Conditions: Hepatitis B
Keywords: Chronic Hepatitis B GSK3228836 Hepatitis B virus surface antigen Nucleos(t)ide therapy Sustained virologic response
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 457
Healthy volunteers: no

Brief summary:
Chronic hepatitis B virus (HBV) infection is a significant worldwide medical problem. GSK3228836 demonstrated target engagement in CHB participants who were not on treatment and in CHB participants on stable nucleos(t)ide therapy. This study is intended to evaluate if treatment with GSK3228836 can achieve sustained virologic response (SVR), that is hepatitis B virus surface antigen (HBsAg) less than (\<) lower limit of quantitation (LLOQ) and HBV deoxyribonucleic acid (DNA) \<LLOQ sustained for 24 weeks post-GSK3228836 treatment end. In addition, the study will also evaluate the safety, tolerability, pharmacokinetic and pharmacodynamic properties of GSK3228836 in the 4 dosing regimens. This study will assess the efficacy and safety of treatment with GSK3228836 in two populations of participants with CHB; participants on stable nucleos(t)ide treatment (Cohort 1) and participants who are not currently on nucleos(t)ide therapy (Cohort 2). For each population, participants will be randomized into one of the 4 different parallel arms to receive treatment. The study will consist of a screening, treatment, and post-treatment follow-up phase. Approximately, 440 participants will be enrolled in the study.

Detailed description:

Arms:
arm 1: Eligible participants on stable nucleos(t)ide treatment will receive 300 milligrams (mg) GSK3228836 once weekly for 24 weeks along with loading dose (LD) of 300 mg GSK3228836 on Day 4 and Day 11. arm 2: Eligible participants on stable nucleos(t)ide treatment will receive 300 mg GSK3228836 once weekly for 12 weeks along with LD of 300 mg GSK3228836 on Day 4 and Day 11 followed by step-down in dose of 150 mg GSK3228836 once weekly for 12 weeks along with placebo to match to maintain participant blinding. arm 3: Eligible participants on stable nucleos(t)ide treatment will receive 300 mg GSK3228836 once weekly for 12 weeks along with LD of 300 mg GSK3228836 on Day 4 and Day 11 followed by placebo once weekly for 12 weeks. arm 4: Eligible participants on stable nucleos(t)ide treatment will receive placebo once weekly for 12 weeks followed by 300 mg GSK3228836 once weekly for 12 weeks along with placebo LD to match on Day 4 and Day 11. arm 5: Eligible participants not currently on nucleos(t)ide therapy will receive 300 mg GSK3228836 once weekly for 24 weeks along with LD of 300 mg GSK3228836 on Day 4 and Day 11. arm 6: Eligible participants not currently on nucleos(t)ide therapy will receive 300 mg GSK3228836 once weekly for 12 weeks along with LD of 300 mg GSK3228836 on Day 4 and Day 11 followed by step-down in dose of 150 mg GSK3228836 once weekly for 12 weeks along with placebo to match to maintain participant blinding. arm 7: Eligible participants not currently on nucleos(t)ide therapy will receive 300 mg GSK3228836 once weekly for 12 weeks along with LD of 300 mg GSK3228836 on Day 4 and Day 11 followed by placebo once weekly for 12 weeks. arm 8: Eligible participants not currently on nucleos(t)ide therapy will receive placebo once weekly for 12 weeks followed by 300 mg GSK3228836 once weekly for 12 weeks along with placebo LD to match on Day 4 and Day 11.

Interventions: intervention 1: GSK3228836 intervention 2: Placebo intervention 3: Nucleos(t)ide therapy
Intervention descriptions: intervention 1: GSK3228836 will be available as a clear colorless to slightly yellow solution for injection at a unit dose strength of 150 mg/mL to be administered subcutaneously once weekly. intervention 2: Placebo will be available as a clear colorless solution for injection to be administered subcutaneously once weekly. intervention 3: Participants receiving nucleos(t)ide therapy upon entry in the study will continue to receive nucleotide therapy for the duration of the study.

Protocol document:
Prot_000.pdf: 
 
 
 
 
Protocol 
 
Study ID:  209668 
 
Official Title of Study: Phase IIb Multi-Center, Randomised, Partial-Blind Parallel 
Cohort Study to Assess the Efficacy and Safety of Treatment with GSK3228836 in 
Participants with Chronic Hepatitis B Virus (B-Clear) 
 
IND Identifier: 122685 
 
EudraCT: 2020‐001083‐29 
 
 
Approval Date of Document: 23-SEP-2021 
 
 


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TITLE PAGE 
Protocol Title: Phase IIb Multi-Center, Randomised, Partial-Blind Parallel Cohort Study 
to Assess the Efficacy and Safety of Treatment with GSK3228836 in Participants with 
Chronic Hepatitis B Virus (B-Clear) 
Protocol Number: 209668 / Amendment 02 
Compound Number 
or Name: 
GSK3228836  
Study Phase: PHASE 2B  
Short Title: Phase 2b Study of GSK3228836 in Participants with Chronic Hepatitis B 
(B-Clear) 
Sponsor Name and Legal Registered Address:  
GlaxoSmithKline Research & Development Limited 
980 Great West Road 
Brentford 
Middlesex, TW8 9GS 
UK 
Regulatory Agency Identifying Number(s): 
IND: IND 122685 
EudraCT number: 2020‐001083‐29 
Approval Date: 23-Sep-2021 
 
 
 
 
 
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: Phase IIb Multi-Center, Randomised, Partial-Blind Parallel Cohort Study 
to Assess the Efficacy and Safety of Treatment with GSK3228836 in Participants with 
Chronic Hepatitis B Virus (B-Clear) 
Protocol Number: 209668 / Amendment 02 
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 02 
23-SEP-2021 
TMF-13956480 
Amendment 01 
10-MAY-2021 
TMF-11803132 
Original Protocol 
09-APR-2020 
2019N420582_00 
Amendment 02: 23-Sep-2021 
This amendment is considered to be 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. 
Overall Rationale for the Amendment:  
The primary driver for this amendment was a request from a regulatory agency to include 
nucleos(t)ide analogue (NA) therapy initiation until hepatitis B flare could be ruled out 
(specifically for the patients who are not receiving NA therapy at baseline). 
Text has also been included to allow additional interim analyses prior to the end of study 
(after all participants have completed treatment) to support asset development planning 
and decision making. 
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 6.5.1 
NA Treatment 
during and 
after the End of 
the Study; 
Section 7.1.1 
Liver 
Chemistry 
Monitoring and 
Stopping 
Criteria 
Table 6 
Added text:  
For participants who are not receiving NA therapy at 
baseline, initiate NA therapy if ALT ≥3x ULN and 
bilirubin >1.5x ULN, as per Section 7.1.1 (Liver 
Chemistry Monitoring and Stopping Criteria). NA therapy 
may be subsequently discontinued if other tests (e.g., 
HBV DNA, HBsAg) rule out hepatitis B flare.  
As per regulatory request in 
consideration of participant safety. 
Section 9.5 
Interim 
Analyses 
Added text: 
Additional interim analyses may be conducted after the 
third interim (at which time all participants will have 
completed treatment and sponsor staff [as specified in 
the blinding plan] will be unblinded), to support 
development planning and decision making. If 
conducted, these analyses will be unblinded to the 
sponsor staff (as specified in the blinding plan) and 
referenced in the clinical study report. 
To allow further review of the data 
prior to end of study (after all 
participants have completed 
treatment). 
 


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TABLE OF CONTENTS 
PAGE 
1. 
PROTOCOL SUMMARY .......................................................................................... 8 
1.1. 
Synopsis ....................................................................................................... 8 
1.2. 
Schema ...................................................................................................... 13 
1.3. 
Schedule of Activities (SoA) ........................................................................ 14 
2. 
INTRODUCTION .................................................................................................... 21 
2.1. 
Study Rationale .......................................................................................... 21 
2.2. 
Background ................................................................................................ 21 
2.3. 
Benefit/Risk Assessment ............................................................................ 23 
2.3.1. 
Risk Assessment ......................................................................... 23 
2.3.1.1. 
Regarding Coronavirus Disease 2019 (COVID-
19) .............................................................................. 26 
2.3.2. 
Benefit Assessment ..................................................................... 26 
2.3.3. 
Overall Benefit: Risk Conclusion .................................................. 26 
3. 
OBJECTIVES AND ENDPOINTS ........................................................................... 27 
4. 
STUDY DESIGN .................................................................................................... 31 
4.1. 
Overall Design ............................................................................................ 31 
4.2. 
Scientific Rationale for Study Design .......................................................... 31 
4.2.1. 
Rationale for Study Blinding ......................................................... 32 
4.2.2. 
Rationale for Placebo-First Arm ................................................... 33 
4.2.3. 
Participant Input into Design ........................................................ 33 
4.3. 
Justification for Dose .................................................................................. 34 
4.4. 
End of Study Definition ............................................................................... 36 
5. 
STUDY POPULATION ........................................................................................... 36 
5.1. 
Inclusion Criteria ......................................................................................... 36 
5.2. 
Exclusion Criteria ........................................................................................ 39 
5.3. 
Lifestyle Considerations .............................................................................. 41 
5.3.1. 
Alcohol and Tobacco ................................................................... 41 
5.3.2. 
Activity ......................................................................................... 41 
5.4. 
Screen Failures........................................................................................... 41 
5.5. 
Additional Participant Enrollment ................................................................ 42 
6. 
STUDY INTERVENTION ........................................................................................ 42 
6.1. 
Study Intervention(s) Administered ............................................................. 42 
6.2. 
Preparation/Handling/Storage/Accountability .............................................. 43 
6.3. 
Measures to Minimize Bias: Randomization and Blinding ........................... 43 
6.4. 
Study Intervention Compliance ................................................................... 44 
6.5. 
Concomitant Therapy.................................................................................. 44 
6.5.1. 
Nucleos(t)ide Treatment during and after the End of the 
Study ........................................................................................... 45 
6.5.2. 
Initiation of Nucleos(t)Ides During GSK3228836 Treatment ......... 45 
6.5.3. 
Initiation of Nucleos(t)ide Therapy Post GSK3228836 
Treatment .................................................................................... 46 
6.5.4. 
Prohibited Medications and Non-Drug Therapies ......................... 46 
6.6. 
Dose Modification ....................................................................................... 46 
6.7. 
Intervention after the End of the Study ........................................................ 46 


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7. 
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL ..................................................................... 47 
7.1. 
Discontinuation of Study Intervention .......................................................... 47 
7.1.1. 
Liver Chemistry Monitoring and Stopping Criteria ........................ 47 
7.1.2. 
Drug Induced Vascular Injury and Complement Stopping 
Criteria ......................................................................................... 50 
7.1.3. 
Haematological Stopping Criteria ................................................. 52 
7.1.4. 
Drug Induced Kidney Injury (Renal) Stopping Criteria .................. 52 
7.1.5. 
Study Intervention Restart or Rechallenge after stopping 
criteria met ................................................................................... 53 
7.2. 
Participant Discontinuation/Withdrawal from the Study ............................... 54 
7.3. 
Lost to Follow Up ........................................................................................ 55 
8. 
STUDY ASSESSMENTS AND PROCEDURES ..................................................... 55 
8.1. 
Efficacy Assessments ................................................................................. 56 
8.2. 
Safety Assessments ................................................................................... 57 
8.2.1. 
Physical Examinations ................................................................. 57 
8.2.2. 
Injection Site Reactions ............................................................... 57 
8.2.3. 
Vital Signs .................................................................................... 57 
8.2.4. 
Electrocardiograms ...................................................................... 58 
8.2.5. 
Clinical Safety Laboratory Assessments ...................................... 58 
8.3. 
Adverse Events and Serious Adverse Events ............................................. 58 
8.3.1. 
Time Period and Frequency for Collecting AE and SAE 
Information ................................................................................... 59 
8.3.2. 
Method of Detecting AEs and SAEs ............................................. 59 
8.3.3. 
Follow-up of AEs and SAEs ......................................................... 59 
8.3.4. 
Regulatory Reporting Requirements for SAEs ............................. 59 
8.3.5. 
Pregnancy ................................................................................... 60 
8.3.6. 
Cardiovascular and Death Events ................................................ 60 
8.3.7. 
Adverse Events of Special Interest .............................................. 61 
8.3.7.1. 
ALT Increases ............................................................ 61 
8.3.7.2. 
Vascular Inflammation and Complement 
Activation .................................................................... 61 
8.3.7.3. 
Thrombocytopenia ...................................................... 61 
8.3.7.4. 
Renal Injury ................................................................ 61 
8.3.7.5. 
Injection Site Reactions .............................................. 62 
8.4. 
Treatment of Overdose ............................................................................... 62 
8.5. 
Pharmacokinetics ....................................................................................... 62 
8.6. 
Pharmacodynamics .................................................................................... 63 
8.7. 
Genetics ..................................................................................................... 64 
8.8. 
Biomarkers ................................................................................................. 64 
8.9. 
HBV Resistance Monitoring ........................................................................ 65 
8.9.1. 
Resistance Analysis based upon HBV DNA Criteria .................... 65 
8.9.2. 
Resistance Analysis based upon HBsAg Criteria ......................... 65 
8.10. 
Patient Reported Outcomes (PROs) ........................................................... 66 
8.10.1. 
Hepatitis B Quality of Life (HBQOL) ............................................. 66 
8.10.2. 
EQ-5D-3L .................................................................................... 66 
8.11. 
Survey Questionnaires ................................................................................ 66 
9. 
STATISTICAL CONSIDERATIONS ........................................................................ 67 
9.1. 
Statistical Hypotheses................................................................................. 67 
9.2. 
Sample Size Determination ........................................................................ 67 


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9.3. 
Populations for Analyses ............................................................................ 69 
9.4. 
Statistical Analyses ..................................................................................... 69 
9.4.1. 
General Considerations ............................................................... 69 
9.4.2. 
Primary Endpoint(s) ..................................................................... 69 
9.4.2.1. 
Primary Estimands ..................................................... 70 
9.4.2.2. 
Supplementary Estimands .......................................... 71 
9.4.2.3. 
Handling of Withdrawal from Study and 
Missing HBsAg and HBV DNA Data ........................... 71 
9.4.3. 
Primary Analyses ......................................................................... 71 
9.4.4. 
Secondary Endpoint(s) ................................................................ 73 
9.4.4.1. 
Estimands for Secondary Objectives: ......................... 73 
9.4.4.2. 
Secondary Efficacy Analyses ..................................... 74 
9.4.4.3. 
Historical placebo: ...................................................... 75 
9.4.5. 
Safety Endpoints .......................................................................... 75 
9.4.6. 
Exploratory Objectives ................................................................. 76 
9.4.6.1. 
Estimand for Exploratory Objectives ........................... 76 
9.4.6.2. 
Participant Population Analyses ................................. 76 
9.4.6.3. 
PK and PK-PD Analyses ............................................ 77 
9.5. 
Interim Analyses ......................................................................................... 77 
9.6. 
Independent Data Monitoring Committee (IDMC) ....................................... 78 
9.7. 
Internal Safety Review Team (SRT) ............................................................ 78 
10. SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS ............................................................................................... 79 
10.1. 
Appendix 1: Regulatory, Ethical, and Study Oversight 
Considerations ............................................................................................ 79 
10.1.1. 
Regulatory and Ethical Considerations ........................................ 79 
10.1.2. 
Financial Disclosure ..................................................................... 79 
10.1.3. 
Informed Consent Process .......................................................... 80 
10.1.4. 
Data Protection ............................................................................ 80 
10.1.5. 
Committees Structure .................................................................. 81 
10.1.6. 
Dissemination of Clinical Study Data ........................................... 81 
10.1.7. 
Data Quality Assurance ............................................................... 82 
10.1.8. 
Source Documents ...................................................................... 83 
10.1.9. 
Study and Site Start and Closure ................................................. 83 
10.1.10. Publication Policy ......................................................................... 84 
10.2. 
Appendix 2: Clinical Laboratory Tests ......................................................... 85 
10.3. 
Appendix 3: Adverse Events: Definitions and Procedures for 
Recording, Evaluating, Follow-up, and Reporting ....................................... 89 
10.3.1. 
Definition of AE ............................................................................ 89 
10.3.2. 
Definition of SAE .......................................................................... 90 
10.3.3. 
Definition of Cardiovascular Events ............................................. 91 
10.3.4. 
Recording and Follow-Up of AE and SAE .................................... 91 
10.3.5. 
Division of AIDS (DAIDS) Table for Grading Severity of 
Adult and Pediatric Adverse Events ............................................. 92 
10.3.6. 
Reporting of SAE to GSK ............................................................. 93 
10.4. 
Appendix 4: Contraceptive Guidance and Collection of Pregnancy 
Information .................................................................................................. 95 
10.4.1. 
Definitions: ................................................................................... 95 
10.4.2. 
Contraception Guidance: ............................................................. 96 
10.4.3. 
Collection of Pregnancy Information: ........................................... 97 
10.5. 
Appendix 5: Genetics .................................................................................. 98 


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10.6. 
Appendix 6: Liver Safety: Required Actions and Follow-up 
Assessments and Study Intervention Restart/Rechallenge 
Guidelines ................................................................................................... 99 
10.7. 
Appendix 7: Country-specific requirements ............................................... 102 
10.7.1. 
China ......................................................................................... 102 
10.7.1.1. China Schedule of Activities ..................................... 102 
10.7.1.2. China Biomarkers and Archived Samples ................. 109 
10.8. 
Appendix 8: Abbreviations and Trademarks .............................................. 110 
10.9. 
Appendix 9: Protocol Amendment History ................................................. 112 
11. REFERENCES ..................................................................................................... 116 
 


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1. 
PROTOCOL SUMMARY 
1.1. 
Synopsis 
Protocol Title: Phase IIb Multi-Center, Randomised, Partial-Blind, Parallel Cohort Study 
to Assess the Efficacy and Safety of Treatment with GSK3228836 in Participants with 
Chronic Hepatitis B Virus (B-Clear) 
Short Title: Phase IIb study of GSK3228836 in Participants with Chronic Hepatitis B 
(B-Clear) 
Rationale: 
Study 209668 is intended to evaluate if treatment with GSK3228836 can achieve 
sustained virologic response (SVR, HBsAg <lower limit of quantitation [LLOQ] and 
HBV DNA <LLOQ sustained for 24 weeks post-GSK3228836 treatment end) with a 
finite course of GSK3228836.  In addition, the study will evaluate the safety, tolerability, 
pharmacokinetic and pharmacodynamic properties of GSK3228836 in the four dosing 
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Key Objectives and Estimand/Endpoints: 
Objectives 
Estimand/Endpoints 
Primary 
Efficacy: To assess the efficacy 
of the three dosing regimens of 
GSK3228836 in participants with 
CHB  
Primary estimands supporting the primary objective are defined as: 
- Population: separate assessment for the following: 
• 
participants with CHB on stable nucleos(t)ide therapy  
• 
participants with CHB not currently on nucleos(t)ide therapy 
- Variable: Participants achieving sustained virologic response (SVR, 
described in Section 9.4.2) for 24 weeks after the planned end of 
GSK3228836 treatment in the absence of rescue medication.  
- Treatments: arms 1, 2, and 3. Estimation of the within-arm response 
rate. 
- Intercurrent events: use of rescue medication, and discontinuation 
of/interruption of/adherence to IP. The use of rescue medication has 
been incorporated into the definition of variable (composite strategy). 
Discontinuation of, interruption of, and adherence to IP will be ignored 
(treatment policy). Wide disruptive events (such as COVID-19 
pandemic) leading to discontinuation of, interruption in, and non-
adherance to GSK3228836 will be handled assuming they had not 
happened (hypothetical strategy). 
- Population summary: proportion of participants who achieve SVR for 
each treatment arm. 
 
The primary estimands for each sub-population is  the proportion of 
participants in each treatment arm 1, 2, and 3 who achieve SVR for 24 
weeks after the planned end of GSK3228836 treatment in the absence 
of rescue medication regardless of completing IP, interruptions in IP or 
adherence to IP had they not been affected by wide disruptive events. 
A supplementary estimand is defined to support the primary objective: 
- the supplementary estimand is defined in the same way as the main 
estimand, except the assessment time frame for participants 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 nucloes(t)ide 
therapy and participants with CHB not currently on nucleos(t)ide therapy 
is the proportion of participants in each treatment arm 1, 2, and 3 who 
achieve SVR for 24 weeks after the actual end of GSK3228836 
treatment in the absence of rescue medication, regardless of 
completing IP, interruptions in IP or adherence to IP, had they not been 
affected by wide disruptive events. 


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Objectives 
Estimand/Endpoints 
Secondary 
Efficacy: To assess the efficacy 
of GSK3228836 on biomarkers 
and virus-specific antibody 
responses  
The estimands supporting this secondary objective are defined as 
follows: 
 
- Population: separate assessment for the following:  
• 
participants with CHB on stable nucleos(t)ide therapy  
• 
participants with CHB not currently on nucleos(t)ide therapy.  
- Treatments: arms 1-4. Estimation within each arm. 
- Intercurrent events: use of rescue medication, and discontinuation 
of/interruption of/adherence to IP. The use of rescue medication will be 
ignored (treatment policy strategy). Discontinuation of, interruption of, 
and adherence to IP will be ignored (treatment policy) 
 
1) Categorical Variables: 
- 
 Achieving HBsAg <LLOQ and HBV DNA <LLOQ at the end of 
treatment. 
- 
Categorical changes from baseline in HBsAg (e.g. <0.5, ≥0.5, ≥1, 
≥1.5, ≥3 log10 IU/mL) and in HBV DNA (e.g., <1, ≥1, ≥2, ≥3 log 
IU/mL) 
- 
ALT normalization (ALT≤ULN) over time in absence of rescue 
medication in participants with baseline ALT>ULN 
- 
HBe antibody (anti-HBeAg) levels 
- Population summary: proportion of participants in each category for 
each treatment arm. 
2)  Continuous Variables: Actual values and change from baseline 
over time of HBsAg and HBV DNA and actual values and change from 
baseline of HBeAg levels; HBs antibody (anti-HBsAg) levels 
- Population summary: mean values and mean changes from 
baseline for each variable in each treatment arm 
3) Time to Event Variable: Time to ALT normalization in absence of 
rescue medication in participants with baseline ALT>ULN 
- Population summary: Turnbull’s estimate for non-parametric 
estimation of time to ALT normalization in each treatment arm 
The group of estimands supporting this objective for each sub-
population is the population summary for each variable in each 
treatment arm 1-4 regardless of completing IP, interruptions in IP or 
adherence to IP and regardless of rescue medication (except for ALT 
normalization which can only be achieved in the absence of rescue 
medication) 
Efficacy: To compare the 
efficacy between 12 weeks, 12 
weeks + 12 weeks step-down, 
and 24 weeks of GSK3228836 
treatment 
The same definition as the primary estimand except treatments and 
population summary are defined as: 
-Treatments: arms 1, 2, and 3. Three treatment comparisons between: 
arms 1 & 2, arms 1 & 3, and arms 2 & 3 
- Population summary: difference in proportion of participants who 
achieve SVR between treatment arms 
 


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Objectives 
Estimand/Endpoints 
The group of estimands supporting this objective for each sub-
population are the difference in each treatment comparisons in the 
proportion of participants who achieve SVR for 24 weeks after the 
planned end of GSK3228836 treatment in the absence of rescue 
medication regardless of completing IP, interruptions in IP or adherence 
to IP had they not been affected by wide disruptive events. 
Pharmacokinetics (PK): To 
characterize GSK3228836 and 
nucleos(t)ide PK in participants 
with CHB 
• In a subset of participants with intensive PK sampling: Derived 
GSK3228836 and nucleos(t)ide plasma PK parameters including, 
but not limited to, area under the concentration-time curve (AUC), 
concentration at the end of the dosing interval (C), maximum 
observed concentration (Cmax), time of maximum observed 
concentration (tmax). 
• 
In all participants: C and terminal half-life (t½) of GSK3228836. 
Overall Design: 
The study is a Phase 2b, multi-center, randomized, partial-blind, parallel cohort study to 
assess the efficacy and safety of treatment with GSK3228836 in two populations of 
patients with CHB (1) participants on stable nucleos(t)ide treatment and (2) participants 
not currently on nucleos(t)ide therapy.  
For each population (participants on stable nucleos[t]ide therapy and participants not 
currently on nucleos(t)ide therapy), participants will be randomized into one of 4 parallel 
arms: 
• 300 mg GSK3228836 once/week for 24 weeks (plus loading doses on Day 4 and 
Day 11); 
• 300 mg GSK3228836 once/week for 12 weeks (plus loading doses on Day 4 and 
Day 11) followed by step-down in dose of 150 mg GSK3228836 once/week (plus 
placebo to match to maintain participant blinding) for 12 weeks; 
• 300 mg GSK3228836 once/week for 12 weeks (plus loading doses on Day 4 and 
Day 11) followed by placebo once/week for 12 weeks; 
• Placebo once/week for 12 weeks followed by 300 mg GSK3228836 once/week for 
12 weeks (plus placebo loading doses to match on Day 4 and Day 11, no loading dose 
for GSK3228836 treatment) 
 
Disclosure Statement:  
This is a parallel group treatment study with 8 arms that is sponsor and participant 
blinded. 
Number of Participants: 
The study will plan to enrol approximately 440 participants.  


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In the case of a disruptive event impacting study treatment dosing, participation, and/or 
withdrawal, the study team may enroll additional participants to within 10% of the 
planned 440. 
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.  
Intervention Groups and Duration: 
The total duration of the study, including screening, treatment, and post-treatment follow-
up, is not expected to exceed 55 weeks for each participant.  
• 45-day screening window. Eligible participants who fall out of the 45-day window 
may be re-screened at the discretion of the Investigator/site 
• 24 weeks treatment with either GSK3228836 and/or placebo 
• 24 weeks post treatment follow-up 
There are no plans for group dose adjustments.  Individual dose adjustments for safety 
are outlined in the monitoring/stopping criteria. 
Data Monitoring or Other Committee: Yes 


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1.2. 
Schema 


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1.3. 
Schedule of Activities (SoA) 
[China specific Schedule of Activities can be found in Appendix 7]. 
Table 1 
Screening 
ASSESSMENTS 
 
Informed Consent 
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 
12-lead ECG 
X 
LABORATORY 
Serum hCG pregnancy test (women of child-bearing potential) 
X 
FSH/Estradiol (to confirm status of women of non-child-bearing potential)1 
X 
Hematology/Chemistry/Urinalysis 
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 
ANCA2 
X 
Total bile acid profile (as available) 
X 
Complement C3, C4, C5a, hsCRP, MCP-1, complement Bb, Ang-2 
X 
1. 
As appropriate to confirm menopause 
2. 
With MPO-ANCA, PR3-ANCA if results are positive or border-line positive 
 


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Table 2 
On Treatment Day 1 to Day 50 
ASSESSMENTS1 
Day 1 
D4 
D8 
D11 
D15 
D22 
D29 
D36 
D43 
D50 
Window 
 
1 day 
3 days 
 
Week 1 
W1 
W2 
W2 
W3 
W4 
W5 
W6 
W7 
W8 
Randomization 
X 
 
 
 
 
 
 
 
 
 
Study treatment dosing 
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 
Concomitant medication review 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Symptom directed exam 
X 
 
 
 
 
 
X 
 
 
 
Vital signs 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Injection site reactions 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Questionnaire (cell phone app, optional) 
X 
 
 
 
 
 
 
 
 
 
Questionnaire (patient feedback on dosing regimen) 
X 
 
 
 
 
 
 
 
 
 
Patient Reported Outcomes Questionnaires: HBQOL, 
EQ-5D 
X 
 
 
 
 
 
 
 
 
 
Laboratory  
 
Pregnancy test (women of child bearing potential)2 
X2 
 
 
 
 
 
X 
 
 
 
Hematology3 [includes platelet count  and WBC] 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
PT, INR, aPTT 
X 
 
 
 
 
 
X 
 
 
 
Chemistry 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
Urinalysis 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
Urine ACR 
X 
 
 
 
X 
 
X 
 
X 
 
HBsAg and HBV DNA 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
Anti- HBsAg 
X 
 
 
 
 
 
X 
 
 
 
Anti-HBeAg 
X 
 
 
 
 
 
X 
 
 
 
HBeAg (only for participants HBeAg positive at 
screening) 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
HBV RNA, HBcrAg, and Sequencing (HBV 
Genotype/phenotype; HBV DNA and/or RNA) 
X 
 
 
 
 
X 
 
 
 
X 
Complement C3, Complement C4, hs-CRP, MCP-1 
X 
 
 
 
X 
 
X 
 
X 
 
Complement C5a, Complement factor Bb 
X 
 
 
 
X 
 
X 
 
X 
 
ANCA, Ang II 
X 
 
 
 
 
 
X 
 
 
 


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ASSESSMENTS1 
Day 1 
D4 
D8 
D11 
D15 
D22 
D29 
D36 
D43 
D50 
Window 
 
1 day 
3 days 
 
Week 1 
W1 
W2 
W2 
W3 
W4 
W5 
W6 
W7 
W8 
PK 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
PBMC Collection for immunophenotyping4 
X 
 
 
 
 
 
 
 
 
 
Soluble Protein (immunology) 
X 
 
 
 
 
X 
 
 
 
X 
PAXGene RNA for expression analysis in whole blood 
X 
 
 
 
X 
 
 
 
 
 
OPTIONAL: Genetics 
X 
 
 
 
 
 
 
 
 
 
Archived Samples [serum; plasma] 
X 
 
 
 
X 
 
X 
 
X 
 
1. 
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 SRM 
2. 
A WOCBP must have both: 
a. 
A confirmed menstrual period prior to the first dose of study intervention; additional evaluation (e.g., amenorrhea in athletes, birth control) should also be 
considered 
b. 
AND a negative highly sensitive pregnancy test [urine or serum] within 24 hours before the first dose of study treatment  
3. 
Hematology- platelet count to be analyzed at local laboratory prior to dose; hematology samples to be collected for central laboratory assessments in parallel 
4. 
Only for selected sites able to transport to the analysis lab as specified in the SRM. 
 


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Table 3 
On-Treatment: Day 57 to Day 162 
Assessments1 
D57 
D64 
D71 
D78 
D85 
D92 
D99 
D106 
D113 
D120 
D127 
D134 
D141 
D148 
D155 
D162 
Window 
 3 days 
 
W9 
W10 
W11 
W12 
W13 
W14 
W15 
W16 
W17 
W18 
W19 
W20 
W21 
W22 
W23 
W24 
Study treatment dosing 
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 
Concomitant medication review 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Symptom directed exam 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
Vital signs 
X 
X 
X 
X 
X 
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 
X 
X 
X 
X 
X 
Questionnaire (cell phone app, 
optional) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Questionnaire (patient feedback 
on dosing regimen) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Laboratory 
 
Pregnancy test (women of child 
bearing potential) 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
Hematology2 [includes platelet 
count and WBC] 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
PT, INR, aPTT 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
Chemistry 
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 
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 
X 
X 
X 
X 
X 
Anti- HBsAg  
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
Anti- HBeAg  
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
HBeAg (only for participants 
HBeAg positive at screening) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
HBV RNA, HBcrAg, and 
Sequencing (HBV 
Genotype/phenotype; HBV DNA 
and/or RNA) 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
Complement C3, Complement 
C4, hs-CRP, MCP-1 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 


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Assessments1 
D57 
D64 
D71 
D78 
D85 
D92 
D99 
D106 
D113 
D120 
D127 
D134 
D141 
D148 
D155 
D162 
Window 
 3 days 
 
W9 
W10 
W11 
W12 
W13 
W14 
W15 
W16 
W17 
W18 
W19 
W20 
W21 
W22 
W23 
W24 
Complement C5a, Complement 
factor Bb 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
ANCA, Ang II 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
PK3 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
PBMC Collection for 
immunophenotyping4 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
Soluble protein (immunology) 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
PAXGene RNA for expression 
analysis in whole blood 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Archived Samples [serum; 
plasma] 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
1. 
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 SRM 
2. 
Hematology- platelet count to be analyzed at local laboratory prior to dose; hematology samples to be collected for central laboratory assessments in parallel 
3. 
In addition to the pre-dose PK sample, intensive PK may be collected for China, Japan, and  country(ies) with participants of non-Asian heritage (TBD) see Table 8 for details 
of intensive PK sample collection 
a. 
 Intensive PK (GSK3228836 and nucleos[t]ide) will be collected at 1 visit between Week 14 (inclusive) and Week 24 (inclusive), selected between the site and participant: 
post dose at 0.5 hr, 1 hr, 1.5 hr, 2 hr, 3 hr, 4 hr, 5 hr, 6 hr, 8 hr, 12 hr, 24 hr, 72 hr, and 168 hr [the site should make all attempts to align the 168 hr post-dose PK with the 
next scheduled visit’s pre-dose PK, see Table 8 for more details] ] 
4. 
Only for selected sites able to transport to the analysis lab as specified in the SRM. 
 


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Table 4 
Off-Treatment Follow-Up  
Assessments1 
 
OT-Day 1 
OT-Day 8 
OT-Day 22 
OT-Day 50 
OT-Day 78 
OT-Day 106 
OT-Day 134 
OT-Day 162 
Early 
Termination 
Window 
 
3 Days 
10 Days 
 
 
 
OT- W1 
OT-W2 
OT-W4 
OT-W8 
OT-W12 
OT-W16 
OT-W20 
OT-W24 
 
Questionnaire 
 
 
Patient Reported Outcomes 
Questionnaire: HBQOL, EQ-5D 
 
 
 
 
 
 
 
X 
X 
Safety Assessments 
 
AE/SAE review 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant medication review 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Symptom directed exam 
X 
X 
 
X 
X 
X 
X 
X 
X 
Vital signs 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Laboratory 
 
Pregnancy test (women of child bearing 
potential) 
X 
 
X 
X 
X 
X 
X 
X 
X 
Hematology2 [includes platelet count 
and WBC] 
X 
X 
X 
X 
X 
X 
X 
X 
X 
PT, INR, aPTT 
X 
 
X 
 
X 
X 
X 
X 
X 
Chemistry 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Urinalysis 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Urine ACR 
X 
X 
X 
X 
X 
X 
X 
X 
X 
HBsAg and HBV DNA 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Anti- HBsAg 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Anti- HBeAg 
X 
X 
X 
X 
X 
X 
X 
X 
X 
HBeAg (only for participants HBeAg 
positive at screening) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
HBV RNA, HBcrAg, and Sequencing 
(HBV Genotype/phenotype; HBV DNA 
and/or RNA) 
X 
 
X 
 
X 
 
X 
X 
X 
Complement C3, Complement C4, hs-
CRP, MCP-1 
 
X 
X 
X 
X 
X 
X 
X 
X 


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Assessments1 
 
OT-Day 1 
OT-Day 8 
OT-Day 22 
OT-Day 50 
OT-Day 78 
OT-Day 106 
OT-Day 134 
OT-Day 162 
Early 
Termination 
Window 
 
3 Days 
10 Days 
 
 
 
OT- W1 
OT-W2 
OT-W4 
OT-W8 
OT-W12 
OT-W16 
OT-W20 
OT-W24 
 
Complement C5a, Complement factor 
Bb 
 
X 
X 
X 
X 
X 
X 
X 
X 
ANCA, Ang II 
X 
 
X 
X 
X 
X 
X 
X 
X 
PK 
X 
X 
X 
X 
X 
X 
X 
X 
X 
PBMC Collection for 
immunophenotyping3 
X 
 
 
 
X 
 
 
X 
X 
Soluble Protein (immunology) 
X 
 
X 
 
X 
 
X 
X 
X 
PAXGene RNA for expression analysis 
in whole blood 
X 
 
 
 
X 
 
 
X 
X 
APRI/Fibrosure 
 
 
 
 
 
 
 
X 
X 
Archived Samples [serum; plasma] 
X 
X 
X 
X 
X 
X 
X 
X 
X 
1. 
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 SRM. 
2. 
Hematology- platelet count analyzed at local laboratory is optional during the off-treatment period; hematology samples to be collected for central laboratory assessments 
(required; if local lab is being drawn, in parallel with local lab sample ). 
3. 
Only for selected sites able to transport to the analysis lab as specified in the SRM. 
 
