investigator should discuss with the Medical Monitor regarding the 
monitoring schedule. 


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If patients worsen to reach ALT Flare definition or ALT Elevation with  hepatic 
dysfunction,manage as above in Section 6.3.1.1. 
Subjects should be followed until laboratory parameters return to baseline up to a 
maximum of 6 months after the initial occurrence of the event. 
6.3.1.3. 
Management of Exacerbation of Hepatitis in Subjects who have 
Discontinued Study Medication 
If laboratory results indicate ALT Flare or ALT Elevation With Hepatic Dysfunction 
and the subject is on no post-study therapy for HBV, the following is recommended: 
 Schedule the subject to return to the clinic as soon as possible (ideally no later than 3 
days after the initial laboratory values were drawn). During the visit, perform a 
clinical assessment of the subject. 
 Check the following laboratory parameters: serum ALT and AST, alkaline 
phosphatase, total and direct bilirubin, INR, and albumin. 
 If the ALT Flare or ALT Elevation With Hepatic Dysfunction is confirmed, 
request the clinical laboratory to conduct reflex testing for plasma HBV DNA, 
serology for HBV (HBsAg, HBeAg, HBeAb, and HBsAb), HDV, HAV IgM and 
HCV. If Plasma HBV DNA is increasing (≥1 log increase), the investigator should 
consider immediate initiation of approved therapy. 
 Subjects should be followed until laboratory parameters return to baseline up to a 
maximum of 6 months after the initial occurrence of the event. 
Please refer to Appendix 4: Lactic Acidosis Guidelines for the recommend 
method for managing lactic acidosis. 
6.3.2. 
Serum Creatinine Elevation 
Serum creatinine values  0.5 mg/dL above baseline should be confirmed by repeat 
testing within 3 calendar days of receipt of results.  
For serum creatinine elevations  0.5 mg/dL above baseline, subjects may continue all 
study medication, but it is recommended that subjects be monitored weekly until the 
serum creatinine returns to the original baseline value or 0.3 mg/dL from baseline. 
All study drugs should be permanently discontinued in the event that repeat testing of 
serum creatinine confirms >2.5 mg/dL. The subject should be followed weekly until the 
serum creatinine reaches within 0.3 mg/dL of the baseline value. 
6.3.3. 
Adverse Events 
The investigator or site staff will be responsible for detecting, documenting and reporting 
events that meet the definition of an AE or SAE. 


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6.3.3.1. 
Definition of an AE 
Any untoward medical occurrence in a patient or clinical investigation subject, 
temporally associated with the use of a medicinal product, whether or not considered 
related to the medicinal product. Any noxious or unintended response to a medicinal 
product related to any dose should be considered an adverse drug reaction (ADR). 
Note: An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally 
associated with the use of a medicinal product.   
Events meeting the definition of an AE include: 
 
Exacerbation of a chronic or intermittent pre-existing condition including either an 
increase in frequency and/or intensity of the condition 
 
New conditions detected or diagnosed after study treatment administration even 
though it may have been present prior to the start of the study 
 
Signs, symptoms, or the clinical sequelae of a suspected interaction 
 
Signs, symptoms, or the clinical sequelae of a suspected overdose of either study 
treatment or a concomitant medication (overdose per se will not be reported as an 
AE/SAE) unless this is an intentional overdose taken with possible suicidal/self-
harming intent.  This should be reported regardless of sequelae. 
“Lack of efficacy” or “failure of expected pharmacological action” per se will not be 
reported as an AE or SAE. However, the signs and symptoms and/or clinical sequelae 
resulting from lack of efficacy will be reported if they fulfil the definition of an AE or 
SAE.   
The signs and symptoms and/or clinical sequelae resulting from lack of efficacy will be 
reported if they fulfill the definition of an AE or SAE.  Also, “lack of efficacy” or 
“failure of expected pharmacological action” also constitutes an AE or SAE. 
Events that do not meet the definition of an AE include: 
 
Medical or surgical procedure (e.g., endoscopy, appendectomy); the condition that 
leads to the procedure is an AE 
 
Situations where an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital) 
 
Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present 
or detected at the start of the study that do not worsen 
 
The disease/disorder being studied, or expected progression, signs, or symptoms of 
the disease/disorder being studied, unless more severe than expected for the subject’s 
condition 


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6.3.3.2. 
Definition of an SAE 
A serious adverse event is any untoward medical occurrence that, at any dose: 
a. 
Results in death 
b. Is life-threatening 
NOTE:  The term 'life-threatening' in the definition of 'serious' refers to an event in 
which the subject was at risk of death at the time of the event.  It does not refer to an 
event, which hypothetically might have caused death, if it were more severe. 
c. 
Requires hospitalisation or prolongation of existing hospitalisation 
NOTE:  In general, hospitalisation 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 out-patient setting.  Complications that occur during hospitalisation are 
AEs.  If a complication prolongs hospitalisation or fulfills any other serious criteria, 
the event is serious.  When in doubt as to whether “hospitalisation” occurred or was 
necessary, the AE should be considered serious. 
Hospitalisation for elective treatment of a pre-existing condition that did not worsen 
from baseline is not considered an AE. 
d. Results in disability/incapacity, or 
NOTE:  The term disability means a substantial disruption of a person’s ability to 
conduct normal life functions.  This definition is not intended to include experiences 
of relatively minor medical significance such as uncomplicated headache, nausea, 
vomiting, diarrhea, influenza, and accidental trauma (e.g. sprained ankle) which may 
interfere or prevent everyday life functions but do not constitute a substantial 
disruption. 
e. 
Is a congenital anomaly/birth defect 
f. 
Medical or scientific judgment should be exercised in deciding whether reporting is 
appropriate in other situations, such as important medical events that may not be 
immediately life-threatening or result in death or hospitalisation but may jeopardise 
the subject or may require medical or surgical intervention to prevent one of the 
other outcomes listed in the above definition.  These should also be considered 
serious.  Examples of such events are invasive or malignant cancers, intensive 
treatment in an emergency room or at home for allergic bronchospasm, blood 
dyscrasias or convulsions that do not result in hospitalisation, or development of 
drug dependency or drug abuse. 
g. All events of possible drug-induced liver injury with hyperbilirubinaemia defined as 
ALT  3xULN and bilirubin  2xULN (>35% direct) (or ALT  3xULN and 
INR>1.5, if INR measured) termed ‘Hy’s Law’ events (INR measurement is not 
required and the threshold value stated will not apply to patients receiving 
anticoagulants). 
NOTE: bilirubin fractionation is performed if testing is available. If testing is 
unavailable, record presence of detectable urinary bilirubin on dipstick indicating 


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direct bilirubin elevations and suggesting liver injury. If testing is unavailable and a 
subject meets the criterion of total bilirubin  2xULN, then the event is still reported 
as an SAE. If INR is obtained, include values on the SAE form. INR elevations >1.5 
suggest severe liver injury.    
6.3.3.3. 
Sentinel Events 
A Sentinel Event is a GSK-defined SAE that is not necessarily drug-related but has been 
associated historically with adverse reactions for other drugs and is therefore worthy of 
heightened pharmacovigilance. Medical monitor review of all SAEs for possible Sentinel 
Events is mandated at GSK.  The GSK medical monitor may request additional clinical 
information on an urgent basis if a possible Sentinel Event is identified on SAE review. 
The current GSK-defined Sentinel Events are listed below: 
 
Acquired Long QT Syndrome 
 
Agranulocytosis/Severe Neutropenia  
 
Anaphylaxis & Anaphylactoid Reactions  
 
Hepatotoxicity 
 
Acute Renal Failure 
 
Seizure 
 
Stevens Johnson syndrome/Toxic epidermal necrosis 
6.3.4. 
Cardiovascular Events 
Investigators will be required to fill out event specific data collection tools for the 
following AEs and SAEs:   
 
Myocardial infarction/unstable angina 
 
Congestive heart failure 
 
Arrhythmias 
 
Valvulopathy 
 
Pulmonary hypertension 
 
Cerebrovascular events/stroke and transient ischemic attack 
 
Peripheral arterial thromboembolism 
 
Deep venous thrombosis/pulmonary embolism 
 
Revascularisation 
6.3.5. 
Death Events 
In addition, all deaths will require a specific death data collection tool to be completed.  
The death data collection tool includes questions regarding cardiovascular (including 
sudden cardiac death) and noncardiovascular death. 


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This information should be recorded in the specific death eCRF within one week of when 
the death is first reported. 
6.3.6. 
Laboratory and Other Safety Assessment Abnormalities 
Reported as AEs and SAEs 
Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) or 
other safety assessments (e.g., ECGs, radiological scans, vital signs measurements), 
including those that worsen from baseline, and felt to be clinically significant in the 
medical and scientific judgement of the investigator are to be recorded as AEs or SAEs. 
However, any clinically significant safety assessments that are associated with the 
underlying disease, unless judged by the investigator to be more severe than expected for 
the subject’s condition, are not to be reported as AEs or SAEs. 
6.3.7. 
Pregnancy 
Any pregnancy that occurs during study participation must be reported using a clinical 
trial pregnancy form.  To ensure subject safety, each pregnancy must be reported to GSK 
within 2 weeks of learning of its occurrence.  The pregnancy must be followed up to 
determine outcome (including premature termination) and status of mother and child.  
Pregnancy complications and elective terminations for medical reasons must be reported 
as an AE or SAE.  Spontaneous abortions must be reported as an SAE. 
Any SAE occurring in association with a pregnancy brought to the investigator’s 
attention after the subject has completed the study and considered by the investigator as 
possibly related to the study treatment, must be promptly reported to GSK. 
In addition, the investigator must attempt to collect pregnancy information on any female 
partners of male study subjects who become pregnant while the subject is enrolled in the 
study.  Pregnancy information must be reported to GSK as described above. 
6.3.8. 
Time Period and Frequency of Detecting AEs and SAEs 
The investigator or site staff is responsible for detecting, documenting and reporting 
events that meet the definition of an AE or SAE. 
AEs will be collected from the start of study treatment and until the follow up contact.   
SAEs will be collected over the same time period as stated above for AEs. However, any 
SAEs assessed as related to study participation (e.g., study treatment, protocol-mandated 
procedures, invasive tests, or change in existing therapy) or related to a GSK concomitant 
medication, will be recorded from the time a subject consents to participate in the study 
up to and including any follow up contact. All SAEs will be reported to GSK within 24 
hours, as indicated in Section 6.3.9.  


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6.3.9. 
Method of Detecting AEs and SAEs 
Care must be taken not to introduce bias when detecting AEs and/or SAEs. Open-ended 
and non-leading verbal questioning of the subject is the preferred method to inquire about 
AE occurrence. Appropriate questions include: 
“How are you feeling?” or for paediatric studies, “How does your child seem to feel?” 
“Have you had any (other) medical problems since your last visit/contact?” or for 
paediatric studies, “Has your child had any (other) medical problems or seem to act 
differently in any way since his/her last visit/contact?” 
“Have you taken any new medicines, other than those provided in this study, since your 
last visit/contact?” or for paediatric studies, ”Has your child needed to take any 
medicines, other than those provided in this study, since his/her last visit/contact?” 
6.3.10. 
Prompt Reporting of Serious Adverse Events and Other Events 
to GSK 
SAEs, pregnancies, medical device incidents, and liver function abnormalities meeting 
pre-defined criteria will be reported promptly by the investigator to GSK as described in 
the following table once the investigator determines that the event meets the protocol 
definition for that event. 
 
Initial Reports 
Follow-up Information on a Previous 
Report 
Type of Event 
Time Frame 
Documents 
Time Frame 
Documents 
All SAEs 
24 hours 
“SAE” data 
collection tool 
 
24 hours 
Updated “SAE” 
data collection tool 
 
Pregnancy 
2 weeks 
“Pregnancy 
Notification Form” 
2 weeks 
“Pregnancy Follow-
up Form” 
ADR(Adverse Drug 
Reaction) 
5 days 
ADR form 
5 days 
ADR form 
 
 
The method of recording, evaluating and follow-up of AEs and SAEs plus procedures for 
completing and transmitting SAE reports to GSK are provided in the SPM.  Procedures 
for post-study AEs/SAEs are provided in the SPM. 
Procedures for documenting, transmitting and follow-up of medical device incidents 
along with the regulatory reporting requirements for medical devices are provided in the 
SPM. 
6.3.10.1. 
Regulatory Reporting Requirements for SAEs 
Prompt notification of SAEs by the investigator to GSK is essential so that legal 
obligations and ethical responsibilities towards the safety of subjects are met. 


