Clinical trial NCT03258710
Conditions: Hepatitis B, Chronic
Keywords: Tenofovir Disoproxil Fumarate safety chronic hepatitis B virological effect
Sponsor: GlaxoSmithKline
Start date: 2017-10-02; Completion date: 2019-11-25
Enrollment: 75 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
Tenofovir Disoproxil Fumarate is a nucleos(t)ide analogue that inhibits Hepatitis B Virus (HBV) growth, and is marketed in Japan with an indication for inhibition of HBV growth in subjects with chronic hepatitis B associated with HBV growth and abnormal liver function. This study has been planned to evaluate the virological effects and safety of switching from ETV to TDF in chronic hepatitis B (hepatitis B e-antigen \[HBeAg\])-positive and HBV- deoxyribonucleic acid (DNA) undetectable subjects. This study is designed as a multi-center, one-arm, post-marketing clinical study to investigate the HBsAg reduction in subjects who have not achieved the long-term goal, the loss of hepatitis B surface antigen (HBsAg). The study will be conducted in HBeAg-positive and HBV-DNA undetectable subjects treated with ETV. After switching ETV to TDF, TDF will be administered for 96 weeks. Approximately 80 subjects will be screened to achieve 65 evaluable subjects.

Detailed description:

Arms: arm 1: Subjects with on-going ETV treatment will be switched to Tenofovir Disoproxil Fumarate treatment. Subjects will start TDF on the day ETV is discontinued, without having overlapping treatment periods. All subjects will receive one tablet of TDF 300 mg once daily orally for 96 weeks.
Interventions: intervention 1: Tenofovir Disoproxil Fumarate
Intervention descriptions: intervention 1: Tenofovir Disoproxil Fumarate is a nucleos(t)ide analogue that inhibits HBV growth. All subjects will receive one tablet of TDF 300 mg once daily orally for 96 weeks.

Protocol documents:
Prot_002.pdf: 
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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. 
• 
The laboratory tests detailed in Table 2 will be performed by the central laboratory. 


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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. 

SAP_001.pdf: 
CONFIDENTIAL
The GlaxoSmithKline group of companies
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1
Division
:
Worldwide Development
Information Type
:
Reporting and Analysis Plan (RAP)
Title
:
Reporting and Analysis Plan for Study 205883:
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
Compound Number 
:
GSK548470
Effective Date 
:
18-SEP-2018
Description:

The purpose of this RAP is to describe the planned analyses and output to be 
included in the Clinical Study Report for Protocol 205883.

This RAP is intended to describe the Safety and Efficacy analyses required for the 
study. 

This RAP will be provided to the study team members to convey the content of the 
Statistical Analysis Complete (SAC) deliverable.
RAP Author(s):
Approver
Date
Approval Method
Study Statistician/ Biostatistics Group 1, 
Biomedical Data Sciences Department, Japan.
Copyright 2018 the GlaxoSmithKline group of companies. All rights reserved.  
Unauthorised copying or use of this information is prohibited.
PPD


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RAP Team Approvals: Approved by (Approvals captured electronically in CARS 
system):
Approver
Date
Approval 
Method
14-SEP-2018
eSignature
DQL/ Data Practice Group 1, Biomedical Data 
Sciences Department, Japan
13-SEP-2018
eSignature
OSL/ Clinical Operation Department, Japan
18-SEP-2018
eSignature
Lead programmer/ Manager, Statistical 
Programming & Reporting Group, Biomedical Data 
Sciences Department, Japan
13-SEP-2018
eSignature
Clinical Scientist/ Respiratory TA Office, 
Medicines Development, Japan 
13-SEP-2018
eSignature
SAP/CIL/ Infectious Disease/ Future Pipelines 
Discovery Office, Medicines Development, Japan
13-SEP-2018
eSignature
Medical Writing/ Manager, Medical Writing 
Office, Medicines Development, Japan
13-SEP-2018
eSignature
Medical Lead/ Manager, MA Immuno-
Inflammation & Infectious Disease Department, 
Japan 
13-SEP-2018
eSignature
Clinical Safety Expert/ PV Information 
Management Service Department., Japan
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD


CONFIDENTIAL
The GlaxoSmithKline group of companies
205883
3
Clinical Statistics and Clinical Programming Line Approvals: Approved by 
(Approvals captured electronically in CARS system):
Approver
Date
Approval Method
18-SEP-2018
eSignature
Clinical Statistics Line Approver/ Manager, 
Biostatistics Group 1, Biomedical Data Sciences 
Department, Japan.
18-SEP-2018
eSignature
Clinical Programming Line Approver / 
Department Manager, Biomedical Data Sciences 
Department, Japan.
PPD
PPD


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TABLE OF CONTENTS
PAGE
1.
INTRODUCTION......................................................................................................7
2.
SUMMARY OF KEY PROTOCOL INFORMATION ..................................................7
2.1.
Changes to the Protocol Defined Statistical Analysis Plan............................7
2.2.
Study Objective(s) and Endpoint(s)...............................................................7
2.3.
Study Design ................................................................................................8
2.4.
Statistical Hypotheses / Statistical Analyses .................................................8
3.
PLANNED ANALYSES ............................................................................................9
3.1.
Interim Analyses ...........................................................................................9
3.2.
Primary Analyses (WEEK 48) .......................................................................9
3.3.
Final Analyses (WEEK 96)............................................................................9
4.
ANALYSIS POPULATIONS ...................................................................................10
4.1.
Protocol Deviations.....................................................................................10
4.2.
Efficacy Evaluable Set ................................................................................10
5.
CONSIDERATIONS FOR DATA ANALYSES AND DATA HANDLING 
CONVENTIONS.....................................................................................................11
5.1.
Study Treatment & Subgroup Display Descriptors ......................................11
5.2.
Baseline Definitions ....................................................................................11
5.3.
Examination of Covariates, Other Strata and Subgroups............................11
5.3.1.
Examination of Subgroups...........................................................11
5.4.
Multiple Comparisons and Multiplicity .........................................................12
5.5.
Other Considerations for Data Analyses and Data Handling 
Conventions................................................................................................13
6.
STUDY POPULATION ANALYSES .......................................................................14
6.1.
Overview of Planned Study Population Analyses........................................14
7.
EFFICACY ANALYSES..........................................................................................15
7.1.
Primary Efficacy Analyses ..........................................................................15
7.1.1.
Endpoint / Variables.....................................................................15
7.1.2.
Summary Measure ......................................................................15
7.1.3.
Population of Interest...................................................................15
7.1.4.
Strategy for Intercurrent (Post-Randomization) Events ................15
7.1.5.
Statistical Analyses / Methods .....................................................15
7.1.5.1.
Overview of Planned Efficacy Analyses......................15
7.1.5.2.
Statistical Methodology Specification..........................16
7.2.
Secondary Efficacy Analyses......................................................................16
7.2.1.
Endpoint / Variables.....................................................................16
7.2.2.
Summary Measure ......................................................................16
7.2.3.
Population of Interest...................................................................16
7.2.4.
Strategy for Intercurrent (Post-Randomization) Events ................16
7.2.5.
Statistical Analyses / Methods .....................................................17
7.2.5.1.
Overview of Planned Efficacy Analyses......................17
7.2.5.2.
Statistical Methodology Specification..........................19


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8.
SAFETY ANALYSES .............................................................................................21
8.1.
Adverse Events Analyses ...........................................................................21
8.2.
Adverse Events of Special Interest Analyses..............................................21
8.3.
Clinical Laboratory Analyses.......................................................................22
8.4.
Other Safety Analyses ................................................................................23
9.
EXPLORATORY EFFICACY ANALYSES ..............................................................25
9.1.
HBsAg Responder/Non-Responder Analyses.............................................25
9.2.
ALT Categories Analyses ...........................................................................26
9.3.
Correlation of virus parameters...................................................................28
9.4.
Background factor of HBsAg Responder/ Non-Responder..........................28
9.5.
Safety Subgroup Analysis...........................................................................29
10. REFERENCES.......................................................................................................30
11. APPENDICES........................................................................................................31
11.1.
Appendix 1: Protocol Deviation Management .............................................31
11.1.1.
Exclusions from Efficacy Evaluable Set .......................................31
11.2.
Appendix 2: Schedule of Activities ..............................................................32
11.2.1.
Protocol Defined Schedule of Events...........................................32
11.3.
Appendix 3: Assessment Windows .............................................................35
11.3.1.
Definitions of Assessment Windows for Analyses........................35
11.3.2.
Selection of Data in the Event of Multiple Records in a 
Window........................................................................................36
11.3.2.1.
Serology, ALT and Laboratory Parameters of 
Interest .......................................................................36
11.3.2.2.
HBV DNA values (log10 IU/mL)..................................37
11.4.
Appendix 4: Study Phases and Treatment States.......................................38
11.4.1.
Study Phases ..............................................................................38
11.4.1.1.
Study Phases for Concomitant Medication .......................38
11.4.2.
Treatment States for AE data.......................................................38
11.5.
Appendix 5: Data Display Standards & Handling Conventions....................39
11.5.1.
Reporting Process .......................................................................39
11.5.2.
Reporting Standards....................................................................39
11.6.
Appendix 6: Derived and Transformed Data ...............................................41
11.6.1.
General........................................................................................41
11.6.2.
Study Population..........................................................................41
11.6.3.
Efficacy........................................................................................42
11.6.4.
Safety ..........................................................................................44
11.7.
Appendix 7: Reporting Standards for Missing Data.....................................47
11.7.1.
Premature Withdrawals................................................................47
11.7.2.
Handling of Missing Data.............................................................47
11.7.2.1.
Handling of Missing and Partial Dates ........................47
11.7.2.2.
Handling of Missing Data for Statistical 
Analysis......................................................................48
11.8.
Appendix 8: Values of Potential Clinical Importance(PCI)...........................49
11.8.1.
LDTA GSI grading scale (LDTA GSI grade).................................49
11.8.2.
GSI modified NIAID Common Toxicity Grading Scale (GSI 
NIAID grade) ................................................................................52
11.9.
Appendix 9: PEGINTERFERON GSKDrug codes.......................................56
11.10. Appendix 10: Viread (Tenofovir Disoproxil Fumarate) Risk 
Management Plan for the EU (Version 22) January 2017 ...........................57


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11.11. Appendix 11: Abbreviations & Trade Marks ................................................59
11.11.1. Abbreviations...............................................................................59
11.11.2. Trademarks .................................................................................59
11.12. Appendix 12: List of Data Displays..............................................................60
11.12.1. Data Display Numbering..............................................................60
11.12.2. Mock Example Shell Referencing ................................................60
11.12.3. Deliverables.................................................................................60
11.12.4. Study Population Tables..............................................................61
11.12.5. Efficacy Tables ............................................................................64
11.12.6. Efficacy Figures ...........................................................................70
11.12.7. Safety Tables...............................................................................72
11.12.8. Safety Figures .............................................................................78
11.12.9. Exploratory Statistical Analysis Tables.........................................79
11.12.10.Exploratory Statistical Analysis Figures .......................................85
11.12.11.ICH Listings..................................................................................91
11.13. Appendix 13: Example Mock Shells for Data Displays ................................98


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1.
INTRODUCTION
The purpose of this reporting and analysis plan (RAP) is to describe the analyses to be 
included in the Clinical Study Report for Protocol:205883.
Revision Chronology:
Ver. 0
18-SEP-2018
Original
2.
SUMMARY OF KEY PROTOCOL INFORMATION
2.1.
Changes to the Protocol Defined Statistical Analysis Plan
There were no changes or deviations to the originally planned statistical analysis 
specified in the protocol amendment 6 (Dated: 5/JUL/2018).
2.2.
Study Objective(s) and Endpoint(s)
Objectives
Endpoints
Primary Objectives
Primary Endpoints

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 Objectives
Secondary Endpoints

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 HBcrAg titer from the baseline at 
week 24, 48 and 96
Safety
Safety Endpoints

To evaluate Safety

AE

Clinical laboratory values

Vital signs

ECG 

Bone density


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2.3.
Study Design
Overview of Study Design and Key Features
ETV 0.5mg tablet QD
TDF 300mg tablet QD
Screening
(within 6 weeks from 
informed consent)
Informed consent/
Preliminary registration
Registration
Week 96
Completion
Design
Features

This study is designed as a multi-center, one-arm, open label, 
prospective study.
Dosing

TDF 300 mg tablet is administered orally once daily for 96 weeks. The 
completed subject is defined as a subject who has completed all steps 
throughout 96 weeks.
Time & 
Events

Refer to Appendix 2: Schedule of Activities.
Treatment 
Assignment

One-arm, open label study (N=65 subjects).
Interim 
Analysis

No interim analysis will be performed for assessment from a statistical 
perspective. 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.
2.4.
Statistical Hypotheses / Statistical Analyses
No formal statistical hypotheses will be tested. Descriptive statistics will be used to 
assess the efficacy and safety objectives. An estimation approach will be used to address 
the efficacy objectives, where point estimates and corresponding 95% confidence 
intervals will be constructed.


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3.
PLANNED ANALYSES
3.1.
Interim Analyses
Interim analysis to make statistical investigations will not be performed in this study. 
3.2.
Primary Analyses (WEEK 48)
The CRF data by Week 48 will be locked when all subjects (excluding withdrawn 
subjects) complete Week48 to collect safety and efficacy data. Safety and efficacy data 
will be analysed after the completion of all required database cleaning activities have 
been completed and database release (DBR) and Data Base Freeze (DBF) has been 
declared by Data Management. 
Even though this is a single arm study, randomisation codes will be distributed according 
to RandAll NG procedures.
3.3.
Final Analyses (WEEK 96)
Week 96 planned analyses will be performed after the completion of the following 
sequential steps:
1. All participants have completed the study as defined in the protocol.
2. All required database cleaning activities have been completed and final DBR and 
DBF has been declared by Data Management.


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4.
ANALYSIS POPULATIONS
Population
Definition / Criteria
Analyses Evaluated
Enrolled

Subjects who provided consent 

Study Population
Screening 
Failure 

Subjects who provided consent but were not 
subsequently administered. 

Study Population
Safety 
Population (SP)

Subjects who have received at least one dose of 
study treatment after enrolment.

Safety
Full Analysis 
Set (FAS)

A population of all subjects enrolled in the study, 
excluding those who meet either of the following 
criteria:
o Have not received any dose of study treatment.
o Have no efficacy data* (HBsAg, HBV-DNA, 
HBcrAg, HBeAg, HBsAb, HBeAb, ALT)
after the start of study treatment.
*: at least 15 days after the start of study 
treatment.

Efficacy
Efficacy 
Evaluable Set
(EES)

A subset of subjects in the FAS defined above and 
evaluable for efficacy.

Efficacy
Refer to Appendix 12 List of Data Displays which details the population used for each display.
4.1.
Protocol Deviations
Important protocol deviations (including deviations related to study inclusion/exclusion 
criteria, conduct of the trial, patient management or patient assessment) will be 
summarised and listed.
Protocol deviations will be tracked by the study team throughout the conduct of the study 
in accordance with the Protocol Deviation Management Plan.
Data will be reviewed prior to freezing the database to ensure all important 
deviations. This dataset will be the basis for the summaries and listings of protocol 
deviations.
A separate summary and listing of all inclusion/exclusion criteria deviations will also be 
provided. This summary will be based on data as recorded on the inclusion/exclusion 
page of the eCRF.
4.2.
Efficacy Evaluable Set
Details of efficacy evaluable set will be provided in Section 11.1.1.


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5.
CONSIDERATIONS FOR DATA ANALYSES AND DATA
HANDLING CONVENTIONS
5.1.
Study Treatment & Subgroup Display Descriptors
Treatment Group Descriptions
RandAll NG 
Data Displays for Reporting 
Code
Description
Description
Order in TLF 
T
T
TDF
1
5.2.
Baseline Definitions
For all endpoints (except as noted in baseline definitions) the baseline value will be the 
latest pre-dose assessment with a non-missing value, including those from unscheduled 
visits. If time is not collected, Day 1 assessments are assumed to be taken prior to first 
dose and used as baseline.
Parameter
Study Assessments Considered 
as Baseline
Baseline Used in Data 
Display
Screening
Day 1 (Pre-
Dose)
Efficacy
HBV-DNA
X
X
Day1
ALT
X
X
Day1
HBeAg/Anti-HBe
X
X
Day1
HBsAg/Anti-HBs
X
X
Day1
HBcrAg
X
Day1
Safety
12 Lead ECG 
X
Screening
Vital Signs
X
X
Day 1 
Haematology 
X
X
Day 1
Clinical Chemistry
X
X
Day 1
Urine Analysis
X
X
Day 1 
Bone density
(absolute)
X
Screening
Unless otherwise stated, if baseline data is missing no derivation will be performed and 
baseline will be set to missing. Note that height and weight in screening will be used for 
demographic characteristics.
5.3.
Examination of Covariates, Other Strata and Subgroups
5.3.1.
Examination of Subgroups
The list of subgroups may be used in descriptive summaries. Additional subgroups of 
clinical interest may also be considered.


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Subgroup
Categories 
Protocol defined liver 
cirrhosis 
Yes, No
Genotype
A, B, C, D
HBsAg subgroup category 
<800 KIU/L, >=800 KIU/L
HBsAg subgroup category 
(Conventional unit)
<800 IU/mL, >=800 IU/mL
AGE category 
<40, 40-49, 50-59, 60-
Former Peg-INF (within 2 
years prior to screening)
Yes, No 
Note: Peg-Interferon codes are listed in Appendix 9.
Exploratory Analysis
Subgroup
Categories 
HBsAg responder / Non-
responder at WEEK 48
<= -0.25 log10 HBsAg, > -0.25 log10 HBsAg
ALT category*1
<60 IU/L, >=60 IU/L
ALT category*2
(Conventional unit)
<60 U/L, >=60 U/L
NOTES:
*1: >=60 IU/L of ALT category is 60 or more than 60 from baseline to WEEK 48
<60 IU/L of ALT category is less than 60 from baseline to WEEK 48
*2: >=60 U/L of ALT category is 60 or more than 60 from baseline to WEEK 48
<60 U/L of ALT category is less than 60 from baseline to WEEK 48
Safety Subgroup Analysis
Subgroup
Categories 
AGE category
<40, 40-49, 50-59, 60-
eGFR (ml/sec/1.73m2)
baseline category
<1, 1<= - <1.5, >=1.5
eGFR (ml/min/1.73m2) 
baseline category
(Conventional unit)
<60, 60<= - <90, >=90
Weight baseline category
<50 kg, >=50 kg
Sex
Male, Female
5.4.
Multiple Comparisons and Multiplicity
Analyses of efficacy endpoints will not be subject to any multiplicity adjustment.