OT: off-treatment; the first off-treatment visit occurs 7 days after the last study treatment dose received, whether planned or last dose given after participant is withdrawn from study 
treatment (e.g., the planned first off-treatment visit occurs on Day 169, 7 days after the Day 162 visit; if participant is withdrawn from study treatment on Day 50, the first off-treatment 
visit occurs on Day 57)


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2. 
INTRODUCTION 
2.1. 
Study Rationale 
This is a Phase 2b study examining multiple dose administration of GSK3228836 in 
participants with CHB. This study will evaluate the efficacy, safety, and PK profile of 
GSK3228836 and provide a first look at differences between efficacy and/or durability of 
HBsAg suppression when GSK3228836 is given as 24 weeks treatment at 300 mg 
GSK3228836 with loading doses, 12 weeks treatment at 300 mg GSK3228836 with 
loading doses followed by 12 weeks treatment at a step-down dose of 150 mg 
GSK3228836, 12 weeks treatment at 300 mg GSK3228836 with loading doses, and 
12 weeks placebo followed by 12 weeks treatment at 300 mg GSK3228836 without 
loading doses. 
Data from this study will provide an assessment of the safety, tolerability, 
pharmacokinetic and pharmacodynamic outcomes of the different dosing regimens and 
identification of the optimal treatment regimen(s), thus supporting subsequent clinical 
studies. 
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) [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 nucleoside or nucleotide (nucleos(t)ide) 
analogue (NA). 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. Treatment with a 
pegylated interferon (PEG-interferon), of which 2 are available, is also approved for CHB 
[Lok, 2009; EASL, 2012] for a defined treatment duration (usually up to 48 weeks). 
Because of their frequent and sometimes severe side effects and high cost versus a small 
gain in treatment response, PEG-interferons are less frequently used than NAs. 
Unfortunately, with both the NAs and PEG-interferon, HBsAg loss and the subsequent 
development of antibodies to HBsAg is rarely achieved. Rates of HBsAg loss following 


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12 months of treatment with either a NA or PEG-interferon generally range from 0 to 3% 
in most studies [Lok, 2009; EASL, 2012]. Loss of HBeAg occurs more frequently 
following treatment with either the NAs or PEG-interferon, approximately 15 to 30% 
after 1 to 2 years of therapy, but off treatment durability is variable and questions remain 
as to whether virologic responses can be maintained over an extended follow-up period. 
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 non-replication competent 
HBsAg (so called “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 covalently closed circular DNA or integrated 
HBV DNA. GSK3228836 directly targets all HBV mRNAs via Ribonuclease H (RNase 
H) mediated degradation, resulting in the reduction of viral proteins including HBsAg. 
GSK32288336 treatment permits examination of whether reduction of HBsAg allows 
resumption of a host immune response against HBV and infected cells and can induce 
HBsAg seroclearance. 
Recently, a functional cure of CHB infection has been endorsed as the endpoint for new 
HBV therapies. Functional cure of CHB infection is defined as sustained seroclearance 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].  


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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. The present study will 
investigate whether pharmacological suppression of HBV antigens up to 24 weeks of 
treatment by GSK3228836 will allow patients to achieve functional cure. 
2.3. 
Benefit/Risk Assessment 
More detailed information about the identified and potential benefits and risks and 
expected adverse events of GSK3228836 may be found in the Investigator’s Brochure. 
2.3.1. 
Risk Assessment 
Risks are summarized in Table 5.  Additional withdrawal/stopping criteria for liver 
chemistry monitoring, drug induced vascular injury (DIVI), hematology, renal function, 
and PK are discussed in Section 7.  Planned dose adjustments for individuals for safety 
are outlined in Section 6.6. 
 
 


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Table 5 
Summary of Potential Risks of Clinical Significance 
Potential Risk of Clinical Significance 
Summary of Data/Rationale for Risk 
Mitigation Strategy 
Investigational Product (IP) [e.g., GSK3228836] 
Nonclinical Risks:  
Drug Induced Vascular Inflammation and Complement 
Activation 
Inflammatory and immune changes are recognized as a 
class effect of antisense oligonucleotide (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 injury 
 
Stopping Criteria: Proposed Monitoring Schedule and 
Stopping Rules for Drug Induced Vascular Injury and 
Complement Activation (see Section 7.1.2) 
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. 
ALT elevations (defined as ALT ≥ 2X ULN) associated with 
HBsAg reductions were observed in 8 out of 18 treatment-
naïve participants in the ISIS 505358-CS3 study (150 mg 
GSK3228836, N=6; 300 mg GSK3228836, N=12).  Among 
the 8 participants with ALT flares, 6 achieved >1 log 
HBsAg reduction, another 2 had >0.5 log HBsAg reduction. 
Laboratory Evaluations: hepatic enzyme monitoring as 
presented in Table 6 
 
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 7.1.3 
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, eGFR, 
urinalysis with microscopy and ACR assessed per the SoA 
tables 
 
Stopping Criteria: Monitoring Schedule and Stopping 
Rules are presented in Section 7.1.4 
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 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 minimize 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. 
 
 


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2.3.1.1. 
Regarding Coronavirus Disease 2019 (COVID-19) 
In addition to the study related risks listed in Table 5, it should be noted that 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 virus strain 
(SARS-CoV-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 hospitalized 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. 
2.3.2. 
Benefit Assessment 
Treatment of CHB with nucleos(t)ide analogues 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 CHB 
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. 
2.3.3. 
Overall Benefit: Risk Conclusion 
Considering the measures taken to minimize risk to participants in this study, the 
potential risks identified in association with GSK3228836 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 ENDPOINTS 
Objectives 
Estimand/Endpoints 
Primary 
Efficacy: To assess the efficacy of the 
three dosing regimens of GSK3228836 
in participants with CHB  
Primary estimands supporting the primary objective are defined 
as: 
- Population: separate assessment for the following: 
• 
participants with CHB on stable nucleos(t)ide therapy  
• 
participants with CHB not currently on nucleos(t)ide 
therapy 
- Variable: Participants achieving sustained virologic response 
(SVR, described in Section 9.4.2) for 24 weeks after the planned 
end of GSK3228836 treatment in the absence of rescue 
medication.  
- Treatments: arms 1, 2, and 3. Estimation of the within-arm 
response rate. 
- Intercurrent events: use of rescue medication, and 
discontinuation of/interruption of/adherence to IP. The use of 
rescue medication has been incorporated into the definition of 
variable (composite strategy). Discontinuation of, interruption of, 
and adherence to IP will be ignored (treatment policy). Wide 
disruptive events (such as COVID-19 pandemic) leading to 
discontinuation of, interruption in, and non-adherance to 
GSK3228836 will be handled assuming they had not happened 
(hypothetical strategy). 
- Population summary: proportion of participants who achieve 
SVR for each treatment arm. 
 
The primary estimands for each sub-population is  the proportion 
of participants in each treatment arm 1, 2, and 3 who achieve 
SVR for 24 weeks after the planned end of GSK3228836 
treatment in the absence of rescue medication regardless of 
completing IP, interruptions in IP or adherence to IP had they not 
been affected by wide disruptive events. 
A supplementary estimand is defined to support the primary 
objective: 
- the supplementary estimand is defined in the same way as the 
main estimand, except the assessment time frame for 
participants 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 nucloes(t)ide therapy and 
participants with CHB not currently on nucleos(t)ide therapy is the 
proportion of participants in each treatment arm 1, 2, and 3 who 
achieve SVR for 24 weeks after the actual end of GSK3228836 
treatment in the absence of rescue medication, regardless of 
completing IP, interruptions in IP or adherence to IP, had they not 
been affected by wide disruptive events. 


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Objectives 
Estimand/Endpoints 
Secondary 
Efficacy: To assess the efficacy of 
GSK3228836 on biomarkers and virus-
specific antibody responses  
The estimands supporting this secondary objective are defined as 
follows: 
 
- Population: separate assessment for the following:  
• 
participants with CHB on stable nucleos(t)ide therapy  
• 
participants with CHB not currently on nucleos(t)ide 
therapy.  
- Treatments: arms 1-4. Estimation within each arm. 
- Intercurrent events: use of rescue medication, and 
discontinuation of/interruption of/adherence to IP. The use of 
rescue medication will be ignored (treatment policy strategy). 
Discontinuation of, interruption of, and adherence to IP will be 
ignored (treatment policy) 
 
2) Categorical Variables: 
- 
 Achieving HBsAg <LLOQ and HBV DNA <LLOQ at the end 
of treatment. 
- 
Categorical changes from baseline in HBsAg (e.g. <0.5, 
≥0.5, ≥1, ≥1.5, ≥3 log10 IU/mL) and in HBV DNA (e.g., <1, 
≥1, ≥2, ≥3 log IU/mL) 
- 
ALT normalization (ALT≤ULN) over time in absence of 
rescue medication in participants with baseline ALT>ULN 
- 
HBe antibody (anti-HBeAg) levels 
- Population summary: proportion of participants in each 
category for each treatment arm. 
2)  Continuous Variables: Actual values and change from 
baseline over time of HBsAg and HBV DNA and actual values 
and change from baseline of HBeAg levels; HBs antibody (anti-
HBsAg) levels 
- Population summary: mean values and mean changes from 
baseline for each variable in each treatment arm 
3) Time to Event Variable: Time to ALT normalization in 
absence of rescue medication in participants with baseline 
ALT>ULN 
- Population summary: Turnbull’s estimate for non-parametric 
estimation of time to ALT normalization in each treatment arm 
The group of estimands supporting this objective for each sub-
population is the population summary for each variable in each 
treatment arm 1-4 regardless of completing IP, interruptions in IP 
or adherence to IP and regardless of rescue medication (except 
for ALT normalization which can only be achieved in the 
absence of rescue medication) 


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Objectives 
Estimand/Endpoints 
Efficacy: To compare the efficacy 
between 12 weeks, 12 weeks + 12 
weeks step-down, and 24 weeks of 
GSK3228836 treatment 
The same definition as the primary estimand except treatments 
and population summary are defined as: 
-Treatments: arms 1, 2, and 3. Three treatment comparisons 
between: arms 1 & 2, arms 1 & 3, and arms 2 & 3 
- Population summary: difference in proportion of participants 
who achieve SVR between treatment arms 
 
The group of estimands supporting this objective for each sub-
population are the difference in each treatment comparisons in 
the proportion of participants who achieve SVR for 24 weeks after 
the planned end of GSK3228836 treatment in the absence of 
rescue medication regardless of completing IP, interruptions in IP 
or adherence to IP had they not been affected by wide disruptive 
events. 
Pharmacokinetics (PK): To 
characterize GSK3228836 and 
nucleos(t)ide PK in participants with 
CHB 
• In a subset of participants with intensive PK sampling: 
Derived GSK3228836 and nucleos(t)ide plasma PK 
parameters including, but not limited to, area under the 
concentration-time curve (AUC), concentration at the end of 
the dosing interval (C), maximum observed concentration 
(Cmax), time of maximum observed concentration (tmax). 
• 
In all participants: C and terminal half-life (t½) of 
GSK3228836. 
Safety 
Safety: To assess the safety and 
tolerability of GSK3228836 when dosed 
for 12 weeks, 12 weeks + 12 weeks 
step-down, and 24 weeks duration in 
participants with CHB 
Clinical assessments including, but not limited to vital signs, 
laboratory measurements and adverse events 
Exploratory 
PK-PD relationships: To evaluate PK-
efficacy relationship and PK-safety 
relationship 
Exploratory graphical analyses will be initially performed for 
efficacy (e.g., HBsAg) and safety endpoints. If a relationship 
between exposure and efficacy and/or safety endpoints is 
present, population PK-PD modelling will be conducted using 
nonlinear mixed effect methods.  
 
The model will assess the effect of various factors (covariates) of 
the modelled efficacy or safety endpoints. Relevant PK-PD model 
endpoints for example:  
• 
apparent clearance 
• 
apparent volume of distribution 
• 
IC50 
• 
random variability 
Efficacy: To compare the efficacy 
between 12 weeks of GSK3228836 
treatment with a loading dose or 
without a loading dose 
The same definition as the primary Estimand except treatments 
and population summary are defined as: 
- Treatments: arm 3 & 4. Treatment comparison between arms 
3&4.  
- Population summary: difference in proportion of participants 
who achieve SVR between treatment arms 3 & 4. 
 
The group of estimands supporting this objective for each sub-


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Objectives 
Estimand/Endpoints 
population are the differences between arms 3 & 4 in the 
proportion of participants who achieve SVR for 24 weeks after the 
planned end of GSK3228836 treatment in the absence of rescue 
medication regardless of completing IP, interruptions in IP or 
adherence to IP had they not been affected by wide disruptive 
events. 
Efficacy: To assess the 
pharmacodynamic effect of 
GSK3228836 on exploratory viral 
biomarkers  
HBV core related antigen (HBcrAg), HBV RNA 
Virology: To assess the effect of 
genotype/phenotype and presence of 
baseline polymorphisms within the 
GSK3228836 binding site to assess the 
effect on treatment response. 
To assess the emergence of mutations 
within the GSK binding site, and 
elsewhere in the hepatitis B genome, 
during and after treatment. 
Sequencing of the viral HBV DNA and/or HBV RNA prior to 
treatment, during treatment and post treatment visits 
Immunology:  To assess the effect of 
12 weeks, 12 weeks + 12 weeks step-
down or 24 weeks treatment with 
GSK3228836 on immunological 
biomarkers. 
To describe the relationship(s) between 
virology biomarkers, including but not 
limited to HBsAg, and immunological 
biomarkers.  
Laboratory measurements of and correlation between the 
following 
• 
Virological biomarkers, as determined by (but not limited 
to) specific viral parameters (HBeAg, HBV DNA, HBV 
RNA, HBcrAg). 
• 
Soluble immunological biomarkers, as determined by 
(but not limited to) levels of circulating cytokines and 
chemokines. 
• 
Markers of immune cell function, as measured by (but 
not limited to) 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  
Patient Reported Outcomes: To 
assess changes from baseline in 
patient reported outcomes following 12 
weeks, 12 weeks + 12 weeks step-
down, and 24 weeks of treatment with 
GSK3228836. 
Change from baseline of HBQOL and EQ-5D. 
 


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4. 
STUDY DESIGN 
4.1. 
Overall Design 
This is a Phase 2b, multi-center, randomized, partial-blind [Sponsor and Participant 
blinded], study to assess efficacy and safety of treatment with GSK3228836 in two 
populations of patients with CHB (1) participants on stable nucleos(t)ide treatment and 
(2) participants not currently on nucleos(t)ide therapy.  
Both populations of patients with CHB will be randomized into one of 4 parallel arms: 
• 300 mg GSK3228836 once/week for 24 weeks (plus loading dose of 300 mg 
GSK3228836 on Day 4 and Day 11); 
• 300 mg GSK3228836 once/week for 12 weeks (plus loading dose of 300 mg 
GSK3228836 on Day 4 and Day 11) followed by step-down in dose of 150 mg (plus 
placebo to match to maintain participant blinding) GSK3228836 once/week for 12 
weeks; 
• 300 mg GSK3228836 once/week for 12 weeks (plus loading dose of 300 mg 
GSK3228836 on Day 4 and Day 11) followed by placebo once/week for 12 weeks; 
• Placebo once/week for 12 weeks followed by 300 mg GSK3228836 once/week for 12 
weeks (plus placebo loading doses to match on Day 4 and Day 11, no loading dose 
for GSK3228836 treatment) 
After the 24 weeks of dosing with GSK3228836 or placebo, there will be a post-
treatment follow-up period of 24 weeks. 
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. 
The study is a partially blinded study where participants will be blinded to the study 
treatment.  The investigators, site staffs and pharmacist will be unblinded.  GSK and 
contract research organization (CRO) team members will be blinded to participants’ 
study treatment and any potentially unblinding information, unless specified otherwise in 
the study blinding management plan (e.g., unblinded site monitors). 
4.2. 
Scientific Rationale for Study Design 
In a previous clinical study (ISIS 505358-CS3), 7 of 12 (58%) of treatment-naïve 
participants dosed with 300 mg GSK3228836 over 4 weeks experienced a ≥0.5 log10 
reduction in HBsAg by Day 29.  Two treatment-naïve participants dosed with 300 mg 
GSK3228836 experienced HBsAg loss that persisted for 102 and 28 days, respectively, 
before the HBsAg became detectable again.   
In participants on stable nucleos(t)ide analogue therapy, 3 of 5 (60%) participants treated 
with 300 mg GSK3228836 achieved HBsAg reductions >3 log10 IU/mL.  Two of five 
participants (40%) treated with 300 mg GSK3228836 achieved HBsAg <LLOQ 
(0.05 IU/mL). One participant reached HBsAg levels <LLOQ on Day 23, but this was not 


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sustained.  HBsAg was detectable on the Day 85 and Day 113 visits.  One participant had 
HBsAg <LLOQ on Day 36 and remained <LLOQ as of the Day 85 visit.  
The proposed Phase 2b study (209668) will evaluate whether up to 24 weeks treatment 
with GSK3228836 results in a clinically meaningful rate of sustained virologic response 
(SVR, HBsAg <LLOQ and HBV DNA <LLOQ) with a finite course of GSK3228836.  
The study will evaluate the efficacy, safety, tolerability, pharmacokinetic and 
pharmacodynamic properties of GSK3228836 when dosed as part of four different dosing 
regimens. 
4.2.1. 
Rationale for Study Blinding 
A partial blind study (participant and sponsor blinded, site staff unblinded) was chosen 
because there is a high probability that the PI and site staff could infer treatment 
assignment due to: 
 
• Differences in the injection force due to the viscosity of GSK3228836 versus placebo 
saline. 
a. GSK3228836 is much more viscous than placebo saline and the 
administrating site staff may be able to infer treatment based on the 
differences in pressure exerted to administer the dose.  
• Color difference of GSK3228836 versus placebo 
• 
Syringes will be wrapped in a colored transparent tape to prevent 
unblinding of the participant. 
• Laboratory results (e.g., platelets, ALT, HBV DNA and HBsAg) needed in the course 
of participant treatment and/or safety management  
a. Platelet decreases and thrombocytopenia have been reported with ASOs. 
In this study thrombocytopenia is an AE of special interest. For safety 
management of the participants, the platelet counts cannot be blinded. 
b. ALT increases are expected to be seen during the course of treatment with 
GSK3228836. In the previous ISIS 505358-CS3 study, where participants 
received up to 4 weeks of 300 mg GSK3228836 treatment, 33% of 
treatment-naïve participants had increase in ALT ≥3x ULN, not associated 
with other chemistry changes (e.g., bilirubin, INR). In order for the 
investigator to better ascertain the etiology of an ALT increase (e.g., drug-
induced liver injury vs therapeutic flare vs nucleos(t)ide treatment failure 
ALT increase), virology data are required. 
c. HBV DNA results are needed to evaluate whether to initiate nucleos(t)ide 
treatment in the event of a sub-optimal response or virological failure in 
response to GSK3228836. Initiation of nucleos(t)ides should reduce the 
risk of development of resistance to GSK3228836. 
Participants will be kept blinded to decrease reporting bias and to decrease risk of missed 
visits during the placebo part of the study.  The Sponsor will remain blinded to minimize 
bias (unless specified otherwise in the study blinding management plan (e.g., unblinded 
site monitors).  The primary endpoint assessments (HBsAg, HBV DNA) are objective 


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laboratory measurements and therefore the unblinding of the site staff will not 
compromise the assessment of the primary endpoint of the study. 
4.2.2. 
Rationale for Placebo-First Arm 
Inflammatory and immune changes are recognized as a class effect of ASOs. Vasculitis 
and/or perivascular inflammation has been described in pre-clinical monkey studies with 
many ASOs, including pre-clinical monkey studies with GSK3228836. However, this 
effect has not been observed in clinical studies with GSK3228836 to date. 
As part of the safety monitoring, inclusion of biomarker panels to look for inflammatory 
and immune activation that would be expected to accompany vascular injury have been 
included. The biomarkers being utilized to monitor for inflammatory and immune 
activation (e.g., complement factors C3, C4, C5a, Bb; ANCA; MCP-1) are exploratory in 
nature with little to no literature around normal values/behaviors in chronic hepatitis B 
patients.  The placebo-first arm (placebo treatment for 12 weeks, 300 mg GSK3228836, 
then off-treatment follow-up for 24 weeks) will be used as a comparator for these 
exploratory safety analyses.  
The placebo-first arm (placebo treatment for 12 weeks, 300 mg GSK3228836 for 12 
weeks, then off-treatment follow-up for 24 weeks) will also provide an assessment for 
loading versus non-loading dose.  Participants in the placebo-first arm will not be 
receiving loading dose when starting their 12 weeks 300 mg GSK3228836 treatment, and 
efficacy results (Week 13-24) may be compared with participants being treated for 12 
weeks of 300 mg GSK3228836 with loading dose (Week 1-12). 
The comparisons/assessments for the placebo-first arm are not statistically powered. 
4.2.3. 
Participant Input into Design 
A small group of patients with CHB were asked to review an example informed consent 
form for the 209668 study.  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. The input from the 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. 


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4.3. 
Justification for Dose 
Dose Levels, Frequency and Duration 
Weekly dosing of GSK3228836 has been evaluated over a four-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) in Week 1 
(Day 4) and Week 2 (Day 11) were included in order to accelerate the achievement of 
steady state concentration in the liver to increase the likelihood of observing anti-HBV 
activity during a short treatment duration.  In study 209668, a study arm will be included 
to explore placebo for 12 weeks followed by weekly dosing of GSK3228836 300 mg for 
12 weeks without the loading doses (see below). 
To date, the highest dose of GSK3228836 evaluated was 2700 mg over 4 weeks (450 mg 
per injection including loading doses; n=3) in healthy volunteers, and 1800 mg over 
4 weeks (300 mg per injection including loading doses; n=18) in participants with CHB. 
In treatment-naïve 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 two participants achieving HBsAg seroclearance 
that persisted for 102 and 28 days, respectively. In participants who achieved HBsAg 
<LLOQ, 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.   
Similar responses were observed in participants in Study ISIS 505358-CS3 on stable NA 
therapy.  Three of 5 GSK3228836-treated participants (60%) achieved HBsAg reductions 
>3 log10 IU/mL.  Two of five participants (40%) treated with 300 mg GSK3228836 
achieved HBsAg <LLOQ (0.05 IU/mL).  One participant reached HBsAg levels <LLOQ 
on Day 23, but this was not sustained.  HBsAg was detectable on the Day 85 and Day 
113 visits.  One participant had HBsAg <LLOQ on Day 36 and remained <LLOQ as of 
the Day 85 visit.  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 209668, 2 different treatment durations (12 weeks and 24 weeks) will be studied 
to assess differences in the efficacy endpoints (e.g., proportion of participants achieving 
seroclearance, durability of response) with GSK3228836 in two populations of patients 
with CHB:  
(1) participants receiving stable nucleos(t)ide treatment and  
(2) participants not currently receiving nucleos(t)ide therapy. 
Study 209668 will also explore the impact on efficacy and safety of decreasing overall 
exposure to GSK3228836 by administrating a step-down dose of 150 mg GSK3228836 
for 12 weeks after an initial 12 weeks of 300 mg GSK3228836 dose.  In each population 
of patients with CHB (participants receiving stable nucleos[t]ide treatment and 


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participants not currently receiving nucleos[t]ide therapy), four different treatment 
regimens of GSK3228836 will be studied in study 209668: 
• 300 mg GSK3228836 once/week for 24 weeks (plus loading doses on Day 4 and 
Day 11); 
• 300 mg GSK3228836 once/week for 12 weeks weeks (plus loading doses on Day 
4 and Day 11) followed by a step-down dose of 150 mg GSK3228836 once/week 
(plus placebo to match to maintain participant blinding) for 12; 
• 300 mg GSK3228836 once/week for 12 weeks (plus loading doses on Day 4 and 
Day 11) followed by placebo once/week for 12 weeks; 
• Placebo once/week for 12 weeks followed by 300 mg GSK3228836 once/week 
for 12 weeks (placebo loading doses to match on Day 4 and Day 11, no loading 
dose for GSK3228836 treatment) 
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 nucleos(t)ide analogues 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 
nucleos(t)ide analogues (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 nucleos(t)ide 
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 normalization 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 nucleos(t)ide analogues 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 


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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 [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 nucleos(t)ide analogues. 
Clinical data from ISIS 505358-CS3 suggest that co-administration of GSK3228836 is 
unlikely to impact efficacy and safety profiles.  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. 
4.4. 
End of Study Definition 
A participant is considered to have completed the study if he/she has completed all 
phases of the study including the last visit. 
The end of the study is defined as the date of the last visit of the last participant in the 
study. 
5. 
STUDY POPULATION 
Prospective approval of protocol deviations to recruitment and enrollment criteria, also 
known as protocol waivers or exemptions, is not permitted. 
5.1. 
Inclusion Criteria 
AGE 
1. At least 18 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 have documented chronic HBV infection ≥6 months prior to 
screening AND 
a. Not currently on nucleos(t)ide analogue therapy population defined as 
participants who never received HBV treatment (treatment naïve) OR 
must have ended nucleos(t)ide therapy at least 6 months prior to the 


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screening visit 
b. OR Currently receiving stable nucleos(t)ide analogue therapy population 
defined as no changes to their nucleos(t)ide regimen from at least 6 
months prior to screening and with no planned changes to the stable 
regimen over the duration of the study 
3. 
Plasma or serum HBsAg concentration >100 IU/mL 
4. 
Plasma or serum HBV DNA concentration 
a. Participants not currently on nucleos(t)ide analogue therapy, plasma or 
serum HBV DNA >2000 IU/mL 
b. Participants who are receiving stable nucleos(t)ide analogue therapy must 
be adequately suppressed, defined as plasma or serum HBV DNA <90 
IU/mL 
5. Alanine Transaminase (ALT) 
a. ALT for treatment naïve participants and for participants who are not 
currently receiving treatment 
i. ALT <3 X ULN will be included initially 
1. If agreed by the IDMC after review of safety data, the ALT 
inclusion criteria may be expanded to include participants 
with ALT <5 X ULN 
b. 
ALT ≤2 X ULN for participants who are receiving stable 
nucleos(t)ide analogue therapy 
SEX 
6. 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)  
2. OR 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 
iii.  A WOCBP must have both 
1. A confirmed menstrual period prior to the first dose of 
study intervention [additional evaluation (e.g., amenorrhea 
in athletes, birth control) should also be considered] 
2. AND a negative highly sensitive pregnancy test [urine or 
serum] within 24 hours before the first dose of study 
treatment 
Contraceptive use by men or women should be consistent with local regulations 
regarding the methods of contraception for those participating in clinical studies. 
Additional requirements for pregnancy testing during and after study intervention 
are located in Appendix 2. 
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 
7. Capable of giving signed informed consent 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 
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 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 of 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 randomization 
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. Positive (or borderline positive) ANCA at screening: 
a. Participants that meet this criteria may be considered for inclusion in the study 
following: 
i. Analysis of MPO-ANCA [pANCA] and PR3-ANCA [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 


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vasculitic/inflammatory/auto-immune condition 
9. 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 
10. 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 
 
PRIOR/CONCOMITANT THERAPY 
11. 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.  
12. Participants for whom immunosuppressive treatment is not advised, including 
therapeutic doses of steroids, will be excluded 
13. Currently taking, or took within 12 months of screening, any interferon-containing 
therapy. 
14. Participants requiring anti-coagulation therapies (for example warfarin, Factor Xa 
inhibitors or anti-platelet agents like clopidogrel) 
 
PRIOR/CONCOMITANT THERAPY 
15. 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). 
16. Prior treatment with any oligonucleotide or small interfering RNA (siRNA) within 12 
months prior to the first dosing day 
 
DIAGNOSTIC ASSESSMENTS 
17. Fridericia’s QT correction formula (QTcF) ≥450 msec (if single electrocardiogram 
[ECG] at screening shows QTcF 450 msec, a mean of triplicate measurements 
should be used to confirm that participant meets exclusion criterion). 
18. Laboratory results as follows 
a. Serum albumin <3.5 g/dL 


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b. Glomerular filtration rate (GFR) <60 mL/min /1.73m2 as calculated by the 
CKD-EPI formula (for Japan, JSN-CKDI equation).  
c. INR >1.25 
d. Platelet count <140 X 109/L 
e. Total bilirubin >1.25 x ULN 
i. 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 
f. 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 
i. 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 the 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 
19. History of/sensitivity to GSK3228836 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. 
Lifestyle Considerations 
5.3.1. 
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 vaporizers) will 
not be permitted while they are in the clinical unit.  
 
5.3.2. 
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. 
5.4. 
Screen Failures 
Screen failures are defined as participants who consent to participate in the clinical study 
but are not subsequently randomized. A minimal set of screen failure information is 


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required to ensure transparent reporting of screen failure participants to meet the 
Consolidated Standards of Reporting Trials (CONSORT) publishing requirements and to 
respond to queries from regulatory authorities. Minimal information includes 
demography, screen failure details, eligibility criteria, 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. 
5.5. 
Additional Participant Enrollment 
The planned number of participants will be approximately 440. 
In the case of a disruptive event (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 may enrol additional participants to within 10% of the planned 440 participants 
to support a sufficient safety database.  
6. 
STUDY INTERVENTION 
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. 
6.1. 
Study Intervention(s) Administered 
Study Treatment 
Study Treatment 
Product Name: 
GSK3228836 
Placebo 
Formulation Description: 
Clear colorless to slightly yellow solution 
Clear colorless 
solution 
Dosage Form: 
Solution for injection 
Solution for injection 
Unit Dose Strength(s)/Dosage 
Level(s): 
150mg/mL; 1.0mL nominal volume per vial  
(minimal overfill per vial) 
Placebo 
Route/Administration/Duration: 
SC, multiple  
(once weekly, up to 168 days, plus loading doses) 
SC, multiple  
(once weekly, up to 
168 days, plus 
loading doses) 
Dosing Instructions: 
Administer two SC injections of GSK3228836 for 300 
mg dose, one SC injection of GSK3228836 for 150 mg 
dose (plus one SC placebo dose for blinding purposes) 
Administer two SC 
injections for placebo 
Manufacturer/Source of 
Procurement: 
GSK GlaxoSmithKline Manufacturing SpA, Parma 
(Italy) 
Locally sourced 
normal Saline 
Method for Individualizing 
Dosage 
Dispensing into syringes 
Dispensing into 
syringes 
SC=subcutaneous 


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The site of injection will be recorded for each participant and dose(s).  Sites of 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 
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. 
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 
authorized 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 labeled storage conditions with access limited to 
the investigator and authorized 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.  
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 Minimize Bias: Randomization and Blinding 
All participants will be centrally randomized 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 summarized in the SoA.  Returned 
study intervention should not be re-dispensed to the participants. 
In case of an emergency, the investigator has the sole responsibility for determining if 
unblinding the participant on their intervention assignment is warranted.  Participant 


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safety must always be the first consideration in making such a determination.  If the 
investigator decides that unblinding to the participant is warranted, the investigator 
should make every effort to contact GSK prior to unblinding the participant to their 
intervention assignment unless this could delay emergency intervention of the participant.  
If a participant’s intervention assignment is unblinded, GSK must be notified within 24 
hours after breaking the blind.  The date and reason that the blind was broken must be 
recorded in the source documentation and case report form, as applicable. 
Participants will be randomized in a 3:3:3:1 ratio to receive study intervention. 
Investigators will be unblinded to each participant’s assigned study intervention 
throughout the course of the study.  
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 
randomization/dispensing has been done accurately. 
A participant may continue in the study if that participant’s intervention assignment is 
unblinded. 
GSK’s Clinical Safety Department staff may unblind the intervention assignment 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. 
6.5. 
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. 


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Concomitant medications, including NAs (see Section 6.5.2 and Section 6.5.3), 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 case 
report form (CRF). 
6.5.1. 
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 (for 
participants on NA therapy at Baseline, participants are expected to continue their NA 
therapy over the duration of the study) and/or start standard of care treatment during the 
study period. 
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. 
For participants who are not receiving NA therapy at baseline, initiate NA therapy if ALT 
≥3x ULN and bilirubin >1.5x ULN, as per Section 7.1.1 (Liver Chemistry Monitoring 
and Stopping Criteria). NA therapy may be subsequently discontinued if other tests (e.g., 
HBV DNA, HBsAg) rule out hepatitis B flare.  
6.5.2. 
Initiation of Nucleos(t)Ides During GSK3228836 Treatment 
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 initiation of NAs for participants not already receiving concomitant NA therapy 
and experience virological breakthrough whilst still receiving GSK3228836 (i.e., haven’t 
completed treatment). 
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 
Initiation of NA therapy should also be considered for participants who are not receiving 
NA therapy at baseline, but are having either no response or only a partial response to 
GSK3228836 treatment (i.e. Treatment Arms 1 to 3, but not Arm 4 in participants not 


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currently on NA therapy). In Arm 4 of the participants not currently on NA therapy, NA 
will be withheld only during the initial 12-week placebo period. During the latter part of 
the study when the participants in Arm 4 are receiving active GSK3228836, NA therapy 
may be initiated as above if there is concern about developing resistance to GSK3228836. 
No response to GSK3228836 treatment is defined as: 
• By Week 12, <1 log decline in HBV DNA level from baseline 
 
Partial response to GSK3228836 treatment is defined as: 
• >1 log decline in HBV DNA, but subsequent plateau of HBV DNA levels such 
that achievement of HBV DNA below the LLOQ is considered unlikely 
 
6.5.3. 
Initiation of Nucleos(t)ide Therapy Post GSK3228836 Treatment 
Upon cessation of GSK3228836 treatment, participants, regardless of their baseline NA 
use or not, may experience virological relapse, DNA replication and an ALT flare.  
Investigators may, at their own discretion and in accordance with local guidelines, decide 
to initiate new or alternative NA therapy in these participants. Any treatment should be 
recorded as a concomitant medication. 
6.5.4. 
Prohibited Medications and Non-Drug Therapies 
The following concomitant medications are not permitted during the study. 
• PEG-interferon or other immunomodulating therapies 
• 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 see Section 7) 
• Prior treatment with any oligonucleotide or small interfering RNA (siRNA) within 12 
months prior to the first dosing 
• Creatine-containing gym supplements  
• Anti-coagulation therapies (e.g., warfarin, Factor Xa inhibitors or anti-platelet agents 
like clopidogrel). 
6.6. 
Dose Modification 
Dose modifications are not planned for this study. 
6.7. 
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. 


