Conditions: Hepatitis B
Keywords: Chronic Hepatitis B GSK3228836 Pegylated interferon Nucleos(t)ide analogue Sustained virologic response
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 108
Healthy volunteers: no

Brief summary:
This study is intended to evaluate if 12 or 24 weeks of treatment with GSK3228836 followed by up to 24 weeks of pegylated interferon (PegIFN) can increase the rate of hepatitis B virus surface antigen (HBsAg) loss in participants on stable nucleos(t)ide analogue (NA) therapy, and whether virologic response can be sustained once PegIFN treatment is discontinued. Participants will be randomized to receive GSK3228836 for 12 or 24 weeks followed by up to 24 weeks of PegIFN.

Detailed description:

Arms:
arm 1: Participants on stable NA therapy received 300 milligrams per week (mg/week) GSK3228836 for 24 weeks (plus a loading dose on Day 4 and 11), followed by Pegylated Interferon (PegIFN) 180 microgram per week (mcg/week) up to 24 weeks. arm 2: Participants on stable NA therapy received 300mg/week GSK3228836 for 12 weeks (plus a loading dose on Day 4 and 11), followed by PegIFN 180 mcg/week up to 24 weeks.

Interventions: intervention 1: GSK3228836 intervention 2: PegIFN intervention 3: NA therapy
Intervention descriptions: intervention 1: Participants will be administered GSK3228836. intervention 2: Participants will be administered PegIFN. intervention 3: Participants will continue to receive their NA therapy for the duration of the study.

Protocol document:
Prot_000.pdf: 
TMF-13966464 
CONFIDENTIAL 
 
GlaxoSmithKline group of companies 
 
209348 
 
Protocol Amd 01 
 
1 
 
TITLE PAGE 
Protocol Title: A Phase IIb Multi-Center, Randomised, Open Label Study to Assess the 
Efficacy and Safety of Sequential Treatment with GSK3228836 followed by Pegylated 
Interferon Alpha 2a in Participants with Chronic Hepatitis B Virus (B-Together) 
Protocol Number: 209348/ Amendment 01 
 
Compound Number: 
GSK3228836 
Brief Title: Phase IIb Study of Sequential GSK3228836 and Peginterferon Treatment in 
Participants with Chronic Hepatitis B (B-Together) 
Study Phase: Phase IIB 
Acronym: B-Together 
Sponsor Name and Legal Registered Address:  
GlaxoSmithKline Research & Development Limited 
980 Great West Road 
Brentford 
Middlesex, TW8 9GS 
UK 
Regulatory Agency Identifying Number(s):  
EudraCT:  2020-002979-35 
IND: IND 122685 
Approval Date: 24-SEP-2021 
Medical Monitor Name and Contact Information:  
Can be found in the Study Reference Manual (SRM) 
Copyright 2021 the GlaxoSmithKline group of companies. All rights reserved.  
Unauthorised copying or use of this information is prohibited. 
 
 


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SPONSOR SIGNATORY: 
Protocol Title: A Phase IIb Multi-Center, Randomised, Open Label Study to Assess the 
Efficacy and Safety of Sequential Treatment with GSK3228836 followed by Pegylated 
Interferon Alpha 2a in Participants with Chronic Hepatitis B Virus (B-Together) 
Protocol Number: 209348 / Amendment 01 
Compound Number or Name: 
GSK3228836 
 
 
 
 
Dickens Theodore, MD, MPH 
Senior Director, Clinical Development  
Immunology and Fibrosis 
GlaxoSmithKline 
 
Date 
The signed page is a separate document. 
 
 
 
 
Medical Monitor Name and Contact Information can be found in the Study Reference 
Manual. 
 


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PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE 
DOCUMENT HISTORY 
Document 
Date 
Document Number 
Amendment 01 
24-SEP-2021 
TMF-13966464 
Original Protocol 
16-OCT-2020 
2020N427224_00 
 
Amendment 01 24-SEP-2021 
This amendment is considered to be non-substantial based on the criteria set forth in 
Article 10(a) of Directive 2001/20/EC of the European Parliament and the Council of the 
European Union because it neither significantly impacts the safety or physical/mental 
integrity of participants nor the scientific value of the study. 
Overall Rationale for the Amendment:  
The primary drivers for this amendment were non-substantial changes, mostly for 
clarification, alignment with Study 209668, and to incorporate recommendations 
suggested in regulatory feedback. 
In addition, minor typographical errors and inconsistencies have been corrected and 
minor editorial changes have been made. Changes made to the text body have been made 
concurrently in the synopsis. 
Section # and 
Name 
Description of Change 
Brief Rationale 
Section 1.3 
Schedule of 
Activities,  
Table 2, Table 2 
Added thyroxine (T4) to thyroid 
assessments. 
Correction. 
Section 1.3 
Schedule of 
Activities  
tables, as required 
and applicable text 
throughout 
Changed “anti-HBsAb” to “anti-
HBsAg” and “anti-HBeAb” to 
“anti-HBeAg.” 
Correction. 
Section 1.3 
Schedule of 
Activities,  
Table 4, Table 5 
Removed separate bilirubin 
assessment as this is included within 
the chemistry assessments. 
Correction. 
Section 1.3 
Schedule of 
Activities  
tables, as required 
Specified that hepatitis B virus 
e-antigen (HBeAg) assessment is 
only for participants who are HBeAg-
positive at Screening. 
Correction. 


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Section # and 
Name 
Description of Change 
Brief Rationale 
and applicable text 
throughout 
Section 1.3 
Schedule of 
Activities, Table 7 
Added footnote to specify that 
neuropsychiatric assessments 
(Columbia Suicide-Severity Rating 
Scale [C-SSRS] and Beck Depression 
Inventory-II [BDI-II]) only need to be 
completed for participants who 
received at least 1 dose of PegIFN.  
Correction. 
Section 1.3 
Schedule of 
Activities, Table 7 
Added pharmacokinetic (PK) 
assessment at early termination visit 
for PegIFN 
Correction. 
Section 3  
Objectives and 
Estimands and 
where applicable 
throughout 
Updated text defining the population 
for the efficacy objectives to align 
with the definition of intent-to-treat 
(ITT) population which will be used 
in efficacy analyses and is defined as 
all randomized subjects. 
To align with Study 209668 
(B-Clear). 
Section 3  
Objectives and 
Estimands and 
Section 9.4.3.1 
Secondary 
Estimands 
Secondary Efficacy Endpoints:  
moved HBe antibody (anti-HBeAg) 
levels from a continuous variable to a 
categorical variable.  
Correction. 
Section 5.2 
Exclusion Criteria 
Medical Conditions Number 3: 
provide clarity that liver biopsy and 
stiffness are historical measurements. 
Provide clarity to investigators 
that these are for historical 
measurements, if available, not 
to be performed for assessment. 
Section 5.3 
Inclusion and 
Exclusion Criteria 
for PegIFN 
Added text to clarify eligibility 
criteria for patients who meet 
GSK3228836 liver monitoring hold 
or stopping criteria to receive 
treatment with PegIFN.  
Clarification requested per the 
Food and Drug Administration 
(FDA). 
Section 5.3 
Table 8 
Eligibility Criteria 
to start PegIFN 
Added “vii)” before “Ocular Exam.” 
Correction. 
Section 6.1 
Study 
Intervention(s) 
Administered 
Changed the address of 
manufacturer/source of PegIFN 
(Roche). 
Correction. 


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Section # and 
Name 
Description of Change 
Brief Rationale 
Section 7.1.1  
GSK3228836 Liver 
Chemistry Stopping 
Criteria 
Added text: 
Cases such as Gilbert syndrome, 
where baseline bilirubin values are 
high, should be discussed with the 
Medical Monitor, to assess if it is a 
case of drug-induced liver injury 
(DILI) or the participant may 
continue with dosing. 
To clarify and identify 
instances where medical 
monitor should be consulted. 
Section 7.1.1  
GSK3228836 Liver 
Chemistry Stopping 
Criteria 
Clarify that the serum acetaminophen 
adduct high performance liquid 
chromatography (HPLC) assay 
(quantifies potential acetaminophen 
contribution to liver injury in 
participants with definite or likely 
acetaminophen use in the preceding 
week) should be conducted if 
available. 
Serum acetaminophen adduct 
high performance liquid 
chromatography assay may not 
be available in all countries. 
Section 7.1.2 
GSK3228863 
Haematological 
Stopping Criteria 
Added text:  
If the platelet count is uninterpretable 
or a decreasing trend is noted below 
lower limit of normal (LLN) 
reference range, re-check the platelet 
counts as soon as possible (the 
investigator may, at their discretion, 
opt to have the participant come to 
their next scheduled visit OR ask the 
participant to come earlier than their 
scheduled visit, as they feel 
appropriate based on review of the 
participant’s clinical presentation and 
laboratory results). Samples showing 
platelet clumping should also be 
repeated. 
Clarification and to provide 
guidance to investigator. 
Section 7.1.3 
GSK3228836 Drug 
Induced Kidney 
Injury (Renal) 
Stopping Criteria 
Updated GSK3228836 drug induced 
kidney injury (renal) treatment 
hold/treatment discontinuation 
criteria to identify changes in albumin 
to creatinine ratio (ACR) and 
estimated glomerular filtration rate 
(eGFR) relative to the pre-dose range 
instead of baseline.  
Clarification and to provide 
guidance to investigator. 
Section 8.2.7.1 
Columbia Suicide 
Severity Rating 
Scale (C-SSRS) 
Removed timeframe from C-SSRS 
screening questions.  
Correction. 


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Section # and 
Name 
Description of Change 
Brief Rationale 
Section 9.5 
Interim Analysis 
Removed interim analysis 1. 
Interim analysis 1 was 
originally planned to determine 
futility and stop enrolment in 
the study. At the time of this 
protocol amendment, it was no 
longer applicable because 
complete enrolment had already 
occurred.   
Section 10.2 
Appendix 2: 
Clinical Laboratory 
Tests 
Table 17 
Changed SAE reporting bilirubin 
≤2X the upper limit of normal (ULN) 
to >2X ULN. 
Correction, due to typo. 
Section 10.3.5 
Reporting of SAE 
to GSK 
Removed bullet that stated the 
investigator must show evidence 
within the electronic case report form 
(eCRF) of review and verification of 
the relationship of each serious 
adverse event (SAE) to 
investigational product (IP)/study 
participation (causality) within 
72 hours of SAE entry into the eCRF. 
To align with updated protocol 
template. 
Throughout 
Minor editorial and document 
formatting revisions 
Minor; therefore have not been 
summarized 
 
 


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TABLE OF CONTENTS 
PAGE 
1. 
PROTOCOL SUMMARY ........................................................................................ 11 
1.1. 
Synopsis ..................................................................................................... 11 
1.2. 
Schema ...................................................................................................... 17 
1.3. 
Schedule of Activities (SoA) ........................................................................ 18 
2. 
INTRODUCTION .................................................................................................... 31 
2.1. 
Study Rationale .......................................................................................... 31 
2.2. 
Background ................................................................................................ 32 
2.3. 
Benefit/Risk Assessment ............................................................................ 34 
2.3.1. 
Risk Assessment ......................................................................... 35 
2.3.2. 
Benefit Assessment ..................................................................... 40 
2.3.3. 
Overall Benefit: Risk Conclusion .................................................. 40 
3. 
OBJECTIVES AND ESTIMANDS ........................................................................... 41 
4. 
STUDY DESIGN .................................................................................................... 46 
4.1. 
Overall Design ............................................................................................ 46 
4.2. 
Scientific Rationale for Study Design .......................................................... 47 
4.2.1. 
Participant Input into Design ........................................................ 50 
4.3. 
Justification for Dose .................................................................................. 50 
4.4. 
End of Study Definition ............................................................................... 52 
5. 
STUDY POPULATION ........................................................................................... 53 
5.1. 
Inclusion Criteria ......................................................................................... 53 
5.2. 
Exclusion Criteria ........................................................................................ 55 
5.3. 
Inclusion and Exclusion Criteria for PegIFN ................................................ 57 
5.4. 
Lifestyle Considerations .............................................................................. 59 
5.4.1. 
Alcohol and Tobacco ................................................................... 59 
5.4.2. 
Activity ......................................................................................... 59 
5.5. 
Screen Failures........................................................................................... 59 
5.6. 
Criteria for Temporarily Delaying Administration of Study 
Intervention ................................................................................................. 59 
6. 
STUDY INTERVENTION(S) AND CONCOMITANT THERAPY .............................. 59 
6.1. 
Study Intervention(s) Administered ............................................................. 60 
6.2. 
Preparation/Handling/Storage/Accountability .............................................. 61 
6.3. 
Measures to Minimise Bias: Randomisation and Blinding ........................... 61 
6.4. 
Study Intervention Compliance ................................................................... 62 
6.5. 
Dose Modification ....................................................................................... 62 
6.6. 
Study Intervention after the End of the Study .............................................. 62 
6.7. 
Treatment of Overdose ............................................................................... 62 
6.8. 
Concomitant Therapy.................................................................................. 63 
6.8.1. 
Nucleos(t)ide Treatment during and after the End of the 
Study ........................................................................................... 63 
6.8.2. 
Prohibited Medications and Non-Drug Therapies ......................... 63 
7. 
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL ..................................................................... 64 


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7.1. 
GSK3228836 Dose Modification and Stopping Criteria ............................... 64 
7.1.1. 
GSK3228836 Liver Chemistry Stopping Criteria .......................... 64 
7.1.2. 
GSK3228836 Haematological Stopping Criteria........................... 67 
7.1.3. 
GSK3228836 Drug Induced Kidney Injury (Renal) 
Stopping Criteria .......................................................................... 68 
7.1.4. 
GSK3228836-Induced Vascular Inflammation and 
Complement Stopping Criteria ..................................................... 69 
7.2. 
PegIFN Dose Modification and Stopping Criteria ........................................ 70 
7.2.1. 
PegIFN Haematological Dose Modification and 
Discontinuation Guidelines .......................................................... 71 
7.2.2. 
PegIFN ALT Elevation Dose Modification and 
Discontinuation Guidelines .......................................................... 71 
7.2.3. 
Psychiatric Disorder Dose Modification and 
Discontinuation Guidelines .......................................................... 71 
7.3. 
Study Intervention Restart or Rechallenge after stopping criteria met ......... 72 
7.4. 
Participant Discontinuation/Withdrawal from the Study ............................... 73 
7.5. 
Lost to Follow Up ........................................................................................ 74 
8. 
STUDY ASSESSMENTS AND PROCEDURES ..................................................... 74 
8.1. 
Efficacy Assessments ................................................................................. 75 
8.2. 
Safety Assessments ................................................................................... 75 
8.2.1. 
Physical Examinations ................................................................. 75 
8.2.2. 
Ophthalmologic Examination for PegIFN ..................................... 75 
8.2.3. 
Vital Signs .................................................................................... 76 
8.2.4. 
Electrocardiograms ...................................................................... 76 
8.2.5. 
Clinical Safety Laboratory Assessments ...................................... 76 
8.2.6. 
Injection Site Reactions ............................................................... 77 
8.2.7. 
Suicidal Ideation and Behaviour Risk Monitoring ......................... 77 
8.2.7.1. 
Columbia Suicide-Severity Rating Scale (C-
SSRS) ........................................................................ 77 
8.2.7.2. 
Beck Depression Inventory-II (BDI-II) ........................... 77 
8.3. 
Adverse Events (AEs), Serious Adverse Events (SAEs) and Other 
Safety Reporting ......................................................................................... 77 
8.3.1. 
Time Period and Frequency for Collecting AE and SAE 
Information ................................................................................... 78 
8.3.2. 
Method of Detecting AEs and SAEs ............................................. 78 
8.3.3. 
Follow-up of AEs and SAEs ......................................................... 78 
8.3.4. 
Regulatory Reporting Requirements for SAEs ............................. 79 
8.3.5. 
Pregnancy ................................................................................... 79 
8.3.6. 
Cardiovascular and Death Events ................................................ 79 
8.3.7. 
GSK3228836-Related Adverse Events of Special Interest ........... 80 
8.3.7.1. 
ALT Increases .............................................................. 80 
8.3.7.2. 
Vascular Inflammation and Complement 
Activation .................................................................... 80 
8.3.7.3. 
Thrombocytopenia ....................................................... 80 
8.3.7.4. 
Renal Injury .................................................................. 80 
8.3.7.5. 
Injection Site Reactions ................................................ 81 
8.4. 
Genetics ..................................................................................................... 81 
8.5. 
Pharmacokinetics ....................................................................................... 81 
8.6. 
Biomarkers ................................................................................................. 81 
8.7. 
Resistance Monitoring ................................................................................ 82 
8.8. 
Independent Data Monitoring Committee .................................................... 83 


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8.9. 
Internal Safety Review Team (SRT) ............................................................ 83 
8.10. 
Medical Resource Utilisation and Health Economics .................................. 83 
9. 
STATISTICAL CONSIDERATIONS ........................................................................ 83 
9.1. 
Statistical Hypotheses................................................................................. 83 
9.2. 
Sample Size Determination ........................................................................ 84 
9.3. 
Analysis Sets .............................................................................................. 86 
9.4. 
Statistical Analyses ..................................................................................... 86 
9.4.1. 
General Considerations ............................................................... 86 
9.4.2. 
Primary Objective ........................................................................ 86 
9.4.2.1. 
Main Estimands............................................................ 87 
9.4.2.2. 
Supplementary Estimands ........................................... 87 
9.4.2.3. 
Handling of Withdrawal from Study and Missing 
HBsAg and HBV DNA Data ........................................ 89 
9.4.2.4. 
Primary Analyses ......................................................... 89 
9.4.3. 
Secondary Endpoints ................................................................... 90 
9.4.3.1. 
Secondary Estimands .................................................. 90 
9.4.3.2. 
Handling of withdrawal from study and missing 
data for secondary endpoints ..................................... 92 
9.4.3.2.1. 
Comparison of efficacy between 
treatment arms ....................................... 92 
9.4.3.2.2. 
Other secondary endpoints ..................... 93 
9.4.3.3. 
Secondary Efficacy Analyses ....................................... 93 
9.4.4. 
Safety Endpoints .......................................................................... 93 
9.4.5. 
Exploratory Endpoints .................................................................. 94 
9.4.5.1. 
PK and PK-PD Analyses .............................................. 94 
9.4.5.2. 
Safety and Tolerability .................................................. 94 
9.4.5.3. 
Efficacy ........................................................................ 95 
9.4.5.4. 
Virology ........................................................................ 95 
9.4.5.5. 
Biomarkers ................................................................... 95 
9.5. 
Interim Analysis .......................................................................................... 95 
10. SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS ............................................................................................... 97 
10.1. 
Appendix 1: Regulatory, Ethical, and Study Oversight 
Considerations ............................................................................................ 97 
10.1.1. 
Regulatory and Ethical Considerations ........................................ 97 
10.1.2. 
Financial Disclosure ..................................................................... 97 
10.1.3. 
Informed Consent Process .......................................................... 98 
10.1.4. 
Data Protection ............................................................................ 98 
10.1.5. 
Committees Structure .................................................................. 99 
10.1.6. 
Dissemination of Clinical Study Data ........................................... 99 
10.1.7. 
Data Quality Assurance ............................................................. 100 
10.1.8. 
Source Documents .................................................................... 101 
10.1.9. 
Study and Site Start and Closure ............................................... 101 
10.1.10. Publication Policy ....................................................................... 102 
10.2. 
Appendix 2: Clinical Laboratory Tests ....................................................... 103 
10.3. 
Appendix 3: AEs and SAEs: Definitions and Procedures for 
Recording, Evaluating, Follow-up, and Reporting ..................................... 106 
10.3.1. 
Definition of AE .......................................................................... 106 
10.3.2. 
Definition of SAE ........................................................................ 107 
10.3.3. 
Definition of Cardiovascular Events ........................................... 108 


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10.3.4. 
Recording and Follow-Up of AE and SAE .................................. 109 
10.3.5. 
Reporting of SAE to GSK ........................................................... 111 
10.4. 
Appendix 4: Contraceptive and Barrier Guidance ..................................... 112 
10.4.1. 
Definitions: ................................................................................. 112 
10.4.2. 
Contraception Guidance: ........................................................... 113 
10.5. 
Appendix 5: Genetics ................................................................................ 116 
10.6. 
Appendix 6: Liver Safety: Required Actions and Follow-up 
Assessments and Study Intervention Restart Guidelines .......................... 117 
10.7. 
Appendix 7: Country-specific requirements ............................................... 120 
10.7.1. 
China ......................................................................................... 120 
10.7.1.1. China Schedule of Activities ....................................... 120 
10.7.1.2. China Biomarkers and Archived Samples .................. 120 
10.8. 
Appendix 8: Abbreviations and Trademarks .............................................. 121 
11. REFERENCES ..................................................................................................... 124 
 


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1. 
PROTOCOL SUMMARY 
1.1. 
Synopsis 
A Phase IIb Multi-Center, Randomised, Open Label Study to Assess the Efficacy and 
Safety of Sequential Treatment with GSK3228836 followed by Pegylated Interferon 
Alpha 2a in Participants with Chronic Hepatitis B Virus (B-Together) 
Brief Title: Phase IIb Study of Sequential GSK3228836 and Peginterferon Treatment in 
Participants with Chronic Hepatitis B (B-Together) 
Rationale: 
Study 209348 is intended to evaluate whether up to 24 weeks of treatment with 
GSK3228836 followed by up to 24 weeks of pegylated interferon (PegIFN) can increase 
the rate of hepatitis B virus surface antigen (HBsAg) loss in participants on stable 
nucleos(t)ide analogue (NA) therapy, and whether virologic response can be sustained 
once PegIFN treatment is discontinued.  Efficacy of sequential therapy with 
GSK3228836 and PegIFN will be compared to treatment with GSK3228836 alone, which 
is being currently being explored in a separate Phase IIb study, 209668.  Study 209348 
will also evaluate the safety and tolerability of the treatment regimen. 
Key Objectives and Estimands:  
Objectives 
Estimands 
Primary 
Efficacy: To investigate the efficacy of two 
different durations of GSK3228836 followed 
by up to 24 weeks of PegIFN therapy in 
participants with CHB on stable NA therapy. 
The main Estimand supporting the primary objective is 
defined as: 
• 
Population: Participants with CHB on stable NA 
therapy  
• 
Treatment: 300 mg GSK3228836 for 12 or 24 weeks 
followed by up to 24 weeks of PegIFN therapy while 
on stable NA therapy 
• 
Variable (Categorical): Participants achieving 
Sustained Virologic Response (SVR) (HBsAg <lower 
limit of quantification (LLOQ) and Hepatitis-B virus 
deoxy-ribonucleic acid (HBV DNA) <LLOQ) for 24 
weeks after the planned end of sequential treatment, 
without use of any rescue medication 
• 
Intercurrent Events: 
o Discontinuation of, interruption in, and non-
adherence to GSK3228836 and PegIFN not 
related to any wide disruptive events (such as 
COVID-19 pandemic) will be ignored (treatment 
policy strategy).  
o Ineligibility to receive PegIFN will be ignored 
(treatment policy strategy) 
o Use of rescue medication (composite strategy). 
o Wide disruptive events (such as COVID-19 
pandemic) leading to discontinuation of, 


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Objectives 
Estimands 
interruption in, and non-adherence to 
GSK3228836 and PegIFN will be handled 
assuming they had not happened (hypothetical 
strategy). 
• 
Population Summary: The percentage of 
participants in each treatment group who achieve 
SVR, without use of any rescue medication 
The main primary estimand supporting the primary 
objective in participants with chronic hepatitis B (CHB) 
on stable NA therapy in each treatment arm is the 
percentage of participants that achieve SVR (HBsAg 
<LLOQ and HBV DNA <LLOQ) for 24 weeks after the 
planned end of sequential treatment in the absence of 
rescue medication, regardless of ineligibility to receive 
PegIFN, discontinuation of, interruption in, and non-
adherence to GSK3228836 and PegIFN, had they not 
been affected by wide disruptive events. 
 
Three supplementary Estimands are defined to support 
the primary objective: 
• 
The first supplementary Estimand is defined in the 
same way as the main Estimand, except the 
assessment time frame for patients achieving SVR 
will be 24 weeks after the actual end of treatment. 
Therefore, the strategy for intercurrent events of 
treatment discontinuation will be while-on-treatment. 
This supplementary estimand supporting the primary 
objective in participants with CHB on stable NA 
therapy in each treatment arm is the percentage of 
participants that achieve SVR (HBsAg <LLOQ and 
HBV DNA <LLOQ) for 24 weeks after the actual end 
of sequential treatment in the absence of rescue 
medication, regardless of ineligibility to receive 
PegIFN, discontinuation of, interruption in, and non-
adherence to GSK3228836 and PegIFN, had they 
not been affected by wide disruptive events. 
 
• 
The second supplementary Estimand is to 
understand the relationship between the PegIFN 
duration and achieving SVR for 24 weeks after the 
actual end of treatment, defined as: 
o Population: Participants with CHB on stable NA 
therapy  
o Treatment: 300 mg GSK3228836 for 12 or 24 
weeks followed by 24 weeks of PegIFN therapy 
while on stable NA therapy 
o Variable: The relationship between SVR for 24 
weeks after actual end of treatment and the 
duration of PegIFN received by participants  
o Intercurrent Events:  


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Objectives 
Estimands 
▪ 
Discontinuation and delayed start of, 
PegIFN, will be accounted to reflect the 
actual duration from the first to the last 
dose of PegIFN received (while-on-
treatment strategy).  
▪ 
Interruption in and other non-adherence 
to PegIFN will be ignored (treatment 
policy strategy) 
▪ 
Discontinuation of, interruption in and 
non-adherence to GSK3228836 will be 
ignored (treatment policy strategy) 
▪ 
Use of rescue medication (composite 
strategy). 
▪ 
Wide disruptive events (such as 
COVID-19 pandemic) leading to 
discontinuation and delayed start of, 
PegIFN will be handled with while-on-
treatment strategy; wide disruptive 
events leading to interruption in and 
other non-adherence to PegIFN will be 
ignored (treatment policy strategy);  
wide disruptive events leading to 
discontinuation of, interruption in, and 
non-adherence to GSK3228836 will be 
ignored (treatment policy strategy). 
o Population Summary: The percentage of 
participants achieving SVR for 24 weeks after 
the actual end of treatment by PegIFN 
treatment duration categorical grouping in each 
treatment arm  
The second supplementary Estimand (supporting the 
primary objective in participants with CHB on stable NA 
therapy) is the percentage of participants achieving SVR 
for 24 weeks after the actual end of treatment by PegIFN 
treatment duration categorical grouping in each 
treatment arm, taking into account discontinuation and 
delayed start of PegIFN, regardless of interruption in and 
other non-adherence to PegIFN, regardless of 
discontinuation of, interruption in and non-adherence to 
GSK3228836. 
 
• 
The third supplementary Estimand is defined in the 
same way as the main Estimand, except the 
strategy for intercurrent events of PegIFN ineligibility 
for more than 12 weeks and/or missing more than 
12 doses of PegIFN will be principal stratum. This 
supplementary Estimand supporting the primary 
objective is the percentage of participants in each 
treatment arm that achieve SVR (HBsAg <LLOQ 
and HBV DNA <LLOQ) for 24 weeks after the 
planned end of sequential treatment in participants 


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Objectives 
Estimands 
with CHB on stable NA therapy and receiving at 
least 12 doses of PegIFN, in the absence of rescue 
medication, regardless of discontinuation of, 
interruptions in or non-adherence to GSK3228836 
had they not been affected by wide disruptive 
events. 
 
Secondary 
Efficacy: To assess the efficacy of 
GSK3228836 and PegIFN therapy on 
biomarkers and virus specific antibody 
responses  
The Estimand supporting the objective is defined as: 
• 
Population: Participants with CHB on stable NA 
therapy; For the time to alanine aminotransferase 
(ALT) normalisation variable, population will be 
aforementioned participants with baseline ALT 
>upper limit normal (ULN). 
• 
Treatment: 300 mg GSK3228836 for 12, or 24 
weeks followed by 24 weeks of PegIFN therapy 
while on stable NA therapy 
• 
Categorical Variables: 
o Achieving HBsAg <LLOQ and HBV DNA 
<LLOQ at two time points: (1) the planned end 
of treatment and (2) at the end of 24 weeks 
follow-up 
o Categorical changes from baseline in HBsAg 
(e.g., <0.5, ≥0.5, ≥1, ≥1.5, ≥3 log10 IU/mL) at 
each scheduled visit or analysis window. 
o ALT normalisation (ALT ≤ULN) over time in 
absence of rescue medication in participants 
with baseline ALT >ULN  
Population summary is the percentage of 
participants in each category for each treatment 
group. 
o HBe antibody (anti-HBeAg) levels. 
• 
Continuous Variables: 
o Actual values and change from baseline over 
time for HBsAg, HBV DNA and hepatitis B virus 
e-antigen (HBeAg) 
o Actual values and change from baseline over 
time for HBs antibody (anti-HBsAg) levels over 
time 
o Actual values and change from baseline over 
time for ALT 
Population summary is the mean values and 
the mean changes from baseline of each 


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Protocol Amd 01 
 
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Objectives 
Estimands 
variable for participants in each treatment 
group. 
• 
Time to Event Variable:  
o Time to ALT normalisation in absence of rescue 
medication in participants with baseline 
ALT>ULN 
Population summary is the Turnbull’s estimator 
for non-parametric estimation of Time to ALT 
normalisation in each treatment arm 
• 
Intercurrent Events: Discontinuation of, interruption 
in, and non-adherence to GSK3228836 and PegIFN 
will be ignored (treatment policy); PegIFN ineligibility 
will be ignored (treatment policy); Rescue 
medication will be ignored (treatment policy), except 
for ALT normalisation which can only be achieved in 
the absence of rescue medication; Wide disruptive 
events (such as COVID-19 pandemic) leading to 
discontinuation of, interruption in, and non-
adherence to GSK3228836 and PegIFN will be 
handled with Treatment Policy Strategy. 
• 
The group of estimands supporting this objective is 
the population summary for each variable in each 
treatment arm in the population regardless of 
discontinuation of, interruption in or non-adherence 
to GSK3228836 and PegIFN, and regardless of 
rescue medication (except for ALT normalisation 
which can only be achieved in the absence of 
rescue medication) or PegIFN ineligibility. 
 
Efficacy: To investigate the durability of 
virologic response after sequential therapy 
with 12 weeks of GSK3228836 followed by 
24 weeks of PegIFN in participants with CHB 
on stable NA therapy for up to 36 weeks off 
treatment 
The same definition as the above secondary estimand, 
focusing on the timepoints following the 24 weeks off-
treatment period in the treatment arm of 300 mg 
GSK3228836 for 12 weeks followed by up to 24 weeks 
of PegIFN therapy while on stable NA therapy.  
Efficacy: To compare efficacy between 
different treatment durations: 
12 or 24 weeks of GSK3228836 followed by 
24 weeks PegIFN 
The same definition as the primary estimand except 
treatments and population summary are defined as: 
• 
Treatments: Arms 1 and 2. One treatment 
comparison between Arms 1 & 2 up to 24 weeks off-
treatment 
• 
Population summary: difference in proportion of 
participants who achieve SVR between treatment 
arms 
The group of estimands supporting this objective in 
participants with CHB on stable NA therapy is the 
difference between treatment arms 1 and 2 in the 
proportion of participants that achieve SVR for 24 weeks 
after the planned end of sequential treatment, in the 
absence of rescue medication, regardless of ineligibility 
to receive PegIFN, regardless of discontinuation of, 


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Protocol Amd 01 
 
16 
 
Objectives 
Estimands 
interruption in or non-adherence to GSK3228836 and 
PegIFN had they not been affected by wide disruptive 
events.  
Overall Design: 
This is a Phase IIb, multi-centre, randomised, open-label study to assess the efficacy and 
safety of sequential treatment with GSK3228836 (300 mg/week for 12 or 24 weeks) 
followed by PegIFN (180 mcg/week for up to 24 weeks) in participants with CHB on 
stable NA therapy.  During the GSK3228836 treatment period a 300 mg loading dose 
will be administered on Day 4 and Day 11.  Participants will continue their NA therapy 
for the duration of the study. 
Brief Summary: 
The purpose of this study is to investigate the efficacy of 12 or 24 weeks of GSK3228836 
followed by up to 24 weeks of PegIFN therapy in participants with CHB on stable NA 
therapy. Study details include: 
Study Duration: 79 weeks 
Treatment Duration: 12 or 24 weeks of GSK3228836 followed by up to 24 weeks of 
PegIFN  
Post-treatment Follow-up: 36 or 24 weeks off treatment follow-up (note NA-therapy will 
continue throughout study) 
Number of Participants: 
This study will enrol approximately 100 participants.  Enrolment, in this case, refers to 
participants who have passed the screening requirements and entered the study. The 
expected screen failure rate for participants is 20%. 
In the case of a disruptive event impacting (e.g., COVID-19, natural disaster), sites and/or 
participants may be unable to conduct/attend dosing visits, conduct/attend follow-up 
visits, participants may be discontinued from study treatment, and/or participants may be 
withdrawn from the study. 
The study team may enrol additional participants to within 10% of the planned 100.  
Note: "Enrolled" means a participant's, or their legally acceptable representative’s, 
agreement to participate in a clinical study following completion of the informed consent 
process and after study personnel have confirmed that all eligibility criteria have been 
met. Potential participants who are screened for the purpose of determining eligibility for 
the study, but do not participate in the study, are not considered enrolled, unless 
otherwise specified by the protocol. 


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Protocol Amd 01 
 
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Intervention Arms and Duration: 
The total duration of the study, including screening, treatment, and post-treatment follow-
up, is not expected to exceed 79 weeks for each participant: 
• Arm 1: 24 weeks GSK3228836 + 24 weeks PegIFN + 24 weeks off-treatment 
• Arm 2: 12 weeks GSK3228836 + 24 weeks PegIFN + 36 weeks off-treatment 
A 45-day screening window is included in the total study duration.  Eligible participants 
who fall outside of the 45-day window may be re-screened at the discretion of the 
Investigator/site. 
There are no plans for group dose adjustments.  Individual dose adjustments for 
GSK3228836 for safety are outlined in the monitoring/stopping criteria.  Individual dose 
adjustments for PegIFN for safety are outlined in the monitoring/stopping criteria and are 
permitted down to 90 mcg/mL. 
Participants that leave the study early will not be replaced. 
Data Monitoring/ Other Committee: Yes 
1.2. 
Schema 
 
 
 
 


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Protocol Amd 01 
 
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1.3. 
Schedule of Activities (SoA) 
Both treatment arms will use the same Screening Table (Table 1).  Separate tables have 
been produced for the GSK3228836 treatment period (Table 2 and Table 3).  Both 
treatment arms will use the same PegIFN Treatment Table (Table 4), Reassessment of 
PegIFN Eligibility Tables (Table 5 and Table 6; only required if participant is ineligible 
to start PegIFN as per Table 4) and Off Treatment Follow-up Table (Table 7). 
[China specific Schedule of Activities can be found in  Appendix 7: Country-specific 
requirements] 
Instructions that are applicable to all treatment arms include: 
• In selected countries/sites, participants will have the option to use a centralised 
home nursing provider. Only selected visits will have the option to be performed 
as a home visit, these will include drug administration, blood draws, participant 
assessments and data collection. The full specifications of the home nursing 
services will be outlined in the Study Reference Manual (SRM).  
• Haematology (platelet count) will be analysed at a local laboratory prior to each 
GSK3228836 dose.  The blood draw can be taken the day before GSK3228836 
dosing.  Results must be available prior to dosing.  Haematology samples will be 
collected for central laboratory assessments in parallel.  After GSK3228836 
treatment is completed, haematology is only collected centrally on weeks of clinic 
visits. 
• If a participant is not eligible to start PegIFN, eligibility will be reassessed.  If the 
participant does not become eligible after 13 weeks, PegIFN will not be initiated 
in order to ensure participants receive at least 12 weeks of PegIFN treatment.  
Irrespective of the week that a participant starts PegIFN, the final dose will be 
given on Study Week 48 for Arm 1 and Week 36 for Arm 2 (Figure 1). 
• PegIFN dosing maybe self-administered at home, where local regulations allow at 
the visits indicated in the SoA (Table 4). 
 


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Protocol Amd 01 
 
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Figure 1 
Schematic of Planned GSK3228836 and PegIFN Dosing Periods and 
Off Treatment Follow-up Period 
 
 
 
 


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Protocol Amd 01 
 
20 
 
Table 1 
Screening (All Treatment Arms) 
ASSESSMENTS 
 
Informed Consent (obtained any time prior to screening) 
X 
Inclusion and exclusion criteria 
X 
Demography 
X 
Medical history (includes substance usage) and current medical conditions  
X 
Medication history and concomitant medication review 
X 
Full physical exam including height and weight 
X 
Vital signs 
X 
Ocular exam (unless completed within 3 months) 
X 
12-lead ECG  
X 
Neuropsychiatric assessment (C-SSRS and BDI-II) 
X 
LABORATORY ASSESSMENTS 
Serum hCG pregnancy test (women of childbearing potential [WOCBP]) 
X 
FSH/Estradiol (to confirm status of women of non-child-bearing potential)1 
X 
Haematology/Chemistry/Urinalysis 
X 
TSH, T4 
X 
Urine ACR 
X 
PT, INR, aPTT 
X 
HIV, hepatitis D, and hepatitis C screen 
X 
Hepatitis B profile (HBsAg, HBV DNA, HBeAg) 
X 
Alpha-fetoprotein 
X 
APRI/ FibroSure 
X 
ANCA (with MPO-ANCA, PR3-ANCA if results are positive or border-line positive) 
X 
Complement C3, C4, C5a, hsCRP, MCP-1, complement Bb, Ang-2 
X 
1. 
As appropriate to confirm menopause 
 
 


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Protocol Amd 01 
21 
 
Table 2 
GSK3228836 Treatment Period: Treatment Arm 1 (Week 1-24) 
Day 
1 
4 
8 
11 
15 
22 
29 
36 
43 
50 
57 
64 
71 
78 
85 
92 
99 
106 
113 
120 
127 
134 
141 148 155 
162 
Week 
1 
1 
2 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
16 
17 
18 
19 
20 
21 
22 
23 
24 
Window (days) 
 
1 day 
2 
3 days 
Randomisation 
X 
 
GSK3228836 dosing 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Safety Assessments 
AE/SAE review 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Conmed review 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Symptom directed exam 
X 
 
 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
Vital signs 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
12 lead ECG 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X4 
X4 
Injection site reactions 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Laboratory Assessments 
Pregnancy test 
(WOCBP) 
X1 
 
 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
Haematology [includes 
platelet and WBC with 
differential] 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
PT, INR, aPTT 
X 
 
 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
X 
TSH, T4 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Chemistry 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Urinalysis 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Urine ACR 
X 
 
 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
HBsAg and HBV DNA 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Anti- HBsAg and anti-
HBeAg 
X 
 
 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
HBeAg3 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Complement C3, C4, 
C5a, Bb, hs-CRP, MCP-
1 
X 
 
 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
ANCA, Ang II 
X 
 
 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
PK GSK3228836 
X 
X 
X 
X 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
HBV RNA, and 
Sequencing (HBV 
genotype/phenotype; 
HBV DNA and/or RNA) 
X 
 
 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 


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Protocol Amd 01 
22 
 
Day 
1 
4 
8 
11 
15 
22 
29 
36 
43 
50 
57 
64 
71 
78 
85 
92 
99 
106 
113 
120 
127 
134 
141 148 155 
162 
Week 
1 
1 
2 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
16 
17 
18 
19 
20 
21 
22 
23 
24 
Window (days) 
 
1 day 
2 
3 days 
HBcrAg 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
PBMC Collection for 
immunophenotyping2 
X 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Soluble Protein 
(immunology) 
X 
 
 
 
X 
 
X 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
PAXGene RNA for 
expression analysis in 
whole blood 
X 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
OPTIONAL: Genetics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Archived Samples 
[serum; plasma] 
X 
 
 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
1. 
A WOCBP must have both a confirmed menstrual period prior to the first dose of study intervention AND a negative highly sensitive pregnancy test [urine or serum] within 24 
hours before the first dose of study treatment (performed locally) 
2. 
Only for selected sites able to transport to the analysis lab as specified in the SRM 
3. 
Only for participants HBeAg positive at screening 
4. 
ECG to be conducted once at any point from Week 23 and prior to initiation of PegIFN 
  
 
 


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Table 3 
GSK3228836 Treatment Period: Treatment Arm 2 (Week 1-12) 
Day 
1 
4 
8 
11 
15 
22 
29 
36 
43 
50 
57 
64 
71 
78 
Week 
1 
1 
2 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
Window (days) 
1 day 
2 
3 days 
Randomisation 
X 
 
GSK3228836 dosing 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Safety Assessments 
AE/SAE review 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant med review 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Symptoms directed exam 
X 
 
 
 
 
 
X 
 
 
 
X 
 
 
 
Vital signs 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
12 lead ECG 
 
 
 
 
 
 
 
 
 
 
 
 
X3 
X3 
Injection site reactions 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Laboratory Assessments 
Pregnancy test (WOCBP) 
X1 
 
 
 
 
 
X 
 
 
 
X 
 
 
 
Haematology [includes platelet and WBC with differential] 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
TSH, T4 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
PT, INR, aPTT 
X 
 
 
 
 
 
X 
 
 
 
X 
 
 
X 
Chemistry 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Urinalysis 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Urine ACR 
X 
 
 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
HBsAg and HBV DNA 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Anti- HBsAg and anti-HBeAg 
X 
 
 
 
 
 
X 
 
 
 
X 
 
 
 
HBeAg (for participants HBeAg positive at screening) 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Complement C3, C4, C5a, Bb, hs-CRP, MCP-1 
X 
 
 
 
X 
 
X 
 
X 
 
X 
 
X 
 
ANCA, Ang II 
X 
 
 
 
 
 
X 
 
 
 
X 
 
 
 
PK GSK3228836 
X 
X 
X 
X 
 
 
 
X 
 
 
 
 
 
X 
HBV RNA, and sequencing (HBV genotype/phenotype, HBV DNA, and/or RNA) 
X 
 
 
 
X 
 
X 
 
X 
 
X 
 
X 
 
HBcrAg 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
PBMC Collection for immunophenotyping2 
X 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
Soluble Protein (immunology) 
X 
 
 
 
X 
 
X 
 
 
X 
 
 
 
X 
PAXGene RNA for expression analysis in whole blood 
X 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
OPTIONAL: Genetics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Protocol Amd 01 
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Day 
1 
4 
8 
11 
15 
22 
29 
36 
43 
50 
57 
64 
71 
78 
Week 
1 
1 
2 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
Window (days) 
1 day 
2 
3 days 
Archived Samples [serum; plasma] 
X 
 
 
 
X 
 
X 
 
X 
 
X 
 
X 
 
1. 
A WOCBP must have both a confirmed menstrual period prior to the first dose of study intervention AND a negative highly sensitive pregnancy test [urine or serum] within 24 
hours before the first dose of study treatment (locally performed) 
2. 
Only for selected sites able to transport to the analysis lab as specified in the SRM  
3. 
ECG to be conducted at any point from Week 11 and prior to initiation of PegIFN 
 
 
 
 
 


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Table 4 
PegIFN Treatment Period 
Participants will be assessed using Column 1 below to determine eligibility to begin treatment with PegIFN and moved to the “Yes” column 
based on the eligibility criteria outlined in Section 5.3.  If a participant is determined to be eligible for PegIFN dosing, they will begin 
PegIFN Dosing on Week 1.  If a participant is determined to be ineligible for PegIFN, see Table 5.  
PegIFN Dosing Week  
1a 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
16 
17 
18 
19 
20 
21 
22 
23 
24 
Window 
3 days 
Confirmed Eligibility for Peg-
IFN 
Confirm 
PegIFN 
Eligibility1 
Yes2 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Clinic visit3 
X 
X 
X 
X 
 
X 
 
X 
 
X 
 
 
X 
 
 
X 
 
 
 
X 
 
 
 
X 
Peg-IFN dosing 
 
X 
X 
X 
X 
X3 
X 
X3 
X 
X3 
X 
X3 
X3 
X 
X3 
X3 
X 
X3 
X3 
X3 
X 
X3 
X3 
X3 
X 
Safety Assessments 
 
 
AE/SAE review 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant medication review 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Symptoms directed exam 
X 
 
 
 
X 
 
 
 
X 
 
 
 
 
X 
 
 
X 
 
 
 
X 
 
 
 
 
Vital signs 
X 
 
X 
X 
X 
 
X 
 
X 
 
X 
 
 
X 
 
 
X 
 
 
 
X 
 
 
 
X 
Injection site reactions 
 
X 
X 
X 
X 
 
X 
 
X 
 
X 
 
 
X 
 
 
X 
 
 
 
X 
 
 
 
X 
Neuropsychiatric assessment 
(C-SSRS and BDI-II) 
X 
 
X 
X 
X 
 
X 
 
X 
 
X 
 
 
X 
 
 
X 
 
 
 
X 
 
 
 
X 
Laboratory Assessments 
 
 
Pregnancy test (WOCBP) 
 
X 
 
 
X 
 
 
 
X 
 
X 
 
 
X 
 
 
X 
 
 
 
X 
 
 
 
X 
Haematology [includes platelet 
and WBC with differential] 4 
 
X 
X 
X 
X 
 
X 
 
X 
 
X 
 
 
X 
 
 
X 
 
 
 
X 
 
 
 
X 
TSH, T4 
 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
X 
PT, INR, aPTT 
 
X 
 
 
X 
 
 
 
 
 
 
 
 
X 
 
 
X 
 
 
 
X 
 
 
 
X 
Chemistry 
 
X 
X 
X 
X 
 
X 
 
X 
 
X 
 
 
X 
 
 
X 
 
 
 
X 
 
 
 
X 
Urinalysis 
 
X 
X 
 
X 
 
 
 
X 
 
 
 
 
X 
 
 
X 
 
 
 
X 
 
 
 
X 
Urine ACR 
 
X 
X 
 
X 
 
 
 
X 
 
 
 
 
X 
 
 
X 
 
 
 
X 
 
 
 
X 
HBsAg and HBV DNA 
 
X 
X 
X 
X 
 
X 
 
X 
 
X 
 
 
X 
 
 
X 
 
 
 
X 
 
 
 
X 
Anti-HBsAg and anti-HBeAg 
 
X 
 
 
X 
 
 
 
X 
 
 
 
 
X 
 
 
X 
 
 
 
X 
 
 
 
X 
HBeAg (for participants HBeAg 
positive at screening) 
 
X 
X 
X 
X 
 
X 
 
X 
 
X 
 
 
X 
 
 
X 
 
 
 
X 
 
 
 
X 


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Protocol Amd 01 
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PegIFN Dosing Week  
1a 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
16 
17 
18 
19 
20 
21 
22 
23 
24 
Window 
3 days 
Complement C3, C4, C5a, Bb, 
hs-CRP, MCP-1 
 
 
X 
 
X 
 
 
 
X 
 
 
 
X 
 
 
X 
 
 
 
X 
 
 
 
 
ANCA, Ang II 
 
X 
 
 
X 
 
 
 
X 
 
 
 
 
X 
 
 
X 
 
 
 
X 
 
 
 
 
PK – PegIFN 
 
X 
X 
 
X 
 
X 
 
 
 
 
 
 
X 
 
 
X 
 
 
 
X 
 
 
 
 
PK –GSK3228836 
 
X 
 
X 
 
 
X 
 
 
 
X 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
HBV RNA, and sequencing 
(HBV genotype/phenotype; 
HBV DNA and/or RNA) 
 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
 
X 
 
 
X 
 
 
 
X 
 
 
 
X 
HBcrAg 
 
X 
 
 
X 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
 
 
X 
 
 
 
 
PBMC Collection for 
immunophenotyping5 
 
X 
 
 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Soluble Protein (immunology) 
 
X 
X 
 
X 
 
X 
 
 
 
 
 
 
X 
 
 
X 
 
 
 
X 
 
 
 
 
PAXGene RNA for expression 
analysis in whole blood 
 
X 
 
 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Archived Samples [serum; 
plasma] 
 
X 
X 
X 
X 
 
X 
 
X 
 
X 
 
 
X 
 
 
X 
 
 
 
X 
 
 
 
X 
a. 
The first planned PegIFN visit occurs 7 days after the planned GSK3228836 dosing period. 
1. 
Assessment of PegIFN eligibility should be based upon pre-dose safety assessments and laboratory assessments from previous visit 
2. 
For specific Peg-IFN eligibility criteria please refer to protocol Section 4.1; If ineligible for PegIFN refer to Table 5. 
3. 
If consistent with local regulations, participants are permitted to self-administer PegIFN at home, site staff may call to assess the participant by phone at this visit and no clinic visit is required.  If 
local regulations or practices prefer to administer PegIFN within the clinic, this can be a clinic visit.   
4. 
Participants in Japan are expected to return for a mid-week haematology assessment during Week 1 and at Week 5 and 7 in accordance with local regulations  
5. 
Only for selected sites able to transport to the analysis lab as specified in the SRM 
 


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Table 5 
Reassessment of PegIFN Eligibility  
If a participant is ineligible for PegIFN dosing immediately (Week 1, Table 4), complete the SoA of PegIFN Eligibility Week 1, Table 5.   
Eligibility for PegIFN will be reassessed following the SoA in Table 5 on PegIFN Eligibility Week 2, 3, 4, 6, 8, 10 and 13.   
If a participant becomes eligible for PegIFN during any of the reassessment visits, the SoA in Table 4 should be followed starting at 
the Week 1 “Yes” column for the remainder of PegIFN dosing visits and stopping at the visit number where the combined PegIFN dosing 
and PegIFN eligibility visits equal “25” – for example, if a participant becomes eligible for PegIFN on PegIFN Eligibility Week 4, the SoA 
in Table 4 should be followed from Week 1 to Week 21 (Table 6). 
PegIFN Eligibility Week  
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
16 
17 
18 
19 
20 
21 
22 
23 
24 
Window 
3 days 
Eligible for PegIFN (Section 4.1) 
No 
No 
No 
No 
 
No 
 
No 
 
No 
 
 
No 
 
 
 
 
 
 
 
 
 
 
 
Clinic visit 
X 
X 
X 
X 
 
X 
 
X 
 
X 
 
 
X 
 
 
X 
 
 
 
X 
 
 
 
X 
Safety Assessments 
 
AE/SAE review 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant medication review 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Symptoms directed exam 
 
X 
X 
X 
 
X 
 
X 
 
X 
 
 
X 
 
 
X 
 
 
 
X 
 
 
 
 
Vital signs 
 
X 
X 
X 
 
X 
 
X 
 
X 
 
 
X 
 
 
X 
 
 
 
X 
 
 
 
X 
Neuropsychiatric assessment (C-
SSRS and BDI-II) 
 
X 
X 
X 
 
X 
 
X 
 
X 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Laboratory Assessments (If not 
Eligible to begin PegIFN 
treatment) 
 
Pregnancy test (WOCBP) 
X 
 
 
X 
 
 
 
X 
 
X 
 
 
X 
 
 
X 
 
 
 
X 
 
 
 
X 
Haematology [includes platelet and 
WBC with differential] 
X 
X 
X 
X 
 
X 
 
X 
 
X 
 
 
X 
 
 
X 
 
 
 
X 
 
 
 
X 
TSH, T4 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
X 
PT, INR, aPTT 
X 
 
 
X 
 
 
 
 
 
 
 
 
X 
 
 
X 
 
 
 
X 
 
 
 
X 
Chemistry 
X 
X 
X 
X 
 
X 
 
X 
 
X 
 
 
X 
 
 
X 
 
 
 
X 
 
 
 
X 
Urinalysis 
X 
X 
 
X 
 
 
 
X 
 
 
 
 
X 
 
 
X 
 
 
 
X 
 
 
 
X 
Urine ACR 
X 
X 
 
X 
 
 
 
X 
 
 
 
 
X 
 
 
X 
 
 
 
X 
 
 
 
X 
HBsAg and HBV DNA 
X 
X 
X 
X 
 
X 
 
X 
 
X 
 
 
X 
 
 
X 
 
 
 
X 
 
 
 
X 


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PegIFN Eligibility Week  
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
16 
17 
18 
19 
20 
21 
22 
23 
24 
Window 
3 days 
Anti- HBsAg and anti-HBeAg 
X 
 
 
X 
 
 
 
X 
 
 
 
 
X 
 
 
X 
 
 
 
X 
 
 
 
X 
HBeAg (for participants HBeAg 
positive at screening) 
X 
X 
X 
X 
 
X 
 
X 
 
X 
 
 
X 
 
 
X 
 
 
 
X 
 
 
 
X 
Complement C3, C4, C5a, Bb, hs-
CRP, MCP-1 
 
X 
 
X 
 
 
 
X 
 
 
 
 
X 
 
 
X 
 
 
 
X 
 
 
 
 
ANCA, Ang II 
X 
 
 
X 
 
 
 
X 
 
 
 
 
X 
 
 
X 
 
 
 
X 
 
 
 
 
PK – GSK3228836 
X 
 
X 
 
 
X 
 
 
 
X 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
HBV RNA and sequencing (HBV 
genotype/phenotype; HBV DNA 
and/or RNA) 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
 
X 
 
 
X 
 
 
 
X 
 
 
 
X 
 HBcrAg 
X 
 
 
X 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
 
 
X 
 
 
 
 
PBMC Collection for 
immunophenotyping1 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Soluble Protein (immunology) 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
PAXGene RNA for expression 
analysis in whole blood 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Archived Samples [serum; plasma] 
X 
X 
X 
X 
 
X 
 
X 
 
X 
 
 
X 
 
 
X 
 
 
 
X 
 
 
 
X 
1. 
Only for selected sites able to transport to the analysis lab as specified in the SRM 
 
 
 
 
 
 


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Table 6 
PegIFN Dosing for Participants becoming Eligible for PegIFN after Week 1 
Become Eligible for PegIFN at PegIFN Eligibility Week (Table 5) PegIFN Dosing (Table 4) should continue until PegIFN Dosing Week 
2 
23 
3 
22 
4 
21 
6 
19 
8 
17 
10 
15 
13 
12 
 
 
 


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Table 7 
Off-Treatment Week (OTW) Follow-up: Week 1-24 (Treatment Arm 1) or Week 1-36 (Treatment Arm 2)  
Assessments 
OTW1a 
OTW2 
OTW4 
OTW8 
OTW12 
OTW18 
OTW24 
OTW301 
OTW361 
Early 
Termination 
Window 
3 days 
NA 
Safety Assessments 
 
AE/SAE review 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant medication review 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Symptoms directed exam 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Vital signs 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Neuropsychiatric assessment (C-SSRS and BDI-II)2 
X 
 
X 
X 
X 
 
X 
 
 
X 
Laboratory Assessments 
 
Pregnancy test (WOCBP) 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
Haematology [includes platelet and WBC with differential] 
X 
 
X 
 
X 
 
X 
 
 
X 
PT, INR, aPTT 
X 
 
X 
 
X 
 
X 
 
 
X 
Chemistry 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Urinalysis 
X 
 
X 
 
X 
 
X 
 
 
X 
Urine ACR 
X 
 
X 
 
X 
 
X 
 
 
X 
HBsAg and HBV DNA 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Anti-HBsAg and anti-HBeAg 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
HBeAg (for participants HBeAg positive at screening) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Complement C3, C4, C5a, Bb, hs-CRP, MCP-1, ANCA, Ang II 
X 
 
 
 
X 
 
X 
 
 
X 
PK for PegIFN2 
X 
X 
X 
X 
 
 
 
 
 
X 
HBV RNA and sequencing (HBV genotype/phenotype; HBV DNA 
and/or RNA) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
HBcrAg 
X 
 
X 
X 
X 
 
X 
 
 
X 
PBMC Collection for immunophenotyping3 
X 
 
 
 
 
 
X 
 
 
X 
PAXGene RNA for expression analysis in whole blood 
X 
 
 
 
X 
 
X 
 
 
X 
Soluble Protein (immunology) 
X 
 
X 
 
X 
 
X 
 
 
X 
Archived Samples [serum; plasma] 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
a. 
The first planned Off treatment visit occurs 7 days after the planned PegIFN dosing period. 
1. 
Only applicable for Treatment Arm 2 
2. 
Only for participants that received at least 1 dose of PegIFN. 
3. 
Only for selected sites able to transport to the analysis lab as specified in the SRM. 
 


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2. 
INTRODUCTION 
2.1. 
Study Rationale 
Chronic hepatitis B (CHB) infection results in progressive liver disease that may lead to 
complications such as cirrhosis, liver failure, and hepatocellular carcinoma. First-line 
therapy for CHB is treatment with a nucleoside or nucleotide (nucleos(t)ide) analogue 
(NA). While these antiviral agents are effective in suppressing hepatitis B virus (HBV) 
replication in both hepatitis B virus e-antigen (HBeAg)-positive and HBeAg-negative 
CHB, patients frequently relapse after treatment is discontinued, particularly if hepatitis B 
virus surface antigen (HBsAg) loss was not achieved. The high rate of relapse in these 
patients is hypothesised to be due to their inability to raise an effective immune response 
to the virus in the presence of high circulating levels of HBsAg, which continues to be 
produced by infected hepatocytes, even in the absence of ongoing viral replication.  
Recently, a functional cure of CHB infection has been endorsed as an endpoint for new 
HBV therapies. Functional cure of CHB infection is defined as sustained loss of HBsAg 
from serum (with or without anti-HBsAg seroconversion) and undetectable HBV DNA in 
serum, after completion of a finite course of treatment [Lok, 2017; Cornberg, 2019].  
Functional cure occurs in only a very small percentage of patients on NA therapy alone 
(approx. 3% per annum) [Lok, 2017]. 
Interferons (IFNs) are a group of immunomodulatory drugs approved as a monotherapy for 
the treatment of certain patients with CHB.  Peginterferons (PegIFN) are indicated for the 
treatment of adult patients with HBeAg positive and HBeAg negative CHB who have 
compensated liver disease and evidence of viral replication and liver inflammation.  
Weekly injections of PegIFN for 48 weeks has been demonstrated to achieve functional 
cure in a small proportion (up to 9%) of CHB patients as monotherapy, or in combination 
with nucleosides (off-label) [Marcellin, 2016].  Patients that have lower levels of serum 
HBsAg before starting treatment with PegIFN have been shown to respond better than 
those with higher levels in clinical trials [Ren, 2019; Lee, 2018]. 
GSK3228836 is being developed for the treatment of CHB and is a 2’-O-(2-methoxyethyl)-
modified chimeric phosphorothioate antisense oligonucleotide (2’-MOE chimeric ASO) 
drug targeted to HBV ribonucleic acid (RNA).  GSK3228836 is complementary to 
sequences present in all HBV-derived RNA transcripts and its hybridisation to the cognate 
RNA results in ribonuclease H-mediated degradation.  It is highly specific for HBV RNA 
transcripts and is not homologous to any regions of the human transcriptome, including 
either a single nucleotide mismatch or with 17 or more consecutive nucleotide matches.  
GSK3228836 is an antisense oligonucleotide that is designed to inhibit the synthesis of 
viral proteins (e.g., HBsAg, HBeAg) by targeting HBV RNA without having a direct effect 
on HBV covalently closed circular DNA (HBV cccDNA) or integrated HBV DNA. 
Treatment of patients with CHB with GSK3228836 will permit examination of whether 
reduction of viral proteins allows resumption of a host immune response against HBV virus 
and infected cells and if longer treatment with GSK3228836 will result in HBsAg loss 
leading to sustained suppression of HBV replication after cessation of all treatments for 
CHB. 