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5.5.
Other Considerations for Data Analyses and Data Handling 
Conventions
Other considerations for data analyses and data handling conventions are outlined in the 
appendices:
Section
Component
11.3
Appendix 3: Assessment Windows
11.4
Appendix 4: Study Phases and Treatment Emergent Adverse Events
11.5
Appendix 5: Data Display Standards & Handling Conventions
11.6
Appendix 6: Derived and Transformed Data
11.7
Appendix 7: Reporting Standards for Missing Data
11.8
Appendix 8: Values of Potential Clinical Importance
11.9
Appendix 9 Listing of Peg-Interferon codes
11.10
Appendix 10 Viread (Tenofovir Disoproxil Fumarate) Risk Management Plan for the EU


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6.
STUDY POPULATION ANALYSES
6.1.
Overview of Planned Study Population Analyses
The study population analyses will be based on the “Safety” or “FAS” or “EES” 
population, unless otherwise specified.
Study population analyses including analyses of subject’s disposition, protocol 
deviations, demographic and baseline characteristics, prior and concomitant medications, 
and exposure and treatment compliance will be based on GSK Core Data Standards.  
Details of the planned displays are presented in Appendix 12: List of Data Displays.
Other baseline characteristics, e.g. virus characteristics (Screening: Genotype, Baseline: 
Serum HBV-DNA, Serum ALT, HBeAg, HBsAg, HBcrAg), Prior medical condition and 
Protocol defined liver cirrhosis will be summarized. To check baseline values for HBsAg, 
HBcrAg, ALT and HBV-DNA, summary statistics at baseline will be shown.
Overview of Planned Study Population Analyses
[Endpoint / Parameter / Display Type]
Data Displays Generated
Table
Figure
Listing
Subject Disposition
Subject Disposition and Reason for Study 
Withdrawal
Y
Y
Screening Status and Reasons for Screen Failure
Y
Y
Protocol Deviations
Important Protocol Deviations
Y
Y
Subjects with Inclusion/Exclusion Criteria 
Deviations
Y
Y
Populations Analysed
Study Populations
Y
Subjects Excluded from EES Population
Y
Demographic and Baseline Characteristics
Demographic Characteristics
Y
Y
Demographic Characteristics for Screening Failure
Y
Y
Age Ranges
Y
Race and Racial Combinations
Y
Y
Other Baseline Characteristics
Y
Y
Medical Conditions and Concomitant Medications
Medical Conditions
Y
Y
Prior Hepatitis Medications
Y
Y
Concomitant Medications
Y
Y
Exposure and Treatment Compliance
Exposure to Study Treatment
Y
Y
Treatment Compliance 
Y
Y
Subgroup
Demographic Characteristics
Y


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NOTES: Y = Yes display generated.
7.
EFFICACY ANALYSES
7.1.
Primary Efficacy Analyses
7.1.1.
Endpoint / Variables
HBsAg responder proportion of subjects with -0.25 or less log10 HBsAg change from 
baseline switching from Entecavir to Tenofovir at Week 48.
7.1.2.
Summary Measure
Proportion of HBsAg responder subjects with -0.25 or less log10 HBsAg change from 
baseline switching from Entecavir to Tenofovir at Week 48.
7.1.3.
Population of Interest
The primary efficacy analyses will be based on the “FAS” population. Also “EES” 
population will be applied to investigate the robustness of the primary result.
7.1.4.
Strategy for Intercurrent (Post-Randomization) Events
If any subjects will be discontinued due to AE or rescue medication before Week 48, data 
collection at Week 48 will not be conducted. However, in order to evaluate primary 
endpoint at Week 48, any subjects withdrawn from the study will be treated as non-
responders (defined as subjects not achieving 0.25 log10 HBsAg reduction from the 
baseline at Week 48).
7.1.5.
Statistical Analyses / Methods
7.1.5.1.
Overview of Planned Efficacy Analyses
[Endpoint / 
Parameter/ Display 
Type]
Absolute
Change from Baseline
Stats 
Analysis
Summar
y
Individu
al
Stats 
Analysis
Summar
y
Individu
al
T
F
L
T
F
F
L
T
F
L
T
F
F
L
HBsAg
HBsAg responder 
proportion 
(WEEK 48）
Y
NOTES:

T = Table, F = Figure, L = Listing, Y = Yes display generated.

Stats Analysis = Represents TFL related to any formal statistical analyses (i.e. modelling) conducted.

Summary = Represents TFL related to any summaries (i.e. descriptive statistics) of the observed raw 
data.

Individual = Represents FL related to any displays of individual subject observed raw data.


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Details of the planned displays are provided in Appendix 12: List of Data Displays and 
will be based on GSK data standards and statistical principles.
Unless otherwise specified, endpoints / variables defined in Section 7.1.1 will be 
summarised using descriptive statistics, and listed.
7.1.5.2.
Statistical Methodology Specification
Endpoint / Variables

HBsAg responder proportion of subjects with -0.25 or less log10 HBsAg change from 
baseline switching from Entecavir to Tenofovir at week 48.
Model Specification

N/A
Model Checking & Diagnostics

N/A
Model Results Presentation

N/A
Subgroup Analyses

The analysis on the primary endpoint will be also performed for subgroups. Subgroup 
analyses are intended to confirm the robustness of results. Refer to Section 5.3.1.
Sensitivity and Supportive Analyses

Supportive Analysis: 
“EES” population will be applied to investigate the robustness of the primary result.
7.2.
Secondary Efficacy Analyses
7.2.1.
Endpoint / Variables
Refer to " Endpoint / Variables and Summary Measure" in Section 7.2.5.2.
7.2.2.
Summary Measure
Refer to " Endpoint / Variables and Summary Measure " in Section 7.2.5.2.
7.2.3.
Population of Interest
The secondary efficacy analyses will be based on the “FAS” or “EES” population, unless 
otherwise specified.
7.2.4.
Strategy for Intercurrent (Post-Randomization) Events
For binomial variables, the strategy for intercurrent events will be according to Section 
7.1.4. For continuous variables, if subjects will be withdrawn from the study due to
adverse events or rescue medication before Week 48/Week 96, data after withdrawal 


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will not be collected, and data analysis will be performed on collected data (i.e. After 
withdrawal, data will not be collected and data will not be imputed.).
7.2.5.
Statistical Analyses / Methods
7.2.5.1.
Overview of Planned Efficacy Analyses
[Endpoint / 
Parameter/ 
Display Type]
Absolute
Change from Baseline
Stats 
Analysis
Summar
y
Individu
al
Stats 
Analysis
Summar
y
Individu
al
T
F
L
T
F
F
L
T
F
L
T
F
F
L
HBsAg
Frequency of 
HBsAg responder 
Proportion
(Study visit up to 
48/96 weeks)
Y
Y
Summary of log10
HBsAg
(Study visit up to 
48/96 weeks)
Y
Y
Y
Y
Y
Y
Summary of 
HBsAg
(Study visit up to 
48/96 weeks)
Y
Y
Y
Y
Frequency of 
HBsAg category
(Study visit up to 
48/96 weeks)
Y
Summary of log10
HBsAg with 
conventional unit
(Study visit up to 
48/96 weeks) 
Y
Y
Y
Y
Y
Y
Summary of 
HBsAg with 
conventional unit
(Study visit up to 
48/96 weeks)
Y
Y
Y
Y
Frequency of 
HBsAg category
with conventional 
unit (Study visit up 
to 48/96 weeks)
Y
Seroconversion
Proportion of 
subjects achieving 
HBsAg loss 
(Study visit up to 
48/96 weeks)
Y
Y
Proportion of 
Y
Y


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[Endpoint / 
Parameter/ 
Display Type]
Absolute
Change from Baseline
Stats 
Analysis
Summar
y
Individu
al
Stats 
Analysis
Summar
y
Individu
al
T
F
L
T
F
F
L
T
F
L
T
F
F
L
subjects achieving 
HBsAg/Ab 
seroconversion a
(Study visit up to 
48/96 weeks)
Proportion of 
subjects achieving 
HBeAg loss 
(Study visit up to 
48/96 weeks)
Y
Y
Proportion of 
subjects achieving 
HBeAg/Ab 
seroconversion 
(Study visit up to 
48/96 weeks)
Y
Y
Virology
Summary of 
HBcrAg
(Study visit up to 
48/96 weeks)
Y
Y
Y
Y
Y
Y
Frequency of 
HBcrAg category 
(Study visit up to 
48/96 weeks)
Y
Summary of HBV-
DNA (Study visit 
up to 48/96 weeks)
Y
Y
Y
Y
Y
Y
Summary of 
HBeAg
(Study visit up to 
48/96 weeks)
Y
Y
Y
Y
Summary ofLog10 
HBeAg
(Study visit up to 
48/96 weeks)
Y
Y
Y
Y
Y
Frequency of 
Virological 
Breakthrough
(Study visit up to 
48/96 weeks)
Y
Y
Summary of 
HBcrAg with 
conventional unit
(Study visit up to 
48/96 weeks) 
Y
Y
Y
Y
Y
Y
Frequency of 
HBcrAg category 
Y


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[Endpoint / 
Parameter/ 
Display Type]
Absolute
Change from Baseline
Stats 
Analysis
Summar
y
Individu
al
Stats 
Analysis
Summar
y
Individu
al
T
F
L
T
F
F
L
T
F
L
T
F
F
L
with conventional 
unit
(Study visit up to 
48/96 weeks) 
ALT
Summary of ALT
(Study visit up to 
48/96 weeks)
Y
Y
Y
Y
Y
Y
Summary of ALT
with conventional 
unit
(Study visit up to 
48/96 weeks)
Y
Y
Y
Y
Y
Y
NOTES:

T = Table, F = Figure, L = Listing, Y = Yes display generated.

Stats Analysis = Represents TFL related to any formal statistical analyses (i.e. modelling) conducted.

Summary = Represents TFL related to any summaries (i.e. descriptive statistics) of the observed raw 
data.

Individual = Represents FL related to any displays of individual subject observed raw data.

HBV-DNA: Source data is log10 IU/mL.

HBcrAg: Source data is log10 IU/mL

Up to 48 weeks: Baseline,4,12,24,36,48 week

UP to 96 weeks: Baseline,4,12,24,36,48,60,72,84,96 week
Details of the planned displays are provided in Appendix 12: List of Data Displays and 
will be based on GSK data standards and statistical principles.
Unless otherwise specified, endpoints / variables defined in Section 7.2.1 will be 
summarised using descriptive statistics, graphically presented (where appropriate) and 
listed.
7.2.5.2.
Statistical Methodology Specification
Endpoint / Variables and Summary Measures

Proportion of HBsAg responder subjects with -0.25 or less log10 HBsAg change from 
baseline switching from Entecavir to Tenofovir (HBsAg responder) up to week 48 
/week96

Summary of log10 HBsAg up to week 48/ week 96 including change from baseline

Summary of HBsAg up to week 48/ week 96 including change from baseline

Frequency of HBsAg category up to week 48/ week 96

Summary of HBV-DNA up to week 48/ week 96 including change from baseline

Summary of HBcrAg up to week 48/ week 96 including change from baseline

Frequency of HBcrAg category up to week 48/ week 96 


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
Summary of ALT up to week 48/ week 96 including change from baseline

Proportion of subjects achieving HBsAg loss up to week 48/ week 96

Proportion of subjects achieving HBsAg/Ab seroconversion up to week 48/ week 96 

Proportion of subjects achieving HBeAg loss up to week 48/ week 96

Proportion of subjects achieving HBeAg/Ab seroconversion up to week 48/ week 96

Summary of HBeAg up to week 48/ week 96 including change from baseline

Summary of log10 HBeAg up to week 48/ week 96 including change from baseline

Proportion of subjects achieving Virological Breakthrough (Week 0 -Week 48 /Week
96)

Summary of log10 HBsAg (conventional unit) up to week 48/ week 96 including 
change from baseline

Summary of HBsAg (conventional unit) up to week 48/ week 96 including change 
from baseline

Frequency of HBsAg category (conventional unit) up to week 48/ week 96

Summary of HBcrAg (conventional unit) up to week 48/ week 96 including change 
from baseline

Frequency of HBcrAg category (conventional unit) up to week 48/ week 96 

Summary of ALT (conventional unit) up to week 48/ week 96 including change from 
baseline
Model Specification

N/A
Model Checking & Diagnostics

N/A
Model Results Presentation

N/A
Subgroup Analyses

The analysis on the secondary endpoint (log10 HBsAg, HBcrAg*, log10 HBeAg) will 
be also performed for subgroups. These subgroup analyses are intended to confirm 
the robustness of results. Refer to Section 5.3.1. 
*: Source data is log10
Sensitivity and Supportive Analyses

Supportive Analysis: 
“EES” population will be applied to investigate the robustness of the primary result 
(HBsAg responder proportional Week 48).


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8.
SAFETY ANALYSES
The safety analyses will be based on the “Safety” population, unless otherwise specified.
8.1.
Adverse Events Analyses
Adverse events analyses including the analysis of adverse events (AEs), Serious adverse 
events (SAEs) and other significant AEs will be based on GSK Core Data Standards. The 
details of the planned displays are provided in Appendix 12: List of Data Displays.
8.2.
Adverse Events of Special Interest Analyses
A comprehensive list of MedDRA terms based on clinical review will be used to identify 
each type of event (See the list of Adverse Event of special interest in Section 11.6.4.). 
Changes to the MedDRA dictionary may occur between the start of the study and the 
time of reporting and/or emerging data from on-going studies may highlight additional 
adverse events of special interest, therefore the list of terms to be used for each event of 
interest and the specific events of interest will be re-reviewed by the Medical Monitor in 
place at the time of reporting.
The details of the planned displays are provided in Appendix 12: List of Data Displays.
Overview of Planned Adverse Event Analyses
Display Type
Absolute
Summary
Individu
al
T
F
L
Adverse Events (AEs)
All AEs by SOC and PT
Y
Y
All AEs by Maximum Intensity
Y
Drug-Related AEs by SOC and PT
Y
Drug-Related AEs by Maximum Intensity
Y
Subject Numbers for Individual AEs
Y
Relationship Between AE SOCs, PT and Verbatim Text
Y
Serious AEs
All Serious AEs
Y
Y
Fatal Serious AEs
Y
Y
Other Significant AEs
AEs Leading to Withdrawal from Study 
Y
Y
AE of special interest
Renal AE
Y
Y
Bone Events
Y
Y
Liver AE
Y
Y
NOTES:

T = Table, F = Figures, L = Listings, Y = Yes display generated, SOC = System Organ Class, PT = 
Preferred Term.


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
Summary = Represents TF related to any summaries (i.e. descriptive statistics) of the observed raw 
data.

Individual = Represents FL related to any displays of individual subject observed raw data.
8.3.
Clinical Laboratory Analyses
Laboratory evaluations including the analyses of Chemistry laboratory tests, Hematology 
laboratory tests, Urinalysis, and liver function tests will be based on GSK Core Data 
Standards. The details of the planned displays are in Appendix 12: List of Data Displays.
Overview of Planned Clinical Laboratory Analyses
Display Type
Absolute
Change from BL
Summar
y
Individu
al
Summary
Indiv
idual
T
F
L
T
F
L
Chemistry
Chemistry Data
Y
Y
Y
Y
Chemistry Results Relative to Normal Range
Y
Creatinine
Y
Y
eGFR
Y
Y
Corrected calcium based on the serum albumin
Y
Y
Chemistry (ALT, ALP, Creatinine, Phosphorus, 
Glucose, Uric acid, eGFR) Data with conventional 
unit
Y
Y
Y
Y
Creatinine with conventional unit
Y
Y
eGFR with conventional unit 
Y
Y
Hematology
Hematology Data
Y
Y
Y
Y
Hematology Results Relative to Normal Range
Y
Urinalysis
Glucose, protein, urinary sediment
Y
Y
β2-microglobulin, β2-microglobulin-creatinine 
ratio, %TRP creatinine, electrolyte (P)
Y
Y
Y
Y
Urinalisis (β2-microglobulin, electrolyte (P),
Creatinine) with conventional unit
Y
Y
Y
Y
Hepatobiliary (Liver)[1]
Liver Monitoring/Stopping Event Reporting
Y
Y
Medical Conditions for Subjects with Liver 
Stopping Events
Y
Y
Substance Use for Subjects with Liver Stopping 
Events
Y
Y
LDTA GSI grade scale 
Treatment-Emergent Laboratory Abnormalities, 
Y
Y


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Display Type
Absolute
Change from BL
Summar
y
Individu
al
Summary
Indiv
idual
T
F
L
T
F
L
LDTA GSI grading scale
LDTA GSI Grade 3/4 Treatment-Emergent 
Laboratory Abnormalities
Y
Y
Treatment-Emergent Marked Laboratory 
Abnormalities, LDTA GSI grading scale
Y
Y
Hepatic Flare
On-Treatment Hepatic Flare
Y
Y
On-Treatment Laboratory Values Relevant to on-
Treatment Hepatic Flare
Y
Y
Renal Parameters
Confirmed Changes in Renal Parameters
Y
Y
Y
GSI Modified NIAID
Treatment-Emergent Laboratory Abnormalities, 
GSI Modified NIAID
Y
Y
GSI Modified NIAID Grade 3/4 Treatment-
Emergent Laboratory Abnormalities
Y
Y
Treatment-Emergent Marked Laboratory 
Abnormalities, GSI Modified NIAID
Y
Y
NOTES:

T = Table, F = Figures, L = Listings, Y = Yes display generated

Summary = Represents TFL related to any summaries (i.e. descriptive statistics) of the observed raw 
data.

Individual = Represents FL related to any displays of individual subject observed raw data.
1: If Hepatobiliary will be occurred.
8.4.
Other Safety Analyses
The analyses of non-laboratory safety test results including ECGs and vital signs will be 
based on GSK Core Data Standards, unless otherwise specified. The details of the 
planned displays are presented in Appendix 12: List of Data Displays.
Overview of Planned Other Safety Analyses
Display Type
Absolute
Change from BL
Summar
y
Individu
al
Summary
Indivi
dual
T
F
L
T
F
L
ECG
ECG Findings
Y
Y


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Display Type
Absolute
Change from BL
Summar
y
Individu
al
Summary
Indivi
dual
T
F
L
T
F
L
ECG Values
Y
Y
Y
Y
Vital Signs
Vitals Values
Y
Y
Y
Y
Others
Bone density (%)*
Y
Y
Y
Bone density (absolute)
Y
Y
Y
Y
Y
NOTES:

T = Table, F = Figures, L = Listings, Y = Yes display generated

Summary = Represents TFL related to any summaries (i.e. descriptive statistics) of the observed raw 
data.

Individual = Represents FL related to any displays of individual subject observed raw data.

*:Bone density (%): %change from baseline

Bone density data: DEXA method will be displayed by position 


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9.
EXPLORATORY EFFICACY ANALYSES
9.1.
HBsAg Responder/Non-Responder Analyses
Summary statistics of efficacy parameter by HBsAg responder/Non-responder at WEEK 
48 will be provided Frequency of HBsAg responder/Non-responder with ALT category 
(<60 IU/L, >=60IU/L) and with ALT category (<60 U/L, >=60 U/L; conventional unit) at 
WEEK 48 will be provided (Cross Table).
Listing of subject numbers for individual HBsAg Responder/Non-Responder Category at 
WEEK 48 will be provided.
These analyses will be based on the “FAS” population, unless otherwise specified. The 
details of the planned displays are presented in Appendix 12: List of Data Displays.
Overview of Planned Exploratory Efficacy Analyses
[Endpoint / 
Parameter/ Display 
Type]
Absolute
Change from Baseline
Stats 
Analysis
Summary
Individual
Stats 
Analysis
Summary
Individual
T
F
L
T
F
F
L
T
F
L
T
F
F
L
HBsAg
Summary of log10
HBsAg 
(Study visit up to 
48/96 weeks)
Y
Y
Y
Y
Y
Summary of log10
HBsAg with 
conventional unit 
(Study visit up to 
48/96 weeks)
Y
Y
Y
Y
Y
Other Efficacy
Summary of HBcrAg
(Study visit up to 
48/96 weeks)
Y
Y
Y
Y
Summary of HBV-
DNA (Study visit up 
to 48/96 weeks)
Y
Y
Y
Y
Summary of ALT
(Study visit up to 
48/96 weeks)
Y
Y
Y
Y
Summary of log10 
HBeAg
(Study visit up to 
48/96 weeks)
Y
Y
Y
Y
Other Efficacy (Conventional unit)
Summary of HBcrAg
with conventional unit 
(Study visit up to 
48/96 weeks)
Y
Y
Y
Y
Summary of ALT 
Y
Y
Y
Y


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[Endpoint / 
Parameter/ Display 
Type]
Absolute
Change from Baseline
Stats 
Analysis
Summary
Individual
Stats 
Analysis
Summary
Individual
T
F
L
T
F
F
L
T
F
L
T
F
F
L
with conventional unit 
(Study visit up to 
48/96 weeks)
NOTES:

T = Table, F = Figure, L = Listing, Y = Yes display generated.

Stats Analysis = Represents TFL related to any formal statistical analyses (i.e. modelling) conducted.

Summary = Represents TFL related to any summaries (i.e. descriptive statistics) of the observed raw 
data.

Individual = Represents FL related to any displays of individual subject observed raw data.

Subject's number for individual HBsAg Responder/Non-Responder category at WEEK 48 will be 
listed.

