Conditions: Hepatitis B
Keywords: Pharmacokinetics Safety Pharmacodynamics Efficacy Chronic Hepatitis B GSK3389404
Allocation: RANDOMIZED | Intervention model: SINGLE_GROUP
Enrollment: 78
Healthy volunteers: no

Brief summary:
GSK3389404 is being developed for the treatment of CHB virus infection. The development goal for GSK3389404 is the establishment of a finite duration treatment that results in sustained suppression of hepatitis B virus (HBV) replication and viral antigen production after cessation of all treatments for CHB due to the restoration of a functional immune response in the absence of high antigen levels. This study is a multicenter, randomized double-Blind (sponsor un-blinded in Part 1), Placebo-controlled Study which will evaluate the safety, tolerability, PK, and PD profile of GSK3389404 in subjects with CHB and aim to establish proof-of-mechanism. The study will be conducted in two parts. Part 1 plans to enroll subjects primarily from the Asia-pacific region, including Japan and will be conducted as a single ascending dose (SAD) study with 5 planned cohorts ranging from 30 milligram (mg) to a maximum of 240 mg GSK3389404. Within each cohort, subjects will be randomized to receive either GSK3389404 or placebo in a 3:1 ratio. Cohorts A, B, C, C1, and D will be conducted in a sequential fashion; Cohort C1 is an optional cohort and may be dosed after Cohort C or in parallel with Cohort D. Part 2 will be conducted as a multiple-dose, dose-ranging study. Subjects will be randomized to different parallel dose levels and regimens or placebo. The dose levels of Part 2 will be selected after a review of Part 1 safety, Pharmacokinetic (PK) and Pharmacodynamic (PD) data. The treatments selected are 60 mg GSK3389404 weekly, 120 mg GSK3389404 bi-weekly, 120 mg GSK3389404 weekly or placebo. An optional Japanese part-2 sub-study is planned. The total study duration for part 1 including screening, treatment, and post-treatment follow-up, will not be expected to exceed 13 weeks for each subject and for part 2, including screening, treatment and post-treatment follow-up, will not be expected to exceed 65 weeks for each subject.

Detailed description:

Arms:
arm 1: Enrolled subjects (HBeAg-positive and/or HBeAg negative) will receive single SC injection of GSK3389404 30 mg or matching placebo arm 2: Enrolled subjects (HBeAg-positive and/or HBeAg negative) will receive single SC injection of GSK3389404 60 mg or matching placebo arm 3: Enrolled subjects (HBeAg-positive and/or HBeAg negative) will receive single SC injection of GSK3389404 120 mg or matching placebo arm 4: Enrolled subjects (HBeAg-positive and/or HBeAg negative) will receive single SC injection of GSK3389404 120 mg or matching placebo arm 5: Enrolled subjects (HBeAg-positive and/or HBeAg negative) will receive single SC injection of GSK3389404 \<= 240 mg or matching placebo arm 6: Enrolled subjects will receive different parallel dose level and regimens of GSK3389404 or placebo SC at dose determined in part 1. The treatments for Part 2 are 60 mg GSK3389404 weekly, 120 mg bi-weekly GSK3389404, 120 mg GSK3389404 weekly or placebo.

Interventions: intervention 1: GSK3389404 intervention 2: Placebo
Intervention descriptions: intervention 1: GSK3389404 is available as Clear colorless to slightly yellow solution for injection. intervention 2: Placebo is available as a Clear colorless solution.

Protocol document:
SAP_002.pdf: 
CONFIDENTIAL
The GlaxoSmithKline group of companies
205670
1
Division
:
Worldwide Development
Information Type
:
Reporting and Analysis Plan (RAP)
Title
:
Reporting and Analysis Plan for 205670: A Double-Blind, 
Placebo-Controlled Study to Assess the Safety, Tolerability, 
Pharmacokinetics and Pharmacodynamics of Single 
Ascending Dose and Multiple Doses of GSK3389404 in 
Chronic Hepatitis B Subjects (Part 2)
Compound Number 
:
GSK3389404
Effective Date 
:
19-NOV-2018
Description:

The purpose of this RAP is to describe the planned analyses and output to be 
included in the Clinical Study Report for Protocol 205670: A Double-Blind, 
Placebo-Controlled Study to Assess the Safety, Tolerability, Pharmacokinetics and 
Pharmacodynamics of Single Ascending Dose and Multiple Doses of GSK3389404 
in Chronic Hepatitis B Subjects (Part 2).
RAP Author(s):
22-AUG-2018
Sr. Biostatistician II, PPD
22-AUG-2018
Sr. Pharmacokineticist, PPD
Copyright 2018 the GlaxoSmithKline group of companies. All rights reserved.  
Unauthorised copying or use of this information is prohibited.
 
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The GlaxoSmithKline group of companies
205670
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RAP Team Approvals:
Approver
Date
Approval Method
Director (ID Clinical Development)
16-NOV-2018
Email
Manager (ID Clinical Operation)
16-NOV-2018
Email
Manager (ID DM)
15-NOV-2018
Email
Manager (ID Clinical Programming)
15-NOV-2018
Email
Director (SERM)
16-NOV-2018
Email
Director (ID Clinical Pharmacology)
19-NOV-2018
Email
Manager (ID Clinical Development)
16-NOV-2018
Email
Clinical Statistics and Clinical Programming Line Approvals:
Approver
Date
Approval Method
15-NOV-2018
Email
Director (ID Clinical Statistics)
16-NOV-2018
Email
Director (ID Clinical Programming)
 
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TABLE OF CONTENTS
PAGE
1.
INTRODUCTION......................................................................................................6
2.
SUMMARY OF KEY PROTOCOL INFORMATION ................................................12
2.1.
Changes to the Protocol Defined Statistical Analysis Plan..........................12
2.2.
Study Objective(s) and Endpoint(s).............................................................12
2.3.
Study Design ..............................................................................................14
2.4.
Statistical Hypotheses.................................................................................16
3.
PLANNED ANALYSES ..........................................................................................16
3.1.
Interim Analyses .........................................................................................16
3.2.
Final Analyses ............................................................................................17
3.2.1.
Part 2: Primary Analysis...............................................................17
3.2.2.
JSS Optional Analysis..................................................................17
3.2.3.
Part 2: 3 month follow up Analysis ...............................................17
3.2.4.
Part 2: 6 month follow up Analysis ...............................................17
3.2.5.
Part 2: End of Study Analysis.......................................................17
4.
ANALYSIS POPULATIONS ...................................................................................18
4.1.
Protocol Deviations.....................................................................................19
5.
CONSIDERATIONS FOR DATA ANALYSES AND DATA HANDLING 
CONVENTIONS.....................................................................................................19
5.1.
Study Treatment & Sub-group Display Descriptors.....................................19
5.2.
Baseline Definitions ....................................................................................20
5.3.
Examination of Covariates, Other Strata and Subgroups............................20
5.3.1.
Examination of Subgroups...........................................................20
5.4.
Other Considerations for Data Analyses and Data Handling 
Conventions................................................................................................20
6.
STUDY POPULATION ANALYSES .......................................................................21
6.1.
Overview of Planned Study Population Analyses........................................21
6.1.1.
Disposition and Withdrawals........................................................22
6.1.2.
Demographic and Baseline Characteristics..................................22
6.1.3.
Prior and Concomitant Medications .............................................22
6.1.4.
Medical History and Current Medical Conditions..........................23
6.1.5.
Treatment Exposure ....................................................................23
7.
EFFICACY ANALYSES..........................................................................................24
7.1.
Primary Efficacy Analyses ..........................................................................24
7.1.1.
Endpoint / Variables.....................................................................24
7.1.2.
Population of Interest...................................................................24
7.1.3.
Statistical Analyses / Methods .....................................................24
7.1.3.1.
Statistical Methodology Specification..........................25
7.2.
Secondary Efficacy Analyses......................................................................27
7.3.
Exploratory Efficacy Analyses.....................................................................28
8.
SAFETY ANALYSES .............................................................................................28
8.1.
Exposure to Study Treatment .....................................................................28
8.2.
Adverse Events Analyses ...........................................................................28
 
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8.3.
Vital Signs...................................................................................................29
8.4.
Injection Site Reactions ..............................................................................30
8.5.
12-lead electrocardiograms (ECGs)............................................................30
8.6.
Laboratory Measurements..........................................................................30
9.
PHARMACOKINETIC ANALYSES (GSK3389404) ................................................31
9.1.
Overview of Planned Pharmacokinetic Analyses ........................................31
9.2.
Drug Concentration Measurements ............................................................32
9.3.
Pharmacokinetic Parameters......................................................................32
9.3.1.
Deriving Pharmacokinetic Parameters.........................................32
9.3.2.
Statistical Analysis of Pharmacokinetic Parameters.....................34
10. SECONDARY STATISTICAL ANALYSES .............................................................34
10.1.
Overview of Planned Pharmacokinetic Analyses ........................................34
11. EXPLORATORY STATISTICAL ANALYSES .........................................................35
11.1.
Overview of Planned PK/PD Analyses........................................................35
11.2.
Overview of Planned PK Analyses by Race................................................35
12. REFERENCES.......................................................................................................36
13. APPENDICES........................................................................................................37
13.1.
Appendix 1: Schedule of Activities ..............................................................37
13.1.1.
Protocol Defined Schedule of Events...........................................37
13.2.
Appendix 2: Assessment Windows .............................................................40
13.2.1.
Definitions of Assessment Windows for Analyses........................40
13.3.
Appendix 3: Study Phases and Treatment Emergent Adverse 
Events ........................................................................................................41
13.3.1.
Study Phases ..............................................................................41
13.3.2.
Treatment Emergent Flag for Adverse Events .............................41
13.4.
Appendix 4: Data Display Standards & Handling Conventions....................42
13.4.1.
Reporting Process .......................................................................42
13.4.2.
Reporting Standards....................................................................42
13.4.3.
Baseline Definition & Derivations .................................................43
13.4.3.1.
Baseline Definitions....................................................43
13.4.3.2.
Derivations and Handling of Missing Baseline 
Data ...........................................................................43
13.5.
Appendix 5: Derived and Transformed Data ...............................................44
13.5.1.
General........................................................................................44
13.5.2.
Study Population..........................................................................44
13.5.3.
Safety ..........................................................................................45
13.5.4.
Pharmacokinetic ..........................................................................46
13.5.5.
Pharmacodynamic.......................................................................47
13.6.
Appendix 6: Reporting Standards for Missing Data.....................................49
13.6.1.
Premature Withdrawals................................................................49
13.6.2.
Handling of Missing Data.............................................................49
13.6.2.1.
Handling of Missing Dates..........................................49
13.6.2.2.
Handling of Partial Dates............................................50
13.7.
Appendix 7: Values of Potential Clinical Importance ...................................51
13.7.1.
ECG.............................................................................................51
13.7.2.
Vital Signs....................................................................................51
 
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13.8.
Appendix 8: Model Checking and Diagnostics for Statistical 
Analyses.....................................................................................................52
13.8.1.
Statistical Analysis Assumptions..................................................52
13.8.2.
Dose Proportionality ....................................................................52
13.9.
Appendix 9: Abbreviations & Trade Marks ..................................................54
13.9.1.
Abbreviations...............................................................................54
13.9.2.
Trademarks .................................................................................55
13.10. Appendix 10: List of Data Displays..............................................................56
13.10.1. Data Display Numbering..............................................................56
13.10.2. Mock Example Shell Referencing ................................................57
13.10.3. Deliverables.................................................................................57
13.10.4. Table of Contents of Data Display ...............................................58
13.10.4.1. Study Population Tables.............................................58
13.10.4.2. Efficacy Tables...........................................................59
13.10.4.3. Efficacy Figures..........................................................60
13.10.4.4. Safety Tables .............................................................62
13.10.4.5. Safety Figures ............................................................66
13.10.4.6. Pharmacokinetic Tables .............................................67
13.10.4.7. Pharmacokinetic Figures ............................................68
13.10.4.8. ICH Listings................................................................70
13.10.4.9. Non-ICH Listings ........................................................73
13.11. Appendix 11: Bayesian Modelling Details ...................................................76
13.11.1. PROC MCMC Parameters Settings and Validation......................76
13.11.2. MCMC Mixing Diagnosis..............................................................77
 
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1.
INTRODUCTION
The purpose of this reporting and analysis plan (RAP) is to describe the analyses to be 
included in the Clinical Study Report for Part 2 of Protocol 205670:
GlaxoSmithKline 
Document Number
Date
Version
2016N277028_00
2016-JUN-21
Original
2016N277028_01
2017-FEB-21
Amendment No. 1
Reasons for the Amendment: To update the subject population in Part 2 from treatment 
naïve to treatment experienced. To increase the maximum total monthly dose in Part 2 
from 240 mg to 480 mg. To reduce complexity and visit burden for subjects. To make 
minor edits for clarity.
2016N277028_02
2017-MAR-03
Amendment No. 2
Reasons for the Amendment: To include patients with ALT less than 5x upper limit of 
normal. To make minor edits for clarity. [Rationale: see Appendix 7]
2016N277028_03
2017-MAR-07
Republishing
Reasons for the Republishing: Protocol title of the published amendment did not match 
the original (2016-JUN-21) protocol title and was corrected. 
2016N277028_04
2017-JUN-28
Amendment No. 3
Reasons for the Amendment: To reduce sample size from 8 subjects (6 active:2 placebo) 
to 4 subjects (3 active:1 placebo) in Part 1. To update the subject population in Part 1 to 
allow inclusion of subjects on nucleos(t)ide therapy and hepatitis B virus e-antigen 
(HBeAg) negative patients into Cohorts A, B, C and D. To remove the requirement for a 
minimum viral load at entry for treatment naïve subjects or subjects that have had prior 
treatment with interferon or nucleosides in Part 1. To update the subject population in 
Parts 1 and 2 to include women of child bearing potential. To update the subject 
population in Parts 1 and 2 to include patients with GFR 60 mL/min after consultation 
with the GSK medical monitor.  To update the overall design and types/numbers of 
subjects that will be enrolled given the addition of an optional Japanese Part 2 sub-study. 
To reduce complexity and visit burden for subjects. To provide information from the 
results of the GSK3389404 first-in-human study 202007. To provide corrections to the 
statistical simulations. To provide minor edits for clarity and typographical errors.
2016N277028_05
2017-OCT-21
Amendment No. 4
To remove females of reproductive potential for Part 1 of study 205670 based on 
feedback from South Korea MFDS. To provide edits for clarity.
 
