A Multi-centre, One-arm Prospective Study to Evaluate Efficacy and Safety of Switching From Entecavir (ETV) to Tenofovir Disoproxil Fumarate (TDF) in Japanese Chronic Hepatitis B HBeAg-positive and HBV-DNA Undetectable Subjects
Phase: PHASE4
Conditions: Hepatitis B, Chronic
Sponsor: GlaxoSmithKline

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TITLE PAGE 
Protocol Title: A multi-centre, one-arm prospective study to evaluate efficacy and safety of switching 
from Entecavir (ETV) to Tenofovir Disoproxil Fumarate (TDF) in Japanese chronic hepatitis B 
HBeAg-positive and HBV-DNA undetectable subjects 
 
Protocol Number: 205883 
Short Title: A study of switching from Entecavir to Tenofovir in subjects with chronic hepatitis B 
 
Compound Number: 
GSK548470 
 
Sponsor 
GlaxoSmithKline K.K. (GSK) 
Akasaka Intercity AIR, 1-8-1, Akasaka, Minato-ku, Tokyo, 107-0052 
Person responsible for study implementation: 
, VP & Head, Development & Medical Affairs Division 
 
Medical Monitor Name and Contact Information will be provided separately. 
 
Approval Date: [5-Jul-2018] 
 
Copyright 2018 the GlaxoSmithKline group of companies.  All rights reserved.  Unauthorised 
copying or use of this information is prohibited. 
PPD

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SPONSOR SIGNATORY: 
 
 
 
[Susie Barnes] 
[VP & Head, Development & Medical Affairs Division] 
 
 
 
Date 
 

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TABLE OF CONTENTS 
Page 
1. 
SYNOPSIS ........................................................................................................................ 6 
2. 
SCHEDULE OF ACTIVITIES (SOA) ............................................................................... 8 
3. 
INTRODUCTION ........................................................................................................... 12 
3.1. 
Study Rationale ...................................................................................................... 12 
3.2. 
Background ............................................................................................................ 12 
3.3. 
Benefit/Risk Assessment ......................................................................................... 12 
3.3.1. 
Risk Assessment ............................................................................................. 13 
3.3.2. 
Benefit Assessment ......................................................................................... 18 
3.3.3. 
Overall Benefit: Risk Conclusion ................................................................... 18 
4. 
OBJECTIVES AND ENDPOINTS .................................................................................. 18 
5. 
STUDY DESIGN ............................................................................................................. 19 
5.1. 
Overall Design ........................................................................................................ 19 
5.2. 
Number of Subjects ................................................................................................ 19 
5.3. 
Participant and Study Completion .......................................................................... 19 
5.4. 
Scientific Rationale for Study Design ...................................................................... 19 
5.5. 
Dose Justification .................................................................................................... 19 
6. 
STUDY POPULATION .................................................................................................. 20 
6.1. 
Inclusion Criteria ................................................................................................... 20 
6.2. 
Exclusion Criteria ................................................................................................... 21 
6.3. 
Lifestyle Restrictions .............................................................................................. 22 
6.4. 
Screen Failures ....................................................................................................... 22 
7. 
TREATMENT ................................................................................................................ 23 
7.1. 
Treatments Administered ....................................................................................... 23 
7.2. 
Dose Modification ................................................................................................... 23 
7.3. 
Method of Treatment Assignment ........................................................................... 23 
7.4. 
Blinding .................................................................................................................. 23 
7.5. 
Preparation/Handling/Storage/Accountability ........................................................ 24 
7.6. 
Treatment Compliance ........................................................................................... 24 
7.7. 
Concomitant Therapy ............................................................................................. 24 
7.8. 
Treatment after the End of the Study ..................................................................... 25 
8. 
DISCONTINUATION CRITERIA .................................................................................. 25 
8.1. 
Discontinuation of Study Treatment ....................................................................... 25 
8.1.1. 
Liver Chemistry Stopping Criteria ................................................................ 25 
8.1.2. 
QTc Stopping Criteria ................................................................................... 26 

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8.1.3. 
Discontinuation Criteria Related to Renal Function Test Values .................... 26 
8.1.4. 
Temporary Discontinuation ........................................................................... 26 
8.1.5. 
Rechallenge .................................................................................................... 26 
8.1.5.1. 
Study Treatment Restart or Rechallenge ............................................... 26 
8.1.6. 
Treatment after Discontinuation of Study Treatment..................................... 27 
8.2. 
Withdrawal from the Study .................................................................................... 27 
8.3. 
Lost to Follow Up ................................................................................................... 27 
9. 
STUDY ASSESSMENTS AND PROCEDURES .............................................................. 28 
9.1. 
Efficacy Assessments .............................................................................................. 28 
9.1.1. 
Virus test ........................................................................................................ 28 
9.1.2. 
Endpoints ....................................................................................................... 29 
9.2. 
Adverse Events ....................................................................................................... 29 
9.2.1. 
Time Period and Frequency for Collecting AE and SAE Information ............ 29 
9.2.2. 
Method of Detecting AEs and SAEs ............................................................... 30 
9.2.3. 
Follow-up of AEs and SAEs ........................................................................... 30 
9.2.4. 
Regulatory Reporting Requirements for SAEs ............................................... 30 
9.2.5. 
Cardiovascular and Death Events .................................................................. 30 
9.2.6. 
Disease-Related Events and/or Disease-Related Outcomes Not 
Qualifying as SAEs ........................................................................................ 31 
9.2.7. 
Pregnancy ...................................................................................................... 31 
9.2.8. 
Medical Device Incidents (Including Malfunctions) ........................................ 31 
9.3. 
Treatment of Overdose ........................................................................................... 31 
9.4. 
Safety Assessments ................................................................................................. 31 
9.4.1. 
Physical Examinations ................................................................................... 32 
9.4.2. 
Vital Signs ...................................................................................................... 32 
9.4.3. 
Electrocardiograms ........................................................................................ 32 
9.4.4. 
Clinical Safety Laboratory Assessments ......................................................... 32 
9.4.5. 
Abdominal Imaging Test ................................................................................ 34 
9.4.6. 
Bone Densitometry ......................................................................................... 34 
9.5. 
Pharmacokinetics ................................................................................................... 34 
9.6. 
Pharmacodynamics................................................................................................. 34 
9.7. 
Genetics .................................................................................................................. 34 
9.8. 
Biomarkers ............................................................................................................. 34 
9.9. 
Health Economics OR Medical Resource Utilization and Health Economics ........... 34 
10. STATISTICAL CONSIDERATIONS ............................................................................. 34 
10.1. 
Sample Size Determination ..................................................................................... 34 
10.1.1. 
Sample Size Assumptions ............................................................................... 34 

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10.1.2. 
Sample Size Sensitivity ................................................................................... 35 
10.1.3. 
Sample Size Re-estimation or Adjustment ...................................................... 35 
10.2. 
Populations for Analyses ......................................................................................... 35 
10.3. 
Statistical Analyses ................................................................................................. 35 
10.3.1. 
Efficacy Analyses ........................................................................................... 36 
10.3.2. 
Safety Analyses .............................................................................................. 36 
10.3.3. 
Interim Analyses ............................................................................................ 37 
10.3.4. 
Handling of Withdrawed Subjects ................................................................. 37 
11. REFERENCES ............................................................................................................... 37 
12. APPENDICES ................................................................................................................. 37 
12.1. 
Appendix 1: Abbreviations and Trademarks .......................................................... 37 
12.2. 
Appendix 2: Study Governance Considerations ...................................................... 39 
12.3. 
Appendix 3: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting .................................................................... 43 
12.4. 
Appendix 4: Contraceptive Guidance and Collection of Pregnancy 
Information ............................................................................................................ 48 
12.5. 
Appendix 5: Liver Safety: Required Actions and Follow-up Assessment and 
Study Treatment Rechallenge Guidelines ............................................................... 50 
12.6. 
Appendix 6: Prohibited Drugs ................................................................................ 53 
12.7. 
Appendix 7: Evaluation of Baseline Values ............................................................. 54 
12.7.1. 
Participant Backgrounds ............................................................................... 54 
12.7.2. 
Diagnosis of Cirrhosis B ................................................................................. 54 
12.7.3. 
Bone densitometry ...................................................................................... 54 
 

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1. SYNOPSIS 
 
Protocol Title: A multi-centre, one-arm prospective study to evaluate efficacy and safety of switching 
from Entecavir (ETV) to Tenofovir Disoproxil Fumarate (TDF) in Japanese chronic hepatitis B 
HBeAg-positive and HBV-DNA undetectable subjects 
 
 
Short Title: A study of switching from Entecavir to Tenofovir in subjects with chronic hepatitis B 
 
Study Rationale: 
This study has been planned to evaluate the virological effects and safety of switching at Day 1 from 
entecavir hydrate (ETV) to tenofovir disoproxil fumarate (TDF) in chronic hepatitis B HBeAg-
positive and HBV-DNA undetectable subjects [< 1.3 log IU/mL (< 20 IU/mL) or < 2.1 Log10 
copies/mL]. 
 
Objectives and Endpoints: 
Objectives 
Endpoints 
Primary 
 
• 
To evaluate the HBsAg reduction potential at 
Week 48 
• 
Proportion of subjects achieving 0.25 Log10 
HBsAg reduction from the baseline at Week 
48 
Secondary 
 
• 
To evaluate the virological effects 
• 
Proportion of subjects achieving 0.25 Log10 
HBsAg reduction from the baseline at Week 
24 and 96 
• 
Proportion of subjects achieving HBsAg loss 
and HBsAg/Ab seroconversion at Week 24, 
48 and 96 
• 
Proportion of subjects achieving HBeAg loss 
and HBeAg/Ab seroconversion at Week 24, 
48 and 96 
• 
Reduction of HBsAg titer from the baseline 
at Week 24, 48 and 96 
• 
Reduction of HB core-related antigen 
(HBcrAg) titer from the baseline at Week 24, 
48 and 96 
• 
To evaluate the safety 
• 
Adverse events (AEs) 
• 
Clinical Laboratory values (hematology, 
clinical chemistry, urinalysis) 
• 
Vital signs (blood pressure, pulse rate, 
temperature) 
• 
12-lead ECG 

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• 
Bone density 
 
Study Design: 
This is a multi-center, one-arm, open-label study. The study will evaluate the efficacy and safety of 
TDF by switching at Day 1 from ETV to TDF in chronic hepatitis B HBeAg-positive and HBV-DNA 
undetectable subjects [< 1.3 log IU/mL (< 20 IU/mL) or < 2.1 Log10 copies/mL]. 
 
 
Number of Subjects: 
Screening, 80 subjects; Subjects eligible for evaluation, 65 subjects 
 
Treatment Groups and Duration: 
 
 
 
ETV 0.5mg tablet QD
TDF 300mg tablet QD
Screening
(within 6 weeks from 
informed consent)
Informed consent/
Preliminary registration
Registration
Week 96
Completion

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2. SCHEDULE OF ACTIVITIES (SOA) 
 

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Procedure 
Screening 
(up to 42 
days 
before 
Day 1)1 
Treatment period 
Discontinuation/Completion 
(Week 96) 
(±14)2 
Day 1 
Week 4 
(±14) 
Week 12, 
24, 36 
(±14) 
Week 48 
(±14) 
Week 60, 72, 84 
(±14) 
Informed Consent 
X1 
 
 
 
 
 
 
Demography  
X 
 
 
 
 
 
 
Abdominal imaging test3 
X 
(X) 
(X) 
(X) 
(X) 
(X) 
X 
Inclusion/Exclusion Criteria4 
X 
 
 
 
 
 
 
Pregnancy Test (females of childbearing 
potential only )5 
X 
X 
X 
X 
X 
X 
X 
 [HIV and HCV screening] 
X 
 
 
 
 
 
 
12-lead ECG 
X 
 
 
 
X 
 
X 
Bone densinometry 
X6 
 
(X)7,8 
(X) 7,8 
(X) 7,8 
(X) 7,8 
X8 
Vital Signs9 
X 
X 
X 
X 
X 
X 
X 
Study treatment dispensation 
 
X 
 
X 
X 
X 
 
Confirmation of investigational product 
compliance  
 
 
X 
X 
X 
X 
X 
AE Assessment 
 
X 
 
X 
SAE Assessment 
 
X 
 
X 
Concomitant Treatment Review 
X 
X 
 
X 
Hematology 10 
X 
X 
X 
X 
X 
X 
X 
Clinical Chemistry 11 
X 
X 
X 
X 
X 
X 
X 
Urinalysis 12 
X 
X 
X 
X 
X 
X 
X 
HBV-DNA 
X 
X 
X 
X 
X 
X 
X 
HBeAg/Anti-HBe 
X 
X 
X 
X 
X 
X 
X 

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Procedure 
Screening 
(up to 42 
days 
before 
Day 1)1 
Treatment period 
Discontinuation/Completion 
(Week 96) 
(±14)2 
Day 1 
Week 4 
(±14) 
Week 12, 
24, 36 
(±14) 
Week 48 
(±14) 
Week 60, 72, 84 
(±14) 
HBsAg/Anti-HBs 
X 
X 
X 
X 
X 
X 
X 
HBcrAg 
 