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GSK has a legal responsibility to notify both the local regulatory authority and other 
regulatory agencies about the safety of a product under clinical investigation.  GSK will 
comply with country specific regulatory requirements relating to safety reporting to the 
regulatory authority, Institutional Review Board (IRB)/Independent Ethics Committee 
(IEC) and investigators. 
Investigator safety reports are prepared for suspected unexpected serious adverse 
reactions according to local regulatory requirements and GSK policy and are forwarded 
to investigators as necessary. 
An investigator who receives an investigator safety report describing a SAE(s) or other 
specific safety information (e.g., summary or listing of SAEs) from GSK will file it with 
the IB and will notify the IRB/IEC, if appropriate according to local requirements. 
Prompt notification of SAEs and non-serious AEs related to study treatment, by the 
investigator to GSK is essential so that legal obligations and ethical responsibilities 
towards the safety of subjects are met. 
6.3.11. 
Other Safety Outcome  
Protocol required laboratory assessments, as defined in Table 1, must be performed by 
the central laboratory, [Peking University Hepatology Institute].  Laboratory assessments 
must be conducted in accordance with the Central Laboratory Manual and Protocol Time 
and Events Schedule.  Laboratory requisition forms must be completed and samples must 
be clearly labelled with the subject number, protocol number, site/centre number, and 
visit date.  Details for the preparation and shipment of samples will be provided by 
[Peking University Hepatology Institute].  Reference ranges for all safety parameters will 
be provided to the site by [Peking University Hepatology Institute]. 
If additional non-protocol specified laboratory assessments are performed at the 
institution’s local laboratory and result in a change in patient management or are 
considered clinically significant by the investigator (e.g., SAE or AE or dose 
modification) the results must be recorded in the subject’s CRF.  Refer to the SPM for 
appropriate processing and handling of samples to avoid duplicate and/or additional 
blood draws.  
6.4. 
Viral Genotyping and Phenotyping 
HBV genotyping will be performed in central lab at screening. 
7. 
DATA MANAGEMENT 
For this study (1-eDM) subject data will be entered into GSK defined electronic case 
report forms (eCRFs), transmitted electronically to GSK or designee and combined with 
data provided from other sources in a validated data system.   
Management of clinical data will be performed in accordance with applicable GSK 
standards and data cleaning procedures to ensure the integrity of the data, e.g., removing 
errors and inconsistencies in the data.  Adverse events and concomitant medications 


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terms will be coded using MedDRA and an internal validated medication dictionary, 
GSKDrug.  In all cases, subject initials will not be collected or transmitted to GSK 
according to GSK policy. 
8. 
DATA ANALYSIS AND STATISTICAL CONSIDERATIONS 
8.1. 
Hypotheses 
No hypotheses applicated. 
8.2. 
Study Design Considerations 
8.2.1. 
Sample Size Assumptions 
Sample sizes are chosen based on feasibility and precision because no hypothesis is 
tested in this study. 
The primary endpoint is the cumulative incidence of newly diagnosed as HCC in 
treatment group from Week 24 to Week 240. 
To decide the number of subjects for analysis, some precision calculations have been 
performed. In the retrospective analysis of GS-US-174-0102 and GS-US-174-0103 trials, 
HCC incidence over 7 years was approximately 4.5% among patients (23% of whom 
were Asian, 25 of whom were genotype B or C) with cirrhosis at baseline. Accordingly, 
we hypothesize that the accumulative incidence of HCC at 240 weeks will be 5% in 
Chinese compensated cirrhotic patients treated with TDF. A sample size of 158 patients 
will allow us to estimate the confidence interval of the incidence with a margin of error at 
3.4%( 0.016-0.084) Assuming a 15% drop out rate, 186 patients are to be recruited. 
• 
Sample size formula:           
  
  
 
 
The main analyses will be performed on mdodified intent-to-treat (mITT) basis, including 
all patients who are assigned to treatment and received study medication. All endpoint 
analyses will use a last observation carried forward (LOCF) approach; that is, the last 
available visit is used as the end point. Changes from baseline to endpoint (LOCF) will 
be analyzed by Wilcoxon signed-rank test.  
8.2.2. 
Sample Size Sensitivity 
The sample size estimates are dependent upon the assumed incidence. If the actual 
treatment difference is around 5%, then the current planned sample size will provide 
adequate power. If the actual treatment difference is smaller than 5%, the actual power 
could be much lower. 
Table 2 
Sample Size Sensitivity Table 
P 
1-p 
Width (half CI) 
N 
5% 
0.95 
0.04 
115 


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5% 
0.95 
0.034 
158 
5% 
0.95 
0.033 
168 
5% 
0.95 
0.032 
179 
5% 
0.95 
0.03 
203 
5% 
0.95 
0.02 
457 
 
8.2.3. 
Sample Size Re-estimation 
No sample size re-estimation is planned. 
8.3. 
Data Analysis Considerations 
8.3.1. 
Analysis Populations 
Three populations will be used in the analysis: 
 Mdodified Intent to Treat (mITT) Population 
The mITT population is defined as all randomised subjects who receive at least one dose 
of study medication.  
 
 Per Protocol (PP) population 
The PP population will consist of subjects in the mITT population with the exception of 
major protocol violators. Details on the definitions of major protocol violators will be 
included in the reporting and analysis plan (RAP).  
 Safety Analysis (SA) population 
The SA population is defined as all subjects who receive at least one dose of study 
medication and have at least one post baseline safety assessment.  
 
All efficacy endpoints will be analysed using the mITT and PP population according to 
the treatment groups to which they were randomised. As this is a superiority study, the 
mITT population is the most conservative approach to statistical analysis; hence, the 
mITT population is of primary interest.  
 
All safety endpoints will be analysed using the SA population according to the actual 
treatment they received.  
8.3.2. 
Analysis Data Sets 
For information on the analysis data sets please refer to the RAP. 
8.3.3. 
Treatment Comparisons 
8.3.3.1. 
Primary Comparisons of Interest 
This is a single-arm cohort study to observe HCC incidence in patients with HBV related 
advanced fibrosis and cirrhosis under TDF treatment. No comparisons are planned. 


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8.3.3.2. 
Other Comparisons of Interest 
No comparisons are planned. 
8.3.4. 
Interim Analysis 
No interim analysis is planned for this study. 
8.3.5. 
Key Elements of Analysis Plan 
Missing data can have an impact upon the interpretation of the trial data. In general, 
values for missing data will not be imputed. 
For the primary analysis of HCC incidence at Week 240, data from non-completers will 
use the last available visit as the end point. 
All serum HBV DNA results below the lower limit of detection will be analysed as being 
the value of the lower limit of detection. 
8.3.5.1. 
Efficacy Analyses 
In this study, data will be summarised as mean, medium, standard deviation, maximum, 
and minimum for continuous variables, and in tables of frequencies and percentages for 
categorical variables. 
 
The primary outcomes of this study were the 5-year cumulative incidence rates of HCC, 
calculated by the Kaplan–Meier method.  
Univariate and multivariable analysis by Cox proportional hazards regression model was 
performed to identify factors associated with HCC. Variables may include serum albumin, 
total bilirubin, and ALT levels, HBeAg status, serum HBV DNA titter and response to 
treatment, etc. Effect sizes are expressed as hazard ratios (HRs) and 95% confidence 
intervals (CIs).  
 
The detail of primary, secondary and other efficacy endpoint analysis will be included in 
the RAP. 
8.3.5.2. 
Safety Analyses 
Clinical safety observations will include: extent of exposure information, AEs, deaths, 
laboratory abnormalities and withdrawals from study. The safety data will be tabulated 
and, where appropriate, a Fisher’s exact test comparing treatment groups will be run.  
Extent of exposure to study drug data will be generated from the study drug 
administration page of CRF. Exposure data will be summarised by treatment group. 
Adverse events will be assigned preferred terms and categorized into body systems 
according to the MedDRA classification of the World Health Organisation terminology. 
The proportion of subjects who experienced AEs will be calculated by dividing the 
number of subjects who experienced the AE during the treatment period by the number of 


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subjects evaluable for safety analysis. Adverse events will be summarised by treatment 
group, and by body system and event within each body system. The following summaries 
of AEs will be provided: 
 
All AEs. 
 
All treatment related AEs. 
 
All SAEs. 
 
All treatment related SAEs. 
 
All AEs leading to permanent discontinuation of study drug. 
 
All AEs leading to permanent discontinuation from the study. 
All AEs that caused a change in dose or temporary interruption of study drug. 
8.3.5.3. 
Viral Genotyping/Phenotyping Analyses 
Viral genotyping of HBV will be performed and recorded at screening. Proportion of 
subjects infected with HBV genotype B/C will be analysed. 
9. 
STUDY CONDUCT CONSIDERATIONS 
9.1. 
Posting of Information on Publicly Available Clinical Trial 
Registers 
Study information from this protocol will be posted on publicly available clinical trial 
registers before enrolment of subjects begins. 
9.2. 
Regulatory and Ethical Considerations, Including the 
Informed Consent Process 
Prior to initiation of a study site, GSK will obtain favourable opinion/approval from the 
appropriate regulatory agency to conduct the study in accordance with ICH Good Clinical 
Practice (GCP) and applicable country-specific regulatory requirements. 
The study will be conducted in accordance with all applicable regulatory requirements. 
The study will be conducted in accordance with ICH GCP, all applicable subject privacy 
requirements, and the ethical principles that are outlined in the Declaration of Helsinki 
2008, including, but not limited to: 
Institutional Review Board (IRB)/Independent Ethics Committee (IEC) review and 
favourable opinion/approval of study protocol and any subsequent amendments. 
Subject informed consent. 
Investigator reporting requirements. 
GSK will provide full details of the above procedures, either verbally, in writing, or 
both. 


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Written informed consent must be obtained from each subject prior to participation in the 
study. 
In approving the clinical protocol the IEC/IRB and, where required, the applicable 
regulatory agency are also approving the optional assessments, unless otherwise 
indicated.  Where permitted by regulatory authorities, approval of the optional 
assessments can occur after approval is obtained for the rest of the study.  If so, then the 
written approval will clearly indicate approval of the optional assessments is being 
deferred and the study, except for the optional assessments, can be initiated.  When the 
optional assessments are not approved, then the approval for the rest of the study will 
clearly indicate this and therefore, the optional assessments will not be conducted. 
9.3. 
Quality Control (Study Monitoring) 
In accordance with applicable regulations, GCP, and GSK procedures, GSK monitors 
will contact the site prior to the start of the study to review with the site staff the protocol, 
study requirements, and their responsibilities to satisfy regulatory, ethical, and GSK 
requirements.  When reviewing data collection procedures, the discussion will include 
identification, agreement and documentation of data items for which the CRF will serve 
as the source document. 
GSK will monitor the study to ensure that the: 
 
Data are authentic, accurate, and complete. 
 
Safety and rights of subjects are being protected. 
 
Study is conducted in accordance with the currently approved protocol and any other 
study agreements, GCP, and all applicable regulatory requirements. 
The investigator and the head of the medical institution (where applicable) agrees to 
allow the monitor direct access to all relevant documents. 
9.4. 
Quality Assurance 
To ensure compliance with GCP and all applicable regulatory requirements, GSK may 
conduct a quality assurance assessment and/or audit of the site records, and the regulatory 
agencies may conduct a regulatory inspection at any time during or after completion of 
the study. In the event of an assessment, audit or inspection, the investigator (and 
institution) must agree to grant the advisor(s), auditor(s) and inspector(s) direct access to 
all relevant documents and to allocate their time and the time of their staff to discuss the 
conduct of the study, any findings/relevant issues and to implement any corrective and/or 
preventative actions to address any findings/issues identified. 
9.5. 
Study and Site Closure 
Upon completion or termination of the study, the GSK monitor will conduct site closure 
activities with the investigator or site staff (as appropriate), in accordance with applicable 
regulations, GCP, and GSK Standard Operating Procedures. 


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GSK reserves the right to temporarily suspend or terminate the study at any time for 
reasons including (but not limited to) safety issues, ethical issues, or severe non-
compliance.  If GSK determines that such action is required, GSK will discuss the 
reasons for taking such action with the investigator or head of the medical institution 
(where applicable).  When feasible, GSK will provide advance notice to the investigator 
or head of the medical institution of the impending action. 
If a study is suspended or terminated for safety reasons, GSK will promptly inform all 
investigators, heads of the medical institutions (where applicable),and/or institutions 
conducting the study.  GSK will also promptly inform the relevant regulatory authorities 
of the suspension/termination along with the reasons for such action.  Where required by 
applicable regulations, the investigator or head of the medical institution must inform the 
IRB/IEC promptly and provide the reason(s) for the suspension/termination. 
9.6. 
Records Retention 
Following closure of the study, the investigator or head of the medical institution (where 
applicable) must maintain all site study records (except for those required by local 
regulations to be maintained elsewhere) in a safe and secure location.  The records must 
be easily accessible when needed (e.g., for a GSK audit or regulatory inspection) and 
must be available for review in conjunction with assessment of the facility, supporting 
systems, and relevant site staff. 
Where permitted by local laws/regulations or institutional policy, some or all of the 
records may be maintained in a format other than hard copy (e.g., microfiche, scanned, 
electronic); however, caution must be exercised before such action is taken.  The 
investigator must ensure that all reproductions are legible and are a true and accurate 
copy of the original.  In addition, they must meet accessibility and retrieval standards, 
including regeneration of a hard copy, if required.  The investigator must also ensure that 
an acceptable back-up of the reproductions exists and that there is an acceptable quality 
control procedure in place for creating the reproductions. 
GSK will inform the investigator of the time period for retaining the site records in order 
to comply with all applicable regulatory requirements.  The minimum retention time will 
meet the strictest standard applicable to a particular site, as dictated by local 
laws/regulations, GSK standard operating procedures, and/or institutional requirements. 
The investigator must notify GSK of any changes in the archival arrangements, including, 
but not limited to archival of records at an off-site facility or transfer of ownership of the 
records in the event that the investigator is no longer associated with the site. 
9.7. 
Provision of Study Results to Investigators, Posting of 
Information on Publicly Available Clinical Trials Registers 
and Publication 
Where required by applicable regulatory requirements, an investigator signatory will be 
identified for the approval of the clinical study report.  The investigator will be provided 
reasonable access to statistical tables, figures, and relevant reports and will have the 


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opportunity to review the complete study results at a GSK site or other mutually-
agreeable location. 
GSK will also provide the investigator with the full summary of the study results.  The 
investigator is encouraged to share the summary results with the study subjects, as 
appropriate. 
GSK will provide the investigator with the randomisation codes for their site only after 
completion of the full statistical analysis. 
The results summary will be posted to the Clinical Study Register no later than eight 
months after the final primary completion date, the date that the final subject was 
examined or received an intervention for the purposes of final collection of data for the 
primary outcome.  In addition, a manuscript will be submitted to a peer reviewed journal 
for publication no later than 18 months after the last subject’s last visit (LSLV).  When 
manuscript publication in a peer reviewed journal is not feasible, a statement will be 
added to the register to explain the reason for not publishing. 
A manuscript will be progressed for publication in the scientific literature if the results 
provide important scientific or medical knowledge. 