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GlaxoSmithKline 
Document Number
Date
Version
2016N277028_06
2018-MAR-06
Amendment No. 5
To update the protocol to include the treatments for Part 2. To include an optional 
additional 9 month off-treatment follow up period. To provide updates to the pre-clinical 
and clinical data. To include management review of un-blinded data. To provide updates 
to the statistical sections. To provide edits for clarity.
2016N277028_07
2018-JUN-13
Amendment No. 6
To correct the planned study duration for subjects. To allow inclusion of subjects with 
ALT 2xULN. To add greater clarity for exclusions 4, 8g, 9, and 11. To provide next 
steps for determining follow-up visit schedules for subjects who meet treatment stopping 
criteria, but are not withdrawn from the study.  To update the Time and Events Table for 
the optional follow-up period. To update the unblinded management review. To 
differentiate between final follow up visits Day 169 or Day 450 (if subjects consent to the 
optional extended follow-up period). To make edits for clarity
Overview
Key Elements of the RAP
Purpose

This reporting and analysis plan (RAP) details planned analyses for Part 2 of 
a clinical study report for study 205670 which will be used to support the 
regulatory submissions for the treatment of subjects with chronic Hepatitis B
(CHB).  
Protocol

This RAP is based on the protocol amendment number 6 [(Dated: 2018-JUN-
13) of study 205670 (GSK Document No.: 2016N277028_07)].
Primary 
Objectives

To assess the safety, tolerability, and PK profile of GSK3389404 in multiple 
(Part 2) administration in subjects with CHB.

To identify one or more efficacious dose(s) and dosing regimen(s) of 
GSK3389404 over a planned duration of 3 months (Part 2).
Primary 
Endpoints

Safety and Tolerability 
As measured by clinical assessments including, but not limited to

Vital signs

Physical examinations

12-lead electrocardiograms (ECGs)

Laboratory measurements (hematology, clinical chemistry, 
coagulation parameters, complement and urinalysis)

Adverse events (AEs), serious adverse events (SAEs), 
discontinuations
 
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Overview
Key Elements of the RAP

Efficacy
Response rate (RR) based on the proportion of subjects with at least a 
1.5 times log 10 IU/mL reduction of hepatitis B surface antigen (HBsAg) 
levels from baseline anytime during the study (part 2).
Secondary 
Endpoint

Pharmacodynamic:
Correlation between GSK3389404 PK parameters and PD parameters, 
including hepatitis B virus (HBV) deoxyribonucleic acid (DNA, as 
appropriate), HBsAg, and HBeAg levels (as appropriate, HBeAg-positive 
subjects).

Pharmacokinetic:
GSK3389404 and ISIS 505358 plasma concentrations (Part 2).
Derived GSK3389404 and ISIS 505358 plasma PK parameters for Japan-
enrolled Japanese sub-study (JSS) subjects including, but not limited to 
area under the concentration-time curve (AUC), maximum observed 
concentration (Cmax), time of maximum observed concentration (tmax), 
terminal half-life (t½), and apparent subcutaneous plasma clearance 
(CL/F).
Study 
Design

Part 2 will be conducted as a randomized, double-blind, placebo-controlled, 
multiple-dose, dose-ranging study. Subjects will be randomized to the 
following dose levels and regimens or placebo. The dose levels and regimens 
for Part 2 are selected after review of safety (at a minimum of adverse events 
[AEs], laboratory chemistry, hematology, and electrocardiogram [ECG]), PK, 
and PD (HBsAg levels and HBV DNA) data from Part 1 (through Day 3) but 
will not exceed a total monthly SC dose of 480 mg.
o
60 mg at weekly
o
120 mg at bi-weekly
o
120 mg at weekly
In Part 2, safety data from a sentinel group (1 subject from each active 
treatment group and the corresponding matching placebo) will be reviewed by 
the GlaxoSmithKline (GSK) internal clinical team or Safety Review Team 
(SRT) in a blinded manner. Randomization for the remainder of subjects in 
Part 2 will continue after safety data from at least 2 weeks of exposure in the 
sentinel group are reviewed. Safety data from all subjects will be reviewed by 
the GSK internal clinical team or SRT in a blinded manner on a regular basis 
thereafter.

A Japanese sub-study was included in Part 2. Subjects will be randomized to 
the following dose levels and regimens or placebo.
 
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Overview
Key Elements of the RAP
o
30mg at weekly
o
60 mg at weekly
o
120 mg at bi-weekly
o
120 mg at weekly

Since this is the first administration of GSK3389404 in subjects with CHB, the 
study design may change based on emerging data (safety, tolerability, and 
PD) from each cohort and/or part.
Planned 
Analyses

In Part 2, the primary analysis will be conducted once the last randomized 
subject in the sentinel group and remainder of subjects have completed the 
Day 85 visit. Treatment assignment will be unblinded for subjects included in 
the analysis. The results of this analysis will be used to characterize safety, 
tolerability and identify efficacious dose and dosing regimen of GSK3889404.

The end of study analysis for Part 2 will be conducted once the last 
randomized subject (sentinel, remainder of subjects, and the optional 
Japanese Part 2 sub-study subjects if applicable) has completed the Day 450 
visit.
Analysis 
Populations

All Subjects Screened Population

Safety Population

Pharmacokinetic Population

Pharmacodynamic Population

Intent-to-Treat (ITT) Population
Hypothesis

One of the primary objectives of Part 2 of this study is to select the 
efficacious dose level and dosing regimen of GSK3389404 as determined by 
the primary endpoint, response rate (RR), based on reduction of HBsAg level 
from baseline. A subject will be considered a responder if there is at least a 
1.5 times log 10 IU/mL reduction of HBsAg levels from baseline anytime 
during the study. A model based probability inference approach in Bayesian 
framework will be used for decision-making as the primary efficacy analysis. 
An active treatment group will be declared efficacious if the posterior 
probability that the difference in the RRs between that active group and the 
placebo is positive, is high (at least 95%), i.e. 
, where 
is the RR in the active group, 
is the RR in the placebo group, and P is the posterior probability.
Primary 
Analyses

Safety
Safety and tolerability parameters (AEs/SAEs, physical exams, vital signs, 
12-lead ECGs, and clinical laboratory measurements) will be listed by 
subject and summarized descriptively by treatment group and HBeAg 
status in tabular or graphical formats, as appropriate.
 
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Overview
Key Elements of the RAP
Exposure to study treatment as the number of doses administered will be 
presented for each treatment group for Part 2.

Efficacy
The RR data will be analyzed using a dose-response model. The 
posterior mean for each active treatment group will be derived from the 
posterior distribution of the response rates using a 3-parameter logistic 
regression model using weakly-informative priors for model parameters. 
Estimates for this model’s parameters will be derived using the data 
generated within each treatment arm, i.e., this model will borrow 
degrees of freedom across active dose levels and regimens therefore 
providing higher power compared to pair-wise comparisons given the 
small sample size of each treatment arm.
A Bayesian logistic regression model (BLRM) (Neuenschwander, 2008)
is considered to find an efficacious dose in this study.
The primary efficacy analysis of Part 2 will be performed after all ongoing 
subjects in Part 2 complete the Day 85 visit. At that time the database 
will be unblinded. Other primary analyses as mentioned above will also 
be performed. The end of study analysis will be performed after all 
ongoing subjects in Part 2 complete the Day 450 visit.
Secondary 
Analyses

Pharmacodynamics
Pharmacodynamic data (HBsAg, HBeAg, and HBV DNA) will be listed by 
subject and summarized descriptively by treatment group/HBeAg status 
in tabular and graphical formats, as appropriate.
Correlations between PD data in HBeAg-positive and HBeAg-negative 
subjects will be explored graphically. 

Pharmacokinetics (ISIS 505358)
GSK3389404 and ISIS 505358 plasma concentration-time data will be 
listed by subject and summarized descriptively by treatment group and 
HBeAg status in tabular and graphical formats.
GSK3389404 and ISIS 505358 PK parameters for the Japan-enrolled 
JSS subjects will be derived from the concentration-time profiles using 
WinNonlin. The derived PK parameters, including but not limited to 
AUC(0-24), AUC(0-∞), Cmax, tmax, and t½, will be listed by subject and 
summarized by treatment group and HBeAg status. Summaries may 
also combine treatment groups as applicable.
Other
Analyses

Subject disposition, demographics, medical history, prior and concomitant 
medications, and study treatment exposure will be listed by subject and 
summarized descriptively for each part of the study separately.

Response will also be measured based on change from baseline in HBeAg 
 
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Overview
Key Elements of the RAP
level in HBeAg-positive subjects. Change from baseline will be summarized 
by treatment group and listed by subject and treatment group for each part of 
the study separately.
 
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2.
SUMMARY OF KEY PROTOCOL INFORMATION
2.1.
Changes to the Protocol Defined Statistical Analysis Plan
There were no changes or deviations to the planned statistical analysis specified in the 
protocol [(Dated: 2018-JUN-13)].
2.2.
Study Objective(s) and Endpoint(s)
Objectives
Endpoints
Primary Objectives
Primary Endpoints

To assess the safety, tolerability, and 
PK profile of GSK3389404 in multiple 
(Part 2) administration in subjects with 
CHB.

Safety and Tolerability 
As measured by clinical assessments including, but 
not limited to
o
Vital signs
o
Physical examinations
o
12-lead electrocardiograms (ECGs)
o
Laboratory measurements (e.g., chemistry, 
hematology)
o
Adverse events

Pharmacokinetic Profile:
Derived GSK3389404 plasma PK parameters 
including, but not limited to area under the 
concentration-time curve (AUC), maximum observed 
concentration (Cmax), time of maximum observed 
concentration (tmax), terminal half-life (t½), and 
apparent subcutaneous plasma clearance (CL/F).

To identify one or more efficacious 
dose(s) and dosing regimen(s) of 
GSK3389404 over a planned duration 
of 3 months (Part 2).

Efficacy
Response rate (RR) based on the proportion of 
subjects with at least a 1.5 times log 10 IU/mL 
reduction of hepatitis B surface antigen (HBsAg) 
levels from baseline anytime during the study
Secondary Objectives
Secondary Endpoints

To assess the PD effect of 
GSK3389404 in subjects with CHB 
(Part 2).

Correlation between GSK3389404 PK parameters and 
PD parameters, including HBV DNA (as appropriate), 
HBsAg, and HBeAg levels (as appropriate, HBeAg-
positive subjects).

To investigate the PK of the 
metabolite of GSK3389404, also 
known as ISIS 505358, following 
single and multiple dose 
administration of GSK3389404 (Part 
2).

Derived ISIS 505358 plasma PK parameters including, 
but not limited to AUC, Cmax, tmax, and t½.
 
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Objectives
Endpoints
Exploratory Objectives
Exploratory Endpoints

To assess PD differences in HBeAg-
positive and HBeAg-negative subjects 
with CHB (Part 2, if applicable).

Correlation between PD parameters, including HBV DNA, 
HBV RNA, HBsAg, and/or hepatitis B core related antigen 
(HBcrAg).

To describe the seroconversion of 
patients, defined as presence of HBV 
surface antibody (HBsAb) (Part 2 
only)

Rate of seroconversion
 
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2.3.
Study Design
Overview of Study Design and Key Features
This is a Phase IIa, multicenter, randomized, double-blind (sponsor un-blinded in Part 1),
placebo-controlled 2-part study to assess the safety, tolerability, PK, and PD profiles of
GSK3389404 in subjects with CHB.
Part 2 will be conducted as a multiple-dose, dose-ranging study.

Subjects will be randomized to different parallel dose levels and regimens or placebo. 

A sentinel group will be dosed first and a safety review conducted before the remainder 
of subjects are dosed.

The following dose levels and regimens are selected for Part 2 main study:
o
60 mg at weekly
o
120 mg at bi-weekly
o
120 mg at weekly

The following dose levels and regimens are selected for Part 2 Japanese sub-study
(JSS):
o
30 mg at weekly
o
60 mg at weekly
o
120 mg at bi-weekly
o
120 mg at weekly
Figure 1
Part 2: Multiple Dose, Dose-Ranging, Study Design Schematic
1. HBeAg positive and negative subjects will be enrolled
2. Two separate randomization schedules will be used. One for the sentinel group and one to complete
enrollment of Part 2 subjects. Randomization for the remainder of subjects in Part 2 will continue after safety
data from at least 2 weeks of exposure in the sentinel group are reviewed.
 