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Efficacy of 4 weeks treatment with GSK3228836 has been investigated in Phase IIa study, 
ISIS 505358-CS3, in both treatment naïve participants and participants on stable NA 
therapy.  Both groups of study participants experienced declines in HBsAg, including some 
achieving HBsAg levels < lower limit of quantification (LLOQ), followed by acute ALT 
elevations (refer to Investigator’s Brochure [GSK Document Number 2019N425040_00]). 
The efficacy and safety of GSK3228836 treatment for up to 24 weeks duration is currently 
being evaluated in a Phase IIb study (Study 209668, NCT04449029).  It is hypothesised 
that additional immunomodulatory therapy (such as PegIFN) may be needed to achieve 
optimal durable HBsAg loss. Study 209348 is intended to evaluate whether up to 24 weeks 
of treatment with GSK3228836 followed by 24 weeks of PegIFN can increase the rate of 
HBsAg loss in participants on stable NA therapy, and whether virologic response can be 
sustained once PegIFN treatment is discontinued.  Efficacy of sequential therapy with 
GSK3228836 and PegIFN will be compared to the response observed with GSK3228836 
in the absence of PegIFN in the Phase IIb study, 209668.  Study 209348 will also evaluate 
the safety and tolerability of the treatment regimen. 
2.2. 
Background 
HBV infection, especially chronic infection, is a significant worldwide medical problem.  
Globally, in 2015, an estimated 257 million people were living with chronic Hepatitis B, 
with only 9% of patients with Hepatitis B being treated. Viral hepatitis led to 1.34 million 
deaths and of these deaths, 66% were the results of complications of CHB infection 
[WHO, 2015]. 
The goal of therapy for CHB is to improve quality of life and survival by preventing 
progression of the disease to cirrhosis, decompensated liver disease, end-stage liver 
disease, hepatocellular carcinoma (HCC), or death. This goal can be achieved if HBV 
replication is suppressed in a sustained manner thereby decreasing the histological activity 
of CHB and reducing the risk of cirrhosis and HCC [Liaw, 2004; Feld, 2009]. In both 
HBeAg-positive and HBeAg-negative CHB, the ultimate treatment endpoint is loss of 
detectable serum hepatitis B surface antigen (HBsAg) and serum HBV DNA [Lok, 2009; 
EASL, 2012]. Loss of HBsAg is preceded by a robust immunological response to HBV 
infection resulting in sustained suppression of serum HBV deoxyribonucleic acid (DNA) 
and disease resolution. 
First-line therapy for CHB is treatment with a NA therapy. While these antiviral agents are 
effective in suppressing HBV replication in both HBeAg-positive and HBeAg-negative 
CHB, patients frequently relapse after treatment is discontinued, particularly if HBsAg loss 
was not achieved. PegIFNs are also approved for treatment of CHB [Lok, 2009; EASL, 
2012] and are dosed for a finite treatment duration (usually up to 48 weeks). Because of 
the frequent and sometimes severe side effects associated with PegIFN and high cost versus 
a small gain in treatment response, PegIFNs are less frequently used than NAs. 
Unfortunately, with both the NAs and PegIFN, HBsAg loss and the subsequent 
development of antibodies to HBsAg are rarely achieved. Rates of HBsAg loss following 
12 months of treatment with either a NA and/or PegIFN generally range from 0 to 3% in 
most studies [Lok, 2009; EASL, 2012], with occasional studies reporting higher rates for 
example ~10% functional cure after TDF+PegIFN for 48 weeks (off-label) [Marcellin, 


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2016]. Thus, most patients on treatment fail to achieve a sustained off-treatment virological 
response and require extended and often life-long therapy to suppress HBV DNA.  
It has been proposed that the continued production of viral antigens by infected hepatocytes 
interferes with immune clearance of both the infected cells and circulating virus particles 
[Vanlandschoot, 2003]. In vitro studies with human peripheral blood mononuclear cells 
(PBMCs) have shown HBsAg impairs the functioning of dendritic cells and inhibits the 
activation of monocytes [Vanlandschoot, 2002; Op den Brouw, 2009]. Further, data 
suggest the production of vast excess of HBsAg (so called non-infectious “sub-viral 
particles”) likely functions as a decoy for host antibody responses. Most chronically 
infected patients produce antibody to HBsAg, but these can only be detected as immune 
complexes due to the vast excess of circulating antigen [Maruyama, 1993]. HBeAg is also 
thought to have a role in immune response evasion through down regulation of the innate 
immune system [Milich, 1998; Wu, 2009; Walsh, 2012]. As noted above, since loss of 
HBsAg expression is rarely achieved while loss of HBeAg expression occurs in a higher 
proportion of the patient population, HBsAg appears to be the main antagonist of immune 
clearance.  
Should the viral antigens be instrumental in preventing clearance of persistent infection by 
the immune system, reducing the expression of these antigens, especially HBsAg, would 
be expected to permit reconstitution of an immune response against HBV [Boni, 2007; 
Boni, 2012; Bertoletti, 2013]. Support for this hypothesis is the observation that 
spontaneous seroconversion and resolution of chronic infection is most likely in patients 
that have lower serum HBsAg levels [Chen, 2012; Höner Zu Siederdissen, 2014].  
Similarly, during treatment with NAs, patients with low HBsAg levels are more likely to 
lose HBsAg and seroconvert to anti-HBs antibody positive than patients with high HBsAg 
levels [Wursthorn, 2010; Jaroszewicz, 2011; Boni, 2012; Höner Zu Siederdissen, 2014].  
A study to examine whether inhibition of HBsAg production for a finite duration would 
lead to sustained suppression of HBV has not been possible up to the present due to the 
lack of specific inhibitors of HBsAg. 
GSK3228836, an antisense oligonucleotide, was designed to inhibit the synthesis of 
HBsAg without having a direct effect on cccDNA or integrated HBV DNA. GSK3228836 
directly targets all HBV messenger RNA (mRNAs) via Ribonuclease H (RNAse H) 
mediated degradation, resulting in the reduction of viral proteins including HBsAg. 
GSK3228836 treatment permits examination of whether reduction of HBsAg allows 
resumption of a host immune response against HBV and infected cells and can suppress 
serum HBsAg to <LLOQ.  GSK3228836 has been designed and selected to minimise risk 
of proinflammatory response associated as a class effect by methylating every cytosine in 
the antisense oligonucleotide (ASO) sequence as well as avoiding the presence of CpG 
motifs that can be recognised by pattern recognition receptors [Henry, 2008].  However, it 
is expected that GSK3228836 may trigger marginal immune activation in the local 
environment of the liver, which may not be readily detectable in periphery.  In turn, the 
intrinsic immunostimulatory activity of GSK3228836 may contribute to the efficacy in 
addition to direct pharmacodynamic response of HBsAg reduction [Yuen, 2019]. 
Recently, a functional cure of CHB infection has been endorsed as the endpoint for new 
HBV therapies [Kim, 2018]. Functional cure of CHB infection is defined as sustained 


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suppression of serum HBsAg to <LLOQ (with or without anti-HBsAg seroconversion,) 
and undetectable HBV DNA in serum, after completion of a finite course of treatment 
[Lok, 2017].  
Functional cure occurs in only a very small percentage of patients on NA therapy alone 
(approx. 3% per annum), meaning that patients frequently relapse once they are taken off 
treatment [Lok, 2017].  The high rate of relapse in these patients is hypothesised to be due 
to their inability to raise an effective immune response to the virus in the presence of high 
circulating levels of HBsAg, which continues to be produced by infected hepatocytes, even 
in the absence of ongoing viral replication.  
2.3. 
Benefit/Risk Assessment 
More detailed information about the identified and potential benefits and risks and 
expected adverse events (AEs) of GSK3228836 may be found in the Investigator’s 
Brochure. Pegylated interferon (Pegasys) was approved by the Food and Drug 
Administration (FDA) for treatment of HBV in 2005. The safety profile of PegIFN is well 
characterised.  More detailed information about the benefit risk profile of PegIFN can be 
found in the prescribing information [Pegasys PI, 2017]. 
In addition to the study related risks listed in the table, it should be noted that Corona Virus 
Disease-19 (COVID-19) is a risk for everyone. The magnitude of the risk depends on the 
prevalence in the population, frequency, duration and closeness of contact with other 
people, use of protective measures, age, ethnicity, sex and co-morbidities including 
medications. 
Currently, there is no evidence that patients with chronic HBV have increased 
susceptibility to severe acute respiratory syndrome coronavirus-2 infection.  Patients with 
uncomplicated viral hepatitis (i.e., without cirrhosis, or history of transplantation or current 
immunosuppressant use) don’t appear to be over-represented in hospitalised or intensive 
care unit cases of COVID-19, and therefore viral hepatitis isn’t considered a risk factor for 
a more severe course of COVID-19 [Fix, 2020; Boettler, 2020]. 
The actual risk of COVID-19 will vary by country and region, so study participants should 
follow any national or local hospital restrictions, as well as specific recommendations from 
their healthcare providers. 


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2.3.1. 
Risk Assessment 
Risks are summarised in the table below.  Additional withdrawal/stopping criteria for liver chemistry, drug induced vascular inflammation 
(DIVI), haematology, renal function, and PK are discussed in Section 7.1. 
Potential Risk of Clinical Significance 
Summary of Data/Rationale for Risk 
Mitigation Strategy 
Investigational Product (IP) [GSK3228836] 
Nonclinical Risks:  
Drug Induced Vascular Inflammation and Complement 
Activation 
Inflammatory and immune changes are recognised as a 
class effect of antisense oligonucleotides (ASOs). 
Vasculitis and/or perivascular inflammation has been 
described in monkey studies with many if not most ASOs. 
 
This effect has not been observed in clinical studies with 
GSK3228836 to date. 
Laboratory Evaluations: Inclusion of biomarker panels 
to look for inflammatory and immune activation that would 
be expected to accompany vascular inflammation 
 
Stopping Criteria: Proposed Monitoring Schedule and 
Stopping Rules for Drug Induced Vascular Inflammation 
and Complement Activation (see Section 7.1.4) 
 
Clinical Risks: 
Drug induced liver injury / ALT Flares  
The liver is a site of accumulation of antisense 
oligonucleotides. Liver findings in nonclinical studies of 
GSK3228836 were generally limited to mild hepatic 
enzyme elevations associated with hepatic vacuolation 
without concomitant histologic evidence of degeneration 
in mice, consistent with findings noted with other 2’-
methoxyethyl (MOE) ASOs. Review of the available 
clinical data indicates liver enzymes are increased on 
treatment with ASOs in a low percentage of patients 
compared to placebo. 
 
Alanine aminotransferase  (ALT) elevations (defined as 
ALT ≥2X upper limit normal (ULN)) were observed in the 
ISIS 505358-CS3 study.  Reductions in HBsAg were 
temporally associated with ALT elevation in all 
11 participants with ALT elevations. HBsAg reduction 
either preceded the ALT elevations or took place 
concomitantly with ALT flares. There were no changes in 
bilirubin. 
Laboratory Evaluations: hepatic enzyme monitoring as 
presented in Table 9 
 
Stopping Criteria: ALT flares are expected in the study 
population. Monitoring and stopping criteria are presented 
in Section 7.1.1 


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Potential Risk of Clinical Significance 
Summary of Data/Rationale for Risk 
Mitigation Strategy 
Thrombocytopenia leading to clinically significant bleeding 
events 
Two types of thrombocytopenia have been described for 
the 2’-MOE ASOs [Chi, 2017; Crooke, 2017].  One type is 
a rapid onset, unpredictable thrombocytopenia.  The other 
more common type is characterised by a gradual decline 
in platelets leading to mild to severe thrombocytopenia 
and can be asymptomatic or associated with mild to 
severe bleeding.  In monkeys given GSK3228836, there 
were incidences of both types in a 39-week study. 
Thrombocytopenia was not reported in the clinical studies 
with GSK3228836 (ISIS 505358-CS1 and ISIS 505358-
CS3) 
Laboratory Evaluations: platelet count  
 
Stopping Criteria: monitoring and stopping criteria are 
presented in Section 7.1.2 
Drug-Induced Kidney Injury 
Glomerulonephritis has been reported with ASOs and is 
thought to be a result of the proinflammatory effect of 
ASOs. 
No adverse events related to renal function were reported 
in Study ISIS 505358-CS3 
Laboratory Evaluations: Serum creatinine, estimated 
glomerular filtration rate (eGFR), urinalysis with 
microscopy and albumin to creatinine ratio (ACR) 
assessed per the SoA tables 
 
Stopping Criteria: Monitoring Schedule and Stopping 
Rules are presented in Section 7.1.3 
Injection site reactions 
Injection site reactions have been reported with ASOs and 
reported in clinical studies with GSK3228836 (ISIS 
505358-CS1 and ISIS 505358-CS3). 
Injection site reactions were the most common study 
treatment-related adverse events (AEs) reported and 
were Grade 1 (mild) and Grade 2 (moderate) in severity. 
Evaluations: Participants are assessed for injection site 
reactions at all visits during the on-treatment period. 
 
In order to minimise the risk of injection site reaction 
(ISR), injections should be rotated within each anatomical 
site or site(s) of injection should be changed 
administration-to-administration. Injection into areas with 
ongoing injection site reactions should be avoided. 
Investigational Product (IP) [PegIFN] 
Clinical Risks1:  
ALT Flares 
Chronic hepatitis B participants experienced transient 
acute exacerbations (flares) of hepatitis B (ALT elevation 
greater than 10-fold higher than the upper limit of normal) 
during PegIFN treatment (12% and 18%) and post-
treatment (7% and 12%) in HBeAg negative and HBeAg 
positive participants, respectively. 
Laboratory Evaluations: hepatic enzyme monitoring as 
presented in the SoA 
 
Stopping Criteria: ALT flares are expected in the study 
population. Monitoring, dose adjustment and stopping 
criteria are based on the Pegasys label and presented in 
Section 7.2 


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Potential Risk of Clinical Significance 
Summary of Data/Rationale for Risk 
Mitigation Strategy 
Severe CNS effects, particularly depression, suicidal 
ideation and attempted suicide 
Severe CNS effects, particularly depression, suicidal 
ideation and attempted suicide have been observed in 
some patients during PegIFN therapy, and even after 
treatment discontinuation mainly during the 6-month 
follow-up period. Other central nervous system (CNS) 
effects including aggressive behaviour (sometimes 
directed against others such as homicidal ideation), 
bipolar disorders, mania, confusion and alterations of 
mental status have been observed with alfa interferons. 
The Columbia Suicide Severity Rating Scale and Beck 
Depression Inventory-II will be completed by participants 
as per the SOA during and post treatment. 
 
Participants displaying evidence of depression will be 
managed as per Table 12. 
 
If participants develop new or worsening psychiatric 
symptoms or if suicidal ideation is identified, treatment 
should be discontinued, and the patient followed up with 
psychiatric intervention as appropriate. 
Refer to Section 8.2.7 Suicidal Ideation and Behaviour 
Risk Monitoring 
 
Decrease in haemoglobin, platelet count, total white blood 
cell (WBC) count and ANC 
PegIFN treatment has been associated with decreases in 
haemoglobin, platelet count, total WBC count and ANC. 
Eligibility for PegIFN treatment will be assessed prior to 
starting treatment as per Section 5.3 
 
Laboratory Evaluations: Haematology monitoring as per 
the SOA. 
Stopping Criteria Dose adjustment and stopping criteria 
are based on the Pegasys label and presented in 
Section 7.2 
Endocrine disorders: 
Thyroid function abnormalities or worsening of pre-
existing thyroid disorders 
 
 
Hypoglycaemia/Hyperglycaemia/Diabetes Mellitus 
 
 
Thyroid function abnormalities or worsening of pre-
existing thyroid disorders have been reported with the use 
of alfa interferons, including PegIFN.  
 
 
 
 
 
Hypoglycaemia, hyperglycaemia and diabetes mellitus 
have been observed with PegIFN.  
 
 
Participants with uncontrolled thyroid function are 
excluded from this study. 
Thyroid function tests will be monitored as per the SOA. 
Abnormalities of thyroid function should be managed 
according to local guidance. If thyroid function cannot be 
adequately managed PegIFN treatment should be 
discontinued. 
 
Participants with uncontrolled diabetes are excluded from 
this study. 
Blood glucose will be monitored throughout the study. 


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Potential Risk of Clinical Significance 
Summary of Data/Rationale for Risk 
Mitigation Strategy 
Abnormalities of blood glucose should be managed 
according to local guidance. If blood glucose cannot be 
adequately managed PegIFN treatment should be 
discontinued. 
 
Cardiovascular disorders: Hypertension, supraventricular 
arrhythmias, congestive heart failure, chest pain and 
myocardial infarction 
These have been associated with alfa interferon 
therapies, including PegIFN.  
Patients with significant/unstable cardiac disease are 
excluded from the study. 
 
Participants will undergo an electrocardiogram (ECG) at 
screening and prior to PegIFN treatment. 
 
If there is any deterioration of cardiovascular status, 
therapy should be suspended or discontinued. 
Retinopathy including retinal haemorrhages, cotton wool 
spots, papilloedema, optic neuropathy and retinal artery 
or vein obstruction which may result in loss of vision 
These have been reported in rare instances with PegIFN.  
All participants will have a baseline eye examination.  
 
Any participant complaining of a change in vision or a 
new visual disturbance will have an urgent eye 
examination and PegIFN should be discontinued.  
Fever/Infections  
Serious infections (bacterial, viral, fungal) and sepsis 
have been reported during treatment with alfa interferons 
including PegIFN.  
Appropriate anti-infective therapy should be started 
immediately, and discontinuation of PegIFN should be 
considered 
Pulmonary symptoms, including dyspnoea, pulmonary 
infiltrates, pneumonia, and pneumonitis 
These have been reported during therapy with PegIFN.  
Participants with clinically significant pulmonary disease 
are excluded from the study. 
 
Any participant developing fever, cough, and dyspnoea or 
other respiratory symptoms must have a chest X ray 
taken. If there is evidence of persistent or unexplained 
pulmonary infiltrates or pulmonary function impairment, 
treatment should be discontinued. 
Exacerbation or provocation of psoriasis. 
Use of PegIFN has been associated with exacerbation or 
provocation of psoriasis. 
In cases of onset or worsening of psoriatic lesions, 
discontinuation of therapy will be considered. 


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Potential Risk of Clinical Significance 
Summary of Data/Rationale for Risk 
Mitigation Strategy 
Development of autoantibodies and autoimmune 
disorders 
These have been reported during treatment with alfa 
interferons.  
Patients with signs or symptoms compatible with 
autoimmune disorders will be evaluated carefully, and the 
benefit-risk of continued interferon therapy should be re-
assessed  
1. 
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2.3.2. 
Benefit Assessment 
Treatment of CHB with NAs has been effective in reducing the long-term complications 
of CHB, but evidence is emerging that HBsAg loss is associated with lower rates of 
hepatocellular carcinoma [Kim, 2014; Yip, 2016]: Even patients who achieve complete 
viral suppression experience significantly lower rates of hepatocellular carcinoma if they 
are able to achieve HBsAg loss.  Thus, there is a need in patients with CHB for a finite 
treatment that allows them to achieve immune control of their infection (functional cure, 
defined as HBsAg loss with HBV DNA suppression), removing the need for lifelong 
therapy and to improve long term disease outcomes, particularly development of 
hepatocellular carcinoma. 
GSK3228836 demonstrated target engagement in CHB patients who were not on treatment 
and in CHB patients on stable NA therapy. Overall, continued clinical development of 
GSK3228836 is supported by the results from the completed study ISIS 505358-CS3.  It is 
not known if there will be any direct therapeutic benefit to the C HB population that will 
be included in this study. However, their participation could potentially contribute to the 
development of an improved treatment for patients with CHB. 
Numerous studies have looked at predictors of response to PegIFN in CHB.  Lower levels 
of baseline HBsAg consistently predict the highest response rates (RR) to PegIFN [Ren, 
2019].  In study ISIS 505358-CS3 it was demonstrated that 4 weeks treatment with 
GSK3228836 weekly resulted in marked declines in serum HBsAg in the majority of 
participants, 
including 
four 
participants 
that 
achieved 
HBsAg 
seroclearance 
(<0.05 IU/mL), but subsequently relapsed.  A GSK3228836 mediated reduction of serum 
HBsAg level prior to starting a short course of PegIFN therapy is expected to result in 
higher rates of HBsAg seroclearance and durability of response than if either agent was 
used alone and provide additional benefit over GSK3228836 treatment alone. 
2.3.3. 
Overall Benefit: Risk Conclusion 
Considering the measures taken to minimise risk to participants in this study, the 
potential risks identified in association with GSK3228836, PegIFN and from COVID-19 
are balanced by the anticipated benefits that may be afforded to participants with CHB. 
 
 


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3. 
OBJECTIVES AND ESTIMANDS  
Objectives 
Estimands and Endpoints 
Primary 
Efficacy: To investigate the efficacy of two 
different durations of GSK3228836 followed 
by up to 24 weeks of PegIFN therapy in 
participants with CHB on stable NA therapy. 
The main Estimand supporting the primary objective is 
defined as: 
• 
Population: Participants with CHB on stable NA 
therapy  
• 
Treatment: 300 mg GSK3228836 for 12 or 24 weeks 
followed by up to 24 weeks of PegIFN therapy while 
on stable NA therapy 
• 
Variable (Categorical): Participants achieving 
Sustained Virologic Response (SVR) (HBsAg 
<LLOQ and HBV DNA <LLOQ) for 24 weeks after 
the planned end of sequential treatment, without use 
of any rescue medication 
• 
Intercurrent Events: 
o Discontinuation of, interruption in, and non-
adherence to GSK3228836 and PegIFN not 
related to any wide disruptive events (such as 
COVID-19 pandemic) will be ignored (treatment 
policy strategy).  
o Ineligibility to receive PegIFN will be ignored 
(treatment policy strategy) 
o Use of rescue medication (composite strategy). 
o Wide disruptive events (such as COVID-19 
pandemic) leading to discontinuation of, 
interruption in, and non-adherence to 
GSK3228836 and PegIFN will be handled 
assuming they had not happened (hypothetical 
strategy). 
• 
Population Summary: The percentage of 
participants in each treatment group who achieve 
SVR, without use of any rescue medication 
The main primary estimand supporting the primary 
objective in participants with CHB on stable NA therapy 
in each treatment arm is the percentage of participants 
that achieve SVR (HBsAg <LLOQ and HBV DNA 
<LLOQ) for 24 weeks after the planned end of sequential 
treatment in the absence of rescue medication, 
regardless of ineligibility to receive PegIFN, 
discontinuation of, interruption in, and non-adherence to 
GSK3228836 and PegIFN, had they not been affected 
by wide disruptive events. 
 
Three supplementary Estimands are defined to support 
the primary objective: 
• 
The first supplementary Estimand is defined in the 
same way as the main Estimand, except the 
assessment time frame for patients achieving SVR 
will be 24 weeks after the actual end of treatment. 


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Objectives 
Estimands and Endpoints 
Therefore, the strategy for intercurrent events of 
treatment discontinuation will be while-on-treatment. 
This supplementary estimand supporting the primary 
objective in participants with CHB on stable NA 
therapy in each treatment arm is the percentage of 
participants that achieve SVR (HBsAg <LLOQ and 
HBV DNA <LLOQ) for 24 weeks after the actual end 
of sequential treatment in the absence of rescue 
medication, regardless of ineligibility to receive 
PegIFN, discontinuation of, interruption in, and non-
adherence to GSK3228836 and PegIFN, had they 
not been affected by wide disruptive events. 
 
• 
The second supplementary Estimand is to 
understand the relationship between the PegIFN 
duration and achieving SVR for 24 weeks after the 
actual end of treatment, defined as: 
o Population: Participants with CHB on stable NA 
therapy  
o Treatment: 300 mg GSK3228836 for 12 or 24 
weeks followed by 24 weeks of PegIFN therapy 
while on stable NA therapy 
o Variable: The relationship between SVR for 24 
weeks after actual end of treatment and the 
duration of PegIFN received by participants  
o Intercurrent Events:  
▪ 
Discontinuation and delayed start of, 
PegIFN, will be accounted to reflect the 
actual duration from the first to the last 
dose of PegIFN received (while-on-
treatment strategy).  
▪ 
Interruption in and other non-adherence 
to PegIFN will be ignored (treatment 
policy strategy) 
▪ 
Discontinuation of, interruption in and 
non-adherence to GSK3228836 will be 
ignored (treatment policy strategy) 
▪ 
Use of rescue medication (composite 
strategy). 
▪ 
Wide disruptive events (such as 
COVID-19 pandemic) leading to 
discontinuation and delayed start of, 
PegIFN will be handled with while-on-
treatment strategy; wide disruptive 
events leading to interruption in and 
other non-adherence to PegIFN will be 
ignored (treatment policy strategy);  
wide disruptive events leading to 
discontinuation of, interruption in, and 


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Objectives 
Estimands and Endpoints 
non-adherence to GSK3228836 will be 
ignored (treatment policy strategy). 
o Population Summary: The percentage of 
participants achieving SVR for 24 weeks after 
the actual end of treatment by PegIFN 
treatment duration categorical grouping in each 
treatment arm  
• 
The second supplementary Estimand (supporting 
the primary objective in participants with CHB on 
stable NA therapy) is the percentage of participants 
achieving SVR for 24 weeks after the actual end of 
treatment by PegIFN treatment duration categorical 
grouping in each treatment arm, taking into account 
discontinuation and delayed start of PegIFN, 
regardless of interruption in and other non-
adherence to PegIFN, regardless of discontinuation 
of, interruption in and non-adherence to 
GSK3228836. 
 
• 
The third supplementary Estimand is defined in the 
same way as the main Estimand, except the 
strategy for intercurrent events of PegIFN ineligibility 
for more than 12 weeks and/or missing more than 
12 doses of PegIFN will be principal stratum. This 
supplementary Estimand supporting the primary 
objective is the percentage of participants in each 
treatment arm that achieve SVR (HBsAg <LLOQ 
and HBV DNA <LLOQ) for 24 weeks after the 
planned end of sequential treatment in participants 
with CHB on stable NA therapy and receiving at 
least 12 doses of PegIFN, in the absence of rescue 
medication, regardless of discontinuation of, 
interruptions in or non-adherence to GSK3228836 
had they not been affected by wide disruptive 
events. 
Secondary 
Efficacy: To assess the efficacy of 
GSK3228836 and PegIFN sequential therapy 
on biomarkers and virus specific antibody 
responses  
The Estimand supporting the objective is defined as: 
• 
Population: Participants with CHB on stable NA 
therapy; For the time to ALT normalisation variable, 
population will be aforementioned participants with 
baseline ALT >ULN. 
• 
Treatment: 300 mg GSK3228836 for 12, or 24 
weeks followed by 24 weeks of PegIFN therapy 
while on stable NA therapy 
• 
Categorical Variables: 
o Achieving HBsAg <LLOQ and HBV DNA 
<LLOQ at two time points: (1) the planned end 


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of treatment and (2) at the end of 24 weeks 
follow-up 
o Categorical changes from baseline in HBsAg 
(e.g., <0.5, ≥0.5, ≥1, ≥1.5, ≥3 log10 IU/mL) at 
each scheduled visit or analysis window. 
o ALT normalisation (ALT ≤ULN) over time in 
absence of rescue medication in participants 
with baseline ALT >ULN  
Population summary is the percentage of 
participants in each category for each treatment 
group. 
o HBe antibody (anti-HBeAg) levels. 
 
• 
Continuous Variables: 
o Actual values and change from baseline over 
time for HBsAg, HBV DNA and HBeAg 
o Actual values and change from baseline over 
time for HBs antibody (anti-HBsAg) levels over 
time 
o Actual values and change from baseline over 
time for ALT 
Population summary is the mean values and 
the mean changes from baseline of each 
variable for participants in each treatment 
group. 
• 
Time to Event Variable:  
o Time to ALT normalisation in absence of rescue 
medication in participants with baseline 
ALT>ULN 
Population summary is the Turnbull’s estimator 
for non-parametric estimation of Time to ALT 
normalisation in each treatment arm 
• 
Intercurrent Events: Discontinuation of, interruption 
in, and non-adherence to GSK3228836 and PegIFN 
will be ignored (treatment policy); PegIFN ineligibility 
will be ignored (treatment policy); Rescue 
medication will be ignored (treatment policy), except 
for ALT normalisation which can only be achieved in 
the absence of rescue medication; Wide disruptive 
events (such as COVID-19 pandemic) leading to 
discontinuation of, interruption in, and non-
adherence to GSK3228836 and PegIFN will be 
handled with Treatment Policy Strategy. 
• 
The group of estimands supporting this objective is 
the population summary for each variable in each 
treatment arm in the population regardless of 
discontinuation of, interruption in or non-adherence 
to GSK3228836 and PegIFN, and regardless of 
rescue medication (except for ALT normalisation 
which can only be achieved in the absence of 
rescue medication) or PegIFN ineligibility. 
 


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Objectives 
Estimands and Endpoints 
Efficacy: To investigate the durability of 
virological response after sequential therapy 
with 12 weeks of GSK3228836 followed by 
24 weeks of PegIFN in participants with CHB 
on stable NA therapy for up to 36 weeks off 
treatment. 
The same definition as the above secondary estimand, 
focusing on the timepoints following the 24 weeks off-
treatment period in the treatment arm of 300 mg 
GSK3228836 for 12 weeks followed by up to 24 weeks 
of PegIFN therapy while on stable NA therapy.  
Efficacy: To compare efficacy between 
different treatment durations: 
12 or 24 weeks of GSK3228836 followed by 
24 weeks PegIFN 
The same definition as the primary estimand except 
treatments and population summary are defined as: 
• 
Treatments: Arms 1 and 2. One treatment 
comparison between Arms 1 & 2 up to 24 weeks off-
treatment 
• 
Population summary: difference in proportion of 
participants who achieve SVR between treatment 
arms 
The group of estimands supporting this objective in 
participants with CHB on stable NA therapy is the 
difference between treatment arms 1 and 2 in the 
proportion of participants that achieve SVR for 24 weeks 
after the planned end of sequential treatment, in the 
absence of rescue medication, regardless of ineligibility 
to receive PegIFN, regardless of discontinuation of, 
interruption in or non-adherence to GSK3228836 and 
PegIFN had they not been affected by wide disruptive 
events. 
Exploratory 
Pharmacokinetics (PK) and PK-
pharmacodynamic (PD) relationships of 
GSK3228836 and PegIFN: To evaluate PK, 
PK-efficacy relationship and PK-safety 
relationship 
Efficacy assessments for PK/PD relationship include but 
not limited to 
• 
Categorical: virologic response, HBsAg level 
<LLOQ, HBV DNA level <LLOQ, and 
seroconversion (anti-HBsAg and anti-HBeAg); 
• 
Change from baseline: HBsAg, HBV DNA, anti-
HBsAg and anti-HBeAg levels; 
• 
Time to event: virologic response (HBsAg and HBV 
DNA levels <LLOQ), nadir of HBsAg and HBV DNA, 
HBsAg level <LLOQ, HBV DNA level <LLOQ, 
seroconversion (anti-HBsAg and anti-HBeAg), and 
peak of ALT flares 
Safety assessments for PK/PD relationship include but 
not limited to vital signs, laboratory measurements and 
adverse events 
PK assessments include but not limited to C and 
terminal half-life (t½). 
Safety and Tolerability: To investigate the 
safety profile of sequential therapy with 
GSK3228836 (up to 24 weeks) followed by 
PegIFN (up to 24 weeks) in participants with 
CHB on stable NA therapy. 
Clinical assessments including laboratory measurements 
and adverse events at timepoints specified in the SoA 


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Objectives 
Estimands and Endpoints 
Biomarkers: To assess the effect of 
GSK3228836 and PegIFN sequential therapy 
on immunological biomarkers. 
 
To describe the relationship(s) between 
virology biomarkers including HBsAg and 
immunological biomarkers. 
 
 
Laboratory measurements of and correlation between 
the following: 
o 
Virological biomarkers, including specific viral 
parameters (HBsAg, HBeAg, HBV DNA, HBV 
RNA, HBcrAg) 
o 
Soluble biomarkers, including levels of circulating 
cytokines and chemokines 
o 
Markers of immune cell function, including relative 
frequencies of immune cell subsets among 
PBMCs, activation status as determined by 
phenotyping and gene expression patterns, and 
functional assays including HBV-specific cytokine 
and/or antibody production 
Timepoints are specified in the SoA 
 
4. 
STUDY DESIGN 
4.1. 
Overall Design 
This is a Phase IIb, multi-centre, randomised, open-label study to assess the efficacy and 
safety of sequential treatment with GSK3228836 (300 mg/week for 12 or 24 weeks) 
followed by PegIFN (180 mcg/week for up to 24 weeks) in participants with CHB on 
stable NA therapy.  During the GSK3228836 treatment period, a 300 mg loading dose 
will be administered on Day 4 and Day 11.  Participants will continue their NA therapy 
for the duration of the study. 
Participants will be randomised (1:1) into one of two parallel treatment arms. 
1. 300 mg GSK3228836 once/week for 24 weeks (plus loading dose on Day 4 and 
11) followed by PegIFN (180 mcg/week for up to 24 weeks). Participants will be 
followed up for an additional 24 weeks (off-treatment phase) once PegIFN 
treatment is complete. 
CCI


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2. 300 mg GSK3228836 once/week for 12 weeks (plus loading dose on Day 4 and 
11) followed by PegIFN (180 mcg/week for up to 24 weeks).  Participants will be 
followed up for an additional 36 weeks (off-treatment phase) once PegIFN 
treatment is complete. 
The planned duration of GSK3228836 is 24 weeks and 12 weeks in Treatment Arm 1 and 
2 respectively.  If a participant prematurely discontinues GSK3228836 treatment the 
participant is encouraged to complete the SoA as per the planned GSK3228836 dosing 
period.  At the end of the planned GSK3228836 dosing period, participants will be re-
assessed for eligibility to start PegIFN treatment based on the label. 
1. Participants immediately eligible for PegIFN will begin treatment 
2. Participants who are not considered eligible will be re-assessed for eligibility and 
may delay start of PegIFN treatment for up to 12 weeks. 
3. Participants who fail to meet PegIFN eligibility criteria by PegIFN Eligibility 
Week 13 (i.e. can no longer receive at least 12 weeks of PegIFN treatment) will 
not receive treatment with PegIFN. 
Note: all participants are expected to end PegIFN treatment at the same time, regardless 
of when they start therapy (Treatment Group 1: all participants should complete treatment 
by Week 48; Treatment Group 2: Week 36). 
As such, the planned treatment duration with PegIFN for participants on study 209348 
may vary from a minimum of 12 weeks to a maximum of 24 weeks. 
Participants will be randomised 1:1. Populations will be stratified based on HBsAg level 
(HBsAg ≤3 log IU/mL and >3 log IU/mL) and whether participants are HBeAg positive 
or negative. Lower HBsAg has been associated with increased likelihood of HBsAg loss 
in patients treated with PegIFN-containing regimens [Ren, 2019; Lee, 2018; Yeo, 2019].  
With existing therapies different responses have also been observed in HBeAg positive 
and negative patient populations [Ren, 2019]. 
4.2. 
Scientific Rationale for Study Design 
The rationale for the proposed study is to evaluate the potential of up to 48 weeks of 
sequential therapy with GSK3228836 and PegIFN to achieve sustained loss of HBsAg and 
HBV DNA in participants on stable NA therapy.  Sustained virologic response is defined 
as undetectable levels of HBsAg and HBV DNA on treatment and maintaining this for a 
minimum of 24 weeks off-treatment (GSK3228836 and PegIFN).   
This Phase IIb study has been designed to answer two questions which are considered 
critical to the overall development of GSK3228836 to achieve functional cure in patients 
with CHB: 
1. Does sequential therapy with GSK3228836 (12 or 24 weeks) followed by up to 
24 weeks of PegIFN result in improved rates of efficacy in NA-controlled CHB 
patients compared to GSK3228836 monotherapy?  


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2. Is the efficacy rate affected by the duration of treatment with GSK3228836 prior to 
starting PegIFN? 
Addressing these questions is critical to our understanding of the potential for sequential 
therapy with immunomodulators to achieve functional cure in patients with CHB, and to 
optimise the duration of treatment with GSK3228836 prior to starting PegIFN (or other 
immunomodulators in future studies). 
The proposed study will investigate efficacy of two different sequential treatment regimens 
with GSK3228836 and PegIFN (Pegasys; Hoffman La-Roche) in participants with CHB 
that are controlled with stable NA therapy. 
Rationale for Patient Population 
Participants will continue their NA therapy for the duration of the study.  Liver flares 
(elevated ALT and related biomarkers) are common occurrences during treatment of CHB 
patients with interferon-containing therapies, and flares were also observed after 4 weeks 
of treatment with GSK3228836 in study ISIS 505358-CS3.  Although we believe these 
flares to be therapeutic in nature and related to immune clearance of HBV from the liver, 
our intention is to manage the risk of possible exacerbations of hepatitis by first evaluating 
proof of concept (POC) in participants whose infection is already under control with stable 
NA therapy.  Patients whose infection is controlled by NAs still have HBsAg detectable in 
serum due to the presence of HBV cccDNA and integrated DNA in infected hepatocytes.  
As such, this patient population has the best benefit:risk profile for early POC studies with 
experimental therapies.  
Rationale for Selection of PegIFN  
PegIFN is an immunomodulatory therapy approved for use in CHB patients.  Rates of 
sustained loss of HBsAg following up to 48 weeks of treatment typically vary from 1- 9% 
at 24 weeks off-treatment follow-up when used in combination with NAs [Ren, 2019]. 
Rationale for Sequential Therapy (GSK3228836 followed by PegIFN) 
Numerous studies have looked at predictors of response to PegIFN use in CHB.  Lower 
levels of baseline HBsAg consistently predict the highest response rate to PegIFN in terms 
of HBsAg loss [Ren, 2019].  In study ISIS 505358-CS3, it was demonstrated that 4 weeks 
treatment with 150 mg or 300 mg GSK3228836 weekly (including loading doses) resulted 
in marked declines in serum HBsAg in the majority of participants, including 4 who 
experienced transient HBsAg seroclearance.  The proposed design of study 209348 tests 
the hypothesis that using GSK3228836 to reduce serum HBsAg load prior to starting a 
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short course of PegIFN therapy will result in higher rates of sustained seroclearance than 
if either agent was used alone.  
Rationale for Duration of GSK3228836 Treatment (12 or 24 weeks) 
The current hypothesis of functional cure is based on the ability of a patient to raise an 
effective immune response to HBV in infected hepatocytes once immunosuppressive 
HBsAg has been lost from the blood.  The duration of suppression of HBsAg required to 
enable reconstitution of anti-HBV immunity is still unknown.  In the majority of 
participants that responded to GSK3228836 in study ISIS 505358-CS3, serum HBsAg 
levels were still declining when treatment was stopped after 4 weeks.  Of note, in 
participants that did not become HBsAg <LLOQ, reductions of HBsAg had not yet reached 
a plateau during treatment, suggesting that continued dosing has the potential to further 
reduce HBsAg levels.  Taken together, the data suggest that a longer duration of treatment 
with GSK3228836 may be required to increase the rate of participants achieving HBsAg 
levels <LLOQ.  In the proposed study, we will investigate 2 different durations of treatment 
with GSK3228836 (12 and 24 weeks at 300 mg/week) prior to starting PegIFN in order to 
optimise rates of sustained seroclearance. 
Rationale for Duration of PegIFN (up to 24 weeks) 
Current PegIFN treatment guidelines recommend 48 weeks treatment.  In this study 
PegIFN will be administered for a maximum of 24 weeks duration.  The rationale for 
administering a shorter duration of PegIFN is: 
1. PegIFN administration is associated with numerous adverse effects and can be 
difficult to tolerate. This may in part explain the low use of PegIFN despite higher 
rates of HBeAg and HBsAg loss compared to nucleos(t)ide therapy.  
2. Shorter duration of PegIFN may be more attractive to providers and patients. 
When GSK has sought advice from external experts on the role of PegIFN 
therapy in the context of our development program, the experts considered up to 
24 weeks of PegIFN reasonable to keep the total duration of treatment i.e. 
approximately 1 year since both GSK3228836 and PegIFN are administered via 
subcutaneous injections. 
3. Lower baseline levels of HBsAg prior to PegIFN therapy have been associated 
with better treatment outcomes.  In this study, the preceding GSK3228836 
treatment is anticipated to reduce HBsAg to lower or even undetectable levels 
prior to administration of PegIFN.  In this context it is unclear whether longer 
duration of PegIFN would be beneficial. 
4. A systematic review of treatment of CHB infection by PegIFN showed that 
PegIFN induced sustained biochemical and virological responses (ALT 
normalisation, HBeAg seroconversion, HBV DNA suppression) in about one-
thirds of patients after 6 or 12 months of therapy. Importantly, the studies with 
longer duration of PegIFN treatment didn’t show greater efficacy for the primary 
endpoints (virological responses), although the rate of HBsAg loss appeared 
slightly better with 12 months of treatment.  


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4.2.1. 
Participant Input into Design 
A small group of patients with CHB were asked to review an example informed consent 
form in related study 209668. The patients provided feedback for more clarity in the 
informed consent form regarding the purpose of the study and optional assessments (e.g., 
biomarkers), mode of administration of GSK3228836, the study burden in both terms of 
visit schedule and duration of visit.  Efforts to reduce the burden of visits were encouraged.  
Input from these patients will be incorporated into the Informed Consent Form.  The study 
team reviewed the blood collection timepoints and made changes to balance participant 
burden with the data/timepoints needed for safety and efficacy analyses. 
Due to the feedback from patients that the number of visits may be challenging (weekly 
visits to the clinic/hospital), the study team are working with countries/sites to provide an 
option where participants may use a centralised home nursing provider.  The home nursing 
providers will go to the participant, decreasing the number of times the participant must 
travel to/from the clinic/hospital.  Only selected visits will have the option to be performed 
as a home visit, these will include drug administration, blood draws, participant 
assessments and data collection. The full specifications of the home nursing services will 
be outlined in the SRM. 
4.3. 
Justification for Dose 
GSK3228836 Dose Levels, Frequency and Duration 
GSK3228836 has been evaluated over a 4-week dosing duration in both healthy volunteers 
(ISIS 505358-CS1 study) and in participants with CHB (ISIS 505358-CS3 study). In both 
studies, GSK3228836 was administered subcutaneously on Study Day 1, 4, 8, 11, 15, and 
22. The loading schedule (i.e. loading doses) on Day 4 and Day 11 was included in order 
to accelerate the achievement of steady state concentration in the liver to increase the 
likelihood of observing anti-HBV activity during such a short treatment duration.  The 
loading schedule for GSK3228836 will be included in both treatment arms of study 
209348. 
To date, the highest dose of GSK3228836 evaluated was 2700 mg over 4 weeks (450 mg 
per injection including loading schedule; n=3) in healthy volunteers, and 1800 mg over 
4 weeks (300 mg per injection including loading schedule; n=17) in participants with CHB. 
In participants with CHB dosed with 300 mg per injection in ISIS 505358-CS3 study, 
continuous HBsAg declines were observed in many participants during GSK3228836 
treatment, with 2 participants achieving HBsAg seroclearance by study Week 4. In both 
participants who achieved seroclearance by Week 4, HBsAg subsequently became 
detectable after discontinuation of GSK3228836 dosing. Moreover, many participants had 
declining HBsAg levels that hadn’t plateaued by the end of treatment. Taken together, the 
data suggest that a longer duration of GSK3228836 therapy may be required to both 
increase the rate of seroclearance and to achieve sustained seroclearance. 
In study 209348, two different treatment durations with GSK3228836 (12 weeks and up to 
24 weeks) will be studied prior to initiating treatment with PegIFN to assess differences in 
the efficacy endpoints (e.g., proportion of participants achieving seroclearance, durability 
of response): 


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1. 300 mg GSK3228836 for 24 weeks followed by up to 24 weeks of PegIFN; 
2. 300 mg GSK3228836 for 12 weeks followed by up to 24 weeks of PegIFN; 
PegIFN 
PegIFN will be dosed according to the SoA (Section 1.3) for CHB patients for up to 
24 weeks.  Numerous clinical studies have evaluated the safety and tolerability of PegIFN 
when dosed with NAs (Ren, 2019).  Except for telbivudine, which is contraindicated in the 
PegIFN label, no worsening of the safety and tolerability profile of PegIFN and/or 
commonly prescribed NAs has been reported when dosed concurrently in CHB patients. 
Co-administration of GSK3228836 and Nucleos(t)ide Analogues 
GSK3228836 is unlikely to be a victim or perpetrator of drug-drug interactions when 
administered with NAs due to their divergent absorption, distribution, metabolism, and 
excretion pathways. 
Drug-drug interactions with GSK3228836 as victim: 
Upon entry into the system circulation, GSK3228836 rapidly becomes highly bound 
(approximately 95%) to serum proteins and is then rapidly distributed to tissues. 
GSK3228836 enters hepatic cells through target-mediated endocytosis and enters renal 
cells through micropinocytosis [Geary, 2008; Bennett, 2010]. GSK3228836 is eliminated 
primarily via nucleolytic degradation by endogenous endonucleases [Geary, 2008]. None 
of these processes is inhibited or induced by small-molecule drugs including NAs (e.g., 
tenofovir, entecavir, lamivudine, adefovir and telbivudine).  
In Cohorts 1-3 of the ISIS 505358-CS3 study, treatment naïve participants were started on 
tenofovir after treatment ended; in Cohort 4, where participants were NA-experienced, the 
majority of participants entered the study on entecavir.  Clinical data from this study 
suggest that co-administration of entecavir is unlikely to impact plasma PK of 
GSK3228836.  GSK3228836 was co-administered with entecavir throughout the treatment 
period in 4 participants in Cohort 4 while administered alone in 18 participants in Cohorts 
1 to 3.  GSK3228836 plasma concentration was comparable with entecavir (n=4) and 
without entecavir (n=18).  Dose normalisation was applied to Cohort 1 as 150 mg of 
GSK3228836 was administered in Cohort 1 as compared to 300 mg in Cohorts 2 to 4.  
Drug-drug interactions with GSK3228836 as perpetrator: 
Tenofovir, entecavir, and other NAs circulated in the blood stream with little binding to 
serum proteins [Bristol-Myers Squibb, 2018; Gilead 2018]. Tenofovir, entecavir, 
lamivudine, adefovir and telbivudine are predominantly renally eliminated from systemic 
circulation [Epivir, 2002; Kearney, 2004; Hepsera, 2012; Tyzeka, 2013; Entecavir, 2015; 
Bristol-Myers Squibb, 2018; Gilead, 2018]. These 5 drugs undergo a combination of 
glomerular filtration and tubular secretion, which have been reported to be mediated by 
one or more of the following transporters: the organic anion transporter (OAT) 1, OAT3, 
the organic cation transporter (OCT) 1, and OCT2 [Cihlar, 2001; Cihlar, 2004; Servais, 
2006; Uwai, 2007; Minuesa, 2009; Yanxiao, 2011; Xu, 2013].  It has been shown that 
2’-MOE ASO is neither a substrate nor an inhibitor of OAT1, OAT3, OCT1 and OCT2 


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[Yu, 2016; Shemesh, 2017]. Therefore, although GSK3228836 was shown to be 
extensively distributed into the kidney in non-clinical studies, it is unlikely to interact with 
tenofovir, entecavir, lamivudine, adefovir, telbivudine, or other NAs. 
In Cohorts 1-3 of the ISIS 505358-CS3 study, treatment naïve participants were started on 
tenofovir after treatment ended; in Cohort 4, where participants were NA-experienced, the 
majority of participants were on entecavir.  Clinical data from this study suggest that 
co-administration of GSK3228836 is unlikely to impact efficacy and safety profiles.  In 
Cohorts 1 to 3 in ISIS 505358-CS3 study, GSK3228836 was administered alone for 
4 weeks, and then tenofovir dosing was started on Study Day 29 (7 days after the last dosing 
of GSK3228836). Given the long plasma and tissue half-life of GSK3228836 
(approximately 3 weeks), there is a period of at least several weeks during which there was 
a substantial presence of both drugs in the plasma, liver and other tissues.  Potent reduction 
of HBV DNA was observed following initiation of tenofovir in all participants.  There were 
no obvious differences in tenofovir potency and efficacy in participants who received 
150 mg of GSK3228836 (Cohort 1), 300 mg of GSK3228836 (Cohorts 2 and 3), and 
placebo (no GSK3228836).  There were no adverse event or clinical laboratory results that 
may indicate a change in tenofovir safety profile due to drug-drug interaction with 
GSK3228836. 
Clinical data suggest that co-administration of GSK3228836 is also unlikely to impact 
tenofovir PK.  In Cohorts 1 to 3 (n=18) in the ISIS 505358-CS3 study, a daily dose of 
300 mg tenofovir was initiated on Day 29 (7 days after the last dose of GSK3228836), and 
the tenofovir pre-dose plasma concentration was measured on Day 36, after tenofovir has 
been dosed for one week.  Hepatic GSK3228836 concentration is at steady state after 
4 weeks of dosing with the loading schedule, and there should be a substantial amount of 
GSK3228836 in the liver on Day 36 (2 weeks after the last dose of GSK3228836) due to 
the hepatic half-life of 3 weeks.  Therefore, pre-dose tenofovir plasma concentration on 
Day 36 was deemed to be appropriate to provide preliminary evidence of impact of 
GSK3228836 on tenofovir PK.  Pre-dose tenofovir plasma concentration on Day 36 was 
comparable to that in the public domain, suggesting that co-administration of GSK3228836 
is unlikely to impact tenofovir PK. 
Clinical data suggest that co-administration of GSK3228836 is unlikely to impact entecavir 
PK. In Cohort 4 in ISIS 505358-CS3 study, entecavir was co-administered with 
GSK3228836 throughout the treatment period in 4 participants and administered alone in 
2 participants (participants on placebo).  Entecavir concentration was comparable in 
participants with GSK3228836 (n=4) and without GSK3228836 (n=2), and comparable to 
that in public domain, suggesting that co-administration of GSK3228836 is unlikely to 
impact entecavir PK 
4.4. 
End of Study Definition 
The end of the study is defined as the date of the last visit of the last participant in the 
study. 
A participant is considered to have completed the study if they completed all phases of 
the study for which they were eligible, including the last visit. 


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5. 
STUDY POPULATION 
Prospective approval of protocol deviations to recruitment and enrollment criteria, also 
known as protocol waivers or exemptions, is not permitted. Participants are eligible to be 
included in the study only if all of the following criteria apply: 
5.1. 
Inclusion Criteria 
AGE 
1. At least 18 to 75 years of age at the time of signing the informed consent [if 
country/site age requirements for consent differ, the more stringent (e.g., higher 
age) restriction will be required for that country/site]. 
TYPE OF PARTICIPANT AND DISEASE CHARACTERISTICS  
2. Participants who are eligible to be treated with PegIFN (Table 8) 
3. Documented chronic HBV infection ≥6 months prior to screening AND currently 
receiving stable NA therapy except telbivudine, defined as no changes to their NA 
regimen from at least 6 months prior to screening and with no planned changes to 
the stable regimen over the duration of the study 
4. Plasma or serum HBsAg concentration >100 IU/mL 
5. Plasma or serum HBV DNA <90 IU/mL 
6. Alanine Transaminase (ALT) ≤2 X ULN  
 
SEX 
7. Male and/or Female 
a. A male participant is eligible to participate if they agree to the following 
during the intervention period and for at least 90 days after the last dose 
of study treatment 
i. Refrain from donating sperm 
ii. AND be abstinent from heterosexual intercourse as their 
preferred and usual lifestyle (abstinent on a long term and 
persistent basis) and agree to remain abstinent OR Must agree to 
use contraception/barrier as detailed below 
1. Agree to use a male condom [and should also be advised 
of the benefit for a female partner to use a highly 
effective method of contraception as a condom may 
break or leak] when having sexual intercourse with a 
woman of childbearing potential who is not currently 
pregnant 
b. A female participant is eligible to participate: 


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i. If she is not pregnant or breastfeeding 
ii. AND at least one of the following conditions applies: 
1. Is not a woman of childbearing potential (WOCBP) as 
defined in Section 10.4 Contraception and Barrier 
Guidance 
2. Is a WOCBP and using a contraceptive method that is 
highly effective (with a failure rate of <1% per year), 
preferably with low user dependency during the 
intervention period and for at least 90 days after the last 
dose of study treatment    
• A WOCBP must have a negative highly sensitive pregnancy test (urine or 
serum as required by local regulations) within 24 hours before the first dose of 
study intervention, see Section 10.2. 
o If a urine test cannot be confirmed as negative (e.g., an ambiguous 
result), a serum pregnancy test is required. In such cases, the participant 
must be excluded from participation if the serum pregnancy result is 
positive. 
Additional requirements for pregnancy testing during and after study 
intervention are located in Section 10.2. 
Contraceptive use by men or women should be consistent with local regulations 
regarding the methods of contraception for those participating in clinical 
studies. 
The investigator is responsible for review of medical history, menstrual history, 
and recent sexual activity to decrease the risk for inclusion of a woman with an 
early undetected pregnancy 
 
INFORMED CONSENT 
8. Capable of giving signed informed consent as described in Section 10.1, which 
includes compliance with the requirements and restrictions listed in the informed 
consent form (ICF) and in this protocol. 
 
 
 


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5.2. 
Exclusion Criteria 
Participants are excluded from the study if any of the following criteria apply: 
MEDICAL CONDITIONS 
1. Clinically significant abnormalities, aside from chronic HBV infection in medical 
history (e.g., moderate-severe liver disease other than chronic HBV, acute coronary 
syndrome within 6 months of screening, major surgery within 3 months of 
screening, significant/unstable cardiac disease, uncontrolled diabetes, bleeding 
diathesis, autoimmune disease, or coagulopathy) or physical examination  
2. Co-infection with: 
a. Current or past history of Hepatitis C virus (HCV) 
b. Human immunodeficiency virus (HIV) 
c. Hepatitis D virus (HDV) 
3. History of or suspected liver cirrhosis and/or evidence of cirrhosis as determined by  
a. Both Aspartate aminotransferase (AST)-Platelet Index (APRI) >2 and 
FibroSure/FibroTest result >0.7  
i. If only one parameter (APRI or FibroSure/FibroTest) result is 
positive, a discussion with the Medical Monitor is required before 
inclusion in study is permitted 
b. Regardless of APRI or Fibrosure/FibroTest score, if the participant meets 
one of the following historical criteria, they will be excluded from the study  
i. Liver biopsy (i.e., Metavir Score F4)  
ii. Liver stiffness >12 kPa  
4. Diagnosed or suspected hepatocellular carcinoma as evidenced by the following 
a. Alpha-fetoprotein concentration ≥200 ng/mL  
b. If the screening alpha fetoprotein concentration is ≥50 ng/mL and 
<200 ng/mL, the absence of liver mass must be documented by imaging 
within 6 months before randomisation 
5. History of malignancy within the past 5 years with the exception of specific 
cancers that are cured by surgical resection (e.g., skin cancer), participants under 
evaluation for possible malignancy are not eligible. 
6. History of vasculitis or presence of symptoms and signs of potential vasculitis [e.g., 
vasculitic rash, skin ulceration, repeated blood detected in urine without identified 
cause]or history/presence of other diseases that may be associated with vasculitis 
condition (e.g., systemic lupus erythematosus, rheumatoid arthritis, relapsing 
polychondritis, mononeuritis multiplex)] 
7. History of extrahepatic disorders possibly related to HBV immune conditions (e.g., 
nephrotic syndrome, any type of glomerulonephritis, polyarteritis nodosa, 
cryoglobulinaemia, uncontrolled hypertension) 
8. Poorly controlled thyroid dysfunction or abnormal thyroid stimulating hormone 
(TSH) levels 
9. Positive (or borderline positive) Anti-neutrophil cytoplasmic antibody (ANCA) at 
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a. Participants that meet these criteria may be considered for inclusion in the 
study following: 
i. Analysis of MPO-ANCA [perinuclear anti-neutrophil cytoplasmic 
antibodies (pANCA)] and PR3-ANCA [classical anti-neutrophil 
cytoplasmic antibodies (cANCA)] AND 
ii. A discussion with the Medical Monitor to review participant’s 
complete medical history to ensure no past history or current 
manifestations of a vasculitic/inflammatory/auto-immune condition 
10. Low C3 at screening AND evidence of past history or current manifestations of 
vasculitic/inflammatory/auto-immune conditions 
a. All participants with low C3 at screening should have their medical history 
discussed with the Medical Monitor prior to enrolment 
11. History of alcohol or drug abuse/dependence 
a. Current alcohol use as judged by investigator to potentially interfere with 
participant compliance 
b. History of or current drug abuse/dependence as judged by the investigator 
to potentially interfere with participant compliance 
i. Refers to illicit drugs and substances with abuse potential. 
Medications that are used by the participant as directed, whether 
over-the-counter or through prescription, are acceptable and would 
not meet the exclusion criteria 
12. Pre-existing severe psychiatric condition or a history of severe psychiatric 
disorders, including severe depression, suicidal ideation and attempted suicide. 
 
PRIOR/CONCOMITANT THERAPY 
13. Currently taking, or took within 3 months of screening, any immunosuppressing 
drugs (e.g., prednisone), other than a short course of therapy (≤2 weeks) or 
topical/inhaled steroid use. 
14. Participants for whom immunosuppressive treatment is not advised, including 
therapeutic doses of steroids. 
15. Patients with prior treatment with Pegylated interferon or interferon are excluded. 
16. Participants requiring anti-coagulation therapies (for example warfarin, Factor Xa 
inhibitors or anti-platelet agents like clopidogrel) 
17. Participants currently taking, or took within 6 months of screening, telbivudine 
 
PRIOR/CONCURRENT CLINICAL STUDY EXPERIENCE 
18. The participant has participated in a clinical trial and has received an 
investigational product within the following time period prior to the first dosing 
day in the current study: 5 half-lives (if known) or twice the duration (if known) of 
the biological effect of the study treatment (whichever is longer) or 90 days (if half-
life or duration is unknown). 


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19. Prior treatment with any oligonucleotide or small interfering RNA (siRNA) within 
12 months prior to the first dosing day 
 
DIAGNOSTIC ASSESSMENTS 
20. Fridericia’s QT correction formula (QTcF) ≥450 msec (if single ECG at screening 
shows QTcF ≥450 msec, a mean of triplicate measurements should be used to 
confirm that participant meets exclusion criterion). 
21. Laboratory results as follows 
a. Serum albumin <3.5 g/dL 
b. Glomerular filtration rate (GFR) <60 mL/min /1.73 m2 as calculated by the 
Chronic Kidney Disease Epidemiologic Collaboration formula (for Japan, 
Japanese Society of Nephrology - Chronic Kidney Disease Initiative 
equation).  
c. International normalised ratio (INR) >1.25 
d. Platelet count <140 X 109/L 
e. Absolute neutrophil count (ANC) <1.5 x 109 cells/L 
f. Baseline haemoglobin <10 g/dL 
g. Total bilirubin >1.25 x ULN.  For participants with benign unconjugated 
hyperbilirubinemia with total bilirubin >1.25 x ULN, discussion for 
inclusion to the study is required with the Medical Monitor 
h. Urine albumin to creatinine ratio (ACR) 0.03 mg/mg (or 30 mg/g). In the 
event of an ACR above this threshold, eligibility may be confirmed by a 
second measurement.  In cases where participants have low urine albumin 
and low urine creatinine levels resulting in a urine ACR calculation 0.03 
mg/mg (or 30 mg/g), the investigator should confirm that participant does 
not have a history of diabetes, hypertension or other risk factors that may 
affect renal function and discuss with the medical monitor, or designee 
 
OTHER EXCLUSIONS 
22. History of/sensitivity to GSK3228836 or interferon-containing therapies, or 
components thereof, or a history of drug or other allergy that, in the opinion of the 
investigator or medical monitor, contraindicates their participation 
 
5.3. 
Inclusion and Exclusion Criteria for PegIFN 
Participants who permanently discontinue GSK3228836 due to a liver stopping event 
(Section 7.1.1) are not eligible for treatment with PegIFN. 
Participants who had GSK3228836 dosing held or whose dose was reduced due to 
Protocol defined liver monitoring criteria (Section 7.1.1) are eligible for PegIFN 
treatment only if: 


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a. ALT is <5xULN and bilirubin/INR are ≤baseline or ULN (whichever is 
higher) at PegIFN eligibility assessment 
AND 
b. Additional lab assessments performed do not suggest drug-induced liver 
injury (DILI) or other condition contraindicated for treatment in the 
PegIFN label. 
For participants who do not meet both of these criteria, eligibility for PegIFN should be 
determined by the investigator based upon a risk/benefit assessment and the following 
PegIFN eligibility criteria (Table 8). 
Note:  If local prescribing PegIFN guidelines are more stringent than the criteria below, 
follow the most stringent criteria. 
• ALT <5 x ULN  
• Platelets >90 x 109/L  
• Absolute Neutrophil Count (ANC) >1.5 x 109/L  
• Haemoglobin 10 g/dL   
In addition: 
• TSH + T4 should be confirmed to be normal and/or adequately controlled 
• The absence of severe psychiatric condition 
• An ophthalmologic examination should have been conducted at screening (or 
results from a prior ophthalmological examination within 3 months of screening 
should have been available).   
Table 8 
Eligibility Criteria to start PegIFN 
Baseline Laboratory Assessment 
Inclusion Criteria 
i) Platelets 
>90 x 109 cells/L 
ii) ANC 
>1.5 x 109 cells/L 
iii) Haemoglobin 
>10 g/dL 
iv) ALT 
<5 x ULN 
v) TSH/T4 
Within normal range or adequately controlled 
vi) Neuropsychiatric Assessment 
No severe psychiatric condition 
vii) Ocular Exam 
No condition contraindicated for PegIFN, however 
periodic examinations maybe required based upon 
screening assessment (refer to Section 8.2.2) 
 


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5.4. 
Lifestyle Considerations 
5.4.1. 
Alcohol and Tobacco 
During each dosing session, participants will abstain from alcohol for 24 hours before the 
start of each scheduled clinic visit until after they leave the clinic.  
Participants who use tobacco products will be instructed that use of nicotine-containing 
products (including nicotine patches and other delivery devices such as vaporisers) will not 
be permitted while they are in the clinical unit.  
5.4.2. 
Activity 
Participants will abstain from strenuous exercise for 48 hours before each blood 
collection for clinical laboratory tests.  For the duration of the study, until final follow-up, 
participants are encouraged to refrain from changing their activity beyond that which they 
normally perform.  Additionally, participants will abstain from taking creatine-containing 
exercise supplements for all parts of the study. 
5.5. 
Screen Failures 
Screen failures are defined as participants who consent to participate in the clinical study 
but are not subsequently randomised. A minimal set of screen failure information is 
required to ensure transparent reporting of screen failure participants to meet the 
Consolidated Standards of Reporting Trials publishing requirements and to respond to 
queries from regulatory authorities. Minimal information includes demography, screen 
failure details, eligibility criteria, any protocol deviations and any serious adverse events 
(SAEs). 
Individuals who do not meet the criteria for participation in this study (screen failure) may 
not be rescreened unless discussed and agreed with the Medical Monitor. Individuals who 
fall out of the screening window, may be rescreened at the discretion of the investigator 
and site.  
5.6. 
Criteria for Temporarily Delaying Administration of Study 
Intervention 
See Section 7.1 for guidance on treatment hold and criteria for temporarily delaying 
GSK3228836 and/or PegIFN. 
6. 
STUDY INTERVENTION(S) AND CONCOMITANT 
THERAPY 
Study intervention is defined as any investigational intervention(s), marketed product(s), 
placebo, or medical device(s) intended to be administered to a study participant according 
to the study protocol. 