Up to 48 weeks: Baseline,4,12,24,36,48 week

UP to 96 weeks: Baseline,4,12,24,36,48,60,72,84,96 week
9.2.
ALT Categories Analyses
Summary statistics of efficacy parameter by ALT category (<60 IU/L, >=60 IU/L) at 
WEEK 48 will be provided.
Summary statistics of efficacy parameter (Conventional unit) by ALT category with 
conventional unit (<60 U/L, >=60 U/L) at WEEK 48 will be provided.
Listing of subject numbers for individual ALT Category (<60 IU/L, >=60 IU/L) at 
WEEK 48 will be provided.
Listing of subject numbers for individual ALT Category with conventional unit (<60 
U/L, >=60 U/L) at WEEK 48 will be provided. 
These analyses will be based on the “FAS” population, unless otherwise specified. The 
details of the planned displays are presented in Appendix 12: List of Data Displays.
Overview of Planned Exploratory Efficacy Analyses
[Endpoint / 
Parameter/ Display 
Type]
Absolute
Change from Baseline
Stats 
Analysis
Summary
Individual
Stats 
Analysis
Summary
Individual
T
F
L
T
F
F
L
T
F
L
T
F
F
L
HBsAg
Summary of log10
HBsAg 
(Study visit up to 
48/96 weeks)
Y
Y
Y
Y
HBsAg with conventional unit ALT category (<60 U/L, >=60 U/L)
Summary of log10
Y
Y
Y
Y


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[Endpoint / 
Parameter/ Display 
Type]
Absolute
Change from Baseline
Stats 
Analysis
Summary
Individual
Stats 
Analysis
Summary
Individual
T
F
L
T
F
F
L
T
F
L
T
F
F
L
HBsAg with 
conventional unit 
(Study visit up to 
48/96 weeks)
Other Efficacy
Summary of HBcrAg
(Study visit up to 
48/96 weeks)
Y
Y
Y
Y
Summary of HBV-
DNA (Study visit up 
to 48/96 weeks)
Y
Y
Y
Y
Summary of ALT
(Study visit up to 
48/96 weeks)
Y
Y
Y
Y
Summary of log10 
HBeAg
(Study visit up to 
48/96 weeks)
Y
Y
Y
Y
Other Efficacy with conventional unit ALT category (<60 U/L, >=60 U/L)
Summary of HBcrAg 
with conventional
unit (Study visit up to 
48/96 weeks)
Y
Y
Y
Y
Summary of HBV-
DNA (Study visit up 
to 48/96 weeks)
Y
Y
Y
Y
Summary of ALT 
with conventional 
unit (Study visit up to 
48/96 weeks)
Y
Y
Y
Y
Summary of log10 
HBeAg
(Study visit up to 
48/96 weeks)
Y
Y
Y
Y
NOTES:

T = Table, F = Figure, L = Listing, Y = Yes display generated.

Stats Analysis = Represents TFL related to any formal statistical analyses (i.e. modelling) conducted.

Summary = Represents TFL related to any summaries (i.e. descriptive statistics) of the observed raw 
data.

Individual = Represents FL related to any displays of individual subject observed raw data.

Subject's number for individual ALT category (<60 IU/L, >=60 IU/L) at WEEK 48 will be listed.


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9.3.
Correlation of virus parameters
These analyses will be based on the “FAS” population, unless otherwise specified.
Following correlation plots will be provided.

log10 HBsAg change from baseline vs ALT change from baseline 
(WEEK24/WEEK48/ WEEK96) 

log10 HBsAg change from baseline vs HBcrAg baseline 
(WEEK24/WEEK48/WEEK96)

log10HBsAg change from baseline vs HBcrAg change from baseline 
(WEEK24/WEEK48/WEEK96)

log10HBsAg change from baseline vs log10HBeAg baseline
(WEEK24/WEEK48/WEEK96)

log10HBsAg change from baseline vs log10 HBeAg change from baseline 
(WEEK24/WEEK48/WEEK96)

log10 HbsAg (conventional unit) change from baseline vs ALT (conventional unit) 
change from baseline (WEEK24/WEEK48/ WEEK96)  

log10 HBsAg (conventional unit) change from baseline vs HBcrAg (conventional 
unit) baseline (WEEK24/WEEK48/WEEK96) 

log10HbsAg (conventional unit) change from baseline vs HBcrAg (conventional unit) 
change from baseline (WEEK24/WEEK48/WEEK96) 

log10HbsAg (conventional unit) change from baseline vs log10HBeAg baseline 
(WEEK24/WEEK48/WEEK96) 

log10HBsAg (conventional unit) change from baseline vs log10 HBeAg change from 
baseline (WEEK24/WEEK48/WEEK96)
9.4.
Background factor of HBsAg Responder/ Non-Responder
To investigate the background factor of HBsAg responder, following summary table on 
HBsAg responder will be provided
The details of the planned displays are presented in Appendix 12: List of Data Displays.
Overview of Planned Background factor of HBsAg responder
[Endpoint / Parameter / Display Type]
Data Displays Generated
Table
Figure
Listing
Demographic and Baseline Characteristics
Demographic Characteristics
Y
Other Baseline Characteristics
Y
Medical Conditions and Concomitant Medications
Medical Conditions
Y
Concomitant Medications
Y
Exposure and Treatment Compliance
Treatment compliance
Y
Exposure to Study Treatment
Y


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NOTES:

Y = Yes display generated.
9.5.
Safety Subgroup Analysis
This analysis will be based on the “SP” population, unless otherwise specified. Summary 
of eGFR, β2-microglobulin-creatinine ratio, %TRP, Serum Creatine, Serum Phosphorous
and Bone density (absolute, %change from baseline) will be provided using subgroup in 
Section of "5.3.1 Examination of Subgroups".
Summary of eGFR (conventional unit), β2-microglobulin-creatinine ratio, %TRP, Serum 
Creatine (conventional unit), Serum Phosphorous (conventional unit) and Bone density 
(absolute, %change from baseline) will be provided using subgroup (conventional unit) in 
Section of "5.3.1 Examination of Subgroups".


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10.
REFERENCES
GlaxoSmithKline Document Number 2017N312381_06: Study Protocol of 205883. 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 (5-JUL-2018).
Payne RB, Little AJ, Williams RB, Milner JR：Interpretation of serum calcium levels in 
patients with abnormal serum proteins. Br Med J 4：643 -646,1973


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11.
APPENDICES
11.1.
Appendix 1: Protocol Deviation Management
Details will be referred latest Protocol Deviation Management Plan and data handling 
will be decided prior to final data base release.
11.1.1.
Exclusions from Efficacy Evaluable Set
A subject meeting any of the following two criteria will be excluded from the efficacy 
evaluable set:

Prohibited Medication was taken from start dosing (Beginning of exposure) to week 
48 visit (Date of visit 48 week)
Corresponding prohibited medications are listed as follow. This will be specified as 
flag ‘Y’ of DV1 dataset (Excluded from analysis population flag, DVXPPFL) from 
Data management.
- Interleukin-2 preparations
- Ursodeoxycholic acid preparations
- Herbal medicine with positive effects on hepatic dysfunction
- Antiviral drugs with an inhibitory effect on HBV growth
- 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)

Treatment compliance from start dosing (Beginning of exposure) to week 48 visit 
(Date of visit 48 week) was deviated.
treatment compliance: <80% or >120% 
Corresponding data that prohibited medication was taken will be received by DV1 dataset 
file from Data management.
Treatment compliance will be calculated from Section 11.6.2 Study Population.


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11.2.
Appendix 2: Schedule of Activities
11.2.1.
Protocol Defined Schedule of Events
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
HBsAg/Anti-HBs
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)
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 in the protocol.
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), 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 HBV DNA level has increased to ≧2 log IU/mL (100 IU/mL) in a case with 
nadir <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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11.3.
Appendix 3: Assessment Windows
11.3.1.
Definitions of Assessment Windows for Analyses
A) The assessment dates of virology (HBsAg, serum HBV-DNA, HBeAg, HBeAg/Ab, 
HBsAg/Ab, HBcrAg) and clinical laboratory test for efficacy (i.e. ALT)
Period 
Nominal Day 
Lowest Day
Highest Day
Screening
-
-42
-1
Baseline (Day1)
1
-
1 
Week 4 
29 
15 
43
Week 12 
85 
44
127
Week 24 
169 
128
211
Week 36 
253 
212
295
Week 48 
337 
296
379
Week 60
421
380
463
Week 72
505
464
547
Week 84
589
548
631
Week 96
673
632
715
B) Safety (Laboratory, ECG, Vital Sign and Bone density) data will not be adapted the 
assessment windows. But ‘COMPLETED/WITHDRAWAL’ need to be assigned to 
corresponding visit, by comparing its date with the assessment window. The 
outsiders, the data being out of any windows will be regarded as ‘Unscheduled’
Period 
Nominal Day 
Lowest Day
Highest Day
Screening
-
-42
-1
Baseline (Day1) 
1
-
1 
Week 4 
29
2 
43
Week 12 
85
44
127
Week 24 
169
128
211


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Period 
Nominal Day 
Lowest Day
Highest Day
Week 36 
253
212
295
Week 48 
337
296
379
Week 60
421
380
463
Week 72
505
464
547
Week 84
589
548
631
Week 96
673
632
715
C) Summary of AE by months will be used below AE occurrence day category (AE for 
48 Week report, AE for final CSR).
(AE occurrence day: 48 Week report)
Months
Days
Month 1
1 - 29 days
Month 2 - 3
30 – 85 days
Month 4 - 6
86 – 169 days
Month 7 - 9
170 – 253 days
Month 10 - 12
254 – 337 days
Month 13 or later
338 days or later
(AE occurrence day: final CSR)
Months
Days
Month 1-12
1 - 337 days
Month 13- 18
338 - 505 days
Month 19- 24
506 - 673 days
Month 25 or later
674 days or later
11.3.2.
Selection of Data in the Event of Multiple Records in a Window
Depending on the statistical method of analysis, single values are required for each 
analysis window. For example, change from baseline by visit usually requires a single 
value. When a single value is needed, the following rules will be used based on the type 
of data that is being analysed.
11.3.2.1.
Serology, ALT and Laboratory Parameters of Interest
The largest value will be included in the analysis when two or more ALT values occur 
within the same visit window. 


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In the event that two or more serology results (HBsAg, HBcrAg, HBeAg, HBsAb, 
HBeAb) occur within the same visit window, then the pair will remain together and the 
last pair of results in the window will be chosen. 
In the event that multiple observations occur within the same visit window for any other 
laboratory parameter, the laboratory value (e.g., mg/dL of serum creatinine) that 
represents the most abnormal value (based on actual value and not on grade) will be used 
in by-visit summaries for the laboratory parameter. In the event that two values within a 
window are of equal abnormality (based on actual value and not on grade), the value 
collected nearest to the nominal date will be used in all summaries.  
11.3.2.2.
HBV DNA values (log10 IU/mL)
1) Select the record closest to the nominal day (e.g. Day 169 for analysis Week 24) for 
that visit. 
2) If there are two visits equidistant from the nominal day, take the latest. 
If there are multiple records on a selected day, take the geometric mean. 
3) If there are two values on the same day, the second may be a retest because there was a 
problem with the first test (for example, specimen hemolyzed). In these cases, the later 
value should be used.


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11.4.
Appendix 4: Study Phases and Treatment States
11.4.1.
Study Phases
Assessments and events will be classified according to the time of occurrence relative to 
the assessment date.
Study Phase
Definition
Pre-Treatment 
Date < Study Treatment Start Date
On-Treatment
Study Treatment Start Date ≤ Date ≤ Study Treatment Stop Date
Post-Treatment
Date > Study Treatment Stop Date 
11.4.1.1.
Study Phases for Concomitant Medication
Study Phase
Definition
Prior
If medication end date is not missing and is before dosing date.
Concomitant
Any medication that is not a prior
NOTES: 

Please refer to Appendix 7: Reporting Standards for Missing Data for handling of missing and partial 
dates for concomitant medication. Use the rules in this table if concomitant medication date is 
completely missing.
11.4.2.
Treatment States for AE data
Adverse events will be classified according to time of occurrence relative to the start 
and/or stop date of the study treatment.
Treatment 
State
Definition
Pre-Treatment
AE Start Date < Study Treatment Start Date
On-Treatment
If AE onset date is on or after treatment start date & on or before treatment 
stop date.
Study Treatment Start Date ≤ AE Start Date ≤ Study Treatment Stop Date
Post-Treatment
If AE onset date is after the treatment stop date.
AE Start Date > Study Treatment Stop Date 
Onset Time 
Since 1st Dose 
(Days)
If Treatment Start Date ˃ AE Onset Date:
= AE Onset Date - Treatment Start Date
If Treatment Start Date ≤ AE Onset Date:
= AE Onset Date - Treatment Start Date +1
Missing otherwise.
Duration (Days) 
AE Resolution Date – AE Onset Date + 1
Drug-related
If relationship is marked ‘YES’ on eCRF OR value is missing.
NOTES: 

If the study treatment stop date is missing, then the AE will be considered to be On-Treatment.


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11.5.
Appendix 5: Data Display Standards & Handling 
Conventions
11.5.1.
Reporting Process
Software

The currently supported versions of SAS software will be used.
Reporting Area
HARP Server
N/A
HARP Compound
N/A
Analysis Datasets 

Analysis datasets will be created according to Legacy GSK A&R dataset standards
Generation of RTF Files

Non-HARP study.
11.5.2.
Reporting Standards
General

The current GSK Integrated Data Standards Library (IDSL) will be applied for reporting, 
unless otherwise stated (IDSL Standards Location: 
https://spope.gsk.com/sites/IDSLLibrary/SitePages/Home.aspx):

4.03 to 4.23: General Principles

5.01 to 5.08: Principles Related to Data Listings

6.01 to 6.11: Principles Related to Summary Tables

7.01 to 7.13: Principles Related to Graphics 

Do not include subject level listings in the main body of the GSK Clinical Study Report. All 
subject level listings should be located in the modular appendices as ICH or non-ICH listings
Formats

GSK IDSL Statistical Principles (5.03 & 6.06.3) for decimal places (DP’s) will be adopted 
for reporting of data based on the raw data collected, unless otherwise stated.

Numeric data will be reported at the precision collected on the eCRF.

The reported precision from non eCRF sources will follow the IDSL statistical principles but 
may be adjusted to a clinically interpretable number of DP’s.

For Insert Endpoint / Parameter the following DP’s places will be applied:

Summary Statistics:

Listings: 
Planned and Actual Time

Reporting for tables, figures and formal statistical analyses:

Planned time relative to dosing will be used in figures, summaries, statistical analyses and 
calculation of any derived parameters, unless otherwise stated.

The impact of any major deviation from the planned assessment times and/or scheduled 
visit days on the analyses and interpretation of the results will be assessed as appropriate.

Reporting for Data Listings: 

Planned and actual time relative to study drug dosing will be shown in listings (Refer to 
IDSL Statistical Principle 5.05.1).

Unscheduled or unplanned readings will be presented within the subject’s listings. 


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Unscheduled Visits

Unscheduled visits will not be included in summary tables.

Unscheduled visits will not be included in figures.

All unscheduled visits will be included in listings.
Descriptive Summary Statistics
Continuous Data
Refer to IDSL Statistical Principle 6.06.1
Categorical Data
N, n, frequency, %
Graphical Displays

Refer to IDSL Statistical Principals 7.01 to 7.13.


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11.6.
Appendix 6: Derived and Transformed Data
11.6.1.
General
Multiple Measurements at One Analysis Time Point

Mean of the measurements will be calculated and used in any derivation of summary 
statistics but if listed, all data will be presented.

If there are two values within a time window the value closest to the target day for 
that window will be used. If values are the same distance from the target, then the 
mean will be taken.

Participants having both High and Low values for Normal Ranges at any post-
baseline visit for safety parameters will be counted in both the High and Low 
categories of “Any visit post-baseline” row of related summary tables. This will also 
be applicable to relevant Potential Clinical Importance summary tables.
Study Day

Calculated as the number of days from administered date:

Ref Date = Missing                       → Study Day = Missing 

Ref Date < First Dose Date   → Study Day = Ref Date – First Dose Date    

Ref Data ≥ First Dose Date   → Study Day = Ref Date – (First Dose Date) + 1
11.6.2.
Study Population
Demographics
Age

Birth date will be presented in listings as ‘YYYY’.

Reference will be treatment(prescribed) date 

Reference date for age calculation will be from dosing start day (Day 1, Visit 2).

Reference date for calculation of age at screening will be from Screening visit (Visit 1) 
date, however this will be from screen failure date for a screen failure subject.

Analysis age group will be categorized (Years):
   <=18, 19-64, 65-74, >=75

Age will be categorized for EudraCT (Years)
   <=17, 18-64, 65-84, >=85
Body Mass Index (BMI)

Calculated as Weight (kg) / [Height (m)2]
Treatment Compliance

Compliance (%) will be calculated based on the formula:  
Compliance (%) = (Prescribed tablet – return tablet) / [(Treatment Stop Date –
Treatment Start Date + 1) x Total daily tablet]

Subjects who were prescribed but did not report a treatment start date will be 
categorised as having zero days of exposure. 


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Treatment Compliance

If there are any treatment breaks during the study, exposure data will be adjusted 
accordingly
e.g. one tablet per 5days, total daily Tablet is 1/5 tablet.
If “As required” in dosing frequency was occurred, previous dosing frequency will be 
used as calculation.
Image of treatment 
prescribed1             Return1
Prescribed2             Returned2
Start1     End1
1 x Daily
Start2   End2 
Every 3 days
Start3   End3
Every 4 days
Start4      End4
As Required

Upper: compliance data, Lower: Exposure data.
Extent of Exposure

Number of days of exposure to study drug will be calculated based on the formula:  
Duration of Exposure in Days = Treatment Stop Date – (Treatment Start Date) + 
1

Subjects who were prescribed but did not report a treatment start date will be 
categorised as having zero days of exposure. 
11.6.3.
Efficacy
HBV- DNA data (log10 IU/mL)

HBV DNA data below the LLQ (1.0 log10IU/mL) for the assay will be set to the lower 
limit minus 0.1 (0.9 log10IU/mL) for calculation of summary statistics for the actual 
HBV DNA values and the change from baseline values by study visit. The original 
values will be provided in the HBV DNA listing. 

Note that if the result will be ‘Not detected’, that data will be also treated in the same 
way (0.9 log10 IU/mL, 1.0 – 0.1 log10 IU/mL) as the below the LLQ.
Virological (HBV- DNA) breakthrough

In a case where a virological (HBV-DNA) 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 HBV DNA level has increased to ≧2 log IU/mL (100 IU/mL) in a case with 
nadir <10 IU/mL) perform the resistance analysis.
HBsAg responder/Non-responder 
HBsAg reduction potential evaluate (log10 observation – log10 baseline).
HBsAg responder: <=-0.25 log10
HBsAg Non-responder: >-0.25 log10


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‘Loss’ of HBeAg, HBsAg,
‘Loss’ of HBeAg and HBsAg means antigen is negative.  
e.g.
HBsAg Loss %: Numbers of subjects with HBsAg loss / Numbers of subjects with 
positive HBsAg at baseline
HBeAg Loss %: Numbers of subjects with HBeAg loss / Numbers of subjects with 
positive HBeAg at baseline
Seroconversion of HBsAg and HBeAg
‘Seroconversion’ of HBsAg and HBeAg means antigen is negative and antibody is 
positive.
e.g.
HBsAg Seroconversion %: Numbers of subjects with HBsAg/Ab Seroconversion /
Numbers of subjects with positive HBsAg and Negative HBsAb at baseline
HBeAg Seroconversion %: Numbers of subjects with HBeAg/Ab Seroconversion /
Numbers of subjects with positive HBeAg and Negative HBeAb at baseline
HBsAg category
HBsAg is categorised as follow:
<80, 80=< - <800, 800=< - <8000, 8000=< - <80000, >=80000 Unit: KIU/L
HBsAg (Conventional unit) category
HBsAg is categorised as follow:
<80, 80=< - <800, 800=< - <8000, 8000=< - <80000, >=80000 Unit: IU/mL
HBcrAg category
HBcrAg is categorised as follow:
<3.0 log10, 3.0=< - <4.0 log10, 4.0=< - <5.0 log10, 5.0=< - <6.0 log10, >=6.0 log10 Unit: 
KU/L
HBcrAg (conventional unit) category
HBcrAg is categorised as follow:
<3.0 log10, 3.0=< - <4.0 log10, 4.0=< - <5.0 log10, 5.0=< - <6.0 log10, >=6.0 log10 Unit: 
U/mL


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11.6.4.
Safety
Adverse Events
AEs of Special Interest
The adverse events of special interest and how they will be identified are outlined below.
For more details, Viread (Tenofovir Disoproxil Fumarate) Risk Management Plan for the 
EU (Version 22, January 2017) or the latest document will be referred (Appendix 10).