X 
X 
X 
X 
X 
X 
Resistant Assay 13 
 
 
(X) 
(X) 
(X) 
(X) 
(X) 
HBV Genotype 
X 
 
 
 
 
 
 
 
1. 
Perform the screening examinations surely within 42 days before starting the study treatment. 
2. 
On completing or discontinuing the study, perform these items within 72 hours after the last dose of the study treatment. 
3. 
For diagnosis of cirrhosis, see Appendix 7. 
4. 
For subject in whom HBsAg value range is confirmed before screening, enter values at 2 time points (with an interval of at least 3 months, and at least 
one point within 1 year from screening) into electronic Case Report Form (eCRF). 
5. 
Perform the pregnancy test (urine test) for only women of childbearing potential or women with less than two years after the last menstruation. On the 
day of starting the study treatment, perform the pregnancy test before the first dose of the study treatment. 
6. 
If the assessment was performed within 1 year prior to screening, it can be substituted as a score at screening. 
7. 
Perform the assessment when the investigator considered necessary from laboratory results. 
8. 
Perform bone densimetry with an interval of at least 4 months. If the assessment was performed within 3 months prior to each visit, do not duplicate the 
procedure. 
9. 
Assess height, weight, blood pressure, pulse rate and temperature. Height is collected at screening only. 
10. Red blood cell count, hemoglobin, hematocrit, white blood cell count (including differential count), platelet count, prothrombin time 
11. AST, ALT, γ-GTP, ALP, LDH, total bilirubin, direct bilirubin, total protein, serum albumin, serum creatinine, creatinine kinase, amylase, lipase, AFP, 
antinuclear antibody titer, electrolyte (Na, K, Cl, Ca, P), blood glucose, uric acid, BUN, hyaluronate, lactic acid (however, assess antinuclear antibody 
titer at screening only, hyaluronate must be assessed at screening but for the visits afterwards assess when necessary), CLcr (calculate from serum 
creatinine based on Cockcroft-Gault formula described in section 6.1) and eGFR. 
12. Urinary sediment, β2-microglobulin, urine creatinine, urine glucose, urine protein, electrolyte (P) 

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13. Perform resistance analysis on lamivudine (LAM), adefovir (ADV), ETV and TDF. In a case where a virological breakthrough has been observed (a 
case where the serum HBV-DNA level has increased from the nadir by at least 1 log IU/mL or an increase of at least 2 log IU/mL (100 IU/mL) if the 
nadir is under 10 IU/mL), perform the resistance analysis. The blood specimen for the resistance analysis must be taken at every visit (excluding the 
starting date of the study treatment). 

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3. INTRODUCTION 
Tenofovir Disoproxil Fumarate (TDF) is a nucleos(t)ide analogue that inhibits HBV growth, and is 
marketed in Japan with an indication for inhibition of HBV growth in patients with chronic hepatitis B 
associated with HBV growth and abnormal liver function. 
  
3.1. 
Study Rationale 
This study has been planned to evaluate the virological effects and safety of switching at Day 1 from 
ETV to TDF in chronic hepatitis B HBeAg-positive and HBV-DNA undetectable subjects. 
 
3.2. 
Background 
Chronic hepatitis B (CHB) generally shows exacerbation over a long term by repeating liver 
inflammation persistently or intermittently. It is known that when chronic hepatitis B is left untreated, 
liver fibrosis proceeds toward the risk for onset of liver failure or liver cancer [Mizokami, 2010]. 
 
There are two options in CHB treatment. One is interferon preparation used by injection and the other 
is nucleos(t)ide analogue used by oral administration. The interferon therapy does not show a high 
response rate, since the therapeutic effect is markedly different depending on the initial HBV-DNA 
level, ALT level and HBV genotype. On the other hand, nucleic acid analogues show a very potent 
effect to suppress HBV growth, but appearance of HBV strains resistant to each nucleos(t)ide 
analogue is problematic. Furthermore, the long-term goal of treatment, the loss of HBsAg, is rarely 
achievable. 
 
It has been reported that TDF demonstrated a superior HBsAg reduction compared to ETV in the 
Japanese phase 3 study [Koike,2018]. Recently, a topic on the effect of TDF on HBsAg reduction is 
often seen at conferences in Japan and HBsAg reduction by nucleos(t)ide analogue is drawing 
attention from the hepatologists. Loss of HBsAg is one of the goals in the 10-year strategy for 
hepatitis research by the Ministry of Health, Labour and Welfare, and HBsAg is considered an 
important surrogate marker in CHB treatment.  
 
Based on the above, evaluation of HBsAg reduction in this study is considered medically and 
clinically significant. 
 
3.3. 
Benefit/Risk Assessment 
More detailed information about the known and expected benefits and risks and reasonably expected 
adverse events of TDF may be found in the Package Insert.        

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3.3.1. 
Risk Assessment 
 
   Potential Risk of Clinical Significance 
 
Summary of Data/Rationale for Risk 
 
Mitigation Strategy 
Investigational Product[GSK548470] 
Renal toxicity 
In nonclinical studies, high levels of serum 
creatinine and chloride, urinary glucose or urinary 
protein, and increase in urine volume, 
karyomegaly, denaturation or reproduction, and 
necrosis of tubular epithelium, interstitial nephritis, 
etc. were observed in rats, dogs, and monkeys. The 
kidney is considered as the target organ of TDF. 
Although not reported in Japanese clinical studies 
conducted in subjects infected with HBV, serious 
renal dysfunction such as renal failure, Fanconi 
syndrome and other proximal renal tubular 
disorders have been reported in overseas clinical 
studies. 
Serious renal dysfunction such as 
acute renal failure and renal tubular necrosis has 
been spontaneously reported overseas during the 
post-marketing use of TDF including preparations 
with the same ingredients indicated for HIV-1 
infection. 
Set the inclusion criteria for subjects with 
creatinine clearance 70 mL/min. 
Set the exclusion criteria for subjects with 
proximal renal tubular disorders. 
Set the dose adjustment when creatinine clearance 
reaches 50 mL/min. 
Included prohibited concomitant drugs that affects 
the kidney. 
Monitor renal function by assessing serum 
creatinine, etc. during this study period and set the 
discontinuation criteria based on the renal function 
values. 
Collect detailed information on the incidence, 
seriousness, and outcome of renal toxicity during 
this study period. 

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   Potential Risk of Clinical Significance 
 
Summary of Data/Rationale for Risk 
 
Mitigation Strategy 
Bone events (fracture, osteomalacia, etc.) 
Effect on serum and urinary phosphorus, range in 
bone metabolism markers, decrease in bone mineral 
density or bone density, etc. were observed in rats 
and monkeys in non-clinical studies. The bone is 
considered the target organ of TDF. 
Tubular epithelium disorder caused by TDF is 
considered to lead to a loss of phosphonate into the 
urine. Accelerated bone resorption associated with 
decreased intestinal absorption of phosphonate is 
also considered responsible for 
bone metabolism disorders leading to bone 
fractures. 
Although not reported in Japanese clinical studies, 
skeletal events such as osteopenia and osteoporosis 
have been reported in overseas clinical studies. 
Fractures and osteomalacia, etc. have been 
spontaneously reported during overseas post-
marketing use of TDF including preparations with 
the same ingredients indicated for HIV-1 infection. 
Exclude subjects with proximal renal tubular 
disorders through exclusion criteria. 
Monitor serum phosphorus, urinary phosphorus, 
and β2-microglobulin levels, etc. and perform bone 
densinometry as necessary, during this study 
period. 
Collect detailed information on the incidence, 
seriousness, and outcome of bone events such as 
fracture and osteomalacia during this study period. 

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   Potential Risk of Clinical Significance 
 
Summary of Data/Rationale for Risk 
 
Mitigation Strategy 
Hepatic dysfunction (exacerbation of hepatitis after 
discontinuation of administration etc) 
Hepatitis may occur by regrowth of virus after 
discontinuation of TDF administration. 
In the overseas clinical study conducted in subjects 
infected with HBV, exacerbation of hepatitis at 2-3 
month post treatment discontinuation was observed 
in 8.75% (7/80 subjects) of the subjects who 
discontinued TDF during the treatment period of up 
to 240 weeks. 
Hepatitis flare may occur during oral antiviral 
therapy in relation to a rapid decrease of virus, 
characterized by abnormal changes in laboratory 
results such as a rapid elevation of ALT and other 
hepatic function. 
Monitor hepatic function by measuring ALT, etc. 
during this study period and set the liver chemistry 
stopping criteria. 
Allow the subjects who meet the stopping criteria 
and who have been withdrawn from TDF treatment 
can start alternative treatment. 
Collect detailed information on the incidence, 
seriousness, and outcome of hepatic dysfunction 
during this study period. 
Pancreatitis 
Increased lipase levels were observed in the 
Japanese clinical study in subjects infected with 
HBV (2.10%, 3/143 subjects). Also, pancreatitis 
and acute pancreatitis were observed in overseas 
clinical studies. 
Although the incidence is lower than in subjects 
infected with HIV, pancreatitis has been 
spontaneously reported in subjects infected with 
HBV in overseas post-marketing studies. 
Collect detailed information on the incidence, 
seriousness, and outcome of pancreatitis during this 
study period. 

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   Potential Risk of Clinical Significance 
 
Summary of Data/Rationale for Risk 
 
Mitigation Strategy 
Lactic acidosis and severe hepatomegaly associated 
with fatty degeneration 
Lactic acidosis may occur due to the DNA 
polymerase inhibiting function of TDF. 
Occurrence of lactic acidosis has been observed in 
overseas clinical studies of TDF. 
Although the incidence is lower than in subjects 
infected with HIV, lactic acidosis has been 
spontaneously reported in subjects infected with 
HBV in overseas post-marketing studies. 
Collect detailed information on the incidence, 
seriousness, and outcome of lactic acidosis and 
severe hepatomegaly associated with 
fatty degeneration during this study period. 
Lipodystrophy  
Although not reported in the Japanese or overseas 
clinical studies in subjects infected with HBV, 
lipodystrophy has been reported in overseas clinical 
studies in subjects infected with HIV-1. 
Although the incidence is lower than in subjects 
infected with HIV-1, lipodystrophy has been 
spontaneously reported in subjects infected with 
HBV in overseas post-marketing studies. 
Collect detailed information on the incidence, 
seriousness, and outcome of lipodystrophy during 
this study period. 
Drug resistance and cross resistance 
Although clinical resistance to TDF has not been 
confirmed, appearance of TDF-resistant viruses 
may exacerbate CHB by causing virologic 
breakthrough (rebound of viral load). 
Although cross-resistance with other drugs has not 
been observed in overseas long-term clinical 
studies of up to 240 weeks, partial cross-resistance 
among HBV reverse transcriptase inhibitors has 
been observed in vitro. 
Monitor HBV DNA levels during this study period 
and perform resistance analysis if virologic 
breakthrough (increase in serum HBV DNA by 
≥1 log IU/mL from the nadir or an increase of at 
least 2 log IU/mL (100 IU/mL) if the nadir is under 
10 IU/mL) is observed. 
 

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   Potential Risk of Clinical Significance 
 
Summary of Data/Rationale for Risk 
 
Mitigation Strategy 
Study procedures 
Change in safety data such as on renal impairment 
and change in efficacy data such as on 
antiviral effect by switching from ETV to TDF 
Although clinical studies conducted overseas 
showed no difference in the change in eGFR levels, 
proportion of subjects with a 20% decrease in 
eGFR was reported to be higher in the TDF group 
than in the ETV group at Week 96 [Sriprayoon 
2017]. 
Although clinical resistance to TDF has not been 
confirmed, appearance of TDF-resistant viruses 
may exacerbate CHB by causing virologic 
breakthrough (rebound of viral load). 
In addition to the mitigation strategy for each of the 
above items, set up a visit at Week 4 to 
obtain/confirm safety and efficacy data at an early 
stage after switching to study treatment. 

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3.3.2. 
Benefit Assessment 
In the JSH Guidelines for the Management of Hepatitis B Virus Infection [Drafting Committee for 
Hepatitis Management Guidelines, the Japan Society of Hepatology 2017], short-term goals of 
antiretroviral therapy include continuous normalization of ALT level and negative conversion of 
HBeAg, and short-term goal for subjects on sequential treatment with nucleos(t)ide analogues is 
negative conversion of HBV DNA. Among these, loss of HBeAg has not been achieved in 
subjects in this study. As a preliminary step to achieve the long-term goal, HBsAg loss, the 
decrease in HBsAg level must be observed. However, subjects in this study show high HBsAg 
levels or no tendency of decrease (fluctuation range of ≥ -0.1 Log10 IU/mL/year). Since HBsAg 
reduction was significantly higher in the TDF group compared to the ETV group in the Japanese 
Phase 3 study [Koike, 2018], switching from ETV to TDF to achieve toward the long-term goal, 
HBsAg loss, is considered beneficial. 
 
3.3.3. 
Overall Benefit: Risk Conclusion 
Considering the endpoints to minimize risks to the subjects enrolled in the study, the known 
potential risks of TDF are justified by the potential benefits to CHB subjects. 
 