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Overview of Study Design and Key Features
3. The sentinel group will consist of at least 1 active and 1 placebo subject per each dosing level and regimen.
Subjects enrolled in the sentinel group are dosed and followed per the Time and Events Tables. Safety data
from all subjects in the sentinel group will be reviewed (must be at least 2 weeks of expsosure, but may
include more data).
4. Matching placebo for each treatment arm (dose/regimen)
5. An optional Japanese Part 2 sub-study is planned. The exact details may be found in a country-specific
protocol amendment/supplement and will not be detailed here. The Japan sub-study may include more
intensive PK monitoring and/or potential overnight/hospital stay.
Dosing
Part 2, Multiple Dose and Dose ranging:

The dose levels and regimens for Part 2 will be selected after a review 
of Part 1 safety, but will not exceed a total monthly dose of 480 mg.

The following dose levels and regimens are selected for Part 2 main 
study:
o
60 mg at weekly
o
120 mg at bi-weekly
o
120 mg at weekly

The following dose levels and regimens are selected for Part 2 
Japanese sub-study (JSS):
o
30 mg at weekly
o
60 mg at weekly
o
120 mg at bi-weekly
o
120 mg at weekly
Treatment 
Assignment
Separate randomization schedules will be generated for each part of the study 
(Part 2 Sentinel, Part 2 Remainder, Part 2 JSS).
Part 2:

Sentinel group ratio: 1:1 for each active treatment group and the 
corresponding matching placebo

Remainder of the Part 2 subjects will be randomized in an 
approximately 10:1 ratio (active: placebo).

The overall randomization ratio of Part 2 will be an approximately 11:2 
ratio (active: placebo).

JSS will have separate randomization ratio
Analysis

In Part 2, the primary analysis will be conducted once the last 
randomized subject in the sentinel group and remainder of subjects 
have completed the Day 85 visit. Treatment assignment will be 
unblinded for subjects included in the analysis. The results of this 
analysis will be used to characterize safety, tolerability and identify 
efficacious dose and dosing regimen of GSK3889404.

If applicable, the analysis of the Japanese sub-study will be conducted 
once the last randomized Japanese subject has completed the Day 85 
and/or Day 169 visit. Treatment assignment for the optional Japanese 
sub-study will be unblinded. The analysis will be reported together with 
the Primary analysis. 

The 3 month follow up analysis for Part 2 will be conducted once last 
randomized subject has completed the Day 169 visit.
 
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Overview of Study Design and Key Features

The 6 month follow up analysis for Part 2 may be conducted once last 
randomized subject has completed the Day 270 visit to support internal 
decision making and/or regulatory interaction.
Rules for 
Safety 
Concern
Part 2:

A sentinel group will be dosed first. 

Safety data from the sentinel group (1 subject from each active 
treatment group and the corresponding matching placebo) will be 
reviewed (must be at least 2 weeks of exposure, but may include more 
data).

The safety review will be conducted by the GSK internal clinical team or 
Safety Review Team (SRT) in a blinded manner. 

Randomization for the remainder of subjects in Part 2 will continue after 
the review of safety data from at least 2 weeks of exposure in the all 
sentinel group subjects.
Type and 
Number of 
Subjects

Adult male and female subjects with CHB between18 and 70 years of 
age, inclusive, and not currently receiving CHB treatment are planned 
for inclusion.

In Part 2, approximately 39 subjects with CHB are planned for 
randomization to study treatment for the main study.

If Japan participates in the optional Japanese Part 2 sub-study, 
approximately 22 subjects may be enrolled.
2.4.
Statistical Hypotheses
One of the primary objectives of Part 2 of this study is to select the efficacious dose level 
and dosing regimen of GSK3389404 as determined by the primary endpoint, response 
rate (RR), based on reduction of HBsAg level from baseline. A subject will be considered 
a responder if there is at least a 1.5 times log 10 copies/mL reduction of HBsAg levels 
from baseline anytime during the study. A model based probability inference approach in 
Bayesian framework will be used for decision-making as the primary efficacy analysis. 
An active treatment group will be declared efficacious if the posterior probability that the 
difference in the RRs between that active group and the placebo is positive, is high (at 
least 90%), i.e. 
, where 
is the RR in the active group, 
is the RR in the placebo group, and P is the posterior probability.
3.
PLANNED ANALYSES
3.1.
Interim Analyses
No formal interim analysis is planned for Part 2. Safety data from a sentinel group will be 
reviewed by the GSK internal clinical team or Safety review team (SRT) in a blinded 
manner. Safety data from all subjects will be reviewed by the GSK internal clinical team 
or SRT in a blinded manner on a regular basis thereafter including a review when all 
subjects completed Day 28 visit. 
 
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A unblinded review of efficacy and safety is planned for project decision. The details of 
unblinded reviewed are included in the unblinded review charter. 
3.2.
Final Analyses
For below analysis, two sets of TLFs will be provided. There will be 

TLFs include data from subjects in main study and JSS (all subjects)

TLFs include data from subjects in JSS only (JSS)
3.2.1.
Part 2: Primary Analysis
In Part 2, the primary analysis will be conducted once the last randomized subject in the 
sentinel group and remainder of subjects have completed the Day 85 visit. Treatment 
assignment will be unblinded for subjects included in the analysis. The results of this 
analysis will be used to characterize safety, tolerability and identify efficacious dose and 
dosing regimen of GSK3889404.
3.2.2.
JSS Optional Analysis
The analysis of Japanese cohort will be conducted and reported together with the Primary 
analysis and 3 month follow up analysis. JSS analysis will be included in 6 month follow 
up analysis and end of study analysis if number of subjects warrant additional analysis. 
3.2.3.
Part 2: 3 month follow up Analysis
The 3 month follow up analysis for Part 2 will be conducted once last randomized subject 
has completed the Day 169 visit.
3.2.4.
Part 2: 6 month follow up Analysis
The 6 month follow up analysis for Part 2 may be conducted once last randomized 
subject has completed the Day 270 visit to support internal decision making and/or 
regulatory interaction.
3.2.5.
Part 2: End of Study Analysis
The end of study analysis for Part 2 will be conducted once the last subject participating 
in the optional follow-up has completed the Day 450 visit.
 
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4.
ANALYSIS POPULATIONS
Population
Definition / Criteria
Analyses Evaluated
All Subjects 
Screened 

The All Subjects Screened Population will 
include all subjects who consent to participate 
in the clinical trial.

The population will be defined separately for 
all subjects and JSS.

Screen failure 
summary.
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 (Reserve, Not Used) are excluded 
from the Enrolled population as they did not 
enter the study.

The population will be defined separately for 
all subjects and JSS.

Study population 
summary
Safety

Include all subjects who receive at least one 
dose of the study treatment (including 
placebo)

This population will be based on the 
treatment the subject actually received.

The population will be defined separately for 
all subjects and JSS.

Safety
Intent-To-Treat
(ITT)

Comprise of all randomized subjects.

This population will be based on the 
treatment to which the subject was 
randomized.

Any subject who receives a treatment 
randomization number will be considered to 
have been randomized.

The population will be defined separately for 
all subjects and JSS.

Efficacy

Study Population
Pharmacokinetic
(PK)

Include all subjects in the Safety population 
for whom at least one evaluable PK sample 
was obtained and analyzed.

PK samples that may be affected by protocol 
deviations will be reviewed by the study team 
and determined whether or not the sample 
will be excluded. 

The population will be defined separately for 
all subjects and JSS

PK
Pharmacodynamic
(PD)

Include all subjects in the Safety population 
who provide evaluable PD data.

PD
 
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Population
Definition / Criteria
Analyses Evaluated

The population will be defined separately for 
all subjects and JSS.JSS
4.1.
Protocol Deviations

Protocol deviations will be tracked by the study team throughout the conduct of the 
study in accordance with the Protocol Deviation Management Plan.
o
Data will be reviewed prior to unblinding and freezing the database to ensure all 
important deviations and deviations which may lead to exclusion from the 
analysis are captured and categorized on the protocol deviations dataset. 
o
This dataset will be the basis for the summaries and listings of protocol 
deviations.
5.
CONSIDERATIONS FOR DATA ANALYSES AND DATA 
HANDLING CONVENTIONS
5.1.
Study Treatment & Sub-group Display Descriptors
Treatment Group Descriptions for Part 2 All Subjects and Part 2 Japanese Sub-Study
Data Displays for Reporting 
Description
Placebo
GSK3389404 30mg Weekly
GSK3389404 60mg Weekly
GSK3389404 120mg bi-weekly
GSK3389404 120mg Weekly
All Active
Total
Placebo (HBeAg-)
GSK3389404 30mg Weekly (HBeAg-)
GSK3389404 60mg Weekly (HBeAg-)
GSK3389404 120mg Bi-Weekly (HBeAg-) 
GSK3389404 120mg Weekly (HBeAg-) 
All Active (HBeAg-)
Placebo (HBeAg+)
GSK3389404 30mg Weekly (HBeAg+) 
GSK3389404 60mg Weekly (HBeAg+) 
GSK3389404 120mg Bi-Weekly(HBeAg+)
GSK3389404 120mg Weekly (HBeAg+)
All Active (HBeAg+)
 
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5.2.
Baseline Definitions
For all endpoints (except as noted in baseline definitions) the baseline value will be the 
last value/assessment before the first dose of the study treatment (Day 1 pre-dose), 
including those from unscheduled visits. If there are multiple assessments collected at the 
same scheduled time (e.g., triplicate 12-lead ECGs), 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.
For hematology tests collected from local lab, actual time was not collected for Day 1
sample. However with site confirmation that the samples were drawn at the same timing 
as other blood draw for central lab, the central lab collected time will be used for the local 
lab records in order to decide if the record is eligible for baseline.
5.3.
Examination of Covariates, Other Strata and Subgroups
5.3.1.
Examination of Subgroups
The list of subgroups may be used in descriptive summaries and statistical analyses. 
Additional subgroups of clinical interest may also be considered.
If the percentage of subjects is small within a particular subgroup, then the subgroup 
categories may be refined prior to unblinding the trial.
Subgroup
Categories 
Baseline HBsAg
<=1000 or > 1000 IU/mL
Race
a.
Japanese or Non-Japanese
b.
Central/South Asian, East Asian, Japanese, South East Asian, 
Other
Country
China, Japan, South Korea, Hong Kong, Other
Gender
Male, Female
HBeAg Status
Positive or Negative
5.4.
Other Considerations for Data Analyses and Data Handling 
Conventions
Table 1 provides an overview of appendices within the RAP for outlining general 
considerations for data analyses and data handling conventions. 
Table 1
Overview of Appendices
Section
Appendix
RAP Section 5 : General Considerations for Data Analyses & Data Handling Conventions
Section 13.1
Appendix 1: Schedule of Activities
Section 13.2
Appendix 2: Assessment Windows
Section 13.3
Appendix 3: Study Phases and Treatment Emergent Adverse Events
 
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Section
Appendix
Section 13.4
Appendix 4: Data Display Standards & Handling Conventions

Reporting Process

Reporting Standards

Baseline Definition & Derivations
Section 13.5
Appendix 5: Derived and Transformed Data

General

Study Population

Safety

Pharmacokinetic

Pharmacodynamic
Section 13.6
Appendix 6: Reporting Standards for Missing Data for Missing Data

Premature Withdrawals

Handling of Missing Data
Section 13.7
Appendix 7: Values of Potential Clinical Importance
Section 13.8
Appendix 8: Model Checking and Diagnostics for Statistical Analyses
Other RAP Appendices
Section 13.9
Appendix 9: Abbreviations & Trade Marks
Section 13.10
Appendix 10: List of Data Displays
Section 13.11
Appendix 11: Bayesian Modelling Details
6.
STUDY POPULATION ANALYSES
6.1.
Overview of Planned Study Population Analyses
The study population analyses will be based on the ITT population, unless otherwise 
specified.
Study population analyses including analyses of subject’s disposition, protocol 
deviations, demographic and baseline characteristics, prior and concomitant medications, 
and exposure and treatment compliance will be based on GSK Core Data Standards. 
Table 2 provides an overview of the planned study population analyses, with full details 
of data displays being presented in Appendix 10: List of Data Displays.
Table 2
Overview of Planned Study Population Analyses
Display Type
Data Displays Generated
Table
Figure
Listing
Randomization
Randomization
Y
Subject Disposition
Number of Subjects Enrolled by Country and Site
Y
Subject Disposition
Y
Screen Failures
Y
Y
Reason for Withdrawals
Y
 
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Display Type
Data Displays Generated
Table
Figure
Listing
Important Protocol Deviations
Y
Y
Demography
Demographics 
Y
Y
Baseline Disease Characteristics 
Y
Y
Race & Racial Combinations
Y
Y
Age Ranges
Y
Subjects Excluded from Study Populations
Y
Medical Condition & Concomitant Medications
Past/Current Medical Conditions
Y
Y
Concomitant Medications
Y
Y
Baseline Nucleos(t)ide Use
Y
Y
NOTES :

Y = Yes display generated.
6.1.1.
Disposition and Withdrawals
All subjects who provide informed consent will be accounted for in this study. In each 
study part, subject disposition will be tabulated for each study treatment and for all 
subjects combined with the number of subjects who complete the study, prematurely 
discontinue, and the reason (primary and secondary, if available) for early 
discontinuation. Summaries will also be provided for number of subjects enrolled by site, 
reasons for screen failure and important protocol deviations.
Listings of inclusion/exclusion criteria deviations, reasons for screen failure, early 
withdrawal, treatment randomization, important protocol deviations and study treatment 
administration will be provided for each study part.
6.1.2.
Demographic and Baseline Characteristics
Individual subject demographics, race and racial combinations, age ranges and subjects 
excluded from study populations will be presented in listings for each study part.  
Demographic characteristics such as age, sex, race, ethnicity, child bearing potential, 
height, weight, and body mass index (BMI) will be summarized and tabulated by
treatment and for all subjects overall for each study part. Descriptive statistics will be 
presented for age, height, weight, and BMI. Frequency counts and percent will be 
presented for age category, sex, race, ethnicity and child bearing potential.
Other baseline characteristics include but not limited to drug/alcohol use, HIV, HDV and 
hepatitis C information at screening, quantitative HBsAg and quantitative HBV DNA, 
HBeAg status [], HBeAg level, and ALT level [x ULN]. 
6.1.3.
Prior and Concomitant Medications
Prior and Concomitant medications will be coded using GSK Drug coding dictionary, 
summarized, and listed for each study part using generic term, verbatim text, and 
indication. The summary of prior and concomitant medications will show the number and 
 
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percentage of subjects taking prior and concomitant medications and corresponding 
Anatomical Therapeutic Chemical (ATC) classification Level 1 (Body System) 
information.
Please refer to Appendix 1 for definition of prior, concomitant and post-treatment 
medications. Handling of partial dates for medications is outlined in Appendix 6:
Reporting Standards for Missing Data.
6.1.4.
Medical History and Current Medical Conditions
Medical history and current medical conditions will be summarized and display the 
number and percentage of subjects for each body system.
6.1.5.
Treatment Exposure
Treatment exposure will be summarized for Part 2 subjects. Summary includes duration 
of treatment, the number of doses administered and total volumes of doses. Dose 
administration for all subjects Part 2 will be displayed in the listing.
 