" Renal-AE” – Acute renal failure (SMQ), Chronic kidney disease (SMQ), 
Proteinuria (SMQ) and preferred terms of potentially renal related AEs.

"Liver AE" – Hepatic failure, fibrosis and cirrhosis and other liver damage-related 
conditions (SMQ), Hepatitis, non-infectious (SMQ), Liver related investigations, 
signs and symptoms (SMQ) and preferred terms of potentially Liver related AEs.

" Bone Events" – Preferred terms of potentially Bone related AEs.
Laboratory Parameters

If a laboratory value which is expected to have a numeric value for summary purposes, 
has a non-detectable level reported in the database, where the numeric value is 
missing, but typically a character value starting with ‘<x’ or ‘>x’ (or indicated as less 
than x or greater than x in the comment field) is present, the number of significant 
digits in the observed values will be used to determine how much to add or subtract in 
order to impute the corresponding numeric value. 
o
Example 1: 2 Significant Digits = ‘< x‘ becomes x – 0.01
o
Example 2: 1 Significant Digit = ‘> x’ becomes x + 0.1
o
Example 3: 0 Significant Digits = ‘< x’ becomes x – 1
Laboratory Assessments
Haematology
Platelet Count, RBC Count, Haemoglobin, Hematocrit, Prothrombin 
time, WBC count with Differential (Neutrophils, Lymphocytes, 
Monocytes, Eosinophils, Basophils)
Clinical Chemistry
BUN, Creatinine, Glucose, Uric acid, Amylase, Potassium, Sodium, 
Calcium, Chloride, Aspartate Aminotransferase (AST), Alanine 
Aminotransferase (ALT), Alkaline phosphatise, γ-GTP Phosphorus, 
Total and direct bilirubin, Total Protein, Albumin, LDH, CK (CPK), 
eGFR, Lipase, AFP, Antinuclear antibody titer [only at the time of 
screening], Hyaluronic acid [Required at screening and as needed 
thereafter.], Lactic Acid
Routine Urinalysis
Glucose, protein, creatinine, electrolyte (P), urinary sediment, β2-
microglobulin
Corrected calcium based on the serum albumin

Corrected calcium based on the serum albumin will be calculated based on the 
following Payne formula.
Corrected calcium (mg/dL) = Serum calcium (mg/dL) + [4 – serum albumin (g/dL)], if 
serum albumin is <4.0 g/dL


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Consideration of the kidney marker

β2-microglobulin-creatinine ratio will be calculated based on the following formula.
Urinary β2-microglobulin (μg/g Cre) =100×Urinary β2-microglobulin (μg/L)/ Urinary 
creatinine (mg/dL)

%TRP will be calculated based on the following formula.
(1 − [urinary phosphorus (mg/dL) × serum creatinine (mg/dL)] /. [serum phosphorus
(mg/dL) × urinary creatinine (mg/dL)]) × 100
Bone density (%)
Bone density (%) = (Bone density observation – Bone density baseline)/ Bone density 
baseline
Creatinine clearance
Creatinine clearance (CLcr) formula: 
(Body weight [kg]) x (140-age in years) / (72 x serum creatinine [mg/dl]) for man
[Note: multiply estimated rate by 0.85 for woman]
ECG (12-lead ECG)
ECG findings, ECG values (Heart rate, PR interval, QRS duration, QT interval, and QTc 
intervals)
Vital Signs
Pulse rate, Blood pressure (Systolic, Diastolic), Temperature, Weight
Gilead Science Institute (GSI) grading laboratory Data
Referred to Gilead Grading Scale for Severity of Laboratory Abnormalities, Laboratory 
grade frequency will be summarized and listed.
Note that grade tables: We will be referred two tables (Section 11.8.1 LDTA (A Liver 
Disease Therapeutic Area) GSI grading scale, Section 11.8.2. GSI modified NIAID 
(National Institute of Allergy and Infectious Disease (US)) Common Toxicity Grading 
Scale) and displayed. GSI modified NIAID common toxicity grading scale will be applied 
on the laboratory data to be aligned with foreign clinical studies of Tenofovir.
Abnormality Grades 
Clinical laboratory results will be graded according to criteria specified in the GSI grading 
score as normal, mild (Grade 1), moderate (Grade 2), severe (Grade 3) or potentially life 
threatening (Grade 4). Some analytes have criteria for both increased and decreased 
levels; analysis for each direction (i.e., increased, decreased) will be presented separately. 
Laboratory abnormalities may be reported as an adverse event, and the clinical grading of 
an event may be different from the quantitative grading depending on the clinical status 
and underlying conditions. 


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Gilead Science Institute (GSI) grading laboratory Data
Treatment-Emergent Abnormalities 
Treatment-emergent laboratory abnormalities are defined as values that increase at least 
one grade from baseline at any on-treatment post-baseline visit. If the relevant baseline 
laboratory data are missing, then the screening laboratory result is used, if this is missing 
then any graded abnormality is considered treatment emergent. 
Treatment-Emergent Marked Abnormalities 
Treatment-emergent marked laboratory abnormalities are defined as values that change 
from normal at baseline to Grade 3 (severe) or 4 (potentially life threatening) at any post-
baseline, on-treatment value, or that change from Grade 1 (mild) at baseline to Grade 4 at 
any post-baseline. If the relevant baseline laboratory data are missing, then the screening 
laboratory result is used; if this is missing then any Grade 3 or 4 on-treatment values are 
considered treatment emergent.
Summaries of Laboratory Abnormalities 
The following summaries (number and percentage of subjects) of treatment-emergent 
laboratory abnormalities will be provided: 
(1)
Treatment-emergent laboratory abnormalities
(2)
Treatment-emergent Grade 3 or Grade 4 laboratory abnormalities  
(3)
Marked laboratory abnormalities 
(4)
Incidence of on-treatment exacerbation of hepatitis defined as (1) elevation of 
ALT > 2 x baseline and > 10 x ULN or (2) abnormal laboratory parameters suggestive of 
worsening hepatic function (abnormal bilirubin ≥ 2mg/dL above baseline, abnormal PT ≥ 
2 sec above baseline, INR ≥ 0.5 over baseline, abnormal albumin ≥ 1g/dL decrease from 
baseline or elevated serum lactate levels > 2 x ULN) along with any ALT elevation (i.e., 1 
grade shift or 2 x previous value)
Note that serum lactate is not measured in the study.
(5)
Confirmed (defined as two consecutive visits) increases in serum creatinine of 0.5 
mg/dL above baseline
(6)
Confirmed (defined as two consecutive visits) occurrence of phosphorus below 2 
mg/dL
(7)
Confirmed (defined as two consecutive visits) calculated creatinine clearance < 50 
mL/min


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11.7.
Appendix 7: Reporting Standards for Missing Data
11.7.1.
Premature Withdrawals
Element
Reporting Detail
General

Subject study completion (i.e. as specified in the protocol) was defined as 
described in the Protocol. 

Withdrawn subjects were not replaced in the study.

All available data from participants who were withdrawn from the study will 
be listed and all available planned data will be included in summary tables and 
figures, unless otherwise specified.

Withdrawal visits will be slotted as per Appendix 3: 
11.7.2.
Handling of Missing Data
Element
Reporting Detail
General

Missing data occurs when any requested data is not provided, leading to blank 
fields on the collection instrument:
o
These data will be indicated by the use of a “blank” in subject listing 
displays. Unless all data for a specific visit are missing in which case the 
data is excluded from the table. 
o
Answers such as “Not applicable” and “Not evaluable” are not considered 
to be missing data and should be displayed as such.
11.7.2.1.
Handling of Missing and Partial Dates
Element
Reporting Detail
General

Partial dates will be displayed as captured in subject listing displays.
Adverse 
Events

The eCRF allows for the possibility of partial dates (i.e., only month and year) 
to be recorded for AE start and end dates; that is, the day of the month may be 
missing. In such a case, the following conventions will be applied for 
calculating the time to onset and the duration of the event:
o
Missing Start Day: First of the month will be used unless this is before the 
start date of study treatment; in this case the study treatment start date will 
be used and hence the event is considered On-treatment as per Appendix 
4: Study Phases and Treatment Emergent Adverse Events.
o
Missing Stop Day: Last day of the month will be used, unless this is after 
the stop date of study treatment; in this case the study treatment stop date 
will be used.

Completely missing start or end dates will remain missing, with no imputation 
applied. Consequently, time to onset and duration of such events will be 
missing.
Concomita
nt 
Medication
s/Medical 
History

Partial dates for any concomitant medications recorded in the CRF will be 
imputed using the following convention:
o
If the partial date is a start date, a '01' will be used for the day and 'Jan' will 
be used for the month
o
If the partial date is a stop date, a '28/29/30/31' will be used for the day 
(dependent on the month and year) and 'Dec' will be used for the month.


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Element
Reporting Detail

The recorded partial date will be displayed in listings.
11.7.2.2.
Handling of Missing Data for Statistical Analysis
Element
Reporting Detail
Withdrawn
Subjects 

In analysing the responder analysis, unless otherwise stated, withdrawn 
subjects reported during the study period will be treated as non-responders. 

For continuous variables, if subjects will be withdrawn from the study due to 
adverse events or rescue medication before Week 48/Week 96, data after 
withdrawal will not be collected, and data analysis will be performed on 
collected data (i.e. After withdrawal, data will not be collected and data will 
not be imputed.).


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11.8.
Appendix 8: Values of Potential Clinical Importance(PCI)
LDTA GSI grading scale (LDTA GSI grade), GSI modified NIAID Common Toxicity 
Grading Scale (GSI NIAID grade) will be treated as PCI.
11.8.1.
LDTA GSI grading scale (LDTA GSI grade)
HEMATOLOGY
Grade 1
Grade 2
Grade 3
Grade 4
Hemoglobin
[Hemoglobin]
10.0 to 10.9 
g/dL
100 to 109 g/L
OR
Any decrease 
from Baseline
2.5 to 3.5 g/dL
25 to 35 g/L
9.0 to 10.0 g/dL
90 to 100 g/L
OR
Any decrease 
from Baseline
3.5 to 4.5 g/dL
35 to 45 g/L
7.0 to 9.0 g/dL
70 to 90 g/L
OR
Any decrease 
from Baseline
4.5 g/dL
45 g/L
7.0 g/dL
70 g/L
Absolute 
Neutrophil Count
(ANC)
[-]
1000 to 
1300/mm3
750 to 
1000/mm3
500 to 
750/mm3
500/mm3
1.00 to 1.30 
GI/L
0.75 to 1.00 
GI/L
0.50 to 0.75 
GI/L
0.50 GI/L
Absolute 
Lymphocyte 
Count
[-]
600 to 650/mm3
0.60 to 0.65 
GI/L
500 to 600/mm3
0.50 to 0.60 
GI/L
350 to 
500/mm3
0.35 to 0.50 
GI/L
350/mm3
0.35 GI/L
Platelets 
[Platelet count]
100,000 to < 
125,000/mm3
100 to 125 
GI/L
50,000 to 
100,000/mm3
50 to 100 GI/L
25,000 to 
50,000/mm3
25 to 50 GI/L
25,000/mm3
25 GI/L
WBCs 
[WBC]
2000/mm3 to 
2500/mm3
1,500 to 
2,000/mm3
1000 to 
1,500/mm3
1000/mm3
2.00 GI/L to 
2.50 GI/L
1.50 to 2.00 
GI/L
1.00 to 1.50 
GI/L
1.00 GI/L


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HEMATOLOGY
Grade 1
Grade 2
Grade 3
Grade 4
Prothrombin Time 
(PT)
[ Prothrombin 
Time]
1.00 to 1.25 
ULN
1.25 to 1.50 
ULN 
1.50 to 3.00 
ULN 
3.00 ULN 
CHEMISTRY
Grade 1
Grade 2
Grade 3
Grade 4
Hyponatremia 
[Sodium]
130 to 135 
mEq/L
125 to 130 
mEq/L
121 to 125 
mEq/L
121 mEq/L
130 to 135 
mmol/L
125 to 130 
mmol/L
121 to 125 
mmol/L
121 mmol/L
Hypernatremia
[Sodium]
146 to 150 
mEq/L
150 to 154 
mEq/L
154 to 159 
mEq/L
159 mEq/L
146 to 150 
mmol/L
150 to 154 
mmol/L
154 to 159 
mmol/L
159 mmol/L
Hypokalemia
[Potassium]
3.0 to 3.4 mEq/L
2.5 to 3.0 
mEq/L
2.0 to 2.5 
mEq/L
2.0 mEq/L
3.0 to 3.4 
mmol/L
2.5 to 3.0 
mmol/L
2.0 to 2.5 
mmol/L
2.0 mmol/L
Hyperkalemia 
[Potassium]
5.6 to 6.0 mEq/L
6.0 to 6.5 
mEq/L
6.5 to 7.0 
mEq/L
7.0 mEq/L
5.6 to 6.0 
mmol/L
6.0 to 6.5 
mmol/L
6.5 to 7.0 
mmol/L
7.0 mmol/L
Hypoglycemia
[Glucose]
55 to 64 mg/dL
40 to 55 mg/dL
30 to 40 mg/dL
30 mg/dL
3.03 to 3.58 
mmol/L
2.20 to 3.03 
mmol/L
1.64 to 2.20 
mmol/L
1.64 mmol/L
Hyperglycemia, 
Nonfasting 
[Glucose]
116 to 160 
mg/dL
160 to 250 
mg/dL
250 to 500 
mg/dL
500 mg/dL
6.42 to 8.91 
mmol/L
8.91 to 13.90 
mmol/L
13.90 to 27.79 
mmol/L
27.79 
mmol/L
Hypocalcemia 
[Calcium]
(corrected for 
albumin)
7.8 to 8.4 mg/dL
7.0 to 7.8 
mg/dL
6.1 to 7.0 
mg/dL
6.1 mg/dL


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CHEMISTRY
Grade 1
Grade 2
Grade 3
Grade 4
Hypercalcemia
[Calcium]
(corrected for 
albumin)
10.6 to 11.5 
mg/dL
11.5 to 12.5 
mg/dL
12.5 to 13.5 
mg/dL
13.5 mg/dL
Hypophosphatemia
[Phosphorous?]
NA
2.0 to 2.5 
mg/dL
1.0 to 2.0 
mg/dL
1.0 mg/dL
0.63 to 0.80 
mmol/L
0.31 to 0.63 
mmol/L
0.31 mmol/L
Hyperbilirubinemia 
[Total bilirubin?]
1.0 to 1.5 
ULN 
1.5 to 2.5 
ULN
2.5 to 5.0 
ULN 
5.0 ULN 
Blood Urea 
Nitrogen
[BUN]
1.25 to 2.50 
ULN 
2.50 to 5.00 
ULN 
5.00 to 10.00 
ULN 
10.00 ULN
Creatinine
[Creatinine]
1.50 to 2.00 
mg/dL
2.00 to 3.00 
mg/dL
3.00 to 6.00 
mg/dL 
6.00 mg/dL
133 to 177 
μmol/L
177 to 265 
μmol/L
265 to 530 
μmol/L
530 μmol/L
Creatine Kinase
[CK]
3.0 to 6.0 
ULN
6.0 to 10.0 
ULN
10.0 to 20.0 
ULN
20.0 ULN
ENZYMES
Grade 1
Grade 2
Grade 3
Grade 4
AST (SGOT) 
[AST]
1.25 to 2.50 
ULN
2.50 to 5.00 
ULN
5.00 to 10.00 
ULN
10.00 ULN
ALT (SGPT)
[ALT]
1.25 to 2.50 
ULN
2.50 to 5.00 
ULN
5.00 to 10.00 
ULN
10.00 ULN
Alkaline 
Phosphatase
[ALP]
1.25 to 2.50 
ULN
2.50 to 5.00 
ULN
5.00 to 10.00 
ULN
10.00 ULN


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ENZYMES
Grade 1
Grade 2
Grade 3
Grade 4
Total Amylase
[Amylase]
1.0 to 1.5 
ULN
1.5 to 2.0 
ULN
2.0 to 5.0 
ULN
5.0 ULN
Albumin
[Albumin]
3.0 g/dL to 
LLN
30 g/L to LLN
2.0 to 3.0 g/dL
20 to 30 g/L
2.0 g/dL
20 g/L
NA
ULN = Upper Limit of Normal; LLN = Lower Limit of Normal
[-]: Not measured 
LDTA: Liver Disease Therapeutic Area （Toxicity Grading Scale）
Although Section 11.8.1 mentioned unit for electrolyte Ca is “mg/dL”, these values were converted values 
based on “mmol/L” unit that is used as one of GSK SI units. For laboratory grading, following grades in the 
table has been applied.
Grade 1
Grade 2
Grade 3
Grade 4
Hypocalcemia 
[Calcium]
(corrected for 
albumin)
1.94 to 2.10 
mmol/L
1.74 to 1.94 
mmol/L
1.51 to 1.74 
mmol/L
1.51 mmol/L
Hypercalcemia
[Calcium]
(corrected for 
albumin)
2.64 to 2.88 
mmol/L
2.88 to 3.13 
mmol/L
3.13 to 3.38 
mmol/L
3.38 mmol/L
11.8.2.
GSI modified NIAID Common Toxicity Grading Scale (GSI NIAID 
grade)
HEMATOLOGY
Grade 1
Grade 2
Grade 3
Grade 4
Hemoglobin
[Hemoglobin]
8.0 – 9.4 g/dL
80 – 94 g/L
7.0 – < 8.0 g/dL
70 – < 80 g/L
6.5– < 7.0 g/dL
65 – < 70 g/L
< 6.5 g/dL
< 65 g/L
Platelets
[Platelet count]
75,000 –
100,000/mm3
75.0 – 100.0 
GI/L
50,000 – < 
75,000/mm3
50.0 – < 75.0 GI/L
25,000 – < 
50,000/mm3
25.0 – < 50.0 
GI/L
< 25,000/mm3
< 25.0 GI/L


