Conditions: Hepatitis B, Chronic
Keywords: Chronic Hepatitis B Tenofovir disoproxil fumarate Failure of multiple NAs treatment
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 213
Healthy volunteers: no

Brief summary:
This is a phase IV, single-arm, open-label, multi-centre study to assess the efficacy of TDF in Chronic hepatitis B (CHB) subjects following failure of multiple Nucleos(t)ide analogues (NAs). The study will enrol 200 CHB subjects following failure of multiple NAs. Subjects will be assessed for eligibility at a screening visit, with eligible subjects returning for a baseline assessment after approximately 4 weeks (Screening phase). In the treatment phase all enrolled subjects will receive open label TDF at a dose of 300 milligrams (mg) orally once daily. All the eligible study subjects will undergo safety and efficacy assessments every 12 weeks for a total of 14 visits. Tenofovir disoproxil fumarate, the oral pro-drug of tenofovir (TFV), is a nucleotide analogue that inhibits viral polymerases by direct binding and after incorporation into deoxyribonucleic acid (DNA), by termination of the DNA) chain. TDF is a highly potent treatment in treatment-naïve and lamivudine (LAM) resistant CHB patients. The purpose of our study is to evaluate the efficacy of TDF treatment in Chinese CHB patients following failure of multiple NAs. In addition, the study will also explore the relationship of baseline factors and early HBV DNA suppression to long-term virological response. The efficacy of TDF in multi-drug resistant patients will be analysed separately. The data generated by this study could then be used to optimize the clinical application of TDF and provide new evidence for management of the HBV infections following failure of multiple NAs. The result of this study will help Chinese physicians better manage the CHB patients following failure of multiple NAs.

Detailed description:

Arms:
arm 1: All enrolled subjects will receive open label TDF at a dose of 300 milligram (mg) orally once daily during the study period.

Interventions: intervention 1: Tenofovir disoproxil fumarate
Intervention descriptions: intervention 1: Tenofovir disoproxil fumarate tablets supplied will be white, almond-shaped, film-coated tablets containing 300 mg of TDF. Each tablet contains the following inactive ingredients: microcrystalline cellulose, lactose monohydrate, pregelatinised starch, croscarmellose sodium, and magnesium stearate.

Protocol document:
Prot_001.pdf: 
2013N184141_00 
CONFIDENTIAL 
 
GlaxoSmithKline group of companies 
 
201215 
PAGE 
Division:  Medical (China) 
Information Type: Clinical Protocol 
Title: 
A multi-centre, single-arm, open-label study to evaluate the 
efficacy and safety of Tenofovir Disoproxil Fumarate(TDF) 
treatment in Chinese chronic hepatitis B (CHB) subjects 
following failure of multiple Nucleos(t)ide analogues(NAs) 
Compound Number: GSK548470 
Development Phase 
IV 
Version Date: 
[21-OCT-2015] 
 
Subject: Tenofovir disoproxil fumarate, Chronic Hepatitis B, Failure of multiple NAs 
treatment 
Author(s): 
 
                   
Copyright 2013 the GlaxoSmithKline group of companies.  All rights reserved.  
Unauthorised copying or use of this information is prohibited. 
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SPONSOR SIGNATORY: 
 
Jia Zhang 
Head of Medical, GSK China Pharmaceuticals 
 
 
Date 
 
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SPONSOR INFORMATION PAGE 
Clinical Study Identifier:   201215 
Sponsor Legal Registered Address: 
GlaxoSmithKline (China) Investment Co., Ltd. 
Building A Ocean International  
Center 56,Mid 4th East Ring Rd,  
Chao Yang district, Beijing, 100025, China 
Telephone:  
 
Sponsor Contact Address 
GlaxoSmithKline (China) Investment Co., Ltd. 
The Headquarters Building  
No.168 Tibet Road (M)  
Shanghai 200001, China 
Telephone:  
 
In some countries, the clinical trial sponsor may be the local GlaxoSmithKline affiliate 
company (or designee). Where applicable, the details of the Sponsor and contact person 
will be provided to the relevant regulatory authority as part of the clinical trial 
submission. 
Sponsor Medical Monitor Contact Information:  
Sponsor Serious Adverse Events (SAE) Contact Information:  
GSK China PV Department  
Fax: 
 
Email: 
 
Regulatory Agency Identifying Number(s): NA 
 
Medical Affairs Manager 
Medical Affairs, GlaxoSmithKline (China) Investment Co., Ltd. 
Telephone: 
 
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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 
1. 
INTRODUCTION .................................................................................................... 14 
1.1. 
Background ................................................................................................ 14 
1.2. 
Rationale .................................................................................................... 15 
1.3. 
Benefit:Risk Assessment ............................................................................ 16 
1.3.1. 
Risk Assessment ......................................................................... 16 
1.3.2. 
Benefit Assessment ..................................................................... 18 
1.3.3. 
Overall Benefit:Risk Conclusion ................................................... 19 
2. 
OBJECTIVE(S) ...................................................................................................... 19 
2.1. 
Primary Objective ....................................................................................... 19 
2.2. 
Secondary Objective ................................................................................... 19 
3. 
INVESTIGATIONAL PLAN ..................................................................................... 20 
3.1. 
Study Design .............................................................................................. 20 
3.2. 
Discussion of Design .................................................................................. 21 
4. 
SUBJECT SELECTION AND WITHDRAWAL CRITERIA ....................................... 21 
4.1. 
Number of Subjects .................................................................................... 21 
4.2. 
Inclusion Criteria ......................................................................................... 21 
4.3. 
Exclusion Criteria ........................................................................................ 22 
4.4. 
Withdrawal Criteria ..................................................................................... 24 
4.5. 
Screening/ Run-in Failures ......................................................................... 24 
5. 
STUDY TREATMENTS .......................................................................................... 24 
5.1. 
Investigational Product and Other Study Treatment .................................... 24 
5.1.1. 
Handling and Storage of Investigational Product .......................... 25 
5.1.2. 
Dosage and Administration .......................................................... 25 
5.2. 
Treatment Assignment ................................................................................ 26 
5.3. 
Blinding ....................................................................................................... 26 
5.4. 
Product Accountability ................................................................................ 26 
5.5. 
Treatment Compliance ................................................................................ 27 
5.6. 
Concomitant Medications and Non-Drug Therapies .................................... 27 
5.6.1. 
Permitted Medications and Non-Drug Therapies .......................... 27 
5.6.2. 
Prohibited Medications and Non-Drug Therapies ......................... 27 
5.7. 
Treatment after the End of the Study .......................................................... 28 
5.8. 
Treatment of Study Drug Overdose ............................................................ 28 
6. 
STUDY ASSESSMENTS AND PROCEDURES ..................................................... 29 
6.1. 
Critical Baseline Assessments .................................................................... 32 
6.2. 
Efficacy ....................................................................................................... 32 
6.2.1. 
Serum/Plasma Storage ................................................................ 32 
6.2.2. 
Virological Endpoint ..................................................................... 32 
6.2.3. 
Biochemical Endpoint .................................................................. 32 
6.2.4. 
Serological Endpoint .................................................................... 32 
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6.2.5. 
Resistance Surveillance ............................................................... 32 
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. 
Adverse Events............................................................................ 35 
6.3.2.1. 
Definition of an AE ...................................................... 36 
6.3.2.2. 
Definition of an SAE ................................................... 37 
6.3.2.3. 
Sentinel Events .......................................................... 37 
6.3.3. 
Laboratory and Other Safety Assessment Abnormalities 
Reported as AEs and SAEs ......................................................... 38 
6.3.4. 
Cardiovascular Events ................................................................. 38 
6.3.5. 
Death Events ............................................................................... 39 
6.3.6. 
Pregnancy ................................................................................... 39 
6.3.7. 
Time Period and Frequency of Detecting AEs and SAEs ............. 39 
6.3.8. 
Method of Detecting AEs and SAEs ............................................. 39 
6.3.9. 
Prompt Reporting of Serious Adverse Events and Other 
Events to GlaxoSmithKline .......................................................... 40 
6.3.9.1. 
Regulatory Reporting Requirements for SAEs ............ 40 
6.3.10. 
Serum Creatinine Elevation ......................................................... 41 
6.3.11. 
Other Safety Outcomes ............................................................... 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 
8.3.4. 
Interim Analysis ........................................................................... 43 
8.3.5. 
Key Elements of Analysis Plan .................................................... 44 
8.3.5.1. 
Efficacy analyses ........................................................ 44 
8.3.5.2. 
Safety analyses .......................................................... 44 
9. 
STUDY CONDUCT CONSIDERATIONS ............................................................... 45 
9.1. 
Posting of Information on Clinicaltrials.gov .................................................. 45 
9.2. 
Regulatory and Ethical Considerations, Including the Informed 
Consent Process ........................................................................................ 45 
9.3. 
Quality Control (Study Monitoring) .............................................................. 45 
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9.4. 
Quality Assurance ....................................................................................... 46 
9.5. 
Study and Site Closure ............................................................................... 46 
9.6. 
Records Retention ...................................................................................... 46 
9.7. 
Provision of Study Results to Investigators, Posting to the Clinical 
Trials Register and Publication ................................................................... 47 
10. REFERENCES ....................................................................................................... 48 
11. APPENDIX ............................................................................................................. 49 
11.1. 
Appendix 1: Estimated Creatinine Clearance Rate (CLcr) Formula 
and Estimated Glomerular Filtration Rate (GFR) Equation .......................... 49 
11.2. 
Appendix 2: Lactic Acidosis Guidelines ....................................................... 50 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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LIST OF ABBREVIATIONS 
ADV 
AE 
Adefovir 
Adverse event 
ALT 
Alanine aminotransferase 
AST 
Aspartate aminotransferase 
BP 
Blood pressure 
CHB 
Chronic hepatitis B 
CRF 
Case report form(s) 
CFDA 
China Food and Drug Administration 
DAPD 
(2R,4R)-4-(2,6-Diaminopurin-9-yl)-1,3-dioxolan-2-
yl]methanol 
DNA 
Deoxyribonucleic acid 
EC 
ETV 
Ethics committee 
Entecavir 
GCP 
Good Clinical Practice (Guidelines) 
HAV 
Hepatitis A virus 
HBeAg 
Hepatitis B e antigen 
HBsAg 
Hepatitis B s antigen 
HBV 
Hepatitis B virus 
HCV 
Hepatitis C virus 
HDV 
Hepatitis delta virus 
HIV 
Human immunodeficiency virus 
IB 
Investigator brochure 
IFN 
INR 
Interferon 
International Normalized Ratio 
IP 
Investigational product 
mITT 
Modified Intent-to-treat (population) 
IUD 
Inter uterine device 
IUS 
LAM 
LdT 
Inter uterine system 
Lamivudine 
Telbivudine 
L-FMAU 
1-(2-fluoro-5-methyl-beta, L-arabinofuranosyl) uracil 
LFT 
Liver function test 
LSLV 
Last subject last visit 
MedDRA 
NAs 
Medical dictionary for regulatory activities 
Nucleos(t)ide analogues  
PP 
Per protocol population 
PT 
Prothrombin time 
QD 
quaque die (Once daily) 
RAP 
Reporting and analysis plan 
SA 
Safety analysis population 
SAE 
Serious adverse event 
SOP 
Standard operating procedure 
SPM 
Study procedures manual 
TDF 
TFV 
Tenofovir disoproxil fumarate 
Tenofovir 
ULN 
Upper limit of the normal range 
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GSK 
GlaxoSmithKline 
 
 
 
 
 
 
 
Trademark Information 
Trademarks of the GlaxoSmithKline 
group of companies 
 
Trademarks not owned by the 
GlaxoSmithKline group of companies 
 Hepododin 
 
Baraclude 
  
 
Viread 
 
 
Sebivo 
 
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PROTOCOL SUMMARY 
Rationale 
Due to the widely use of  the low genetic barrier drugs as LAM(lamivudine), 
ADV(adefovir), and LdT(telbivudine), the number of patients who experienced treatment 
failure to different NA-treatment regimens has rapidly increased and poses a growing 
problem in daily clinical practice in China.  
 
Tenofovir disoproxil fumarate (TDF), the oral pro-drug of tenofovir (TFV), is a potent 
treatment for treatment-naïve and LAM-resistant CHB patients. 
 