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10. 
REFERENCES 
 Chen, Y.-C., Chu, C.-M., Yeh, C.-T., & Liaw, Y.-F. (2007). Natural course following the 
onset of cirrhosis in patients with chronic hepatitis B: a long-term follow-up study. 
Hepatology international, 1(1), 267–73. doi:10.1007/s12072-007-5001-0 
Chinese Society of Hepatology, & Chinese Society of Infectious Diseases. (2011). 
Guideline on the prevention and treatment of chronic hepatitis B. Chin J Hepatol, 
19(1), 13–24. 
Di Marco, V., Marzano, A., Lampertico, P., Andreone, P., Santantonio, T., Almasio, P. 
L., … Craxì, A. (2004). Clinical outcome of HBeAg-negative chronic hepatitis B in 
relation to virological response to lamivudine. Hepatology (Baltimore, Md.), 40(4), 
883–91. doi:10.1002/hep.20381 
Eun, J. R., Lee, H. J., Kim, T. N., & Lee, K. S. (2010). Risk assessment for the 
development of hepatocellular carcinoma: according to on-treatment viral response 
during long-term lamivudine therapy in hepatitis B virus-related liver disease. 
Journal of hepatology, 53(1), 118–25. doi:10.1016/j.jhep.2010.02.026 
Hosaka, T., Suzuki, F., Kobayashi, M., Seko, Y., Kawamura, Y., Sezaki, H., … Kumada, 
H. (2013). Long-term entecavir treatment reduces hepatocellular carcinoma 
incidence in patients with hepatitis B virus infection. Hepatology (Baltimore, Md.), 
58(1), 98–107. doi:10.1002/hep.26180 
Kitrinos, K. M., Corsa, A., Liu, Y., Flaherty, J., Lampart, A. S., Marcellin, P., … Miller, 
M. D. (2013). No detectable resistance to tenofovir disoproxil fumarate after 6 years 
of therapy in patients with chronic hepatitis B. Hepatology (Baltimore, Md.). 
doi:10.1002/hep.26686 
Lai, C.-L., & Yuen, M.-F. (2013). Prevention of hepatitis B virus-related hepatocellular 
carcinoma with antiviral therapy. Hepatology (Baltimore, Md.), 57(1), 399–408. 
doi:10.1002/hep.25937 
Liaw, Y.-F., Kao, J.-H., Piratvisuth, T., Chan, H. L. Y., Chien, R.-N., Liu, C.-J., … 
Omata, M. (2012). Asian-Pacific consensus statement on the management of chronic 
hepatitis B: a 2012 update. Hepatology International, 6(3), 531–561. 
doi:10.1007/s12072-012-9365-4 
Liaw, Y.-F., Sung, J. J. Y., Chow, W. C., Farrell, G., Lee, C.-Z., Yuen, H., … Sabbat, J. 
(2004). Lamivudine for patients with chronic hepatitis B and advanced liver disease. 
The New England journal of medicine, 351(15), 1521–31. 
doi:10.1056/NEJMoa033364 
Marcellin, P., Gane, E., Buti, M., Afdhal, N., Sievert, W., Jacobson, I. M., … Heathcote, 
E. J. (2013). Regression of cirrhosis during treatment with tenofovir disoproxil 


2013N184338_00 
CONFIDENTIAL 
201213 
 
 
 
Version: 3.0/27-March-2016 
50 
 
fumarate for chronic hepatitis B: a 5-year open-label follow-up study. Lancet, 
381(9865), 468–75. doi:10.1016/S0140-6736(12)61425-1 
Marcellin, P., Heathcote, E. J., Buti, M., Gane, E., de Man, R. a, Krastev, Z., … 
Rousseau, F. (2008). Tenofovir disoproxil fumarate versus adefovir dipivoxil for 
chronic hepatitis B. The New England journal of medicine, 359(23), 2442–55. 
doi:10.1056/NEJMoa0802878 
Nguyen, V. T. T., Law, M. G., & Dore, G. J. (2009). Hepatitis B-related hepatocellular 
carcinoma: epidemiological characteristics and disease burden. Journal of viral 
hepatitis, 16(7), 453–63. doi:10.1111/j.1365-2893.2009.01117.x 
Papatheodoridis, G. V, Dalekos, G. N., & Yurday-, C. (2013). Risk and risk factors of 
hepatocellular carcinoma ( HCC ) in Caucasian chronic hepatitis B ( CHB ) patients 
with or without cirrhosis treated with entecavir ( ETV ) or teno- fovir ( TDF ). 
Hepatology (Baltimore, Md.), 58(Suppl), 302A. 
Review Panel for Liver Stiffness Measurement. (2013). Recommendations for the clinical 
application of transient elastography in liver fibrosis assessment. Zhonghua Gan 
Zang Bing Za Zhi, 21(6), 420–424. doi:10.3760/cma.j.10.3760/cma.j.issn.1007-
3418.2013.06.009 
Wong, G. L.-H., Chan, H. L.-Y., Chan, H.-Y., Tse, P. C.-H., Tse, Y.-K., Mak, C. W.-
H., … Wong, V. W.-S. (2013). Accuracy of risk scores for patients with chronic 
hepatitis B receiving entecavir treatment. Gastroenterology, 144(5), 933–44. 
doi:10.1053/j.gastro.2013.02.002 
Zhang, Y., Zhang, H., Elizabeth, A., & Liu, X. (2012). Epidemiology of Hepatitis B and 
Associated Liver Diseases in China. Chinese Medical Sciences Journal, 27(4), 243–
248. doi:10.1016/S1001-9294(13)60009-7 
 


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11.2. 
Appendix 2: Estimated creatinine clearance rate (CLcr)  
Formula and Estimated Glomerular Filtration Rate (GFR) 
Equation 
         CLcr using Cockcroft-Gault (CG) formula： 
CLcr=[(140-Age)×Ideal Body Weight(kg)]/[72×Scr(mg/dL)] 
Scr=Serum Creatinine in mg/dL；for female Multiplied by the coefficient of 0.85 
Note: If actual body weight (ABW) is lower than ideal weight body (IBW), ABW 
should be used. Calculation Formula for IBW: 
（Male）IBW=50kg+2.3kg×[Height(Inch)-60] 
（Female）IBW=45.5kg+2.3kg×[Height(Inch)-60] 
1Inch=2.54cm 
         GFR Equation: 
Glomerular filtration rate is estimated by Chronic kidney disease (CKD)-Epidemiology 
Collaboration (EPI) equation: 
GFR(mL/min per 1.73 m2) = 141 × min(Scr/κ, 1)α × max(Scr/κ, 1)−1.209 × 0.993Age [ × 
1.018 if female] [ × 1.159 if black],  
where Scr is serum creatinine (mg/dl), κ is 0.7 for females and 0.9 for males, α is −0.329 
for females and −0.411 for males, min is the minimum of Scr/κ or 1, and max is the 
maximum of Scr/κ or 1 
 


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2013N184338_00 
CONFIDENTIAL 
201213 
 
 
 
Version: 3.0/27-March-2016 
55 
 
11.4. 
Appendix 4: Lactic Acidosis Guidelines 
Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been 
reported with the use of nucleoside analogues alone or in combination with other 
antiretrovirals. Most of these cases have been in women. Obesity and prolonged 
nucleoside exposure may be risk factors; however, cases have also been reported in 
subjects with no known risk factors.  
Guidelines for management of symptomatic hyperlactatemia and asymptomatic 
hyperlactatemia are outlined in Section A and B below and are derived from the AACTG 
Lactic Acidosis Guidelines. Section C outlines venous lactate collection techniques. 
Section A. Symptomatic Hyperlactatemia 
Symptomatic hyperlactatemia is defined as a clinical suspicion of hyperlactatemia 
characterised by new, otherwise unexplained and persistent ( 2 weeks) occurrence of 
one or more of the following symptoms: 
 
Nausea and vomiting. 
 
Abdominal pain or gastric discomfort. 
 
Abdominal distention. 
 
Increased LFTs. 
 
Unexplained fatigue. 
 
Dyspnoea. 
AND 
Venous lactate level >2 x ULN confirmed by repeat venous lactate analysis within 
1 week and, if persistently elevated, arterial lactate with blood gas analysis.  
If the repeat venous lactate is elevated confirmation with an arterial lactate specimen and 
arterial blood gas (pH, PO2, PCO2, bicarbonate, oxygen saturation) should be performed 
within 48 h. If the arterial specimen contains lactate at a level >2 x ULN, the subject 
should be discontinued from the study and alternative therapy started. Subjects should be 
monitored weekly until signs and symptoms resolve. Hyperlactatemia should be followed 
until levels return to <2 x ULN. 
An elevated anion gap in a subject with metabolic acidosis suggests the diagnosis of 
lactic acidosis. It can be suspected when the sum of anions minus the sum of 
cations [(Na+ + K+)  (Cl- + HCO3)] exceeds 18 mEq/L (18 mmol/L) in the absence of 
other causes of increased anion gap such as renal failure, salicylate ingestion or other 
poisoning, or significant ketonemia (e.g., diabetic ketoacidosis, alcohol).  
Management of symptomatic subjects with lactate levels of 1–2 x ULN is left to the 
discretion of the Investigator. As some of the symptoms are sufficiently vague (e.g., 
fatigue) to be present in everyone, serial repeat testing is encouraged with plans to 
modify the regimen if the lactate level rises to >2 x ULN as outlined above. 


2013N184338_00 
CONFIDENTIAL 
201213 
 
 
 
Version: 3.0/27-March-2016 
56 
 
Section B. Asymptomatic Hyperlactatemia 
In asymptomatic subjects, lactic acidosis will be defined as hyperlactatemia >4 x ULN. 
Any subject with a lactate level >2 x ULN but  4 x ULN, should be questioned closely 
for symptoms (described above) and have a repeat venous sample obtained in 1 week, 
and, if confirmed, subsequently at monthly intervals.  
If the subject fulfils the definition for asymptomatic hyperlactatemia, repeat venous 
lactate should be obtained within a week with confirmation of a more than four-fold 
venous elevation in lactate by arterial lactate measurement and arterial blood gas (pH, 
PO2, PCO2, bicarbonate, oxygen saturation) within 48 h. If confirmed, the subject should 
be discontinued from the study and alternative therapy instituted. Hyperlactatemia should 
be followed until levels return to <2 x ULN. 
Section C. Specimen Collection 
Venous lactate levels are highly dependent on collection techniques. It is therefore 
recommended that the instructions below be followed closely. High lactate levels should 
be repeated for verification. If carefully collected, venous lactate level is equivalent to an 
arterial collection in most clinical situations. If it is not possible to collect the specimen 
without hand clenching or prolonged tourniquet time, an arterial lactate should be 
considered, as this will help exclude falsely elevated lactate levels.  
Have subject sit, relaxed for 5 minutes prior to venepuncture. 
1. Instruct subject not to clench the fist before or during the procedure and to relax the 
hand as much as possible. 
2. If possible, do not use a tourniquet. If a tourniquet is necessary, then apply tourniquet 
lightly and draw lactate first before the other samples with the tourniquet still in 
place. 
3. Collect the blood in a chilled gray-top (sodium fluoride-potassium oxalate) tube. 
4. Place the specimen immediately on ice and send to the laboratory for immediate 
processing, preferably within 30 minutes of collection. 
5.  If random lactate is elevated, then repeat as above with the following additional 
subject instructions: no alcohol within 24 h, no exercise within 8 h, and no food or 
drink except water within 4 h of the draw. 
 

SAP_001.pdf: 
GlaxoSmithKline (China) Investment Co., Ltd.                                    Version： 2.0 
Protocol 201213                                                               Feb 26, 2021 
 
 
1 
 
 
 
Statistical Analysis Plan 
 
 
 
 
 
 
 
A prospective, multi-center, cohort study to evaluate the 
efficacy and safety of Tenofovir Disoproxil Fumarate (TDF) 
therapy in Chinese chronic hepatitis B (CHB) subjects with 
advanced fibrosis & compensated cirrhosis 
 
 
 
 
 
Sponsor: GlaxoSmithKline (China) Investment Co., Ltd. 
Version: 2.0 
Date: Feb 26, 2021 
201213 | Statistical Analysis Plan  Amendment 1 26 Feb 2021 | TMF-11944565 | 1.0


GlaxoSmithKline (China) Investment Co., Ltd.                                    Version： 2.0 
Protocol 201213                                                               Feb 26, 2021 
 
 
2 
 
 
 
Protocol Number: 201213 
 
 
A prospective, multi-center, cohort study to evaluate the efficacy and 
safety of Tenofovir Disoproxil Fumarate (TDF) therapy in Chinese 
chronic hepatitis B (CHB) subjects with advanced fibrosis & 
compensated cirrhosis 
 
 
Statistical Analysis Plan 
Version 2.0 
Feb 26, 2021 
 
 
Prepared by: 
 
R&G PharmaStudies Co., Ltd. 
 