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6.1. 
Study Intervention(s) Administered 
Study Treatment 
Study Treatment 
Product Name: 
GSK3228836 
PegIFN  
Formulation Description: 
Clear colourless to slightly yellow 
solution 
Injection for subcutaneous use.  
The commercial product is used 
unmodified, except a label is applied to 
indicate clinical investigational use. 
Dosage Form: 
Solution for injection 
Solution for injection 
Unit Dose Strength(s)/Dosage 
Level(s): 
150 mg/mL; 1.0 mL nominal volume 
per vial (minimal overfill per vial) 
180 mcg/0.5 mL; pre-filled syringe 
Route/Administration/Duration: 
SC, multiple (once weekly up to 24 
weeks, plus loading doses) 
180 mcg/week, SC, up to 24 weeks 
Dosing Instructions: 
Administer two SC injections for 300 
mg dose. 
Administer SC injection; refer to label 
Manufacturer/Source of 
Procurement: 
GSK GlaxoSmithKline Manufacturing 
SpA, Parma (Italy) 
F Hoffmann-La Roche AG, Wurmisweg, 
4303 Kaiseraugst, Switzerland. 
Method for Individualising 
Dosage 
Dispensing into syringes 
Pre-filled syringe that contains 
graduation marks corresponding to 180 
micrograms (mcg), 135 mcg and 90 mcg 
SC=subcutaneous;  
GSK3228836 injection instructions 
The site of GSK3228836 injection will be recorded for each participant and dose(s).  
Sites of GSK3228836 injection are listed in order of preference and are a guide for the 
clinical staff. 
1. 
Abdominal quadrants 
2. 
Thighs 
3. 
Outer area of the upper arms 
4. 
Buttocks 
GSK3228836 injections should be rotated within each anatomical site or site(s) of 
injection should be changed administration-to-administration. Injection into areas with 
ongoing injection site reactions should be avoided. 
PegIFN injection instructions 
PegIFN is administered by subcutaneous injection in the abdomen or thigh. PegIFN should 
be inspected visually for particulate matter and discoloration before administration, and 
not used if particulate matter is visible or product is discoloured. 
A participant may self-inject PegIFN only if the physician determines that it is appropriate, 
and the patient agrees to medical follow-up as necessary and has been trained in proper 
injection technique. 
Discard the unused portion in excess of the labelled volume. Use only one vial or prefilled 
syringe or disposable auto-injector per dose. 


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6.2. 
Preparation/Handling/Storage/Accountability 
The investigator or designee must confirm appropriate temperature conditions have been 
maintained during transit for all study intervention received and any discrepancies are 
reported and resolved before use of the study intervention. 
Only participants enrolled in the study may receive study intervention and only authorised 
site staff may supply or administer study intervention.  All study interventions must be 
stored in a secure, environmentally controlled, and monitored (manual or automated) area 
in accordance with the labelled storage conditions with access limited to the investigator 
and authorised site staff. 
The investigator, institution, or the head of the medical institution (where applicable) is 
responsible for study intervention accountability, reconciliation, and record maintenance 
(i.e., receipt, reconciliation, and final disposition records). 
Further guidance and information for the final disposition of unused study intervention are 
provided in the Study Reference Manual (SRM).  
Under normal conditions of handling and administration, study intervention is not expected 
to pose significant safety risks to site staff.  Take adequate precautions to avoid direct eye 
or skin contact and the generation of aerosols or mists.  In the case of unintentional 
occupational exposure notify the monitor, Medical Monitor and/or GSK study contact. 
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 GSK. 
6.3. 
Measures to Minimise Bias: Randomisation and Blinding 
All participants will be centrally randomised using an Interactive Voice/Web Response 
System (IVRS/IWRS).  Before the study is initiated, the telephone number and call-in 
directions for the IVRS and/or the log in information and directions for the IWRS will be 
provided to each site. 
Study intervention will be dispensed at the study visits summarised in the SoA.  Returned 
study intervention should not be re-dispensed to the participants. 
Participants will be randomised in a 1:1 ratio to receive study intervention. Investigators 
and the participants will be unblinded to study intervention throughout the course of the 
study. Allocation will be concealed by central blocking to protect against foreknowledge 
of allocation pre-randomisation. 
GSK is unblinded however the risk of potential bias will be mitigated by the following 
steps:  
• Dummy randomisation schedule will be used by Biostatistics during preparatory 
programming activities, although this will not completely mask treatment 
assignment due to the different visit/regimen schedules for each arm. 
• Where feasible, limit the central teams exposure to virological biomarkers 
including HbsAg, HbsAb and HBV DNA. 


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• Details will be included in separate blinding plans.  
Unblinded monitors and, in the event of a Quality Assurance audit, the auditor(s) will be 
allowed access to unblinded study intervention records at the site(s) to verify that 
randomisation/dispensing has been done accurately. 
GSK’s Clinical Safety Department staff may reveal the treatment allocation for any 
participant with an SAE.  If the SAE requires that an expedited regulatory report be sent to 
one or more regulatory agencies, a copy of the report, identifying the participant’s 
intervention assignment, may be sent to investigators in accordance with local regulations 
and/or GSK policy. 
6.4. 
Study Intervention Compliance 
When participants are dosed at the site, they will receive study intervention directly from 
the investigator or designee, under medical supervision.  The date and time of each dose 
administered in the clinic will be recorded in the source documents.  The dose of study 
intervention and study participant identification will be confirmed at the time of dosing by 
a member of the study site staff other than the person administering the study intervention. 
Participants may self-inject PegIFN during specified visits in the PegIFN treatment phase 
(see Table 4) as allowed per country requirements.  Site staff will telephone to confirm 
the dose as described above.  
6.5. 
Dose Modification 
Dose modifications of GSK3228836 are not planned for this study.  Dose modifications 
of PegIFN are allowed per Section 7.2. 
6.6. 
Study Intervention after the End of the Study 
No intervention is planned at the end of the study, although participants may be asked to 
enrol in a long-term roll-over study based on their response. 
6.7. 
Treatment of Overdose 
For this study, any dose of GSK3228836 greater than 300 mg within a 24-hour time period 
will be considered an overdose. 
GSK does not recommend specific treatment for an overdose. 
In the event of an overdose, the investigator should: 
• Contact the Medical Monitor immediately. 
• Closely monitor the participant for AE/SAE and laboratory abnormalities until 
GSK3228836 can no longer be detected systemically (at least 105 days). 
• Obtain a plasma sample for PK analysis within 1 day from the date of the last 
dose of study intervention if requested by the Medical Monitor (determined on a 
case-by-case basis). 


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• Document the quantity of the excess dose as well as the duration of the 
overdosing in the case report form (CRF). 
Decisions regarding dose interruptions or dose modifications of PegIFN will be made by 
the investigator in consultation with the Medical Monitor based on the clinical evaluation 
of the participant. 
6.8. 
Concomitant Therapy 
Any medication or vaccine (including over-the-counter or prescription medicines, 
vitamins, and/or herbal supplements or other specific categories of interest) that the 
participant is receiving at the time of enrollment 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. 
Concomitant medications, including NA therapy, should be recorded. 
Traditional Chinese medicine (TCM) and/or acupuncture as it relates to CHB therapy 
should be avoided during the duration of the study.  If participants report use of TCM 
and/or acupuncture, then details must be recorded in the concomitant medication CRF. 
6.8.1. 
Nucleos(t)ide Treatment during and after the End of the Study  
The investigator is responsible for ensuring that consideration has been given to the care 
of the participant’s medical condition, and that participants are able to continue their 
therapy over the duration of the study. 
The investigator is responsible for ensuring that consideration has been given to the post-
study care of the participant’s medical condition, whether or not GSK is providing specific 
post-study treatment. 
6.8.2. 
Prohibited Medications and Non-Drug Therapies 
The following concomitant medications for GSK3228836 are not permitted during the 
study: 
• Immunosuppressing drug (e.g., prednisone) use >2 weeks duration from 3 months 
prior to Screening through the final Follow-up visit (see Section 5.2), unless 
required for safety 
• Prior treatment with any oligonucleotide or small interfering RNA (siRNA) 
within 12 months prior to the first dosing 
• Creatine-containing gym supplements  
• Anticoagulation therapy 
• Anti-platelet therapy 


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Refer to the local label for prohibited concomitant medications for PegIFN [Pegasys, 
2017]. Telbivudine is contraindicated in the PegIFN label; the combination of telbivudine 
with interferon products (such as peginterferon) to treat hepatitis may increase the risk of 
peripheral neuropathy [Tyzeka, 2013]. 
7. 
DISCONTINUATION OF STUDY INTERVENTION AND 
PARTICIPANT DISCONTINUATION/WITHDRAWAL 
A participant may withdraw from the study treatment at any time at his/her own request or 
may be withdrawn at any time at the discretion of the Investigator for safety, behavioural 
or administrative reasons.  In rare instances, it may be necessary for a participant to 
permanently discontinue (definitive discontinuation) study intervention.  Participants that 
withdraw from treatment for any reason should be encouraged to complete all their on-
treatment and follow-up visits and assessments.  Every effort should be made to complete 
the early termination (ET) study procedures and observations if the participant does not 
enter post-treatment follow-up. 
Any laboratory parameter that meets the stopping criteria should be repeated to confirm 
the value prior to withdrawal. 
For participants meeting the stopping criteria (Section 7.1- Section 7.2), participants should 
be monitored until laboratory abnormalities resolve, stabilise, or return to within baseline 
values as indicated.  The participant must then attend the visits specified in the SoA.  See 
the SoA for data to be collected at the time of discontinuation of study intervention and 
follow-up and for any further evaluations that need to be completed. 
7.1. 
GSK3228836 Dose Modification and Stopping Criteria 
7.1.1. 
GSK3228836 Liver Chemistry Stopping Criteria 
Liver chemistry stopping, and increased monitoring criteria have been designed to assure 
participant safety and to evaluate liver event etiology.  Study intervention will be 
discontinued for a participant if the liver stopping criteria are met. Restart/re-challenge 
guidelines are presented in Section 10.6 (Appendix 6). 
Discontinuation of study intervention for abnormal liver tests is required when: 
• a participant meets one of the conditions outlined in Table 9. 
• when in the presence of abnormal liver chemistries not meeting protocol-specified 
stopping rules, the investigator believes study intervention discontinuation is in 
the best interest of the participant.  
Table 9 lists the criteria for withholding or discontinuing the study medication in a study 
participant with elevation of ALT.  Additional testing will be performed (see safety 
follow-up procedures for participants who meet increased monitoring or stopping criteria), 
and the participant monitored until liver chemistry abnormalities resolve, stabilise, or 
return to within baseline values.  The participant must then attend the follow-up visits 
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Every attempt must be made to have the participant evaluated (within 24 hours) for repeat 
assessment of liver chemistries and additional testing and close monitoring (a specialist or 
hepatology consultation is recommended).  Participants must be monitored weekly until 
liver chemistry abnormalities (ALT, AST, alkaline phosphatase, bilirubin) resolve, 
stabilise, or return to within baseline values.  Upon completion of the safety follow-up 
procedures (see below), the participant must attend the follow-up visits specified in the 
SoA. 
Table 9 
GSK3228836 Liver Chemistry Monitoring and Stopping Criteria 
ALT Level 
Monitoring Plan 
Discontinuation 
 
10 x ULN ≤ALT <12 x ULN 
and 
Bilirubin ≤1.5 x ULN  
and 
INR ≤1.5 (if available) 
Monitor twice weekly 
Additional lab assessments 
Permanently discontinue IMP if 
ALT >10 x ULN >4 weeks 
 
 
ALT 12 x ULN 
and 
Bilirubin ≤1.5 x ULN  
and 
INR ≤1.5 (if available) 
Hold dose 
Monitor twice weekly 
Additional lab assessments if not 
already done 
Take off hold: GSK3228836 150 
mg SC weekly when ALT <10 x 
ULN; increasing dose to 300 mg 
(if applicable) should be agreed 
with Medical Monitor 
Permanently discontinue IMP if 
any of the following apply: 
• 
ALT 10 x ULN >4 weeks 
• 
ALT 12 x ULN recurs after 
IMP taken off hold 
ALT 3 x ULN 
and 
1.5 x ULN <bilirubin ≤2 x ULN 
(>35% direct) 
and 
INR 1.5 (if available) 
Hold dose 
Monitor twice weekly 
Additional lab assessments if not 
already done 
Take off hold: GSK3228836 150 
mg SC weekly when bilirubin 
returns to <1.5 x ULN; increasing 
dose to 300 mg (if applicable) 
should be agreed with Medical 
Monitor 
Permanently discontinue IMP if 
the following recurs after IMP 
taken off hold: 
1.5 x ULN <bilirubin ≤2 x ULN 
(>35% direct) 
And 
INR 1.5 (if available) 
ALT 3 x ULN and any of the 
following apply: 
• 
bilirubin >2 x ULN 
(>35% direct) 
• 
associated with the 
appearance  
or worsening of 
hepatitis symptoms 
• 
INR >1.5 (if available) 
 
Permanently discontinue IMP 
 
Monitor twice weekly until stable 
ALT 
 
Additional lab assessments if not 
already done 
ALT = alanine aminotransferase; IMP = investigational medicinal product; ULN = upper limit of normal 
 


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*Notes: 
• Any abnormal laboratory parameters that meet the criteria for individual treatment 
discontinuation must be confirmed by retest of a new collection of blood samples 
as soon as possible.  
• Deterioration considered clinically significant from the baseline in the liver 
parameters must be confirmed by retesting ALT, total bilirubin, direct bilirubin 
and INR (if available). 
• If one criterion in the list above is met and confirmed by retesting, further 
treatment may be discontinued for this participant after discussion with the 
Medical Monitor.  Results of retesting must be evaluated before the next dose is 
administered. 
• Monitor participant until liver chemistry abnormalities resolve, stabilise, or return 
to within baseline values. 
• Cases such as Gilbert syndrome, where baseline bilirubin values are high, should 
be discussed with the Medical Monitor, to assess if it is a case of DILI or the 
participant may continue with dosing. 
The procedures listed below are to be followed if a participant meets any of the liver 
chemistry stopping criteria defined in Table 9: 
Notify the Medical Monitor within 24 hours of learning of the abnormality to confirm the 
participant’s study treatment cessation and follow-up. 
Complete the Liver Event CRF. 
Complete the “Safety Follow-up Procedures” listed below. 
Safety Follow-up Procedures for Participants Who Meet Any of The Liver 
Monitoring and Stopping Criteria: 
Viral hepatitis serology including: 
o Hepatitis A IgM antibody; 
o Cytomegalovirus IgM antibody;  
o Epstein-Barr viral capsid antigen IgM antibody (or if unavailable, obtain 
heterophile antibody or monospot testing);  
o Hepatitis E IgM antibody. 
o Hepatitis B virus DNA load 
o Hepatitis C virus RNA load 
o Hepatitis D virus antibody 
• Obtain a blood sample for pharmacokinetic (PK) analysis as soon as possible 
following the occurrence of an event. Record the date/time of the PK blood 
sample collection and the date/time of the last dose of study treatment prior to 
blood sample collection on the CRF. If the date or time of the last dose is unclear, 
provide the participant’s best approximation. Instructions for sample handling and 
shipping are included in the SRM. 


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• Serum creatine phosphokinase (CPK) and lactate dehydrogenase (LDH). 
• Review fractionated bilirubin 
• Assess eosinophilia 
• Record the appearance or worsening of clinical symptoms of hepatitis (fatigue, 
nausea, vomiting, right upper quadrant pain or tenderness, fever, rash or 
eosinophilia) as relevant on the Adverse Event (AE) CRF. 
• Record use of concomitant medications, acetaminophen, herbal remedies, other 
over the counter medications, or putative hepatotoxins on the Concomitant 
Medications CRF. 
• Record alcohol use on the Liver Events CRF. 
The following are required for participants who meet the ALT and bilirubin stopping 
criteria but are optional for other abnormal liver chemistries. 
• Anti-nuclear antibody, anti-smooth muscle antibody, Type 1 anti-liver kidney 
microsomal antibodies and quantitative total immunoglobulin G (IgG or gamma 
globulins). 
• Serum acetaminophen adduct high performance liquid chromatography (HPLC) 
assay (quantifies potential acetaminophen contribution to liver injury in 
participants with definite or likely acetaminophen use in the preceding week 
[James, 2009]), if available. 
• Liver imaging (ultrasound, magnetic resonance, or computerised tomography) or 
Liver biopsy to evaluate liver disease. 
• The Liver Imaging and/or Liver Biopsy CRFs are also to be completed if these 
tests are performed. 
7.1.2. 
GSK3228836 Haematological Stopping Criteria  
If a participant develops signs or symptoms of thrombocytopenia, obtain a platelet count 
(local lab) as soon as possible and hold dosing until the platelet count is confirmed. 
If the platelet count is uninterpretable or a decreasing trend is noted below the lower limit 
of normal (LLN) reference range, re-check the platelet counts as soon as possible (the 
investigator may, at their discretion, opt to have the participant come to their next 
scheduled visit OR ask the participant to come earlier than their scheduled visit, as they 
feel appropriate based on review of the participants clinical presentation and laboratory 
results). Samples showing platelet clumping should also be repeated. 
Participants with platelet values below 75 x 109/L will undergo further assessment 
including, but not necessarily limited to, anti-platelet antibodies. If the participant has a 
positive anti-platelet antibody, study treatment should be discontinued permanently. 
Monitor until platelet abnormalities resolve, stabilise, or return to within baseline values. 


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Table 10 
GSK3228836 Haematological Stopping Criteria 
Platelet Count 
Monitoring 
Treatment 
75 X 109/L 
≤Platelets <100 X 
109/L 
Monitor weekly, results of local platelet 
count must be available prior to dosing 
Hold treatment until platelets return to 100 
x109/L 
[if positive for anti-platelet antibodies, study 
treatment should be discontinued immediately] 
50 X 109/L ≤ 
Platelets <75 X 
109/L 
Monitor every 2-3 days until three 
successive measurements 75 x109/L, 
then weekly 
Assess anti-platelet antibodies 
<50 x 109/L 
Monitor daily until 25 x109/L, monitor 
every 2-3 days until three successive 
measurements 75 x109/L, then weekly 
until platelets ≥100 x109/L 
Assess anti-platelet antibodies 
Discontinue treatment permanently 
Glucocorticoids recommended (unless the 
participant has a medical contraindication to 
receiving glucocorticoids), and discontinuation of 
any antiplatelet medicinal products/non-steroidal 
anti-inflammatory drugs/anticoagulants 
7.1.3. 
GSK3228836 Drug Induced Kidney Injury (Renal) Stopping 
Criteria 
If any of the following are observed, results should be confirmed, and if confirmed, 
further evaluation for alternative causes should be pursued in consultation with the 
Medical Monitor: 
• Persistent ACR ≥0.03 mg/mg (≥30 mg/g) 
• Blood in urinalysis ≥5 red blood cells (RBC) per high power field (HPF) 
confirmed by urine microscopy 
• Persistent elevation of serum creatinine (>26.52 µmol/L or 0.3 mg/dL change 
from baseline) 
Following confirmation of the criteria above, further evaluation may include but not be 
limited to a 24-hour urine analysis, consultation with a nephrology specialist, renal 
ultrasound, urine microscopy, serum urea and creatinine, platelet count, urgent serum 
vasculitis screen (including ANCA, antinuclear antibody [ANA], double stranded 
deoxyribonucleic acid [dsDNA], cryoglobulins), serum protein electrophoresis 
(SPEP)/urine protein electrophoresis (UPEP), and complement panel (C3, C4, C5a, and 
Bb). Further evaluation and actions should be determined by the investigator in 
consultation with the Medical Monitor. 
Treatment Hold/Treatment Discontinuation 
• Hold study treatment in participants who develop ACR ≥0.5 mg/mg (500 mg/g), 
or eGFR >25% reduction from pre-dose range, pending consultation with the 
Medical Monitor and further evaluation of the cause. 
o If a dose is held, once eGFR increases to within baseline, ACR decreases 
to <0.5 mg/mg (500 mg/g), or the underlying cause of the decline in renal 


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function is corrected, weekly dosing may be reinitiated after consultation 
with the Medical Monitor 
o Participants must be monitored weekly until ACR or eGFR resolve, 
stabilize, or return to within pre-dose range 
• Hold study treatment in participants with ACR ≥2 mg/mg (2000 mg/g), perform 
further evaluation for acute glomerulonephritis, as clinically indicated. If acute 
glomerulonephritis is confirmed or probable (i.e., meets clinical definition of 
rapidly progressive glomerulonephritis [RPGN] if biopsy not feasible), 
GSK3228836 should be permanently discontinued 
o Participants must be monitored weekly until ACR resolves, stabilizes, or 
returns to within baseline values 
• Delay in treatment of suspected RPGN should be avoided. 
7.1.4. 
GSK3228836-Induced Vascular Inflammation and Complement 
Stopping Criteria 
If any of the following are observed, results should be confirmed with a repeat sample 
collection and analysis, and if confirmed, further evaluation for alternative causes should 
be pursued in consultation with the Medical Monitor. 
Repeat sample collection of C3, C4, Bb, C5a would be triggered by changes in the clinical 
signs and symptoms of complement activation (2 + haematuria; increasing urine ACR; 
vasculitic or purpuric rash; peripheral neuropathy; jaundice). Additional complement 
analyses for example CH50, Factor B level, Factor H level, sC5b-9 should also be 
considered in discussion with the Medical Monitor and Safety Panels. 
• Persisting & deteriorating longitudinal trends in change from baseline for C3 
and/or C4 defined as: 
o If participant’s baseline C3 and/or C4 is within the lab’s normal range at 
baseline: there is a sequential decline in C3 and/or C4 once levels have 
fallen below LLN for 4 weeks OR 
o If participant’s baseline C3 and/or C4 is below the lab’s LLN at baseline: 
there is further sequential decline in C3 and/or C4 for 4 weeks OR 
o Regardless of baseline C3 and/or C4 level: there is a 80% reduction in the 
participant’s C3 and/or C4 level at any point AND 
o There is an associated 3-fold increase in Bb and/or C5a from participant’s 
baseline OR 
o There are associated biochemical sequelae for example, a rising high 
sensitivity C-reactive protein (hs-CRP); rising monocyte chemoattractant 
protein (MCP-1); new thrombocytopenia, new renal impairment with no 
other explanation such as intercurrent infection OR 


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o There are associated clinical sequelae, for example, 2 + haematuria; 
increasing urine ACR; vasculitic or purpuric rash; peripheral neuropathy; 
jaundice OR 
o There is new cANCA or pANCA positivity 
• Persisting & deteriorating longitudinal trends in change from baseline for Bb 
and/or C5a where 
o There is a 3-fold increase in Bb and/or C5a over baseline AND 
o This is persisting or increasing week on week in sequential data plots OR 
o There are associated biochemical sequelae for example, a rising hs-CRP; 
rising MCP-1, new thrombocytopenia, new renal impairment with no other 
explanation such as intercurrent infection OR 
o There are associated clinical sequelae, for example, 2 + haematuria; 
increasing urine ACR, vasculitic or purpuric rash; peripheral neuropathy; 
jaundice or any combination of these OR 
o There is new cANCA or pANCA positivity 
Treatment Hold/Treatment Discontinuation 
• Hold study treatment during evaluation of alternative causes for decreased C3 
and/or C4 associated with increased inflammatory markers including one or more 
of hs-CRP, MCP-1, Bb and C5a 
• Discontinue study treatment permanently if persistent change from baseline 
(4 weeks) in biomarker pattern (decreased C3/C4 associated with increased 
inflammatory markers including one or more of hs-CRP, MCP-1, Bb, C5a) 
without clear alternative explanation. 
• Discontinue study treatment permanently if suspect clinical sequelae of 
complement activation, DIVI, vasculitis or autoimmunity regardless of 
biomarkers changes or persistence. 
7.2. 
PegIFN Dose Modification and Stopping Criteria 
Discontinuation of treatment with PegIFN should be considered in any participant with an 
adverse event where the risk of continued treatment outweighs the potential benefit (see 
Section 2.3.1). 
When dose modification is required for moderate to severe adverse reactions, both clinical 
and laboratory, initial dose reduction to 135 mcg is generally adequate (Pegasys PI, 2017). 
However, in some cases a reduction to 90 mcg is necessary. Dose increase to, or towards 
the original dose may be considered if the adverse reaction abates. 
 


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7.2.1. 
PegIFN Haematological Dose Modification and Discontinuation 
Guidelines 
Table 11 
PegIFN Haematological Dose Modification Guidelines1 
Laboratory Values 
Reduce PegIFN dose if: 
Discontinue PegIFN if: 
Absolute Neutrophil Count 
(ANC) 
<750 cells/mm3 reduce to 135 mcg 
(in some cases reduction to 90 mcg 
may be necessary) 
<500 cells/mm3 treatment should be 
suspended until ANC values return to 
more than 1000 cell/mm3 
Initially reinstitute at 90 mcg and monitor 
ANC 
Platelet Count 
<50 x 109 cells/L reduce to 90 mcg 
<25 X 109 cells/L 
Haemoglobin 
 
Hb <8.5 g/dL 
1. 
 Not applicable to sites in Japan 
After dose reduction or discontinuation, the patient should be monitored weekly until lab 
values return to within baseline values. 
7.2.2. 
PegIFN ALT Elevation Dose Modification and Discontinuation 
Guidelines 
In participants with elevations in ALT (greater than 5 x ULN), more frequent monitoring 
of liver function should be performed and consideration should be given to either 
reducing the dose to 135 mcg or temporarily discontinuing treatment. After reduction or 
withholding, therapy can be resumed after ALT flares subside.  
In participants with persistent, severe hepatitis B flares (ALT greater than 10 X ULN), 
consideration should be given to discontinuation of treatment.  If ALT increases are 
progressive despite dose reduction or accompanied by increased bilirubin or evidence of 
hepatic decompensation, therapy should be immediately discontinued.  When practicable, 
abnormal laboratory results should be confirmed as soon as possible following 
notification of the investigator. 
7.2.3. 
Psychiatric Disorder Dose Modification and Discontinuation 
Guidelines 
Participants will be monitored for evidence of depression and other psychiatric symptoms 
by the Columbia Suicide-Severity Rating Scale (C-SSRS) and Beck Depression 
Inventory-II (BDI-II). Participants displaying new or worsening symptoms of depression 
will be managed as per Table 12. 
If new or worsening psychiatric symptoms (other than depression) are identified or if 
suicidal ideation is identified, PegIFN should be discontinued and the participant 
followed up with psychiatric intervention as appropriate. 


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Table 12 
PegIFN Dose Modification and Stopping Criteria for Depression 
Depression 
Severity  
Initial Management (4-8 weeks) 
Depression Status 
Dose Modification 
Visit Schedule 
Remains stable 
Improves 
Worsens 
Mild 
No change 
Evaluate once 
weekly by visit 
and/or phone 
Continue weekly 
visit schedule 
Resume normal visit 
schedule 
 
(See 
moderate or 
severe 
depression) 
Moderate 
Decrease PegIFN 
dose to 135 mcg 
(in some cases 
reduction to 90 
mcg may be 
needed) 
Evaluate once 
weekly (office 
visit at least 
every other 
week) 
 
Consider 
psychiatric 
consultation. 
Continue 
reduced dosing 
 
If symptoms improve 
and are stable for 4 
weeks, may resume 
normal visit 
schedule. Continue 
reduced dosing or 
return to normal 
dose 
(See severe 
depression) 
 
Severe 
Discontinue 
PegIFN 
permanently  
Obtain 
immediate 
psychiatric 
consultation  
Psychiatric therapy necessary  
7.3. 
Study Intervention Restart or Rechallenge after stopping 
criteria met 
GSK3228836 rechallenge after stopping criteria are met (i.e., study treatment 
discontinued) by any participant in this study is not allowed.  
GSK3228836 restart may be considered only for liver events as follows:  
Restart Following Transient Resolving Liver Stopping Events Not Related to 
GSK3228836 
Restart refers to resuming study intervention following liver stopping events in which there 
is a clear underlying cause (other than DILI) of the liver event (e.g., biliary obstruction, 
pancreatic events, hypotension, acute viral hepatitis). Furthermore, restart is not permitted 
following liver stopping event when the underlying cause was alcohol-related hepatitis. 
• Approval by GSK for study intervention restart can be considered where: 
o Investigator requests consideration for study intervention restart if liver 
chemistries have a clear underlying cause (e.g., biliary obstruction, 
hypotension and liver chemistries have improved to normal or are within 
1.5 x baseline and ALT <3 x ULN). 
o Possible study intervention-induced liver injury has been excluded by the 
investigator and the study team. This includes the absence of markers of 
hypersensitivity (otherwise unexplained fever, rash, eosinophilia). Where a 
study intervention has a confirmed genetic marker associated with liver 


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injury, the presence of the marker should be excluded. If study intervention-
related liver injury cannot be excluded, the guidance on rechallenge will 
apply. 
o There is no evidence of alcohol-related hepatitis. 
o Institutional Review Boards (IRB)/Independent Ethics Committees (IEC) 
approval, if required, of study intervention restart has been obtained. 
If restart of study intervention is approved by GSK Medical Governance in writing: 
• The participant must be provided with a clear description of the possible benefits 
and risks of study intervention administration including the possibility of recurrent, 
more severe liver injury or death.  
• The participant must also provide signed informed consent specifically for the 
restart of study intervention. Documentation of informed consent must be recorded 
in the study file.  
• Study intervention must be administered at the dose specified by GSK 
• Participants approved by GSK for restart of study intervention must return to the 
clinic twice a week for liver function tests until stable liver function tests have been 
demonstrated and then standard laboratory monitoring may resume as per protocol. 
• If the participant meets protocol-defined liver chemistry stopping criteria after 
study intervention restart, study intervention should be permanently discontinued. 
• The Medical Monitor and the IRB/IEC must be informed of the outcome for the 
participant following study intervention restart. 
• GSK must be notified of any adverse events. 
For treatment that has been placed on hold, please follow the guidelines above (Section 
7.1.1 to Section 7.2.3). 
7.4. 
Participant Discontinuation/Withdrawal from the Study 
• A participant 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, 
behavioural, or compliance reasons. This is expected to be uncommon. 
• The investigator may ask participants to withdraw from study treatment, but 
continue with post-treatment follow up visits instead of withdrawing completely 
from the study. 
• At the time of discontinuing from the study, if possible, an early discontinuation 
visit should be conducted, as shown in the SoA. See 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. 
• The participant will be permanently discontinued both from the study intervention 
and from the study at that time. 


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• If the participant 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 participant 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. 
7.5. 
Lost to Follow Up 
A participant 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.  
The following actions must be taken if a participant fails to return to the clinic for a required 
study visit: 
• The site must attempt to contact the participant and reschedule the missed visit as 
soon as possible and counsel the participant 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 participant is deemed lost to follow up, the investigator or designee must 
make every effort to regain contact with the participant (where possible, 3 
telephone calls and, if necessary, a certified letter to the participant’s last known 
mailing address or local equivalent methods). These contact attempts should be 
documented in the participant’s medical record. 
• Should the participant continue to be unreachable, he/she will be considered to 
have withdrawn from the study.  
Discontinuation of specific sites or of the study as a whole are handled as part of Section 
10.1 (Appendix 1). 
8. 
STUDY ASSESSMENTS AND PROCEDURES 
• Study procedures and their timing are summarised in the SoA (see Section 1.3). 
• In selected sites/countries, participants will have the option to use a centralised 
home nursing provider. Only selected visits will have the option to be performed 
as a home visit, these will include drug administration, blood draws, participant 
assessments and data collection. The full specifications of the home nursing 
services will be outlined in the SRM  
• 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 participant should continue or 
discontinue study intervention. 
• 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 participants meet all eligibility criteria. The investigator will maintain a 


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screening log to record details of all participants screened and to confirm 
eligibility or record reasons for screening failure, as applicable.  
• Procedures conducted as part of the participant’s routine clinical management 
(e.g., blood count) and obtained before signing of ICF may be utilised 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. 
8.1. 
Efficacy Assessments 
The primary objective measurement for efficacy in this study is the assessment of 
GSK3228836 treatment followed by PegIFN on serum HBsAg levels in participants with 
CHB.  The primary efficacy endpoint is achieving serum HBsAg level <LLOQ. 
Any HBsAg greater than LLOQ after achieving HBsAg seroclearance needs to be 
confirmed by re-test within 1 week of receiving the test result.  The re-test result will be 
used if the first test is not confirmed. 
HBsAg and HBV DNA are collected for primary and secondary efficacy endpoints as per 
the SoA (see Section 1.3).  Details of sample collection can be found in the SRM. 
8.2. 
Safety Assessments 
Planned time points for all safety assessments are provided in the SoA. Additional time 
points for safety tests (such as vital signs, physical exams and laboratory safety tests) 
may be added during the course of the study based on newly available data to ensure 
appropriate safety monitoring. 
8.2.1. 
Physical Examinations 
A complete physical exam will be conducted at the Screening visit.  Symptoms directed 
exam will be conducted at all other time points.  
• A complete physical exam will include, at a minimum, assessment of the 
dermatologic, cardiovascular, respiratory, gastrointestinal, and neurological 
systems. Height and weight will also be measured and recorded (with participant 
wearing daytime clothing with no shoes).  
• Investigators should pay special attention to clinical signs related to previous 
serious illnesses. 
8.2.2. 
Ophthalmologic Examination for PegIFN  
• All patients should receive an eye examination prior to initiation of PegIFN (SoA, 
Table 1). Patients with pre-existing ophthalmologic disorders (e.g., diabetic or 
hypertensive retinopathy) should receive periodic ophthalmologic exams during 
PegIFN therapy.  Any patient who develops ocular symptoms must have a prompt 
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8.2.3. 
Vital Signs 
Temperature, pulse rate, respiratory 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 participant in a quiet setting without distractions (e.g., television, cell phones). 
Vital signs will be measured after 5 minutes rest and will include temperature, systolic and 
diastolic blood pressure, and pulse and respiratory rate.  
If assessments are scheduled for the same nominal time, then 12-lead ECG and vital signs 
must be completed prior to blood collection. The order of conducting the 12-lead ECG and 
vital sign measurements is flexible but should allow the blood collection to occur at the 
exact nominal time. 
8.2.4. 
Electrocardiograms 
Single 12-lead ECG will be obtained locally as outlined in the SoA (see Section 1.3) using 
an ECG machine that automatically calculates the heart rate and measures PR, QRS, QT, 
and QTc intervals. Manual calculation, if an automatic calculation is not available, is 
acceptable. 
8.2.5. 
Clinical Safety Laboratory Assessments 
Refer to Section 10.2 (Appendix 2) for the list of clinical laboratory tests to be performed 
and to the SoA for the timing and frequency (see Section 1.3).  
The 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 to be more severe than expected for the participant’s condition. 
All laboratory tests with values considered clinically significantly abnormal during 
participation in the study 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. 
If such values do not return to normal/baseline or are still considered significantly 
abnormal by the investigator by the participant’s last visit, additional follow-up should be 
discussed with the sponsor.  
All protocol-required laboratory assessments, as defined in Section 10.2 (Appendix 2), 
must be conducted in accordance with the laboratory manual and the SoA. 
If laboratory values from non-protocol specified laboratory tests performed at the 
institution’s local laboratory require a change in participant management or are considered 
clinically significant by the investigator (e.g., SAE or AE or dose modification), then the 
results must be recorded. 


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8.2.6. 
Injection Site Reactions  
Injection Site Reactions (ISRs) are any experiences which occur at the site of injection of 
the study treatment. Participants will be monitored closely for ISRs and ISRs should be 
recorded as AEs. Injection site reactions will be graded according to the criteria provided 
in the Division of AIDS (DAIDS) grading table (see Section 10.3 (Appendix 3)). 
8.2.7. 
Suicidal Ideation and Behaviour Risk Monitoring 
PegIFN is related to products with an increased risk of suicidal ideation or behaviour.  
Participants being treated with PegIFN should be monitored appropriately and observed 
closely for suicidal ideation and behaviour or any other unusual changes in behaviour. 
Participants who experience signs of suicidal ideation or behaviour, should undergo a risk 
assessment. All factors contributing to Suicidal Ideation and Behaviour should be 
evaluated and consideration should be given to discontinuation of the study intervention.  
When informed consent or assent has been given, families and caregivers of participants 
being treated with PegIFN should be alerted about the need to monitor participants for the 
emergence of unusual changes in behaviour, as well as the emergence of suicidal ideation 
and behaviour and to report such symptoms immediately to the study investigator. 
Baseline assessment of suicidal ideation and behaviour will be monitored during this study 
using the C-SSRS and BDI-II. 
8.2.7.1. 
Columbia Suicide-Severity Rating Scale (C-SSRS) 
Assessment of treatment-emergent suicidality will be monitored during this study using the 
C-SSRS. The definitions of behavioural suicidal events used in this scale are based on those 
used in the Columbia Suicide History Form [Posner, 2007]. Questions are asked on suicidal 
behaviour, suicidal ideation, and intensity of ideation. Screening visit questions will be in 
relation to lifetime experiences and current experiences, and all subsequent questioning in 
relation to the last assessment. The C-SSRS is to be administered as a patient completed 
questionnaire specified in the SoA (Section 1.3).   
8.2.7.2. 
Beck Depression Inventory-II (BDI-II) 
The BDI-II is a 21-item questionnaire used to assess the intensity of depression in clinical 
and normal patients. The questionnaire will be administered by appropriate site personnel 
as specified in the SoA (Section 1.3).  
8.3. 
Adverse Events (AEs), Serious Adverse Events (SAEs) and 
Other Safety Reporting 
The definitions of an AE or SAE can be found in Section 10.3 (Appendix 3). 
AEs will be reported by the participant (or, when appropriate, by a caregiver, surrogate, or 
the participant’s legally authorised representative). 


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The investigator and any qualified 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 intervention or the study, 
or that caused the participant to discontinue the study intervention (see Section 7).  
8.3.1. 
Time Period and Frequency for Collecting AE and SAE 
Information 
All AEs and SAEs will be collected from the signing of the informed consent form until 
the final follow-up visit at the time points specified in the SoA (Section 1.3).  However, 
AEs and SAEs that occur prior to the first administration of investigational medicinal 
product should be recorded only if assessed as related to study participation (e.g., 
protocol-mandated procedures or invasive tests). 
Medical occurrences that begin before the start of study intervention but after obtaining 
informed consent will be recorded on the Medical History/Current Medical Conditions 
section of the CRF not the AE section. 
All SAEs will be recorded and reported to the sponsor or designee immediately and under 
no circumstance should this exceed 24 hours, as indicated in Section 10.3 (Appendix 3). 
The investigator will submit any updated SAE data to the sponsor within 24 hours of it 
being available. 
Investigators are not obligated to actively seek AEs or SAEs after the conclusion of the 
study participation. However, if the investigator learns of any SAE, including a death, at 
any time after a participant has been discharged from the study, and he/she considers the 
event to be reasonably related to the study intervention or study participation, the 
investigator must promptly notify the sponsor. 
8.3.2. 
Method of Detecting AEs and SAEs 
The method of recording, evaluating, and assessing causality of AEs and SAEs and the 
procedures for completing and transmitting SAE reports are provided in Section 10.3  
(Appendix 3). 
Care will be taken not to introduce bias when detecting AE and/or SAE.  Open-ended and 
non-leading verbal questioning of the participant is the preferred method to inquire about 
AE occurrence.  
8.3.3. 
Follow-up of AEs and SAEs 
After the initial AE/SAE report, the investigator is required to proactively follow each 
participant at subsequent visits/contacts. All SAEs will be followed until the event is 
resolved, stabilised, otherwise explained, or the participant is lost to follow-up (as defined 
in Section 7.5 Lost to Follow Up). Further information on follow-up procedures is given 
in Section 10.3  (Appendix 3). 


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8.3.4. 
Regulatory Reporting Requirements for SAEs 
Prompt notification by the investigator to the sponsor of a SAE is essential so that legal 
obligations and ethical responsibilities towards the safety of participants and the safety of 
a study intervention 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 intervention under clinical investigation. 
The sponsor will comply with country-specific regulatory requirements relating to safety 
reporting to the regulatory authority, IRB/IEC, and investigators. 
Investigator safety reports must be prepared for suspected unexpected serious adverse 
reactions 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 SAEs) 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. 
8.3.5. 
Pregnancy 
• Details of all pregnancies in female participants will be collected after the start of 
study intervention and until no longer than 6 to 8 weeks following the estimated 
delivery date. 
• If a pregnancy is reported, the investigator should inform GSK within 24 hours of 
learning of the pregnancy and should follow the procedures outlined in Section 
10.4 (Appendix 4). 
• Abnormal pregnancy outcomes (e.g., spontaneous abortion, foetal death, stillbirth, 
congenital anomalies, ectopic pregnancy) are considered SAEs and will be 
reported as such. 
8.3.6. 
Cardiovascular and Death Events 
For any cardiovascular events detailed in Section 10.3 (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 cardiac death) and non-cardiovascular death.  
The CV CRFs are presented as queries in response to reporting of certain CV medical 
dictionary for regulatory activities 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. 


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8.3.7. 
GSK3228836-Related Adverse Events of Special Interest  
8.3.7.1. 
ALT Increases 
The liver is a site of accumulation of antisense oligonucleotides and this has been exploited 
in the treatment of liver related diseases.  
Outside the setting of disease reactivation or rebound viremia, the etiology of ALT increase 
(flares) in CHB patients is currently uncertain. It has been postulated that ALT flares are 
evidence of reactivation of the immune system in the liver with accompanying clearance 
of infected hepatocytes, particularly when observed during immunotherapy or spontaneous 
loss of HBsAg. Therapeutic ALT flares have been shown to correlate with antiviral effect 
in blood (i.e. declines in HBV DNA, and/or HBsAg). 
A monitoring strategy of ALT is presented in Section 7.1.1 
8.3.7.2. 
Vascular Inflammation and Complement Activation 
Inflammatory and immune changes are recognised as a class effect of ASOs.  Despite the 
low risk for ASO-related vascular adverse events in patients, the nature of the toxicity 
demands a conservative approach to care and monitoring to ensure the safety of 
participants.  Because the complement-mediated mechanism of vascular inflammation in 
monkeys has been well established, a monitoring strategy has been proposed in patients 
that encompasses a multi-pronged approach for monitoring of this toxicity, from separate 
mechanistic, phenotypic and organ-specific perspectives. 
Vascular inflammation will be monitored through various inflammatory markers (e.g., 
complement factors, hs-CRP, ANCA, MCP-1) and presence of clinical signs and 
symptoms. 
A monitoring strategy of vasculitis and complement activation is presented in Section 
7.1.4 
8.3.7.3. 
Thrombocytopenia 
Thrombocytopenia, decreased platelets, is a well-recognised toxicity associated with ASOs 
and is monitorable in the clinic. Two types of thrombocytopenia have been described by 
the FDA amongst the 2-MOE ASOs.  One type is a rapid onset, unpredictable 
thrombocytopenia that may present with mild or moderate bleeding, however, catastrophic, 
fatal bleeding can occur.  The other more common type is characterised by a gradual 
decline in platelets leading to mild to severe thrombocytopenia and can be asymptomatic 
or associated with mild to severe bleeding. 
A monitoring strategy of platelet count is presented in Section 7.1.2 
8.3.7.4. 
Renal Injury 
Glomerulonephritis, including rapidly progressing glomerulonephritis, has been reported 
with ASOs and is thought to be a result of the proinflammatory effect of ASOs.  
Accumulation of antisense oligonucleotides in proximal tubule cells of the kidney, is 


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thought to sometimes lead to increased tubular proteinuria (as described in preclinical 
studies).  Increases in urine protein have been described in the clinic. 
A monitoring strategy of renal function (e.g., serum creatinine, ACR) is presented in 
Section 7.1.3 
8.3.7.5. 
Injection Site Reactions 
Injection site reactions were the most commonly reported treatment-related adverse event 
in previous studies with GSK3228836. Injection site reactions included, but were not 
limited to, pain, erythema and pruritus. Injection site reactions will be assessed at all dosing 
visits and, if present, should be reported as AEs. 
8.4. 
Genetics 
A blood sample for DNA isolation will be collected from participants who have 
consented to participate in the genetics analysis component of the study. Participation is 
optional. Participants who do not wish to participate in the genetic research may still 
participate in the study. 
In the event of DNA extraction failure, a replacement genetic blood sample may be 
requested from the participant. Signed informed consent will be required to obtain a 
replacement sample unless it was included in the original consent. 
See Section 10.5 for Information regarding genetic research. Details on processes for 
collection and shipment and destruction of these samples can be found in the SRM. 
8.5. 
Pharmacokinetics 
Blood samples will be collected pre-dose for measurement of GSK3228836 and PegIFN 
trough plasma concentrations and plasma concentrations during the terminal elimination 
phase as specified in the SoA (see Section 1.3).  PK samples collected during the off 
treatment period at visits specified in the SoA can be collected at any time. 
• Instructions for the collection and handling of biological samples will be provided 
by the sponsor. The actual date and time (24 hour clock time) of each sample will 
be recorded. 
• PK samples will be used to evaluate the PK of GSK3228836 and PegIFN, and to 
explore PK-PD relationships.  
• Samples collected for PK analyses may also be used to evaluate safety or efficacy 
aspects related to concerns arising during or after the study. 
8.6. 
Biomarkers 
Collection of blood samples for exploratory biomarker research is also part of this study. 
These exploratory biomarker samples will be collected to evaluate the pathobiology of 
CHB, the participants’ response to GSK3228836, or the participants’ response to the virus 
following treatment. In addition, continuing research may identify other proteins, 


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transcripts or biomarkers related to GSK3228836 treatment, the response to GSK3228836 
or the pathogenesis of CHB, which will be evaluated in these samples. 
• Blood samples, including serum, plasma, PBMCs and PAXgene tubes will be 
collected to evaluate virologic and immune biomarkers related to the pathogenesis 
of CHB and the participants’ response to GSK3228836, PegIFN or both.  Samples 
will be collected according to the schedule described in the SoA and as detailed in 
the study reference manual provided separately to sites. 
• GSK may store samples for up to 15 years after the end of the study to achieve 
study objectives and for follow-up exploration of the laboratory findings and/or 
AEs (e.g., measurement of cytokine or chemokine levels, measurement of 
antibodies, etc.).  The archive samples may also be used for studying biomarkers 
that may be affected by treatment, such as HBcrAg, indoleamine 2, 3 dioxygenase 
(IDO), or other immune-related responses.  Additionally, samples may be used for 
further research by GSK or others such as universities or other companies to 
contribute to the understanding of chronic hepatitis B or other diseases, the 
development of related or new treatments or research methods. 
For China, see Appendix 7: Country-specific requirements on biomarkers. 
8.7. 
Resistance Monitoring 
The barrier to development of GSK3228836 resistance is unknown.  Population sequencing 
of isolates from Study ISIS 505358-CS3 did not detect the development of mutations in 
the GSK3228836 binding site following 4 weeks of GSK3228836 monotherapy.   
The risk of resistance development is expected to be lowest in participants receiving 
concomitant NA therapy due to the suppression of HBV viral replication.  Ongoing viral 
replication during GSK3228836 treatment (e.g., due to virological breakthrough) may 
increase the risk of the development of resistance.  Investigators should therefore consider 
resistance monitoring for participants who experience virological breakthrough whilst still 
receiving GSK3228836 (i.e., haven’t completed treatment). 
Samples collected for viral genotyping and phenotyping may be used for HBV resistance 
mutation analysis. Viral DNA and/or viral RNA will be extracted from participant samples 
and the viral genome will be DNA sequenced to determine whether mutations have 
occurred in the GSK3228836 binding region or elsewhere in the genome (and if applicable, 
whether any known nucleos(t)ide resistance mutations are present in the polymerase coding 
region).  
Resistance monitoring will be conducted on all baseline isolates to identify pre-existing 
substitutions.  Sequencing of the viral RNA will be attempted in participants receiving 
stable NA therapy and having low DNA levels (e.g., <LLOQ).  Additional resistance 
monitoring will be conducted and will include, but not limited to, the analysis of isolates 
from participants experiencing virological failure during or post treatment as defined 
below.  Confirmation of resistance should be done within 1 week after results are received.  


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Virological breakthrough is defined as one of the following confirmed (2 sequential 
visits) lab results: 
• ≥1 log increase from nadir of HBV DNA  
• HBV DNA becoming quantifiable after being below the LLOQ 
HBsAg levels for each participant will be measured throughout the study. In addition to 
the standard HBV DNA virological failure criteria defined above, HBV resistance 
monitoring will also include analysis of isolates from participants with sub-optimal HBsAg 
levels in the absence of detectable HBV DNA. 
8.8. 
Independent Data Monitoring Committee 
An independent data monitoring committee (IDMC) will review ongoing unblinded safety 
data in this study and the planned interim analysis is described in Section 9.5. The IDMC 
will meet on a regular basis as outlined in the charter. The IDMC/Review Board charter 
will describe the procedures related to IDMC operations in greater detail. For details on 
the IDMC, refer to Section 10.1.5. 
8.9. 
Internal Safety Review Team (SRT) 
A separate internal safety review team will meet to review all participants safety data on a 
regular basis to ensure any new or emerging safety issues are identified and managed in a 
timely manner. 
8.10. 
Medical Resource Utilisation and Health Economics 
Health Economics/Medical Resource Utilisation and Health Economics parameters are 
not evaluated in this study. 
9. 
STATISTICAL CONSIDERATIONS 
9.1. 
Statistical Hypotheses 
The primary objective of the study is to investigate the effectiveness of GSK3228836 and 
PegIFN sequential therapy in CHB patients on stable NA therapy. The primary endpoint is 
achieving a sustained virologic response (SVR, HBsAg <LLOQ and HBV DNA <LLOQ) 
for 24 weeks after the planned end of GSK3228836 and PegIFN sequential treatment in 
the absence of rescue medication. Rescue medication is defined as any medication initiated 
for the purpose of antiviral suppression other than the background stable NA therapy. A 
secondary objective is to compare the efficacy between 24 and 12 weeks of GSK3228836 
treatment followed by PegIFN for up to 24 weeks, measured by the proportion of 
participants that achieve virologic response at the planned end of sequential treatment and 
sustained for six months or more post-treatment. The aim of the study is to provide 
evidence for efficacy of GSK3228836 and PegIFN sequential therapy in reaching sustained 
virologic response, and to inform selection of treatment regimen for Phase III trials based 
on the comparison between the two arms.  


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The primary aim for the study is descriptive, hence no formal hypothesis testing is planned. 
A probability inference approach will be used for decision-making. The primary 
assessment of interest is the SVR rate of each treatment group. The point estimates for 
SVR and 95% credible intervals will be calculated using a Bayesian probability approach; 
in addition, posterior probabilities that the true SVR in each treatment arm is greater than 
a range of clinically meaningful response rates will be provided. 
Comparisons between treatment arms as defined in the key secondary objectives will be 
assessed using probability inference approaches. 
9.2. 
Sample Size Determination 
For the entire study, approximately 100 participants will be enrolled and randomised to 
achieve approximately 50 participants in each treatment group:  
• 24 weeks treatment of GSK3228836 followed by up to 24 weeks treatment of 
PegIFN  
• 12 weeks treatment of GSK3228836 followed by up to 24 weeks treatment of 
PegIFN  
It is assumed that the number of responders follows a Binomial distribution, with a 
weakly informative prior (Beta (0.5, 0.5)) for the true RR. The precision for a range of 
RRs with 95% credible intervals are shown in Table 13. 
Table 13 
95% Credible Interval of Response Rate 
Number of Responders 
Response Rate 
95% Credible Interval* 
9 
18% 
9% - 30% 
10 
20% 
11% - 33% 
11 
22% 
12% - 35% 
12 
24% 
14% - 37% 
13 
26% 
15% - 39% 
14 
28% 
17% - 41% 
15 
30% 
19% - 44% 
16 
32% 
20% - 46% 
17 
34% 
22%-48% 
18 
36% 
24% - 50% 
19 
38% 
26% - 52% 
20 
40% 
27% - 54% 
*95% equal-tailed interval 
The historical RR of a combination therapy of NA and PegIFN was 10% [Ren, 2019; Lee, 
2018]. The lower bounds of 95% credible intervals will exclude the RR of 10% if observed 
RR is greater than or equal to 20% (10 responders out of 50 participants) in an arm. 


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The posterior probabilities that the true sustained virologic RR is greater than a range of 
RRs will be calculated from the implied Beta posterior, given the actual number of 
responders observed.  
The operating characteristics based on at least 65% posterior confidence that the true rate 
exceeds a threshold of interest, are shown in Table 14, for various sample sizes, and true 
cure rates. The operating characteristics shown are based on a Bayesian inference without 
consideration of baseline stratification factors. 
Table 14 
End of Study Operating Characteristics by Sample Size 
Criterion 
Sample 
size per 
arm 
Minimum number (%) of 
responders required to 
meet Criterion 
Probability of meeting criterion under 
various assumptions 
True 
SVR rate 
= 20% 
True 
SVR rate 
= 30% 
True 
SVR rate 
= 35% 
True SVR 
rate = 
40% 
Probability (true 
response rate > 
20%) > 65% 
30 
7 (23%) 
39% 
84% 
94% 
98% 
40 
9 (23%) 
41% 
89% 
97% 
99% 
50 
12 (24%) 
29% 
86% 
97% 
99% 
60 
14 (23%) 
31% 
90% 
98% 
100% 
Probability (true 
response rate > 
30%) > 65% 
30 
10 (33%) 
6% 
41% 
64% 
82% 
40 
14 (35%) 
2% 
30% 
56% 
79% 
50 
17 (34%) 
1% 
32% 
61% 
84% 
60 
20 (33%) 
1% 
33% 
65% 
88% 
Probability (true 
response rate > 
40%) > 65% 
30 
14 (47%) 
0% 
4% 
13% 
29% 
40 
18 (45%) 
0% 
3% 
12% 
31% 
50 
22 (44%) 
0% 
3% 
12% 
33% 
60 
26 (43%) 
0% 
2% 
11% 
34% 
Based on these operating characteristics, for a true RR of 30%, the proposed sample size 
of n=50 for each arm has ~86% probability of confirming a true response of at least 20%, 
and if the true rate is 40%, there is an 84% chance of confirming a true response of at least 
30%.  There are no plans for sample size re-estimation. 


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9.3. 
Analysis Sets 
For the purpose of analyses, the following populations are defined: 
Population 
Description 
Screened 
All participants who were screened for eligibility 
Enrolled 
o 
All participants who passed screening and entered the study 
o 
Note screening failures (who never passed screening even if rescreened) 
and participants screened but never enrolled into the study are excluded 
from the Enrolled population as they did not enter the study 
Intent-to-treat (ITT) 
• 
All randomised participants. 
• 
This population will be based on the treatment the participant was 
randomised to 
• 
Any participant who receives a treatment randomisation number will be 
considered to have been randomised 
Safety 
• 
All participants who were randomised and received at least one dose of 
study treatment 
• 
This population will be based on the treatment the participant received. 
Pharmacokinetics (PK) 
• 
All participants in the Safety population who received an active study 
treatment and had at least 1 non-missing PK assessment (Non-quantifiable 
[NQ] values will be considered as non-missing values) 
• 
Note: PK samples that may be affected by protocol deviations will be 
reviewed by the study team to determine whether or not the sample will be 
excluded 
Pharmacodynamics (PD) 
All participants in the Safety population for whom a Pharmacodynamic sample was 
obtained and analysed. 
9.4. 
Statistical Analyses 
The statistical analysis plan critical component will be finalised prior to the first patient 
first visit. The full statistical analysis plan will include a more technical and detailed 
description of the statistical analyses described in this section. This section is a summary 
of the planned statistical analyses of the most important endpoints including primary and 
key secondary endpoints. No adjustments will be made for multiplicity. 
9.4.1. 
General Considerations 
Unless otherwise specified, baseline will be the last value/assessment before the first dose 
of study treatment (Day 1 pre-dose). If there are multiple assessments collected at the same 
scheduled time, the average of these assessments will be used as the baseline. 
9.4.2. 
Primary Objective 
The primary analysis for the primary objective will be conducted once the last participant 
has completed the Week 72 visit and database lock has achieved. 
The primary efficacy endpoint is achieving a sustained virologic response for 24 weeks 
after the planned end of GSK3228836 and PegIFN sequential treatment in the absence of 
rescue medication. Sustained virologic response is defined as observing HBsAg <LLOQ 
and HBV DNA <LLOQ at each analysis window in the 24 weeks after the end of sequential 
treatment. Analysis windows for the post sequential treatment assessments will be defined 
in the analysis plan. 


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HBsAg and HBV DNA from the week of end-of-treatment to Off-Treatment Week 24 
will be used to assess the primary endpoint for each arm. 
9.4.2.1. 
Main Estimands 
Main Estimands supporting the primary objective are defined as: 
• Population: Participants with CHB on stable NA therapy  
• Treatment: 300 mg GSK3228836 for 12 or 24 weeks followed by up to 24 weeks 
of PegIFN therapy while on stable NA therapy 
• Variable (Categorical): Participants achieving Sustained Virologic Response 
(HBsAg <LLOQ and HBV DNA <LLOQ) for 24 weeks after the planned end of 
sequential treatment, without use of any rescue medication 
• Intercurrent Events:  
o Discontinuation of, interruption in, and non-adherence to GSK3228836 and 
PegIFN not related to any wide disruptive events (such as COVID-19 
pandemic) will be ignored (treatment policy strategy). 
o Ineligibility to receive PegIFN will be ignored (treatment policy strategy)  
o Use of rescue medication (composite strategy).  
o Wide disruptive events (such as COVID-19 pandemic) leading to 
discontinuation of, interruption in, and non-adherence to GSK3228836 and 
PegIFN will be handled assuming they had not happened (hypothetical 
strategy). 
• Population-level Summary: The percentage of participants in each treatment 
group who achieve Sustained Virologic Response (HBsAg <LLOQ and HBV 
DNA <LLOQ) for 24 weeks after the planned end of sequential treatment, 
without use of any rescue medication  
9.4.2.2. 
Supplementary Estimands 
Three supplementary Estimands are defined to support the primary objective. 
The first supplementary Estimand is defined in the same way as the main Estimand, except 
the assessment time frame for patients achieving SVR will be 24 weeks after the actual end 
of treatment. Therefore, the strategy for intercurrent events of treatment discontinuation 
will be while-on-treatment. This supplementary estimand supporting the primary objective 
in participants with CHB on stable NA therapy in each treatment arm is the percentage of 
participants that achieve SVR (HBsAg <LLOQ and HBV DNA <LLOQ) for 24 weeks 
after the actual end of sequential treatment in the absence of rescue medication, regardless 
of ineligibility to receive PegIFN, discontinuation of, interruption in or non-adherence to 
GSK3228836 and PegIFN, had they not been affected by wide disruptive events. 