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7. 
DISCONTINUATION OF STUDY INTERVENTION AND 
PARTICIPANT DISCONTINUATION/WITHDRAWAL 
7.1. 
Discontinuation of Study Intervention 
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.  Participants that are discontinued from treatment 
will enter the post-treatment period unless consent is withdrawn.  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 
In rare instances, it may be necessary for a participant to permanently discontinue 
(definitive discontinuation) study intervention.  If study intervention is definitively 
discontinued, the participant may remain in the study to be evaluated for safety and 
efficacy assessments. For participants meeting the stopping criteria (Section 7.1.1- 
Section 7.1.4), participants should be monitored until laboratory abnormalities resolve, 
stabilize, or return to within baseline values as indicated.  The participant must then 
attend the follow-up 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. 
7.1.1. 
Liver Chemistry Monitoring and Stopping Criteria 
Liver chemistry monitoring and stopping 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. 
Discontinuation of study intervention for abnormal liver tests is required when: 
• a participant meets one of the discontinuation conditions outlined in Table 6 
• 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 6 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, stabilize, or 
return to within baseline values.  The participant must then attend the follow-up visits 
specified in the SoA. 
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 twice 
weekly until liver chemistry abnormalities (ALT, AST, alkaline phosphatase, bilirubin) 


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resolve, stabilize, 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 6 
Liver Chemistry Monitoring and Stopping Criteria- 
ALT Level 
Monitoring Plan 
Discontinuation 
 
10x ULN ≤ ALT <12x ULN 
and 
Bilirubin ≤1.5x ULN  
and 
INR ≤1.5 (if available) 
Monitor twice weekly 
Additional lab assessments 
Permanently discontinue 
IMP if ALT >10x ULN 
>4 weeks 
 
 
ALT 12x ULN 
and 
Bilirubin≤1.5x ULN  
and 
INR ≤1.5 (if available) 
Hold dose 
Monitor twice weekly 
Additional lab assessments if not 
already done 
Take off hold: 150 mg SC weekly 
when ALT <10x ULN; increasing dose 
to 300 mg (if applicable) should be 
agreed with Medical Monitor 
 
Permanently discontinue 
IMP if any of the following 
apply: 
• 
ALT 10x ULN 
>4 weeks 
• 
ALT 12x ULN recurs 
after IMP taken off hold 
ALT 3x ULN 
and 
1.5x ULN <bilirubin ≤2x ULN 
(>35% direct) 
and 
INR ≤1.5 (if available) 
Hold dose 
Monitor twice weekly 
Additional lab assessments if not 
already done 
Take off hold: 150 mg SC weekly 
when bilirubin returns to <1.5x ULN; 
increasing dose to 300 mg (if 
applicable) should be agreed with 
Medical Monitor 
 
For participants not receiving NA 
therapy at baseline, initiate NA 
therapy1 
 
Permanently discontinue 
IMP if the following recurs 
after IMP taken off hold: 
1.5x ULN <bilirubin ≤2x 
ULN (>35% direct) 
And 
INR 1.5 (if available) 
ALT 3x ULN and any of the 
following apply: 
• 
bilirubin >2x 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  
For participants not 
receiving NA therapy at 


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ALT Level 
Monitoring Plan 
Discontinuation 
baseline, initiate NA 
therapy1 
ALT = alanine aminotransferase; IMP = investigational medicinal product; ULN = upper limit of normal 
1. NA therapy may be subsequently discontinued if other tests (e.g., HBV DNA, HBsAg) rule out hepatitis B flare. 
 
*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, stabilize, 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 
event criteria defined in Table 6: 
• 
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 


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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 Study 
Reference Manual (SRM). 
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 Alcohol 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 computerized tomography) 
or Liver biopsy to evaluate liver disease. 
o The Liver Imaging and/or Liver Biopsy CRFs are also to be completed if these 
tests are performed. 
7.1.2. 
Drug Induced Vascular Injury 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. 


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1. Persisting & deteriorating longitudinal trends in change from baseline for 
C3 and/or C4 defined as: 
a. 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 
b. 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 
c. 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 
d. There is an associated ≥3-fold increase in Bb and/or C5a from 
participant’s baseline OR 
e. There are associated biochemical sequelae for example, a rising high 
sensitivity C-reactive protein (hs-CRP); rising monocyte chemoattractant 
protein-1 (MCP-1); new thrombocytopenia, new renal impairment with no 
other explanation such as intercurrent infection OR 
f. There are associated clinical sequelae, for example, ≥2+ haematuria; 
increasing urine ACR; vasculitic or purpuric rash; peripheral neuropathy; 
jaundice OR 
g. There is new cANCA or pANCA positivity 
 
2. Persisting & deteriorating longitudinal trends in change from baseline for 
Bb and/or C5a where 
a. There is a ≥3-fold increase in Bb and/or C5a over baseline 
AND 
b. This is persisting or increasing week on week in sequential data plots OR 
c. There are associated biochemical sequelae for example, a rising hsCRP; 
rising MCP-1, new thrombocytopenia, new renal impairment with no 
other explanation such as intercurrent infection OR 
d. 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 
e. 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 hsCRP, MCP-1, Bb, C5a) without 
clear alternative explanation. 
• Discontinue study treatment permanently if suspect clinical sequelae of 
complement activation, drug induced vascular injury, vasculitis or auto-immunity 
regardless of biomarkers changes or persistence. 


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7.1.3. 
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 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. 
 
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, stabilize, or return to within baseline values. 
 
Table 7 
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 ≤ 
Platelets1 <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/NSAIDs/anticoagulants 
 
7.1.4. 
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 RBC per high power field (HPF) confirmed by urine 
microscopy 


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• Persistent elevation of serum creatinine (>26.52 mol/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, ANA, 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 
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. 
7.1.5. 
Study Intervention Restart or Rechallenge after stopping criteria 
met 
Study intervention rechallenge after stopping criteria are met (i.e., study treatment 
discontinued) by any participant in this study is not allowed. Study intervention restart 
may be considered only for liver events as follows: 
Restart Following Transient Resolving Liver Stopping Events Not Related to Study 
Intervention 
Restart refers to resuming study intervention following liver stopping events in which 
there is a clear underlying cause (other than drug-induced liver injury [DILI]) of the liver 
event (e.g. biliary obstruction, pancreatic events, hypotension, acute viral hepatitis). 


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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 <3xULN). 
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 Institutional Review Boards (IRB)/Independent Ethics Committees (IEC) 
approval of study intervention restart has been obtained (if required). 
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 (refer to Section 10.1.3). 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 7.1.4). 
7.2. 
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, 
behavioral, compliance or administrative reasons.  


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• 
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 termination 
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. 
• 
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. 
7.3. 
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 
Appendix 1. 
8. 
STUDY ASSESSMENTS AND PROCEDURES 
• Study procedures and their timing are summarized in the SoA.  
• 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 


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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 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 utilized for screening or 
baseline purposes provided the procedure met the protocol-specified criteria and was 
performed within the time frame defined in the SoA. 
• 
Repeat or unscheduled samples may be taken for safety reasons or for technical 
issues with the samples. 
8.1. 
Efficacy Assessments 
The primary objective measurements for efficacy include: 
• HBsAg 
• HBV DNA  
HBsAg and HBV DNA are collected as per the SoA.  Details of sample collection can be 
found in the SRM. 
The primary efficacy endpoint is sustained virologic response, which is a composite 
endpoint defined as HBsAg <LLOQ and HBV DNA <LLOQ at the end of GSK3228836 
treatment which is sustained for 24 weeks post-GSK3228836 treatment.  Seroclearance 
refers to participants with HBsAg and HBV DNA <LLOQ (with or without the formation 
of HBs-antibody).  Seroconversion refers to participants with HBsAg and HBV DNA 
<LLOQ plus formation of HBs-antibody.  Both terms are used to evaluate efficacy. For 
the purposes of this study, sustained response is defined as a continuous 24 weeks from 
end of GSK3228836 treatment during which levels of HBsAg in serum remain less than 
LLOQ and HBV DNA less than LLOQ. 
Any HBsAg greater than LLOQ or HBV DNA greater than LLOQ after achieving 
HBsAg seroclearance and HBV DNA suppression 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. 


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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.  Symptom-directed  
exams 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).  
• A symptom-directed exam will include, at a minimum, assessments of the 
dermatologic, cardiovascular, respiratory, and gastrointestinal systems. 
• Investigators should pay special attention to clinical signs related to previous serious 
illnesses. 
8.2.2. 
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 Appendix 3). 
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 in a semi-supine position (preferred, but not 
required) 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. 


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8.2.4. 
Electrocardiograms 
The ECG is for screening purposes only. 
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 Appendix 2 for the list of clinical laboratory tests to be performed and to the 
SoA for the timing and frequency.  
• 
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 Appendix 2, must be 
conducted in accordance with the laboratory manual and the SoA. 
8.3. 
Adverse Events and Serious Adverse Events 
The definitions of an AE or SAE can be found in Appendix 3. 
AEs will be reported by the participant (or, when appropriate, by a caregiver, surrogate, 
or the participant's legally authorized representative). 
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).  


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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 
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 
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 
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, stabilized, otherwise explained, or the participant is lost to follow-up (as 
defined in Section 7.3). Further information on follow-up procedures is given in 
Appendix 3. 
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.  


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• 
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. 
• 
For all studies except those utilizing medical devices investigator safety reports 
must be prepared for suspected unexpected serious adverse reactions (SUSAR) 
according to local regulatory requirements and sponsor policy and forwarded to 
investigators as necessary. 
• 
An investigator who receives an investigator safety report describing a SAE or 
other specific safety information e.g., summary or listing of 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 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 
Appendix 4. 
• Abnormal pregnancy outcomes (e.g., spontaneous abortion, fetal death, stillbirth, 
congenital anomalies, ectopic pregnancy) are considered SAE. 
8.3.6. 
Cardiovascular and Death Events 
For any cardiovascular events 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 (MedDRA) terms.  The CV information should be 
recorded in the specific cardiovascular section of the CRF within one week of receipt of a 
CV Event data query prompting its completion. 
The Death CRF is provided immediately after the occurrence or outcome of death is 
reported. Initial and follow-up reports regarding death must be completed within one 
week of when the death is reported. 


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8.3.7. 
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 aetiology 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 recognized 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 
participants 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 
7.1.2 
8.3.7.3. 
Thrombocytopenia 
Thrombocytopenia, decreased platelets, is a well-recognized 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 7.1.3 
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., SCr, ACR) is presented in Section 7.1.4 
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. 
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: 
1. Contact the Medical Monitor immediately. 
2. Closely monitor the participant for AE/SAE and laboratory abnormalities until 
GSK3228836 can no longer be detected systemically (at least 105 days). 
3. 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). 
4. Document the quantity of the excess dose as well as the duration of the overdosing in 
the CRF. 
Decisions regarding dose interruptions or modifications will be made by the investigator 
in consultation with the Medical Monitor based on the clinical evaluation of the 
participant. 
8.5. 
Pharmacokinetics 
Blood samples will be collected for measurement of plasma concentrations of 
GSK3228836 and/or nucleos(t)ide as specified in the SoA. 
• For standard PK sampling, one pre-dose PK sample at each visit during the treatment 
period (except for Day 4 and Day 11) and one PK sample at any time at each visit 
during the off-treatment period will be collected in participants from all 8 study arms. 
• For intensive PK sampling, a maximum of 13 samples in addition to the standard PK 
sampling may be collected from 39 participants who were on stable NA therapy at 
baseline (13 in each region of Japan, China, and non-Asian country/ies) at one 
additional time point during the study.  The intensive PK sampling will be collected 
at one visit between Week 14 (inclusive) and Week 24 (inclusive), chosen between 
the site and participant. See Table 8 for sample collection timings.  The timing of 


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sampling may be altered during the course of the study based on newly available data 
(e.g., to obtain data closer to the time of peak plasma concentrations) to ensure 
appropriate monitoring. 
• At the visit for intensive PK sampling, GSK3228836 and nucleos(t)ide will be 
administered as close together as possible, and the date and time (24-hour clock time) 
of administration of both drugs will be recorded. Instructions for drug administration 
at the visit for intensive PK sampling will be provided by the sponsor.  See SRM for 
details. 
• 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. 
• Standard PK samples will be used to evaluate the PK of GSK3228836, and explore 
PK-PD relationships. 
• For participants in the intensive PK sampling, samples will be used to evaluate the 
PK of GSK3228836 and nucleos(t)ide therapy. See Table 8.  
• Samples collected for PK analyses may also be used to evaluate safety or efficacy 
aspects related to concerns arising during or after the study. 
• Genetic analyses will not be performed on these plasma samples unless consent for 
this was included in the informed consent. Participant confidentiality will be 
maintained. At visits during which plasma samples for the determination of multiple 
aspects of GSK3228836 will be taken, one sample of sufficient volume can be used. 
• Drug concentration information and accompanied CRF information that would 
unblind the study will not be reported to blinded GSK personnel until the study has 
been unblinded.  See SRM for details. 
Table 8 
Sample Collection Schedule for Intensive PK Sampling 
 
Pre-
Dose 
0.5 
hr 
1 
hr 
1.5 
hr 
2 
hr 
3 
hr 
4 
hr 
5 
hr 
6 
hr 
8 
hr 
12 
hr 
24 
hr 
72 
hr 
168 
hr1 
GSK3228836 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Nucleos(t)ide 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
1. 
The 168 hr timepoint occurs approx. 7 days (24 hrs) after the dose. The site should align this PK timepoint 
collection with the next study visit as close to the nominal timepoint as possible (24 hrs), then the 168 hr PK can 
be collected as the next pre-dose PK sample (for example if the participant has their intensive PK visit at Week 16 
then the pre-dose PK at Week 17 would suffice and a separate 168 hr PK collection is not required, decreasing 
the participant’s scheduling burden) 
8.6. 
Pharmacodynamics 
Pharmacodynamic parameters explored in this study will include but are not limited to: 
• Categorical: virologic response, seroclearance (HBsAg), HBV DNA level below 
LLOQ, and seroconversion (HBsAb and HBeAb); 


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• Change from baseline: HBsAg, HBV DNA, HBeAg, and HBsAb levels. 
• Time to event: virologic response, nadir of HBsAg and HBV DNA, seroclearance 
(HBsAg), HBV DNA level below LLOQ, seroconversion (HBsAb and HBeAb); 
peak of ALT flares; 
• Safety assessments including but not limited to vital signs, electrocardiograms, 
laboratory measurements and adverse events. 
8.7. 
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 Appendix 5 for information regarding genetic research.  Details on processes for 
collection and shipment and destruction of these samples can be found in the SRM. 
8.8. 
Biomarkers 
Collection of samples for other biomarker research is also part of this study. These 
exploratory biomarker samples will be collected to evaluate the pathogenesis of CHB; the 
absorption, distribution, metabolism, or excretion of GSK3228836; or the participant’s 
response to GSK3228836. In addition, continuing research may identify other proteins, 
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 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. 
• 
GSK may store samples for up to 15 years after the end of the study. The 
archived samples may be used for the purpose of follow-up exploration of 
laboratory findings and/or AEs (e.g., measurement of cytokine or chemokine 
levels, measurement of additional markers of kidney function, measurement of 
antibodies, etc.).  The archive samples may also be used for studying biomarkers 
that may be affected by treatment, such as HBcrAg, HBV RNA or 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. 


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For China, see Appendix 7 on biomarkers. 
8.9. 
HBV Resistance Monitoring 
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 DNA <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. 
8.9.1. 
Resistance Analysis based upon HBV DNA Criteria 
HBV DNA for each participant will be measured throughout the study. HBV resistance 
monitoring will include analysis of isolates from participants experiencing virological 
failure. 
Virologic failure is defined as the following confirmed (2 sequential) lab results; 
• 
≥1 log increase from nadir of HBV DNA OR 
• 
HBV DNA becoming quantifiable after being below the LLOQ OR 
• 
Never achieved HBV DNA levels less than LLOQ 
8.9.2. 
Resistance Analysis based upon HBsAg Criteria 
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 experiencing HBsAg 
seroreversion in the absence of detectable HBV DNA.   
HBsAg seroreversion is defined as the following confirmed (2 sequential) lab results; 
• 
≥1 log increase from nadir of HBV HBsAg OR 
• 
HBV HBsAg becoming quantifiable after being below the LLOQ OR 
• 
Never achieved HBsAg levels less than LLOQ 


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8.10. 
Patient Reported Outcomes (PROs) 
8.10.1. 
Hepatitis B Quality of Life (HBQOL) 
The HBQOL has been designed to assess quality of life in patients with Hepatitis B. It 
consists of 31 items and 6 domains: psychological well-being, anticipation anxiety, 
vitality, stigma, transmissibility and vulnerability. Response options range from 1 to 5 
with higher scores indicating more severe impact of Hepatitis B than lower scores.   
8.10.2. 
EQ-5D-3L 
The EuroQOL (EQ-5D-3L) is a standardized instrument for use as a measure of health 
status that is applicable to a wide range of health conditions and treatments.  It provides a 
simple descriptive profile and a single index value for health status that can be used in 
evaluation of health care. The EQ-5D-3L is designed for self-completion by patients, and 
is cognitively undemanding, taking only a few minutes to complete.  Instructions to 
participants are included in the questionnaire. 
The EQ-5D-3L consists of 2 parts: the EQ-5D descriptive items and the EQ visual analog 
scale (EQ VAS).  The EQ-5D comprises 5 dimensions including mobility, self-care, 
usual activities, pain/discomfort and anxiety/depression.  Each dimension is ranked on 3 
levels.  The participant is asked to indicate his/her health state by ticking in the box 
against the most appropriate statement for each of the 5 dimensions. 
The EQ VAS records the participant’s self-rated health on a vertical VAS with endpoints 
labelled “the best health you can imagine” and “the worst health you can imagine”.  The 
instructions ask the participant to mark an X on the scale to indicate how your health is 
TODAY and then to write the number marked on the scale in the box below the scale. 
8.11. 
Survey Questionnaires 
Patient App 
Participants will be provided the option of downloading a patient app on their cellphone 
at the start of the study, which will be used primarily to assist in visit tracking and 
providing general information about the study.  
This app will contain an optional survey that participants can complete and will ask 
questions about their experience participating in the study.  No formal analysis will be 
conducted on this data.  This data will be used to drive patient focus in future studies with 
GSK3228836. 
Patient Feedback on Dosing Regiment 
Participants will be asked questions about their experience of the dosing regimen used in 
the study.  This data may be used to drive patient focus in future studies with 
GSK3228836. 


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9. 
STATISTICAL CONSIDERATIONS 
9.1. 
Statistical Hypotheses 
The primary objective of the study is to assess the efficacy of three dosing regimens 
(arms 1, 2, and 3) of GSK3228836 in participants with CHB as described in Section 4.1.  
Note that loading vs. no loading dose (arm 3 vs. arm 4) is assessed in an exploratory 
objective. The primary endpoint is achieving a sustained virologic response (HBsAg 
<LLOQ and HBV DNA <LLOQ) for 24 weeks after the planned end of GSK3228836 
treatment in the absence of rescue medication.  Rescue medication is defined as any 
medication initiated for the purpose of antiviral suppression. 
An estimation approach with no hypothesis testing will be used to address the primary 
objective.  The primary assessments of interest are the point estimate of SVR rate and 
95% credible intervals; 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.  The point estimates for SVR will be calculated using a Bayesian probability 
approach.  Comparisons 
between treatment 
arms as 
defined in 
the key 
secondary/exploratory objectives will be assessed using probability inference approaches. 
9.2. 
Sample Size Determination 
Approximately 440 participants are planned to be randomly assigned to study 
intervention. 
For each population, there will be approximately 66 participants assigned in each of the 
first three arms.  There will be approximately 22 participants assigned in the fourth arm. 
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 response rate.  The precision for a 
range of response rates with 95% credible intervals are shown in Table 9. 
Table 9 
95% Credible Interval of Response Rate by Sample Size 
Sample size per arm 
Number of responders 
Response rate 
95% credible interval* 
22 
2 
9% 
1% – 23% 
3 
14% 
3% - 30% 
4 
18% 
5% - 36% 
5 
23% 
8% - 41% 
6 
27% 
11% - 46% 
66 
6 
9% 
3% - 17% 
9 
14% 
6% - 23% 
12 
18% 
10% - 28% 
15 
23% 
13% - 33% 
18 
27% 
17% - 38% 
*95% highest posterior density interval 


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The lower bounds of 95% credible intervals will exclude the historical placebo response 
rate of 3% if observed response rate is greater than or equal to 14% in arms 1-3 or 18% in 
arm 4.  
The posterior probabilities that the true sustained virologic response rate is greater than a 
range of response rates will be calculated from the implied Beta posterior, given the 
actual number of responders observed. 
The operating characteristics  based on at least 75% posterior confidence that the true rate 
exceeds a threshold of interest, are shown in Table 10, for various sample sizes, and true 
cure rates.  The operating characteristics shown are based on a Bayesian model without 
consideration of baseline stratification factors and expected to be similar to operating 
characteristics from the hierarchical model defined in Section 9.4.3.  
Table 10 
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 Resp 
Rate=5% 
True Resp 
Rate=20% 
True Resp 
Rate=25% 
True Resp 
Rate=30% 
Probability (true 
response 
rate>15%)>75% 
22 
5 (23%) 
0% 
46% 
68% 
84% 
44 
9 (20%) 
0% 
53% 
81% 
91% 
66 
12 (18%) 
0% 
69% 
93% 
99% 
88 
16 (18%) 
0% 
71% 
95% 
100% 
Probability (true 
response 
rate>20%)>75% 
22 
6 (27%) 
0% 
27% 
48% 
69% 
44 
11 (25%) 
0% 
25% 
56% 
81% 
66 
16 (24%) 
0% 
23% 
60% 
88% 
88 
21 (24%) 
0% 
22% 
64% 
92% 
Probability (true 
response 
rate>25%)>75% 
22 
7 (32%) 
0% 
13% 
30% 
51% 
44 
13 (30%) 
0% 
9% 
29% 
58% 
66 
19 (29%) 
0% 
6% 
28% 
63% 
88 
25 (28%) 
0% 
4% 
27% 
67% 
Note: If the true response rate is 0%, the probability of meeting each criterion is 0% for all sample sizes. 
 
Based on these operating characteristics, for a true response rate of 20%, the proposed 
sample-size of n=66 for arms 1 – 3 has ~70% probability of confirming a true response of 
at least 15%, and if the true rate is 30%, there is an 88% chance of confirming a true 
response of at least 20%.  
There are no plans for sample size re-estimation. 


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9.3. 
Populations for Analyses 
The following populations are defined: 
Population 
Description 
Screened 
All participants who were screened for eligibility 
Enrolled 
• 
All participants who passed screening and entered the study 
• 
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 randomized participants. 
• 
This population will be based on the treatment the participant was 
randomized to 
• 
Any participant who receives a treatment randomization number will be 
considered to have been randomized 
Safety 
• 
All participants who were randomized and received at least one dose of 
study treatment 
• 
This population will be based on the treatment the participant received. 
• 
 Note: Participants who were not randomized but received at least one dose 
of study treatment will be listed  
Pharmacokinetic (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 
Pharmacodynamic (PD) 
All participants in the Safety population for whom a Pharmacodynamic sample 
was obtained and analysed. 
 
9.4. 
Statistical Analyses 
The statistical analysis plan will be finalized prior to unblinding and it 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.  All summaries and 
analyses will be conducted separately for the 2 populations (on nucleos(t)ide treatment 
and not currently on nucleos(t)ide treatment).  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 (Day1 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 Endpoint(s) 
Analyses will be conducted separately for the on nucleos(t)ide treatment and not 
currently on nucleos(t)ide treatment populations. The primary analysis for the primary 


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endpoint will be conducted once the last participant has completed the Week 48 visit and 
database lock has been achieved.  
The primary efficacy endpoint is achieving a sustained virologic response for 24 weeks 
after the planned end of GSK3228836 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 GSK3228836 
treatment.  Analysis windows for the post GSK3228836 treatment assessments will be 
defined in the analysis plan. 
HBsAg and HBV DNA from Week 24 to Off-Treatment Week 24 will be used to assess 
the primary endpoint for arms 1 and 2, and the exploratory endpoint for arm 4. For dosing 
schedule of arms 1, 2, and 4, see Section 4.1. 
 
For arm 3, because of the shortened time on treatment (12 weeks instead of 24 weeks), 
post-treatment visit schedules will not match those of arms 1 and 2. To avoid risk of bias 
the following visits have been selected for arm 3 to match the number and timing of visit 
windows for measuring off-treatment virologic responses in arms 1 and 2 to evaluate the 
primary endpoint 
o Week 12, 13, 14, 16, 20, 24, off-treatment Week 4, 8, 12 
9.4.2.1. 
Primary Estimands 
Primary Estimands supporting the primary objective are defined as: 
- Population: separate assessment for the following: 
• 
participants with CHB on stable nucleos(t)ide therapy  
• 
participants with CHB not currently on nucleos(t)ide therapy 
- Variable: Sustained virologic response (SVR) for 24 weeks after the planned end of 
GSK3228836 treatment in the absence of rescue medication. 
- Treatments: arms 1, 2, and 3.  Estimation of the within-arm response rate.  Note: arm 4 
is described in Section 9.4.2.2 
- Intercurrent events: use of rescue medication, and discontinuation of/interruption 
of/adherence to IP.  The use of rescue medication has been incorporated into the 
definition of variable (composite strategy).  Discontinuation of, interruption of, and 
adherence to IP will be ignored (treatment policy). Wide disruptive events (such as 
COVID-19 pandemic) leading to discontinuation of, interruption in, and non-adherence 
to GSK3228836 will be handled assuming they had not happened (hypothetical strategy). 
 
- Population summary: proportion of participants who achieve SVR for each treatment 
arm. 
 
The primary estimands for each sub-population is the proportion of participants in each 
treatment arm 1, 2, and 3 who achieve SVR for 24 weeks after the planned end of 
GSK3228836 treatment in the absence of rescue medication regardless of completing IP, 
interruptions in IP or adherence to IP had they not been affected by wide disruptive 
events. 
 


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9.4.2.2. 
Supplementary Estimands 
A supplementary estimand is defined to support the primary objective. The 
supplementary estimand is defined in the same way as the main estimand, except the 
assessment time frame for participants 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 nucloes(t)ide therapy and 
participants with CHB not currently on nucleos(t)ide therapy is the proportion of 
participants in each treatment arm 1, 2, and 3 who achieve SVR for 24 weeks after the 
actual end of GSK3228836 treatment in the absence of rescue medication, regardless of 
completing IP, interruptions in IP or adherence to IP, 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 endpoint.  
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 primary estimands, a sensitivity analysis will be performed using the 
Bayesian model described in Section 9.4.3 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. 
Primary Analyses 
All analyses will be conducted separately for the 2 populations (on nucleos(t)ide 
treatment and not currently on nucleos(t)ide treatment).  The participant population will 
not be included as a stratification factor in the analysis model.  
The primary assessments of interest are the point estimate of sustained virologic response 
rate and 95% credible intervals; in addition, posterior probabilities that the true virologic 
response rate 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 response rate for each arm incorporating the baseline stratification 
factors [Jones, 2011]. 
Model for each arm: 


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Priors:  
 
The four strata and representation of the two baseline stratification factors B1 and B2 in 
the model are shown in Table 11.  
Table 11 
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)  (0) 
B2- (Negative) (0) 
2: HBsAg >3 log IU/mL and Negative HBeAg 
B1+  (>3 log IU/mL) (1) 
B2-  (Negative) (0) 
3: HBsAg 3 log IU/mL and Positive HBeAg 
B1-  (3 log IU/mL) (0) 
B2+  (Positive) (1) 
4: HBsAg >3 log IU/mL and Positive HBeAg 
B1+  >3 log IU/mL) (1) 
B2+  (Positive) (1) 
For each arm, the posterior distribution of SVR rate P(pg|data), g=1,2,3,4 will be derived 
for each stratum using the model specified above.  
The posterior distribution of the arm-level SVR rate will be derived using a mixture of 
the posterior distributions of SVR rate for each stratum in that arm. The weights are 
proportional to the sample size of each stratum. 


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Posterior probability of sustained virologic response rate exceeding a range of clinically 
meaningful response rates will be generated using the approach specified above for each 
arm. 
9.4.4. 
Secondary Endpoint(s) 
9.4.4.1. 
Estimands for Secondary Objectives:  
All analyses will be conducted separately for the 2 populations (on nucleos(t)ide 
treatment and not currently on nucleos(t)ide treatment). 
Two groups of estimands are defined for the secondary efficacy objectives.  
Categorical definitions for secondary analyses will be provided in the RAP. 
Estimands supporting secondary objective of assessing the efficacy of GSK3228836 on 
biomarkers and virus-specific antibody responses are defined as follows: 
- Population: one subpopulation of participants with CHB on stable nucleos(t)ide 
therapy and a second subpopulation of participants with CHB not currently on 
nucleos(t)ide therapy.  
- Treatments: arms 1-4. Estimation within each arm. 
- Intercurrent events: use of rescue medication, and discontinuation of/interruption 
of/adherence to IP. The use of rescue medication will be ignored (treatment policy 
strategy). Discontinuation of, interruption of, and adherence to IP will be ignored 
(treatment policy) 
1) Categorical Variables: 
- 
Achieving HBsAg <LLOQ and HBV DNA <LLOQ at the end of treatment. 
- 
Categorical changes from baseline in HBsAg (e.g. <0.5, ≥0.5, ≥1, ≥1.5, ≥3 log10 
IU/mL) and in HBV DNA (e.g. <1, ≥1, ≥2, ≥3 log IU/mL). Additional categories 
of changes from baseline may be added in the RAP.  
- 
ALT normalization (ALT≤ULN) over time in absence of rescue medication in 
participants with baseline ALT>ULN 
- 
HBe antibody (anti-HBeAg ) levels 
- Population summary: proportion of participants in each category for each 
treatment arm. 
2) Continuous Variables: Actual values and change from baseline over time of HBsAg 
and HBV DNA and actual values and change from baseline of HBeAg levels; HBs 
antibody (anti-HBsAg) levels.  
- Population summary: mean values and mean changes from baseline for each variable 
in each treatment arm 
3) Time to Event Variable: Time to ALT normalization in absence of rescue medication 
in participants with baseline ALT>ULN 


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- Population summary: Turnbull’s estimator for non-parametric estimation of Time to 
ALT normalization in each treatment arm 
The group of estimands supporting this objective for each sub-population are the 
population summary for each variable in each treatment arm 1-4 regardless of completing 
IP, interruptions in IP or adherence to IP and regardless of rescue medication (except for 
ALT normalization which can only be achieved in the absence of rescue medication). 
Missing data for variables defined above (except for Time to ALT normalization) will be 
ignored, only available data will be summarized.  For participants who withdraw from the 
study or Participants with ALT>ULN at the end of study, time to ALT normalization will 
be censored at the time of last visit. No sensitivity analysis is planned for the group of 
estimands supporting this objective. Further details will be provided in the RAP.  
• 
Estimands supporting secondary objective of comparing the efficacy between 12 
weeks, 12 weeks + 12 weeks step-down, and 24 weeks of GSK3228836 treatment are 
defined as follows: 
- Population: separate assessment for the following: 
• 
participants with CHB on stable nucleos(t)ide therapy  
• 
participants with CHB not currently on nucleos(t)ide therapy 
- Variable: Sustained virologic response (SVR) for 24 weeks after the 
planned end of GSK3228836 treatment in the absence of rescue medication. 
- Treatments: arms 1, 2, and 3.  Three treatment comparisons between: arms 
1 and 2, arms 1 and 3, and arms 2 and 3. 
- Intercurrent events: use of rescue medication, and discontinuation 
of/interruption of/adherence to IP.  The use of rescue medication has been 
incorporated 
into 
the 
definition 
of 
variable 
(composite 
strategy).  
Discontinuation of, interruption of, and adherence to IP will be ignored 
(treatment policy). Wide disruptive events (such as COVID-19 pandemic) 
leading to discontinuation of, interruption in, and non-adherence to 
GSK3228836 will be handled assuming they had not happened (hypothetical 
strategy).   
- Population summary: difference in proportion of participants who achieve 
SVR between treatment arms. 
The group of estimands supporting this objective for each sub-population are the 
difference in each treatment comparisons in the proportion of participants who achieve 
SVR for 24 weeks after the planned end of GSK3228836 treatment in the absence of 
rescue medication regardless of completing IP, interruptions in IP or adherence to IP had 
they not been affected by wide disruptive events. 
The non-responder imputation described in Section 9.4.2.2 will be used when HBsAg and 
HBV DNA data are missing from visits required to derive the endpoint. Further details 
will be provided in the RAP. 
9.4.4.2. 
Secondary Efficacy Analyses 
Secondary efficacy comparisons of interest include difference in sustained virologic 
response rate between following treatment arms: 


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o Arm 1 vs. Arm 2 
o Arm 1 vs. Arm 3 
o Arm 2 vs. Arm 3 
 
Comparisons between the treatment arms will be conducted using a similar model 
specified in Section 9.4.3 but defining θg as the log odds ratio of treatment effect 
comparing one treatment arm to another treatment arm.  The point estimates of 
differences in sustained virologic response rate with 95% credible intervals will be 
calculated for the treatment comparisons described in the estimands.  Details of the model 
are included in the RAP.  
9.4.4.3. 
Historical placebo: 
Summary-level historical placebo data over 48 weeks from publications may be included 
in a supplementary analysis.  A longitudinal model including historical response at 12, 24 
and 48 weeks of placebo treatment will be constructed.  For the first 12-week period, the 
model will allow dynamic borrowing from historical placebo data to the concurrent 
placebo in Weeks 1-12 in arm 4. Furthermore, the model will provide longitudinal 
prediction of response at Week 24 and Week 48 for participants in arm 4 (had they 
continued on Placebo rather than switching to GSK3228836 treatment).  Descriptive 
comparisons will be included in summary tables and figures as appropriate.  Further 
details will be provided in the RAP. 
9.4.5. 
Safety Endpoints 
Safety analyses 
All analyses will be conducted separately for the 2 populations (on nucleos(t)ide 
treatment and not currently on nucleos(t)ide treatment). 
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 summarized by treatment arm. 
The proportion of participants reporting adverse events (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 summarized by visit and treatment group.  In addition, the maximum post-
baseline toxicity grade (based on DAIDS categories) will be tabulated by treatment arm.  