4. OBJECTIVES AND ENDPOINTS 
Objectives 
Endpoints 
Primary 
• 
To evaluate the HBsAg reduction potential 
at Week 48 
 
• 
Proportion of subjects achieving 0.25 
Log10 HBsAg reduction from the baseline 
at Week 48  
Secondary 
• 
To evaluate the virological effects 
 
 
• 
Proportion of subjects achieving 0.25 
Log10 HBsAg reduction from the baseline 
at Week 24 and 96 
• 
Proportion of subjects achieving HBsAg 
loss and HBsAg/Ab seroconversion at 
Week 24, 48 and 96 
• 
Proportion of subjects achieving HBeAg 
loss and HBeAg/Ab seroconversion at 
Week 24, 48 and 96 
• 
Reduction of HBsAg titer from the 
baseline at Week 24, 48 and 96 
• 
Reduction of HB core-related antigen 
(HBcrAg) titerfrom the baseline at Week 
24, 48 and 96 
• 
To evaluate the safety  
• 
Adverse events (AEs) 
• 
Clinical laboratory results (hematology, 
clinical chemistry and urinalysis) 
• 
Vital signs (blood pressure, pulse rate, 
temperature) 
• 
12-lead ECG 
• 
Bone density 

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5. STUDY DESIGN 
5.1. 
Overall Design 
 
 
This study is designed as a multi-center, one-arm, post-marketing clinical study. 
The study will be conducted in CHB HBeAg-positive and HBV-DNA undetectable [< 1.3 log 
IU/mL (< 20 IU/mL) or < 2.1 Log10 copies/mL] treated with ETV. 
After switching ETV to TDF at Day 1, TDF will be administered for 96 weeks. 
 
5.2. 
Number of Subjects 
Approximately 80 subjects will be screened to achieve 65 evaluable subjects. 
 
5.3. 
Participant and Study Completion 
A subject is considered to have completed the study if he/she has completed all phases of the 
study including the last visit or the last scheduled procedure shown in the Schedule of Activities 
(SOA). 
 
The end of the study is defined as the date of the last scheduled procedure shown in the SOA for 
the last subject in the trial. 
 
5.4. 
Scientific Rationale for Study Design 
In this study, on-going ETV treatment is switched to TDF treatment at Day 1 in CHB HBV-DNA 
undetectable subjects [< 1.3 log IU/mL (< 20 IU/mL) or < 2.1 Log10 copies/mL]. With regards to 
the negative conversion of HBV-DNA which is listed as a short-term goal of antiretroviral therapy 
in the JSH Guidelines for the Management of Hepatitis B Virus Infection, the target subjects are 
those who are well controlled by ETV treatment. However, as for the negative conversion of 
HBeAg which is also listed as a short-term goal, the target subjects are those who have not 
achieved this goal. In addition, this study is designed to investigate the HBsAg reduction in 
subjects who have not achieved the long-term goal, the loss of HBsAg. The Japanese phase 3 
study demonstrated superior HBsAg reduction in TDF treated group compared to the ETV treated 
group.  
The switching of treatment in this study is performed by starting TDF on the day ETV is 
discontinued, without having overlapping treatment periods. Since both ETV and TDF are once-
daily drugs and the blood concentration of TDF reaches its peak at 1.2 ± 0.5 hr, the method of 
switching treatment is considered appropriate. 
 
5.5. 
Dose Justification 
As this is a post-marketing clinical study, the dosage and administration of TDF will be 300 mg 
once daily in accordance with the product package insert. 
ETV 0.5mg tablet QD
TDF 300mg tablet QD
Screening
(within 6 weeks from 
informed consent)
Informed consent/
Preliminary registration
Registration
Week 96
Completion

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6. STUDY POPULATION 
Prospective approval of protocol deviations to recruitment and enrollment criteria, also known as 
protocol waivers or exemptions, is not permitted. 
 
6.1. 
Inclusion Criteria 
Subjects are eligible to be included in the study only if all of the following criteria apply: 
Inclusion Criteria 
Screening Day 1 
1. 
Subjects must be 20 to 69 years of age inclusive, at the time of 
signing the informed consent 
X 
 
2. 
Male and female 
A female subject is eligible to participate if she is not pregnant and 
not breastfeeding (see Appendix 4), and at least one of the 
following conditions applies:  
 
i) 
Not a woman of childbearing potential (WOCBP) as 
defined in Appendix 4 
OR 
ii) 
A WOCBP who agrees to follow the contraceptive 
guidance in Appendix 4 during the treatment period and 
for at least 4 days after the last dose of study treatment 
X 
(X: For 
females, 
confirmation 
of 
pregnancy 
test only) 
3. 
Capable of giving signed informed consent form (ICF) as described 
in Appendix 2, which includes compliance with the requirements 
and restrictions listed in the ICF and in this protocol.   
X 
 
4. 
Subjects with CHB (excluding hospitalized patients) 
X 
 
5. 
Subjects treated with ETV for at least 2 years prior to initiation of 
study treatment. 
 
X 
6. 
The serum HBV-DNA level at screening is below the limit of 
quantitation [< 1.3 log IU/mL (< 20 IU/mL) or < 2.1 Log10 
copies/mL]. 
 
X 
7. 
Subjects with serum HBeAg positive at screening  
 
X 
8. 
Meet either of the following serum HBsAg levels at screening. 
 
• 
Serum HBsAg ≥ 800 IU/ml 
• 
Serum HBsAg 80 < to < 800 IU/ml 
and fluctuation decrease is within -0.1 Log10 IU/ml per year 
(Confirming the fluctuation range before screening must be 
determined using the value which has already been measured. 
Using preserved serum specimen for retest is prohibited.) 
 
X 
9. 
Meet all of the following criteria at screening 
• 
Creatinine clearance (CLcr)  70 mL/min 
CLcr is calculated using the following Cockcroft-Gault 
formula. 
Male: CLcr = (body weight [kg] × [140-age in years]) / (72 × 
serum creatinine [mg/dL]) 
Female: CLcr = CLcr (male) × 0.85 
• 
Hemoglobin ≥ 8 g/dL 
 
X 

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• 
WBC  1,000 /mm3 
 
6.2. 
Exclusion Criteria 
Subjects are excluded from the study if any of the following criteria apply: 
Exclusion Criteria 
Screening Day 1 
1. 
QTc > 450 msec or > 480 msec for subjects with bundle branch 
block 
  Note: 
• 
QT interval (QTcB) corrected by the Bazett formula, QT 
interval (QTcF) corrected by the Fridericia formula and/or QT 
intervals corrected by other formulae. Interpreted by computer 
or re-interpreted manually. 
• 
The QT Interval correction formula used for 
inclusion/exclusion criteria and discontinuation criteria for 
each subject should be determined prior to study initiation. 
Multiple correction formulae cannot be used for QTc 
calculation for each subject and the lowest QTc value cannot 
be used for enrolment or discontinuation of subjects.   
X 
 
2. 
Received any interferon or HB vaccine therapy within 24 weeks 
prior to initiation of the study treatment. 
 
X 
3. 
Received overdose of nonsteroidal anti-inflammatory drugs 
(NSAIDs) (excluding temporary or topical use) within 7 days prior 
to initiation of the study treatment. 
 
X 
4. 
Received any of the following drugs within 8 weeks prior to 
initiation of the study treatment (excluding topical products such as 
ointment and/or cream etc).  
• 
Drugs causing renal impairment (e.g., aminoglycosides, 
amphotericin B, vancomycin, foscarnet, cisplatin, 
pentamidine, tacrolimus, cyclosporine, some contrast 
mediums [ionic high-osmolar contrast media, ionic low-
osmolar contrast media] 
• 
Competitors of renal excretion (except temporary use, e.g., 
probenecid) 
• 
Immunosuppressants (e.g., azathioprine, cycolphosphamide) 
or chemotherapeutics (e.g., etoposide) 
• 
Glucocorticoid preparation 
 
X 
5. 
Received TDF, ADV or TAF within 2 years prior to initiation of 
the study treatment 
 
X 
6. 
Participation in another clinical study within 6 months prior to 
screening, or planned participation in another clinical study 
simultaneously with this study. 
X 
 
7. 
Co-infection with HIV or HCV 
 
X 
8. 
Subjects with serious complication other than compensated CHB 
(cancer, significant renal, cardiovascular, pulmonary, or 
neurological disease, uncontrollable diabetes, etc.) 
X 
 

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9. 
Received or have a plan for solid organ or bone marrow 
transplantation 
X 
 
10. Has proximal tubulopathy.  
X 
 
11. Subjects with decompensated CHB who meet the following. 
• 
Direct bilirubin > 1.5 × ULN, PT < 60%, platelets < 
75,000/mm3 and serum albumin < 3.0 g/dL 
 
X 
12. Diagnosed as an autoimmune hepatitis, excluding CHB 
 
X 
13. Subjects with or suspected of having hepatocellular carcinoma 
(HCC) (including both primary and metastatic) from diagnostic 
imaging at screening, or with serum α-fetoprotein (AFP) > 50 
ng/mL at screening 
 
X 
14. History of HCC (except subjects who underwent resection or 
received curative treatment by radiofrequency, and with AFP ≤ 10 
ng/mL at screening) 
 
X 
15. Woman who is pregnant, possibly pregnant, lactating or planning a 
pregnancy during the study period. 
X 
(X: 
confirmation 
of 
pregnancy 
test only) 
16. Psychiatry disorder or cognitive disorder that may affect the 
subject’s ability to give informed consent or to follow specified 
study procedures. 
X 
 
17. Subjects with a history of alcohol or drug abuse 
X 
 
18. Subjects whom the investigator (or sub-investigator) considers 
ineligible for the study. 
X 
 
19. Subjects with hypersensitivity to study treatments or their 
components, nucleoside and/or nucleotide analogues. Subjects with 
drug allergy that, in the investigator’s (sub-investigator’s) [or 
medical monitor’s] opinion, labelled contraindication for 
participation in the study, or other allergy. 
X 
 
 
6.3. 
Lifestyle Restrictions 
There are no specific lifestyle restrictions in this study. 
6.4. 
Screen Failures 
Screen failures are defined as subjects who consent to participate in the clinical study but are not 
subsequently entered in the study. A minimal set of screen failure information is required to 
ensure transparent reporting of screen failure subjects to meet the Consolidated Standards of 
Reporting Trials (CONSORT) publishing requirements and to respond to queries from regulatory 
authorities. Minimal information includes demography, screen failure details, eligibility criteria, 
and any serious adverse events (SAEs). 
Information on screen failures as to which participation criteria was not met should be entered into 
electronic Case Report Form (eCRF) dividing into categories, “failures at screening” and “failures 
prior to study treatment.” For participation criteria to be confirmed at screening and Day 1, refer to 
Inclusion Criteria and Exclusion Criteria sections. 
Individuals who do not meet the criteria for participation in this study (screen failure), regarding to 
inclusion criteria 4 to 9 or exclusion criteria 2 to 6, may be rescreened for one time only if it is 

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confirmed that all inclusion criteria are met and exclusion criteria are not met except exclusion 
criterion 3 after the next visit. There should be an interval of 12 weeks before rescreening. 
Rescreened subjects should be assigned to the new subject number as from the initial screening. 
7. TREATMENT 
Study treatment is defined as any investigational treatment(s), marketed product(s), placebo, or 
medical device(s) intended to be administered to a study subject according to the study protocol. 
The study treatment in this study indicates Tenozet tablet 300 mg as described in Section 7.1. 
 
7.1. 
Treatments Administered 
Study Treatment 
Name: 
Tenofovir Disoproxil Fumarate (Tenozet Tablet 300 mg) 
Dosage formulation: 
Film-coated tablets 
Unit dose 
strength(s)/Dosage 
level(s): 
300 mg/dose, once daily 
Route of 
Administration 
Oral 
Dosing instructions: 
 
1 tablet per dose 
Packaging and 
Labeling 
 
A commercially available product, Tenozet Tablets 300 mg, will be used 
for study treatment. 
Manufacturer: 
GlaxoSmithKline K.K. 
 
7.2. 
Dose Modification 
In case of CLcr ˂ 50 mL/min, study treatment dose intervals are adjusted in accordance with 
Table 1: 
 
Table 1   Guidelines for administration corresponding to decreased renal function 
CLcr (mL/min) 
Administration method 
30 - 49 mL/min 
300 mg once every 2 days 
10 - 29 mL/min 
300 mg once every 3-4 days 
Hemodialysis subjects 
300 mg following dialysis every 7 daysnote) or 300 
mg after a total of approximately12 hours of 
dialysis 
Note) After hemodialysis. Pharmacokinetics in subjects with CLcr <10 mL/minute without 
hemodialysis has not been evaluated. 
 
7.3. 
Method of Treatment Assignment 
There is no randomization in this study. 
 
7.4. 
Blinding 
This is an open-label study. 
 

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7.5. 
Preparation/Handling/Storage/Accountability 
1. 
The study treatment, Tenozet Tablets, will be used from existing stock of the medical 
institution or dispensed by the medical institution. The sponsor will not provide study 
treatments. 
2. 
Storage and management of study treatment should follow the package insert and procedures 
of each medical institution. 
3. 
Prescription and medication instruction to subjects should follow the procedures of each 
medical institution. 
4. 
The investigator (sub-investigator)/designated staff of the medical institution should 
document the amount of study treatment dispensed to and the amount taken by subject in the 
chart (source document). 
 