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The second supplementary Estimand is to understand the relationship between the PegIFN 
duration and achieving SVR for 24 weeks after the actual end of treatment, defined as: 
• Population: Participants with CHB on stable NA therapy  
• Treatment: 300 mg GSK3228836 for 12 or 24 weeks followed by up to 24 weeks 
of PegIFN therapy while on stable NA therapy 
• Variable: The relationship between SVR for 24 weeks after actual end of 
treatment and of PegIFN received by participants before completion or 
discontinuation of each treatment 
• Intercurrent Events:  
o Discontinuation and delayed start of PegIFN will be accounted to reflect the 
actual duration from the first to the last dose of PegIFN received (while-on-
treatment strategy).  
o Interruption in and other non-adherence to PegIFN will be ignored 
(treatment policy strategy). 
o Discontinuation of, interruption in and non-adherence to GSK3228836 will 
be ignored (treatment policy strategy). 
o Use of rescue medication (composite strategy). 
o Wide disruptive events (such as COVID-19 pandemic) leading to 
discontinuation and delayed start of PegIFN will be handled with while-on-
treatment strategy; wide disruptive events leading to interruption in and 
other non-adherence to PegIFN will be ignored (treatment policy strategy); 
wide disruptive events leading to discontinuation of, interruption in, and 
non-adherence to GSK3228836 will be ignored (treatment policy strategy). 
• Population Summary: The percentage of participants achieving SVR for 24 weeks 
after the actual end of treatment by PegIFN treatment duration categorical 
grouping (groupings to be defined in the RAP) in each treatment arm. 
The second supplementary Estimand (supporting the primary objective in participants with 
CHB on stable NA therapy) is percentage of participants achieving SVR for 24 weeks after 
the actual end of treatment by PegIFN treatment duration categorical grouping in each 
treatment arm, taking into account discontinuation and delayed start of PegIFN, regardless 
of interruption in and other non-adherence to PegIFN, regardless of discontinuation of, 
interruption in and non-adherence to GSK3228836. The PegIFN treatment duration will 
support interpretation of the percentage of participants achieving SVR for 24 weeks after 
the actual end of treatment, especially if participants discontinue from PegIFN early or 
delay start of PegIFN due to ineligibility. 
The third supplementary Estimand is defined in the same way as the main Estimand, except 
the strategy for intercurrent events of PegIFN ineligibility for more than 12 weeks (i.e. can 
no longer receive at least 12 weeks of PegIFN treatment) and/or missing at least 12 doses 


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of PegIFN will be principal stratum. This supplementary Estimand supporting the primary 
objective is the percentage of participants in each treatment arm that achieve SVR (HBsAg 
<LLOQ and HBV DNA <LLOQ) for 24 weeks after the planned end of sequential 
treatment in participants with CHB on stable NA therapy and receiving at least 12 doses of 
PegIFN, in the absence of rescue medication, regardless of discontinuation of, interruptions 
in or non-adherence to GSK3228836 had they not been affected by wide disruptive events. 
9.4.2.3. 
Handling of Withdrawal from Study and Missing HBsAg and HBV DNA 
Data 
Two approaches will be used to determine a participant’s response when HBsAg and HBV 
DNA data are missing from visits required to derive the primary Estimand.  
1) For participants where wide disruptive events (such as COVID-19 pandemic) prevent 
assessment of the primary outcome, SVR will be imputed using all available data for 
participants for whom SVR can be assessed. For other participants where SVR in the 
absence of rescue medication cannot be ascertained due to missing data (withdrawal from 
the study or missing due to other reasons, but not due to a wide disruptive event), the 
participant will be assumed not to have achieved SVR (non-responder imputation). 
2) For the main estimand supporting the primary objective, a sensitivity analysis will be 
performed using the Bayesian model described in Section 9.4.2.4 assuming missing at 
random whereby a participant’s response will be imputed using all available data (on and 
off treatment values) for participants who completed the study.  
9.4.2.4. 
Primary Analyses 
The primary assessments of interest are the point estimate of sustained virologic RR and 
95% credible intervals; in addition, posterior probabilities that the true virologic RR in each 
treatment arm is greater than a range of values will be provided. 
A Bayesian hierarchical model will be used to estimate the posterior probability of 
sustained virologic RR incorporating the baseline stratification factors [Jones, 2011]. 
Main effects for each of the 2 strata will be included as independent parameters in the 
model denoted γk (k = 1, 2); Interactions between the 2 levels of stratification factors are 
anticipated to be small, and so will be modelled as exchangeable random effects (ψg) 
centred on zero to enable borrowing of information about the RR across strata. 
𝜃𝑔= 𝜏+ 𝛾1𝐼{𝐵1+} + 𝛾2𝐼{𝐵2+} + 𝜓𝑔 
𝜏~𝑁𝑜𝑟𝑚𝑎𝑙 (0, 106)  
𝛾𝑘~𝑁𝑜𝑟𝑚𝑎𝑙 (0, 106), 𝑘= 1, 2  
𝜓𝑔~𝑁𝑜𝑟𝑚𝑎𝑙 (0, 𝜔2), 𝑔= 1, 2, 3, 4 
𝜔~𝐻𝑎𝑙𝑓−𝑁𝑜𝑟𝑚𝑎𝑙 (1) 


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Where θg is defined as the log odds of treatment response, index g =1, 2, 3, and 4 on the 
random effect ψ refers to each of the 4 possible combinations of strata levels. The 
parameter τ+ ψ1 represents the treatment effect in reference stratum (HBsAg ≤3 log IU/mL 
and Negative HBeAg), while g denotes a random stratum effect in group g. 
The four stratum and representation of the two baseline stratification factors B1 and B2 in 
the model are shown in Table 15. 
Table 15 
Baseline Stratification Factors for Four Stratum 
Stratum 
B1: HBsAg 
B2: HBeAg 
1: HBsAg <3 log IU/mL and Negative HBeAg 
B1- (≤3 log IU/mL) 
B2- (Negative) 
2: HBsAg ≥3 log IU/mL and Negative HBeAg 
B1+ (>3 log IU/mL) 
B2- (Negative) 
3: HBsAg <3 log IU/mL and Positive HBeAg 
B1- (≤3 log IU/mL) 
B2+ (Positive) 
4: HBsAg ≥3 log IU/mL and Positive HBeAg 
B1+ (>3 log IU/mL) 
B2+ (Positive) 
 
The point estimates of sustained virologic RR in each treatment arms with 95% credible 
intervals will be calculated. Handling of withdrawal from study and missing HBsAg and 
HBV DNA data is described in Section 9.4.2.3. 
Posterior probability of sustained virologic RR exceeding a range of clinically 
meaningful RRs will be generated using the model specified. 
9.4.3. 
Secondary Endpoints 
9.4.3.1. 
Secondary Estimands 
Three groups of estimands are defined for the secondary efficacy objectives. Categorical 
definitions for secondary analyses will be provided in the RAP. 
1. Estimands supporting secondary objective of assessing the efficacy of GSK3228836 
and PegIFN sequential therapy on biomarkers and virus specific antibody responses 
are defined as follows: 
• Population: Participants with CHB on stable NA therapy; For the time to ALT 
normalisation variable, population will be aforementioned participants with 
baseline ALT >ULN. 
• Treatment: 300 mg GSK3228836 for 12 or 24 weeks followed by up to 24 weeks 
of PegIFN therapy while on stable NA therapy 
• Intercurrent Events: Discontinuation of, interruption in, and non-adherence to 
GSK3228836 and PegIFN will be ignored (treatment policy). PegIFN ineligibility 
will be ignored (treatment policy); Rescue medication will be ignored (treatment 
policy), except for ALT normalisation which can only be achieved in the absence 


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of rescue medication; Wide disruptive events (such as COVID-19 pandemic) 
leading to discontinuation of, interruption in, and non-adherence to GSK3228836 
and PegIFN will be ignored (treatment policy strategy). 
• Categorical Variables: 
o Achieving HBsAg <LLOQ and HBV DNA <LLOQ at two time points: (1) 
the planned end of treatment and (2) at the end of 24 weeks follow-up 
o Categorical changes from baseline in HBsAg (e.g., <0.5, ≥0.5, ≥1, ≥1.5, ≥3 
log10 IU/mL).  
o ALT normalisation (ALT≤ULN) over time in absence of rescue medication 
in participants with baseline ALT>ULN 
o HBe antibody (anti-HBeAg) levels 
• Population summary of Categorical Variables: percentage of participants in each 
category for each treatment arm 
• Continuous Variables:  
o Actual values and change from baseline over time of HBsAg, HBV DNA, 
and HBeAg levels  
o Actual values and change from baseline over time for HBs antibody (anti-
HBsAg) levels over time  
o Actual values and change from baseline over time for ALT. 
• Population summary of Continuous Variables: mean values and mean changes 
from baseline of each variable for participants in each treatment arm 
• Time to Event Variable:  
o Time to ALT normalisation in absence of rescue medication in participants 
with baseline ALT>ULN 
• Population summary of Time to Event Variable: Turnbull’s estimator for non-
parametric estimation of Time to ALT normalisation in each treatment arm 
The estimands supporting this objective are the population summary for each variable in 
each treatment arm in the population regardless of discontinuation of, interruption in, or 
non-adherence to planned treatment, and regardless of rescue medication (except for ALT 
normalisation which can only be achieved in the absence of rescue medication) or PegIFN 
ineligibility.   
Missing data for variables defined above will be ignored, only available data will be 
summarised. Further details will be provided in the report and analysis plan (RAP). 
2. Estimands supporting secondary objective of investigating the durability of virological 
response after sequential therapy with 12 weeks of GSK3228836 followed by up to 
24 weeks of PegIFN in participants with CHB on stable NA therapy for up to 36 weeks 


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off treatment are defined the same as the above secondary estimand, focusing on the 
timepoints following the 24 weeks off-treatment period. 
3. Estimands supporting secondary objective of comparing efficacy between treatment 
arms of 12 and 24 weeks of GSK3228836 followed by up to 24 weeks of PegIFN are 
defined as follows: 
• Population: Participants with CHB on stable NA therapy  
• Treatment: 300 mg GSK3228836 for 12 or 24 weeks followed by up to 24 weeks 
of PegIFN therapy while on stable NA therapy. One treatment comparison between 
Arms 1 and 2 up to 24 weeks off-treatment 
• Categorical Variables: 
o Achieving SVR (HBsAg <LLOQ and HBV DNA <LLOQ) at the planned end 
of sequential treatment and over the 24 weeks follow-up. 
o Population Summary of Categorical Variables: difference in percentage of 
participants who achieve SVR between treatment arms. 
• Intercurrent Events: Discontinuation of, interruption in, and non-adherence to 
GSK3228836 and PegIFN will be ignored (treatment policy). PegIFN ineligibility 
will be ignored (treatment policy); Participants who have used rescue medication 
will be counted as non-responders (composite strategy); Wide disruptive events 
(such as COVID-19 pandemic) leading to discontinuation of, interruption in, and 
non-adherence to GSK3228836 and PegIFN will be handled assuming they had 
not happened (hypothetical strategy). 
The estimands supporting this objective in participants with CHB on stable NA therapy for 
the treatment comparison is the difference between treatment arms 1 and 2 in the proportion 
of participants that achieve SVR for 24 weeks after the planned end of sequential treatment, 
in the absence of rescue medication, regardless of ineligibility to receive PegIFN, 
regardless of discontinuation of, interruptions in or non-adherence to GSK3228836 and 
PegIFN, had they not been affected by wide disruptive events.   
9.4.3.2. 
Handling of withdrawal from study and missing data for secondary 
endpoints  
9.4.3.2.1. Comparison of efficacy between treatment arms 
Two approaches will be used to determine a participant’s response when HBsAg and HBV 
DNA data are missing from visits required to derive the secondary estimand of comparing 
efficacy between treatment of 12 and 24 weeks of GSK3228836 followed by up to 
24 weeks of PegIFN  
1) For participants where wide disruptive events (such as COVID-19 pandemic) prevent 
assessment of the HBsAg and HBV DNA required to derive SVR, SVR will be imputed 
using all available data for participants for whom SVR can be assessed. For other 
participants where SVR in the absence of rescue medication cannot be ascertained due to 
missing data (withdrawal from the study or missing due to other reasons, but not due to a 


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wide disruptive event), the participant will be assumed not to have achieved SVR (non-
responder imputation). 
2) For the estimand supporting the objective of comparing efficacy between treatment 
arms, a sensitivity analysis will be performed using the Bayesian model described in 
Section 9.4.3.3 assuming missing at random whereby a participant’s response will be 
imputed using all available data (on and off treatment values) for participants who 
completed the study.  
9.4.3.2.2. Other secondary endpoints 
Other than the HBsAg and HBV DNA data supporting the secondary objective of 
comparing efficacy between treatment arms, missing data for variables defined in any other 
secondary or exploratory estimand will be ignored, assuming missing completely at 
random. 
9.4.3.3. 
Secondary Efficacy Analyses  
The secondary efficacy comparison of interest is the difference in sustained virologic RR 
for 24 weeks after the planned end of sequential treatment between treatment arms: 
• Arm 1 vs. Arm 2 in percentage of participants achieving SVR for 24 weeks after 
the planned end of sequential treatment, without use of any rescue medication. 
The model in Section 9.4.2.4 will be used to separately estimate the log odds of response 
for each treatment arm.  Comparisons between the treatment arms will be conducted by 
taking difference of log odds.  The point estimates of differences in sustained virologic RR 
with 95% credible intervals will be calculated for the treatment comparisons described in 
the estimands.  Handling of withdrawal from study and missing HBsAg and HBV DNA 
data is described in Section 9.4.3.2.  Details of the model will be included in the RAP. 
9.4.4. 
Safety Endpoints 
All safety analyses will be based on the Safety Population. 
Exposure to study medication, measured by the number of injections and proportion of 
planned number of injections of study drug, will be summarised by treatment arm. 
The proportion of participants reporting AEs will be tabulated for each treatment arm. The 
following summaries of AEs will be provided: 
• 
Incidence and severity of All AEs; 
• 
Incidence and severity of treatment related AEs; 
• 
Incidence and severity of AEs leading to withdrawal from study; 
• 
Incidence of serious AEs (SAEs). 
 
Laboratory data, vital signs and ECG data (absolute values and change from Baseline) will 
be summarised by visit and treatment arm.  In addition, the maximum postbaseline toxicity 
grade (based on DAIDS categories) will be tabulated by treatment arm. 


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9.4.5. 
Exploratory Endpoints 
9.4.5.1. 
PK and PK-PD Analyses 
Pharmacokinetics (PK) of GSK3228836 and PegIFN will be characterised. In all 
participants, C and terminal half-life (t½) will be estimated, as data permit. 
PK-PD relationships including PK-efficacy relationships and PK-safety relationships will 
be evaluated, as data permit: 
• Efficacy assessments for PK/PD relationship include but not limited to: 
o Categorical: virologic response, seroclearance (HBsAg <LLOQ, HBV DNA 
<LLOQ), and seroconversion (anti-HBsAg and anti-HBeAg); 
o Change from baseline: HBsAg, HBV DNA, anti-HBsAg and anti-HBeAg 
levels; 
o Time to event: virologic response (HBsAg and HBV DNA levels < LLOQ), 
nadir of HBsAg and HBV DNA, HBsAg<LLOQ, HBV DNA <LLOQ, 
seroconversion (anti-HBsAg and anti-HBeAg), peak of ALT flares 
• Safety assessments for PK/PD relationship include but not limited to vital signs, 
laboratory measurements and adverse events 
• PK assessments include but not limited to C and terminal half-life (t½). 
9.4.5.2. 
Safety and Tolerability 
The safety profile of sequential therapy with GSK3228836 (up to 24 weeks) followed by 
PegIFN (up to 24 weeks) in participants with CHB on stable NA therapy will be 
investigated.  
• Clinical assessments include laboratory measurements and adverse events at 
timepoints specified in the SoA. 
CCI


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9.4.5.5. 
Biomarkers 
The effect of GSK3228836 and PegIFN sequential therapy on immunological biomarkers 
will be assessed. The relationship(s) between virology biomarkers including HBsAg and 
immunological biomarkers will be described.  
• Biomarker assessments include Laboratory measurements of and correlation 
between the following: 
o Virological biomarkers, including specific viral parameters (HBeAg, HBV 
DNA, HBV RNA, HBcrAg) 
o Soluble biomarkers, including levels of circulating cytokines and chemokines 
o Markers of immune cell function, including relative frequencies of immune cell 
subsets among PBMCs, activation status as determined by phenotyping and 
gene expression patterns, and functional assays including HBV-specific 
cytokine and/or antibody production 
Timepoints are specified in the SoA. 
Details of exploratory analyses for exploratory efficacy, virology, and biomarker will be 
provided in the RAP. The results of HBcrAg, HBV RNA, virology and biomarker 
investigations may be reported separately from the main clinical study report. All endpoints 
of interest from all comparisons will be descriptively and/or graphically summarised as 
appropriate to the data. 
9.5. 
Interim Analysis 
One interim analysis is planned for the study in addition to regular IDMC safety reviews 
(see Section 10.1.5). The interim analysis will be based on the ITT population. 
CCI


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The approximate timing, endpoint and criteria for the interim analysis is summarised in 
Table 16.   
Table 16 
Interim Analysis Timing, Endpoint and Decision Rule 
Interim 
Timing 
Endpoint 
Decision Rule 
1 
All participants 
complete end-of-
treatment visit 
Sustained virologic 
response rate 
(primary endpoint) 
The predicted end-of-study sustained virologic response 
rate will be modelled to support development plan decision 
making. No option to stop the trial at this point as all 
participants will have completed treatment. 
The RAP will describe the planned interim analysis in greater detail. 
 


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10. 
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS 
10.1. 
Appendix 1: Regulatory, Ethical, and Study Oversight 
Considerations 
10.1.1. 
Regulatory and Ethical Considerations 
• This study will be conducted in accordance with the protocol and with: 
o Consensus ethical principles derived from international guidelines including the 
Declaration of Helsinki and Council for International Organizations of Medical 
Sciences (CIOMS) International Ethical Guidelines 
o Applicable International Conference on Harmonisation (ICH) Good Clinical 
Practice (GCP) Guidelines 
o Applicable laws and regulations 
• The protocol, protocol amendments, ICF, IB, 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 participants.  
• Protocols and any substantial amendments to the protocol will require health 
authority approval prior to initiation except for changes necessary to eliminate an 
immediate hazard to study participants. 
• The investigator will be responsible for the following: 
o 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/IEC 
o Notifying the IRB/IEC of SAE or other significant safety findings as required 
by IRB/IEC procedures 
o Providing oversight of the conduct of the study at the site and adherence to 
requirements of 21 CFR, ICH guidelines, the IRB/IEC, European regulation 
536/2014 for clinical studies (if applicable), ), European Medical Device 
Regulation 2017/745 for clinical device research (if applicable), and all other 
applicable local regulations 
10.1.2. 
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. 


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10.1.3. 
Informed Consent Process 
• The investigator or his/her representative will explain the nature of the study to 
the participant or their legally authorised representative and answer all questions 
regarding the study.  
• Participants must be informed that their participation is voluntary. Participants or 
their legally authorised representative will be required to sign a statement of 
informed consent that meets the requirements of 21 CFR 50, local regulations, 
ICH guidelines, Health Insurance Portability and Accountability Act 
requirements, where applicable, and the IRB/IEC or study centre.  
• The medical record must include a statement that written informed consent was 
obtained before the participant was enrolled in the study and the date the written 
consent was obtained. The authorised person obtaining the informed consent must 
also sign the ICF. 
• Participants 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 participant or their legally 
authorised representative.  
A participant who is rescreened is not required to sign another ICF if the rescreening 
occurs within 45 days from the previous ICF signature date. 
GSK (alone or working with others) may use participant’s coded study data and samples 
and other information to carry out this study; understand the results of this study; learn 
more about GSK3228836 or about the study disease; publish the results of these research 
efforts; work with government agencies or insurers to have GSK3228836 approved for 
medical use or approved for payment coverage.  
The ICF contains a separate section that addresses the use of participant data and 
remaining samples for optional further research. Where approved by the IRB/IEC, the 
investigator or authorised designee will inform each participant of the possibility of 
further research. Participants 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 participant’s agreement to allow any 
participant data and/or remaining leftover samples to be used for further research not 
related to the study/disease. Participants who decline further research will tick the 
corresponding “No” box. 
10.1.4. 
Data Protection 
• Participants will be assigned a unique identifier by the sponsor. Any participant 
records or datasets that are transferred to the sponsor will contain the identifier 
only; participant names or any information which would make the participant 
identifiable will not be transferred.  
• The participant 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 


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disclosure must also be explained to the participant who will be required to give 
consent for their data to be used as described in the informed consent.  
• The participant must be informed that his/her medical records may be examined 
by Clinical Quality Assurance auditors or other authorised personnel appointed by 
the sponsor, by appropriate IRB/IEC members, and by inspectors from regulatory 
authorities. 
10.1.5. 
Committees Structure 
Independent Data Monitoring Committee: The overall responsibility of the IDMC, which 
consists of at least 2 physicians and 1 statistician, is to protect the ethical and safety 
interests of participants recruited into clinical studies while ensuring the scientific 
validity of the studies. The IDMC will meet at predefined times for each study, as well as 
ad hoc (as deemed appropriate), to evaluate the risk versus benefit of GSK3228836. 
Specific responsibilities of the IDMC include:  
• Reviewing the IDMC Charter supplied by GSK and making any 
recommendations for changes to GSK; all IDMC members must approve and sign 
the Charter prior to enrolling the first patient into the study. 
• Determining the type of information needed for review of efficacy/safety data, as 
required, in the context of benefit/risk. 
• Recommending the format for the presentation of this information. 
• Reviewing data collection methods, safety/efficacy monitoring procedures and 
making recommendations for additions or adjustments to the trial design 
following interim analysis. 
GSK is responsible for the selection of IDMC members.  The IDMC Chairperson may 
assist in selecting IDMC members.  The skills and experiences necessary to properly 
fulfil the role of the IDMC (e.g., relevant medical specialties) require careful 
consideration and have been pre-specified by GSK.  In the event that a member is unable 
to continue participation on the IDMC, GSK, in conjunction with the IDMC Chairperson, 
will recommend a replacement.  GSK has the final decision on the replacement.  No 
substitution of members is permissible for individual meetings. 
10.1.6. 
Dissemination of Clinical Study Data 
• 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 also provide all investigators who participated in the study with a 
summary of the study results and will tell the investigators what treatment their 
patients received.  The investigator(s) is/are encouraged to share the summary 
results with the study participants, as appropriate. 


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• The procedures and timing for public disclosure of the protocol and results 
summary and for development of a manuscript for publication for this study will 
be in accordance with GSK Policy. 
• GSK intends to make anonymised patient-level data from this trial available to 
external researchers for scientific analyses or to conduct further research that can 
help advance medical science or improve patient care. This helps ensure the data 
provided by trial participants are used to maximum effect in the creation of 
knowledge and understanding 
10.1.7. 
Data Quality Assurance 
• All participant data relating to the study will be recorded on printed or electronic 
CRF 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. 
• Quality tolerance limits (QTLs) will be pre-defined in the trial master file to 
identify systematic issues that can impact participant safety and/or reliability of 
study results. These pre-defined parameters will be monitored during and at the 
end of the study and all deviations from the QTLs and remedial actions taken will 
be summarised in the clinical study report. 
• The investigator must permit study-related monitoring, audits, IRB/IEC review, 
and regulatory agency inspections and provide direct access to source data 
documents.  
• Monitoring details describing strategy including definition of study critical data 
items and processes (e.g., risk-based initiatives in operations and quality such as 
Risk Management and Mitigation Strategies and Analytical Risk-Based 
Monitoring), methods, responsibilities and requirements, including handling of 
noncompliance issues and monitoring techniques (central, remote, or on-site 
monitoring) are provided in the Monitoring Plan. 
• The sponsor or designee is responsible for the data management of this study 
including quality checking of the data.  
• The sponsor assumes accountability for actions delegated to other individuals 
(e.g., Contract Research Organisations [CRO]). 
• 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.  


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10.1.8. 
Source Documents 
• Source documents provide evidence for the existence of the participant 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. Also, current medical records must be 
available. 
• Definition of what constitutes source data and its origin can be found in the RAP. 
• The investigator must maintain accurate documentation (source data) that 
supports the information entered in the CRF. 
• Study monitors will perform ongoing source data verification to confirm that data 
entered into the CRF by authorised site personnel are accurate, complete, and 
verifiable from source documents; that the safety and rights of participants are 
being protected; and that the study is being conducted in accordance with the 
currently approved protocol and any other study agreements, ICH GCP, and all 
applicable regulatory requirements.  
10.1.9. 
Study and Site Start and Closure 
The study start date is the date on which the clinical study will be open for recruitment of 
participants. 
The first act of recruitment is the first site open and will be the study start date. 
Study/Site Termination 
GSK or 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 or no recruitment of participants (evaluated after a reasonable amount 
of time) by the investigator 
• Discontinuation of further study intervention development 
 


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If the study is prematurely terminated or suspended, the sponsor shall promptly inform 
the investigators, the IECs/IRBs, the regulatory authorities, and any CRO(s) used in the 
study of the reason for termination or suspension, as specified by the applicable 
regulatory requirements. The investigator shall promptly inform the participant and 
should assure appropriate participant therapy and/or follow-up 
10.1.10. 
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 multicentre studies only in their entirety and not as 
individual site data. In this case, a coordinating investigator will be designated by 
mutual agreement. 
• Authorship will be determined by mutual agreement and in line with International 
Committee of Medical Journal Editors authorship requirements. 


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10.2. 
Appendix 2: Clinical Laboratory Tests 
The tests detailed in Table 17 will be performed by the central laboratory.  
Local laboratory results are required for analysis of platelets during the GSK3228836 
dosing period. The blood draw can be taken the day before GSK3228836 dosing.  Results 
must be available prior to dosing.  A sample for central analysis is obtained in parallel. 
Otherwise, local laboratory results are only required in the event that the central laboratory 
results are not available in time for either study intervention administration and/or response 
evaluation. If a local sample is required, it is important that the sample for central analysis 
is obtained in parallel.  
Protocol-specific requirements for inclusion or exclusion of participants are detailed in 
Section 5 of the protocol. 
Additional tests may be performed at any time during the study as determined necessary 
by the investigator or required by local regulations. 
Pregnancy Testing:  
Refer to Section 5.1 Inclusion Criteria for screening pregnancy criteria.  Pregnancy 
testing (urine or serum as required by local regulations) should be conducted according to 
the Schedule of Assessments (Section 1.3) during the study.  Additional serum or urine 
pregnancy tests may be performed, as determined necessary by the investigator or 
required by local regulation, to establish the absence of pregnancy at any time during 
participation in the study. 
Table 17 
Protocol-Required Safety Laboratory Tests 
Laboratory 
Assessments 
Parameters 
Haematology 
Platelet Count1  
RBC Indices: 
mean corpuscular volume  
mean corpuscular 
haemoglobin 
WBC count (with Differential if WBC 
abnormal): 
Neutrophils 
Lymphocytes 
Monocytes 
Eosinophils 
Basophils 
RBC Count 
Haemoglobin 
Haematocrit 
Clinical 
Chemistry 
Blood Urea 
Nitrogen 
Potassium 
Aspartate 
Aminotransferase 
/ Serum Glutamic-
Oxaloacetic 
Transaminase 
Total, indirect and direct 
bilirubin 
 
Creatinine 
Sodium 
Alanine 
Aminotransferase/ 
Serum Glutamic-
Pyruvic 
Transaminase 
Total Protein 
Glucose 
Calcium 
Alkaline 
phosphatase 
Albumin 
Routine 
Urinalysis 
• 
By dipstick 
• 
Microscopic examination (if blood or protein is abnormal) 


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Laboratory 
Assessments 
Parameters 
Pregnancy 
testing 
• 
Highly sensitive urine or serum human chorionic gonadotropin (hCG) pregnancy test (as 
needed for women of childbearing potential)2 
Other Tests 
• 
Follicle-stimulating hormone and oestradiol (as needed only) 
• 
Serology (HIV antibody, hepatitis C virus antibody, and hepatitis D virus antibody) 
• 
Hepatitis B serology (HBsAg, anti-HBsAg, anti-HBeAg, HBV DNA, HBV RNA, HBcrAg) 
• 
Other laboratory: TSH/T4, prothrombin time (PT), INR, activated partial 
thromboplastin time (aPTT), Alpha-fetoprotein, ANCA (MPO-ANCA, PR3-ANCA), 
APRI/Fibrosure, Complement factors C3, C4, C5a, and Bb, hs-CRP, MCP-1, 
angiopoietin II, PBMC, soluble protein, PAX Gene 
• 
Urine ACR 
• 
Optional collections: Genetic sample 
• 
Viral Sequencing: HBV Genotype, HBV DNA, HBV RNA 
 
All study-required laboratory assessments will be performed by a central laboratory, with the 
exception: 
• 
Platelet counts for investigator decisions may be drawn at local laboratory 
 
Additional tests 
listed under 
safety follow-up 
processes 
Liver Chemistry Stopping Criteria3 
• 
Viral hepatitis serology including: 
o 
Hepatitis A IgM antibody; 
o 
Cytomegalovirus IgM antibody;  
o 
Epstein-Barr viral capsid antigen IgM antibody (or if unavailable, obtain 
heterophile antibody or monospot testing);  
o 
Hepatitis E IgM antibody 
o 
Hepatitis B virus DNA load 
o 
Hepatitis C virus RNA load 
o 
Hepatitis D virus antibody 
• 
PK sample 
• 
Serum CPK LDH. 
• 
Fractionated bilirubin, Anti-nuclear antibody, anti-smooth muscle antibody, Type 1 
anti-liver kidney microsomal antibodies and quantitative total immunoglobulin G (IgG 
or gamma globulins). 
• 
Serum acetaminophen adduct HPLC assay 
Drug Induced Vascular Inflammation and Complement Stopping Criteria 
• 
CH50 
• 
Factor B level 
• 
Factor H level 
• 
sC5b-9 


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Laboratory 
Assessments 
Parameters 
Haematological Stopping Criteria 
• 
anti-platelet antibodies 
Drug Induced Kidney Injury Stopping Criteria 
• 
24-hour urine analysis 
• 
renal ultrasound 
• 
urine microscopy 
• 
serum urea and creatinine 
• 
platelets 
• 
urgent serum vasculitis screen [including ANCA, ANA, dsDNA, cryoglobulins] 
• 
 SPEP/ UPEP 
• 
complement panel (C3, C4, C5a and Bb) 
NOTES: 
1. 
Platelets will require local/central lab collection while participants are GSK3228836 on-treatment. The blood 
draw can be taken the day before GSK3228836 dosing.  Results must be available prior to dosing.   
2. 
Urine testing will be standard for the protocol unless serum testing is required by local regulation or IRB/IEC or 
if urine testing is unavailable  
3. 
Details of liver chemistry stopping criteria and required actions and follow-up assessments after liver stopping 
or monitoring event are given in Section 7.1 and Appendix 6.  All events of ALT 3 × upper limit of normal 
(ULN) and bilirubin >2 × ULN (>35% direct bilirubin) or ALT 3 × ULN and international normalised ratio (INR) 
>1.5, if INR measured, which may indicate severe liver injury (possible Hy’s Law), must be reported as an SAE 
(excluding studies of hepatic impairment or cirrhosis). 
 


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10.3. 
Appendix 3: AEs and SAEs: Definitions and Procedures for 
Recording, Evaluating, Follow-up, and Reporting 
10.3.1. 
Definition of AE 
AE Definition 
• An AE is any untoward medical occurrence in a clinical study participant, 
temporally associated with the use of a study intervention, whether or not 
considered related to the study intervention. 
NOTE: An AE can therefore be any unfavourable and unintended sign (including 
an abnormal laboratory finding), symptom, or disease (new or exacerbated) 
temporally associated with the use of a study intervention. 
 
Definition of Unsolicited and Solicited AE 
• An unsolicited adverse event is an adverse event that was not solicited using a 
Participant Diary and that is communicated by a participant/ legally acceptable 
representative (LAR(s)) who has signed the informed consent. Unsolicited AEs 
include serious and non-serious AEs. 
• Potential unsolicited AEs may be medically attended (i.e., symptoms or illnesses 
requiring a hospitalisation, or emergency room visit, or visit to/by a health care 
provider). The participants/LAR(s) will be instructed to contact the site as soon as 
possible to report medically attended event(s), as well as any events that, though 
not medically attended, are of participant /LAR’s concern. Detailed information 
about reported unsolicited AEs will be collected by qualified site personnel and 
documented in the participant’s records. 
• Unsolicited AEs that are not medically attended nor perceived as a concern by 
participant/LAR(s) will be collected during interview with the participants/ LAR(s) 
and by review of available medical records at the next visit. 
• Solicited AEs are predefined local at the injection site and systemic events for 
which the participant is specifically questioned, and which are noted by the 
participant in their diary.  
 
Events Meeting the AE Definition 
• Any abnormal laboratory test results (haematology, 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 or part of underlying disease). 


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• 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 intervention administration even 
though it may have been present before the start of the study. 
• Signs, symptoms, or the clinical sequelae of a suspected intervention- intervention 
interaction. 
• Signs, symptoms, or the clinical sequelae of a suspected overdose of either study 
intervention 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 other abnormal safety 
assessments which are associated with the underlying disease, unless judged by the 
investigator to be more severe than expected for the participant’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 
participant’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. 
 
10.3.2. 
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., hospitalisation for signs/symptoms of the disease under study, 
death due to progression of disease). 
An SAE is defined as any serious adverse event that, at any dose: 
a. Results in death 
b. Is life-threatening 


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The term ‘life-threatening’ in the definition of ‘serious’ refers to an event in which the 
participant 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 hospitalisation or prolongation of existing hospitalisation 
• In general, hospitalisation signifies that the participant has been admitted 
(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 
hospitalisation are AE. If a complication prolongs hospitalisation or fulfils any 
other serious criteria, the event is serious. When in doubt as to whether 
“hospitalisation” occurred or was necessary, the AE should be considered 
serious. 
• Hospitalisation for elective treatment of a pre-existing condition that did not 
worsen from baseline is not considered an AE. 
d. Results in persistent or significant disability/incapacity 
The term disability means a substantial disruption of a person’s ability to conduct 
normal life functions. 
This definition is not intended to include experiences of relatively minor medical 
significance such as uncomplicated headache, nausea, vomiting, diarrhoea, 
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 by the investigator in 
deciding whether SAE reporting is appropriate in other situations such as 
significant medical events that may jeopardise the participant 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. 
o Examples of such events include invasive or malignant cancers, 
intensive treatment for allergic bronchospasm, blood dyscrasias, 
convulsions, or development of intervention dependency or intervention 
abuse. 
 
10.3.3. 
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: 


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• Myocardial infarction/unstable angina 
• Congestive heart failure 
• Arrhythmias 
• Valvulopathy 
• Pulmonary hypertension 
• Cerebrovascular events/stroke and transient ischemic attack 
• Peripheral arterial thromboembolism 
• Deep venous thrombosis/pulmonary embolism 
• Revascularisation 
 
10.3.4. 
Recording and Follow-Up of 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. 
• It is not acceptable for the investigator to send photocopies of the participant’s 
medical records to GSK in lieu of completion of the GSK required form. 
• There may be instances when copies of medical records for certain cases are 
requested by GSK. In this case, all participant identifiers, with the exception of the 
participant 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 1 of the following categories:  
• Mild: An event that is easily tolerated by the participant, causing minimal 
discomfort and not interfering with everyday activities. 
• Moderate: An event that causes sufficient 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. Severe is a category utilised for 
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• 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 intervention and 
each occurrence of each AE/SAE. 
• 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 intervention 
administration will be considered and investigated. 
• The 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 participant dies during participation in the study or during a recognised 
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 submitted 
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• 
The investigator will submit any updated SAE data to GSK within 24 hours of 
receipt of the information. 
The DAIDS Table [DAIDS, 2017] is used for grading AEs and provided as a guidance 
for patient management for the consideration of the PI.  The DAIDS table will be used to 
grade the severity of an AE that is not specifically identified in the grading table. In 
addition, all deaths related to an AE are to be classified as grade 5.  
The DAIDS Table is available at the following link: 
https://rsc.niaid.nih.gov/clinical-research-sites/grading-severity-adult-pediatric-adverse-
events-corrected-version-two-one 
10.3.5. 
Reporting of SAE to GSK 
SAE Reporting to GSK via Electronic Data Collection Tool 
• The primary mechanism for reporting SAE to GSK will be the electronic data 
collection tool. 
• If the electronic system is unavailable, then the site will use the paper SAE data 
collection tool (see next section) to report the event within 24 hours. 
• The site will enter the SAE data into the electronic system as soon as it becomes 
available. 
• After the study is completed at a given site, the electronic data collection tool 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 participant or receives updated 
data on a previously reported SAE after the electronic data collection tool has been 
taken off-line, then the site can report this information on a paper SAE form (see 
next section) or to the medical monitor by telephone. 
• 
Contacts for SAE reporting can be found in the SRM. 
 
SAE Reporting to GSK via Paper Data Collection Tool 
• Facsimile transmission of the SAE paper data collection tool is the preferred 
method to transmit this information to the 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 data collection tool 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 data collection tool within the designated reporting time 
frames. 
• 
Contacts for SAE reporting can be found in the SRM. 
 


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10.4. 
Appendix 4: Contraceptive and Barrier Guidance 
10.4.1. 
Definitions: 
Woman of Childbearing Potential (WOCBP) 
Women in the following categories are considered WOCBP (fertile): 
1. Following menarche 
2. From the time of menarche until becoming post-menopausal unless permanently 
sterile (see below) 
Notes: 
• A postmenopausal state is defined as no menses for 12 months without an 
alternative medical cause. 
o 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, confirmation with more than one FSH 
measurement is required.  
o Females on HRT and whose menopausal status is in doubt will be required to 
use one of the non-oestrogen 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 enrollment. 
• Permanent sterilisation methods (for the purpose of this study) include: 
o Documented hysterectomy 
o Documented bilateral salpingectomy 
o Documented bilateral oophorectomy 
For individuals with permanent infertility due to an alternate medical cause other than the 
above, (e.g., Mullerian agenesis, androgen insensitivity, gonadal dysgenesis), investigator 
discretion should be applied to determining study entry. 
 
Note: Documentation can come from the site personnel’s review of the participant’s 
medical records, medical examination, or medical history interview. 
 
If fertility is unclear (e.g., amenorrhea in adolescents or athletes) and a menstrual cycle 
cannot be confirmed before first dose of study intervention, additional evaluation should 
be considered. 
Woman of Nonchildbearing Potential (WONCBP) 
Women in the following categories are considered WONCBP: 
• Premenopausal female with permanent infertility due to one of the following (for 
the purpose of this study): 


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• Documented hysterectomy 
• Documented bilateral salpingectomy 
• Documented bilateral oophorectomy 
For individuals with permanent infertility due to an alternate medical cause other than the 
above, (e.g., Mullerian agenesis, androgen insensitivity, gonadal dysgenesis), investigator 
discretion should be applied to determining study entry. 
Note: Documentation can come from the site personnel’s review of the participant’s 
medical records, medical examination, or medical history interview. 
• Postmenopausal female 
A postmenopausal state is defined as no menses for 12 months without an alternative 
medical cause. 
o 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, confirmation with more than one FSH 
measurement is required. 
o Females on HRT and whose menopausal status is in doubt must discontinue 
HRT to allow confirmation of postmenopausal status before study enrollment. 
10.4.2. 
Contraception Guidance: 
CONTRACEPTIVESa ALLOWED DURING THE STUDY INCLUDE: 
Highly Effective Methodsb That Have Low User Dependency Failure rate of <1% per year 
when used consistently and correctly. 
Implantable progestogen-only hormone contraception associated with inhibition of 
ovulationb 
Intrauterine device 
Intrauterine hormone-releasing system b 
Bilateral tubal occlusion 
Azoospermic partner (vasectomised or due to a medical cause) 
Azoospermia is a highly effective contraceptive method provided that the partner is 
the sole sexual partner of the woman of childbearing potential and the absence of 
sperm has been confirmed. If not, an additional highly effective method of 
contraception should be used. Spermatogenesis cycle is approximately 90 days. 
Note: documentation of azoospermia for a male participant can come from the site 
personnel’s review of the participant’s medical records, medical examination, or 
medical history interview.) 
Highly Effective Methodsb That Are User Dependent Failure rate of <1% per year when used 
consistently and correctly. 


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Combined (oestrogen- and progestogen-containing) hormonal contraception associated 
with inhibition of ovulationc 
• oral 
• intravaginal 
• transdermal 
• injectable 
Progestogen-only hormone contraception associated with inhibition of ovulationc 
• oral 
• injectable 
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 intervention. 
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 participant. 
Effective Methodsd That Are Not Considered Highly Effective Failure rate of ≥1% per year when 
used consistently and correctly. 
Progestogen-only oral hormonal contraception where inhibition of ovulation is not the 
primary mode of action 
Male or female condom with or without spermicidee 
Cervical cap, diaphragm, or sponge with spermicide 
A combination of male condom with either cervical cap, diaphragm, or sponge with 
spermicide (double-barrier methods)c 
a. 
Contraceptive use by men or women should be consistent with local regulations regarding the use of 
contraceptive methods for those participating in clinical studies. 
b. 
Failure rate of <1% per year when used consistently and correctly. Typical use failure rates differ from those 
when used consistently and correctly. 
c. 
If locally required, in accordance with Clinical Trial Facilitation Group guidelines, acceptable contraceptive 
methods are limited to those which inhibit ovulation as the primary mode of action. 
d. 
Considered effective, but not highly effective - failure rate of ≥1% per year.  Periodic abstinence (calendar, 
sympto-thermal, post-ovulation methods), withdrawal (coitus interruptus), spermicides only, and lactational 
amenorrhea method are not acceptable methods of contraception.  
e. 
Male condom and female condom should not be used together (due to risk of failure from friction). 
 


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Collection of Pregnancy Information: 
Female Participants who become pregnant 
Investigator will collect pregnancy information on any female participant, who becomes 
pregnant while participating in this study.  
The initial information will be recorded on the appropriate form and submitted to GSK 
within 24 hours of learning of a participant's pregnancy.  
Participant will be followed to determine the outcome of the pregnancy. The investigator 
will collect follow up information on participant 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 foetal 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 for medical reasons will be reported as an AE or 
SAE.  
A spontaneous abortion (occurring at <22 weeks gestational age) or still birth (occurring 
at >22 weeks gestational age) 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 intervention 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 participants, he or she may learn of an SAE through spontaneous reporting.  
Any female participant who becomes pregnant while participating will discontinue study 
intervention or be withdrawn from the study. 


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10.5. 
Appendix 5: Genetics 
USE/ANALYSIS OF DNA 
• Genetic variation may impact a participant’s response to study intervention, 
susceptibility, severity and progression of disease. Variable response to study 
intervention may be due to genetic determinants that impact drug absorption, 
distribution, metabolism, and excretion; mechanism of action of the drug; disease 
etiology; and/or molecular subtype of the disease being treated. Therefore, where 
local regulations and IRB/IEC allow, a blood sample will be collected for DNA 
analysis. 
• DNA samples will be used for research related to GSK3228836 or chronic 
hepatitis B and related diseases. They may also be used to develop tests/assays 
including diagnostic tests) related to GSK3228836 or other 2’-MOE ASOs, and 
CHB. Genetic research may consist of the analysis of one or more candidate 
genes or the analysis of genetic markers throughout the genome or analysis of the 
entire genome (as appropriate). 
• Additional analyses may be conducted if it is hypothesised that this may help 
further understand the clinical data.  
• The samples may be analysed as part of a multi-study assessment of genetic 
factors involved in the response to GSK3228836 or study interventions of this 
class. The results of genetic analyses may be reported in the clinical study report 
or in a separate study summary. 
• The sponsor will store the DNA samples in a secure storage space with adequate 
measures to protect confidentiality.  
• The samples will be retained while research on GSK3228836 (or study 
interventions of this class) or chronic hepatitis B continues but no longer than 
15 years after the last participant last visit or other period as per local 
requirements. 


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10.6. 
Appendix 6: Liver Safety: Required Actions and Follow-up 
Assessments and Study Intervention Restart Guidelines 
Phase 2 liver chemistry stopping and increased monitoring criteria have been 
designed to assure participant safety and evaluate liver event etiology.  
The procedures listed below are to be followed if a participant meets any of the liver 
chemistry stopping criteria defined in Section 7.1. 
If criteria for permanent discontinuation of IP are met, immediately withdraw the 
participant from study treatment.  
Notify the Medical Monitor within 24 hours of learning of the abnormality to confirm 
the participant’s study treatment cessation and follow-up. 
Complete the Liver Event CRF. 
Complete the “Safety Follow-up Procedures” listed below. 
Safety Follow-up Procedures for Participants Who Meet Any of The 
Stopping Criteria: 
Viral hepatitis serology including: 
o Hepatitis A IgM antibody; 
o Cytomegalovirus IgM antibody;  
o Epstein-Barr viral capsid antigen IgM antibody (or if unavailable, obtain 
heterophile antibody or monospot testing);  
o Hepatitis E IgM antibody. 
o Hepatitis C virus RNA load 
o Hepatitis D virus antibody 
• Obtain a blood sample for PK analysis as soon as possible following the 
occurrence of an event. Record the date/time of the PK blood sample collection 
and the date/time of the last dose of study treatment prior to blood sample 
collection on the CRF. If the date or time of the last dose is unclear, provide the 
participant’s best approximation. Instructions for sample handling and shipping 
are included in the SRM. 
o CPK and LDH. 
o Review fractionated bilirubin 
o Assess eosinophilia 
o Record the appearance or worsening of clinical symptoms of hepatitis 
(fatigue, nausea, vomiting, right upper quadrant pain or tenderness, fever, 
rash or eosinophilia) as relevant on the AE CRF. 
o Record use of concomitant medications, acetaminophen, herbal remedies, 
other over the counter medications, or putative hepatotoxins on the 
Concomitant Medications CRF. 


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o Record alcohol use on the Liver Events CRF. 
The following are required for participants who meet the ALT and bilirubin 
stopping criteria but are optional for other abnormal liver chemistries. 
 
• Anti-nuclear antibody, anti-smooth muscle antibody, Type 1 anti-liver kidney 
microsomal antibodies and quantitative total immunoglobulin G (IgG or gamma 
globulins). 
• Serum acetaminophen HPLC assay (quantifies potential acetaminophen 
contribution to liver injury in participants with definite or likely acetaminophen 
use in the preceding week [James, 2009]). 
• Liver imaging (ultrasound, magnetic resonance, or computerised tomography) or 
Liver biopsy to evaluate liver disease. 
• The Liver Imaging and/or Liver Biopsy CRFs are also to be completed if these 
tests are performed. 
 
GSK3228836 rechallenge after stopping criteria are met (i.e., study treatment 
discontinued) by any participant in this study is not allowed.  
GSK3228836 restart may be considered only for liver events as follows: 
Restart Following Transient Resolving Liver Stopping Events Not Related to 
GSK3228836 
Restart refers to resuming study intervention following liver stopping events in which there 
is a clear underlying cause (other than DILI]) of the liver event (e.g., biliary obstruction, 
pancreatic events, hypotension, acute viral hepatitis). Furthermore, restart is not permitted 
following liver stopping event when the underlying cause was alcohol-related hepatitis. 
• Approval by GSK for study intervention restart can be considered where: 
o Investigator requests consideration for study intervention restart if liver 
chemistries have a clear underlying cause (e.g., biliary obstruction, 
hypotension and liver chemistries have improved to normal or are within 
1.5 x baseline and ALT <3 x ULN). 
o Possible study intervention-induced liver injury has been excluded by the 
investigator and the study team. This includes the absence of markers of 
hypersensitivity (otherwise unexplained fever, rash, eosinophilia). Where 
a study intervention has a confirmed genetic marker associated with liver 
injury, the presence of the marker should be excluded. If study 
intervention-related liver injury cannot be excluded, the guidance on 
rechallenge will apply. 
o There is no evidence of alcohol-related hepatitis. 
o IRB/IEC approval of study intervention restart, if required, has been 
obtained. 


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If restart of study intervention is approved by GSK Medical Governance in writing: 
• The participant must be provided with a clear description of the possible benefits 
and risks of study intervention administration including the possibility of recurrent, 
more severe liver injury or death.  
• The participant must also provide signed informed consent specifically for the 
restart of study intervention. Documentation of informed consent must be recorded 
in the study file.  
• Study intervention must be administered at the dose specified by GSK 
• Participants approved by GSK for restart of study intervention must return to the 
clinic twice a week for liver function tests until stable liver function tests have been 
demonstrated and then standard laboratory monitoring may resume as per protocol. 
• If the participant meets protocol-defined liver chemistry stopping criteria after 
study intervention restart, study intervention should be permanently discontinued. 
• The Medical Monitor and the IRB/IEC must be informed of the outcome for the 
participant following study intervention restart. 
• GSK must be notified of any adverse events. 
 


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10.7. 
Appendix 7: Country-specific requirements 
10.7.1. 
China  
The following sections outline China-specific changes from the main protocol. In China, 
collection of exploratory/biomarker labs will be contingent on agreements with China 
regulatory, Human Genetics Resources Administration of China (HGRAC). 
10.7.1.1. 
China Schedule of Activities  
The SoA in China will be completed as per Section 1.3, however collection of the 
following laboratory assessments will be contingent on agreements with CHINA 
regulatory (HGRAC) and will be optional for Chinese participants: 
• PBMC Collection for immunophenotyping 
• Soluble Protein (Immunology) 
• PAXGene RNA for expression analysis in whole blood 
10.7.1.2. 
China Biomarkers and Archived Samples 
For China, collection of PBMCs, plasma protein, PAXgene RNA, and genetic samples 
will be contingent on agreements with China regulatory (HGRAC) and will be optional 
for Chinese participants. Depending on the agreements with China regulatory and ethics 
committees, all or some of these biomarkers will be made optional for Chinese 
participants. 
• Blood samples, including serum, plasma, PBMCs and PAXgene tubes, will be 
collected to evaluate virologic and immune biomarkers related to the pathogenesis 
of CHB and the participant’s response to GSK3228836. Samples will be collected 
according to the schedule described in the SoA and as detailed in the laboratory 
manual provided separately to sites. 
 
• For China-stored samples (e.g., archived samples) may be used for the purposes 
of follow-up exploration of laboratory findings and/or AEs (e.g., see Section 7 for 
additional analyses in case of an AE or SAE). 
CCI


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10.8. 
Appendix 8: Abbreviations and Trademarks 
ACR 
albumin to creatinine ratio 
AE 
adverse event 
ALT 
alanine aminotransferase 
ANA 
antinuclear antibody 
ANC 
absolute neutrophil count 
ANCA 
anti-neutrophil cytoplasmic antibody 
cANCA 
classical anti-neutrophil cytoplasmic antibodies 
pANCA 
perinuclear anti-neutrophil cytoplasmic antibodies 
APRI 
aspartate aminotransferase-platelet index 
aPTT 
activated partial thromboplastin time 
ASO 
antisense oligonucleotide  
AST 
aspartate aminotransferase 
BDI-II 
Beck Depression Inventory-II 
cccDNA 
covalently closed circular DNA 
CHB 
chronic hepatitis B 
Ct 
concentration  
CNS 
central nervous system 
COVID-19 
Corona Virus Disease-19 
CPK 
creatine phosphokinase 
CRF 
case report form 
CRO 
contract research organisation 
C-SSRS 
Columbia Suicide-Severity Rating Scale 
CV 
cardiovascular 
DAIDS 
Division of Acquired Immune Deficiency Syndrome 
DIVI 
drug induced vascular inflammation 
DILI 
drug induced liver injury 
dL 
decilitres 
DNA 
deoxyribonucleic acid 
dsDNA 
double stranded deoxyribonucleic acid 
eCRF 
electronic case report form 
ECG 
electrocardiogram 
ET 
early termination 
FDA 
Food and Drug Administration 
FSH 
follicle stimulating hormone 
GCP 
Good Clinical Practice 
GFR 
glomerular filtration rate 
eGFR 
Estimated glomerular filtration rate 
GSK 
GlaxoSmithKline 
HBcrAg 
hepatitis B core-related antigen 
Anti-HBeAg 
hepatitis B virus e-antigen antibody 
HBeAg 
hepatitis B virus e-antigen 
Anti- HBsAg 
hepatitis B virus surface antibody 
HBsAg 
hepatitis B virus surface antigen 
HBV 
hepatitis B virus 
HCC 
hepatocellular carcinoma 
hCG 
human chorionic gonadotropin 
HCV 
hepatitis C virus 
HDV 
hepatitis D virus 
HGRAC 
human Genetics Resources Administration of China 
HIV 
human immunodeficiency virus 
HPF 
high-power field 
HPLC 
high performance liquid chromatography 
HRT 
hormonal replacement therapy 


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hs-CRP 
high sensitivity C-reactive protein 
IB 
Investigator’s Brochure 
ICF 
informed consent form 
ICH 
International Conference on Harmonisation 
IDMC 
independent data monitoring committee 
IDO 
indoleamine 2,3 dioxygenase 
IEC 
Independent Ethics Committee 
IFN 
Interferon 
IMP 
investigational medicinal product 
INR 
international normalised ratio 
IP 
investigational product 
IRB 
Institutional Review Board 
ISR 
injection site reaction 
IVRS/IWRS 
Interactive Voice/Web Response System 
ITT 
Intent-to-Treat 
IU 
international units 
IP 
Investigational Product 
Kg 
kilograms 
kPa 
kilopascals 
L 
litres 
LAR(s) 
Legally acceptable representative 
LDH 
lactate dehydrogenase 
LLN 
lower limit of normal 
LLOQ 
lower limit of quantification 
m2 
square meters 
MCP 
monocyte chemoattractant protein 
mEq 
milliequivalents 
mcg 
microgram 
mg 
milligrams 
Min 
minutes 
mL 
millilitres 
mm3 
cubic millimetres 
MOE 
methoxyethyl 
msec 
milliseconds 
MSDS 
Material Safety Data Sheet 
NA 
nucleos(t)ide analogue 
Ng 
nanograms 
Nucleos(t)ide 
nucleoside or nucleotide 
OAT 
organic anion transporter 
OCT 
organic cation transporter 
PBMC 
peripheral blood mononuclear cells 
PD 
pharmacodynamics(s) 
PEG 
pegylated 
PegIFN 
peginterferon 
PK 
pharmacokinetic(s) 
POC 
proof of concept 
PT 
prothrombin time 
QTcF 
Fridericia’s QT correction formula 
QTLs 
quality tolerance limits 
RAP 
reporting and Analysis Plan 
RBC 
red blood cell 
RNA 
ribonucleic acid  
RNAse H 
Ribonuclease H 
mRNA 
Messenger RNA 
RPGN 
rapidly progressive glomerulonephritis 


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RR 
response rate 
SAE 
serious adverse event 
SC 
subcutaneous(ly) 
siRNA 
small interfering ribonucleic acid 
SoA 
Schedule of Activities 
SPEP 
serum protein electrophoresis 
SRM 
Study Reference Manual 
SRT 
Safety Review Team 
SVR 
Sustained Virologic Response 
t½ 
terminal half-life 
TCM 
traditional Chinese medicine 
TSH 
thyroid stimulating hormone  
U 
units 
UA 
urinalysis 
µg 
micrograms 
ULN 
upper limit of normal 
UPEP 
urine protein electrophoresis 
mol 
micromole 
WBC 
white blood cell 
WOCBP 
women of childbearing potential 
WONCBP 
woman of non-childbearing potential 
 
Trademark Information 
Trademarks of the GlaxoSmithKline 
group of companies 
 
Trademarks not owned by the 
GlaxoSmithKline group of companies 
NONE 
 
PAXgene 
 
 
Pegasys 
 


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11. 
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SAP_001.pdf: 
Statistical Analysis Plan Amendment 4
Study ID:  209348
Official Title of Study: Phase IIb Multi-Center, Randomised, Open Label Study to 
Assess the Efficacy and Safety of Sequential Treatment with GSK3228836 followed by 
Pegylated Interferon Alpha 2a in Participants with Chronic Hepatitis B Virus (B-
Together) 
NCT number: NCT04676724 
Date of Document: 22-MAR-2023


CONFIDENTIAL 
The GlaxoSmithKline group of companies 
I Information Type: 
Statistical Analysis Plan (SAP) 
TITLE PAGE 
209348 
do more 
feel better 
twlonger 
Protocol Title: 
Phase lib Multi-Center, Randomised, Open Label Study to 
Assess the Efficacy and Safety of Sequential Treatment with 
GSK3228836 followed by Pegylated Interferon Alpha 2a in 
Participants with Chronic Hepatitis B Virus (B-Together) 
Study Number: 
209348 
Compound Number: GSK3228836 
Abbreviated Title: 
Phase lib Study of Sequential GSK3228836 and Peginterferon 
Treatment in Participants with Chronic Hepatitis B (B­
Together) 
Acronym: 
B-Together
Sponsor Name: GlaxoSmithKline Research & Development Limited 
Regulatory Agency Identifier Number(s) 
Regish-y 
IND 
EudraCT 
ID 
IND 22685 
2020-002979-35 
Copyright 2023 the GlaxoSmithKline group of companies. All rights 
reserved. Unauthorised copying or use of this information is prohibited. 
XBU Statistical Analysis Plan (SAP) Template v1 .0 24 March 2021
Page 1 of 77 


C O N FI D E N TI A L  
 
 
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T A B L E O F C O N T E N T S  
 
1.  
I N T R O D U C TI O N ...................................................................................................... 9  
1. 1.  
O bj e cti v e s, E sti m a n d s a n d E n d p oi nt s  ........................................................... 9  
1. 2.  
St u d y D e si g n  .............................................................................................. 1 3  
2.  
S T A TI S T I C A L H Y P O T H E S E S ............................................................................... 1 4  
2. 1.  
M ulti pli cit y A dj u st m e nt  ................................................................................ 1 4  
3.  
A N A L Y SI S S E T S  ................................................................................................... 1 5  
4.  
S T A TI S TI C A L A N A L Y S E S  ..................................................................................... 1 6  
4. 1.  
G e n er al C o n si d er ati o n s  .............................................................................. 1 6  
4. 1. 1.  
G e n er al M et h o d ol o g y  .................................................................. 1 7  
4. 1. 2.  
B a s eli n e D efi niti o n  ....................................................................... 1 7  
4. 1. 3.  
R el a p s e D efi niti o n  ........................................................................ 1 7  
4. 2.  
Pri m ar y E n d p oi nt A n al y s e s  ......................................................................... 1 9  
4. 2. 1.  
D efi niti o n of E sti m a n d s  ................................................................ 1 9  
4. 2. 2.  
M ai n A n al yti c al A p pr o a c h  ............................................................ 2 0  
4. 2. 3.  
S e n siti vit y A n al y s e s  ..................................................................... 2 6  
4. 2. 4.  
S u p pl e m e nt ar y E sti m a n d s  ........................................................... 2 6  
4. 2. 5.  
A d diti o n al  E sti m a n d s  ................................................................... 2 9  
4. 3.  
S e c o n d ar y E n d p oi nt A n al y s e s  .................................................................... 2 9  
4. 3. 1.  
S e c o n d ar y E n d p oi nt s  ................................................................... 2 9  
4. 4.  
E x pl or at or y E n d p oi nt A n al y s e s  ................................................................... 3 4  
4. 4. 1.  
Effi c a c y A n al y s e s  ......................................................................... 3 4  
4. 4. 2.  
P h ar m a c o ki n eti c ( P K) A n al y s e s  ................................................... 3 7  
4. 4. 3.  
S af et y a n d T ol er a bilit y  ................................................................. 3 9  
4. 4. 4.  
P h ar m a c o d y n a mi c Eff e ct of G S K 3 2 2 8 8 3 6 a n d P e gI F N 
S e q u e nti al T h er a p y o n E x pl or at or y Bi o m ar k er s  ........................... 3 9  
4. 4. 5.  
Vir ol o g y A n al y s e s  ........................................................................ 3 9  
4. 4. 6.  
Bi o m ar k er A n al y s e s  ..................................................................... 4 1  
4. 5.  
S af et y A n al y s e s  .......................................................................................... 4 1  
4. 5. 1.  
E xt e nt of E x p o s ur e  ...................................................................... 4 1  
4. 5. 2.  
A d v er s e E v e nt s ............................................................................ 4 2  
4. 5. 3.  
A d diti o n al S af et y A s s e s s m e nt s  .................................................... 4 5  
4. 6.  
Ot h er A n al y s e s  ........................................................................................... 4 7  
4. 6. 1.  
S u b gr o u p A n al y s e s  ...................................................................... 4 7  


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4. 6. 2.  
S u b p o p ul ati o n s t o S u p p ort R e g ul at or y C o n s ult ati o n  .................... 4 8  
4. 7.  
I nt eri m A n al y s e s ......................................................................................... 4 9  
4. 7. 1.  
Pri m ar y E n d p oi nt s / V ari a bl e s  ...................................................... 5 0  
4. 7. 2.  
Ot h er E n d p oi nt s / V ari a bl e s  ......................................................... 5 0  
4. 7. 3.  
St ati sti c al A n al y s e s / M et h o d s  ..................................................... 5 1  
4. 7. 4.  
I nt er c urr e nt E v e nt s ...................................................................... 5 4  
4. 7. 5.  
S u b gr o u p A n al y s e s  ...................................................................... 5 6  
4. 7. 6.  
S e n siti vit y A n al y s e s  ..................................................................... 5 6  
4. 7. 7.  
S u p pl e m e nt ar y A n al y s e s  ............................................................. 5 6  
4. 7. 8.  
E x pl or at or y A n al y s e s  ................................................................... 5 6  
4. 8.  
C h a n g e s t o Pr ot o c ol D efi n e d A n al y s e s  ....................................................... 5 6  
5.  
S A M P L E SI Z E D E T E R MI N A TI O N  ......................................................................... 5 8  
6.  
S U P P O R TI N G D O C U M E N T A TI O N  ....................................................................... 6 0  
6. 1.  
A p p e n di x 1: St u d y P o p ul ati o n A n al y s e s  ...................................................... 6 0  
6. 1. 1.  
P arti ci p a nt Di s p o siti o n  ................................................................. 6 0  
6. 1. 2.  
D e m o gr a p hi c a n d B a s eli n e C h ar a ct eri sti c s  .................................. 6 0  
6. 1. 3.  
Pr ot o c ol D e vi ati o n s  ...................................................................... 6 1  
6. 1. 4.  
Pri or a n d C o n c o mit a nt M e di c ati o n s  ............................................. 6 1  
6. 1. 5.  
St u d y I nt er v e nti o n C o m pli a n c e  .................................................... 6 1  
6. 1. 6.  
A d diti o n al A n al y s e s D u e t o t h e C O VI D -1 9 P a n d e mi c  .................. 6 2  
6. 2.  
A p p e n di x 2: D at a D eri v ati o n R ul e s  ............................................................. 6 3  
6. 2. 1.  
Crit eri a f or P ot e nti al Cli ni c al I m p ort a n c e  ...................................... 6 3  
6. 2. 2.  
St u d y P h a s e a n d P eri o d  .............................................................. 6 3  
6. 2. 3.  
St u d y D a y a n d R ef er e n c e D at e s  .................................................. 6 4  
6. 2. 4.  
M ulti pl e M e a s ur e m e nt s at O n e A n al y si s Ti m e P oi nt  .................... 6 5  
6. 2. 5.  
St u d y P h a s e s f or C o n c o mit a nt M e di c ati o n  ................................... 6 5  
6. 2. 6.  
Tr e at m e nt E m er g e nt Fl a g f or A d v er s e E v e nt s  ............................. 6 6  
6. 2. 7.  
M E T A VI R Fi br o si s S c or e  ............................................................. 6 6  
6. 2. 8.  
A s s e s s m e nt Wi n d o w s f or E arl y T er mi n ati o n  ................................ 6 6  
6. 2. 9.  
H a n dli n g of Mi s si n g a n d P arti al D at e s  ......................................... 6 9  
6. 3.  
A p p e n di x 3: A b br e vi ati o n s  .......................................................................... 7 2  
6. 3. 1.  
Tr a d e m ar k s  ................................................................................. 7 6  
7.  
R E F E R E N C E S  ....................................................................................................... 7 7  


C O N FI D E N TI A L  
 
 
2 0 9 3 4 8  
X B U St ati sti c al A n al y si s Pl a n ( S A P)  T e m pl at e v 1. 0 2 4 M ar c h 2 0 2 1  
P a g e 4  of 7 7  
 
V er si o n H i st or y 
S A P 
Versi o n  
A p pr o v al D ate  
Pr ot oc ol V ersi o n  
( D ate) o n w hic h 
S A P is B ase d  
C h a n ge  
R ati o n ale  
S A P 
v. 1. 0  
1 7 -Dec -2 0 2 1  
2 0 9 3 4 8 v. 1. 0  
( 1 6-Oct -2 0 2 0)   
N A  
Ori gi nal 
versi o n  
S A P 
v. 2. 0  
1 9 -J ul-2 0 2 2  
2 0 9 3 4 8 A m d v. 1 . 0 
(2 4 -Se p -2 0 2 1 ) 
U p date d t o 
i ncl u de 
details of I A.  
I A has bee n 
a d de d t o t he 
mai n st u d y 
S A P f or 
practicalit y 
reas o ns i nstea d 
of bei n g 
descri be d i n a 
se parat e 
d oc u me nt . 
S A P 
v. 3. 0  
 
2 2 Mar 2 0 2 3  
2 0 9 3 4 8 A m d v. 1. 0  
( 2 4-Se p -2 0 2 1)  
U p dates t o 
esti ma n d 
strate g y 
w or di n g  
t hr o u g h o ut 
 
W or di n g 
u p date f or 
clarit y a n d 
c o nsiste nc y 
wit h rece nt 
esti ma n d 
strate g y 
g ui deli nes  
 
Secti o n 
4. 2. 5. 2  A d d 
a d diti o nal 
esti ma n d 
strate g y f or 
pri mar y 
e n d p oi nt  
 
Esti ma n d 
a d de d t o 
i n vesti gate 
i m pact of wi de 
disr u pti ve 
e ve nts o n 
pri mar y 
e n d p oi nt  
 


C O N FI D E N TI A L  
 
 
2 0 9 3 4 8  
X B U St ati sti c al A n al y si s Pl a n ( S A P)  T e m pl at e v 1. 0 2 4 M ar c h 2 0 2 1  
P a g e 5  of 7 7  
 
S A P 
Versi o n  
A p pr o v al D ate  
Pr ot oc ol V ersi o n  
( D ate) o n w hic h 
S A P is B ase d  
C h a n ge  
R ati o n ale  
M o ve 
decisi o n -
ma ki n g t o t he 
i D R C c harter 
Decisi o n 
ma ki n g 
fra me w or k has 
bee n m o ve d t o 
si m plif y a n d 
re d uce c o nte nt 
i n S A P 
 
 
 
Secti o n 
4. 5. 2. 1  
Re m o val of 
I S Rs fr o m 
A E SIs  
Re m o val of 
I S R fr o m 
A E SIs as per 
ne w  safet y 
re p orti n g 
g ui deli nes  
S A P 
v. 4 . 0 
 
2 2 Mar 2 0 2 3  
2 0 9 3 4 8 A m d v. 1. 0  
( 2 4-Se p -2 0 2 1)  
Secti o n 4. 1. 3 
A d de d 
Rela pse 
Defi niti o ns  
A d diti o nal 
o ut p uts f or E o S 
i ncl u de rela ps e 
rates o n 
G S K 3 2 2 8 8 3 6, 
Pe gI F N, a n d 
O T. Rela pse is 
als o defi ne d 
differe ntl y  f or 
t he 
c o nser vati ve 
a n d m o difie d 
defi niti o ns of 
S V R.  
 