 
 
 
 
Author: 
                                           ____________________ 
Senior Statistical Analyst 
Signature 
R&G PharmaStudies Co., Ltd.  
Date: _______________ 
 
 
 
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PPD


GlaxoSmithKline (China) Investment Co., Ltd.                                    Version： 2.0 
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Approval 
 
 
                                     
 
____________________ 
Statistician 
Signature 
GlaxoSmithKline (China) Investment Co., Ltd. 
Date: __________________ 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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TABLE OF CONTENTS 
 
1. 
INTRODUCTION .................................................................................................................... 8 
2. 
STUDY OBJECTIVE ............................................................................................................... 8 
2.1 
Primary objective ......................................................................................................... 8 
2.2 
Secondary objective ..................................................................................................... 8 
3. 
STUDY DESIGN ...................................................................................................................... 8 
3.1 
Overall study design ..................................................................................................... 8 
3.2 
Sample size................................................................................................................. 10 
3.2.1 
Sample size Assumptions ................................................................................... 10 
3.2.2 
Sample Size Sensitivity ..................................................................................... 11 
4. 
ANALYSIS SET ..................................................................................................................... 11 
5. 
STUDY ENDPONITS ............................................................................................................ 12 
5.1 
Primary endpoint ........................................................................................................ 12 
5.2 
Secondary endpoints .................................................................................................. 12 
5.3 
Exploratory endpoints ................................................................................................ 13 
6. 
STATISTICAL CONSIDERATIONS ..................................................................................... 14 
6.1 
General rule ................................................................................................................ 14 
6.2 
Data handling ............................................................................................................. 15 
7. 
STATISTICAL ANALYSIS .................................................................................................... 15 
7.1 
Subject screening, disposition and protocol deviations .............................................. 15 
7.2 
Subject Information .................................................................................................... 16 
7.2.1 
Demographics and baseline characteristics ........................................................ 16 
7.2.2 
Medical history .................................................................................................. 16 
7.2.3 
Inclusion and exclusion criteria ......................................................................... 17 
7.3 
Treatments and medications ....................................................................................... 17 
7.3.1 
Prior and concomitant medication ..................................................................... 17 
7.3.2 
Exposure of TDF and treatment compliance ..................................................... 18 
7.3.3 
Rescue Treatment ............................................................................................... 18 
7.3.4 
Non-drug therapies ............................................................................................ 18 
7.4 
Efficacy analysis ........................................................................................................ 19 
7.4.1 
Analysis of primary variables ............................................................................ 19 
7.4.2 
Analysis of secondary variables ......................................................................... 20 
7.4.3 
Exploratory analysis .......................................................................................... 23 
7.5 
Safety analysis ............................................................................................................ 25 
7.5.1 
Adverse events ................................................................................................... 26 
7.5.2 
Vital sign ............................................................................................................ 27 
7.5.3 
Laboratory assessments ..................................................................................... 27 
7.5.4 
Physical examination ......................................................................................... 28 
7.5.5 
B-ultrasound ...................................................................................................... 28 
8. 
APPENDIX ............................................................................................................................. 29 
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8.1 
Appendix 1: Description of Inclusion/Exclusion Criteria .......................................... 29 
8.2 
Appendix 2: CHILDS-PUGH SCORE*..................................................................... 32 
8.3 
Appendix 3: Treatment-emergent Laboratory Abnormalities Grading Scale ............. 33 
8.4 
Appendix 4: Formulas and Equations ........................................................................ 34 
8.5 
Appendix 5: REACH-B Model .................................................................................. 35 
9. 
MOCK TABLES, LISTINGS AND GRAPHS (TLGS) .......................................................... 35 
 
 
 
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LIST OF ABBREVIATIONS 
 
Abbreviation  
Description of Abbreviation 
ADV 
Adefovir 
AE 
Adverse event 
ALT 
Alanine aminotransferase 
CFDA 
China Food and Drug Administration 
CHB 
Chronic hepatitis B 
95% CI 
95% Confidence Interval 
DNA 
Deoxyribonucleic acid 
ETV 
Entecavir 
HBeAg 
Hepatitis B e antigen 
HBsAg 
Hepatitis B s antigen 
HBV 
Hepatitis B virus 
HCV 
Hepatitis C virus 
INR 
International Normalized Ratio 
LAM 
Lamivudine 
LdT 
Telbivudine 
mITT 
Modified Intent-to-treat (population) 
NAs 
Nucleos(t)ide analogues 
PP 
Per protocol (population) 
PT 
Prothrombin time 
SA 
Safety analysis (population) 
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GlaxoSmithKline (China) Investment Co., Ltd.                                    Version： 2.0 
Protocol 201213                                                               Feb 26, 2021 
 
 
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Abbreviation  
Description of Abbreviation 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SD 
Standard deviation 
TDF 
Tenofovir disoproxil fumarate 
TEAE 
Treatment-emergent adverse events 
ULN 
Upper limit of the normal range 
 
 
Trademark Information 
 
Trademarks of the GlaxoSmithKline 
group of companies 
 
Trademarks not owned by the 
GlaxoSmithKline group of companies 
Hepododin 
 
Viread 
 
 
Sebivo 
 
 
Baraclude 
 
 
 
 
 
 
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GlaxoSmithKline (China) Investment Co., Ltd.                                    Version： 2.0 
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1. INTRODUCTION 
The purpose of this statistical analysis plan (SAP) is to describe the procedures to be used for 
analyzing and reporting the efficacy and safety for study 201213. It should be used in conjunction 
with the following documents: study protocol, case report form, and shells for tables, listings and 
graphs. This SAP is based on the final protocol (Version 3.0, March 27, 2016). 
 
2. STUDY OBJECTIVE 
2.1 
Primary objective 
• 
To evaluate the incidence of hepatocellular carcinoma (HCC) during 240-weeks of TDF 300mg 
QD treatment in Chinese CHB subjects with advanced fibrosis and compensated cirrhosis. 
• 
To evaluate the rate of disease progression during 240-weeks of TDF 300mg QD treatment in 
Chinese CHB subjects with advanced fibrosis and compensated cirrhosis.  
2.2 
Secondary objective 
• 
To evaluate the efficacy and safety of 240 weeks of TDF 300mg QD treatment in Chinese CHB 
subjects with advanced fibrosis and compensated cirrhosis.  
 
3. STUDY DESIGN 
3.1 
Overall study design 
This is a prospective, multi-centre, open-label, cohort study to investigate efficacy and safety of 
Tenofovir Disoproxil Fumarate (TDF) treatment in Chinese CHB subjects with advanced fibrosis 
and compensated cirrhosis. The study will enroll 186 subjects with a diagnosis of CHB and 
advanced fibrosis or compensated cirrhosis. 
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Screen phase (≤4 weeks): Written informed consent must be obtained from each subject prior to 
participation in the study. Subjects considered eligible to enroll in the study will be assessed at a 
screening visit as described in Table 1 to decide if they meet the study criteria. Between Screen visit 
and baseline visit, subjects will not receive investigational product. 
Treatment phase: 186 subjects will be administered TDF 300 mg QD and undergo regular safety 
and efficacy assessments every 12 weeks for a total of up to 240 weeks (see Table 1). Subjects will 
be questioned about adverse events, concurrent medications, and study drug accountability; blood 
will be taken for hematology and biochemistry profiles; serum samples will be tested for HBV 
markers, and the prothrombin time will be measured. Serum samples will be collected at Week 12, 
24, 36, 48, 60, 72, 84, and 96 and every 24 weeks thereafter and analyzed for HBV DNA levels at 
a central laboratory. Abdominal ultrasound, the prothrombin time and serum alpha-fetoprotein test 
will be performed every visit. If abdominal ultrasound reports a liver mass or nodule, CT or MRI 
will be performed. At baseline and Week 216, 100 of subjects will take liver biopsy to evaluate liver 
histological changes pre and post TDF treatment. All subjects will be followed through to Week 240. 
Rescue treatment could be optionally initiated in subjects with unsatisfied response to TDF, at the 
discretion of the investigator if  
• 
Subjects have confirmed virological breakthrough as defined by ≥ one log10 IU/mL increase in 
HBV DNA from nadir determined by two sequential HBV DNA measurements at least 1 month 
apart, or  
• 
Subjects have HBV DNA ≥ 200 IU/ml at week 48 and afterwards have ≤ one log10 IU/mL 
decrease in HBV DNA at two consecutive visits, confirmed by a third visit at least one month 
apart. 
Confirmation of HBV DNA test will require an additional visit to collect serum sample. To receive 
rescue treatment subjects must have investigational product (IP) compliance > 80% in the last 
regular visits period (usually 12 weeks). Add-on combination with a nucleoside agent (LAM, ETV 
or LdT) is acceptable rescue treatment in this study, as to investigator’s decision. Before rescue 
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treatment, serum sample should be collected for resistance testing.  
Subjects who reach primary endpoint (i.e. develop liver complications or HCC) may withdraw from 
study. Investigator and subjects can decide whether to continue study drug. Subjects who continue 
to take study drug will be followed as per the original schedule until Week 240. During the follow-
up period, AEs, concomitant medication, vital signs, hepatitis B virus DNA, haematology, chemistry 
and prothrombin will be evaluated. Serum/plasma storage also will be conducted.  
Supplementary study conduct information not mandated to be present in this protocol is provided 
in the accompanying Study Procedures Manual (SPM). The SPM will provide the site personnel 
with administrative and detailed technical information that does not affect subject safety. 
3.2 
Sample size 
3.2.1 Sample size Assumptions 
Sample sizes are chosen based on feasibility and precision because no hypothesis is tested in this 
study. 
To decide the number of subjects for analysis, some precision calculations have been performed for 
the primary endpoint HCC incidence. In the retrospective analysis of GS-US-174-0102 and GS-US-
174-0103 trials, HCC incidence over 7 years was approximately 4.5% among patients (23% of 
whom were Asian, 25 of whom were genotype B or C) with cirrhosis at baseline. Accordingly, we 
hypothesize that the accumulative incidence of HCC at 240 weeks will be 5% in Chinese 
compensated cirrhotic patients treated with TDF. The precision is calculated by the following:  
𝑃𝑟𝑒𝑐𝑖𝑠𝑖𝑜𝑛= 𝑍1−𝛼/2 √𝑝(1 −𝑝)
𝑁
  
where Z is the critical value of normal distribution corresponding to the probability of 1-α/2 
(corresponding to (1- α)*100% confidence interval), and p is the percentage of patients who were 
diagnosed HCC during 240 weeks. Precision is half of the width of 95% confidence interval for the 
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GlaxoSmithKline (China) Investment Co., Ltd.                                    Version： 2.0 
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point estimate. A sample size of 158 patients will allow us to estimate the confidence interval of the 
incidence with a margin of error at 3.4 % (0.016-0.084). Assuming a 15% drop out rate, 186 patients 
are to be recruited.  
3.2.2 Sample Size Sensitivity 
The sample size estimates are dependent upon the assumed incidence.   
Different sample sizes and corresponding precisions are provided in the table below. It assumes the 
percentage of patients HCC is 5%. 
P 
1-p 
Width (half CI) 
N 
5% 
0.95 
0.04 
115 
5% 
0.95 
0.034 
158 
5% 
0.95 
0.033 
168 
5% 
0.95 
0.032 
179 
5% 
0.95 
0.03 
203 
5% 
0.95 
0.02 
457 
 
4. ANALYSIS SET 
• 
Modified Intent-to-treat (mITT) Population 
The mITT population is defined as all recruited subjects who receive at least one dose of study 
medication. 
• 
Per Protocol (PP) population 
The PP population will consist of subjects in the mITT population who have no major protocol 
deviations that impact efficacy evaluation. 
• 
Safety Analysis (SA) population 
The SA population is defined as all subjects who receive at least one dose of study medication and 
have at least one post baseline safety assessment. 
All efficacy endpoints will be analyzed using the mITT population and PP population will be used 
for primary endpoints. All safety endpoints will be analyzed using the SA population. 
 
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5. STUDY ENDPONITS 
5.1 
Primary endpoint 
• 
The cumulative incidence of newly diagnosed hepatocellular carcinoma (HCC) at Week 240, 
the subject must meet one of the following criteria: 
o 
Without HCC before Week 24 
o 
A histological diagnosis of HCC (i.e. by biopsy or at post-mortem); 
o 
In patients with nodules > 2 cm, identification of typical HCC characteristics 
(hypervascular in the arterial phase with washout in the portal venous or delayed phases) 
by 4-phase multidetector CT scan or dynamic contrast-enhanced MRI; 
o 
In patients with nodules > 1 cm, identification of typical HCC characteristics by both 
techniques (4-phase multidetector CT and dynamic contrast-enhanced MRI).  
• 
The cumulative incidence of disease progression at Week 240, defined as the first occurrence 
of any one of the following criteria: 
o 
An increase in Childs-Pugh score (as defined in Appendix 2) of 2 or more points from 
baseline;  
o 
An increase in Childs-Pugh score of 2 or more points, solely based on laboratory 
parameters (i.e. bilirubin, prothrombin time and/or albumin), confirmed between two 
consecutive visits at least one month apart; 
o 
Spontaneous bacterial peritonitis (with proven sepsis);  
o 
Renal insufficiency defined as a decrease in creatinine clearance to ≤50 mL/minute 
confirmed on two occasions at least one week apart (calculated from serum creatinine 
concentration);  
o 
Bleeding gastric/oesophageal varices;  
o 
Hepatocellular carcinoma;  
o 
Liver-related death. 
5.2 
Secondary endpoints 
• 
Cumulative incidence of newly diagnosed HCC at Week 48, Week 96, Week 144, and Week 
192. 
• 
Cumulative incidence of disease progression at Week 48, Week 96, Week 144, and Week 192. 
• 
The mean changes of liver stiffness measurement (LSM) at Week 12, Week 24, Week 36, Week 
48, Week 96, Week 144, Week 192 and Week 240 for patients with baseline ALT > ULN, 
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baseline ALT ≤ ULN and overall.  
• 
Change of fibrosis stage for subjects with baseline ALT > ULN and ALT ≤ ULN.  
• 
Change of non-invasive liver fibrosis evaluation index (GPR, APRI and FIB-4, defined in 
Section 8.5, appendix 5) from baseline by visit.  
• 
The proportion of subjects with serum HBV DNA < 20 IU/mL or serum HBV DNA < 69 IU/mL 
(Roche COBAS Taqman HBV Test) at Week 12, Week 24, Week 36, Week 48, Week 96, Week 
144, Week 192 and Week 240 
• 
The mean log10 IU/mL reduction in serum HBV DNA at Week 12, Week 24, Week 36, Week 
48, Week 96, Week 144, Week 192 and Week 240 compared with baseline 
• 
The proportion of subjects with ALT normalization at Week 48, Week 96, Week 144, Week 192 
and Week 240 in subjects who have abnormal ALT at baseline 
• 
For HBeAg positive subjects: the proportion of subjects achieving HBeAg loss, HBeAg 
seroconversion or HBsAg loss and HBsAg seroconversion at Week 24, Week 48, Week 96, 
Week 144, Week 192 and Week 240 
• 
For HBeAg negative subjects: the proportion of subjects achieving HBsAg loss and HBsAg 
seroconversion at Week 48, Week 96, Week 144, Week 192 and Week 240 
• 
Incidence of virological breakthrough as defined by 1 log10 IU/mL increase in HBV DNA from 
nadir (as determined by two sequential HBV DNA measurements at least 1 month apart, or the 
last on-treatment measurement) overall and by each visit 
• 
The proportion of subject with unsatisfactory response, overall and by each visit. 
Unsatisfactory response is defined as subjects who have HBV DNA ≥200 IU/mL at week 48 
and afterwards have ≤1 log10 IU/mL decrease in HBV DNA at two consecutive tests, 
confirmed by a third visit (additional visit) at least one month apart 
• 
Subject safety as determined by adverse events and laboratory assessments 
 
5.3 
Exploratory endpoints 
• 
Incidence of TDF resistance substitutions (if identified) at Week 48, Week 96, Week 144, Week 
192 and Week 240 
• 
Baseline or on-treatment risk factors for HCC/disease progression (e.g. gender, age, HBV DNA, 
genotype, HBeAg sero-status, ALT, platelets, treatment response, etc.)  
• 
Impact of HBV DNA and virologic response on change of liver stiffness measurement (LSM). 
• 
The mean changes of LSM by visit. 
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• 
Time to improvement of fibrosis. 
• 
The Relationship between baseline variables or on-treatment variables and improvement of 
fibrosis. 
• 
Proportion of LSM improvement and of fibrosis stage improvement. 
• 
Analyses of correlation coefficients between LSM and ALT level. 
• 
Correlation coefficients between variables change at Week 12 and 24 and LSM change at 
Week240.  
• 
Predicted and observed HCC risks at week 240 by REACH-B model. 
• 
Decline in LSM from baseline to Week 240. 
• 
Mean estimated glomerular filtration rate (eGFR) over time by baseline eGFR, mean creatinine 
clearance rate (Ccr) over time by baseline Ccr, mean serum phosphorus over time.  
• 
Change of average LSM/ALT by visit, change of average LSM by visit, change of median of 
LSM by visit, change of average GPR APRI FIB-4 by visit, change of median of GPR APRI 
FIB-4 by visit, change of fibrosis stage by visit. 
 