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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 
summarized as appropriate to the data. 
9.4.6. 
Exploratory Objectives 
9.4.6.1. 
Estimand for Exploratory Objectives 
• Estimands supporting exploratory objective of comparing the efficacy between 
12 weeks of GSK3228836 treatment with a loading dose or without a loading dose 
are defined as follows: 
- Population: separate assessment for the following: 
• 
participants with CHB on stable nucleos(t)ide therapy  
• 
participants with CHB not currently on nucleos(t)ide therapy 
- Variable: Sustained virologic response (SVR) for 24 weeks after the 
planned end of GSK3228836 treatment in the absence of rescue medication. 
- Treatments: arm 3 and 4. Treatment comparison between arms 3 and 4. 
- Intercurrent events: use of rescue medication, and discontinuation 
of/interruption of/adherence to IP.  The use of rescue medication has been 
incorporated into the definition of variable (composite strategy).  
Discontinuation of, interruption of, and adherence to IP will be ignored 
(treatment policy). Wide disruptive events (such as COVID-19 pandemic) 
leading to discontinuation of, interruption in, and non-adherence to  
GSK3228836 will be handled assuming they had not happened (hypothetical 
strategy). 
- Population summary: difference in proportion of participants who achieve 
SVR between treatment arms 3 and 4. 
 
The group of estimands supporting this objective for each sub-population are the 
differences between arms 3 and 4 in the proportion of participants who achieve SVR for 
24 weeks after the planned end of GSK3228836 treatment in the absence of rescue 
medication regardless of completing IP, interruptions in IP or adherence to IP had they 
not been affected by wide disruptive events. 
 
The non-responder imputation described in Section 9.4.2.2will be used when HBsAg and 
HBV DNA data are missing from visits required to derive the endpoint. Further details 
will be provided in the RAP. 
 
Comparisons between the treatment arms 3 and 4 will be conducted using the same 
model specified in Section 9.4.2.2 but defining θg as the log odds ratio of treatment effect 
comparing one treatment arm to another treatment arm, further details will be included in 
the RAP. 
9.4.6.2. 
Participant Population Analyses 
Participant disposition, treatment status, demographics, baseline characteristics (that 
include year of birth, sex, race, and ethnicity), medical history, prior and concomitant 


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medications, study treatment exposure will be summarized descriptively and listed by 
participant. The participant’s baseline characteristics may be used to derive differences (if 
any) between the pharmacokinetic parameters of different racial groups (e.g., Chinese, 
Japanese vs non-Asian) as per the request of regulatory bodies. 
9.4.6.3. 
PK and PK-PD Analyses 
Pharmacokinetics (PK) of GSK3228836 and nucleos(t)ide will be characterized. In all 
participants, C and terminal half-life (t½) will be estimated. In participants with 
intensive PK sampling, GSK3228836 and nucleos(t)ide plasma PK parameters will be 
derived, including but not limited to AUC, C, Cmax, and tmax. 
Population PK model: A Population PK model will be developed to describe the time-
course of plasma PK of GSK3228836 in HBV patients. The data will be analyzed using 
nonlinear mixed effect modeling to estimate the PK parameters of GSK3228836 and the 
associated between-subject variabilities in addition to the residual variability. Covariate 
modeling and model qualification will be conducted. Additional details on the modeling 
process will be detailed in the population PK-PD analysis plan and the results will be 
reported separately.  
PK-PD model: Various PK-PD relationships including PK-efficacy and PK-safety 
relationships will initially be explored graphically; if a relationship between exposure and 
efficacy and/or safety endpoints is present, population PK-PD modeling will be 
conducted using nonlinear mixed effect methods. These models will characterize the 
exposure-response relationships and will define the factors (covariates) that may be 
predictors of efficacy and safety. Additional details of PK-PD analyses will be provided 
in the population PK-PD analysis plan and the results will be reported separately. 
9.5. 
Interim Analyses 
Three interim analyses are planned for the study in addition to regular IDMC safety 
reviews (See Section 9.6).   
All interim analyses will be conducted separately for participants on stable nucleos(t)ide 
treatment and participants not currently on nucleos(t)ide therapy.  Where possible, the 
interim analyses will be scheduled such that both populations are assessed at the same 
time. All interim analysis will be based on the ITT population. 
The approximate timing, endpoint and criteria for each interim analysis are summarized 
in Table 12. The IDMC will review and approve the timing, endpoint and decision 
criteria for the planned interim analyses and the final approved framework will be 
included in the IDMC charter. 
Additional interim analyses may be conducted after the third interim (at which time all 
participants will have completed treatment and sponsor staff [as specified in the blinding 
plan] will be unblinded), to support development planning and decision making. If 
conducted, these analyses will be unblinded to the sponsor staff (as specified in the 
blinding plan) and referenced in the clinical study report.  


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Table 12 
Interim analysis timing, endpoint and decision rule 
Interim  Timing 
Endpoint 
Decision Rule 
Note 
1 
~ 30% participants 
complete Week 12 
Week 12 response rate 
(≥0.5 log10 decline in 
HBsAg at Week 12) 
Stop sub-population if all 
participants’ Week 12 
response rate is predicted to 
be very low 
Arms 1 -3 
combined 
2 
~ 50% participants 
complete Week 24 
Week 24 response rate 
(HBsAg <LLOQ and 
HBV DNA <LLOQ at 
Week 24) 
Stop sub-population if all 
participants’ Week 24 
response rate is predicted to 
be very low 
Arms 1 &2 
combined 
3 
All participants 
complete Week 24 
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. 
 
9.6. 
Independent Data Monitoring Committee (IDMC)  
An independent data monitoring committee (IDMC) will review ongoing unblinded 
safety data in this study and the planned interim analysis 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. 
The first data review meeting will be held approximately 18 weeks post first-subject-first-
dose (the initial dry run will be blinded with a data cut at approximately 12 weeks post-
first subject first dose [FSFD]).  Thereafter, the frequency of scheduled meetings depends 
on subject enrolment, information accumulated and safety event rates but will occur 
approximately every 3 months.  At the first meeting the IDMC may consider if the 
benefit risk assessment is acceptable to expand the ALT inclusion criterion threshold 
(from ALT<3xULN to <5xULN) for participants not receiving nucleos(t)ide therapy.  
Review of the ALT threshold will continue at each meeting as required. 
9.7. 
Internal Safety Review Team (SRT) 
A separate internal safety review team will meet to review all participants’ blinded safety 
data on a regular basis. 


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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: 
• Consensus ethical principles derived from international guidelines 
including the Declaration of Helsinki and Council for International 
Organizations of Medical Sciences (CIOMS) International Ethical 
Guidelines 
• Applicable ICH Good Clinical Practice (GCP) Guidelines 
• Applicable laws and regulations 
• 
The protocol, protocol amendments, ICF, Investigator Brochure, and other 
relevant documents (e.g., advertisements) must be submitted to an IRB/IEC by 
the investigator and reviewed and approved by the IRB/IEC before the study is 
initiated.  
• 
Any amendments to the protocol will require IEC/IRB approval before 
implementation of changes made to the study design, except for changes 
necessary to eliminate an immediate hazard to study participants.  
• 
The investigator will be responsible for the following: 
• Providing written summaries of the status of the study to the IRB/IEC 
annually or more frequently in accordance with the requirements, policies, 
and procedures established by the IRB/EC 
• Notifying the IRB/IEC of SAE or other significant safety findings as 
required by IRB/IEC procedures 
• 
Providing oversight of the conduct of the study at the site and adherence 
to requirements of 21 CFR, ICH guidelines, the IRB/IEC, European 
regulation 536/2014 for clinical studies (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 his/her legally authorized representative and answer all 
questions regarding the study.  
• 
Participants must be informed that their participation is voluntary. Participants 
or their legally authorized 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 (HIPAA) 
requirements, where applicable, and the IRB/IEC or study center.  
• 
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 authorized 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 the participant’s 
legally authorized 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. The investigator or authorised designee 
will inform each participant of the possibility of further research not related to the 
study/disease. 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 tick box 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 authorized personnel appointed 
by the sponsor, by appropriate IRB/IEC members, and by inspectors from 
regulatory authorities. 
 
10.1.5. 
Committees Structure 
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:  
1. 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 participant into the study. 
2. Determining the type of information needed for review of efficacy/safety data, as 
required, in the context of benefit/risk. 
3. Recommending the format for the presentation of this information. 
4. Reviewing data collection methods, safety/efficacy monitoring procedures and 
making recommendations for additions or adjustments to the trial design following 
interim analyses (IA). 
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 the investigator with the full summary of the study 
results.  The investigator is 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 anonymized participant-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.  
• 
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 (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 Organizations). 
• 
Study monitors will perform ongoing source data verification to confirm that 
data entered into the CRF by authorized site personnel are accurate, complete, 
and verifiable from source documents; that the safety and rights of 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.  
• 
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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• 
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 summarized in the clinical study report. 
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 can be found in the RAP. 
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. 
GSK or its designee reserves the right to close the study site or terminate the study at any 
time for any reason at the sole discretion of GSK. Study sites will be closed upon study 
completion. A study site is considered closed when all required documents and study 
supplies have been collected and a study-site closure visit has been performed. 
The investigator may initiate study-site closure at any time, provided there is reasonable 
cause and sufficient notice is given in advance of the intended termination. 
Reasons for the early closure of a study site by the sponsor or investigator may include 
but are not limited to: 
• 
Failure of the investigator to comply with the protocol, the requirements of the 
IRB/IEC or local health authorities, the sponsor's procedures, or GCP guidelines 
• 
Inadequate recruitment of participants by the investigator 
• 
Discontinuation of further study intervention development 
If the study is prematurely terminated or suspended, the sponsor shall promptly inform 
the Investigators, the IECs/IRBs, the regulatory authorities, and any contract research 
organization(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. 


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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 multicenter 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 13 will be performed by the central laboratory.  Local 
laboratory samples may still be collected as needed by the site. 
• 
Local laboratory results are required for analysis of platelets during the dosing 
period, and be available for the investigator’s review prior to dosing. A sample 
for central analysis is obtained at the same time 
• 
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 at the same time. 
• 
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. 
• 
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 the participant's participation in the 
study. 
Table 13 
Protocol-Required Safety Laboratory Assessments 
Laboratory 
Assessments 
Parameters 
Hematology 
Platelet Count1  
RBC Indices: 
MCV 
MCH 
 
WBC count (with 
Differential if WBC 
abnormal): 
Neutrophils 
Lymphocytes 
Monocytes 
Eosinophils 
Basophils 
RBC Count 
Hemoglobin 
Hematocrit 
Clinical 
Chemistry 
Blood Urea 
Nitrogen (BUN) 
Potassium 
Aspartate 
Aminotransferase 
(AST)/ Serum 
Glutamic-
Oxaloacetic 
Transaminase 
(SGOT) 
Total, indirect, 
and direct 
bilirubin 
 
Creatinine 
Sodium 
Alanine 
Aminotransferase 
 (ALT)/ Serum 
Total Protein 


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Laboratory 
Assessments 
Parameters 
Glutamic-Pyruvic 
Transaminase 
(SGPT) 
 
Glucose 
Calcium 
Alkaline 
phosphatase 
Albumin 
Routine 
Urinalysis 
• By dipstick 
• Microscopic examination (if blood or protein is abnormal) 
Other Tests 
• Follicle-stimulating hormone and estradiol (as needed only) 
• Highly sensitive urine or serum human chorionic gonadotropin (hCG) 
pregnancy test (as needed for women of childbearing potential)2 
• Total bile acid 
• Serology (HIV antibody, hepatitis C virus antibody, and hepatitis D virus 
antibody) 
• Hepatitis B serology (hepatitis B surface antigen [HBsAg], hepatitis B 
surface antibody [anti-HBsAg], hepatitis B e antigen [HBeAg], hepatitis B e 
antibody [anti-HBeAg], Hepatitis B virus DNA [HBV DNA], Hepatitis B virus 
RNA [HBV RNA], Hepatitis B core related antigen [HBcrAg]) 
• Other laboratory: PT, INR, activated partial thromboplastin time (aPTT), 
Alpha-fetoprotein, ANCA (MPO-ANCA, PR3-ANCA), APRI/Fibrosure, 
Complement factors C3, C4, and Bb, hs-CRP, MCP-1, angiopoetin II, 
PBMC, soluble protein, PAX Gene 
• Urine ACR 
• Optional collections: genetic sample 
• Viral Sequencing: HBV Genotype/phenotype, 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 


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Laboratory 
Assessments 
Parameters 
o Hepatitis B virus DNA load 
o Hepatitis C virus RNA load 
o Hepatitis D virus antibody 
• PK sample 
• Serum creatine phosphokinase (CPK) and lactate dehydrogenase 
(LDH). 
• Fractionate 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 high performance liquid chromatography 
(HPLC) assay 
Drug Induced Vascular Injury and Complement Stopping Criteria 
• CH50 
• Factor B level 
• Factor H level 
• sC5b-9 
Hematological 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 
•  serum protein electrophoresis (SPEP)/urine protein electrophoresis 
(UPEP) 
• complement panel (C3, C4, C5a and Bb) 
 


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NOTES : 
1. 
Platelets will require local/central lab collection while participants are on-treatment; local lab will be optional for 
sites during the post-treatment period 
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 7.  All events of ALT 3 × upper limit of normal (ULN) and 
bilirubin >2 × ULN (>35% direct bilirubin) or ALT 3 × ULN and international normalized 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: Adverse Events: 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 unfavorable and unintended sign (including 
an abnormal laboratory finding), symptom, or disease (new or exacerbated) 
temporally associated with the use of a study intervention. 
 
Events Meeting the AE Definition 
• 
Any abnormal laboratory test results (hematology, clinical chemistry, or 
urinalysis) or other safety assessments (e.g., ECG, radiological scans, vital signs 
measurements), including those that worsen from baseline, considered clinically 
significant in the medical and scientific judgment of the investigator (i.e., not 
related to progression of underlying disease). 
• 
Exacerbation of a chronic or intermittent pre-existing condition including either 
an increase in frequency and/or intensity of the condition. 
• 
New conditions detected or diagnosed after study intervention administration 
even though it may have been present before the start of the study. 
• 
Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction. 
• 
Signs, symptoms, or the clinical sequelae of a suspected overdose of either study 
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 fulfill 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 


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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., hospitalization for signs/symptoms of the disease under study, 
death due to progression of disease). 
A SAE is defined as any untoward medical occurrence that, at any dose: 
o Results in death 
o Is life-threatening 
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. 
Requires inpatient hospitalization or prolongation of existing hospitalization 
• In general, hospitalization signifies that the participant has been detained (usually 
involving at least an overnight stay) at the hospital or emergency ward for 
observation and/or treatment that would not have been appropriate in the 
physician’s office or outpatient setting. Complications that occur during 
hospitalization are AE. If a complication prolongs hospitalization or fulfills any 
other serious criteria, the event is serious. When in doubt as to whether 
“hospitalization” occurred or was necessary, the AE should be considered serious. 
• Hospitalization for elective treatment of a pre-existing condition that did not 
worsen from baseline is not considered an AE. 
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, diarrhea, 
influenza, and accidental trauma (e.g. sprained ankle) which may interfere with 
or prevent everyday life functions but do not constitute a substantial disruption. 


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Is a congenital anomaly/birth defect 
Other situations: 
• 
Medical or scientific judgment should be exercised in deciding whether SAE 
reporting is appropriate in other situations such as important medical events that 
may not be immediately life-threatening or result in death or hospitalization but 
may jeopardize the 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. 
• 
Examples of such events include invasive or malignant cancers, intensive 
treatment in an emergency room or at home for allergic bronchospasm, blood 
dyscrasias or convulsions that do not result in hospitalization, or development of 
drug dependency or drug abuse. 
 
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: 
• Myocardial infarction/unstable angina 
• Congestive heart failure 
• Arrhythmias 
• 
Valvulopathy 
• 
Pulmonary hypertension 
• 
Cerebrovascular events/stroke and transient ischemic attack 
• 
Peripheral arterial thromboembolism 
• 
Deep venous thrombosis/pulmonary embolism 
• 
Revascularization 
 
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 in the CRF. 
• 
It is not acceptable for the investigator to send photocopies of the participant’s 


T M F -1 3 9 5 6 4 8 0  
C O N FI D E N TI A L  
 
 
2 0 9 6 6 8  
 
Pr ot o c ol A m d 0 2  
 
9 2  
 
me dical rec or ds t o G S K i n lie u of c o m pleti o n of t he G S K / A E/ S A E C R F pa ge.  
•  
T here ma y b e i nsta nces w he n c o pies of m e dical r ec or ds f or certai n cas es are 
re q ueste d b y G S K. I n t his case, all partici pa nt i de ntifiers, wit h t he e x ce pti o n of 
t he partici pa nt n u m ber, will be re dact e d o n t he c o pies of t he me dical r ec or ds 
bef ore s u b missi o n t o G S K.  
•  
T he i n vesti gat or will atte m pt t o esta blis h a dia g n osis of t he e ve nt base d o n si g ns, 
s y m pt o ms, a n d/ or ot her cli nical inf or mati o n. W he ne ver p ossi ble, t he dia g n osis 
( n ot t he i n di vi d ual si g ns/s y m pt o ms) will be d oc u me nte d as t he A E/ S A E. 
A s s e ss m e nt of I nt e n sit y  
T he i n vesti gat or will assess i nte nsit y f or eac h A E a n d S A E re p ort e d d uri n g t he st u d y a n d 
assi g n it t o 1 of t he f oll o wi n g cate g ories:  
•  
Mil d: A n e ve nt t hat is easil y t olerate d b y t h e parti ci pa nt, ca usi n g mi ni mal 
disc o mf ort a n d n ot i nterferi n g wit h e ver y d a y a cti vities. 
•  
M o derate: A n e ve nt t hat ca uses s ufficie nt disc o mf ort a n d i nterferes wit h n or mal 
e ver y da y acti vities.  
•  
Se vere: A n e v e nt t hat pre ve nts n or mal e ver y d a y acti vities. A n A E t hat is 
assesse d as se v ere s h o ul d n ot be c o nf use d wit h a n S A E. Se vere is a cate g or y 
utilize d f or rati n g t he i nte nsit y of a n e ve nt; a n d b ot h A E a n d S A E ca n b e 
assesse d as se v ere.  
A n e ve nt is defi ne d as ‘s eri o us’ w he n it meets at least 1 of t he pre defi n e d o utc o mes 
as descri be d i n t he d efi niti o n of a n S A E, N O T w h e n it is rate d as se vere . 
1 0. 3. 5.  
Di vi si o n of AI D S ( D AI D S) T a bl e f or Gr a di n g S e v erit y of A d ult a n d 
P e di atri c A d v er s e E v e nt s  
T he D AI D S T a ble [ D AI D S , 2 0 1 7 ] will be use d t o gra de t he s e verit y of a n A E t hat is n ot 
s pecificall y i de ntifie d i n t he gra di n g ta ble. I n a d diti o n,
are t o 
be classifie d as gra de 5.   
T he D AI D S T a ble is a vaila ble at t he f oll o wi n g li n k:  
htt ps://rsc. niai d. ni h. g o v/cli nical -researc h-sites/ gra di n g-se v erit y-a d ult-p e diatric -a d verse-
e ve nts -c orrecte d -versi o n -t w o-o ne   
A s s e ss m e nt of C a u s alit y  
•  
T he i n vesti gat or is o bli gate d t o assess t he relati o ns hi p bet wee n st u d y i nter ve nti o n 
a n d eac h occ urre n ce of  eac h A E/ S A E.  
•  
A "reas o na bl e p ossi bilit y" of a relati o ns hi p c o n ve ys t hat t here are facts, e vi de nce, 
a n d/ or ar g u me nts t o s u g gest a ca us al relati o ns hi p, rat her t ha n a rel ati o ns hi p 
ca n n ot be r ule d o ut.  
•  
T he i n vesti gat or will use cli nical j u d g me nt t o deter mi ne t he relati o ns hi p.  
C CI


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• 
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. 
 
10.3.6. 
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) in order to report the event within 24 hours. 
• 
The site will enter the SAE data into the electronic system as soon as it becomes 
available. 
• 
The investigator or medically-qualified sub-investigator must show evidence 
within the eCRF of review and verification of the relationship of each SAE to 
IP/study participation (causality) within 72 hours of SAE entry into the eCRF. 
• 
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. 
 


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SAE Reporting to GSK via Paper CRF 
• 
Facsimile transmission of the SAE paper CRF is the preferred method to transmit 
this information to the Medical Monitor. 
• 
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 CRF pages 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 Guidance and Collection of 
Pregnancy Information 
10.4.1. 
Definitions: 
Woman of Childbearing Potential (WOCBP) 
A woman is considered fertile following menarche and until becoming post-menopausal 
unless permanently sterile (see below). 
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. 
Women in the following categories are not considered WOCBP 
• Premenarchal 
• Premenopausal female with 1 of the following: 
• 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), 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.  
• 
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.  
• Females on HRT and whose menopausal status is in doubt will be required to 
use one of the non-estrogen 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. 
 
 


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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 (IUD) 
• 
Intrauterine hormone-releasing system (IUS) b 
• 
Bilateral tubal occlusion 
• 
Vasectomized partner 
Note: Vasectomized partner 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. 
• 
Highly Effective Methodsb That Are User Dependent Failure rate of <1% per year 
when used consistently and correctly. 
• 
Combined (estrogen- 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 
• 
Note: 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. 
• 
ACCEPTABLE METHODSd 
• 
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 


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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 (CTFG) 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 
amenorrhoea method (LAM) are not acceptable methods of contraception.  
e. 
Male condom and female condom should not be used together (due to risk of failure with friction). 
 
10.4.3. 
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 fetal status 
(presence or absence of anomalies) or indication for procedure.  
• 
While pregnancy itself is not considered to be an AE or SAE, any pregnancy 
complication or elective termination of a pregnancy 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 CHB 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 of DNA samples may be conducted if it is hypothesized that 
this may help further understand the clinical data.  
• 
The samples may be analyzed 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 CHB 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/Rechallenge 
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 7.1.1. 
• 
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 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 Study Reference Manual (SRM). 
• Serum creatine phosphokinase (CPK) and lactate dehydrogenase (LDH). 
• Fractionate bilirubin, if total bilirubin  1.5 X upper limit of normal (ULN) 
• 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. 


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• 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 computerized tomography) 
or Liver biopsy to evaluate liver disease. 
o The Liver Imaging and/or Liver Biopsy CRFs are also to be completed if these 
tests are performed. 
Restart Following Transient Resolving Liver Stopping Events Not Related to Study 
Intervention 
Restart refers to resuming study intervention following liver stopping events in which 
there is a clear underlying cause (other than drug-induced liver injury [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: 
• 
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 <3xULN). 
• 
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. 
• 
There is no evidence of alcohol-related hepatitis. 
• 
Institutional Review Boards (IRB)/Independent Ethics Committees (IEC) 
approval of study intervention restart (as 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 (HGRAC), otherwise the SoA should be the same as the main study 
protocol. 
10.7.1.1. 
China Schedule of Activities 
Table 14 
Screening 
ASSESSMENTS 
 
Informed Consent 
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 
12-lead ECG 
X 
LABORATORY 
Serum hCG pregnancy test (women of child-bearing potential) 
X 
FSH/Estradiol (to confirm status of women of non-child-bearing potential)1 
X 
Hematology/Chemistry/Urinalysis 
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 
ANCA2  
X 
Total bile acid profile (as available) 
X 
Complement C3, C4, C5a, hsCRP, MCP-1, complement Bb, Ang-2 
X 
1. 
As appropriate to confirm menopause 
2. 
With MPO-ANCA, PR3-ANCA if results are positive or border-line positive 


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Table 15 
On Treatment Day 1 to Day 50 
ASSESSMENTS1 
Day 1 
 
D4 
D8 
D11 
D15 
D22 
D29 
D36 
D43 
D50 
Window 
 
1 day 
3 days 
 
Week 1 
W1 
W2 
W2 
W3 
W4 
W5 
W6 
W7 
W8 
Randomization 
X 
 
 
 
 
 
 
 
 
 
Study treatment dosing 
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 
Concomitant medication review 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Symptom directed exam 
X 
 
 
 
 
 
X 
 
 
 
Vital signs 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Injection site reactions 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Questionnaire (cell phone app, 
optional) 
X 
 
 
 
 
 
 
 
 
 
Questionnaire (patient feedback on 
dosing regimen) 
X 
 
 
 
 
 
 
 
 
 
Patient Reported Outcomes 
Questionnaires: HBQoL, EQ-5D 
X 
 
 
 
 
 
 
 
 
 
Laboratory  
 
Pregnancy test (women of child 
bearing potential)2 
X2 
 
 
 
 
 
X 
 
 
 
Hematology3 [includes platelet count  
and WBC] 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
PT, INR, aPTT 
X 
 
 
 
 
 
X 
 
 
 
Chemistry 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
Urinalysis 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
Urine ACR 
X 
 
 
 
X 
 
X 
 
X 
 
HBsAg and HBV DNA 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
Anti- HBsAg 
X 
 
 
 
 
 
X 
 
 
 
Anti-HBeAg 
X 
 
 
 
 
 
X 
 
 
 
HBeAg (only for participants HBeAg 
positive at screening) 
X 
 
X 
 
X 
X 
X 
X 
X 
X 


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ASSESSMENTS1 
Day 1 
 
D4 
D8 
D11 
D15 
D22 
D29 
D36 
D43 
D50 
Window 
 
1 day 
3 days 
 
Week 1 
W1 
W2 
W2 
W3 
W4 
W5 
W6 
W7 
W8 
HBV RNA, HBcrAg  and Sequencing 
(HBV Genotype/phenotype; HBV 
DNA and/or RNA) 
X 
 
 
 
 
X 
 
 
 
X 
Complement C3, Complement C4, 
hs-CRP, MCP-1 
X 
 
 
 
X 
 
X 
 
X 
 
Complement C5a, Complement 
factor Bb 
X 
 
 
 
X 
 
X 
 
X 
 
ANCA, Ang II 
X 
 
 
 
 
 
X 
 
 
 
PK 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
PBMC Collection for 
immunophenotyping4 
X 
 
 
 
 
 
 
 
 
 
Soluble Protein (immunology) 4 
X 
 
 
 
 
X 
 
 
 
X 
PAXGene RNA for expression 
analysis in whole blood4 
X 
 
 
 
 
 
 
 
 
 
OPTIONAL: Genetics4 
X 
 
 
 
 
 
 
 
 
 
Archived Samples [serum; plasma] 
X 
 
 
 
X 
 
X 
 
X 
 
1. 
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 SRM 
2. 
A WOCBP must have both: 
a. 
A confirmed menstrual period prior to the first dose of study intervention; additional evaluation (e.g., amenorrhea in athletes, birth control) should also be 
considered 
b. 
AND a negative highly sensitive pregnancy test [urine or serum] within 24 hours before the first dose of study treatment  
3. 
Hematology- platelet count to be analyzed at local laboratory prior to dose; hematology samples to be collected for central laboratory assessments in parallel  
4. 
In China, collection of these labs will be contingent on agreements with China regulatory (HGRAC), and will be optional for Chinese participants 
 


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Table 16 
On-Treatment: Day 57 to Day 162 
Assessments1 
D57 
D64 
D71 
D78 
D85 
D92 
D99 
D106 
D113 
D120 
D127 
D134 
D141 
D148 
D155 
D162 
Window 
3 days 
 
W9 
W10 
W11 
W12 
W13 
W14 
W15 
W16 
W17 
W18 
W19 
W20 
W21 
W22 
W23 
W24 
Study treatment dosing 
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 
Concomitant 
medication review 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Symptom directed 
exam 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
Vital signs 
X 
X 
X 
X 
X 
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 
X 
X 
X 
X 
X 
Questionnaire (cell 
phone app; optional) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Questionnaire (patient 
feedback on dosing 
regimen) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Laboratory 
 
Pregnancy test (women 
of child bearing 
potential) 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
Hematology2 [includes 
platelet count, and 
WBC] 
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 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Chemistry 
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 
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 
X 
X 
X 
X 
X 
Anti- HBsAg  
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
Anti- HBeAg 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
HBeAg (only for 
participants HBeAg 
positive at screening) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 


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Assessments1 
D57 
D64 
D71 
D78 
D85 
D92 
D99 
D106 
D113 
D120 
D127 
D134 
D141 
D148 
D155 
D162 
Window 
3 days 
 
W9 
W10 
W11 
W12 
W13 
W14 
W15 
W16 
W17 
W18 
W19 
W20 
W21 
W22 
W23 
W24 
HBV RNA, HBcrAg and 
Sequencing (HBV 
Genotype/phenotype; 
HBV DNA and/or RNA) 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
Complement C3, 
Complement C4, hs-
CRP, MCP-1 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
Complement C5a, 
Complement factor Bb 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
ANCA, Ang II 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
PK3 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
PBMC Collection for 
immunophenotyping4 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
Soluble protein 
(immunology) 4 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
PAXGene RNA for 
expression analysis in 
whole blood4 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Archived Samples 
[serum; plasma] 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
1. 
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 
SRM 
2. 
Hematology- platelet count to be analyzed at local laboratory prior to dose; hematology samples to be collected for central laboratory assessments in parallel 
3. 
In addition to the pre-dose sample Intensive PK collection may be collected for China, Japan, and country(ies) with participants of non-Asian heritage (TBD) See Table 8 for 
details of intensive PK sample collection 
Intensive PK  (GSK3228836 and nucleos[t]ide) will be collected at one visit between Week 14 (inclusive) and Week 24 (inclusive) chosen between the site and participant: 
post dose at 0.5 hr, 1 hr, 1.5 hr, 2 hr, 3 hr, 4 hr, 5 hr, 6 hr, 8 hr, 12 hr, 24 hr, 72 hr, and 168 hr  [the site should make all attempts to align the 168 hr post-dose PK with the 
next scheduled visit’s pre-dose PK, see Table 8 for more details] 
4. 
For China, collection of these labs will be contingent on agreements with China regulatory (HGRAC), and will be optional for Chinese participants 
 
 


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Table 17 
Off-Treatment Follow-Up  
Assessments1 
 
OT-Day 1  
OT-Day 8  
OT-Day 22  
OT-Day 50  
OT-Day 78  
OT-Day 106   OT-Day 134  OT-Day 162  
Early 
Termination 
Window 
 
 3 days 
 10 days 
 
 
 
OT- W1 
OT-W2 
OT-W4 
OT-W8 
OT-W12 
OT-W16 
OT-W20 
OT-W24 
 
Safety Assessments 
 
AE/SAE review 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant medication review 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Symptom directed exam 
X 
X 
 
X 
X 
X 
X 
X 
X 
Vital signs 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Patient Reported Outcomes 
Questionnaire: HBQOL, EQ-5D 
 
 
 
 
 
 
 
X 
 
Laboratory  
 
Pregnancy test (women of child bearing 
potential) 
X 
 
X 
X 
X 
X 
X 
X 
X 
Hematology2 [includes platelet count, 
and WBC] 
X 
X 
X 
X 
X 
X 
X 
X 
X 
PT, INR, aPTT 
X 
 
X 
 
X 
X 
X 
X 
X 
Chemistry 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Urinalysis 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Urine ACR 
X 
X 
X 
X 
X 
X 
X 
X 
X 
HBsAg and HBV DNA 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Anti- HBsAg 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Anti- HBeAg  
X 
X 
X 
X 
X 
X 
X 
X 
X 
HBeAg (only for participants HBeAg 
positive at screening) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
HBV RNA, HBcrAg and Sequencing 
(HBV Genotype/phenotype; HBV DNA 
and/or RNA) 
X 
 
X 
 
X 
 
X 
X 
X 
Complement C3, Complement C4, hs-
CRP, MCP-1 
 
X 
X 
X 
X 
X 
X 
X 
X 
Complement C5a, Complement factor 
 
X 
X 
X 
X 
X 
X 
X 
X 


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Assessments1 
 
OT-Day 1  
OT-Day 8  
OT-Day 22  
OT-Day 50  
OT-Day 78  
OT-Day 106   OT-Day 134  OT-Day 162  
Early 
Termination 
Window 
 
 3 days 
 10 days 
 
 
 
OT- W1 
OT-W2 
OT-W4 
OT-W8 
OT-W12 
OT-W16 
OT-W20 
OT-W24 
 
Bb 
ANCA, Ang II 
X 
 
X 
X 
X 
X 
X 
X 
X 
PK 
X 
X 
X 
X 
X 
X 
X 
X 
X 
PBMC Collection for 
immunophenotyping3 
X 
 
 
 
X 
 
 
X 
X 
Soluble Protein (immunology)3 
X 
 
X 
 
X 
 
X 
X 
X 
PAXGene RNA for expression analysis 
in whole blood3 
X 
 
 
 
X 
 
 
X 
X 
APRI/Fibrosure 
 
 
 
 
 
 
 
X 
X 
Archived Samples [serum; plasma] 
X 
X 
X 
X 
X 
X 
X 
X 
X 
1. 
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 SRM 
2. 
Hematology- platelet count analyzed at local laboratory is optional during the off-treatment period; hematology samples to be collected for central laboratory 
assessments (required; if local lab is being drawn, in parallel with local lab sample) 
3. 
For China, collection of these labs will be contingent on agreements with China regulatory (HGRAC), and will be optional for Chinese participants 
 
OT: off-treatment; the first off-treatment visit occurs 7 days after the last study treatment dose received, whether planned or last dose given after 
participant is withdrawn from study treatment (e.g., the planned first off-treatment visit occurs on Day 169, 7 days after the Day 162 visit; if participant is 
withdrawn from study treatment on Day 50, the first off-treatment visit occurs on Day 57) 


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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. 
 
Collection of samples for other biomarker research is part of this study. These 
exploratory biomarker samples will be collected to evaluate the pathogenesis of CHB; the 
absorption, distribution, metabolism, or excretion of GSK3228836; or the participant’s 
response to GSK3228836. In addition, continuing research may identify other proteins, 
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 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).  
 