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7.
EFFICACY ANALYSES
7.1.
Primary Efficacy Analyses
The primary efficacy objective (Part 2 only) is to select an efficacious dose level and 
dosing regimen of GSK3389404 as determined by the primary endpoint RR.
7.1.1.
Endpoint / Variables
The primary efficacy analyses endpoint is response rate (RR) where response is based on 
reduction of HBsAg level from baseline. A subject will be considered a responder if there 
is at least 1.5 log 10 IU/mL reduction of HBsAg levels from baseline (i.e., less or equal to 
10-1.5 (or 3.16%) of baseline value) anytime during the study. If subject has no post-
baseline assessment of HBsAg levels, subject will be considered a non-responder.
For different analysis in Section 3.2 Final Analyses, responses will be evaluated based on 
HBsAg level within corresponding efficacy visit windows:
-
Primary analysis: (baseline, day 85 + 4 (day89)]
-
3m FU analysis: (baseline, day 169 + 51 (day 220)]
-
6m FU analysis: (baseline, day 270 + 45 (day 315)]
-
End of Study analysis: anytime post-baseline
If all HBsAg assessments are missing in the above efficacy visit windows, the subject 
will be imputed as a non-responder for the corresponding analysis window. For 
categorical HBsAg data (i.e. responder or failure), if a data point is missing and is 
preceded (-2 week) and followed (+2 week) in time by values that are “< 0.05” then the 
missing data point is set to “< 0.05”; otherwise the data point was considered a failure (ie, 
≥ 0.05).
7.1.2.
Population of Interest 
The primary efficacy analyses will be based on the ITT population, unless otherwise 
specified.
7.1.3.
Statistical Analyses / Methods
Details of the planned displays are provided in Appendix 10: List of Data Displays and
will be based on GSK data standards and statistical principles.
Unless otherwise specified, endpoints / variables defined in Section 7.1.1 will be 
summarised using descriptive statistics, graphically presented (where appropriate) and 
listed.
 
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7.1.3.1.
Statistical Methodology Specification
Endpoint(s)

Response Rate (RR) 
Model Specification

The primary efficacy objective is only for Part 2 on ITT population.

Bayesian logistic regression model (BLRM) (Neuenschwander, 2008) will be used for dose-
response. The posterior mean for each active treatment group will be derived from the 
posterior distribution of the response rates using a 3-parameter logistic regression model using 
weakly-informative priors for model parameters.

Response is based on reduction of HBsAg level from baseline. A subject will be considered a 
responder if there is at least 1.5 times log 10 IU/mL reduction of HBsAg levels from baseline 
(i.e., less or equal to 10-1.5 (or 3.16%) of baseline value) anytime during the study. If subject 
has no post-baseline assessment of HBsAg levels, subject will be considered a non-responder.

For dose 
and regimen
, the number of subjects with a response 
in a treatment 
arm of size 
is binomial. Therefore 
, with RR:
,
Where 
is the response rate for active treatment group with dose 
(total dose per 4 
weeks) and regimen 
(
for regimen ‘bi-weekly’ and 
for regimen ‘weekly’); 
= 480 mg is a reference dose allowing for the interpretation of 
as the odds of a 
response at 
; 
is the change in the log-odds of a response by a unit increase in log-dose; 
is the change in the log-odds of a response due to change in regimen. 

Weakly informative priors are assumed:

Posterior distribution of response rates of active treatment arms will be generated using BLRM.

Posterior distribution of response rates of placebo arm will be generated separately from a 
Beta distribution using highly entropic prior, i.e., Beta (0.1, 0.1), since it is not expected to have 
any responder in the placebo arm. Placebo injections will be given in different dosing regimens 
for the purpose of maintaining the blind. However, all placebo subjects across dosing regimens 
will be combined in 1 group for analysis, since no difference in RR is expected if placebo is 
administered in different dosing regimens.

In Part 2, GSK3389404 treatment efficacy will be declared if the posterior probability that the 
difference in the RRs between that active group and the placebo is positive and is high (at 
least 90%), i.e.,
where 
is the RR in active group, 
is the RR in placebo, and P is the posterior probability.
Model Results Presentation

Number of responders, posterior mean and 95% equal-tail credible interval of the RR will be 
reported by each treatment arm and placebo. For each treatment arm, the corresponding 
will also be reported. All data relating to responses will be listed 
(including baseline HBsAg levels and minimum post-baseline HBsAg levels).

Actual values and change from Baseline values of HBeAg level will be summarized by 
scheduled assessment and for worst case.
 
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Sensitivity and Supportive Analyses

A supportive analysis will also be performed using pair-wise comparison in Bayesian 
framework using the same criteria as mentioned above. For pair-wise model, the RR 
regardless active or placebo, will have the following model:
where 
has the following prior:

Besides BLRM model and pair-wise comparison results under NRI, both models will also be 
run for observed case for sensitivity analysis. 

To support analysis on RR, HBsAg value, change from baseline and proportion of subjects 
achieving 1.5 log decline will be summarized by visit window as shown below:
Visit ID
Nominal Day
Lower Limit Upper Limit
Baseline
1
Day 8
8
2
11
Day 15
15
12
18
Day 22
22
19
25
Day 29
29
26
32
Day 36
36
33
39
Day 43
43
40
46
Day 50
50
47
53
Day 57
57
54
60
Day 64
64
61
67
Day 71
71
68
74
Day 78
78
75
81
Day 85
85
82
88
Day 92
92
89
95
Day 99
99
96
106
Day 113
113
107
127
Day 141
141
128
155
Day 169
169
156
220
Day 270
270
221
315
Day 360
360
316
405
Day 450
450
406
Last visit day
If there are two or more values within a time window, the record with smallest values for that 
window will be used. 
 
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7.2.
Secondary Efficacy Analyses
The secondary efficacy analyses will be based on the ITT population, unless otherwise 
specified.
Pharmacodynamic data (HBsAg, HBeAg, HBV DNA) will be listed by subject and 
summarized descriptively by treatment group/HBeAg status in tabular and graphical 
formats, as appropriate. Analysis of HBV RNA and HBcrAg will be provided in a 
separate RAP. 
Nadir, Time to Nadir, and Change from Baseline to Nadir of HBsAg and HBeAg will be 
listed summarized by treatment group and HBeAg status as appropriate. 
Correlations between HBsAg in HBeAg-positive and HBeAg-negative subjects will be 
explored graphically. 
Correlations between individual PD data for HBsAg and data for ALT will be explored 
graphically.
Table 3 provides an overview of the planned pharmacodynamic analyses, with full details 
of data displays being presented in Appendix 10: List of Data Displays.
Table 3
Overview of Planned Pharmacodynamic Analyses
[Endpoint / Parameter/ 
Display Type]
Untransformed
Absolute
Change from Baseline
Stats 
Analysis
Summary
Individual
Stats 
Analysis
Summary
Individual
T
F
L
T
F
F
L
T
F
L
T
F
F
L
HBsAg Values
Y
Y
[1]
Y
Y
Y
[1]
Y
HBeAg Values
Y
Y
[1]
Y
Y
Y
[1]
Y
HBV DNA Values
Y
HBsAg Nadir, time to Nadir 
and change from baseline to 
Nadir, 
Y
HBeAg Nadir, time to Nadir 
and change from baseline to 
Nadir
Y
Y
Correlations between HBsAg
HBeAg-positive and HBeAg-
negative subjects
Y
Correlations between HBsAg, 
HBV DNA, HBeAg, and ALT 
data
Y
Y
Y
 
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NOTES:

T = Table, F = Figure, L = Listing, Y = Yes display generated.

Stats Analysis = Represents TFL related to any formal statistical analyses (i.e. modelling) conducted.

Summary = Represents TFL related to any summaries (descriptive statistics) of the observed raw data.

Individual = Represents FL related to any displays of individual subject observed raw data.
1.
Separate Mean (+ SD) and Median plots will be generated.
7.3.
Exploratory Efficacy Analyses
For Part 2, the rate of seroconversion will be analyzed based on ITT population. The 
seroconversion is defined as presence of HBV surface antibody (HBsAb) (>= 10 IU/L)
and HBsAg seroclearance (defined as HBsAg < 0.05 IU/mL),. Number of subject with 
seroconversion and the 95% confidence interval of the rate will be reported by each 
treatment arm and placebo.
8.
SAFETY ANALYSES
The safety analyses will be based on the “Safety” population for each study part, unless 
otherwise specified.
8.1.
Exposure to Study Treatment
Exposure to study treatment including the compliance of the number of doses 
administered and duration of exposure will be presented for each treatment group for Part 
2. A dose is defined as one planned administration of the study drug (e.g. two injections 
in the same visit is considered as one dose). Dose administration for Part 2 will also be 
displayed in separate listings.
The planned number of dose administered is determined by the subjects’ arm regimen 
(i.e. 6 for Bi-weekly, and 12 for weekly across 12-week treatment). If the subject 
terminated the study early, his planned number of dose administered is calculated by
-
If weekly dose regimen: floor [(end of study date – first dose date)/7] + 1
-
If Bi-weekly dose regimen: floor [(end of study date – first dose date)/14] + 1
The compliance of the number of doses administered will be summarized by categories: 
‘< 75%’, ’75 - < 100%’ and ‘100%’.
8.2.
Adverse Events Analyses
Adverse events will be coded using MedDRA version 18.1. The AEs will be summarized 
by frequency and percentage of the subjects in safety population and will be sorted by 
System Organ Classes (SOC) in descending order for the total group, secondly by 
Preferred Term (PT) in descending order for the total group. Adverse events will be 
summarized in various subsets, including treatment-emergent AEs (TEAEs) by maximum 
causality, by maximum intensity, leading to treatment discontinuation and SAEs.
A TEAE is defined as an AE with start date between the first dose date of the study 
medication until the follow-up visit. Any AE starting before the first dose date or after the 
 
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follow-up visit will not be included in any summary analyses but will be displayed in the 
listings.
Adverse event severity is classified as mild (grade = 1), moderate (grade = 2), severe 
(grade = 3), potentially life threatening (grade = 4) or resulting in death (grade = 5). 
Adverse events starting after the first dose of study medication with a missing severity 
will be classified as severe. If a subject reports an adverse event more than once within 
that system organ class (SOC)/ preferred term (PT), the AE with the worst case severity 
will be used in the corresponding severity summaries.
Relationship to study medication, as indicated by the Investigator, is classified as “not 
related” or “related”. Adverse events with a missing relationship to study medication will 
be regarded as “related” to study medication. If a subject reports the same AE more than 
once within that SOC/ PT, the AE with the worst case relationship to study medication 
will be used in the corresponding relationship summaries.
All AE tabulations will be performed by treatment and maximum grade and will include 
the number and percentage of subjects.  For each study part, incidence of AEs will be 
tabulated by SOC, PT and maximum grade. 
All AEs leading to withdrawal from study will be identified by using the variable 
pertaining to outcome of the Adverse Events page of the (e)CRF, and listed separately for 
each study part.
Serious adverse events (SAEs), including deaths, are those events recorded as “Serious” 
on the Adverse Events page of the (e)CRF, and will be listed separately for each study 
part.
Listing of various adverse events experienced by individual subjects and relationship 
between SOC and verbatim text will be provided for each study part.
AEs will be graded by the clinic using the DAIDS Table for Grading the Severity of 
Adult and Paediatric Adverse Events (National Institute of Allergy and Infectious 
Diseases) as defined in the following link:
Division of AIDS (DAIDS) Table for Grading the Severity of Adult and Pediatric 
Adverse Events, Version 2.0, November 2014
For completely missing or partial missing AE start date or end date, imputation rules will 
be applied following Appendix 6.
8.3.
Vital Signs
Vital signs will be measured after 5 minutes of rest in the semi-supine or supine position. 
Temperature and respiration rate will be collected as single measurements. 
Vital sign data, as well as change from baseline, will be summarized for each parameter 
by scheduled assessment.  
 