6. STATISTICAL CONSIDERATIONS 
6.1 
General rule 
All analysis will be conducted using SAS Version 9.2 or higher (SAS Institute, Cary, NC). For 
continuous variables, descriptive statistics will be presented as the mean, standard deviation, 
minimum, median, maximum, and the number of observations, unless otherwise specified. For 
categorical variables, the number and percentage for each of the categories will be presented. Counts 
that are zero will be displayed as “0”. Unless otherwise specified, the denominator for all 
percentages will be based on the number of subjects in the analysis set of that treatment group. 
Baseline is defined as the last assessment before administration of the study drug. 
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6.2 
Data handling 
Missing data can have an impact upon the interpretation of the trial data. In general, values for 
missing data will not be imputed unless otherwise specified. For baseline value, if it is missing at 
baseline visit, then the latest non-missing value of screening will be used to replace. 
All serum HBV DNA results below the lower limit of detection (<20 IU/mL) or results of “not 
detected” will be analyzed as being the value of the lower limit of quantification, which is 20 IU/mL. 
For patients whose week 240 visits were influenced by COVID-19, a safety follow-up were added 
for these subjects. The missing week 240 will be imputed from safety follow-up visit in the analysis 
of primary endpoints. Please refer to section 7.4 for details. 
 
 
7. STATISTICAL ANALYSIS 
7.1 
Subject screening, disposition and protocol deviations 
The screening failure subjects and the reasons for screening failure will be summarized by the 
numbers and percentages. The percentages are based on the number of screening failure subjects. 
The disposition of subjects will be summarized, including the numbers and percentages of subjects 
for the following categories: all enrolled subjects, subjects completed the study, subjects early 
discontinued from the study, subjects in the modified intent to treat population, subjects in the per-
protocol population, and subjects in the safety analysis population. All percentages are based on the 
number of all enrolled subjects.  
The primary reason for subject premature discontinuation from study will also be summarized. The 
reasons for discontinuation will include voluntarily discontinue participation, lost to follow-up, lack 
of efficacy, subjects with treatment interruptions of ≥28 consecutive days, adverse event, 
intercurrent illness, protocol violations, pregnancy, and other reason. A listing will be provided. 
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Major protocol deviations will be summarized and listed for mITT population. Subject counts and 
percentages will be displayed by the following deviation categories:  
•    Eligibility criteria not met 
•    Excluded medication, vaccine or device 
•    Assessment or time point completion 
•    Wrong study treatment/administration/dose 
Major protocol deviations which results in the exclusion of the subject from PP population will be 
discussed, determined, and documented by study team before final database lock. A listing of subject 
disposition in analysis data sets will be provide. 
7.2 
Subject Information 
7.2.1 Demographics and baseline characteristics 
Demographic include subject age, sex (Male/Female), race (Asian/Others), and baseline 
characteristics for subjects include subject height, weight, BMI, systolic blood pressure, diastolic 
blood pressure, pulse, respiratory rate, body temperature, liver stiffness measurement, LSM for 
patient with ALT>ULN or ALT≤ULN, creatinine level, serum phosphorus, eGFR, creatinine 
clearance rate, HBV DNA , alcohol abuse, drug abuse, history of medication hypersensitivity, family 
history of hepatitis B and hepatoma, liver cirrhosis, hypertension, HBeAg, Childs-Pugh score, ALT, 
liver biopsy, and HBV genotype. Age will be calculated as the difference of the year of informed 
consent date and year of birth. Percentages for categorical data will be calculated based on the 
number of subjects in the analysis set of the corresponding population. Descriptive statistics will be 
used for continuous data. Listings of demographics and baseline characteristics will also be provided. 
Age (Year) = Year of Informed Consent Date - Year of Birth 
7.2.2 Medical history 
Medical history will include any acute and chronic medical conditions including medication of 
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chronic hepatitis B, medical history/current medical conditions, history of treatment, relevant 
surgeries. Medical history will be listed by system organ class and preferred term coded in MedDRA 
17.0.  
7.2.3 Inclusion and exclusion criteria 
Subjects must meet all specified inclusion and none of the exclusion criteria in order to be eligible 
to participate in the study. Inclusion and exclusion criteria information will be presented in the listing.  
7.3 
Treatments and medications 
7.3.1 Prior and concomitant medication 
Prior medication is defined as all the drugs taken by the subjects prior to the first dose date of TDF. 
Concomitant medication is defined as all the drugs taken by the subjects from the first dose date of 
TDF to completion of the study.  
If medication start date is on or after the date of first dose of study drug, then medication will be 
summarized as concomitant medication regardless of whether medication end date is missing or not. 
If medication end date is before the date of first dose of study drug, then medication will be 
summarized as prior medication regardless of whether medication start date is missing or not. Note 
that medication that started prior to the date of first dose of study drug and continued after dosing 
will be summarized as prior medication and separately as concomitant medication. 
All medications will be coded according to WHO drug dictionary (Version: WHODDE 2016Q3) 
and Anatomical Therapeutic Chemical (ATC) coding.  
Prior and concomitant medications will be listed separately. Medication class, medication name, 
indications, total daily dose, unit, route, start date and end date will be presented in the listing. 
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7.3.2 Exposure of TDF and treatment compliance 
Exposure of TDF information including dose start date, end date, duration of study drug and dosing 
compliance will be presented in the listing. 
The duration in days of study drug exposure from first dose date to the last dose date will be 
summarized by descriptive statistics, including n, mean, sd, Q1, median, Q3, range.  
The duration of the drug exposure (day) = Last dose date - First dose date + 1 
Treatment compliance, defined as actual taken amount divided by expected taken amount per 
protocol times 100, will be summarized by descriptive statistics for mITT. The formulas for 
calculating the treatment compliance are as follows: 
Treatment Compliance (%) = Actual taken amount×100 / Expected taken amount 
Drug accountability information including date (dispensed or returned), dispensed amount, returned 
amount, lost amount, expected taken amount, actual taken amount, missing amount, and treatment 
compliance will be presented in the listing. 
7.3.3 Rescue Treatment 
Rescue treatment information including rescue treatment name, frequency, reason taken, other 
reason taken, start date, end date will be presented in the listing. If no patient received rescue 
treatment, the listing will not be presented. 
7.3.4 Non-drug therapies 
Non-drug therapy information including therapy details, start and end date, and the reason for use 
will be presented in the listing. If no patient received rescue treatment, the listing will not be 
presented. 
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7.4 
Efficacy analysis 
All analysis will be conducted in mITT, unless otherwise specified. 
7.4.1 Analysis of primary variables 
The primary efficacy endpoints for this study are the 240-Week cumulative incidence of newly 
diagnosed HCC and 240-Week cumulative incidence of disease progression. The newly diagnosed 
HCC is defined as HCC cases from Week 24 to Week 240. The analysis will be performed in mITT 
and PP population. 
• 
Nominal cumulative incidence of newly diagnosed HCC at week 240 is defined as the 
percentage of patient who are newly diagnosed as HCC from Week 24 visit to Week 240 
visit in overall patients. Nominal cumulative incidence of HCC will be summarized by 
frequency, percentage and its 95% two-sided Wald CI. When the value of the newly 
diagnosed HCC at week 240 is missing due to the epidemic of COVID-19, the missing 
value may be imputed with the value at the safety follow-up visit. Different missing 
imputation scenarios will be assessed for the primary analysis and sensitivity analyses, 
details are provided in below table in which “Y” means the missing value will be imputed 
with the value at the safety follow-up visit. 
Difference between planned 
Week 240 visit and actual 
safety follow up visit   
Medication taken after 
previous visit 
Primary 
Endpoints 
Sensitivity 
Analysis 1 
Sensitivity 
Analysis2 
<=28 days 
Any 
Y 
Y 
Y 
>28 days 
GSK 
Y 
N 
Y 
Domestic  
Y 
N 
N 
Both GSK & domestic 
Y 
N 
N 
Lost to follow up 
NA 
N 
N 
N 
 
• 
Nominal cumulative incidence of disease progression at week 240 is defined as the 
percentage of patient who have disease progression before Week 240 visit in overall 
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patients. Nominal cumulative incidence of disease progression will be summarized by 
frequency, percentage and its 95% two-sided Wald CI. When the value of the disease 
progression at week 240 is missing due to the epidemic of COVID-19, the missing value 
will be imputed with the value at the safety follow-up visit. No sensitive analysis is planned.  
• 
Cumulative incidence of newly diagnosed HCC/disease progression at week 240 and its 
95% CI will be estimated from the Kaplan–Meier analysis. Time to newly diagnosed 
HCC/disease progression is defined as the interval between the date of first treatment dose 
and the analysis date. The rules of analysis date are described in the following table: 
Patient’s Condition 
Status 
Analysis date 
Diagnosed HCC/disease progression on visit 
Event 
Date of diagnosis 
Reported SAE related with HCC/disease 
progression between visits 
Event 
Date of diagnosis 
Complete study without HCC/disease 
progression 
Censor 
Date of study complete 
Lost follow up/ Early withdraws 
Censor 
Date of last visit with the adequate 
diagnosis data 
  
7.4.2 Analysis of secondary variables 
 
7.4.2.1 Nominal Cumulative Incidence and Nominal Incidence by visit 
As defined in previous, the nominal cumulative incidence of newly diagnosed HCC and the nominal 
cumulative incidence of disease progression at Week 48, Week 96, Week 144, and Week 192 will 
be summarized by frequency, percentage and its 95% two-sided Wald CI. The analysis will be 
performed in mITT. Figures of nominal cumulative incidence of HCC/disease progress by each visit 
will be product respectively. 
The nominal incidence at visit is defined as the percentage of subjects who had event during the 
previous visit to the current visit. The nominal incidence of newly diagnosed HCC and disease 
progression at each visit from Week 36 (Week 36, 48, 60, 72, 84, 96, 108, 120, 132, 144, 156, 168, 
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180, 192, 204, 216 and 240) will be summarized by frequency, percentage and its 95% two-sided 
Wald CI. 
 
7.4.2.2 Cumulative incidence by visit 
The cumulative incidence of newly diagnosed HCC and the cumulative incidence of disease 
progression at week 48, week 96, week 144, and week 192 will be estimated from the Kaplan–Meier 
analysis. Event or censoring rules are the same with cumulative incidence of week 240, as described 
in section 7.4.1. Figures of nominal cumulative incidence of HCC/disease progress by each visit 
will be product respectively. 
 