 


C O N FI D E N TI A L  
 
 
2 0 9 3 4 8  
X B U St ati sti c al A n al y si s Pl a n ( S A P)  T e m pl at e v 1. 0 2 4 M ar c h 2 0 2 1  
P a g e 6  of 7 7  
 
S A P 
Versi o n  
A p pr o v al D ate  
Pr ot oc ol V ersi o n  
( D ate) o n w hic h 
S A P is B ase d  
C h a n ge  
R ati o n ale  
Secti o n 4. 2. 2  
M o del 
si m plificati o n 
b y c o m bi ni n g 
data acr oss 
b ot h 
treat me nt 
ar ms a n d 
re m o val of 
ra n d o m 
effect fr o m 
Ba yesi a n 
m o del  
A d dresses t he 
q uasi -c o m plete 
se parati o n of 
t he res p o nse 
varia ble w h e n 
t he m o del is 
r u n se paratel y 
f or eac h 
treat me nt ar m 
( ori gi n al 
m o del). I n 
a d diti o n, t he 
para meter 
esti mates f or 
t he ori gi nal 
hierarc hical 
m o del d o n ot 
c o n ver ge, a n d 
t he hierarc hical 
m o del 
dia g n ostics are 
p o or.  
Secti o n 
4. 2. 2. 1  
Defi niti o n of 
w orst case 
selecti o n 
wit hi n 
a nal ysis 
wi n d o ws  
Ali g n me nt 
wit h 
c o nser vati ve 
a n d m o difie d 
defi niti o ns of 
S V R  
Secti o n 
4. 2. 2. 2  
C o m bi ne d 
Secti o ns f or 
Ha n dli n g 
Missi n g Data 
O n -
treat me nt, 
E n d of 
Treat me nt, 
Mai ntai n 
c o nsiste nc y 
wit h ha n dli n g 
i nterc urre nt 
e ve nts a n d 
missi n g data 
t hr o u g h o ut t he 
st u d y 


C O N FI D E N TI A L  
 
 
2 0 9 3 4 8  
X B U St ati sti c al A n al y si s Pl a n ( S A P)  T e m pl at e v 1. 0 2 4 M ar c h 2 0 2 1  
P a g e 7  of 7 7  
 
S A P 
Versi o n  
A p pr o v al D ate  
Pr ot oc ol V ersi o n  
( D ate) o n w hic h 
S A P is B ase d  
C h a n ge  
R ati o n ale  
a n d P ost -
treat me nt 
Secti o n 
4. 3. 1. 1  
A d de d Ti me 
fr o m Be pi 
E O T t o 
Rela pse b y 
H Bs A g 
Cate g ories 
E n d p oi nt  
A d de d Ti me t o 
E ve nt e n d p oi nt 
a nal ys e d 
d uri n g 
a d mi nistrati ve 
I As ( AI As) 
Secti o n 4. 4. 1  
M o ve d 
E x pl orat or y 
Efficac y 
E n d p oi nts t o 
mai n b o d y of 
S A P wit h 
refere nce i n 
t he I A 
secti o n  
Pr o vi de clarif y 
t hat 
e x pl orat or y 
e n d p oi nts will 
be pr o d uce d 
f or b ot h t he 
pla n ne d I A a n d 
f or E o S 
Secti o n 
4. 5. 3. 1  
A d de d 
i nf or mati o n 
o n ha n dli n g 
d u plicate 
L A B val u es 
at t he sa me 
date/ 
ti me p oi nt 
Clarit y f or 
pr o gra m mi n g 
p ur p oses  


C O N FI D E N TI A L  
 
 
2 0 9 3 4 8  
X B U St ati sti c al A n al y si s Pl a n ( S A P)  T e m pl at e v 1. 0 2 4 M ar c h 2 0 2 1  
P a g e 8  of 7 7  
 
S A P 
Versi o n  
A p pr o v al D ate  
Pr ot oc ol V ersi o n  
( D ate) o n w hic h 
S A P is B ase d  
C h a n ge  
R ati o n ale  
Secti o n 6. 1. 5  
U p date t o 
st u d y 
i nter ve nti o n 
c o m plia nce 
a n d st u d y 
d ose 
c o m plia nce 
calc ulati o ns  
A dj ust f or 
Pe gI F N 
treat me nt 
peri o d  


C O N FI D E N TI A L  
 
 
2 0 9 3 4 8  
X B U St ati sti c al A n al y si s Pl a n ( S A P)  T e m pl at e v 1. 0 2 4 M ar c h 2 0 2 1  
P a g e 9  of 7 7  
 
1.  
I N T R O D U C TI O N 
T he p ur p ose of t his Statistical A nal ysis Pla n  (S A P ) is t o descri be t he fi nal pla n ne d a nal yses 
t o be i ncl u de d i n t he Cli nical St u d y Re p ort ( C S R ) f or St u d y 2 0 9 3 4 8 , a n d t o descri be t h e 
a nal ys es t o be perf or me d f or t he  pre -s pecifi e d i nteri m a nal ysis, w hic h will be use d i n earl y 
C o m mit t o P hase 3 ( C 2 P 3) decisi o n ma ki n g . 
1. 1.  
O bj e cti v e s, E sti m a n d s a n d E n d p oi nt s  
St u d y 2 0 9 3 4 8 is i nte n de d t o e val uat e w het h er u p t o 2 4 wee ks of treat me nt wit h 
G S K 3 2 2 8 8 3 6 f oll o we d b y u p t o 2 4 wee ks of pe g yl ate d i n terfer o n ( Pe gI F N) ca n i ncrease 
t he rat e of he p atitis B vir us s urface a nti ge n ( H Bs A g) l oss i n p artici pa nts o n sta ble 
n ucle os(t)i de a nal o g ue ( N A) t hera p y, a n d w het her vir ol o gic res p o nse ca n b e s ustai ne d o nce 
Pe gI F N treat me nt is disc o nti n ue d. St u d y 2 0 9 3 4 8 wil l als o e v al uate t he safet y a n d 
t olera bilit y of t he treat me nt re gi me n. I n a d diti o n, p har mac o ki netic, vir ol o g y, a n d 
bi o mar ker ass ess me nts will be e val uate d f or e x pl orat or y p ur p oses.  
O bjecti ves a n d Esti m a n ds:  
O bj e cti ve s  
E sti m a n d s a n d E n d p oi nt s  
Pri m ary  
Effic acy: T o i nv esti gat e t h e effic acy of t w o 
diff er e nt d ur atio ns of G S K 3 2 28 8 3 6 f oll o w e d 
by u p t o 2 4 w e eks of P egI F N th er a py i n 
p articip a nts wit h C H B o n sta ble N A t h er a py.  
T h e m ai n Esti m a n d s u p porti n g t h e pri m ary obj ectiv e is 
d efi n e d as:  
• 
P o p ul atio n: P artici p ants with C H B o n st a ble N A 
t h er a py  
• 
Tr e at m e nt: 3 0 0 m g G S K 32 2 88 3 6 f or 1 2 or 2 4 w e eks 
f oll o w e d by u p t o 2 4 w e eks of P e gI F N t h er a py w hil e 
o n st a bl e N A t h er a py  
• 
V ari a bl e ( Cate g oric al): P articipa nts ac hi evi n g 
S ust ai n ed Vir olo gic R es p o ns e ( S V R ) ( H Bs A g 
< L L O Q a n d H B V D N A < L L O Q) f or 2 4 w e eks after 
t h e pl a nn e d en d of s e q u enti al tr e at m e nt, wit h o ut us e 
of a ny r esc ue m e dic ati o n  
• 
I nt erc urr e nt Ev e nts: 
o  Disc o nti n u ati o n of, i nt err upti o n i n, a n d n o n -
a d h er e nc e t o G S K 3 2 2 8 83 6 a nd P e gI F N n ot 
r el at e d to a ny wi d e disr u ptiv e ev e nts (s uc h as 
C O VI D -1 9 p a n d e mic) will be ig n or e d (tr e at m e nt 
p olicy strat e gy).  
o  I n eli gi bility to r ec eiv e P egI F N will b e i g n or e d 
(tr e at m e nt p olicy str at egy) 
o  Us e of r esc u e m e dic atio n (c o m p osit e strat e gy).  
o  Wi d e disr u ptiv e ev e nts (s uc h as C O VI D -1 9 
p a n d e mic) le a di ng t o disco nti nu ati o n of, 
i nt err u pti o n i n, a n d n o n-a d here nc e t o 
G S K 3 2 2 8 8 36 a n d P egI F N will b e h a n dl e d 
ass u mi n g th ey h a d n ot h a p pen e d ( hy pot h etic al 
str at e gy). 
• 
P o p ul atio n S u m m ary: Th e p erc e nt a g e of 
p articip a nts i n eac h tre at m ent gr o u p w h o ac hi ev e 
S V R, wit h o ut us e of a ny r esc ue m e dic atio n  


C O N FI D E N TI A L  
 
 
2 0 9 3 4 8  
X B U St ati sti c al A n al y si s Pl a n ( S A P)  T e m pl at e v 1. 0 2 4 M ar c h 2 0 2 1  
P a g e 1 0  of 7 7  
 
O bj e cti ve s  
E sti m a n d s a n d E n d p oi nt s  
T h e m ai n pri m ary esti m a n d s up p orti n g t h e pri m ary 
o bj ectiv e i n p articip a nts wit h C H B o n st a ble N A t h er a py 
i n e ach tr e at m e nt ar m is t h e perc e nt a ge of p artici p a nts 
t h at ac hi eve S V R ( H Bs A g < L L O Q a nd H B V D N A 
< L L O Q) f or 2 4 w eeks aft er t he pl a n n ed e n d of s e qu e ntial 
tr e at m e nt i n t he a bse nc e of r esc u e m e dic atio n, 
r e g ar dl ess of i n eli gi bility t o receiv e P e gI F N, 
disc onti n uati o n of, int err u pti o n i n, a n d n o n -a dh er e nc e t o 
G S K 3 2 2 8 8 36 a n d P egI F N, h ad t h ey not b e en aff ect e d 
by wi d e disr u ptiv e ev ents.  
 
T hr e e s up pl e m e nt ary Esti m a nds ar e defi n ed t o su p p ort 
t h e pri mary o bj ectiv e: 
• 
T h e first s u p pl e me nt ary Esti ma n d is d efi ne d i n t h e 
s a m e w ay as th e mai n Esti m an d, exc e pt t he 
ass ess me nt ti m e fr a m e f or pati e nts ac hievi ng S V R 
will b e 24 w e eks aft er th e act ual e n d of tr e at m e nt. 
T h er ef or e, th e strat e gy f or i nterc urr e nt ev e nts of 
tr e at m e nt disc o nti n u ati o n will b e w hil e-on -tr e at me nt. 
T his su p ple m e ntary esti ma n d s u p p orti n g t he pri mary 
o bj ectiv e i n p articip a nts wit h C H B o n st a ble N A 
t h er a py i n e ac h tr e at m e nt ar m is t h e p erc ent a g e of 
p articip a nts t h at ac hiev e S V R ( H Bs A g < L L O Q a n d 
H B V D N A < L L O Q) f or 2 4 w eeks aft er t h e act u al e n d 
of s e q ue nti al tr e at m e nt i n t h e a bs e nc e of r esc ue 
m e dicati o n, r e g ar dl ess of in eligi bility t o r ec eiv e 
P e gI F N, disc o ntin u at io n of, i nterr u pti o n i n, a nd n o n-
a d h er e nc e t o G S K 3 2 2 8 83 6 a nd P e gI F N, h a d th ey 
n ot b e e n aff ect e d by wi d e disru ptiv e ev e nts.  
 
• 
T h e s ec o n d s u p ple m e nt ary Esti m a n d is to 
u n d erst an d t h e rel ati o nshi p b et w e e n t h e P e gI F N 
d ur ati o n a n d ac hi evi n g S V R f or 2 4 w e eks aft er  th e 
act u al e n d of tr e at me nt, defi n ed as:  
o  P o p ul atio n: P artici p ants with C H B o n st a ble N A 
t h er a py  
o  Tr e at m e nt: 3 0 0 m g G S K 32 2 88 3 6 f or 1 2 or 2 4 
w e eks f oll o w e d by 2 4 w e eks of P e gI F N t h er a py 
w hil e o n st a ble N A t h er a py  
o  V ari a bl e: Th e r elati o ns hi p b et w e e n S V R f or 2 4 
w e eks after actu al en d of tr eat m e nt a nd t h e 
d ur ati o n of P e gI F N r ec eiv e d by p artici p ants  
o  I nt erc urr e nt Ev e nts:  
▪ 
Disc o nti n u ati o n a nd d elay e d st art of, 
P e gI F N, will b e acc o u nt ed t o refl ect th e 
act u al d ur atio n fr o m t h e first t o t h e l ast 
d os e of Pe gI F N r ec eiv ed ( while -o n -
tr e at m e nt str at egy).  


C O N FI D E N TI A L  
 
 
2 0 9 3 4 8  
X B U St ati sti c al A n al y si s Pl a n ( S A P)  T e m pl at e v 1. 0 2 4 M ar c h 2 0 2 1  
P a g e 1 1  of 7 7  
 
O bj e cti ve s  
E sti m a n d s a n d E n d p oi nt s  
▪ 
I nt err u ptio n i n a n d oth er n o n-ad h er e nce 
t o P e gI F N will b e i gn or e d (tr eat m e nt 
p olicy strat e gy)  
▪ 
Disc o nti n u ati o n of, i nt err upti o n i n a n d 
n o n -a d h er enc e to G S K 3 22 8 8 36 will b e 
i g n or e d (tre at m ent p olicy str ate gy) 
▪ 
Us e of r esc u e m e dic atio n (c o m p osit e 
str at e gy). 
▪ 
Wi d e disr u ptiv e ev e nts (s uc h as 
C O VI D -1 9 p a n d e mic) l e a di n g t o 
disc onti n uati o n a n d del aye d start of, 
P e gI F N will b e h a n dl e d wit h whil e -o n -
tr e at m e nt str at egy; wi de disr uptiv e 
ev e nts l e a di n g to i nt erru pti on in a n d 
ot h er n o n -ad h er e nc e t o Pe gI F N will b e 
i g n or e d (tre at m ent p olicy str ate gy);  
wi d e disru ptiv e eve nts l e a di n g t o 
disc onti n uati o n of, int err u pti o n i n, a n d 
n o n -a d h er enc e to G S K 3 22 8 8 36 will b e 
i g n or e d (tre at m ent p olicy str ate gy). 
o  P o p ul atio n S u m m ary: Th e p erc e nt a g e of 
p articip a nts ac hi evi n g S V R f or 2 4 w e eks aft er 
t h e act ual e nd of tr eat m e nt by P e gI F N 
tr e at m e nt d ur atio n cat e g oric al gr o u pi n g i n eac h 
tr e at m e nt ar m  
• 
T h e s ec o n d s u p ple m e nt ary Esti m a n d (s u p porti n g 
t h e pri mary o bj ectiv e i n p articip a nts with C H B o n 
st a bl e N A t her a py) is th e p erce nt a g e of p artici p ants 
ac hi evi n g S V R f or 2 4 w e eks aft er t h e act u al e n d of 
tr e at m e nt by P e gI F N tr e at me nt d ur ati on c ate g oric al 
gr o u pi n g i n eac h tr eat m ent ar m, t aki n g int o acc o u nt 
disc onti n uati o n a n d del a ye d start of P e gI F N, 
r e g ar dl ess of i nt err upti o n i n a nd ot h er n on-
a d h er e nc e t o P e gI F N, r e g ar dless of disc o nti n u ati o n 
of, i nt err upti o n i n a nd n o n -ad her e nc e to 
G S K 3 2 2 8 8 36.  
• 
T h e t hir d s u p pl e m ent ary Esti ma n d is d efi ne d i n t h e 
s a m e w ay as th e mai n Esti m an d, exc e pt t he 
str at e gy f or i nt erc urr ent eve nts of P e gI F N i n eli gi bility 
f or m or e t ha n 1 2 w eeks a n d/ or missi n g m or e t ha n 
1 2 d os es of P egI F N will b e princi p al str atu m. T his 
s u p pl e m e ntary Esti m a nd s u pporti n g t he pri mary 
o bj ectiv e is t he p erce nt a ge of p articip a nts i n e ac h 
tr e at m e nt ar m t hat achi eve S V R ( H Bs A g < L L O Q 
a n d H B V D N A < L L O Q) for 2 4 w e eks after t h e 
pl a n n e d e n d of s e qu e ntial tr e at m e nt in p artici p ants 
wit h C H B o n st a bl e N A t h er a py a n d r ec eivi n g at 
l e ast 12 d os es of P e gI F N, i n th e a bs enc e of r esc u e 
m e dicati o n, r e g a r dl ess of disco nti n u ati o n of, 
i nt err u pti o ns i n or no n-a d her enc e t o G S K 3 2 2 8 83 6 


C O N FI D E N TI A L  
 
 
2 0 9 3 4 8  
X B U St ati sti c al A n al y si s Pl a n ( S A P)  T e m pl at e v 1. 0 2 4 M ar c h 2 0 2 1  
P a g e 1 2  of 7 7  
 
O bj e cti ve s  
E sti m a n d s a n d E n d p oi nt s  
h a d t h ey n ot be e n affect ed by wi d e disru ptiv e 
ev e nts. 


C O N FI D E N TI A L  
 
 
2 0 9 3 4 8  
X B U St ati sti c al A n al y si s Pl a n ( S A P)  T e m pl at e v 1. 0 2 4 M ar c h 2 0 2 1  
P a g e 1 3  of 7 7  
 
1. 2.  
St u d y D e si g n  
O ver vie w of St u d y Desi g n a n d Ke y Fe at ures  
 
De si g n F e at ure s   
•  
P h as e II b, m ulti -c ent er, r a nd o mis e d, o p e n l a b el st udy t o 
ass ess t he effic acy a n d s af ety of s e q ue nti al tr e at m e nt with 
G S K 3 2 2 8 8 36 f oll o w e d by P e gyl at e d I nt erf er on Al p ha 2 a in 
p articip a nts  wit h C H B w hil e o n st a bl e n ucl e os(t)i d e tre at m ent . 
St u d y I nt er v e nti o n   
•  
Ar m 1: 3 0 0 m g G S K 3 2 2 8 8 36 o nc e/ w e ek f or 2 4 w e eks ( pl us 
l o a di ng d oses of 3 0 0 m g G S K3 2 2 8 8 3 6 o n D ay 4 a n d D ay 1 1) 
f oll o w e d by P e gI F N ( 18 0 mc g/ w e ek f or u p t o 2 4 w e eks). 
•  
Ar m 2: 3 0 0 m g G S K 3 2 2 8 8 36 o nc e/ w e ek f or 1 2 w e eks ( pl us 
l o a di ng d oses of 3 0 0 m g G S K3 2 2 8 8 3 6 o n D ay 4 a n d D ay 1 1) 
f oll o w e d by P e gI F N ( 18 0 mc g/ w e ek f or u p t o 2 4 w e eks). 
St u d y 
I nt erv e nti o n A s si g n m e nt   
•  
P artici pa nts will b e r a n d o mised i n a 1:1 r atio t o r ec eive st udy 
i nt erv enti o n. A p pr oxi m at ely 100 p artici p a nts ar e pl a n ne d t o 
b e e nr oll e d in t h e st u dy. T h e st u dy t e a m m ay e nrol a dditi on al 
p articip a nts t o wit hi n 1 0 % of t he pl a n ne d 1 0 0.  
I nt eri m A n al y se s  
•  
A d mi nistr ativ e I nteri m a n aly es :  i nt eri m a n alys es  t o s u pp ort 
i nt er n al d ecisio n m aki n g at multi pl e ti m ep oi nts t hr ou g h o ut t he 
st u dy.  
•  
Pl a n n e d efficacy Int eri m a n alysis : all partici p a nts c o m pl et e 
t h e e n d -of -tre at me nt visit a n d a s uffici e nt n u mb er of 
p articip a nts c o m pl ete off -tr e at m e nt f oll o w-u p i n or d er t o 
ass ess t he pr o b ability of C 2 P 3. 
•  
I n d e p e n de nt D at a M o nitori n g  C o m mitt ee ( I D M C) s afety 
r evi e w: a ppr oxi m at ely ev ery 3 m o nt hs.  


C O N FI D E N TI A L  
 
 
2 0 9 3 4 8  
X B U St ati sti c al A n al y si s Pl a n ( S A P)  T e m pl at e v 1. 0 2 4 M ar c h 2 0 2 1  
P a g e 1 3  of 7 7  
 
1. 2.  
St u d y D e si g n  
O ver vie w of St u d y Desi g n a n d Ke y Fe at ures  
 
De si g n F e at ure s   
•  
P h as e II b, m ulti -c ent er, r a nd o mis e d, o p e n l a b el st udy t o 
ass ess t he effic acy a n d s af ety of s e q ue nti al tr e at m e nt with 
G S K 3 2 2 8 8 36 f oll o w e d by P e gyl at e d I nt erf er on Al p ha 2 a in 
p articip a nts  wit h C H B w hil e o n st a bl e n ucl e os(t)i d e tre at m ent . 
St u d y I nt er v e nti o n   
•  
Ar m 1: 3 0 0 m g G S K 3 2 2 8 8 36 o nc e/ w e ek f or 2 4 w e eks ( pl us 
l o a di ng d oses of 3 0 0 m g G S K3 2 2 8 8 3 6 o n D ay 4 a n d D ay 1 1) 
f oll o w e d by P e gI F N ( 18 0 mc g/ w e ek f or u p t o 2 4 w e eks). 
•  
Ar m 2: 3 0 0 m g G S K 3 2 2 8 8 36 o nc e/ w e ek f or 1 2 w e eks ( pl us 
l o a di ng d oses of 3 0 0 m g G S K3 2 2 8 8 3 6 o n D ay 4 a n d D ay 1 1) 
f oll o w e d by P e gI F N ( 18 0 mc g/ w e ek f or u p t o 2 4 w e eks). 
St u d y 
I nt erv e nti o n A s si g n m e nt   
•  
P artici pa nts will b e r a n d o mised i n a 1:1 r atio t o r ec eive st udy 
i nt erv enti o n. A p pr oxi m at ely 100 p artici p a nts ar e pl a n ne d t o 
b e e nr oll e d in t h e st u dy. T h e st u dy t e a m m ay e nrol a dditi on al 
p articip a nts t o wit hi n 1 0 % of t he pl a n ne d 1 0 0.  
I nt eri m A n al y se s  
•  
A d mi nistr ativ e I nteri m a n aly es :  i nt eri m a n alys es  t o s u pp ort 
i nt er n al d ecisio n m aki n g at multi pl e ti m ep oi nts t hr ou g h o ut t he 
st u dy.  
•  
Pl a n n e d efficacy Int eri m a n alysis : all partici p a nts c o m pl et e 
t h e e n d -of -tre at me nt visit a n d a s uffici e nt n u mb er of 
p articip a nts c o m pl ete off -tr e at m e nt f oll o w-u p i n or d er t o 
ass ess t he pr o b ability of C 2 P 3. 
•  
I n d e p e n de nt D at a M o nitori n g  C o m mitt ee ( I D M C) s afety 
r evi e w: a ppr oxi m at ely ev ery 3 m o nt hs.  


C O N FI D E N TI A L  
 
 
2 0 9 3 4 8  
X B U St ati sti c al A n al y si s Pl a n ( S A P)  T e m pl at e v 1. 0 2 4 M ar c h 2 0 2 1  
P a g e 1 4  of 7 7  
 
2.  
S T A TI S TI C A L H Y P O T H E S E S  
T he pri mar y o bj ecti ve of t he st u d y is t o i n vesti gat e t he effecti ve ness of G S K 3 2 2 8 8 3 6 a n d 
Pe gI F N se q u e ntial t hera p y i n C H B partici pa nts  o n sta ble N A t hera p y. T he pri mar y 
e n d p oi nt is ac hie vi n g a s ustai ne d vir ol o gic res p o nse (S V R , H Bs A g < L L O Q a n d H B V 
D N A < L L O Q) f or 2 4 w ee ks after t he pla n ne d e n d of G S K 3 2 2 8 8 3 6 a n d Pe gI F N s e q ue ntial 
treat me nt i n t he a bse nce of resc ue me dicati o n. Resc ue me dicati o n is defi ne d as a n y 
me dicati o n i nitiate d f or t he p ur p ose of a nti viral s u p pre ssi o n ot her t ha n t he bac k gr o u n d 
sta ble N A t hera p y. 
A sec o n d ar y o bjecti ve is t o c o m p are t he efficac y bet w ee n 2 4 a n d 1 2 wee ks of 
G S K 3 2 2 8 8 3 6 treat me nt f oll o we d b y Pe gI F N f or u p t o 2 4 wee ks, meas ure d b y t h e 
pr o p orti o n of p artici pa nts t hat ac hie ve vir ol o gic res p o nse at t he pl a n ne d e n d of s e q ue ntial 
treat me nt a nd s ustai ne d f or si x m o nt hs or m ore p ost -treat me nt. T he ai m of t he st u d y is t o 
pr o vi de e vi de nce f or effi cac y of G S K 3 2 2 8 8 3 6 a n d Pe gI F N se q u e ntial t hera p y i n reac hi n g 
s ustai ne d vir ol o gic res p o nse, a n d t o i nf or m selecti o n of treat me nt re gi me n f or P hase III 
trials base d o n t he c o m paris o n bet wee n t he t w o ar ms.  
T he pri mar y ai m f or t he st u d y is des cri pti ve, he nce n o f or mal h y p ot hesis testi n g is pla n ne d. 
A pr o ba bilit y i nfere nce a p pr oac h 
will be use d f or decisi o n -ma ki n g. T he pri mar y 
assess me nt of i nterest is t he S V R  rate of eac h tr eat me nt gr o u p. T h e p oi nt esti mates f or 
S V R  a n d 9 5 % cre di ble i nter vals will be calc ulate d usi n g a Ba yesia n pr o ba bilit y a p pr oac h . 
In a d diti o n, p osteri or pr o ba bilities t hat t he tr ue S V R  i n eac h treat me nt ar m is greater t ha n 
a ra n ge of cli nicall y mea ni n gf ul res p o nse rates will be pr o vi de d.  
C o m paris o ns bet wee n treat me nt ar ms as defi ne d i n t he ke y sec o n dar y o bj ecti ves will be 
assesse d usi n g pr o ba bilit y i nfere n ce a p pr oac h es.  
 
2. 1.  
M ulti pli cit y A dj u st m e nt  
N o a dj ust me nts will be ma de f or m ulti plicit y.  


C O N FI D E N TI A L  
 
 
2 0 9 3 4 8  
X B U St ati sti c al A n al y si s Pl a n ( S A P)  T e m pl at e v 1. 0 2 4 M ar c h 2 0 2 1  
P a g e 1 5  of 7 7  
 
3.  
A N A L Y SI S S E T S  
T he f oll o wi n g p o p ul ati o ns are defi ne d f or t h e a nal ys es:  
A n al ysis Set  
Defi niti o n / Criteri a  
A n al yses E v al u ate d  
Scr e e n e d    
•  
All p artici p ants w h o w ere scree n e d f or 
eli gi bility.  
St u dy P o p ul ati on   
E nr oll e d   
•  
All p artici p ants w h o p ass e d scr e e ni n g ( m et 
eli gi bility crit eri a) a n d ent er e d th e st u dy.  
•  
N ot e scr e eni n g f ailur es ( wh o nev er p ass e d 
scr e e ni n g ev e n if r escr e e n ed) a n d p artici pa nts 
scr e e ne d b ut n ev er e nr oll e d int o t h e stu dy ar e 
excl ud e d fr o m t h e Enr oll ed p op ul ati on as t h ey 
di d n ot e nt er t he st udy.  
St u d y P o p ul ati on  
I T T  
•  
All r a n d o mise d p articip a nts.  
•  
T his p op ul ati o n will b e b as ed o n t h e tr eat m e nt 
t h e p artici p ant w as r an d o mis ed t o. 
•  
A ny p artici p ant w h o r ec eives a tr e at m e nt 
r a n d o mis atio n n u m b er will b e c o nsid er e d to 
h av e b ee n r a n do mis e d.  
Effic acy   
S af ety   
•  
All p artici p ants w h o w ere r a n do mis ed a n d 
r ec eive d at l e ast o n e dos e of st u dy tr e at m e nt.  
•  
T his p op ul ati o n will b e b as ed o n t h e tr eat m e nt 
t h e p artici p ant r eceiv ed. 
•  
N ot e: P artici p a nts w h o w er e not r a n d o mis ed 
b ut r ec eiv e d at l east on e d os e of st u dy 
tr e at m e nt will be list e d. 
S af ety   
Vir ol o gy   
P h ar m ac oki n etic ( P K)   
•  
All p artici p ants i n t h e S af ety po p ul atio n w h o 
r ec eive d a n activ e st u dy tr e at m e nt a nd h a d at 
l e ast 1 n o n-missi n g P K ass ess m e nt ( No n -
q u a ntifi a bl e [ N Q] val u es will be c o nsi d er ed as 
n o n -missin g v al u es)  
•  
N ot e: P K s a m pl es th at may be aff ect ed by 
pr ot oc ol d evi atio ns will b e revie w e d by t he 
st u dy te a m to d et er mi n e w h eth er  t h e sa m pl e 
will b e excl u d e d.  
P K   
P h ar m ac ody n a mic 
( P D)  
•  
All p artici p ants i n t h e S af ety po p ul atio n f or 
w h o m a P h ar mac o dy n a mic s a m pl e w as 
o bt ai n ed a n d a n alys e d.  
P D   


C O N FI D E N TI A L  
 
 
2 0 9 3 4 8  
X B U St ati sti c al A n al y si s Pl a n ( S A P)  T e m pl at e v 1. 0 2 4 M ar c h 2 0 2 1  
P a g e 1 6  of 7 7  
 
4.  
S T A TI S TI C A L A N A L Y S E S  
4. 1.  
G e n er al C o n si d er ati o n s  
All a nal ys es will be perf or me d base d  o n t h e p o p ulati o n of partici pa nts wit h C H B o n sta ble 
n ucle os(t)i de t hera p y . 
T he f oll o wi n g d efi niti o ns a n d a b bre viati o ns will be use d t hr o u g h o ut t o defi ne ti me p oi nts 
f or ke y effic ac y e n d p oi nts  a n d esti ma n d criteri a:  
Ti me p oi nt  
Defi niti o n  
A b bre vi ati o n  
 
E n d of treat me nt  
E n d of se q ue ntial treat me nt of 
G S K 3 2 2 8 8 3 6 a n d 
Pe gi nterfer o n . T i me p oi nt is 
e x pecte d at  w ee k 4 8/ 3 6 f or 
Ar m 1/ A r m 2 . 
 
E o T  
E n d of off -tr eatme nt 
f oll o w-u p after e n d of 
treat me nt  
E n d of 2 4 wee ks of off -
treat me nt f oll o w-u p after e n d 
of treat me nt . T i me p oi nt is 
e x pecte d at wee k 7 2/ 6 0 f or 
Ar m  1/ Ar m  2  
 
E o T + 2 4 w ks  
 
E n d of st u d y 
Fi nal sc he d ule d  assess me nt 
visit . Ti me p oi nt is e x pecte d 
at wee k 7 2  f or Ar m  1/ Ar m  2  
 
E o S  
 
T he f oll o wi n g defi niti o ns  a n d a b bre viati o ns will be use d t o defi ne  re p orti n g of sc h e d ule d 
effic ac y visits : 
Ti me p oi nt  
Defi niti o n  
A b bre vi ati o n  
Sc he d ule d E n d of 
G S K 3 2 2 8 8 3 6 a n d Pe gI F N 
Se q ue ntial Treat me nt  
Sc he d ule d visit Wee k 4 8 
i n Ar m 1 a n d Sc he d ule d 
visit Wee k 3 6 i n Ar m 2.  
Pe gI F N W 3 6/ W 4 8  
Sc he d ule d E n d of 2 4 
Wee ks after Se q u e ntial 
Treat me nt  
Sc he d ule d visit Wee k 7 2 
i n Ar m 1 a n d Sc he d ule d 
visit W ee k 6 0 i n Ar m 2.  
O T -W 2 4  


C O N FI D E N TI A L  
 
 
2 0 9 3 4 8  
X B U St ati sti c al A n al y si s Pl a n ( S A P)  T e m pl at e v 1. 0 2 4 M ar c h 2 0 2 1  
P a g e 1 7  of 7 7  
 
4. 1. 1.  
G e n er al M et h o d ol o g y  
Partici pa nts w h o pre mat urel y wit h dre w fr o m st u d y will n ot  be re place d.  
I n t he case of i nc orrect ra n d o mizati o n stratificati o n assi g n me nt at t he ti me of 
ra n d o mizati o n, t he a nal ys es will be perf or m e d base d o n t he act u al strat u m per data 
c ollecte d i n t he baseli n e la b electr o ni c Case Re p ort F or m ( eC R F ).  I n t he case of 
ra n d o mizati o n t o t he i nc orrect strata (i.e., if a H Bs A g s u bject  is ra n d o mise d t o t he H B e A g 
strata, or vice versa), a nal ysis will be perf or me d base d o n t he act ual strata t he s u bject 
s h o ul d ha ve bee n assi g n e d t o. 
U nless ot her wise s pecifie d, c o nti n u o us data will be s u m marize d usi n g descri pti ve 
statistics: n, mea n, sta n dar d de viati o n (st d), me dia n, mi ni m u m, a n d ma xi m u m. Cate g orical 
data will be s u m marize d a s t he n u m ber a n d p erce nta ge of partici pa nt s i n eac h cate g or y. 
U nless ot her wise s pecifie d, C Is will use  9 5 % c o nfi de nce le vels.  
 
 
H B V D N A, H Bs A g a n d H Be A g le vels bel o w t he L L O Q will be i m p ute d f or s u m maries 
of act ual val u es a n d c h a n ge fr o m baseli ne. T he n u meric val ues f or H B V D N A < L L O Q 
( L L O Q = 2 0 I U/ m L) will be i m p ute d as 1 9. 9. T he n u meric val ues f or H Bs A g < L L O Q 
( L L O Q = 0. 0 5 I U/ m L) will be i m p ute d as 0. 0 4. T he n u meric val ues f or H Be A g < L L O Q 
( L L O Q = 0. 0 6 U/ m L) will be i m p ute d as 0. 0 5.” 
 
H B V D N A (I U/ m L) a n d H B V R N A (c o pies/ m L) l e vels t hat are “ T N D” will be i m p ute d 
as 1. H Bcr A g ( L o g 1 0 U/ m L) val ues t hat are “ T N D” will be i m p ute d as 0.  Val ues < L L O Q 
are i m p ute d bas e d o n t he n u m ber of si g nifica nt di gits, si milar t o ot her la b para meters.  
 
4. 1. 2.  
B a s eli n e D efi niti o n  
F or all e n d p oi nts (e x ce pt as n ote d i n bas eli ne defi niti o ns) t he baseli ne v al ue will be t he 
latest pre-d ose assess me nt wit h a n o n -missi n g val ue, i ncl u di n g t h ose fr o m u nsc he d ule d 
visits. If ti me is n ot c ollecte d, Da y 1 assess me nts are ass u me d t o be ta ke n pri or t o first  d ose 
a n d use d as baseli ne.  If t here are m ulti ple ass ess me nts c ollecte d at t he sa me sc he d ule d 
ti me, t he a vera ge of t hes e assess me nts will be use d as t he baseli ne. 
U nless ot her wise st ate d, if baseli ne d ata is missi n g n o d eri vati o n will be p erf or me d a n d 
base li ne will be set t o missi n g. 
Baseli ne of esti mate d gl o mer ular filtrati o n rat e ( e G F R) is defi ne d as t he mea n of all pre-
d ose val ues, fr o m s cree ni n g t o Da y 1 pre -d os e ass ess me nt.  
4. 1. 3.  
R el a p s e D efi niti o n  
O ne wa y t o ill ustrate res p o nse d ura bilit y a n d t he be nefit of a d di n g Pe gI F N se q ue ntial 
t hera p y is t o c o nsi der ti m e t o rela pse a m o n g Be pi a n d/ or Pe gI F N E n d of Treat me nt 
(E O T ) res p o n ders. T i me t o rela pse fr o m e n d of Be pi treat me nt will be calc ulate d usi n g 
t he Be pir o virs e n E O T  wi n d o w wit h t he f oll o wi n g li mits referre d t o i n Secti o n 4. 2. 2. 1 . 
 


C O N FI D E N TI A L  
 
 
2 0 9 3 4 8  
X B U St ati sti c al A n al y si s Pl a n ( S A P)  T e m pl at e v 1. 0 2 4 M ar c h 2 0 2 1  
P a g e 1 8  of 7 7  
 
O nl y partici pa nts w h o were vir ol o gic res p o n ders at  t he e n d of Be pir o virs e n E O T ( See 
Secti o n 4. 2 . 2. 1 wi n d o wi n g r ules) wit h o ut a n y pri or resc u e me dicat i o n will be c o nsi dere d .  
 
T he start date us e d t o meas ure t he ti me t o rel a pse will be t he date of t he first visit i n t he 
a p pr o priate wi n d o w w here  t he partici pa nt is a res p o n der a n d remai ns a res p o n der at all 
s u bse q ue nt visits wit hi n t he wi n d o w. Res p o nse a n d rela pse rates ca n be e val uate d u n der 
t he c o nser vati ve a n d m o difie d defi niti o n of S V R. 
 
Disc o nti n uati o n  i nterr u pti o n i n, or n o n-a d here nce t o G S K 3 2 2 8 8 3 6 a n d Pe gI F N  relate d or 
u nrelate d t o wi de disr u pti ve e ve nts ( W D Es)  will be a nal yse d as c ollecte d w he n 
deter mi ni n g rela pse (treat me nt p olic y strate g y). 
 
4. 1. 3. 1.  
R el a p s e u n d er C o n s er v ati v e D efi niti o n ( S V R)  
Rela pse date is defi ne d as t he first visit after t he  ap pr o priate  wi n d o w e n d d ate w here  
o bser ve d dat a  f or eit her H Bs A g or H B V D N A is greater t ha n  t he l o wer li mit of 
q ua ntificati o n ( L L O Q)  or t he use of res c ue me di cati o n .  
4. 1. 3. 2.  
R el a p s e u n d er t h e M o difi e d D efi niti o n of S V R  
Rela pse date is defi ne d as t he first visit af ter t he a p pr o priate  wi n d o w e n d d ate w here  
o bser ve d dat a f or eit her H Bs A g or H B V D N A is > L L O Q  at t w o c o nsec uti ve visits  f or t he 
sa me para meter or t he us e of res c ue me dicati o n . 
A n y o bs er vati o n of H Bs A g L L O Q or H B V D N A L L O Q at a visit m ust be c o nfir me d 
i n di vi d uall y at a c o ns ec uti ve visit (i ncl u di n g u nsc he d ule d visits or t he first visit after t he 
e n d of t he a n al ysis wi n d o w).  


C O N FI D E N TI A L  
 
 
2 0 9 3 4 8  
X B U St ati sti c al A n al y si s Pl a n ( S A P)  T e m pl at e v 1. 0 2 4 M ar c h 2 0 2 1  
P a g e 1 9  of 7 7  
 
4. 2.  
Pri m ar y E n d p oi nt A n al y s e s  
H Bs A g a n d H B V D N A  assess me nts  fr o m t he e n d of treat me nt a n al ysis wi n d o w  (Wee k 4 8  
or Wee k 3 6 f or Ar m 1 a n d Ar m 2 res pecti vel y ) t o t he off -tr eat me nt Wee k 2 4 a nal ysis 
wi n d o w will be use d t o a nal yse t h e pri mar y e n d p oi nt f or eac h ar m. The pri mar y a nal ysis 
f or t he pri mar y e n d p oi nt will be c o n d u cte d o n ce t he data base l oc k h as bee n ac hie ve d  a n d 
t he last partici pa nt has c o m plete d t he Wee k 7 2 visit.  
T he pri mar y efficac y e n d p oi nt is ac hie vi n g a s ustai ne d vir ol o gic res p o nse f or 2 4 wee ks 
after t he pla n n e d e n d of G S K 3 2 2 8 8 3 6 a n d Pe gI F N se q ue ntial treat me nt i n t he a bse nce of 
resc ue m e dicati o n. S ustai ne d vir ol o gic res p o nse  (S V R ) is defi ne d as o bs er vi n g H Bs A g 
< L L O Q a n d H B V D N A < L L O Q at eac h a nal ysis wi n d o w i n t he 2 4 wee ks after t he e n d of 
se q ue ntial treat me nt. A n al ysis wi n d o ws f or t he p ost G S K 3 2 2 8 8 3 6 treat m e nt assess me nts 
are defi ne d i n Secti o n 4. 2. 2. 1 . 
A n esti mati o n a p pr oac h wit h n o h y p ot hesis testi n g will be use d t o a d dress t he pri mar y 
o bjecti ve.  T he pri mar y assess me nts of i nterest are t he p oi nt esti mate of S V R  rate a n d 9 5 % 
cre di ble i nter vals . In a d diti o n, p osteri or pr o ba bilities t hat t he tr ue S V R  rate i n eac h 
treat me nt ar m is greater t ha n a ra n ge of cli nicall y mea ni n gf ul res p o nse rates will be 
pr o vi de d. T he p oi nt esti mates f or S V R  will be calc ulate d usi n g a Ba yesia n pr o b a bilit y 
a p pr oac h. 
C o m paris o ns 
bet wee n 
tr eat me nt 
ar ms 
as 
d efi ne d 
i n 
t he 
k e y 
sec o n dar y/ e x pl orat or y o bjecti ves will be assesse d usi n g pr o ba bilit y i nfere n ce a p pr oac h es.  
 
4. 2. 1.  
D efi niti o n of E sti m a n d s  
T he pri mar y  esti ma n d s u p p orti n g t he pri mar y o bjecti ve is defi ne d as:  
•  P o p ul ati o n:  Partici pa nts wit h C H B o n sta ble N A t hera p y .  
•  Tre at me nt:  3 0 0 m g G S K 3 2 2 8 8 3 6 f or 1 2 or 2 4 wee ks f oll o we d b y u p t o 2 4 wee ks 
of Pe gI F N t h era p y w hile o n sta ble N A t hera p y.  
•  V ari a ble ( C ate g o ric al):  Partici pa nts ac hie vi n g s ustai ne d vir ol o gic res p o nse  
(S V R ) ( H Bs A g < L L O Q a n d H B V D N A < L L O Q) f or 2 4 wee ks after t he pla n ne d 
e n d of se q ue ntial treat me nt, wit h o ut  t he use of res c ue me dicati o n.  
•  I nterc urre nt E ve nts: 
o  F or d isc o nti n uati o n of, interr u pti o n i n, or  n o n -a d here nce t o G S K 3 2 2 8 8 3 6 
or  Pe gI F N  u n rel ate d t o a n y wi de disr u pti ve e v e nts (s uc h as C O VI D-1 9 
pa n de mic) , t he data will be a nal yse d as c oll ecte d  (treat me nt p olic y 
strate g y). 
o  F or partici p a nts  t hat are i neli gi ble t o recei v e Pe gI F N, t he data will be  
a nal ys e d as c ollecte d  (treat me nt p olic y str ate g y).  
o  Use of resc ue me dicati o n  will be i nc or p orate d i n t he defi niti o n of t he 
e n d p oi nt (c o m p osite strat e g y). 
o  F or w i de disr u pti ve e v e nts (s uc h as C O VI D-1 9 pa n de mic) lea di n g t o 
disc o nti n uati o n of, si g nifica nt i nterr u pti o n i n, or  n o n -a d here nce t o 
G S K 3 2 2 8 8 3 6 a n d Pe gI F N , data c ollecte d after t h e i nterc urre nt e v e nt  will 


C O N FI D E N TI A L  
 
 
2 0 9 3 4 8  
X B U St ati sti c al A n al y si s Pl a n ( S A P)  T e m pl at e v 1. 0 2 4 M ar c h 2 0 2 1  
P a g e 2 0  of 7 7  
 
be set  t o missi n g a n d t he res p o nse will be i m p ute d ass u mi n g missi n g at 
ra n d o m i n t he Ba yesia n m o del. A d diti o nal details pr o vi de d i n Secti o n 
4. 2. 2. 2  ( h y p ot h etical strate g y). 
•  P o p ul ati o n S u m m a r y:  T he perce nt a ge of partici pa nts i n eac h treat me nt gr o u p w h o 
ac hie ve s ustai ne d vir ol o gic res p o nse (S V R ) ( H Bs A g < L L O Q a n d H B V D N A 
< L L O Q) f or 2 4 wee ks aft er t he pla n ne d e n d of se q ue ntial treat me nt  wit h o ut resc ue 
me dicati o n usa ge . 
 
4. 2. 2.  
M ai n A n al yti c al A p pr o a c h  
A Ba yesia n m o del will be fitte d usi n g  Mar k o v C hai n M o nte Carl o  (M C M C ) met h o ds , a n d 
will be use d t o esti ma te t he p osteri or pr o ba bilit y of S V R  s ustai ne d vir ol o gic res p o nse f or 
eac h ar m i nc or p orati n g t he baseli ne a n al ysis stratificati o n fact ors (Ta ble 1 ) [J o nes, 2 0 1 1].  
 
T he m o del bel o w differs fr o m t he  Ba yesia n  hierarc hical m o del  s pecifie d i n t he 2 0 9 3 4 8 
Pr ot oc ol A m e nd me nt  v. 1. 0 ( 2 4 -Se p -2 0 2 1 ), T his hi erarc hical m o del i ncl u de d a ra n d o m 
effect ψ g    f or eac h strata, a n i nteract i o n ter m f or tr eat me nt b y strat u m, a n d was a p plie d 
se parat el y f or eac h ar m.  H o we ver, w he n t he m o d el was r u n o n dat a fr o m t he 
a d mi nistrati ve i nteri m a nal yses  ( AI As) (see Secti o n 4. 7 ), t here were strat u m wit h zer o 
c o u nts  w hic h ca us e d  perfect pre dicti o n of t h e res p o nse varia ble f or s o me v alues  of t he 
pre dict ors  ( q uasi-c o m plete se parati o n). T o a d dress t his iss ue, t he hierarc hi cal m o del was 
si m plifie d t o t he Ba yesia n l o gistic re gressi o n m o del bel o w , wit h o nl y fi x e d effects a n d 
c o m bi ne d data acr oss ar ms.  
 
T he n u m ber of res p o n ders is ass u me d t o f oll o w a bi n o mial distri b uti o n : 
𝑁𝑢𝑚𝑏𝑒𝑟 𝑜𝑓 𝑟𝑒𝑠𝑝𝑜𝑛𝑑𝑒𝑟𝑠 𝑟𝑔~ 𝐵𝑖𝑛𝑜𝑚𝑖𝑎𝑙(𝑛𝑔,𝑝𝑔),
𝑔= 1 ,2 ,3 ,4  
w here we defi ne r g as t he n u m ber of S V R  res p o n d ers a m o n g ng p artici pa nts, p g as S V R  
rate 
𝑟𝑔
𝑛𝑔, a n d i n de x g  refers t o t he strat u m n u m ber as defi ne d i n Ta ble 1  b el o w.  
 
T he a nal ysis m o del is defi ne d as:  
 
𝜃𝑔 =  𝑙𝑜𝑔𝑖𝑡( 𝑃𝑔) = l o g(
𝑃𝑔
1 −𝑃𝑔) =  𝜏 + 𝛾1 𝐼{𝐵1 +} + 𝛾2 𝐼{𝐵2 +} +  𝛾3  𝐼{Ar m } 
w here τ, 𝛾1 , 𝛾2 , are all para meters. T h us, 
 
θ 1  =  τ 
 
θ 2  =  τ + γ 1  
 
θ 3 =  τ + γ 2  
 
θ 4 =  τ + γ 1 +  γ 2  


C O N FI D E N TI A L  
 
 
2 0 9 3 4 8  
X B U St ati sti c al A n al y si s Pl a n ( S A P)  T e m pl at e v 1. 0 2 4 M ar c h 2 0 2 1  
P a g e 2 1  of 7 7  
 
 
Pri ors:  
𝑁 ~  𝑢𝑚𝑏𝑒𝑟𝑜 ( 0, 1 0 6 ) 
𝑓𝑟 ~  𝑒𝑠𝑝𝑜𝑛𝑑( 0 ,1 0 6 ) ,𝑒= 1 ,2  
 
T a bl e 1  
B a s eli n e A n al y si s Str at a  
Strat u m  
B 1: H B s A g 
B 2: H B e A g 
1: H Bs A g ≤3 l o g I U/ m L a n d N e g ative H B e A g  
B 1- ( ≤3 l o g I U/ mL) 
B 2- ( Ne g ativ e) 
2: H Bs A g > 3 l og I U/ m L a n d Ne g ative H B e A g  
B 1 + ( > 3 l o g I U/ m L) 
B 2- ( Ne g ativ e) 
3: H Bs A g ≤3 l o g I U/ m L a n d P ositiv e H B e A g  
B 1- ( ≤3 l o g I U/ mL) 
B 2 + ( P ositiv e) 
4: H Bs A g > 3 l og I U/ m L a n d Positiv e H B e A g  
B 1 + ( > 3 l o g I U/ m L) 
B 2 + ( P ositiv e) 
 
T he p oi nt esti mates a n d 9 5 % cre di ble i nter vals of s ustai ne d vir ol o gic res p o nse rate i n 
eac h of t h e treat me nt ar ms will be calc ulate d.   
F or eac h ar m, t he p osteri or distri b uti o n of  S V R  rate P( pg| data), g = 1, 2, 3, 4 will be deri ve d 
f or eac h a n al ysis strat u m usi n g t he m o del s pe cifie d a b o ve: 
𝑟(𝑠1 |𝑟𝑔𝐵𝑖) = 𝑛(
𝑜𝑚1
1 + 𝑖𝑎1 |𝑙𝑛𝑔𝑝) 
𝑔(𝑔2 |𝑟𝑔𝑛𝑔) = 𝜃(
𝑔𝑙2
1 + 𝑜𝑔2 |𝑖𝑡𝑃𝑔) 
𝑃(𝑔3 |𝑃𝑔𝜏𝛾) = 𝐼(
𝐵𝛾3
1 + 𝐼𝐵3 |𝛾𝐼𝛾𝛾) 
𝑃(𝑝4 |𝑑𝑎𝑡𝑎) = 𝑃(
𝑒𝜃4
1 + 𝑒𝜃4 |𝑑𝑎𝑡𝑎) 
 
T he p osteri or distri b uti o n of t he ar m -le vel S V R  rate will be deri ve d usi n g a mi xt ure of t he 
p osteri or distri b uti o ns of S V R  rate f or eac h a nal ysis strat u m i n t hat ar m. T he wei g hts are 
pr o p orti o nal t o t he sa m ple siz e of eac h a nal ysis str at u m i n e ac h ar m: 
𝑃(𝑝|𝑑𝑎𝑡𝑎) = ∑
𝑤𝑔𝑃(𝑝𝑔|𝑑𝑎𝑡𝑎)
4
𝑔= 1
, w here 𝑤𝑔=
𝑛𝑔
∑
𝑛𝑔
4
𝑔= 1
 
P osteri or pr o ba bilities  of S V R  rates e x cee di n g a ra n ge of cli nicall y mea ni n gf ul res p o nse 
rates, e. g. , 3 0 %, 3 5 %, 4 0 %,  will be ge n erat e d usi n g t he a p pr oac h s p ecifie d a b o ve f or eac h  
ar m. If m o n ot hera p y i n st u d y 2 0 9 6 6 8 ( B -Clear) is dee me d s uccessf ul , t he n p osteri or 
pr o ba bilit ies will be deri ve d  f or a differe nce > 1 0 % a n d < 1 5 % of t he S V R  rates b et wee n 
a n y B -T o get h er  ar m a n d t he B -Clear c h ose n  ar m t o e val uat e w het her se q ue ntial t hera p y is 
s uccessf ul.  


C O N FI D E N TI A L  
 
 
2 0 9 3 4 8  
X B U St ati sti c al A n al y si s Pl a n ( S A P)  T e m pl at e v 1. 0 2 4 M ar c h 2 0 2 1  
P a g e 2 2  of 7 7  
 
4. 2. 2. 1.  
Vi sit W i n d o wi n g a n d M ulti pl e M e a s ur e m e nt s at O n e A n al y si s T i m e p oi nt 
Visit wi n d o wi n g  f or t h e pri mar y e n d-p oi nt  will be a p plie d as s pecifie d i n Ta ble 2  a n d Ta ble 
3 , a n d t he wi n d o we d res ults will be use d t o det er mi ne t he pri mar y e n d p oi nt of S V R . 
U nsc he d ule d assess me nts will be i ncl u de d i n t he a nal ysis wi n d o w. N o i m p utati o n of 
missi n g data will be perf or me d pri or t o visit wi n d o wi n g.  
 
If t here are m ulti ple val ues wit hi n a n a nal ysis wi n d o w t he f oll o wi n g r ules will be a p plie d: 
 
F or t he e n d of G S K 3 2 2 8 8 3 6 treat me nt a n d Pe gI F N treat me nt  a nal ysis ti me p oi nt s, the latest 
a vaila ble assess me nt i n t he wi n d o w will be selecte d , wit h t he w orst  n o n -missi n g val ue  
c h ose n first. T he w orst  case or deri n g is as f oll o ws: 
 
1.  N o Vir ol o gi c Res p o nse  
2.  Missi n g d ue t o W D E
1  
3.  Vir ol o gic Res p o ns e  
4.  Missi n g ( u nrel ate d t o W D Es) 
 
F or p ost e n d of s e q ue ntial treat me nt a nal ysis ti me p oi nts:  
 
1.  W orst n o n -missi n g val ue i n t he a nal ysis wi n d o w  will be selecte d . 
a)  If val u es are t he sa m e, t he n t he v al ue cl osest t o t ar get d a y will b e sel ecte d. If 
t here are m ulti ple val ues e q ui dista nt fr o m t he tar get da y, t he earliest will be 
selecte d. 
b)  If all v al ues wit hi n a n a n al ysis wi n d o w are missi n g, t he n t he res ult is missi n g 
f or t he a n al ysis wi n d o w. 
2.  W o rst val ue is defi ne d i n t he or der of hi g h est act u al val ue, t he n < L L O Q, a n d t he n 
T N D.  
                                                 
 
 
 
1 Missi n g d ue t o W D E will be c o nsi dere d base d o n w het her ori gi nal val ue f or t he assess me nt  is missi n g or 
is a no n -res p o nse. If t he ori gi nal val ue at a n assess me nt is ‘ N o Vir ol o gic Res p o nse’ pri or t o i m p utati o n f or 
W D Es, t he n  t he assess me nt will be classifie d as ‘Missi n g t o d ue W D Es ’. If t he ori gi nal val ue at a n 
assess me nt is ‘ Missi n g’ pri or t o i m p utati o n f or W D Es, t he n t he p rece di n g n o n -missi n g val ue  wit hi n t he 
wi n d o w  will be selecte d.  


