Clinical trial NCT04544956
Conditions: Hepatitis B
Keywords: Hepatitis B virus GSK3228836 Fine needle aspiration Intrahepatic immunophenotyping
Sponsor: GlaxoSmithKline
Start date: 2020-10-06; Completion date: 2023-11-30
Enrollment: 12 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
Hepatitis B virus (HBV) infection, especially chronic, is a significant worldwide medical problem. This is an exploratory study of the therapeutic mechanism of GSK3228836 in participants with chronic hepatitis B (CHB) on stable nucleos(t)ide therapy (which is the first line therapy for CHB). This study is a Phase IIa, multi-center open label exploratory study of the therapeutic mechanism of GSK3228836 in participants with hepatitis B virus e-antigen (HBeAg)-negative CHB on stable nucleos(t)ide therapy using repeat fine needle aspirations of the liver for intrahepatic immunophenotyping. It will investigate the virologic and immunologic correlates of hepatitis B virus surface antigen (HBsAg) loss observed in participants when treated for 12 weeks with 300 milligrams (mg) GSK3228836. Repeat fine needle aspirates of the liver will be performed to enable analysis of liver-resident immune cells to investigate any immunomodulatory properties of GSK3228836 and to study the biology of underlying treatment-associated liver flares. The study will consist of a screening, treatment, and post-treatment follow-up phase. Approximately 20 participants will be enrolled in the study.

Detailed description:

Arms: arm 1: Participants on stable nucleos(t)ide therapy will receive GSK3228836 300 mg subcutaneously (SC) weekly once for 12 weeks along with a loading dose of GSK3228836 300 mg in Week 1 (Day 4) and Week 2 (Day 11).
Interventions: intervention 1: GSK3228836 intervention 2: Nucleos(t)ide therapy
Intervention descriptions: intervention 1: GSK3228836 will be available as a clear colorless to slightly yellow solution for injection in 150 mg/milliliters (mL) vial to be administered SC once weekly. intervention 2: Participants receiving nucleos(t)ide therapy upon entry in the study will continue to receive nucleos(t)ide therapy for the duration of the study.

Protocol documents:
Prot_000.pdf: 
TMF-11822142 
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GlaxoSmithKline group of companies 
 
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TITLE PAGE 
Protocol Title: B-Fine: An open label, single arm study to mechanistically interrogate 
the therapeutic effect of GSK3228836 in patients with Chronic Hepatitis B via 
intrahepatic immunophenotyping 
Protocol Number: 212602/Amendment 01 
Compound Number  
GSK3228836  
 
Brief Title: A mechanistic study of GSK3228836 with fine needle aspiration (FNA) in 
Participants with Chronic Hepatitis B 
Study Phase: PHASE IIA 
Acronym: B-Fine  
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: 122685 
EudraCT: 2020-002000-39 
Approval Date: 15-MAR-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: B-Fine: An open label, single arm study to mechanistically interrogate 
the therapeutic effect of GSK3228836 in patients with Chronic Hepatitis B via 
intrahepatic immunophenotyping 
Protocol Number: 212602/Amendment 01 
 
 
 
 
 
Dickens Theodore, MD 
Senior Director, Clinical Development,  
Infectious Diseases, 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 
DNG Number 
Amendment 01 
15-MAR-2021 
TMF-11822142 
Original Protocol 
29-MAY-2020 
2020N434303_00 
 
Amendment 01 15-MAR-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:  
 
 
  
Other key changes include:  
• a description of the risk of Covid-19 infection in the hepatis B population, added at the 
request of the Medicines & Healthcare products Regulatory Agency (MHRA). 
• an update to the time to maximum alanine aminotransferase (ALT) analysis method. 
• additional guidance and clarity for Investigators has been added. 
• corrections to visit windows and visit numbering in the schedule of activities (SoA). 
In addition, minor typographical errors and inconsistencies have been corrected and 
minor editorial changes have been made. 
Section # and Name 
Description of Change 
Brief Rationale 
Section 1.1 Synopsis: 
Key Objectives and 
Endpoints 
HBe antibody (anti-HBeAg) levels have 
been re-classified as a categorical 
variable (previously a continuous 
variable) 
This corrects an error in the original 
protocol. 
 
The analysis method for the time to 
maximum ALT has been updated from 
Kaplan-Meier to Turnbull 
As visit spacing gets longer over time, 
interval censored method is more 
appropriate.  
Section 1.3: Schedule 
of Activities 
The Day 11 visit window was been 
updated from 3 days to 1 day 
Updated to avoid potential overlap of 
the Day 8 and Day 11 visits 
 
Collection of PBMC samples for 
immunophenotyping updated from 
“Baseline, Day 8 (Week 2), Day 15 
(Week 3), Day 29 (Week 5), Day 85 
(Week 13), Day 162 (Week 24), Day 
246 (Week 36) and Early Withdrawal” to 
“Baseline, Day 29 (Week 5), Day 246 
(Week 36) and Early Withdrawal.” 
Amended to reduce sampling timepoints 
due to increased blood volume required 
for PBMC analysis. 
CCI


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Section # and Name 
Description of Change 
Brief Rationale 
 
The description of the standard 
examination has been updated from 
brief physical exam to symptoms 
directed exam 
Updated to reflect risk reduction 
practices in limiting physical contact due 
to COVID-19 and to align with 
assessments covered by home nursing 
licenses.  
 
Clarification has been added that PK 
sample should be collected pre-dose. 
This corrects an error in the original 
protocol. 
 
Guidance has been added that a fine 
needle aspiration (FNA) sample not to 
be collected if the participant has 
already withdrawn from treatment 
Updated to reduce burden on 
participants who no longer wish to 
continue study treatment. 
 
A urine or serum pregnancy test has 
been added as an optional assessment 
at Day 1 
Added for instances where the 
Screening serum human chorionic 
gonadotrophin (hCG) pregnancy test 
was >24 hours pre-dose first dose. 
 
The Week 28, 32 and 36 day numbers 
have been updated to Day 190, 218 and 
246, respectively. 
This corrects an error in the original 
protocol. 
 
The collection of samples for genetic 
resource have been removed from the 
SoA at all timepoints other than Week -1 
(Baseline) 
This corrects an error in the original 
protocol. 
Section 2.3.1: Risk 
Assessment 
Additional text added on risk with 
COVID-19 infection 
Provide description of risk of COVID-19 
infection in hepatitis B population 
Section 2.3.3 Overall 
Benefit: Risk 
Conclusion 
Additional text added on benefit/risk with 
COVID-19 infection 
Include COVID-19 risk in the overall 
benefit:risk assessment 
Section 3: Objectives 
and Endpoints 
HBe antibody (anti-HBeAg) levels have 
been re-classified as a categorical 
variable (previously a continuous 
variable) 
This corrects an error in the original 
protocol. 
 
The analysis method for the time to 
maximum ALT has been updated from 
Kaplan-Meier to Turnbull 
As visit spacing gets longer over time, 
interval censored method is more 
appropriate. Turnbull method chosen, 
and this is consistent with Study 209348 
(B-Together).  
 
Immunophenotyping added to list of 
possible measures for markers of 
immune cell function 
To further expand the list of potential 
measures which may be used in the 
investigation of immune cell function. 
Section 5.2 Exclusion 
Criteria 
Exclusion criteria 8 and 9 have been re-
written 
Re-written following a request for 
clarification following protocol review by 
the MHRA. 
Section 6.3: Measures 
to Minimize Bias: 
Randomization and 
Blinding 
Additional text added on bias mitigation 
Updated to include reference to the 
blinding plan 
Section 6.8.2 
Prohibited Medications 
and Non-Drug 
Therapies 
Included anti-coagulation therapies as 
prohibited medication and non-drug 
therapies 
To be consistent with exclusion criteria 


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Section # and Name 
Description of Change 
Brief Rationale 
Section 7.1.1: Liver 
Chemistry Monitoring 
and Stopping Criteria 
Additional text added in ‘Bold’  
• Any clinically significant 
deterioration from the baseline in the 
liver parameters must be confirmed 
by retesting ALT, total bilirubin, direct 
bilirubin, and INR (if available).  
• Cases such as Gilbert syndrome, 
where baseline bilirubin values are 
high, should be discussed with the 
medical monitor, to assess if it is a 
case of drug-induced liver injury 
(DILI) or the participant may 
continue with dosing. 
To clarify and identify instances where 
advice from the medical monitor should 
be sought  
Section 7.1.3: 
Haematological 
Stopping Criteria 
Additional text added around 
haematological stopping criteria 
Updated to provide additional clarity. 
Section 7.1.5: Study 
Intervention Restart or 
Rechallenge after 
Stopping Criteria Met 
Added text in ‘Bold’ as follows: 
Institutional Review Boards 
(IRB)/Independent Ethics Committees 
(IEC) approval of study intervention 
restart has been obtained (if required). 
This corrects an error in the original 
protocol. 
Section 8.2.1: Physical 
Examinations 
Description of post-baseline brief 
physical examination updated to 
symptoms directed examination 
Updated to reflect risk reduction 
practices in limiting physical contact due 
to COVID-19 and to align with 
assessments covered by home nursing 
licenses.  
Section 8.2.3: Vital 
Signs 
Requirement for vital sign measurement 
in a semi-supine position removed. 
Updated as not required. 
Section 9.4.4: 
Secondary Endpoint(s) 
HBe antibody (anti-HBeAg) changed 
from a continuous to a categorical 
variable 
This is to represent the data which have 
received since the start of the study.  
 
The analysis method for the time to 
maximum ALT has been updated from 
Kaplan-Meier to Turnbull 
As visit spacing gets longer over time, 
interval censored method is more 
appropriate.  
Section 9.6: 
Independent Data 
Monitoring Committee 
(IDMC) 
Additional detail added regarding the 
timing of IDMC safety reviews  
Updated to describe the planned safety 
reviews  
Section 10.2: Appendix 
2 Clinical Laboratory 
Tests 
Additional text regarding processing of 
PBMC samples 
Updated to allow for local laboratory 
processing of PBMC samples. 
 
Bilirubin SAE reporting requirements 
updated from 2xULN to 2xULN 
To correct an error in the definition.  
Section 10.6: Appendix 
6: Liver Safety: 
Required Actions and 
Follow-up 
Assessments and 
Study Intervention 
Restart Guidelines 
Added text in ‘Bold’ as follows: 
Institutional Review Boards 
(IRB)/Independent Ethics Committees 
(IEC) approval of study intervention 
restart has been obtained (if required). 
 
This corrects an error in the original 
protocol. 


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TABLE OF CONTENTS 
PAGE 
PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE ..................................... 3 
1. 
PROTOCOL SUMMARY .......................................................................................... 9 
1.1. 
Synopsis ....................................................................................................... 9 
1.2. 
Schema ...................................................................................................... 13 
1.3. 
Schedule of Activities (SoA) ........................................................................ 13 
2. 
INTRODUCTION .................................................................................................... 19 
2.1. 
Study Rationale .......................................................................................... 19 
2.2. 
Background ................................................................................................ 19 
2.3. 
Benefit/Risk Assessment ............................................................................ 21 
2.3.1. 
Risk Assessment ......................................................................... 21 
2.3.2. 
Benefit Assessment ..................................................................... 24 
2.3.3. 
Overall Benefit: Risk Conclusion .................................................. 24 
3. 
OBJECTIVES AND ENDPOINTS ........................................................................... 25 
4. 
STUDY DESIGN .................................................................................................... 28 
4.1. 
Overall Design ............................................................................................ 28 
4.2. 
Scientific Rationale for Study Design .......................................................... 28 
4.2.1. 
Participant Input into Design ........................................................ 32 
4.3. 
Justification for Dose .................................................................................. 32 
4.4. 
End of Study Definition ............................................................................... 34 
5. 
STUDY POPULATION ........................................................................................... 34 
5.1. 
Inclusion Criteria ......................................................................................... 35 
5.2. 
Exclusion Criteria ........................................................................................ 36 
5.3. 
Lifestyle Considerations .............................................................................. 39 
5.3.1. 
Alcohol and Tobacco ................................................................... 39 
5.3.2. 
Activity ......................................................................................... 39 
5.4. 
Screen Failures........................................................................................... 39 
5.5. 
Criteria for Temporarily Delaying Administration of Study 
Intervention ................................................................................................. 39 
6. 
STUDY INTERVENTION(S) AND CONCOMITANT THERAPY .............................. 40 
6.1. 
Study Intervention(s) Administered ............................................................. 40 
6.2. 
Preparation/Handling/Storage/Accountability .............................................. 40 
6.3. 
Measures to Minimize Bias: Randomization and Blinding ........................... 41 
6.4. 
Study Intervention Compliance ................................................................... 41 
6.5. 
Dose Modification ....................................................................................... 41 
6.6. 
Continued Access to Study Intervention after the End of the Study ............ 41 
6.7. 
Treatment of Overdose ............................................................................... 41 
6.8. 
Concomitant Therapy.................................................................................. 42 
6.8.1. 
Nucleos(t)ide Treatment during and after the End of the 
Study ........................................................................................... 42 
6.8.2. 
Prohibited Medications and Non-Drug Therapies ......................... 42 
7. 
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL ..................................................................... 43 
7.1. 
Discontinuation of Study Intervention .......................................................... 43 


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7.1.1. 
Liver Chemistry Monitoring and Stopping Criteria ........................ 43 
7.1.2. 
Drug Induced Vascular Inflammation and Complement 
Stopping Criteria .......................................................................... 46 
7.1.3. 
Haematological Stopping Criteria ................................................. 47 
7.1.4. 
Drug Induced Kidney Injury (Renal) Stopping Criteria .................. 48 
7.1.5. 
Study Intervention Restart or Rechallenge after Stopping 
Criteria Met .................................................................................. 49 
7.2. 
Participant Discontinuation/Withdrawal from the Study ............................... 50 
7.3. 
Lost to Follow Up ........................................................................................ 51 
8. 
STUDY ASSESSMENTS AND PROCEDURES ..................................................... 51 
8.1. 
Efficacy Assessments ................................................................................. 52 
8.2. 
Safety Assessments ................................................................................... 52 
8.2.2. 
Injection Site Reactions ............................................................... 52 
8.2.5. 
Clinical Safety Laboratory Assessments ...................................... 53 
8.2.6. 
Adverse Events and Serious Adverse Events .............................. 54 
8.2.6.1. 
Time Period and Frequency for Collecting AE 
and SAE Information .................................................. 54 
8.2.6.2. 
Method of Detecting AEs and SAEs ........................... 54 
8.2.6.3. 
Follow-up of AEs and SAEs ........................................ 54 
8.2.6.4. 
Regulatory Reporting Requirements for SAEs ............ 55 
8.2.8. 
Cardiovascular and Death Events ................................................ 55 
8.2.9. 
Adverse Events of Special Interest .............................................. 56 
8.2.9.1. 
ALT Increases ............................................................ 56 
8.2.9.2. 
Vascular Inflammation and Complement 
Activation .................................................................... 56 
8.2.9.3. 
Thrombocytopenia ...................................................... 56 
8.2.9.4. 
Renal Injury ................................................................ 56 
8.2.9.5. 
Injection Site Reactions .............................................. 57 
8.3. 
Pharmacokinetics ....................................................................................... 57 
8.4. 
Biomarkers ................................................................................................. 57 
8.5. 
Resistance Monitoring ................................................................................ 58 
8.6. 
Medical Resource Utilization and Health Economics .................................. 59 
9. 
STATISTICAL CONSIDERATIONS ........................................................................ 59 
9.1. 
Statistical Hypotheses................................................................................. 59 
9.2. 
Sample Size Determination ........................................................................ 59 
9.3. 
Analysis Sets .............................................................................................. 62 
9.4. 
Statistical Analyses ..................................................................................... 62 
9.4.1. 
General Considerations ............................................................... 62 
9.4.2. 
Primary Endpoint(s) ..................................................................... 62 
9.4.3. 
Primary Analyses ......................................................................... 63 
9.4.4. 
Secondary Endpoint(s) ................................................................ 64 
9.4.5. 
Safety Endpoints .......................................................................... 66 
9.4.6. 
Exploratory Endpoint(s) ............................................................... 66 
9.5. 
Interim Analysis .......................................................................................... 67 
9.6. 
Independent Data Monitoring Committee (IDMC) ....................................... 67 
10. SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS ............................................................................................... 68 
10.1. 
Appendix 1: Regulatory, Ethical, and Study Oversight 
Considerations ............................................................................................ 68 


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10.1.1. 
Regulatory and Ethical Considerations ........................................ 68 
10.1.2. 
Financial Disclosure ..................................................................... 68 
10.1.3. 
Informed Consent Process .......................................................... 69 
10.1.4. 
Data Protection ............................................................................ 69 
10.1.5. 
Committees Structure .................................................................. 70 
10.1.6. 
Dissemination of Clinical Study Data ........................................... 70 
10.1.7. 
Data Quality Assurance ............................................................... 71 
10.1.8. 
Source Documents ...................................................................... 72 
10.1.9. 
Study and Site Start and Closure ................................................. 72 
10.1.10. Publication Policy ......................................................................... 73 
10.2. 
Appendix 2: Clinical Laboratory Tests ......................................................... 74 
10.3. 
Appendix 3: AEs and SAEs: Definitions and Procedures for 
Recording, Evaluating, Follow-up, and Reporting ....................................... 77 
10.3.1. 
Definition of AE ............................................................................ 77 
10.3.2. 
Definition of SAE .......................................................................... 78 
10.3.3. 
Definition of Cardiovascular Events ............................................. 79 
10.3.4. 
Recording and Follow-Up of AE and SAE .................................... 80 
10.3.5. 
Reporting of SAE to GSK ............................................................. 82 
10.4. 
Appendix 4: Contraceptive and Barrier Guidance ....................................... 83 
10.4.1. 
Definitions: ................................................................................... 83 
10.4.2. 
Contraception Guidance: ............................................................. 84 
10.4.3. 
Collection of Pregnancy Information: ........................................... 85 
10.5. 
Appendix 5: Genetics .................................................................................. 86 
10.6. 
Appendix 6: Liver Safety: Required Actions and Follow-up 
Assessments and Study Intervention Restart Guidelines ............................ 87 
10.7. 
Appendix 7: Abbreviations and Trademarks ................................................ 90 
11. REFERENCES ....................................................................................................... 93 
 


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1. 
PROTOCOL SUMMARY 
1.1. 
Synopsis 
Title: 
B-Fine: An open label, single arm study to mechanistically interrogate the therapeutic 
effect of GSK3228836 in patients with Chronic Hepatitis B via intrahepatic 
immunophenotyping 
Rationale: 
B-Fine is an exploratory study of the therapeutic mechanism of GSK3228836 in 
participants with chronic hepatitis B (CHB) on stable nucleos(t)ide therapy.  The study will 
investigate the virologic and immunologic correlates of HBsAg loss observed in 
participants when treated for 12 weeks with 300 mg GSK3228836.  Repeat fine needle 
aspirates of the liver will be performed to enable analysis of liver-resident immune cells to 
investigate any immunomodulatory properties of GSK3228836 and to study the biology of 
underlying treatment-associated liver flares.  Longitudinal analyses of blood-borne 
inflammatory signatures and virological assessments of CHB infection will be performed 
in parallel. 
Key Objectives and Endpoints: 
Objectives 
Estimands/Endpoints 
Primary 
Efficacy: To assess the effect of 
12 weeks of GSK3228836 on 
serum hepatitis B virus surface 
antigen (HBsAg) levels in 
participants with CHB 
The Primary Estimand supporting the primary objective of the study is 
defined as:  
• 
Population: Participants with CHB who receive at least one dose of 
investigational product (IP) 
• 
Treatment: 300 mg GSK3228836 for 12 weeks (also on stable 
nucleos(t)ide therapy) 
• 
Variable: Achieving serum HBsAg level <lower limit of quantitation 
(LLOQ) at any time point up to and including Week 12 without the 
use of pegylated (PEG)-interferon or other immunomodulator 
therapies 
• 
Population-level summary: Percent of participants that achieve 
serum HBsAg level <LLOQ 
• 
Intercurrent events: Discontinuation of, interruption of, and 
adherence to IP will be ignored (treatment policy). 
 
The primary estimand is the percentage of participants with CHB receiving 
300 mg GSK3228836 for 12 weeks (with at least one dose of IP) who 
achieve serum HBsAg level <LLOQ at any time point up to and including 
Week 12 without the use of PEG-interferon or other immunomodulator 
therapies, regardless of completing IP, interruptions in IP or adherence to IP. 