7.4.2.3 Other secondary variables 
The number and percentage will be presented respectively for secondary variables including: 
• 
The proportion of subjects with serum HBV DNA < 20 IU/mL or serum HBV DNA < 69 IU/mL 
(Roche COBAS Taqman HBV Test) at Week 12, Week 24, Week 36, Week 48, Week 96, Week 
144, Week 192 and Week 240. 
• 
The proportion of subjects with serum HBV DNA < 20 IU/mL (Roche COBAS Taqman HBV 
Test) by baseline HBeAg status (HBeAg Positive and HBeAg Negative) at Week 48, Week 96, 
Week 144, Week 192 and Week 240.  
• 
The proportion of subjects with serum HBV DNA < 20 IU/mL (Roche COBAS Taqman HBV 
Test) by baseline HBV DNA level (≥6 Log10 IU/mL and <6 Log10 IU/mL) at Week 48, Week 
96, Week 144, Week 192 and Week 240.  
• 
The proportion of subjects with ALT normalization at Week 48, Week 96, Week 144, Week 192 
and Week 240 in subjects who have abnormal ALT at baseline, based on the lab report.  
• 
The proportion of subjects with ALT normalization at Week 48, Week 96, Week 144, Week 192 
and Week 240 in subjects who have abnormal ALT at baseline, based on AASLD criteria. 
Abnormal ALT by AASLD criteria is ≥19 U/L for women and ≥30 U/L for men. 
• 
For HBeAg positive subjects: the proportion of subjects achieving HBeAg loss, HBeAg 
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seroconversion or HBsAg loss and HBsAg seroconversion at Week 48, Week 96, Week 144, 
Week 192 and Week 240. 
• 
For HBeAg negative subjects: the proportion of subjects achieving HBsAg loss and HBsAg 
seroconversion at Week 48, Week 96, Week 144, Week 192 and Week 240. 
• 
Incidence of virological breakthrough as defined by 1 log10 IU/mL increase in HBV DNA from 
nadir (as determined by two sequential HBV DNA measurements at least 1 month apart, or the 
last on-treatment measurement) overall and by visit. 
• 
The proportion of subject with unsatisfactory response overall and by each visit. Unsatisfactory 
response is defined as subjects who have HBV DNA ≥200 IU/mL at week 48 and afterwards 
have ≤1 log10 IU/mL decrease in HBV DNA at two consecutive tests, confirmed by a third 
visit (additional visit) at least one month apart. 
• 
The proportion of subjects with histological improvement (a reduction of two or more points 
in the Knodell necroinflammatory score with no increase in fibrosis) at Week 216 in the subset 
of subjects with paired baseline and Week 216 liver biopsies.  
• 
The proportion of subjects with cirrhosis reversal (a reduction of one or more points in the 
Ishak score and no evidence of cirrhosis) at Week 216 in the subset of subjects with paired 
baseline and Week 216 liver biopsies and with a baseline Ishak score higher than or equal to 
five 
• 
Change of fibrosis stage measured by LSM for subjects with baseline ALT > ULN and ALT ≤ 
ULN, by baseline fibrosis stage. The fibrosis stage is measured by LSM value, based on the 
following rules: 
◼ 
For patient with baseline ALT>ULN: F0/1: LSM<9.4 kPA, F2: 9.4 kPa≤LSM<12.4 kPa, 
F3: 12.4 kPa≤LSM<17.5 kpa, F4: LSM≥17.5 kpa 
◼ 
For patient with baseline ALT≤ULN: F0/1: LSM<6.0 kPA, F2: 6.0 kPa≤LSM<9.0 kPa, 
F3: 9.0 kPa≤LSM<12.0 kpa, F4: LSM≥12.0 kpa 
Also, two-sided 95% CI will be calculated for each percentage. 
Below endpoints will be summarized by descriptive statistics as the mean, standard deviation, 
minimum, median, maximum, and the number of observations. 
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• 
The mean changes of liver stiffness measurement (LSM) at Week 12, Week 24, Week 36, Week 
48, Week 96, Week 144, Week 192 and Week 240 for patients with baseline ALT > ULN, 
baseline ALT ≤ ULN and overall.  
• 
The mean log10 IU/mL reduction in serum HBV DNA at Week 12, Week 24, Week 36, Week 
48, Week 96, Week 144, Week 192 and Week 240 compared with baseline. And the result of 
log10 HBV DNA at each visit will be summarized for whole period. 
In addition, line plots of the proportion of subjects with HBV DNA< 20IU/mL and <69 IU/mL by 
visit, mean HBV DNA (log10) over time by baseline ALT significance and a bubble plot for 
distribution of HBV DNA levels overtime will be provide. Newly diagnosed HCC, disease 
progression events, hepatitis B five item, liver stiffness measurement (LSM) and Childs-Pugh score 
will be listed. 
7.4.3 Exploratory analysis 
Incidence of TDF resistance substitutions such as mutation change, drug resistance test results will 
be summarized in patients with unsatisfied virological response, viral breakthrough, or discontinued 
treatment with HBV DNA≥20 IU/mL. 
Univariate and multivariate analysis by logistic regression model will be performed to identify 
baseline or on-treatment risk factors associated with HCC and disease progression, if applicable. 
The factors will include gender, age, genotype, baseline HBV DNA category (≥2000 or <2000, 
IU/mL), baseline HBeAg sero-status, baseline ALT value, baseline LSM value, Week 24 treatment 
response, Week 48 treatment response. Treatment response is defined as serum HBV DNA < 20 
IU/mL. Multivariate analysis will include sex, age and the factors with P≤0.20 in univariate 
analysis. 
Time to HCC/disease progression will be analyzed by cox model. Univariate will be conducted to 
include all above factors and the selection of multivariate analysis will follow the same rule. 
Impact of HBV DNA and virologic response on change of LSM will be summarized by shift table 
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of descriptive statistics as the mean, standard deviation, minimum, median, maximum, and the 
number of observations. 
The mean changes and percent of the changes of liver stiffness measurement in each visit will be 
summarized by descriptive statistics as the mean, standard deviation, minimum, median, maximum, 
and the number of observations for patients with advanced fibrosis and compensated cirrhosis. 
Compensated cirrhosis is defined as LSM ≥12.0 Kpa (ALT ≤ULN) or LSM ≥17.5 Kpa 
(ALT>ULN); advanced fibrosis is defined as 9.0 Kpa ≤LSM < 12.0 Kpa (ALT≤ULN) or 12.4 
Kpa ≤LSM < 17.5 Kpa (ALT>ULN). 
Time to improvement of fibrosis will be analyzed by cox regression. Improvement of fibrosis is 
defined as at least 30% decrease of LSM compared with baseline. Univariate analysis will include 
gender, age, genotype, baseline HBV DNA category (≥2000 or <2000, IU/mL), baseline HBeAg 
sero-status, baseline ALT value, Week 24 treatment response, Week 48 treatment response. 
Treatment response is defined as serum HBV DNA < 20 IU/mL. Multivariate analysis will include 
sex, age and the factors with P≤0.20 in univariate analysis. 
The relationship between baseline variables or on-treatment variables and improvement of fibrosis 
will be analysis by univariate and multivariate logistic model. Univariate analysis will include 
gender, age, BMI category (<25 or ≥25 kg/𝑚2), baseline HBV DNA (≥2000 or <2000, IU/mL), 
baseline HBeAg sero-status, baseline ALT value, baseline LSM value, baseline total bilirubin, 
HBeAg loss at Week 24, treatment response at Week 24 and Week 48, ALT normalized or not at 
Week 24 and Week 48, change from baseline of LSM at Week 12 and Week 24, change from baseline 
of GGT at Week 24. Multivariate analysis will include sex, age and the factors with P≤0.20 in 
univariate analysis. 
Proportion of LSM improvement will be summarized at Week48, Week96, Week144, Week192 and 
Week240 for patients with baseline LSM result in following groups: LSM improved (LSM 
decreased from baseline≥30%), LSM stable (LSM decreased from baseline < 30% or no change 
from baseline), and LSM deteriorate (LSM increase from baseline). 
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Proportion of fibrosis stage improvement will be summarized at Week 48, Week 96, Week 144, 
Week 192 and Week 240 for patients of fibrosis stage measured by fibrosis improved from baseline, 
≥2 stage fibrosis stage improved from baseline, ≥1 stage fibrosis stage, no change from baseline, 
fibrosis stage increase from baseline. 
Analyses of correlation coefficients between LSM and ALT level will be analyzed by Pearson 
correlation coefficients and P-value during every 48 weeks by patients with ALT normal at baseline, 
patients with abnormal at baseline and overall. 
Correlation coefficients between variables change at Week 12 and 24 and LSM change at Week240 
will be analyzed by correlation coefficients and P-value. The change from baseline of Gamma-
Glutamyltransferase (GGT), Total Bilirubin (TBIL), Albumin (ALB), International Normalized 
Ratio (INR) and LSM will be included in the analysis of correlation coefficients at Week 12, 
platelets (PLT), GPR, APRI, FIB-4 and all the variables included at Week 12 will be included in the 
analysis of correlation coefficients at Week 24.  
A 5-years predicted HCC risks by REACH-B model (see Section 8.5) and observed HCC risks 
(cumulative incidence of HCC) at Week 240 will be presented in table. Decline in LSM from 
baseline to Week 240 by visit will be analyzed by a line plot. 
In addition, a listing of HBV DNA result will be provided for the following patients:  
• 
Patients with virological breakthrough (defined as 1 log increase in HBV DNA from nadir 
determined by two sequential HBV DNA measurements). 
• 
Patients with unsatisfied virological response: defined as subjects have HBV DNA ≥ 200 IU/ml 
at week 48 and afterwards have ≤ 1 log10 IU/mL decrease in HBV DNA at two consecutive 
visits, confirmed by a third visit at least one month apart.  
 
7.5 
Safety analysis 
Safety endpoints include adverse events, vital signs, laboratory assessments, physical examination, 
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and B-ultrasound. The analysis will be conducted in SA population. 
7.5.1 Adverse events 
AEs will be classified into standardized medical terminology from the verbatim description 
(investigator term) using the Medical Dictionary for Regulatory Activities (MedDRA). Verbatim 
description and MedDRA level terms, including the system organ class, preferred term, and lower 
level term, for all AEs will be presented in the data listings. In table summaries, the denominator 
for percentages will be the number of subjects in the treatment group within the safety analysis 
population. AEs are coded according to (MedDRA) version 17.0.  
TEAE is defined as AE occurred on or after the first dose date of study drug. TEAEs will be 
presented by system organ class and preferred term. The subject level incidence is only one 
occurrence of a preferred term/system organ class per subject. If a subject reports multiple AEs 
under the same preferred term, then the count of subject level incidences for that preferred term will 
only be incremented by one. If a subject reports multiple AEs under the same system organ class, 
then the count of subject level incidences for that system organ class will also only be incremented 
by one. System organ classes will be presented in descending order of total frequency of subject 
level occurrences. Within each system organ class, preferred terms are presented in the same 
descending order of total frequency of subject level occurrences.  
An overall summary table of AE will be provided, including summaries of all AEs, all TEAEs, all 
treatment related TEAEs, all serious TEAEs, all treatment related serious TEAEs, all TEAEs leading 
to permanent discontinuation of study drug, all TEAEs leading to permanent discontinuation from 
the study, and all TEAEs that caused a change in dose or temporary interruption of study drug. 
Listings will be provided correspondingly. 
All TEAEs and all serious TEAEs will be summarized by SOC and PT, and by intensity. All TEAEs 
will also be summarized by relationship to study drug. 
 