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Vital signs (blood pressure, heart rate, temperature, and weight) will also be listed for 
each subject.  
The number and percentage of subjects out of clinical concern range will be also 
presented in a summary table.
8.4.
Injection Site Reactions
Injection site reactions will be reported as adverse events.
8.5.
12-lead electrocardiograms (ECGs)
The following ECG parameters will be reported for each study part (msec): PR, QRS, QT, 
QTc, QTcF and HR (bpm). All ECGs will be collected after 5 minutes of rest in the semi-
supine or supine position. Triplicate 12-lead ECGs will be obtained at the Screening visit 
and pre-dose on Day 1. Single 12-lead ECGs will be obtained at all other time points. The 
average of these assessments will be used as the baseline per Section 13.4.3.1. Also the 
average will be the representative of the subject at all other time points.
Summary tables including actual values and change from Baseline values will be 
presented for each ECG results by scheduled assessment.
An ECG outlier analysis will be performed showing the proportion of subjects out of 
clinical concern range. The overall interpretation of the ECG results (Normal; Abnormal; 
Not Clinically Significant; and Abnormal, Clinically Significant) will also be 
summarized.
8.6.
Laboratory Measurements
Central laboratory results will be included in the reporting of this study for hematology, 
clinical chemistry, complement factors and urinalysis.  
Protocol-specified clinical laboratory tests will be summarized using descriptive statistics.  
The statistics will be presented for baseline, as defined in Section 13.4.3.1, and change 
from baseline to each scheduled assessment. Presentations will use reported units, as 
provided by the labs. Based upon laboratory normal ranges, the laboratory test results 
will be categorized according to the normal range as low (below the lower limit), normal 
(within normal range) and high (above upper limit).
The protocol required parameters to be analyzed are as follows:

Hematology: Platelet count, RBC count (MCV, MCH), Hemoglobin, Hematocrit, 
Reticulocyte count, and WBC count with differential*: Neutrophils, 
Lymphocytes, Monocytes, Eosinophils, Basophils.

Clinical Chemistry: BUN, Creatinine, GFR, Uric acid, Glucose, Potassium, 
Sodium, Calcium, Phosphorous, Magnesium, AST, ALT, ALP, GGT, CPK, Total 
and direct bilirubin, Total protein, Albumin, hs-CRP.

Coagulation: INR, PT, aPTT

Complement: C3, C4, C5a, Bb
 
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*If WBC total count exist and either WBC differential absolute count or percentage exist 
for the same visit and date, then the other will be derived as below: 
-
Differential Count = WBC total count * differential %
-
Differential % = differential count/WBC total count
The normal range and normal indicator will be left blank. DAIDS grade will be derived 
for WBC differential count for both collected record and converted record.
Complement factors will be summarized using change between maximum level observed 
post-dose (considering all time points) and pre-study drug administration. Percent change 
relative to pre-study drug administration will be presented.
Clinical laboratory abnormalities will be graded based on the DAIDS Table for Grading 
the Severity of Adult and Paediatric Adverse Events (National Institute of Allergy and 
Infectious Diseases) will be applied to hematology, chemistry and urinalysis only. 
Abnormalities (DAIDS Grade 1 or higher) for individual subjects will be listed.
Separate summary tables for hematology, chemistry laboratory tests and urinalysis tests 
will be produced.
9.
PHARMACOKINETIC ANALYSES (GSK3389404)
9.1.
Overview of Planned Pharmacokinetic Analyses
This section documents the planned PK analysis for GSK3389404; PK analysis for the 
metabolite, ISIS 505358, is detailed in Section 10.1.
The PK analyses will be based on the “Pharmacokinetic” population, defined for main 
study (rest of world) and JSS subjects. Japanese subjects in the rest of world group of 
Part 2 will only be assigned to the main study (rest of world) PK population.
GSK3389404 plasma concentration-time data will be listed by subject and summarized 
descriptively by treatment group, dosage in once, and HBeAg status in tabular and 
graphical formats.
GSK3389404 PK parameters will be derived from the concentration-time profiles using 
WinNonlin for Day 1 data for the JSS subjects enrolled in Japan. The derived PK 
parameters will be listed by subject and summarized by treatment group, dosage in 
once,and HBeAg status. 
Table 4 provides an overview of the planned analyses, with full details being presented in
Appendix 10: List of Data Displays.
 
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Table 4
Overview of Planned Pharmacokinetic Analyses for GSK3389404
Endpoints
Untransformed
Log-Transformed
Stats Analysis
Summary
Individual
Stats Analysis
Summary
Individual
T
F
L
T
F
F
L
T
F
L
T
F
F
L
Plasma Drug 
Concentrations
Y
Y 
[1] 
[2]
Y 
[1]
Y
Derived PK 
Parameters
Y
Y
Y
Y
Y
NOTES :

T = Table, F = Figure, L = Listings, Y = Display generated.

Stats Analysis = Represents TFL related to any formal statistical analyses (i.e. modelling) conducted.

Summary = Represents TFL related to any summaries (i.e. descriptive statistics) of the observed raw data.

Individual = Represents FL related to any displays of individual subject observed raw data.
1.
Linear and Semi-Log plots will be created on the same display.
2.
Separate Mean (+ SD) and Median plots will be generated.    
9.2.
Drug Concentration Measurements
Refer to Appendix 5: (Derived and Transformed Data).
9.3.
Pharmacokinetic Parameters
9.3.1.
Deriving Pharmacokinetic Parameters

Refer to Appendix 5: (Derived and Transformed Data) for the treatment of 
concentrations below the assay’s lower limit of quantification (LLOQ).

The PK parameters will be calculated by standard non-compartmental analysis 
according to current working practices and using Phoenix WinNonlin® 6.4 or higher 
(Pharsight Corporation, a Certara Company, Princeton, NJ), and/or SAS® Version 9.3
or higher. Graphics will be prepared using the same version of SAS®.

All calculations of non-compartmental parameters will be based on actual sampling 
times.

Pharmacokinetic parameters described in Table 5 will be determined from the plasma 
concentration-time data, as data permits, for GSK3389404 on Day 1 for subjects 
enrolled in Japan in the JSS:

Dose-normalized Cmax and AUCs will be also calculated and will be summarized by 
treatment using descriptive statistics
 
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Table 5
Derived Pharmacokinetic Parameters (Part 2 – JSS)
ParameterParameter
Parameter Description
AUC(0-t)
Area under the concentration-time curve from time zero to the time of the last 
quantifiable concentration (ng·h/mL) will be calculated using the linear trapezoidal 
rule for each incremental trapezoid and the log trapezoidal rule for each decremental 
trapezoid.
AUC(0-∞)
Area under the concentration-time curve extrapolated to infinity (ng·h/mL) will be 
calculated by linear up/log down trapezoidal summation as: 
AUC = AUC(0-t) + C(t) / z
AUC(0-8)
Area under the concentration-time curve in the plasma from time zero to 8 
hours post-dose (ng·h/mL), calculated by linear up/log down trapezoidal 
summation.  Actual elapsed time at 8 hours post-dose will be used for the 
calculation.
AUC(0-24)
Area under the concentration-time curve in the plasma from time zero to 24 hours 
post-dose (ng·h/mL), calculated by linear up/log down trapezoidal summation.  
Actual elapsed time at 24 hours post-dose will be used for the calculation.
%AUCex
The percentage of AUC(0-∞) obtained by extrapolation (%). %AUCex will be calculated 
as:
[AUC(0-∞) – AUC(0-t)] / AUC(0-∞) x 100
Cmax
Maximum observed concentration in plasma (ng/mL), determined directly from the 
concentration-time data.
Tmax
Time to reach Cmax (h), determined directly from the concentration-time data.
T½
Apparent terminal half-life (h) will be calculated as: 
t½ = ln2 / z
z
Apparent terminal rate constant (1/h), determined by linear regression of the terminal 
points of the log-linear concentration-time curve.  Visual assessment will be used 
to identify the terminal linear phase of the concentration-time profile.  A minimum of 
3 data points will be used for determination.
Tlag
Lag time before observation of quantifiable concentrations in plasma (h), obtained 
directly from the observed concentration versus time data.
CL/F
Apparent plasma clearance after extravascular dosing (L/h), calculated as 
administered dose divided by AUC(0-∞).  No dose adjustments are needed for this 
calculation.  
Vz/F
Apparent plasma volume of distribution after extravascular dosing (L), calculated as 
CL/F divided by z.
NOTES:

Additional parameters, such as Lambda_z diagnostic parameters, may be included as required.
 
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9.3.2.
Statistical Analysis of Pharmacokinetic Parameters
The following pharmacokinetic statistical analyses will only be performed if sufficient 
data is available (i.e. if subjects have well defined plasma profiles). 
Pharmacokinetic Statistical Analyses
Endpoint(s)

All endpoints will be natural-log transformed prior to the analysis

Dose Proportionality: AUC(0-t), AUC(0-∞), and Cmax for JSS 
Model Specification

Dose Proportionality will be assessed separately by means of power model: Y=α∙Xβ using 
the least-squares linear regression model: [ln(Y) = α+ β∙ln(X)], where Y denotes the PK 
parameter being analyzed and X denotes dose. 
o
PK parameters will be log transformed prior to analysis
o
For single dosing, Day 1 data from JSS may be combined as appropriate
o
If the power model does not show dose proportionality then pairwise analysis of 
variance (ANOVA) may be used as an exploratory analysis to understand the dose 
where dose proportionality fails
Model Checking & Diagnostics

Refer to Appendix 8: Model Checking and Diagnostics for Statistical Analyses
Model Results Presentation

Dose Proportionality: The intercept α and the slope β with corresponding 90% CIs will be 
estimated and presented for each PK parameter
In addition, the PK-dose relationship will be investigated graphically in order to assess 
dose proportionality of GSK3389404 using AUC(0-t), AUC(0-∞), and Cmax by dosage in 
once. Graphs will show display either raw PK parameter values or dose-normalized 
values.
10.
SECONDARY STATISTICAL ANALYSES
10.1.
Overview of Planned Pharmacokinetic Analyses
The PK analyses of ISIS 505358 data will be based on the PK population and will follow 
that described for GSK3389404 (Section 9).
ISIS 505358 plasma concentration-time data will be listed by subject and summarized 
descriptively by treatment group, dosage in once, and HBeAg status in tabular and 
graphical formats.
ISIS 505358 PK parameters for subjects in the JSS enrolled in Japan will be derived from 
the concentration-time profiles using WinNonlin if data permit. The derived PK 
parameters will be listed by subject and, if appropriate, will be summarized by treatment 
 
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group and HBeAg status. Of note, CL/F and Vz/F will not be calculated for ISIS 505358 
(Table 5).
Dose proportionality analysis will be performed on ISIS 505358 PK parameter data, as 
data permit.
11.
EXPLORATORY STATISTICAL ANALYSES
11.1.
Overview of Planned PK/PD Analyses
For JSS subjects, correlation between PK parameters (AUC(0-∞) and Cmax) (Day 1) and 
PD parameters (Nadir, Time to Nadir, and Change from Baseline to Nadir) will be 
explored graphically.
11.2.
Overview of Planned PK Analyses by Race
GSK3389404 plasma PK exposure parameters (AUC(0-t), AUC(0-∞), and Cmax) will be 
compared between non-Japanese Asian subjects (Part 1), JSS, and healthy Caucasian 
subjects (FIH study 202007). Box plots paired with individual value scatter plots will be 
prepared for each PK parameter for the comparison of population. 
 
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12.
REFERENCES
Neuenschwander, B., Branson, M., & Gsponer, T. (2008). Critical aspects of the 
Bayesian approach to Phase I cancer trials. Statistics in Medicine, 27:2420-39.
Brooks, S., Gelman, A. (1998). General Methods for Monitoring Convergence of 
Iterative Simulations. Journal of Computational and Graphical Statistics, Volume 7, 
Number 4, Pages 434–455.
GlaxoSmithKline Document Number 2016N277028_07, A Double-Blind, Placebo-
Controlled Study to Assess the Safety, Tolerability, Pharmacokinetics and 
Pharmacodynamics of Single Ascending Dose and Multiple Doses of GSK3389404 in 
Chronic Hepatitis B Subjects. 2018.
 
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13.
APPENDICES
13.1.
Appendix 1: Schedule of Activities
13.1.1.
Protocol Defined Schedule of Events
 
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13.2.
Appendix 2: Assessment Windows
13.2.1.
Definitions of Assessment Windows for Analyses
For different analysis in Section 3.2 Final Analyses, responses will be evaluated based on 
HBsAg level within corresponding efficacy visit windows:
-
Primary analysis: (baseline, day 85 + 4 (day89)]
-
3m FU analysis: (baseline, day 169 + 51 (day 220)]
-
6m FU analysis: (baseline, day 270 + 45 (day 315)]
-
End of Study analysis: anytime post-baseline
To support analysis on RR, HBsAg value, change from baseline and proportion of 
subjects achieving 1.5 log decline will be summarized by visit window as shown below:
Visit ID
Nominal Day
Lower Limit Upper Limit
Baseline
1
Day 8
8
2
11
Day 15
15
12
18
Day 22
22
19
25
Day 29
29
26
32
Day 36
36
33
39
Day 43
43
40
46
Day 50
50
47
53
Day 57
57
54
60
Day 64
64
61
67
Day 71
71
68
74
Day 78
78
75
81
Day 85
85
82
88
Day 92
92
89
95
Day 99
99
96
106
Day 113
113
107
127
Day 141
141
128
155
Day 169
169
156
220
Day 270
270
221
315
Day 360
360
316
405
Day 450
450
406
Last visit day
If there are two or more values within a time window, the value closest to the target day 
for that window will be used. If values are the same distance from the target, then the 
mean will be taken.
 