• 
Under normal conditions of handling and administration, study treatment is not expected to 
pose a significant safety risks to the site staff. 
• 
A Material Safety Data Sheet (MSDS)/equivalent document describing occupational hazards 
and recommended handling precautions either will be provided to the investigator, where this 
is required by local laws, or is available upon request from the medical institution. 
 
7.6. 
Treatment Compliance 
• 
When subjects self-administer study treatment(s) at home, compliance with Tenozet Tablets 
300 mg will be assessed through querying the subject during the site visits and documented 
in the source documents and eCRF. A record of the number of Tenozet Tablets 300 mg 
dispensed to and taken by each subject must be maintained. Treatment start and stop dates, 
including those for dose reductions will also be recorded in the eCRF. 
 
7.7. 
Concomitant Therapy 
Any medication or vaccine (including over-the-counter or prescription medicines, vitamins, and/or 
herbal supplements) that the subject is receiving at the time of enrolment or receives during the 
study must be recorded along with: 
• 
reason for use 
• 
dates of administration including start and end dates 
• 
dosage information including dose and frequency 
The Medical Monitor should be contacted if there are any questions regarding concomitant or 
prior therapy. 
 
Permitted Concomitant Drugs 
Appendix 6: Drug not specified in “Prohibited Drugs” may be used concomitantly. However, on 
using the following drugs concomitantly, the instructions shown below should be taken into 
consideration. It is permitted to use a contrast medium considered less influential on the kidney, 
only in a case where an imaging test by CT or MRI needing a contrast medium is clinically 
necessary in order not to miss the onset of liver cancer. 
 
• 
Non- ionic low osmolar contrast media, contrast media for MRI 
 
Note: Each contrast medium should be administered carefully paying attention to the renal 
functions by, e.g., securing the urine amount with transfusion of physiological saline before and 

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after using the contrast medium as the measures to prevent renal impairment of the contrast 
medium. Furthermore, more careful administration is necessary in case of using the contrast 
medium in subjects with decreased renal function. 
 
Prohibited Concomitant Drugs 
During the period from the start to completion of study treatment, concomitant use of the drugs 
listed in “Appendix 6: Prohibited drugs” will be prohibited due to the possibility of having the 
impact on efficacy and safety evaluation.   
However, the following drug, which is listed in “Appendix 6: Prohibited drugs,” may be used for 
the purpose of liver supporting therapy. 
 
1. 
Ursodeoxycholic acid preparations 
When the ALT or AST level exceeds 10 times the ULN, rescue medication may be used after 
consultation with the medical monitor of the sponsor. Rescue medication name, date administered, 
and administration method must be documented. 
  
7.8. 
Treatment after the End of the Study 
After the completion of study treatment and subject’s last visit, the investigator (sub-investigator) 
will perform the treatment considered most appropriate for each subject. The investigator (sub-
investigator) is responsible for considering the subject’s medical care whether or not the sponsor 
provides specific treatment after study completion. 
 
8. DISCONTINUATION CRITERIA 
8.1. 
Discontinuation of Study Treatment 
8.1.1. 
Liver Chemistry Stopping Criteria 
Liver chemistry stopping and increased monitoring criteria have been designed to assure 
subject safety and evaluate liver event etiology. 
If a subject corresponds to any of the following conditions, discontinuation of study treatment due 
to abnormal liver function test result is required. 
 
• 
When a subject corresponds to any of the following conditions 
• 
Bilirubin ≥ 2 times ULN and direct bilirubin > 35% 
• 
International Normalized Ratio (INR) > 1.5 without the administration of warfarin 
• 
Evidence of clinical liver decompensation (development of encephalopathy, ascites, 
hypoalbuminemia [albumin ≤ 3 g/dL]) or variceal bleeding 
• 
ALT ≥ 20 times ULN in the absence of increased bilirubin or evidence of clinical 
decompensation, if persisting ≥ 2 weeks or accompanied by worsening hepatitis 
symptoms. 
OR 
The investigator (sub-investigator) considered it to be in the best interest of the subject to 
discontinue study treatment, although the abnormal liver function test values of the subject do not 
meet the criteria for discontinuation specified in the protocol. 
 
Required actions after liver event and the follow-up assessment section are shown in Appendix 5. 
 

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8.1.2. 
QTc Stopping Criteria 
• 
The same QT correction formula must be used for each individual subject to determine 
eligibility for and discontinuation from the study. This formula may not be changed or 
substituted once the subject has been enrolled. 
• 
For example, if a subject is eligible for the protocol based on QTcB, then QTcB must be 
used for discontinuation of this individual subject as well. 
• 
Once the QT correction formula has been chosen for a subject’s eligibility, the same 
formula must continue to be used for that subject for all QTc data being collected for 
data analysis. Safety ECGs and other non-protocol specified ECGs are an exception. 
• 
The QTc should be based on single ECG. 
 
If ECG results show the following, the subject should be withdrawn from the study. 
• 
QTc > 500 msec or uncorrected QT > 600 msec 
 
For subjects with bundle branch block, the following stopping criteria should be followed. 
Baseline value in subjects with bundle branch block Stopping criteria in subjects with bundle 
branch block 
< 450 msec 
> 500 msec 
450 - 480 msec 
≥530 msec 
 
See the SOA for data to be collected at the time of treatment discontinuation of study and follow-
up and for any further evaluations that need to be completed. 
 
8.1.3. 
Discontinuation Criteria Related to Renal Function Test Values 
The discontinuation criteria and follow-up observation criteria related to renal function test 
values will be specified in order to secure the safety of the subjects. 
 
Serum creatinine values  0.5 mg/dL above baseline should be confirmed by repeat testing within 
3 calendar days of receipt of results before the study treatment is discontinued. (However, if such 
a delay of study treatment discontinuation concerns the safety of subject, study treatment should 
be discontinued immediately.) For serum creatinine elevation  0.5 mg/dL above baseline, 
subjects may continue all study medication, but it is recommended that subjects should be 
monitored weekly until the serum creatinine returned to the original baseline value or  0.3 mg/dL 
from baseline. 
All study treatments should be permanently discontinued in the event that repeated testing 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. 
 
8.1.4. 
Temporary Discontinuation 
Subjects who stopped study treatment will be withdrawn from this study. 
 
8.1.5. 
Rechallenge 
8.1.5.1. 
Study Treatment Restart or Rechallenge 
Study treatment restart or rechallenge is not allowed if study subject meets any of the stopping 
criteria specified in each section under 8.1. 
 

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8.1.6. 
Treatment after Discontinuation of Study Treatment 
Subjects who meet stopping criteria and who have been withdrawn from study treatment can start 
alternative treatment. 
8.2. 
Withdrawal from the Study 
If one of the following events 1) to 6) occurs in a subject, the investigator (or sub-investigator) 
should withdraw that subject from the study: 
  
1） When the subject is lost to follow-up. 
2） When the subject or subject’s legally acceptable representative wishes to withdraw from 
the study. 
3） When it is confirmed that the subject is pregnant. 
4） When the subject meets QTc stopping criteria (refer to 8.1.2. QTc stopping criteria). 
5） When the subject stopping criteria related to hepatic or renal function test values (refer 
to 8.1.1. Liver Chemistry Stopping Criteria or 8.1.3. Discontinuation Criteria Related to 
Renal Function Test Values). 
6） When the study is prematurely terminated for other reasons not directly related to the 
study 
If one of the following events 7) to 11) occurs in asubject, the investigator (or sub-investigator) 
may, at their discretion, withdraw that subject from the study: 
7） When it is difficult to continue the study due to an adverse event (s) (Refer to the 
package insert of Tenozet Tablets 300 mg). 
8） When a protocol deviation is found 
9） When it is difficult to continue the study due to exacerbation of the primary disease or a 
complication 
10） When the disease being studied resolved 
11） When the investigator (or sub-investigator) considers necessary to withdraw the subject 
from the study for other reasons.  
 
If one of the following events 1) to 11) occurs, reason for withdrawal and date of withdrawal 
should be entered into eCRF while taking necessary measures. If the consent is withdrawed, the 
reason must be entered into eCRF. 
 
• 
A subject may withdraw from the study at any time at his/her own request, or may be 
withdrawn at any time at the discretion of the investigator for safety, behavioral, compliance 
or administrative reasons. 
• 
If the subject withdraws consent for disclosure of future information, the sponsor may retain 
and continue to use any data collected before such a withdrawal of consent. 
• 
If a subject withdraws from the study, he/she may request destruction of any samples taken 
and not tested, and the investigator must document this in the site study records. 
• 
Refer to the SOA for data to be collected at the time of study discontinuation and follow-up 
and for any further evaluations that need to be completed. 
 
8.3. 
Lost to Follow Up 
A subject will be considered lost to follow-up if he or she repeatedly fails to return for scheduled 
visits and is unable to be contacted by the study site. 

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The following actions must be taken if a subject fails to return to the clinic for a required study 
visit: 
• 
The site must attempt to contact the subject and reschedule the missed visit as soon as 
possible and counsel the subject on the importance of maintaining the assigned visit schedule 
and ascertain whether or not the participant wishes to and/or should continue in the study. 
• 
Before a subject is deemed lost to follow up, the investigator or designee must make every 
effort to regain contact with the subject (where possible, 3 telephone calls and, if necessary, a 
certified letter to the subject’s last known mailing address or local equivalent methods). 
These contact attempts should be documented in the subject’s medical record. 
• 
Should the subject continue to be unreachable, he/she will be considered to have withdrawn 
from the study with a primary reason of lost to follow-up. 
 
9. STUDY ASSESSMENTS AND PROCEDURES 
• 
Study procedures and their timing are summarized in the SOA. 
• 
Protocol waivers or exemptions are not allowed. 
• 
Immediate safety concerns should be discussed with the sponsor immediately upon 
occurrence or awareness to determine if the subject should continue or discontinue study 
treatment. 
• 
Adherence to the study design requirements, including those specified in the SOA, is 
essential and required for study conduct. 
• 
All screening evaluations must be completed and reviewed to confirm that potential subjects 
meet all eligibility criteria. The investigator will maintain a screening log to record details of 
all subjects screened and to confirm eligibility or record reasons for screening failure, as 
applicable. 
• 
Procedures conducted as part of the subject’s routine clinical management (e.g., blood count) 
and obtained before signing of ICF may be utilized for screening or baseline purposes 
provided the procedure met the protocol-specified criteria and was performed within the time 
frame defined in the SOA. 
• 
Repeat or unscheduled samples may be taken for safety reasons or for technical issues with 
the samples. 
 
9.1. 
Efficacy Assessments 
9.1.1. 
Virus test 
According to theSOA, the following virus tests will be performed on the specified days. These 
tests will be performed centrally at SRL Inc. in principle. The test results will be reported to each 
study site and the sponsor. 
• 
HIV, HCV (only at the time of screening) 
• 
HBV Genotype (only at the time of screening) 
• 
HBV-DNA levels (at screening, Day 1 of administration, Week 4, every 12 weeks) 
• 
HBe Ag/Ab, HBs Ag/Ab (quantitation) (at the time of screening, Day 1 of administration, 
Week 4, every 12 weeks) 
• 
HB cr Ag (Day 1 of administration, Week 4, every 12 weeks) 
• 
LAM resistance analysis, ADV resistance analysis, ETV resistance analysis, TDF resistance 
analysis (a case where the serum HBV-DNA level has increased from the nadir by at least 
1 log IU/mL or an increase of at least 2 log IU/mL (100 IU/mL) if the nadir is under 10 
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The blood sample for the resistance analysis should surely be taken at each visit and the resistance 
analysis will be performed in the above cases. Blood samples taken for resistance analysis will be 
stored at SRL Inc. until completion of study. 
 
9.1.2. 
Endpoints 
Primary Endpoint 
1. 
Proportion of subjects achieving 0.25 Log10 HBsAg reduction from the baseline at Week 48 
 
Secondary Endpoints 
1. 
Proportion of subjects achieving 0.25 Log10 HBsAg reduction from the baseline at Week 24 
and 96 
2. 
Proportion of subjects achieving HBsAg loss and HBsAg/Ab seroconversion at Week 24, 48 
and 96 
3. 
Proportion of subjects achieving HBeAg loss and HBeAg/Ab seroconversion at Week 24, 48 
and 96 
4. 
Reduction of HBsAg titer from the baseline at Week 24, 48 and 96 
5. 
Reduction of HBcrAg titer from the baseline at Week 24, 48 and 96 
 
9.2. 
Adverse Events 
The definitions of an AE or SAE can be found in Appendix 3. 
The investigator and any designees are responsible for detecting, documenting, and reporting 
events that meet the definition of an AE or SAE and remain responsible for following up AEs that 
are serious, considered related to the study treatment or the study, or that caused the subjectto 
discontinue the study treatment (see Section 8). 
 