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Objectives 
Estimands/Endpoints 
Secondary 
Efficacy: To assess sustainability 
of serum HBsAg loss by 
GSK3228836 for up to 24 weeks 
off-treatment. 
The Estimand supporting the objective is defined as: 
• Population:  Participants with CHB who receive at least one dose of 
IP 
• Treatment: 300 mg GSK3228836 for 12 weeks (also on stable 
nucleos(t)ide therapy) 
• Variables:   
o Sustained HBsAg Response (HBsAg <LLOQ) for 24 weeks 
after the planned end of GSK3228836 treatment 
▪ HBsAg from Week 13 to Week 36 will be used to assess 
sustained HBsAg response after the planned end of 
GSK3228836 treatment without the use of PEG-interferon or 
other immunomodulator therapies.  
o Sustained HBsAg Response (HBsAg <LLOQ) for 24 weeks 
after the actual end of GSK3228836 treatment 
▪ HBsAg for 24 weeks after end of actual treatment will also 
be used to assess sustained HBsAg response after the 
actual end of GSK3228836 treatment without the use of 
PEG-interferon or other immunomodulator therapies. 
• 
Intercurrent events: Discontinuation of, interruption of, and 
adherence to IP will be ignored (treatment policy).  
The group of estimands supporting this objective in participants with CHB 
receiving 300 mg GSK3228836 for 12 weeks (with at least one dose of IP) is 
the percentage of participants for each variable regardless of completing IP, 
interruptions in IP or adherence to IP, without the use of PEG-interferon or 
other immunomodulator therapies. 
Efficacy: To assess sustainability 
of serum HBsAg and HBV DNA 
loss by GSK3228836 for up to 24 
weeks off treatment. 
The Estimand supporting the objective is defined as: 
• Population: Participants with CHB who receive at least one dose of 
IP 
• Treatment: 300 mg GSK3228836 for 12 weeks (also on stable 
nucleos(t)ide therapy) 
• Variables: 
o Sustained Virologic Response (HBsAg <LLOQ and HBV DNA 
<LLOQ) for 24 weeks after the planned end of GSK3228836 
treatment without the use of PEG-interferon or other 
immunomodulator therapies. 
▪ HBsAg and HBV DNA from Week 13 to Week 36 will be used 
to assess sustained virologic response after the planned end 
of GSK GSK3228836 treatment. 
o Sustained Virologic Response (HBsAg <LLOQ and HBV DNA 
<LLOQ) for 24 weeks after the actual end of GSK3228836 
treatment without the use of PEG-interferon or other 
immunomodulator therapies 
▪ HBsAg and HBV DNA for 24 weeks after end of actual 
treatment will be used to assess sustained virologic response 
after the actual end of GSK3228836 treatment. 
• Intercurrent events: Discontinuation of, interruption of, and 
adherence to IP will be ignored (treatment policy).  
 
The group of estimands supporting this objective in participants with CHB 
receiving 300 mg GSK3228836 for 12 weeks (with at least one dose of IP) is 
the percentage of participants for each variable regardless of completing IP, 
interruptions in IP or adherence to IP, without the use of PEG-interferon or 
other immunomodulator therapies. 


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Objectives 
Estimands/Endpoints 
Efficacy: To assess the effect of 
12 weeks GSK3228836 on 
biomarkers and virus-specific 
antibody responses  
Estimands supporting the secondary objective of assessing the effect of 
12 weeks GSK3228836 on biomarkers and virus-specific antibody responses 
are defined as follows:  
• Population: Participants with CHB who receive at least one dose of 
IP 
• Treatment: 300 mg GSK3228836 for 12 weeks (also on stable 
nucleos(t)ide therapy) 
• Intercurrent events: Discontinuation of, interruption of, adherence to 
IP will be ignored (treatment policy). PEG-interferon or other 
immunomodulator therapies will be handled with hypothetical 
strategy. 
1) Categorical Variables: 
• Achieving:  
o HBsAg <LLOQ over time 
o HBV DNA <LLOQ over time 
o HBsAg and HBV DNA <LLOQ over time 
• Categorical changes from baseline in HBsAg (e.g. <0.5, 0.5, 1, 
1.5, 3 log10 IU/mL) over time. 
• ALT>3X ULN at over time 
• 
HBe antibody (anti-HBeAg) levels over time 
Population summary: percentage of participants in each category. 
2) Continuous Variables:  
• Actual values and change from baseline over time for HBsAg and 
HBV DNA  
• HBs antibody (anti-HBsAg) levels over time 
• Area under the curve (AUC) for ALT on treatment (12 weeks), 
during follow up (24 weeks), and on treatment + follow up (36 
weeks). 
Population summary: mean values and/or mean changes from baseline for 
each variable  
3) Time to Event Variable 
• Time to Maximum ALT (ALT must be greater than 3xULN) during 
36 weeks of treatment + follow up 
Population summary: Turnbull estimate for median Time to Maximum ALT 
(>3xULN) 
The group of estimands supporting this objective in participants with CHB 
receiving 300 mg GSK3228836 for 12 weeks (with at least one dose of IP) are 
the population summary for each variable in the absence of PEG-interferon or 
other immunomodulator therapies, regardless of completing IP, interruptions 
in IP, or adherence to IP.  
Overall Design: 
This study is a Phase IIa, multi-centre open label exploratory study of the therapeutic 
mechanism of GSK3228836 in participants with HBeAg-negative CHB on stable 
nucleos(t)ide therapy using repeat fine needle aspirations of the liver for intrahepatic 
immunophenotyping. 
The study consists of a single treatment arm 
1. 300 mg GSK3228836 for 12 weeks (loading schedule on Day 4 and Day 11).  
Participants will continue to receive their stable nucleos(t)ide therapy. 


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After the 12 weeks of dosing with GSK3228836, there will be a post-treatment follow-up 
period of 24 weeks. 
 
Brief Summary: 
The purpose of this study is to determine the therapeutic mechanism of GSK3228836 in 
participants with CHB. Study details include: 
Study Duration: 37 weeks (45 weeks if include screening and flexible visit windows) 
Treatment Duration: 12 weeks 
Visit Frequency: Twice a week for the first 2 weeks, once a week through Week 14, once 
at Week 16, and once every 4 weeks thereafter 
Study Hypothesis: GSK3228836 treatment will result in phenotypic changes in 
intrahepatic immunity associated with loss of HBsAg and treatment-emergent changes in 
ALT 
Health Measurement/Observation: HBsAg <LLOQ 
Number of Participants: 
The study will enrol approximately 20 participants, but no more than 24. 
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 
and eligibility process. 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 45 weeks. 
o 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 
o Up to 1 week of pre-treatment assessments (including baseline FNA) 
o 12 weeks treatment with GSK3228836 
o 24 weeks post treatment follow-up (+ up to 10 days) 
There are no plans for dose adjustments.  Individual dose adjustments for safety are 
outlined in the monitoring/stopping criteria. 
Data Monitoring/ Other Committee: Yes 


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1.2. 
Schema 
 
 
An optional 6th FNA may be included between Weeks 6 and 36 following discussion between investigator and medical 
monitor. 
1.3. 
Schedule of Activities (SoA) 
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.  Home visits may include drug administration, blood draws, participant assessments 
and data collection. The full specifications of the home nursing services will be outlined 
in the study reference manual (SRM). 
Table 1 
Screening 
ASSESSMENTS (45 Day window) 
 
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 ASSESSMENTS 
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/Fibrotest 
X 
ANCA2 
X 
Complement C3, C4, C5a, hsCRP, MCP-1, complement Bb, Ang-II 
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 -7 to Day 50 
Assessments 
Day -7 to Day -1 
D1 
D4 
D8 
D11 
D15 
D22 
D29 
D36 
D43 
D50 
 
Week-1 (Baseline) 
W1 
W1 
W2 
W2 
W3 
W4 
W5 
W6 
W7 
W8 
Window 
 
1 day 
 3 days 
Study treatment dosing1 
 
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 
Concomitant medication review 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Symptoms directed exam 
X 
X 
 
 
 
 
 
X 
 
 
 
Vital signs 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Injection site reactions 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Laboratory  
 
Pregnancy test (women of child bearing potential)2 
X 
 
 
 
 
 
 
X 
 
 
 
Hematology3[includes platelet count and WBC] 
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 
Urinalysis 
X 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
Urine ACR 
X 
X 
 
 
 
X 
 
X 
 
X 
 
HBsAg and HBV DNA 
X 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
Anti-HBsAg  
X 
 
 
 
 
 
 
X 
 
 
 
Anti-HBeAg  
X 
 
 
 
 
 
 
X 
 
 
 
HBV RNA, HBcrAg, and sequencing (HBV genotype/phenotype, HBV DNA and/or RNA) 
X 
 
 
 
 
X 
X 
X 
 
 
X 
Complement C3, Complement C4, hs-CRP, MCP-1 
X 
X 
 
 
 
X 
 
X 
 
X 
 
Complement C5a, Complement factor Bb 
X 
X 
 
 
 
X 
 
X 
 
X 
 
ANCA, Ang II 
X 
X 
 
 
 
 
 
X 
 
 
 
PK4 
 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
Fine needle aspiration of liver5 
X 
 
 
 
 
X6 
 
X6 
 
 
 
PBMC Collection for immunophenotyping 
X 
 
 
 
 
 
 
X 
 
 
 
Soluble Protein  
X 
 
 
X 
 
X 
X 
X 
 
 
X 
PAXGene RNA for expression analysis in whole blood 
X 
 
 
X 
 
X 
 
X 
 
 
 
Genetics 
X 
 
 
 
 
 
 
 
 
 
 
Archived samples [serum; plasma] 
X 
 
 
X 
 
X 
 
X 
 
X 
 


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Assessments 
Day -7 to Day -1 
D1 
D4 
D8 
D11 
D15 
D22 
D29 
D36 
D43 
D50 
 
Week-1 (Baseline) 
W1 
W1 
W2 
W2 
W3 
W4 
W5 
W6 
W7 
W8 
Optional Assessments 
 
Urine or serum pregnancy test7 
 
X 
 
 
 
 
 
 
 
 
 
Optional: fine needle aspiration of liver8 
 
 
 
 
 
 
 
 
X 
X 
X 
Optional: PBMC Collection for immunophenotyping9 
 
 
 
 
 
 
 
 
X 
X 
X 
Optional: Soluble Protein9 
 
 
 
 
 
 
 
 
X 
X 
X 
Optional: PAXGene RNA for expression analysis in whole blood9 
 
 
 
 
 
 
 
 
X 
X 
X 
 
1. Dosing to occur only after the completion of all assessments to determine dosing is safe to proceed 
2. Women of childbearing potential (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] 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. PK samples are to be taken pre-dose 
5. FNA will only be collected if the investigator deems it appropriate  
6. Within 3 hours after study treatment dosing in Week 3 and Week 5.  Sample not to be collected if the participant has already withdrawn from treatment. 
7. Only to be conducted for women of child-bearing potential if the Screening serum hCG pregnancy test was >24 hours pre-dose first dose. 
8. An optional additional FNA may be collected anytime between Week 6 and Week 36 following discussion between investigator and medical monitor based on unexpected changes 
in HBsAg or ALT. Only 1 additional FNA may be collected for each participant. 
9. Only to be collected if the optional FNA is collected at this visit and has not already been collected as part of the standard assessments. 
 


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Table 3 
On-Treatment Day 57 to Day 78 
Assessments 
D57 
D64 
D71 
D78 
 
W9 
W10 
W11 
W12 
Window 
 3 days 
Study treatment dosing 
X 
X 
X 
X 
Safety Assessments 
 
AE/SAE review 
X 
X 
X 
X 
Concomitant medication review 
X 
X 
X 
X 
Symptoms directed exam 
X 
 
 
 
Vital signs 
X 
X 
X 
X 
Injection site reactions 
X 
X 
X 
X 
Laboratory  
 
Pregnancy test (women of child bearing potential) 
X 
 
 
 
Hematology1 [includes platelet count and WBC with differential] 
X 
X 
X 
X 
PT, INR, aPTT 
X 
 
 
 
Chemistry 
X 
X 
X 
X 
Urinalysis 
X 
X 
X 
X 
Urine ACR 
X 
 
X 
 
HBsAg and HBV DNA 
X 
X 
X 
X 
Anti-HBsAg  
X 
 
 
 
Anti-HBeAg  
X 
 
 
 
HBV RNA, HBcrAg, and Sequencing (HBV genotype/phenotype; HBV DNA and/or RNA) 
 
 
 
X 
Complement C3, Complement C4, hs-CRP, MCP-1 
X 
 
X 
 
Complement C5a, Complement factor Bb 
X 
 
X 
 
ANCA, Ang II 
X 
 
 
 
PK2 
X 
X 
X 
X 
Soluble Protein 
 
 
 
X 
Archived samples [serum; plasma] 
X 
 
X 
 
Optional Assessments 
 
Optional: fine needle aspiration of liver3 
X 
X 
X 
X 
Optional: PBMC Collection for immunophenotyping3 
X 
X 
X 
X 
Optional: Soluble Protein4 
X 
X 
X 
X 
Optional: PAXGene RNA for expression analysis in whole blood4 
X 
X 
X 
X 


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1. 
Hematology- platelet count to be analyzed at local laboratory prior to dose; hematology samples to be collected for central laboratory assessments in parallel 
2. 
PK samples are to be taken pre-dose. 
3. 
An optional additional FNA may be collected anytime between Week 6 and Week 36 following discussion between investigator and medical monitor based on unexpected changes 
in HBsAg or ALT. Only 1 additional FNA may be collected for each participant. 
4. 
Only to be collected if the optional FNA is collected at this visit and has not already been collected as part of the standard assessments. 
 
Table 4 
Off-Treatment Follow-Up Day 85 to Day 246 
Assessments 
 
Day 85 
Day 92 
Day 106 
Day 134 
Day 162 
Day 190 
Day 218 
Day 246 
Early 
Termination 
 
 
W 13 
W 14 
W 16 
W 20 
W 24 
W 28 
W 32 
W 36 
NA 
Window 
 3 days 
 10 days 
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 
Symptoms 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 
Hematology1 (includes platelet count, 
and WBC with differential) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
PT, INR, aPTT 
X 
X 
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 
HBV RNA, HBcrAg, and Sequencing 
(HBV genotype/phenotype; HBV DNA 
and/or RNA) 
X 
 
X 
 
X 
X 
X 
X 
X 


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Assessments 
 
Day 85 
Day 92 
Day 106 
Day 134 
Day 162 
Day 190 
Day 218 
Day 246 
Early 
Termination 
 
 
W 13 
W 14 
W 16 
W 20 
W 24 
W 28 
W 32 
W 36 
NA 
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 
X 
X 
X 
X 
PK 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Fine Needle Aspiration of Liver2 
X 
 
 
 
 
 
 
X 
X 
PBMC Collection for 
immunophenotyping 
 
 
 
 
 
 
 
X 
X 
PAXGene RNA for expression analysis 
in whole blood 
X 
 
 
 
X 
 
 
X 
X 
Soluble Protein  
X 
 
X 
 
X 
 
X 
X 
X 
APRI/Fibrosure 
 
 
 
 
 
 
 
X 
X 
Archived Samples [serum; plasma] 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Optional Assessments 
 
Optional: fine needle aspiration of liver3 
 
X 
X 
X 
X 
X 
X 
 
 
Optional: PBMC Collection for 
immunophenotyping4 
 
X 
X 
X 
X 
X 
X 
 
 
Optional: Soluble Protein4 
 
X 
X 
X 
X 
X 
X 
 
 
Optional: PAXGene RNA for 
expression analysis in whole blood4 
 
X 
X 
X 
X 
X 
X 
 
 
1. 
Hematology- platelet count analyzed at local laboratory is optional during the off-treatment period; hematology samples to be collected for central laboratory assessments 
2. 
FNA will only be collected if the investigator deems it appropriate 
3. An optional additional FNA may be collected anytime between Week 6 and Week 36 following discussion between investigator and medical monitor based on unexpected 
changes in HBsAg or ALT. Only 1 additional FNA may be collected for each participant. 
4. 
Only to be collected if the optional FNA is collected at this visit and has not already been collected as part of the standard assessments. 
 


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2. 
INTRODUCTION 
2.1. 
Study Rationale  
B-Fine is an exploratory study of the therapeutic mechanism of GSK3228836 in 
participants with HBeAg-negative CHB on stable nucleos(t)ide therapy.  The study will 
investigate the virologic and immunologic correlates of HBsAg loss observed in 
participants when treated for 12 weeks with GSK3228836.  Repeat fine needle aspirates of 
the liver will be performed to enable analysis of liver-resident immune cells to investigate 
any immunomodulatory properties of GSK3228836 and to study the biology of underlying 
treatment-associated liver flares.  Longitudinal analyses of blood-borne inflammatory 
signatures and virological assessments of CHB infection will be performed in parallel. 
2.2. 
Background 
HBV infection, especially chronic infection, is a significant worldwide medical problem.  
Globally, in 2015, an estimated 257 million people were living with chronic Hepatitis B, 
with only 9% of patients with Hepatitis B being treated. Viral hepatitis led to 1.34 million 
deaths and of these deaths, 66% were the results of complications of CHB infection [WHO, 
2015]. 
The goal of therapy for CHB is to improve quality of life and survival by preventing 
progression of the disease to cirrhosis, decompensated liver disease, end-stage liver 
disease, hepatocellular carcinoma (HCC), or death. This goal can be achieved if HBV 
replication is suppressed in a sustained manner thereby decreasing the histological activity 
of CHB and reducing the risk of cirrhosis and HCC [Liaw, 2004; Feld, 2009]. In both 
HBeAg-positive and HBeAg-negative CHB, the ultimate treatment endpoint is loss of 
detectable serum hepatitis B surface antigen (HBsAg) and serum HBV DNA [Lok, 2009; 
EASL, 2012]. Loss of HBsAg is preceded by a robust immunological response to HBV 
infection resulting in sustained suppression of serum HBV deoxyribonucleic acid (DNA) 
and disease resolution. 
First-line therapy for CHB is treatment with a 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 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 


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


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suppression of serum HBsAg to <LLOQ (with or without anti-HBsAg seroconversion,) 
and undetectable HBV DNA in serum, after completion of a finite course of treatment 
[Lok, 2017].  
Functional cure occurs in only a very small percentage of patients on NA therapy alone 
(approx. 3% per annum), meaning that patients frequently relapse once they are taken off 
treatment [Lok, 2017].  The high rate of relapse in these patients is hypothesised to be due 
to their inability to raise an effective immune response to the virus in the presence of high 
circulating levels of HBsAg, which continues to be produced by infected hepatocytes, even 
in the absence of ongoing viral replication.  
2.3. 
Benefit/Risk Assessment 
More detailed information about the identified and potential benefits and risks and 
expected adverse events 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, drug induced vascular inflammation (DIVI), hematology, renal function, and 
PK are discussed in Section 7. 
 


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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 oligonucleotides (ASOs). 
Vasculitis and/or perivascular inflammation has been 
described in monkey studies with many if not most ASOs. 
 
This effect has not been observed in clinical studies with 
GSK3228836 to date. 
Laboratory Evaluations: Inclusion of biomarker panels 
to look for inflammatory and immune activation that would 
be expected to accompany vascular inflammation 
 
Stopping Criteria: Proposed Monitoring Schedule and 
Stopping Rules for Drug Induced Vascular Inflammation 
and Complement Activation (see Section 7.1.2) 
 
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 7 
 
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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Regarding 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 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 
Estimands/Endpoints 
Primary 
Efficacy: To assess the effect of 12 
weeks of GSK3228836 on serum 
HBsAg levels in participants with CHB 
The Primary Estimand supporting the primary objective of the study is 
defined as:  
• 
Population: Participants with CHB who receive at least one 
dose of IP 
• 
Treatment: 300 mg GSK3228836 for 12 weeks (also on stable 
nucleos(t)ide therapy) 
• 
Variable: Achieving serum HBsAg level <LLOQ at any time 
point up to and including Week 12 without the use of PEG-
interferon or other immunomodulator therapies 
• 
Population-level summary: Percent of participants that achieve 
serum HBsAg level <LLOQ 
• 
Intercurrent events: Discontinuation of, interruption of, and 
adherence to IP will be ignored (treatment policy).  
The primary estimand is the percentage of participants with CHB 
receiving 300 mg GSK3228836 for 12 weeks (with at least one dose of 
IP) who achieve serum HBsAg level <LLOQ at any time point up to and 
including Week 12, without the use of PEG-interferon or other 
immunomodulator therapies, regardless of completing IP, interruptions in 
IP or adherence to IP. 
Secondary 
Efficacy: To assess sustainability of 
serum HBsAg loss by GSK3228836 for 
up to 24 weeks off-treatment. 
The Estimand supporting the objective is defined as: 
• 
Population:  Participants with CHB who receive at least one 
dose of IP 
• 
Treatment: 300 mg GSK3228836 for 12 weeks (also on stable 
nucleos(t)ide therapy) 
• 
Variables:   
o Sustained HBsAg Response (HBsAg <LLOQ) for 
24 weeks after the planned end of GSK3228836 treatment 
▪ HBsAg from Week 13 to Week 36 will be used to 
assess sustained HBsAg response after the planned 
end of GSK3228836 treatment without the use of PEG-
interferon or other immunomodulator therapies.  
o Sustained HBsAg Response (HBsAg <LLOQ) for 
24 weeks after the actual end of GSK3228836 treatment 
▪ HBsAg for 24 weeks after end of actual treatment will 
also be used to assess sustained HBsAg response 
after the actual end of GSK3228836 treatment without 
the use of PEG-interferon or other immunomodulator 
therapies. 
• 
Intercurrent events: Discontinuation of, interruption of, and 
adherence to IP will be ignored (treatment policy).   
The group of estimands supporting this objective in participants with 
CHB receiving 300 mg GSK3228836 for 12 weeks (with at least one 
dose of IP) is the percentage of participants for each variable regardless 
of completing IP, interruptions in IP or adherence to IP, without the use 
of PEG-interferon or other immunomodulator therapies. 