Until recently, data on the efficacy of TDF treatment following failure of multiple NA 
regimens were limited. Patterson [Patterson, 2011]and Van Bommel [van Bommel, 2010] 
have both examined the impact of prior LAM and ADV sequential therapy on response to 
TDF. Although LAM resistance did not influence the efficacy of TDF, the effect of pre-
existing ADV resistance was more variable. In the Patterson study, the presence of 
detectable ADV resistance mutations at baseline did not affect the rate of HBV DNA 
decline during TDF therapy which was not the case in the study by van Bommel.The 
apparent discrepancy between these may be the difference in baseline HBV DNA titre.  
The mean baseline HBV DNA viral load in van Bommel’s study was much higher 
compared to the baseline HBV DNA in the Patterson study (>8.0 log10 copies/mL and 6.0 
log10 copies/ml, respectively).Due to the fact that both studies had relatively small 
numbers of patients, it is still yet to be determined how ADV-R impacts response rates to 
TDF.  
Our  study is a phase IV study and will evaluate the efficacy and safety of TDF treatment 
in Chinese CHB patients following failure of multiple NAs. In addition, the efficacy in 
patients harboring multi-drug resistance mutations prior to initiating TDF will be also 
evaluated. The result ofthis study will help Chinese physicians better manage the CHB 
patients following failure of multiple NAs. 
Objective(s)  
Primary Objective 
• 
To assess the proportion of multiple NA treatment failure chronic hepatitis B 
patients that achieve HBV DNA<20 IU/mL at week 144 of TDF treatment. 
Secondary Objective 
• To assess the efficacy of TDF following failure of multiple NAs by evaluating 
serum HBV DNA, ALT and serological responses at week 48, 96 and 144. 
• To assess the efficacy of TDF in patients harboring multi-drug resistance 
mutations prior to initiating TDF.  
• To evaluate the safety of TDF following failure of multiple NAs. 
• Evaluate the impact of the baseline characteristics (viral titer, mutation patterns, 
etc.) and early HBV DNA suppression on response to TDF. 
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Study Design 
This is a single-arm, open-label, multi-centre study to assess the efficacy of TDF in CHB 
patients following failure of multiple NAs. 
The study will enrol 200 CHB patients following failure of multiple NAs. All the eligible 
study subjects will undergo safety and efficacy assessments every 12 weeks for a total of 
14 visits.  
Screen phase (Visit 1): About 230 subjects will be assessed for eligibility at a screening 
visit, with eligible patients returning for a baseline assessment after approximately 4 
weeks. Multiple NAs treatment failure is defined as HBV DNA higher than 200 IU/ml 
after two or more different NA(s) treatments (i.e. initiate with mono-therapy, followed by 
add-on/switch rescue therapy; at least 6 months continuous treatment for each regimen, 
total duration to be no less than 12 months). At Visit 1 all the testing will be performed 
locally except for the HBV DNA quantification which will be measured by a central lab. 
The subjects will maintain their pre-existing treatment from screening visit to baseline 
visit. All subjects will provide written informed consent before screening. 
Treatment phase (Visits 2 to 14): In the 144 weeks open label period, all enrolled subjects 
will receive open label TDF at a dose of 300mg orally once daily. At each visit, subjects 
will be questioned about adverse events, concurrent medications, and study drug 
accountability; take chemistry (liver function, blood glucose, creatine phosphokinase) 
test; take electrolytes (sodium, potassium, chloridum, phosphorus and calcium) test; take 
pregnancy test; take urinalysis test; take renal function (blood creatinine clearance, blood 
urea nitrogen and blood uric acid) test. Blood routine and International Normalized 
Ratio(INR) and  HBV markers will be measured every 24 weeks. Abdominal ultrasound 
and serum alpha-fetoprotein test will be tested every 24 weeks. Serum samples will be 
collected and analyzed for HBV DNA levels in a central lab from visit 2 to 14.At visit 2, 
resistance surveillance of the HBV polymerase gene will be performed for all subjects at 
baseline by direct sequencing. 
During the treatment phase, rescue therapy will be initiated in those study subjects that do 
not achieve satisfied response to TDF, defined as 
•  Experiencing virological breakthrough (defined as HBV DNA level increase ≥1 
log10 IU/ml above the treatment nadir, confirmed on an additional visit),OR 
• Subjects have HBV DNA ≥200IU/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. 
Meanwhile, subjects to be received rescue therapy must have investigational product (IP) 
compliance > 80% in the last regular visits period (usually 12 weeks). 
Another NA(s) without cross-resistance (eg. LAM, LdT, or ETV) will be added, the 
choice to be decided by the investigator. 
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Additional Visit: During the treatment phase, subjects who do not achieve satisfied 
response to TDF(eg.experience virological breakthrough or HBV DNA level does not 
continue to decline,) need to perform another  HBV DNA test  at an additional visit at 
least one month apart. Before rescue treatment initiation, serum sample should be 
collected for resistance testing. 
 
During the treatment phase, patients that have evidence of HBsAg loss or seroconversion 
and HBeAg loss/seroconversion (for baseline HBeAg positive subjects) and HBV DNA < 
20 IU/ml at any two consecutive visits at least 3 months apart will enter a non-treatment 
observational arm of the study, and will be followed up until the end of the study 
according to protocol-defined assessments and procedures. Study treatment should be 
stopped within 15 days of the result confirming that the subject meets the criteria. 
If a patient in the non-treatment observational arm subsequently develops HBV DNA ≥20 
IU/ml, HBsAg re-emerges, and ALT > 1.5 ULN, they will be eligible to be re-treated 
with TDF up to week 144 of the study. Once the treatment is restarted, the patients should 
be followed at least every 12 weeks as protocol defined and the data will be entered as 
the corresponding scheduled visit. 
 
Study Endpoints/Assessments 
Primary Endpoint 
• 
The proportion of subjects with serum HBV DNA <20 IU/ml at week 144.  
Secondary Endpoints 
• 
The proportion of subjects with serum HBV DNA <20 IU/ml at week 48 and 96. 
• 
The proportion of subjects in the subgroup with confirmed multi-drug resistance 
at baseline with serum HBV DNA <20 IU/ml at week 48, 96 and 144. 
• 
The log10 reduction in serum HBV DNA at Week 48, 96 and144. 
• 
For HBeAg positive subjects: the proportion of subjects achieving HBeAg loss, 
HBeAg seroconversion or HBsAg loss and HBsAg seroconversion at Week 48, 
96, and 144. 
• 
For HBeAg negative subjects: the proportion of subjects achieving HBsAg loss 
and HBsAg seroconversion at Week 48, 96, and 144. 
• 
The proportion of subjects with ALT normalization at Week 48, 96, and 144 in 
subjects who have abnormal ALT at baseline. 
• 
Incidence of subjects who experience viral breakthrough (defined as  ≥ 1 log 
increase in HBV DNA from nadir determined by two sequential HBV DNA 
measurements) up to week 144. 
• 
Subject safety as determined by adverse events and laboratory assessments. 
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Exploratory Endpoints 
• 
Evaluate the impact of the baseline virological characteristics (viral titer, 
mutation patterns, etc.) and early HBV DNA suppression on response to TDF at 
week 144. 
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1. 
INTRODUCTION 
1.1. 
Background 
Chronic infection with hepatitis B virus (HBV) affects more than 350 million people 
worldwide and continues to be an important cause of morbidity and mortality, and source 
of potential new infections[Lai, 2003; Perz, 2006]. Chronic hepatitis B (CHB) has a 
broad clinical spectrum ranging from a severe, rapidly progressive illness to an 
asymptomatic, stable illness. Between one-quarter and one-third of people chronically 
infected with HBV are expected to develop progressive liver disease[Lee, 1997]. An 
estimated one million people die annually from the complications of hepatitis B, making 
CHB one of the top ten leading causes of death worldwide[Lai, 2003]. 
Effective suppression of viral replication amends the course of the disease and decreases 
morbidity. However, if viral replication resumes as a result of the development of 
resistance mutations, the clinical benefit is lost. Therefore, one aim of therapy for the 
treatment of CHB is to suppress viral replication in a potent and durable fashion to 
prevent the emergence of complications. Most CHB patients require long-term therapy, 
so oral antiviral drugs with potent antiviral activity, a low rate of HBV antiviral 
resistance and proven long-term safety are needed. 
In the last two decades, revolutionary changes happened in the management of chronic 
hepatitis B virus (HBV) infection. Nucleos(t)ide analogues (NAs) target the reverse 
transcriptase of hepatitis B virus (HBV), and are potent inhibitors of viral replication. In 
China lamivudine (LAM) was approved for the treatment of chronic hepatitis B in 1999. 
Subsequently, adefovir (ADV) and entecavir (ETV) were launched at 2005 in China. 
Then telbivudine (LdT) was licensed by CFDA (China Food and Drug Administration) in 
2008. According to the international guidelines [European Association For The Study Of 
The  Liver, 2012; Liaw, 2012; Lok, 2009], ETV and TDF should be considered for initial 
therapy for naïve patients because of superior viral suppression low risk of resistance 
development. But in a resource-limited country such as China, LAM, ADV and LdT 
remain widely used. The major problem with LAM is the high incidence of resistance, 
with up to 70% of patients developing drug related mutations after 4 years of treatment 
[Lai, 2003]. This makes it unsuitable for use as the first line oral antiviral drug in most 
circumstances. But in China LAM is still accepted as a first line antiviral agent because 
of its relatively low daily cost and well-established safety profile. Thus, the number of 
LAM resistant patients is high and management of LAM resistance is becoming a 
challenge for Chinese physicians.  
 
The treatment options for patients who develop LAM resistance have been limited. ETV 
is potent and proven to have a high genetic barrier to resistance in NA-naïve HBV 
patients. After five years of ETV mono-therapy, only 1.2% of treatment naïve patients 
developed genotypic resistance to ETV [Tenney, 2009]. However, ETV was less potent 
and the frequency of resistance was increased in LAM refractory chronic HBV patients 
[Sherman, 2008; Sherman, 2006].  After five years of treatment, 51% of LAM-refractory 
patients showed genotypic ETV-resistance and in 43% a virological breakthrough was 
also observed [Tenney, 2009]. Another option for LAM resistant patients is LAM plus 
ADV combination therapy. This approach can reduce the risk of multi-drug resistance, 
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but the HBV DNA suppression may not be adequate. Recent studies from Asia 
demonstrated that only 22.6% to 41.3% [Chung, 2011; Ryu, 2010; Sheng, 2011; Son, 
2012] of LAM resistant patients achieved HBV DNA undetectable after 48 weeks of 
ADV+LAM treatment.  
 
The prevalence of CHB patients with drug-resistance mutations has rapidly increased.  A 
population-based cross-sectional investigation[Liu, 2011] showed drug-resistant 
mutations were detected in 560 of 1803 NA(s) treatment experienced patients, 
comprising 214 patients that had received LAM, 35 patients that had received ADV, 5 
patients that had received LdT , and 306 patients that had received either sequential 
monotherapies  or combination NA(s) therapies. Therefore, the number of patients who 
experience treatment failure to different NA-treatment regimens poses a growing problem 
in daily clinical practice in China. 
 
1.2. 
Rationale 
Tenofovir disoproxil fumarate (TDF), the oral pro-drug of tenofovir (TFV), is a 
nucleotide analogue that inhibits viral polymerases by direct binding and after 
incorporation into DNA, by termination of the DNA chain [Heijtink, 1994]. TDF is a 
highly potent treatment in treatment-naïve and LAM resistant CHB patients [Baran, 
2013]. In vitro studies have shown that HBV strains expressing the ADV resistance-
associated substitutions rtA181V and/or rtN236T showed reductions in susceptibility to 
TDF ranging from 2.9-fold to 10-fold that of wild-type virus[Brunelle, 2005; Villet, 
2008], but clinical trials[Berg, 2010] showed TDF mono-therapy resulted in complete 
viral suppression in the majority of patients with partial response to ADV by week 48, 
suggesting that this drug may be an effective treatment for patients who have previously 
failed treatment with different NAs. 
 
Until recently, data on the efficacy of TDF treatment following failure of multiple NAs 
were limited. Patterson and colleagues reported the results of a prospectively conducted 
study that evaluated TDF treatment in CHB patients who had previously failed with 
LAM and followed by at least 24 weeks of ADV treatment. Serum HBV DNA at study 
entry were >105 copies/ml and >104 copies/ml in HBeAg-positive (n=40) and HBeAg 
negative patients (n=20), respectively. Those receiving combination ADV and LAM were 
switched to TDF plus LAM, and those on ADV monotherapy were switched to TDF 
monotherapy. At week 48 and 96, 27/59 (46%) and 38/59 (64%) patients achieved a 
HBV DNA <15 IU/mL. HBV DNA response was independent of baseline LAM therapy 
or mutations conferring ADV resistance. In another study, van Bommel and colleagues 
also investigated efficacy of TDF in patients with prior failure or resistance to different 
NAs. Of the 131 eligible patients in this retrospective study, 121 patients (93%) were 
LAM-experienced and 110 (85%) were ADV-experienced. Most patients had previously 
received sequential therapy with LAM and ADV (56%) or combination therapy with 
LAM and ADV (22%) after HBV DNA breakthrough during monotherapy. Three 
patients showed no response to ETV treatment. Resistance analysis in 113 of the 131 
patients revealed genotypic LAM and ADV resistance in 62% and 19% of patients, 
respectively. The overall cumulative proportion of patients achieving HBV DNA levels 
<400 copies/ml was 79% after a mean treatment duration of 23 months. Although LAM 
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resistance did not influence the antiviral efficacy of TDF, the presence of ADV resistance 
impaired TDF efficacy (100% versus 52% probability of HBV DNA <400 copies/ml, 
respectively). The apparent discrepancy between two studies may be explained by the 
different baseline HBV DNA titre. The mean baseline HBV DNA viral load in van 
Bommel’s study was much higher compared to the baseline HBV DNA in the Patterson 
study (>8.0 log10 copies/mL and 6.0 log10 copies/ml, respectively).  Due to the fact that 
both studies had relatively small numbers of patients, it is still yet to be determined how 
ADV-R impacts response rates to TDF.  
 
Our phase IV study is a multi-centre, prospective study and is expected to enrol a number 
of subjects(up to 20%) with confirmed multi-drug resistance (although the exact 
proportion of total subjects is unknown).  The purpose of our study is to evaluate the 
efficacy of TDF treatment in Chinese CHB patients following failure of multiple NAs. In 
addition, we will also explore the relationship of baseline factors and early HBV DNA 
suppression to long-term virological response. The efficacy of TDF in multi-drug 
resistant patients will be analysed separately. The data generated by this study could then 
be used to optimize the clinical application of TDF and provide new evidence for 
management of the HBV infections following failure of multiple NAs. 
 