9.2.1. 
Time Period and Frequency for Collecting AE and SAE Information 
• 
All SAEs will be collected from the start of study treatment until completion/discontinuation 
of study at the time points specified in the SOA (Section 2). However, study participation 
(e.g., study treatment, procedures specified in the protocol, invasive testing, or change from 
the current therapy) or all SAEs considered associated with GSK products will be recorded 
from the time the subjectgave consent to participation in the study. 
• 
All AEs will be collected from the start of treatment until completion/discontinuation of the 
study at the time points specified in the SOA (Section 2). 
• 
Medical occurrences that begin before the start of study treatment but after obtaining 
informed consent will be recorded on the Medical History/Current Medical Conditions 
section of the case report form (CRF) not the AE section. 
• 
All SAEs will be recorded and reported immediately, but no longer than 24 hours in any 
circumstances, to the sponsor or designee as indicated in Appendix 3. The investigator (sub-
investigator) will submit any updated SAE data to the sponsor within 24 hours of it being 
available. 
• 
Investigators (sub-investigators) are not obligated to actively seek AEs or SAEs in former 
study subjects. However, if the investigator learns of any SAE, including a death, at any time 
after a subjecthas been discharged from the study, and he/she considers the event to be 
reasonably related to the study treatment or study participation, the investigator must 
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• 
The method of recording, evaluating, and assessing causality of AEs and SAEs and the 
procedures for completing and transmitting SAE reports are provided in Appendix 3. 
• 
All non-serious AEs considered associated with the study treatment in the post-marketing 
clinical study will be recorded and reported to the sponsor or designee within 24 hours of it 
being available as indicated in Appendix 3. 
 
9.2.2. 
Method of Detecting AEs and SAEs 
Care will be taken not to introduce bias when detecting AE and/or SAE. Open-ended and non-
leading verbal questioning of the subjectis the preferred method to inquire about AE occurrence. 
 
9.2.3. 
Follow-up of AEs and SAEs 
After the initial AE/SAE report, the investigator is required to proactively follow each subjectat 
subsequent visits/contacts. All SAEs will be followed until the event is resolved, stabilized, 
otherwise explained, or the subjectis lost to follow-up (as defined in Section 8.3). Further 
information on follow-up procedures is given in Appendix 3. 
 
Non-serious AEs considered associated with the study treatment in the post-marketing clinical 
study will also be followed. 
 
9.2.4. 
Regulatory Reporting Requirements for SAEs 
• 
Prompt notification by the investigator to the sponsor of an SAE is essential so that legal 
obligations and ethical responsibilities towards the safety of subjects and the safety of a study 
treatment under clinical investigation are met. 
• 
The sponsor has a legal responsibility to notify both the local regulatory authority and other 
regulatory agencies about the safety of a study treatment under clinical investigation. The 
sponsor will comply with country-specific regulatory requirements relating to safety 
reporting to the regulatory authority, Institutional Review Boards (IRB)/Independent Ethics 
Committees (IEC), and investigators. 
• 
Investigator safety reports must be prepared for suspected unexpected serious adverse 
reactions (SUSAR) according to local regulatory requirements and sponsor policy and 
forwarded to investigators as necessary. 
• 
An investigator who receives an investigator safety report describing a SAE or other specific 
safety information (e.g., summary or listing of SAE) from the sponsor will review and then 
file it along with the Investigator’s Brochure and will notify the IRB/IEC, if appropriate 
according to local requirements. 
• 
Prompt notification to the sponsor of non-serious AEs considered associated with the study 
treatment in post-marketing clinical study is essential so that legal obligations and ethical 
responsibilities towards the safety of subjects and the safety of a study treatment under 
clinical investigation are met. 
 
9.2.5. 
Cardiovascular and Death Events 
For any cardiovascular events detailed in Appendix 3 and all deaths, whether or not they are 
considered SAEs, specific Cardiovascular (CV) and Death sections of the CRF will be required to 
be completed. These sections include questions regarding cardiovascular (including sudden 
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The CV CRFs are presented as queries in response to reporting of certain CV MedDRA terms. 
The CV information should be recorded in the specific cardiovascular section of the CRF within 
one week of receipt of a CV Event data query prompting its completion. 
The Death CRF is provided immediately after the occurrence or outcome of death is reported. 
Initial and follow-up reports regarding death must be completed within one week of when the 
death is reported. 
 
9.2.6. 
Disease-Related Events and/or Disease-Related Outcomes Not Qualifying as SAEs 
Not applicable 
 
9.2.7. 
Pregnancy 
• 
Details of all pregnancies in female subjects will be collected after the start of study 
treatment until 4 days after the last dose. 
• 
If a pregnancy is reported, the investigator (sub-investigator) should inform GSK within 24 
hours of learning of the pregnancy and should follow the procedures outlined in Appendix 4. 
• 
Abnormal pregnancy outcomes (e.g., spontaneous abortion, fetal death, stillbirth, congenital 
anomalies, ectopic pregnancy) are considered SAEs. 
 
9.2.8. 
Medical Device Incidents (Including Malfunctions) 
Not applicable 
 
9.3. 
Treatment of Overdose 
For this study, any dose of TDF greater than 300 mg within a 1-day period will be considered an 
overdose. 
The package insert of TDF (Tenozet Tablets 300 mg) describes overdose as follows. 
 
No case of overdose of TDF has been reported and specific signs and symptoms at the time of 
overdose are unknown. Closely monitor the subjectfor adverse reactions to TDF at the time of 
overdose and perform symptomatic therapy as needed. TDF can partially be removed by 
hemodialysis. Tenofovir removal by peritoneal dialysis has not been examined. 
 
In the event of an overdose, the investigator (sub-investigator) should: 
1. 
Contact the Medical Monitor immediately. 
2. 
Closely monitor the subject for AE/SAE and laboratory abnormalities until Tenofovir can no 
longer be detected (at least 4 days). 
3. 
Obtain a plasma sample for PK analysis within 24 hours from the date of the last dose of 
study treatment if requested by the Medical Monitor (determined on a case-by-case basis). 
4. 
Document the quantity of the excess dose as well as the duration of the overdosing in the 
CRF. 
 
Decisions regarding dose interruptions or modifications will be made by the investigator (sub-
investigator) in consultation with the sponsor’s Medical Monitor based on the clinical evaluation 
of the subject. 
 
9.4. 
Safety Assessments 
Planned time points for all safety assessments are provided in the SOA. 

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9.4.1. 
Physical Examinations 
• 
A complete physical examination will include, at a minimum, assessments of the Skin, 
Cardiovascular, Respiratory, Gastrointestinal and Neurological systems. Height and weight 
will also be measured and recorded. 
• 
A brief physical examination will include, at a minimum, assessments of the skin, lungs, 
cardiovascular system, and abdomen (liver and spleen). 
• 
Investigator (sub-investigator) should pay special attention to clinical signs related to 
previous serious illnesses. 
 
9.4.2. 
Vital Signs 
• 
Temperature (axillary), pulse rate, and blood pressure will be assessed. 
• 
Blood pressure and pulse measurements will be assessed with a completely automated 
device. Manual techniques will be used only if an automated device is not available.  
• 
Blood pressure and pulse measurements should be preceded by at least 5 minutes of rest for 
the subjectin a quiet setting without distractions (e.g., television, cell phones). 
• 
Vital signs (to be taken before blood collection for laboratory tests) will consist of 1 pulse 
and 3 blood pressure measurements (3 consecutive blood pressure readings will be recorded 
at intervals of at least 1 minute). The average of the 3 blood pressure readings will be 
recorded on the CRF. 
 
9.4.3. 
Electrocardiograms 
• 
Single 12-lead ECG will be obtained as outlined in the SOA (Section 2) at screening, Week 
48, at discontinuation or completion of study, and that automatically calculates the heart rate 
and measures PR, QRS, QT, and QTc intervals. Refer to Section 8.1.2 for QTc withdrawal 
criteria and additional QTc readings that may be necessary. 
• 
The measured ECG Waveforms will be retained at each medical institution in paper or 
electronic form.  
 
9.4.4. 
Clinical Safety Laboratory Assessments 
• 
Refer to Table 2 for the list of clinical laboratory tests to be performed and to the SOA for 
the timing and frequency. 
• 
The investigator (sub-investigator) must review the laboratory report, document this review, 
and record any clinically relevant changes occurring during the study in the AE section of the 
CRF. The laboratory reports must be filed with the source documents. Clinically significant 
abnormal laboratory findings are those which are not associated with the underlying disease, 
unless judged by the investigator (sub-investigator) to be more severe than expected for the 
subject's condition. 
• 
All laboratory tests with values considered clinically significantly abnormal during 
participation in the study or within 4 days after the last dose of study treatment should be 
repeated until the values return to normal or baseline or are no longer considered 
significantly abnormal by the investigator or medical monitor. 
• 
If such values do not return to normal/baseline within a period of time judged reasonable by 
the investigator, the etiology should be identified and the sponsor notified. 
• 
All protocol-required laboratory assessments, as defined in Table 2, must be conducted in 
accordance with the laboratory manual and the SOA. 
• 
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• 
Protocol-specific inclusion/exclusion criteria for subjects are included in Section 6 of the 
protocol. 
• 
Additional tests may be performed at any time during the study as determined necessary by 
the investigator (sub-investigator) or required by local regulations.  
 
Table 2   Protocol-Required Safety Laboratory Assessments 
Laboratory 
Assessments  
Parameters 
Hematology 
Platelet Count 
Hemoglobin 
WBC count with 
Differential: 
Neutrophils 
Lymphocytes 
Monocytes 
Eosinophils 
Basophils 
RBC Count 
Hematocrit 
Prothrombin time 
Clinical 
Chemistry1 
Blood urea 
nitrogen (BUN) 
LDH 
Aspartate 
Aminotransferase  
(AST)/ Serum 
Glutamic-
Oxaloacetic 
Transaminase 
(SGOT)  
Total and direct 
bilirubin 
Creatinine 
CLcr 
Alanine 
Aminotransferase 
(ALT)/ Serum 
Glutamic-Pyruvic 
Transaminase 
(SGPT) 
Total Protein  
 
 
Glucose [fasting 
not required] 
eGFR 
Alkaline 
phosphatase (ALP) 
γ-GTP 
Albumin 
Creatine kinase 
Amylase 
Lipase  
AFP 
Antinuclear 
antibody titer [only 
at the time of 
screening] 
Electrolyte (Na, K, 
Cl, Ca, P) 
Uric acid 
Hyaluronic acid 
[Required at 
screening and as 
needed thereafter.] 
Lactic Acid 
 
 
Urinalysis 
Glucose, protein, creatinine, electrolyte (P), urinary sediment, β2-microglobulin 
Other screening 
tests 
Human chorionic gonadotrophic hormone (hCG) pregnancy test (for women of 
childbearing potential and if required)2 
Notes:  
1. 
Details of liver chemistry stopping criteria, required actions after liver events and follow-up 
assessments are provided in Section 8.1 and Appendix 5.  

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2. 
Local urine testing will be standard for the protocol unless serum testing is required by local 
regulation or IRB/IEC. 
 
9.4.5. 
Abdominal Imaging Test 
Abdominal imaging test will be performed to diagnose HCC and hepatic cirrhosis in accordance 
with the SOA (Section 2). 
 
9.4.6. 
Bone Densitometry 
Bone densitometry will be performed using DEXA, SEXA, or ultrasound in accordance with the 
SOA (Section 2). Refer to Appendix 7. 
 
9.5. 
Pharmacokinetics 
PK parameters are not evaluated in this study. 
 
9.6. 
Pharmacodynamics 
Pharmacodynamic parameters are not evaluated in this study. 
 
9.7. 
Genetics 
Genetics are not evaluated in this study. 
 
9.8. 
Biomarkers 
Biomarkers are not evaluated in this study. 
 
9.9. 
Health Economics OR Medical Resource Utilization and Health Economics 
Health Economics/Medical Resource Utilization and Health Economics parameters are not 
evaluated in this study. 
 
10. STATISTICAL CONSIDERATIONS   
This is an open-label uncontrolled study to evaluate the virological effects and safety of switching 
at Day 1 from ETV to TDF 300 mg once daily in Japanese CHB HBeAg-positive and HBV-DNA 
undetectable subjects [< 1.3 log IU/mL (< 20 IU/mL) or < 2.1 Log10 copies/mL].  
Exploratory investigation will therefore be performed and no confirmatory hypotheses will be 
tested. Descriptive summary will be used to assess the efficacy and safety objectives.  
 
10.1. Sample Size Determination 
10.1.1. 
Sample Size Assumptions 
Although no confirmatory hypotheses will be tested in this study, the sample size has been 
examined using the expected responder rate and threshold rate. Assuming the proportion of 
subjects achieving 0.25 Log10 HBsAg reduction from the baseline (proportion of HBsAg 
responder) at Week 48 to be 20%, the proportion of HBsAg responder in subjects not switched to 
TDF-based regimens on the basis of results of ETV treatment to be 6% (threshold rate), and 
significance level (two tailed) to be 5%, the sample size with at least 90% power is calculated to 
be 57. Allowing for a dropout rate of 10%, the sample size is calculated to be 64 and thus the 
target sample size was set at approximately 65. 
 

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10.1.2. 
Sample Size Sensitivity 
Table 3 shows the sample sizes needed to have an at least 80% or 90% power, assuming a 15% to 
25% expected proportion of subjects achieving 0.25 Log10 HBsAg reduction from the baseline and 
a 6% to 10% threshold proportion of subjects. 
 