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Objectives 
Estimands/Endpoints 
Efficacy: To assess sustainability of 
serum HBsAg and HBV DNA loss by 
GSK3228836 for up to 24 weeks off 
treatment. 
The Estimand supporting the objective is defined as: 
• 
Population: Participants with CHB who receive at least one 
dose of IP 
• 
Treatment: 300 mg GSK3228836 for 12 weeks (also on stable 
nucleos(t)ide therapy) 
• 
Variables: 
o Sustained Virologic Response (HBsAg <LLOQ and HBV 
DNA <LLOQ) for 24 weeks after the planned end of 
GSK3228836 treatment 
▪ HBsAg and HBV DNA from Week 13 to Week 36 will 
be used to assess sustained virologic response after 
the planned end of  GSK3228836 treatment without the 
use of PEG-interferon or other immunomodulator 
therapies. 
o Sustained Virologic Response (HBsAg <LLOQ and HBV 
DNA <LLOQ) for 24 weeks after the actual end of 
GSK3228836 treatment 
▪ HBsAg and HBV DNA for 24 weeks after end of actual 
treatment will be used to assess sustained virologic 
response after the actual end of GSK3228836 
treatment without the use of PEG-interferon or other 
immunomodulator therapies. 
• 
Intercurrent events: Discontinuation of, interruption of, and 
adherence to IP will be ignored (treatment policy).   
The group of estimands supporting this objective in participants with 
CHB receiving 300 mg GSK3228836 for 12 weeks (with at least one 
dose of IP) is the percentage of participants for each variable regardless 
of completing IP, interruptions in IP or adherence to IP, without the use 
of PEG-interferon or other immunomodulator therapies. 
Efficacy: To assess the effect of 12 
weeks GSK3228836 on biomarkers and 
virus-specific antibody responses 
Estimands supporting the secondary objective of assessing the effect of 
12 weeks GSK3228836 on biomarkers and virus-specific antibody 
responses are defined as follows:  
• 
Population: Participants with CHB who receive at least one 
dose of IP 
• 
Treatment: 300 mg GSK3228836 for 12 weeks (also on stable 
nucleos(t)ide therapy) 
• 
Intercurrent events: Discontinuation of, interruption of, 
adherence to IP will be ignored (treatment policy). PEG-
interferon or other immunomodulator therapies will be handled 
with hypothetical strategy. 
1) Categorical Variables: 
• 
Achieving:  
o HBsAg <LLOQ over time 
o HBV DNA <LLOQ over time 
o HBsAg and HBV DNA <LLOQ over time 
• 
Categorical changes from baseline in HBsAg (e.g. <0.5, 0.5, 
1, 1.5, 3 log10 IU/mL) over time. 
• 
ALT>3X ULN at over time 
• 
HBe antibody (anti-HBeAg) levels over time 
Population summary: percentage of participants in each category. 
2) Continuous Variables:  
• 
Actual values and change from baseline over time for HBsAg 
and HBV DNA  


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Objectives 
Estimands/Endpoints 
• 
HBs antibody (anti-HBsAg) levels over time 
• 
Area under the curve (AUC) for ALT on treatment (12 weeks), 
during follow up (24 weeks), and on treatment + follow up (36 
weeks). 
 
Population summary: mean values and/or mean changes from baseline 
for each variable  
3) Time to Event Variable 
• 
Time to Maximum ALT (ALT must be greater than 3xULN) 
during 36 weeks of treatment + follow up 
 
Population summary: Turnbull estimate for median Time to Maximum ALT 
(>3xULN) 
The group of estimands supporting this objective in participants with CHB 
receiving 300 mg GSK3228836 for 12 weeks (with at least one dose of IP) 
are the population summary for each variable in the absence of PEG-
interferon or other immunomodulator therapies, regardless of completing 
IP, interruptions in IP, or adherence to IP.  
Safety 
Safety: To assess the safety and 
tolerability of GSK3228836 when dosed 
for 12 weeks in participants with CHB 
Clinical assessments including, but not limited to vital signs, laboratory 
measurements and adverse events 
Exploratory 
CCI


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Objectives 
Estimands/Endpoints 
4. 
STUDY DESIGN 
4.1. 
Overall Design 
This study is a Phase IIa, multi-centre open label exploratory study of the therapeutic 
mechanism of GSK3228836 in participants with HBeAg-negative CHB on stable 
nucleos(t)ide therapy using repeat fine needle aspirations of the liver for intrahepatic 
immunophenotyping (see Section 1.2). 
The study consists of a single treatment arm: 
1. 300 mg GSK3228836 for 12 weeks (loading schedule on Day 4 and Day 11).  
Participants will continue to receive their stable nucleos(t)ide therapy. 
After the 12 weeks of dosing with GSK3228836, there will be a post-treatment follow-up 
period of 24 weeks.  An Independent Data Monitoring Committee (IDMC) will review the 
data (see Section 10.1.5). 
4.2. 
Scientific Rationale for Study Design 
The overall objective of the study is to investigate the therapeutic mechanism of 
GSK3228836 in the liver using repeat fine needle aspirates to phenotype changes in 
intrahepatic immunity that are associated with loss of HBsAg and treatment-emergent 
changes in ALT. 
Understanding the interplay between the virology of CHB and the host immune system 
will be key to the rational, evidence-based selection of biomarkers of response, 
optimisation of therapeutic approaches and selection of combination treatment regimens 
[Gill, 2019]. 
Study ISIS 505358-CS3 has already demonstrated efficacy of up to 4 weeks treatment with 
GSK3228836 on serum HBsAg levels in treatment naïve and nucleos(t)ide-controlled 
participants, with concomitant reversible elevations in serum ALT, believed to be 
indicative of HBV-targeted immune responses against infected hepatocytes. 
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Additional comprehensive investigation of the mechanism of action of GSK3228836 in the 
liver compartment is essential: 
• To determine whether GSK3228836 has an immunomodulatory mechanism of 
action in addition to its previously described direct antiviral effects on HBV 
mRNA. 
• To investigate the relationship between GSK3228836-mediated suppression of 
HBsAg, ALT flares and the potential for functional cure. 
• To investigate immunological and/or virological correlates of HBsAg-suppression 
that may enable future response-guided therapy.  
• To identify novel immunological pathways or targets with the potential to improve 
functional cure rates when used in combination or sequence with GSK3228836. 
Study 212602 (B-Fine) will investigate 12 weeks treatment with 300 mg/week 
GSK3228836 (including loading doses on Day 4 and Day 11 used in Study ISIS 505358-
CS3).   
Rationale for study population 
In study 212602 (B-Fine), participants expected to have the highest chance of achieving 
HBsAg level <LLOQ with 12 weeks of treatment with GSK3228836 will be enrolled.  The 
following criteria have been included to aid selection of the optimal population to best 
study intrahepatic and peripheral virological and immunological correlates of HBsAg loss 
and treatment-emergent ALT elevations. 
• Patients on stable nucleos(t)ide therapy 
• Patients who are HBeAg-negative 
Selection of nucleos(t)ide-controlled CHB patients 
Efficacy of 4 weeks treatment with GSK3228836 has been investigated in Phase IIa study, 
ISIS 505358-CS3, in both treatment naïve participants and participants on stable 
nucleos(t)ide therapy.  Both groups of study participants experienced declines in HBsAg, 
including some achieving HBsAg levels <LLOQ, followed by acute ALT elevations (refer 
to Investigator’s Brochure [GSK Document Number 2019N425040_00]).   
Although there are some differences in regional treatment guidelines for starting 
nucleos(t)ide therapy, most indicate the initiation of treatment at the onset of active 
hepatitis, defined as high levels of HBV DNA and elevated ALT [EASL, 2017; Sarin 2016; 
Terrault, 2018].  Treatment with nucleos(t)ides is very effective in controlling HBV 
replication and acute hepatitis over a treatment period of approximately 6 months, resulting 
in undetectable levels of HBV DNA in the blood and normalisation of ALT.  As these 
patients typically require lifelong therapy with frequent monitoring, they are a common 
patient subpopulation within speciality hepatology centres and clinics. 
Patients whose infection is controlled by nucleos(t)ides still have high levels of HBsAg in 
serum due to the presence of high levels of HBV cccDNA and integrated DNA in infected 
hepatocytes.  A recently completed GSK-sponsored Phase IIa study (205670) investigated 
safety, tolerability, pharmacokinetics and pharmacodynamics of a related HBV-targeted 


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antisense oligonucleotide (ASO), GSK3389404, in nucleos(t)ide-controlled participants 
with HBeAg-positive and HBeAg-negative CHB. Part 2 of the study enrolled 66 
participants (18 HBeAg-positive, 48 HBeAg-negative) in the Asia-Pacific region, 
including Hong Kong, China, Japan, Philippines, Singapore and South Korea.  Mean (SD) 
baseline serum HBsAg was 2.94 (0.56) log10 IU/ml, with 4/66 participants having baseline 
serum HBsAg levels above 10,000 IU/ml [GSK Document Number 2020N429086_00]. 
CHB patients on stable nucleos(t) therapy have been selected for study 212602 as they are 
considered to have the most favourable benefit:risk profile for early PoM/PoC studies with 
experimental therapies targeting HBsAg as an endpoint [Lok, 2017]. 
Selection of HBeAg-negative patients  
The utility of serum HBsAg as a predictor of treatment response in CHB has been widely 
investigated, particularly in those treated with PEG-interferons.  Lower serum HBsAg at 
baseline and rapid early declines on-treatment have both been associated with higher rates 
of sustained loss of HBsAg and functional cure [Lee, 2018; Liu 2018].  Although the 
relationship between baseline serum HBsAg and response to GSK3228836 has yet to be 
established, it is reasonable to assume that participants with lower levels of HBsAg at 
screening will be more likely to achieve HBsAg levels <LLOQ on treatment.  As HBeAg-
negative patients typically have lower levels of serum HBsAg than HBeAg-positive 
patients, the HBeAg-negative population has been selected for study 212602 in order to 
enrich for potential responders. 
Previous GSK clinical experience in CHB supports the observation that serum HBsAg 
levels are lower in HBeAg-negative patients than HBeAg-positive patients.  In study ISIS 
505538-CS3, there were a wide range of baseline HBsAg levels reported across all 4 
Cohorts (entry criteria for serum HBsAg >50 IU/mL).  Final data from that study highlight, 
as expected, a lower baseline HBsAg level in HBeAg-negative than HBeAg-positive 
participants.  In Cohort 4 of study ISIS 505538-CS3, which included only HBeAg-negative 
participants on stable nucleos(t)ide therapy (n=7), baseline serum HBsAg levels ranged 
from 173.7-30,943 IU/mL.  Only one participant in Cohort 4 had a baseline serum HBsAg 
level above 10,000 IU/mL [GSK Document Number 2020N429086_00].  A recently 
completed GSK-sponsored Phase IIa study (205670) investigated safety, tolerability, 
pharmacokinetics and pharmacodynamics of a related HBV-targeted ASO, GSK3389404, 
in nucleos(t)ide-controlled participants with HBeAg-positive and HBeAg-negative CHB.  
This study recruited 66 participants (18 HBeAg-positive, 48 HBeAg-negative) in the Asia-
Pacific region, including Hong Kong, China, Japan, Philippines, Singapore and South 
Korea.  Mean (SD) baseline serum HBsAg was 2.86 (0.51) log10 IU/mL in HBeAg-
negative participants compared to 3.04 (0.56) IU/ml in HBeAg-positive participants [GSK 
Document Number 2020N429086_00].  
Rationale for studying 12 weeks of treatment with GSK3228836 
The current hypothesis of functional cure is based on the ability of a patient to raise an 
effective immune response to HBV in infected hepatocytes once immunosuppressive 
HBsAg has been lost from the blood.  The duration of suppression of HBsAg required to 
enable reconstitution of anti-HBV immunity is still unknown.  In study ISIS 505358-CS3 
treatment of participants with CHB on stable nucleos(t)ide therapy with 300 mg/week of 


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GSK3228836 for 4 weeks duration was associated with reductions in HBsAg.  Median 
decline in HBsAg from baseline over 4 weeks was -3.166 IU/ml, with two participants 
achieving HBsAg levels <LLOQ while on treatment, or shortly after.  Both of these 
participants saw reversable elevations in ALT to >3X ULN after HBsAg had fallen 
<LLOQ.   Of note, in participants that did not become HBsAg <LLOQ, reductions of 
HBsAg had not yet reached a plateau during treatment, suggesting that continued dosing 
has the potential to further reduce HBsAg levels.  Taken together, the data suggest that a 
longer duration of treatment with GSK3228836 may be required to increase the rate of 
participants achieving HBsAg levels <LLOQ.  Twelve weeks duration of treatment with 
300 mg GSK3228836 has been selected as optimal to assess the primary endpoint of 
achieving HBsAg < LLOQ in study 212602. Longer durations of treatment (up to 24 
weeks) will be explored in other clinical trials during the development of GSK3228836 in 
order to optimise efficacy in terms of sustained virological response and functional cure. 
Rationale for inclusion of fine needle aspirates of the liver 
To date, much of what is understood of the virology and immunobiology of CHB infection 
has come from studies of the peripheral blood compartment of infected patients in 
observational and a limited number of interventional clinical studies.  More recently, a 
small number of studies using conventional liver biopsy or alternative liver-sampling 
techniques to study liver resident immune subtypes have revealed substantial differences 
between the systemic and liver compartments, including defective T-cell-mediated 
immunity against HBV in the liver of chronically infected patients [Gill, 2019]. 
Where liver biopsies were once considered routine in the diagnosis and monitoring of liver 
disease in patients with CHB, they have been mostly replaced by non-invasive tests in 
recent years, limiting the opportunity to study the liver-resident immune subpopulations in 
clinical studies.  Research papers have recently described the use of fine needle aspirates 
(FNAs) as a rapid and better-tolerated alternative to conventional core biopsies for 
sampling intrahepatic immune cells, including T-cells and cells of the innate immune 
system, such as liver-resident NK cells.  This novel technique has been shown to be safe 
and effective for repeat sampling of the same patient over several weeks/months, 
permitting longitudinal analysis of immune responses to therapeutic interventions in 
clinical trials for the first time [Gill, 2019; Tjwa, 2016; Sprengers, 2005]. 
In study 212602, it is proposed to perform a total of 5 FNAs at preselected timepoints (plus 
up to 1 optional FNA) during the 45-week study duration (see Section 1.2).  The timing of 
FNAs has been selected to assess intrahepatic immunological changes at different stages 
of treatment with GSK3228836, and in the follow-up period (Table 6) 


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Table 6 
Timepoints for Fine Needle Aspirates 
FNA 
number 
Time point (Study 
Week) 
Description 
1 
Week -1 
Baseline sample 
2 
Week 3 
Early on-treatment. Preceding anticipated marked declines in serum HBsAg 
level. 
3 
Week 5 
Anticipated start of HBsAg level <LLOQ in responders and start of ALT flare 
(Based on review of efficacy data in study ISIS 505358-CS3). 
4 
Week 13 
End of treatment  
5 
Week 36 
End of follow-up 
6 
(Optional) 
Any between Week 6 
and Week 36 
To be determined following discussion between investigator and medical 
monitor. May be triggered by changes in serum HBsAg levels or ALT. 
4.2.1. 
Participant Input into Design 
A small group of patients with CHB were asked to review an example informed consent 
form in related study 209668. The patients provided feedback for more clarity in the 
informed consent form regarding the purpose of the study and optional assessments (e.g. 
biomarkers), mode of administration of GSK3228836, the study burden in both terms of 
visit schedule and duration of visit.  Efforts to reduce the burden of visits were encouraged.  
Input from these patients will be incorporated into the Informed Consent Form.  The study 
team reviewed the blood collection timepoints and made changes to balance participant 
burden with the data/timepoints needed for safety and efficacy analyses. 
Due to the feedback from patients that the number of visits may be challenging (weekly 
visits to the clinic/hospital), the study team are working with countries/sites to provide an 
option where participants may use a centralised home nursing provider.  The home nursing 
providers will go to the participant, decreasing the number of times the participant must 
travel to/from the clinic/hospital.  Only selected visits will have the option to be performed 
as a home visit, these will include drug administration, blood draws, participant 
assessments and data collection. The full specifications of the home nursing services will 
be outlined in the SRM. 
4.3. 
Justification for Dose 
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.   
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 


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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 level <LLOQ that 
persisted for 102 and 28 days, respectively. In both participants who achieved HBsAg level 
<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 
nucleos(t)ide therapy.  Three of five 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 participants achieving 
and sustaining HBsAg levels <LLOQ. 
Study 212602 will explore weekly dosing of GSK3228836 300 mg for 12 weeks (with 
the loading doses) in participants on stable nucleos(t)ide therapy. 
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.  


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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; 
Baraclude, 2015; Bristol-Myers Squibb, 2018; Gilead, 2018]. These 5 drugs undergo a 
combination of glomerular filtration and tubular secretion, which have been reported to be 
mediated by one or more of the following transporters: the organic anion transporter (OAT) 
1, OAT3, the organic cation transporter (OCT) 1, and OCT2 [Cihlar, 2001; Cihlar, 2004; 
Servais, 2006; Uwai, 2007; Minuesa, 2009; Yanxiao, 2011; Xu, 2013]. It has been shown 
that 2'-MOE ASO is neither a substrate nor an inhibitor of OAT1, OAT3, OCT1 and OCT2 
[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. 


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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 currently receiving stable nucleos(t)ide analogue therapy, 
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 must be adequately suppressed, 
defined as plasma or serum HBV DNA <90 IU/mL 
5. HBeAg-negative 
6. Alanine Transaminase (ALT) ≤2 X ULN  
SEX 
7. Male and/or Female 
a. A male participant is eligible to participate if they agree to the following 
during the intervention period and for at least 90 days after the last dose of 
study treatment 
i. 
Refrain from donating sperm 
ii. 
AND be abstinent from heterosexual intercourse as their 
preferred and usual lifestyle (abstinent on a long term and 
persistent basis) and agree to remain abstinent OR Must agree 
to use contraception/barrier as detailed below 
1. Agree to use a male condom [and should also be advised of 
the benefit for a female partner to use a highly effective 
method of contraception as a condom may break or leak] 
when having sexual intercourse with a woman of 
childbearing potential who is not currently pregnant 
b. A female participant is eligible to participate: 
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 


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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 included in Appendix 4 of the protocol 
The investigator is responsible for review of medical history, menstrual history, 
and recent sexual activity to decrease the risk for inclusion of a woman with an 
early undetected pregnancy 
 
INFORMED CONSENT 
8. Capable of giving signed informed consent as described in Section 10.1 which 
includes compliance with the requirements and restrictions listed in the 
informed consent form (ICF) and in this protocol. 
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: 
• Current or past history of Hepatitis C virus (HCV) 
• Human immunodeficiency virus (HIV) 
• Hepatitis D virus (HDV) 
3. History of or suspected liver cirrhosis and/or evidence of cirrhosis as determined by 
• 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 
• Regardless of APRI or Fibrosure/FibroTest score participants will be 
excluded from the study if their past history includes one of the following 
criteria: 


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i. Liver biopsy showing Metavir 4 or equivalent 
ii. Liver stiffness >12 kPa  
4. Diagnosed or suspected hepatocellular carcinoma as evidenced by the following 
• Alpha-fetoprotein concentration ≥200 ng/mL  
• 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 enrolment. 
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 by itself won’t be an exclusion 
criterion - but if results are borderline positive or positive: 
• Participants that meet this criteria may be considered for inclusion 
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 vasculitic/inflammatory/auto-immune condition 
9. Low C3 at screening or baseline AND evidence of past history or current 
manifestations of vasculitic/inflammatory/auto-immune conditions 
• 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 
• Current alcohol use as judged by investigator to potentially interfere with 
participant compliance 
• 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 
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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 
• Serum albumin <3.5 g/dL 
• Glomerular filtration rate (GFR) <60 mL/min /1.73m2 as calculated by the 
CKD-EPI formula. 
• INR >1.25 
• Platelet count <140 X 109/L 
• 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 
• 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 
 


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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 enrolled. A minimal set of screen failure information is required 
to ensure transparent reporting of screen failure participants to meet the Consolidated 
Standards of Reporting Trials (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. 
Criteria for Temporarily Delaying Administration of Study 
Intervention 
See Section 7.1 for guidance on treatment hold and criteria for temporarily delaying 
GSK3228836. 