1.3. 
Benefit:Risk Assessment 
Summaries of findings from both clinical and non-clinical studies conducted with TDF 
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 
Potential Risk of Clinical 
Significance 
Data/Rationale for Risk 
 
 
Mitigation Strategy 
 
 
Investigational Product (IP)  
Renal toxicity 
TDF 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. 
• All study drugs should 
be permanently 
discontinued in the 
event that repeat testing 
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of serum creatinine 
confirms >2 mg/dL. 
The subject should be 
followed weekly until 
the serum creatinine 
reaches within 0.3 
mg/dL elevation of the 
baseline value. (See 
section 6.3.9) 
Bone events  
 
Decreases in Bone mineral 
density (BMD) has been reported 
in adults and pediatric patients.  
• 
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, have been 
reported with the use of 
nucleoside analogs, including 
VIREAD, in combination with 
other antiretrovirals. 
• 
Guidelines for 
management of lactic 
acidosis are outlined in 
Appendix 1. 
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 
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 
• 
Estimated creatinine 
clearance will be 
assessed in all patients 
every 12 during 
treatment with TDF 
• 
TDF should be avoided 
with concurrent or 
recent use of a 
nephrotoxic agent 
according to the 
protocol(See 
section5.6.2) 
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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 withdrawal 
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. 
The effectiveness of TDF has been characterized in a large range of adult populations 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. 
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.  
No mutations associated with TDF resistance have been identified in viremic subjects 
(HBV DNA > 400 copies/ml) treated with TDF. 
A total of one hundred fifty-two subjects initiating TDF therapy in published studies 
(i.e.global studies 0102, 0103, 0106, 0108, and 0121) harbored HBV with known 
resistance substitutions to HBV nucleos(t)ide analogue reverse transcriptase inhibitors: 
14 with ADV resistance-associated substitutions (rtA181S/T/V and/or rtN236T), 135 
with LAM resistance-associated substitutions (rtM204I/V), and 3 with both ADV and 
LAM resistance-associated substitutions. Following up to 240 weeks of TDF treatment, 
11 of the 14 subjects with ADV-resistant HBV, 124 of the 135 subjects with LAM-
resistant HBV, and 2 of the 3 subjects with both ADV- and LAM-resistant HBV achieved 
and maintained virologic suppression (HBV DNA less than 400 copies/mL). Three of the 
5 subjects whose virus harbored both the rtA181T/V and rtN236T substitutions remained 
viremic. 
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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 in the setting of prior 
exposure to the NAs. 
2. 
OBJECTIVE(S) 
2.1. 
Primary Objective 
• 
To assess the proportion of  multiple NA treatment failure chronic hepatitis B 
patients that achieves HBV DNA<20 IU/mL at week 144 of TDF treatment 
2.2. 
Secondary Objective 
To assess the efficacy of TDF following failure of multiple NAs by evaluating serum 
HBV DNA, ALT and serological responses at week 48, 96 and 144. 
• The proportion of subjects with serum HBV DNA <20 IU/ml at week 48 and 96. 
• The log10 reduction in serum HBV DNA at Week 48, 96, and144. 
• For HBeAg positive subjects: the proportion of subjects achieving HBeAg loss, 
HBeAg seroconversion or HBsAg loss and HBsAg seroconversion at Week 48, 
96, and 144. 
• For HBeAg negative subjects: the proportion of subjects achieving HBsAg loss 
and HBsAg seroconversion at Week 48, 96, and 144. 
• The proportion of subjects with ALT normalization at Week 48, 96, and 144 in 
subjects who have abnormal ALT at baseline. 
• Incidence of subjects who experience viral breakthrough (defined as  ≥ 1 log 
increase in HBV DNA from nadir determined by two sequential HBV DNA 
measurements) up to week 144. 
 
To assess the efficacy of TDF in a subgroup with confirmed multi-drug resistance. 
• The proportion of subjects with multi-drug resistance mutations at baseline who 
achieve serum HBV DNA <20 IU/ml at week 48, 96, and 144.  
 
To evaluate the safety of TDF following failure of multiple NAs. 
 
To evaluate the impact of the baseline characteristics (viral titer, mutation patterns, etc.) 
and early HBV DNA suppression on response to TDF at week 144. 
 
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3. 
INVESTIGATIONAL PLAN 
3.1. 
Study Design 
This is a single-arm, open-label, multi-centre study to assess the efficacy of TDF in CHB 
patients following failure of multiple NAs. 
The study will enrol 200 CHB patients following failure of multiple NAs. All the eligible 
study subjects will undergo safety and efficacy assessments every 12 weeks for a total of 
14 visits.  
Screen phase (Visit 1): About 230 subjects will be assessed for eligibility at a screening 
visit, with eligible patients returning for a baseline assessment after approximately 4 
weeks. Multiple NAs treatment failure is defined as HBV DNA higher than 200 IU/ml 
after two or more different NA(s) treatments (i.e. initiate with mono-therapy followed by 
add-on/switch rescue therapy; at least 6 months continuous treatment for each regimen, 
total duration to be no less than 12 months).  At visit 1 all the testing will be performed 
locally except for the HBV DNA quantification which will be measured by a central lab. 
The subjects will maintain their current treatment from screening visit to baseline visit. 
All subjects will provide written informed consent before screening. 
Treatment phase (Visits 2 to 14): In the 144 weeks open label period, all enrolled subjects 
will receive open label TDF at a dose of 300mg orally once daily. At each visit, subjects 
will be questioned about adverse events, concurrent medications, and study drug 
accountability; take chemistry (liver function, blood glucose, creatine phosphokinase) 
test; take electrolytes (sodium, potassium, chloridum, phosphorus and calcium) test; take 
pregnancy test; take urinalysis test; take renal function(blood creatinine clearance, blood 
urea nitrogen and blood uric acid) test. Blood routine and International Normalized 
Ratio(INR) and  HBV markers will be measured every 24 weeks. Abdominal ultrasound 
and serum alpha-fetoprotein test will be tested every 24 weeks. Serum samples will be 
collected and analyzed for HBV DNA levels in a central lab from visit 2 to 14. 
At the visit 2, resistance surveillance of the HBV polymerase gene will be performed by 
direct sequencing for all subjects at baseline. 
During the treatment phase, rescue therapy will be initiated in those study subjects that do 
not achieve satisfied response to TDF, defined as:  
• Experiencing virological breakthrough (defined as HBV DNA level increase ≥1 
log10 IU/ml above the treatment nadir, confirmed on an additional visit, OR 
• Subjects have HBV DNA ≥200IU/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. 
Meanwhile, subjects to be received rescue therapy must have investigational product (IP) 
compliance > 80% in the last regular visits period (usually 12 weeks). 
Another NA(s) without cross-resistance (eg. LAM, LdT, or ETV) will be added, the 
choice to be decided by the investigator. 
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Additional Visit: During the treatment phase, subjects who do not achieve satisfied 
response to TDF (eg.experience virological breakthrough or HBV DNA level does not 
continue to decline,) need to perform another HBV DNA test at an additional visit at least 
one month apart. Before rescue treatment initiation, serum sample should be collected for 
resistance testing. 
During the treatment phase, patients that have evidence of HBsAg loss or seroconversion 
and HBeAg loss/seroconversion (for baseline HBeAg positive subjects) and HBV DNA < 
20 IU/ml at any two consecutive visits at least 3 months apart will enter a non-treatment 
observational arm of the study, and will be followed up until the end of the study 
according to protocol-defined assessments and procedures. Study treatment should be 
stopped within 15 days of the result confirming that the subject meets the criteria. 
If a patient in the non-treatment observational arm subsequently develops HBV DNA ≥20 
IU/ml, HBsAg re-emerges, and ALT > 1.5 ULN, they will be eligible to be re-treated 
with TDF up to week 144 of the study. Once the treatment is restarted, the patients should 
be followed at least every 12 weeks as protocol defined and the data will be entered as 
the corresponding scheduled visit. 
 
 
3.2. 
Discussion of Design 
The study is designed to evaluate the efficacy of TDF treatment in CHB patients 
following failure of multiple NAs.  
4. 
SUBJECT SELECTION AND WITHDRAWAL CRITERIA 
4.1. 
Number of Subjects 
200 qualified subjects will be included in this study and receive the TDF 300mg QD. 
 
Subjects number 
Screen   
230 
Enrolled 
200 
Completed/evaluable 170 
 
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).  
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.    
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Subjects eligible for enrolment in the study must meet all of the following criterion: 
1. Aged between 18–65years (inclusive). 
2. Male or female; 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 baseline, 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 
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 or 
cervical/vault caps) with a vaginal spermicidal agent (foam/gel/film 
/cream/suppository). 
3. The ability to understand and sign a written informed consent prior to any study-
related procedure and comply with the requirements of the study. 
4. Positive HBsAg for more than 6 months, and anti-HBs negative. 
5. Serum HBV DNA level ≥200 IU/ml at study screening (Use central lab results). 
6. Experienced multiple NAs treatment failure which is defined as HBV DNA higher 
than 200 IU/ml after two or more different NA(s) treatments (i.e. initiate with mono-
therapy, followed by add-on/switch rescue therapy; at least 6 months continuous 
treatment for each regimen, total duration to be no less than 12 months). In addition, 
subjects judged by the treating physician to have adhered to previous NA therapy. 
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: 
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1. Hepatocellular carcinoma as evidenced by one of the following: 
• 
Suspicious foci on ultrasound or radiological examination. 
• 
Normal ultrasound but serum alpha-fetoprotein >20 ng/ml at screening.  
2. Clinical signs of decompensated liver disease at baseline. These may include but are 
not limited to: 
• 
Total serum bilirubin >1.5 x ULN. 
• 
International Normalized Ratio >1.3 
• 
Serum albumin <32g/L.  
• 
History of clinical hepatic decompensation (e.g., ascites, variceal bleeding, 
or encephalopathy).  
3. Creatinine clearance less than 70 ml/min. 
4. Alanine aminotransferase >10 times ULN at screening or history of acute 
exacerbation leading to transient decompensation. 
5. Haemoglobin <8g/dL, absolute neutrophil count <1.0 x 109/L, platelets <75 x 109/L. 
6. 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. 
7. Evidence of active liver disease due to autoimmune hepatitis (antinuclear antibody 
titre >1:160) 
8. 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. 
9. 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. 
10. A female who is breastfeeding or plan to breast. 
11. Use of immunosuppressive therapy, immunomodulatory therapy (including PEG-
IFN and short-acting interferon or thymosin α,), systemic cytotoxic agents within the 
previous 6 months prior to screening. 
12. Planned for liver transplantation or previous liver transplantation.  
13. Receipt of TDF within 6 months prior to screening. 
14. 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. 
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15. History of hypersensitivity to nucleoside and/or nucleotide analogues and/or any 
component of study medication. 
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 
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 days were allowed to continue in 
the study. Subjects with treatment interruptions of ≥ 28 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, pregnancy, protocol violations, 
administrative reasons or other reasons at any time. The reason for withdrawal from the 
study must be recorded in the case report form (CRF). Subjects who have received at 
least one dose of study drug and permanently discontinue study drug for any reason, the 
investigator was required to perform the evaluations 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 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 
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(bisPOC-PMPA) of TFV (PMPA), an acyclic nucleoside phosphonate (nucleotide) 
analogue of adenosine 5’-monophosphate. TDF 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 “GILEAD” and “4331” 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.  
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 do not achieve satisfied response to TDF will add another drug without 
cross resistant to TDF 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. 
The contents of the label will be in accordance with all applicable regulatory 
requirements. 
5.1.1. 
Handling and Storage of Investigational Product 
No preparation of investigational product is required at site. 
Under normal conditions of handling and administration, investigational product (IP) is 
not expected to pose significant safety risks to site staff. A Material Safety Data Sheet 
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 
GlaxoSmithKline upon request. 
Investigational product must be stored in a secure area under the appropriate physical 
conditions for the product at room temperature lower than 30° C. Access to and 
administration of the IP 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 Tenofovir disoproxil fumarate (TDF ) 300 mg once 
daily during the study period. 
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 
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supplies, including partially used or empty bottles, must be accounted for and the 
dispensing logs must be verified by the study monitor prior to destruction or return.  
Dose reduction in the patients with renal insufficiency 
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 
TDF 300 mg every 
24 h 
TDF 300 mg every 
48 h 
TDF 300 mg every 
72 h 
TDF 300 mg every 7 
days or after a total 
of approximately 12 
h of dialysisb 
LAM tablets 100mg 
every 24h 
Use of LAM tablets is prohibited 
ETV tablets 0.5mg 
every 24h 
ETV tablets 0.5mg 
every 48h 
ETV tablets 0.5mg 
every 72h 
ETV tablets 0.5mg 
every 5 to 7 daysc 
LdT tablets 600mg 
every 24h 
LdT tablets 600mg 
every 48h 
LdT tablets 600mg 
every 72h 
LdT tablets 600mg 
every 96hd 
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. If administered on a hemodialysis day, administer ETV after the hemodialysis session. 
d. When administered on hemodialysis days, administer LdT after hemodialysis. 
5.2. 
Treatment Assignment 
This is an open label, single arm study. 
5.3. 
Blinding 
NA 
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 
the study. 
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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 
eCRF. 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 therapies, immunomodulatory 
therapies (including IFN or thymosin α), systemic cytotoxic agents, oral antiviral agents 
(e.g., didanosine, LAM, ADV, ETV, LdT, other medicinal products containing TDF, 
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 except for the 
drugs which are allowed in the  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.  
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 
must be entered into the eCRF. However, agents containing bicyclol, bifendate or 
schisandra will not be permitted in any situation.  
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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 Drug 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. In these circumstances it is 
the responsibility of the Investigator to obtain as much clinical data as possible, including 
blood samples to determine TDF, LAM, LdT or ETVdrug levels , 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) 
Baseline 
(Day 0) 
Treatment Period (Week)2 
 
Additional 
Visit 
Subjects who 
do not achieve 
satisfied 
response to 
TDF 
Early Withdrawal  
(Week off treatment) 
12w± 
6days 
24w± 
6days 
36w± 
6days 
48w± 
6days 
60w± 
6days 
72w± 
6days 
84w± 
6days 
96w± 
6days 
108w±
6days 
120w±
6days 
132w±
6days 
144w±
6days 
12w±6days 
Visit 
1 
Visit 
2 
Visit 
3 
Visit 
4 
Visit  
5 
Visit 
6 
Visit 
7 
Visit 
8 
Visit 
9 
Visit 
10 
Visit 
11 
Visit 
12 
Visit 
13 
Visit 
14 
Written informed consent 
√ 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Subject demography3 
√ 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history 
√4 
√5 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion 
criteria 
√ 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Concomitant medication6 
 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
 
√ 
Physical examination7 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
 
√ 
Vital signs8 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
 
√ 
Adverse events 
 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
 
√ 
Serious adverse events 
 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
 
√ 
Laboratory assessments 
Haematology 
√ 
√ 
 
√ 
 
√ 
 
√ 
 
√ 
 
√ 
 
√ 
 
√ 
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Chemistry (liver function, 
blood glucose, creatine 
phosphokinase) 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
 