Table 3    Sample size calculation 
Threshold (%)  
The proportion of 
HbsAg responder at 
Week 48 (%) 
≥ 80% power (N) 
≥ 90% power (N) 
 
6 
15 
82 
116 
20 
55 
57 
25 
55 
55 
 
8 
15 
156 
215 
20 
61 
86 
25 
40 
45 
 
10 
15 
341 
455 
20 
94 
132 
25 
49 
64 
 
10.1.3. 
Sample Size Re-estimation or Adjustment 
No sample size re-estimation will be performed. 
  
10.2. Populations for Analyses 
For analysis purposes, the following populations are defined: 
Population 
Description 
Enrolled 
 
Subjects who provided consent 
Screen failures 
Subjects who provided consent but were not subsequently 
administered 
Safety Population: SP 
Subjects who have received at least 1 dose of study treatment after 
enrolment. 
Full Analysis Set: FAS 
A population of all subjects enrolled in the study, excluding those 
who meet either of the following criteria. 
• 
Have not received any dose of study treatment. 
• 
Have no efficacy data after the start of study treatment. 
Efficacy Evaluable Set: 
EES 
A subset of subjects in the FAS defined above and evaluable for 
efficacy. 
Refer to Report and analysis plan (RAP) for more details. 
 
10.3. Statistical Analyses 
The data in this study will be presented in the form of tables and/or graphs and descriptively 
summarized in accordance with the Integrated Data Standards Library (IDSL) of the sponsor 
(GSK). 
Detailed analyses will be described in the Report and analysis plan (RAP). 
 

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10.3.1. 
Efficacy Analyses 
Efficacy analyses will be performed on the FAS. Primary endpoint analyses will be performed 
also on EES. 
Statistical methods 
The primary endpoint is the proportion of subjects achieving 0.25 Log10 HBsAg reduction from 
the baseline at Week 48, and the responder rate and its two-sided 95% confidence interval will be 
calculated.  
As the secondary analysis, the responder rate (%) at Week 24 and Week 96 and its two-sided 
95% confidence interval will also be calculated. 
Analyses similar to the primary analysis will also be performed in subgroups (disease, genotype, 
etc.). These subgroup analyses are intended to assess the robustness of results.  
Subgroup: 
• 
Disease (CHB, liver cirrhosis) 
• 
Genotype (A, B, C, D) 
 
Centrally measured virus testing results will be used for both the primary endpoint and efficacy 
endpoints  
 
10.3.2. 
Safety Analyses  
Safety analyses will be performed on the SP. 
Statistical methods 
Adverse events 
All adverse events occurred during the study period will be coded with the latest version of 
Medical Dictionary for Regulatory Activities (MedDRA) and classified by System Organ Class 
(SOC) and Preferred Term (PT). 
The adverse events, the adverse events causally related with the investigational product, the 
adverse events resulting in discontinuation of the study, the severe adverse events and the serious 
adverse events will be summarized, and all the adverse events will be listed.  
The frequency and incidence of AE of interest (renal adverse events, hepatic adverse events, and 
skeletal adverse events) will also be summarized.  
 
Clinical Laboratory Tests 
As for the clinical laboratory values (hematology, clinical chemistry, urinalysis), the summary 
statistics (number of subjects, mean, median, SD, minimum, maximum) of observed values at 
each evaluation time point and variation from baseline will be calculated. Shift table from 
baseline to each evaluation time point will be generated. The measured value for each parameter 
will be included in the data listings. In addition, subjects found to have test values out of the 
reference range will be listed. 
 
Vital Signs 
For changes in vital signs (blood pressure, pulse rate, temperature) from baseline to each 
assessment point, the summary statistics (number of subjects, mean, median, SD, minimum, 
maximum) will be calculated. The measured value for each parameter will be included in the data 
listings. 
 

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10.3.3. 
Interim Analyses 
No interim analysis to make statistical investigations will be performed in this study. However, the 
CRF data by Week 48 will be locked when all subjects (excluding withdrawn subjects) complete 
Week 48 to collect safety and efficacy data. 
 
10.3.4. 
Handling of Withdrawed Subjects 
In analyzing the primary endpoint, unless otherwise stated, withdrawed subjects reported during 
the study period will be treated as non-responders. Other imputation methods will be examined.  
 
11. REFERENCES 
Koike K, Suyama K, Ito H, et al. A randomized prospective study showing the non-inferiority of 
tenofovir to entecavir in treatment-naïve chronic hepatitis B patients. Hepatol Res. 2018;48(1):59-
68 
 
 
Sriprayoon T,Mahidol C,Ungtrakul T, et al. Efficacy and safety of entecavir versus tenofovir 
treatment in chronic hepatitis B patients: A randomized controlled trial. Hepatol Res. 
2017;47(3):E161-E168 
 
Tenozet Tablets 300 mg (Tenofovir Disoproxil Fumarate) Package Insert. Dec 2017. 
 
The Drafting Committee for Hepatitis Management Guidelines, the Japan Society of Hepatology 
Guidelines for the Management of Hepatitis B Virus Infection (version 3). Aug 2017 
 
Masashi Mizokami, Eiji Tanaka, Kazuaki Chayama, et al. Diagnosis and Treatment of Hepatitis B. 
Liver. 2010;51:243-60.  
 
12. APPENDICES 
12.1. Appendix 1: Abbreviations and Trademarks 
Abbreviations 
ADV 
Adefovir pivoxil  
AE 
Adverse Event  
ALP 
Alkaline Phosphatase  
ALT 
Alanine Aminotransferase 
AST 
Asparate Aminotransferase  
CLcr 
Creatinine Clearance  
eCRF 
Electronic Case Report Form  
ETV 
Entecavir hydrate  
eGFR 
Estimated Glomerular Filtration Rate  
FDA 
Food and Drug Administration  
GCP 
Good Clinical Practice  
GSK 
GlaxoSmithKline  
γ-GTP 
γ-glutamyltranspeptidase  
HCC 
Hepatocellular carcinoma 
IEC 
Independent Ethics Committee  

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INR 
International Normalized Ratio  
IRB 
Institutional Review Board  
ITT 
Intent-To-Treat 
LAM 
Lamivudine  
MedDRA 
Medical Dictionary for Regulatory Activities  
PCD 
Primary completion date 
PK 
Pharmacokinetics  
PMDA 
Pharmaceuticals and Medical Devices Agency  
PP 
Per Protocol  
PT 
Preferred Term  
RAP 
Reporting and Analysis Plan  
SAE 
Serious Adverse Event  
SD 
Standard Deviation  
SOA 
Schedule of Activities  
SOC 
System Organ Class  
SRM 
Study Reference Manual  
TAF 
Tenofovir Alafenamide Fumarate 
TDF 
Tenofovir Disoproxil Fumarate  
ULN 
Upper Limit of Normal  
 
Trademark 
Trademarks of the GlaxoSmithKline 
group of companies 
 
Trademarks not owned by the 
GlaxoSmithKline group of companies 
 
 
Tenozet 
 
 
 
 

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12.2. Appendix 2: Study Governance Considerations 
 
Regulatory and Ethical Considerations 
• 
This study will be conducted in accordance with the protocol and with:  
• 
Consensus ethical principles derived from international guidelines including the 
Declaration of Helsinki and Council for International Organizations of Medical 
Sciences (CIOMS) International Ethical Guidelines 
• 
Applicable ICH Good Clinical Practice (GCP) Guidelines 
• 
The Ordinance on Standards for Conduct of Clinical Trials (MHW Ordinance No. 28 
dated March 27, 1997) and applicable laws and regulations regarding quality of 
medicinal products and medical devices, efficacy and safety assurance, etc. 
• 
The Ordinance on Good Post-Marketing Study (MHLW Ordinance No.171 dated 
December 20, 2004) 
• 
The protocol, protocol amendments, ICF, Investigator Brochure, and other relevant 
documents (e.g., advertisements) must be submitted to an IRB/IEC by the investigator and 
reviewed and approved by the IRB/IEC before the study is initiated.  
• 
Any amendments to the protocol will require IEC/IRB approval before implementation of 
changes made to the study design, except for changes necessary to eliminate an immediate 
hazard to study subjects.  
• 
The investigator will be responsible for the following:  
• 
Providing written summaries of the status of the study to the IRB/IEC annually or more 
frequently in accordance with the requirements, policies, and procedures established by 
the IRB/EC 
• 
Notifying the IRB/IEC of SAE or other significant safety findings as required by 
IRB/IEC procedures 
• 
Providing oversight of the conduct of the study at the site, ICH guidelines, the IRB/IEC, 
and all other applicable regulations 
 
Financial Disclosure 
Investigators and sub-investigators will provide the sponsor with sufficient, accurate financial 
information as requested to allow the sponsor to submit complete and accurate financial 
certification or disclosure statements to the appropriate regulatory authorities. Investigators are 
responsible for providing information on financial interests during the course of the study and for 
1 year after completion of the study.  
 
Informed Consent Process 
Prior to subjects' participation in the study, the investigator (sub-investigator) will fully explain 
the study using patient information to the subject considered as appropriate or/and to his/her 
legally authorized representative. During this period, provide the subjects opportunities to ask 
questions and sufficient time and obtain the consent form signed or signed/sealed dated with the 
date of consent by the subject and/or his/her legally authorized representative. Subjects may take 
home the Patient Information/Consent Form to consider about the participation at home. The 
person who provides explanation and the study collaborator who provides supplemental 
explanation will sign or sign/seal with the date signed. If a witness is required, the witness should 
also sign or sign/seal with the date witnessed. The investigator (sub-investigator) will attach the 
original of the above signed or signed/sealed, and dated Consent Form (and the Patient 
Information) to the original medical records such as medical chart, retain (follow the storage 

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regulations of the medical institution, if any), and hand the copy to the subject or his/her legally 
authorized representative.  
 
• 
The investigator (sub-investigator) or his/her representative will explain the nature of the 
study to the subject or his/her legally authorized representative and answer all questions 
regarding the study. 
• 
Subjects must be informed that their participation is voluntary. The medical record must 
include a statement that written informed consent was obtained before the subject was 
enrolled in the study and the date the written consent was obtained. The authorized person 
obtaining the informed consent must also sign the ICF. 
• 
Subjects must be re-consented to the most current version of the ICF(s) during their 
participation in the study. 
• 
A copy of the ICF(s) must be provided to the subject or the subject’s legally authorized 
representative. 
• 
Subjects who are rescreened are required to sign a new ICF. 
 
The ICF may contain a separate section that addresses the use of remaining mandatory samples for 
optional exploratory research in accordance with SOP-GSKF-410. The investigator or authorized 
designee will explain to each subject the objectives of the exploratory research. Subjects will be 
told that they are free to refuse to participate and may withdraw their consent at any time and for 
any reason during the storage period. A separate signature will be required to document a subject's 
agreement to allow any remaining specimens to be used for exploratory research. Subjects who 
decline to participate will not provide this separate signature. 
 
Data Protection 
 
• 
Subjects will be assigned a unique identifier by the sponsor. Any subject records or datasets 
that are transferred to the sponsor will contain the identifier only; subject names or any 
information which would make the subject identifiable will not be transferred.  
• 
The subject must be informed that his/her personal study-related data will be used by the 
sponsor in accordance with local data protection law. The level of disclosure must also be 
explained to the subject.  
• 
The subject must be informed that his/her medical records may be examined by Clinical 
Quality Assurance auditors or other authorized personnel appointed by the sponsor, by 
appropriate IRB/IEC members, and by inspectors from regulatory authorities.  
 
 
Publication Policy 
 
• 
The results of this study may be published or presented at scientific meetings. If this is 
foreseen, the investigator agrees to submit all manuscripts or abstracts to the sponsor before 
submission. This allows the sponsor to protect proprietary information and to provide 
comments.  
• 
The sponsor will comply with the requirements for publication of study results. In 
accordance with standard editorial and ethical practice, the sponsor will generally support 
publication of multicenter studies only in their entirety and not as individual site data. In this 
case, a coordinating investigator will be designated by mutual agreement.  

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• 
Authorship will be determined by mutual agreement and in line with International Committee 
of Medical Journal Editors authorship requirements.  
 
 
Dissemination of Clinical Study Data    
 
Prior to enrolment of subjects, the study information derived from this protocol will be made 
publicly available on the Clinical Trial Registry System including the website 
(www.ClinTrials.gov) of the National Institutes of Health (NIH). 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 GSK site 
or other mutually agreeable location. 
GSK will provide the investigator with the full summary of the study results. The investigator will 
share the summary results with the study subjects, as appropriate. 
The results summary will be posted to the GSK Clinical Study Register within 12 months of the 
PCD or LSLV, whichever is earlier, or any decision to terminate the study. In addition, a 
manuscript will be submitted to a peer-reviewed journal for publication within 18 months of the 
LSLV or any decision to terminate the study. When manuscript publication in a peer-reviewed 
journal is not feasible, further study information will be posted to the GSK Clinical Study Register 
to supplement the results summary.   
 