C O N FI D E N TI A L  
 
 
2 0 9 3 4 8  
X B U St ati sti c al A n al y si s Pl a n ( S A P)  T e m pl at e v 1. 0 2 4 M ar c h 2 0 2 1  
P a g e 2 3  of 7 7  
 
T a bl e 2  
Pri m ar y E n d p oi nt A n al y si s  Vi sit  W i n d o w s f or Ar m 1 
A n al ysis 
Set  
P ar a meter  
T ar get 
St u d y 
D a y  
A n al ysis Wi n d o w  
A n al ysis 
Ti me p oi nt  
Pr ot oc ol 
Visit  
Be gi n ni n g 
Ti me p oi nt  
E n di n g 
Ti me p oi nt  
Effic acy  
H Bs A g a n d 
H B V D N A  
1 6 2 
1 4 8 
Mi ni m u m of 
( 1 8 2, P e gI F N 
First D osi n g 
St u dy d ay)  
E n d of 
G S K 3 2 2 8 8 36 
tr e at m e nt 
W e ek 2 4  
Effic acy  
H Bs A g a n d 
H B V D N A  
3 3 0 
2 9 5 
3 5 0 
E n d of 
P e gI F N  
tr e at m e nt / 
E o T  
W e ek 4 8 
Effic acy  
H Bs A g a n d 
H B V D N A  
3 8 6 
3 5 1 
4 0 6 
P ost P e gI F N  
tr e at m e nt 
W e ek 8  
Off - 
tr e at m e nt 
W e ek 8  
Effic acy  
H Bs A g a n d 
H B V D N A  
4 5 6 
4 0 7 
4 6 2 
P ost P e gI F N  
tr e at m e nt 
W e ek 1 8 
Off - 
tr e at m e nt 
W e ek  1 8 
Effic acy  
H Bs A g a n d 
H B V D N A  
4 9 8 
4 6 3 
5 1 8 
P ost P e gI F N  
tr e at m e nt 
W e ek 2 4  
Off - 
tr e at m e nt 
W e ek 2 4  
 
T a bl e 3  
Pri m ar y E n d p oi nt A n al y si s  Vi sit  W i n d o w s f or Ar m 2 
A n al ysis 
Set  
P ar a meter  
T ar get 
St u d y 
D a y  
A n al ysis Wi n d o w  
A n al ysis 
Ti me p oi nt  
Pr ot oc ol 
Visit  
Be gi n ni n g 
Ti me p oi nt  
E n di n g 
Ti me p oi nt  
Effic acy  
H Bs A g a n d 
H B V D N A  
7 8  
6 4  
Mi ni m u m of 
( 9 8, P e gI F N 
First D osi n g 
St u dy d ay)  
E n d of 
G S K 3 2 2 8 8 36 
tr e at m e nt 
W e ek 1 2  
Effic acy  
H Bs A g a n d 
H B V D N A  
2 4 6 
2 1 1 
2 6 6 
E n d of 
P e gI F N  
Tr e at m e nt  / 
E o T  
W e ek 3 6  
Effic acy  
H Bs A g a n d 
H B V D N A  
3 0 2 
2 6 7 
3 2 2 
P ost P e gI F N  
tr e at m e nt 
W e ek 8  
Off - 
tr e at m e nt 
W e ek 8  
Effic acy  
H Bs A g a n d 
H B V D N A  
3 7 2 
3 2 3 
3 7 8 
P ost P e gI F N  
tr e at m e nt 
W e ek 1 8  
Off - 
tr e at m e nt 
W e ek 1 8  
Effic acy  
H Bs A g a n d 
H B V D N A  
4 1 4 
3 7 9 
4 3 4 
P ost P e gI F N  
tr e at m e nt 
W e ek 2 4  
Off - 
tr e at m e nt 
W e ek 2 4  


C O N FI D E N TI A L  
 
 
2 0 9 3 4 8  
X B U St ati sti c al A n al y si s Pl a n ( S A P)  T e m pl at e v 1. 0 2 4 M ar c h 2 0 2 1  
P a g e 2 4  of 7 7  
 
 
T he pri mar y a nal ysis will be base d o n pla n ne d e n d of treat me nt re gar dless of w het h er a 
patie nt disc o nti n ue d treat me nt.  
F or t he first a n d s ec o n d s u p ple me ntar y esti ma n ds descri be d i n Secti o n 4. 2. 4. 1  a nd Secti o n 
4. 2. 4. 2 , S V R  will be meas ure d fr o m act ual rat her t ha n pla n ne d e n d of treat me nt a n d t he 
a nal ysis wi n d o ws s h o ul d be a me n de d acc or di n gl y. F or t hese esti ma n ds, t he date of last 
d ose s h o ul d be treat e d as t he refere nce dat e a n d t he r ules i n Ta ble 4  s h o ul d be use d t o 
deter mi ne t he e n d p oi nt of S V R . 
 
T a bl e 4  
S u p pl e m e nt ar y E n d p oi nt A n al y si s Vi sit W i n d o w s f or Ar m 1  a n d Ar m 2  
A n al y si s 
S et / 
D o m ai n  
P ar a m et er  
R ef er e n c e 
D a y  
A n al y si s Wi n d o w  
A n al y si s Ti m e p oi nt  
B e gi n ni n g 
Ti m e p oi nt  
E n di n g 
Ti m e p oi nt  
Effic acy  
 
H Bs A g a n d H B V 
D N A  
R ef er e nc e 
d at e 
R ef er e nc e 
d at e - 3 5 
R ef er e nc e dat e 
+ 2 0 
E n d of Act u al  
tr e at m e nt 
Effic acy  
 
H Bs A g a n d H B V 
D N A  
R ef er e nc e 
d at e + 5 6  
R ef er e nc e 
d at e + 2 1 
R ef er e nc e dat e 
+ 7 6 
P ost tr e at m e nt W eek 
8  
Effic acy  
 
H Bs A g a n d H B V 
D N A  
R ef er e nc e 
d at e + 1 26  
R ef er e nc e 
d at e + 7 7 
R ef er e nc e dat e 
+ 1 3 2 
P ost tr e at m e nt W eek 
1 8  
Effic acy  
 
H Bs A g a n d H B V 
D N A  
R ef er e nc e 
d at e + 1 68  
R ef er e nc e 
d at e + 1 33 
R ef er e nc e dat e 
+ 1 8 8 
P ost tr e at m e nt W eek 
2 4  
 
If all a nal ysis wi n d o ws ha ve n o n-missi n g res p o nse i nf or mati o n, a partici pa nt’s res p o nse 
( Res p o n der or N o n-res p o n der) is deter mi ne d as f oll o ws: 
1.  If res c ue me dicati o n was use d d uri n g o n-treat me nt or off-tr eat me nt peri o d, t he n 
t he partici pa nt is a n o n-res p o n der. 
2.  If H Bs A g < L L O Q a n d H B V D N A < L L O Q i n eac h of t he a nal ysis wi n d o ws, 
t he n t he partici pa nt is a res p o n der, ot her wise t he p artici pa nt is n o n-res p o n d er.  
3.  A res ult  of T N D is c o nsi dere d as < L L O Q.  
4. 2. 2. 2.  
I nt er c urr e nt E v e nt s a n d Mi s si n g D at a 
Interc urre nt e v e nts d uri n g t he o n -tr eat me nt p hase of t he st u d y ca n res ult i n misse d o n-
treat me nt visits a n d partici pa nt data n ot b ei n g c oll ecte d . T his missi n g data ca n  p ote ntiall y 
c o nf o u n d t he i nter pretati o n of t he pri mar y e n d p oi nt. T he i nterc urre nt e ve nt of use of resc u e 
me dicati o n has bee n i nc or p orate d i nt o t he defi niti o n of  t he varia ble (c o m p osite strate g y). 
T he i nterc urre nt e ve nt of disc o nti n uati o n of, i nterr u pti o n of, a n d a d here nce t o 
i n vesti gati o nal pr o d uct (I P) u nrelate d  t o wi de disr u pti ve e ve nts ( W D Es) will be a n al ys e d 
as c ollecte d (treat me nt p olic y).  
 


C O N FI D E N TI A L  
 
 
2 0 9 3 4 8  
X B U St ati sti c al A n al y si s Pl a n ( S A P)  T e m pl at e v 1. 0 2 4 M ar c h 2 0 2 1  
P a g e 2 5  of 7 7  
 
Mi s si n g Pri m ar y D at a  O n -Tr e at m e nt , E n d of Tr e at m e nt ( E O T)  a n d Off -Tr e at m e nt  
F or p artici pa nts w here 
W D Es o n -treat me nt res ult i n disc o nti n uati o n of, si g nifica nt 
i nterr u pti o n of, a n d a d h ere nce t o i n vesti gati o nal pr o d uct (I P), a n d t he partici pa nt ret ur ns t o 
t he st u d y a n d has dat a i n t he o n -treat me nt peri o d, t he data will be ha n dle d i n t he f oll o wi n g 
t w o wa ys:  
1.  F or o bser ve d V R res p o n ders, t he data will be a nal ys e d as c ollect e d (treat me nt 
p olic y). N o i m p utati o n of missi n g data will be perf or me d.  
2.  F or o bser ve d V R n o n -res p on ders, data c ollecte d after t he i nterc urre nt e ve nt will be 
set t o missi n g. T heir S V R res p o nse will be i m p ute d ass u mi n g missi n g at ra n d o m 
usi n g all a v aila ble d ata fr o m p artici pa nts f or w h o m S V R ca n be assesse d 
( h y p ot hetic al strate g y).   
Si g nifica nt i nterr u p ti o n/ n o n-a d here nce is defi n e d as a ga p of > = 2 1 da ys b et wee n tr eat me nt 
d oses at a n y ti me d uri n g t he o n -treat me nt peri o d (e x cl u di n g t he Pe gI F N  Eli gi bilit y Peri o d ). 
T he fi nal i nfere nce fr o m t he Ba yesi a n m o del will acc o u nt f or t he missi n g data ass u mi n g 
M A R.  E n d of treat me nt ( E o T) V R res p o nse will b e deter mi ne d usi n g t he e n d of treat me nt 
a nal ysis wi n d o w s defi ne d i n  Ta ble 2 , Ta ble 3 , a n d Ta ble 4 . I n t he a bs e nce of resc ue 
me dicati o n usa ge, i f all H Bs A g a n d H B V DN A data wit hi n t he a nal ysis wi n d o w f or t he 
E o T  visit is missi n g a n d t he missi n g ness is n ot d ue t o wi de disr u pti ve e ve nts, the s u bject 
will be c o nsi dere d as a n S V R  n o n -res p o n der. N o i m p utati o n of missi n g d ata will be 
perf or me d.  
If all H Bs A g a n d H B V D N A data wit hi n t he a n al ysis wi n d o w f or t h e E O T visit is missi n g  
d ue t o a W D E , a n d t he part ici pa nt wit h dra ws fr o m t he st u d y  d ue t o t he 
W D E , t he 
partici pa nt  will be classifie d as n ot reac hi n g E O T at f oll o w -u p.  Data after t he i nterc urre nt 
e ve nt will be set t o missi n g, a n d  t heir S V R  res p o nse will be i m p ute d ass u mi n g missi n g at 
ra n d o m usi n g all a vaila bl e data fr o m partici pa nts f or w h o m S V R ca n be ass esse d.  
If all H Bs A g a n d H B V D N A data wit hi n t he a n al ysis wi n d o w f or t h e E O T visit is missi n g  
d ue t o a W D E, b ut t he partici pa nt later ret ur ns t o st u d y a n d has n o n -missi n g data i n a n 
a nal ysis wi n d o w, t h e dat a will be ha n dle d i n t he f oll o wi n g t w o wa ys:  
1.  F or o bser ve d V R res p o n ders, t he data will be a nal ys e d as c ollect e d (treat me nt 
p olic y).  N o i m p utati o n  of missi n g data  will be perf or me d.  
2.  F or o bser ve d V R n o n -res p o n ders, data c ollecte d after t he i nterc urre nt e ve nt will be 
set t o missi n g. T heir S V R res p o nse will be i m p ute d ass u mi n g missi n g at ra n d o m 
usi n g all a v aila ble d ata fr o m p artici pa nts f or w h o m S V R ca n be assess e d  
( hy p ot hetic al strate g y).   
If all H Bs A g a n d H B V D N A data wit hi n a n a nal ysis wi n d o w after t he pla n ne d e n d of 
se q ue ntial treat me nt ( E o T) is missi n g u nrelate d  t o wi de disr u pti ve e v e nts, missi n g data will 
be c o nsi dere d as a n S V R  n o n -res p o nd er. N o i m p ut ati o n of m issi n g d ata will be perf or me d. 
If all H Bs A g a n d H B V D N A data wit hi n a n a nal ysis wi n d o w after t he pla n ne d e n d of 
se q ue ntial treat me nt ( E o T) is missi n g d ue t o wi de disr u pti ve e ve nts , t he partici pa nt’s S V R 
stat us will  be c o nsi deri n g as missi n g d ue t o W D E.  Data aft er t h e i nterc urre nt e ve nt will be 
set t o missi n g, a n d the S V R res p o nse will be i m p ute d usi n g all a vaila ble data fr o m 
partici pa nts f or w h o m S V R ca n be ass esse d.   


C O N FI D E N TI A L  
 
 
2 0 9 3 4 8  
X B U St ati sti c al A n al y si s Pl a n ( S A P)  T e m pl at e v 1. 0 2 4 M ar c h 2 0 2 1  
P a g e 2 6  of 7 7  
 
If t he partici pa nt has a n y H Bs A g ≥L L O Q or H B V D N A ≥L L O Q or res c ue me dicati o n  
usa ge  at or aft er t he pl a n n e d e n d of se q ue ntial tr eat me nt ( E o T), t he s u bj ect will be classifie d 
as a n S V R  n o n -res p o n d er. N o i m p utati o n of missi n g dat a will be perf or me d.  
If a partici pa nt has a n y assess me nts t hat are affecte d b y a wi de disr u pti ve e ve nt, b ut t he 
partici pa nt’s H Bs A g a n d H B V D N A wit hi n a n a nal ysis wi n d o w are c ollecte d a n d t he 
partici pa nt is a V R res p o n der, t he s u bject will be classifie d as a n  S V R res p o n der . 
 
4. 2. 2. 3.  
M o d el C h e c ki n g a n d Di a g n o sti c s –  M C M C Mi xi n g Di a g n o si s  
T w o sa m pli n g c hai ns will be r u n, wit h differi n g starti n g val ues a n d eac h wit h a b ur n -i n 
peri o d of 5, 0 0 0 sa m ples, t o e ns ure a de q uate sa m pli n g fr o m t he p osteri or. T he starti n g 
val ues will be as desc ri be d a b o ve i n Secti o n  4. 2. 2 . 
Mi xi n g will be re gar de d as “eac h c hai n is i n de pe n de ntl y realizi n g val ues si milar t o t h ose 
f or w hic h t he ot h er c h ai ns ha ve als o sa m ple d. ” A de q uate mi xi n g will be c o ncl u de d if t he 
c hai ns meet f oll o wi n g c o n diti o ns:  
1.  T he Br o o ks -Gel ma n Rati o ( B G R) ( Br o o ks , 1 9 9 8) f or eac h para meter is i n t he 
i nter val ( 0. 8, 1. 2).   
2.  Eac h c h ai n a p pears mi x we ll, u p o n vis ual i ns pecti o n of eac h c hai n’s tr ace 
pl ot, i ncl u di n g assessi n g t he m ut ual o verla p of t he c hai ns f or eac h p ara m eter.  
3.  Eac h ker nel de nsit y pl ot a p pears s m o ot h u p o n vis ual i ns pecti o n.  
 
4. 2. 3.  
S e n siti vit y A n al y s e s  
F or t he pri mar y esti ma n d, a se nsiti vit y a nal ysis will be perf or me d usi n g t he Ba yesia n 
m o del descri be d i n Secti o n 4. 2. 2 . T he fi nal i nfere nce fr o m t he Ba yesia n m o del will acc o u nt 
f or t he missi n g dat a ass u mi n g M A R, re gar dless of t he reas o n f or missi n g ness. 
 
4. 2. 4.  
S u p pl e m e nt ar y E sti m a n d s  
T he f oll o wi n g s u p ple m e ntar y esti ma n ds are defi n e d t o s u p p ort t he pri mar y  o bjecti ve.  
 
4. 2. 4. 1.  
M e a s uri n g S V R  fr o m A ct u al E n d of Tr e at m e nt i n st e a d of Pla n n e d E n d 
of Tr e at m e nt  
T he first s u p ple me ntar y esti ma n d is defi ne d i n t he sa me wa y as t he pri mar y esti ma n d, 
e x ce pt t he assess me nt ti me fra me f or partici pa nts  ac hie vi n g S V R will be 2 4 wee ks after 
t he act ual e n d of treat me nt. T he esti ma n d strate g y f or ha n dli n g treat me nt disc o nti n uati o n 
u nrelate d t o wi de disr u pti ve e ve nts  will be w hile -o n -treat me nt, w hic h calc ulates t he 
act ual d urati o n fr o m t he first t o t he last d ose of treat me nt recei ve d. See Secti o n 4. 2. 1  f or 
a d diti o nal details.  
 


C O N FI D E N TI A L  
 
 
2 0 9 3 4 8  
X B U St ati sti c al A n al y si s Pl a n ( S A P)  T e m pl at e v 1. 0 2 4 M ar c h 2 0 2 1  
P a g e 2 7  of 7 7  
 
4. 2. 4. 2.  
M e a s uri n g S V R  fr o m A ct u al E n d of Tr e at m e nt b y C at e g ori c al 
S u b gr o u p s of P e gI F N Tr e at m e nt D ur ati o n  
T he sec o n d s u p ple me ntar y esti ma n d s u p p orti n g t h e pri mar y o bjecti ve m eas ures S V R  fr o m 
act ual e n d of treat me nt b y cate g orical s u b gr o u ps of Pe gI F N treat me nt d ur ati o n.  
T he sec o n d s u p ple me nt ar y esti ma n d is defi n e d as:  
•  P o p ul ati o n:  Partici pa nts wit h C H B o n sta bl e N A t hera p y  t hat are eli gi ble f or 
Pe gI F N . 
•  Tre at me nt:  3 0 0 m g G S K 3 2 2 8 8 3 6 f or 1 2 or 2 4 wee ks f oll o we d b y u p t o 2 4 wee ks 
of Pe gI F N t h era p y w hile o n sta ble N A t hera p y.  
•  V ari a ble:  T he perce nta ge of partici pa nts t hat ac hie ve S V R  f or 2 4 wee ks after t he 
act ual e n d of s e q ue ntial treat me nt  wit h o ut  t he use of resc u e me dicati o n 


C O N FI D E N TI A L  
 
 
2 0 9 3 4 8  
X B U St ati sti c al A n al y si s Pl a n ( S A P)  T e m pl at e v 1. 0 2 4 M ar c h 2 0 2 1  
P a g e 2 8  of 7 7  
 
•  I nterc urre nt E ve nts: 
o  Si g nifica nt  interr u pti o n i n or  n o n -a d here nce t o Pe gI F N  relate d or u nrelate d 
t o W D Es will be a nal yse d as c ollecte d (treat me nt p olic y strat e g y). 
o  Disc o nti n uati o n a n d dela ye d start of Pe gI F N relat e d or u nrelate d t o W D Es 
will be ha n dle d b y calc ul ati n g  t he act u al d urati o n usi n g t he first t o t he last 
d ose of Pe gI F N recei ve d ( w hile -o n -tr eat me nt strat e g y). 
o  Use of resc ue me dicati o n will be i nc or p orate d i n  t he defi niti o n of t he 
e n d p oi nt  (c o m p osite strat e g y). 
•  
P o p ul ati o n S u m m ar y:  T he perce nta ge of partici pa nts ac hie vi n g S V R  f or 2 4 wee ks 
after t he act ual e n d of treat me nt b y Pe gI F N treat m e nt d urati o n cate g orical gr o u pi n g  
of at least 1 2, 1 6, 2 0, a n d 2 4 wee ks of Pe gI F N  tr eat me nt i n eac h treat me nt ar m.  
 
4. 2. 4. 3.  
M e a s uri n g S V R  fr o m Pl a n n e d  E n d of Tr e at m e nt f or P arti ci p a nt s w h o 
R e c ei v e d At L e a st T w el v e D o s e s of P e gI F N  
T he t hir d s u p ple me ntar y esti ma n d e x a mi nes  t he effect of t he i nterc urre nt e ve nt of a 
partici pa nt faili n g t o me et Pe gI F N eli gi bilit y criteria b y Pe gI F N Eli gi bilit y Wee k 1 3 (i.e. 
ca n n o l o n ger recei ve at least 1 2 wee ks of Pe gI F N treat me nt) . T h e esti ma n d strate g y f or 
t his i nterc urre nt e v e nt will be pri nci pal strat u m, w hic h restricts t he p o p ulati o n t o 
partici pa n ts f or w h o m t he i nterc urre nt e ve nt di d n ot occ ur. T he t hir d s u p ple me ntar y 
esti ma n d is defi ne d as:  
•  P o p ul ati o n:  Partici pa nts wit h C H B o n sta ble N A t hera p y  t hat ha ve recei ve d at least 
1 2 d oses of Pe gI F N  
•  Tre at me nt:  3 0 0 m g G S K 3 2 2 8 8 3 6 f or 1 2 or 2 4 wee ks f oll o we d b y u p t o 2 4 wee ks 
of Pe gI F N t h era p y w hile o n sta ble N A t hera p y.  
•  V ari a ble:  T he perce nta ge of partici pa nts t hat ac hie ve S V R f or 2 4 wee ks after t he 
pla n ne d  e n d of s e q ue ntial treat me nt wit h o ut t he use of res c ue me dicati o n  
•  I nterc urre nt E ve nts: 
o  F or disc o nti n uati o n of, i nterr u pti o n i n, or  n o n -a d here nce t o G S K 3 2 2 8 8 3 6 
or  Pe gI F N  u nrel ate d t o a n y wi de disr u pti ve e v e nts (s uc h as C O VI D -1 9 
pa n de mic), t he data will be a nal yse d as c oll ecte d (treat me nt p olic y 
strate g y). 
o  F or partici p a nts  t hat are i neli gi ble t o recei v e Pe gI F N, t he data will be 
a nal ys e d as c ollecte d (treat me nt p olic y str ate g y).  
o  Use of resc ue me dicati o n will be i nc or p orate d i n t he defi niti o n of t he 
e n d p oi nt (c o m p osite strat e g y).  
o  F or wi de disr u pti ve e v e nts (s uc h a s C O VI D-1 9 pa n de mic) lea di n g t o 
disc o nti n uati o n of, si g nifica nt i nterr u pti o n i n, or n o n -a d here nce t o 
G S K 3 2 2 8 8 3 6 a n d Pe gI F N, data c ollecte d after t h e i nterc urre nt e v e nt will 
be set t o missi n g a n d t he res p o nse will be i m p ute d ass u mi n g missi n g at 
ra n d o m i n t he Ba yesia n m o del  ( h y p ot hetical strat e g y). 


C O N FI D E N TI A L  
 
 
2 0 9 3 4 8  
X B U St ati sti c al A n al y si s Pl a n ( S A P)  T e m pl at e v 1. 0 2 4 M ar c h 2 0 2 1  
P a g e 2 9  of 7 7  
 
•  P o p ul ati o n S u m m a r y:  T he perce nt a ge of partici pa nts i n eac h treat me nt gr o u p w h o 
ac hie ve S V R f or 2 4 wee ks after t he pla n ne d e n d of se q ue ntial treat me nt wit h o ut 
use of a n y resc ue m e dicati o n.  
 
4. 2. 5.  
A d diti o n al  E sti m a n d s  
T he f oll o wi n g a d diti o nal esti ma n ds are i ncl u de d t o s u p p ort t he pri mar y o bjecti ve.  
 
4. 2. 5. 1.  
U si n g a M o difi e d D efi niti o n of S V R  
N ote f or t his secti o n: u p o n re vie w of AI A res ults, t his defi niti o n d oes n ot meet t he scie ntific 
i nte nt of t he m o difie d d efi niti o n of S V R. T he defi niti o n of m o difie d S V R descri be d i n t his 
secti o n will be pr o gra m me d as is. T he i nte n de d a p plicati o n of t his defi niti o n will be 
d oc u me nte d i n n ote t o file ( N T Fs) f or t his st u d y a n d f or B -clear ( 2 0 9 6 6 8).  
A n a d diti o nal esti ma n d is defi ne d i n t he sa me  wa y as t he pri mar y esti ma n d, e x ce pt t he 
p o p ulati o n s u m mar y is d efi ne d usi n g a m o difie d d efi niti o n of s ustai ne d vir ol o gic res p o nse 
( S V R) f or 2 4 wee ks aft er t he pla n ne d e n d of se q u e ntial treat me nt ( E o T) i n t he a bse nce of 
resc ue me dicati o n.  T he m o difie d defi niti o n of S V R is o bser vi n g H Bs A g < L L O Q a n d H B V 
D N A < L L O Q at eac h a n al ysis wi n d o w i n t he 2 4 wee ks aft er t he pla n ne d e n d of se q ue ntial 
treat me nt ( E o T). A n y o bs er vati o n of H Bs A g L L O Q or H B V D N A L L O Q at a visit m ust 
be c o nfir m e d i n di vi d uall y at a c o ns ec uti v e visit (i ncl u di n g u nsc h e d ule d visits or t he first 
visit after t he e n d of t he a nal ysis wi n d o w). If t he c o nsec uti ve visit f or t he sa me para meter 
is als o L L O Q, t he S V R stat us f or t he partici pa nt at t he i nitial visit will be a n S V R n o n -
res p o n der. If t he c o nsec uti ve visit f or t h e sa m e para meter is als o L L O Q, t he S V R stat us 
f or t he p artici pa nt at t he i nitial visit will be a n S V R res p o n der u n der t he m o difie d 
defi niti o n.  
 
4. 2. 5. 2.  
I m p a ct of W D E o n S V R 
A n a d diti o nal esti ma n d is defi ne d i n t he s a me wa y as t he pri mar y esti ma n d , e x ce pt f or h o w 
t he s u bjects wit h missi n g visits d ue t o a W D E lea di n g t o disc o nti n uati o n of, i nterr u pti o n 
i n, or n o n-a d here nce t o G S K 3 2 2 8 8 3 6 or Pe gI F N are ha n dle d. F or t hese p artici pa nts t hat 
restart G S K 3 2 2 8 8 3 6 or Pe gI F N, d ata will be a nal yse d as c ollecte d  (treat me nt p olic y 
strate g y). 
 
4. 3.  
S e c o n d ar y  E n d p oi nt A n al y s e s  
4. 3. 1.  
S e c o n d ar y E n d p oi nt s  
F or t he sec o n dar y e n d -p oi nts relati n g t o “ Ac hi e vi n g H Bs A g < L L O Q a n d H B V D N A 
< L L O Q”, i n Secti o n 4. 3. 1 , t he sa me a nal ysis visit wi n d o ws f or Ar m 1 a n d Ar m 2 will be 
use d as defi ne d i n Ta ble 2  Ta ble 1 a n d T a ble 3  res pecti vel y.  
F or ot her s ec o n d ar y e n d p oi nts (act ual val ues a n d c ha n ge fr o m b aseli ne o ver ti me, 
a nti b o d y le v els o ver ti me, etc.) t he dat a will be s u m marize d as c ollecte d.  T hree gr o u ps of 
esti ma n ds are defi ne d bel o w f or t he ke y s ec o n d ar y efficac y o bjecti ves. 


C O N FI D E N TI A L  
 
 
2 0 9 3 4 8  
X B U St ati sti c al A n al y si s Pl a n ( S A P)  T e m pl at e v 1. 0 2 4 M ar c h 2 0 2 1  
P a g e 3 0  of 7 7  
 
4. 3. 1. 1.  
Effi c a c y of G S K 3 2 2 8 8 3 6 a n d P e gI F N S e q u e nti al T h er a p y o n B i o m ar k er s 
a n d V ir u s S p e cifi c A nti b o d y R e s p o n s e s  
T he esti ma n d strate g y s u p p orti n g t his sec o n d ar y o bjecti ve is defi ne d b el o w. Missi n g data 
f or varia bl es defi ne d b el o w, e x ce pt f or ti me t o A L T n or malisati o n, will be  a nal yse d as 
c ollecte d. Onl y a v aila ble data will be s u m marise d.  
•  P o p ul ati o n:  Partici pa nts wit h C H B o n sta ble N A t hera p y; F or t he ti me t o A L T 
n or malisati o n varia ble, p o p ulati o n 
will be af ore me nti o ne d partic i pa nts 
wit h 
baseli ne A L T > U L N.  
•  Tre at me nt:  3 0 0 m g G S K 3 2 2 8 8 3 6 f or 1 2 or 2 4 wee ks f oll o we d b y u p t o 2 4 wee ks 
of Pe gI F N t h era p y w hile o n sta ble N A t hera p y . 
•  I nterc urre nt E ve nts:  
o  Disc o nti n uati o n of, i nterr u pti o n i n, a n d n o n -a d here nce t o G S K 3 2 2 8 8 3 6 a n d 
Pe gI F N a nal yse d as c ollecte d  (treat me nt p olic y).  
o  Pe gI F N i neli gi bilit y will be a nal yse d as c ollecte d (treat me nt p olic y) 
o  Resc ue me dicati o n will be a nal yse d as c ollecte d (treat me nt p olic y), e x ce pt 
f or A L T n or malisati o n w hic h ca n o nl y b e ac hie ve d i n t he a bse nce of res c ue 
me dicati o n .  
o  Wi de disr u pti ve e ve nts (s uc h as 
C O VI D -1 9 pa n de mic) lea di n g t o 
disc o nti n uati o n of, i nterr u pti o n i n, or n o n -a d here nce t o G S K 3 2 2 8 8 3 6 a n d 
Pe gI F N will be a nal yse d as c ollecte d (treat me nt p olic y strat e g y). 
C at e g ori c al V ari a bl e s  
T he f oll o wi n g cate g orical varia bles are defi ne d f or t he o bjecti ve:  
•  Ac hie vi n g H Bs A g < L L O Q a n d H B V D N A < L L O Q at t w o ti me p oi nts: ( 1) t he 
pla n ne d e n d of tr eat me nt a nal ysis wi n d o w a n d ( 2) at t he e n d of 2 4 wee ks f oll o w-
u p  a nal ysis wi n d o w . Dat a will be prese nt e d o verall a n d b y t he b aseli ne 
stratificati o n fact ors defi ne d i n Ta ble 1 . A nal ysis wi n d o ws at pla n ne d e n d of treat 
a n d e n d of 2 4 w ee ks f oll o w -u p will be i de ntical t o t h ose f or t he pri mar y e n d p oi nt 
(see Ta bl e 2  a n d T a ble 3 ). 
•  Cate g orical c h a n ges fr o m baseli ne i n H B s A g (e. g., < 0. 5, ≥0. 5, ≥1, ≥1. 5, ≥3 l o g 1 0 
I U/ m L) a n d i n H B V D N A (e. g., < 1, ≥1, ≥2, ≥3 l o g 1 0  I U/ m L). C ha n ge fr o m 
baseli ne will be pres e nte d at eac h visit a n d f or t he f oll o wi n g ti me peri o ds: u p t o 
a n d i ncl u di n g Wee k 6, u p t o a n d i ncl u di n g Wee k 1 2, u p t o a n d i ncl u di n g Wee k 
2 4, u p t o a n d i ncl u di n g off -treat me nt Wee k 2 4 . Data will be pres e nte d o verall a n d 
b y  t he b aseli ne stratificati o n fact ors  defi ne d i n Ta ble 1 . Data will be s u m marize d 
usi n g pla n ne d visits.  
•  A L T n or malis ati o n ( A L T ≤U L N) o v er ti me i n a bse nce of resc u e me dicati o n i n 
partici pa nts wit h baseli ne A L T > U L N . 
•  H Be a nti b o d y (a nti -H Be A g) le vels.  
P o p ul ati o n S u m m ar y:  P erce nta ge of partici pa nts i n eac h cate g or y f or eac h treat me nt 
ar m. 


C O N FI D E N TI A L  
 
 
2 0 9 3 4 8  
X B U St ati sti c al A n al y si s Pl a n ( S A P)  T e m pl at e v 1. 0 2 4 M ar c h 2 0 2 1  
P a g e 3 1  of 7 7  
 
C o nti n u o u s V ari a bl e s  
C o nti n u o us varia bles f or t he sec o n dar y o bjecti ve are defi n e d as f oll o ws:  
•  Act ual val ues a n d c ha n ge fr o m baseli ne o v er ti me of H Bs A g, H B V D N A, a n d 
H Be A g le vels  (o nl y i n H Be A g P ositi ve Partici pa nts  at baseli ne). 
•  Act ual val ues a n d c ha n ge fr o m bas eli ne o ver ti me f or H Bs a nti b o d y (a nti- H Bs A g) 
le vels. 
•  Act ual val ues a n d c ha n ge fr o m baseli ne o v er ti me f or A L T.  
P o p ul ati o n S u m m ar y : M ea n val ues a n d mea n c ha n ges fr o m b aseli ne of eac h v aria ble f or 
partici pa nts i n eac h treat me nt ar m . 
Ti m e t o E v e nt V ari a bl e s : 
A ti me t o  e ve nt varia ble f or t his o bjecti ve is defi n e d as:  
•  Ti me t o A L T n or malisati o n i n a bse n ce of resc ue me dicati o n i n p artici pa nts wit h 
baseli ne A L T > U L N . 
P o p ul ati o n S u m m a r y:  T ur n b ull’s esti mat or f or n o n para metri c esti mati o n of Ti me t o A L T 
n or malisati o n i n eac h tr eat me nt ar m . 
A L T n or malizati o n is defi ne d i n p artici pa nts  wit h A L T > U L N at bas eli ne as a ret ur n t o 
< U L N ( U L N = 4 0 f or m ales a n d 3 3 i n fe males). Ti me t o A L T n or malizati o n is defi ne d as 
ti me fr o m baseli ne t o t he first f oll o w-u p w here s u bject’s A L T has ret ur ne d t o n or mal.  
F or p artici pa nts w h o wit h dra w fr o m t he st u d y or Partici pa nts wit h A L T > U L N at t he e n d 
of st u d y  ( E o S), ti me t o A L T n or m alizati o n will be ce ns ore d after t he ti me of t he last visit 
wit h n o n -missi n g A L T v al ue a v aila ble . Partici pa nts w h o recei ve resc ue me dicati o n ca n n ot 
g o o n t o ac hie v e t he e ve nt of ‘ A L T n or malizati o n i n t he a bse n ce of resc u e me dicati o n’; 
s uc h partici pa nts will be ce ns ore d at t he e n d of t h e f oll o w u p peri o d . 
I n or der t o d eter mi ne if t h e a d diti o n of a Pe gI F N tr eat me nt after c o m pleti n g 1 2 or 2 4-wee ks 
of Be pir o virse n dela ys rela pse, an a d diti o nal ti me t o e ve nt varia ble is d efi n e d as f oll o ws:  
•  Ti me fr o m Be pi E O T t o Rela pse b y H Bs A g Cate g ories  
P o p ul ati o n s u m m ar y : s u m mar y statistics of t he ti me fr o m Be pir o virs e n e n d of treat me nt 
t o rela pse i ncl u di n g: N( %) wit h rela pse, mea n, sta n dar d de viatio n, me dia n, mi ni m u m, a n d 
ma xi m u m usi n g t he n u m ber of partici pa nts ac hie vi n g V R at Be pi E O T. A d diti o nall y, a 
Ka pla n -Mei er pl ot a n d ass ociate d perce ntiles will be pr o d uce d t o pr o vi de a gra p hical 
c o m paris o n of ti me t o rel a pse bet wee n treat me nt ar ms.  
 
O nl y pa rtici pa nts w h o were vir ol o gic res p o n ders at t he e n d of Be pir o virse n treat me nt will 
be c o nsi dere d, si nce t h e y are t he o nl y o nes w h o ca n rela pse. Ti me t o rela pse is defi ne d as 
t he first ti me p oi nt w here t he p artici pa nt ca n n o l o n ger b e c o nsi dere d a res p o n der b y t h e 
pri mar y esti ma n d f or t he c o nser vati ve defi niti o n. T his i ncl u des o bser ve d ele vati o n(s) i n 
eit her H Bs A g or H B V D N A or resc ue me di cati o n usa ge. Ge n erall y, ti me fr o m e n d of 
Be pir o virs e n treat me nt t o rela pse will be cal c ulate d fr o m t he date of t he pla n n e d Wee k 2 4 
or 1 2 visit (f or ar ms 1 a n d 2 res pecti vel y), w here H Bs A g < L L O Q a n d H B V D N A < L L O Q, 


C O N FI D E N TI A L  
 
 
2 0 9 3 4 8  
X B U St ati sti c al A n al y si s Pl a n ( S A P)  T e m pl at e v 1. 0 2 4 M ar c h 2 0 2 1  
P a g e 3 2  of 7 7  
 
u ntil t he first visit after t he pla n ne d Wee k 2 4 or 1 2 visit w here H Bs A g > = L L O Q or H B V 
D N A > = L L O Q.  
4. 3. 1. 2.  
D ur a bilit y of V ir ol o gi c al R e s p o n s e aft er S e q u e nti al T h er a p y wit h 1 2 
W e e k s of G S K 3 2 2 8 8 3 6 F oll o w e d b y u p t o 2 4 W e e k s of P e gI F N  
T he esti ma n d strate g y s u p p orti n g t his  sec o n dar y o bjecti ve  is  t he sa me strate g y defi ne d i n 
Secti o n 4. 3. 1. 1  a n d f oc uses o n t he ti me p oi nts f oll o wi n g t he 2 4 wee ks off -treat me nt 
peri o d (i.e., Wee k 3 0 a n d Wee k 3 6 ). 
4. 3. 1. 3.  
C o m p ari s o n of E ffi c a c y B et w e e n T r e at m e nt A r m s of 1 2 a n d 2 4 W e e k s 
of G S K 3 2 2 8 8 3 6 F oll o w e d b y u p t o 2 4 W e e k s of P e gI F N  
T he esti ma n d strate g y f or t his o bjecti ve  are d efi ne d as f oll o ws:  
•  P o p ul ati o n:  Partici pa nts 
wit h 
C H B o n sta ble 
N A t hera p y , re gar dl ess of 
disc o nti n uati o n of, i nterr u pti o ns i n or a d here nce t o G S K 3 2 2 8 8 3 6 or Pe gI F N, ha d 
t he y not be e n affecte d b y wi de disr u pti ve e ve nts .  
•  Tre at me nt:  3 0 0 m g G S K 3 2 2 8 8 3 6 f or 1 2 or 2 4 wee ks f oll o we d b y u p t o 2 4 wee ks 
of Pe gI F N t hera p y w hile o n sta ble N A t hera p y. O ne treat me nt c o m paris o n bet wee n 
Ar ms 1 a n d 2 u p t o 2 4 w ee ks off  tr eat me nt. 


C O N FI D E N TI A L  
 
 
2 0 9 3 4 8  
X B U St ati sti c al A n al y si s Pl a n ( S A P)  T e m pl at e v 1. 0 2 4 M ar c h 2 0 2 1  
P a g e 3 3  of 7 7  
 
•  I nterc urre nt Eve nts:   
o  Disc o nti n uati o n of, i nterr u pti o n i n, a n d n o n -a d here nce t o G S K 3 2 2 8 8 3 6 a n d 
Pe gI F N will be a nal yse d as c ollecte d (treat me nt p olic y). 
o  Pe gI F N i neli gi bilit y will be a nal yse d as c ollecte d (treat me nt p olic y) 
o  Partici pa nts w h o ha ve us e d resc u e me dicati o n will be  i nc or p orat e d i n t he 
defi niti o n of t he e n d p oi nt (c o m p osite strate g y) 
o  F or w i de disr u pti ve e ve nts (s uc h as C O VI D-1 9 pa n de mic) lea di n g t o 
disc o nti n uati o n of, si g nifica nt i nterr u pti o n i n, or n o n -a d here nce t o 
G S K 3 2 2 8 8 3 6 or Pe gI F N , data c ollecte d after t h e i nterc urre nt e ve nt will be 
set t o missi n g a n d t he res p o nse will be i m p ute d usi n g all a v aila ble data f or 
partici pa nts f or w h o m S V R  ca n be ass esse d. ( h y p ot hetical strate g y). 
P o p ul ati o n S u m m ar y:  Differe nce i n p erce nta ge of partici pa nts w h o ac hie ve S V R f or 2 4 
wee ks after t he pla n n e d e n d of se q ue ntial treat me nt bet wee n treat me nt ar ms  
 
C at e g ori c al  V ari a bl e s  
T he f oll o wi n g cate g orical varia bles are defi ne d f or t his o bjecti ve:  
•  Ac hie vi n g S V R  ( H Bs A g < L L O Q a n d H B V D N A < L L O Q) at t he pla n ne d e n d of 
se q ue ntial treat me nt a n d o ver t he 2 4 wee ks f oll o w-u p  f or eac h tr eat me nt ar m. 
M ai n A n al yti c al A p pr o a c h  
T he sec o n dar y effic ac y c o m paris o n of i nterest is t he differe nce i n s ustai ne d vir ol o gic 
res p o nse rate f or 2 4 wee ks after t he pla n ne d e n d of se q ue ntial treat me nt bet w ee n tr eatme nt 
ar ms: 
•  Ar m 1 vs. Ar m 2 i n perce nta ge of p artici pa nts ac hie vi n g S V R  f or 2 4 wee ks after 
t he pla n ne d e n d of s e q ue ntial treat me nt, wit h o ut use of a n y resc ue m e dicati o n. 
C o m paris o n bet wee n treat me nt ar ms will be ma de b y calc ulati n g t he differe nce b et wee n 
t he p osteri or distri b uti o ns of t he res p o nse rate i n eac h ar m w hic h will be s u m marise d t o 
o btai n p osteri or mea ns a n d CIs. Sa m ples fr o m t he p osteri or distri b uti o n of t he res p o nse 
rates i n eac h ar m will als o be use d t o o btai n p osteri or pr o ba bilities of i nterest. T he p oi nt 
esti mates of differe nces i n S V R  rate wit h 9 5 % cre di ble i nter vals will be cal c ulate d f or t h e 
treat me nt c o m paris o ns descri be d i n t he esti ma n ds. P osteri or pr o ba bilities Pr( Ar m 1 –  Ar m 
2 > 0) a n d Pr( Ar m 2 –  Ar m 1 > -0. 0 5) will be prese nte d t o ai d selecti o n of treat me nt 
regi me n.  
M o d el C h e c ki n g a n d Di a g n o sti c s  –  M C M C Mi xi n g Di a g n o si s  
T he sa me a p pr oac h i n m o del c hec ki n g a n d dia g n ostics will be a p plie d as f or t h e pri mar y 
a nal ysis  (S ecti o n 4. 2. 2. 3 ). 


C O N FI D E N TI A L  
 
 
2 0 9 3 4 8  
X B U St ati sti c al A n al y si s Pl a n ( S A P)  T e m pl at e v 1. 0 2 4 M ar c h 2 0 2 1  
P a g e 3 4  of 7 7  
 
4. 3. 1. 4.  
S e n siti vit y A n al y s e s  
F or t he esti ma n d s u p p orti n g t he o bjecti ve of c o m pari n g efficac y bet wee n treat me nt ar ms, 
a se nsiti vit y a n al ysis will be perf or me d usi n g t h e Ba yesi a n m o del descri be d i n Se cti o n 
4. 2. 2  ass u mi n g missi n g at ra n d o m w here b y a p artici pa nt’s res p o ns e will be  i m p ute d usi n g 
all a vaila ble data ( o n - a n d off-treat me nt val ues) f or partici pa nts w h o c o m plete d t he st u d y.  
4. 3. 1. 5.  
Ot h er S e c o n d ar y E n d p oi nt s  
Ot her t ha n t he H Bs A g a n d H B V D N A data s u p p orti n g t he sec o n d ar y o bjecti ve of 
c o m pari n g effi cac y b et w ee n treat me nt ar ms, missi n g data f or varia bl es defi ne d i n a n y ot her 
sec o n dar y or e x pl orat or y esti ma n d will b e a nal yse d as c ollect e d , ass u mi n g missi n g 
c o m pletel y at ra n d o m.  
4. 4.  
E x pl or at or y E n d p oi nt A n al y s e s  
C CI


C O N FI D E N TI A L  
 
 
2 0 9 3 4 8  
X B U St ati sti c al A n al y si s Pl a n ( S A P)  T e m pl at e v 1. 0 2 4 M ar c h 2 0 2 1  
P a g e 3 5  of 7 7  
 
C CI


C O N FI D E N TI A L  
 
 
2 0 9 3 4 8  
X B U St ati sti c al A n al y si s Pl a n ( S A P)  T e m pl at e v 1. 0 2 4 M ar c h 2 0 2 1  
P a g e 3 6  of 7 7  
 
C CI


C O N FI D E N TI A L  
 
 
2 0 9 3 4 8  
X B U St ati sti c al A n al y si s Pl a n ( S A P)  T e m pl at e v 1. 0 2 4 M ar c h 2 0 2 1  
P a g e 3 7  of 7 7  
 
4. 4. 2.  
P h ar m a c o ki n eti c ( P K)  A n al y s e s  
P har mac o ki netic  a nal ys es 
will be b ase d o n t he P o p P K a nal ysis i nstea d of t h e 
p har mac o ki netic p o p ul ati o n , as n o i nte nsi ve P K was c ollecte d.  
C o ntr olle d earl y access t o u n bli n de d P K a n d P K P D relate d data will be gra nte d t o t h e 
desi g nat e d re prese nt ati ve(s) t o perf or m t he p o p ulati o n P K a n d P K P D dataset pre parati o n, 
m o del de vel o p me nt a n d a n y P K re vie w necessar y f or pla n ne d or u n pla n ne d s afet y re vie ws.  
C CI


C O N FI D E N TI A L  
 
 
2 0 9 3 4 8  
X B U St ati sti c al A n al y si s Pl a n ( S A P)  T e m pl at e v 1. 0 2 4 M ar c h 2 0 2 1  
P a g e 3 8  of 7 7  
 
4. 4. 2. 1.  
P K E n d p oi nt s / V ari a bl e s  
P K  of G S K 3 2 2 8 8 3 6 a n d Pe gI F N will be c haracterise d. I n all p artici pa nts, G S K 3 2 2 8 8 3 6 
a n d Pe gI F N c o n ce ntr ati o n at t he e n d of d osi n g i nter val (C ) a n d ter mi nal half-life (t ½) will 
be esti mate d, as dat a per mit s. 
P K  para meters will be calc ulate d b y st a n dar d n o n -c o m part me ntal a nal ysis usi n g t he 
c urre ntl y s u p p orte d v ersi o n of 
Wi n N o nli n. 
All calc ulati o ns of n o n -c o m part me ntal 
para meters will be base d o n act ual sa m pli n g ti mes. P K  para meters liste d will be deter mi ne d 
fr o m t he plas ma c o n ce ntr ati o n-ti me data, as data per mits. 
 
T a bl e 6  
P K  P ar a m et er s a n d P ar a m et er D e s cri pti o n  
P ar a meter  
D at a  
A n al yte  
P ar a meter Descri pti o n  
C  
All 
P artici pa nts  
G S K 3 2 2 8 8 36  
P e gI F N  
C o nc e ntr ati o n at t h e e nd of t he d osin g i nterv al . 
t ½ 
All 
P artici pa nts  
G S K 3 2 2 8 8 36  
P e gI F N  
T er mi n al h alf -lif e d et er mi n e d usi n g 
c o nc entr ati ons c oll ect e d d uri ng t h e off-tr eat m ent 
p eri o d .  
C  = c o nce ntrati o n at t he e n d of d osi n g i nter val;  t ½ = ter mi nal half-life. 
4. 4. 2. 2.  
St ati sti c al A n al y s e s / M et h o d s  
U nless ot her wise s pecifi e d, e n d p oi nts/ varia bles defi ne d i n  Ta ble 6  will be s u m marise d 
usi n g descri pti ve statistics, gra p hi call y prese nte d ( w here a p pr o priat e) a n d liste d. 
Descri pti ve statistics f or c o nti n u o us varia bles will s u m marise n, arit h metic mea n, S D, 9 5 % 
CI, me di a n, mi ni m u m, ma xi m u m, ge o metric m ea n wit h ass ociate d 9 5 % CI, a n d t he 
bet wee n -p artici pa nt C V ( % C V b) f or t he ge o metri c mea n. 
P K para met ers ( C  a n d t ½ ) of G S K 3 2 2 8 8 3 6 a n d Pe gI F N  will be s u m maris e d a n d liste d b y 
treat me nt ar m, I P, a n d st u d y visit ( o nly a p plies t o C ). P K C-ti me pl ots will be create d 
a n d c o m pare d b y t he sa m e fact ors.  
4. 4. 2. 3.  
P K -P D E n d p oi nt s / V ari a bl e s  
P K -P D relati o ns hi ps i ncl u di n g P K -efficac y relati o ns hi ps a n d P K -safet y relati o ns hi ps will 
be e val uat e d  usi n g t he  pre -s pecifi e d i nteri m a n d e n d of st u d y dat a, as data per mits. 
T o e val uate P K -effic ac y relati o ns hi p a n d P K -safet y relati o ns hi p, e x pl orat or y gra p hical 
a nal ys es will be i nitiall y perf or me d f or effi cac y a n d safet y e n d p oi nts. If a relati o ns hi p 
bet wee n e x p os ure a n d efficac y a n d/ or safet y e n d p oi nts is prese nt, p o p ulati o n P K -P D 
m o delli n g ma y be c o n d u cte d usi n g n o nli near mi x e d effect met h o ds. Data fr o m t his st u d y 
ma y b e c o m bi ne d wit h ot her st u dies f or p o p ulati o n P K/ P D m o delli n g.   
F ull details of P K -P D a n d P o p ulati o n P K a nal ysis will be descri be d i n a se parate a n al ysis 
pla n de v el o pe d b y C P M S.  Res ults of t he P K -P D a n al yses  will be s u m marize d i n a se parate 
re p ort.  


C O N FI D E N TI A L  
 
 
2 0 9 3 4 8  
X B U St ati sti c al A n al y si s Pl a n ( S A P)  T e m pl at e v 1. 0 2 4 M ar c h 2 0 2 1  
P a g e 3 9  of 7 7  
 
Effi c a c y A s s e s s m e nt s  
Efficac y ass ess me nts f or P K -P D rel ati o ns hi p ma y i n cl u de b ut are n ot li mite d t o , as dat a 
per mits : 
•  C ate g oric al:  v ir ol o gi c res p o nse, 
ser ocleara nce ( H Bs A g 
< L L O Q, 
H B V 
D N A < L L O Q), a n d s er oc o n versi o n (a nti -H Bs A g a n d a nti -H Be A g) . 
•  C h a n ge fr o m B aseli ne:  H Bs A g, H B V D N A, a nti -H Bs A g a n d a nti -H Be A g le vels . 
•  Ti me t o E ve nt:  v ir ol o gi c res p o nse ( H Bs A g a n d H B V D N A l e vels < L L O Q), na dir 
of H Bs A g a n d H B V D N A, H Bs A g < L L O Q, H B V D N A < L L O Q, s er oc o n v ersi o n 
(a nti-H Bs A g a n d a nti -H Be A g), pea k of A L T fl ares . 
S af et y A s s e s s m e nt s  
Safet y assess me nts f or P K -P D relati o ns hi p i ncl u de b ut are n ot li mite d t o vital si g ns, 
la b orat or y me as ure me nts a n d A Es . 
P K A s s e s s m e nt s  
P K assess me nts i ncl u de b ut are n ot li mite d t o C  a n d ter mi nal half -life (t ½). Data fr o m t his 
st u d y ma y be c o m bi ne d wit h ot her st u dies f or p o p ulati o n P K m o delli n g.   
4. 4. 3.  
S af et y a n d T ol er a bilit y  
T he safet y pr ofile of se q ue ntial t hera p y wit h G S K 3 2 2 8 8 3 6 ( u p t o 2 4 w ee ks) f oll o we d b y 
Pe gI F N ( u p t o 2 4 w ee ks) i n partici pa nts wit h C H B o n sta ble N A t h era p y will be 
i n vesti gate d. 
Cli nical 
assess me nts 
f or safet y 
a n d t olera bilit y 
e val u ati o n i ncl u d e la b orat or y 
meas ure me nts a n d A Es  at ti me p oi nts s pecifie d i n t he S o A.  
4. 4. 4.  
P h ar m a c o d y n a mi c  E ff e ct of G S K 3 2 2 8 8 3 6 a n d P e gI F N  S e q u e nti al 
T h er a p y o n E x pl or at or y B i o m ar k er s 
T he p har mac o d y n a mic effect of G S K 3 2 2 8 8 3 6 a n d Pe gI F N s e q ue ntial t hera p y will be 
assesse d o n t he e x pl orat or y viral bi o mar kers  H B V c ore relat e d a nti ge n ( H Bcr A g)  a n d H B V 
R N A at ti me p oi nts s pecifie d i n t he S o A.  Details will be descri be d i n a s e parate P K -P D 
a nal ysis pla n d e vel o pe d b y C P M S.  
C CI


C O N FI D E N TI A L  
 
 
2 0 9 3 4 8  
X B U St ati sti c al A n al y si s Pl a n ( S A P)  T e m pl at e v 1. 0 2 4 M ar c h 2 0 2 1  
P a g e 4 0  of 7 7  
 
C CI


C O N FI D E N TI A L  
 
 
2 0 9 3 4 8  
X B U St ati sti c al A n al y si s Pl a n ( S A P)  T e m pl at e v 1. 0 2 4 M ar c h 2 0 2 1  
P a g e 4 1  of 7 7  
 
 
 
4. 4. 6.  
Bi o m ar k er  A n al y s e s  
T he effect of G S K 3 2 2 8 8 3 6 a n d Pe gI F N se q ue ntial t hera p y o n i m m u n ol o gi cal bi o mar kers 
will be assesse d. T he relati o ns hi p(s) bet wee n vir ol o g y bi o mar kers i ncl u di n g H Bs A g a n d 
i m m u n ol o gical bi o mar kers will be descri be d. Details of t he i m m u n ol o g y e n d p oi nts will 
be i ncl u de d i n a se p arat e bi o mar ker a n al ysis pla n.  
4. 5.  
S af et y A n al y s e s  
All safet y a nal yses will be base d o n t he Safet y p o p ulati o n.  
E x p os ure t o st u d y me di cati o n, meas ure d b y t he n u m ber of i njecti o ns a n d pr o p orti o n of  
pla n ne d n u m ber of i njecti o ns of st u d y dr u g, will b e s u m marise d b y treat me nt ar m.  
4. 5. 1.  
E xt e nt of E x p o s ur e  
E xte nt of e x p os ure will be s u m marize d b y prese nti n g n u m ber of partici pa nts  i n vari o us 
e x p os ure d urati o n cate g ories, o verall d urati o n of e x p os ure, a n d st u d y i nter ve nti o n 
c o m plia nce.  
N u m ber of da ys of e x p os ure t o st u d y dr u g will be calc ulate d s e paratel y f or G S K 3 2 2 8 8 3 6 
a n d Pe gI F N  base d o n t he f or m ula:  
•  D urati o n of E x p os ure i n Da ys = Last i njecti o n dat e –  First i njecti o n date + 1  
T he d urati o n of e x p os ure i n wee ks will be cal c ulat e d as d urati o n of e x p os ure i n d a ys 
di vi de d b y 7 . 
T he c u m ulati ve act ual d ose will be calc ulat e d  se paratel y f or G S K 3 2 2 8 8 3 6 a n d Pe gI F N 
base d o n t he f or m ula:  
•  C u m ulati ve Act ual D ose = S u m of D ose a d mi nistere d d uri n g G S K 3 2 2 8 8 3 6 or 
Pe gI F N d osi n g peri o d  
T he d ose i nte nsit y ( m g/ w k) will be calc ulat e d se paratel y f or G S K 3 2 2 8 8 3 6 a n d Pe gI F N 
base d o n t he f or m ula:  
•  D ose I nte nsit y = C u m ulati ve Act ual D ose / T otal Act ual N u m ber of Wee ks of 
D ose a d mi nistrati o n  
 
C CI


C O N FI D E N TI A L  
 
 
2 0 9 3 4 8  
X B U St ati sti c al A n al y si s Pl a n ( S A P)  T e m pl at e v 1. 0 2 4 M ar c h 2 0 2 1  
P a g e 4 2  of 7 7  
 
T he c u m ulati ve i njecte d v ol u me will be calc ulate d se parat el y f or G S K 3 2 2 8 8 3 6 a n d 
Pe gI F N b ase d o n t he f or m ula:  
•  C u m ulati ve I nje cte d V ol u me = S u m of I njecte d V ol u me  d uri n g G S K 3 2 2 8 8 3 6 or 
Pe gI F N d osi n g peri o d  
 
T he wee kl y i njecte d v ol u me ( m L/ w k) will be cal c ulate d se paratel y f or G S K 3 2 2 8 8 3 6 a n d 
Pe gI F N b ase d o n t he f or m ula:  
•  Wee kl y I nje cte d V ol u me = C u m ulati ve I nj ecte d V ol u me / T otal Act ual N u m ber 
of Wee ks of D ose a d mi nist rati o n 
4. 5. 2.  
A d v er s e E v e nt s  
All A E s u m maries will be base d o n treat me nt e mer ge nt e ve nts u nless ot her wise s pecifie d. 
A n a d verse e v e nt ( A E) is c o nsi dere d treat me nt e m er ge nt if t he A E o nset date is o n or after 
treat me nt start date. If A E start date is c o m pletel y missi n g a n d t he e n d date is o n or after 
t he treat me nt start date, t he A E will be ass u me d t o be treat me nt e mer ge nt. A Es wit h o nset 
date o n or after start dat e of treat me nt wit h G S K 3 2 2 8 8 3 6  will  be  classifie d as occ urri n g  
d uri n g  t he G S K 3 2 2 8 8 3 6 treat me nt peri o d, a n d A Es wit h o nset date o n or after start d ate of 
treat me nt wit h Pe gI F N  will be classifie d as occ urri n g d uri n g t he Pe gI F N  tr eat me nt peri o d. 
A Es starti n g aft er e n d of G S K 3 2 2 8 8 3 6 treat me nt peri o d a n d pri or t o Pe gI F N  treat me nt start 
will be  c o nsi dere d as A Es occ urri n g d uri n g Pe gI F N  eli gi bilit y p eri o d.  
A d verse e ve nts will be c o de d usi n g t he latest v ersi o n of M e dical Dicti o nar y f or Re g ulat or y 
A ut h orities ( Me d D R A ) c o di n g dicti o nar y, t o gi ve a preferre d ter m a n d a s yste m or ga n 
class. T hese prefe rre d ter ms a n d s yste m or ga n classes will be use d w he n s u m marizi n g t he 
data.  
T he se verit y of A Es a n d S A Es will be deter mi ne d b y t he i n vesti gat or acc or di n g t o t he 
‘Di visi o n of Ac q uire d I m m u ne Deficie nc y S y n dr o me ( D AI D S) T a ble f or Gra di n g t he 
Se verit y of A d ul t a n d Pe diatric A d verse E ve nts ( 2 0 1 7)’, u nless s pecifie d ot her wise i n t he 
pr ot oc ol.   F or A Es b y m a xi m u m deter mi ne d gra de s u m mar y t a bles, f or A Es occ urre d m or e 
t ha n o nce, t h e m ost se vere i nte nsit y will be i ncl u de d i n s u m maries. Rel ati o ns hi p t o st u d y 
treat me nt, as i n dicate d b y t h e i n vesti gat or, is classifie d as n ot relate d or  relate d t o 
G S K 3 2 2 8 3 6 , Pe gI F N , or b ot h. A d verse e ve nts wit h a missi n g relati o ns hi p t o st u d y 
treat me nt will be re gar de d as relate d t o t he o n g oi n g st u d y treat me nt or t he last st u d y 
treat me nt if n o treat me nt is recei ve d at t he ti me of A Es. 