√ 
Pregnancy test9 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
 
√ 
HCV/HDV/HIV 
√ 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
ANA 
√ 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
B-ultrasound11 
√ 
 
 
√ 
 
√ 
 
√ 
 
√ 
 
√ 
 
√ 
 
√ 
AFP 
√ 
 
 
√ 
 
√ 
 
√ 
 
√ 
 
√ 
 
√ 
 
√ 
Urinalysis12 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
 
√ 
Electrolytes (Sodium, 
potassium, chloridum, 
phosphorus and calcium) 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
 
√ 
 International Normalized 
Ratio(INR) 
√ 
√ 
 
√ 
 
√ 
 
√ 
 
√ 
 
√ 
 
√ 
 
√ 
Renal function(Blood 
Creatinine clearance, 
blood urea nitrogen and 
blood uric acid) 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
 
√ 
HBV DNA10,13 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
HBeAg/Anti-HBe 
√ 
√ 
 
√ 
 
√ 
 
√ 
 
√ 
 
√ 
 
√ 
 
√ 
HBsAg/Anti-HBs 
√ 
√ 
 
√ 
 
√ 
 
√ 
 
√ 
 
√ 
 
√ 
 
√ 
Resistance  
surveillance10,14 
 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
 
Investigational product 
 
 
 
 
Study drug dispensed 
and reconciliation of drug 
dupply15 
 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
 
√ 
Serum and plasma 
storage 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
Version： 2.1/21-OCT-2015 
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2013N184141_00 
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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 
Demographic data includes birth date, gender and race 
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 Tests will be performed at central lab.  
11 B ultrasound examination include liver, pancreas, spleen, gall bladder and kidney. 
12 Urinalysis: urine glucose, ketones, specific gravity, blood, pH and protein. 
13 HBV DNA will be tested using Roche COBAS Taqman HBV test (LLD:20IU/ML). 
14 Resistance surveillance will be performed at baseline or under the condition defined in protocol by direct sequencing of the polymerase gene. See Section 6.2.5 
15 Each study visit: All study medication to be collected and reconciled. 
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6.1. 
Critical Baseline Assessments 
Subjects will be screened within 4 weeks prior to enrolment to determine eligibility for 
participation in the study. The assessments to be performed are listed in Table 1. 
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. 
Virological Endpoint 
To evaluate the proportion of subjects with HBV DNA< 20 IU/mL at week 48,96 ,144 
and viral load change over time, HBV DNA level will be quantified using the sensitive 
HBV test in central lab at times outlined in Table 1. 
6.2.3. 
Biochemical Endpoint 
To evaluate the ALT normalization at week 48, 96 and 144, ALT will be measured at 
times outlined in Table 1. 
6.2.4. 
Serological Endpoint 
To evaluate the serological response at week 48, 96 and 144, HBeAg/anti-HBe and 
HBsAg/anti-HBs will be measured at times outlined in Table 1. 
6.2.5. 
Resistance Surveillance 
Resistance surveillance including genotypic analysis of the HBV polymerase gene will be 
performed on stored serum by direct sequencing using a central laboratory in the 
following situations:  
• 
All subjects at baseline. 
• 
Subjects that do not achieve satisfied response to TDF(see section 3.1) 
• 
Subjects remain HBV DNA detectable at week 48, 96, or their last visit in 
the study. 
Version： 2.1/21-OCT-2015 
32 
 


2 0 1 3 N 1 8 4 1 4 1 _ 0 0  
C O N FI D E N TI A L  
 
 
 
2 0 1 2 1 5  
6. 3.  
S af et y  
6. 3. 1.  
O n -Tr e at m e nt A L T Fl ar e, A L T El e v ati o n Wit h or Wit h o ut H e p ati c 
D y sf u n cti o n, a n d P o st -Tr e at m e nt E x a c er b ati o n of H e p atiti s 
M a n a g e m e nt  
D E FI NI TI O N S  
A L T F L A R E  
A L T B ot h > 2 x baseli ne 
val ue a n d > 1 0 x U L N 
See Secti o n 6. 3. 1. 1  
A L T E L E V A TI O N Wit h 
H E P A TI C D Y S F U N C TI O N  
A L T B ot h > 2 x na dir val u e 
a n d > 5 x U L N wit h e vi de nce 
of w orse n e d he patic f u ncti o n 
(e. g. Direct 
Bilir u bi n > 1. 5 m g/ d L I N R ≥
1. 7, or a b n or mal ser u m 
al b u mi n ≤2. 7) 
See Secti o n 6. 3. 1. 1  
A L T E L E V A TI O N A L O N E  
A L T B ot h > 2 x na dir val u e 
a n d > 5 x U L N 
See Secti o n 6. 3. 1. 2  
6. 3. 1. 1.  
M a n a g e m e nt of A L T Fl ar e or A L T El e v ati o n Wit h H e p ati c D y sf u n cti o n i n 
S u bj e ct s R e c ei vi n g St u d y M e di c ati o n  
If la b orat or y res ults i n dicate A L T Fl are or  A L T Ele v ati o n Wit h He p atic D ysf u ncti o n 
t he f oll o wi n g is rec o m me n de d: 
 
S c he d ule t he s u bject t o ret ur n t o t he cli nic as s o o n as p ossi ble (i d eall y wit hi n 3 da ys 
after i nitial la b orat or y res ults were dra w n). D uri n g t he visit, a cli nical assess me nt of t he 
s u bject will be perf or me d. T he assess me nt s h o ul d i ncl u de a p h ysical e x a mi nati o n a n d 
e val uati o n of t he s u bject’s me ntal stat us.  
C he c k t he f oll o wi n g la b orat or y para m eters: ser u m A L T a n d A S T, al kali ne 
p h os p hatase, t otal a n d dir ect bilir u bi n, I N R, a n d ser u m al b u mi n. 
If the A L T Fl are or A L T Ele v ati o n Wit h He p atic D ysf u ncti o n  is c o nfir me d, 
re q uest t he cli nical la b or at or y t o c o n d uct refle x testi n g f or plas ma H B V D N A, ser ol o g y 
f or H B V ( H Bs A g, H Be A g, H Be A b, a n d H Bs A b), H D V, H A V I g M, H C V, a n d H E V 
Bas e d o n t h e res ults of t h e c o nfir mat or y t ests, t he f oll o wi n g treat me nt m o dificati o ns are 
rec o m me n de d: 
E vi de nce of w orse ni n g H B V i nf ecti o n:  
•  If Plas ma H B V D N A is i ncreasi n g ( ≥1 l o g i ncreas e), t he i n vesti gat or s h o ul d disc uss 
i nitiati o n of a d diti o nal t hera p y wit h t he me dical m o nit or. 
V ersi o n ： 2. 1/2 1 -O C T -2 0 1 5  
3 3  
 


2013N184141_00 
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201215 
 
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. 
 
If patients worsen to reach ALT Flare definition or ALT Elevation with  hepatic 
dysfunction,manage as above in Section 6.3.1.1. 
 
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2013N184141_00 
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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 2 for the recommend method for managing lactic acidosis 
6.3.2. 
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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6.3.2.1. 
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. 
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.  For marketed medicinal products, this 
also includes failure to produce expected benefits (i.e., lack of efficacy), abuse or misuse. 
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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6.3.2.2. 
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. 
6.3.2.3. 
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: 
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2013N184141_00 
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• 
Acquired Long QT Syndrome 
• 
Agranulocytosis/Severe Neutropenia  
• 
Anaphylaxis & Anaphylactoid Reactions  
• 
Hepatotoxicity 
• 
Acute Renal Failure 
• 
Seizure 
• 
Stevens Johnson syndrome/Toxic epidermal necrosis 
6.3.3. 
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.  
6.3.4. 
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 
This information should be recorded in the specific cardiovascular eCRF within one week 
of when the AE/SAE(s) are first reported. 
 
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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. 
This information should be recorded in the specific death eCRF within one week of when 
the death is first reported. 
6.3.6. 
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. 
6.3.7. 
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 6.3.8.  
6.3.8. 
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?” 
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“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?” 
6.3.9. 
Prompt Reporting of Serious Adverse Events and Other Events 
to GlaxoSmithKline 
Serious adverse events, pregnancies and liver function abnormalities meeting pre-defined 
criteria will be reported promptly by the Investigator to GlaxoSmithKline 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 h 
“SAE” data 
collection tool 
24 h 
Updated “SAE” 
data collection tool 
Pregnancy 
2 Weeks 
Pregnancy 
Notification Form 
2 Weeks 
Pregnancy Follow-
up Form 
Adverse Drug 
Reaction 
(ADR) 
5 calendar 
days 
ADR 
Form 
5 calendar days 
ADR  Follow-up 
Form 
6.3.9.1. 
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. 
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. 
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6.3.10. 
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 >2.0 mg/dL. The subject should be followed weekly until the 
serum creatinine reaches within 0.3 mg/dL of the baseline value. 
6.3.11. 
Other Safety Outcomes 
Laboratory Assessments 
All protocol required laboratory assessments, as defined in Table 1, must be performed 
by the central laboratory, [Guangzhou Tigermed Research Institution Co., 
Ltd].  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 [Guangzhou Tigermed Research Institution Co., 
Ltd].  Reference ranges for all safety parameters will be provided to the site by 
[Guangzhou Tigermed Research Institution Co., Ltd]. 
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.   
 
7. 
DATA MANAGEMENT 
For this study subject data will be collected using GlaxoSmithKline defined CRFs and 
combined with data provided from other sources in a validated data system. 
Management of clinical data will be performed in accordance with applicable 
GlaxoSmithKline 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 terms will be coded using MedDRA and an internal validated 
medication dictionary, GSK Drug. [An appropriate medical dictionary that covers all 
approved drugs in the region will be referenced.] Original CRFs will be retained by 
GlaxoSmithKline, while the Investigator will retain a copy. In all cases, subject initials 
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will not be collected or transmitted to GlaxoSmithKline, according to GlaxoSmithKline 
policy.  
8. 
DATA ANALYSIS AND STATISTICAL CONSIDERATIONS 
8.1. 
Hypotheses 
No hypothesis is tested in this study. 
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 proportion of subjects with serum HBV DNA <20 IU/ml of 
TDF in multiple NAs treatment failure patients at Week 144. 
To decide the number of subjects for analysis, some precision calculations have been 
performed. From our historical data, we hypothesize that the proportion of subjects with 
serum HBV DNA <20 IU/ml in multiple NAs treatment failure patients treated with TDF 
at Week 144 was 80%. A sample size of 170 patients will allow us to estimate the 
confidence interval of the incidence with a margin of error at ± 6% (range from 74-86%). 
Assuming a dropout rate of 15 per cent during a 144 week period, the number of patients 
required overall is estimated to be 200. 
Formulae for the sample size estimation. 
As Margin of error is: E = z𝑐ට𝑝(1−𝑝)
𝑛
 
So, the sample size required is:    N = p(1 −𝑝) ቀ
𝑧𝑐
𝑒ቁ
2
 
8.2.2. 
Sample Size Sensitivity 
The sample size estimate is sensitive to the assumed proportions and the margin of error. 
The estimated sample size for several scenarios is presented in Table 2.  
Table 2 
Sample Size Sensitivity Table 
Assumed 
proportion 
Margin of 
error 
95% confidence 
interval 
Sample Size 
75% 
5% 
(70%,80%) 
288 
75% 
6% 
(69%,81%) 
200 
75% 
7% 
(68%,82%) 
147 
80% 
5% 
(75%,85%) 
246 
80% 
6% 
(74%,86%) 
170 
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80% 
7% 
(73%,87%) 
125 
85% 
5% 
(80%,90%) 
196 
85% 
6% 
(79%,91%) 
136 
85% 
7% 
(78%,92%) 
100 
 
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: 
• 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 with the exception of 
major protocol violators. 
  
• 
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.  
 
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 
It is a single arm study and no comparison will be performed. 
8.3.4. 
Interim Analysis 
No interim analysis is planned for this study. 
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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 unless otherwise specified. 
All serum HBV DNA results below the lower limit of detection will be analysed as being 
the value of the lower limit of detection. 
For the primary analysis of HBV DNA<20IU /ml at Week 144, data from non-completers 
will be considered to be “failures”. 
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. 
 
For the primary endpoint, descriptive analysis will be used to evaluate the efficacy of 
TDF in multiple NAs treatment failure patients.  
 
Multiple-factor analysis will be used to assess the baseline variables that were 
significantly associated with HBV DNA negativity at week 144. 
 