Data Quality Assurance 
 
• 
All subject data relating to the study will be recorded on electronic CRF (eCRF) unless 
transmitted to the sponsor or designee electronically (e.g., laboratory data). The investigator 
is responsible for verifying that data entries are accurate and correct by physically or 
electronically signing the CRF. 
• 
The investigator must maintain accurate documentation (source data) that supports the 
information entered in the CRF. 
• 
The investigator must permit study-related monitoring, audits, IRB/IEC review, and 
regulatory agency inspections and provide direct access to source data documents. 
• 
The sponsor or designee is responsible for the data management of this study including 
quality checking of the data.  
• 
Study monitors will perform ongoing source data verification to confirm that data entered 
into the CRF by authorized site personnel are accurate, complete, and verifiable from source 
documents; that the safety and rights of subjects are being protected; and that the study is 
being conducted in accordance with the latest approved protocol and any other study 
agreements, ICH, GCP, and all applicable regulatory requirements. 
• 
Records and documents, including signed ICF, pertaining to the conduct of this study must 
be retained by the investigator for 25 years from the issue of the final Clinical Study Report 
(CSR)/ equivalent summary unless local regulations or institutional policies require a longer 
retention period. No records may be destroyed during the retention period without the written 
approval of the sponsor. No records may be transferred to another location or party without 
written notification to the sponsor. 
 
Source Documents 

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• 
Source documents provide evidence for the existence of the subject and substantiate the 
integrity of the data collected. Source documents are filed at the investigator’s site. 
• 
Data reported on the CRF or entered in the eCRF that are transcribed from source documents 
must be consistent with the source documents or the discrepancies must be explained. The 
investigator may need to request previous medical records or transfer records, depending on 
the study. In addition, current medical records must be available. 
• 
Definition of what constitutes source data can be found in the source document 
correspondence list. 
 
Study and Site Closure 
 
GSK or its designee reserves the right to close the study site or terminate the study at any time for 
any reason at the sole discretion of GSK. Study sites will be closed upon study completion. A 
study site is considered closed when all required documents and study supplies have been 
collected and a study-site closure visit has been performed.  
The investigator may initiate study-site closure at any time, provided there is reasonable cause and 
sufficient notice is given in advance of the intended termination.  
Reasons for the early closure of a study site by the sponsor or investigator may include but are not 
limited to: 
• 
Failure of the investigator to comply with the protocol, the requirements of the IRB/IEC or 
local health authorities, the sponsor's procedures, or GCP guidelines  
• 
Inadequate recruitment of subjects by the investigator  
• 
Discontinuation of marketing of the investigational product  
 
 
Study Period 
August 2017 to December 2019 
 
Implementation system 
Attachment 1 provides the sponsor information. Attachment 2 provides a list of medical 
institutions and investigators.   

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12.3. Appendix 3: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting 
 
Definition of AE    
AE Definition 
• 
An AE is any untoward medical occurrence in a clinical study subject, temporally 
associated with the use of a study treatment, whether or not considered related to the study 
treatment. 
• 
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 study treatment. 
 
Events Meeting the AE Definition 
• 
Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) or other 
safety assessments (e.g., ECG, radiological scans, vital signs measurements), including 
those that worsen from baseline, considered clinically significant in the medical and 
scientific judgment of the investigator (i.e., not related to progression of underlying 
disease). 
• 
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 before the start of the study. 
• 
Signs, symptoms, or the clinical sequelae of a suspected drug-drug 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 it is 
an intentional overdose taken with possible suicidal/self-harming intent. Such overdoses 
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. Such instances will be captured in the efficacy assessments. 
However, the signs, symptoms, and/or clinical sequelae resulting from lack of efficacy will 
be reported as AE or SAE if they fulfil the definition of an AE or SAE. 
 
Events NOT Meeting the AE Definition 
• 
Any clinically significant abnormal laboratory findings or changes in other safety 
assessments which are associated with the underlying disease, unless judged by the 
investigator to be more severe than expected for the subject’s condition. 
• 
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. 
• 
Medical or surgical procedure (e.g., endoscopy, appendectomy): the condition that leads to 
the procedure is the AE. 
• 
Situations in which 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. 
 
 

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Definition of SAE 
If an event is not an AE per definition above, then it cannot be an SAE even if serious conditions 
are met (e.g., hospitalization for signs/symptoms of the disease under study, death due to 
progression of disease). 
 
A SAE is defined as any untoward medical occurrence that, at any dose: 
a. 
Results in death 
b. 
Is life-threatening 
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 inpatient hospitalization or prolongation of existing hospitalization 
In general, hospitalization signifies that the subject has been detained (usually involving at least 
an overnight stay) at the hospital or emergency ward for observation and/or treatment that would 
not have been appropriate in the physician’s office or outpatient setting. Complications that occur 
during hospitalization are AEs. If a complication prolongs hospitalization or fulfills any other 
serious criteria, the event is serious. When in doubt as to whether “hospitalization” occurred or 
was necessary, the AE should be considered serious. 
Hospitalization for elective treatment of a pre-existing condition that did not worsen from 
baseline is not considered an AE. 
d. 
Results in persistent disability/incapacity 
• 
The term 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 with or prevent everyday life 
functions but do not constitute a substantial disruption. 
e. 
Is a congenital anomaly/birth defect 
f. 
Other situations: 
• 
Medical or scientific judgment should be exercised in deciding whether SAE reporting is 
appropriate in other situations such as important medical events that may not be 
immediately life-threatening or result in death or hospitalization but may jeopardize the 
subject or may require medical or surgical intervention to prevent one of the other outcomes 
listed in the above definition. These events should usually be considered serious. 
Examples of such events include 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 hospitalization, or development of drug dependency or drug abuse. 
g. 
Events meeting liver chemistry stopping criteria  
• 
Bilirubin ≥ 2 times ULN and >35% direct bilirubin 
• 
International Normalized Ratio (INR) > 1.5 in absence of warfarin 
• 
Evidence of clinical decompensation (development of encephalopathy, ascites, 
hypoalbuminea [albumin  3g/dL]), or variceal bleeding 
• 
ALT ≥ 20 times ULN in the absence of increased bilirubin or evidence of clinical 
decompensation, if persisting ≥ 2 weeks or accompanied by worsening hepatitis symptoms 
 
 

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Definition of Cardiovascular Events 
Cardiovascular Events (CV) Definition: 
Investigators will be required to fill out the specific CV event page of the CRF 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 
• 
Revascularization 
 
Recording AE and SAE 
AE and SAE Recording 
• 
When an AE/SAE occurs, it is the responsibility of the investigator to review all 
documentation (e.g., hospital progress notes, laboratory, and diagnostics reports) related to 
the event. 
• 
The investigator will then record all relevant AE/SAE information in the CRF. 
• 
It is not acceptable for the investigator to send photocopies of the subject’s medical records 
to GSK in lieu of completion of the GSK /AE/SAE CRF page. 
• 
There may be instances when copies of medical records for certain cases are requested by 
GSK. In this case, all subject identifiers, with the exception of the subject number, will be 
redacted on the copies of the medical records before submission to GSK. 
• 
The investigator will attempt to establish a diagnosis of the event based on signs, symptoms, 
and/or other clinical information. Whenever possible, the diagnosis (not the individual 
signs/symptoms) will be documented as the AE/SAE. 
 
Assessment of Intensity 
The investigator will make an assessment of intensity for each AE and SAE reported during the 
study and assign it to one of the following categories:  
• 
Mild: An event that is easily tolerated by the subject, causing minimal discomfort and not 
interfering with everyday activities. 
• 
Moderate: An event that causes sufficiently discomfort and interferes with normal everyday 
activities. 
• 
Severe: An event that prevents normal everyday activities. An AE that is assessed as severe 
should not be confused with an SAE. Severity is a category utilized for rating the intensity 
of an event; and both AE and SAE can be assessed as severe. 
An event is defined as ‘serious’ when it meets at least 1 of the predefined outcomes as described 
in the definition of an SAE, NOT when it is rated as severe. 
 
Assessment of Causality 
• 
The investigator is obligated to assess the relationship between study treatment and each 
occurrence of each AE/SAE. 

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• 
A "reasonable possibility" of a relationship conveys that there are facts, evidence, and/or 
arguments to suggest a causal relationship, rather than a relationship cannot be ruled out. 
• 
The investigator will use clinical judgment to determine the relationship. 
• 
Alternative causes, such as underlying disease(s), concomitant therapy, and other risk 
factors, as well as the temporal relationship of the event to study treatment administration 
will be considered and investigated. 
• 
The investigator (sub-investigator) will also consult the Investigator’s Brochure (IB) and/or 
Product Information, for marketed products, in his/her assessment. 
• 
For each AE/SAE, the investigator must document in the medical notes that he/she has 
reviewed the AE/SAE and has provided an assessment of causality. 
• 
There may be situations in which an SAE has occurred and the investigator has minimal 
information to include in the initial report to GSK. However, it is very important that the 
investigator always make an assessment of causality for every event before the initial 
transmission of the SAE data to GSK. 
• 
The investigator may change his/her opinion of causality in light of follow-up information 
and send an SAE follow-up report with the updated causality assessment. 
• 
The causality assessment is one of the criteria used when determining regulatory reporting 
requirements. 
 
Follow-up of AE and SAE 
• 
The investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as medically indicated or as requested by GSK to 
elucidate the nature and/or causality of the AE or SAE as fully as possible. This may include 
additional laboratory tests or investigations, histopathological examinations, or consultation 
with other health care professionals. 
• 
If a subject dies during participation in the study or during a recognized follow-up period, 
the investigator will provide GSK with a copy of any post-mortem findings including 
histopathology.  
• 
New or updated information will be recorded in the originally completed CRF. 
• 
The investigator will submit any updated SAE data to GSK within 24 hours of receipt of the 
information. 
• 
Any updated data on non-SAEs considered associated with the use of study treatment in the 
post-marketing study will be submitted by the investigator to GSK within 24 hours of 
receipt of the information.  
 
Reporting of SAE to GSK 
SAE Reporting to GSK via eCRF 
• 
The primary mechanism for reporting SAE to GSK will be the eCRF . 
• 
If the electronic system is unavailable for more than 24 hours, then the site will use the 
paper SAE data collection tool (see next section).  
• 
The site will enter the SAE data into the electronic system as soon as it becomes available. 
• 
The investigator or medically-qualified sub-investigator must show evidence within the 
eCRF (e.g., check review box, signature, etc.) of review and verification of the relationship 
of each SAE to IP/study participation (causality) within 72 hours of SAE entry into the 
eCRF. 

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• 
After the study is completed at a given site, the eCRF will be taken off-line to prevent the 
entry of new data or changes to existing data. 
• 
If a site receives a report of a new SAE from a study subject or receives updated data on a 
previously reported SAE after the eCRF has been taken off-line, then the site can report this 
new or updated information on a paper SAE form (see next section) or to the sponsor’s 
medical monitor/study contact by telephone.  
• 
Contacts for SAE reporting can be found in Attachment 1. 
• 
The non-SAEs considered associated with the use of study treatment in the post-marketing 
clinical study should be reported in the same manner.  
 
SAE Reporting to GSK via Paper CRF  
• 
Facsimile transmission of the SAE paper CRF is the preferred method to transmit this 
information to the sponsor’s medical monitor or the SAE coordinator. 
• 
In rare circumstances and in the absence of facsimile equipment, notification by telephone is 
acceptable with a copy of the SAE pages of the CRF sent by overnight mail or courier 
service. 
• 
Initial notification via telephone does not replace the need for the investigator to complete 
and sign the SAE CRF pages within the designated reporting time frames. 
• 
Contacts for SAE reporting can be found in Attachment 1. 
• 
The non-SAEs considered associated with the use of study treatment in the post-marketing 
clinical study should be reported in the same manner.  
 

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12.4. Appendix 4: Contraceptive Guidance and Collection of Pregnancy Information 
 
Definitions 
Woman of Childbearing Potential (WOCBP) 
A woman is considered fertile following menarche and until becoming post-menopausal unless 
permanently sterile (see below) 
 
Women in the following categories are not considered WOCBP 
1. 
Premenarchal 
2. 
Premenopausal female with ONE of the following: 
• 
Documented hysterectomy 
• 
Documented bilateral salpingectomy 
• 
Documented bilateral oophorectomy 
Note: Documentation can come from the site personnel’s review of subject’s medical records, 
medical examination, or medical history interview.  
 
3. 
Postmenopausal female 
• 
A postmenopausal state is defined as no menses for 12 months without an alternative 
medical cause. A high follicle stimulating hormone (FSH) level in the postmenopausal 
range may be used to confirm a postmenopausal state in women not using hormonal 
contraception or hormonal replacement therapy (HRT). However, in the absence of 12 
months of amenorrhea, a single FSH measurement is insufficient. 
• 
Females on HRT and whose menopausal status is in doubt will be required to use one of 
the non-hormonal highly effective contraception methods if they wish to continue their 
HRT during the study. Otherwise, they must discontinue HRT to allow confirmation of 
postmenopausal status before study enrolment. 
 
Contraception Guidance 
Female subjects 
 
Female subjects of childbearing potential are eligible to participate if they agree to use a highly 
effective method of contraception consistently and correctly as described in Table 4. 
 
Table 4   Highly effective contraception methods 
Highly Effective Contraceptive Methods That Are User Dependent a 
Failure rate of <1% per year when used consistently and correctly. 
Combined (estrogen- and progestogen-containing ) hormonal contraception associated with 
inhibition of ovulationb 
• 
Oral 
Highly Effective Methods That Are User Independent 
• 
Intrauterine device (IUD) 
• 
Intrauterine hormone-releasing system (IUS) 
Vasectomized partner 
 (A vasectomized partner is a highly effective contraception method provided that the partner is 
the sole male sexual partner of the WOCBP and the absence of sperm has been confirmed. If not, 
an additional highly effective method of contraception should be used.) 