 


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10.8. 
Appendix 8: Abbreviations and Trademarks 
ACR 
albumin to creatinine ratio 
AE 
adverse event 
ALT 
alanine aminotransferase 
APRI 
aspartate aminotransferase-platelet index 
aPTT 
activated partial thromboplastin time 
ASO 
antisense oligonucleotide  
AST 
aspartate aminotransferase 
AUC 
area under the concentration-time curve 
BUN 
blood urea nitrogen 
CHB 
chronic hepatitis B 
CL/F 
apparent subcutaneous plasma clearance 
CKD-EPI 
Chronic Kidney Disease Epidemiologic Collaboration 
Cmax 
maximum observed concentration 
Ct 
concentration  
CONSORT 
consolidated standards of reporting trials 
CRF 
case report form 
CRO 
contract research organization 
CV 
cardiovascular 
DAIDS 
Division of Acquired Immune Deficiency Syndrome 
dL 
deciliters 
DNA 
deoxyribonucleic acid 
ECG 
electrocardiogram 
ET 
early termination 
FSH 
follicle stimulating hormone 
GCP 
good clinical practice 
GFR 
glomerular filtration rate 
GSK 
GlaxoSmithKline 
H 
hours 
HBcrAg 
hepatitis B core-related antigen 
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 
HIV 
human immunodeficiency virus 
HPLC 
High performance liquid chromatography 
HPF 
high-power field 
hs-CRP 
high sensitivity C-reactive protein 
IB 
investigator’s brochure 
ICH 
international conference on harmonisation 
IDMC 
Independent Data Monitoring Committee 
IDO 
indoleamine 2,3 dioxygenase 
IEC 
independent ethics committee 
IND 
investigational new drug 
INR 
international normalized ratio 
ISR 
injection site reaction 
ITT 
intent-to-treat 
IU 
international units 
Kg 
kilograms 
kPa 
kilopascals 


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L 
liters 
LDH 
lactate dehydrogenase 
LLOQ 
lower limit of quantification 
m2 
square meters 
MedDRA 
medical dictionary for regulatory activities 
Mg 
milligrams 
Min 
minutes 
mL 
milliliters 
mm3 
cubic millimeters 
MOE 
methoxyethyl 
Msec 
milliseconds 
MSDS 
material safety data sheet 
NA 
nucleos(t)ide analog 
Ng 
nanograms 
Nucleos(t)ide 
nucleoside or nucleotide 
PBMC 
peripheral blood mononuclear cells 
PD 
pharmacodynamics(s) 
PEG 
pegylated 
PK 
pharmacokinetic(s) 
PT 
prothrombin time 
QTcF 
Fridericia’s QT correction formula 
RAP 
reporting and analysis plan 
RBC 
red blood cell 
RNA 
ribonucleic acid  
RR 
response rate 
SAE 
serious adverse event 
SC 
subcutaneous(ly) 
siRNA 
small interfering ribonucleic acid 
SOP 
standard operating procedure 
SPEP 
serum protein electrophoresis 
SRM 
study reference manual 
SVR 
sustained virologic response 
t½ 
terminal half-life 
TCM 
traditional Chinese medicine 
tmax 
time of maximum observed concentration 
U 
units 
UA 
urinalysis 
g 
micrograms 
ULN 
upper limit of normal 
UPEP 
urine protein electrophoresis 
mol 
micromole 
WBC 
white blood cell 
 
Trademark Information 
Trademarks of the GlaxoSmithKline 
group of companies 
 
Trademarks not owned by the 
GlaxoSmithKline group of companies 
NONE 
 
None 
 
 


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10.9. 
Appendix 9: Protocol Amendment History 
The Protocol Amendment Summary of Changes Table for the current amendment is 
located directly before the Table of Contents (TOC). 
Amendment 01: 10-MAY-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 
Europe 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 and further directives due to the COVID-19 pandemic. 
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 
Throughout, as 
appropriate 
Changed the primary estimand text from: "sustained 
virologic response for 24 weeks after the end of 
GSK3228836 treatment in the absence of rescue 
medication.", to: 
“sustained virologic response for 24 weeks after the 
planned end of GSK3228836 treatment in the absence 
of rescue medication." 
Some participants may withdraw from 
treatment early, the word “planned” 
has been added to clarify that for the 
primary estimand, SVR is assessed 
24 weeks after the planned end of 
treatment, not the actual end of 
treatment. 
Throughout, as 
appropriate 
Changed subject to participant. 
Current guidelines. 
Schedule of 
Activities 
tables, all and 
Section 8.2.1 
Physical 
Examinations 
Changed brief physical exam to symptom directed 
exam. 
Updated to reflect risk reduction 
practices in limiting physical contact 
due to COVID-19 and to align with 
assessment covered by home 
nursing licenses. 
Schedule of 
Activities  
tables, as 
required and 
applicable text 
throughout 
Added phenotype for HBV RNA, HBcrAg, and 
Sequencing (HBV Genotype/phenotype; HBV DNA 
and/or RNA). 
To provide clarity that sequencing will 
also be used to understand HBV 
phenotype. 
Schedule of 
Activities  
tables, as 
required 
Added footnote (only for selected sites able to transport 
to the analysis lab within the timeframe specified in the 
SRM) to entry for PBMC collection for 
immunophenotyping. 
To allow flexibility for sites that are 
not equipped to transport the PBMC 
samples in a timely fashion. 
Schedule of 
Activities,  
Table 4 and 
Table 17 
(China) 
Remove optional genetics sample from the Off-
treatment follow-up visits in the Schedule of Activities.  
Genetics sampling is only required at 
Day 1. The off-treatment follow-up 
sample was included in error. 
Section 2.3.1.1  
Added section titled Regarding COVID-19. 
To inform of (no known additional) 


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Section # and 
Name 
Description of Change 
Brief Rationale 
risk of COVID-19 for HBV 
participants. 
Section 3  
Key Objectives 
and 
Estimand/Endp
oints table and 
Section 9.4.2.2 
A supplementary estimand for the primary endpoint was 
added. 
Some participants may withdraw from 
treatment early, a supplementary 
estimand that assesses SVR 24 
weeks after the actual end of 
treatment is included to support the 
primary objective. 
Section 3  
Key Objectives 
and 
Estimand/Endp
oints table and 
Section 9.4.4.1 
Estimands for 
Secondary 
Objective 
Secondary Efficacy Endpoints:  
moved HBe-antibody (anti-HBeAg) levels from a 
continuous variable to a categorical variable.  
Correction. 
Section 3  
Key Objectives 
and 
Estimand/Endp
oints table and 
Section 9.4.4.1 
Estimands for 
Secondary 
Objective 
Secondary Efficacy Endpoints; Population summary: 
changed statistical estimator from Kaplan-Meier to 
Turnbull. 
Given the data will be interval-
censored, Turnbull’s method is more 
appropriate than Kaplan-Meier 
method. 
Section 3  
Key Objectives 
and 
Estimand/Endp
oints table 
Secondary Efficacy Endpoints; Pharmacokinetics: 
removed PK derivations for apparent plasma clearance 
and apparent subcutaneous plasma clearance for 
GSK3228836 and apparent oral plasma clearance for 
nucleos(t)ide. 
Apparent plasma clearance = 
Dose/AUC, with DOSE being 
constant, “apparent plasma 
clearance” reflects the same PK 
characteristics as AUC, thus 
redundant and can be removed. 
Section 3 
Estimand/Endp
oints 
corresponding 
to Exploratory 
PK-PD 
relationships 
Exploratory PK-PD endpoints changed from descriptive 
statistical summaries to PK-PD model dependent 
parameter outputs as endpoints. 
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 5.2 
Exclusion 
Criteria 
Medical Conditions Number 8: 
ANCA 
Updated to provide clear parameters 
for exclusion. 
Section 5.2 
Exclusion 
Criteria 
Medical Conditions Number 9: 
C3 
Updated to provide clear parameters 
for exclusion. 
Section 6.5.2 
Initiation of 
Nucleos(t)ides 
During 
GSK3228836 
Treatment 
Allowing for use of NA therapy in Arm 4 of the study 
(after the NA-restriction period, while on active 
GSK3228836), if there is concern about developing 
resistance to GSK3228836. 
Updated to provide clarity as 
participants in Arm 4 do not start 
GSK3228836 until after Week 12. 


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Section # and 
Name 
Description of Change 
Brief Rationale 
Section 6.5.4 
Prohibited 
Medications 
and Non-Drug 
Therapies 
Addition of anticoagulation therapies. 
To make clear that anti-coagulation 
therapy is a prohibited medication as 
per the exclusion criteria. 
Table 6 
Liver 
Monitoring and 
Stopping 
Criteria 
Updated to include discussions with Medical Monitor 
and clarification for taking patients off hold, as the 
terminology of “restart” should be used for the re-start 
criteria after a patient is permanently discontinued from 
treatment. 
Clarification. 
Section 7.1.1  
Liver 
Chemistry 
Monitoring and 
Stopping 
Criteria 
Added twice (in bold): Participants must be monitored 
twice weekly until liver chemistry abnormalities (ALT, 
AST, alkaline phosphatase, bilirubin) resolve, 
stabilize, or return to within baseline values. 
Corrected to align with the monitoring 
plan in Table 6. 
Section 7.1.1  
Liver 
Chemistry 
Monitoring and 
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 DILI or the 
participant may continue with dosing. 
To clarify and identify instance where 
medical monitor should be consulted. 
Section 7.1.1  
Liver 
Chemistry 
Monitoring and 
Stopping 
Criteria 
Updated to include clarification that clinically significant 
lab changes should be confirmed, to correct Liver 
Events CRF to Liver Alcohol CRF. 
Clarification/correction. 
Section 7.1.1  
Liver 
Chemistry 
Monitoring and 
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 7.1.3 
Haematological 
Stopping 
Criteria 
Added text (in bold):  
If the platelet count is uninterpretable or a decreasing 
trend is noted below 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). 
Clarification and to provide guidance 
to investigator. 


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Section # and 
Name 
Description of Change 
Brief Rationale 
Section 7.1.4 
Drug Induced 
Kidney Injury 
(Renal) 
Stopping 
Criteria 
Treatment Hold/Treatment Discontinuation 
changed baseline to pre-dose range for ACR and eGFR 
changes. 
Clarification. The investigator may 
take into account natural fluctuations, 
as may be seen in the pre-dose 
screening or Day 1 values, in 
assessing changes in these 
parameters for the hold/stopping 
criteria. 
Section 8.3.1 
Time Period 
and Frequency 
for Collecting 
AE and SAE 
Information 
Updated timing for recording AE/SAE as related to 
informed consent/dose administration.  
Clarification. 
9.4 Statistical 
Analysis 
Updated all sections to provide clarity that statistical 
summaries and analyses will be conducted separately 
for the 2 population (on nucleos(t)ide treatment and not 
currently on nucleos(t)ide treatment). 
Clarification. 
Section 9.4.3  
Primary 
Analyses 
Amended specification of Bayesian model. 
Model specification was amended to 
improve clarity and avoid repetition. 
Table 11  
Updates to clarify stratification factors for the 4 stratum. 
Clarification/Correction. 
Table 13 
Changed SAE reporting bilirubin <2X ULN to >2X ULN. 
Correction, due to typo. 
Section 9.4.6.3 
PK and PK-PD 
Analyses 
Added description of Population PK model, removed 
efficacy and safety assessments (described in 
Objective/Endpoints). 
Correction. Exploratory graphical 
analyses will be initially performed for 
efficacy and safety endpoints.  
Only If a relationship (exposure and 
efficacy and/or safety endpoints) is 
present will further modeling be 
conducted. 
Section 9.6 
Independent 
Data 
Monitoring 
Committee 
(IDMC) 
Additional text added around IDMC safety reviews and 
IDMC review of ALT criteria. 
Updated to describe the planned 
safety reviews and to provide clarity 
around when IDMC would review 
safety data to expand ALT inclusion 
criteria for treatment naïve 
participants and for participants who 
are not currently receiving treatment. 
Section 10.3.5 
Division of 
AIDS (DAIDS) 
Table for 
Grading 
Severity of 
Adult and 
Pediatric 
Adverse 
Events 
Removed criteria that are contained within the DAIDs 
table.  
Correction. 
Section 10.6 
Appendix 6 
Added re-start guidelines. 
Re-start guidelines were presented in 
Section 7.1.5 but were not included in 
the appendices. 
Section 10.7.1 
Corrected China Schedule of Activities, previously 
addressed in China-specific amendment. 
To align with global Schedule of 
Activities. 
 


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11. 
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Bennett CF and Swayze EE. RNA targeting therapeutics: molecular mechanisms of 
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Bertoletti A, Ferrari C. Innate and adaptive immune responses in chronic hepatitis B virus 
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Boettler T, Newsome PN, Mondelli MU, Maticic M, Cordero E, Cornberg M, Berg T. 
Care of patients with liver disease during the COVID-19 pandemic: EASL-ESCMID 
position paper. JHEP Rep. 2020;2(3):100113.  
Boni C, Fisicaro P, Valdatta C, Amadei B, Di Vincenzo P, Giuberti T, et al. 
Characterization of hepatitis B virus (HBV)-specific T-cell dysfunction in chronic HBV 
infection. J Virol 2007;81:4215-25. 
Boni C, Laccabue D, Lampertico P, Giuberti T, Vigano M, Schivazappa S, et al. Restored 
function of HBV-specific T cells after long-term effective therapy with nucleos(t)ide 
analogues. Gastroenterology 2012;143:963-73. 
Bristol-Myers Squibb Company. Baraclude prescribing information (USA). 12/2018 
revision. 
Chen YC, Jeng WJ, Chu CM, Liaw YF. Decreasing levels of HBsAg predict HBsAg 
seroclearance in patients with inactive chronic hepatitis B virus infection. Clin 
Gastroenterol Hepatol 2012; 10: 297-302. 
Chi X, Gatti P, Papoian T. Safety of antisense oligonucleotide and siRNA-based 
therapeutics, Drug Discovery Today,(2017)  22 (5): 823-833, ISSN 1359-6446, 
https://doi.org/10.1016/j.drudis.2017.01.013. 
Cihlar T, Bleasby K, Roy A, Prichard J. Abstr. 44th Intersci. Conf. Antimicrob. Agents 
Chemother., abstr. A448, 2004. 
Cihlar T, Ho ES, Lin DC, et al. Human renal organic anion transporter 1 (hOAT1) and its 
role in the nephrotoxicity of antiviral nucleotide analogs. Nucleosides Nucleotides 
Nucleic Acids 2001; 20: 641-648.  
Crooke ST, Baker BF, Wiztum JL, Kwoh TJ, Pham NC, Salgado et al.  The effects of 2’-
O-Methoxyethyl containgin antisense oligonucleotides on platelets in human clinical 
trials.  Nucleic Acid Ther 2017; 27(3):121-129.  
Division of AIDS. Division of AIDS (DAIDS) Table for Grading the Severity of Adult 
and Pediatric Adverse Events Version 2.0. National Institutes of Health; Institute of 


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Allergy and Infectious Diseases, Bethesda, MD; 2017. Available at: http://rsc.tech-
res.com/Document/safetyandpharmacovigilance/DAIDS_AE_Grading_Table_v2.1_2017
.pdf  
Epivir (Lamivudine) [package insert]. GlaxoSmithKline. Research Triangle Park (NC); 
2002. 
European Association for the Study of the Liver (EASL). 2017 Clinical Practice 
Guidelines on the management of hepatitis B virus infection. Electronic address: 
easloffice@easloffice.eu; J Hepatol. 2017 Aug;67(2):370-398. doi: 
10.1016/j.jhep.2017.03.021. 
European Association for the Study of the Liver (EASL). EASL clinical practice 
guidelines: Management of chronic hepatitis B virus infection. J Hepatol 
2012;57:167-85. 
Feld JJ, Wong DK, Heathcote EJ. Endpoints of therapy in chronic hepatitis B. 
Hepatology 2009;49(5 Suppl):S96-S102. 
Fix OK, Hameed B, Fontana RJ, Kwok RM, McGuire BM, Mulligan DC, et al. Clinical 
Best Practice Advice for Hepatology and Liver Transplant Providers During the 
COVID-19 Pandemic: AASLD Expert Panel Consensus Statement. Hepatology. 
2020;72(1):287-304.  
Geary RS, Yu RZ, Siwkowski A, Levin AA. Pharmacokinetic/pharmacodynamics 
properties of phosphorothioate 2ʹ-O-(2-methoxyethyl)-modified antisense 
oligonucleotides in animals and man. In Crooke ST, editor. Antisense Drug Technology: 
Principles, Strategies and Applications, 2nd Edition. Boca Raton, FL. Taylor & Francis 
Group 2008; 305-326.  
Gilead Sciences Inc. Viread prescribing information (USA). 12/2018 revision. 
Hepsera (Adefovir dipivoxil) [package insert]. Gilead Sciences, Inc. Foster City (CA); 
2012.  
Höner Zu Siederdissen C, Cornberg M. The role of HBsAg levels in the current 
management of chronic HBV infection. Ann Gastroenterol 2014;27(2):105-112. 
James LP, Letzig L, Simpson PM, Capparelli E, Roberts DW, Hinson JA et al. 
Pharmacokinetics of Acetaminophen-Adduct in Adults with Acetaminophen Overdose 
and Acute Liver Failure. Drug Metab Dispos 2009;37:1779-84. 
Jaroszewicz J, Ho H, Markova A, Deterding K, Schlue K, Raupach R, et al. Hepatitis B 
surface antigen (HBsAg) decrease and serum interferon-inducible protein-10 levels as 
predictive markers for HBsAg loss during treatment with nucleoside/nucleotide 
analogues. Antivir Ther 2011; 16(6): 915-924. 


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118 
 
Jones HE, Ohlssen DI, Neuenschwander B, Racine A, Branson M. Bayesian models for 
subgroup analysis in clinical trials.Clin Trials. 2011 Apr; 8(2): 129–143. Published online 
2011 Jan 31. doi: 10.1177/1740774510396933 
Kearney B, Flaherty J, Shah J. Tenofovir disoproxil fumarate: clinical pharmacology and 
pharmacokinetics. Clin Pharmacokinet 2004;439:595‐612 
Kim GA, Lee HC, Kim MJ, Ha Y, Park EJ, An J, et al.  Incidence of hepatocellular 
carcinoma after HBsAg seroclearance in chronic hepatitis B patients: A need for 
surveillance. J Hepatol. 2014;62(5), 1092–99. https://doi.org/10.1016/j.jhep.2014.11.031  
Liaw YF, Sung JJ, Chow WC, Farrell G, Lee CZ, Yuen H, et al. Cirrhosis Asian 
Lamivudine Multicenter Study Group. Lamivudine for patients with chronic hepatitis B 
and advanced liver disease. N Engl J Med 2004;351:1521-31. 
Lok AS, Zoulim F, Dusheiko G, Ghany MG. Hepatitis B cure: From discovery to 
regulatory approval. Hepatol. 2017 Oct;66(4):1296-1313. doi: 10.1002/hep.29323. Epub 
2017 Aug 1. 
Lok ASF, McMahon BJ. Chronic hepatitis B: Update 2009. AASLD practice guidelines. 
Hepatol 2009;50:1-36. 
Maruyama T, McLachlan A, Iino S, Koike K, Kurokawa K, Milich DR, et al. The 
serology of chronic hepatitis B infection revisited. J Clin Invest 1993; 91:2586-95. 
Milich DR, Chen MK, Hughes JL, Jones JE. The secreted hepatitis B precore antigen can 
modulate the immune response to the nucleocapsid: a mechanism for persistence. J 
Immunol 1998;160:2013-21. 
Minuesa G, Volk C, Molina-Arcas M, Gorboulev V, Erkizia I, Arndt P, et al. Transport 
of lamivudine [(-)-beta-L-2’,3’-dideoxy-3’-thiacytidine] and high-affinity interaction of 
nucleoside reverse transcriptase inhibitors with human organic cation transporters 1, 2, 
and 3. J Pharmacol Exp Ther 2009;329:252–61. 
Op den Brouw M L, Binda RS, van Roosmalen MH, Protzer U, Janssen HLA, van de 
Molen RG, et al. Hepatitis B virus surface antigen impairs myeloid dendritic cell 
function: a possible immune escape mechanism of hepatitis B virus. Immunol 
2009;126:280-89. 
Servais A, Lechat P, Zahr N, Urien S, Aymard G, Jaudon MC, et al. Tubular transporters 
and clearance of adefovir. Eur J Pharmacol 2006;540:168-74. 
Shemesh CS, Yu RZ, Warren MS, Liu M, Jahic M, Nichols B, et al. Assessment of the 
drug interaction potential of unconjugated and galNAc3-conjugated 2′-MOE ASOs. Mol 
Therapy: Nuc Acids 2017; 9: 34-47. 
Tyzeka (Telbivudine) [package insert]. Novartis Pharmaceuticals Corporation. East 
Hanover (NJ); 2013.  


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Uwai Y, Ida H, Tsuji Y, Toshiya K, Kenichi I. Renal transport of adefovir, cidofovir, and 
tenofovir by SLC22A family members (hOAT1, hOAT3, and hOCT2). Pharm Res 2007; 
24: 811-815. 
Vanlandschoot P, Leroux-Roels G. Viral apoptotic mimicry: an immune evasion strategy 
developed by the hepatitis B virus? Trends Immunol 2003;24:144-47. 
Vanlandschoot P, Van Houtte F, Roobrouck A, Farhoudi A, Leroux-Roels G. Hepatitis B 
virus surface antigen suppresses the activation of monocytes through interaction with a 
serum protein and a monocyte-specific receptor. J Gen Virol 2002;83:1281-89. 
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promise. Yonsei Med J 2012;53:875-85. 
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persons with chronic hepatitis B infection. March 2015. 
Wu J, Meng Z, Jiang M, Pei R, Trippler M, Broering R et al. Hepatitis B virus suppresses 
toll-like receptor-mediated innate immune responses in murine parenchymal and 
nonparenchymal liver cells. Hepatology 2009;49:1132-40. 
Wursthorn K, Jung M, Riva A, et al. Kinetics of hepatitis B surface antigen decline 
during 3 years of telbivudine treatment in hepatitis B e antigen-positive patients. Hepatol 
2010; 52(5): 1611-1620. 
Xu Q, Wang C, Meng Q. OAT1 and OAT3: targets of drug-drug interaction between 
entecavir and JBP485. Eur J Pharm Sci 2013; 48: 650-657.  
Yanxiao C, Ruijuan X, Jin Y, Lei C, Qian W, Xuefen Y, et al. Organic anion and cation 
transporters are possibly involved in renal excretion of entecavir in rats. Life Sci 
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outcome in patients with hepatitis B related hepatocellular carcinoma? Transl 
Gastroenterol Hepatol; 2016.1:51. 
Yu RZ, Warren MS, Watanabe T, et al. Lack of interactions between an antisense 
oligonucleotide with 2'-O-(2- methoxyethyl) modifications and major drug transporters. 
Nucleic Acid Ther 2016; 26: 111-117.  
 

SAP_001.pdf: 
 
 
 
 
Statistical Analysis Plan 
 
Study ID:  209668 
 
Official Title of Study: Reporting and Analysis Plan for Phase IIb Multi-Center, 
Randomised, Partial-Blind Parallel Cohort Study to Assess the Efficacy and Safety of 
Treatment with GSK3228836 in Participants with Chronic Hepatitis B Virus (B-Clear) 
 
IND Identifier: 122685 
 
EudraCT: 2020‐001083‐29 
 
Approval Date of Document: 14-APR-2022 
 
 


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XBU Statistical Analysis Plan (SAP) Template v1.0  24 March 2021 
Information Type: 
Statistical Analysis Plan (SAP) 
 
TITLE PAGE 
Protocol Title: 
Reporting and Analysis Plan for Phase IIb Multi-Center, 
Randomised, Partial-Blind Parallel Cohort Study to Assess the 
Efficacy and Safety of Treatment with GSK3228836 in 
Participants with Chronic Hepatitis B Virus (B-Clear) 
 
 
Study Number: 
209668 
Compound Number: GSK3228836 
Abbreviated Title: 
Phase IIb study of GSK3228836 in Participants with Chronic 
Hepatitis B (B-Clear) 
Acronym: 
B-Clear 
 
Sponsor Name: GlaxoSmithKline Research & Development Limited  
Regulatory Agency Identifier Number(s)  
 
Registry 
 
ID 
IND 
IND 122685 
 
 
 
Copyright 2022 the GlaxoSmithKline group of companies. All rights reserved. 
Unauthorised copying or use of this information is prohibited. 
 


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XBU Statistical Analysis Plan (SAP) Template v1.0  24 March 2021 
TABLE OF CONTENTS 
PAGE 
TITLE PAGE ................................................................................................................... 1 
VERSION HISTORY ....................................................................................................... 4 
1. 
INTRODUCTION ...................................................................................................... 9 
1.1. 
Objectives, Estimands and Endpoints ........................................................... 9 
1.2. 
Study Design .............................................................................................. 14 
2. 
STATISTICAL HYPOTHESES ............................................................................... 15 
2.1. 
Multiplicity Adjustment ................................................................................ 15 
3. 
ANALYSIS SETS ................................................................................................... 15 
4. 
STATISTICAL ANALYSES ..................................................................................... 17 
4.1. 
General Considerations .............................................................................. 17 
4.1.1. 
General Methodology .................................................................. 17 
4.1.2. 
Baseline Definition ....................................................................... 17 
4.2. 
Primary Endpoint(s) Analyses ..................................................................... 18 
4.2.1. 
Definition of estimands ................................................................. 18 
4.2.2. 
Main analytical approach ............................................................. 19 
4.2.3. 
Sensitivity analyses ..................................................................... 24 
4.2.4. 
Additional estimands .................................................................... 24 
4.3. 
Secondary Endpoint(s) Analyses ................................................................ 26 
4.3.1. 
Key secondary endpoint(s) .......................................................... 26 
DEFINITION OF ESTIMANDS ...................................................................................... 28 
MAIN ANALYTICAL APPROACH .................................................................................. 29 
REGIMEN SELECTION APPROACH ........................................................................... 29 
OPERATING CHARACTERISTICS FOR REGIMEN SELECTION ................................ 30 
4.3.2. 
Supportive secondary endpoint(s) ............................................... 31 
4.3.3. 
Pharmacokinetic Secondary Endpoints ........................................ 31 
4.4. 
Exploratory Endpoints Analyses ................................................................. 33 
4.4.1. 
Exploratory Efficacy Endpoints .................................................... 33 
4.4.2. 
Exploratory PK-PD Endpoints ...................................................... 34 
4.4.3. 
Exploratory Virology Endpoints .................................................... 35 
4.4.4. 
Exploratory Immunology Endpoints.............................................. 37 
4.4.5. 
Exploratory PRO Endpoints ......................................................... 37 
4.5. 
Safety Analyses .......................................................................................... 37 
4.5.1. 
Extent of Exposure ...................................................................... 38 
4.5.2. 
Adverse Events............................................................................ 38 
4.5.3. 
Additional Safety Assessments .................................................... 40 
4.6. 
Other Analyses ........................................................................................... 42 
4.6.1. 
Subgroup analyses ...................................................................... 42 
4.6.2. 
Subpopulations to Support Regulatory Consultation .................... 44 


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4.6.3. 
Concordance of virologic response at Week 6, Week 12, 
Week 18 and Week 24 and achieving SVR .................................. 44 
4.6.4. 
Association between HBV DNA TND and relapse ........................ 45 
4.6.5. 
Determining the optimal cut point of baseline HBsAg to 
predict response .......................................................................... 45 
4.6.6. 
Predictors of SVR response ......................................................... 46 
4.6.7. 
Other variables and/or parameters............................................... 47 
4.7. 
Interim Analyses ......................................................................................... 47 
4.8. 
Changes to Protocol Defined Analyses ....................................................... 47 
5. 
SAMPLE SIZE DETERMINATION ......................................................................... 48 
6. 
SUPPORTING DOCUMENTATION ....................................................................... 51 
6.1. 
Appendix 1 Study Population Analyses ....................................................... 51 
6.1.1. 
Participant Disposition ................................................................. 51 
6.1.2. 
Demographic and Baseline Characteristics .................................. 51 
6.1.3. 
Protocol Deviations ...................................................................... 52 
6.1.4. 
Prior and Concomitant Medications ............................................. 52 
6.1.5. 
Study Intervention Compliance .................................................... 52 
6.1.6. 
Additional Analyses Due to the COVID-19 Pandemic .................. 53 
6.2. 
Appendix 2 Data Derivation Rules .............................................................. 54 
6.2.1. 
Criteria for Potential Clinical Importance ...................................... 54 
6.2.2. 
Assessment Windows .................................................................. 54 
6.2.3. 
Study Period ................................................................................ 55 
6.2.4. 
Study Day and Reference Dates .................................................. 55 
6.2.5. 
Multiple measurements at One Analysis Time Point .................... 56 
6.2.6. 
Handling of Partial Dates ............................................................. 56 
TRADEMARKS ............................................................................................................. 58 
7. 
REFERENCES ....................................................................................................... 59 
 


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XBU Statistical Analysis Plan (SAP) Template v1.0  24 March 2021 
Version history 
SAP 
Version 
Approval 
Date 
Protocol Version 
(Date) on which 
SAP is Based 
Change 
Rationale 
SAP 
amendment 
02 
14 Apr 
2022 
209668 / 
Amendment 1 
(10-May-2021) 
Section 4.4.1.1: Replaced text “The same model as specified in Section 4.2.2 
will be used, but θg will be defined as the log odds ratio of treatment effect 
comparing one treatment arm to another treatment arm.” with “Comparisons 
between arms will be made by calculating differences between the posterior 
distributions of the response rate in each arm which will be summarised to 
obtain posterior means and CIs. Samples from the posterior distribution of 
the response rates in each arm will also be used to obtain posterior 
probabilities of interest (e.g. Pr(Arm 1 – Arm 2 > -5% | Data)).” 
Correction 
 
 
 
Section 4.4.5: Included references for HBQoL and EQ-5D scoring 
procedures. 
Clarification 
 
 
 
Section 4.6.1 (Table 7): Added additional HBsAg subgroup. 
Defined HBV RNA and HBcrAg subgroup categories. 
Addition/ Clarification 
 
 
 
Section 4.5.3.1: Corrected repeated text “negative to post-baseline Positive, 
baseline value no change, and baseline Negative to post-baseline Positive” 
Correction 
 
 
 
Section 4.6.1: Removed text describing statistical analysis of subgroups. 
Only descriptive stats will be presented for subgroup analyses. 
Correction 
SAP 
amendment 
01 
11-Feb-
2022 
209668 / 
Amendment 1 
(10-May-2021) 
Sections 4.1.1: Added parameters HBV DNA and HBcrAg 
Omission - Parameters HBV 
DNA and HBcrAg were not 
previously included in the raw 
data but will be presented at end 
of study. 
 
 
 
Sections 4.4.1.3: Added parameters HBV DNA and HBcrAg 
Omission - Parameters HBV 
DNA and HBcrAg were not 


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XBU Statistical Analysis Plan (SAP) Template v1.0  24 March 2021 
SAP 
Version 
Approval 
Date 
Protocol Version 
(Date) on which 
SAP is Based 
Change 
Rationale 
previously included in the raw 
data but will be presented at end 
of study. 
 
 
 
Section 4.2.2 Updated format of formulae 
Formatting only 
 
 
 
Section 4.2.2.1 Updated visit windowing for the end of treatment analysis 
timepoint 
To ensure that on-treatment 
values are not used when there 
is a more appropriate end of 
treatment value available. 
 
 
 
Section 4.2.4.4 Added clarifying text “Subjects who have a value of HBsAg 
LLOQ or HBV DNA LLOQ at their last visit, which cannot be confirmed 
due to no further follow up, will be treated as non-responders.” 
Clarification 
 
 
 
Section 4.3.1.1: clarifying text added to population section.  
Clarification,  
 
 
 
Section 4.3.1.1: Update to deal with intercurrent events for the proportion of 
participants achieving HBsAg <LLOQ and HBV DNA <LLOQ in the absence 
of rescue medication at the end of treatment analysis window in the same way 
as for the primary efficacy endpoint. 
Included text to state outputs that will be presented by subgroups/ strata. 
Update for consistency 
 
 
 
Section 4.3.1.1: Added HBs antibody variable, which was omitted from the 
previous version. 
Omission 
 
 
 
Section 4.3.1.1: modified text for censoring 
Omission 
 
 
 
Section 4.3.1.2: Replaced text “The same model as specified in Section 4.2.2 
will be used, but θg will be defined as the log odds ratio of treatment effect 
comparing one treatment arm to another treatment arm.” with “Comparisons 
Correction 


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XBU Statistical Analysis Plan (SAP) Template v1.0  24 March 2021 
SAP 
Version 
Approval 
Date 
Protocol Version 
(Date) on which 
SAP is Based 
Change 
Rationale 
between arms will be made by calculating differences between the posterior 
distributions of the response rate in each arm which will be summarised to 
obtain posterior means and CIs. Samples from the posterior distribution of 
the response rates in each arm will also be used to obtain posterior 
probabilities of interest (e.g. Pr(Arm 1 – Arm 2 > -5% | Data)).” 
 
 
 
Section 4.3.3.4: Added text “(separately for tenofovir disoproxil fumarate 
and tenofovir alafenamide)” 
Clarification 
 
 
 
Section 4.4.3: Updated to state that all virology analyses will be performed 
using the safety population 
Correction 
 
 
 
Section 4.4.3.1: Reworded section on how final reported genotype will be 
derived for clarification. 
Amended text to make it clearer when to use visit and when to use analysis 
window. 
Clarification 
 
 
 
Section 4.4.3.2: Added text to explain how to identify nucleotide changes 
 
This text was omitted from the 
first version of the SAP as it 
was not yet finalised 
 
 
 
Section 4.4.3.2: Amended text to make it clearer when to use visit and when 
to use analysis window. 
Clarification 
 
 
 
Section 4.4.3.2: Addition of table showing mutation by response for binding 
site mutations with >=1% allelic frequency 
Addition at request of virology 
expert. 
 
 
 
Section 4.5: Addition of text “To allow comparison between safety in active 
treatment vs placebo, and loading dose vs no loading dose, selected safety 
displays will be presented by study Weeks 1 – 12, Weeks 13 – 24, and 
Weeks 25 – 48; refer to the OPS for details of which outputs should be 
Clarification 


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XBU Statistical Analysis Plan (SAP) Template v1.0  24 March 2021 
SAP 
Version 
Approval 
Date 
Protocol Version 
(Date) on which 
SAP is Based 
Change 
Rationale 
presented by Week, and refer to Section 6.2.2.2 for definitions of assessment 
windows for adverse events.” 
 
 
 
Section 4.5.2: Addition of summaries Serious, Non-serious and Drug-Related 
AEs by SOC and PT (number of subjects and occurrences) ). This will be 
presented for Overall, and for Week 1 – 12, Week 13 – 24, and Week 25 – 
Week 48.  
And Serious Fatal and Non-Fatal Drug-Related AEs by Overall Frequency 
Omission 
 
 
 
Section 4.5.2.3 Removal of text “Common AEs” 
All AEs are presented for this 
study, not only common AEs. 
 