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HEMATOLOGY
Grade 1
Grade 2
Grade 3
Grade 4
WBCs
[WBC]
3000/mm3- < 
LLN
3.0 GI/L - < 
LLN
2000 – < 
3000/mm3
2.0 – < 3.0 GI/L
1000 – < 
2000/mm3
1.0 – < 2.0 GI/L
< 1000/ mm3
< 1.0 GI/L
Prothrombin Time 
(PT)
[Prothrombin 
Time]
> 1.00 – 1.25 × 
ULN
> 1.25 – 1.50 × 
ULN
> 1.50 – 3.00 × 
ULN
> 3.00 × ULN
CHEMISTRY
Grade 1
Grade 2
Grade 3
Grade 4
Hyponatremia
[Sodium]
130 mEq/L – < 
LLN
130 mmol/L – < 
LLN
123– < 130 
mEq/L
123– < 130 
mmol/L
116 – < 123 
mEq/L
116 – < 123 
mmol/L
< 116 mEq/L
< 116 mmol/L
Hypernatremia
[Sodium]
> ULN – 150 
mEq/L
> ULN – 150 
mmol/L
> 150 – 157 
mEq/L
> 150 – 157 
mmol/L
> 157 – 165 
mEq/L
> 157 – 165 
mmol/L
> 165 mEq/L
> 165 mmol/L
Hypokalemia
[Potassium]
3.0 mEq/L – < 
LLN
3.0 mmol/L – < 
LLN
2.5 – < 3.0 mEq/L
2.5 – < 3.0 
mmol/L
2.0 – < 2.5 
mEq/L
2.0 – < 2.5 
mmol/L
< 2.0 mEq/L
< 2.0 mmol/L
Hyperkalemia
[Potassium]
5.6 – 6.0 mEq/L
5.6 – 6.0 
mmol/L
> 6.0 – 6.5 mEq/L
> 6.0 – 6.5 
mmol/L
> 6.5 – 7.0 
mEq/L
> 6.5 – 7.0 
mmol/L
> 7.0 mEq/L
> 7.0 mmol/L
Hypoglycemia
[Glucose]
55 – 64 mg/dL
3.03 – 3.57 
mmol/L
40 – < 55 mg/dL
2.20 - < 3.03 
mmol/L
30 – < 40 mg/dL
1.64 - < 2.20 
mmol/L
< 30 mg/dL
< 1.64 mmol/L
Hyperglycemia 
(nonfasting and
no prior diabetes)
[Glucose]
> ULN – 160 
mg/dL
> ULN – 8.90 
mmol/L
> 160 - 250 
mg/dL
> 8.90 – 13.90 
mmol/L
> 250 – 500 
mg/dL
> 13.90 – 27.77 
mmol/L
> 500 mg/dL
> 27.77 
mmol/L


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CHEMISTRY
Grade 1
Grade 2
Grade 3
Grade 4
Hypocalcemia
(corrected for 
albumin)
[Calcium]
7.8 mg/dL – < 
LLN
1.94 mmol/L - < 
LLN
7.0 – < 7.8 mg/dL
1.74 - < 1.94 
mmol/L
6.1 – < 7.0 
mg/dL
1.52 - < 1.74 
mmol/L
< 6.1 mg/dL
< 1.52 mmol/L
Hypercalcemia
(corrected for 
albumin)
[Calcium]
> ULN – 11.5 
mg/dL
> ULN – 2.88 
mmol/L
> 11.5 – 12.5 
mg/dL
> 2.88 – 3.13 
mmol/L
> 12.5 – 13.5 
mg/dL
> 3.13 – 3.38 
mmol/L
> 13.5 mg/dL
> 3.38 mmol/L
Hypophosphatemia
[Phosphorous]
2.0 mg/dL – < 
LLN
0.63 mmol/L - < 
LLN
1.5 – < 2.0 mg/dL
0.47 - < 0.63 
mmol/L
1.0 – < 1.5 
mg/dL
0.31 - < 0.47 
mmol/L
< 1.0 mg/dL
< 0.31 mmol/L
Hyperbilirubinemia
[Total Bilirubin]
> 1.0 – 1.5 × 
ULN
> 1.5 – 2.5 × ULN
> 2.5 – 5.0 × 
ULN
> 5.0 × ULN
Blood Urea 
Nitrogen
[Urea/BUN]
1.25 – 2.50 × 
ULN
> 2.50 – 5.00 × 
ULN
> 5.00 – 10.00 × 
ULN
> 10.00 × ULN
Hyperuricemia
[Uric acid]
> ULN – 10.0 
mg/dL
> ULN – 0.59 
mmol/L
> 10.0 – 12.0 
mg/dL
> 0.59 – 0.71 
mmol/L
> 12.0 – 15.0 
mg/dL
> 0.71 – 0.89 
mmol/L
> 15.0 mg/dL
> 0.89 mmol/L
Hypouricemia
[Uric acid]
1.5 mg/dL - < 
LLN
0.09 mmol/L - < 
LLN
1.0 - <1.5 mg/dL
0.06 – < 0.09 
mmol/L
0.5 - < 1.0 
mg/dL
0.03 – < 0.06 
mmol/L
< 0.5 mg/dL
< 0.03 mmol/L
Creatinine
[Creatinine]
M: >1.5 – 2.0 
mg/dL
F: >1.3 – 1.8 
mg/dL
M: >137 – 181 
micromol/L
F: >119 – 163 
micromol/L
M: > 2.0 – 3.0 
mg/dL
F: > 1.8 – 2.8 
mg/dL
M: > 181 – 269 
micromol/L
F: > 163 – 252 
micromol/L
M: > 3.0 – 6.0 
mg/dL
F: > 2.8 – 5.8 
mg/dL
M: > 269 – 535 
micromol/L
F: > 252 – 517 
micromol/L
M: > 6.0 
mg/dL
F: > 5.8 mg/dL
M: > 535 
micromol/L
F: > 517 
micromol/L
Creatine Kinase
[Creatine 
Kinase/CK(CPK)]
3.0 - < 6.0 × 
ULN
6.0 – < 10.0 × 
ULN
10.0 - < 20.0 × 
ULN
≥ 20.0 × ULN


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ENZYMES
Grade 1
Grade 2
Grade 3
Grade 4
AST (SGOT)
[AST]
1.25 – 2.50 × 
ULN
> 2.50 – 5.00 × 
ULN
> 5.00 – 10.00 × 
ULN
> 10.00 × ULN
ALT (SGPT)
[ALT]
1.25 – 2.50 × 
ULN
> 2.50 – 5.00 × 
ULN
> 5.00 – 10.00 × 
ULN
> 10.00 × ULN
GGT
[GGT]
1.25 – 2.50 × 
ULN
> 2.50 – 5.00 × 
ULN
> 5.00 – 10.00 × 
ULN
> 10.00 × ULN
Alkaline 
Phosphatase
[ALP]
1.25 – 2.50 × 
ULN
> 2.50 – 5.00 × 
ULN
> 5.00 – 10.00 × 
ULN
> 10.00 × ULN
Total Amylase
[Amylase]
> 1.0 – 1.5 × 
ULN
> 1.5 – 2.0 × ULN
> 2.0 – 5.0 × 
ULN
> 5.0 × ULN
Lipase
[Lipase]
> 1.0 – 1.5 × 
ULN
> 1.5 – 2.0 × ULN
> 2.0 – 5.0 × 
ULN
> 5.0 × ULN
Albumin
[Albumin]
3.0 g/dL - < 
LLN
30 g/L - < LLN
2.0 - < 3.0 g/dL
20 – < 30 g/L
< 2.0 g/dL
< 20 g/L
—
ULN = Upper Limit of Normal; LLN = Lower Limit of Normal
[-]: not measured in the study
NIAID: National Institute of Allergy and Infectious Disease (US)


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11.9.
Appendix 9: PEGINTERFERON GSKDrug codes
Term Name
Code
PEGINTERFERON ALFA-2B + RIBAVIRIN
53239301
PEGINTERFERON NOS
53332901
PEGINTERFERON ALFA-2A
51080801
PEGINTERFERON ALFA
59758801
PEGINTERFERON ALFA-2B
51090301
PEGINTERFERON BETA 1A
59122901
PEGINTERFERON ALFA-2A + RIBAVIRIN
53239401
PEGINTERFERON ALFA
59758801
PEGINTERFERON ALFA-2A
51080801
PEGINTERFERON ALFA-2A + RIBAVIRIN
53239401
PEGINTERFERON ALFA-2B
51090301
PEGINTERFERON ALFA-2B + RIBAVIRIN
53239301
PEGINTERFERON BETA 1A
59122901
PEGINTERFERON LAMBDA-1A
59611101
PEGINTERFERON NOS
53332901
ROPEGINTERFERON ALFA-2B
59745201


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11.10.
Appendix 10: Viread (Tenofovir Disoproxil Fumarate) Risk 
Management Plan for the EU (Version 22) January 2017
MedDRA terms (Version 17.0)

Renal toxicity

Bone Events due to Proximal Renal Tubulopathy/Loss of Bone Mineral Density 
(BMD)


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
Post-Treatment Hepatic Flares in HBV Monoinfected and HIV-1/HBV Coinfected Patients


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11.11.
Appendix 11: Abbreviations & Trade Marks
11.11.1.
Abbreviations
Abbreviation
Description
AE
Adverse Event
A&R
Analysis and Reporting 
CI
Confidence Interval
CLcr
Creatinine Clearance
CSR
Clinical Study Report
DOB
Date of Birth
DP
Decimal Places
eCRF
Electronic Case Record Form
GSI
Gilead Science Institute
GSK
GlaxoSmithKline
HARP
Harmonisation for Analysis and Reporting Program
ICH
International Conference on Harmonisation
IDSL
Integrated Data Standards Library
IP
Investigational Product
LDTA
Liver Disease Therapeutic Area （Toxicity Grading Scale）
NIAID
National Institute of Allergy and Infectious Disease (US)
PCI
Potential Clinical Importance 
PDMP
Protocol Deviation Management Plan
QC
Quality Control
RAP
Reporting & Analysis Plan
SAC
Statistical Analysis Complete
SOP
Standard Operation Procedure
TFL
Tables, Figures & Listings 
11.11.2.
Trademarks
Trademarks of the GlaxoSmithKline 
Group of Companies
Trademarks not owned by the 
GlaxoSmithKline Group of 
Companies
None
SAS
Viread


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11.12.
Appendix 12: List of Data Displays
11.12.1.
Data Display Numbering
The following numbering will be applied for RAP generated displays:
Section
Tables
Figures
Study Population
1.1 to 1.23
-
Efficacy
2.1 to 2.61
2.1 to 2.15
Safety
3.1 to 3.40
3.1 to 3.10
Exploratory
4.1 to 4.42
4.1 to 4.48
Section
Listings
ICH Listings
1 to 72
11.12.2.
Mock Example Shell Referencing
Non IDSL specifications will be referenced as indicated and if required example mock-up 
displays provided in Appendix 13: Example Mock Shells for Data Displays.
Section
Figure
Table
Listing
Study Population
POP_Fn
POP_Tn
POP_Ln
Efficacy
EFF_Fn
EFF_Tn
EFF_Ln
Safety
SAFE_Fn
SAFE_Tn
SAFE_Ln
NOTES: 

Non-Standard displays are indicated in the ‘IDSL / Example Shell’ or ‘Programming Notes’ column as 
‘[Non-Standard] + Reference.’
11.12.3.
Deliverables
Delivery Priority 1
Description
SAC [1]
48W Statistical Analysis Complete
SAC [2]
96W (Final) Statistical Analysis Complete
NOTES: 
1.
Indicates priority (i.e. order) in which displays will be generated for the reporting effort


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11.12.4.
Study Population Tables
Study Population Tables
No.
Population
IDSL / 
Example 
Shell
Title
Programming Notes
Deliverable 
[Priority]
Subject Disposition
1.1.
Safety
ES1
Summary of Subject Disposition
Completed or withdrawn and the 
reason for withdrawal.
SAC [1,2]
1.2.
Enrolled
ES6
Summary of Screening Status and Reasons for Screen 
Failure
The number (%) of Prescribed or 
screening failure subjects as the 
screening status, and the reason for 
screening failure.
SAC [1,2]
Protocol Deviation
1.3.
Safety
IE1
Summary of Inclusion/Exclusion Criteria Deviations
SAC [1,2]
1.4.
Safety 
DV1
Summary of Important Protocol Deviations (48W/96W)
SAC [1,2]
Population Analysed
1.5.
Enrolled
SP1
Summary of Study Populations (48W/96W)
SAC [1,2]
Demographic and Baseline Characteristics
1.6.
Safety
DM1
Summary of Demographic Characteristics (SP) 
Age category:<=18, 19-64, 65-74, 
>=75
SAC [1,2]
1.7.
FAS
DM1
Summary of Demographic Characteristics (FAS) 
Age category:<=18, 19-64, 65-74, 
>=75
SAC [1,2]
1.8.
EES
DM1
Summary of Demographic Characteristics (EES,48W) 
Age category:<=18, 19-64, 65-74, 
>=75
SAC [1]
1.9.
Screening 
Failure
DM1
Summary of Demographic Characteristics for Screening 
Failure
Age category:<=18, 19-64, 65-74, 
>=75
SAC [1]
1.10.
Enrolled
DM11
Summary of Age Ranges
<=17, 18-64, 65-84, >=85
SAC [1,2]


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Study Population Tables
No.
Population
IDSL / 
Example 
Shell
Title
Programming Notes
Deliverable 
[Priority]
1.11.
Safety
DM5
Summary of Race and Racial Combinations (SP)
SAC [1,2]
1.12.
FAS
DM5
Summary of Race and Racial Combinations (FAS)
SAC [1,2]
1.13.
EES
DM5
Summary of Race and Racial Combinations (EES, 48W)
SAC [1]
1.14.
Safety
Study specific
Summary of Other Baseline Characteristics (SP)
Include eGFR Subgroup category
Genotype categories (A, B, C, D)
SAC [1,2]
1.15.
FAS
Study specific
Summary of Other Baseline Characteristics (FAS)
Include Subgroup category
Genotype categories (A, B, C, D)
SAC [1,2]
1.16.
EES
Study specific
Summary of Other Baseline Characteristics (EES,48W)
Include Subgroup category
Genotype categories (A, B, C, D)
SAC [1]
Prior and Concomitant Medications
1.17.
Safety
MH4
Summary of Prior Medical Conditions
SAC [1,2]
1.18.
Safety
CM1
Summary of Prior Hepatitis Medications
SAC [1,2]
1.19.
Safety
CM1
Summary of Concomitant Medications
SAC [1,2]
Exposure and Treatment Compliance
1.20.
FAS
Study specific
Summary of Treatment compliance (FAS)
Note: calculation formula
Sum of [(IPCOMPLY.DISPNUM -
IPCOMPLY.RETRNNUM)] / sum 
of [(EXPOSURE.EXENDT –
EXPOSURE.EXSTDT + 1) × 1]
“Sum of” is cumulative visit
SAC [1,2]
1.21.
EES
Study specific
Summary of Treatment compliance (EES,48W)
SAC [1]


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Study Population Tables
No.
Population
IDSL / 
Example 
Shell
Title
Programming Notes
Deliverable 
[Priority]
1.22.
Safety
EX1
Duration of Exposure to Study Drug (SP)
SAC [1,2]
Subgroup
1.23.
FAS
Study specific
Summary of Other Baseline Characteristics by subgroup 
(FAS)
Protocol defined liver cirrhosis 
(Yes, No), Genotype (A, B, C, D), 
HBsAg subgroup category (<800 
KIU/L, >=800 KIU/L), AGE 
category (<40, 40-49, 50-59, 60-), 
Former Peg-INF (Yes, No)
HBsAg subgroup category with 
conventional unit) (<800 IU/mL, 
>=800 IU/mL)
SAC [1,2]


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11.12.5.
Efficacy Tables
Efficacy: Tables
No.
Population
IDSL / 
Example 
Shell
Title
Programming Notes
Deliverable 
[Priority]
Primary Endpoint: HBsAg
2.1.
FAS
Study specific
Proportion of subjects with HBsAg achieving 0.25 Log10 
HBsAg reduction from the baseline (HBsAg responder) 
(FAS,48W, Missing at worse)
Proportion with 95% CI
SAC [1]
2.2.
EES
Study specific
Proportion of subjects with HBsAg achieving 0.25 Log10 
HBsAg reduction from the baseline (HBsAg responder) 
(EES,48W, Missing at worse)
Proportion with 95% CI
SAC [1]
2.3.
FAS
Study specific
Summary of log10 HBsAg (Baseline, FAS)
SAC [1]
2.4.
EES
Study specific
Summary of log10 HBsAg (Baseline, EES)
SAC [1]
2.5.
FAS
Study specific
Proportion of subjects with HBsAg achieving 0.25 Log10 
HBsAg reduction from the baseline by Subgroup (FAS, 
48W/96W, Missing at worse)
Protocol defined Liver cirrhosis 
(Yes, No), Genotype (A, B, C, D), 
HBsAg subgroup category (<800 
KIU/L, >=800 KIU/L), AGE 
category (<40, 40-49, 50-59, 60-), 
Former Peg-INF (Yes, No), HBsAg 
subgroup category (Conventional 
unit) (<800 IU/mL, >=800 IU/mL)
Proportion with 95% CI
SAC [1,2]
2.6.
EES
Study specific
Proportion of subjects with HBsAg achieving 0.25 Log10 
HBsAg reduction from the baseline by Subgroup (EES, 
48W, Missing at worse)
Protocol defined liver cirrhosis 
(Yes, No), Genotype (A, B, C, D), 
HBsAg subgroup category (<800 
KIU/L, >=800 KIU/L), AGE 
category (<40, 40-49, 50-59, 60-), 
Former Peg-INF (Yes, No), HBsAg 
subgroup category (Conventional 
unit) (<800 IU/mL, >=800 IU/mL)
Proportion with 95% CI
SAC [1]


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Efficacy: Tables
No.
Population
IDSL / 
Example 
Shell
Title
Programming Notes
Deliverable 
[Priority]
Secondary Endpoint: HBsAg
2.7.
FAS
Study specific
Proportion of subjects with HBsAg achieving 0.25 Log10 
HBsAg reduction from the baseline (HBsAg responder) 
by study visit up to WEEK 48/WEEK 96 (FAS, Missing 
at worse)
Proportion with 95% CI
SAC [1,2]
2.8.
FAS
Study specific
Summary of log10 HBsAg by study visit up to WEEK 
48/WEEK 96 (FAS)
Change from baseline is included.
SAC [1,2]
2.9.
EES
Study specific
Summary of log10 HBsAg by study visit up to WEEK 48 
(EES) 
Change from baseline is included.
SAC [1]
2.10.
FAS
Study specific
Summary of HBsAg by study visit up to WEEK 
48/WEEK 96 (FAS)
Change from baseline is included.
SAC [1,2]
2.11.
EES
Study specific
Summary of HBsAg by study visit up to WEEK 48 (EES)
Change from baseline is included.
SAC [1]
2.12.
FAS
Study specific
Frequency of HBsAg category by study visit up to WEEK 
48/WEEK 96 (FAS)
HBsAg category: <80, 80<= -
<800, 800<= - <8000, 8000<= -
<80000, >=80000 Unit: KIU/L
SAC [1,2]
2.13.
EES
Study specific
Frequency of HBsAg category by study visit up to WEEK 
48 (EES)
HBsAg category: <80, 80<= -
<800, 800<= - <8000, 8000<= -
<80000, >=80000 Unit: KIU/L
SAC [1]
2.14.
FAS
Study specific
Summary of log10 HBsAg (Conventional unit) by study 
visit up to WEEK 48/WEEK 96 (FAS)
Change from baseline is included.
SAC [1,2]
2.15.
FAS
Study specific
Summary of HBsAg (Conventional unit) by study visit up 
to WEEK 48/WEEK 96 (FAS)
Change from baseline is included.
SAC [1,2]
2.16.
FAS
Study specific
Frequency of HBsAg category (Conventional unit) by 
study visit up to WEEK 48/WEEK 96 (FAS)
HBsAg category: <80, 80<= -
<800, 800<= - <8000, 8000<= -
<80000, >=80000 Unit: IU/mL
SAC [1,2]
Seroconversion
2.17.
FAS
Study specific
Proportion of subjects with HBsAg Loss by Study Visit 
up to WEEK 48/WEEK 96 (FAS)
% Numbers of subjects with 
HBsAg loss/Numbers of subjects 
with positive HBsAg at baseline
SAC [1,2]