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.  
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 
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. 
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• 
All AEs that caused a change in dose or temporary interruption of study 
drug. 
9. 
STUDY CONDUCT CONSIDERATIONS 
9.1. 
Posting of Information on Clinicaltrials.gov 
Study information from this protocol will be posted on clinicaltrials.gov before enrolment 
of subjects begins. 
9.2. 
Regulatory and Ethical Considerations, Including the 
Informed Consent Process 
Prior to initiation of a study site, GlaxoSmithKline will obtain approval from the 
appropriate regulatory agency to conduct the study in accordance with applicable 
country-specific regulatory requirements, including those required under a United States 
of America Investigational New Drug application. 
The study will be conducted in accordance with Good Clinical Practice (GCP), all 
applicable subject privacy requirements, and the ethical principles that are outlined in the 
Declaration of Helsinki 2008, including, but not limited to: 
• 
Ethics committee review and approval of study protocol and any subsequent 
amendments. 
• 
Subject informed consent. 
• 
Investigator reporting requirements. 
GlaxoSmithKline will provide full details of the above procedures, either verbally, in 
writing or both. 
Written informed consent must be obtained from each subject prior to participation in the 
study. 
9.3. 
Quality Control (Study Monitoring) 
In accordance with applicable regulations, GCP and GlaxoSmithKline procedures, 
GlaxoSmithKline 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 GlaxoSmithKline 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. 
GlaxoSmithKline 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. 
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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, 
GlaxoSmithKline may conduct a quality assurance 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 audit or inspection, the Investigator (and 
institution) must agree to grant the auditor(s) and inspector(s) direct access to all relevant 
documents and to allocate their time and the time of their staff to discuss any 
findings/relevant issues. 
9.5. 
Study and Site Closure 
Upon completion or termination of the study, the GlaxoSmithKline monitor will conduct 
site closure activities with the Investigator or site staff (as appropriate), in accordance 
with applicable regulations, GCP and GlaxoSmithKline Standard Operating Procedures 
(SOPs). 
GlaxoSmithKline 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 GlaxoSmithKline determines that such action is required, 
GlaxoSmithKline will discuss the reasons for taking such action with the Investigator or 
head of the medical institution (where applicable). When feasible, GlaxoSmithKline 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, GlaxoSmithKline will promptly 
inform all Investigators, heads of the medical institutions (where applicable) and/or 
institutions conducting the study. GlaxoSmithKline 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 EC 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 GlaxoSmithKline 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 
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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. 
GlaxoSmithKline 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, GlaxoSmithKline SOPs and/or institutional requirements. 
The Investigator must notify GlaxoSmithKline 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 to the 
Clinical Trials Register 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 
opportunity to review the complete study results at a GlaxoSmithKline site or other 
mutually agreeable location. 
GlaxoSmithKline 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. 
GlaxoSmithKline 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 at the time of the first 
regulatory approval or within 12 months of any decision to terminate development. In 
addition, a manuscript will be submitted to a peer-reviewed journal for publication within 
12 months of the first approval or within 12 months of any decision to terminate 
development. When manuscript publication in a peer-reviewed journal is not feasible, 
further study information will be posted to the GlaxoSmithKline Clinical Study Register 
to supplement the results summary.  
The results summary will be posted to the Clinical Study Register no later than 
12 months after last subject last visit (LSLV) or sooner if required by legal agreement, 
local law or regulation. In addition, a manuscript will be submitted to a peer-reviewed 
journal for publication within 18 months of LSLV. When manuscript publication in a 
peer-reviewed journal is not feasible, further study information will be posted to the 
GlaxoSmithKline Clinical Study Register to supplement the results summary.  
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 
Baran, B., O. M. Soyer, A. C. Ormeci, et al. Efficacy of tenofovir in patients with 
Lamivudine failure is not different from that in nucleoside/nucleotide analogue-
naive patients with chronic hepatitis B, Antimicrob Agents Chemother, 2013; 57: 
1790-1796. 
Berg, T., P. Marcellin, F. Zoulim, et al. Tenofovir is effective alone or with emtricitabine 
in adefovir-treated patients with chronic-hepatitis B virus infection, 
Gastroenterology, 2010; 139: 1207-1217. 
Brunelle, M. N., A. C. Jacquard, C. Pichoud, et al. Susceptibility to antivirals of a human 
HBV strain with mutations conferring resistance to both lamivudine and adefovir, 
Hepatology, 2005; 41: 1391-1398. 
Chung, G. E., W. Kim, K. L. Lee, et al. Add-on adefovir is superior to a switch to 
entecavir as rescue therapy for Lamivudine-resistant chronic hepatitis B, Dig Dis 
Sci, 2011; 56: 2130-2136. 
European Association For The Study Of The  Liver. EASL clinical practice guidelines: 
Management of chronic hepatitis B virus infection, J Hepatol, 2012; 57: 167-185. 
Heijtink, R. A., J. Kruining, G. A. de Wilde, et al. Inhibitory effects of acyclic nucleoside 
phosphonates on human hepatitis B virus and duck hepatitis B virus infections in 
tissue culture, Antimicrob Agents Chemother, 1994; 38: 2180-2182. 
Lai, C. L., J. Dienstag, E. Schiff, et al. Prevalence and clinical correlates of YMDD 
variants during lamivudine therapy for patients with chronic hepatitis B, Clin 
Infect Dis, 2003; 36: 687-696. 
Lai, C. L., V. Ratziu, M. F. Yuen, et al. Viral hepatitis B, Lancet, 2003; 362: 2089-2094. 
Lee, W. M. Hepatitis B virus infection, N Engl J Med, 1997; 337: 1733-1745. 
Liaw, Yun-Fan, Jia-Horng Kao, Teerha Piratvisuth, et al. Asian-Pacific consensus 
statement on the management of chronic hepatitis B: a 2012 update, Hepatology 
International, 2012; 6: 531-561. 
Liu, Y., C. Wang, Y. Zhong, et al. Genotypic resistance profile of hepatitis B virus (HBV) 
in a large cohort of nucleos(t)ide analogue-experienced Chinese patients with 
chronic HBV infection, J Viral Hepat, 2011; 18: e29-39. 
Lok, A. S., and B. J. McMahon. Chronic hepatitis B: update 2009, Hepatology, 2009; 50: 
661-662. 
Patterson, S. J., J. George, S. I. Strasser, et al. Tenofovir disoproxil fumarate rescue 
therapy following failure of both lamivudine and adefovir dipivoxil in chronic 
hepatitis B, Gut, 2011; 60: 247-254. 
Perz, J. F., G. L. Armstrong, L. A. Farrington, et al. The contributions of hepatitis B virus 
and hepatitis C virus infections to cirrhosis and primary liver cancer worldwide, J 
Hepatol, 2006; 45: 529-538. 
Ryu, H. J., J. M. Lee, S. H. Ahn, et al. Efficacy of adefovir add-on lamivudine rescue 
therapy compared with switching to entecavir monotherapy in patients with 
lamivudine-resistant chronic hepatitis B, J Med Virol, 2010; 82: 1835-1842. 
Sheng, Y. J., J. Y. Liu, S. W. Tong, et al. Lamivudine plus adefovir combination therapy 
versus entecavir monotherapy for lamivudine-resistant chronic hepatitis B: a 
systematic review and meta-analysis, Virol J, 2011; 8: 393. 
Sherman, M., C. Yurdaydin, H. Simsek, et al. Entecavir therapy for lamivudine-
refractory chronic hepatitis B: improved virologic, biochemical, and serology 
outcomes through 96 weeks, Hepatology, 2008; 48: 99-108. 
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Sherman, M., C. Yurdaydin, J. Sollano, et al. Entecavir for treatment of lamivudine-
refractory, HBeAg-positive chronic hepatitis B, Gastroenterology, 2006; 130: 
2039-2049. 
Son, C. Y., H. J. Ryu, J. M. Lee, et al. Lamivudine plus adefovir vs. entecavir in HBeAg-
positive hepatitis B with sequential treatment failure of lamivudine and adefovir, 
Liver Int, 2012; 32: 1179-1185. 
Tenney, D. J., R. E. Rose, C. J. Baldick, et al. Long-term monitoring shows hepatitis B 
virus resistance to entecavir in nucleoside-naive patients is rare through 5 years of 
therapy, Hepatology, 2009; 49: 1503-1514. 
van Bommel, F., R. A. de Man, H. Wedemeyer, et al. Long-term efficacy of tenofovir 
monotherapy for hepatitis B virus-monoinfected patients after failure of 
nucleoside/nucleotide analogues, Hepatology, 2010; 51: 73-80. 
Villet, S., C. Pichoud, G. Billioud, et al. Impact of hepatitis B virus rtA181V/T mutants 
on hepatitis B treatment failure, J Hepatol, 2008; 48: 747-755. 
Zoulim, F., and S. Locarnini. Management of treatment failure in chronic hepatitis B, J 
Hepatol, 2012; 56 Suppl 1: S112-122. 
 
 
11. 
APPENDIX 
 
11.1. 
Appendix 1: Estimated Creatinine Clearance Rate (CLcr) 
Formula and Estimated Glomerular Filtration Rate (GFR) 
Equation 
Creatinine clearance rate(CLcr)  using Cockcroft-Gault (CG) formula： 
CLcr=[(140-Age)×Ideal Body  Weight(kg)]/[72×Scr(mg/dl)] 
Scr=Serum Creatinine in mg/dl；for femal Multiplied by the coefficient of 0.85 
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(Inches)-60] 
(Female)IBW=45.5kg+2.3kg×[Height(Inches)-60] 
1Inch=2.54cm 
 
Glomerular filtration rate is estimated by Chronic kidney disease (CKD)-Epidemiology 
Collaboration (EPI) equation: 
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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 
 
11.2. 
Appendix 2: 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. 
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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. 
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.  
1. Have subject sit, relaxed for 5 minutes prior to venepuncture. 
2. Instruct subject not to clench the fist before or during the procedure and to relax the 
hand as much as possible. 
3. 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. 
4. Collect the blood in a chilled gray-top (sodium fluoride-potassium oxalate) tube. 
5. Place the specimen immediately on ice and send to the laboratory for immediate 
processing, preferably within 30 minutes of collection. 
6.  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. 
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201215 Protocol Amendment Summary                                                               CONFIDENTIAL 
GlaxoSmithKline group of companies 
 
                                                                  page 1 of 4 
 
 
 
Protocol Amendment Summary 1 
 
Protocol Number:201215 
 
 
Protocol Title：A multi-centre, single-arm, open-label study to evaluate the efficacy and safety of 
Tenofovir Disoproxil Fumarate(TDF) treatment in Chinese chronic hepatitis B (CHB) subjects following 
failure of multiple Nucleos(t)ide analogues(NAs) 
 
 
 Clinical Study Identifier: 201215 
 
Sponsor Legal Registered Address: 
GlaxoSmithKline (China) Investment Co., Ltd. 
 
 
 
 
 
 
 
 
 
 
Confidential 
Copyright 2013 the GlaxoSmithKline group of companies.  All rights reserved.  Unauthorised copying or use 
of this information is prohibited. 


201215 Protocol Amendment Summary                                                               CONFIDENTIAL 
GlaxoSmithKline group of companies 
 
                                                                  page 2 of 4 
 
Protocol Amendment Summary 1 
This protocol amendment summary applies to all sites in China.  
Summary of amendment changes with rationale.  
 
Section 
Previous Text   (Version: 1.0/16-May-2014) 
Revised Text(Version: 2.0/27-May-2015) 
Rationale 
4.3. 
Exclusion 
Criteria 
Page 23 
1.Hepatocellular carcinoma as evidenced by one of the 
following: 
• 
Suspicious foci on ultrasound or radiological 
examination. 
• 
Normal ultrasound but a history of rising serum 
alpha-fetoprotein and serum alpha-fetoprotein >20 ng/ml 
at screening. 
1.Hepatocellular carcinoma as evidenced by one of 
the following: 
• 
Suspicious foci on ultrasound or radiological 
examination. 
• 
Normal ultrasound but a history of rising 
serum alpha-fetoprotein and serum alpha-fetoprotein 
>20 ng/ml at screening. 
History of rising 
serum alpha-
fetoprotein maybe 
due to chronic 
inflammation instead 
of carcinoma. And 
such history is not 
usually reliable but 
better to be regarded 
as only reference but 
not solid evidence for 
diagnosis. 
Table 1 Time and 
Events Table 
Page 30 
 
Early Withdrawal  
Add Pregnancy test, AFP, B ultrasound examination  
and reconciliation of drug supply 
For safety reason. 
6.2.5. Resistance 
Surveillance 
Page 32 
• 
Subjects that do not achieve satisfied response to 
TDF(see section 3.2) 
• 
Subjects that do not achieve satisfied response 
to TDF(see section 3.21) 
Correct the reference. 
TABLE OF 
CONTENTS 
11.1. 
Appendix 1: Estimated Glomerular Filtration Rate 
(GFR) Equation 
11.1. 
Appendix 1: Estimated creatinine 
clearance rate (CLcr) using Cockcroft-
Gault formula and Estimated 
Glomerular Filtration Rate (GFR) 
Equation 
Consistence with the 
content of Appendix 
11.1 


201215 Protocol Amendment Summary                                                               CONFIDENTIAL 
GlaxoSmithKline group of companies 
 
                                                                  page 3 of 4 
 
11.1 Appendix 1 
Page 49 
11.1 
Appendix 1: Estimated Glomerular Filtration 
Rate (GFR) Equation 
         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 
 
11.1 
Appendix 1: Estimated Creatinine 
Clearance Rate (CLcr) Formula and 
Estimated Glomerular Filtration Rate 
(GFR) Equation 
Creatinine clearance rate(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 body  weight (IBW), ABW should be used.  
Calculation Formula for IBW: 
(Male)IBW=50kg+2.3kg×[Height(Inches)-60] 
(Female)IBW=45.5kg+2.3kg×[Height(Inches)-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 
CLcr is a little 
different from GRF.  
In the protocol, the 
renal insufficiency 
was defined by serum 
creatinine clearance. 
So we provide the 
CLcr calculation 
(Cockcroft-
Gault, CG) formula. 


201215 Protocol Amendment Summary                                                               CONFIDENTIAL 
GlaxoSmithKline group of companies 
 
                                                                  page 4 of 4 
 
 
6.3.9. Prompt 
Reporting of 
Serious Adverse 
Events and Other 
Events to 
GlaxoSmithKline 
Page 40 
 
Initial Reports 
Follow-up 
Information on a 
Previous Report 
Type of 
Event 
Time 
Frame 
Documen
ts 
Time 
Frame 
Documen
ts 
All SAEs 
24 h 
“SAE” 
data 
collection 
tool 
24 h 
Updated 
“SAE” 
data 
collection 
tool  
Pregnancy 
2 
Weeks 
Pregnanc
y 
Notificatio
n Form 
2 Weeks Pregnanc
y Follow-
up Form 
 
 
Initial Reports 
Follow-up 
Information on a 
Previous Report 
Type of 
Event 
Time 
Frame 
Docume
nts 
Time 
Frame 
Docume
nts 
All SAEs 
24 h 
“SAE” 
data 
collection 
tool 
24 h 
Updated 
“SAE” 
data 
collection 
tool  
Pregnancy 
2 
Weeks 
Pregnan
cy 
Notificati
on Form 
2 Weeks Pregnan
cy 
Follow-
up Form 
Adverse 
Drug 
Reaction 
(ADR) 
5 
calend
ar days 
ADR 
Form 
5 
calendar 
days 
ADR  
Follow-
up 
Form 
To align with new 
local 
pharmacovigilance 
requirements. 
SPONSOR 
INFORMATION 
PAGE 
Page 3 
Sponsor Medical Monitor Contact Information:  
 
 
Medical Affairs Physician 
Medical Affairs, GlaxoSmithKline (China) Investment 
Co., Ltd. 
Telephone:
Cell phone:
Sponsor Medical Monitor Contact Information:  
 
 
Medical Affairs Manager 
Medical Affairs, GlaxoSmithKline (China) Investment 
Co., Ltd. 
Telephone: 
 
 
Role transition. 
SPONSOR 
INFORMATION 
PAGE 
Page 3 
Sponsor Serious Adverse Events (SAE) Contact Information:  
GSK China PV Department  
Fax: 
 
Email:  
  
Sponsor Serious Adverse Events (SAE) Contact 
Information:  
GSK China PV Department  
Fax: 
 
Email: 
 
 
 
Information update 
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD


201215 Protocol Amendment Summary                                                               CONFIDENTIAL 
GlaxoSmithKline group of companies 
 
 
Protocol Amendment Summary 2 
 
Protocol Number:201215 
 
 
Protocol Title：A multi-centre, single-arm, open-label study to evaluate the efficacy and safety of 
Tenofovir Disoproxil Fumarate(TDF) treatment in Chinese chronic hepatitis B (CHB) subjects following 
failure of multiple Nucleos(t)ide analogues(NAs) 
 
 
 Clinical Study Identifier: 201215 
 
Sponsor Legal Registered Address: 
GlaxoSmithKline (China) Investment Co., Ltd. 
 