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6. 
STUDY INTERVENTION(S) AND CONCOMITANT 
THERAPY 
Study intervention is defined as any investigational intervention(s), marketed product(s), 
placebo, or medical device(s) intended to be administered to a study participant according 
to the study protocol. 
6.1. 
Study Intervention(s) Administered 
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 labelled 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.  
CCI


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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 
This is an open-label study with one treatment arm.  Randomization and blinding are not 
applicable.  As the study is unblinded, the risk of potential bias will be mitigated by 
ensuring that, where feasible, the GSK central team’s exposure to virological biomarker 
results, including HBsAg, HBsAb and HBV DNA, is limited.  Details will be included in 
separate blinding plans. 
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. 
Dose Modification 
Dose modifications are not planned for this study. 
6.6. 
Continued Access to Study Intervention after the End of the 
Study 
No intervention is planned at the end of the study, although participants may be asked to 
enrol in a long-term roll-over study based on their response. 
6.7. 
Treatment of Overdose 
For this study, any dose of GSK3228836 greater than 300 mg within a 24-hour time period 
will be considered an overdose. 
GSK does not recommend specific treatment for an overdose. 
In the event of an overdose, the investigator should: 
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). 


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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. 
6.8. 
Concomitant Therapy 
Any medication or vaccine (including over-the-counter or prescription medicines, 
vitamins, and/or herbal supplements or other specific categories of interest) that the 
participant is receiving at the time of enrollment or receives during the study must be 
recorded along with: 
• reason for use 
• dates of administration including start and end dates 
• dosage information including dose and frequency 
The Medical Monitor should be contacted if there are any questions regarding concomitant 
or prior therapy. 
Concomitant medications, including nucleos(t)ides, 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). 
6.8.1. 
Nucleos(t)ide Treatment during and after the End of the Study  
The investigator is responsible for ensuring that consideration has been given to the care 
of the participant’s medical condition, and that participants are able to continue their 
therapy over the duration of the study. 
The investigator is responsible for ensuring that consideration has been given to the post-
study care of the participant’s medical condition, whether or not GSK is providing specific 
post-study treatment. 
6.8.2. 
Prohibited Medications and Non-Drug Therapies 
The following concomitant medications 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 
• Prior treatment with any oligonucleotide or small interfering RNA (siRNA) within 
12 months prior to the first dosing through the final Follow-up visit 


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• Creatine-containing gym supplements  
• Anti-coagulation therapies (for example warfarin, Factor Xa inhibitors or 
anti-platelet agents like clopidogrel).  Note: occasional use of aspirin is permitted, 
please consult the medical monitor if needed.  
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.  In rare instances, it may be necessary for a participant to 
permanently discontinue (definitive discontinuation) study intervention.  Participants that 
withdraw from treatment for any reason should be encouraged to complete all their on-
treatment and follow-up visits and assessments.  Should the participant not wish to continue 
with weekly visits in the on-treatment window, a reduced visit schedule may be considered. 
The reduced visit schedule should include Weeks 3, 5 and 12 and all specified assessments 
as a minimum.  Every effort should be made to complete the early termination (ET) study 
procedures and observations if the participant does not enter post-treatment follow-up. 
Any laboratory parameter that meets the stopping criteria should be repeated to confirm 
the value prior to withdrawal 
For participants meeting the stopping criteria (Section 7.1.1- Section 7.1.4), participants 
should be monitored until laboratory abnormalities resolve, stabilize, or return to within 
baseline values (i.e., pre-dose) as indicated.  The participant must then attend the visits 
specified in the SoA.  See the SoA for data to be collected at the time of discontinuation of 
study intervention and follow-up and for any further evaluations that need to be completed. 
7.1.1. 
Liver Chemistry Monitoring and Stopping Criteria 
Liver chemistry stopping, and increased monitoring criteria have been designed to assure 
participant safety and to evaluate liver event etiology.  Study intervention will be 
discontinued for a participant if the liver stopping criteria are met.  
Discontinuation of study intervention for abnormal liver tests is required when: 
• a participant meets one of the conditions outlined in Table 7. 
• 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 7 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. 


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Every attempt must be made to have the participant evaluated (within 24 hours) for repeat 
assessment of liver chemistries and additional testing and close monitoring (a specialist or 
hepatology consultation is recommended).  Participants must be monitored weekly until 
liver chemistry abnormalities (ALT, AST, alkaline phosphatase, bilirubin) resolve, 
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 7 
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 
 
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 
ALT = alanine aminotransferase; IMP = investigational medicinal product; ULN = upper limit of normal 
*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.  


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• Any clinically significant deterioration 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 drug-induce liver 
injury (DILI) or the participant may continue with dosing. 
The procedures listed below are to be followed if a participant meets any of the liver 
chemistry stopping criteria defined in Table 7: 
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 case report form (CRF). 
Complete the “Safety Follow-up Procedures” listed below. 
Safety Follow-up Procedures for Participants Who Meet Any of The Liver 
Monitoring and Stopping Criteria: 
Viral hepatitis serology including: 
o Hepatitis A IgM antibody; 
o Cytomegalovirus IgM antibody;  
o Epstein-Barr viral capsid antigen IgM antibody (or if unavailable, obtain 
heterophile antibody or monospot testing);  
o Hepatitis E IgM antibody; 
o Hepatitis B virus DNA load; 
o Hepatitis C virus RNA load; 
o Hepatitis D virus antibody. 
• Obtain a blood sample for pharmacokinetic (PK) analysis as soon as possible 
following the occurrence of an event. Record the date/time of the PK blood sample 
collection and the date/time of the last dose of study treatment prior to blood sample 
collection on the CRF. If the date or time of the last dose is unclear, provide the 
participant’s best approximation. Instructions for sample handling and shipping are 
included in the Study Reference Manual (SRM). 
• Serum creatine phosphokinase (CPK) and lactate dehydrogenase (LDH). 
• Review fractionated bilirubin 
• Assess eosinophilia 


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• Record the appearance or worsening of clinical symptoms of hepatitis (fatigue, 
nausea, vomiting, right upper quadrant pain or tenderness, fever, rash or eosinophilia) 
as relevant on the Adverse Event (AE) CRF. 
• Record use of concomitant medications, acetaminophen, herbal remedies, other over 
the counter medications, or putative hepatotoxins on the Concomitant Medications 
CRF. 
• Record alcohol use on the Liver Events CRF. 
The following are required for participants who meet the ALT and bilirubin 
stopping criteria but are optional for other abnormal liver chemistries. 
• Anti-nuclear antibody, anti-smooth muscle antibody, Type 1 anti-liver kidney 
microsomal antibodies and quantitative total immunoglobulin G (IgG or 
gamma globulins). 
• Serum acetaminophen adduct high performance liquid chromatography 
(HPLC) assay (quantifies potential acetaminophen contribution to liver injury 
in participants with definite or likely acetaminophen use in the preceding 
week [James, 2009]). 
• 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 Inflammation and Complement Stopping 
Criteria 
If any of the following are observed, results should be confirmed with a repeat sample 
collection and analysis, and if confirmed, further evaluation for alternative causes should 
be pursued in consultation with the Medical Monitor. 
Repeat sample collection of C3, C4, Bb, C5a would be triggered by changes in the clinical 
signs and symptoms of complement activation (2+ haematuria; increasing urine ACR; 
vasculitic or purpuric rash; peripheral neuropathy; jaundice). Additional complement 
analyses for example CH50, Factor B level, Factor H level, sC5b-9 should also be 
considered in discussion with the Medical Monitor and Safety Panels. 
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 the lower limit of normal (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 


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e. There are associated biochemical sequelae for example, a rising high 
sensitivity C-reactive protein (hs-CRP); rising monocyte chemoattractant 
protein (MCP-1); new thrombocytopenia, new renal impairment with no 
other explanation such as intercurrent infection OR 
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 hs-CRP; 
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 hs-CRP, MCP-1, Bb, C5a) 
without clear alternative explanation. 
• Discontinue study treatment permanently if suspect clinical sequelae of 
complement activation, drug induced vascular inflammation, vasculitis or auto-
immunity regardless of biomarkers changes or persistence. 
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. 


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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 8 
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 
Participant Level Stopping Criteria 
• Hold study treatment in participants who develop ACR ≥0.5 mg/mg (500 mg/g), or 
eGFR >25% reduction from baseline, 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 
• 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 
• Delay in treatment of suspected RPGN should be avoided. 
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: 


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• Persistent ACR 0.03 mg/mg (30 mg/g) 
• Blood in urinalysis 5 RBC per high power field (HPF) confirmed by urine 
microscopy 
• 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. 
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 DILI) of the liver event (e.g. biliary obstruction, 
pancreatic events, hypotension, acute viral hepatitis). Furthermore, restart is not permitted 
following liver stopping event when the underlying cause was alcohol-related hepatitis. 
• 
Approval by GSK for study intervention restart can be considered where: 
o Investigator requests consideration for study intervention restart if liver chemistries 
have a clear underlying cause (e.g., biliary obstruction, hypotension and liver 
chemistries have improved to normal or are within 1.5 x baseline and ALT 
<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). 


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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. 
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 
o 
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.  
o 
The investigator may ask participants to withdraw from study treatment but 
continue with visits instead of withdrawing completely from the study. 
o 
At the time of discontinuing from the study, if possible, an early termination visit 
should be conducted, as shown in the SoA (see Section 1.3). 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. 
o 
The participant will be permanently discontinued both from the study intervention 
and from the study at that time. 
o 
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. 
o 
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. 
 


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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 (see Section 1.3). 
• In selected sites/countries, participants will have the option to use a centralised 
home nursing provider. Only selected visits will have the option to be performed 
as a home visit, these will include drug administration, blood draws, participant 
assessments and data collection. The full specifications of the home nursing 
services will be outlined in the SRM  
• Protocol waivers or exemptions are not allowed  
• Immediate safety concerns should be discussed with the sponsor immediately 
upon occurrence or awareness to determine if the participant should continue or 
discontinue study intervention. 
• Adherence to the study design requirements, including those specified in the SoA, 
is essential and required for study conduct. 
• All screening evaluations must be completed and reviewed to confirm that 
potential participants meet all eligibility criteria. The investigator will maintain a 
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 


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screening or baseline purposes provided the procedure met the protocol-specified 
criteria and was performed within the time frame defined in the SoA. 
• Repeat or unscheduled samples may be taken for safety reasons or for technical 
issues with the samples. 
8.1. 
Efficacy Assessments 
The primary objective measurement for efficacy in this study is the assessment of 12 
weeks of GSK3228836 treatment on serum HBsAg levels in participants with CHB.  The 
primary efficacy endpoint is achieving serum HBsAg level <LLOQ by Week 12. 
Any HBsAg greater than LLOQ after achieving HBsAg seroclearance needs to be 
confirmed by re-test within 1 week of receiving the test result.  The re-test result will be 
used if the first test is not confirmed. 
HBsAg and HBV DNA are collected for primary and secondary efficacy endpoints as per 
the SoA (see Section 1.3).  Details of sample collection can be found in the SRM. 
8.2. 
Safety Assessments 
Planned time points for all safety assessments are provided in the SoA (see Section 1.3). 
Additional time points for safety tests (such as vital signs, physical exams and laboratory 
safety tests) may be added during the course of the study based on newly available data to 
ensure appropriate safety monitoring. 
8.2.1. 
Physical Examinations 
A complete physical exam will be conducted at the Screening visit.  Symptoms directed 
exams will be conducted at all other time points (please refer to the SRM for details).  
• A complete physical exam will include, at a minimum, assessment of the 
dermatologic, cardiovascular, respiratory, gastrointestinal, and neurological 
systems. Height and weight will also be measured and recorded (with participant 
wearing daytime clothing with no shoes).  
• Investigators should pay special attention to clinical signs related to previous 
serious illnesses. 
8.2.2. 
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 the following in relation to 
ISRs and ISRs should be recorded as AEs:  
• Pain or tenderness 
• Erythema or redness 
• Induration or swelling  
• Pruritus  


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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 after 5 minutes rest and will include temperature, systolic and 
diastolic blood pressure, and pulse and respiratory rate.  
If assessments are scheduled for the same nominal time, then 12-lead ECG and vital signs 
must be completed prior to blood collection. The order of conducting the 12-lead ECG and 
vital sign measurements is flexible but should allow the blood collection to occur at the 
exact nominal time. 
8.2.4. 
Electrocardiograms 
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 (see Section 1.3).  
The investigator must review the laboratory report, document this review, and record any 
clinically relevant changes occurring during the study in the AE section of the CRF. The 
laboratory reports must be filed with the source documents. Clinically significant abnormal 
laboratory findings are those which are not associated with the underlying disease, unless 
judged by the investigator to be more severe than expected for the participant's condition. 
All laboratory tests with values considered clinically significantly abnormal during 
participation in the study should be repeated until the values return to normal or baseline 
or are no longer considered significantly abnormal by the investigator or Medical Monitor.  
If such values do not return to normal/baseline within a period of time judged reasonable 
by the investigator, the etiology should be identified, and the sponsor notified. 
If such values do not return to normal/baseline or are still considered significantly 
abnormal by the investigator by the participant’s last visit, additional follow-up should be 
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All protocol-required laboratory assessments, as defined in Appendix 2, must be conducted 
in accordance with the laboratory manual and the SoA. 
8.2.6. 
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).  
8.2.6.1. 
Time Period and Frequency for Collecting AE and SAE Information 
All AEs and SAEs will be collected from the signing of the informed consent form until 
the final follow-up visit at the time points specified in the SoA (Section 1.3).  However, 
AEs and SAEs that occur prior to the first administration of investigational medicinal 
product should be recorded only if assessed as related to study participation (e.g., protocol-
mandated procedures or invasive tests). 
Medical occurrences that begin before the start of study intervention but after obtaining 
informed consent will be recorded on the Medical History/Current Medical Conditions 
section of the case report form (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. 
8.2.6.2. 
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.  
8.2.6.3. 
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. 


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8.2.6.4. 
Regulatory Reporting Requirements for SAEs 
Prompt notification by the investigator to the sponsor of a SAE is essential so that legal 
obligations and ethical responsibilities towards the safety of participants and the safety of 
a study intervention under clinical investigation are met.  
The sponsor has a legal responsibility to notify both the local regulatory authority and other 
regulatory agencies about the safety of a study intervention under clinical investigation. 
The sponsor will comply with country-specific regulatory requirements relating to safety 
reporting to the regulatory authority, Institutional Review Boards (IRB)/Independent 
Ethics Committees (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. 
8.2.7. 
Pregnancy 
Details of all pregnancies in female participants will be collected after the start of study 
intervention and until no longer than 6 to 8 weeks following the estimated delivery date. 
If a pregnancy is reported, the investigator should inform GSK within 24 hours of learning 
of the pregnancy and should follow the procedures outlined in Appendix 4. 
Abnormal pregnancy outcomes (e.g., spontaneous abortion, fetal death, stillbirth, 
congenital anomalies, ectopic pregnancy) are considered SAE. 
8.2.8. 
Cardiovascular and Death Events 
For any cardiovascular events detailed in Appendix 3 and all deaths, whether or not they 
are considered SAEs, specific Cardiovascular (CV) and Death sections of the CRF will be 
required to be completed. These sections include questions regarding cardiovascular 
(including sudden 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 
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8.2.9. 
Adverse Events of Special Interest  
8.2.9.1. 
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. 
8.2.9.2. 
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 patients 
that encompasses a multi-pronged approach for monitoring of this toxicity, from separate 
mechanistic, phenotypic and organ-specific perspectives. 
Vascular inflammation will be monitored through various inflammatory markers (e.g., 
complement factors, hs-CRP, ANCA, MCP-1) and presence of clinical signs and 
symptoms. 
A monitoring strategy of vasculitis and complement activation is presented in Section 
7.1.2 
8.2.9.3. 
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. 
8.2.9.4. 
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. 
8.2.9.5. 
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. 
8.3. 
Pharmacokinetics 
Blood samples will be collected for measurement of GSK3228836 trough plasma 
concentrations and plasma concentrations during the terminal elimination phase as 
specified in the SoA (see Section 1.3). 
•
Instructions for the collection and handling of biological samples will be provided by
the sponsor. The actual date and time (24-hour clock time) of each sample will be
recorded.
•
PK samples will be used to evaluate the PK of GSK3228836, and explore PK-PD
relationships.
•
Samples collected for PK analyses may also be used to evaluate safety or efficacy
aspects related to concerns arising during or after the study.
8.4. 
Biomarkers 
 
 
. 
 
 
 
  
CCI
CCI
CCI


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8.5. 
Resistance Monitoring 
The barrier to development of GSK3228836 resistance is unknown.  Population sequencing 
of isolates from Study ISIS 505358-CS3 did not detect the development of mutations in 
the GSK3228836 binding site following 4 weeks of GSK3228836 monotherapy.   
The risk of resistance development is expected to be lowest in participants receiving 
concomitant NA therapy due to the suppression of HBV viral replication.  Ongoing viral 
replication during GSK3228836 treatment (e.g., due to virological breakthrough) may 
increase the risk of the development of resistance.  Investigators should therefore consider 
resistance monitoring for participants who experience virological breakthrough whilst still 
receiving GSK3228836 (i.e., haven’t completed treatment). 
 