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7.5.2 Vital sign 
Vital signs including systolic blood pressure (mmHg), diastolic blood pressure (mmHg), pulse 
(beats/minute), respiratory rate (breaths/minute), body temperature (℃) and weight (kg) will be 
descriptively summarized by visit. Changes from baseline to each individual post-baseline visit will 
also be presented. 
A listing of vital signs will be provided. 
7.5.3 Laboratory assessments 
Summary tables of hematology and blood chemistry by visit will be provided including the changes 
from baseline for each post-baseline visits. Descriptive statistics will be used for quantitative 
variables. For qualitative variables, the number and percentage for each parameter will be presented.  
Treatment-emergent grade 3 or grade 4 laboratory abnormalities are defined as values that increase 
at least one grade from baseline and get Grade 3 (severe) or 4 (potentially life threatening) at any 
post-baseline value (as defined in Appendix 3). If the relevant baseline laboratory data are missing, 
then the screening laboratory result will be used; if it is missing then any Grade 3 or 4 post-baseline 
values are considered treatment emergent. 
The following summaries (number and percentage of subjects) of treatment-emergent laboratory 
abnormalities will be provided: 
• 
Treatment-emergent Grade 3 or Grade 4 laboratory abnormalities 
• 
Incidence of on-treatment hepatitis exacerbation defined as bilirubin ≥ 2 times ULN or albumin 
≤ 3 g/dL or ALT ≥ 20 times ULN (and ≥ 2 times baseline) 
• 
Confirmed (defined as two consecutive visits) serum creatinine ≥ 0.5 mg/dL above baseline 
• 
Confirmed (defined as two consecutive visits) serum phosphate < 2 mg/dL 
• 
Calculated creatinine clearance < 50 mL/min 
Mean estimated glomerular filtration rate (eGFR) over time by baseline eGFR, mean creatinine 
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clearance rate (Ccr) over time by baseline Ccr, mean serum phosphorus over time will be analyzed 
by line plots, respectively. 
Change of average LSM/ALT by visit, change of average LSM by visit, change of median of LSM 
by visit, change of average GPR/APRI/FIB-4 by visit, change of median of GPR/APRI/FIB-4 by 
visit, change of fibrosis stage by visit will be analyzed by line plots, respectively. 
In addition, listings of hematology, blood chemistry, blood coagulation, urinalysis, pregnancy test, 
and alpha fetoprotein (AFP) will be provided. 
7.5.4 Physical examination 
A listing of physical examination will be provided. The result of physical examination will be 
presented as “Not Done”, “Normal” or “Abnormal”.  
7.5.5 B-ultrasound 
B-ultrasound examination results will be recorded in 3-level (normal, abnormal not clinically 
significant, or abnormal clinically significant). All B-ultrasound data will be presented in the listing.  
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8. APPENDIX 
8.1 
Appendix 1: Description of Inclusion/Exclusion Criteria 
Seq No 
Type 
Description 
1 
Inclusion 
Age 18-60 years(inclusive) 
2 
Inclusion 
Presence of HBsAg in serum at screening and for at least 6 months before screening 
assessment  
3 
Inclusion 
Serum HBV DNA ≥ 2000 IU/mL if HBeAg positive at screening (with or without ALT 
elevation); or serum HBV DNA ≥ 200 IU/mL if HBeAg negative at screening (with or 
without ALT elevation) 
4 
Inclusion 
Pathologically or clinically diagnosed as advanced fibrosis or compensated cirrhosis 
defined as one of following(a or b) :  
a. Liver biopsy showing advanced fibrosis or cirrhosis (Ishak score ≥ 4 or Fibrosis 
stage ≥ S3 by Scheuer Score, or within the previous 6 months before baseline and 
provided that no treatment likely to improve liver histology has been taken since). 
The slides must be available for review by an independent histopathologist.  
b. Clinical diagnosis: liver stiffness measure (LSM) > 12.4 kpa (ALT > ULN) or 
LSM > 9.0 kpa (ALT ≤ ULN), plus one of the following:  
• 
Endoscopy-proven gastroesophageal or gastric varices, non-cirrhotic portal 
hypertension excluded;  
• 
Abdominal ultrasound or CT found changes indicating cirrhosis, irregular 
liver surface or nodularity, with/without splenomegaly(depth of spleen > 4.0 
cm or spleen length >13 cm);  
• 
Blood platelets <100 x109/L (and other causes of thrombocytopenia 
excluded);   
5 
Inclusion 
Ability to give written informed consent  
6 
Inclusion 
A female is eligible to enter and participate in this study if she is of:  
a. 
Non-childbearing potential (i.e., physiologically incapable of becoming pregnant, 
including any female who is post-menopausal), or  
b. 
Child-bearing potential, has a negative urine pregnancy test at screening, and 
agrees to one of the following methods for avoidance of pregnancy during the 
period of the study and until 30 days after last dose of study medication:  
• 
Oral contraceptive, either combined or progestogen alone.  
• 
Injectable progestogen.  
• 
Implants of levonorgestrel.  
• 
Oestrogenic vaginal ring.  
• 
Percutaneous contraceptive patches.  
• 
Intrauterine device (IUD) or intrauterine system (IUS) showing that the 
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Seq No 
Type 
Description 
expected failure rate is less than 1% per year as stated in the IUD or IUS 
product label.  
• 
Has a male partner who is sterilised.  
• 
Double barrier method: condom and an occlusive cap (diaphragm 
orcervical/vault caps) with a vaginal spermicidal agent (foam/gel/film 
/cream/suppository).    
7 
Inclusion 
Agreement not to participate in any other investigational trials or to undertake other HBV 
systemic antiviral or IFN regimens during participation in this study.  
1 
Exclusion 
Hepatocellular carcinoma as evidenced by one of the following: 
• 
Suspicious foci on ultrasound or radiological examination. 
• 
Normal ultrasound but serum alpha-fetoprotein >50 ng/ml at screening. 
2 
Exclusion 
ALT >10 times ULN at screening or history of acute exacerbation leading to transient 
decompensation.  
3 
Exclusion 
Documented co-infection with hepatitis A (HAV), hepatitis C (HCV), hepatitis delta 
virus (HDV), hepatitis E virus (HEV) or HIV. For HCV co-infection, subjects who are 
anti-HCV positive and in whom HCV RNA is undetectable are considered to be not 
eligible for enrolment.  
4 
Exclusion 
Evidence of active liver disease due to autoimmune hepatitis (antinuclear antibody 
titre >1:160)  
5 
Exclusion 
Decompensated liver disease as indicated by any of the following:  
a. 
serum bilirubin >1.5 x ULN.  
b. 
prothrombin time activity <60% or INR>1.5  
c. 
Serum albumin <32g/L.  
d. 
History of previous clinical hepatic decompensation (e.g., ascites, variceal 
bleeding, or encephalopathy).  
6 
Exclusion 
Planned for liver transplantation or previous liver transplantation.  
7 
Exclusion 
Creatinine clearance less than 70 ml/min.  
8 
Exclusion 
Haemoglobin < 10 g/dL, white blood cell (WBC) count <1.5 x 109/L, platelets < 50 x 
109/L.  
9 
Exclusion 
Any serious or active medical or psychiatric illnesses other than hepatitis B which, in 
the opinion of the Investigator, would interfere with subject treatment, assessment or 
compliance with the protocol. This would include any uncontrolled clinically 
significant renal, cardiac, pulmonary, vascular, neurogenic, digestive, metabolic 
(diabetes, thyroid disorders, adrenal disease), immunodeficiency disorders, 
pathological fractures or cancer.  
10 
Exclusion 
Active alcohol or drug abuse or history of alcohol or drug abuse considered by the 
Investigator to be sufficient to hinder compliance with treatment, participation in the 
study or clinical significance of results.  
11 
Exclusion 
A female who is breastfeeding or plan to breastfeed.  
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Seq No 
Type 
Description 
12 
Exclusion 
Use of immunosuppressive therapy, immunomodulatory therapy (including IFN or 
thymosin α,), systemic cytotoxic agents, chronic antiviral agents including Chinese 
herbal medicines known to have activity against HBV (e.g., LAM, adefovir, ETV LdT 
or hepatitis B immunoglobulin (HBIg)) within the previous 6 months prior to screening 
into this study 
13 
Exclusion 
Have ever received TDF or any medicinal products containing the above mentioned 
antiviral agents or any investigative anti-HBV treatments (e.g., emtricitabine (FTC), 
(2R, 4R)-4-(2,6-Diaminopurin-9-yl)-1,3-dioxolan-2-yl]methanol (DAPD) and 1-(2-
fluoro-5-methyl-beta, Larabinofuranosyl) uracil (L-FMAU)). 
14 
Exclusion 
History of hypersensitivity to nucleoside and/or nucleotide analogues and/or any 
component of study medication.  
15 
Exclusion 
Therapy with nephrotoxic drugs (e.g., aminoglycosides, amphotercin B, vancomycin, 
cidofovir, foscarnet, cis-platinum, pentamidine etc.) or competitors of renal excretion 
(e.g., probenecid) within 2 months prior to study screening or the expectation that 
subject will receive any of these during the course of the study.  
16 
Exclusion 
Inability to comply with study requirements as determined by the study Investigator.  
 
 
 
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8.2 
Appendix 2: CHILDS-PUGH SCORE* 
Component 
Score Given 
 
 
Childs-Pugh Classification  
Childs-Pugh Class
= score 
  
Childs-Pugh Class
= score 
  
Childs-Pugh Class
= score
 
 
* Reference: Haozhu Chen, Guowei Lin. Practice of internal medicine. Edition 13. Beijing: 
People's Medical Publishing House, 2009:2082 
 
 
 
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CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI - This section contained Clinical Outcome Assessment data collection questionnaires or indices, which are protected 
by third party copyright laws and therefore have been excluded.


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8.3 
Appendix 3: Treatment-emergent Laboratory Abnormalities 
Grading Scale 
Hematology 
 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Hemogolobin 
10.0 to 10.9 g/dL 
100 to 109 g/L 
OR 
Any decrease from 
baseline 
2.5 to < 3.5 g/dL 
25 to < 35 g/L 
9.0 to < 10.0 g/dL 
90 to < 100 g/L 
OR 
Any decrease from 
baseline 
3.5 to < 4.5 g/dL 
35 to < 45 g/L 
7.0 to < 9.0 g/dL 
70 to < 90 g/L 
OR 
Any decrease from 
baseline 
≥ 4.5 g/dL 
≥ 45 g/L 
< 7.0 g/dL 
< 70 g/L 
Neutrophil (ANC) 
1000 to 1300 /mm3 
1.00 to 1.30 GI/L 
750 to < 1000 /mm3 
0.75 to < 1.00 GI/L 
500 to < 750 /mm3 
0.50 to < 0.75 GI/L 
< 500 /mm3 
< 0.50 GI/L 
Lymphocyte 
600 to 650 /mm3 
0.60 to 0.65 GI/L 
500 to < 600 /mm3 
0.50 to < 0.60 GI/L 
350 to < 500 /mm3 
0.35 to < 0.50 GI/L 
< 350 /mm3 
< 0.35 GI/L 
Platelets 
100,000 to < 125,000 
/mm3 
100 to < 125 GI/L 
50,000 to <  
100,000 /mm3 
50 to < 100 GI/L 
25,000 to <  
50,000 /mm3 
25 to < 50 GI/L 
< 25,000 /mm3 
< 25 GI/L 
White Blood Cell 
2000 to 2500 /mm3 
2.00 to 2.50 GI/L 
1500 to < 2000 /mm3 
1.50 to < 2.00 GI/L 
1000 to < 1500 /mm3 
1.00 to < 1.50 GI/L 
< 1000 /mm3 
< 1.00 GI/L 
Blood Chemistry 
ALT (SGOT) 
1.25 to 2.50×ULN 
> 2.50 to 5.00×ULN 
> 5.00 to 10.0×ULN 
> 10.0×ULN 
AST (SGPT) 
1.25 to 2.50×ULN 
> 2.50 to 5.00×ULN 
> 5.00 to 10.0×ULN 
> 10.0×ULN 
Alkaline 
Phosphatase 
1.25 to 2.50×ULN 
> 2.50 to 5.00×ULN 
> 5.00 to 10.0×ULN 
> 10.0×ULN 
Albumin 
3.0 g/dL to < LLN 
30 g/L to < LLN 
2.0 to < 3.0 g/dL 
20 to < 30 g/L 
< 2.0 g/dL 
< 20 g/L 
NA 
Hyponatremia 
130 to 135 mEq/L 
130 to 135 mmol/L 
125 to < 130 mEq/L 
125 to < 130 mmol/L 
121 to < 125 mEq/L 
121 to < 125 mmol/L 
< 121 mEq/L 
< 121 mmol/L 
Hypernatremia 
146 to 150 mEq/L 
146 to 150 mmol/L 
> 150 to 154 mEq/L 
> 150 to 154 mmol/L 
> 154 to 159 mEq/L 
> 154 to 159 mmol/L 
> 159 mEq/L 
> 159 mmol/L 
Hypokalemia 
3.0 to 3.4 mEq/L 
3.0 to 3.4 mmol/L 
2.5 to < 3.0 mEq/L 
2.5 to < 3.0 mmol/L 
2.0 to < 2.5 mEq/L 
2.0 to < 2.5 mmol/L 
< 2.0 mEq/L 
< 2.0 mmol/L 
Hyperkalemia 
5.6 to 6.0 mEq/L 
5.6 to 6.0 mmol/L 
> 6.0 to 6.5 mEq/L 
> 6.0 to 6.5 mmol/L 
> 6.5 to 7.0 mEq/L 
> 6.5 to 7.0 mmol/L 
> 7.0 mEq/L 
> 7.0 mmol/L 
Hypoglycemia 
(Fasting) 
55 to 64 mg/dL 
3.03 to 3.58 mmol/L 
40 to < 55 mg/dL 
2.20 to < 3.03 mmol/L 
30 to < 40 mg/dL 
1.64 to < 2.20 mmol/L 
< 30 mg/dL 
< 1.64 mmol/L 
Calcium (Increase) 
2.65 – 2.88 mmol/L 
2.89 – 3.13 mmol/L 
3.14 – 3.38 mmol/L 
> 3.38 mmol/L 
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Calcium (Decrease) 
1.95 – 2.10 mmol/L 
1.75 – 1.94 mmol/L 
1.53 – 1.74 mmol/L 
< 1.53 mmol/L 
Phosphorus 
(Decrease) 
NA 
2.0 to < 2.5 mg/dL 
0.63 to < 0.80 mmol/L 
1.0 to < 2.0 mg/dL 
0.31 to < 0.630 mmol/L 
< 1.0 mg/dL 
< 0.31mmol/L 
Hyperbilirubinemia 
> 1.0 to 1.5×ULN 
> 1.5 to 2.5×ULN 
> 2.5 to 5.0×ULN 
> 5.0×ULN 
Blood Urea 
Nitrogen 
1.25 to 2.50×ULN 
> 2.50 to 5.00×ULN 
> 5.00 to 10.0×ULN 
> 10.0×ULN 
Serum Creatinine 
> 1.5 to 2.0 mg/dL 
> 133 to 177 µmol/L 
> 2.0 to 3.0 mg/dL 
> 177 to 265 µmol/L 
> 3.0 to 6.0 mg/dL 
> 265 to 530 µmol/L 
> 6.0 mg/dL 
> 530 µmol/L 
Creatinine 
Phosphokinase 
3.0 to < 6.0×ULN 
6.0 to < 10.0×ULN 
10.0 to < 20.0×ULN 
≥ 20.0×ULN 
Blood Coagulation 
Prothrombin Time 
> 1.00 to 1.25×ULN 
> 1.25 to 1.50×ULN 
> 1.50 to 3.00×ULN 
> 3.00×ULN 
 
8.4 
Appendix 4: Formulas and Equations 
Ccr:  
Cockcroft-Gault (CG) formula：  
𝑪𝒄𝒓= (140 −Age) × Ideal Body Weight(kg)
72 × Scr(mg/dL) 
 
Note: If actual body weight (ABW) is lower than ideal body weight (IBW), ABW should be used. 
Calculation Formula for IBW:  
（Male）𝐼𝐵𝑊= 50𝑘𝑔+ 2.3𝑘𝑔× [𝐻𝑒𝑖𝑔ℎ𝑡(𝐼𝑛𝑐ℎ) −60]  
（Female）𝐼𝐵𝑊= 45.5𝑘𝑔+ 2.3𝑘𝑔× [𝐻𝑒𝑖𝑔ℎ𝑡(𝐼𝑛𝑐ℎ) −60]  
1 𝐼𝑛𝑐ℎ= 2.54𝑐𝑚  
 
Scr: 
(Male) 𝑆𝑐𝑟= 𝑆𝑒𝑟𝑢𝑚 𝐶𝑟𝑒𝑎𝑡𝑖𝑛𝑖𝑛𝑒 (𝑚𝑔/𝑑𝐿) 
(Female) 𝑆𝑐𝑟= 𝑆𝑒𝑟𝑢𝑚 𝐶𝑟𝑒𝑎𝑡𝑖𝑛𝑖𝑛𝑒 (𝑚𝑔/𝑑𝐿) ∗ 0.85  
GFR:  
Chronic kidney disease (CKD)-Epidemiology Collaboration (EPI) equation:  
eGFR(mL/min per 1.73 m2) = 141 × min(Scr/κ, 1)α × max(Scr/κ, 1)−1.209 × 0.993Age [ × 1.018 if 
female] [ × 1.159 if black], where Scr is serum creatinine (mg/dl), κ is 0.7 for females and 0.9 for 
males, α is −0.329 for females and −0.411 for males, min is the minimum of Scr/κ or 1, and max is 
the maximum of Scr/κ or 1 
 
Non-invasive liver fibrosis evaluation index: 
GPR (gamma glutamyl transpeptidase to platelet ratio): 
𝐺𝑃𝑅=
𝐺𝐺𝑇(/𝑈𝐿𝑁)
𝑃𝐿𝑇 𝑐𝑜𝑢𝑛𝑡𝑠(109/𝐿) × 100 
APRI (aspartate aminotransferase to platelet ratio index): 
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𝐴𝑃𝑅𝐼=
𝐴𝑆𝑇(/𝑈𝐿𝑁)
𝑃𝐿𝑇 𝑐𝑜𝑢𝑛𝑡𝑠(109/𝐿) × 100 
FIB-4 (fibrosis 4 score): 
𝐹𝐼𝐵−4 =
𝐴𝑔𝑒(𝑌𝑒𝑎𝑟𝑠) × 𝐴𝑆𝑇(𝐼𝑈/𝐿)
𝑃𝐿𝑇 𝑐𝑜𝑢𝑛𝑡𝑠(109/𝐿) × [𝐴𝐿𝑇(𝐼𝑈/𝐿)]1/2  
 
8.5 
Appendix 5: REACH-B Model  
𝐻𝐶𝐶 𝑟𝑖𝑠𝑘= 1 −𝑃0
exp(𝐹), 𝑤ℎ𝑒𝑟𝑒 
 F = (0.78798(if male) + 0.09859*(age) +  
0.38823(if 15≤ALT <44) + 0.96311(if ALT ≥45) + 0.81308 (if HBeAg positive) + 
0.11648(if 300≤HBV DNA≤9999) + 1.31467(if 104 ≤HBV DNA ≤105 −1) +  
2.27028(if 105 ≤HBV DNA ≤106 −1) + 2.09258(if HBV DNA ≥106) - 6.12796 
𝑃0 = 0.99650 if 5 –year HCC risk is estimated. 
 