 
 
Section 4.5.3.1: Added text “Ang-II will be included in the immunology 
summaries and listings and additionally a listing of all Ang-II lab values will 
be presented. Plots showing mean actual and change from baseline values of 
Ang-II over time will be presented. ” 
This text was excluded from the 
original SAP as the data were 
not expected to be available 
until after EoS. 
 
 
 
Section 4.5.3.2: Removed Grade 0 
Correction – there is no Grade 0 
in DAIDS 
 
 
 
Section 4.6.3: Addition of concordance of virologic response & SVR 
Additional analysis requested at 
IA3 
 
 
 
Section 4.6.4: Addition of association between HBV DNA TND and relapse 
Additional analysis requested at 
IA3 
 
 
 
Section 4.6.5: Addition of cut point analysis 
Additional analysis requested at 
IA3 


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XBU Statistical Analysis Plan (SAP) Template v1.0  24 March 2021 
SAP 
Version 
Approval 
Date 
Protocol Version 
(Date) on which 
SAP is Based 
Change 
Rationale 
 
 
 
Section 4.6.6: Addition of predictors of response analysis 
Additional analysis requested at 
IA3 
 
 
 
Section 4.6.7 Addition of listings 3 
Clinical request 
 
 
 
Section 4.8: Removal of text to state that we will include a supplementary 
estimand to measure SVR from the actual end of treatment instead of 
planned end of treatment 
Analysis is included in Protocol 
Amendment 01 
 
 
 
Section 6.1.2: Removed baseline characteristics from demographic 
characteristics table and added clarification on which summary stats to use for 
continuous characteristics. 
Added listing of nucleos(t)ide treatment at baseline for the on stable 
nucleos(t)ide cohort 
Correction & omission 
 
 
 
Section 6.2.2: Added text to describe visit windowing for early termination 
visits and AEs 
Clarification / omission 
 
 
 
Section 6.2.3: Added text “Off Treatment Day 1 occurs 7 days after the last 
study treatment dose received, regardless of whether the participant 
completes treatment as planned or the participant is withdrawn from study 
treatment.” 
Clarification 
 
 
 
Section 6.2.6: “Duration of Hep B infection (years) will be calculated based 
on year only” 
Based on data, only year of 
diagnosis is known in most 
cases. 
SAP 
09-Aug-
2021 
209668 / 
Amendment 1 
(10-May-2021) 
Not Applicable 
Original version 


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XBU Statistical Analysis Plan (SAP) Template v1.0  24 March 2021 
1. 
INTRODUCTION 
The purpose of this Statistical Analysis Plan (SAP) is to describe the planned analyses to 
be included in the CSR for Study 209668. Details of the final analyses are provided. Details 
of interim analyses are provided in separate Interim Analysis Reporting and Analysis Plans. 
1.1. 
Objectives, Estimands and Endpoints 
Objectives 
Endpoints 
Primary 
 
Efficacy: To assess the 
efficacy of the three dosing 
regimens of GSK3228836 in 
participants with CHB  
Primary estimands supporting the primary objective are defined 
as: 
- Population: separate assessment for the following: 
• participants with CHB on stable nucleos(t)ide therapy  
• participants with CHB not currently on nucleos(t)ide 
therapy 
- Variable: Participants achieving sustained virologic response 
(SVR, described in Section 4.2) for 24 weeks after the planned 
end of GSK3228836 treatment in the absence of rescue 
medication.  
- Treatments: arms 1, 2, and 3. Estimation of the within-arm 
response rate. 
- Intercurrent events: use of rescue medication, and 
discontinuation of/interruption of/adherence to IP. The use of 
rescue medication has been incorporated into the definition of 
variable (composite strategy). Discontinuation of, interruption of, 
and adherence to IP will be ignored (treatment policy). Wide 
disruptive events (such as COVID-19 pandemic) leading to 
discontinuation of, interruption of, and non-adherence to 
GSK3228836 will be handled assuming they had not happened 
(hypothetical strategy). 
- Population summary: proportion of participants who achieve 
SVR for each treatment arm. 
 
The primary estimands for each sub-population is the proportion 
of participants in each treatment arm 1, 2, and 3 who achieve 
SVR for 24 weeks after the planned end of GSK3228836 
treatment in the absence of rescue medication regardless of 
completing IP, interruptions in IP or adherence to IP had they 
not been affected by wide disruptive events. 
A supplementary estimand is defined to support the primary 
objective: 


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Objectives 
Endpoints 
- the supplementary estimand is defined in the same way as the 
main estimand, except the assessment time frame for 
participants 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 nucloes(t)ide therapy and 
participants with CHB not currently on nucleos(t)ide therapy is 
the proportion of participants in each treatment arm 1, 2, and 3 
who achieve SVR for 24 weeks after the actual end of 
GSK3228836 treatment in the absence of rescue medication, 
regardless of completing IP, interruptions in IP or adherence to 
IP, had they not been affected by wide disruptive events. 
Secondary 
 
Efficacy: To assess the 
efficacy of GSK3228836 on 
biomarkers and virus-specific 
antibody responses 
The estimands supporting this secondary objective are defined 
as follows: 
- Population: separate assessment for the following:  
• participants with CHB on stable nucleos(t)ide therapy  
• participants with CHB not currently on nucleos(t)ide 
therapy.  
- Treatments: arms 1-4. Estimation within each arm. 
- Intercurrent events: use of rescue medication, and 
discontinuation of/interruption of/adherence to IP. The use of 
rescue medication will be ignored (treatment policy strategy). 
Discontinuation of, interruption of, and adherence to IP will be 
ignored (treatment policy) 
1) Categorical Variables: 
• Achieving HBsAg <LLOQ and HBV DNA <LLOQ at the 
end of treatment. 
• Categorical changes from baseline in HBsAg (e.g., 
<0.5, ≥0.5, ≥1, ≥1.5, ≥3 log10 IU/mL) and in HBV DNA 
(e.g., <1, ≥1, ≥2, ≥3 log IU/mL) 
• ALT normalization (ALT≤ULN) over time in absence of 
rescue medication in participants with baseline 
ALT>ULN 
• HBe antibody (anti-HBeAg) levels 
- Population summary: proportion of participants in each 
category for each treatment arm. 
 
2)  Continuous Variables: Actual values and change from 
baseline over time of HBsAg and HBV DNA and actual values 


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Objectives 
Endpoints 
and change from baseline of HBeAg levels; HBs antibody (anti-
HBsAg) levels 
- Population summary: mean values and mean changes from 
baseline for each variable in each treatment arm 
 
3) Time to Event Variable: Time to ALT normalization in 
absence of rescue medication in participants with baseline 
ALT>ULN 
- Population summary: Turnbull’s estimate for non-parametric 
estimation of time to ALT normalization in each treatment arm 
The group of estimands supporting this objective for each sub-
population is the population summary for each variable in each 
treatment arm 1-4 regardless of completing IP, interruptions in 
IP or adherence to IP and regardless of rescue medication 
(except for ALT normalization which can only be achieved in the 
absence of rescue medication) 
Efficacy: To compare the 
efficacy between 12 weeks, 
12 weeks + 12 weeks step-
down, and 24 weeks of 
GSK3228836 treatment 
The same definition as the primary estimand except treatments 
and population summary are defined as: 
-Treatments: arms 1, 2, and 3. Three treatment comparisons 
between: arms 1 & 2, arms 1 & 3, and arms 2 & 3 
- Population summary: difference in proportion of participants 
who achieve SVR between treatment arms 
 
The group of estimands supporting this objective for each sub-
population are the difference in each treatment comparisons in 
the proportion of participants who achieve SVR for 24 weeks 
after the planned end of GSK3228836 treatment in the absence 
of rescue medication regardless of completing IP, interruptions 
in IP or adherence to IP had they not been affected by wide 
disruptive events. 
Pharmacokinetics (PK): To 
characterize GSK3228836 
and nucleos(t)ide PK in 
participants with CHB 
• In a subset of participants with intensive PK sampling: 
Derived GSK3228836 and nucleos(t)ide plasma PK 
parameters including, but not limited to, area under the 
concentration-time curve (AUC), concentration at the 
end of the dosing interval (C), maximum observed 
concentration (Cmax), time of maximum observed 
concentration (tmax). 
• In all participants: C and terminal half-life (t½) of 
GSK3228836. 


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Objectives 
Endpoints 
Safety 
 
Safety: To assess the safety 
and tolerability of 
GSK3228836 when dosed for 
12 weeks, 12 weeks + 12 
weeks step-down, and 24 
weeks duration in participants 
with CHB 
Clinical assessments including, but not limited to vital signs, 
laboratory measurements and adverse events. 
Exploratory 
 
PK-PD relationships: To 
evaluate PK-efficacy 
relationship and PK-safety 
relationship 
Exploratory graphical analyses will be initially performed for 
efficacy (e.g., HBsAg) and safety endpoints. If a relationship 
between exposure and efficacy and/or safety endpoints is 
present, population PK-PD modelling will be conducted using 
nonlinear mixed effect methods.  
The model will assess the effect of various factors (covariates) 
of the modelled efficacy or safety endpoints. Relevant PK-PD 
model endpoints for example:  
• apparent clearance 
• apparent volume of distribution 
• IC50 
• random variability 
Efficacy: To compare the 
efficacy between 12 weeks of 
GSK3228836 treatment with 
a loading dose or without a 
loading dose 
The same definition as the primary Estimand except treatments 
and population summary are defined as: 
- Treatments: arm 3 & 4. Treatment comparison between arms 
3&4.  
- Population summary: difference in proportion of participants 
who achieve SVR between treatment arms 3 & 4. 
The group of estimands supporting this objective for each sub-
population are the differences between arms 3 & 4 in the 
proportion of participants who achieve SVR for 24 weeks after 
the planned end of GSK3228836 treatment in the absence of 
rescue medication regardless of completing IP, interruptions in 
IP or adherence to IP had they not been affected by wide 
disruptive events. 
Efficacy: To assess the 
pharmacodynamic effect of 
GSK3228836 on exploratory 
viral biomarkers 
HBV core related antigen (HBcrAg), HBV RNA 
Virology: To assess the 
effect of genotype/phenotype 
Sequencing of the viral HBV DNA and/or HBV RNA prior to 
treatment, during treatment and post treatment visits 


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Objectives 
Endpoints 
and presence of baseline 
polymorphisms within the 
GSK3228836 binding site to 
assess the effect on 
treatment response. 
To assess the emergence of 
mutations within the GSK 
binding site, and elsewhere in 
the hepatitis B genome, 
during and after treatment. 
Immunology: To assess the 
effect of 12 weeks, 12 weeks 
+ 12 weeks step-down or 24 
weeks treatment with 
GSK3228836 on 
immunological biomarkers. 
To describe the 
relationship(s) between 
virology biomarkers, including 
but not limited to HBsAg, and 
immunological biomarkers. 
Laboratory measurements of and correlation between the 
following 
Virological biomarkers, as determined by (but not limited to) 
specific viral parameters (HBeAg, HBV DNA, HBV RNA, 
HBcrAg). 
Soluble immunological biomarkers, as determined by (but not 
limited to) levels of circulating cytokines and chemokines. 
Markers of immune cell function, as measured by (but not 
limited to) 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. 
Patient Reported 
Outcomes: To assess 
changes from baseline in 
patient reported outcomes 
following 12 weeks, 12 weeks 
+ 12 weeks step-down, and 
24 weeks of treatment with 
GSK3228836. 
Change from baseline of HBQOL and EQ-5D. 
 
 
 


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1.2. 
Study Design 
Overview of Study Design and Key Features 
 
Design 
Features 
• Phase IIb, multi-center, randomized, partial-blind, parallel cohort study 
to assess efficacy and safety of treatment with GSK3228836 in two 
populations of patients with CHB (1) participants on stable 
nucleos(t)ide treatment and (2) participants not currently on 
nucleos(t)ide therapy. 
Study 
Intervention 
• Arm 1. 300 mg GSK3228836 once/week for 24 weeks (plus loading 
doses of 300 mg GSK3228836 on Day 4 and Day 11). 
• Arm 2. 300 mg GSK3228836 once/week for 12 weeks (plus loading 
doses of 300 mg GSK3228836 on Day 4 and Day 11) followed by step-
down in dose of 150 mg (plus placebo to match to maintain participant 
blinding) GSK3228836 once/week for 12 weeks. 
• Arm 3. 300 mg GSK3228836 once/week for 12 weeks (plus loading 
doses of 300 mg GSK3228836 on Day 4 and Day 11) followed by 
placebo once/week for 12 weeks. 
• Arm 4. Placebo once/week for 12 weeks followed by 300 mg 
GSK3228836 once/week for 12 weeks (plus placebo loading doses to 
match on Day 4 and Day 11, no loading dose for GSK3228836 
treatment). 
Study 
Intervention 
Assignment 
• Participants will be randomized in a 3:3:3:1 ratio to receive study 
intervention. 
Interim 
Analysis 
• Separately for participants on stable nucleos(t)ide treatment and 
participants currently not on nucleos(t)ide treatment, there are 3 interim 
analyses planned for the study.  
• Interim 1: approximately 30% participants complete Week 12 to assess 
safety and futility.  
• Interim 2: approximately 50% participants complete Week 24 to assess 
safety and futility. 


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Overview of Study Design and Key Features 
• Interim 3: all participants complete Week 24 and 50% of the on stable 
nucleos(t)ide treatment participants complete 24 weeks post-
GSK3228836 planned end of treatment, to assess safety and efficacy. 
• IDMC safety review: periodic safety review (approximately every 3 
months). 
 
2. 
STATISTICAL HYPOTHESES  
The primary objective of the study is to assess the efficacy of three dosing regimens (arms 
1, 2, and 3) of GSK3228836 in participants with CHB as described in Section 4.1.  Note 
that loading vs. no loading dose (arm 3 vs. arm 4) is assessed in an exploratory objective. 
The primary endpoint is achieving a sustained virologic response (HBsAg <LLOQ and 
HBV DNA <LLOQ) for 24 weeks after the planned end of GSK3228836 treatment in the 
absence of rescue medication.  Rescue medication is defined as any medication initiated 
for the purpose of antiviral suppression. 
An estimation approach with no hypothesis testing will be used to address the primary 
objective.  The primary assessments of interest are the point estimate of SVR rate and 95% 
credible intervals; 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.  The 
point estimates for SVR will be calculated using a Bayesian probability approach.  
Comparisons between treatment arms as defined in the key secondary/exploratory 
objectives will be assessed using probability inference approaches. 
 
2.1. 
Multiplicity Adjustment 
Not Applicable. 
3. 
ANALYSIS SETS 
Analysis Set 
Definition / Criteria 
Analyses 
Evaluated 
Screened  
All participants who were screened for eligibility. 
• Study 
Population 
Enrolled 
• All participants who passed screening and 
entered the study. 
• Note screening failures (who never passed 
screening even if rescreened) and 
participants screened but never enrolled into 
the study are excluded from the Enrolled 
analysis set as they did not enter the study. 
• Study 
Population 
ITT 
• All randomized participants  
• This population will be based on the 
treatment the participant was randomized to. 
• Efficacy 
• PRO 


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Analysis Set 
Definition / Criteria 
Analyses 
Evaluated 
• Any participant who receives a treatment 
randomization number will be considered to 
have been randomized. 
• Data will be reported according to the 
randomized study intervention. 
Safety 
• All participants who received at least one 
dose of study treatment. 
• This population will be based on the 
treatment the participant received. 
• Note participants who were randomized but 
received at least one dose of study treatment 
will be listed. 
• Safety 
• Virology 
Pharmacokinetic 
(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. 
• PK 
Pharmacodynamic 
(PD) 
All participants in the Safety population for whom a 
Pharmacodynamic sample was obtained and 
analysed. 
• PD 
 


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4. 
STATISTICAL ANALYSES 
4.1. 
General Considerations 
All analyses will be performed separately for the following populations: 
• 
Participants with CHB on stable nucleos(t)ide therapy. 
• 
Participants with CHB not currently on nucleos(t)ide therapy. 
4.1.1. 
General Methodology 
Participants who prematurely withdrew from study will not be replaced.  
In the case of wrong randomization stratification assigned at the time of randomization, the 
analyses will be performed based on the actual stratum per data collected in the baseline 
lab eCRF. In the case of randomization to the incorrect cohort (i.e., if a naïve participant is 
randomised to the on stable nucleos(t)ide treatment cohort, or vice versa), analysis will be 
performed based on the actual cohort the subject should have been assigned to. 
Confidence intervals will use 95% confidence levels unless otherwise specified.  
Unless otherwise specified, continuous data will be summarized using descriptive 
statistics: n, mean, standard deviation (std), median, minimum and maximum. Categorical 
data will be summarized as the number and percentage of participants in each category. 
HBV DNA (as appropriate), HBV RNA, HBcrAg, HBsAg, HBeAg levels that are below 
the LLOQ will be imputed for summaries of actual values and change from baseline.  
The number of significant digits in the LLOQ will be used to determine how much to add 
or subtract in order to impute the corresponding numeric value. 
• Example 1: 2 Significant Digits = ‘< x’ becomes x – 0.01 
• Example 2: 1 Significant Digit = ‘< x’ becomes x - 0.1 
• Example 3: 0 Significant Digit = ‘< x’ becomes x – 1 
 
HBV DNA (IU/mL) and HBV RNA (copies/mL) levels that are “TND” will be imputed 
as 1. HBcrAg (Log10 U/mL) values that are “TND” will be imputed as 0. 
4.1.2. 
Baseline Definition 
For all endpoints (except as noted in baseline definitions) the baseline value will be the 
latest pre-dose (GSK or placebo) assessment with a non-missing value, including those 
from unscheduled visits. If time is not collected or time of assessment equals that of the 
first dose, Day 1 assessments are assumed to be taken prior to first dose and used as 
baseline. If there are multiple assessments collected at the same scheduled time, the average 
of these assessments will be used as the baseline. 
Unless otherwise stated, if baseline data is missing no derivation will be performed and 
baseline will be set to missing. 


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Baseline of eGFR and serum creatinine is defined as the mean of all pre-dose values, from 
screening to Day 1 pre-dose assessment. 
4.2. 
Primary Endpoint(s) Analyses 
The primary analysis for the primary endpoint will be conducted once the last participant 
has completed the Week 48 visit and database lock has been achieved.  
An estimation approach with no hypothesis testing will be used to address the primary 
objective.  The primary assessments of interest are the point estimate of SVR rate and 95% 
credible intervals; in addition, posterior probabilities that the true SVR rate in each 
treatment arm is greater than a range of clinically meaningful response rates will be 
provided. The point estimates for SVR will be calculated using a Bayesian probability 
approach. 
Comparisons 
between 
treatment 
arms 
as 
defined 
in 
the 
key 
secondary/exploratory objectives will be assessed using probability inference approaches. 
The primary efficacy endpoint is achieving a sustained virologic response for 24 weeks 
after the planned end of GSK3228836 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 GSK3228836 treatment. 
Analysis windows for the post GSK3228836 treatment assessments are defined in Section 
4.2.2.1. 
HBsAg and HBV DNA from Week 24 to Off-Treatment Week 24 will be used to assess 
the primary endpoint for arms 1 and 2, and the exploratory endpoint for arm 4. For dosing 
schedule of arms 1, 2, and 4, see Section 1.2. 
 
For arm 3, because of the shortened time on GSK3228836 treatment (12 weeks instead of 
24 weeks), post-treatment visit schedules will not match those of arms 1 and 2. To avoid 
risk of bias the following visits have been selected for arm 3 to match the number and 
timing of visit windows for measuring off-treatment virologic responses in arms 1 and 2 to 
evaluate the primary endpoint: 
o Week 12, 13, 14, 16, 20, 24, off-treatment Week 4, 8, 12. 
 
4.2.1. 
Definition of estimands 
Primary Estimands supporting the primary objective are defined as: 
- Population: separate assessment for the following: 
• 
participants with CHB on stable nucleos(t)ide therapy  
• 
participants with CHB not currently on nucleos(t)ide therapy 
- Variable: Sustained virologic response (SVR) for 24 weeks after the planned end of 
GSK3228836 treatment in the absence of rescue medication. 
- Treatments: arms 1, 2, and 3.  Estimation of the within-arm response rate.  Note: arm 4 
is described in Section 4.4.1 
- Intercurrent events: use of rescue medication, and discontinuation of/interruption 
of/adherence to IP.  The use of rescue medication has been incorporated into the definition 
of variable (composite strategy). Discontinuation of, interruption of, and adherence to IP 
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(such as COVID-19 pandemic) leading to discontinuation of, interruption of, and non-
adherence to GSK3228836 will be handled assuming they had not happened (hypothetical 
strategy). 
 
- Population summary: proportion of participants who achieve SVR for each treatment 
arm. 
 
The primary estimands for each sub-population is the proportion of participants in each 
treatment arm 1, 2, and 3 who achieve SVR for 24 weeks after the planned end of 
GSK3228836 treatment in the absence of rescue medication regardless of completing IP, 
interruptions in IP or adherence to IP had they not been affected by wide disruptive events. 
 
4.2.2. 
Main analytical approach 
The participant population (on nucelos(t)ide treatment or not currently on nucleos(t)ide 
treatment) will not be included as a stratification factor in the analysis model, as each 
population will be analyzed separately.  
A Bayesian hierarchical model will be fitted using MCMC methods, and will be used to 
estimate the posterior probability of sustained virologic response rate for each arm 
incorporating the baseline analysis stratification factors (Table 1) [Jones, 2011].  
Model for each arm: 
𝑁𝑢𝑚𝑏𝑒𝑟 𝑜𝑓 𝑟𝑒𝑠𝑝𝑜𝑛𝑑𝑒𝑟𝑠 𝑟𝑔~𝐵𝑖𝑛𝑜𝑚𝑖𝑎𝑙(𝑛𝑔, 𝑝𝑔),
𝑔= 1, 2, 3, 4 
𝜃𝑔= 𝑙𝑜𝑔𝑖𝑡(𝑃𝑔) = log (
𝑃𝑔
1 −𝑃𝑔
) = 𝛾0 + 𝛾1𝐼{𝐵1+} + 𝛾2𝐼{𝐵2+} + 𝜓𝑔,
𝑔= 1, 2, 3, 4 
Where 𝛾0, 𝛾1, 𝛾2, 𝜓𝑔 are all parameters. Thus, 
𝜃1 = 𝛾0 + 𝜓1 
𝜃2 = 𝛾0 + 𝛾1 + 𝜓2 
𝜃3 = 𝛾0 + 𝛾2 + 𝜓3 
𝜃4 = 𝛾0 + 𝛾1 + 𝛾2 + 𝜓4 
Priors:  
𝛾𝑘~𝑁𝑜𝑟𝑚𝑎𝑙(0, 106) , 𝑘= 0, 1, 2 
𝜓𝑔 ~ 𝑁𝑜𝑟𝑚𝑎𝑙(0, 𝜔2 ), 𝑔= 1, 2, 3, 4 
𝜔~𝐻𝑎𝑙𝑓−𝑛𝑜𝑟𝑚𝑎𝑙(1) 


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Where we define rg as the number of SVR responders among ng participants, pg as SVR 
rate 
𝑟𝑔
𝑛𝑔, θg as the log odds of treatment response log(
𝑝𝑔
1−𝑝𝑔), index g =1,...,4 refers to the 
analysis stratum number, 𝛾𝑘 represent fixed effects of baseline analysis stratification 
factors (see  below),  and 𝜓𝑔 denotes a random effect in analysis stratum g. 
The four analysis strata and representation of the two baseline analysis stratification factors 
B1 and B2 in the model are shown in Table 1. 


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Table 1 
Baseline Analysis Strata  
Stratum 
B1: HBsAg (𝐼{𝐵1+}) 
B2: HBeAg (𝐼{𝐵2+}) 
1: HBsAg <3 log IU/mL and Negative HBeAg 
B1- (<3 log IU/mL) (0) 
B2- (Negative) (0) 
2: HBsAg >3 log IU/mL and Negative HBeAg 
B1+ (>3 log IU/mL) (1) 
B2- (Negative) (0) 
3: HBsAg <3 log IU/mL and Positive HBeAg 
B1- (<3 log IU/mL) (0) 
B2+ (Positive) (1) 
4: HBsAg >3 log IU/mL and Positive HBeAg 
B1+ (>3 log IU/mL) (1) 
B2+ (Positive) (1) 
For each arm, the posterior distribution of SVR rate P(pg|data), g=1,2,3,4 will be derived 
for each analysis stratum using the model specified above.  
𝑃(𝑝1|𝑑𝑎𝑡𝑎) = 𝑃(
𝑒𝜃1
1 + 𝑒𝜃1 |𝑑𝑎𝑡𝑎) 
𝑃(𝑝2|𝑑𝑎𝑡𝑎) = 𝑃(
𝑒𝜃2
1 + 𝑒𝜃2 |𝑑𝑎𝑡𝑎) 
𝑃(𝑝3|𝑑𝑎𝑡𝑎) = 𝑃(
𝑒𝜃3
1 + 𝑒𝜃3 |𝑑𝑎𝑡𝑎) 
𝑃(𝑝4|𝑑𝑎𝑡𝑎) = 𝑃(
𝑒𝜃4
1 + 𝑒𝜃4 |𝑑𝑎𝑡𝑎) 
 
The posterior distribution of the arm-level SVR rate will be derived using a mixture of the 
posterior distributions of SVR rate for each analysis stratum in that arm. The weights are 
proportional to the sample size of each analysis stratum in each arm. 
 
𝑃(𝑝|𝑑𝑎𝑡𝑎) = ∑
𝑤𝑔𝑃(𝑝𝑔|𝑑𝑎𝑡𝑎)
4
𝑔=1
, where 𝑤𝑔=
𝑛𝑔
∑
𝑛𝑔
4
𝑔=1
 
Posterior probability of SVR rate exceeding a range of clinically meaningful response rates, 
e.g., 10%, 15%, 20%, will be generated using the approach specified above for each arm.  
4.2.2.1. 
Visit windowing and multiple measurements at one analysis timepoint 
Visit windowing for the primary endpoint will be applied as specified in Table 2 and Table 
3 and the windowed results will be used to determine the primary endpoint of SVR. 
Unscheduled assessments will be included in the analysis window. No imputation of 
missing data will be performed prior to visit windowing. 
If there are multiple values within an analysis window the following rules will be applied: 
For the End of ‘836 Treatment Analysis Timepoint: 
1. The latest available assessment in the window will be selected. 


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For Post ‘836 Treatment Analysis Timepoints: 
1. Worst non-missing value in the analysis window will be selected, if values are the 
same then the value closest to target day will be selected. If there are multiple 
values equidistant from the target day, the earliest will be selected. If all values 
within an analysis window are missing, then the result is missing for the analysis 
window. 
2. Worst value is defined in the order of: highest actual value, then <LLOQ, and then 
TND. 
Table 2 
Primary endpoint analysis windows for Arms 1, 2 and 4 
Analysis 
Set / 
Domain 
Parameter      
(if applicable) 
Target 
Study 
Day  
Analysis Window 
Analysis 
Timepoint 
Protocol 
Visit 
Beginning 
Timepoint 
Ending 
Timepoint 
Efficacy 
HBsAg and 
HBV DNA 
162 
148 
182 
End of ‘836 
Treatment 
Week 24 
 
 
218 
183 
238 
Post ‘836 
treatment Week 8 
Off 
treatment 
Week 8 
 
 
274 
239 
294 
Post ‘836 
treatment Week 16 
Off 
treatment 
Week 16 
 
 
330 
295 
350 
Post ‘836 
treatment Week 24 
Off 
treatment 
Week 24 
 
Table 3 
Primary endpoint analysis windows for Arm 3 
Analysis 
Set / 
Domain 
Parameter      
(if applicable) 
Target 
Study 
Day 
Analysis Window 
Analysis 
Timepoint 
Protocol 
Visit 
Beginning 
Timepoint 
Ending 
Timepoint 
Efficacy 
 
HBsAg and 
HBV DNA 
78 
64 
98 
End of ‘836 
Treatment 
Week 12 
 
 
134 
99 
154 
Post ‘836 
treatment Week 8 
Week 20 
 
 
190 
155 
210 
Post ‘836 
treatment Week 
16 
Off 
treatment 
Week 4 
 
 
246 
211 
266 
Post ‘836 
treatment Week 
24 
Off 
treatment 
Week 12 
 
The primary analysis will be based on planned end of treatment regardless of whether a 
patient discontinued treatment early.  


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For the second supplementary estimand described in Section 4.2.4.2, SVR will be 
measured from actual rather than planned end of treatment and the analysis windows 
should be amended accordingly. For this estimand, the date of last dose should be treated 
as the reference date and the rules in Table 4 should be used to determine the endpoint of 
SVR. 
Table 4 
Supplementary endpoint analysis windows Arms 1, 2, 3 and 4 
Analysis 
Set / 
Domain 
Parameter      (if 
applicable) 
Reference 
day 
Analysis Window 
Analysis Timepoint 
Beginning 
Timepoint 
Ending 
Timepoint 
Efficacy 
 
HBsAg and HBV 
DNA 
Reference 
date 
Reference 
date - 14 
Reference date 
+ 20 
End of ‘836 
Treatment 
 
 
Reference 
date + 56 
Reference 
date + 21 
Reference date 
+ 76 
Post ‘836 treatment 
Week 8 
 
 
Reference 
date + 112 
Reference 
date + 77 
Reference date 
+ 132 
Post ‘836 treatment 
Week 16 
 
 
Reference 
date + 168 
Reference 
date + 133 
Reference date 
+ 188 
Post ‘836 treatment 
Week 24 
 
4.2.2.2. 
Intercurrent Events and Missing data 
The intercurrent event of use of rescue medication has been incorporated into the definition 
of variable (composite strategy). The intercurrent event of discontinuation of, interruption 
of, and adherence to IP not due to wide disruptive event will be ignored (treatment policy).  
To prevent the efficacy of GSK3228836 being penalized for uncontrollable and unusual 
events (i.e. wide disruptive events such as the COVID-19 pandemic), if a wide disruptive 
event leads to discontinuation of GSK3228836 or significant interruption/non-adherence 
to GSK3228836, this will be handled assuming the intercurrent event had not happened 
(hypothetical strategy). Significant interruption/non-adherence is defined as a gap of >=21 
days between treatment doses at any time during the on-treatment period. According the 
hypothetical strategy, any data collected after the intercurrent event will be set to missing.  
If all analysis windows have non-missing response information, a participant’s response 
(Responder or Non-responder) is determined as follows: 
1. If rescue medication was used, then the participant is a non-responder. 
2. If HBsAg <LLOQ and HBV DNA <LLOQ in each of the analysis window, then 
the participant is a Responder, otherwise the participant is non-responder. Note: 
A result of TND is considered as <LLOQ.  
The following approach will be used to determine a participant’s response when HBsAg 
and HBV DNA data are missing from visits required to derive the primary endpoint:  
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 


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participants for whom SVR can be assessed. The final inference from the hierarchical 
Bayesian model will account for the missing data assuming MAR. 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). 
After the imputation above, if there is missing data in at least one analysis window then 
the participant is a non-responder. 
4.2.2.3. 
 Model Checking & Diagnostics - MCMC Mixing Diagnosis  
Two sampling chains will be run, with differing starting values and each with a burn-in 
period of 5,000 samples, to ensure adequate sampling from the posterior. The starting 
values will be as above Section 4.2.2. 
Mixing will be regarded as “each chain is independently realizing values similar to those 
for which the other chains have also sampled.” Adequate mixing will be concluded if the 
chains meet following conditions: 
1. 
The Brooks-Gelman Ratio (BGR) (Brooks SP, 1998) for each parameter is in the 
interval (0.8, 1.2).   
2. 
Each chain appears mix well, upon visual inspection of each chain’s trace plot, 
including assessing the mutual overlap of the chains for each parameter.  
3. 
Each kernel density plot appears smooth upon visual inspection. 
4.2.3. 
Sensitivity analyses 
For the primary estimand, a sensitivity analysis will be performed using the Bayesian 
model described in Section 4.2.2, 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.  
4.2.4. 
Additional estimands 
The following supplementary estimands are defined to support the primary objective.  
4.2.4.1. 
Using Hypothetical Strategy to Deal with ICE of Discontinuation of, 
Interruption of, and Adherence to IP 
The first supplementary estimand is defined in the same way as the primary estimand, 
except the intercurrent event of discontinuation of, interruption of, and adherence to IP will 
be handled assuming they had not happened (hypothetical strategy). Discontinuation of 
GSK3228836 or significant interruption/non-adherence to GSK3228836 will be handled 
assuming the intercurrent event had not happened (hypothetical strategy). Significant 
interruption/non-adherence is defined as a gap of >=21 days between treatment doses at 
any time during the on-treatment period. According the hypothetical strategy, any data 
collected after the intercurrent event will be set to missing. 