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13.3.
Appendix 3: Study Phases and Treatment Emergent 
Adverse Events
13.3.1.
Study Phases
Study Phase
Definition
Pre-Treatment 
Date < Study Treatment Start Date
On-Treatment
Study Treatment Start Date ≤Date ≤ Study Treatment Stop Date 
Post-Treatment
Date > Study Treatment Stop Date
13.3.2.
Treatment Emergent Flag for Adverse Events
Flag
Definition
Treatment 
Emergent

If AE onset date is on or after treatment start date & on or before follow up date 
(450 study day).

Study Treatment Start Date ≤ AE Start Date ≤ (450 study day).].
NOTES: 

If the study treatment stop date is missing, then the AE will be considered to be On-Treatment.

Time of study treatment dosing and start/stop time of AEs should be considered, if collected.
 
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13.4.
Appendix 4: Data Display Standards & Handling 
Conventions
13.4.1.
Reporting Process
Software
The currently supported versions of SAS software, R, WinBUGS and WinNonLin software will be used.
Reporting Area
HARP Server
us1salx00259
HARP Compound
GSK3389404
Analysis Datasets 

Analysis datasets will be created according to CDISC standards (SDTM IG Version 3.2 & ADaM IG 
Version 1.0

For creation of ADaM datasets (ADCM/ADAE), the same version of dictionary datasets will be 
implemented in SDTM.
Generation of RTF Files

RTF files will be generated.
13.4.2.
Reporting Standards
General
o
The current GSK Integrated Data Standards Library (IDSL) will be applied for reporting, unless 
otherwise stated (IDSL Standards Location: https://spope.gsk.com/sites/IDSLLibrary/SitePages/Home.aspx):
o
4.03 to 4.23: General Principles
o
5.01 to 5.08: Principles Related to Data Listings
o
6.01 to 6.11: Principles Related to Summary Tables
o
7.01 to 7.13: Principles Related to Graphics 
Formats
o
GSK IDSL Statistical Principles (5.03 & 6.06.3) for decimal places (DP’s) will be adopted for reporting of 
data based on the raw data collected, unless otherwise stated.
o
Numeric data will be reported at the precision collected on the eCRF.
o
The reported precision from non eCRF sources will follow the IDSL statistical principles but may be 
adjusted to a clinically interpretable number of DP’s. 
Planned and Actual Time
o
Reporting for tables, figures and formal statistical analyses:

Planned time relative to dosing will be used in figures, summaries, statistical analyses and 
calculation of any derived parameters, unless otherwise stated.

The impact of any major deviation from the planned assessment times and/or scheduled visit days 
on the analyses and interpretation of the results will be assessed as appropriate.
o
Reporting for Data Listings: 

Planned and actual time relative to study drug dosing will be shown in listings (Refer to IDSL 
Statistical Principle 5.05.1).

Unscheduled or unplanned readings will be presented within the subject’s listings. 
Unscheduled Visits
o
Unscheduled visits will not be included in summary tables and/or figures.
o
All unscheduled visits will be included in listings.
 
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Reporting of Pharmacokinetic Concentration Data
Descriptive 
Summary Statistics
Refer to IDSL Statistical Principle 6.06.1
Assign zero to NQ values (Refer to GUI_51487 for further details)
Descriptive Summary Statistics
Continuous Data
Refer to IDSL Statistical Principle 6.06.1
Categorical Data
N, n, frequency, %
Graphical Displays
o
Refer to IDSL Statistical Principals 7.01 to 7.13.
Reporting of Pharmacokinetic Parameters
Descriptive Summary 
Statistics
N, n, arithmetic mean, 95% CI of arithmetic mean, standard deviation (SD), 
%CV, median, minimum, and maximum.
Descriptive Summary 
Statistics (Log 
Transformed)
N, n, geometric mean, 95% CI of geometric mean, standard deviation (SD) 
of log-transformed data and between geometric coefficient of variation 
(CVb/w (%)) will be reported.
[1] CVb (%) = √ (exp(SD2) – 1) * 100
(SD = SD of log transformed data) 
Parameters Not 
Being Log 
Transformed
tmax, %AUCex, tlag, z, z lower, z upper, z no. of points, rsq
Listings
Interval, number of observations included in calculation of z, regression coefficient 
and percent AUC extrapolated (%AUCex)
13.4.3.
Baseline Definition & Derivations
13.4.3.1.
Baseline Definitions
For all endpoints (expect as noted in baseline definitions) the baseline value will be the
last value/assessment before the first dose of the study treatment (Day 1 pre-dose). If 
there are multiple assessments collected at the same scheduled time (e.g., triplicate 12-
lead ECGs), the average of these assessments will be used as the baseline.
13.4.3.2.
Derivations and Handling of Missing Baseline Data
Definition
Reporting Details
Change from Baseline
= Post-Dose Visit Value – Baseline
% Change from Baseline
= 100 x [(Post-Dose Visit Value – Baseline) / Baseline]
Maximum Change from Baseline
= Calculate the change from baseline at each given timepoint 
   and determine the maximum change
NOTES:

Unless otherwise specified, the baseline definitions specified in Section 13.4.3.1 Baseline Definitions will be used 
for derivations for endpoints / parameters and indicated on summaries and listings.

Unless otherwise stated, if baseline data is missing no derivation will be performed and will be set to missing.

The baseline definition will be footnoted on all change from baseline displays.
 
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13.5.
Appendix 5: Derived and Transformed Data
13.5.1.
General
Multiple Measurements at One Time Point
o
Mean of the measurements will be calculated and used in any derivation of summary statistics 
but if listed, all data will be presented.
o
If there are two values within a time window the value closest to the target day for that window 
will be used. If values are the same distance from the target then the mean will be taken.
o
Subjects having both High and Low values for Normal Ranges at any post-baseline visits for 
safety parameters will be counted in both the High and Low categories of “Any visit post-
baseline” row of related summary tables. This will also be applicable to relevant Potential 
Clinical Importance summary tables.
Study Day
o
Calculated as the number of days from randomization date:

Ref Date = Missing                       → Study Day = Missing 

Ref Date < Randomization Date   → Study Day = Ref Date – Randomization Date    

Ref Data ≥ Randomization Date   → Study Day = Ref Date – (Randomization Date) + 1  
13.5.2.
Study Population
Demographics
Age
o
GSK standard IDSL algorithms will be used for calculating age where birth date will be imputed 
as follows:
o
Any subject with a missing day will have this imputed as day ‘15’. 
o
Any subject with a missing date and month will have this imputed as ‘30th June’.
o
Birth date will be presented in listings as ‘YYYY’.
Body Mass Index (BMI)
o
Calculated as Weight (kg) / Height (m)2
Extent of Exposure
o
Number of days of exposure to study drug will be calculated based on the formula:  
Duration of Exposure in Days = Treatment Stop Date – (Treatment Start Date) + 1
o
Subjects who were randomized but did not report a treatment start date will be categorised as 
having zero days of exposure. 
o
The cumulative dose will be based on the formula:
Cumulative Dose = Sum of (Number of Days x Total Daily Dose)
o
If there are any treatment breaks during the study, exposure data will be adjusted accordingly.
Laboratory Parameters
o
If a laboratory value which is expected to have a numeric value for summary purposes, has a 
non-detectable level reported in the database, where the numeric value is missing, but typically 
 
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Laboratory Parameters
a character value starting with ‘<x’ or ‘>x’ (or indicated as less than x or greater than x in the 
comment field) is present, the number of significant digits in the observed values will be used to 
determine how much to add or subtract in order to impute the corresponding numeric value. 
o
Example 1: 2 Significant Digits = ‘< x ‘ becomes x – 0.01
o
Example 2: 1 Significant Digit   = ‘> x’ becomes x + 0.1
o
Example 3: 0 Significant Digits = ‘< x’ becomes x – 1    
13.5.3.
Safety
ECG Parameters
RR Interval
o
IF RR interval (msec) is not provided directly, then RR can be derived as:
[1] If QTcB is machine read & QTcF is not provided, then:
[2] If QTcF is machine read and QTcB is not provided, then: 
o
If ECGs are manually read, the RR value preceding the measurement QT interval should be a 
collected value THEN do not derive.
Corrected QT Intervals
o
When not entered directly in the eCRF, corrected QT intervals by Bazett’s (QTcB) and 
Fredericia’s (QTcF) formulas will be calculated, in msec, depending on the availability of other 
measurements.
o
IF RR interval (msec) is provided then missing QTcB and/or QTcF will be derived as: 
Laboratory Parameters
o
If a laboratory value which is expected to have a numeric value for summary purposes, has a 
non-detectable level reported in the database, where the numeric value is missing, but typically 
a character value starting with ‘<x’ or ‘>x’ (or indicated as less than x or greater than x in the 
comment field) is present, the number of significant digits in the observed values will be used to 
determine how much to add or subtract in order to impute the corresponding numeric value. 
o
Example 1: 2 Significant Digits = ‘< x ‘ becomes x – 0.01
o
Example 2: 1 Significant Digit   = ‘> x’ becomes x + 0.1
o
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13.5.4.
Pharmacokinetic

Derived GSK3389404 plasma PK parameters including, but not limited to area under the 
concentration-time curve (AUC), maximum observed concentration (Cmax), time of maximum 
observed concentration (tmax), terminal half-life (t½), and apparent subcutaneous plasma 
clearance (CL/F).

Derived ISIS 505358 plasma PK parameters including, but not limited to AUC, Cmax, tmax, and t½.
PK Concentrations and Parameters
o
How to Handle Values below the Quantification Limit
For the calculation of individual pharmacokinetic profiles
If one or more non-quantifiable (NQ) values occur in a profile before the first measurable
concentration, they will be assigned a value of zero concentration. For linear plots, zero
concentration value(s) before the first measurable concentration will be included in the
plot. For semilogarithmic log-linear plots, zero concentration value(s) before the first 
measurable concentration will be assigned a missing value.
If a single NQ value occurs between measurable concentrations in a profile, the NQ
should generally be omitted (set to missing) in the derivation of pharmacokinetic
parameters, statistical analysis, and the individual subject plots.
If two or more NQ values occur in succession between measurable concentrations, the
profile will be deemed to have terminated at the last measurable concentration prior to
these NQs. For the purpose of individual subject plots, these NQs will be set to 0, and the
subsequent measurable concentrations will be retained. For the derivation of
pharmacokinetic parameters, these NQs and any subsequent measurable concentrations
will be omitted (set to missing).
NQs which occur after the last measurable concentration will be omitted (set to missing)
in the derivation of pharmacokinetic parameters and from the individual subject plots. In 
some circumstances, there may be a pharmacokinetic rationale for fluctuation resulting in 
non-measurable concentrations in the middle of the concentration-time profile (e.g.,
entero-hepatic recycling, erratic absorption from transdermal/inhaled formulations). In
these cases, the NQ values could be set to missing or to some other values (e.g., ½ LLQ)
and subsequent valid concentrations may be retained. A reference line indicating LLQ
would then be included in plots.
For the calculation of mean or median pharmacokinetic profiles
When estimating the mean or median value for the concentration at a given time point
(i.e., descriptive mean or median curve), the following guidelines should be considered:
All NQ values will be set to zero except when an individual NQ falls between two
quantifiable values, in which case it will be omitted from the calculation of mean or
median profiles. Measurable concentrations which follow more than one consecutive mid-
profile NQ will be omitted (set to missing).
The mean/median value at a time-point where one or more samples have NQ values will
be reported (in tabular or graphical fashion) even if the mean/median value is below the
LLQ of the assay. For linear plots, zero concentration value(s) will be included in the plot. 
 
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
Derived GSK3389404 plasma PK parameters including, but not limited to area under the 
concentration-time curve (AUC), maximum observed concentration (Cmax), time of maximum 
observed concentration (tmax), terminal half-life (t½), and apparent subcutaneous plasma 
clearance (CL/F).

Derived ISIS 505358 plasma PK parameters including, but not limited to AUC, Cmax, tmax, and t½.
For semilogarithmic log-linear plots, zero concentration value(s) will be assigned a missing 
value. Zero mean or median values will be included in summary tables.
In certain cases, the NQ values could be set to missing or to some other values (e.g., 
½ LLQ) with proper scientific justification(s). A reference line indicating LLQ would then
be included in plots.
It should be noted that a high proportion of NQ values may affect the standard deviation
(SD); if more than 30% of values are imputed, then SD will not be displayed. Any table of 
summary statistics for concentration-time data will report N (number of subjects in the
analysis population), n (number of subjects with non-missing values) and number imputed 
(number of subjects with imputed values (i.e., NQ assigned zero concentration). BQL 
(Below the Quantification Limit) may be displayed in listings by legacy systems instead 
of NQ; these abbreviations are interchangeable and mean that a sample has been received, 
analyzed and a concentration below the LLQ of the assay found.
Scientific judgement and prior knowledge should always be used in applying these
guidelines.
How to Handle Anomalous Concentration Values
Individual concentrations deemed to be anomalous will be excluded from the
pharmacokinetic analysis and median and mean profiles; such anomalous values will be
identified (e.g., flagged by an asterisk or an appropriate footnote) in the data listings of the 
study report. Anomalous values are those that are inconsistent with known or expected 
pharmacokinetic behaviour of the drug, and are not defined in a statistical outlier sense. 
Clear justification must be provided in the report for exclusion of any data. Individual 
plasma concentration-time profiles by actual time and median/mean profiles by treatment 
(dose) by nominal time will be plotted.  Each of the figures will contain one plot on the 
untransformed scale (i.e., a linear plot) and one plot on the loge-transformed scale (i.e., 
semilogarithmic log-linear plot). In addition, a plot showing all individual subjects for 
each treatment (dose) will be produced (both linear and semilogarithmic log-linear).
13.5.5.
Pharmacodynamic 

Correlation between PD parameters, including HBV DNA, HBeAg and HBsAg.
PD Values and Parameters
o
HBV DNA (as appropriate), HBsAg, HBeAg levels that are below the LLOQ will be imputed as
the number of significant digits in the LLOQ will be used to determine how much to add or subtract 
in order to impute the corresponding numeric value. 
o
Example 1: 2 Significant Digits = ‘< x ‘ becomes x – 0.01
o
Example 2: 1 Significant Digit = ‘< x’ becomes x - 0.1
 
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
Correlation between PD parameters, including HBV DNA, HBeAg and HBsAg.
o
Example 3: 0 Significant Digits = ‘< x’ becomes x – 1    
o
In the scenario of multiple BLQ values, the Time to Nadir will be to the first BLQ value.
 