 
 
  
 
 
HBsAg levels for each participant will be measured throughout the study. In addition to 
the standard HBV DNA virological failure criteria defined above, HBV resistance 
monitoring will also include analysis of isolates from participants with sub-optimal HBsAg 
levels in the absence of detectable HBV DNA. 
CCI
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8.6. 
Medical Resource Utilization and Health Economics 
Medical Resource Utilization and Health Economics parameters are not evaluated in this 
study. 
9. 
STATISTICAL CONSIDERATIONS 
9.1. 
Statistical Hypotheses 
The primary objective of the study is to assess the efficacy of 12 weeks of GSK3228836 
treatment in Hepatitis B e-antigen negative participants on nucleos(t)ide analogue therapy. 
The primary endpoint is achieving serum HBsAg level <LLOQ by Week 12 (at any time 
point up to and including Week 12) without the use of PEG-interferon or other 
immunomodulator therapies in CHB participants who receive at least one dose of IP. 
An estimation approach with no hypothesis testing will be used to address the primary 
objective. The primary assessment of interest is the point estimate of percent of participants 
achieving serum HBsAg level <LLOQ (without the use of PEG-interferon or other 
immunomodulator therapies) by Week 12 with the 95% credible interval. Other 
intercurrent events such as discontinuation of, interruption of, and adherence to IP will be 
ignored (treatment policy). In addition, posterior probabilities that the true percent is 
greater than the desired threshold of 50% will be provided using a Bayesian probability 
approach.  
9.2. 
Sample Size Determination 
Approximately 20 participants will be targeted to assign to treatment. 
Primary Endpoint 
It is assumed that the number of participants achieving serum HBsAg level <LLOQ by 
Week 12 without the use of PEG-interferon or other immunomodulator therapies follows 
a Binomial distribution, with a weakly informative prior beta (0.5, 0.5) for the true 
response. The precision for a range of true response rates with 95% credible intervals are 
shown in Table 9. 
Table 9 
95% Credible Interval for Percent of Participants achieving HBsAg 
<LLOQ by Week 12 
Sample size 
per arm 
Number of Participants 
with HBsAg <LLOQ 
Percent of Participants 
with HBsAg <LLOQ 
95% Credible 
Interval* 
20 
8 
40% 
20% – 61% 
10 
50% 
29% - 71% 
12 
60% 
39% - 80% 
14 
70% 
50% - 87% 
16 
80% 
61% - 94% 
*95% highest posterior density interval 


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With 20 participants, if the observed response rate is 60%, 70% and 80%, then the lower 
bound of the 95% credible interval excludes values below 39%, 50% and 61%, 
respectively. The posterior probability that the percent of participants achieving 
HBsAg<LLOQ by Week 12 is greater than 50% 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 
percentage of participants achieving serum HBsAg level <LLOQ exceeds 50% (desired for 
further mechanistic exploration of the therapeutic effects of GSK3228836 via intrahepatic 
immunophenotyping) are shown in Table 10, for various assumed sample sizes and true 
response rates. A weakly informative prior beta (0.5, 0.5) is used. With a sample size of 20 
participants, if there are at least 12 participants achieving HBsAg <LLOQ (observed 
percent of 60%) then the posterior probability that the true percent is greater than 50% will 
be greater than 75%. 
Table 10 
Study Operating Characteristics by Sample Size 
Criteria 
Sample 
Size 
Min N (%) of 
Participants 
with HBsAg 
<LLOQ 
required for 
meeting 
Criteria 
  
Probability of Meeting Criteria 
 if True Response Rate = 
30% 
40% 
50% 
60% 
65% 
70% 
75% 
Probability 
(true 
response rate 
>50%)>75% 
10 
7 (70%) 
1% 
5% 
17% 
38% 
51% 
65% 
78% 
15 
9 (60%) 
2% 
10% 
30% 
61% 
75% 
87% 
94% 
18 
11 (61%) 
1% 
6% 
24% 
56% 
73% 
86% 
94% 
20 
12 (60%) 
1% 
6% 
25% 
60% 
76% 
89% 
96% 
24 
14 (58%) 
0% 
5% 
27% 
65% 
82% 
93% 
98% 
30 
17 (57%) 
0% 
5% 
29% 
71% 
87% 
96% 
99% 
 * response rate defined as percent of participants achieving HBsAg<LLOQ by Week 12 
Based on these operating characteristics, for a true response rate of 60%, the proposed 
sample-size of 20 has 60% probability of confirming a true rate of at least 50%, and if the 
true rate is 70%, there is an 89% chance of confirming a true rate greater than 50%. 
Biomarker Endpoints 
Given a sample size of 20, the confidence intervals for the ratio in change from baseline in 
RNAseq (signature) scores between those achieving versus not achieving HBsAg<LLOQ 
are shown below, assuming a range of effect sizes and between-participant coefficients of 
variation (CVb).   
Example of one scenario with 60% of the participants achieving HBsAg < LLOQ is given 
below. With relatively smaller between participant variability and larger effect size, a 
sample size of 20 is appropriate to achieve an acceptable level of precision in detecting the 
differential responses in biomarker outcomes corresponding to HBsAg responses. For 


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example, in the scenario where 60% of participants achieve HBsAg <LLOQ, if CVb = 0.4, 
the 95% CI excludes 1 for geometric mean ratios of 0.6 and below, and for 1.7 and above. 
12 Participants (60%) Achieving HBsAg<LLOQ) 
CVb 
95% CI for Ratio of Geometric Mean of Fold Change from Baseline for Participants 
achieving vs. not achieving HBsAg<LLOQ 
0.6 
0.8 
1 
1.2 
1.4 
1.7 
2.0 
0.2 
[0.50, 0.73] 
[0.66, 0.97] 
[0.83, 1.21] 
[0.99, 1.45] 
[1.16, 1.69] 
[1.41, 2.06] 
[1.65, 2.42] 
0.4 
[0.41, 0.87] 
[0.55, 1.16] 
[0.69, 1.45] 
[0.83, 1.74] 
[0.97, 2.03] 
[1.17, 2.46] 
[1.38, 2.89] 
0.6 
[0.35, 1.02] 
[0.47, 1.36] 
[0.59, 1.70] 
[0.71, 2.04] 
[0.82, 2.38] 
[1.00, 2.89] 
[1.18, 3.40] 
0.8 
[0.31, 1.18] 
[0.41, 1.57] 
[0.51, 1.96] 
[0.61, 2.36] 
[0.71, 2.75] 
[0.87, 3.34] 
[1.02, 3.93] 
1 
[0.27, 1.33] 
[0.36, 1.78] 
[0.45, 2.22] 
[0.54, 2.67] 
[0.63, 3.11] 
[0.77, 3.78] 
[0.90, 4.44] 
1.5 
[0.21, 1.70] 
[0.28, 2.27] 
[0.35, 2.83] 
[0.42, 3.40] 
[0.49, 3.97] 
[0.60, 4.81] 
[0.71, 5.66] 
There are no plans for sample size re-estimation. In certain cases, including but not limited 
to higher than anticipated drop-out rate, higher than anticipated rates of efficacy, or large 
variability in ALT flare patterns, the sample size may be increased to no more than 24. 


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9.3. 
Analysis Sets 
For the purpose of analysis, the following analysis sets are defined: 
Participant Analysis Set 
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 participants who received at least one dose of study treatment 
Safety 
All participants who received at least one dose of study treatment 
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 analyzed. 
 
Defined Analysis Data 
Sets 
Description 
Analysis set for primary 
estimand 
All Intent to Treat Participants including all observations on and off treatment.  
Analysis set for secondary 
estimands 
All Intent to Treat Participants including all observations on and off treatment. 
 
9.4. 
Statistical Analyses 
The statistical analysis plan will be finalized prior to database release.  This section is a 
summary of the planned statistical analyses of the most important endpoints including 
primary and key secondary endpoints. The statistical analysis plan will include a more 
technical and detailed description of the statistical analyses described in this section. 
9.4.1. 
General Considerations 
Unless otherwise specified, baseline will be the last value/assessment before the first dose 
of study treatment (Day 1 pre-dose).  If there are multiple assessments collected at the same 
scheduled time, the average of these assessments will be used as the baseline. 
9.4.2. 
Primary Endpoint(s) 
The primary analysis will be conducted once the last participant has completed the 
Week 36 visit (completed 24-weeks of follow-up period) and database lock has been 


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achieved.  The primary efficacy endpoint is achieving serum HBsAg level <LLOQ at any 
time point during 12-weeks (including Week 12) of GSK3228836 treatment. 
The Primary Estimand supporting the primary objective of the study is defined as:  
• Population: Participants with CHB who receive at least 1 dose of IP 
• Treatment: 300 mg GSK3228836 for 12 weeks (also on stable nucleos(t)ide 
therapy) 
• Variable: Achieving serum HBsAg level <LLOQ at any time point up to and 
including Week 12 without the use of PEG-interferon or other immunomodulator 
therapies 
• Population-level summary: Percent of participants that achieve serum HBsAg 
level <LLOQ at any time point up to and including Week 12  
• Intercurrent events: Discontinuation of, interruption of, and adherence to IP will 
be ignored (treatment policy).  
The primary estimand is the percentage of participants with CHB receiving 300 mg 
GSK3228836 for 12 weeks (with at least one dose of IP) who achieve serum HBsAg 
level <LLOQ at any time point up to and including Week 12, without the use of PEG-
interferon or other immunomodulator therapies, regardless of completing IP, 
interruptions in IP or adherence to IP. If PEG-interferon or other immunomodulator 
therapies are used, then the participant’s primary outcome will be treated as a failure. 
9.4.3. 
Primary Analyses 
Point estimate of the percentage as well as the 95% credible interval (Highest Density 
Interval, HDI) of participants achieving serum HBsAg level <LLOQ by Week 12 will be 
provided. 
A Bayesian approach will be used to estimate the posterior probability of participants that 
achieve serum HBsAg level <LLOQ by week 12 exceeding 50%.  A weakly informative 
prior beta (0.5, 0.5) will be used. 
Let Y be the number of responders from N participants,  
Y~ Binomial (N, p) 
Where p is virologic response rate.  
The posterior distribution for p is 
P(p|y, N) ~ Beta (y + 0.5, N – y + 0.5)  
The posterior probability that the true rate of participants achieving LLOQ by Week 12 
being greater than 50% will be calculated from the posterior distribution. 
Additional analyses for the primary endpoint may be included as supportive analyses. 


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9.4.4. 
Secondary Endpoint(s) 
Estimands supporting the secondary objective of assessing sustainability of serum HBsAg 
loss by GSK3228836 for up to 24 weeks off-treatment are defined as follows: 
• The group of estimands supporting this objective in participants with CHB 
receiving 300 mg GSK3228836 for 12 weeks (with at least one dose of IP) is the 
percentage of participants for each variable regardless of completing IP, 
interruptions in IP or adherence to IP, without the use of PEG-interferon or other 
immunomodulator therapies. If PEG-interferon or other immunomodulator 
therapies are used then the participant’s outcome will be treated as a failure. 
 
• Variables: 
o Sustained HBsAg Response (HBsAg <LLOQ) for 24 weeks after the 
planned end of GSK3228836 treatment without the use of PEG-interferon 
or other immunomodulator therapies 
▪ HBsAg from Week 13 to Week 36 will be used to assess sustained 
HBsAg response after the planned end of GSK3228836 treatment.  
o Sustained HBsAg Response (HBsAg <LLOQ) for 24 weeks after the 
actual end of GSK3228836 treatment without the use of PEG-interferon or 
other immunomodulator therapies 
▪ HBsAg for 24 weeks after end of actual treatment will also be used 
to assess sustained HBsAg response after the actual end of 
GSK3228836 treatment. 
 
• Population Summary: percentage of participants for each variable. 
 
• Analysis windows for the post GSK3228836 treatment assessments will be 
defined in the analysis plan. 
 
Estimands supporting the secondary objective of assessing sustainability of serum HBsAg 
and HBV DNA (Sustained Virologic Response) loss by GSK3228836 for up to 24 weeks 
off treatment are defined as follows: 
• The group of estimands supporting this objective in participants with CHB 
receiving 300 mg GSK3228836 for 12 weeks (with at least one dose of IP) is the 
percentage of participants for each variable regardless of completing IP, 
interruptions in IP or adherence to IP, without the use of PEG-interferon or other 
immunomodulator therapies. If PEG-interferon or other immunomodulator 
therapies are used then the participant’s outcome will be treated as a failure. 
 
• Variables: 
o Sustained Virologic Response (HBsAg <LLOQ and HBV DNA <LLOQ) 
for 24 weeks after the planned end of GSK3228836 treatment 


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▪ HBsAg and HBV DNA from Week 13 to Week 36 will be used to 
assess sustained virologic response after the planned end of 
GSK3228836 treatment without the use of PEG-interferon or other 
immunomodulator therapies. 
o Sustained Virologic Response (HBsAg <LLOQ and HBV DNA <LLOQ) 
for 24 weeks after the actual end of GSK3228836 treatment 
▪ HBsAg and HBV DNA for 24 weeks after end of actual treatment 
will be used to assess sustained virologic response after the actual 
end of GSK3228836 treatment without the use of PEG-interferon or 
other immunomodulator therapies. 
 
• Population Summary: percentage of participants for each variable. 
 
• Analysis windows for the post GSK3228836 treatment assessments will be defined 
in the analysis plan. 
 
Estimands supporting the secondary objective of assessing the effect of 12 weeks 
GSK3228836 on biomarkers and virus-specific antibody responses are defined as follows: 
- Population: Participants with CHB who receive at least one dose of IP 
- Treatment: 300 mg GSK3228836 for 12 weeks (also on stable nucleos(t)ide therapy) 
- Intercurrent events: Discontinuation of, interruption of, adherence to IP will be ignored 
(treatment policy). PEG-interferon or other immunomodulator therapies will be handled 
with hypothetical strategy. 
1) Categorical Variables: 
• Achieving HBsAg <LLOQ over time 
• Achieving HBV DNA <LLOQ over time 
• Achieving HBsAg <LLOQ and HBV DNA <LLOQ over time 
• Categorical changes from baseline in HBsAg (e.g. <0.5, ≥0.5, ≥1, ≥1.5, ≥3 log10 
IU/mL) over time 
• ALT>3X ULN over time 
• Categorical changes from baseline in HBe antibody (anti-HBeAg)  
• Additional categories of changes from baseline may be added in the RAP.  
 
- Population summary: Percent of participants in each category. 
2) Continuous Variables:  
• Actual values and change from baseline over time for HBsAg and HBV DNA  
• HBs antibody (anti-HBsAg) levels over time 
• Area under the curve (AUC) for ALT on treatment (12 weeks), during follow up 
(24 weeks), and on treatment + follow up (36 weeks). 


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- Population summary: mean values and/or mean changes from baseline for each variable  
3) Time to Event Variable 
• Time to Maximum ALT (ALT must be greater than 3xULN) during 36 weeks 
(treatment + follow up) 
 
- Population summary: Turnbull estimate for median Time to Maximum ALT (>3xULN) 
Missing data for variables in this group of estimands will be ignored, only available data 
will be summarized. Outcome will be assumed missing (Missing At Random) from the 
timepoint when participants first receive PEG-interferon or other immunomodulator 
therapies. 
Further details will be provided in the RAP. 
9.4.5. 
Safety Endpoints 
All safety analyses will be based on the Safety Population.  
Exposure to study medication, measured by the number of injections and percent of 
planned number of injections of study drug, will be summarized. 
The percent of participants reporting adverse events (AEs) will be tabulated.  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 and vital signs (absolute values and change from baseline) will be 
summarized by visit.  In addition, the maximum post-baseline toxicity grade (based on 
DAIDS categories) will be tabulated.  
9.4.6. 
Exploratory Endpoint(s) 
CCI


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9.5. 
Interim Analysis 
Data will be incorporated into regular safety reviews by an IDMC and may be used to 
supplement the safety data review for the Phase IIb B-Clear study [GSK Document 
Number 2019N420582_00, Study 209668].  
9.6. 
Independent Data Monitoring Committee (IDMC) 
An independent data monitoring committee (IDMC) will review ongoing safety data in this 
study as described in Section 9.5.  The IDMC will meet on a regular basis as outlined in 
the charter.  
The first data review meeting will be held approximately 18 weeks post first-participant-
first-dose (data cut at approximately 12 weeks post-first participant first dose [FPFD]).  
Thereafter, the frequency of scheduled meetings depends on participant enrolment, 
information accumulated and safety event rates but will occur approximately every 
3 months.   
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. 
CCI


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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, IB, and other relevant documents (e.g., 
advertisements) must be submitted to an IRB/IEC by the investigator and 
reviewed and approved by the IRB/IEC before the study is initiated.  
• Any amendments to the protocol will require IEC/IRB approval before 
implementation of changes made to the study design, except for changes 
necessary to eliminate an immediate hazard to study participants.  
• Protocols and any substantial amendments to the protocol will require health 
authority approval prior to initiation except for changes necessary to eliminate an 
immediate hazard to study participants. 
• The investigator will be responsible for the following: 
• 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), European Medical 
Device Regulation 2017/745 for clinical device research (if applicable), 
and all other applicable local regulations 
10.1.2. 
Financial Disclosure 
Investigators and sub-investigators will provide the sponsor with sufficient, accurate 
financial information as requested to allow the sponsor to submit complete and accurate 
financial certification or disclosure statements to the appropriate regulatory authorities. 


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Investigators are responsible for providing information on financial interests during the 
course of the study and for 1 year after completion of the study. 
10.1.3. 
Informed Consent Process 
o 
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.  
o 
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.  
o 
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. 
o 
Participants must be re-consented to the most current version of the ICF(s) 
during their participation in the study.  
o 
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 
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• 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 
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 
Independent Data Monitoring Committee: The overall responsibility of the IDMC, which 
consists of at least 2 physicians and 1 statistician, is to protect the ethical and safety 
interests of participants recruited into clinical studies while ensuring the scientific 
validity of the studies. The IDMC will meet at predefined times for each study, as well as 
ad hoc (as deemed appropriate), to evaluate the risk versus benefit of GSK3228836. 
Specific responsibilities of the IDMC include:  
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 patient 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. 
Internal Safety Review Team (SRT):  A separate internal safety review team will meet to 
review all participants’ safety data on a regular basis. 
10.1.6. 
Dissemination of Clinical Study Data 
o 
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. 


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o 
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. 
o 
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. 
o 
GSK intends to make anonymized patient-level data from this trial available to 
external researchers for scientific analyses or to conduct further research that can 
help advance medical science or improve patient care. This helps ensure the data 
provided by trial participants are used to maximum effect in the creation of 
knowledge and understanding. 
10.1.7. 
Data Quality Assurance 
o 
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.  
o 
The investigator must maintain accurate documentation (source data) that 
supports the information entered in the CRF.  
o 
The investigator must permit study-related monitoring, audits, IRB/IEC review, 
and regulatory agency inspections and provide direct access to source data 
documents.  
o 
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. 
o 
The sponsor or designee is responsible for the data management of this study 
including quality checking of the data.  
o 
The sponsor assumes accountability for actions delegated to other individuals 
(e.g., Contract Research Organizations). 
o 
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.  
o 
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 
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No records may be transferred to another location or party without written 
notification to the sponsor.  
o 
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 and its origin can be found in the RAP 
• The investigator must maintain accurate documentation (source data) that 
supports the information entered in the CRF. 
• Study monitors will perform ongoing source data verification to confirm that data 
entered into the CRF by 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.  
 
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. 