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This supplementary estimand supporting the primary objective in participants with CHB 
on stable nucloes(t)ide therapy and participants with CHB not currently on nucleos(t)ide 
therapy is the proportion of participants in each treatment arm 1, 2, 3 and 4 who achieve 
SVR for 24 weeks after the planned end of GSK3228836 treatment in the absence of rescue 
medication, had they not been affected by discontinuation of IP, interruptions in IP, 
adherence to IP, or wide disruptive events. 
4.2.4.2. 
Measuring SVR from Actual End of Treatment instead of Planned End 
of Treatment 
The second supplementary estimand is defined in the same way as the primary estimand, 
except the assessment time frame for participants 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 nucleos(t)ide therapy and participants 
with CHB not currently on nucleos(t)ide therapy is the proportion of participants in each 
treatment arm 1, 2, 3 and 4 who achieve SVR for 24 weeks after the actual end of 
GSK3228836 treatment in the absence of rescue medication, regardless of completing IP, 
interruptions in IP or adherence to IP, had they not been affected by wide disruptive events. 
4.2.4.3. 
Using Principal Stratum Strategy to Deal with Protocol Deviations 
The third supplementary estimand is defined in the same way as the primary estimand, 
except for the population, variable and intercurrent events definitions. The population is 
participants with CHB not currently on nucleos(t)ide therapy. The variable for this 
estimand will be defined as sustained virologic response (SVR) for 24 weeks after the 
planned end of GSK3228836 treatment in the absence of rescue medication for medical 
reasons. The intercurrent event of use of rescue medication will be separated into two: 
1. Use of rescue medication for medical reasons 
2. Use of rescue medication because of a protocol deviation 
The use of rescue medication for medical reasons has been incorporated into the definition 
of variable (composite strategy). The use of rescue medication because of a protocol 
deviation will be handled by excluding these participants from the analysis (principal 
stratum strategy). This supplementary estimand supporting the primary objective in 
participants with CHB not currently on nucleos(t)ide therapy is the proportion of 
participants in each treatment arm 1, 2, 3 and 4 who achieve SVR for 24 weeks after the 
planned end of GSK3228836 treatment in the stratum of participants who did not use 
rescue medication in error, in the absence of rescue medication for medical reasons, 
regardless of completing IP, interruptions in IP or adherence to IP, had they not been 
affected by wide disruptive events. 
4.2.4.4. 
Using a Modified Definition of SVR 
The fourth supplementary estimand is defined in the same way as the primary estimand, 
except the variable is defined using a modified definition of sustained virologic response 
(SVR) for 24 weeks after the planned end of GSK3228836 treatment in the absence of 
rescue medication.  The modified definition of sustained virologic response is defined as 


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observing HBsAg <LLOQ and HBV DNA <LLOQ at each analysis window in the 24 
weeks after the end of GSK3228836 treatment. Any observation of HBsAg LLOQ or 
HBV DNA LLOQ must be confirmed at a consecutive visit (including unscheduled visits) 
for the patient to be classed as having lost their SVR.  
Subjects who have a value of HBsAg LLOQ or HBV DNA LLOQ at their last visit, 
which cannot be confirmed due to no further follow up, will be treated as non-responders. 
This supplementary estimand supporting the primary objective in participants with CHB 
on stable nucloes(t)ide therapy and participants with CHB not currently on nucleos(t)ide 
therapy is the proportion of participants in each treatment arm 1, 2, 3 and 4 who achieve 
the modified definition of SVR for 24 weeks after the planned end of GSK3228836 
treatment in the absence of rescue medication, regardless of completing IP, interruptions 
in IP or adherence to IP, had they not been affected by wide disruptive events.  
4.3. 
Secondary Endpoint(s) Analyses 
4.3.1. 
Key secondary endpoint(s) 
4.3.1.1. 
Efficacy of GSK3228836 on biomarkers and virus-specific antibody 
response 
The group of estimands supporting the secondary objective of assessing the efficacy of 
GSK3228836 on biomarkers and virus-specific antibody responses for each sub-population 
are the population summary for each variable in each treatment arm 1-4.  
Missing data for variables defined above (except for Time to ALT normalization) will be 
ignored, only available data will be summarized. No sensitivity analysis is planned for the 
group of estimands supporting this objective. 
Estimands supporting this objective are defined as follows: 
- Population: one subpopulation of participants with CHB on stable nucleos(t)ide therapy 
and a second subpopulation of participants with CHB not currently on nucleos(t)ide 
therapy. For the time to ALT normalization endpoint, only subjects with ALT>ULN at 
baseline will be included. For summaries of HBe antibody (anti-HBeAg) levels, only 
participants who are HBeAg Positive at baseline will be included. 
- Treatments: arms 1-4. Estimation within each arm. 
- Intercurrent events: For the proportion of participants achieving HBsAg <LLOQ and 
HBV DNA <LLOQ in the absence of rescue medication at the end of treatment analysis 
window, end of treatment will be determined using the end of treatment analysis window 
defined in Section 4.2.2. In line with the primary endpoint, missing data not due to wide 
disruptive events will be imputed as non-response. Missing data due to wide disruptive 
events will be ignored without any imputation. 
Other endpoints will be summarized regardless of completing IP, interruptions in IP or 
adherence to IP (treatment policy strategy) and regardless of rescue medication (except 


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for ALT normalization which can only be achieved in the absence of rescue medication). 
HBV DNA, HBsAg, HBeAg levels that are below the LLOQ will be imputed for 
summaries of actual values and change from baseline following the rules in Section 4.1.1. 
1) Categorical Variables: 
• 
Achieving HBsAg <LLOQ and HBV DNA <LLOQ at the end of treatment analysis 
window. Data will be presented overall and by baseline stratification factors (HBsAg 
<3 log IU/mL and Negative HBeAg; BsAg >3 log IU/mL and Negative HBeAg; 
HBsAg <3 log IU/mL and Positive HBeAg; HBsAg >3 log IU/mL and Positive 
HBeAg; HBsAg <3 log IU/mL and All HBeAg; All HBsAg and Negative HBeAg; 
HBsAg <3 log IU/mL and All HBeAg; All HBsAg and Positive HBeAg) 
• 
Categorical changes from baseline in HBsAg (e.g., <0.5, ≥0.5, ≥1, ≥1.5, ≥3 log10 
IU/mL) and in HBV DNA (e.g., <1, ≥1, ≥2, ≥3 log IU/mL). Change from baseline 
will be presented at each visit and for the following time periods: up to and including 
Week 6, Up to and including Week 12, Up to and including Week 24, Up to and 
including off-treatment Week 24. Data will be presented overall and by baseline 
stratification factors (HBsAg <3 log IU/mL and Negative HBeAg; BsAg >3 log 
IU/mL and Negative HBeAg; HBsAg <3 log IU/mL and Positive HBeAg; HBsAg 
>3 log IU/mL and Positive HBeAg; HBsAg <3 log IU/mL and All HBeAg; All 
HBsAg and Negative HBeAg; HBsAg <3 log IU/mL and All HBeAg; All HBsAg 
and Positive HBeAg) 
• 
ALT normalization (ALT≤ULN) over time in absence of rescue medication in 
participants with baseline ALT>ULN  
• 
HBe antibody (anti-HBeAg) levels in HBeAg Positive patients 
• 
HBs antibody (anti-HBsAg) levels (HBs Antibody >=11.5 IU/L is HBs antibody 
positive and HBs Antibody <11.5 IU/L is HBs antibody negative) 
- Population summary: proportion of participants in each category for each treatment 
arm. 
2) Continuous Variables:  
• 
Actual values and change from baseline over time of HBsAg and HBV DNA  
• 
Actual values and change from baseline of HBeAg levels 
• 
HBs antibody (anti-HBsAg) levels  
- Population summary: mean values and mean changes from baseline for each variable in 
each treatment arm. 
3) Time to Event Variable:  


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• 
Time to ALT normalization in absence of rescue medication in participants with 
baseline ALT>ULN. 
- Population summary: Turnbull’s estimator for the non-parametric estimation of time to 
ALT normalization in each treatment arm. 
ALT normalization is defined in subjects with ALT>ULN at baseline as a return to ULN 
(ULN = 40 for males and 33 in females). Time to ALT normalization is defined as time 
from baseline to the first follow-up where subject’s ALT has returned to normal.  
For participants who withdraw from the study or Participants with ALT>ULN at the end 
of study, time to ALT normalization will be censored at the time of last visit with non-
missing ALT value available. Participants who receive rescue medication cannot go on to 
achieve the event of ‘ALT normalization in the absence of rescue medication’; such 
participants will be censored at the end of the follow up period.  
4.3.1.2. 
Comparison of efficacy between arms 1, 2 and 3 
Definition of Estimands 
Estimands supporting secondary objective of comparing the efficacy between arms 1, 2, 
and 3 are defined as follows: 
- Population: separate assessment for the following: 
• 
participants with CHB on stable nucleos(t)ide therapy  
• 
participants with CHB not currently on nucleos(t)ide therapy 
- Variable: Sustained virologic response (SVR) for 24 weeks after the end of GSK3228836 
treatment in the absence of rescue medication. 
- Treatments: arms 1, 2, and 3.  Three treatment comparisons between: arms 1 and 2, arms 
1 and 3, and arms 2 and 3. 
- Intercurrent events: use of rescue medication, and discontinuation of/interruption 
of/adherence to IP.  The use of rescue medication has been incorporated into the definition 
of variable (composite strategy).  Discontinuation of, interruption of, and adherence to IP 
will be ignored (treatment policy). Wide disruptive events (such as COVID-19 pandemic) 
leading to discontinuation of, interruption of, and non-adherence to GSK3228836 will be 
handled assuming they had not happened (hypothetical strategy). 
- Population summary: difference in proportion of participants who achieve SVR between 
treatment arms. 
The group of estimands supporting this objective for each sub-population are the difference 
in each treatment comparisons in the proportion of participants who achieve SVR for 24 
weeks after the end of GSK3228836 treatment in the absence of rescue medication 
regardless of completing IP, interruptions in IP or adherence to IP had they not been 
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The non-responder imputation described in Section 4.2.2 will be used when HBsAg and 
HBV DNA data are missing from visits required to derive the endpoint.  
Main analytical approach 
Comparisons between arms will be made by calculating differences between the posterior 
distributions of the response rate in each arm which will be summarised to obtain posterior 
means and CIs. Samples from the posterior distribution of the response rates in each arm 
will also be used to obtain posterior probabilities of interest (e.g. Pr(Arm 1 – Arm 2 > -5% 
| Data)).The point estimates of differences in sustained virologic response rate with 95% 
credible intervals will be calculated for the treatment comparisons described in the 
estimands. 
Posterior probability for the differences of following comparisons will also be reported; 
1. Arm 1 vs. Arm 2 
2. Arm 1 vs. Arm 3 
3. Arm 2 vs. Arm 3 
Regimen Selection Approach 
If success criteria is met for more than one arm, regimen selection will be conducted. The 
non-inferiority (NI) decision rules for two-treatment comparison is Posterior Prob(less 
intensive arm SVR rate – more intensive arm SVR rate > -5%) > 65%. The arms are ordered 
in intensity from 1 (most intensive) to 4 (least intensive).  
For each comparison, the posterior distribution of difference in SVR rate will be derived 
and the posterior probability (less intensive arm SVR rate – more intensive arm SVR rate 
> -5%) will be obtained based on the model described in Main analytical approach present 
under Section 4.3.1.2. If posterior probability is >65%, EoS NI rule is met. 
If 2 arms meet the success rule, NI comparison between the 2 arms will be conducted. If 
the NI rule is met, then select the less intensive arm, otherwise select the more intensive 
arm. 
If 3 arms meet the success rule, sequential two-treatment comparisons will be conducted 
for the 3 arms. The regimen selection follows the decision tree below. 


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If 4 arms meet the success rule, sequential two-treatment comparisons will be conducted 
for the 4 arms. The regimen selection follows the decision tree below. 
 
Operating Characteristics for Regimen Selection 
The Operating characteristics of regimen selection are summarized in Table 5 for a range 
of scenarios. 


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Table 5 
Operating Characteristics for Regimen Selection 
Arm 1 
True 
rate 
Arm 2 
True 
rate 
Arm 3 
True 
rate 
Arm 4 
True 
rate 
Prob of 
selecting 
arm 1 
Prob of 
selecting 
arm 2 
Prob of 
selecting 
arm 3 
Prob of 
selecting 
arm 4 
Prob of 
selecting 
none 
30% 
30% 
30% 
30% 
16% 
21% 
28% 
35% 
0% 
30% 
30% 
30% 
25% 
19% 
26% 
36% 
19% 
0% 
30% 
30% 
25% 
30% 
21% 
29% 
11% 
39% 
0% 
30% 
25% 
30% 
30% 
21% 
7% 
33% 
39% 
0% 
25% 
30% 
30% 
30% 
4% 
23% 
33% 
39% 
0% 
30% 
30% 
25% 
25% 
26% 
37% 
15% 
22% 
0% 
30% 
25% 
30% 
25% 
26% 
9% 
43% 
22% 
0% 
25% 
30% 
30% 
25% 
6% 
30% 
43% 
22% 
0% 
30% 
25% 
25% 
30% 
30% 
11% 
14% 
44% 
1% 
25% 
30% 
25% 
30% 
7% 
34% 
14% 
44% 
1% 
25% 
25% 
30% 
30% 
7% 
8% 
40% 
44% 
1% 
30% 
25% 
25% 
25% 
38% 
15% 
19% 
26% 
1% 
25% 
30% 
25% 
25% 
9% 
44% 
19% 
27% 
1% 
25% 
25% 
30% 
25% 
9% 
11% 
52% 
27% 
1% 
25% 
25% 
25% 
30% 
11% 
15% 
19% 
53% 
2% 
4.3.2. 
Supportive secondary endpoint(s) 
Historical placebo control 
If historical individual patient-level data are available, a longitudinal model including 
historical response at 12, 24 and 48 weeks of placebo treatment will be constructed.  For 
the first 12-week period, the model will allow dynamic borrowing from historical placebo 
data to the concurrent placebo in Weeks 1-12 in arm 4. Furthermore, the model will provide 
longitudinal prediction of response at Week 24 and Week 48 for participants in arm 4 (had 
they continued on Placebo rather than switching to GSK3228836 treatment).  
4.3.3. 
Pharmacokinetic Secondary Endpoints 
4.3.3.1. 
Endpoint / Variables 
Pharmacokinetics (PK) of GSK3228836 and nucleos(t)ide will be characterized. In all 
participants, GSK3228836 C and terminal half-life (t½) will be estimated. In participants 
with intensive PK sampling, GSK3228836 and nucleos(t)ide plasma PK parameters will 
be derived, including but not limited to AUC, C, Cmax and tmax. 
4.3.3.2. 
Derived Pharmacokinetic Parameters 
Pharmacokinetic parameters will be calculated by standard non-compartmental analysis 
using the currently supported version of WinNonlin. All calculations of non-
compartmental parameters will be based on actual sampling times. Pharmacokinetic 


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parameters listed will be determined from the plasma concentration-time data, as data 
permits. 
Table 6 
Pharmacokinetic Parameters and Parameter Description 
Parameter 
Data 
Analyte 
Parameter Description 
AUC(0-24) 
Intensive PK  
GSK3228836 
Nucleos(t)ide 
Area under the concentration-time curve from 
time zero up to 24 hours post-dose.  
AUC(0-168) 
Intensive PK 
GSK3228836 
Area under the concentration-time curve from 
time zero up to 168 hours post-dose.  
C 
Intensive PK 
Nucleos(t)ide 
Concentration at the end of the dosing interval 
C 
Sparse PK – 
All Subjects 
GSK3228836 
Concentration at the end of the dosing interval 
Cmax 
Intensive PK 
GSK3228836 
Nucleos(t)ide 
Maximum observed concentration 
tmax 
Intensive PK 
GSK3228836 
Nucleos(t)ide 
Time of maximum observed concentration 
t½ 
Sparse PK – 
All Subjects 
GSK3228836 
Terminal half-life determined using 
concentrations collected during the off-treatment 
period  
 
Sparse PK is collected weekly during the dosing period and at certain pre-specified visits 
during the off-treatment period. Intensive PK is collected at one visit between Week 14 
(inclusive) and week 24 (inclusive). 
4.3.3.3. 
Population of Interest  
The secondary pharmacokinetic analyses will be based on the Pharmacokinetic (PK) 
population, unless otherwise specified.  
4.3.3.4. 
Statistical Analyses / Methods 
Unless otherwise specified, endpoints / variables defined in Table 6 will be summarised 
using descriptive statistics, graphically presented (where appropriate) and listed. 
Descriptive statistics for continuous variables will summarise n, arithmetic mean, SD, 95% 
CI, median, minimum, maximum, geometric mean with associated 95% CI, and the 
between-participant CV (%CVb) for the geometric mean. For sparse PK summary of C 
and t1/2, additionally present 5th and 95th percentile. 
Sparse PK parameters (C and t1/2) of GSK3228836 will be summarised and listed by 
treatment arm, study visit (only applies to C), geographic region (All participants, China, 
Japan and East Asia). Sparse C-time plots will be created and compared by the same 
factors. 
Intensive PK parameters (AUC(0-24), AUC(0-168), Cmax and tmax) of GSK3228836 will 
be summarised and listed by dose level (150mg and 300mg). Intensive concentration-time 
plots will be created and compared by the same factors. 


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Intensive PK parameters (AUC(0-24), C, Cmax and tmax) of nucleos(t)ide will be 
summarised and listed separately for tenofovir (separately for tenofovir disoproxil 
fumarate and tenofovir alafenamide) and entecavir. Intensive concentration-time plots will 
be created separately for tenofovir (separately for tenofovir disoproxil fumarate and 
tenofovir alafenamide) and entecavir. 
Refer to Section 4.6 for more information on geographic region subpopulations. 
4.4. 
Exploratory Endpoints Analyses 
4.4.1. 
Exploratory Efficacy Endpoints 
In addition to the exploratory analyses described in this section, all primary and secondary 
endpoints assessed for Arms 1, 2, and 3 will also be assessed as exploratory analyses in 
Arm 4. 
4.4.1.1. 
Comparison of efficacy between 12 weeks of GSK3228836 treatment 
with a loading dose or without a loading dose 
Estimands supporting exploratory objective of comparing the efficacy between 12 weeks 
of GSK3228836 treatment with a loading dose or without a loading dose are defined as 
follows: 
- Population: separate assessment for the following: 
• 
participants with CHB on stable nucleos(t)ide therapy. 
• 
participants with CHB not currently on nucleos(t)ide therapy. 
- Variable: Sustained virologic response (SVR) for 24 weeks after the end of GSK3228836 
treatment in the absence of rescue medication. 
- Treatments: arm 3 and 4. Treatment comparison between arms 3 and 4. 
- Intercurrent events: use of rescue medication, and discontinuation of/interruption 
of/adherence to IP.  The use of rescue medication has been incorporated into the definition 
of variable (composite strategy).  Discontinuation of, interruption of, and adherence to IP 
will be ignored (treatment policy). Wide disruptive events (such as COVID-19 pandemic) 
leading to discontinuation of, interruption of, and non-adherence to GSK3228836 will be 
handled assuming they had not happened (hypothetical strategy). 
- Population summary: difference in proportion of participants who achieve SVR between 
treatment arms 3 and 4. 
 
The group of estimands supporting this objective for each sub-population are the 
differences between arms 3 and 4 in the proportion of participants who achieve SVR for 
24 weeks after the end of GSK3228836 treatment in the absence of rescue medication 
regardless of completing IP, interruptions in IP or adherence to IP had they not been 
affected by wide disruptive events. 
The non-responder imputation described in Section 4.2.2 will be used when HBsAg and 
HBV DNA data are missing from visits required to derive the endpoint.  
 
Comparisons between arms will be made by calculating differences between the posterior 
distributions of the response rate in each arm which will be summarised to obtain posterior 


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means and CIs. Samples from the posterior distribution of the response rates in each arm 
will also be used to obtain posterior probabilities of interest (e.g. Pr(Arm 1 – Arm 2 > -5% 
| Data)).The point estimates of differences in sustained virologic response rate with 95% 
credible intervals will be calculated for the treatment comparisons described in the 
estimands. 
 
 
4.4.1.2. 
Concordance of virologic response at Week 6, Week 12 and Week 24 
and achieving SVR 
The concordance of virologic response (HBV DNA < LLOQ and HBsAg < LLOQ) at on-
treatment timepoints of interest with achieving SVR will be explored. Number of subjects 
with an early response (Yes or No) will be cross tabulated with SVR (Yes or No) for on-
treatment visits Week 6, Week 12 and Week 24 separately. Positive Predictive Value and 
Negative Predictive Value will be presented.   
4.4.1.3. 
Pharmacodynamic effect of GSK3228836 on exploratory biomarkers 
The pharmacodynamic effect of GSK3228836 on exploratory biomarkers (HBcrAg, HBV 
RNA) will be assessed.  
Summary tables and figures will be created to show HBcrAg and HBV RNA (for units 
copies/mL and log10 copies/mL) over time. Additionally, summaries of HBcrAg by 
HBeAg status, and HBV RNA for RoW (excluding China) and China population will be 
presented.  
For end of treatment visit only, a summary of HBcrAg and HBV RNA for subjects with/or 
without HBsAg < LLOQ at end of treatment will be presented, by SVR status.  
Further details will be described in a separate PK-PD analysis plan developed by CPMS. 
4.4.2. 
Exploratory PK-PD Endpoints 
To evaluate PK-efficacy relationship and PK-safety relationship, exploratory graphical 
analyses will be initially performed for efficacy (e.g., HBsAg) and safety endpoints. If a 
relationship between exposure and efficacy and/or safety endpoints is present, population 
PK-PD modelling will be conducted using nonlinear mixed effect methods.  
The model will assess the effect of various factors (covariates) of the modelled efficacy or 
safety endpoints. Relevant PK-PD model endpoints for example:  
• 
apparent clearance 
• 
apparent volume of distribution 
• 
IC50 
• 
random variability 


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Full details of PK-PD and Population PK analysis will be described in a separate analysis 
plan developed by CPMS. 
4.4.3. 
Exploratory Virology Endpoints 
The virology analyses will be based on the “Safety” population.  
Missing data for the endpoints in this section will be ignored without any imputation. 
4.4.3.1. 
HBV Genotype 
HBV Genotype will be collected in the eCRF as well as identified by HBV Sequence. HBV 
Genotype from both data sources will be listed and the listing will include the final reported 
genotype.  
For subjects with genotype both collected in the eCRF and determined by HBV Sequence 
the final reported genotype will be determined as follows:  
For participants on stable nucleos(t)ide treatment:  
• 
Genotype reported in the eCRF will take precedence 
For participants currently not on nucleos(t)ide treatment:  
• 
If the if the sequence genotype was derived from DNA, the HBV Sequence genotype 
will take precedence.  
• 
If the if the sequence genotype was derived from RNA (i.e. rather than DNA due to 
low DNA levels hence RNA sequencing was employed), the genotype reported in 
the eCRF will take precedence – similar to the participants on stable nucleos(t)ide. 
 
Data from the Week 1 Day 1 visit will be used to determine HBV genotype by HBV DNA 
or RNA sequencing. However, as HBV genotype should not change over time, if a 
participant missed the Week 1 Day 1 visit, HBV genotype can be determined from a later 
sample if available. 
The number of participants with each final reported genotype will be presented by arm and 
overall. 
Baseline log HBsAg, change from baseline in log HBsAg at End of GSK836 Treatment 
visit (Week 12 / Week 24) and Off GSK836 Treatment Week 24 visit (Week 36 / Week 
48), number of subjects achieving HBsAg < LLOQ at any time up to End of GSK836 
Treatment visit (Week 12 / Week 24) or Off  GSK836 Treatment Week 24 visit (Week 36 
/ Week 48), and mean time to achieving HBsAg < LLOQ will be presented for each arm 
separately. Results will be summarized by baseline final reported genotype. 
For participants currently not on nucleos(t)ide treatment only, baseline log HBV DNA,  
change from baseline in log HBV DNA at End of GSK836 Treatment visit (Week 12 / 


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Week 24) and Off GSK836 Treatment Week 24 visit (Week 36 / Week 48), number of 
subjects achieving HBV DNA < LLOQ at any time up to End of GSK836 Treatment visit 
(Week 12 / Week 24) and Off GSK836 Treatment Week 24 visit (Week 36 / Week 48), 
and mean time to achieving HBV DNA < LLOQ will be presented for each arm separately. 
Results will be summarized by baseline final reported genotype. 
4.4.3.2. 
HBV Sequences 
Baseline and treatment emergent nucleotide changes both within HBV binding site and 
outside of the HBV binding site will be summarized by number of subjects for each arm 
and overall and data will be listed.  
The following steps can be followed to identify nucleotide changes within the HBV binding 
site: 
1. Identify nucleotide sequence records 
2. Identify the 20ntd binding site of HBV at the following locations: 1581 – 1600 
3. If the allelic frequency meets the threshold for a mutation flag as a mutation 
 
Participants who have data in the PF dataset but have no binding site mutations will be 
considered Wild Type for the binding site. 
Mutations that are reported for >1 genetic location of interest will only be reported once. 
Unless otherwise specified, a >=5% threshold of allelic frequency will be used to report a 
mutation vs wild type and only observations meeting this threshold will be included in 
summary tables. However, mutations >=1% and <5% will be reported in the Listing of 
Mutations in the Binding Site in Participants with Mutation at Any Time for full 
transparency. Mutations will be reported as “variant” if >=15% and “minority species”, 
>=5% and <15%. 
Development of a mutation during therapy (i.e. treatment emergent) will be defined as a 
substitution present at <5% at baseline but detected at >=5% post baseline. 
Baseline log HBsAg, change from baseline in log HbsAg at End of GSK836 Treatment 
visit (Week 12 / Week 24) and Off GSK836 Treatment Week 24 visit (Week 36 / Week 
48), number of subjects achieving HbsAg < LLOQ at any time up to End of GSK836 
Treatment visit (Week 12 / Week 24) and Off GSK836 Treatment Week 24 visit (Week 36 
/ Week 48), and mean time to achieving HbsAg < LLOQ will be presented for each arm 
separately. Results will be summarized by baseline binding site polymorphism. 
For participants currently not on nucleos(t)ide treatment only, baseline log HBV DNA,  
change from baseline in log HBV DNA at End of GSK836 Treatment visit (Week 12 / 
Week 24) and Off GSK836 Treatment Week 24 visit (Week 36 / Week 48), number of 
subjects achieving HBV DNA < LLOQ at any time up to End of GSK836 Treatment visit 
(Week 12 / Week 24)  and Off GSK836 Treatment Week 24 visit (Week 36 / Week 48), 
and mean time to achieving HBV DNA < LLOQ will be presented for each arm separately. 
Results will be summarized by baseline binding site polymorphism. 


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For all observed mutations in the binding site at baseline and for frequently (e.g. in >=5% 
subjects) observed mutations outside of the binding site at baseline, a 2x2 contingency table 
of mutation (present / absent) vs. response at end of GSK836 treatment (Yes / No) and 
response at Off GSK836 Treatment Week 24 (Yes / No) will be presented. Response at 
end of GSK836 treatment will be defined as HBV DNA < LLOQ, HBsAg < LLOQ and no 
rescue medication at the end of treatment analysis window. Response at 24 weeks off 
GSK836 treatment will be defined as SVR.  The table will be repeated using a >=1% 
threshold of allelic frequency, for all mutations in the binding site only. 
4.4.4. 
Exploratory Immunology Endpoints 
Details of the immunology endpoints will be included in a separate biomarker analysis 
plan. 
4.4.5. 
Exploratory PRO Endpoints 
Patient reported outcomes, the HBQOL and the EQ-5D, will be analysed using the ITT 
analysis set. 
For HBQOL summary statistics for actual values and changes from baseline in overall 
score and each of the 6 domains (psychological well-being, anticipation anxiety, vitality, 
stigma, transmissibility and vulnerability) will be displayed by visit for Arms 1, 2, 3 and 
4. HBQoL v1.0 (Spiegel BM, 2007) will be used to derive scores for HBQoL.  
The EQ-5D quality of life instrument provides a utility score and thermometer score. The 
descriptive system comprises 5 dimensions: mobility, self-care, usual activities, 
pain/discomfort, and anxiety/depression with 3 levels for each dimension from level 1 = 
no problem to level 3 = extreme problems.  
The health state is defined by combining the levels of answers from each of the 5 questions. 
Each health state is referred to in terms of a 5-digit code. For example, state 11111 indicates 
no problems on any of the 5 dimensions, while state 11223 indicates no problems walking 
about, no problems with self-care, some problems with performing usual activities, 
moderate pain or discomfort and extremely anxious or depressed. 
The health state 5-digit code is translated into the utility score, which is valued up to one 
(representing perfect health) with lower values meaning worse state, according to the 
methodology described in Dolan P., 1997. The UK values set described in Dolan P., 1997 
will be used for all subjects regardless of their country origin. 
Summary statistics for actual values and changes from baseline in EQ-5D thermometer and 
utility scores will be presented by visit for Arms 1, 2, 3 and 4.  
A listing of the utility score and thermometer values will be produced. 
4.5. 
Safety Analyses 
The safety analyses will be based on the Safety Analysis Set, unless otherwise specified. 
To allow comparison between safety in active treatment vs placebo, and loading dose vs 


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no loading dose, selected safety displays will be presented by study Weeks 1 – 12, Weeks 
13 – 24, and Weeks 25 – 48; refer to the OPS for details of which outputs should be 
presented by Week, and refer to Section 6.2.2.2 for definitions of assessment windows for 
adverse events. 
4.5.1. 
Extent of Exposure 
Extent of exposure will be summarized using summary statistics. Number of subjects with  
< 6 weeks <= 12 weeks exposure, <= 24 weeks exposure, > 24 weeks exposure will be 
presented, and the overall duration of exposure (see Output and Programming Specification 
for deviation of overall duration of exposure) will be summarized. Study intervention 
compliance will be summarized as described in Section 6.1.5.Adverse Events 
Number of days of exposure to study drug will be calculated based on the formula:   
Duration of Exposure in Days = Last injection date – First injection date + 1 
 
The cumulative dose will be based on the formula: 
Cumulative Dose = Number of Injections of 300mg x 300mg + Number of Injections of 
150mg x 150mg 
4.5.2. 
Adverse Events 
An adverse event (AE) is considered treatment emergent if the AE onset date is on or after 
treatment start date. If AE start date is completely missing and the end date is on or after 
the treatment start date, the AE will be assumed to be treatment emergent. All AE 
summaries will be based on treatment emergent events unless otherwise specified. 
Adverse events will be coded using the latest version of MedDRA coding dictionary, to 
give a preferred term and a system organ class. These preferred terms and system organ 
classes will be used when summarising the data. The severity of AEs and SAEs will be 
determined by the investigator according to the DAIDS grading system Version 2.1 
[National Institute of Allergy and Infectious Diseases. Division of AIDS, 2017], unless 
specified otherwise in the protocol.  
For AEs by maximum grade summary tables, if a participant reports an AE more than once 
within an SOC/PT, the AE with the most severe intensity will be included in summaries. 
Relationship to study treatment, as indicated by the investigator, is classified as “not 
related” or “related”. Adverse events with a missing relationship to study treatment will be 
regarded as “related” to study treatment. 
The followingtable AE summaries will be presented: 
1. AEs overview: summarize the number and percentage of participants with any 
adverse event, AEs related to study treatment, AEs leading to permanent 
discontinuation of study treatment, withdrawal from the study, any serious 
adverse events (SAE), SAEs related to study treatment, fatal SAEs and fatal SAEs 
related to study treatment.  
2. All AEs by system organ class (SOC) and preferred term (PT)  


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3. All AEs by SOC and PT and maximum grade  
4. All drug-related AEs by SOC and PT  
5. All drug-related AEs by SOC and PT and maximum grade  
6. Serious AEs (SAEs) by SOC and PT  
7. AEs leading to withdrawal from the study by SOC and PT  
8. AEs leading to permanent discontinuation of investigational product by SOC and 
PT  
9. AEs leading to withdrawal from the study by SOC and PT and maximum grade  
10. AEs leading to permanent discontinuation of investigational product by SOC and 
PT and maximum grade  
11. Fatal AEs by SOC and PT 
12. AEs by overall frequency 
13. Serious, Non-serious and Drug-Related AEs by SOC and PT (number of subjects 
and occurrences). This will be presented for Overall, and for Week 1 – 12, Week 
13 – 24, and Week 25 – Week 48.  
14. Serious Fatal and Non-Fatal Drug-Related AEs by Overall Frequency 
Number of participants with AEs will be summarized if it is not specified otherwise.  
In summary tables where AEs are presented by SOC, PT, and maximum grade, SOCs will 
be sorted in descending order of the total incidence then alphabetically, PTs will be sorted 
in descending order of the total incidence then alphabetically within the SOC.  
For completely missing or partial missing AE start date or end date, imputation rules will 
be applied following the rules stated in the Output and Programming Specification. 
 Deaths will be listed including primary cause of death. 
4.5.2.1. 
Adverse Events of Special Interest 
The following AEs of special interest will be reported:  
• 
ALT increase 
• 
Vascular inflammation and complement activation 
• 
Thrombocytopenia 
• 
Renal injury 
• 
Injection site reactions 
An up to date list of specific MedDRA Queries (SMQs), high level terms (HLTs) or 
individual preferred terms (PTs) used to identify AESIs is periodically updated and stored 
in a central location. At the time of DBR, the latest version of the terms will be extracted 
and used to identify AESIs. 
All AEs of special interest will be summarized by SOC and PT, and also summarized by 
SOC, PT and maximum grade. Serious AESIs will be summarized by SOC and PT. All 
AEs of special interest will be listed.  


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Separate outputs will be created for each AESI category (ALT increase, vascular 
inflammation and complement activation, thrombocytopenia, renal injury and injection site 
reactions) to explore the data in more detail if data permits.  
Event Characteristics: The characteristics of all event occurrences during the post-baseline 
period will be summarized, which looks at event characteristics (serious, drug-related, 
leading to withdrawal, severe or Grade 3-4, fatal), number of events per participant, 
outcome, maximum grade or intensity and action taken.   
4.5.2.2. 
COVID-19 Assessment and COVID-19 AEs 
A standardized MedDRA Query (SMQ) will be used to identify all COVID-19 AEs. 
The overall incidence of AEs and SAEs of COVID-19, COVID-19 AEs leading to study 
intervention discontinuation, COVID-19 AEs leading to study withdrawal, and Grade 3 
and 4 COVID-19 AEs / severe COVID-19 AEs will be summarized. The incidence of these 
events at individual PT level can be obtained from the standard AE/SAE summaries. 
COVID-19 assessments for participants with potential, suspected or confirmed COVID-19 
AEs will be summarized.  
If >5% participants overall report ≥1 COVID-19 AE, then onset and duration of the first 
occurrence of COVID-19 AEs, and COVID-19 AE symptoms (from the COVID-19 eCRF 
page) will be summarized. The same rule will apply to COVID-19 SAEs. 
4.5.3. 
Additional Safety Assessments 
4.5.3.1. 
Laboratory Data 
Only central lab data will be used for summary analyses and figures; local lab data will be 
included in listings, as appropriate.  
Summary statistics for changes from baseline for each numeric parameter at each visit will 
be presented, separately for all clinical chemistry parameters, all hematology parameters 
and all urinalysis parameters.   
For immunology parameters, summary statistics for actual value and change from baseline 
data for each parameter at each visit will be presented, separately for all numeric 
parameters. Listings will also be created.  
Ang-II will be included in the immunology summaries and listings and additionally a 
listing of all Ang-II lab values will be presented. Plots showing mean actual and change 
from baseline values of Ang-II over time will be presented.  
For categorical immunology parameters c-ANCA and p-ANCA, summary table of baseline 
Negative to post-baseline Positive, baseline value no change, and baseline Positive to post-
baseline Negative will be created. Listing will be created as well.  