 
 
 
 
 
 
 
 
 
Confidential 
Copyright 2013 the GlaxoSmithKline group of companies.  All rights reserved.  Unauthorised copying or use 
of this information is prohibited. 
 
                                                                  page 1 of 2 
 


201215 Protocol Amendment Summary                                                               CONFIDENTIAL 
GlaxoSmithKline group of companies 
Protocol Amendment Summary 2 
This protocol amendment summary applies to all sites in China.  
Summary of amendment changes with rationale.  
 
 
Section 
Previous Text   ( Version: 2.0/27-May-2015) 
Revised Text(Version: 2.1/21-Oct-2015) 
Rationale 
3.1. 
Study 
Design 
Page 11 
Abdominal ultrasound and serum alpha-fetoprotein test 
will be tested every 48 weeks. 
Abdominal ultrasound and serum alpha-fetoprotein 
test will be tested every 48 24 weeks. 
According to the 
protocol, abdominal 
ultrasound and serum 
alpha-fetoprotein test 
will be tested every 48 
weeks. But the 
guidelines for the 
treatment of persons 
with Chronic Hepatitis 
B recommend: Routine 
surveillance for HCC 
with abdominal 
ultrasound and alpha-
fetoprotein testing 
every six months.  
For safety reason, we 
decided to adjust the 
abdominal ultrasound 
and alpha-fetoprotein 
testing every 24weeks. 
3.1. 
Study 
Design 
Page 20 
Abdominal ultrasound and serum alpha-fetoprotein test 
will be tested every 48 weeks. 
Abdominal ultrasound and serum alpha-fetoprotein 
test will be tested every 48 24 weeks. 
Table 1 Time and 
Events Table 
Page 30 
 
Add AFP, B ultrasound examination at 24w, 72w 
and 120w. 
 
                                                                  page 2 of 2 
 

SAP_000.pdf: 
GlaxoSmithKline (China) Investment Co., Ltd.                                    Version：Final 
Protocol 201215                                                               Dec 03, 2018 
 
1 
 
 
Statistical Analysis Plan 
 
 
 
 
 
 
 
A multi-centre, single-arm, open-label study to evaluate the 
efficacy and safety of Tenofovir Disoproxil Fumarate (TDF) 
treatment in Chinese chronic hepatitis B (CHB) subjects 
following failure of multiple Nucleos(t)ide analogues(NAs) 
 
 
 
 
 
 
Sponsor: GlaxoSmithKline (China) Investment Co., Ltd. 
Version: Final 
Date: Dec 03, 2018 
 


PPD
PPD
PPD
PPD
PPD


GlaxoSmithKline (China) Investment Co., Ltd.                                    Version：Final 
Protocol 201215                                                               Dec 03, 2018 
 
3 
 
Approval 
 
 
 
 
 
____________________                                   Date: __________________ 
Statistician 
GlaxoSmithKline (China) Investment Co., Ltd. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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TABLE OF CONTENTS 
 
1. INTRODUCTION ........................................................................................................................ 7 
2. STUDY OBJECTIVE ................................................................................................................... 7 
2.1 Primary objective ................................................................................................................ 7 
2.2 Secondary objective ............................................................................................................ 7 
3. STUDY DESIGN .......................................................................................................................... 7 
3.1 Overall study design ............................................................................................................ 7 
3.2 Sample size ......................................................................................................................... 8 
4. ANALYSIS SET ........................................................................................................................... 9 
5. STUDY ENDPONITS .................................................................................................................. 9 
5.1 Primary endpoint ................................................................................................................. 9 
5.2 Secondary endpoints ......................................................................................................... 10 
5.3 Exploratory endpoints ....................................................................................................... 10 
6. STATISTICAL CONSIDERATIONS ......................................................................................... 11 
6.1 General rule ....................................................................................................................... 11 
6.2 Data handling .................................................................................................................... 11 
7. STATISTICAL ANALYSIS ........................................................................................................ 11 
7.1 Subject screening, disposition and protocol deviations ..................................................... 11 
7.2 Subject Information ........................................................................................................... 12 
7.2.1 Demographics and baseline characteristics ............................................................ 12 
7.2.2 Medical history ...................................................................................................... 13 
7.2.3 Inclusion and exclusion criteria .............................................................................. 13 
7.3 Treatments and medications .............................................................................................. 13 
7.3.1 Prior and concomitant medication .......................................................................... 13 
7.3.2 Non-drug therapies ................................................................................................. 14 
7.3.3 Treatment compliance ............................................................................................ 14 
7.4 Efficacy analysis ............................................................................................................... 15 
7.4.1 Analysis of primary variable .................................................................................. 15 
7.4.2 Analysis of secondary variables ............................................................................. 15 
7.4.3 Exploratory analysis ............................................................................................... 16 
7.5 Safety analysis................................................................................................................... 17 
7.5.1 Adverse events ....................................................................................................... 17 
7.5.2 Vital sign ................................................................................................................ 18 
7.5.3 Laboratory assessments .......................................................................................... 18 
7.5.4 Physical examination ............................................................................................. 19 
7.5.5 B-ultrasound ........................................................................................................... 19 
8. Appendix ..................................................................................................................................... 20 
8.1 Description of Inclusion/Exclusion Criteria .............................................................. 20 
8.2 Treatment-emergent Laboratory Abnormalities Grading Scale................................. 22 
8.3 Examples for Mutation Changes ............................................................................... 23 
9. MOCK TABLES, LISTINGS AND GRAPHS (TLGS).............................................................. 25 
 


GlaxoSmithKline (China) Investment Co., Ltd.                                    Version：Final 
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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 
eCRF 
Electronic case report form 
HBeAg 
Hepatitis B e antigen 
HBsAg 
Hepatitis B s antigen 
HBV 
Hepatitis B virus 
HCV 
Hepatitis C virus 
ICF 
Informed consent form 
INR 
International Normalized Ratio 
LAM 
Lamivudine 
LdT 
Telbivudine 
mITT 
Modified Intent-to-treat (population) 
NAs 
Nucleos(t)ide analogues 
OR 
Odds Ratio 
PP 
Per protocol (population) 


GlaxoSmithKline (China) Investment Co., Ltd.                                    Version：Final 
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Abbreviation  
Description of Abbreviation 
PT 
Prothrombin time 
SA 
Safety analysis (population) 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SD 
Standard deviation 
TDF 
Tenofovir disoproxil fumarate 
TEAE 
Treatment-emergent adverse events 
 
 
Trademark Information 
 
Trademarks of the GlaxoSmithKline 
group of companies 
 
Trademarks not owned by the 
GlaxoSmithKline group of companies 
Hepododin 
 
Baraclude 
 
 
Viread 
 
 
Sebivo 
 
 
 
 
 
 


GlaxoSmithKline (China) Investment Co., Ltd.                                    Version：Final 
Protocol 201215                                                               Dec 03, 2018 
 
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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 201215. 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 2.1, OCT 21, 2015). 
 
2. STUDY OBJECTIVE 
2.1 Primary objective 
To assess the proportion of multiple NA treatment failure chronic hepatitis B patients that achieve 
HBV DNA<20 IU/mL at week 144 of TDF treatment. 
 
2.2 Secondary objective 
To assess the efficacy of TDF following failure of multiple NAs by evaluating serum HBV DNA, 
ALT and serological responses at week 48, 96 and 144. 
To assess the efficacy of TDF in patients harboring multi-drug resistance mutations prior to 
initiating TDF. 
To evaluate the safety of TDF following failure of multiple NAs. 
Evaluate the impact of the baseline characteristics (viral titer, mutation patterns, etc.) and early 
HBV DNA suppression on response to TDF. 
 
3. STUDY DESIGN 
3.1 Overall study design 
This is a single-arm, open-label, multi-centre study to assess the efficacy of TDF in CHB patients 
following failure of multiple NAs. 
 
The study will enroll 200 CHB patients following failure of multiple NAs. All the eligible study 
subjects will undergo safety and efficacy assessments every 12 weeks for a total of 14 visits. 
 


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Screen phase (Visit 1): About 230 subjects will be assessed for eligibility at a screening visit, with 
eligible patients returning for a baseline assessment after approximately 4 weeks. Multiple NAs 
treatment failure is defined as HBV DNA higher than 200 IU/mL after two or more different NA(s) 
treatments (i.e. initiate with mono-therapy followed by add-on/switch rescue therapy; at least 6 
months continuous treatment for each regimen, total duration to be no less than 12 months). At visit 
1 all the testing will be performed locally except for the HBV DNA quantification which will be 
measured by a central lab. The subjects will maintain their current treatment from screening visit to 
baseline visit. All subjects will provide written informed consent before screening. 
 
Treatment phase (Visits 2 to 14): In the 144 weeks open label period, all enrolled subjects will 
receive open label TDF at a dose of 300mg orally once daily. At each visit, subjects will be 
questioned about adverse events, concurrent medications, and study drug accountability; take 
chemistry (liver function, blood glucose, creatine phosphokinase) test; take electrolytes (sodium, 
potassium, chloridum, phosphorus and calcium) test; take pregnancy test; take urinalysis test; take 
renal function (blood creatinine clearance, bloodurea nitrogen and blood uric acid) test. Blood 
routine and International Normalized Ratio(INR) and HBV markers will be measured every 24 
weeks. Abdominal ultrasound and serum alpha-fetoprotein test will be tested every 24 weeks. Serum 
samples will be collected and analyzed for HBV DNA levels in a central lab from visit 2 to 14. At 
the visit 2, resistance surveillance of the HBV polymerase gene will be performed by direct 
sequencing for all subjects at baseline. 
 
No formal interim analysis was planned. Key analysis outputs will be provided annually with the 
48-week and 96-week cutoff data for publication purpose. No adjustment for multiplicity will be 
made for the analysis in different period. 
 
3.2 Sample size 
Sample sizes are chosen based on feasibility and precision because no hypothesis is tested in this 
study. The primary endpoint is the proportion of subjects with serum HBV DNA <20 IU/mL of TDF 
in multiple NAs treatment failure patients at Week 144. 


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To decide the number of subjects for analysis, some precision calculations have been performed.  
From our historical data, we hypothesize that the proportion of subjects with serum HBV DNA  
<20 IU/mL in multiple NAs treatment failure patients treated with TDF at Week 144 was 80%. A 
sample size of 170 patients will allow us to estimate the confidence interval of the incidence with a 
margin of error at 6% (range from 74-86%). Assuming a dropout rate of 15 per cent during a 144 
week period, the number of patients required overall is estimated to be 200. 
 
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 the safety and 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 and PP population. All safety endpoints will 
be analyzed using the SA population according to the actual treatment they received. 
 
5. STUDY ENDPONITS 
5.1 Primary endpoint 
The primary endpoint is the proportion of subjects with serum HBV DNA <20 IU/mL at week 144. 
 


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5.2 Secondary endpoints 
The proportion of subjects with virological response (serum HBV DNA <20 IU/mL and serum 
HBV DNA <69 IU/mL, respectively) at week 48 and 96. 
The proportion of subjects with virological response (serum HBV DNA <20 IU/mL and serum 
HBV DNA <69 IU/mL, respectively) at week 48, 96 and 144 in the subgroup with confirmed 
multi-drug resistance at baseline. 
The log10 reduction in serum HBV DNA at Week 48, 96 and 144. 
For HBeAg positive subjects: the proportion of subjects achieving HBeAg loss, HBeAg 
seroconversion or HBsAg loss and HBsAg seroconversion at Week 48, 96 and 144. 
For HBeAg negative subjects: the proportion of subjects achieving HBsAg loss and HBsAg 
seroconversion at Week 48, 96 and 144. 
The proportion of subjects with ALT normalization at Week 48, 96 and 144 in subjects who have 
abnormal ALT at baseline. 
Incidence of subjects who experience viral breakthrough (defined as 1 log increase in HBV 
DNA from nadir determined by two sequential HBV DNA measurements) up to week 144. 
Subject safety as determined by adverse events and laboratory assessments. 
 
5.3 Exploratory endpoints 
Evaluate the impact of the baseline host and virological characteristics (HBV DNA level, 
resistance type, HBeAg status, prior treatment with ADV, prior treatment with ETV, prior 
treatment with IFN, overall duration of prior NA treatment, compliance, cirrhosis, ALT level, 
age, gender, BMI, AST, r-GT, platelets, INR, total bilirubin, albumin, etc.) and early HBV DNA 
suppression on response to TDF at week 144. 
Time to virological response to TDF (defined as HBV DNA <20 IU/mL) for overall and subjects 
with different patterns of mutation. 
 


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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. 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. 
 
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. 
 
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 the primary endpoint analyses and other analyses of response (success, failure) at a 
particular time point, a discontinued subject was considered as "failure" for all efficacy responses 
post termination. And the missing values of categorical efficacy endpoints (success, failure) will 
be imputed as "failure" at the analysis visits. 
 