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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. 
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 11 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 in parallel 
Otherwise, local laboratory results are only required in the event that the central laboratory 
results are not available in time for either study intervention administration and/or response 
evaluation. If a local sample is required, it is important that the sample for central analysis 
is obtained in parallel.  
Protocol-specific requirements for inclusion or exclusion of participants are detailed in 
Section 5 of the protocol. 
Additional tests may be performed at any time during the study as determined necessary 
by the investigator or required by local regulations. 
Pregnancy Testing:  
Refer to Section 5.1 Inclusion Criteria for screening pregnancy criteria.  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 11 
Protocol-Required Laboratory Tests 
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 
Glutamic-Pyruvic 
Transaminase 
(SGPT) 
Total Protein 


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Laboratory 
Assessments 
Parameters 
 
Glucose 
Calcium 
Alkaline 
phosphatase 
Albumin 
Routine 
Urinalysis 
• By dipstick 
• Microscopic examination (if blood or protein is abnormal) 
Pregnancy 
testing 
• Highly sensitive urine or serum human chorionic gonadotropin (hCG) 
pregnancy test (as needed for women of childbearing potential)2 
Other Tests 
• Follicle-stimulating hormone and estradiol (as needed only) 
• 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 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, aPTT, Alpha-fetoprotein, ANCA (MPO-ANCA, 
PR3-ANCA), APRI/Fibrosure, Complement factors C3, C4, C5a, and Bb, 
hs-CRP, MCP-1, angiopoetin II, PBMC, soluble protein, PAX Gene 
• Urine ACR 
• Genetic sample 
• Viral Sequencing: HBV Genotype, HBV DNA, HBV RNA 
 
All study-required laboratory assessments will be performed by a central 
laboratory, with the exception: 
• Platelet counts for investigator decisions may be drawn at local laboratory 
• PBMCs may be processed at the local laboratory as agreed with the 
Sponsor in advance. 
Additional tests 
listed under 
safety follow-up 
processes 
Liver Chemistry Stopping Criteria3 
• Viral hepatitis serology including: 
o Hepatitis A IgM antibody; 
o Cytomegalovirus IgM antibody;  
o Epstein-Barr viral capsid antigen IgM antibody (or if 
unavailable, obtain heterophile antibody or monospot 
testing);  
o Hepatitis E IgM antibody 
o Hepatitis B virus DNA load 
o Hepatitis C virus RNA load 
o Hepatitis D virus antibody 
• PK sample 
• Serum creatine phosphokinase (CPK) and lactate dehydrogenase 
(LDH). 
• Fractionated bilirubin, Anti-nuclear antibody, anti-smooth muscle 
antibody, Type 1 anti-liver kidney microsomal antibodies and 
quantitative total immunoglobulin G (IgG or gamma globulins). 
• Serum acetaminophen adduct high performance liquid 
chromatography (HPLC) assay 


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


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• New conditions detected or diagnosed after study intervention administration even 
though it may have been present before the start of the study. 
• Signs, symptoms, or the clinical sequelae of a suspected intervention- intervention 
interaction. 
• Signs, symptoms, or the clinical sequelae of a suspected overdose of either study 
intervention or a concomitant medication. Overdose per se will not be reported as 
an AE/SAE unless it is an intentional overdose taken with possible suicidal/self-
harming intent. Such overdoses should be reported regardless of sequelae. 
• "Lack of efficacy" or "failure of expected pharmacological action" per se will not 
be reported as an AE or SAE. Such instances will be captured in the efficacy 
assessments. However, the signs, symptoms, and/or clinical sequelae resulting from 
lack of efficacy will be reported as AE or SAE if they 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 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 
An SAE is defined as any serious adverse event that, at any dose: 
a. Results in death 
b. Is life-threatening 
The term 'life-threatening' in the definition of 'serious' refers to an event in which the 
participant was at risk of death at the time of the event. It does not refer to an event, 
which hypothetically might have caused death, if it were more severe. 
c. Requires inpatient hospitalization or prolongation of existing hospitalization 
• In general, hospitalization signifies that the participant has been admitted 
(usually involving at least an overnight stay) at the hospital or emergency ward 


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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. 
d. Results in persistent or significant disability/incapacity 
• The term disability means a substantial disruption of a person’s ability to 
conduct normal life functions. 
• This definition is not intended to include experiences of relatively minor 
medical significance such as uncomplicated headache, nausea, vomiting, 
diarrhea, influenza, and accidental trauma (e.g. sprained ankle) which may 
interfere with or prevent everyday life functions but do not constitute a 
substantial disruption. 
e. Is a congenital anomaly/birth defect 
f. Is a suspected transmission of any infectious agent via an authorised medicinal 
product 
g. Other situations: 
• Possible Hy’s Law case: ALT≥3xULN AND total bilirubin ≥2xULN (>35% 
direct bilirubin) or international normalized ratio (INR) >1.5 must be reported 
as SAE 
• Medical or scientific judgment should be exercised by the investigator in 
deciding whether SAE reporting is appropriate in other situations such as 
significant medical events that may 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. 
o Examples of such events include invasive or malignant cancers, 
intensive treatment for allergic bronchospasm, blood dyscrasias,  
convulsions, or development of intervention dependency or intervention 
abuse. 
10.3.3. 
Definition of Cardiovascular Events 
Cardiovascular Events (CV) Definition: 
Investigators will be required to fill out the specific CV event page of the CRF for the 
following AEs and SAEs: 
• Myocardial infarction/unstable angina 


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• 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 
medical records to GSK in lieu of completion of the GSK required form. 
• There may be instances when copies of medical records for certain cases are 
requested by GSK. In this case, all participant identifiers, with the exception of the 
participant number, will be redacted on the copies of the medical records before 
submission to GSK. 
• The investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information. Whenever possible, the diagnosis (not 
the individual signs/symptoms) will be documented as the AE/SAE. 
Assessment of Intensity 
The investigator will assess the intensity for each AE and SAE reported during the 
study and assign it to 1 of the following categories:  
• Mild: An event that is easily tolerated by the participant, causing minimal 
discomfort and not interfering with everyday activities. 
• Moderate: An event that causes sufficient discomfort and interferes with normal 
everyday activities. 
• Severe: An event that prevents normal everyday activities. An AE that is assessed 
as severe should not be confused with an SAE. Severe is a category utilized for 
rating the intensity of an event; and both AE and SAE can be assessed as severe. 
• An event is defined as ‘serious’ when it meets at least 1 of the predefined outcomes 
as described in the definition of an SAE, NOT when it is rated as severe. 


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Assessment of Causality 
The investigator is obligated to assess the relationship between study intervention and 
each occurrence of each AE/SAE. 
• A "reasonable possibility" of a relationship conveys that there are facts, evidence, 
and/or arguments to suggest a causal relationship, rather than a relationship cannot 
be ruled out. 
• The investigator will use clinical judgment to determine the relationship. 
• Alternative causes, such as underlying disease(s), concomitant therapy, and other 
risk factors, as well as the temporal relationship of the event to study intervention 
administration will be considered and investigated. 
• The investigator will also consult the Investigator’s Brochure (IB) and/or Product 
Information, for marketed products, in his/her assessment. 
• For each AE/SAE, the investigator must document in the medical notes that he/she 
has reviewed the AE/SAE and has provided an assessment of causality. 
• There may be situations in which an SAE has occurred, and the investigator has 
minimal information to include in the initial report to GSK. However, it is very 
important that the investigator always make an assessment of causality for 
every event before the initial transmission of the SAE data to GSK. 
• The investigator may change his/her opinion of causality in light of follow-up 
information and send an SAE follow-up report with the updated causality 
assessment. 
• 
The causality assessment is one of the criteria used when determining regulatory 
reporting requirements. 
 
Follow-up of AE and SAE 
• The investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as medically indicated or as requested by GSK to 
elucidate the nature and/or causality of the AE or SAE as fully as possible. This 
may include additional laboratory tests or investigations, histopathological 
examinations, or consultation with other health care professionals. 
• If a participant dies during participation in the study or during a recognized follow-
up period, the investigator will provide GSK with a copy of any post-mortem 
findings including histopathology. 
• New or updated information will be recorded in the originally submitted 
documents. 
• 
The investigator will submit any updated SAE data to GSK within 24 hours of 
receipt of the information. 
 
The DAIDS Table [DAIDS, 2017] is used for grading AEs and provided as a guidance 
for patient management for the consideration of the PI.  The DAIDS table will be used to 


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grade the severity of an AE that is not specifically identified in the grading table. In 
addition, all deaths related to an AE are to be classified as grade 5.  
The DAIDS Table is available at the following link: 
https://rsc.niaid.nih.gov/clinical-research-sites/grading-severity-adult-pediatric-adverse-
events-corrected-version-two-one  
 
10.3.5. 
Reporting of SAE to GSK 
SAE Reporting to GSK via Electronic Data Collection Tool 
• The primary mechanism for reporting SAE to GSK will be the electronic data 
collection tool. 
• If the electronic system is unavailable, then the site will use the paper SAE data 
collection tool (see next section) to report the event within 24 hours. 
• The site will enter the SAE data into the electronic system as soon as it becomes 
available. 
• The investigator or medically-qualified sub-investigator must show evidence within 
the eCRF (e.g., check review box, signature, etc.) of review and verification of the 
relationship of each SAE to IP/study participation (causality) within 72 hours of 
SAE entry into the eCRF. 
• After the study is completed at a given site, the electronic data collection tool will 
be taken off-line to prevent the entry of new data or changes to existing data. 
• If a site receives a report of a new SAE from a study participant or receives updated 
data on a previously reported SAE after the electronic data collection tool has been 
taken off-line, then the site can report this information on a paper SAE form (see 
next section) or to the medical monitor by telephone. 
• 
Contacts for SAE reporting can be found in the SRM. 
 
SAE Reporting to GSK via Paper Data Collection Tool 
• Facsimile transmission of the SAE paper data collection tool is the preferred 
method to transmit this information to the medical monitor. 
• In rare circumstances and in the absence of facsimile equipment, notification by 
telephone is acceptable with a copy of the SAE data collection tool sent by 
overnight mail or courier service. 
• Initial notification via telephone does not replace the need for the investigator to 
complete and sign the SAE data collection tool within the designated reporting time 
frames. 
• 
Contacts for SAE reporting can be found in the study reference manual. 
 


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


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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 
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. 


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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 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. 
If criteria for permanent discontinuation of IP are met, immediately withdraw the 
participant from study treatment.  
Notify the Medical Monitor within 24 hours of learning of the abnormality to confirm 
the participant’s study treatment cessation and follow-up. 
Complete the Liver Event CRF. 
Complete the “Safety Follow-up Procedures” listed below. 
Safety Follow-up Procedures for Participants Who Meet Any of The 
Stopping Criteria: 
Viral hepatitis serology including: 
o Hepatitis A IgM antibody; 
o Cytomegalovirus IgM antibody;  
o Epstein-Barr viral capsid antigen IgM antibody (or if unavailable, obtain 
heterophile antibody or monospot testing);  
o Hepatitis E IgM antibody. 
o Hepatitis C virus RNA load 
o Hepatitis D virus antibody 
• Obtain a blood sample for 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. 


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• 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]). 
• 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. 
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). 
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). 


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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: Abbreviations and Trademarks 
ACR 
albumin to creatinine ratio 
AE 
adverse event 
ALK 
alkaline phosphatase 
ALT 
alanine aminotransferase 
ANC 
absolute neutrophil count 
ANCA 
Anti-neutrophil cytoplasmic antibody 
APRI 
aspartate aminotransferase-platelet index 
aPTT 
activated partial thromboplastin time 
ASGPR 
asialoglycoprotein receptor 
ASO 
antisense oligonucleotide  
AST 
aspartate aminotransferase 
AUC 
area under the concentration-time curve 
AUC(0-24) 
area under the concentration-time curve from time zero (pre-dose) to 24 
hours post-dose 
AUC(0-) 
area under the concentration-time curve from time zero (pre-dose) 
extrapolated to infinite time 
BLRM 
Bayesian logistic regression model 
BMI 
body mass index 
BMD 
bone mineral density 
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 
CRA 
Clinical Research Associate 
CRF 
case report form 
CRO 
contract research organization 
CV 
cardiovascular 
DAIDS 
Division of Acquired Immune Deficiency Syndrome 
DILI 
drug-induced liver injury 
dL 
deciliters 
DMPK 
drug metabolism and pharmacokinetics 
DNA 
deoxyribonucleic acid 
EC90 
concentration that produces 90% of maximal effect 
EC99 
concentration that produces 99% of maximal effect 
ECG 
electrocardiogram 
EPIP 
Electronic Protocol Inquiry Platform 
ET 
early termination 
FNA 
fine needle aspiration 
FPFD 
first participant, first dose 
FSH 
follicle stimulating hormone 
GalNAc 
N-acetyl galactosamine 
GCP 
Good Clinical Practice 
GCSP 
Global Clinical Safety and Pharmacovigilance 
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 


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HBV 
hepatitis B virus 
HCC 
hepatocellular carcinoma 
hCG 
human chorionic gonadotropin 
HCV 
hepatitis C virus 
HDV 
hepatitis D virus 
HIV 
human immunodeficiency virus 
HPF 
high-power field 
hs-CRP 
high sensitivity C-reactive protein 
IB 
Investigator’s Brochure 
ICH 
International Conference on Harmonisation 
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 
L 
liters 
Lb 
pounds 
LDH 
lactate dehydrogenase 
LLN 
lower limit of normal 
LLOQ 
lower limit of quantification 
m2 
square meters 
MCMC 
Markov Chain Monte Carlo 
MCP 
monocyte chemoattractant protein 
MedDRA 
Medical Dictionary for Regulatory Activities 
mEq 
milliequivalents 
Mg 
milligrams 
MHRA 
Medicines and Healthcare products Regulatory Agency 
Min 
minutes 
mL 
milliliters 
mm3 
cubic millimeters 
MOE 
methoxyethyl 
Msec 
milliseconds 
MSDS 
Material Safety Data Sheet 
NA 
nucleos(t)ide analog 
NCA 
non-compartmental analysis 
Ng 
nanograms 
NOAEL 
no observed adverse effect level 
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 
RRACT 
response rate in the active group 
RRPBO 
Response rate in the placebo group 
SAD 
single ascending dose 


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SAE 
serious adverse event 
SC 
subcutaneous(ly) 
siRNA 
small interfering ribonucleic acid 
SoA 
schedule of activities 
SOP 
standard operating procedure 
SPEP 
serum protein electrophoresis 
SRM 
Study Reference Manual 
SRT 
Safety Review Team 
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 
WOCBP 
women of childbearing potential 
 
Trademark Information 
Trademarks of the GlaxoSmithKline 
group of companies 
 
Trademarks not owned by the 
GlaxoSmithKline group of companies 
NONE 
 
SAS 
 
 
WinNonlin 
 
 


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Geary RS, Yu RZ, Siwkowski A, Levin AA. Pharmacokinetic/pharmacodynamics 
properties of phosphorothioate 2ʹ-O-(2-methoxyethyl)-modified antisense 
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Drug Technology: Principles, Strategies and Applications; Toxicologic properties of 2'-
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1075-1084. doi: 10.1093/infdis/jiy272. 
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chronic hepatitis B: from HBsAg to HBV RNA.  World J Hepatol. 2018 Sep;10(9): 603-
611. doi:10.4254/wjh.v10.i9.603  
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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. 
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serology of chronic hepatitis B infection revisited. J Clin Invest 1993; 91:2586-95. 
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AASLD 2019 Nov 8-11 Boston. 

SAP_001.pdf: 
 
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212602 
 
 
 
Page 1 of 48 
 
Information Type: Statistical Analysis Plan (SAP) 
 
TITLE PAGE 
Protocol Title: 
B-Fine: An open label, single arm study to mechanistically 
interrogate the therapeutic effect of GSK3228836 in patients 
with Chronic Hepatitis B via intrahepatic immunophenotyping 
Study Number: 
212602  
Compound 
Number: 
GSK3228836 
Abbreviated Title: 
A mechanistic study of GSK3228836 with fine needle 
aspiration (FNA) in Participants with Chronic Hepatitis B 
Acronym: 
B-Fine 
 
Sponsor Name: GlaxoSmithKline Research & Development Limited  
Regulatory Agency Identifier Number(s)  
 
Registry 
 
ID 
CT.gov 
NCT04544956 
 
 
 
Copyright 2023 the GlaxoSmithKline group of companies. All rights reserved.  
Unauthorised copying or use of this information is prohibited. 
 


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212602 
 
Page 2 of 48 
 
TABLE OF CONTENTS 
PAGE 
TABLE OF CONTENTS .................................................................................................. 2 
1. 
INTRODUCTION ...................................................................................................... 9 
1.1. 
Objectives, Estimands and Endpoints ........................................................... 9 
1.2. 
Study Design .............................................................................................. 16 
2. 
STATISTICAL HYPOTHESES ............................................................................... 17 
2.1. 
Multiplicity Adjustment ................................................................................ 17 
3. 
ANALYSIS SETS ................................................................................................... 18 
4. 
STATISTICAL ANALYSES ..................................................................................... 18 
4.1. 
General Considerations .............................................................................. 18 
4.1.1. 
General Methodology .................................................................. 18 
4.1.2. 
Baseline Definition ....................................................................... 19 
4.2. 
Primary Endpoint(s) Analyses ..................................................................... 19 
4.2.1. 
Definition of estimands ................................................................. 19 
4.2.2. 
Main analytical approach ............................................................. 20 
4.3. 
Secondary Endpoint(s) Analyses ................................................................ 21 
4.3.1. 
Key secondary endpoint(s) .......................................................... 21 
4.4. 
Exploratory Endpoint(s) Analyses ............................................................... 26 
4.5. 
Safety Analyses .......................................................................................... 28 
4.5.1. 
Extent of Exposure ...................................................................... 28 
4.5.2. 
Adverse Events............................................................................ 28 
4.5.3. 
Additional Safety Assessments .................................................... 31 
4.6. 
Other Analyses ........................................................................................... 33 
4.6.1. 
Subgroup analyses ...................................................................... 33 
4.7. 
Interim Analyses ......................................................................................... 33 
4.8. 
Changes to Protocol Defined Analyses ....................................................... 33 
5. 
SAMPLE SIZE DETERMINATION ......................................................................... 34 
6. 
SUPPORTING DOCUMENTATION ....................................................................... 37 
6.1. 
Appendix 1 Study Population Analyses ....................................................... 37 
6.1.1. 
Participant Disposition ................................................................. 37 
6.1.2. 
Demographic and Baseline Characteristics .................................. 37 
6.1.3. 
Protocol Deviations ...................................................................... 38 
6.1.4. 
Prior and Concomitant Medications ............................................. 38 
6.1.5. 
Study Intervention Compliance .................................................... 38 
6.1.6. 
Additional Analyses Due to the COVID-19 Pandemic .................. 39 
6.2. 
Appendix 2 Data Derivations Rule .............................................................. 40 
6.2.1. 
Criteria for Potential Clinical Importance ...................................... 40 
6.2.2. 
Study Period ................................................................................ 40 
6.2.3. 
Study Day and Reference Dates .................................................. 40 
CCI


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6.2.4. 
Assessment Windows for Early Termination ................................ 40 
6.2.5. 
Assessment Windows for Analyses and Multiple 
Measurements at One Analysis Timepoint ................................... 41 
6.2.6. 
Multiple measurements at One Analysis Time Point .................... 44 
6.2.7. 
Handling of Partial Dates ............................................................. 44 
7. 
REFERENCES ....................................................................................................... 48 
 


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Page 4 of 48 
 
Version history 
SAP 
Version 
Approval Date 
Protocol Version 
(Date) on which 
SAP is Based 
Change 
Rationale 
SAP 
amendme
nt 1 
28 Jun 2023 
Protocol 
Amendment 01, 
15Mar2021; 
Protocol 
Amendment 
1/CAN-1, 22-
Jul2021 
Section 1: 
Details of 
administrative 
interim 
analysis added.  
Requirement to 
add details to 
SAP.  
 
 
 
Section 4.1.1: 
Removed 
mention of 
HBeAg 
imputation. 
Only collecting 
HBeAg at 
Baseline, so 
imputation rules 
not required for 
this variable.  
 
 
 
Section 3: 
Removed 
Pharmacodyna
mic (PD) 
population.  
 
PD population is 
not used for any 
output.  
 
 
 
Section 4.3.1.3, 
for Time-to-
Event: Added 
clarification on 
censoring  
 
Detail missed 
previously.  
 
 
 
Section 4.1.1: 
Updating 
imputing rules 
around values 
<LLOQ, TND 
values and 
significant 
digits. 
 
Implementing 
learning from 
other studies.  


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Page 5 of 48 
 
SAP 
Version 
Approval Date 
Protocol Version 
(Date) on which 
SAP is Based 
Change 
Rationale 
 
 
 
Section 2: 
Added 
reference to 
OPS for terms 
for Peg-
interferon and 
other 
immunomodul
ator therapies.  
For clarity. 
 
 
 
Section 4.6.1 
(Table 7): 
Added 
additional 
HBsAg 
subgroup. 
Addition/clarifica
tion 
 
 
 
Section 4.6.1: 
Removed text 
describing 
statistical 
analysis of 
subgroups. 
Only 
descriptive 
stats will be 
presented for 
subgroup 
analyses. 
Correction 
 
 
 
Section 4.1.1 
and Section 
4.4.1.3: 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. 
 
 
 
Section 4.2.2.1 
Updated visit 
windowing for 
the end of 
To ensure that on-
treatment values 
are not used when 
there is a more 


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Page 6 of 48 
 
SAP 
Version 
Approval Date 
Protocol Version 
(Date) on which 
SAP is Based 
Change 
Rationale 
treatment 
analysis 
timepoint 
appropriate end of 
treatment value 
available. 
 
 
 
Section 4.3.1.1: 
Added HBs 
antibody 
variable, which 
was omitted 
from the 
previous 
version. 
Omission 
 
 
 
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. 
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: 
Addition of 
table showing 
mutation by 
response for 
Addition at 
request of 
virology expert. 