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For coagulation parameters Prothrombin Intl. Normalized Ratio (INR), Prothrombin Time 
(PT) and Activated Partial Thromboplastin Time (aPTT), summary statistics for actual at 
each visit will be presented. Listing will be created as well.  
Shift tables for laboratory parameters showing baseline toxicity versus maximum post-
baseline (on-treatment and off-treatment periods combined) toxicity for each grade 
(Grade1, Grade 2, etc.) for chemistry and hematology parameters will be provided.   
Increase to Grade 3 or higher lab abnormalities for platelets, ALT, AST, INR, total 
bilirubin, serum creatinine, eGFR, ACR will be summarized.   
Laboratory values outside of normal range will be summarized and listed.  
Grading categories for laboratory tests are determined using the DAIDS grading system 
Version 2.1 [National Institute of Allergy and Infectious Diseases. Division of AIDS, July 
2017].  
Summary of post-baseline hepatobiliary laboratory abnormalities will be provided.   
Liver monitoring and stopping event reporting will be summarized and listed. The Liver 
monitoring and stopping criteria are described in the protocol Section 7.1.1.  
The worst-case urinalysis results post-baseline (on-treatment and off-treatment periods 
combined) relative to baseline will be summarized. 
Potential Drug induced vascular injury and complement monitoring/stopping event will be 
summarized and listed based on laboratory parameters (C3, C4, Bb, C5a, hs-CRP, MCP-
1, p-ANCA, c-ANCA, eGFR, Bilirubin, and platelet count). The Drug Induced Vascular 
Injury and Complement monitoring and hold or stopping criteria are described in the 
protocol Section 7.1.2. 
Haematological monitoring/stopping event will be summarized and listed based on 
laboratory parameters (platelet count and anti-platelet antibodies). The haematological 
monitoring and stopping criteria are described in the protocol Section 7.1.3. 
Potential Drug induced kidney injury (renal) monitoring and hold or stopping events will 
be identified programmatically and will be summarized and listed based on laboratory 
parameters (ACR, Urinalysis RBC, serum creatinine, and eGFR). The kidney injury 
monitoring and stopping criteria are described in the protocol Section 7.1.4. 
Hold/stopping event profile will be provided for any subject who has met hold or stopping 
criteria specified in protocol Section 7.1. Relevant information will be reported, including 
baseline characteristics, AEs/SAEs, concomitant medication, medical history/current 
medical conditions, study treatment administration details, laboratory values, and 
individual line plots of complement (C3/C4/C5a/Bb), inflammatory markers (hs-
CRP/MCP-1), serum creatinine/creatinine clearance or eGFR/ACR, and platelet count. 
 


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4.5.3.2. 
Vital Signs 
Summaries of grade increase in temperature, systolic blood pressure (SBP) and diastolic 
blood pressure (DBP) will be provided separately. These summaries will display the 
number and percentage of participants with any grade increase, increase to Grade 2, 
increase to Grade 3 and increase to Grade 4 (for temperature only), for worst case post-
baseline only. The summaries will be produced for worst case post baseline only. The 
DAIDS grading system Version 2.1 [National Institute of Allergy and Infectious 
Diseases. Division of AIDS, 2017], will be used for grading: The grade definition for 
temperature is: Grade 1 (38.0C – <38.6C), Grade 2 (38.6C – <39.3C), Grade 3 (39.3C 
– <40.0C), Grade 4 (>=40.0C). The grade definition for SBP is: Grade 1 (140-159), 
Grade 2 (160-179), Grade 3 (>=180). The grade definition for DBP is: Grade 1 (90-99), 
Grade 2 (100-109), Grade 3 (>=110). DAIDs does not include a Grade 0, please refer to 
the Output and Programming Specification (OPS) for instruction on how to present values 
that don’t meet the criteria for Grade 1+. Subjects with missing baseline values are assumed 
to have a normal baseline value. 
4.6. 
Other Analyses 
4.6.1. 
Subgroup analyses 
Descriptive summary by subgroups as defined in Table 7 will be provided. Summary 
statistics (n (%)) for the number of SVR responders will be reported by subgroups for each 
treatment arm. No statistical comparison between subgroups will be performed. 
If the number of participants is too small (<5 per subgroup category) within a subgroup, 
then the subgroup categories may be redefined prior to unblinding the study.  
In addition, selected summaries will be presented by baseline analysis stratification factors 
and/or subgroups, as detailed in the OPS. 
Table 7 
Subgroups & Subgroup Categories 
Subgroup 
Categories  
HBeAg Status 
Positive or Negative 
Baseline HBsAg (log10 IU/mL) 
Low (≤ 3 log10 IU/mL), High (>3log10 IU/mL) 
<=3, >3-3.5, >3.5-4 and >4 
Low (<=3000 IU/mL), High (3000 IU/mL) 
Baseline HBV DNA level (log10 
IU/mL) 
For participants on stable nucleos(t)ide therapy: 
- Not applicable 
 
For participants not currently on nucleos(t)ide therapy: 
<=6 ; >6 
<=4, >4 - <=6, >6 
Age group 
EMA: <18; ≥18-64; ≥65 – 84, ≥85 
FDAAA: ≤18; ≥19-64; ≥65 
Clinical and Epi (Group 1): <50, ≥50  
 


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Subgroup 
Categories  
Sex 
Male, Female 
Race 
American Indian or Alaska Native; Asian; Black or African American; 
Native Hawaiian or Other Pacific Islander; White 
 
If enough data are available (≥5 patients per group per arm) Asian 
may be further categorised as Asian – Central/South Asian Heritage; 
Asian – Japanese Heritage; Asian – East Asian Heritage; Asian – 
South East Asian Heritage or a combination of these, and White may 
be further categorises as White – Arabic/North African Heritage; 
White – White/Caucasian/European Heritage 
Baseline viral genotype 
For participants with CHB on stable nucleos(t)ide therapy: 
- B; C; Other, Unknown 
For participants with CHB not currently on nucleos(t)ide therapy: 
- B; C; Other; Unknown. If enough data are available (≥5 patients per 
group per arm), Other may be further categorised into observed 
genotypes 
Baseline substitution in the 
binding site 
For participants with CHB not currently on nucleos(t)ide therapy only: 
Present; Absent 
Baseline BMI 
<30, ≥30 
Baseline ALT 
<=ULN; >ULN 
Baseline METAVIR Fibrosis 
Score 
If enough data are available (≥5 patients per group per arm): 
F0 – F2 ; F3 
For on-NUC population only: 
Time on current NUC 
<3 years; >=3 years 
For on-NUC population only: 
Type of NUC 
TAF&TDF vs Entecavir vs Other 
For Treatment naïve group only: 
Immune tolerance 
For participants with CHB not currently on nucleos(t)ide therapy: 
Immune-tolerant; Not immune-tolerant 
 
Subjects are defined as immune tolerant if they meet all of the 
following criteria: Treatment naïve (i.e. no prior medications reported 
on the Prior Medications CRF), HBeAg positive (>=0.09 U/mL), ALT 
normal (<= 33 IU/mL in females; <=40 IU/mL in males) and HBV DNA 
>10^6 IU/mL 
Duration of Hep B Infection 
<5 years, ≥ 5 years - <10 years, ≥ 10 years - <20 years, ≥ 20 years 
Phase of HBV Infection (Strict 
Criteria) 
Phase 1; Phase 2; Other HBeAg-positive; Phase 3; Phase 4; Other 
HBeAg-negative, where phases are defined as below. 
 
Phase 1 = HBeAg-positive, ALT <= ULN during screening and at 
baseline, HBV DNA > 106 IU/ml during screening and at baseline 
Phase 2 = HBeAg-positive, ALT > ULN either during screening or at 
baseline, HBV DNA > 104 IU/ml during screening and at baseline 
Other HBeAg-positive = HBeAg-positive, neither Phase 1 nor Phase 
2 
Phase 3 = HBeAg-negative, ALT <= ULN during screening and at 
baseline, HBV DNA < 20,000 IU/ml during screening and at baseline 
Phase 4 = HBeAg-negative, ALT > ULN either during screening or at 


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Subgroup 
Categories  
baseline, HBV DNA > 2,000 IU/ml during screening and at baseline 
Other HBeAg-negative = HBeAg-negative, neither Phase 3 nor 
Phase 4 
Phase of HBV Infection (Loose 
Criteria) 
Phase 1 loose; Phase 2 loose; Phase 3 loose; Phase 4 loose, where 
phases are defined as below. 
 
Phase 1 loose= HBeAg-positive, ALT <= ULN during screening and 
at baseline 
Phase 2 loose = HBeAg-positive, ALT > ULN either during screening 
or at baseline 
Phase 3 loose = HBeAg-negative, ALT <= ULN during screening and 
at baseline 
Phase 4 loose = HBeAg-negative, ALT > ULN either during screening 
or at baseline 
HBV RNA level 
 
Target not detected; Target detected 
HBcrAg 
Low (<= 3 log10 U/mL); High (> 3 log10 U/mL) 
 
4.6.2. 
Subpopulations to Support Regulatory Consultation  
To support consultation with regulators, key study population, efficacy, safety and 
pharmacokinetic analysis will be repeated in the following subpopulations:  
Japan subpopulation: All subjects of Japanese heritage enrolled at sites in Japan  
China mainland subpopulation: All subjects enrolled at sites in China Mainland  
East Asia subpopulation: All subjects of a relevant Asian heritage (Asian – Japanese 
Heritage, Asian – East Asian Heritage or Asian – South East Asian Heritage) enrolled at 
sites in Hong Kong, Taiwan, Japan, South Korea, China mainland.  
 
4.6.3. 
Concordance of virologic response at Week 6, Week 12, Week 18 
and Week 24 and achieving SVR 
The concordance of early virologic response (HBV DNA < LLOQ and HBsAg < LLOQ) 
at on-treatment timepoints of interest with achieving SVR will be explored. Number of 
participants with an early virologic response (Yes or No) will be cross tabulated with SVR 
(Yes or No) for on-treatment visits Week 6, Week 12, Week 18 and Week 24 separately. 
Positive Predictive Value and Negative Predictive Value will be presented, calculated as: 
Positive Predictive Value = Number of True Positives / (Number of True Positives + 
Number of False Positives) 
A true positive is defined as a participant with an early response who goes on to achieve 
SVR. A False positive is a participant with an early response who does not achieve SVR. 


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Negative Predictive Value = Number of True Negatives / (Number of True Negatives + 
Number of False Negatives) 
A true negative is defined as a participant without early response who does not achieve 
SVR. A false negative is a participant without early response who goes on to achieve SVR. 
The table will be presented separately for each arm, and also for Arms 1, 2, and 3 combined. 
4.6.4. 
Association between HBV DNA TND and relapse 
In participants who achieve a virologic response (HBsAg < LLOQ and HBV DNA < 
LLOQ) in the absence of rescue medication at the End of GSK3228836 Treatment visit 
(Week 12 / Week 24), a cross tabulation of achieving HBV DNA TND / not achieving 
HBV DNA TND vs. no relapse / relapse at 8, 16 and 24 weeks after end of treatment will 
be produced. The Off-Treatment timepoints will be based on the time since planned end of 
GSK836 treatment visit rather than visit labels in the schedule of assessments. The table 
will be repeated for each arm and overall. Data will also be listed. 
4.6.5. 
Determining the optimal cut point of baseline HBsAg to predict 
response 
ROC analysis will be used to estimate a single cut-point that can best be used to predict 
SVR. Baseline HBsAg will be plotted against SVR status and a ROC curve will be 
produced. A table showing the specificity (1-false positive rate), sensitivity (true positive 
rate) and accuracy for each cut-off will be presented. The optimal cut-off will be 
determined from the cut-off with the highest accuracy. The outputs will be displayed for 
each arm separately, and overall. 
False Positive Rate, True Positive Rate and Accuracy are calculated as: 
False Positive Rate = number of False Positives (FP) / number with Actual Outcome = 
Negative (Neg) 
True Positive Rate = number of True Positives (TP) / number with Actual Outcome = 
Positive (Pos) 
Accuracy = number of True Positives (TP) + Number of True Negatives (TN) / number 
with Actual Outcome = Positive (Pos) + number with Actual Outcome = Negative (Neg) 
Where counts for FP, TP, TN, Neg and Pos are defined as shown in Table 8. 
Table 8 
Classification of conditions for ROC analysis 
 
Predicted Outcome 
Positive (PPos) (Predicted 
SVR) 
Negative 
(PNeg) 
(Predicted No SVR) 
Actual 
Outcome 
Positive (Pos) (SVR) 
True Positive (TP) 
False Negative (FN) 
Negative (Neg) (No SVR) 
False Positive (FP) 
True Negative (TN) 
 


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If the original value <= cut-off then the predicted outcome is positive (i.e. predicted 
SVR=yes). If original value > cut-off then the predicted outcome is negative (i.e. predicted 
SVR=no) 
4.6.6. 
Predictors of SVR response 
If sufficient data are available, an exploratory analysis will be performed to identify 
predictors of SVR response. 
The following continuous baseline variables will be considered for inclusion in the model, 
additional clinically relevant variables may be considered: 
Age (years), BMI, HBsAg (log10 IU/mL), HBV DNA (log10 IU/mL), HBcrAg (log10 
U/mL), HBV RNA (copies/mL), ALT (IU/L), Platelet count, APRI Score, eGFR, Urine 
Albumin (g/dL), Serum Creatinine (umol/L), ACR (g/mol), Length of Diagnosis (Years) 
The following categorical baseline variables will be considered for inclusion in the model, 
additional clinically relevant variables may be considered: 
Sex (Male; Female), Race (American Indian or Alaska Native; Asian; Black or African 
American; Native Hawaiian or Other Pacific Islander; White), HBsAg (<=3 log10 IU/mL; 
>3 log10 IU/mL), HBeAg Status (Positive; Negative), HBV Genotype (A, B; C; D, E, 
Other; Unknown), Metavir Score (F0, F0-F1, F1, F1-F2, F2, F2-F3, F3, F3-F4, F4), Prior 
Interferon Use (Yes, No), Method of Transmission (Vertical, Horizontal, Unknown, Prefer 
not to Say and Other), Nucleos(t)ide Use (type of Nucleos(t)ide). 
If appropriate, continuous variables may be separated into categories, using the subgroup 
categories from Section 4.6.1 or another appropriate categorisation (e.g. median split). 
Additional clinically relevant variables may be considered. 
The definition of response for the analyses described in this section is SVR as defined for 
the primary efficacy analysis. 
A summary of the number and proportion of SVR successes will be provided for each 
category of the variables considered as potential predictors of response. For continuous 
variables a median split will be used to categorise the data in the summary. 
Summary statistics (n, Mean (SD) & 95% CI, Median, Min, Max for continuous variables 
and n (%) for categorical variables) for potential predictors of response in participants with 
and without SVR will also be presented by arm and overall. 
Summaries will be graphically presented using boxplots (for continuous variables) and 
Forest style plots (for categorical variables). For boxplots, response (responder vs non-
responder) will be shown on the x-axis and baseline characteristic value will be shown on 
the y-axis. The Forest style plot will show the proportion of participants in each category 
who have a response. 
Summary tables and figures will be presented by treatment arm and overall. 


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A predictive logistic regression model will be built using a forward stepwise selection 
approach using the Akaike Information Criterion (AIC). The model will use Firth’s 
penalised likelihood approach to avoid the potential issue of separation [Heinze G, 2002]. 
Analysis stratification values (HBsAg (<=3 log10 IU/mL; >3 log10 IU/mL), HBeAg Status 
(Positive; Negative)) will be included in the model, regardless of their impact on AIC. The 
order in which other covariates will be included in the algorithm will be determined prior 
to fitting the model, and will be based on clinical understanding of the most relevant / 
readily available predictors of response. Variables with a high proportion of missing data 
at baseline (e.g. data missing for >10% participants) will not be included in the model 
selection procedure. The final model will be the model with the minimum AIC. All arms 
will be included in a single model and arm will be included in the model. If there are enough 
SVR successes in a single arm (>= 5 SVR success in an arm), the model selection process 
will be repeated including data from the single arm only. 
4.6.7. 
Other variables and/or parameters 
Fibrosis Score is collected at baseline and End of Study (or Early Termination). A shift 
table for Metavir fibrosis score showing baseline score and End of Study (or Early 
Termination) score will be provided for each arm, overall and by baseline HBeAg status.   
A listing of participants who went above and stayed above >=90 IU/mL HBV DNA will 
be presented. All visits will be presented for these participants.  
A listing showing (quantitative) values of HBeAg at Baseline & Day 1 will be presented 
for subjects who are anti-HBeAg positive at baseline. A listing showing (quantitative) 
values of HBsAg at Baseline & Day 1 will be presented for subjects who are anti-HBsAg 
positive (i.e. HBs Antibody >=11.5 IU/L) at baseline. 
4.7. 
Interim Analyses 
Details of interim analyses are provided in separate Interim Analysis Reporting and 
Analysis Plans. 
4.8. 
Changes to Protocol Defined Analyses 
Changes from the originally planned statistical analysis specified in the protocol are 
detailed in Table 9. 
Table 9 
Changes to Protocol Defined Analysis Plan 
Protocol 
Defined 
Analysis 
SAP Defined Analysis 
Rationale for Changes 
• 
NA - addition 
• 
SAP Section 4.2.4.3: Addition 
of a supplementary estimand 
that uses a principal stratum 
strategy to deal with protocol 
deviations 
• 
A number of subjects in the not currently on 
nucleos(t)ide therapy population started 
nucleos(t)ide therapy on day 1 because of a 
misunderstanding of the protocol. In the main 
estimand these participants will be treated as 
failures on day 1. However, as these patients 
never had the chance to respond because of an 


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Protocol 
Defined 
Analysis 
SAP Defined Analysis 
Rationale for Changes 
operational error, this estimand will be used to 
counter the main estimand, 
• 
NA - addition 
• 
SAP Section 4.2.4.4: Addition 
of a supplementary estimand 
to assess efficacy using a 
modified definition of SVR 
• 
There are a number of subjects with single lab 
values that are aberrant in terms of the 
individual’s overall trajectory of response. There 
is some evidence that the aberrant values have 
occurred because of an unresolvable error at 
the site/lab. As the issues cannot be resolved in 
the data, this estimand will be used to support 
the primary objective. 
 
5. 
SAMPLE SIZE DETERMINATION 
Approximately 440 participants are planned to be randomly assigned to study intervention. 
For each population, there will be approximately 66 participants assigned in each of the 
first three arms. There will be approximately 22 participants assigned in the fourth arm. 
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 response rate. The precision for a range of 
response rates with 95% credible intervals are shown in Table 10. 
Table 10 
95% Credible Interval of Response Rate by Sample Size 
Sample size per arm 
Number of responders 
Response rate 
95% credible interval* 
22 
2 
9% 
1% – 23% 
3 
14% 
3% - 30% 
4 
18% 
5% - 36% 
5 
23% 
8% - 41% 
6 
27% 
11% - 46% 
66 
6 
9% 
3% - 17% 
9 
14% 
6% - 23% 
12 
18% 
10% - 28% 
15 
23% 
13% - 33% 
18 
27% 
17% - 38% 
*95% highest posterior density interval 
The lower bounds of 95% credible intervals will exclude the historical placebo response 
rate of 3% if observed response rate is greater than or equal to 14% in arms 1-3 or 18% in 
arm 4.  
The posterior probabilities that the true sustained virologic response rate is greater than a 
range of response rates will be calculated from the implied Beta posterior, given the actual 
number of responders observed. 


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The operating characteristics based on at least 75% posterior confidence that the true rate 
exceeds a threshold of interest, are shown in Table 11, for various sample sizes, and true 
cure rates.  The operating characteristics shown are based on a Bayesian model without 
consideration of baseline analysis stratification factors and expected to be similar to 
operating characteristics from the hierarchical model defined in Section 4.2.2.  


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Table 11 
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 Resp 
Rate=5% 
True Resp 
Rate=20% 
True Resp 
Rate=25% 
True Resp 
Rate=30% 
Probability (true 
response 
rate>15%)>75% 
22 
5 (23%) 
0% 
46% 
68% 
84% 
44 
9 (20%) 
0% 
53% 
81% 
91% 
66 
12 (18%) 
0% 
69% 
93% 
99% 
88 
16 (18%) 
0% 
71% 
95% 
100% 
Probability (true 
response 
rate>20%)>75% 
22 
6 (27%) 
0% 
27% 
48% 
69% 
44 
11 (25%) 
0% 
25% 
56% 
81% 
66 
16 (24%) 
0% 
23% 
60% 
88% 
88 
21 (24%) 
0% 
22% 
64% 
92% 
Probability (true 
response 
rate>25%)>75% 
22 
7 (32%) 
0% 
13% 
30% 
51% 
44 
13 (30%) 
0% 
9% 
29% 
58% 
66 
19 (29%) 
0% 
6% 
28% 
63% 
88 
25 (28%) 
0% 
4% 
27% 
67% 
Note: If the true response rate is 0%, the probability of meeting each criterion is 0% for all sample sizes. 
 
Based on these operating characteristics, for a true response rate of 20%, the proposed 
sample-size of n = 66 for arms 1 – 3 has ~70% probability of confirming a true response 
of at least 15%, and if the true rate is 30%, there is an 88% chance of confirming a true 
response of at least 20%.  
There are no plans for sample size re-estimation. 


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6. 
SUPPORTING DOCUMENTATION 
6.1. 
Appendix 1 Study Population Analyses 
Unless otherwise specified, the study population analyses will be based on the Enrolled 
Analysis Set. A summary of the number of participants in each of the participant level 
analysis set will be provided. 
A listing of subjects excluded from any population will be presented. 
In this multicentre global study, enrolment will be presented by country and site. 
6.1.1. 
Participant Disposition 
A summary of the number and percentage of patients who were screened including screen 
failures will be provided. Reasons for failure will be included. 
A summary of the number and percentage of participants who completed the study as well 
as those who prematurely withdrew from the study will be provided. Reasons for study 
withdrawal will be summarized.  
A summary of study intervention status will be provided. This display will show the 
number and percentage of participants who completed the scheduled study intervention, or 
who discontinued study intervention prematurely, as well as primary reasons for 
discontinuation of study intervention. 
Summaries of disposition, adverse events leading to withdrawal and reasons for withdrawal 
will be presented by Study Period, as defined in the Output and Programming 
Specification. 
Listings of reasons for study withdrawal, screen failure and study treatment discontinuation 
will be provided. 
6.1.2. 
Demographic and Baseline Characteristics 
Unless otherwise stated, study population analyses will be based on the Enrolled 
population. 
Study population analyses including analyses of participant’s disposition, protocol 
deviations, demographic and baseline characteristics, prior and concomitant medications, 
nucleos(t)ide treatment starting after randomization, medical history and exposure and 
treatment compliance will be presented. 
Demographic characteristics including sex, age, ethnicity, race, height and weight will be 
summarized with descriptive statistics. 
Baseline characteristics including but not limited to BMI, hypertension, NSAID use, 
TDF/TAF containing medications use, ADV containing medications use, diabetes, eGFR, 
serum creatinine, urine ACR, platelets, ANC, complement C3, complement C4, 


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complement C5a, complement Bb, C Reactive Protein, MCP-1, c-ANCA, p-ANCA and 
subgroup categories listed in Section 4.6.1 will be summarized with descriptive statistics. 
Continuous characteristics will be presented using summary statistics (n, Mean (SD), 
Median, Min, Max) and may also be categorized and summarised using n (%). 
Hepatitis B characteristics, as collected on the Hep B Disease Characteristics eCRF, will 
be summarized using descriptive statistics, and will be listed. 
A table and listing of nucleos(t)ide treatment at baseline will be presented for the on stable 
nucleos(t)ide cohort.  
6.1.3. 
Protocol Deviations 
Important protocol deviations will be summarized. 
Protocol deviations will be tracked by the study team throughout the conduct of the study. 
These protocol deviations will be reviewed to identify those considered as important as 
follows: 
o Data will be reviewed prior to unblinding and freezing the database to ensure all 
important deviations (where possible without knowing the study intervention 
details) are captured and categorised in the protocol deviations dataset.  
o This dataset will be the basis for the summaries of important protocol deviations. 
 
6.1.4. 
Prior and Concomitant Medications 
Concomitant medications will be coded using the GSK Drug dictionary. The summary of 
concomitant medications will be provided by ingredient, i.e., multi-ingredient medications 
will be summarized for each individual ingredient rather than a combination of ingredients. 
The summary will be created using ingredient base names, i.e., ingredients with the same 
base name but different salt will appear under one base name in the summary. Anatomical 
Therapeutic Chemical (ATC) classifications will not appear in the summary.  
A prior medication is defined as any medications that is ended prior to the date of first dose 
of study drug. 
Medications initiated after the first dose of study drug or initiated prior to the first dose of 
study drug and continued after the first dose of study drug will be counted as concomitant 
medications. A medication that cannot be determined as prior or concomitant medication 
due to partially or completely missing start/stop date will be counted as both prior and 
concomitant medication. 
6.1.5. 
Study Intervention Compliance 
A summary of overall compliance for GSK3228836 based on the exposure data will be 
produced. Overall compliance will be summarized using descriptive statistics as well as 
the categories <80%, 80%-100%, and >100%.  


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Compliance will be summarized both in terms of number of injections administered and 
total dose received during the planned on-treatment period. 
Study intervention Compliance (%) = [Number of actual doses / Number of planned doses] 
*100. 
Study dose Compliance (%) = [Actual Total Dose / Planned Total Dose] * 100 
6.1.6. 
Additional Analyses Due to the COVID-19 Pandemic 
A participant is defined as having a suspected, probable or confirmed COVID-19 infection 
during the study if the answer is “Confirmed”, “Probable” or “Suspected” to the case 
diagnosis question from the COVID-19 coronavirus infection assessment eCRF. Numbers 
of participants with a suspected, probable or confirmed COVID-19 infection, and of 
COVID-19 test results will be summarized. 
If a high proportion (>5% overall) of participants have a suspected, probable or confirmed 
COVID-19 infection, the following data displays will be produced: 
• Summary of current (and/or past) medical conditions for participants with COVID-
19 adverse events. 
• Summary of baseline characteristics for participants with COVID-19 adverse 
events. 
 


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6.2. 
Appendix 2 Data Derivation Rules 
6.2.1. 
Criteria for Potential Clinical Importance 
Grading categories for laboratory tests are determined using the DAIDS grading system 
Version 2.1 [National Institute of Allergy and Infectious Diseases. Division of AIDS, 
2017].  
No Laboratory tests values of potential clinical importance are defined. Laboratory values 
outside of normal range will be summarized and listed. 
6.2.2. 
Assessment Windows 
Refer to Section 4.2.2.1 for details of visit windowing for the main efficacy estimands. 
Unless otherwise specified, no windowing will be applied to unscheduled visits. Planned 
time relative to dosing will be used in figures, summaries, statistical analyses and 
calculation of any derived parameters, unless otherwise stated. Unscheduled visits will not 
be included in summary tables and/or figures except from determining response for 
primary endpoint as described in Section 4.2.2.1 and summaries over “any time on 
treatment” or “any visit post-baseline”. Unscheduled visits will be included in listings. 
Laboratory and vital signs data collected at Early Termination Visits will be assigned to 
assessment windows, according to the actual date. 
6.2.2.1. 
Definitions of Assessment Windows for Early Termination Visits 
Laboratory and vital signs data collected at Early Termination Visits will be assigned to 
assessment windows, according to the actual date. 
Analysis 
Set / 
Domain 
Parameter      
(if applicable) 
Target  
Analysis Window 
Analysis 
Timepoint 
Beginning 
Timepoint 
Ending 
Timepoint 
Lab, Vital 
Signs 
Numeric 
parameters 
1 
1 
2 
Week 1 Day 1 
 
 
4 
3 
6 
Week 1 Day 4 
 
 
8 
7 
9 
Week 2 Day 8 
 
 
11 
10 
12 
Week 2 Day 11 
 
 
15 
13 
18 
Week 3 
 
 
22 
19 
25 
Week 4 
 
 
1+7(x-1) 
1+7(x-1)-3 
1+7(x-1)+3 
Week x 
 
 
169 
166 
172 
OT-Week 1 
 
 
176 
173 
179 
OT-Week 2 
 
 
190 
180 
203 
OT-Week 4 
 
 
218 
204 
231 
OT-Week 8 
 
 
246 
232 
259 
OT-Week 12 
 
 
274 
260 
287 
OT-Week 16 


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302 
288 
315 
OT-Week 20 
 
 
330 
316 
340 
OT-Week 24 
Notes: 
1. Week x includes on-treatment weeks 5 – 24 
2. Visit windows are to be used for windowing of Early Termination visits only 
6.2.2.2. 
Definitions of Assessment Windows for Adverse Events 
To allow comparison between safety in active treatment vs placebo, and loading dose vs 
no loading dose, selected safety displays will be presented by study Weeks 1 – 12, Weeks 
13 – 24, and Weeks 25 – 48. Adverse events are not associated with a specific visit 
therefore the study week they are assigned to will be based on the AE start date. 
Analysis 
Set / 
Domain 
Parameter      
(if applicable) 
Analysis Window 
Analysis 
Timepoint 
Beginning 
Timepoint 
Ending 
Timepoint 
Adverse 
Events 
All 
1 
81 
Weeks 1 – 12 
 
 
82 
165 
Weeks 13 – 24 
 
 
166 
- 
Weeks 25 – 48 
 
6.2.3. 
Study Period 
Assessments and events will be classified according to the time of occurrence relative to 
the study intervention period. Off Treatment Day 1 occurs 7 days after the last study 
treatment dose received, regardless of whether the participant completes treatment as 
planned or the participant is withdrawn from study treatment. 
Study Intervention Period 
Definition 
Pre-Treatment  
Date ≤ Study Treatment Start Date 
On-Treatment 
Study Treatment Start Date < Date ≤ Off Treatment Day 1 – 1 day 
Post-Treatment 
Date ≥ Off Treatment Day 1 
 
6.2.4. 
Study Day and Reference Dates 
The study reference date is the study treatment start date and will be used to calculate study 
day for safety and efficacy measures.  
The study day is calculated as below: 
• Assessment Date = Missing              → Study Day = Missing  
• Assessment Date < Reference Date → Study Day = Assessment Date – Ref Date 
• Assessment Date ≥ Reference Date → Study Day = Assessment Date – Ref Date + 
1     


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6.2.5. 
Multiple measurements at One Analysis Time Point 
Multiple Measurements at One Analysis Time Point 
• 
Handling of multiple measurements within an analysis window for primary endpoint is described in 
Section 4.2.2 
• 
Assessments on unscheduled visit will not be included in the tables of summary statistics by visit but 
will be included in the associated listings. Also, such assessments on unscheduled visit will be used 
for the “any time on-treatment” or “Any visit post-baseline” time point. 
• 
If there are multiple assessments on scheduled visit within visit window, will query the site to identify 
the valid assessment as the assessment for the scheduled visit. 
• 
Participants having both High and Low values for Normal Ranges at any post-baseline visit for safety 
parameters will be counted in both the High and Low categories of “Any visit post-baseline” row of 
related summary tables.  
 
6.2.6. 
Handling of Partial Dates 
Element 
Reporting Detail 
General 
• 
Partial dates will be displayed as captured in participant listing 
displays.   
• 
However, where necessary, display macros may impute dates as 
temporary variables for sorting data in listings only. In addition, 
partial dates may be imputed for ‘slotting’ data to study phases or 
for specific analysis purposes as outlined below. 
• 
Imputed partial dates will not be used to derive study day, time to 
onset or duration (e.g., time to onset or duration of adverse events), 
or elapsed time variables (e.g., time since diagnosis). 
• 
Duration of Hep B infection (years) will be calculated based on 
year only 
Adverse Events 
• 
Partial dates for AE recorded in the CRF will be imputed using the 
following conventions: 
Missing start 
day 
• 
If study intervention start date is missing (i.e. 
participant did not start study intervention), then set 
start date = 1st of month. 
• 
Else if study intervention start date is not missing: 
o If month and year of start date = month 
and year of study intervention start date, 
then 
▪ 
If stop date contains a full date 
and stop date is earlier than study 
intervention start date, then set 
start date= 1st of month. 
▪ 
Else set start date = study 
intervention start date. 
o Else set start date = 1st of month. 


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Element 
Reporting Detail 
Missing start 
day and month 
• 
If study intervention start date is missing (i.e. 
participant did not start study intervention), then set 
start date = January 1. 
• 
Else if study intervention start date is not missing: 
o If year of start date = year of study 
intervention start date, then 
▪ 
If stop date contains a full date 
and stop date is earlier than study 
intervention start date, then set 
start date = January 1. 
▪ 
Else set start date = study 
intervention start date. 
o Else set start date = January 1. 
Missing end 
day  
A '28/29/30/31' will be used for the day (dependent on 
the month and year). 
Missing end 
day and month 
No Imputation 
Completely 
missing 
start/end date 
No imputation 
Concomitant 
Medications/Medical 
History 
• 
Partial dates for any concomitant medications recorded in the CRF 
will be imputed using the following convention: 
 
Missing start day 
• 
If study intervention start date is missing (i.e. 
participant did not start study intervention), then 
set start date = 1st of month. 
• 
Else if study intervention start date is not missing: 
o 
If month and year of start date = month 
and year of study intervention start date, 
then 
▪ 
If stop date contains a full date 
and stop date is earlier than study 
intervention start date, then set 
start date= 1st of month. 
▪ Else set start date = study 
intervention start date. 
o 
Else set start date = 1st of month. 
Missing start day 
and month 
• 
If study intervention start date is missing (i.e. 
participant did not start study intervention), then 
set start date = January 1. 
• 
Else if study intervention start date is not missing: 


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Element 
Reporting Detail 
o 
If year of start date = year of study 
intervention start date, then 
▪ 
If stop date contains a full date 
and stop date is earlier than 
study intervention start date, then 
set start date = January 1. 
▪ 
Else set start date = study. 
intervention start date. 
o 
Else set start date = January 1. 
Missing end day 
A '28/29/30/31' will be used for the day (dependent on 
the month and year).  
Missing end day 
and month 
A '31' will be used for the day and 'Dec' will be used for 
the month. 
Completely 
missing 
start/end date 
No imputation 
 
TRADEMARKS 
Trademarks of the GlaxoSmithKline 
Group of Companies 
 
Trademarks not owned by the 
GlaxoSmithKline Group of Companies 
None 
 
WinNonlin 
 
 


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7. 
REFERENCES 
Brooks SP, Gelman A. General methods for monitoring convergence of iterative 
simulations. Journal of Computational and Graphical Statistics. 1998;7:434–455. 
Dolan P. Modeling valuations for EuroQol health states. Med Care 1997; 35(11): 1095-
108  
Heinze G, Schemper M. A solution to the problem of separation in logistic regression. 
Statist. Med. 2002;21:2409–2419 
Jones HE, Ohlssen DI, Neuenschwander B, Racine A, Branson M. Bayesian models for 
subgroup analysis in clinical trials. Clin Trials. 2011;8:129–143 
National Institute of Allergy and Infectious Diseases. Division of AIDS (DAIDS) Table 
for Grading the Severity of Adult and Pediatric Adverse Events, Version 2.1, JULY 
2017 
Spiegel BM, Bolus R, Han S, Tong M, Esrailian E, Talley J, Tran T, Smith J, Karsan HA, 
Durazo F, Bacon B, Martin P, Younossi Z, Hwa-Ong S, Kanwal F. Development and 
validation of a disease-targeted quality of life instrument in chronic hepatitis B: the 
hepatitis B quality of life instrument, version 1.0. Hepatology. 2007 Jul;46(1):113-21