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Efficacy: Tables
No.
Population
IDSL / 
Example 
Shell
Title
Programming Notes
Deliverable 
[Priority]
2.18.
EES
Study specific
Proportion of subjects with HBsAg Loss by Study Visit 
up to WEEK 48 (EES)
% Numbers of subjects with 
HBsAg loss/Numbers of 
subjects with positive HBsAg at 
baseline
SAC [1]
2.19.
FAS
Study specific
Proportion of subjects with HBsAg/Ab Seroconversion by 
Study Visit up to WEEK 48/WEEK 96 (FAS)
% Numbers of subjects with 
HBsAg/Ab 
Seroconversion/Numbers of 
subjects with positive HBsAg and 
Negative HBsAb at baseline
SAC [1,2]
2.20.
EES
Study specific
Proportion of subjects with HBsAg/Ab Seroconversion by 
Study Visit up to WEEK 48 (EES)
% Numbers of subjects with 
HBsAg/Ab 
Seroconversion/Numbers of 
subjects with positive HBsAg and 
Negative HBsAb at baseline
SAC [1]
2.21.
FAS
Study specific
Proportion of subjects with HBeAg Loss by Study Visit 
up to WEEK 48/WEEK 96 (FAS)
%: Numbers of subjects with 
HBeAg loss/Numbers of subjects 
with positive HBeAg at baseline
SAC [1,2]
2.22.
EES
Study specific
Proportion of subjects with HBeAg Loss by Study Visit 
up to WEEK 48 (EES)
%: Numbers of subjects with 
HBeAg loss/Numbers of subjects 
with positive HBeAg at baseline
SAC [1]
2.23.
FAS
Study specific
Proportion of subjects with HBeAg/Ab Seroconversion by 
Study Visit up to WEEK 48/WEEK 96 (FAS)
% Numbers of subjects with 
HBeAg/Ab 
Seroconversion/Numbers of 
subjects with positive HBeAg and 
Negative HBeAb at baseline
SAC [1,2]
2.24.
EES
Study specific
Proportion of subjects with HBeAg/Ab Seroconversion by 
Study Visit up to WEEK 48 (EES)
% Numbers of subjects with 
HBeAg/Ab 
Seroconversion/Numbers of 
subjects with positive HBeAg and 
Negative HBeAb at baseline
SAC [1]


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Efficacy: Tables
No.
Population
IDSL / 
Example 
Shell
Title
Programming Notes
Deliverable 
[Priority]
Virology
2.25.
FAS
Study specific
Summary of HBcrAg by Study Visit up to WEEK 
48/WEEK 96 (FAS)
Change from baseline is included.
SAC [1,2]
2.26.
FAS
Study specific
Frequency of HBcrAg category by Study Visit up to 
WEEK 48/WEEK 96 (FAS)
HBcrAg category:
<3.0 log10, 3.0<= - <4.0 log10, 
4.0<= -<5.0 log10, 5.0<= - <6.0 
log10, >=6.0 log10 Unit: KU/L
SAC [1,2]
2.27.
FAS
Study specific
Proportion of subjects with HBV-DNA < 1.0 log10 
IU/mL by Study Visit up to WEEK 48/WEEK 96 (FAS)
<1.0 log10 IU/mL, >=1.0 log10 
IU/mL
SAC [1,2]
2.28.
FAS
Study specific
Summary of HBV-DNA by Study Visit up to WEEK 
48/WEEK 96 (FAS)
Change from baseline is included.
SAC [1,2]
2.29.
FAS
Study specific
Summary of HBeAg by Study Visit up to WEEK 48 
/WEEK 96 (FAS)
Change from baseline is included.
SAC [1,2]
2.30.
FAS
Study specific
Summary of log10 HBeAg by Study Visit up to WEEK 48 
/WEEK 96 (FAS)
Change from baseline is included.
SAC [1,2]
2.31.
FAS
Study specific
Frequency of Virological Breakthrough (WEEK 0 –
WEEK 48/WEEK 96) (FAS)
Change from baseline is included.
SAC [1,2]
2.32.
FAS
Study specific
Summary of HBcrAg (Conventional unit) by Study Visit 
up to WEEK 48/WEEK 96 (FAS)
HBcrAg category:
<3.0 log10, 3.0<= - <4.0 log10, 
4.0<= -<5.0 log10, 5.0<= - <6.0 
log10, >=6.0 log10 Unit: U/mL
SAC [1,2]
2.33.
FAS
Study specific
Frequency of HBcrAg category (Conventional unit) by 
Study Visit up to WEEK 48/WEEK 96 (FAS)
SAC [1,2]
ALT
2.34.
FAS
Study specific
Summary of ALT by Study Visit up to WEEK 48/WEEK 
96 (FAS)
Change from baseline is included
SAC [1,2]
2.35.
FAS
Study specific
Summary of ALT (Conventional unit) by Study Visit up 
to WEEK 48/WEEK 96 (FAS)
Change from baseline is included
SAC [1,2]


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Efficacy: Tables
No.
Population
IDSL / 
Example 
Shell
Title
Programming Notes
Deliverable 
[Priority]
Subgroup
2.36.
FAS
Study specific
Summary of log10 HBsAg by Protocol defined liver 
cirrhosis (FAS, 48W/96W)
Change from baseline is included
SAC [1,2]
2.37.
FAS
Study specific
Summary of log10 HBsAg by Genotype (FAS, 
48W/96W)
Change from baseline is included
SAC [1,2]
2.38.
FAS
Study specific
Summary of log10 HBsAg by HBsAg subgroup category 
(FAS, 48W/96W)
Change from baseline is included
SAC [1,2]
2.39.
FAS
Study specific
Summary of log10 HBsAg by AGE category (FAS, 
48W/96W)
Change from baseline is included
SAC [1,2]
2.40.
FAS
Study specific
Summary of log10 HBsAg by Former Peg-INF (FAS, 
48W/96W)
Change from baseline is included
SAC [1,2]
2.41.
FAS
Study specific
Summary of HBcrAg by Protocol defined liver cirrhosis
(FAS, 48W/96W)
Change from baseline is included
SAC [1,2]
2.42.
FAS
Study specific
Summary of HBcrAg by Genotype (FAS, 48W/96W)
Change from baseline is 
included
SAC [1,2]
2.43.
FAS
Study specific
Summary of HBcrAg by HBsAg subgroup category (FAS, 
48W/96W)
Change from baseline is included
SAC [1,2]
2.44.
FAS
Study specific
Summary of HBcrAg by AGE category (FAS, 48W/96W)
Change from baseline is included
SAC [1,2]
2.45.
FAS
Study specific
Summary of HBcrAg by Former Peg-INF (FAS, 
48W/96W)
Change from baseline is included
SAC [1,2]
2.46.
FAS
Study specific
Summary of log10 HBeAg by Protocol defined liver 
cirrhosis (FAS, 48W/96W)
SAC [1,2]
2.47.
FAS
Study specific
Summary of log10 HBeAg by Genotype (FAS, 
48W/96W)
SAC [1,2]
2.48.
FAS
Study specific
Summary of log10 HBeAg by HBsAg subgroup category 
(FAS, 48W/96W)
SAC [1,2]
2.49.
FAS
Study specific
Summary of log10 HBeAg by AGE category (FAS, 
48W/96W)
SAC [1,2]


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Efficacy: Tables
No.
Population
IDSL / 
Example 
Shell
Title
Programming Notes
Deliverable 
[Priority]
2.50.
FAS
Study specific
Summary of log10 HBeAg by Former Peg-INF (FAS, 
48W/96W)
SAC [1,2]
2.51.
FAS
Study specific
Summary of log10 HBsAg (Conventional unit) by 
Protocol defined liver cirrhosis (FAS, 48W/96W)
Change from baseline is included
SAC [1,2]
2.52.
FAS
Study specific
Summary of log10 HBsAg (Conventional unit) by 
Genotype (FAS, 48W/96W)
Change from baseline is included
SAC [1,2]
2.53.
FAS
Study specific
Summary of log10 HBsAg (Conventional unit) by HBsAg 
subgroup category (Conventional unit) (FAS, 48W/96W)
Change from baseline is included
SAC [1,2]
2.54.
FAS
Study specific
Summary of log10 HBsAg (Conventional unit) by AGE 
category (FAS, 48W/96W)
Change from baseline is included
SAC [1,2]
2.55.
FAS
Study specific
Summary of log10 HBsAg (Conventional unit) by Former 
Peg-INF (FAS, 48W/96W)
Change from baseline is included
SAC [1,2]
2.56.
FAS
Study specific
Summary of HBcrAg (Conventional unit) by Protocol 
defined liver cirrhosis (FAS, 48W/96W)
Change from baseline is included
SAC [1,2]
2.57.
FAS
Study specific
Summary of HBcrAg (Conventional unit) by Genotype 
(FAS, 48W/96W)
Change from baseline is included
SAC [1,2]
2.58.
FAS
Study specific
Summary of HBcrAg (Conventional unit) by HBsAg 
subgroup category (Conventional unit) (FAS, 48W/96W)
Change from baseline is included
SAC [1,2]
2.59.
FAS
Study specific
Summary of HBcrAg (Conventional unit) by AGE 
category (FAS, 48W/96W)
Change from baseline is included
SAC [1,2]
2.60.
FAS
Study specific
Summary of HBcrAg (Conventional unit) by Former Peg-
INF (FAS, 48W/96W)
Change from baseline is included
SAC [1,2]
2.61.
FAS
Study specific
Summary of log10 HBeAg by HBsAg subgroup category 
(Conventional unit) (FAS, 48W/96W)
SAC [1,2]


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70
11.12.6.
Efficacy Figures
Efficacy: Figures
No.
Population
IDSL / 
Example 
Shell
Title
Programming Notes
Deliverable 
[Priority]
HBsAg
2.1.
FAS
Study specific
Log10 HBsAg by Study Visit up to WEEK 48/WEEK 96: 
Mean (SD) Plots (FAS)
SD plots
SAC [1,2]
2.2.
FAS
Study specific
Log10 HBsAg Change from Baseline by Study Visit up to 
WEEK 48/WEEK 96: Mean (SD) Plots (FAS)
SD plots
SAC [1,2]
2.3.
FAS
Study specific
Log10 HBsAg (Conventional unit) by Study Visit up to 
WEEK 48/WEEK 96: Mean (SD) Plots (FAS)
SD plots
SAC [1,2]
2.4.
FAS
Study specific
Log10 HBsAg (Conventional unit) Change from Baseline 
by Study Visit up to WEEK 48/WEEK 96: Mean (SD) 
Plots (FAS)
SD plots
SAC [1,2]
Virology
2.5.
FAS
Study specific
HBcrAg by Study Visit up to WEEK 48/WEEK 96: Mean 
(SD) Plots (FAS)
SD plots
SAC [1,2]
2.6.
FAS
Study specific
HBcrAg Change from Baseline by Study Visit up to 
WEEK 48/WEEK 96: Mean (SD) Plots (FAS)
SD plots
SAC [1,2]
2.7.
FAS
Study specific
HBV-DNA by Study Visit up to WEEK 48/WEEK 96: 
Mean (SD) Plots (FAS)
SD plots
SAC [1,2]
2.8.
FAS
Study specific
HBV-DNA Change from Baseline by Study Visit up to 
WEEK 48/WEEK 96: Mean (SD) Plots (FAS)
SD plots
SAC [1,2]
2.9.
FAS
Study specific
Log10 HBeAg Change from Baseline by Study Visit up to 
WEEK 48/WEEK 96: Mean (SD) Plots (FAS)
SD plots
SAC [1,2]
2.10.
FAS
Study specific
HBcrAg (Conventional unit) by Study Visit up to WEEK 
48/WEEK 96: Mean (SD) Plots (FAS)
SD plots
SAC [1,2]
2.11.
FAS
Study specific
HBcrAg (Conventional unit) Change from Baseline by 
Study Visit up to WEEK 48/WEEK 96: Mean (SD) Plots 
(FAS)
SD plots
SAC [1,2]


CONFIDENTIAL
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71
Efficacy: Figures
No.
Population
IDSL / 
Example 
Shell
Title
Programming Notes
Deliverable 
[Priority]
ALT
2.12.
FAS
Study specific
ALT by Study Visit up to WEEK 48/WEEK 96: Mean 
(SD) Plots (FAS)
SD plots
SAC [1,2]
2.13.
FAS
Study specific
ALT Change from Baseline by Study Visit up to WEEK 
48/WEEK 96: Mean (SD) Plots (FAS)
SD plots
SAC [1,2]
2.14.
FAS
Study specific
ALT (Conventional unit) by Study Visit up to WEEK 
48/WEEK 96: Mean (SD) Plots (FAS)
SD plots
SAC [1,2]
2.15.
FAS
Study specific
ALT (Conventional unit) Change from Baseline by Study 
Visit up to WEEK 48/WEEK 96: Mean (SD) Plots (FAS)
SD plots
SAC [1,2]


CONFIDENTIAL
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72
11.12.7.
Safety Tables
Safety: Tables
No.
Population
IDSL /
Example 
Shell
Title
Programming Notes
Deliverable 
[Priority]
Adverse Events (AEs)
3.1.
Safety
AE1
Summary of Adverse Events by System Organ Class and 
Preferred Term (WEEK 48/WEEK 96: on Treatment 
Period)
SAC [1,2]
3.2.
Safety
AE1
Summary of Non-Serious Adverse Events by System 
Organ Class and Preferred Term, >=5% (WEEK 
48/WEEK 96: on Treatment Period for FDAAA)
SAC [1,2]
3.3.
Safety
AE5A
Summary of Adverse Events by Maximum Intensity 
(WEEK 48/WEEK 96: on Treatment Period)
SAC [1,2]
3.4.
Safety
AE1
Summary of Drug-Related Adverse Events by System 
Organ Class and Preferred Term (WEEK 48/WEEK 96:
on Treatment Period)
SAC [1,2]
3.5.
Safety
AE5
Summary of Drug-Related Adverse Events by Maximum 
Intensity (WEEK 48/WEEK 96: on Treatment Period)
SAC [1,2]
3.6.
Safety
AE1
Summary of Adverse Events by 3 Months (WEEK 48 on 
Treatment Period)
SAC [1]
3.7.
Safety
AE1
Summary of Adverse Events by 6 Months (WEEK 96 on 
Treatment Period)
SAC [2]
Serious and Other Significant Adverse Events
3.8.
Safety
AE1
Summary of Serious Adverse Events by System Organ 
Class and Preferred Term (WEEK 48/WEEK 96: on 
Treatment Period)
SAC [1,2]


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73
Safety: Tables
No.
Population
IDSL /
Example 
Shell
Title
Programming Notes
Deliverable 
[Priority]
3.9.
Safety
AE1
Summary of Fatal Serious Adverse Events by System 
Organ Class and Preferred Term (WEEK 48/WEEK 96: 
on Treatment Period)
SAC [1,2]
3.10.
Safety
AE1
Summary of Adverse Events Leading to Permanent 
Discontinuation of Study Drug by System Organ Class 
and Preferred Term (WEEK 48/WEEK 96: on Treatment 
Period)
SAC [1,2]
AE of Interest
3.11.
Safety
AE1
Summary of Renal AE as AE of Interest (WEEK 
48/WEEK 96: on Treatment Period)
SAC [1,2]
3.12.
Safety
AE1
Summary of Bone Events as AE of Interest (WEEK 
48/WEEK 96: on Treatment Period)
SAC [1,2]
3.13.
Safety
AE1
Summary of Liver AE as AE of Interest (WEEK 
48/WEEK 96: on Treatment Period)
SAC [1,2]
Laboratory: Chemistry 
3.14.
Safety
LB1
Summary of Chemistry Data
Change from baseline is included.
Corrected calcium based on the 
serum albumin is included.
Creatinine clearance is included.
SAC [1,2]
3.15.
Safety
LB1
Summary of Chemistry Results Relative to Normal Range
SAC [1,2]
3.16.
Safety
LB1
Summary of Chemistry Data (ALT, ALP, Creatinine, 
Phosphorus, Glucose, Uric acid, eGFR) with conventional 
unit
Change from baseline is included.
SAC [1,2]
Laboratory: Hematology
3.17.
Safety
LB1
Summary of Hematology Data
Change from baseline is included
SAC [1,2]


CONFIDENTIAL
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74
Safety: Tables
No.
Population
IDSL /
Example 
Shell
Title
Programming Notes
Deliverable 
[Priority]
3.18.
Safety
LB1
Summary of Hematology Results Relative to Normal 
Range
SAC [1,2]
Laboratory: Urinalysis
3.19.
Safety
UR3b
Summary of Urinalysis (Glucose, protein, urinary 
sediment,) Data
SAC [1,2]
3.20.
Safety
LB1
Summary of Urinalysis (β2-microglobulin, β2-
microglobulin-creatinine ratio, %TRP, creatinine, 
electrolyte (P))
Change from baseline is included
SAC [1,2]
3.21.
Safety
LB1
Summary of Urinalysis (β2-microglobulin, electrolyte (P), 
creatinine) with conventional unit
Change from baseline is included
SAC [1,2]
Laboratory: Hepatobiliary (Liver)
3.22.
Safety
LIVER1
Summary of Liver Monitoring/Stopping Event Reporting
SAC [1,2]
3.23.
Safety
MH4
Summary of Medical Conditions for Subjects with Liver 
Stopping Events 
SAC [1,2]
3.24.
Safety
LIVER10
Summary of Hepatobiliary Laboratory Abnormalities
SAC [1,2]
LDTA GSI grade scale
3.25.
Safety
Study specific
Summary of Treatment-Emergent Laboratory 
Abnormalities, LDTA GSI Grading Scale (WEEK 
48/WEEK 96 on Treatment Period)
SAC [1,2]
3.26.
Safety
Study specific
Summary of LDTA GSI Grade 3/4 Treatment-Emergent 
Laboratory Abnormalities (WEEK 48/WEEK 96 on 
Treatment Period)
SAC [1,2]
3.27.
Safety
Study specific
Summary of Treatment-Emergent Marked Laboratory 
Abnormalities, LDTA GSI Grading Scale (WEEK 
48/WEEK 96 on Treatment Period)
See Section 11.6.4 safety,
Gilead Science Institute (GSI) 
grading laboratory Data,
Treatment-Emergent Marked 
Abnormalities
SAC [1,2]


CONFIDENTIAL
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75
Safety: Tables
No.
Population
IDSL /
Example 
Shell
Title
Programming Notes
Deliverable 
[Priority]
Hepatic Flare
3.28.
Safety
Study specific
Summary of On-Treatment Hepatic Flare (WEEK 
48/WEEK 96 on Treatment Period)
SAC [1,2]
3.29.
Safety
Study specific
Summary of On-Treatment Laboratory Values Relevant to 
on-Treatment Hepatic Flare (WEEK 48/WEEK 96 on 
Treatment Period)
SAC [1,2]


CONFIDENTIAL
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76
Safety: Tables
No.
Population
IDSL /
Example 
Shell
Title
Programming Notes
Deliverable 
[Priority]
Renal Parameters
3.30.
Safety
Study specific
Summary of Confirmed Changes in Renal Parameters 
(WEEK 48/WEEK 96 on treatment period)
SAC [1,2]
GSI Modified NIAID
3.31.
Safety
Study specific
Summary of Treatment-Emergent Laboratory 
Abnormalities, GSI Modified NIAID (WEEK 48/WEEK 
96 on Treatment Period)
SAC [1,2]
3.32.
Safety
Study specific
Summary of GSI Modified NIAID Grade 3/4 Treatment-
Emergent Laboratory Abnormalities (WEEK 48/WEEK 
96 on Treatment Period)
SAC [1,2]
3.33.
Safety
Study specific
Summary of Treatment-Emergent Marked Laboratory 
Abnormalities, GSI Modified NIAID (WEEK 48/WEEK 
96 on Treatment Period)
See Section 11.6.4 safety,
Gilead Science Institute (GSI) 
grading laboratory Data,
Treatment-Emergent Marked 
Abnormalities
SAC [1,2]
ECG
3.34.
Safety
EG1
Summary of ECG Findings 
SAC [1,2]
3.35.
Safety
EG2
Summary of ECG Values
SAC [1,2]
3.36.
Safety
EG2
Summary of Change from Baseline in ECG Values
SAC [1,2]
Vital Signs
3.37.
Safety
VS1
Summary of Vital Signs
SAC [1,2]
3.38.
Safety
VS1
Summary of Change from Baseline in Vital Signs
SAC [1,2]
Others
3.39.
Safety
VS1
Summary of Percent Change from Baseline in Bone 
Density (DEXA method: %) by position
SAC [1,2]


CONFIDENTIAL
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77
Safety: Tables
No.
Population
IDSL /
Example 
Shell
Title
Programming Notes
Deliverable 
[Priority]
3.40.
Safety
VS1
Summary of Bone Density (DEXA method: absolute) by 
position
Change from baseline is included.
SAC [1,2]