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Page 7 of 48 
 
SAP 
Version 
Approval Date 
Protocol Version 
(Date) on which 
SAP is Based 
Change 
Rationale 
binding site 
mutations with 
>=1% allelic 
frequency 
 
 
 
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 
Correction & 
omission 
 
 
 
Section 6.2.2: 
Updated  text 
to describe 
visit 
windowing for 
early 
termination 
visits  
Clarification  
 
 
 
Section 6.2.3: 
Added text 
“Off Treatment 
Day 1 occurs 7 
days after the 
last study 
treatment dose 
received, 
Clarification 


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Page 8 of 48 
 
SAP 
Version 
Approval Date 
Protocol Version 
(Date) on which 
SAP is Based 
Change 
Rationale 
regardless of 
whether the 
participant 
completes 
treatment as 
planned or the 
participant is 
withdrawn 
from study 
treatment.” 
SAP 
V1.0 
03 Dec 2021 
Protocol 
Amendment 01, 
15Mar2021; 
Protocol 
Amendment 
1/CAN-1, 22-
Jul2021 
Not Applicable 
Original version 
 


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Page 9 of 48 
 
1. 
INTRODUCTION 
The purpose of this SAP is to describe the planned analyses to be included in the CSR for 
Study 212602. Details of the planned interim analysis are detailed in a separate Interim 
Analysis Reporting Analysis Plan.  
An administrative interim analysis will be conducted when the first 10 subjects have fully 
complete and clean data. A reduced set of outputs will be produced as detailed in the 
OPS.  
1.1. 
Objectives, Estimands and Endpoints 
Objectives 
Endpoints 
Primary 
 
Efficacy: To assess the effect of 12 
weeks of GSK3228836 on serum 
HBsAg levels in participants with 
CHB 
The Primary Estimand supporting the primary 
objective of the study is defined as:  
• 
Population: Participants with CHB who receive 
at least one dose of IP 
• 
Treatment: 300 mg GSK3228836 for 12 weeks 
(also on stable nucleos(t)ide therapy)  
• 
Variable: Achieving serum HBsAg level <LLOQ 
at any time point up to and including Week 12 
without the use of PEG-interferon or other 
immunomodulator therapies.  
• 
Population-level summary: Percent of 
participants that achieve serum HBsAg level < 
LLOQ at any time point up to and including 
Week 12 
• 
Intercurrent events: Discontinuation of, 
interruption of, and adherence to IP will be 
ignored (treatment policy). 
The primary estimand is the percentage of 
participants with CHB receiving 300 mg GSK3228836 
for 12 weeks (with at least one dose of IP) who 
achieve serum HBsAg level <LLOQ at any time point 
up to and including Week 12, without the use of PEG-
interferon or other immunomodulator therapies, 
regardless of completing IP, interruptions in IP or 
adherence to IP. 
Secondary 
 


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Objectives 
Endpoints 
Efficacy: To assess sustainability 
of serum HBsAg loss by 
GSK3228836 for up to 24 weeks 
off-treatment. 
The Estimand supporting the objective is defined as: 
• 
Population: Participants with CHB who receive 
at least one dose of IP 
• 
Treatment: 300 mg GSK3228836 for 12 weeks 
(also on stable nucleos(t)ide therapy) 
• 
Variables: 
o Sustained HBsAg Response (HBsAg 
<LLOQ) for 24 weeks after the 
planned end of GSK3228836 
treatment 
▪ 
HBsAg from Week 13 to Week 
36 will be used to assess 
sustained HBsAg response 
after the planned end of 
GSK3228836 treatment 
without the use of PEG-
interferon or other 
immunomodulator therapies. 
o Sustained HBsAg Response (HBsAg 
<LLOQ) for 24 weeks after the actual 
end of GSK3228836 treatment 
▪ 
HBsAg for 24 weeks after end 
of actual treatment will also 
be used to assess sustained 
HBsAg response after the 
actual end of GSK3228836 
treatment without the use of 
PEG-interferon or other 
immunomodulator therapies. 
• 
Intercurrent events: Discontinuation of, 
interruption of, and adherence to IP will be 
ignored (treatment policy). 
 
The group of estimands supporting this objective in 
participants with CHB receiving 300 mg GSK3228836 
for 12 weeks (with at least one dose of IP) is the 
percentage of participants for each variable regardless 
of completing IP, interruptions in IP or adherence to 


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Page 11 of 48 
 
Objectives 
Endpoints 
IP, without the use of PEG-interferon or other 
immunomodulator therapies. 
Efficacy: To assess sustainability 
of serum HBsAg and HBV DNA 
loss by GSK3228836 for up to 24 
weeks off treatment. 
The Estimand supporting the objective is defined as: 
• 
Population: Participants with CHB who receive 
at least one dose of IP 
• 
Treatment: 300 mg GSK3228836 for 12 weeks 
(also on stable nucleos(t)ide therapy)  
• 
Variables: 
• 
Sustained Virologic Response (HBsAg 
<LLOQ and HBV DNA <LLOQ) for 24 
weeks after the planned end of GSK3228836. 
• 
HBsAg and HBV DNA from Week 13 to 
Week 36 will be used to assess sustained 
virologic response after the planned end 
of GSK3228836 treatment without the 
use of PEG-interferon or other 
immunomodulator therapies. 
• 
Sustained Virologic Response (HBsAg 
<LLOQ and HBV DNA <LLOQ) for 24 
weeks after the actual end of GSK3228836 
treatment 
• 
HBsAg and HBV DNA for 24 weeks 
after end of actual treatment will be used 
to assess sustained virologic response 
after the actual end of GSK3228836 
treatment without the use of PEG-
interferon or other immunomodulator 
therapies 
• 
Intercurrent events: Discontinuation of, 
interruption of, and adherence to IP will 
be ignored (treatment policy). 
 
The group of estimands supporting this objective 
in participants with CHB receiving 300 mg 
GSK3228836 for 12 weeks (with at least one dose 
of IP) is the percentage of participants for each 


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Page 12 of 48 
 
Objectives 
Endpoints 
variable regardless of completing IP, interruptions 
in IP or adherence to IP, without the use of PEG-
interferon or other immunomodulator therapies. 
Efficacy: To assess the effect of 
12 weeks GSK3228836 on 
biomarkers and virus-specific 
antibody response.  
Estimands supporting the secondary objective of 
assessing the effect of 12 weeks GSK3228836 on 
biomarkers and virus-specific antibody responses 
are defined as follows: 
• 
Population: Participants with CHB who 
receive at least one dose of IP  
• 
Treatment: 300 mg GSK3228836 for 12 
weeks (also on stable nucleos(t)ide 
therapy) 
• 
Intercurrent events: Discontinuation of, 
interruption of, adherence to IP will be 
ignored (treatment policy). 
PEGinterferon or other 
immunomodulator therapies will be 
handled with hypothetical strategy. 
1. Categorical Variables:  
• 
Achieving:  
• 
HBsAg <LLOQ over time 
• 
HBV DNA <LLOQ over time 
• 
HBsAg and HBV DNA <LLOQ over 
time 
• 
Categorical changes from baseline in 
HBsAg (e.g. <0.5, ≥0.5, ≥1, ≥1.5, ≥3 
log10 IU/mL) over time.  
• 
ALT>3X ULN at over time 
• 
HBe antibody (anti-HBeAg) levels over 
time 
Population summary: percentage of participants in 
each category. 
2. Continuous Variables: 
• 
Actual values and change from baseline 
over time for HBsAg and HBV DNA  


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Objectives 
Endpoints 
• 
HBs antibody (anti-HBsAg) and HBe 
antibody (anti-HBeAg) levels over time  
• 
Area under the curve (AUC) for ALT on 
treatment (12 weeks), during follow up 
(24 weeks), and on treatment + follow up 
(36 weeks) 
Population summary: mean values and/or mean 
changes from baseline for each variable 
1. Time to Event Variable  
• 
Time to Maximum ALT (ALT must be 
greater than 3xULN) during 36 weeks of 
treatment + follow up 
Population summary: Turnbull estimate for 
median Time to Maximum ALT (>3xULN)  
The group of estimands supporting this objective 
in participants with CHB receiving 300 mg 
GSK3228836 for 12 weeks (with at least one dose 
of IP) are the population summary for each 
variable in the absence of PEGinterferon or other 
immunomodulator therapies, regardless of 
completing IP, interruptions in IP, or adherence to 
IP. 
Safety 
 
Safety: To assess the safety and 
tolerability of GSK3228836 when 
dosed for 12 weeks in participants 
with CHB 
Clinical assessments including, but not limited to vital 
signs, laboratory measurements and adverse events 
Exploratory 
 
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Objectives 
Endpoints 
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Objectives 
Endpoints 
 
 
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1.2. 
Study Design 
Overview of Study Design and Key Features 
 
The schema for all countries except Canada is as follows:  
 
The schema for Canada is as follows:  
Note: The key difference between the two schema, is the following: Canada site has 
one less scheduled FNA than the other sites. 
Design 
Features 
• 
Phase IIa, single arm, multi-centre open label exploratory study of the 
therapeutic mechanism of GSK3228836 in participants with HBeAg-
negative CHB on stable nucleos(t)ide therapy using repeat fine needle 
aspirations of the liver for intrahepatic immunophenotyping 
• 
The total duration of the study, including screening, treatment and 
post-treatment follow-up, is not expected to exceed 45 weeks. 


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Overview of Study Design and Key Features 
Study 
interventio
n 
• 
300 mg GSK3228836 for 12 weeks (loading schedule on Day 4 and 
Day 11). Participants will continue to receive their stable 
nucleos(t)ide therapy 
Study 
interventio
n 
Assignment 
• 
N/A. This is a single arm study.  
Interim 
Analysis 
• 
Data will be incorporated into regular safety reviews by an IDMC and 
may be used to supplement the safety data review for the Phase IIb 
B-Clear study (approximately every 3 months).  
• 
There are 2 interims planned for this study, which align with the 
following timepoints in the Phase IIb B-Clear study:  
o Interim 1: approximately 30% participants complete Week 12 
to assess safety and futility.  
o Interim 2: approximately 50% participants complete Week 24 
to assess safety and futility. 
• 
Further details found in a separate Interim Analysis Reporting 
Analysis Plan.   
 
2. 
STATISTICAL HYPOTHESES  
The primary objective of the study is to assess the efficacy of 12 weeks of GSK3228836 
treatment in Hepatitis B e-antigen negative participants on nucleos(t)ide analogue 
therapy. The primary endpoint is achieving serum HBsAg level <LLOQ by Week 12 (at 
any time point up to and including Week 12) without the use of PEG-interferon or other 
immunomodulator therapies in CHB participants who receive at least one dose of IP. For 
list of terms for PEG-interferon or other therapies, refer to Output and Programming 
Specification. 
An estimation approach with no hypothesis testing will be used to address the primary 
objective. The primary assessment of interest is the point estimate of percent of 
participants achieving serum HBsAg level <LLOQ (without the use of PEG-interferon or 
other immunomodulator therapies) by Week 12 with the 95% credible interval. Other 
intercurrent events such as discontinuation of, interruption of, and adherence to IP will be 
ignored (treatment policy). In addition, posterior probabilities that the true percent is 
greater than the desired threshold of 50% will be provided using a Bayesian probability 
approach. 
2.1. 
Multiplicity Adjustment 
Analyses of efficacy endpoints will not be subject to any multiplicity adjustment. 
 


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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 population as they 
did not enter the study 
• 
Study 
Population 
Safety 
• 
All participants who received at least one dose 
of study treatment 
• 
Safety 
• 
Virology 
ITT 
• 
All participants who received at least one dose 
of study treatment 
• 
Note: As no randomization took place on this 
study, Safety and ITT analysis set will contain 
the same set of participants.  
• 
Efficacy 
• 
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 
 
Defined Analysis Data 
Sets 
Description 
Analysis set for primary 
estimand 
All Intent to Treat Participants including all observations on and off treatment.  
Analysis set for secondary 
estimands 
All Intent to Treat Participants including all observations on and off treatment. 
 
4. 
STATISTICAL ANALYSES 
4.1. 
General Considerations 
4.1.1. 
General Methodology 
Participants who prematurely withdrew from study will not be replaced.  
Confidence intervals will use 95% confidence levels unless otherwise specified.  


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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 and HBsAg levels that are below the 
LLOQ will be imputed for summaries of actual values and change from baseline.  
The numeric values for HBV DNA <LLOQ (LLOQ=20 IU/mL) will be imputed as 19.9. 
The numeric values for HBsAg <LLOQ (LLOQ=0.05 IU/mL) will be imputed as 0.04. For 
HBV RNA and HBcrAg, values <LLOQ are imputed based on the number of significant 
digits, similar to other lab parameters. For further handling of significant digits, please see 
OPS. 
 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 assessment with a non-missing value, including those from unscheduled 
visits. If time is not collected, Day 1 assessments are assumed to be taken prior to first dose 
and used as baseline. 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. 
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 will be conducted once the last participant has completed the Week 
36 visit (completed 24-weeks of follow-up period) and database lock has been achieved. 
The primary efficacy endpoint is achieving serum HBsAg level <LLOQ at any time point 
during 12-weeks (including Week 12) of GSK3228836 treatment. HBsAg at any time 
point up to and including Week 12 will be used to assess the primary endpoint. 
 
4.2.1. 
Definition of estimands 
The Primary Estimand supporting the primary objective of the study is defined as:  
• Population: Participants with CHB who receive at least 1 dose of IP 
• Treatment: 300 mg GSK3228836 for 12 weeks (also on stable nucleos(t)ide 
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• Variable: Achieving serum HBsAg level <LLOQ at any time point up to and 
including Week 12 without the use of PEG-interferon or other immunomodulator 
therapies 
• Population-level summary: Percent of participants that achieve serum HBsAg 
level <LLOQ at any time point up to and including Week 12  
• Intercurrent events: Discontinuation of, interruption of, and adherence to IP will 
be ignored (treatment policy).  
 
The primary estimand is the percentage of participants with CHB receiving 300 mg 
GSK3228836 for 12 weeks (with at least one dose of IP) who achieve serum HBsAg 
level <LLOQ at any time point up to and including Week 12, without the use of PEG-
interferon or other immunomodulator therapies, regardless of completing IP, 
interruptions in IP or adherence to IP. If PEG-interferon or other immunomodulator 
therapies are used, then the participant’s primary outcome will be treated as a non-
responder. 
 
4.2.2. 
Main analytical approach 
The primary assessments of interest are the point estimate and the 95% credible interval 
of achieving serum HBsAg level <LLOQ up to and including Week 12.  
In addition, posterior probability that the true virologic response rate is greater than 50% 
will be provided. A Bayesian approach will be used to estimate the posterior probability. 
A weakly informative prior beta (0.5, 0.5) will be used.  
Let Y be the number of responders from N participants,  
Y~ Binomial (N, p)  
Where p is virologic response rate.  
The posterior distribution for p is P(p|y, N) ~ Beta (y + 0.5, N – y + 0.5)  
The posterior probability that the true rate of participants achieving LLOQ by Week 12 
being greater than 50% will be calculated from the posterior distribution.  
The following will be presented:  
Model Results Presentation 
• 
Number and percent of participants achieving serum HBsAg level <LLOQ by Week 
12. 
• 
Posterior 95% credible interval (Highest Density Interval, HDI) of participants 
achieving serum HBsAg level <LLOQ by Week 12. 
• 
Posterior probability that the true rate of participants achieving LLOQ by Week 12 
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4.2.2.1. 
Intercurrent Events and Missing Data  
The intercurrent event of discontinuation of, interruption of, and adherence to IP will be 
ignored (treatment policy). 
A participant’s response (Responder or Non-responder) is determined as follows: 
• 
If participant took rescue medication of PEG-interferon or other immunomodulator 
therapies during 12 week treatment period or during 24 week follow-up period then 
participant is Non-Responder 
• 
Else if participant reached HBsAg < LLOQ at any point during the 12 week treatment 
period then participant is a Responder.  
• 
Otherwise participant is Non-Responder.  
 
If a participant has missing data during the 12 week treatment period, but still falls under 
the responder then they will still be considered a responder.   
HBsAg values at any timepoint up to and including Week 12 are considered, including 
Unscheduled visits. See Section 6.2.5 for details on upper bound of analysis date.  
4.3. 
Secondary Endpoint(s) Analyses 
4.3.1. 
Key secondary endpoint(s) 
4.3.1.1. 
Sustainability of Serum HBsAg loss 
Definition of estimands 
Estimands supporting the secondary objective of assessing sustainability of serum HBsAg 
loss by GSK3228836 for up to 24 weeks off-treatment are defined as follows: 
• The group of estimands supporting this objective in participants with CHB 
receiving 300 mg GSK3228836 for 12 weeks (with at least one dose of IP) is the 
percentage of participants for each variable regardless of completing IP, 
interruptions in IP or adherence to IP, without the use of PEG-interferon or other 
immunomodulator therapies. If PEG-interferon or other immunomodulator 
therapies are used then the participant’s outcome will be treated as a non-
responder. 
 
• Variables: 
o Sustained HBsAg Response (HBsAg <LLOQ) for 24 weeks after the 
planned end of GSK3228836 treatment without the use of PEG-interferon 
or other immunomodulator therapies 
▪ HBsAg from Week 13 to Week 36 will be used to assess sustained 
HBsAg response after the planned end of GSK3228836 treatment.  


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o Sustained HBsAg Response (HBsAg <LLOQ) for 24 weeks after the actual 
end of GSK3228836 treatment without the use of PEG-interferon or other 
immunomodulator therapies 
▪ HBsAg for 24 weeks after end of actual treatment will also be 
used to assess sustained HBsAg response after the actual end of 
GSK3228836 treatment. 
 
• Population Summary: percentage of participants for each variable. 
Main analytical approach 
Percentages will be summarised and presented for:  
• 
Sustainability of Serum HBsAg loss  
Analysis windows for the post GSK3228836 treatment assessments are defined in Section 
6.2.5. 
If all analysis windows have non-missing response information, a participant’s response 
(Responder or Non-responder) for sustained HBsAg response after the planned end of 
GSK3228836 treatment is determined as follows: 
• 
If participant took PEG-interferon or other immunomodulator therapies during 12 week 
treatment period or 24 week follow-up period then participant is Non-Responder 
• 
Else if participant had sustained HBsAg response (HBsAg <LLOQ) for 24 weeks after 
planned end of GSK3228836 treatment then participant is a Responder.  
• 
Otherwise participant is Non-Responder.  
 
If all analysis windows have non-missing response information, a participant’s response 
(Responder or Non-responder) for sustained HBsAg response after the actual end of 
GSK3228836 treatment is determined as follows: 
• 
If participant took PEG-interferon or other immunomodulator therapies during 24 week 
follow-up period then participant is Non-Responder 
• 
Else if participant had sustained HBsAg response (HBsAg <LLOQ) for 24 weeks after 
actual end of GSK3228836 treatment then participant is a Responder.  
• 
Otherwise participant is Non-Responder.  
 
For participants where sustained HBsAg response in the absence of PEG-interferon or 
other immunomodulator therapies cannot be ascertained due to missing data (withdrawal 
from the study or missing due to other reasons), the participant will be assumed not to have 
achieved SVR (non-responder imputation). 
 


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4.3.1.2. 
Sustainability of Serum HBsAg and HBV DNA loss (Sustained Virologic 
Response) 
Definition of estimands 
Estimands supporting the secondary objective of assessing sustainability of serum HBsAg 
and HBV DNA (Sustained Virologic Response) loss by GSK3228836 for up to 24 weeks 
off treatment are defined as follows: 
• The group of estimands supporting this objective in participants with CHB 
receiving 300 mg GSK3228836 for 12 weeks (with at least one dose of IP) is the 
percentage of participants for each variable regardless of completing IP, 
interruptions in IP or adherence to IP, without the use of PEG-interferon or other 
immunomodulator therapies. If PEG-interferon or other immunomodulator 
therapies are used then the participant’s outcome will be treated as a non-
responder. 
 
• Variables: 
o Sustained Virologic Response (HBsAg <LLOQ and HBV DNA <LLOQ) for 24 
weeks after the planned end of GSK3228836 treatment 
▪ HBsAg and HBV DNA from Week 13 to Week 36 will be used to 
assess sustained virologic response after the planned end of 
GSK3228836 treatment without the use of PEG-interferon or other 
immunomodulator therapies. 
o Sustained Virologic Response (HBsAg <LLOQ and HBV DNA <LLOQ) for 24 
weeks after the actual end of GSK3228836 treatment 
▪ HBsAg and HBV DNA for 24 weeks after end of actual treatment will 
be used to assess sustained virologic response after the actual end 
of GSK3228836 treatment without the use of PEG-interferon or 
other immunomodulator therapies. 
 
• Population Summary: percentage of participants for each variable. 
Main analytical approach 
Percentages will be summarised and presented for:  
• 
Sustainability of Serum HBsAg and HBV DNA loss (Sustained Virologic Response).  
 
Analysis windows for the post GSK3228836 treatment assessments are defined in Section 
6.2.5. 
If all analysis windows have non-missing response information, a participant’s response 
(Responder or Non-responder) for sustained virologic response after the planned end of 
GSK3228836 treatment is determined as follows: 


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• 
If participant took PEG-interferon or other immunomodulator therapies during 12 week 
treatment period or 24 week follow-up period then participant is Non-Responder 
• 
Else if participant had sustained virologic response (HBsAg <LLOQ and HBV DNA <LLOQ) 
for 24 weeks after planned end of GSK3228836 treatment then participant is a 
Responder.  
• 
Otherwise participant is Non-Responder.  
 
If all analysis windows have non-missing response information, a participant’s response 
(Responder or Non-responder) for sustained virologic response after the actual end of 
GSK3228836 treatment is determined as follows: 
• 
If participant took PEG-interferon or other immunomodulator therapies during 12 week 
treatment period or 24 week follow-up period then participant is Non-Responder 
• 
Else if participant had sustained virologic response (HBsAg <LLOQ and HBV DNA <LLOQ) 
for 24 weeks after actual end of GSK3228836 treatment then participant is a Responder.  
• 
Otherwise participant is Non-Responder.  
 