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13.6.
Appendix 6: Reporting Standards for Missing Data
13.6.1.
Premature Withdrawals
Element
Reporting Detail
General

Subject study completion (i.e. as specified in the protocol) was defined as 
below:
o
A completed subject in Part 1 is one who has completed Day 60 visit. 
An ongoing subject who misses the Day 60 visit will be considered as 
lost to follow-up.
o
A completed subject in Part 2 is one who has completed Day 450 visit. 
An ongoing subject who misses the Day 450 visit will be considered as 
lost to follow up.

Withdrawn subjects will be replaced in Part 1 but not be replaced in Part 2.

All available data from subjects who were withdrawn from the study will be listed 
and all available planned data will be included in summary tables and figures, 
unless otherwise specified.
13.6.2.
Handling of Missing Data
Element
Reporting Detail
General

Missing data occurs when any requested data is not provided, leading to blank 
fields on the collection instrument:
o
These data will be indicated by the use of a “blank” in subject listing 
displays. Unless all data for a specific visit are missing in which case the 
data is excluded from the table. 
o
Answers such as “Not applicable” and “Not evaluable” are not considered to 
be missing data and should be displayed as such.
Outliers

Any subjects excluded from the summaries and/or statistical analyses will be 
documented along with the reason for exclusion in the clinical study report.
13.6.2.1.
Handling of Missing Dates
Element
Reporting Detail
General
Partial dates will be displayed as captured in subject listing displays.
Adverse 
Events

The eCRF allows for the possibility of partial dates (i.e., only month and year) to 
be recorded for AE start and end dates; that is, the day of the month may be 
missing. In such a case, the following conventions will be applied for calculating 
the time to onset and the duration of the event:
o
Missing Start Day: First of the month will be used unless this is before the 
start date of study treatment; in this case the study treatment start date will 
be used and hence the event is considered On-treatment as per Appendix 3
Study Phases and Treatment Emergent Adverse Events.
o
Missing Stop Day: Last day of the month will be used, unless this is after the 
stop date of study treatment; in this case the study treatment stop date will 
 
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Element
Reporting Detail
be used.

Completely missing start or end dates will remain missing, with no imputation 
applied. Consequently, time to onset and duration of such events will be 
missing.

Start or end dates which are completely missing (i.e. no year specified) will 
remain missing, with no imputation applied.
13.6.2.2.
Handling of Partial Dates
Element
Reporting Detail
Concomitant 
Medications

Partial dates for any concomitant medications recorded in the CRF will be 
imputed using the following convention:
o
If the partial date is a start date, a ‘01’ will be used for the day and ‘Jan’ will 
be used for the month
o
If the partial date is a stop date, a ‘28/29/30/31’ will be used for the day 
(dependent on the month and year) and ‘Dec’ will be used for the month.

The recorded partial date will be displayed in listings.
Adverse 
Events

Any partial dates for adverse events will be raised to data management. If the 
full date cannot be ascertained, the following assumptions will be made:
o
If the partial date is a start date, a ‘01’ will be used for the day and ‘Jan’ will 
be used for the month. 
o
However, if these results in a date prior to Day 1 and the event could 
possibly have occurred during treatment from the partial information, then 
the Week 1 Day 1 date will be assumed to be the start date. 
o
The AE will then be considered to start on-treatment (worst case).
o
If the partial date is a stop date, a ‘28/29/30/31’ will be used for the day 
(dependent on the month and year) and ‘Dec’ will be used for the month.

The recorded partial date will be displayed in listings.
 
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13.7.
Appendix 7: Values of Potential Clinical Importance
13.7.1.
ECG
ECG Parameter
Units
Clinical Concern Range
Lower
Upper
Absolute
Absolute QTc Interval
msec
> 450
Absolute PR Interval
msec
< 110 
> 220 
Absolute QRS Interval
msec
< 75 
> 110 
Change from Baseline
Increase from Baseline QTc
msec
> 60
13.7.2.
Vital Signs
Vital Sign Parameter
(Absolute)
Units
Clinical Concern Range
Lower
Upper
Systolic Blood Pressure
mmHg
< 85
> 160
Diastolic Blood Pressure
mmHg
< 45
> 100
Heart Rate
bpm
< 40
> 110
 
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13.8.
Appendix 8: Model Checking and Diagnostics for Statistical 
Analyses
13.8.1.
Statistical Analysis Assumptions
Endpoint(s)

PK endpoints AUC and Cmax
Analysis

Mixed effects

Model assumptions will be applied, but appropriate adjustments maybe made based on the 
data.

The Kenward and Roger method for approximating the denominator degrees of freedom and 
correcting for bias in the estimated variance-covariance of the fixed effects will be used.
13.8.2.
Dose Proportionality
Dose proportionality of GSK3389404 and ISIS 505358following single-dose administration in JSS 
will be studied using the power model
y = × (dose)
where y denotes the PK parameter being analyzed [AUC(0-t), AUC(0-∞), and Cmax]. 
Dose proportionality implies that β = 1 and will be assessed by estimating β along with its 90% 
confidence interval. The exponent, β, in the power model will be estimated by regressing the loge-
transformed PK parameter on loge-transformed dose.
Log(y)=log(α) + β * log(dose)
The power model will be fitted by restricted maximum likelihood (REML) using SAS Proc Mixed, 
with subject as a random effect or a fixed effect power model will be fitted. The mean slope will be 
estimated from the power model and the corresponding 90% confidence interval calculated. Point 
estimates and confidence intervals for the slope will be reported to 4 decimal places with no 
rounding.
An example of SAS code is included here for the power model approach.
ODS output solution=stat
Proc Mixed;
class subject;
model logPKvar = logdose /cl alpha=0.1 solution ddfm=kr
run;
If the power model does not show dose proportionality then pairwise analysis of variance (ANOVA) 
may be used as an exploratory analysis to understand the dose where dose proportionality fails. 
PK parameters will be normalized to the reference dose (30 mg) and then log-transformed prior to 
 
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the analysis. Dose will be treated as a categorical variable. Point estimates and 90% confidence 
intervals for AUCs and Cmax will be reported to 4 decimal places with no rounding.
An example of SAS code is also included here for the ANOVA approach.
ODS output solution=stat;
Proc Mixed;
class subject treatment; /* treatments are different dose groups 
*/
model logdnPKvar = treatment/cl alpha=0.1 solution;;
lsmeans treatment; /* assuming one ref and three test treatments 
*/
estimate ‘test1 vs ref’ treatment -1 1 0 0 /cl alpha=0.1;
estimate ‘test2 vs ref’ treatment -1 0 1 0 /cl alpha=0.1;
estimate ‘test3 vs ref’ treatment -1 0 0 1 /cl alpha=0.1;
run;
 
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13.9.
Appendix 9: Abbreviations & Trade Marks
13.9.1.
Abbreviations
Abbreviation
Description
z
Apparent terminal rate constant
%AUCex
The percentage of AUC(0-∞) obtained by extrapolation
AdaM
Analysis Data Model
AE
Adverse Event
AIC
Akaike’s Information Criteria
AUC
Area under the concentration-time
AUC(0-t)
Area under the concentration-time curve from time zero to the time of 
the last quantifiable concentration
AUC(0-∞)
Area under the concentration-time curve extrapolated to infinity
AUC(0-24)
Area under the concentration-time curve in the plasma from time zero to 
24 hours post-dose
A&R
Analysis and Reporting 
C24
Concentration in the plasma at 24 hours after dosing
CDISC
Clinical Data Interchange Standards Consortium
Change from 
Baseline to 
Nadir
Minimum observed change from baseline pharmacodynamic value
CI
Confidence Interval
CL/F
Apparent plasma clearance after extravascular
Cmax
Maximum observed concentration in plasma
CPMS
Clinical Pharmacology Modelling & Simulation
CS
Clinical Statistics
CSR
Clinical Study Report
CTR
Clinical Trial Register
CVb / CVw
Coefficient of Variation (Between) / Coefficient of Variation (Within)
DOB
Date of Birth
DP
Decimal Places
eCRF
Electronic Case Record Form
GUI
Guidance
HbeAg
Hepatitis B e-antigen
HbsAg
Hepatitis B virus surface antigen
HBV
Hepatitis B Virus
IA
Interim Analysis
ICH
International Conference on Harmonisation
IDMC
Independent Data Monitoring Committee 
IDSL
Integrated Data Standards Library
IMMS
International Modules Management System
IP
Investigational Product
ITT
Intent-To-Treat
JSS
Japan Sub-study
LLOQ
Lower limit of quantification
 
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Abbreviation
Description
LLOD
Lower limit of detection
LOC
Last Observation Carries Forward
MMRM
Mixed Model Repeated Measures
Nadir
Minimum observed pharmacodynamic value
NQ
Non-quantifiable
PCI
Potential Clinical Importance 
PD
Pharmacodynamic
PDMP
Protocol Deviation Management Plan
PK
Pharmacokinetic
PP
Per Protocol
QC
Quality Control
QTcF
Frederica’s QT Interval Corrected for Heart Rate
QTcB
Bazett’s QT Interval Corrected for Heart Rate
RAP
Reporting & Analysis Plan
RAMOS
Randomization & Medication Ordering System 
SAC
Statistical Analysis Complete
SDTM
Study Data Tabulation Model
SOP
Standard Operation Procedure
t½
Apparent terminal half-life
TA
Therapeutic Area
Time to Nadir
Time to reach Nadir
TFL
Tables, Figures & Listings 
tlag
Lag time before observation of quantifiable concentrations in plasma
tmax
Time to reach Cmax
Vz/F
Apparent plasma volume of distribution after extravascular
GSK
GlaxoSmithKline
13.9.2.
Trademarks
Trademarks of the GlaxoSmithKline 
Group of Companies
Trademarks not owned by the 
GlaxoSmithKline Group of Companies
None
WinNonlin
SAS
 
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13.10.
Appendix 10: List of Data Displays
13.10.1.
Data Display Numbering
The following numbering will be applied for RAP generated displays. The all subjects set 
will start with x.1xx; the corresponding TLFs for JSS only will be x.2xx. For listing, all 
subjects (combo) will use 1 – 100 range, while JSS will use 201-300 range. For subgroup 
table, only combo set will be generated. Below TOC only lists the combo set. 
Section (All subjects)
Tables
Figures
Study Population (Part 2)
1.101 to 1.116
N/A
Efficacy (Part 2)
2.101 to 2.116
2.101 to 2.117
Safety (Part 2)
3.101 to 3.125
3.101 to 3.114
Pharmacokinetic (Part 2)
4.201 to 4.306
4.201 to 4.310
Section (All subjects)
Listings
ICH Listings
1 to 30
Other Listings
1 to 9
Section (JSS)
Tables
Figures
Study Population (Part 2)
1.201 to 1.216
N/A
Efficacy (Part 2)
2.201 to 2.216
2.201 to 2.217
Safety (Part 2)
3.201 to 3.225
3.201 to 3.214
Pharmacokinetic (Part 2)
4.201 to 4.306
4.201 to 4.310
Section (JSS)
Listings
ICH Listings
201 to 231
Other Listings
201 to 213
 
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13.10.2.
Mock Example Shell Referencing
Mock shell will be in a separate document. 
13.10.3.
Deliverables
Delivery [Priority] [1]
Description
PA [HL]
Primary Analysis headline
PA [1]
Primary Analysis
3m FU [1]
3 month FU
6m FU [1]
6 month FU
EOS [1]
End of Study
NOTES: 
1.
Indicates priority (i.e. order) in which displays will be generated for the reporting effort
 
 
 
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13.10.4.
Table of Contents of Data Display
13.10.4.1. Study Population Tables
Study Population Tables
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming 
Notes
Deliverable 
PA
3mFU
6mFU
EOS
1.101
[ITT]
ES1
Summary of Subject Disposition (Part 2)
x
x
x
x
1.102
[Screened 
Population]
ES6
Summary of Screening Status and Reasons for Screening 
Failure (Part 2)
x
x
x
1.103
[Screened 
Population]
NS1
Summary of Enrolled Subjects by Country and Site ID (Part 
2)
x
x
x
1.104
[ITT]
DV1
Summary of Important Protocol Deviations (Part 2)
X
x
x
x
1.105
[ITT]
DM1
Summary of Demographic Characteristics (Part 2)
HL
x
x
1.106
[ITT]
DM1
Summary of Demographic Characteristics by Sub-Group 
(Part 2)
x
x
x
1.107
[ITT]
DM1
Summary of Baseline Disease Characteristics (Part 2)
HL
x
x
1.108
[ITT]
DM1
Summary of Baseline Disease Characteristics by Subgroup 
(Part 2)
x
X
x
1.109
[ITT]
DM11
Summary of Age Ranges (Part 2)
x
X
x
1.110
[ITT]
DM5
Summary of Race and Racial Combinations (Part 2)
x
X
x
1.111
[ITT]
MH4
Summary of Past Medical Conditions (Part 2)
x
X
x
1.112
[ITT]
CM1
Summary of Prior Medications (Part 2)
x
X
x
1.113
[ITT]
CM1
Summary of Concomitant Medications (Part 2)
x
X
x
x
1.114
[ITT]
CM1
Summary of Baseline Nucleos(t)ide Use (Part 2)
x
X
x
1.115
[ITT]
MH4
Summary of Current Medical Conditions (Part 2)
x
X
x
 