CONFIDENTIAL
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11.12.8.
Safety Figures
Safety: Figures
No.
Population
IDSL / 
Example 
Shell
Title
Programming Notes
Deliverable 
[Priority]
Laboratory: Chemistry
3.1.
Safety
Study specific
Creatinine by Study Visit: Mean (SD) Plots
SD plots
SAC [1,2]
3.2.
Safety
Study specific
Creatinine Change from Baseline by Study Visit: Mean
(SD) Plots
SD plots
SAC [1,2]
3.3.
Safety
Study specific
eGFR by Study Visit: Mean (SD) Plots
SD plots
SAC [1,2]
3.4.
Safety
Study specific
eGFR Change from Baseline by Study Visit: Mean (SD)
Plots
SD plots
SAC [1,2]
3.5.
Safety
Study specific
Creatinine (Conventional unit) by Study Visit: Mean (SD)
Plots
SD plots
SAC [1,2]
3.6.
Safety
Study specific
Creatinine (Conventional unit) Change from Baseline with 
conventional unit by Study Visit: Mean (SD) Plots
SD plots
SAC [1,2]
3.7.
Safety
Study specific
eGFR (Conventional unit) by Study Visit: Mean (SD)
Plots
SD plots
SAC [1,2]
3.8.
Safety
Study specific
eGFR (Conventional unit) Change from Baseline by 
Study Visit: Mean (SD) Plots
SD plots
SAC [1,2]
Laboratory: Other
3.9.
Safety
Study specific
Bone Density (DEXA method, absolute) by position: 
Mean (SD) Plots for change from baseline
DEXA method SD plots
SAC [1,2]
3.10.
Safety
Study specific
Bone Density (DEXA method, %) by position: Mean (SD) 
Plots for %change from baseline
DEXA method SD plots
SAC [1,2]


CONFIDENTIAL
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79
11.12.9.
Exploratory Statistical Analysis Tables
Exploratory Statistical Analysis Tables
No.
Population
IDSL / 
Example 
Shell
Title
Programming Notes
Deliverable 
[Priority]
HBsAg Responder/Non-Responder
4.1.
FAS
Study specific
Frequency of HBsAg Responder/Non-responder with 
ALT category (<60 IU/L, >=60IU/L) at WEEK 48
SAC [1]
4.2.
FAS
Study specific
Frequency of HBsAg Responder/Non-responder with 
ALT category (Conventional unit) (<60 U/L, >=60U/L) at 
WEEK 48
SAC [1]
HBsAg Responder/Non-Responder: HBsAg
4.3.
FAS
Study specific
Summary of log10 HBsAg during Study Visit up to 
WEEK 48/WEEK 96 by HBsAg Responder / Non-
responder (FAS)
Change from baseline is included
SAC [1,2]
4.4.
FAS
Study specific
Summary of log10 HBsAg (Conventional unit) during 
Study Visit up to WEEK 48/WEEK 96 by HBsAg 
Responder / Non-responder (FAS)
Change from baseline is included
SAC [1,2]
HBsAg Responder/Non-Responder: Other Efficacy
4.5.
FAS
Study specific
Summary of HBcrAg during Study Visit up to WEEK 
48/WEEK 96 by HBsAg Responder / Non-responder 
(FAS)
Change from baseline is included
SAC [1,2]
4.6.
FAS
Study specific
Summary of HBV-DNA during Study Visit up to WEEK 
48/WEEK 96 by HBsAg Responder / Non-responder 
(FAS)
Change from baseline is included
SAC [1,2]
4.7.
FAS
Study specific
Summary of ALT during Study Visit up to WEEK 
48/WEEK 96 by HBsAg Responder / Non-responder 
(FAS)
Change from baseline is included
SAC [1,2]
4.8.
FAS
Study specific
Summary of ALT category (<60 IU/L, >=60 IU/L) during 
Study Visit up to WEEK 48/WEEK 96 by HBsAg 
Responder / Non-responder (FAS)
SAC [1,2]


CONFIDENTIAL
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80
Exploratory Statistical Analysis Tables
No.
Population
IDSL / 
Example 
Shell
Title
Programming Notes
Deliverable 
[Priority]
4.9.
FAS
Study specific
Summary of log10 HBeAg during Study Visit up to 
WEEK 48/WEEK 96 by HBsAg Responder / Non-
responder (FAS)
Change from baseline is included
SAC [1,2]
4.10.
FAS
Study specific
Summary of HBcrAg (Conventional unit) during Study 
Visit up to WEEK 48/WEEK 96 by HBsAg Responder / 
Non-responder (FAS)
Change from baseline is included
SAC [1,2]
4.11.
FAS
Study specific
Summary of ALT (Conventional unit) during Study Visit 
up to WEEK 48/WEEK 96 by HBsAg Responder / Non-
responder (FAS)
Change from baseline is included
SAC [1,2]
4.12.
FAS
Study specific
Summary of ALT category (Conventional unit) (<60 U/L, 
>=60 U/L) during Study Visit up to WEEK 48/WEEK 96 
by HBsAg Responder / Non-responder (FAS)
SAC [1,2]
ALT Category (<60 IU/L, >=60 IU/L): HBsAg
4.13.
FAS
Study specific
Summary of log10 HBsAg during Study Visit up to 
WEEK 48/WEEK 96 by ALT Category (<60IU/L, 
>=60IU/L) (FAS)
Change from baseline is included
SAC [1,2]
4.14.
FAS
Study specific
Summary of log10 HBsAg (Conventional unit) during 
Study Visit up to WEEK 48/WEEK 96 by ALT Category 
(Conventional unit) (<60U/L, >=60U/L) (FAS)
Change from baseline is included
SAC [1,2]
ALT Category (<60 IU/L, >=60 IU/L): Other Efficacy
4.15.
FAS
Study specific
Summary of HBcrAg during Study Visit up to WEEK 
48/WEEK 96 by ALT Category (<60 IU/L, >=60I U/L) 
(FAS)
Change from baseline is included
SAC [1,2]
4.16.
FAS
Study specific
Summary HBV-DNA during Study Visit up to WEEK 
48/WEEK 96 by ALT Category (<60 IU/L, >=60 IU/L) 
(FAS)
Change from baseline is included
SAC [1,2]
4.17.
FAS
Study specific
Summary of ALT during Study Visit up to WEEK 
48/WEEK 96 by ALT Category (<60 IU/L, >=60 IU/L) 
(FAS)
Change from baseline is included
SAC [1,2]


CONFIDENTIAL
205883
81
Exploratory Statistical Analysis Tables
No.
Population
IDSL / 
Example 
Shell
Title
Programming Notes
Deliverable 
[Priority]
4.18.
FAS
Study specific
Summary of log10 HBeAg during Study Visit up to 
WEEK 48/WEEK 96 by ALT Category (<60 IU/L, >=60 
IU/L) (FAS)
Change from baseline is included
SAC [1,2]
ALT Category (<60 U/L, >=60 U/L): Other Efficacy
4.19.
FAS
Study specific
Summary of HBcrAg (Conventional unit) during Study 
Visit up to WEEK 48/WEEK 96 by ALT Category 
(Conventional unit) (<60 U/L, >=60 U/L) (FAS)
Change from baseline is included
SAC [1,2]
4.20.
FAS
Study specific
Summary HBV-DNA during Study Visit up to WEEK 
48/WEEK 96 by ALT Category (Conventional unit) (<60 
U/L, >=60 U/L) (FAS)
Change from baseline is included
SAC [1,2]
4.21.
FAS
Study specific
Summary of ALT (Conventional unit) during Study Visit 
up to WEEK 48/WEEK 96 by ALT Category 
(Conventional unit) (<60 U/L, >=60 U/L) (FAS)
Change from baseline is included
SAC [1,2]
4.22.
FAS
Study specific
Summary of log10 HBeAg during Study Visit up to 
WEEK 48/WEEK 96 by ALT Category (Conventional 
unit) (<60 U/L, >=60 U/L) (FAS)
Change from baseline is included
SAC [1,2]
Background of HBsAg Responder/ Non-Responder: Demographic and Baseline Characteristics
4.23.
FAS
DM1
Summary of Demographic Characteristics by HBsAg 
Responder / Non-responder (FAS) 
SAC [1]
4.24.
FAS
Study specific
Summary of Other Baseline Characteristics by HBsAg 
Responder / Non-responder (FAS)
SAC [1]
Background of HBsAg Responder/ Non-Responder: Medical Conditions and Concomitant Medications
4.25.
FAS
MH4
Summary of Prior Medical Conditions by HBsAg 
Responder / Non-responder (FAS)
SAC [1]
4.26.
FAS
CM1
Summary of Concomitant Medications by HBsAg 
Responder / Non-responder (FAS)
SAC [1]
Background of HBsAg Responder/ Non-Responder: Exposure and Treatment Compliance
4.27.
FAS
Study specific
Summary of Treatment Compliance by HBsAg 
Responder / Non-responder (FAS)
SAC [1]


CONFIDENTIAL
205883
82
Exploratory Statistical Analysis Tables
No.
Population
IDSL / 
Example 
Shell
Title
Programming Notes
Deliverable 
[Priority]
4.28.
FAS
EX1
Duration of Exposure to Study Drug by HBsAg 
Responder / Non-responder(FAS)
SAC [1]
Safety Subgroup Analysis
4.29.
Safety
Study specific
Summary of eGFR by Subgroup (SP)
AGE category (<40, 40-49, 50-59, 
60-), eGFR baseline category (<1, 
1<= - <1.5, >=1.5), Weight 
baseline category (<50 kg, >=50 
kg), Sex (male, female) 
SAC [1,2]
4.30.
Safety
Study specific
Summary of Beta2-microglobulin-creatinine ratio by 
Subgroup (SP)
AGE category (<40, 40-49, 50-59, 
60-), eGFR baseline category (<1, 
1<= - <1.5, >=1.5), Weight 
baseline category (<50 kg, >=50 
kg), Sex (male, female) 
SAC [1,2]
4.31.
Safety
Study specific
Summary of %TRP by Subgroup (SP)
AGE category (<40, 40-49, 50-59, 
60-), eGFR baseline category (<1, 
<=1- <1.5, >=1.5), Weight baseline 
category (<50 kg, >=50 kg), Sex 
(male, female) 
SAC [1,2]
4.32.
Safety
Study specific
Summary of Serum Creatine by Subgroup (SP)
AGE category (<40, 40-49, 50-59, 
60-), eGFR baseline category (<1, 
1<= - <1.5, >=1.5), Weight 
baseline category (<50 kg, >=50 
kg), Sex (male, female) 
SAC [1,2]
4.33.
Safety
Study specific
Summary of Serum Phosphorus by Subgroup (SP)
AGE category (<40, 40-49, 50-59, 
60-), eGFR baseline category (<1, 
1<= - <1.5, >=1.5), Weight 
baseline category (<50 kg, >=50 
kg), Sex (male, female) 
SAC [1,2]


CONFIDENTIAL
205883
83
Exploratory Statistical Analysis Tables
No.
Population
IDSL / 
Example 
Shell
Title
Programming Notes
Deliverable 
[Priority]
4.34.
Safety
Study specific
Summary of Bone density(absolute) by Subgroup (SP)
Change from baseline is included.
AGE category (<40, 40-49, 50-59, 
60-), eGFR baseline category (<1, 
1<= - <1.5, >=1.5), Weight 
baseline category (<50 kg, >=50 
kg), Sex (male, female) 
SAC [1,2]
4.35.
Safety
Study specific
Summary of Bone density (%change from baseline) by 
Subgroup (SP)
AGE category (<40, 40-49, 50-59, 
60-), eGFR baseline category (<1, 
1<= - <1.5, >=1.5), Weight 
baseline category (<50 kg, >=50 
kg), Sex (male, female) 
SAC [1,2]
4.36.
Safety
Study specific
Summary of eGFR (Conventional unit) by Subgroup (SP)
AGE category (<40, 40-49, 50-59, 
60-), eGFR baseline category (<60, 
60<= - <90, >=90), Weight 
baseline category (<50 kg, >=50 
kg), Sex (male, female) 
SAC [1,2]
4.37.
Safety
Study specific
Summary of Beta2-microglobulin-creatinine ratio by 
Subgroup (SP)
AGE category (<40, 40-49, 50-59, 
60-), eGFR baseline category (<60, 
60<= - <90, >=90), Weight 
baseline category (<50 kg, >=50 
kg), Sex (male, female) 
SAC [1,2]
4.38.
Safety
Study specific
Summary of %TRP by Subgroup (SP)
AGE category (<40, 40-49, 50-59, 
60-), eGFR baseline category (<60, 
60 <= - <90 >=90), Weight 
baseline category (<50 kg, >=50 
kg), Sex (male, female) 
SAC [1,2]
4.39.
Safety
Study specific
Summary of Serum Creatine (Conventional unit) by 
Subgroup (SP)
AGE category (<40, 40-49, 50-59, 
60-), eGFR baseline category (<60, 
60<= - <90, >=90), Weight 
baseline category (<50 kg, >=50 
kg), Sex (male, female) 
SAC [1,2]


CONFIDENTIAL
205883
84
Exploratory Statistical Analysis Tables
No.
Population
IDSL / 
Example 
Shell
Title
Programming Notes
Deliverable 
[Priority]
4.40.
Safety
Study specific
Summary of Serum Phosphorous (Conventional unit) by 
Subgroup (SP)
AGE category (<40, 40-49, 50-59, 
60-), eGFR baseline category (<60, 
60<= - <90, >=90), Weight 
baseline category (<50 kg, >=50 
kg), Sex (male, female) 
SAC [1,2]
4.41.
Safety
Study specific
Summary of Bone density(absolute) by Subgroup (SP)
Change from baseline is included.
AGE category (<40, 40-49, 50-59, 
60-), eGFR baseline category (<60, 
60<= - <90, >=90), Weight 
baseline category (<50 kg, >=50 
kg), Sex (male, female)
SAC [1,2]
4.42.
Safety
Study specific
Summary of Bone density (%change from baseline) by 
Subgroup (SP)
AGE category (<40, 40-49, 50-59, 
60-), eGFR baseline category (<60, 
60<= - <90, >=90), Weight 
baseline category (<50 kg, >=50 
kg), Sex (male, female) 
SAC [1,2]


CONFIDENTIAL
205883
85
11.12.10. Exploratory Statistical Analysis Figures
Exploratory Statistical Analysis Figures
No.
Population
IDSL / 
Example 
Shell
Title
Programming Notes
Deliverable 
[Priority]
HBsAg Responder/Non-Responder: HBsAg
4.1.
FAS
Study 
specific
Log10 HBsAg during Study Visit up to WEEK 
48/WEEK 96 by HBsAg Responder / Non-responder: 
Mean (SD) Plots (FAS)
SD plot
SAC [1,2]
4.2.
FAS
Study 
specific
Log10 HBsAg Change from Baseline during Study Visit 
up to WEEK 48/WEEK 96 by HBsAg Responder / Non-
responder: Mean (SD) Plots (FAS)
SD plot
SAC [1,2]
4.3.
FAS
Study 
specific
Log10 HBsAg Change from Baseline during Study Visit 
up to WEEK 48/WEEK 96 by HBsAg Responder / Non-
responder: Individual Plots (FAS)
SAC [1,2]
HBsAg Responder/Non-Responder: HBsAg (Conventional unit)
4.4.
FAS
Study 
specific
Log10 HBsAg (Conventional unit) during Study Visit up 
to WEEK 48/WEEK 96 by HBsAg Responder / Non-
responder: Mean (SD) Plots (FAS)
SD plot
SAC [1,2]
4.5.
FAS
Study 
specific
Log10 HBsAg (Conventional unit) Change from Baseline 
during Study Visit up to WEEK 48/WEEK 96 by HBsAg 
Responder / Non-responder: Mean (SD) Plots (FAS)
SD plot
SAC [1,2]
4.6.
FAS
Study 
specific
Log10 HBsAg (Conventional unit) Change from Baseline 
during Study Visit up to WEEK 48/WEEK 96 by HBsAg 
Responder / Non-responder: Individual Plots (FAS)
SAC [1,2]
HBsAg Responder/Non-Responder: Other Efficacy
4.7.
FAS
Study 
specific
HBcrAg during Study Visit up to WEEK 48/WEEK 96 
by HBsAg Responder / Non-responder: Mean (SD) Plots 
(FAS)
SD plot
SAC [1,2]
4.8.
FAS
Study 
specific
HBcrAg Change from Baseline during Study Visit up to 
WEEK 48 /WEEK 96 by HBsAg Responder / Non-
responder: Mean (SD) Plots (FAS)
SD plot
SAC [1,2]


CONFIDENTIAL
205883
86
Exploratory Statistical Analysis Figures
No.
Population
IDSL / 
Example 
Shell
Title
Programming Notes
Deliverable 
[Priority]
4.9.
FAS
Study 
specific
HBV-DNA during Study Visit up to WEEK 48/WEEK 
96 by HBsAg Responder / Non-responder: Mean (SD) 
Plots (FAS)
SD plot
SAC [1,2]
4.10.
FAS
Study 
specific
HBV-DNA Change from Baseline during Study Visit up 
to WEEK 48/WEEK 96 by HBsAg Responder / Non-
responder: Mean (SD) Plots (FAS)
SD plot
SAC [1,2]
4.11.
FAS
Study 
specific
ALT during Study Visit up to WEEK 48/WEEK 96 by 
HBsAg Responder / Non-responder, Mean (SD) Plots 
(FAS)
SD plot
SAC [1,2]
4.12.
FAS
Study 
specific
ALT Change from Baseline during Study Visit up to 
WEEK 48/WEEK 96 by HBsAg Responder / Non-
responder: Mean (SD) Plots (FAS)
SD plot
SAC [1,2]
4.13.
FAS
Study 
specific
Log10 HBeAg during Study Visit up to WEEK 
48/WEEK 96 by HBsAg Responder / Non-responder; 
Mean (SD) Plots (FAS)
SD plot
SAC [1,2]
4.14.
FAS
Study 
specific
Log10 HBeAg Change from Baseline during Study Visit 
up to WEEK 48/WEEK 96 by HBsAg Responder / Non-
responder: Mean (SD) Plots (FAS)
SD plot
SAC [1,2]
HBsAg Responder/Non-Responder: Other Efficacy (Conventional unit)
4.15.
FAS
Study 
specific
HBcrAg (Conventional unit) during Study Visit up to 
WEEK 48/WEEK 96 by HBsAg Responder / Non-
responder: Mean (SD) Plots (FAS)
SD plot
SAC [1,2]
4.16.
FAS
Study 
specific
HBcrAg (Conventional unit) Change from Baseline 
during Study Visit up to WEEK 48 /WEEK 96 by HBsAg
Responder / Non-responder: Mean (SD) Plots (FAS)
SD plot
SAC [1,2]
4.17.
FAS
Study 
specific
ALT (Conventional unit) during Study Visit up to WEEK 
48/WEEK 96 by HBsAg Responder / Non-responder, 
Mean (SD) Plots (FAS)
SD plot
SAC [1,2]