For participants where sustained virologic response in the absence of PEG-interferon or 
other immunomodulator therapies cannot be ascertained due to missing data (withdrawal 
from the study or missing due to other reasons), the participant will be assumed not to have 
achieved SVR (non-responder imputation). 
 
4.3.1.3. 
Effect of 12 weeks GSK3228836 on biomarkers and virus-specific 
antibody responses 
Definition of estimands 
Estimands supporting the secondary objective of assessing the effect of 12 weeks 
GSK3228836 on biomarkers and virus-specific antibody responses are defined as follows: 
- Population: Participants with CHB who receive at least one dose of IP 
- Treatment: 300 mg GSK3228836 for 12 weeks (also on stable nucleos(t)ide therapy) 
- Intercurrent events: Discontinuation of, interruption of, adherence to IP will be ignored 
(treatment policy). For the categorical variable summaries, and continuous variable 
summaries, PEG-interferon or other immunomodulator therapies will be handled with 
hypothetical strategy. 
- Variables: 
1) Categorical Variables: 
• Achieving HBsAg <LLOQ over time 
• Achieving HBV DNA <LLOQ over time 
• Achieving HBsAg <LLOQ and HBV DNA <LLOQ over time 


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• HBe antibody (anti-HBeAg) levels over time 
• Categorical changes from baseline in HBsAg (e.g. <0.5, ≥0.5, ≥1, ≥1.5, ≥3 log10 
IU/mL) over time 
Note: <0.5 category includes subjects with no change or an increase in HBsAg 
from baseline.  
• ALT>3X ULN over time 
• 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: Percent of participants in each category. 
2) Continuous Variables:  
• Actual values and change from baseline over time for HBsAg and HBV DNA  
• HBs antibody (anti-HBsAg) levels over time 
• Area under the curve (AUC) for ALT on treatment (12 weeks), during follow up 
(24 weeks), and on treatment + follow up (36 weeks). 
 
- Population summary: mean values and/or mean changes from baseline for each variable  
3) Time to Event Variable 
• Time to First Occurrence of Maximum ALT (ALT must be greater than 3xULN) 
during 36 weeks ( treatment + follow up) 
Time to first occurrence of maximum ALT (first peak in ALT) during 36 week (treatment + 
follow-up) is defined as time from baseline to the time of first peak in ALT. 
Outcome will be assumed missing (Missing At Random) from the timepoint when subjects 
first receive PEG-interferon or other immunomodulator therapies. 
• Time to First Occurrence of Maximum ALT (ALT must be greater than 3xULN) 
during 12 week on-treatment period 
Time to first occurrence of maximum ALT (first peak in ALT) during 12 week treatment 
period is defined as time from baseline to the time of first peak in ALT (given the peak 
occurred during 12 weeks of study treatment. See Section 6.2.2 for definition of on-
treatment period.  
Outcome will be assumed missing (Missing At Random) from the timepoint when 
subjects first receive PEG-interferon or other immunomodulator therapies. 
• Time to First Occurrence of Maximum ALT (ALT must be greater than 3xULN) 
during 24 week follow-up period 
Time to first occurrence of maximum ALT (first peak in ALT) during 24 week off treatment 
period is defined as time from last dose of study treatment to the time of first peak in ALT 
occurring after study treatment had ended. See Section 6.2.2 for definition of post-
treatment period. 


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Outcome will be assumed missing (Missing At Random) from the timepoint when subjects 
first receive PEG-interferon or other immunomodulator therapies. 
• Time to Maximum ALT (ALT must be greater than 3xULN) during 36 weeks ( 
treatment + follow up) 
Time to maximum ALT (maximum peak in ALT) during 36 week (treatment + follow-up) is 
defined as time from baseline to the time of first peak in ALT.  
 
For this analysis, taking PEG-interferon or other immunomodulator therapies will be 
ignored. Participants will be censored at the last record within the specified time period. 
- Population summary: Turnbull estimate for median Time to Maximum ALT (>3xULN)   
Missing data for variables in this group of estimands will be ignored, only available data 
will be summarized.  
4.4. 
Exploratory Endpoint(s) Analyses 
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4.5. 
Safety Analyses 
The safety analyses will be based on the Safety Analysis Set, unless otherwise specified. 
4.5.1. 
Extent of Exposure 
Extent of exposure will be summarized using summary statistics. Number of subjects with  
< 6 weeks, ≥6 – 12 weeks exposure will be presented, and the overall duration of exposure 
will be summarized. Study intervention compliance will be summarized as described in 
Section 6.1.5. 
Number of days of exposure to study drug for each participant 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 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 
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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 following 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)  
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. Non-serious AEs by SOC and PT  
14. Non-serious drug-related AEs by overall frequency  
15. Serious fatal and non-fatal 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.  


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For completely missing or partial missing AE start date or end date, imputation rules will 
be applied following the rules stated in Section 6.2.7. 
 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 
 
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.  
Separate outputs will be created for each AESI category (ALT increase, vascular 
inflammation and complement activation, thrombocytopenia and renal injury) 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 COVID-19 AEs will be summarized. 
If >5% participants 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. 


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4.5.2.3. 
Impact of COVID-19 Pandemic on Safety Results 
The impact of the COVID-19 pandemic on the safety results will be assessed. Pandemic 
measures began in different countries at different times. A dataset containing the date 
when pandemic measures began, as determined by the GSK country Issue Management 
Teams (IMT), will be used to determine the start date of each wave of pandemic 
measures within each country. 
Summaries of the incidence rates of AEs, Common AEs, SAEs and Grade 3 and 4 AEs / 
severe AEs, before (AE onset date < pandemic measure start date) and after (AE onset 
date >= pandemic measure start date) the start of the COVID-19 pandemic will be 
produced, overall and by country/region, gender and age group (<18, 18-64, >=65). 
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.  
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.  
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, 
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Summary of post-baseline hepatobiliary laboratory abnormalities will be provided based 
on both planned and unplanned assessments (e.g. unscheduled visit, monitoring event).   
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. 
 
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 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). The summaries 
will be produced for worst case post baseline only. 
 


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4.6. 
Other Analyses 
4.6.1. 
Subgroup analyses 
The list of subgroups below will be used in descriptive summaries of baseline 
characteristics and may be examined for study outcomes. Summary statistics (n(%)) for the  
number of responders of the HBsAg <LLOQ response rate will be reported by subgroups. 
No statistical comparison between subgroups will be performed. 
If the percentage of participants is small within a particular subgroup, then the subgroup 
categories may be redefined. Given the small sample size of this study, if all subjects fall 
into one single subgroup category, then subgroup analyses for study outcomes will not be 
necessary and therefore will not be performed. Additional subgroups of clinical interest 
may also be considered. 
Subgroup 
Categories  
Baseline HBsAg 
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) 
Duration of Hep B Infection 
<5 years, ≥ 5 years - <10 years, ≥ 10 years - <20 years, ≥ 20 years 
Hep B Infection Route 
Vertical transmission (e.g., from mother to child); From childhood; 
Injectable Drugs; Sexual Contact; Blood transfusion; Work exposure 
(e.g., needle stick); Unknown; Other/prefer not to say 
Baseline viral genotype 
B, C, Other, Unknown 
Baseline BMI 
<30, ≥30 
 
4.7. 
Interim Analyses 
Data will be incorporated into regular safety reviews by an IDMC and may be used to 
supplement the safety data review for the Phase IIb B-Clear study [GSK Document 
Number 2019N420582_00, Study 209668]. 
Details of study interim analyses are provided in a 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 1. 
Table 1 
Changes to Protocol Defined Analysis Plan 
Protocol Defined Analysis 
SAP Defined Analysis 
Rationale for Changes 
Section 4.3.1.3, single table presented 
for:  
 
Time to Event Variable • Time to 
Maximum ALT (ALT must be greater 
than 3xULN) during 36 weeks of 
Now presenting 4 tables instead of 
one:  
• 
Summary of Time to 
First Occurrence of 
Maximum ALT  
• 
At the time of writing the 
protocol, it was expected that 
only one peak in ALT would 
be seen. We have since seen 
on other studies, that more 
than one peak can occur.  


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Protocol Defined Analysis 
SAP Defined Analysis 
Rationale for Changes 
treatment + follow up Population 
summary: Turnbull estimate for median 
Time to Maximum ALT (>3xULN) 
• 
Summary of Time to 
First Occurrence of 
Maximum ALT during 12 
week treatment period  
• 
Summary of Time to 
First Occurrence of 
Maximum ALT after 
GSK3228836 treatment 
• 
Summary of Time to 
Maximum ALT 
• 
The first analysis, is the 
analysis which was originally 
intended for the study looking 
at the first peak.   
• 
The other analyses reflect our 
newly updated learning for 
ALT, since the time of writing 
the protocol. 
 
5. 
SAMPLE SIZE DETERMINATION 
Approximately 20 participants will be targeted to assign to treatment. 
Primary Endpoint 
It is assumed that the number of participants achieving serum HBsAg level <LLOQ by 
Week 12 without the use of PEG-interferon or other immunomodulator therapies follows 
a Binomial distribution, with a weakly informative prior beta(0.5, 0.5) for the true response. 
The precision for a range of true response rates with 95% credible intervals are shown in 
Table 2. 
Table 2 
95% Credible Interval for Percent of Participants achieving HBsAg 
<LLOQ by Week 12 
Sample size 
per arm 
Number of Participants 
with HBsAg <LLOQ 
Percent of Participants 
with HBsAg <LLOQ 
95% Credible 
Interval* 
20 
8 
40% 
20% – 61% 
10 
50% 
29% - 71% 
12 
60% 
39% - 80% 
14 
70% 
50% - 87% 
16 
80% 
61% - 94% 
*95% highest posterior density interval 
With 20 participants, if the observed response rate is 60%, 70% and 80%, then the lower 
bound of the 95% credible interval excludes values below 39%, 50% and 61%, 
respectively. The posterior probability that the percent of participants achieving 
HBsAg<LLOQ by Week 12 is greater than 50% 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 
percentage of participants achieving serum HBsAg level <LLOQ exceeds 50% (desired for 
further mechanistic exploration of the therapeutic effects of GSK3228836 via intrahepatic 
immunophenotyping) are shown in Table 3, for various assumed sample sizes and true 
response rates. A weakly informative prior beta (0.5, 0.5) is used. With a sample size of 20 
participants, if there are at least 12 participants achieving HBsAg <LLOQ (observed 
percent of 60%) then the posterior probability that the true percent is greater than 50% will 
be greater than 75%. 


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Table 3 
Study Operating Characteristics by Sample Size 
Criteria 
Sample 
Size 
Min N (%) of 
Participants 
with HBsAg 
<LLOQ 
required for 
meeting 
Criteria 
  
Probability of Meeting Criteria 
 if True Response Rate = 
30% 
40% 
50% 
60% 
65% 
70% 
75% 
Probability 
(true 
response rate 
>50%)>75% 
10 
7 (70%) 
1% 
5% 
17% 
38% 
51% 
65% 
78% 
15 
9 (60%) 
2% 
10% 
30% 
61% 
75% 
87% 
94% 
18 
11 (61%) 
1% 
6% 
24% 
56% 
73% 
86% 
94% 
20 
12 (60%) 
1% 
6% 
25% 
60% 
76% 
89% 
96% 
24 
14 (58%) 
0% 
5% 
27% 
65% 
82% 
93% 
98% 
30 
17 (57%) 
0% 
5% 
29% 
71% 
87% 
96% 
99% 
 * response rate defined as percent of participants achieving HBsAg<LLOQ by Week 12 
Based on these operating characteristics, for a true response rate of 60%, the proposed 
sample-size of 20 has 60% probability of confirming a true rate of at least 50%, and if the 
true rate is 70%, there is an 89% chance of confirming a true rate greater than 50%. 
Biomarker Endpoints 
Given a sample size of 20, the confidence intervals for the ratio in change from baseline in 
RNAseq (signature) scores between those achieving versus not achieving HBsAg<LLOQ 
are shown below, assuming a range of effect sizes and between-participant coefficients of 
variation (CVb).   
Example of one scenario with 60% of the participants achieving HBsAg < LLOQ is given 
below. With relatively smaller between participant variability and larger effect size, a 
sample size of 20 is appropriate to achieve an acceptable level of precision in detecting the 
differential responses in biomarker outcomes corresponding to HBsAg responses. For 
example, in the scenario where 60% of participants achieve HBsAg <LLOQ, if CVb = 0.4, 
the 95% CI excludes 1 for geometric mean ratios of 0.6 and below, and for 1.7 and above. 
12 Participants (60%) Achieving HBsAg<LLOQ) 
CVb 
95% CI for Ratio of Geometric Mean of Fold Change from Baseline for Participants 
achieving vs. not achieving HBsAg<LLOQ 
0.6 
0.8 
1 
1.2 
1.4 
1.7 
2.0 
0.2 
[0.50, 0.73] 
[0.66, 0.97] 
[0.83, 1.21] 
[0.99, 1.45] 
[1.16, 1.69] 
[1.41, 2.06] 
[1.65, 2.42] 
0.4 
[0.41, 0.87] 
[0.55, 1.16] 
[0.69, 1.45] 
[0.83, 1.74] 
[0.97, 2.03] 
[1.17, 2.46] 
[1.38, 2.89] 
0.6 
[0.35, 1.02] 
[0.47, 1.36] 
[0.59, 1.70] 
[0.71, 2.04] 
[0.82, 2.38] 
[1.00, 2.89] 
[1.18, 3.40] 
0.8 
[0.31, 1.18] 
[0.41, 1.57] 
[0.51, 1.96] 
[0.61, 2.36] 
[0.71, 2.75] 
[0.87, 3.34] 
[1.02, 3.93] 
1 
[0.27, 1.33] 
[0.36, 1.78] 
[0.45, 2.22] 
[0.54, 2.67] 
[0.63, 3.11] 
[0.77, 3.78] 
[0.90, 4.44] 
1.5 
[0.21, 1.70] 
[0.28, 2.27] 
[0.35, 2.83] 
[0.42, 3.40] 
[0.49, 3.97] 
[0.60, 4.81] 
[0.71, 5.66] 


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There are no plans for sample size re-estimation. In certain cases, including but not limited 
to higher than anticipated drop-out rate, higher than anticipated rates of efficacy, or large 
variability in ALT flare patterns, the sample size may be increased to no more than 24. 


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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, and will be based on the Screened Analysis Set. 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. 
A listing and summary of number of planned and completed FNA’s per patient will be 
presented.   
 
6.1.2. 
Demographic and Baseline Characteristics 
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. 


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Baseline characteristics including hypertension, NSAID, TDF/TAF containing 
medications use, ADV containing medications use, diabetes, eGFR, serum creatinine, urine 
ACR, platelets, ANC, complement C3, complement C4, 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.  
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.  
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 freezing the database to ensure all important 
deviations 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% and ≥80% - 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. 
Additionally, if greater than 5% 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 Derivations Rule 
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. 
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  
Date1 ≤ Study Treatment Start Date 
On-Treatment 
Study Treatment Start Date < Date1 ≤ Off Treatment Day 1 – 1 day 
Post-Treatment 
Date1 ≥ Off Treatment Day 1 
1 Date is the start date of the assessment/event. 
 
6.2.3. 
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     
6.2.4. 
Assessment Windows for Early Termination 
Unless otherwise specified, unscheduled visits will not be mapped to a visit window, and 
will be listed only.  
Assessment for Early Termination visits are as follows:  


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Analysis 
Set / 
Domain 
Parameter 
(if 
applicable) 
Target  
Analysis Window 
Analysis 
Timepoint 
Beginning 
Timepoint 
(Days) 
Ending 
Timepoint 
(Days) 
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 Day 
15 
 
 
22 
19 
25 
Week 4 
 
 
1+7(x-1) 
1+7(x-1)-3 
1+7(x-1)+3 
Week x 
 
 
85 
82 
88 
OT-Week 1 
 
 
92 
89 
95 
OT-Week 2 
 
 
106 
96 
119 
OT-Week 4 
 
 
134 
120 
147 
OT-Week 8 
 
 
162 
148 
175 
OT-Week 
12 
 
 
190 
176 
203 
OT-Week 
16 
 
 
218 
204 
231 
OT-Week 
20 
 
 
246 
232 
246 
OT-Week 
24 
 
6.2.5. 
Assessment Windows for Analyses and Multiple Measurements 
at One Analysis Timepoint 
The primary endpoint is defined as “Achieving serum HBsAg level <LLOQ at any time 
point up to and including Week 12 without the use of PEG-interferon or other 
immunomodulator therapies”. No analysis window will be assigned and all values up to 
Week 12, including unscheduled visit results, will be considered. The upper bound of the 
analysis date is defined as:  
 
Target day of the Week 12 visit (78) + 3 days 
 
Note: 3 days as allowed for the Week 12 dosing. 
 
For secondary endpoints: 


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• sustained Virologic Response (HBsAg <LLOQ and HBV DNA <LLOQ)  
• sustained HBsAg Response (HBsAg <LLOQ) for 24 weeks  
 
after the planned end of GSK3228836 treatment (all values including unscheduled visit 
results will be considered): 
 
 
Parameter      
(if applicable) 
Target Study 
Day 
Analysis Window 
Analysis 
Timepoint 
Protocol 
Visit 
Beginning 
Timepoint 
Ending 
Timepoint 
Efficacy 
 
HBsAg and 
HBV DNA; or 
HBsAg 
78 
64 
98 
End of ‘836 
Treatment – 
Planned  
Week 12 
 
 
134 
99 
154 
Post ‘836 
treatment 
Week 8 – 
Planned 
Week 20 
 
 
190 
155 
210 
Post ‘836 
treatment 
Week 16 – 
Planned 
Week 28 
 
 
246 
211 
266 
Post ‘836 
treatment 
Week 24 – 
Planned 
Week 36 
 
For secondary endpoints: 
• sustained Virologic Response(HBsAg <LLOQ and HBV DNA<LLOQ)  
• sustained HBsAg Response(HBsAg <LLOQ) 24 weeks  
 
after the actual end of GSK3228836 treatment (all values including unscheduled visit 
results will be considered): 
 
 
Parameter      
(if applicable) 
Target Study 
Day 
Analysis Window 
Analysis 
Timepoint 
Protocol 
Visit 
Beginning 
Timepoint 
Ending 
Timepoint 
Efficacy 
 
HBsAg and 
HBV DNA; or 
HBsAg 
X = Target 
study day of 
the last 
treatment 
dose 
Max (X-14, 
1) 
 
X+20 
 
End of ‘836 
Treatment - 
Actual 
- 
 
 
X + 56 
X+21 
X + 76 
Post ‘836 
treatment 
Week 8 - 
Actual 
- 
 
 
X + 112 
X+ 77 
X + 132 
Post ‘836 
treatment 
- 


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Parameter      
(if applicable) 
Target Study 
Day 
Analysis Window 
Analysis 
Timepoint 
Protocol 
Visit 
Beginning 
Timepoint 
Ending 
Timepoint 
Week 16 - 
Actual 
 
 
X + 168 
X + 133 
X + 188 
Post ‘836 
treatment 
Week 24 - 
Actual 
- 
 
 
1. 
For example, if the subject received the last treatment dosing at the W2/D8 visit, 
then the target day is 8; if the subject received the last treatment dosing at the 
W2/D11 visit (loading schedule), then the target day is 11; if the subject received the 
last treatment dosing at the W9/D57 visit, then the target day is 57.  
 
For the End of ‘836 Treatment Analysis Timepoint, if there are multiple values within an 
analysis window the following rules will be applied: 
1. The latest available assessment in the window will be selected. 
 
For Post ‘836 Treatment Analysis Timepoints, if there are multiple values within an 
analysis window the following rules will be applied: 
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 in 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. 
 


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6.2.6. 
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. 
• 
If after window assignment of Early Termination visits there are multiple valid assessments of a 
parameter within the same window, then the following hierarchy will be used to determine the value 
to be used for summary statistics of observed values: 
o the assessment closest to the window target Study Day; 
o if there are multiple assessments equidistant from the target Study Day, then the mean 
of these values will be used. 
• 
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.  
 
6.2.7. 
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). In addition, 
imputed dates are not used for deriving the last contact date in 
overall survival analysis dataset. 
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 


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Element 
Reporting Detail 
▪ 
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. 
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: 
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.       
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: 


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Element 
Reporting Detail 
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. 
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: 
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.       
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 
 
 


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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 
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