C O N FI D E N TI A L  
 
 
2 0 9 3 4 8  
X B U St ati sti c al A n al y si s Pl a n ( S A P)  T e m pl at e v 1. 0 2 4 M ar c h 2 0 2 1  
P a g e 4 3  of 7 7  
 
T he f oll o wi n g A E s u m maries will be pres e nte d  o v erall a n d b y tr eat me nt ar m : 
1.  A Es o ver vie w: s u m mari ze t he n u m ber a n d perce nta ge of p artici pa nts wit h a n y 
a d verse e v e nt, A Es relate d t o st u d y treat me nt, A E s lea di n g t o per ma ne nt 
disc o nti n uati o n of st u d y treat me nt, wit h dra wal fr o m t he st u d y, a n y s eri o us 
a d verse e v e nts ( S A E), S A Es relate d t o st u d y treat me nt, fatal S A Es a n d fatal S A Es 
relate d t o st u d y treat me nt.  
2.  All A Es b y s yste m or ga n class ( S O C) a n d preferre d ter m ( P T)  
3.  All A Es b y S O C a n d P T a n d ma xi m u m gra de  
4.  All dr u g -relate d A Es b y S O C a n d P T  
5.  All dr u g -relate d A Es b y S O C a n d P T a n d ma xi m u m gra d e  
6.  Seri o us A Es ( S A Es) b y S O C a n d P T  
7.  Seri o us A Es ( S A Es) b y S O C a n d P T  a n d ma xi m u m gra d e  
8.  Seri o us A d verse E v e nts b y syste m o r ga n class a n d p referre d ter m (n u m ber of 
partici pa nts  a n d o cc urre n ces)  
9.  A Es lea di n g t o wit h dra w al fr o m t he st u d y b y S O C a n d P T  
1 0.  A Es lea di n g t o wit h dra w al fr o m t he st u d y b y S O C a n d P T a n d ma xi m u m gra de  
1 1.  A Es lea di n g t o per ma n e nt disc o nti n uati o n of st u d y treat me nt b y S O C a n d P T  
1 2.  A Es  lea di n g t o p er ma n e nt disc o nti n uati o n of st u d y treat me nt b y S O C a n d P T a n d 
ma xi m u m gra de  
1 3.  Seri o u s fatal a n d n o n-fat al dr u g/relate d  A Es b y S O C a n d P T  
1 4.  A Es b y o v erall fre q ue n c y  
1 5.  N o n -seri o us A Es b y S O C a n d P T ( n u m ber of partici pa nts  a n d occ urre nces)  
1 6.  N o n -Seri o us d r u g-relate d ad verse eve nts b y o verall  fre q ue n c y   
T he a b o v e liste d s u m maries will als o be pres e nte d  se paratel y f or e v e nts occ urri n g d uri n g 
treat me nt wit h G S K 3 2 2 8 8 3 6 a n d Pe gI F N , o v erall a n d b y tr eat me nt ar m  wit hi n eac h 
treat me nt peri o d. Dr u g -relate d A Es will be s u m marise d f or t he t w o treat me nt peri o ds as 
f oll o ws: 
1.  S u m mar y of G S K 3 2 2 8 8 3 6 d r u g-relate d ad verse ev e nts b y syste m o r ga n class a n d 
p referre d ter m  
2.  S u m mar y of G S K 3 2 2 8 8 3 6 d r u g-relate d ad verse ev e nts b y syste m o r ga n class a n d 
p referre d ter m a n d m a xi m u m g ra d e 
3.  S u m mar y of Pe gI F N d r u g-relate d ad verse eve nts b y syst e m o r ga n class a n d 
p referre d ter m  
4.  S u m mar y of Pe gI F N d r u g-relate d ad verse eve nts b y syst e m o r ga n class a n d 
p referre d ter m a n d m a xi m u m g ra d e 
N u m ber of partici pa nts wit h A Es will be s u m marize d if it is n ot s pecifie d ot her wise.  
I n s u m mar y t a bles w h ere A Es are pres e nte d b y S O C, P T, a n d m a xi m u m gra de, S O Cs will 
be s orte d i n desce n di n g or der of t he t otal i nci de n ce t he n al p ha beticall y, P Ts will be s orte d 
i n desce n di n g or der of t h e t otal i nci de nce t he n al p ha beticall y wit hi n t he S O C.  


C O N FI D E N TI A L  
 
 
2 0 9 3 4 8  
X B U St ati sti c al A n al y si s Pl a n ( S A P)  T e m pl at e v 1. 0 2 4 M ar c h 2 0 2 1  
P a g e 4 4  of 7 7  
 
F or c o m pletel y missi n g or partial missi n g A E start date or e n d d ate, i m p utati o n r ules will 
be a p plie d f oll o wi n g r ules state d i n t he O ut p ut a n d Pr o gra m mi n g S pecifi cati o ns ( O P S ). 
Deat hs will be liste d i ncl u di n g pri mar y ca use of deat h.  
4. 5. 2. 1.  
A d v er s e E v e nt s of S p e ci al I nt er e st  
T he f oll o wi n g A Es of s p ecial i nterest will be re p orte d:  
•  
A L T i n crease  
•  
Vasc ular i nfl a m mati o n a n d c o m ple me nt acti vati o n  
•  
T hr o m b oc yt o p e nia  
•  
Re nal i nj ur y  
A n u p -t o-dat e  list of s p ecific M e d D R A Q ueries ( S M Qs), hi g h le vel ter ms ( H L Ts) or 
i n di vi d ual preferre d ter ms ( P Ts) use d t o i de ntif y a d verse e ve nts of s peci al i nterest ( A E SIs ) 
is peri o dicall y u p dat e d a n d st ore d i n a ce ntral l ocati o n. At t he ti me of data base l oc k, t he 
latest versi o n of t he ter ms will be e xtracte d a n d us e d t o i de ntif y A E SIs. 
All A Es  of s pecial i nterest will be s u m marize d b y S O C a n d P T, a n d, als o s u m marize d b y 
S O C, P T a n d ma xi m u m gra de. Seri o us A E SIs will be s u m marize d b y S O C a n d P T. All 
A Es of s pecial i nterest will be liste d.  
Se parate o ut p uts will b e create d f or eac h A E SI cate g or y ( A L T i ncrease, vasc ular 
i nfla m mati o n a n d c o m ple me nt acti vati o n, t hr o m b oc yt o p e nia, re n al i nj ur y) t o e x pl ore t he 
data i n m ore detail if dat a per mits.  
E ve nt C haract eristics: T he  c haracteristics of all e v e nt occ urre nces d uri n g t he p ost -baseli ne 
peri o d will be s u m marize d, w hic h l o o ks at e ve nt c haracteristics (seri o us, dr u g -relate d, 
lea di n g t o wit h dr a wal, se vere or Gra de 3-4, fatal), n u m ber of e v e nts per partici pa nt, 
o utc o me, ma xi m u m gra d e or i nte nsit y a n d acti o n t a ke n.  
4. 5. 2. 2.  
C O VI D -1 9 A s s e s s m e nt a n d C O VI D -1 9 A E s  
A sta n d ar dize d Me d D R A Q uer y ( S M Q) will be use d t o i de ntif y all C O VI D -1 9 A Es.  
T he o verall i nci de nce of A Es a n d S A Es of C O VI D -1 9, C O VI D -1 9 A Es lea di n g t o st u d y 
i nter ve nti o n disc o nti n uati o n, C O VI D-1 9 A Es lea di n g t o st u d y wit h dra wal, a n d Gra d e 3 
a n d 4 C O VI D -1 9 A Es / se vere C O VI D-1 9 A Es will be s u m marize d. T he i nci de nce of t hese 
e ve nts at i n di vi d ual P T le vel ca n be o bt ai ne d fr o m t he sta n dar d A E/ S A E s u m maries.  
C O VI D -1 9 ass ess me nts f or partici pa nts wit h p ote ntial, s us pecte d or c o nfir me d C O VI D -1 9 
A Es will be s u m mariz e d.  
If > 5 % p artici pa nts o verall re p ort ≥1 C O VI D-1 9 A E, t he n o nset a n d d urati o n of t he first 
occ urre nce of C O VI D -1 9 A Es, a n d C O VI D -1 9 A E s y m pt o ms (fr o m t he C O VI D -1 9 e C R F 
pa ge) will be s u m marize d. T he sa me r ule will a p pl y t o C O VI D -1 9 S A Es.  
4. 5. 2. 3.  
I m p a ct of C O VI D-1 9 P a n d e mi c o n S af et y R e s ult s  
T he i m pact of t he C O VI D -1 9 pa n de mic o n t he safet y res ults will be assesse d. Pa n de mic 
meas ures be ga n i n differe nt c o u ntries at differe nt ti mes. A d ataset c o ntai ni n g t he dat e w he n 
pa n de mic meas ures b e ga n, as deter mi ne d b y t he G S K c o u n tr y Iss ue Ma n a ge me nt Tea ms 


C O N FI D E N TI A L  
 
 
2 0 9 3 4 8  
X B U St ati sti c al A n al y si s Pl a n ( S A P)  T e m pl at e v 1. 0 2 4 M ar c h 2 0 2 1  
P a g e 4 5  of 7 7  
 
(I M T), will be use d t o deter mi ne t he start dat e of eac h wa v e of pa n de mic m eas ures wit hi n 
eac h c o u ntr y.  
S u m maries of t he i nci de nce rates of A Es, S A Es , a n d Gra de 3 a n d 4 A Es / se vere A Es , 
bef ore ( A E o nset date < pa n de mic meas ure st art date) a n d after ( A E o nset date > = 
pa n de mic me as ure start date) t he start of t h e C O VI D -1 9 p a n de mic will be pr o d uce d, 
o verall a n d b y c o u ntr y/re gi o n, ge n d er , a n d a ge gr o u p.  
4. 5. 3.  
A d diti o n al S af et y A s s e s s m e nt s  
4. 5. 3. 1.  
L a b or at or y D at a  
O nl y ce ntral la b data will be use d  f or s u m mar y a n al yses a n d fi g ures; l ocal la b data will be 
i ncl u de d i n listi n gs, as a p pr o priate.  
 If n or mal L A B ra n ges are c ollecte d a n d t here are d u plicate L A B rec or ds at t he sa me 
date/ti me p oi nt, t he  “ w orst -case” val ue will be sel ecte d . S pecificall y: 
•  F or L A B res ult > L o wer N or mal ra n ge, select M a xi m u m of La b res ult ( A V A L).  
•  F or L A B res ult < = L o w er N or mal ra n ge, select mi ni m u m of La b res ult ( A V A L).  
F or vir ol o g y L A B para m eters, i f ti me i nf or mati o n is missi n g fr o m c ollecti o n a n d fr o m t he 
test perf or me d, t h e maxi m u m la b val ue s h o ul d be selecte d.  If first r u n h as val ues  o utsi de 
acce pta nce criteria, a n d t he sa m ple was re -r u n, t he latest L A B res ult s h o ul d be selecte d b y 
t he ve n d or. 
S u m mar y statistics f or c h a n ges fr o m baseli ne f or eac h n u meric para meter at eac h visi t will 
be pres e nte d, s e paratel y f or all cli nical c he mistr y p ara meters, all h ae mat ol o g y p ara m eters,  
a n d all uri nal ysis para m eters.   
F or i m m u n ol o g y p ara m eters, s u m mar y statistics f or act ual val ue a n d c ha n ge fr o m baseli ne 
data f or eac h para meter at eac h visi t will be prese nte d, se paratel y f or all n u meric 
para meters. Listi n gs will als o be create d.  
F or cate g orical i m m u n ol o g y para meters c -A N C A a n d p -A N C A, s u m mar y t a ble of baseli ne 
Ne gati ve t o p ost -baseli ne P ositi ve, baseli ne val ue n o c ha n ge, a n d bas eli ne P ositi ve  t o p ost-
baseli ne Ne gati ve  will be creat e d. Listi n g will be create d as well.  
F or c o a g ulati o n para m eters p r ot hr o m bi n i nter nati o nal n or malise d  rati o (I N R), p r ot hr o m bi n 
ti me ( P Ttest) a n d acti vate d p artial thr o m b o plasti n ti me (a P T T), s u m mar y statistics f or act ual 
at eac h visit will be pres e nte d. Listi n g will be create d as well.  
S hift ta bles f or la b orat or y p ara m eters s h o wi n g b aseli ne t o xicit y vers us ma xi m u m p ost -
baseli ne ( o n -treat me nt a n d off-treat me nt peri o ds c o m bi ne d) t o xicit y f or eac h gra d e 
( Gra d e 1, Gra de 2, etc.) f or c he mistr y a n d hae mat ol o g y para meters will be pr o vi de d.   
I n crease t o 
Gra de 3 or hi g h er la b a b n or m alities f or plat elets, 
A L T, as partate 
a mi n otra nsferase ( A S T ), I N R, t otal bilir u bi n, ser u m creati ni ne, e G F R, alb u mi n t o 
creati ni ne rati o (A C R ) will be s u m marize d.   
La b orat or y v al ues o utsi de of n or mal r a n ge will be s u m marize d a n d liste d.  
Gra di n g cat e g ories f or la b orat or y tests are deter mi ne d usi n g t he D AI D S gra di n g s yste m 
Versi o n 2. 1 [ Nati o nal I nstit ute of Aller g y a n d I nfecti o us Diseases.  Di visi o n of AI D S , 
2 0 1 7].  


C O N FI D E N TI A L  
 
 
2 0 9 3 4 8  
X B U St ati sti c al A n al y si s Pl a n ( S A P)  T e m pl at e v 1. 0 2 4 M ar c h 2 0 2 1  
P a g e 4 6  of 7 7  
 
S u m mar y of p ost -b aseli ne he pat o biliar y la b orat or y a b n or malities will be pr o vi de d.   
T he w orst -case uri nal ysis res u lts p ost-baseli ne ( o n -treat me nt a n d off-treat me nt peri o ds 
c o m bi ne d) rel ati ve t o bas eli ne will be s u m marize d.  
S u m maries of res ult s hifts fr o m baseli ne, w orst -case res ults p ost -baseli ne relati ve t o 
baseli ne, a n d res ults wit h i ncrease t o > = ma xi m u m t o xicit y gra d e p ost -baseli ne  f or 
c he mistr y, h a e mat ol o g y, uri nal ysis, a n d i m m u n ol o g y as a p pli ca bl e, will als o be prese nte d  
f or treat me nt wit h G S K 3 2 2 8 8 3 6 a n d Pe gI F N  s e paratel y, b y treat me nt ar m a n d i n t otal 
wit hi n eac h treat me nt peri o d.  
G S K 3 2 2 8 8 3 6 l i ver c he mistr y m o n it ori n g a n d st o p pi n g e ve nt re p orti n g will be s u m marize d 
a n d liste d. T he li ver m o nit ori n g a n d st o p pi n g criteria are des cri be d i n t he pr ot oc ol Secti o n 
7. 1. 1.  
G S K 3 2 2 8 8 3 6 h ae mat ol o gic al m o nit ori n g a n d st o p pi n g e ve nts will be s u m marize d a n d 
liste d base d o n la b orat or y p ara m eters ( plat elet c o u nt a n d a nti-platelet a nti b o dies) . T he 
hae mat ol o gical st o p pi n g criteria are d escri be d i n t he pr ot oc ol Secti o n 7. 1. 2.  
G S K 3 2 2 8 8 3 6 d r u g i n d uc e d ki d ne y i nj ur y (re n al) m o nit ori n g a n d h ol d  or st o p pi n g e v e nts 
will be i de ntifie d pr o gra m maticall y a n d will be s u m marize d a n d liste d  base d o n la b orat or y 
para meters ( A C R, u ri nal ysis re d bl o o d cells (R B C ), ser u m creati ni ne, a n d e G F R). T h e 
ki d ne y i nj ur y m o nit ori n g a n d st o p pi n g criteria are descri be d i n t he pr ot o c ol Secti o n 7. 1. 3 . 
Dr u g i n d uce d vas c ular i nj ur y a n d c o m ple m e nt 
m o nit ori n g/st o p pi n g e ve nt 
will be 
s u m marize d a n d liste d base d o n la b orat or y para meters (C 3, C 4, B b, C 5a, hs -C R P, M C P -
1, p -A N C A, c -A N C A, e G F R, b ilir u bi n, a n d platelet c o u nt). T he d r u g in d uce d v asc ul ar 
inj ur y a n d co m ple me nt m o nit ori n g a n d h ol d /st o p pi n g criteria are descri b e d i n t he pr ot oc ol 
Secti o n 7. 1. 4.  
H ol d/st o p pi n g e ve nt pr ofile f or G S K 3 2 2 8 8 3 6 will be pr o vi de d f or a n y s u bject w h o has met 
h ol d or st o p pi n g criteria s pecifie d i n pr ot oc ol Secti o n 7. 1. Rele va nt i nf or mati o n will be 
re p orte d, i ncl u di n g bas eli ne c haracteristics, A Es/ S A Es, c o nc o mita nt me dicati o n, me dical 
hist or y/c urre nt me dical c o n diti o n s, st u d y tr eat me nt a d mi nistrati o n details, la b orat or y 
val ues, a n d i n di vi d ual li ne pl ots of c o m ple me nt ( C 3/ C 4/ C 5a/ B b), i nfla m mat or y mar kers 
( hs-C R P/ M C P -1), ser u m creati ni ne/creati ni ne cleara nce or e G F R/ A C R, a n d platelet c o u nt.  
Hae mat ol o gical  (a bs ol ut e ne utr o p hil c o u nt ( A N C ), platelet c o u nt, hae m o gl o bi n), A L T 
ele vati o n (greater t ha n 5 x U L N, greater t ha n 1 0 X U L N)  a n d ps yc hiatri c dis or der  (C -
S V R R S, B DI -II) d ose m o dificati o n a n d disc o nti n uati o n g ui deli nes  f or Pe gI F N  will be 
s u m marize d a n d are descri be d i n  pr ot oc ol Secti o n  7. 2. 1, Secti o n 7. 2. 2 , a n d Secti o n 7. 2. 3  
res pecti vel y. 
G S K 3 2 2 8 8 3 6 r estart after li ver st o p pi n g criteria h as bee n met will be s u m marize d base d 
o n A L T, bilir u bi n , a n d I N R, a n d is descri be d i n pr ot oc ol Secti o n  7. 3.  
4. 5. 3. 2.  
Vit al Si g n s  
S u m maries of gra d e i ncrease i n te m p erat ur e, s yst olic bl o o d press ure ( S B P) a n d diast olic 
bl o o d press ure ( D B P) will be pr o vi de d se paratel y. T hes e s u m maries will dis pla y t he 
n u m ber a n d perce nt a ge of partici pa nts wit h a n y gra d e i ncreas e, i ncreas e t o Gra de 2, 
i ncreas e t o Gra de 3 a n d i ncreas e t o Gra de 4 (f or te m perat ur e o nl y), f or w orst case p ost -


C O N FI D E N TI A L  
 
 
2 0 9 3 4 8  
X B U St ati sti c al A n al y si s Pl a n ( S A P)  T e m pl at e v 1. 0 2 4 M ar c h 2 0 2 1  
P a g e 4 7  of 7 7  
 
baseli ne o nl y. T h e gra d e defi niti o n f or  n o n -a xil lar y t e m perat ure is: Gra de 1 ( 3 8. 0C –  
< 3 8. 6 C), Gra d e 2 ( 3 8. 6 C –  < 3 9. 3 C), Gra de 3 ( 3 9. 3 C –  < 4 0. 0 C), Gra de 4 ( > = 4 0. 0 C). 
T he gra de defi niti o n f or S B P is : Gra de 1 ( 1 4 0 -1 5 9), Gra de 2 ( 1 6 0 -1 7 9), Gra de 3 ( > = 1 8 0). 
T he gra de defi niti o n f or D B P is : Gra de 1 ( 9 0 -9 9), Gra d e 2 ( 1 0 0 -1 0 9), Gra de 3 ( > = 1 1 0). 
T he s u m maries will be pr o d uce d f or w orst cas e p ost baseli ne o nl y.  
4. 5. 3. 3.  
El e ctr o c ar di o gr a m ( E C G ) 
E C G data  (a bs ol ute v al ues a n d c ha n ge fr o m Bas eli ne) will be s u m marise d b y visit a n d 
treat me nt ar m o nl y f or t he e n d of st u d y a n al ysis a n d w o n’t be i ncl u de d i n t he i nteri m 
a nal ysis o ut p uts . 
4. 6.  
Ot h er A n al y s e s  
4. 6. 1.  
S u b gr o u p A n al y s e s  
Descri pti ve s u m maries b y s u b gr o u ps defi ne d i n  Ta ble 7  will be pr o vi de d. N u m ber of 
res p o n ders, p osteri or me a n a n d 9 5 % e q ual-tail cre di ble i nter val of t h e S V R  res p o nse rate 
will be re p orte d b y s u b gr o u ps as defi ne d i n t he m o del s pecificati o n secti o n f or eac h 
treat me nt ar m. T h e c orres p o n di n g p osteri or pr o ba bilit y of S V R  rate e x cee di n g a ra n ge of 
cli nicall y m ea ni n gf ul res p o nse rat es will als o b e re p orte d b y s u b gr o u ps as defi ne d i n t he 
m o del s pecificati o n secti o n f or eac h tr eat me nt ar m. N o statistical c o m paris o n bet wee n 
s u b gr o u ps will be p erf or me d. 
If t h e n u m ber of partici p a nts is t o o s mall ( < 5 per s u b gr o u p cate g or y) wit hi n a s u b gr o u p, 
t he n t he s u b gr o u p cate g ories ma y be re defi n e d pri or t o u n bli n di n g t he st u d y. If t he cate g or y 
ca n n ot be refi ne d f urt h er, t he n descri pti ve rat h er t ha n statistical s u m maries ma y be 
prese nte d f or t he s pecific s u b gr o u p. 
 
T a bl e 7  
S u b gr o u p s a n d S u b gr o u p C at e g ori e s  
S u b g r o u p 
C at e g ori e s  
H B e A g St at us  
P ositiv e (0. 0 9 U/ mL) ; N e g ativ e  ( < 0. 0 9 U/ m L) 
B as eli ne H Bs A g  
L o w ( ≤ 3 l o g 1 0 I U/ m L) ; Hi gh ( > 3l o g 1 0 I U/ m L)  
< = 3, > 3 -3. 5, > 3. 5 -4 a n d > 4  
A g e gr o u p  
E M A:  < 1 8; ≥1 8 -6 4; ≥6 5 –  8 4, ≥8 5 : F D A A A:  ≤1 8; ≥1 9 -6 4; ≥6 5  
Cli ni c al a n d E pi ( Gr o u p 1):  <5 0 ; ≥50  
S ex  
M al e ; Fe m al e  
Rac e  
A m eric a n I n dia n or Al ask a N ativ e; Asi a n; Black or Africa n A m eric an; N ativ e 
H a w aii a n or Ot h er P acific Isl an d er; W hite  
B as eli ne viral g en oty pe  A; B; C; D; Ot h er ; U nkn o w n  
B as eli ne B MI  
< 3 0 ; ≥3 0  
B as eli ne A L T  
< = UL N; > U L N ; = < UL N, > U L N t o < = 2x U L N, > 2x U L N t o < = 3x U L N,  > 3x 
U L N t o < = 5x U L N, > 5x U L N to < = 1 0x U L N, >1 0x  
B as eli ne M E T A VI R  
Fi br osis Sc ore  
If e n o u g h d at a are avail abl e ( ≥5 p articip a nts  p er gr ou p p er ar m):  
F 0 –  F 2 ; F 3  
Ti m e o n c urr e nt N U C  
<  3 y e ars; > = 3 y e ars  
Ty p e of  c urr e nt N U C  
T A F /T D F ; E nt ec avir ; Ot h er  


C O N FI D E N TI A L  
 
 
2 0 9 3 4 8  
X B U St ati sti c al A n al y si s Pl a n ( S A P)  T e m pl at e v 1. 0 2 4 M ar c h 2 0 2 1  
P a g e 4 8  of 7 7  
 
S u b g r o u p 
C at e g ori e s  
Dur ati o n of H ep B 
I nf ectio n 
< 5 y e ars ; ≥ 5 y ears - < 10 y e ars ; ≥ 1 0 y ears - < 20 y ears ; ≥ 20 y e ars  
B as eli ne m utati o ns i n 
t h e bin di n g sit e  
Pr es e nt ; A bs e nt 
P h as e of H B V I nf ecti on 
( Strict Crit eria) 
P h as e 1; P has e 2; Ot her H B e A g -p ositiv e; P has e 3; P h as e 4; Ot h er H B e A g -
n e g ativ e, w h er e p h ases ar e defi n e d as b el o w.  
 
P h as e 1 = H B e A g -positiv e, A L T < = UL N d uri n g scr ee ni n g a nd at b as eli ne, 
H B V D N A > 1 0 6 I U/ ml d uri n g scr e e ni ng a n d at b as elin e 
P h as e 2 = H B e A g -positiv e,  A L T > UL N eit h er duri n g scr e enin g or at bas eli n e, 
H B V D N A > 1 0 4 I U/ ml d uri n g scr e e ni ng a n d at b as elin e 
Ot h er H B e A g -p ositiv e = H B e Ag -p ositiv e, n eit her P h ase 1 n or P h as e 2  
P h as e 3 = H B e A g -ne g ativ e, AL T < = UL N d uri n g scre e ni ng an d at b as elin e, 
H B V D N A < 2 0, 0 0 0 I U/ ml d urin g scr ee ni ng a n d at b aseli ne  
P h as e 4 = H B e A g -ne g ativ e, AL T > UL N eit h er d uri n g scr ee ni n g or at b as eli n e, 
H B V D N A > 2, 0 0 0 I U/ ml d uri ng scr e eni n g a n d at b as eli n e  
Ot h er H B e A g -n e gative = H B e A g -n e g ativ e, n eit h er P h as e 3 n or P h as e 4  
P h as e of H B V I n f ecti on 
( L o os e Criteri a) 
P h as e 1 l o ose; P h ase 2 l oos e; P h as e 3 l o ose; P h ase 4 lo os e, w h er e p h as es 
ar e d efi ne d as b el o w.  
 
P h as e 1 l o ose = H B e A g -p ositiv e, A L T < = UL N d urin g scr e e nin g a n d at b aseli n e  
P h as e 2 l o ose = H B e A g -p ositiv e, A L T > U L N eit h er d uri n g scr e e ni ng or at 
b as eli n e  
P h as e 3 l o ose = H B e A g -n e g ativ e, A L T < = U L N d uri n g scr eeni n g a nd at 
b as eli n e  
P h as e 4 l o ose = H B e A g -n e g ativ e, A L T > U L N eit h er d uri n g scr e e ni ng or at 
b as eli n e  
 
4. 6. 2.  
S u b p o p ul ati o n s t o S u p p ort R e g ul at or y C o n s ult ati o n  
T o s u p p ort c o ns ultati o n wit h re g ulat ors, k e y  st u d y p o p ulati o n, efficac y, safet y, a n d 
p har mac o ki netic a nal ysis will be  re p eate d f or t he f oll o wi n g s u b p o p ulati o ns i n t he e n d of 
st u d y a nal ysis: 
 
J a p a n s u b p o p ul ati o n : All partici pa nts  of Ja pa nese herita ge e nr olle d at sites i n J a pa n.  
 
C hi n a m ai nl a n d s u b p o p ul ati o n : All partici pa nts  e nr olle d at sites i n C hi na Mai nla n d.  
 
E ast Asi a s u b p o p ul ati o n : All partici pa nts  of a rele va nt Asia n herita ge ( Asia n –  J a pa nese 
Herita ge, Asi a n –  East Asia n Herita ge or Asia n –  S o ut h East Asia n Herita ge) e nr ol le d at 
sites i n J a pa n, S o ut h K orea a n d C hi na mai nla n d.  
 


C O N FI D E N TI A L  
 
 
2 0 9 3 4 8  
X B U St ati sti c al A n al y si s Pl a n ( S A P)  T e m pl at e v 1. 0 2 4 M ar c h 2 0 2 1  
P a g e 4 9  of 7 7  
 
4. 7.  
I nt eri m A n al y se s  
A p pr o xi matel y e v er y 3 m o nt hs, a n e xter nal I D M C will re vie w res ults t hr o u g h o ut t he st u d y 
t o peri o dicall y e v al uate s afet y dat a. T w o i nteri m a nal yses will be c o n d u cte d f or t he st u d y 
i n a d diti o n t o re g ular I D M C safet y re vie ws.  
T here will be a n i nitial u n pla n n e d, i.e. n ot pre-s pecifie d i n t he pr ot oc ol, i nt eri m a nal ysis of 
u n bli n de d effi cac y data t o s u p p ort i nter nal decisi o n ma ki n g at a D e vel o p me nt R e vie w 
B oar d ( D R B) meeti n g f or t he G S K 3 2 2 8 8 3 6 platf or m trial ( St u d y 2 1 8 3 0 9) pla n ne d f or 2 1 -
A pr -2 0 2 2. O nl y a s mall s u b -tea m of pr oject-le vel t ea m me m bers will vie w t hese u n bli n de d 
res ults a n d n o c ha n ges t o trial c o n d uct or pri mar y e n d p oi nt a nal ys es will be ma de bas e d o n 
t he res ults of t his i nteri m a nal ysis. F urt her details descri bi n g t his u n pla n ne d a nal ysis will 
be pr o v i de d i n a se p arat e a nal ysis o utli ne d oc u m e nt. 
A d diti o nall y, a s eries of a d mi nistrati ve i nteri m a nal yses ( AI As) n ot pla n ne d f or i n t h e 
pr ot oc ol c o m me nce d Se pte m ber -2 0 2 2 (see n ote t o file: T M F -1 4 8 5 9 4 2 2 a n d A nal ysis 
O utli ne T M F -1 4 9 1 7 1 9 0) f or t he p ur p ose of de ter mi ni n g w het her i nter nal G S K res o urce 
s h o ul d be all ocate d at-ris k f or f ut ure de vel o p me nt of be pir o virse n f oll o we d b y P e gI F N 
se q ue ntial treat me nt. T h ese f ut ure a d mi nistrati ve i nteri ms will be pr o vi de d o n a n o n g oi n g 
basis  (a p pr o xi matel y m o nt hl y) t o t he G S K i nter nal Data Re vie w C o m mittee (i D R C) f or 
refere nce t o s u p p ort t heir f or mal d ecisi o n-ma ki n g.  Bel o w is a ta ble wit h t he m o nt hl y 
pr ojecti o ns f or t he n u m ber of s u bjects wit h S V R data i n eac h ar m a v aila ble at eac h AI A 
(a n d pla n ne d I A). F ull details of t he  i nter nal d ecisi o n-mar ki n g fra me w or k are i ncl u de d i n 
t he iD R C c harter.  
 
T a bl e 8  
P r oj e cti o n s f or t h e N u m b er of s u bj e ct s wit h Pri m ar y E n d p oi nt  
A v ail a bl e at pl a n n e d I A ( PI A) a n d e a c h AI A  
N ote : Se pte m ber a n d O ct o ber 2 0 2 2 AI As o cc urre d pri or t o t his i D R C bei n g de vel o pe d 
a n d a p pr o ve d.  Details are i ncl u de d i n t he ta ble bel o w f or a ware n ess.  
 
R e vi e w 
M o nt h  
D at a C ut  
AI A/ 
Pl a n n e d I A  
T otal 
n u m b er of 
s u bj e ct s  
Pr oj e ct e d n u m ber of 
s u bj e ct s at Pri mar y E n d 
p oi nt ( O T W K 2 4)  
 
Ar m 1  
Pr oj e ct e d n u m ber of  
s u bj e ct s at Pri mar y E n d 
p oi nt ( O T W K 2 4)  
 
Ar m 2  
S e p 2 2  
2 2 A ug 22  
AI A  
2 8  
1  
2 7  
Oct 2 2  
0 3 Oct2 2  
AI A  
5 8  
1 3  
4 5  
N ov 2 2  
1 1 Oct2 2  
PI A  
6 6  
1 8  
4 8  
D ec 2 2  
2 8 N ov 2 2  
AI A  
8 8  
3 5  
5 3  
J a n 2 3 
0 9J an 2 3  
AI A  
1 0 0  
4 7  
5 3  


C O N FI D E N TI A L  
 
 
2 0 9 3 4 8  
X B U St ati sti c al A n al y si s Pl a n ( S A P)  T e m pl at e v 1. 0 2 4 M ar c h 2 0 2 1  
P a g e 5 0  of 7 7  
 
 
T here will als o be a  pla n ne d  i nteri m a nal ysis as pre-s pecifie d i n t he pr ot oc ol. T he iD R C 
will ha ve pri mar y re vie w res p o nsi bilit y of t he pre -s pecifie d i nteri m a nal ysis res ults a n d 
deter mi ne if t h e dat a s u p p ort a n earl y C o m mit t o P hase 3 ( C 2 P 3) rec o m me n dati o n  t o D R B.  
T he  pre -s p ecifie d i nteri m a nal ysis will be tri g gere d w he n all partici pa nts c o m plete t he e n d 
of treat me nt  ( E o T) visit ( Wee k 4 8 f or Ar m 1 a n d Wee k 3 6 f or Ar m 2), a n d  a s ufficie nt 
n u m ber of partici pa nts  ha ve c o m plete d t h e 2 4 -wee k off -tr eat me nt f oll o w-u p peri o d  
( E oT + 2 4 w ks ) i n or der t o assess t he pr o ba bilit y of C 2 P 3. At t his ti me p oi nt, it is e x pecte d 
t hat a p pr o xi matel y 1 8  partici pa nts  i n Ar m 1 a n d 4 8  partici pa nts  i n Ar m 2 will be c o m pleters 
at t he ti me of I A, i.e., partici pa nts  w h o will ha ve reac he d t he e n d of t he 2 4 wee k  off -
treat me nt f oll o w-u p peri o d  ( E oT + 2 4 w ks ).  
T he pri mar y o bjecti ve of t he  pre -s pecifi e d i nteri m a nal ysis is earl y ass ess me nt of pr o gra m-
le vel f utilit y a n d s u ccess. F ull d etails of t he i nter nal decisi o n -mar ki n g fra me w or k f or t h e 
pla n ne d I A are i ncl u d e d i n t he iD R C c harter .  
4. 7. 1.  
Pri m ar y E n d p oi nt s / V ari a bl e s  
All partici pa nts  are a ntici pate d t o ha ve  reac he d t he pla n ne d e n d of s e q ue ntial treat me nt 
( E o T) at t he ti me of i nteri m a nal ysis. T he pri mar y e n d p oi nts of i nterest f or t he i nteri m 
a nal ysis t o ass ess f utilit y a n d s uccess  (as per t he i D R C c harter) i n eac h ar m are:  
1)  T he n u m ber of p artici pa nts  w h o ha ve reac h e d 2 4 wee ks after t he pla n ne d e n d of 
se q ue ntial treat me nt ( E oT + 2 4 w ks)  a n d h a ve vir ol o gical res p o nse ( V R ) at t he 
pla n ne d e n d of tr eat me nt ( E o T) visit wi n d o w i n t he a bse nce of resc u e me di cati o n. 
2)  T he n u m ber a n d pr o p orti o n of partici pa nts  ac hie vi n g S V R  ( H Bs A g < L L O Q a n d 
H B V D N A < L L O Q) f or 2 4 wee ks after t he pla n ne d e n d of tr eat me nt  
( E o T + 2 4 w ks) i n t he a bse nce of resc ue m e dicati o n: 
•  Ar m 1: Wee k 7 2 a nal ysis wi n d o w S V R  rate  
•  Ar m 2: Wee k 6 0 a nal ysis wi n d o w S V R  rate 
3)  T he n u m ber of partici pa nts  w h o ha v e n ot yet reac he d 2 4 wee ks after t he pla n ne d 
e n d of s e q ue ntial treat me nt  (E o T + 2 4 w ks) a n d h a v e V R at pla n ne d e n d of tr eat me nt  
( E o T) visit wi n d o w  i n t he a bse nce of resc u e me di cati o n. 
4)  T he n u m ber of partici pa nts  w h o ha v e n ot yet reac he d 2 4 wee ks after t he pla n ne d 
e n d of se q u e ntial treat me nt ( E o T + 2 4 w ks) a n d ha ve s ustai ne d vir ol o gic res p o nse 
fr o m pla n ne d e n d of tr eat me nt ( E o T) t o I A d ata c ut-off dat e  i n t he a bs e nce of resc ue 
me dicati o n . 
 
4. 7. 2.  
Ot h er E n d p oi nt s / V ari a bl e s  
T he f oll o wi n g e n d p oi nts, i n a d diti o n t o pri mar y e n d p oi nts, will be s u m marise d usi n g 
descri pti ve statistics b y treat me nt ar m. All of t h e e n d p oi nts bel o w e x ce pt f or 8, 1 3,  a n d 1 4-
2 1 are als o i ncl u d e d a n d defi ne d  i n t he e n d of st u d y a n al ys es. 
1)  S u m mar y of pr o p orti o n of partici pa nts  w h o ac hi e ve H Bs A g < L L O Q a n d H B V 
D N A < L L O Q o ver ti me.  


C O N FI D E N TI A L  
 
 
2 0 9 3 4 8  
X B U St ati sti c al A n al y si s Pl a n ( S A P)  T e m pl at e v 1. 0 2 4 M ar c h 2 0 2 1  
P a g e 5 1  of 7 7  
 
2)  S u m mar y of pr o p orti o n of partici pa nts  w h o ac hi e ve H Bs A g < L L O Q a n d H B V 
D N A < L L O Q at e n d of treat me nt b y bas eli ne stratificati o n. 
3)  S u m mar y of p r o p orti o n of p artici pa nts  w h o ac hie ve d < 0. 5, ≥0. 5, ≥1, ≥1. 5, ≥3 
l o g 1 0 I U/ m L decli ne i n H Bs A g  o ver ti me b y bas eli ne stratificati o n . 
4)  S u m mar y of p r o p orti o n of partici pa nts  w h o ac hie ve d < 1, ≥1, ≥2, ≥3 l o g 1 0 I U/ m L 
decli ne i n H B V D N A  o v er ti me b y b aseli ne str atificati o n.  
5)  S u m mar y of act ual val ues a n d c ha n ge fr o m baseli ne o ver ti me o f H Bs A g 
(l o g 1 0 I U/ m L) a n d H B V D N A  (l o g 1 0 I U/ m L). 
6)  S u m mar y of act ual val ues a n d c ha n ge fr o m baseli ne o ver ti me of H Bs A g 
(l o g 1 0 I U/ m L) a n d H B V D N A (l o g 1 0 I U/ m L) b y ge n ot y p e.  
7)  S u m mar y of H Be anti b o d y ( anti -H Be A g) le vels o ver ti me i n H Be A g p ositi ve 
partici pa nts . 
8)  S u m mar y of H Be anti b o d y ( anti -H Be A g) le vels o ver ti me i n H Be A g p ositi ve 
partici pa nts  w h o  a c hie ve S V R . 
9)  S u m mar y of act ual val u es a n d c ha n ge fr o m baseli ne o ver ti me of H Bs a nti b o d y 
(a nti-H Bs A g) . 
1 0)  S u m mar y of H Bs a nti b o d y (a nti -H Bs A g) le v els  o ver ti me . 
1 1)  S u m mar y of H Bs a nti b o d y (a nti -H Bs A g) le vels o ver ti me i n p artici pa nts  w h o 
ac hie ve S V R . 
1 2)  Pr o p orti o n of partici pa nts  w h o ac hie ve d A L T n or malizati o n wit h Baseli ne A L T 
> U L N o ver ti me . 
1 3)  S u m mar y of pr o p orti o n of partici pa nts  w h o ac hie ve d H B V D N A T N D o ver ti me. 
1 4)  S u m mar y of c o nc or da nce of a n earl y v ir ol o gic res p o nse wit h ac hie vi n g S V R  at 
Pe gI F N  o n -treat me nt v isits W ee k 6, Wee k 1 3, Wee k 1 6, Wee k 2 0,  a n d Wee k 2 4 . 
1 5)  Ass ociati o n  bet wee n H B V D N A ‘Tar get N ot Detecte d ’ a n d rela pse i n partici pa nts  
w h o ac hie v e v ir ol o gi c res p o nse at en d of treat me nt. 
1 6)  S u m mar y of R O C anal ysis f or b aseli ne H Bs A g as a p re dict or of S V R  i n partici pa nts  
w h o reac he d e n d of off -tr eat me nt f oll o w-u p ( E o T + 2 4 w ks ) b y I A . 
1 7)  S u m mar y of b aseli ne ch aracteristics f or res p o n d ers a n d n o n -res p o n d ers . 
1 8)  S u m mar y of S V R  rat es f or v aria bles p ote ntiall y ass ociate d wit h res p o nse . 
1 9)  Statistical anal ysis of v aria bles ass ociat e d wit h S V R  s uccess - lo gistic re gressi o n –  
all ar ms. 
2 0)  Statistical anal ysis of v aria bles ass ociat e d wit h S V R  s uccess - lo gistic re gressi o n –  
Ar m 1 3 0 0 m g G S K 3 2 2 8 8 3 6 x 2 4 W + Pe gI F N x 2 4 W . 
2 1)  Statistical anal ysis of v aria bles ass ociat e d wit h S V R  s uccess - lo gistic re gressi o n –  
Ar m 2 3 0 0 m g G S K 3 2 2 8 8 3 6 x 1 2 W + Pe gI F N x 2 4 W . 
4. 7. 3.  
St ati sti c al A n al y s e s / M et h o d s  
A n esti mati o n a p pr oac h wit h n o h y p ot hesis testi n g will be use d t o a d dress t he pri mar y 
o bjecti ve  (see Secti o n 4. 7. 3. 1 ). T he a n al ysis will be c o n d ucte d s e paratel y f or eac h ar m.  
E n d p oi nts / varia bles s pecifie d i n Secti o n  4. 7. 1  a n d Secti o n 4. 7. 2  (e n d p oi nts 1-1 3)  will be 
s u m marise d usi n g des cri pti ve statistics, gra p hicall y prese nte d ( w h ere a p pr o priate), a n d 
liste d. 
E n d p oi nts 1 4 -2 1  will be  a nal ys e d as d escri be d i n Secti o n 4. 7. 8  as a p pr o pri ate.   


C O N FI D E N TI A L  
 
 
2 0 9 3 4 8  
X B U St ati sti c al A n al y si s Pl a n ( S A P)  T e m pl at e v 1. 0 2 4 M ar c h 2 0 2 1  
P a g e 5 2  of 7 7  
 
4. 7. 3. 1.  
M o d el S p e cifi c ati o n  a n d D e ci si o n Crit eri a  
Pre dicti ve pr o ba bilit y  of meeti n g S V R t hres h ol ds  ( 3 0 or 3 5 %)  will  be  prese nte d f or b ot h 
ar ms. 
F or t he p osteri or pr o ba bilit y of S V R rate , wit h c o m plete data, t he n u m ber of res p o n ders is 
ass u me d t o f oll o w a Bi n o mial distri b uti o n  
 
Y ~ Bi n o mial ( N, p)  
w here p is t he res p o nse rate, wit h a n o n -i nf or m ati ve pri or Beta  ( 0. 5, 0. 5), a n d t he p osteri or 
distri b uti o n f or p is  
P r o b( p| y, N) ~ Beta ( y + 0. 5, N –  y + 0. 5)  
At t he defi ne d ti me of i nt eri m, partici pa nts  will be at o ne of t w o sta ges i n ter ms of 
f oll o w-u p i n t he st u d y:  
1.  St a ge 1:  partici pa nts  eli gi ble f or e n d of off -treat me nt f oll o w-u p ( E o T + 2 4 w ks ) 
assess me nt at I A  (i n cl u di n g partici p a nts  w h o h a ve c o m plete d at least o ne visit 
wit hi n t heir E o T + 2 4 w ks  assess me nt  wi n d o w  a n d earl y ter mi nati o n partici pa nts  
w h o s h o ul d ha ve c o m plete d at least o n e visit wit hi n t heir  E o T + 2 4 w ks  assess me nt 
wi n d o w  b y t he ti me of t h e I A data c ut). 
•  T he V R s uccess/fail ure rate at t he e n d of treat me nt a n d S V R  s uccess/fail ure 
rate at t he e n d of 2 4-wee k off -tr eat me nt f oll o w-u p peri o d  ( E oT + 2 4 w ks ) will 
be k n o w n f or t hes e partici pa nts . 
•  Partici pa nts  w h o fail t o ac hie ve V R at e n d of treat me nt  or fail t o s ustai n a 
V R fr o m e n d of treat me nt  ( E o T) t o t he e n d of f oll o w-u p  ( E oT + 2 4 w ks ), will 
be classifie d as S V R  fail ures. 
•  Partici pa nts  ac hie vi n g S V R  at t he e n d of f oll o w -u p ( E oT + 2 4 w ks ) will be 
c o nsi dere d S V R  s uccesses. 
2.  St a ge 2:  Partici pa nts  n ot yet eli gi ble f or e n d of off-treat me nt f oll o w-u p 
( E o T + 2 4 w ks)  assess me nt, i.e., partici pa nts  bet w ee n e n d of tr eat me nt  ( E o T) a n d 
E o T + 2 4 w ks  b y t he ti me of I A data c ut.  
•  F or t hes e partici p a nts , t he V R s uccess/fail ure rate at t he e n d of treat me nt 
( E o T) a n d S V R  s uccess/fail ure rate t o t he p oi nt of I A dat a c ut will be 
k n o w n.  
•  Partici pa nts  w h o fail t o ac hie ve V R at e n d of tr eat me nt  ( E o T) or fail t o 
s ustai n a V R fr o m e n d of treat me nt  ( E o T) t o t he p oi nt of I A data c ut-off, 
will be  classifie d as S V R  fail ures. 
•  Partici pa nts  ac hie vi n g S V R  at t he ti me of I A data c ut will be c o nsi dere d as 
p ote ntial S V R  s uccesses. 
Partici pa nts  w h o wit h dra w pri or t o c o m pleti n g t h eir S V R  assess me nt  will be c o nsi dere d 
as fail ures.  T h e n u m ber of V R/ S V R  s uccesses f or partici pa nts  at t he t w o sta ges are 
s u m marise d i n Ta ble 9 . 


C O N FI D E N TI A L  
 
 
2 0 9 3 4 8  
X B U St ati sti c al A n al y si s Pl a n ( S A P)  T e m pl at e v 1. 0 2 4 M ar c h 2 0 2 1  
P a g e 5 3  of 7 7  
 
T a bl e 9  
Int eri m A n al y si s  St a g e s of F oll o w -U p  
 
St a ge 1: ( n.eli g) 
St a ge 2: ( n. neli g = N –  n.eli g)  
V R S uccess at E o T  
V R S uccess at E o T 
a n d S V R  at I A  
V R S uccess at E o T 
b ut n ot S V R  at I A  
V R  S u c c e s s e s 
nvr 1 
nvr 2 
nvr 3 
S V R  S u c c e s s e s 
n S V R 1  
n S V R 2  
0  
S V R  F ail ur e s (i n cl. 
V R r el a p s e  or l o st -
t o-f oll o w-u p)  
nvr 1 –  n S V R 1 
nvr 2 –  n S V R 2 
n vr3 
E o T = e n d of treat me nt;  I A = i nteri m a nal ysis; n.eli g = eli gi ble f or E oT + 2 4 w ks  assess me nt at 
I A; n. neli g = n ot eli gi ble f or E o T + 2 4 w ks  assess me nt at I A; n vr = n u m ber of vir ol o gic res p o nses;  
n S V R  = n u m ber of s ustai ne d vir ol o gic res p o nses. 
 
F or eac h ar m, t h e pre dicti ve pr o ba bilit y of m eeti n g t he e n d of off -treat me nt f oll o w-u p 
( E oT + 2 4 w ks ) s u ccess r ule is deter mi ne d fr o m 
•  n S V R 1 ( k n o w n) o ut of n vr 1, a n d  
•  t he p osteri or pre di cti ve distri b uti o n f or n S V R 2 o ut of n vr 2 + n vr 3.  
F or partici p a nts  eli gi ble f or e n d of off -tr eat me nt f oll o w-u p ( E o T + 2 4 w ks) assess me nt at I A 
, t he S V R  s uccess is ass u me d t o f oll o w a bi n o mial distri b uti o n 
Y  ~  Bi n o mial ( n vr 1, p)  
w here p is t he S V R  rat e, wit h a n o n-i nf or mati ve pri or Bet a ( 0. 5, 0. 5). If S V R  s uccess is 
o btai ne d, t he p osteri or distri b uti o n of p is  
P r o b( p|n S V R 1, n vr 1) ~ Beta ( n S V R 1 + 0. 5, n vr 1 –  n S V R 1 + 0. 5)  
F or Sta ge 2 p artici pa nts , t he pre dicte d n u m ber of S V R  s uccesses ca n be o btai ne d fr o m  
t he tr u ncate d Beta-Bi n o mial distri b uti o n  
n S V R 2 | n S V R 1,  n vr 1, n vr 2, n vr 3 ~ Beta -Bi n o mial  ( n vr 2 +  n vr 3,  
0. 5  +  n S V R 1,  
0. 5  +  n vr 1  - n S V R 1)  
w here  n vr 2 + n vr 3 is t he t o tal n u m ber of partici p a nts  w h o were V R s uccesses at E o T  b ut 
are i neli gi ble f or e n d of off-treat me nt f oll o w-u p assess me nt at I A . T he  ma xi m u m 
pre dicte d  n u m ber of S V R s uccesses ( n S V R 2 ) ma y n ot e xcee d t h e n u m ber of  pa rtici pa nts 
t hat ha ve t he p ote ntial t o  ac hie ve S V R . T h us, n S V R 2 m ust be  i n t he ra n ge [ 0, n vr 2]. 
 


C O N FI D E N TI A L  
 
 
2 0 9 3 4 8  
X B U St ati sti c al A n al y si s Pl a n ( S A P)  T e m pl at e v 1. 0 2 4 M ar c h 2 0 2 1  
P a g e 5 4  of 7 7  
 
T he pre di cti o n m o del f or t he “c o m plete data” n u m ber of S V R  s uccesses will acc o u nt f or 
the n u m ber of partici pa nts  w h o ha v e reac h e d e n d of treat me nt  ( E o T) b ut n ot  t he e n d of off -
treat me nt f oll o w-u p ( E o T + 2 4 w ks ) a n d ha v e faile d t o  eit her ac hie ve  V R  or s ustai n V R. F or 
t hese partici pa nts , it is i m p ossi ble f or t he m t o ac hie ve S V R  a n d m ust be acc o u nte d f or i n 
t he m o del. 
T he pre dict e d n u m ber of res p o n ders f or c o m plete data is n S V R 1 + n S V R 2, w here n S V R 2 
is o btai ne d fr o m t he tr u ncate d Beta-Bi n o mial ( n vr 2 + n vr 3, 0. 5 + n S V R 1, 0. 5 + n vr 1 − 
n S V R 1) distri b uti o n, wit h t he n u m ber of pre dicte d a d diti o nal S V R  e ve nts (n S V R 2) bei n g  
≤ t he n u m ber of partici pa nts wit h S V R  pe n di n g.  
4. 7. 3. 2.  
M o d el C h e c ki n g a n d Di a g n o sti c s  
N o m o del c hec ki n g is pla n ne d f or t he i nteri m a n al ysis.  
 
4. 7. 4.  
I nt er c urr e nt E v e nt s 
E n d p oi nts i n Secti o n  4. 7. 1  a n d Secti o n 4. 7. 2  will be s u m marize d  re gar dless of 
disc o nti n uati o n of, i nterr u pti o n i n,  or  n o n -a d here nce t o G S K 3 2 2 8 8 3 6 or Pe gI F N  treat me nt 
u n relate d t o wi de disr u pti ve e ve nts (treat me nt p olic y str ate g y). F or parti ci pa nts w here 
W D Es o n -treat me nt res ult i n disc o nti n uati o n of, si g nifica nt i nterr u pti o n of, a n d a d here n ce 
t o i n vesti gati o nal pr o d uct (I P), a n d t he partici p a nt wit h dra ws fr o m t he st u d y, data c ollecte d 
after t he i nterc urre nt e ve nt will be set t o missi n g a n d t heir S V R res p o ns e will be i m p ute d 
usi n g all a vaila ble data f or partici pa nt s f or w h o m S V R ca n be assesse d ( h y p ot hetic al 
strate g y). 
If t he p artici pa nts ta k e resc ue me dicati o n p ost-bas eli ne a n d b ef ore /at t he assess me nt of t he 
e n d p oi nts, t he partici pa nts will be c o nsi dere d as n o n -res p o n ders i n t he i nteri m a nal ysis 
(c o m p osite strate gy).   
Wi de disr u pti ve e ve nt i n cl u des C O VI D -1 9 pa n d e mic relate d visit s. T he i m pact will be  
ca pt ure d o n C O VI D -1 9 e C R F pa ge.  
F or p artici pa nts w h o ac hi e ve d V R at e n d of treat m e nt  ( E o T) a n d m ai ntai ne d it u ntil t he 
ti me of I A, b ut ha ve n ot r eac h e d e n d of f oll o w-u p ( E o T + 2 4 w ks ), d ata for f ut ure visits 
will n ot be classifie d as missi n g.  T hese partici pa nts  will be classifie d as  p ote ntial S V R  
res p o n ders.  
Ass u mi n g t hat n o resc ue me dicati o n was ta ke n , missi n g data at t he vari o us sta ges of t he 
st u d y f or e n d p oi nts descri be d  i n Secti o n 4. 7. 1  will be ha n dle d as d escri be d bel o w.  
4. 7. 4. 1.  
Mi s si n g Pri m ar y D at a at E n d of Tr e at m e nt   
E n d  of tr eat me nt  ( E o T) V R res p o nse will b e deter mi ne d usi n g t he e n d of tr eat me nt a n al ysis 
wi n d o w defi n e d i n Secti o n  4. 2. 2. 1 . If all H Bs A g a n d H B V D N A data wit hi n t he a n al ysis 
wi n d o w f o r t he e n d of treat me nt visit is missi n g a n d t he missi n g ness is n ot d ue t o wi de 
disr u pti ve e ve nts , n o i m p utati o n of missi n g data will be perf or me d,  a n d t he s u bject will be 
c o nsi dere d  as a n o n -res p o n der. 
If all H Bs A g a n d H B V D N A data wit hi n t he a n al ysis wi n do w f or t h e E O T visit is missi n g  
d ue t o a 
W D E, a n d t he partici pa nt wit h dra ws fr o m t he st u d y, t he partici pa nt will be 


C O N FI D E N TI A L  
 
 
2 0 9 3 4 8  
X B U St ati sti c al A n al y si s Pl a n ( S A P)  T e m pl at e v 1. 0 2 4 M ar c h 2 0 2 1  
P a g e 5 5  of 7 7  
 
classifie d as n ot reac hi n g E O T at f oll o w -u p.  Data after t he i nterc urre nt e ve nt will be set t o 
missi n g . 
If all H Bs A g a n d H B V D N A data wit hin t he a n al ysis wi n d o w f or t h e E O T visit is missi n g  
d ue t o a W D E, b ut t he partici pa nt later ret ur ns t o st u d y a n d ha s n o n -missi n g data i n a  l ater  
a nal ysis wi n d o w, t h e dat a will be ha n dle d i n t he f oll o wi n g t w o wa ys:  
1.  F or o bser ve d V R res p o n ders, t he data will be a nal ys e d as c ollect e d (treat me nt 
p olic y).  
2.  F or o bser ve d V R n o n -res p o n ders, data c ollecte d after t he i nterc urre nt e ve nt will be 
set t o missi n g. T he res p o nse will be i m p ute d ass u mi n g missi n g at ra n d o m usi n g all 
a vaila ble dat a fr o m p artici pa nts f or w h o m S V R ca n be assesse d ( h y p ot hetical 
strate g y).   
 
4. 7. 4. 2.  
Mi s si n g Pri m ar y D at a P o st  E n d of Tr e at m e nt  
If all H Bs A g a n d H B V D N A data wit hi n a n a nal ysis wi n d o w p ost t he pla n ne d e n d of 
se q ue ntial treat me nt ( E o T) a n d bef ore/ at t he assess me nt is missi n g  n ot d ue t o wi de 
disr u pti ve e ve nts , missi n g dat a will be c o nsi dere d as a n o n -res p o nse. 
If all H Bs A g a n d H B V D N A data wit hi n a n a nal ysis wi n d o w p ost t he pla n ne d e n d of 
se q ue ntial treat me nt ( E o T) a n d bef ore/at t he assess me nt is missi n g  d u e t o wi de disr u pti ve 
e ve nts (s uc h as C O VI D -1 9 pa n de mic) a n d t he p artici pa nt d oes n’t ha v e a n y H Bs A g ≥L L O Q 
or H B V D N A ≥L L O Q  or resc ue me di cati o n at or p ost pla n ne d e n d of se q u e ntial treat me nt 
( E o T), t he s u bject will be  classifie d as a p ote ntial S V R  res p o n der a n d will be c o u nte d 
a m o n g n u m ber of partici pa nts wit h V R s uccess at e n d of treat me nt  ( E o T) a n d mai ntai ne d 
u ntil I A ( n vr 2 i n Ta ble 9 ). 
If a partici pa nt  has a n y assess me nt s t hat are affecte d  b y a wi de disr u pti ve e ve nt, b ut t he 
partici pa nt’s H Bs A g a n d H B V D N A wit hi n a n a nal ysis wi n d o w are c ollecte d  a n d t he 
partici pa nt is a V R res p o n der, t he s u bject will be classifie d as a p ote ntial S V R res p o n der 
a n d will be c o u nte d a m o n g n u m b e r of partici pa nts wit h V R s uccess at e n d of tr eat me nt 
( E o T) a n d mai ntai n e d u ntil I A ( n vr 2 i n Ta ble 9 ). 
4. 7. 4. 3.  
Mi s si n g D at a  f or Ot h er E n d p oi nt s 
I n S ecti o n 4. 7. 2 , for t he pr o p orti o n of partici pa nts i n eac h tr eat me nt ar m w h o ac hi e ve 
H Bs A g < L L O Q a n d H B V D N A < L L O Q i n t he a bse nce of resc u e me dicati o n at t he e n d of 
treat me nt ( E o T), t he o ut c o me will be deter mi ne d usi n g t he e n d of treat me nt a nal ysis 
wi n d o w defi ne d i n Secti o n  4. 2. 2. 1 . I n li ne wit h t he pri mar y e n d p oi nt, missi n g d ata n ot d ue 
t o wi de disr u pti ve e ve nts will be i m p ute d as a n o n -res p o nse. Missi n g data d ue t o wi de 
disr u pti ve e ve nts will be a nal ys e d  as c ollecte d w it h o ut a n y i m p utati o n. 
Ot her e n d p oi nts will be s u m marize d re gar dless of c o m pleti n g I P, i nterr u pti o ns i n I P or 
a d here n ce t o I P a n d re gar dless of res c ue me di cati o n (e x ce pt f or A L T n or m alizati o n w hic h 
ca n o nl y be ac hie v e d i n t he a bse nce of resc u e m e dicati o n a n d pr o p orti o n of partici pa nts 
w h o ac hie ve H Bs A g < L L O Q a n d H B V D N A < L L O Q). Missi n g data f or t hese e n d p oi nts 
will b e a nal ys e d as c ollecte d  wit h o ut a n y i m p utati o n . Onl y a vaila bl e data will be 
s u m marize d. 


C O N FI D E N TI A L  
 
 
2 0 9 3 4 8  
X B U St ati sti c al A n al y si s Pl a n ( S A P)  T e m pl at e v 1. 0 2 4 M ar c h 2 0 2 1  
P a g e 5 6  of 7 7  
 
H B V D N A, H Bs A g, H Be A g le vels t hat are b el o w t he L L O Q wi ll be i m p ute d f or 
s u m maries of act ual val u es a n d c h a n ge fr o m baseli ne f oll o wi n g t he sa me r ul es as i n Secti o n 
4. 1. 1 . 
4. 7. 5.  
S u b gr o u p A n al y s e s  
Descri pti ve s u m mar ies b y baseli ne strata s u b gr o u ps defi ne d i n  Secti o n 4. 2. 2  will be 
pr o vi de d  as s pecifie d i n t he O P S . Pr o p orti o n of partici pa nts wit h H Bs A g < L L O Q a n d H B V 
D N A < L L O Q at e n d of tr eat me nt  will be pres e nte d b y s u b gr o u ps  d efi ne d i n  Secti o n  4. 6. 1 . 
N o statistical c o m paris o n  bet wee n s u b gr o u ps will be perf or me d.  
4. 7. 6.  
S e n siti vit y A n al y s e s  
T he a nal ysis usi n g t h e m o difie d defi niti o n of S V R , as detaile d i n S ecti o n 4. 7. 3. 1 , will be 
re peat e d at t he i nteri m a n al ysis. 
F or t he i nteri m a n al ysis, partici pa nts  w h o ha v e a v al ue of H Bs A g  L L O Q or H B V D N A 
 L L O Q at t he ir last visit, w hic h ca n n ot be c o nfir me d d ue t o n o f urt her f oll o w u p, will be 
treate d as res p o n ders/ p ote ntial res p o n ders as t he f oll o w-u p is i nc o m plete . 
4. 7. 7.  
S u p pl e m e nt ar y A n al y s e s  
I n a d diti o n t o t he mai n a nal ysis, a s u p ple me nt ar y a nal ysis will b e p erf or m e d t o  e val uate 
w het her t here is a n i m pact o n t he pri mar y o utc o me  if H B V D N A T N D  is o bser ve d. F or 
t his esti ma n d, t he o utc o me of S V R  is defi ne d as o bser vi n g H Bs A g < L L O Q a n d H B V D N A 
T N D at eac h a n al ysis wi n d o w f or 2 4 wee ks after t he pla n ne d e n d of treat me nt  ( E o T). All 
ot her ele me nts of t his esti ma n d are defi ne d i n t he sa me wa y as i n t he  m ai n a nal ysis.  
 