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 


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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. 
 
Protocol deviations will be summarized and listed for mITT population. Subject counts and 
percentages will be displayed by the following deviation categories:  
・Poor compliance, defined as taking < 80% or > 120% of the required number of tablets 
・Take the prohibited medication specified in protocol during the treatment period 
・With actual visit day being more than 14 days deviated from the schedule visit day 
・Had other significant protocol violations that were thought to affect the efficacy evaluation 
 
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. 
 
7.2 Subject Information 
7.2.1 Demographics and baseline characteristics 
Demographic and baseline characteristics for subjects include subject age, sex (Male/Female), race 
(Asian/Others), weight, height, BMI, systolic blood pressure, diastolic blood pressure, pulse, 
respiratory, body temperature, alcohol abuse, drug abuse, history of medication hypersensitivity, 
cirrhosis and resistance mutations. Percentages for categorical data will be calculated based on the 
number of subjects in the analysis set of that treatment group. Descriptive statistics will be used for 
continuous data. A listing of demographics and baseline characteristics will also be provided. Age 
will be calculated by 
 
Age (Year) = Year of Informed Consent Date - Year of Birth + 1 


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7.2.2 Medical history 
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. 
 
Medical history will be listed by system organ class and preferred term coded in MedDRA 17.0.  
 
The previous treatment of chronic hepatitis B will also be summarized by drug categories (LAM, 
LdT, ETV, ADV, IFN) with drug duration >6 months. Drugs with duration ≤6 months will not be 
counted. 
 
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: all the drugs taken by the subjects prior to the first dose date of TDF. 
 
Concomitant medication: 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 first dose date of TDF, 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 first dose date of TDF, 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 first dose date of TDF and continued after dosing will be summarized as 


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14 
 
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.  
 
Medication class, medication name, indications, total daily dose, unit, route, start date and end date 
will be presented in the listing. 
 
7.3.2 Non-drug therapies 
For subjects who receive any non-drug therapy will be recorded on eCRF. Non-drug therapy 
information including therapy details, start and end date, and the reason for use will be presented in 
the listing. 
 
7.3.3 Treatment compliance 
The duration in days of study drug exposure from first dose date to the last dose date will be 
summarized by descriptive statistics.  
 
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.  
 


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7.4 Efficacy analysis 
This analysis will be conducted in mITT and PP population. 
7.4.1 Analysis of primary variable 
The primary efficacy endpoint for this study is the proportion of subjects with serum HBV DNA 
<20 IU/mL at week 144. Primary efficacy endpoints are evaluated by count and percentage, and 
two-sided 95% CI will also be provided based on normal approximation and continuity correction.  
 
7.4.2 Analysis of secondary variables 
Analysis for secondary variable of the log10 reduction in serum HBV DNA by patterns of mutation 
and overall per visit will be summarized by descriptive statistics as the mean, standard deviation, 
two-sided 95%CI, minimum, median, maximum, and the number of observations. The patterns of 
mutation will be summarized by 2 categories. One includes wild-type, LAM-R, ADV-R and ETV-
R. The other one includes wild-type, ADV-R single mutation (A181T/V; N236T), ADV-R double 
mutation (A181T/V+N236T)) and other mutation. Nominal P values between different patterns of 
mutation will be provided at week 24, 48, 96, 144. Individual HBV DNA levels of subjects with 
genotypic resistance to ADV (A181T/V+N236T) will be summarized over time by figure. 
 
In addition, the number and percentage will be presented respectively for secondary variables 
including: 
 
The proportion of subjects with virological response (serum HBV DNA <20 IU/mL and 
serum HBV DNA <69 IU/mL, separately) by visit 
 
The proportion of subjects with virological response (serum HBV DNA <20 IU/mL and 
serum HBV DNA <69 IU/mL, separately) by visit in the subgroup with confirmed multi-drug 
resistance at baseline 
 
The proportion of subjects with virological response(serum HBV DNA <20 IU/mL and 
serum HBV DNA <69 IU/mL, separately) by visit in the subgroup with medical history 
(previously exposed to ADV >6 months or not, ETV >6 months or not) (Subjects with 
ETV >6 months will be separated as ETV-R and non ETV-R) 
 
The proportion of subjects achieving HBeAg loss, HBeAg seroconversion, HBsAg loss and 


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HBsAg seroconversion at Week 48, 96 and 144 for HBeAg positive subjects 
 
The proportion of subjects achieving HBsAg loss and HBsAg seroconversion at Week 48, 96 
and 144 for HBeAg negative subjects 
 
The proportion of subjects with ALT normalization at week 48, 96 and 144 in subjects who 
have abnormal ALT at baseline 
 
The incidence of subjects who experience viral breakthrough (defined as 1 log increase in 
HBV DNA from nadir determined by two sequential HBV DNA measurements) 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 
 
Mutation pattern change from baseline at week 48, 96, 144 
Also, two-sided 95% CI will be calculated for each percentage. 
 
7.4.3 Exploratory analysis 
The exploratory analysis is to evaluate the impact of the baseline host and virological characteristics 
(viral titer, mutation patterns, etc.) and early HBV DNA suppression on response to TDF at week 
144. Multiple-factor logistic regression analysis will be used to assess the baseline variables that 
were significantly associated with HBV DNA negativity at week 144. The factors includeHBV DNA 
level, resistance type, HBeAg status, prior treatment with ADV, prior treatment with ETV, overall 
duration of prior NA treatment, compliance, cirrhosis, ALT level, age, gender, BMI, AST, r-GT, 
platelets, INR, total bilirubin, albumin, etc. The OR and 95% CI of each factor will be provided in 
the table. 
 
Time to virological response to TDF defined as HBV DNA <20 IU/mL, as a time-to-event variable, 
will be analyzed by Kaplan-Meier curve for overall and subjects with different patterns of mutation. 
Log-rank test will be performed separately for each of the following factors: HBV DNA level, 
HBeAg status, prior treatment with ADV, resistance type (ADV or not), cirrhosis, compliance and 


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17 
 
patterns of mutation. Cox regression model will be conducted to include all above factors and 
additional factors: prior treatment with IFN, ALT level, age, and gender. 
 
In addition, three listings will be provided for  
 
The ALT for patients with any HBeAg Loss, HBeAg Seroconversion, HBsAg Loss and HBsAg 
Seroconversion over time 
 
The relationship between HBV DNA and medical history for previously exposed to NAs >6 
months 
 
The HBV DNA for patients with virological breakthrough (defined as 1 log increase in HBV 
DNA from nadir determined by two sequential HBV DNA measurements), and 
 
The HBV DNA for patients with unsatisfactory response (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). 
 
7.5 Safety analysis 
Safety endpoints include adverse events, vital signs, laboratory assessments, physical examination, 
and B-ultrasound. This 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 


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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.  
 
The following summaries of AEs will be provided: 
 
All AEs. 
 
All TEAEs. 
 
All treatment related TEAEs. 
 
All serious TEAEs. 
 
All non-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. 
 
All TEAEs that caused a change in dose or temporary interruption of study drug. 
 
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 clinic visit. Changes from Baseline to each individual post-Baseline 
visit will also be presented. 
 
7.5.3 Laboratory assessments 
Results for clinical laboratory evaluations including: hematology, blood chemistry, blood 
coagulation, hepatitis B five items, pregnancy test, urinalysis and alpha fetoprotein (AFP) will be 
conducted at various visits as specified in the Study Schedule of the protocol. Descriptive statistics 
will be used for quantitative variables. For qualitative variables, the number and percentage for each 


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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. If the relevant baseline laboratory data are missing, then the screening 
laboratory result is 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) increase in serum creatinine of 0.5 mg/dL above 
baseline 
 
Calculated creatinine clearance < 50 mL/min 
 
7.5.4 Physical examination 
The result of physical examination will be categorized as “Not Done”, “Normal” or “Abnormal”. 
The detailed information including date of physical examination and the result of body system for 
each subject will be presented in the listing. 
 
7.5.5 B-ultrasound 
B-ultrasound examination include sliver, pancreas, spleen, gall bladder and kidney. It is assessed 
based on 3-level system (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 Description of Inclusion/Exclusion Criteria 
Seq No 
Type 
Description 
1 
Inclusion 
Aged between 18–65years (inclusive).  
2 
Inclusion 
Male or female; 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 baseline, 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 
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 or 
cervical/vault caps) with a vaginal spermicidal agent (foam/gel/film 
/cream/suppository).  
3 
Inclusion 
The ability to understand and sign a written informed consent prior to any study-related 
procedure and comply with the requirements of the study.  
4 
Inclusion 
Positive HBsAg for more than 6 months, and anti-HBs negative.  
5 
Inclusion 
Serum HBV DNA level ≥200 IU/ml at study screening (Use central lab results).  
6 
Inclusion 
Experienced multiple NAs treatment failure which is defined as HBV DNA greater than 
200 IU/ml after at least two NAs treatment (at least 6 months continuous treatment for 
each NA(s), total duration is no less than 12 months). In addition, subjects judged by the 
treating physician to have adhered to previous NA therapy.  
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 >20 ng/ml at screening. 
2 
Exclusion 
Clinical signs of decompensated liver disease at baseline. These may include but are 
not limited to:  
1) Total serum bilirubin >1.5 x ULN.  
2) International Normalized Ratio >1.3  
3) Serum albumin <32g/L.  
4) History of clinical hepatic decompensation (e.g., ascites, variceal bleeding, or 
encephalopathy).  


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Seq No 
Type 
Description 
3 
Exclusion 
Creatinine clearance less than 70 ml/min.  
4 
Exclusion 
Alanine aminotransferase >10 times ULN at screening or history of acute exacerbation 
leading to transient decompensation.  
5 
Exclusion 
Haemoglobin <8g/dL, absolute neutrophil count <1.0 x 109/L, platelets <75 x 109/L.  
6 
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.  
7 
Exclusion 
Evidence of active liver disease due to autoimmune hepatitis (antinuclear antibody 
titre >1:160)  
8 
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.  
9 
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.  
10 
Exclusion 
A female who is breastfeeding or plan to breast.  
11 
Exclusion 
Use of immunosuppressive therapy, immunomodulatory therapy (including PEG-IFN 
and short-acting interferon or thymosin,), systemic cytotoxic agents within the 
previous 6 months prior to screening.  
12 
Exclusion 
Planned for liver transplantation or previous liver transplantation.  
13 
Exclusion 
Receipt of TDF within 6 months prior to screening.  
14 
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.  
15 
Exclusion 
History of hypersensitivity to nucleoside and/or nucleotide analogues and/or any 
component of study medication.  
16 
Exclusion 
Inability to comply with study requirements as determined by the study Investigator.  
 
 
 


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8.2 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 
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 


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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 
 
 
8.3 Examples for Mutation Changes 
# 
Senario 
Examples 
Caregory 
Code *** 
Result 
Comments 
Baseline 
Week 48 
Baseline 
Week 48 
1 
No change for “Result” and 
“comments” at all visits 
W 
W 
 
 
NCW 
2 
No change for “Result” and 
“comments” at all visits 
W 
W 
A100C 
A100C 
3 
No change for “Result” and 
“comments” at all visits 
Mutant A* + 
Mutant B* 
Mutant A* + 
Mutant B* 
 
 
NCC 
4 
No change for “Result” and 
“comments” at all visits 
Mutant* A 
Mutant* A 
T200C, 
C300D 
T200C, 
C300D 
5 
“Result” no change, but with 
emerging “Comments” 
W 
W 
 
A100C 
CNCM 
6 
“Result” no change, but with 
“Comments” changed 
W 
W 
A100C 
 
7 
“Result” no change, but with 
emerging “Comments” 
Mutant* A 
Mutant* A 
 
T200C/A 
8 
“Result” no change, but with 
“Comments” changed 
Mutant* A 
Mutant* A 
T200C 
T200C, 
A201C 
9 
“Result” changed to “Mutant” 
W 
Mutant* 
 
 
CCM 
10 
“Result” changed to “Mutant” 
with emerging “Comments” 
W 
Mutant* 
 
T200C 
11 
“Result” changed to “Mutant” 
with “Comments” changed** 
W 
Mutant A* + 
Mutant B* 
A100C 
T200C 
12 
“Result” changed to other 
types of “Mutant” 
Mutant* A 
Mutant* B 
 
 
13 
“Result” changed with 
“Comments” changed** 
Mutant* A 
Mutant* B 
T200C 
T200C, 
A250C 
14 
“Result” changed with 
“Comments” changed** 
Mutant* A 
W 
T200C 
 


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15 
“Result” is “UN” 
W 
UN/IN 
 
 
UN 
16 
“Result” is “UN” 
UN 
W/UN 
 
 
17 
“Result” is “UN” 
W 
UN 
L220I, 
A222T 
 
18 
“Result” is “UN” 
V214A/V 
UN 
L220I, 
A222T 
 
* Mutant: mutations other than ‘Wild Type’, ‘UN’ or ‘IN’ 
** if one subject has both “confirmed mutation” and “non-confirmed mutation”, “confirmed mutation” will be set 
as the “category”. 
*** NCW:  
No changes from baseline – Wild type at baseline 
   NCC:  
No changes from baseline – Confirmed NA-related mutation at baseline 
   CCM:  
Mutation Changes from baseline – Change from baseline about confirmed NA-related mutation 
   CNCM: 
Mutation Changes from baseline – Change from baseline about non-confirmed mutation 
   UN: 
 
Invalid sequence or DNA sequence undetectable 
 
 
 
 


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9. MOCK TABLES, LISTINGS AND GRAPHS (TLGS) 
Mock TLGs will be provided in a separate document. 
Identifier 
Output Title 
Annual 
Report 
Table 1.1  
Disposition 
X 
Table 1.2    
Major Protocol Deviations - mITT 
X 
Table 2.1.1 
Demographics - mITT 
 