9. MOCK TABLES, LISTINGS AND GRAPHS (TLGS) 
Mock TLGs will be provided in a separate document.  
 
TFL 
Number 
Title 
Table 
1.1 
Disposition 
Table 
1.2 
Major Protocol Deviations - mITT 
Table 
2.1.1 
Demographics - mITT 
Table 
2.1.2 
Baseline Characteristics - mITT 
Table 
3.1 
Compliance and Duration of the Study Drug - mITT 
Table 
4.1.1 
The Nominal Cumulative Incidence of Newly Diagnosed 
Hepatocellular Carcinoma (HCC) at Week 240 - mITT 
Table 
4.1.2 
The Nominal Cumulative Incidence of Newly Diagnosed 
Hepatocellular Carcinoma (HCC) at Week 240 - PP 
Table 
4.1.3 
The Cumulative Incidence of Newly Diagnosed Hepatocellular 
Carcinoma (HCC) - mITT 
Table 
4.1.4 
The Cumulative Incidence of Newly Diagnosed Hepatocellular 
Carcinoma (HCC) - PP 
Table 
4.2.1 
The Nominal Cumulative Incidence of Disease Progression at 
Week 240 - mITT 
Table 
4.2.2 
The Nominal Cumulative Incidence of Disease Progression at 
Week 240 - PP 
Table 
4.2.3 
The Cumulative Incidence of Disease Progression - mITT 
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Table 
4.2.4 
The Cumulative Incidence of Disease Progression - PP 
Table 
4.3.1 
The Nominal Cumulative Incidence of Newly Diagnosed 
Hepatocellular Carcinoma (HCC) by Visit - mITT 
Table 
4.3.3 
The Nominal Incidence of Newly Diagnosed Hepatocellular 
Carcinoma (HCC) by Visit - mITT 
Table 
4.4.1 
The Nominal Cumulative Incidence of Disease Progression by 
Visit - mITT 
Table 
4.5.1 
The Proportion of Subjects with Virological Response (Serum 
HBV DNA <20 IU/mL) by Visit - mITT 
Table 
4.5.1.1 
The Proportion of Subjects with Virological Response (Serum 
HBV DNA <20 IU/mL) by Baseline HBeAg Status (HBeAg 
Positive and HBeAg Negative) by Visit - mITT 
Table 
4.5.1.2 
The Proportion of Subjects with Virological Response (Serum 
HBV DNA <20 IU/mL) by Baseline HBV DNA Level (≥6 Log10 
IU/mL and <6 Log10 IU/mL) by Visit – mITT 
Table 
4.5.3 
The Proportion of Subjects with Virological Response (Serum 
HBV DNA <69 IU/mL) by Visit - mITT 
Table 
4.6.1 
The Proportion of Subjects with ALT Normalization (Lab) at 
Week 48, 96, 144, 192 and 240 in Subjects Who Have 
Abnormal ALT at Baseline - mITT 
Table 
4.6.1.1 
The Proportion of Subjects with ALT Normalization (AASLD 
Criteria) at Week 48, 96, 144, 192 and 240 in Subjects Who 
Have Abnormal ALT at Baseline - mITT 
Table 
4.7.1 
The Proportion of Subjects Achieving HBeAg Loss, HBeAg 
Seroconversion, HBsAg Loss and HBsAg Seroconversion at 
Week 48, 96, 144, 192 and 240 for Subjects with Positive 
HBeAg at Baseline - mITT 
Table 
4.7.3 
The Proportion of Subjects Achieving HBsAg Loss and HBsAg 
Seroconversion at Week 48, 96, 144, 192 and 240 for Subjects 
with Negative HBeAg at Baseline - mITT 
Table 
4.8.1 
Change from Baseline for the log10 IU/mL in Serum HBV DNA 
by Visit - mITT 
Table 
4.9.1 
Incidence of Subjects Who Experience Viral Breakthrough by 
Visit - mITT 
Table 
4.9.3 
Incidence of Subjects With Unsatisfied Response by Visit - 
mITT 
Table 
4.10.1 
The Proportion of Subjects with Histological Improvement - 
mITT 
Table 
4.11.1 
The Proportion of Subjects with Cirrhosis Reversal - mITT 
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Table 
4.12.1 
The Mean Changes of Liver Stiffness Measurement by Visit - 
mITT 
Table 
4.12.3.1.1 Shift from Baseline in Fibrosis Stage for Patients with Baseline 
ALT > ULN - mITT 
Table 
4.12.3.2.1 Shift from Baseline in Fibrosis Stage for Patients with Baseline 
ALT ≤ ULN - mITT 
Table 
4.12.3.3 
Shift from Baseline in Fibrosis Stage - mITT 
Table 
4.13.1 
Incidence of TDF Resistance Substitutions - mITT 
Table 
4.14.1 
The Relationship Between Baseline Variables or On-treatment 
Variables and Newly Diagnosed Hepatocellular Carcinoma 
(HCC) - mITT 
Table 
4.14.3 
The Relationship Between Baseline Variables or On-treatment 
Variables and Disease Progression - mITT 
Table 
4.17.1 
Cox Regression Analysis for Time to Newly Diagnosed 
Hepatocellular Carcinoma (HCC) - mITT 
Table 
4.17.3 
Cox Regression Analysis for Time to Disease Progression - 
mITT 
Table 
4.18.1 
Impact of HBV DNA and Virologic Response on Change of 
LSM - mITT 
Table 
4.18.3 
The Mean Changes of Liver Stiffness Measurement by Visit for 
Patients with Advanced Fibrosis and Compensated Cirrhosis - 
mITT 
Table 
4.18.3.1 
The % Changes of Liver Stiffness from baseline by Visit for 
Patients with Advanced Fibrosis and Compensated Cirrhosis - 
mITT 
Table 
4.19.7 
Cox Regression Analysis for Time to Improvement of Fibrosis - 
mITT 
Table 
4.20.3 
The Relationship Between Baseline Variables or On-treatment 
Variables and Improvement of Fibrosis - mITT 
Table 
4.21.1 
Proportion of LSM Improvement - mITT 
Table 
4.21.3 
Proportion of LSM Stage Improvement - mITT 
Table 
4.22.1 
Analyses of correlation coefficients between LSM and ALT level 
- mITT 
Table 
4.23.1 
Analyses of correlation coefficients between Variables Change 
at Week 12 and 24 and LSM Change at Week240 - mITT 
Table 
4.24.1 
Predicted and Observed Risk of HCC at Week240 - mITT 
Table 
5.3.4 
Mean values in Non-invasive fibrosis - SA 
Table 
5.1.1 
Overall Summary of Adverse Events - SA 
Table 
5.1.2.1 
All TEAEs by System Organ Class and Preferred Term - SA 
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Table 
5.1.2.2 
All Serious TEAEs by System Organ Class and Preferred Term - 
SA 
Table 
5.1.3.1 
All TEAEs by Relationship to Study Drug – SA 
Table 
5.1.3.2 
All Serious TEAEs by Relationship to Study Drug - SA 
Table 
5.1.4.1 
All TEAEs by Intensity – SA 
Table 
5.1.4.2 
All Serious TEAEs by Intensity - SA 
Table 
5.2 
Change from Baseline in Vital Signs - SA 
Table 
5.3.1 
Change from Baseline in Hematology - SA 
Table 
5.3.2 
Change from Baseline in Blood Chemistry - SA 
Table 
5.3.3 
Subjects with Treatment-emergent Laboratory Abnormalities - 
SA 
Listing 
1.1 
Disposition – mITT 
Listing 
1.2 
Analysis Set 
Listing 
1.3 
Major Protocol Deviations - mITT 
Listing 
2.1.1 
Demographics - mITT 
Listing 
2.1.2 
Baseline Characteristics - mITT 
Listing 
2.2.1 
Treatment History of Chronic Hepatitis B - mITT 
Listing 
2.3.1 
Medical History - mITT 
Listing 
2.3.2 
History of Treatment - mITT 
Listing 
2.3.3 
Relevant Surgery - mITT 
Listing 
2.4 
Inclusion and Exclusion Criteria - mITT 
Listing 
3.1.1 
Prior Medications - mITT 
Listing 
3.1.2 
Concomitant Medications - mITT 
Listing 
3.1.3 
Non-Drug Therapies - mITT 
Listing 
3.2.2 
Drug Accountability - mITT 
Listing 
3.3.1 
Rescue Treatment - mITT 
Listing 
4.1 
Newly Diagnosed Hepatocellular Carcinoma (HCC) and 
Disease Progression Events - mITT 
Listing 
4.2 
HBV DNA - mITT 
Listing 
4.2.3 
Listing of Subjects Mutation - mITT 
Listing 
4.3 
Hepatitis B Five Item – mITT 
Listing 
4.4 
Liver Stiffness Measurement – mITT 
Listing 
4.5 
Childs-Pugh Score – mITT 
Listing 
5.1.1 
Non-Serious Treatment-emergent Adverse Events - SA 
Listing 
5.1.2 
Serious Treatment-emergent Adverse Events - SA 
Listing 
5.1.3 
Treatment Related Treatment-emergent Adverse Events - SA 
Listing 
5.1.4 
Treatment-emergent Adverse Events Leading to Permanent 
Discontinuation of Study Drug - SA 
Listing 
5.1.5 
Treatment-emergent Adverse Events Leading to Permanent 
Discontinuation from the Study - SA 
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Listing 
5.2 
Vital Signs - SA 
Listing 
5.3.1 
Hematology - SA 
Listing 
5.3.2 
Blood Chemistry - SA 
Listing 
5.3.3 
Blood Coagulation - SA 
Listing 
5.3.4 
Urinalysis - SA 
Listing 
5.3.5 
Pregnancy Test - SA 
Listing 
5.3.6 
Alpha Fetoprotein (AFP) – SA 
Listing 
5.4 
Physical Examination - SA 
Listing 
5.5 
B-ULTRASOUND - SA 
Figure 
4.1.1 
The Cumulative Incidence (95% CI) of Newly Diagnosed 
Hepatocellular Carcinoma (HCC) Over Time in Subjects - mITT 
Figure 
4.2.1 
The Cumulative Incidence (95% CI) of Disease Progression 
Over Time - mITT 
Figure 
4.5.1 
The Proportion (95% CI) of Subjects with HBV DNA <20 IU/mL 
Over Time - mITT 
Figure 
4.5.1.1 
The Proportion (95% CI) of Subjects with HBV DNA <69 IU/mL 
Over Time - mITT 
Figure 
4.8.1.1 
Mean HBV DNA Log10 IU/mL Over Time by Baseline ALT 
Significance - mITT 
Figure 
4.8.3 
Distribution of HBV DNA levels Over Time - mITT 
Figure 
4.15.1 
Kaplan-Meier Curves for Newly Diagnosed Hepatocellular 
Carcinoma (HCC) – mITT 
Figure 
4.15.1.1.1 Kaplan-Meier Curves for Newly Diagnosed Hepatocellular 
Carcinoma (HCC) in Subjects with Platelets <100 - mITT 
Figure 
4.15.1.1.2 Kaplan-Meier Curves for Newly Diagnosed Hepatocellular 
Carcinoma (HCC) in Subjects with Platelets >=100 - mITT 
Figure 
4.15.3 
Kaplan-Meier Curves for Disease Progression – mITT 
Figure 
4.15.3.1.1 Kaplan-Meier Curves for Disease Progression in Subjects with 
Platelets <100 - mITT 
Figure 
4.15.3.1.2 Kaplan-Meier Curves for Disease Progression in Subjects with 
Platelets >=100 - mITT 
Figure 
4.18.3.1 
Decline in LSM from baseline to Week 240 - mITT 
Figure 
5.3.1.1 
Mean Estimated Glomerular Filtration Rate Over Time by 
Baseline eGFR - SA 
Figure 
5.3.1.2 
Mean Creatinine Clearance Rate Over Time by Baseline Ccr - 
SA 
Figure 
5.3.2 
Mean Serum Phosphorus Over Time - SA 
Figure 
6.1.1 
Change of Average LSM/ALT By Visit - mITT 
Figure 
6.1.2 
Change of Average LSM By Visit - mITT 
Figure 
6.1.3 
Change of Median of LSM By Visit - mITT 
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Figure 
6.3.1 
Change of Average GPR APRI FIB-4 By Visit - mITT 
Figure 
6.3.2 
Change of Median of GPR APRI FIB-4 By Visit - mITT 
Figure 
6.4.1 
Change of Fibrosis Stage By Visit - mITT 
 
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