4. 7. 8.  
E x pl or at or y A n al y s e s  
4. 7. 8. 1.  
Effi c a c y A n al y s e s  
Refer t o Secti o n 4. 4. 1  f or details. 
 
4. 8.  
C h a n g e s t o Pr ot o c ol D efi n e d A n al y s e s  
C ha n ges fr o m t he ori gi nall y pla n ne d statistical a nal ysis s pecifie d i n t he pr ot oc ol are 
detaile d i n Ta ble 1 0  


C O N FI D E N TI A L  
 
 
2 0 9 3 4 8  
X B U St ati sti c al A n al y si s Pl a n ( S A P)  T e m pl at e v 1. 0 2 4 M ar c h 2 0 2 1  
P a g e 5 7  of 7 7  
 
T a bl e 1 0  
C h a n g e s t o Pr ot o c ol D efi n e d A n al y s e s  
Pr ot oc ol D efi ne d 
A n al ysis  
S A P Defi ne d A n al ysis  
R ati o n ale f or C h a n ges  
S ecti o n 3  
O bj ectives a nd 
Esti m a nds a nd w h er e 
a p plic a bl e t hr o u gh o ut  
U p d at e d t ext d efi ni n g t h e p opul ati o n f or 
t h e effic acy o bjectiv es alig n wit h t h e 
d efi niti o n of i nt ent -t o-tr e at (I T T) 
p o p ul ati o n w hic h will b e us e d in efficacy 
a n alys es a n d is d efi n e d as all r a n d o miz e d 
p articip a nts . 
T o ali gn wit h St u dy 2 0 96 6 8 
( B-Cl e ar).  
S ecti o n 3  
O bj ectives a nd 
Esti m a nds a nd 
S ecti o n  9. 4. 3. 1  
S ec o n d ary Esti m a n ds  
S ec o n d ary Efficacy E n d p oints:  
m ov e d H B e a nti bo dy ( anti -H Be A g) l ev els 
fr o m a c o nti nu o us v aria bl e to a 
c at e g oric al v aria bl e.  
C orr ecti o n.  
N A –  a d diti on  
S A P S ecti o n 4.2. 5. 1 : A dditi onal  esti m a nd 
t o assess effic acy usi n g a m odifi e d 
d efi niti o n of S V R  
R ati o n al e is bas e d o n B -cl e ar 
st u dy, i. e. th er e ar e p ossi ble 
s u bj ects with sin gl e l a b v al u es t h at 
ar e a b err a nt i n t er ms of t h e 
i n divi d u al’s ov er all tr aj ect ory of 
r es p o ns e. T h ere is s o me evi de nc e 
t h at t h e ab err a nt v al ues hav e 
occ urr ed b eca us e of a n 
u nr es olv a bl e err or at t h e sit e/la b. 
As t h e iss u es ca n n ot be r es olve d i n 
t h e d at a, t his a n alysis will b e us e d 
t o s u p port t h e pri m ary o bjective. 
S ecti o n 9. 5  I nt eri m 
A n alysis  
U n pl a n n e d i nt eri m a nalysis a dd e d  
S u p p ort of int er n al d ecisi o ns for 
pl atf or m tri al ( Stu dy 21 8 3 0 9)  


C O N FI D E N TI A L  
 
 
2 0 9 3 4 8  
X B U St ati sti c al A n al y si s Pl a n ( S A P)  T e m pl at e v 1. 0 2 4 M ar c h 2 0 2 1  
P a g e 5 8  of 7 7  
 
5.  
S A M P L E SI Z E D E T E R MI N A TI O N  
F or t he e ntire st u d y, a p pr o xi matel y 1 0 0 p artici pa nts will be e nr olle d a n d ra n d o mise d t o 
ac hie ve a p pr o xi matel y 5 0 partici pa nts i n eac h treat me nt gr o u p:  
•  2 4 wee ks treat me nt of G S K 3 2 2 8 8 3 6 f oll o we d b y u p t o 2 4 wee ks tr eat me nt of 
Pe gI F N  
•  1 2 wee ks treat me nt of G S K 3 2 2 8 8 3 6 f oll o we d b y u p  t o 2 4 wee ks tr eat me nt of 
Pe gI F N  
It is ass u me d t hat t he n u m ber of res p o n d ers f oll o ws a Bi n o mial distri b uti o n, wit h a wea kl y 
i nf or mati ve pri or ( Bet a ( 0. 5, 0. 5)) f or t he tr ue R R. T he precisi o n f or a ra n ge of R Rs wit h 
9 5 % cre di ble i nter vals are s h o w n i n Ta ble 1 1 . 
 
T a bl e 1 1  
9 5 % Cr e di bl e I nt er v al of R e s p o n s e R at e  
N u m ber of Res p o n ders  
Res p o nse R ate  
9 5 % Cre di ble I nter v al *  
9  
1 8 %  
9 % - 3 0 %  
1 0  
2 0 %  
1 1 % - 3 3 %  
1 1  
2 2 %  
1 2 % - 3 5 %  
1 2  
2 4 %  
1 4 % - 3 7 %  
1 3  
2 6 %  
1 5 % - 3 9 %  
1 4  
2 8 %  
1 7 % - 4 1 %  
1 5  
3 0 %  
1 9 % - 4 4 %  
1 6  
3 2 %  
2 0 % - 4 6 %  
1 7  
3 4 %  
2 2 %  - 4 8 %  
1 8  
3 6 %  
2 4 % - 5 0 %  
1 9  
3 8 %  
2 6 % - 5 2 %  
2 0  
4 0 %  
2 7 % - 5 4 %  
* 9 5 % e q ual -taile d i nter val 
 
T he hist orical R R of a c o m bi nati o n t hera p y of N A a n d Pe gI F N was 1 0 % wit h 4 8 wee k’s 
treat me nt [Re n , 2 0 1 9; Lee , 2 0 1 8]. T he  l o wer b o u n ds of 9 5 % cre di ble i nter vals will e x cl u de 
t he R R of 1 0 % if o bser ve d R R is greater t ha n or e q ual t o 2 0 % ( 1 0 res p o n ders o ut of 5 0 
partici pa nts) i n a n ar m.  
T he p osteri or pr o ba bilities t hat t he tr ue s ustai ne d vir ol o gic R R is greater t ha n a ra n ge of 
R Rs will be calc ulate d fr o m t he i m plie d Beta p osteri or, gi ve n t he act ual n u m ber of  
res p o n ders o bs er ve d. 
T he o perati n g c h aracteristics base d o n at least 6 5 % p osteri or c o nfi d e nce t hat t he tr u e rate 
e x cee ds a t hres h ol d of i nterest, are s h o w n i n  Ta ble 1 2  f or v ari o us sa m pl e siz es a n d tr ue 


C O N FI D E N TI A L  
 
 
2 0 9 3 4 8  
X B U St ati sti c al A n al y si s Pl a n ( S A P)  T e m pl at e v 1. 0 2 4 M ar c h 2 0 2 1  
P a g e 5 9  of 7 7  
 
c ure rates. T he o perati n g c haracteristics s h o w n are base d o n a Ba yesia n i nfere nce wit h o ut 
c o nsi derati o n of bas eli ne stratificati o n fact ors . 
 
T a bl e 1 2  
E n d of st u d y ( E o T + 2 4 w k s ) O p er ati n g C h ar a ct eri sti c s b y S a m pl e Si z e  
Criteri o n  
S a m ple 
Size per 
Ar m  
Mi ni m u m 
N u m ber 
( %) or 
Res p o n ders 
Re q uire d 
t o Meet 
Criteri o n  
Pr o b a bilit y of Meeti n g Criteri o n u n der 
V ari o us Ass u m pti o ns  
Tr ue 
S V R  rate 
= 2 0 %  
Tr ue 
S V R  r ate 
= 3 0 %  
Tr ue 
S V R  r ate 
= 3 5 %  
Tr ue 
S V R  r ate 
= 4 0 %  
Pr o b a bility 
(tr u e 
r es p o ns e r at e 
> 2 0 %) > 
6 5 %  
3 0  
7 ( 2 3 %) 
3 9 %  
8 4 %  
9 4 %  
9 8 %  
4 0  
9 ( 2 3 %) 
4 1 %  
8 9 %  
9 7 %  
9 9 %  
5 0  
1 2 ( 2 4 %) 
2 9 %  
8 6 %  
9 7 %  
9 9 %  
6 0  
1 4 ( 2 3 %) 
3 1 %  
9 0 %  
9 8 %  
1 0 0 %  
Pr o b a bility 
(tr u e 
r es p o ns e r at e 
> 3 0 %) > 
6 5 %  
3 0  
1 0 ( 3 3 %) 
6 %  
4 1 %  
6 4 %  
8 2 %  
4 0  
1 4 ( 3 5 %) 
2 %  
3 0 %  
5 6 %  
7 9 %  
5 0  
1 7 ( 3 4 %) 
1 %  
3 2 %  
6 1 %  
8 4 %  
6 0  
2 0 ( 3 3 %) 
1 %  
3 3 %  
6 5 %  
8 8 %  
Pr o b a bility 
(tr u e 
r es p o ns e r at e 
> 4 0 %) > 
6 5 %  
3 0  
1 4 ( 4 7 %) 
0 %  
4 %  
1 2 %  
2 9 %  
4 0  
1 8 ( 4 5 %) 
0 %  
3 %  
1 2 %  
3 1 %  
5 0  
2 2 ( 4 4 %) 
0 %  
3 %  
1 2 %  
3 3 %  
6 0  
2 6 ( 4 3 %) 
0 %  
2 %  
1 1 %  
3 4 %  
 
Base d o n t hese o perati n g c haracteristics, f or a tr u e R R of 3 0 %, t he pr o p os e d sa m ple siz e 
of n = 5 0 f or eac h ar m has ~ 8 6 % pr o ba bilit y of c o nfir mi n g a tr ue res p o nse of at least 2 0 %, 
a n d if t he tr ue rat e is 4 0 %, t here  is a n 8 4 % c ha nce of c o nfir mi n g a tr u e res p o nse of at least 
3 0 %. T here are n o pla ns f or sa m ple siz e re -esti mati o n.  
 
 


C O N FI D E N TI A L  
 
 
2 0 9 3 4 8  
X B U St ati sti c al A n al y si s Pl a n ( S A P)  T e m pl at e v 1. 0 2 4 M ar c h 2 0 2 1  
P a g e 6 0  of 7 7  
 
6.  
S U P P O R TI N G D O C U M E N T A TI O N  
6. 1.  
A p p e n di x 1 : St u d y P o p ul ati o n A n al y s e s  
U nless ot her wise s pecifi e d, t he st u d y p o p ulati o n a nal ys es will be base d o n t he E nr olle d 
A nal ysis Set. A s u m mar y of t he n u m ber a n d p erce nta ge of p artici pa nts i n eac h of t he 
partici pa nt le vel a nal ysis set will be pr o vi de d. Partici pa nts  e x cl u de d fr o m vari o us st u d y 
p o p ulati o ns will be prese nte d i n a listi n g.  
S u bject e nr ol me nt will be prese nt e d b y c o u ntr y a n d site I D.  
F or t he i nteri m a nal ysis, a ta ble s h o wi n g t he a m o u nt of pe n di n g data will be pr o d uce d f or 
partici pa nts wit h S V R  stat us u n k n o w n d ue t o t he m n ot ha vi n g reac he d t he en d of  off -
treat me nt f oll o w-u p ( E o T + 2 4 w ks ) at t he ti me of I A . Assess me nt of pe n di n g dat a s h o ul d 
be perf or me d bas e d o n o cc urre nce of e n d p oi nt a n al ysis wi n d o w visits.  
6. 1. 1.  
P arti ci p a nt Di s p o siti o n  
A s u m mar y of t he n u m ber of partici pa nts w h o were scree ne d i ncl u di n g n u m ber a n d 
perce nt a ge of scree n fail ures will be pr o vi de d. I n a d diti o n, reas o ns f or scree n fail ure will 
be prese nt e d.  
A s u m mar y of t he n u m ber a n d perce nta ge of partici pa nts w h o c o m plete d t he st u d y as well 
as t h ose w h o pre m at urel y wit h dr e w fr o m t he st u d y will be pr o vi d e d. Reas o ns f or st u d y 
disc o nti n uati o n will be s u m marize d.  
A s u m mar y of st u d y i nt er ve nti o n stat us will be pr o vi de d. T his dis pla y will s h o w t he 
n u m ber a n d p erce nta ge of partici pa nts 
w h o ha ve c o m plete d t he sc he d ule d st u d y 
i nter ve nti o n or ha ve dis c o nti n ue d st u d y i nter ve nti o n pre mat urel y, as well as pri mar y 
reas o ns f or disc o nti n uati o n of st u d y i nter ve nti o n. 
Reas o ns f or scree n fail ures, st u d y wit h dr a wal a n d st u d y treat me nt disc o nti n uati o n will als o 
be prese nt e d i n listi n gs.  
6. 1. 2.  
D e m o gr a p hi c a n d B a s eli n e C h ar a ct eri sti c s  
U nless ot her wise state d, st u d y p o p ulati o n a na l ys es will be b ase d o n t he E nr olle d 
p o p ulati o n . 
St u d y p o p ul ati o n a nal yses i ncl u di n g a n al ys es of partici pa nt’s dis p ositi o n, pr ot oc ol 
de viati o ns, de m o gra p hic a n d baseli ne c h aracteristi cs, pri or a n d c o n c o mita nt me dicati o ns, 
n ucle os(t)i de  tr eat me nt o n g oi n g at  ra n d o mizati o n, 
me dical hist or y a n d e x p os ure a n d 
treat me nt c o m plia nce will be prese nte d. 
D e m o gra p hic c haracteristics i ncl u di n g se x, a ge, et h nicit y, race, hei g ht, wei g ht will be 
s u m marize d wit h descri pti ve statistics.  
Baseli ne c h aracteristics i ncl u di n g B o d y Mass I n de x ( B MI ), h y p erte nsi o n, n o n -ster oi dal 
a nti-i nfla m mat or y dr u gs (N S AI D s), te n of o vir dis o pr o xil f u marate (T D F )/te n ofo vir  
alafe n a mi de ( T A F ) c o ntai ni n g 
me dicati o ns us e, A D V c o ntai ni n g 
me dicati o ns use , 
d ia betes, e G F R , ser u m creati ni ne , uri ne 
A C R, platelets, A N C , co m ple me nt 
C 3, 
co m ple me nt C 4 , co m ple me nt C 5a , co m ple me nt B b , C R P , M C P -1 , c-A N C A , p-A N C A , a n d 
s u b gr o u p cate g ories (liste d i n Secti o n 4. 6 ) will be s u m marize d wit h descri pti ve statistics.  


C O N FI D E N TI A L  
 
 
2 0 9 3 4 8  
X B U St ati sti c al A n al y si s Pl a n ( S A P)  T e m pl at e v 1. 0 2 4 M ar c h 2 0 2 1  
P a g e 6 1  of 7 7  
 
He patitis B c haract eristics, as c ollecte d o n t he He p atitis B Disease C haract eristics e C R F , 
will be s u m mariz e d usi n g des cri pti ve statistics a n d will be liste d.  
6. 1. 3.  
Pr ot o c ol D e vi ati o n s  
I m p ort a nt pr ot oc ol de viati o ns will be s u m marize d. 
Pr ot oc ol de viati o ns will be trac k e d b y t he st u d y t ea m t hr o u g h o ut t he c o n d uct of t he st u d y. 
T hese pr ot o c ol de viati o ns will be re vie we d t o i d e ntif y t h os e c o nsi d ere d as i m p orta nt as 
f oll o ws: 
•  Data will be re vie we d pri or t o u n bli n di n g a n d freezi n g t he data base t o e ns ure all 
i m p orta nt de viati o ns ( w here p ossi ble wit h o ut k n o wi n g t he st u d y i nter ve nti o n 
details) are ca pt ur e d a n d cate g orise d i n t he pr ot oc ol de viati o ns dataset.  
•  T his dataset will be t he b asis f or t he s u m maries of i m p orta nt pr ot oc ol de viati o ns.  
6. 1. 4.  
Pri or  a n d  C o n c o mit a nt M e di c ati o n s  
C o nc o mita nt me dicati o ns will be c o de d usi n g t he G S K Dr u g dicti o nar y . T he s u m mar y of 
c o nc o mita nt me dicati o ns will be pr o vi de d b y i n gre die nt, i.e., m ulti -i n gre die nt me dicati o ns 
will be s u m marize d f or eac h i n di vi d ual i n gre die nt rat her t ha n a c o m bi nati o n of i n gre die nts. 
T he s u m mar y will be create d usi n g i n gre die nt bas e na mes, i.e., i n gre die nts wit h t he s a me 
base n a me b ut differe nt s alt will a p pear u n der o ne base n a me i n t he s u m mar y. A nat o mical 
T hera p e utic C he mical ( A T C) classificati o ns will n ot a p pear i n t he s u m mar y.  
A pri or me dicati o n is defi ne d as a n y me dicati o ns t hat is e n de d pri or t o t he date of first d ose 
of st u d y dr u g.  
Me dicati o ns i nitiate d after t he first d ose of st u d y dr u g or i nitiate d pri or t o t he first d ose of 
st u d y dr u g a n d c o nti n ue d after t he first d ose of st u d y dr u g will be c o u nte d as c o nc o mita nt 
me dicati o ns. A me dicati o n t hat ca n n ot be deter mi ne d as pri or or c o nc o mita nt me dicati o n 
d ue t o partiall y or c o m pletel y missi n g start/st o p date will be c o u nt e d as b ot h pri or a n d 
c o nc o mita nt me dicati o n . 
6. 1. 5.  
St u d y I nt er v e nti o n C o m pli a n c e  
A s u m mar y of o verall c o m plia nce f or G S K 3 2 2 8 8 3 6  a n d Pe gI F N  base d o n t he e x p os ure 
data will be pr o d uce d.  O verall c o m plia nce will be s u m marize d usi n g descri pti ve statistics 
as well  as t he cate g ories < 8 0 %, 8 0 % -1 0 0 %, a n d > 1 0 0 %.   
C o m plia nce will be s u m mariz e d b ot h i n ter ms of n u m ber of i njecti o ns a d mi nistere d a n d 
t otal d ose recei ve d d uri n g t he pla n n e d o n -tr eat me nt peri o d. 
Perce nta ge of c o m plia n ce will be calc ulat e d as f oll o ws:  
St u dy i nterve nti o n C o m pli a nce ( %) = ( N u m ber of act u al d oses[ 1] / N u m ber of pl a n ne d 
d oses) * 1 0 0  
St u dy d ose C o m pli a nce ( %) = ( T ot al C u m ul ative Act u al D ose [ 2] / T ot al C u m ul ative 
Pl a n ne d D ose) * 1 0 0  


C O N FI D E N TI A L  
 
 
2 0 9 3 4 8  
X B U St ati sti c al A n al y si s Pl a n ( S A P)  T e m pl at e v 1. 0 2 4 M ar c h 2 0 2 1  
P a g e 6 2  of 7 7  
 
1)  G S K 3 2 2 8 8 3 6 : - T he pla n ne d n u m ber of d os es are 2 6 or 1 4 f or Ar m 1 & Ar m 2 
res pecti vel y. T h e Pla n ne d T otal C u m ulati ve D ose  is calc ulate d b y m ulti pl yi n g 
n u m ber of pla n ne d d os es  a n d d ose t hat is, 3 0 0 m g.  
Pl a n ne d T ot al C u m ul ative D ose = N u m ber of pl a n ne d d oses * 3 0 0 m g  
2)  Pe gI F N: - T h e pla n ne d n u m ber of d oses are 2 4 if s u bject be c o mes eli gi ble f or 
Pe gI F N Wee k 1. If s u bject bec o mes eli gi ble after Pe gI F N Wee k 1, t h e n f oll o w 
Pr ot oc ol ta ble 6 t o i de ntif y n u m ber of pla n ne d d os es –  
 
T he Pla n ne d T otal C u m ulati ve D ose  is calc ul ate d b y m ulti pl yi n g nu m ber of 
pla n ne d d oses  a n d d os e t hat is,  1 8 0 mc g.  
Pl a n ne d T ot al C u m ul ative D ose = N u m ber of pl a n ne d d oses * 1 8 0 m cg  
[ 1] : S u bject mi g ht recei v e re d uced  d ose t hat is s m aller t ha n t he n u m ber of i njecti o ns. 
Re d uce d d ose s h o ul d be still c o u nte d as ‘ o ne’ d ose f or N u m ber of act u al d oses  
calc ulati o ns.  
[ 2] : Refer t o S A P Secti o n 4. 5. 1  
6. 1. 6.  
A d diti o n al A n al y s e s D u e t o t h e C O VI D -1 9 P a n d e mi c  
A partici p a nt is defi ne d as ha vi n g a s us pecte d, pr o ba ble , or c o nfir me d C O VI D -1 9 i n fecti o n 
d uri n g t he st u d y if t he a ns wer is ’C o nfir me d‘, ’ Pr o ba ble ‘, or ’S us pect e d ‘ t o t he case 
dia g n osis q u esti o n fr o m t he C O VI D -1 9 c or o na vir us i nfecti o n assess me nt e C R F. N u m bers 
of partici pa nts wit h a s us pecte d, pr o ba ble , or c o nfir me d C O VI D -1 9 i nf ecti o n, a n d of 
C O VI D -1 9 test r es ults will be s u m marize d.  
If a hi g h pr o p orti o n ( > 5 % o verall) of partici pa nts h a ve a s us pecte d, pr o ba bl e , o r c o nfir me d 
C O VI D -1 9 i nfecti o n, t he f oll o wi n g data dis pla ys will be pr o d uce d:  
•  S u m mar y of curre nt (a n d/ or p ast) m e dical co n diti o ns f or p artici pa nts wit h C O VI D -
1 9 ad verse eve nts . 
•  S u m mar y of b aseli ne c haract eristics f or partici pa nts  wit h C O VI D -1 9 ad verse 
eve nts . 
 
 


C O N FI D E N TI A L  
 
 
2 0 9 3 4 8  
X B U St ati sti c al A n al y si s Pl a n ( S A P)  T e m pl at e v 1. 0 2 4 M ar c h 2 0 2 1  
P a g e 6 3  of 7 7  
 
6. 2.  
A p p e n di x 2 : D at a D eri v ati o n R ul e s  
6. 2. 1.  
Crit eri a f or P ot e nti al Cli ni c al I m p ort a n c e  
Gra di n g cat e g ories f or la b orat or y tests are deter mi ne d usi n g t he D AI D S gra di n g s yste m 
Versi o n 2. 1 [ Nati o nal I nstit ute of Aller g y a n d I nfecti o us Diseases.  Di visi o n of AI D S , 
2 0 1 7].  
N o La b orat or y tests val u es of p ote ntial cli nical i m p orta nce ( P CI) are defi ne d. La b orat or y 
val ues o utsi de of n or mal ra n ge will be s u m marize d a n d liste d.  
 
6. 2. 2.  
St u d y P h a s e a n d P eri o d  
Safet y a ssess me nts a n d e ve nts will be classifie d acc or di n g t o t he ti me of occ urr e nce 
relati ve t o t he st u d y i nter ve nti o n peri o d. 
T a bl e 1 3  
St u d y P h a s e D efi niti o n s  
St u d y I nter ve nti o n 
P h ase  
Defi niti o n  
Pr e -Tr e at m e nt  
F or Ass ess me nts –   
    D at e 1 ≤ St u dy Tr e at m e nt Start D at e  
 
F or Ev e nts –   
    D at e 1 < St u dy Tr eat m e nt Start D at e  
O n -Tr e at m e nt  
F or Ass ess me nts –   
     St u dy Tre at m ent St art Dat e < D at e 1 <  L ast Tr eat m e nt St op D at e  + 7  
d ays  
 
F or Ev e nts –   
    St u dy Tr eat m ent St art Dat e ≤ D at e 1 < L ast Tr e at m e nt St op D at e  + 7 
d ays  
P ost -Tr e at me nt  
D at e 1 ≥ L ast Tr e at me nt St o p  D at e  + 7 d ays  
1 Date is t he start date of t he assess me nt/e ve nt.  
 
T a bl e 1 4  
St u d y P eri o d D efi niti o n s  
St u d y I nt er v e nti o n Peri o d  
D efi niti o n  
G S K 3 2 2 8 8 36 Tr e at m e nt 
P eri o d  
F or Ass ess me nts –   
All A n alysis Ti me p oints wit hi n : W K 1 D A Y 1  t o a d ay prior P E GI F N 
E LI GI BI LI T Y W K 1 D A Y 1 * 
 
F or Ev e nts –   
    St u dy Tr eat m ent St art Dat e ≤ D at e 1 < G S K 8 3 6 L ast Tr e at m e nt D at e + 
7 d ays  
P e gI F N Eli gi bility  P eri od  
F or Ass ess me nts –   
All A n alysis Ti me p oints wit hi n :  
1) P E GI F N E LI GI BI LI T Y W K 1 D A Y 1 t o a d ay pri or P E GI F N D O SI N G 
W K 1 D A Y 1 * 
a n d   
2) P E GI F N A S S E S S M E N T W K 1 4 t o a d ay prior O T -W1 O T -D A Y 1 * 


C O N FI D E N TI A L  
 
 
2 0 9 3 4 8  
X B U St ati sti c al A n al y si s Pl a n ( S A P)  T e m pl at e v 1. 0 2 4 M ar c h 2 0 2 1  
P a g e 6 4  of 7 7  
 
St u d y I nt er v e nti o n Peri o d  
D efi niti o n  
 
F or Ev e nts –   
G S K 8 3 6 L ast Tr e at m e nt D ate + 7 d ays  ≤ D at e 1 <  P e gI F N  Tre at m e nt  
St art D at e  
*if s u bject wit hdr e w or n ev er rec eive d P e gI F N dosin g  b ef ore P e gI F N 
D osi n g Visit t he n e nd of p eri od w o ul d b e ‘ L ast P e gI F N Ass ess m ent 
W e ek St o p D ate  + 7  days’  
P e gI F N Tr e at m ent P eri o d  
F or Ass ess me nts –   
All A n alysis Ti me p oints wit hi n : P E GI F N D O SI N G W K 1 D A Y 1 t o a d ay 
pri or O T -W1 O T -D A Y 1 * 
 
F or Ev e nts –   
P e gI F N Tr e at m ent St art Dat e  ≤ D at e 1 <  P e gI F N Tr e at m e nt St o p  D at e + 
7  d ays  
F oll o w -u p P eri o d  
F or Ass ess me nts –   
All A n alysis Ti me p oints wit hi n : O T -W 1 O T -D A Y 1 * o n w ar ds   
 
F or Ev e nts –   
If s u bject nev er r ec eiv e d P e gI F N d osi n g a n d di d n ot disc o ntin u e o n -
tr e at m e nt -  D at e 1 ≥ L ast P e gI F N Ass ess m e nt W e ek Sto p Dat e + 7 
d ays  
Els e D at e 1 ≥ Last Tr eat m e nt St o p D at e + 7 days  
1 Date is t he start date of t he assess me nt/e ve nt . 
* If  a s u bj ect wit h drew  earl y or s ki p pe d peri o d(s) , c o nsi der start of ne xt peri o d a nal ysis 
ti me p oi nt. If a nal ysis ti me p oi nt is  n ot c ollecte d , use c orres p o n di n g pla n ne d  start visit da y  i n 
Secti o n 6. 2. 8 . 
 
6. 2. 3.  
St u d y D a y a n d R ef er e n c e D at e s  
T he st u d y refere nce date is t he st u d y treat me nt st art date a n d will be us e d t o calc ulate st u d y 
da y f or safet y a n d effic ac y me as ures.  
T he st u d y d a y is calc ulat e d as bel o w:  
•  Assess me nt Date = Missi n g             → St u d y Da y = Missi n g  
•  Assess me nt Date < Refere nce Date → St u d y Da y = Assess me nt Date –  Ref ere nce  
Date  
•  Assess me nt Date ≥ Refere nce Dat e → St u d y Da y = Assess me nt Date –  Ref ere nce  
Date + 1     
 


C O N FI D E N TI A L  
 
 
2 0 9 3 4 8  
X B U St ati sti c al A n al y si s Pl a n ( S A P)  T e m pl at e v 1. 0 2 4 M ar c h 2 0 2 1  
P a g e 6 5  of 7 7  
 
6. 2. 4.  
M ulti pl e M e a s ur e m e nt s at O n e A n al y si s Ti m e P oi nt  
T a bl e 1 5  
M ulti pl e M e a s ur e m e nt s at O n e A n al y si s Ti m e P oi nt  
Defi niti o n  
 
•  
Ha n dli n g of m ulti pl e m eas ur e m e nts withi n an a n alysis wi ndo w f or pri m ary e n dp oi nt is d escri b e d i n 
S ecti o n 4. 2. 2 
•  
Ass ess m e nts o n u nsc h e d ul e d visit will n ot b e i ncl u d e d i n t he t a bl es of s u m m ary statistics by visit b ut 
will b e i nclu d e d i n t h e associate d listi n gs. Als o, s uc h ass ess m e nts o n u nsc h ed ul e d visit will b e use d 
f or t h e “ a ny ti m e o n-tr eat m ent” or “ A ny visit p ost-b as eli n e” ti m e p oint.  
•  
If t h er e ar e m ulti pl e ass ess m ents o n sc h ed ul ed visit withi n visit wi n do w, will qu ery th e sit e to i d e ntify 
t h e v ali d ass essme nt as t h e ass ess m ent f or t he sch e d ul e d visit.  
•  
P artici pa nts havin g b oth Hi g h a n d L o w v al u es f or N or mal R an g es at a ny p ost -bas eli n e visit f or s af ety 
p ar a m et ers will b e c o u nt ed i n b ot h t h e Hig h a n d L o w c ate g ori es of “ A ny visit p ost -b as eli n e” r o w of 
r el at e d s u m m ary ta bl es.  
•  
If aft er wi n do w assi g n me nt of E arly T er mi n ati o n visits t h ere ar e m ulti pl e v ali d ass ess me nts of a 
p ar a m et er wit hi n t h e sa m e wi nd o w (s e e  S ecti o n  6. 2. 8 ), th e n th e f ollo wi n g hi er archy will b e us e d t o 
d et er min e t h e v al ue t o be us ed f or s u m m ary st atistics of o bserv e d val u es:  
o  t h e ass ess m e nt cl os est t o t h e wi n d o w t ar g et St udy D ay. 
o  if t h er e are m ulti ple ass ess m ents e q ui dist a nt fr o m t h e t ar g et St u dy D ay, th e n t he m e an 
of t h es e v alu es will b e us ed . 
•  
If n or m al L A B r a n g es ar e c oll ect e d a nd t h er e ar e d u plicat e L A B r ec or ds at t h e s a m e 
d at e/ti m e p oint, t h e t h e “ w orst -c as e” v al ue will b e s el ecte d. Sp ecific ally: 
o  F or L A B r es ult > L o w er Nor mal r a n g e, s el ect  Maxi m u m of L ab r es ult ( A V A L).  
o  F or L A B r es ult < = L o w er Nor mal r a n g e, s elect mi ni m u m of La b r es ult ( A V A L).  
 
 
 
6. 2. 5.  
St u d y P h a s e s f or C o n c o mit a nt M e di c ati o n  
Please refer t o Secti o n  6. 2. 9  f or ha n dli n g of missi n g a n d partial dates f or c o nc o mita nt 
me dicati o n. Use t he r ules i n t his ta ble if c o nc o mita nt me dicati o n date is c o m pletel y missi n g.  
T a bl e 1 6  
D efi nit i o n of Pri or a n d C o n c o mit a nt M e di c ati o n s 
St u d y P h ase  
Defi niti o n  
Pri or  
A pri or m e dic ati o n is d efi n e d as a ny m e dic atio n t h at h as e n de d pri or to 
t h e d at e of first d ose of st u dy dr u g. 
Co nc o mita nt  
M e dicati o ns i niti ate d aft er t h e first d os e of st u dy dr u g or i niti at e d pri or to 
t h e first d ose of stu dy dr u g a nd c o ntin u e d aft er t h e first d os e of st u dy 
dr u g will b e c ou nt e d as c o nc o mit a nt m e dic atio ns. A m e dic atio n c a n not 
b e d et er mi n e d as pri or or c o nco mit a nt m e dic ati o n d ue t o parti ally or 
c o m pl et ely missi n g start/sto p d at e will b e co u nt e d as bot h pri or a n d 
c o nc o mit ant m e dic ati o n. 
 
 


C O N FI D E N TI A L  
 
 
2 0 9 3 4 8  
X B U St ati sti c al A n al y si s Pl a n ( S A P)  T e m pl at e v 1. 0 2 4 M ar c h 2 0 2 1  
P a g e 6 6  of 7 7  
 
6. 2. 6.  
Tr e at m e nt E m er g e nt Fl a g f or A d v er s e E v e nt s  
If t he st u d y treat me nt st o p date is missi n g, t he n t he A E will be classifie d as o n -treat me nt. 
Ti me of st u d y tr eat me nt d osi n g a n d start/st o p ti me  of A Es s h o ul d be c o nsi dere d, if  
c ollecte d.  
T a bl e 1 7  
D efi niti o n of Tr e at m e nt E m er g e nt A d v er s e E v e nt s  
Fl a g  
Defi niti o n  
Tr e at m e nt E m er g e nt  
• 
St u dy Tr e at m e nt St art D at e ≤ A E St art D at e  
 
6. 2. 7.  
M E T A VI R  Fi br o si s S c or e  
T he M E T A VI R sc ore det er mi ne d fr o m t he Fi br osis sc ore  is pres e nte d i n ta ble bel o w.  
T a bl e 1 8  
M E T A VI R Fi br o si s S c or e  
Fi br osis Sc ore  
M E T A VI R  
C o m me nt  
≤0. 2 1 
St a g e F 0  
N o fi br osis  
> 0. 2 1 –  0.2 7 
F 0 -F 1  
  
> 0. 2 7 –  0.3 1 
F 1  
P ort al Fi br osis  
> 0. 3 1 –  0.4 8 
St a g e F 1  –  F2  
  
> 0. 4 8 –  0.5 8 
St a g e F 2  
Bri d gi n g fi br osis with f e w s epta 
> 0. 5 8 –  0.7 2 
St a g e F 3  
Bri d gi n g fi br osis  with  m a ny sept a  
> 0. 7 2 –  0.7 4 
St a g e F 3 –  F4  
  
> 0. 7 4  
St a g e F 4  
Cirr h osis  
htt ps:// w w w.l a bc or p.c o m/t ests/r el at e d -doc u me nts/L 9 4 6 5, access e d 1 1J an 2 0 2 2.  
 
6. 2. 8.  
A s s e s s m e nt Wi n d o w s f or E arl y T er mi n ati o n  
U nless ot her wise s pecifie d, n o wi n d o wi n g will be a p plie d t o u nsc he d ule d visits. Pla n ne d 
ti me relati ve t o d osi n g will be use d i n fi g ures, s u m maries, statistical a nal ys es,  a n d 
calc ulati o n of a n y d eri ve d para m eters, u nless ot her wise state d. U nsc he d ul e d visits will n ot 
be i ncl u de d i n s u m mar y ta bles a n d/ or fi g ures e x ce pt fr o m deter mi ni n g res p o nse f or 
pri mar y e n d p oi nt as descri be d i n Secti o n  4. 2. 2  a n d s u m maries o ver “a n y ti m e o n treat me nt” 
or “a n y visit p ost -baseli n e”. U nsc h e d ule d visits will be i ncl u de d i n listi n gs.  
 
 


C O N FI D E N TI A L  
 
 
2 0 9 3 4 8  
X B U St ati sti c al A n al y si s Pl a n ( S A P)  T e m pl at e v 1. 0 2 4 M ar c h 2 0 2 1  
P a g e 6 7  of 7 7  
 
La b orat or y a n d vital si g ns data c ollecte d at Earl y Te r mi nati o n Visits will be assi g ne d t o 
assess me nt wi n d o ws, acc or di n g t o t he act ual date.  
 
T a bl e 1 9  
E arl y T er mi n ati o n Vi sit Wi n d o wi n g  
A n al ysis 
Set / 
D o m ai n  
T ar get st u d y d a y  
A n al ysis Wi n d o w  
A n al ysis Ti me p oi nt  
St art d a y  
E n d d a y  
G S K3 2 2 8 8 3 6 Ar m 1 a n d Ar m 2  
L a b, Vit al 
Si g ns  
1  
1  
2  
W e ek 1 D ay 1  
 
4  
3  
6  
W e ek 1 D ay 4  
 
8  
7  
9  
W e ek 2 D ay 8  
 
1 1  
1 0  
1 2  
W e ek 2 D ay 1 1  
 
1 5  
1 3  
1 8  
W e ek 3 D ay 1 5  
 
2 2  
1 9  
2 5  
W e ek 4 D ay 2 2  
 
1 + 7*(x -1) 
1 + 7*(x -1) -3 
1 + 7*(x -1) + 3 
W e ek x D ay 1 + 7*(x -1) 
P e gI F N Ar m 1 D o si n g W e e ks*  
L a b 
Vit al Si g ns  
1 + 7*( 2 3 +y +z)  
1 + 7*( 2 3 +y +z) -3 
1 + 7*( 2 3 +y +z) + 3  
P e gI F N D osi n g We ek y 
D ay 1  
P e gI F N Ar m 2 D o si n g W e e ks*  
L a b 
Vit al Si g ns  
1 + 7*( 1 1 +y +z)  
1 + 7*( 1 1 +y +z) -3 
1 + 7*( 1 1 +y +z) + 3  
P e gI F N D osi n g We ek y 
D ay 1  
P e gI F N Ar m 1 Eli gi bilit y ( N o D o si n g) W e e k s ( u p t o 1 3)  
L a b 
Vit al Si g ns  
1 + 7*( 2 3 + u)  
1 + 7*( 2 3 + u) -3 
1 + 7*( 2 3 + u) + 3  
P e gI F N Eli gi bility W e ek 
u D ay 1  
P e gI F N Ar m 2 Eli gi bilit y ( N o D o si n g) W e e k s ( u p t o 1 3)  
L a b 
Vit al Si g ns  
1 + 7*( 1 1 + u)  
1 + 7*( 1 1 + u) -3 
1 + 7*( 1 1 + u) + 3  
P e gI F N Eli gi bility W e ek 
u D ay 1  


C O N FI D E N TI A L  
 
 
2 0 9 3 4 8  
X B U St ati sti c al A n al y si s Pl a n ( S A P)  T e m pl at e v 1. 0 2 4 M ar c h 2 0 2 1  
P a g e 6 8  of 7 7  
 
A n al ysis 
Set / 
D o m ai n  
T ar get st u d y d a y  
A n al ysis Wi n d o w  
A n al ysis Ti me p oi nt  
St art d a y  
E n d d a y  
P e gI F N Ar m 1 N o D o si n g As s e s s m e nt We e k s ( w e e k 1 4 o n w ar d s)  
L a b 
Vit al Si g ns  
1 + 7*( 2 3 +v)  
1 + 7*( 2 3 +v) -3 
1 + 7*( 2 3 +v) + 3  
P e gI F N As ess m e nt 
W e ek v  
P e gI F N Ar m 2 N o D o si n g As s e s s m e nt We e k s ( w e e k 1 4 o n w ar d s)  
L a b 
Vit al Si g ns  
1 + 7*( 1 1 +v)  
1 + 7*( 1 1 +v) -3 
1 + 7*( 1 1 +v) + 3  
P e gI F N Ass ess m ent 
W e ek v  
Off -Tre at m e nt W ee k ( O T W) F oll o w -u p Ar m 1  
L a b 
Vit al Si g ns  
3 3 7 
3 3 4 
3 4 0 
Off -Tr e at m e nt W eek 1  
 
3 4 4 
3 4 1 
3 4 7 
Off -Tr e at m e nt W eek 2  
 
3 5 8 
3 4 8 
3 7 2 
Off -Tr e at m e nt W eek 4  
 
3 8 6 
3 7 3 
4 0 0 
Off -Tr e at m e nt W eek 8  
 
4 1 4 
4 0 1 
4 3 5 
Off -Tr e at m e nt W eek 
1 2  
 
4 5 6 
4 3 6 
4 7 7 
Off -Tr e at m e nt W eek 
1 8  
 
4 9 8 
4 7 8 
5 1 8 
Off -Tr e at m e nt W eek 
2 4  
Off -Tre at m e nt W ee k ( O T W) F oll o w -u p Ar m 2  
L a b 
Vit al Si g ns  
2 5 3 
2 5 0 
2 5 6 
Off -Tr e at m e nt W eek 1  
 
2 6 0 
2 5 7 
2 6 3 
Off -Tr e at m e nt W eek 2  
 
2 7 4 
2 6 4 
2 8 8 
Off -Tr e at m e nt W eek 4  
 
3 0 2 
2 8 9 
3 1 6 
Off -Tr e at m e nt W eek 8  
 
3 3 0 
3 1 7 
3 5 1 
Off -Tr e at m e nt W eek 1 2  
 
3 7 2 
3 5 2 
3 9 3 
Off -Tr e at m e nt W eek 1 8  


C O N FI D E N TI A L  
 
 
2 0 9 3 4 8  
X B U St ati sti c al A n al y si s Pl a n ( S A P)  T e m pl at e v 1. 0 2 4 M ar c h 2 0 2 1  
P a g e 6 9  of 7 7  
 
A n al ysis 
Set / 
D o m ai n  
T ar get st u d y d a y  
A n al ysis Wi n d o w  
A n al ysis Ti me p oi nt  
St art d a y  
E n d d a y  
 
4 1 4 
3 9 4 
4 3 5 
Off -Tr e at m e nt W eek 2 4  
 
4 5 6 
4 3 6 
4 7 7 
Off -Tr e at m e nt W eek 3 0  
 
4 9 8 
4 7 8 
5 1 8 
Off -Tr e at m e nt W eek 3 6  
* O nl y if s u bject starte d Pe gI F N treat me nt.  
1.  Wee k x i ncl u des o n -treat me nt wee ks 5 –  2 4 f or treat me nt wit h G S K 3 2 2 8 8 3 6.  
2.  Wee k y i ncl u des o n -treat me nt wee ks 1 –  2 4 f or treat me nt wit h Pe gI F N.  
3.  Wee k u i ncl u des Pe gI F N Eli gi bilit y wee ks 1 –  1 3.  
4.  Wee k v i ncl u des Pe gI F N Eli gi bilit y wee ks 1 4 –  2 4.  
5.  z is t he t otal n u m ber of Pe gI F N i neli gi bilit y wee ks pri or t o Pe gI F N treat me nt. 
6.  Visit wi n d o ws are t o be use d f or wi n d o wi n g of Earl y Ter mi nati o n visits o nl y.  
 
6. 2. 9.  
H a n dli n g of Mi s si n g a n d P arti al D at e s  
T a bl e 2 0  
R ul e s f or H a n dli n g Mi s si n g a n d P arti al D at e s  
Ele me nt  
Re p orti n g Det ail  
G e n er al  
•  
P arti al d at es will b e displ aye d as c a pt ur e d i n p artici pa nt listing dis pl ays.   
•  
H o w ev er, w h er e n ec ess ary, dis pl ay m acr os m ay i m p ute d at es as t e m p or ary 
v ari a bl es for s orti n g d at a i n listi n gs only. I n a d diti on, p artial dat es may b e 
i m p ut ed f or ‘sl otti n g’ d at a to stu dy p h as es or f or s p ecific a n alysis p ur p os es as 
o utli n ed b elo w.  
•  
I m p ut e d p arti al d at es will n ot be us e d to d eriv e st u dy d ay, ti me t o o ns et or 
d ur ati o n (e. g., ti m e to o nset or d ur ati o n of a dv ers e ev ents), or el a pse d ti m e 
v aria bl es ( e. g., ti m e si nce di agn osis). I n a dditio n, i m p ut e d d at es ar e not use d 
f or d erivi n g t he l ast c ont act d at e i n ov er all s urviv al a n alysis dat as et. 
A dv ers e Ev e nts  
•  
P arti al d at es f or A E r ec or de d in t h e C R F will be i mp ut e d usi ng t h e f oll o wi n g 
c o nv enti o ns: 
Missi n g st art day  
•  
If st u dy i nt erv e nti o n st art d ate is missi n g (i.e., 
p articip a nt di d n ot st art st u dy int erv e nti o n), t he n set 
st art d ate = 1st of mo nt h. 
•  
Els e if st u dy i nterv e nti o n st art d at e is n ot missi n g:  
o  If m o nt h a n d y e ar of st art dat e = m o nt h a n d 
y e ar of st u dy i nt erv e nti o n st art d at e, t h en  
▪ 
If st o p dat e co nt ains a full d at e a n d 
st o p d ate is e arli er t h a n st u dy 
i nt erv enti o n st art dat e, t he n s et st art 
d at e = 1st of mo nt h.  
▪ 
Els e s et st art d at e = st u dy 
i nt erv enti o n st art dat e. 


C O N FI D E N TI A L  
 
 
2 0 9 3 4 8  
X B U St ati sti c al A n al y si s Pl a n ( S A P)  T e m pl at e v 1. 0 2 4 M ar c h 2 0 2 1  
P a g e 7 0  of 7 7  
 
Ele me nt  
Re p orti n g Det ail  
o  Els e s et st art d at e = 1st of m ont h.  
Missi n g st art day 
a n d m o nt h  
•  
If st u dy i nt erv e nti o n st art d ate is missi n g (i.e., 
p articip a nt di d n ot st art st u dy int erv e nti o n), t he n set 
st art d ate = J an u ary 1. 
•  
Els e if st u dy i nterv e nti o n st art d at e is n ot missi n g:  
o  If y e ar of st art d at e = y e ar of study 
i nt erv enti o n st art dat e, t he n 
▪ 
If st o p dat e co nt ains a full d at e a n d 
st o p d ate is e arli er t h a n st u dy 
i nt erv enti o n st art dat e, t he n s et st art 
d at e = Ja n u ary 1.  
▪ 
Els e s et st art d at e = st u dy 
i nt erv enti o n st art dat e. 
o  Els e s et st art d at e = J a n uary 1.  
Missi n g en d d ay  
A ' 2 8/ 2 9/ 3 0/ 3 1' will b e us e d for t h e d ay ( d e p e nd e nt on t h e 
m o nt h an d y ear).  
Missi n g en d d ay 
a n d m o nt h  
N o I m p ut ati o n . 
C o m pl et ely 
missi n g st art/ en d 
d at e 
N o i m p ut ati o n . 
 
 
 
Co nc o mita nt 
M e dicati o ns/ Me dical 
Hist ory  
•  
P arti al d at es f or a ny c o nc o mita nt m e dic ati o ns r ec or de d i n t he C R F will b e 
i m p ut ed usi n g t h e f ollo wi n g c onv e ntio n: 
 
Missi n g st art day  
•  
If st u dy i nt erv e nti o n st art d ate is missi n g 
(i. e., p articip a nt di d n ot st art stu dy 
i nt erv enti o n), t h e n s et st art d ate = 1st of 
m o nt h.  
•  
Els e if st u dy i nterv e nti o n st art d at e is n ot 
missi n g:  
o  If m o nt h a n d y e ar of st art dat e = 
m o nt h an d y ear of st u dy 
i nt erv enti o n st art dat e, t he n 
▪ 
If st o p dat e co nt ains a full 
d at e a n d st o p d at e is 
e arli er th a n stu dy 
i nt erv enti o n st art dat e, 
t h e n s et st art d at e = 1st of 
m o nt h . 


C O N FI D E N TI A L  
 
 
2 0 9 3 4 8  
X B U St ati sti c al A n al y si s Pl a n ( S A P)  T e m pl at e v 1. 0 2 4 M ar c h 2 0 2 1  
P a g e 7 1  of 7 7  
 
Ele me nt  
Re p orti n g Det ail  
▪ 
Els e s et st art d at e = st u dy 
i nt erv enti o n st art dat e. 
o  Els e s et st art d at e = 1st of m ont h.  
Missi n g st art day a nd 
m o nt h  
•  
If st u dy i nt erv e nti o n st art d ate is missi n g 
(i. e., p articip a nt di d n ot st art stu dy 
i nt erv enti o n), t h e n s et st art d ate = J a n uary 1. 
•  
Els e if st u dy i nterv e nti o n st art d at e is n ot 
missi n g:  
o  If y e ar of st art d at e = y e ar of stu dy 
i nt erv enti o n st art dat e, t he n 
▪ 
If st o p dat e co nt ains a full 
d at e a n d st o p d at e is 
e arli er th a n stu dy 
i nt erv enti o n st art dat e, 
t h e n s et st art d at e = 
J a n u ary 1. 
▪ 
Els e s et st art d at e = st u dy. 
i nt erv enti o n st art dat e. 
o  Els e s et st art d at e = J a n uary 1.  
Missi n g en d d ay  
A ' 2 8/ 2 9/ 3 0/ 3 1' will b e us e d for t h e d ay ( d e p e nd e nt on 
t h e m o nth a n d y e ar).  
Missi n g en d d ay a n d 
m o nt h  
A ' 3 1' will b e use d f or th e d ay a n d ' D ec' will b e us e d 
f or t h e mo nt h. 
C o m pl et ely missi n g 
st art/ e n d d at e 
N o i m p ut ati o n  
 
 
 
 


C O N FI D E N TI A L  
 
 
2 0 9 3 4 8  
X B U St ati sti c al A n al y si s Pl a n ( S A P)  T e m pl at e v 1. 0 2 4 M ar c h 2 0 2 1  
P a g e 7 2  of 7 7  
 
6. 3.  
A p p e n di x 3: A b br e vi ati o n s  
T a bl e 2 1  
Li st of A b br e vi ati o n s  
A b bre vi ati o n  
Descri pti o n  
A Da M  
A n alysis D at a M o d el  
A D R G  
A n alysis D at a R evi e w er’s G uid e  
A C R  
Al b u mi n t o cr eati ni n e r ati o 
A E  
A dv ers e ev e nt  
A E SI  
A dv ers e ev e nt of s pecial i nt erest  
AI C  
Ak aik e I nf or mati o n Crit eri a  
A L T  
Al a ni n e a mi notr a nsf er as e  
A N C  
A bs ol ut e n e utr op hil c o u nt  
A N C A  
A nti -n e utr o phil cyt opl as mic a nti b o dy  
A P RI  
As p art at e a mi notr a nsf er as e t o pl at elet  r atio i n d ex 
a P T T  
Activ ate d p arti al t hro m b opl astin ti m e  
A S T  
As p art at e a mi notr a nsf er as e  
A T C  
A n at o mic al T her a p e utic C h e mic al  
B b  
Fr a g m e nt of c o m pl e m e nt fact or B  
B DI -II 
B eck D e pr essio n I nv e nt ory -II 
B G R  
Br o oks -Gel ma n r atio  
B MI  
B o dy M ass I nd ex  
C2 P 3  
C o m mit t o P h as e 3  
C3  
C o m pl e me nt co m p o ne nt 3  
C4  
C o m pl e me nt co m p o ne nt 4  
C5 a  
C o m pl e me nt co m p o ne nt 5 a  
c-A N C A  
Cyt o pl as mic A N C A  
p -A N C A  
P eri n ucle ar A N C A  


C O N FI D E N TI A L  
 
 
2 0 9 3 4 8  
X B U St ati sti c al A n al y si s Pl a n ( S A P)  T e m pl at e v 1. 0 2 4 M ar c h 2 0 2 1  
P a g e 7 3  of 7 7  
 
A b bre vi ati o n  
Descri pti o n  
C DI S C  
Cli nic al D at a I nt erc h an g e St and ar ds C o ns orti u m  
C H B  
C hr o nic H e p atitis B  
CI  
C o nfi d e nc e  i nterv al 
C O VI D1 9  
C or o n avir us dis e as e 2 0 19  
C P M S  
Cli nic al P h ar mac ol o gy M o d ellin g a n d Si m ul ati o n  
Cτ  
C o nc e ntr ati o n at t h e e nd of t he d osin g i nterv al  
C S R  
Cli nic al St u dy R e p ort  
C -S V R R S  
C ol u m bi a -Suici d e S everity R ati n g Sc al e  
C V  
C o efficie nt of v ari ati o n  
% C V b 
C o efficie nt of v ari ati o n ( bet w ee n)  
D AI D S  
Divisio n o f Ac q uir ed I m m u n e D efici e ncy Sy n dr o m e  
D B P  
Di ast olic bl o o d pressur e  
D B R  
D at a b as e rel e as e  
D P  
D eci m al pl ac e  
D R B  
D ev el o p m e nt R evi e w B o ar d  
D R C  
D at a R evi e w C o m mitt ee  
E C G  
El ectr ocar di o gra m  
e C R F  
El ectr o nic  C ase R e p ort F or m  
e G F R 
Esti m ate d gl o m er ul ar filtr ati on r at e  
F D A  
F o o d a n d Dr ug A d ministrati o n  
F D A A A  
F o o d a n d Dr ug A d ministrati o n Cli nic al A m e nd m e nts Act  
E M A  
E ur o p e a n Me dici n es A g e ncy  
E o T  
E n d of s eq u e ntial tr eat m e nt of G S K 3 2 2 8 8 36 a n d P egi nt erf ero n  
E o T + 2 4 wks  
E n d of 2 4 w e eks of off -tr e at me nt f ollo w-u p aft er e n d of tr e at m e nt  
E o S  
E n d of st udy, i. e. fin al st u dy visit p er pr ot ocol  


C O N FI D E N TI A L  
 
 
2 0 9 3 4 8  
X B U St ati sti c al A n al y si s Pl a n ( S A P)  T e m pl at e v 1. 0 2 4 M ar c h 2 0 2 1  
P a g e 7 4  of 7 7  
 
A b bre vi ati o n  
Descri pti o n  
F P  
F als e positiv e  
G S K  
Gl axo S mit h Kli n e  
H Bcr Ag  
 
H e p atitis b c ore -r el ate d a nti g en 
A nti -H B e A g  
H e p atitis B vir us e -a nti b o dy  
H B e A g  
H e p atitis B vir us e -a nti g e n  
A nti -H Bs A g  
H e p atitis B vir us surf ac e a nti bo dy  
H Bs A g  
H e p atitis B vir us surf ac e a nti ge n  
H B V D N A  
H e p atitis B vir us d eoxyri b o n ucl eic aci d  
H B V R N A  
H e p atitis B vir us ri bo n ucl eic aci d  
HL T  
Hi g h l evel t er m  
hs -C R P  
Hi g h -s e nsitivity C-r e activ e protei n 
I A 
Pr e -s p ecifi e d Int eri m A n alysis 
I D M C 
I n d e p e n de nt D at a M o nitori n g C o m mitt ee 
I P 
I nv esti g atio n al pr o d uct 
I N R 
I nt er n atio n al n or m aliz ed r ati o 
I T T 
I nt e nt-t o-tr eat 
L L O Q  
L o w er li mit of Q u a ntific ati on  
M A R  
Missi n g at r a n d o m 
M C M C  
M ark ov C h ai n M o nt e C arl o  
M C P -1  
M o n ocyt e c h e m oattr act a nt pr ot ei n -1 
M e d D R A  
M e dical Dicti o n ary f or R e gul atory A ut h oriti es  
M M R M  
Mix e d M o del R e p e at e d Me as ur es  
N A  
N ucl e os(t)i d e an al og u e  
Ne g  
N e g ativ e  


C O N FI D E N TI A L  
 
 
2 0 9 3 4 8  
X B U St ati sti c al A n al y si s Pl a n ( S A P)  T e m pl at e v 1. 0 2 4 M ar c h 2 0 2 1  
P a g e 7 5  of 7 7  
 
A b bre vi ati o n  
Descri pti o n  
NI  
N o n -i nf eri ority 
N S AI D  
N o n -st er oi dal a nti -i nfl a m m at ory dr u g 
N U C  
N ucl e os(t)i d e  
N V R  
N u m b er of vir olo gic r es p ons es  
N S V R  
N u m b er of s ust ai n e d vir ol o gic r es p o ns es 
O Cs  
O p er atin g C h ar act eristics  
O P S  
O ut p ut a n d Pr o gr a m min g S p ecific ati o n  
P B M Cs  
P eri p h er al bl o od m o no n ucl e ar c ells  
P CI  
P ot e nti al Cli nic al I m p ort anc e  
P D  
P h ar m ac ody n a mic  
P e gI F N  
P e gyl at ed i nterf er o n  
P K  
P h ar m ac oki n etic  
P os  
P ositiv e  
P T  
Pr ef err e d t er m  
P T t est 
Pr ot hr o m bin ti me  
R B C  
R e d bl o o d c ells  
R O C  
R ec eiv er o p er ati n g c h ar act eristic  
R R  
R es p o nse r at e  
S A C  
St atistic al A nalysis Co m pl et e  
S A E  
S eri o us A dv ers e Ev e nt  
S B P  
Syst olic bl o o d pressur e  
S D  
St a n d ar d d evi ati o n  
S D T M  
St u dy D at a T ab ul ati o n M o d el  
S V R  
S ust ai n ed virol o gic r es p o ns e  
S M Q  
St a n d ar dis e d Me d D R A Q u ery  


C O N FI D E N TI A L  
 
 
2 0 9 3 4 8  
X B U St ati sti c al A n al y si s Pl a n ( S A P)  T e m pl at e v 1. 0 2 4 M ar c h 2 0 2 1  
P a g e 7 6  of 7 7  
 
A b bre vi ati o n  
Descri pti o n  
S o A  
Sc h e d ule of ass ess me nts  
S O C  
Syst e m Or g a n Cl ass  
t ½ 
T er mi n al h alf -lif e 
T A F  
T e n of ovir al afe n a mi d e  
T D F  
T e n of ovir dis o pr oxil fu m ar ate  
T N  
Tr u e n e g ativ e  
T N D  
T ar g et n ot d et ect e d  
T P  
Tr u e p ositiv e  
UL N  
U p p er li mit of nor m al  
V R  
Vir ol o gic r esp o nse  
 
6. 3. 1.  
Tr a d e m ar k s  
Tr a de m a r ks of t he 
Gl a x o S mit h Kli ne  Gr o u p of 
C o m p a nies  
 
Tr a de m a r ks n ot o w ne d b y t he 
Gl a x o S mit h Kli ne  Gr o u p of 
C o m p a nies  
N o ne  
 
Wi n N o nli n  
 
 


C O N FI D E N TI A L  
 
 
2 0 9 3 4 8  
X B U St ati sti c al A n al y si s Pl a n ( S A P)  T e m pl at e v 1. 0 2 4 M ar c h 2 0 2 1  
P a g e 7 7  of 7 7  
 
7.  
R E F E R E N C E S  
Br o o ks, S. P. a n d G el ma n, A. ( 1 9 9 8) Alter n ati ve Met h o ds f or M o nit ori n g C o n ver ge nce of 
Iterati ve Si m ulati o ns. J o ur nal of C o m p utati o nal a n d Gra p hical Statistics 7, 4 3 4 – 4 5 5.  
Hei nz e G, Sc he m per M. A s ol uti o n t o t he pr o ble m of se parati o n i n l o gistic re gressi o n. 
Statist. Me d. 2 0 0 2; 2 1: 2 4 0 9 – 2 4 1 9  
J o nes H E, O hlsse n DI, Ne ue nsc h wa n der B, Raci ne A, Bra ns o n M. Ba yesia n m o dels f or 
s u b gr o u p a nal ysis i n cli nical trials. Cli n Trial s. 2 0 1 1; 8: 1 2 9 – 1 4 3.  
Lee I C, Ya n g S V R, Lee CJ, S u C W, 
Wa n g YJ, La n K H, et al. 2 0 1 8. 'I n ci de nce a n d 
Pre dict ors of H Bs A g L oss After Pe gi nterfer o n T hera p y i n H Be A g -Ne gati ve C hr o nic 
He patitis B: A M ultice nt er, L o n g -ter m F oll o w-u p St u d y', J I nfect Dis , 2 0 1 8: 1 0 75 -8 4.  
Nati o nal I nstit ute of Aller g y a n d I nfecti o us Diseases.  Di visi o n of AI D S  ( D AI D S) T a ble 
f or Gra di n g t he Se verit y of A d ult a n d Pe diatric  A d verse E ve nts, Versi o n 2. 1, J U L Y 2 0 1 7.   
Re n H, H ua n g Y. 2 0 1 9. ' Effects of pe g ylate d i nterfer o n -al p ha bas e d t hera pie s o n f u ncti o nal 
c ure a n d t he ris k of he pat ocell ular carci n o ma de vel o p me nt i n patie nts wit h c hr o nic 
he patitis B', J Vir al He p at , 2 6 S u p pl 1: 5-3 1.  
Wic kli n, Ric k. ( 2 0 1 3). Si m ul ati n g D at a wit h S A S ® . Car y, N C: S A S I nstit ute I n c.