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Sexual abstinence 
(Sexual abstinence is considered a highly effective method only if defined as refraining from 
heterosexual intercourse during the entire period of risk associated with the study drug. The 
reliability of sexual abstinence needs to be evaluated in relation to the duration of the study and 
the preferred and usual lifestyle of the subject.) 
NOTES: 
a. 
Typical use failure rates may differ from those when used consistently and correctly. Use 
should be consistent with local regulations regarding the use of contraceptive methods for 
subjects in clinical studies. 
b. 
Hormonal contraception may be susceptible to interaction with the study treatment, which 
may reduce the efficacy of the contraceptive method. In this case, two highly effective 
methods of contraception should be utilized during the treatment period and for at least 4 
days after the last dose of study treatment. 
 
Pregnancy Testing 
• 
WOCBP should only be included after a confirmed menstrual period and a negative highly 
sensitive urine pregnancy test. 
• 
Additional pregnancy testing is not required during the treatment and after the last dose of 
study treatment and as required locally. 
• 
Pregnancy testing will be performed whenever a menstrual cycle is missed or when 
pregnancy is otherwise suspected.  
• 
Pregnancy testing will be performed using the test kit approved by the sponsor and in 
accordance with instructions provided in its package insert. 
 
Collection of Pregnancy Information  
Female Subjects who become pregnant 
• 
Investigator will collect pregnancy information on any female subject, who becomes 
pregnant while participating in this study.  
• 
Information will be recorded on the appropriate form and submitted to GSK within 24 hours 
of learning of a subject's pregnancy. 
• 
Subject will be followed to determine the outcome of the pregnancy. The investigator will 
collect follow up information on subject and neonate, which will be forwarded to GSK 
Generally, follow-up will not be required for longer than 6 to 8 weeks beyond the estimated 
delivery date. 
• 
Any termination of pregnancy will be reported, regardless of fetal status (presence or absence 
of anomalies) or indication for procedure. 
• 
While pregnancy itself is not considered to be an AE or SAE, any pregnancy complication or 
elective termination of a pregnancy will be reported as an AE or SAE. 
• 
A spontaneous abortion is always considered to be an SAE and will be reported as such. 
• 
Any SAE occurring as a result of a post-study pregnancy which is considered reasonably 
related to the study treatment by the investigator, will be reported to GSK as described in 
Appendix 3. While the investigator is not obligated to actively seek this information in 
former study subjects, he or she may learn of an SAE through spontaneous reporting. 
 
Any female subject who becomes pregnant while participating 
• 
Will be withdrawn from the study 

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12.5. Appendix 5: Liver Safety: Required Actions and Follow-up Assessment and 
Study Treatment Rechallenge Guidelines 
 
Liver chemistry stopping and follow-up assessment criteria in phase III-IV studies will be 
specified in order to secure the safety of the subjects and evaluate the etiology of liver events. 
  
Liver chemistry stopping criteria and required follow-up assessment in phase III-IV studies 
                     Liver chemistry stopping criteria 
Bilirubin1 
Bilirubin  2 times ULN and >35% direct bilirubin 
INR1 
INR > 1.5 in absence of warfarin 
Symptoms 
Evidence of clinical decompensation (development of encephalopathy, ascites, 
hypoalbuminea [albumin  3g/dL]), or variceal bleeding 
ALT  20 times ULN in the absence of increased bilirubin or evidence of clinical 
decompensation, if persisting  2 weeks or accompanied by worsening hepatitis 
symptoms 
Required actions and liver event endpoints 
Actions to be taken 
Liver event endpoints 
• 
Discontinue study treatment immediately 
• 
Report the information to the sponsor 
within 24 hours. 
• 
If the event meets SAE criteria as well, 
enter necessary information in the “Liver 
Event” and “SAE” sections of the CRF.1   
• 
Investigate the liver event endpoints (refer 
to the right column for endpoints). 
• 
Subjects will be followed up until the liver 
function test value becomes normal, 
stabilizes or returns to the baseline level 
(refer to the “Follow-up assessment” 
below).  
• 
The study treatment must not be re-
initiated/re-administered to subjects. 
 
 
Follow-up assessment: 
Bilirubin or INR Criteria: 
• 
The liver function tests (ALT, AST, ALP, 
bilirubin) should be performed again 
within 24 hours and liver event endpoints 
will be examined (refer to the right column 
for endpoints). 
• 
Follow-up will be performed twice a week 
until the liver function test value becomes 
normal, stabilizes or returns to the baseline 
level. 
• 
Serum testing2 related to virus hepatitis 
• 
Measure the INR and monitor each liver 
function test value until decreasing trend is 
observed in transaminase levels. 
• 
Only the subjects who were complicated 
with CHB at the time of enrolment 
(confirmed by positive hepatitis B surface 
antigen (HBsAg)): HBV-DNA quantitative 
analysis 
• 
Obtain blood sample for PK analysis 
within 24 hours after the last dose.3 
• 
Serum creatine phosphokinase (CPK) and 
lactate dehydrogenase (LDH) 
 
• 
Fractionate bilirubin, if total bilirubin  2 x 
ULN 
• 
Obtain blood count including WBC 
differential to assess eosinophilia  
• 
Record the occurrence and worsening of 
clinical symptoms4 of hepatic impairment 
or hypersensitivity on the AE CRF. 
• 
Record use of concomitant medications 
including acetaminophen, herbal remedies, 
and other over the counter medications on 
the concomitant medications CRF. 
• 
Record alcohol intake on the liver event 
CRF. 

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• 
Complete the liver imaging and/or liver 
biopsy CRFs if these tests are performed. 
 
Other criteria: 
• 
Subjects with ALT  20 times ULN who 
otherwise do not meet other stopping 
criteria outlined above can continue study 
medication, but should be monitored 
weekly. 
• 
If, after 2 weeks of monitoring, ALT < 20 
times ULN, subjects should be monitored 
twice monthly until the liver function test 
value becomes normal, stabilizes or returns 
to the baseline level. However, if during 
the monitoring period, subjects meet the 
liver chemistry threshold stopping criteria 
or are unable to return for weekly follow-
up, investigational product must be 
stopped and follow-up will be performed 
until the liver function test value becomes 
normal, stabilizes or returns to the baseline 
level.  
• 
HBV-DNA level resistance analysis (only 
in the subject who has shown virological 
breakthrough) 
• 
HBeAg/Ab 
• 
Prothrombin time 
 
Bilirubin or INR criteria: 
• 
Quantitative determinations of antinuclear 
antibody, antismooth muscle antibody, 
anti-liver/kidney microsome antibody type 
I and immunoglobulin G (IgG) or gamma-
globulin 
• 
Perform liver imaging (ultrasound, 
magnetic resource, or computerized 
tomography) and/or liver biopsy to 
evaluate liver disease and record on the 
liver event CRF. 
 
 
1. 
Events indicating severe liver injury (possible Hy’s Law) (bilirubin ≥ 2 times ULN and 
>35% direct bilirubin, or INR > 1.5 in the absence of warfarin) must be reported as an 
SAE. 
2. 
Hepatitis A IgM antibody, hepatitis B surface antigen (HBsAg) and hepatitis B core antibody 
(IgM), hepatitis C RNA, cytomegalovirus IgM antibody, Epstein-Barr virus capsid antigen 
IgM antibody (if not feasible, perform the heterophile agglutination test), hepatitis E IgM 
antibody or hepatitis E RNA 
3. 
Record the date/time of the PK blood sample draw and the date/time of the last dose of 
investigational product prior to blood sample draw on the CRF. If the date or time of the last 
dose is unclear, provide the subject’s best approximation. If the date/time of the last dose 
cannot be approximated OR a PK sample cannot be collected in the time period indicated 
above, do not obtain a PK sample. Refer to the Study Reference Manual (SRM) for 
procedures for handling and transferring samples. 
4. 
Symptoms considered to be related to liver impairment (fatigue, nausea, vomiting, right 
upper quadrant pain or tenderness, jaundice, etc.), or symptoms considered to be related to 
hypersensitivity (fever, rash, eosinophilia, etc.). 
  
References 
James LP, Letzig L, Simpson PM, Capparelli E, Roberts DW, Hinson JA, Davern TJ, Lee WM. 
Pharmacokinetics of Acetaminophen-Adduct in Adults with Acetaminophen Overdose and Acute 
Liver Failure. Drug Metab Dispos 2009; 37:1779-1784. 
 
Le Gal F, Gordien E, Affolabi D, Hanslik T, Alloui C, Dény P, Gault E.  Quantification of 
Hepatitis Delta Virus RNA in Serum by Consensus Real-Time PCR Indicates Different Patterns of 

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Virological Response to Interferon Therapy in Chronically Infected Patients.  J Clin Microbiol. 
2005;43(5):2363–2369. 
 

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12.6. Appendix 6: Prohibited Drugs   
 
Prohibit the use of the below drugs from the initiation of the study treatment: 
• 
Interleukin-2 preparations 
• 
Ursodeoxycholic acid preparations 
• 
Herbal medicine with positive effects on hepatic dysfunction 
• 
Antiviral drugs with an inhibitory effect on HBV growth (excluding ADV and TAF, which 
should be prohibited from the day of the informed consent) 
 
TDF is prohibited from the day of the consent until the day before the initiation of the study 
treatment (TDF will be administered as an investigational product from Day 1) 
 
Prohibit the use of the below drugs from the day of the informed consent: 
• 
Other investigational products 
• 
Interferon preparations 
• 
HB vaccine therapy 
• 
Glucocorticoid preparations (excluding topical preparations such as ointment and cream) 
• 
Immunosuppressants (e.g., azathioprine and cyclophosphamide) or chemotherapeutic agents 
(e.g., etoposide) (excluding topical preparations such as ointment and cream) 
• 
Drugs influential on the renal functions shown below (excluding topical preparations such as 
ointment and cream) 
• 
Nephrotoxic drugs (e.g., aminoglycoside-class antibiotics, amphotericin B, vancomycin, 
foscarnet, cisplatin, pentamidine, tacrolimus, cyclosporine, some contrast media [ionic 
high osmolar contrast medium, ionic low osmolar contrast media]) 
• 
Drugs competing in renal excretion (excluding temporary use, e.g., probenecid) 
 
Prohibit the use of the below drugs influential on the renal functions within 7 days prior to 
initiation of the study treatment: 
• 
Overdose NSAIDs (excluding temporary or topical use) 

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12.7. Appendix 7: Evaluation of Baseline Values 
12.7.1. 
Participant Backgrounds 
At the time of screening, the following items will be examined and recorded in the eCRF. 
• 
Birth year, gender, race 
• 
Time of diagnosis of CHB/cirrhosis B 
• 
Cardiovascular history/risk factors 
• 
History related to liver disease  
• 
Complications 
• 
Name of the drug for the treatment of CHB and treatment period within 2 years 
• 
History of alcohol consumption and smoking 
• 
Family history of cardiovascular risk factors 
• 
Measured values at 2 time points (with an interval of at least 3 months, and at least one point 
within 1 year from screening ) for subjects in whom changes in HBsAg before screening can 
be confirmed. 
 
 
12.7.2. 
Diagnosis of Cirrhosis B 
Cirrhosis will be diagnosed when applicable to either of the following.  
• 
A case where definite diagnosis of cirrhosis has been made by liver biopsy or 
abdominoscopy performed within one year before obtaining consent 
• 
A case where cirrhosis can be diagnosed in clinical overall diagnosis including abdominal 
imaging tests (ultrasonography, CT, MRI, etc.) (see Table 5) 
 
Table 5   Cirrhosis diagnosis criteria1 
 
Test item 
Criterion 
Hematology 
Platelet count 
≤ 120,000 /μL 
Clinical Chemistry 
Hyaluronate level 
≥ 100 ng/mL 
Abdominal imaging test2 
Ultrasonography, CT, MRI, etc. 1. 
Concavity and convexity 
on the liver surface 
2. 
Echo pattern changes in 
the hepatic parenchyma 
3. 
Findings of portal 
hypertension 
1. 
Cirrhosis is diagnosed when all the criteria are met. Use the results of hematology, clinical 
chemistry and abdominal imaging test obtained at the time of screening. 
2. 
One of the criteria 1 to 3 must be met for abdominal imaging tests. 
 
12.7.3. 
Bone densitometry 
Perform densitometry on either lumbar spine or femur, using DEXA (refer to Table 6). If there is a 
difficulty to perform with DEXA or on either lumbar spine or femur, other region (radius or 
calcaneus) or other method (SEXA or ultrasound) may be selected. 
 
Table 6    Region to perform bone densitometry 
 
Preferred 
Substitute 
Method 
DEXA 
SEXA 
Ultrasound 

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Region 
lumbar spine 
femur 
radius1 
calcaneus1 
radius 
calcaneus 
calcaneus 
1. 
Measure this region if the lumbar spine or femur is not available 
 
If densitometry is required during the study or at study completion/discontinuation, use the same 
method and region performed at baseline.