CONFIDENTIAL
205883
87
Exploratory Statistical Analysis Figures
No.
Population
IDSL / 
Example 
Shell
Title
Programming Notes
Deliverable 
[Priority]
4.18.
FAS
Study 
specific
ALT (Conventional unit) Change from Baseline during 
Study Visit up to WEEK 48/WEEK 96 by HBsAg 
Responder / Non-responder: Mean (SD) Plots (FAS)
SD plot
SAC [1,2]
ALT Category (<60 IU/L, >=60 IU/L): HBsAg
4.19.
FAS
Study 
specific
Log10 HBsAg during Study Visit up to WEEK 
48/WEEK 96 by ALT Category (<60 IU/L, >=60 IU/L): 
Mean (SD) Plots (FAS)
SD plot
SAC [1,2]
4.20.
FAS
Study 
specific
Log10 HBsAg Change from Baseline during Study Visit 
up to WEEK 48/WEEK 96 by ALT Category (<60 IU/L, 
>=60 IU/L): Mean (SD) Plots (FAS)
SD plot
SAC [1,2]
ALT Category (<60 U/L, >=60 U/L): HBsAg (Conventional unit)
4.21.
FAS
Study 
specific
Log10 HBsAg (Conventional unit) during Study Visit up 
to WEEK 48/WEEK 96 by ALT Category (Conventional 
unit) (<60 U/L, >=60 U/L): Mean (SD) Plots (FAS)
SD plot
SAC [1,2]
4.22.
FAS
Study 
specific
Log10 HBsAg (Conventional unit) Change from Baseline 
during Study Visit up to WEEK 48/WEEK 96 by ALT 
Category (Conventional unit) (<60 U/L, >=60 U/L): 
Mean (SD) Plots (FAS)
SD plot
SAC [1,2]
ALT Category (<60 IU/L, >=60 IU/L): Other Efficacy
4.23.
FAS
Study 
specific
HBcrAg during Study Visit up to WEEK 48/WEEK 96 
by ALT Category (<60 IU/L, >=60 IU/L): Mean (SD) 
Plots (FAS)
SD plot
SAC [1,2]
4.24.
FAS
Study 
specific
HBcrAg Change from Baseline during Study Visit up to
WEEK 48/WEEK 96 by ALT Category (<60 IU/L, >=60 
IU/L): Mean (SD) Plots (FAS)
SD plot
SAC [1,2]
4.25.
FAS
Study 
specific
HBV-DNA during Study Visit up to WEEK 48/WEEK 
96 by ALT Category (<60 IU/L, >=60 IU/L): Mean (SD) 
Plots (FAS)
SD plot
SAC [1,2]


CONFIDENTIAL
205883
88
Exploratory Statistical Analysis Figures
No.
Population
IDSL / 
Example 
Shell
Title
Programming Notes
Deliverable 
[Priority]
4.26.
FAS
Study 
specific
HBV-DNA Change from Baseline during Study Visit up 
to WEEK 48/WEEK 96 by ALT Category (<60 IU/L, 
>=60 IU/L): Mean (SD) Plots (FAS)
SD plot
SAC [1,2]
4.27.
FAS
Study 
specific
ALT during Study Visit up to WEEK 48/WEEK 96 by 
ALT Category (<60 IU/L, >=60 IU/L): Mean (SD) Plots 
(FAS)
SD plot
SAC [1,2]
4.28.
FAS
Study 
specific
ALT Change from Baseline during Study Visit up to 
WEEK 48/WEEK 96 by ALT Category (<60 IU/L, >=60 
IU/L): Mean (SD) Plots (FAS)
SD plot
SAC [1,2]
4.29.
FAS
Study 
specific
Log10 HBeAg during Study Visit up to WEEK 
48/WEEK 96 by ALT Category (<60 IU/L, >=60 IU/L): 
Mean (SD) Plots (FAS)
SD plot
SAC [1,2]
4.30.
FAS
Study 
specific
Log10 HBeAg Change from Baseline during Study Visit 
up to WEEK 48/WEEK 96 by ALT Category (<60 IU/L, 
>=60 IU/L): Mean (SD) Plots (FAS)
SD plot
SAC [1,2]
ALT Category (<60 U/L, >=60 U/L): Other Efficacy (Conventional unit)
4.31.
FAS
Study 
specific
HBcrAg (Conventional unit) during Study Visit up to 
WEEK 48/WEEK 96 by ALT Category (Conventional 
unit) (<60 U/L, >=60 U/L): Mean (SD) Plots (FAS)
SD plot
SAC [1,2]
4.32.
FAS
Study 
specific
HBcrAg (Conventional unit) Change from Baseline 
during Study Visit up to WEEK 48/WEEK 96 by ALT 
Category (Conventional unit) (<60 U/L, >=60 U/L): 
Mean (SD) Plots (FAS)
SD plot
SAC [1,2]
4.33.
FAS
Study 
specific
HBV-DNA during Study Visit up to WEEK 48/WEEK 
96 by ALT Category (Conventional unit) (<60 U/L, >=60 
U/L): Mean (SD) Plots (FAS)
SD plot
SAC [1,2]
4.34.
FAS
Study 
specific
HBV-DNA Change from Baseline during Study Visit up 
to WEEK 48/WEEK 96 by ALT Category (Conventional 
unit) (<60 U/L, >=60 U/L): Mean (SD) Plots (FAS)
SD plot
SAC [1,2]


CONFIDENTIAL
205883
89
Exploratory Statistical Analysis Figures
No.
Population
IDSL / 
Example 
Shell
Title
Programming Notes
Deliverable 
[Priority]
4.35.
FAS
Study 
specific
ALT (Conventional unit) during Study Visit up to WEEK 
48/WEEK 96 by ALT Category (Conventional unit) (<60 
U/L, >=60 U/L): Mean (SD) Plots (FAS)
SD plot
SAC [1,2]
4.36.
FAS
Study 
specific
ALT (Conventional unit) Change from Baseline during 
Study Visit up to WEEK 48/WEEK 96 by ALT Category 
(Conventional unit) (<60 U/L, >=60 U/L): Mean (SD) 
Plots (FAS)
SD plot
SAC [1,2]
4.37.
FAS
Study 
specific
Log10 HBeAg during Study Visit up to WEEK 
48/WEEK 96 by ALT Category (Conventional unit) (<60 
U/L, >=60 U/L): Mean (SD) Plots (FAS)
SD plot
SAC [1,2]
4.38.
FAS
Study 
specific
Log10 HBeAg Change from Baseline during Study Visit 
up to WEEK 48/WEEK 96 by ALT Category 
(Conventional unit) (<60 U/L, >=60 U/L): Mean (SD) 
Plots (FAS)
SD plot
SAC [1,2]
Correlation of virus parameters
4.39.
FAS
Study 
specific
Log10 HBsAg Change from Baseline vs ALT Change 
from Baseline at WEEK24/WEEK 48/WEEK 96 (FAS)
X axis:Log10 HBsAg Change from 
Baseline
SAC [1,2]
4.40.
FAS
Study 
specific
Log10 HBsAg Change from Baseline vs HBcrAg 
Baseline at WEEK24/WEEK 48/WEEK 96 (FAS)
X axis:Log10 HBsAg Change from 
Baseline
SAC [1,2]
4.41.
FAS
Study 
specific
Log10 HBsAg Change from Baseline vs HBcrAg Change 
from Baseline at WEEK24/WEEK 48/WEEK 96 (FAS)
X axis:Log10 HBsAg Change from 
Baseline
SAC [1,2]
4.42.
FAS
Study 
specific
Log10 HBsAg Change from Baseline vs log10 HBeAg 
Baseline at WEEK24/WEEK 48/WEEK 96 (FAS)
X axis:Log10 HBsAg Change from 
Baseline
SAC [1,2]
4.43.
FAS
Study 
specific
Log10 HBsAg Change from Baseline vs log10 HBeAg 
Change from Baseline at WEEK24/WEEK 48/WEEK 96 
(FAS)
X axis:Log10 HBsAg Change from 
Baseline
SAC [1,2]


CONFIDENTIAL
205883
90
Exploratory Statistical Analysis Figures
No.
Population
IDSL / 
Example 
Shell
Title
Programming Notes
Deliverable 
[Priority]
Correlation of virus parameters (Conventional unit)
4.44.
FAS
Study 
specific
Log10 HBsAg (Conventional unit) Change from Baseline 
vs ALT (Conventional unit) Change from Baseline at 
WEEK24/WEEK 48/WEEK 96 (FAS)
X axis:Log10 HBsAg 
(Conventional unit) Change from 
Baseline
SAC [1,2]
4.45.
FAS
Study 
specific
Log10 HBsAg (Conventional unit) Change from Baseline 
vs HBcrAg (Conventional unit) Baseline at 
WEEK24/WEEK 48/WEEK 96 (FAS)
X axis:Log10 HBsAg 
(Conventional unit) Change from 
Baseline
SAC [1,2]
4.46.
FAS
Study 
specific
Log10 HBsAg (Conventional unit) Change from Baseline 
vs HBcrAg (Conventional unit) Change from Baseline at 
WEEK24/WEEK 48/WEEK 96 (FAS)
X axis:Log10 HBsAg 
(Conventional unit) Change from 
Baseline
SAC [1,2]
4.47.
FAS
Study 
specific
Log10 HBsAg (Conventional unit) Change from Baseline 
vs log10 HBeAg Baseline at WEEK24/WEEK 48/WEEK 
96 (FAS)
X axis:Log10 HBsAg 
(Conventional unit) Change from 
Baseline
SAC [1,2]
4.48.
FAS
Study 
specific
Log10 HBsAg (Conventional unit) Change from Baseline 
vs log10 HBeAg Change from Baseline at 
WEEK24/WEEK 48/WEEK 96 (FAS)
X axis:Log10 HBsAg 
(Conventional unit) Change from 
Baseline
SAC [1,2]


CONFIDENTIAL
205883
91
11.12.11. ICH Listings
ICH: Listings
No.
Population
IDSL / 
Example 
Shell
Title
Programming Notes
Deliverable 
[Priority]
Subject Disposition
1.
Screened
ES7
Listing of Reasons for Screen Failure
SAC [1,2]
2.
Safety 
ES2 
Listing of Reasons for Study Withdrawal
SAC [1,2]
3.
Safety 
SD2
Listing of Reasons for Study Treatment Discontinuation
SAC [1,2]
Protocol Deviations
4.
Safety 
DV2
Listing of Important Protocol Deviations 
SAC [1,2]
5.
Screened
IE3
Listing of Participants with Inclusion/Exclusion Criteria 
Deviations
SAC [1,2]
Populations Analysed
6.
Safety 
SP3
Listing of Subjects Excluded from EES Population (48W)
SAC [1]
Demographic and Baseline Characteristics
7.
Safety 
DM2
Listing of Demographic Characteristic
“Age at Screening” is added.
SAC [1,2]
8.
Screening 
Failure
DM2
Listing of Demographic Characteristics for Screening 
Failure Subjects
SAC [1]
9.
Safety 
DM9
Listing of Race
SAC [1,2]
10.
Screening 
Failure
DM9
Listing of Race for Screening Failure Subjects
Treatment is not needed to display.
SAC [1]
11.
Safety 
Study 
specific
Listing of Other Baseline Characteristics
SAC [1,2]


CONFIDENTIAL
205883
92
ICH: Listings
No.
Population
IDSL / 
Example 
Shell
Title
Programming Notes
Deliverable 
[Priority]
Medical Conditions and Concomitant Medications
12.
Safety
MH2
Listing of Medical Conditions (48W/96W)
SAC [1,2]
13.
Safety
CM3
Listing of Prior Hepatitis Medications
SAC [1]
14.
Safety 
CM3
Listing of Concomitant Medications (48W/96W)
SAC [1,2]
Exposure and Treatment Compliance
15.
Safety 
Study 
specific
Listing of Treatment Compliance (48W/96W)
SAC [1,2]
16.
Safety 
EX3
Listing of Exposure Data (48W/96W)
SAC [1,2]
Efficacy: HBsAg
17.
FAS 
Study 
specific
Listing of Efficacy Data (HBsAg Responder)
Log10 HBsAg Change from 
Baseline is included.
SAC [1,2]
18.
FAS
Study 
specific
Listing of Efficacy Data (log10 HBsAg)
Change from Baseline is included.
SAC [1,2]
19.
FAS 
Study 
specific
Listing of Efficacy Data (HBsAg)
Change from Baseline is included.
SAC [1,2]
20.
FAS 
Study 
specific
Listing of Efficacy Data (log10 HBsAg: Conventional 
unit)
Change from Baseline is included.
SAC [1,2]
21.
FAS 
Study 
specific
Listing of Efficacy Data (HBsAg: Conventional unit)
Change from Baseline is included.
SAC [1,2]
Efficacy: Seroconversion
22.
FAS 
Study 
specific
Listing of Efficacy Data (HBsAg)
Include POS/NEG data. 
SAC [1,2]


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ICH: Listings
No.
Population
IDSL / 
Example 
Shell
Title
Programming Notes
Deliverable 
[Priority]
23.
FAS 
Study 
specific
Listing of Efficacy Data (HBsAb)
SAC [1,2]
24.
FAS 
Study 
specific
Listing of Efficacy Data (HBeAg)
Include POS/NEG data
log 10 HBeAg is included
SAC [1,2]
25.
FAS 
Study 
specific
Listing of Efficacy Data (HBeAb)
SAC [1,2]
Efficacy: Virology
26.
FAS 
Study 
specific
Listing of Efficacy Data (HBcrAg)
Change from Baseline is included.
SAC [1,2]
27.
FAS 
Study 
specific
Listing of Efficacy Data (HBV-DNA)
log10 HBV-DNA data, log10 
HBV-DNA Change from Baseline 
is included.
SAC [1,2]
28.
FAS
Study 
Specifics 
Listing of Efficacy Data (Virologic Breakthrough)
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 HBV DNA level has 
increased to ≧2 log IU/mL (100 
IU/mL) in a case with nadir <10 
IU/mL) from Day1 to 
WEEK48/WEEK96.
SAC [1,2]
29.
FAS 
Study 
specific
Listing of Efficacy Data (HBcrAg: Conventional unit)
Change from Baseline is included.
SAC [1,2]
Efficacy: ALT
30.
FAS 
Study 
specific
Listing of Efficacy Data (ALT)
Change from Baseline is included.
SAC [1,2]


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94
ICH: Listings
No.
Population
IDSL / 
Example 
Shell
Title
Programming Notes
Deliverable 
[Priority]
31.
FAS 
Study 
specific
Listing of Efficacy Data (ALT: Conventional unit)
Change from Baseline is included.
SAC [1,2]
Adverse Events
32.
Safety
AE8
Listing of All Adverse Events 
SAC [1,2]
33.
Safety
AE7
Listing of Subject Numbers for Individual Adverse 
Events 
SAC [1,2]
34.
Safety
AE2
Listing of Relationship Between Adverse Event System 
Organ Classes, Preferred Terms, and Verbatim Text
SAC [1,2]
Serious Adverse Events
35.
Safety
AE8
Listing of Serious Adverse Events
SAC [1,2]
36.
Safety
AE8
Listing of Fatal Serious Adverse Events
SAC [1,2]
Other significant Adverse Events
37.
Safety
AE8 
Listing of Other Significant Adverse Events Leading to 
Withdrawal from Study
SAC [1,2]
AE of interest
38.
Safety
AE8
Listing of Renal AE as AE of Interest
SAC [1,2]
39.
Safety
AE8
Listing of Bone Events as AE of Interest
SAC [1,2]
40.
Safety
AE8
Listing of Liver AE as AE of Interest
SAC [1,2]
Clinical Laboratory: Chemistry
41.
Safety
LB5
Listing of All Chemistry Data
Change from Baseline is included.
Corrected calcium based on the 
serum albumin is included.
SAC [1,2]


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ICH: Listings
No.
Population
IDSL / 
Example 
Shell
Title
Programming Notes
Deliverable 
[Priority]
42.
Safety
LB5
Listing of Chemistry Data (ALT, ALP, Creatinine, 
Phosphorus, Glucose, Uric acid, eGFR) with 
conventional unit
Change from baseline is included.
SAC [1,2]
Clinical Laboratory: Hematology
43.
Safety
LB5
Listing of All Hematology Data
Change from Baseline is included.
SAC [1,2]
Clinical Laboratory: Urinalysis
44.
Safety
LB14
Listing of Urinalysis (Glucose, protein, urinary 
sediment,) Data
SAC [1,2]
45.
Safety
UR2A
Listing of Urinalysis (β2-microglobulin, β2-
microglobulin-creatinine ratio, %TRP, creatinine, 
electrolyte (P))
Change from Baseline is included.
SAC [1,2]
46.
Safety
URA2
Listing of Urinalysis (β2-microglobulin, electrolyte (P), 
creatinine) with conventional unit
Change from baseline is included
SAC [1,2]
Hepatobiliary (Liver)
47.
Safety
Liver5
Listing of Liver Monitoring/Stopping Event Reporting
IDSL
SAC [1,2]
48.
Safety
MH2
Listing of Medical Conditions for Participants with Liver 
Stopping Events
IDSL
SAC [1,2]
49.
Safety
Liver13
Listing of Hepatobiliary Laboratory Abnormalities
IDSL
SAC [1,2]
LDTA GSI grade scale 
50.
Safety
LB5
Listing of Treatment-Emergent Laboratory Abnormalities 
(LDTA GSI grade)
Include Marked Laboratory 
Abnormalities
SAC [1,2]
51.
Safety
LB5
Listing of LDTA GSI Grade 3/4 Treatment-Emergent 
Laboratory Abnormalities
SAC [1,2]
52.
Safety
LB5
Listing of All Hematology Data with LDTA GSI Grade
SAC [1,2]


CONFIDENTIAL
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96
ICH: Listings
No.
Population
IDSL / 
Example 
Shell
Title
Programming Notes
Deliverable 
[Priority]
53.
Safety
LB5
Listing of All Chemistry Data with LDTA GSI Grade
SAC [1,2]
Hepatic Flare
54.
Safety
Study 
specific
Listing of on-Treatment Hepatic Flare
SAC [1,2]
55.
Safety
Study 
specific
Listing of On-Treatment Laboratory Values Relevant to 
On-Treatment Hepatic Flare
SAC [1,2]
Renal Parameters
56.
Safety
LB5
Listing of Subjects with Cond Serum Creatinine Increase 
of 0.5 mg/dL Above Baseline (or Last Value on Drug)
SAC [1,2]
57.
Safety
LB5
Listing of Subjects with Confirmed Serum Phosphorus 
<= 2 mg/dL (or Last Value on Drug)
SAC [1,2]
58.
Safety
LB5
Listing of Subjects with Confirmed Creatinine Clearance 
< 50 mL/min (or Last Value on Drug)
SAC [1,2]
GSI Modified NIAID
59.
Safety
Study 
specific
Listing of Treatment-Emergent Laboratory Abnormalities 
(GSI Modified NIAID)
Include Marked Laboratory 
Abnormalities
SAC [1,2]
60.
Safety
Study 
specific
Listing of Grade 3/4 Treatment-Emergent Laboratory 
Abnormalities (GSI Modified NIAID)
SAC [1,2]
61.
Safety
LB5
Listing of All Hematology Data with GSI Modified 
NIAID
SAC [1,2]
62.
Safety
LB5
Listing of All Chemistry Data with GSI Modified NIAID
SAC [1,2]
ECG
63.
Safety 
EG3
Listing of All ECG Values
SAC [1,2]


CONFIDENTIAL
205883
97
ICH: Listings
No.
Population
IDSL / 
Example 
Shell
Title
Programming Notes
Deliverable 
[Priority]
64.
Safety 
EG3
Listing of Change from Baseline in ECG Values
Listing will be divided as 64.1 and 
64.2
SAC [1,2]
65.
Safety 
EG5
Listing of ECG Findings
Listing will be divided as 65.1 and 
65.2
SAC [1,2]
Vital Signs
66.
Safety 
VS4
Listing of All Vital Signs
SAC [1,2]
67.
Safety
VS4
Listing of Change from Baseline in Vital Signs
SAC [1,2]
Others
68.
Safety 
Study 
specific
Listing of All Bone density for %change from Baseline
include all method and position.
SAC [1,2]
69.
Safety 
Study 
specific
Listing of All Bone density (Absolute)
include all method and position.
SAC [1,2]
Explanatory Statistical Analysis
70.
Safety
Study 
specific
Listing of subject numbers for individual HBsAg 
Responder/Non-Responder Category at WEEK 
48/WEEK 96
SAC [1,2]
71.
Safety
Study 
specific
Listing of subject numbers for individual ALT Category 
(<60 IU/L, >=60 IU/L) at WEEK 48/WEEK 96
SAC [1,2]
72.
Safety
Study 
specific
Listing of subject numbers for individual ALT Category 
(Conventional unit) (<60 U/L, >=60 U/L) at WEEK 
48/WEEK 96
SAC [1,2]


CONFIDENTIAL
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98
11.13.
Appendix 13: Example Mock Shells for Data Displays
Mock-up displays will be provided separately.