Table 2.1.2 
Baseline Characteristics - mITT 
 
Table 2.1.3 
Resistance Mutations at Baseline - mITT 
 
Table 2.2 
Previous Treatment of Chronic Hepatitis B - mITT 
 
Table 3.1    
Compliance and Duration of the Study Drug - mITT 
X 
Table 4.1.1    
The Proportion of Subjects with Serum HBV DNA <20 IU/mL at 
Week 144 - mITT 
 
Table 4.1.2    
The Proportion of Subjects with Serum HBV DNA <20 IU/mL at 
Week 144 - PP 
 
Table 4.2.1    
The Proportion of Subjects with Virological Response (Serum 
HBV DNA <20 IU/mL and Serum HBV DNA <69 IU/mL) by 
Visit - mITT 
X 
Table 4.2.2    
The Proportion of Subjects with Virological Response (Serum 
HBV DNA <20 IU/mL and Serum HBV DNA <69 IU/mL) by 
Visit - PP 
X 
Table 4.3.1    
The Proportion of Subjects with Virological Response (Serum 
HBV DNA <20 IU/mL and Serum HBV DNA <69 IU/mL) by 
Visit in the Subgroup with Confirmed Multi-drug Resistance at 
Baseline - mITT 
X 
Table 4.3.2    
The Proportion of Subjects with Virological Response (Serum 
HBV DNA <20 IU/mL and Serum HBV DNA <69 IU/mL) by 
Visit in the Subgroup with Confirmed Multi-drug Resistance at 
Baseline - PP 
X 
Table 4.4.1 
The Proportion of Subjects with Virological Response (Serum 
HBV DNA <20 IU/mL and Serum HBV DNA <69 IU/mL) by 
Visit in the Subgroup with Medical History (Previously Exposed 
to ADV >6 Months or Not, ETV >6 Months (ETV-R and Non 
ETV-R) or Not) - mITT 
 
Table 4.4.2    
The Proportion of Subjects with Virological Response (Serum 
HBV DNA <20 IU/mL and Serum HBV DNA <69 IU/mL) by 
Visit in the Subgroup with Medical History (Previously Exposed 
to ADV >6 Months or Not, ETV >6 Months (ETV-R and Non 
ETV-R) or Not) - PP 
 


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Identifier 
Output Title 
Annual 
Report 
Table 4.5.1    
The Proportion of Subjects Achieving HBeAg Loss, HBeAg 
Seroconversion, HBsAg Loss and HBsAg Seroconversion at 
Week 48, 96 and 144 for Subjects with Positive HBeAg at 
Baseline - mITT 
 
Table 4.5.2    
The Proportion of Subjects Achieving HBeAg Loss, HBeAg 
Seroconversion, HBsAg Loss and HBsAg Seroconversion at 
Week 48, 96 and 144 for Subjects with Positive HBeAg at 
Baseline - PP 
 
Table 4.5.3 
The Proportion of Subjects Achieving HBsAg Loss and HBsAg 
Seroconversion at Week 48, 96 and 144 for Subjects with 
Negative HBeAg at Baseline - mITT 
 
Table 4.5.4 
The Proportion of Subjects Achieving HBsAg Loss and HBsAg 
Seroconversion at Week 48, 96 and 144 for Subjects with 
Negative HBeAg at Baseline - PP 
 
Table 4.6.1    
The Proportion of Subjects with ALT Normalization at Week 48, 
96 and 144 in Subjects Who Have Abnormal ALT at Baseline - 
mITT 
X 
Table 4.6.2    
The Proportion of Subjects with ALT Normalization at Week 48, 
96 and 144 in Subjects Who Have Abnormal ALT at Baseline - PP 
X 
Table 4.7.1    
Change from Baseline for the log10 Reduction in Serum HBV 
DNA by Visit - mITT 
X 
Table 4.7.1.1    Mean log10 IU/mL in Serum HBV DNA by Patterns of Mutation 
Category 1 Over Time - mITT 
X 
Table 4.7.1.2    Mean log10 IU/mL in Serum HBV DNA by Patterns of Mutation 
Category 2 Over Time - mITT 
X 
Table 4.7.2    
Change from Baseline for the log10 Reduction in Serum HBV 
DNA by Visit- PP 
X 
Table 4.7.2.1    Mean log10 IU/mL in Serum HBV DNA by Patterns of Mutation 
Category 1 Over Time - PP 
X 
Table 4.7.2.2    Mean log10 IU/mL in Serum HBV DNA by Patterns of Mutation 
Category 2 Over Time - PP 
X 
Table 4.7.3 
Incidence of Subjects Who Experience Viral Breakthrough by 
Visit - mITT 
X (Week 
96) 
Table 4.7.4 
Incidence of Subjects Who Experience Viral Breakthrough by 
Visit - PP 
X (Week 
96) 
Table 4.8.1    
Incidence of Subjects with Unsatisfactory Response by Visit - 
mITT 
X (Week 
96) 
Table 4.8.2    
Incidence of Subjects with Unsatisfactory Response by Visit - PP 
X (Week 
96) 
Table 4.8.3 
Mutation Pattern Change from Baseline at Week 48, 96, 144 - 
mITT 
X 


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Identifier 
Output Title 
Annual 
Report 
Table 4.8.4 
Mutation Pattern Change from Baseline at Week 48, 96, 144 - PP 
X 
Table 4.9.1    
The Relationship Between Baseline Variables and Virological 
Response (Serum HBV DNA <20 IU/mL) at Week 144 - mITT 
 
Table 4.9.2    
The Relationship Between Baseline Variables and Virological 
Response (Serum HBV DNA <20 IU/mL) at Week 144 - PP 
 
Table 4.10.1    Time to Virological Response (Serum HBV DNA <20 IU/mL) - 
mITT 
 
Table 4.10.2    Time to Virological Response (Serum HBV DNA <20 IU/mL) - 
PP 
 
Table 4.11.1    Log-rank Test for Time to Virological Response (Serum HBV 
DNA <20 IU/mL) - mITT 
 
Table 4.11.2    Log-rank Test for Time to Virological Response (Serum HBV 
DNA <20 IU/mL) - PP 
 
Table 4.12.1 
Cox Regression Analysis for Time to Virological Response 
(Serum HBV DNA <20 IU/mL) - mITT 
 
Table 4.12.2 
Cox Regression Analysis for Time to Virological Response 
(Serum HBV DNA <20 IU/mL) - PP 
 
Table 5.1.1    
Overall Summary of Adverse Events - SA 
X 
Table 5.1.2.1    All TEAEs by System Organ Class and Preferred Term - SA 
X 
Table 5.1.2.2    All Serious TEAEs by System Organ Class and Preferred Term - 
SA 
X 
Table 5.1.2.3    All Non-Serious TEAEs by System Organ Class and Preferred 
Term - SA 
X 
Table 5.1.3.1    All TEAEs by Relationship to Study Drug - SA 
X 
Table 5.1.3.2    All Serious TEAEs by Relationship to Study Drug - SA 
X 
Table 5.1.4.1    All TEAEs by Intensity - SA 
X 
Table 5.1.4.2    All Serious TEAEs by Intensity - SA 
X 
Table 5.2    
Change from Baseline in Vital Signs - SA 
X 
Table 5.3.1    
Change from Baseline in Hematology - SA 
X 
Table 5.3.2    
Change from Baseline in Blood Chemistry - SA 
X 
Table 5.3.3 
Subjects with Treatment-emergent Laboratory Abnormalities - SA 
X 
Listing 1.1    
Disposition - mITT 
X 
Listing 1.2 
Analysis Set - mITT 
X 
Listing 1.3 
Major Protocol Deviations - mITT 
X 
Listing 2.1.1 
Demographics - mITT 
X 
Listing 2.1.2 
Baseline Characteristics - mITT 
X 
Listing 2.1.3.1 
HBV Variant at Baseline - mITT 
X 
Listing 2.1.3.2 
Level of Susceptibility at Baseline - mITT 
X 
Listing 2.2.1.1  Diagnosis of Chronic Hepatitis B (Section 1) - mITT 
X 
Listing 2.2.1.2  Diagnosis of Chronic Hepatitis B (Section 2) - mITT 
X 
Listing 2.2.2.1  Treatment History of Chronic Hepatitis B (Section 1) - mITT 
X 


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Identifier 
Output Title 
Annual 
Report 
Listing 2.2.2.2  Treatment History of Chronic Hepatitis B (Section 2) - mITT 
X 
Listing 2.2.2.3  Treatment History of Chronic Hepatitis B (Section 3) - mITT 
X 
Listing 2.3.1    Medical History - mITT 
X 
Listing 2.3.2    Past History of Treatment - mITT 
X 
Listing 2.3.3    Relevant Surgery - mITT 
X 
Listing 2.4    
Inclusion and Exclusion Criteria - mITT 
X 
Listing 3.1.1    Prior Medications - mITT 
X 
Listing 3.1.2    Concomitant Medications - mITT 
X 
Listing 3.1.3    Non-Drug Therapies - mITT 
X 
Listing 3.2.1    Study Drug Exposure - mITT 
X 
Listing 3.2.2    Drug Accountability - mITT 
X 
Listing 4.1    
HBV DNA - mITT 
X 
Listing 4.1.1 
Relationship Between HBV DNA and Medical History - mITT 
X 
Listing 4.1.2 
HBV DNA for Patients with Virological Breakthrough - mITT 
X 
Listing 4.1.3 
HBV DNA for Patients with Unsatisfactory Response - mITT 
X 
Listing 4.2    
Hepatitis B Five Item - mITT 
X 
Listing 4.3 
ALT for patients with any HBeAg Loss, HBeAg Seroconversion, 
HBsAg Loss and HBsAg Seroconversion - mITT 
X 
Listing 5.1.1    Non-Serious Treatment-emergent Adverse Events - SA 
X 
Listing 5.1.2    Serious Treatment-emergent Adverse Events - SA 
X 
Listing 5.1.3 
Treatment Related Treatment-emergent Adverse Events - SA 
X 
Listing 5.2    
Vital Signs - SA 
X 
Listing 5.3.1    Hematology - SA 
X 
Listing 5.3.2    Blood Chemistry - SA 
X 
Listing 5.3.3    Blood Coagulation - SA 
X 
Listing 5.3.4    Urinalysis - SA 
X 
Listing 5.3.5    Pregnancy Test - SA 
X 
Listing 5.3.6    Alpha Fetoprotein (AFP) - SA 
X 
Listing 5.4    
Physical Examination - SA 
X 
Listing 5.5    
B-ULTRASOUND - SA 
X 
Listing 5.6    
CV Event - SA 
X 
Figure 4.1.1  
Proportion (95% CI) of Subjects with HBV DNA <20 IU/mL 
Over Time - mITT 
X 
Figure 4.1.2  
Proportion (95% CI) of Subjects with HBV DNA <20 IU/mL 
Over Time - PP 
X 
Figure 4.1.3 
Proportion (95% CI) of Subjects with HBV DNA <69 IU/mL 
Over Time - mITT 
X 
Figure 4.1.4 
Proportion (95% CI) of Subjects with HBV DNA <69 IU/mL 
Over Time - PP 
X 
Figure 4.5.1  
Mean Log10 Copies/mL Reduction from Baseline in HBV DNA 
Over Time - mITT 
X 


GlaxoSmithKline (China) Investment Co., Ltd.                                    Version：Final 
Protocol 201215                                                               Dec 03, 2018 
 
29 
 
Identifier 
Output Title 
Annual 
Report 
Figure 4.5.2  
Mean Log10 Copies/mL Reduction from Baseline in HBV DNA 
Over Time - PP 
X 
Figure 4.5.3 
Distribution of HBV DNA levels Over Time - mITT 
X 
Figure 4.7.1.1 
Mean Log10 IU/mL in HBV DNA by Patterns of Mutation 
Category 1 Over Time - mITT 
X 
Figure 4.7.1.2 
Mean Log10 IU/mL in HBV DNA by Patterns of Mutation 
Category 2 Over Time - mITT 
X 
Figure 4.7.2.1 
Mean Log10 IU/mL in HBV DNA by Patterns of Mutation 
Category 1 Over Time - PP 
X 
Figure 4.7.2.2 
Mean Log10 IU/mL in HBV DNA by Patterns of Mutation 
Category 2 Over Time - PP 
X 
Figure 4.7.3 
Mean Log10 IU/mL in HBV DNA by Medical History 
(Previously Exposed to ADV >6 Months or Not) Over Time - 
mITT 
X 
Figure 4.7.4 
Mean Log10 IU/mL in HBV DNA by Medical History 
(Previously Exposed to ADV >6 Months or Not) Over Time - PP 
X 
Figure 4.8.1 
Individual Courses of HBV DNA Levels of Subjects with 
Genotypic Resistance to ADV (A181T/V+N236T) - mITT 
X 
Figure 4.10.1  
Kaplan-Meier Curves for Virological Response (Serum HBV 
DNA <20 IU/mL) - mITT 
 
Figure 4.10.1.1  Kaplan-Meier Curves for Virological Response (Serum HBV 
DNA <20 IU/mL) by Patterns of Mutation Category 1 - mITT 
 
Figure 4.10.1.2  Kaplan-Meier Curves for Virological Response (Serum HBV 
DNA <20 IU/mL) by Patterns of Mutation Category 2 - mITT 
 
Figure 4.10.2  
Kaplan-Meier Curves for Virological Response (Serum HBV 
DNA <20 IU/mL) - PP 
 
Figure 4.10.2.1  Kaplan-Meier Curves for Virological Response (Serum HBV 
DNA <20 IU/mL) by Patterns of Mutation Category 1 - PP 
 
Figure 4.10.2.2  Kaplan-Meier Curves for Virological Response (Serum HBV 
DNA <20 IU/mL) by Patterns of Mutation Category 2 - PP 
 
Figure 5.3.1  
Mean Estimated Glomerular Filtration Rate Change from Baseline 
Over Time - mITT 
 
Figure 5.3.2  
Mean Estimated Glomerular Filtration Rate Change from Baseline 
Over Time - PP 
X 
Figure 5.3.3  
Mean Serum Phosphorus Change from Baseline Over Time - 
mITT 
 
Figure 5.3.4  
Mean Serum Phosphorus Change from Baseline Over Time - PP 
X