 
 
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Study Population Tables
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming 
Notes
Deliverable 
PA
3mFU
6mFU
EOS
1.116
[ITT]
Summary of Exposure (Part 2)
HL
X
x
13.10.4.2. Efficacy Tables
Efficacy Tables
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming 
Notes
Deliverable 
PA
3mFU
6mFU
EOS
2.101
[ITT]
RE1a
Summary of Response Rate, Missing = Failure (Part 2)
HL
x
x
x
2.102
[ITT]
Summary of Response Rate by Sub-group, Missing = 
Failure (Part 2)
x
x
x
x
2.103
[ITT]
RE1a
Summary of Response Rate, Observed Case (Part 2)
x
x
x
x
2.104
[ITT]
Summary of Response Rate by Subgroup, Observed 
Case (Part 2)
x
x
x
x
2.105
[ITT]
RE1a
Summary of HBsAg Outcome, Missing = Failure (Part 
2)
x
x
x
x
2.106
[ITT]
LB1
Summary of HBsAg (log10 IU/ml) Change from 
Baseline by Visit (Part 2)
HL
x
x
x
2.107
[ITT]
Summary of HBsAg (log10 IU/ml) Change from 
Baseline by Visit and Subgroup (Part 2)
x
x
x
x
2.108
[ITT]
LB1
Summary of HBsAg (log10 IU/ml) by Visit (Part 2)
x
x
x
x
2.109
[ITT]
Summary proportion of Subject Achieving HBsAg
>=1.5 log decline (Part 2)
HL
x
x
x
 
 
 
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Efficacy Tables
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming 
Notes
Deliverable 
PA
3mFU
6mFU
EOS
2.110
[ITT]
Summary of HBeAg (log10 IU/ml) by Visit (Part 2)
x
x
x
x
2.111
[ITT]
Summary of HBeAg (log10 IU/ml) Change from 
Baseline by Visit (Part 2)
x
x
x
x
2.112
[ITT]
Summary of Nadir and Time to Nadir for HBsAg, 
HBeAg
x
x
x
x
2.113
[ITT]
Summary of Change from Baseline to Nadir for HBsAg, 
HBeAg
x
x
x
x
2.114
[ITT]
Proportion of Subjects with HBsAg <0.05 IU/mL by 
Visit - Missing = Failure Analysis
HL
x
x
x
2.115
[ITT]
RE1a
Summary of Rate of Seroconversion (Part 2)
x
x
x
x
2.116
[ITT]
Summary of HBsAb (positive/negative) by visit
x
x
x
x
13.10.4.3. Efficacy Figures
Efficacy Figures
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
Deliverable 
PA
3mFU
6mFU
EOS
2.101
[ITT]
Forest Plot of Posterior Mean Response Rate - BLRM 
(Part 2)
x
x
x
x
2.102
[ITT]
Density Plot of Posterior Distribution of Response Rate 
by Dose Group and Dosing Regimen - BLRM (Part 2)
x
x
x
x
2.103
[ITT]
RE8a
Waterfall Plot of Percentage Change at Maximum 
Reduction from Baseline in HBsAg (Part 2)
x
x
x
x
2.104
[ITT]
Forest Plot of Rate of Seroconversion (Part 2)
x
x
x
x
 
 
 
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Efficacy Figures
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
Deliverable 
PA
3mFU
6mFU
EOS
2.105
[ITT]
Plot of Mean HBsAg (log10 IU/ml) Change from 
Baseline (Part 2)
HL
x
x
x
2.106
[ITT]
Plot of Mean HBsAg (log10 IU/ml) Value by Visit (Part 
2)
x
x
x
x
2.107
[ITT]
Individual Plot of HBsAg (log10 IU/ml) Change from 
Baseline by Treatment (Part 2)
x
x
x
x
2.108
[ITT]
Individual Plot of HBsAg (log10 IU/ml) Value by 
Treatment (Part 2)
x
x
x
x
2.109
[ITT]
Individual Plot of HBsAg (log10 IU/ml) Value Overlay 
by Treatment (Part 2)
x
x
x
x
2.110
[ITT]
Individual Plot of HBsAg (log10 IU/ml) Value and ALT 
Profile (Part 2)
x
x
x
x
2.111
[ITT]
Individual HBsAg (log10 IU/ml) Change from Baseline 
and ALT Profile (Part 2)
HL
x
x
x
2.112
[ITT]
Individual HBeAg (log10 IU/ml) Change from Baseline 
(Part 2)
x
x
x
x
2.113
[ITT]
Individual HBeAg (log10 IU/ml) Value (Part 2)
x
x
x
x
 
 
 
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Efficacy Figures
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
Deliverable 
PA
3mFU
6mFU
EOS
2.114
[ITT]
Individual Plot of HBsAg, HBeAg and HBV DNA (log10 
scale) Change from Baseline vs ALT (Part 2)
HL
x
x
x
2.115
[ITT]
Box Plot for HBsAg by HBeAg Status (Part 2)
x
x
x
x
2.116
[ITT]
Box Plot of HBsAg Nadir, Time to Nadir and Change 
from baseline to Nadir by HBeAg Status (Part 2)
x
x
x
x
2.117
[ITT]
Individual HBsAg (log10 IU/ml) Change from Baseline 
and ALT Profile – Fix Y Scale (Part 2)
Use one fix scale for 
HBsAg data on all 
subjects and use one 
fix scale for ALT on all 
subjects
HL
x
x
x
13.10.4.4. Safety Tables
Safety: Tables
No.
Population
IDSL / TST ID 
/ Example 
Shell
Title
Programming 
Notes
Deliverable
PA
3mFU
6mFU
EOS
Adverse Events
3.101
[Safety]
AE5B
Summary of Adverse Events by System Organ Class and 
Preferred Term and Maximum Grade (Part 2)
x
x
x
x
3.102
[Safety]
AE5B
Summary of All Drug-Related Adverse Events by System 
Organ Class and Preferred Term and Maximum Grade 
(Part 2)
x
x
x
x
 
 
 
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Safety: Tables
No.
Population
IDSL / TST ID 
/ Example 
Shell
Title
Programming 
Notes
Deliverable
PA
3mFU
6mFU
EOS
3.103
[Safety]
AE5B
Summary of Non-Serious Adverse Events by System 
Organ Class and Preferred Term and maximum Grade 
(Part 2)
x
x
x
x
3.104
[Safety]
AE3
Summary of Adverse Events by Overall Frequency (Part 
2)
HL
x
x
x
3.105
[Safety]
AE3
Summary of Grade 2-4 Adverse Events by Overall 
Frequency (Part 2)
x
x
x
x
3.106
[Safety]
AE3
Summary of Drug-Related Grade 2-4 Adverse Events by 
Overall Frequency (Part 2)
x
x
x
x
3.107
[Safety]
Overall Summary of Adverse Events and Lab 
Abnormalities (Part 2)
HL
x
x
x
3.121
[Safety]
AE5B
Summary of SAE by Overall Frequency
HL
x
x
x
3.122
[Safety]
AE5B
Summary of Adverse Events Leading to Permanent 
Discontinuation of Study Treatment or Withdrawal from 
Study 
x
x
x
x
3.123
[Safety]
AE15
Summary of All Non-serious Adverse Events by System 
Organ Class and Preferred Term (Number of Subjects 
and Occurrences)
x
x
x
x
 
 
 
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Safety: Tables
No.
Population
IDSL / TST ID 
/ Example 
Shell
Title
Programming 
Notes
Deliverable
PA
3mFU
6mFU
EOS
3.124
[Safety]
Summary of Adverse Events by System Organ Class and 
Preferred Term and Maximum Grade and Subgroup (Part 
2)
x
x
x
x
3.125
[Safety]
Summary of All Drug-Related Adverse Events by System 
Organ Class and Preferred Term and Maximum Grade 
and Subgroup (Part 2)
x
x
x
x
Lab
3.108
[Safety]
LB1
Summary of Chemistry Changes from Baseline by Visit 
(Part 2)
x
x
x
x
3.109
[Safety]
Summary of Chemistry Maximum Grade by Category 
(Part 2)
x
x
x
x
3.110
[Safety]
LB1
Summary of Hematology Changes from Baseline by Visit 
(Part 2)
x
x
3.111
[Safety]
Summary of Hematology Maximum Grade by Category 
(Part 2)
x
x
3.112
[Safety]
LB1
Summary of Urinalysis Changes from Baseline by Visit 
(Part 2)
x
x
3.113
[Safety]
LB2
Summary of Coagulation Lab Data (Part 2)
x
x
x
x
3.114
[Safety]
Summary of Complement Product Levels after Study 
Drug Dose (Part 2)
x
x
x
x
ECG
3.115
[Safety]
EG1
Summary of ECG Findings (Part 2)
x
x
3.116
[Safety]
EG2
Summary of ECG Changes from Baseline by Visit (Part 2)
x
x
 
 
 
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Safety: Tables
No.
Population
IDSL / TST ID 
/ Example 
Shell
Title
Programming 
Notes
Deliverable
PA
3mFU
6mFU
EOS
3.117
[Safety]
CP_EG11
Summary of Maximum Emergent QTc Values by 
Category (Part 2)
x
x
3.118
[Safety]
CP_EG12
Summary of Maximum Change from Baseline in QTc 
Values by Category (Part 2)
x
x
Vital Signs
3.119
[Safety]
VS1
Summary of Vital Sign Changes from Baseline by Visit 
(Part 2)
x
x
3.120
[Safety]
Summary of Vital Sign Values by Category (Part 2)
x
x
 
 
 
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13.10.4.5. Safety Figures
Safety: Figures
No.
Populatio
n
IDSL / TST ID / 
Example Shell
Title
Programmin
g Notes
Deliverable
PA
3mFU
6mFU
EOS
Lab
3.101
[Safety]
LIVER9
Scatter Plot of Maximum vs. Baseline for ALT (Part 2)
x
x
x
x
3.102
[Safety]
LIVER9
Scatter Plot of Maximum ALT vs. Maximum Total 
Bilirubin (Part 2)
x
x
x
x
3.103
[Safety]
Mean Plot of Liver Functions (Part 2)
HL
x
x
x
3.104
[Safety]
Individual Line Plot of Liver Functions (Part 2)
HL
x
x
x
3.105
[Safety]
Mean Plot of Coagulation Tests (Part 2)
x
x
x
x
3.106
[Safety]
Individual Line Plot of Coagulation Tests (Part 2)
x
x
x
x
3.107
[Safety]
Individual Line Plot of Chemistry Lab Tests (Part 2)
x
x
x
x
3.108
[Safety]
Mean Plot of Chemistry Lab Tests (Part 2)
HL
x
x
x
3.109
[Safety]
Individual Line Plot of Chemistry Lab Tests Overlay by 
Treatment (Part 2)
HL
x
x
x
3.110
[Safety]
Individual Line Plot of Hematology Lab Tests (Part 2)
x
x
3.111
[Safety]
AE10
On-treatment Adverse Events occur in more than 1 
Subject Sorted by Relative Risk (Part 2)
x
x
x
x
3.112
[Safety]
Mean Plot of Chemistry Lab Tests Change from 
Baseline 
HL
x
3.113
[Safety]
Mean Plot of Hematology Lab Tests Change from 
Baseline
HL
x
3.114
[Safety]
Individual Line Plot of Hematology Lab Tests Overlay 
by Treatment (Part 2)
x
x
 
 
 
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13.10.4.6. Pharmacokinetic Tables
Pharmacokinetic: Tables
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
4.101
[PK]
PK01
Summary of GSK3389404 Plasma Pharmacokinetic Concentration-Time 
Data [ng/mL] by Treatment Group and HBeAg Status (Part 2)
PA / 3m FU
4.102
[PK]
PK01
Summary of ISIS 505358 Plasma Pharmacokinetic Concentration-Time Data 
[ng/mL] by Treatment Group and HBeAg Status (Part 2)
PA / 3m FU
4.203
[PK]
PK03
Summary of Derived GSK3389404 Plasma Pharmacokinetic Parameters for 
Day 1by Treatment Group, Dosage in Once and HBeAg Status (JSS)
JSS subjects enrolled in 
Japan only
PA 
4.204
[PK]
PK03
Summary of Derived ISIS 505358 Plasma Pharmacokinetic Parameters for 
Day 1 by Treatment Group, Dosage in Once and HBeAg Status (JSS)
JSS subjects enrolled in 
Japan only
PA
4.205
[PK]
PK05
Summary of Log-Transformed Derived GSK3389404 Plasma 
Pharmacokinetic Parameters for Day 1 by Treatment Group, Dosage in 
Once and HBeAg Status (JSS)
JSS subjects enrolled in 
Japan only
PA 
4.206
[PK]
PK05
Summary of Log-Transformed Derived ISIS 505358 Plasma 
Pharmacokinetic Parameters for Day 1 by Treatment Group, Dosage in 
Once and HBeAg Status (JSS)
JSS subjects enrolled in 
Japan only
PA 
4.207
[PK]
PK03
Summary of Derived GSK3389404 Plasma Dose-Normalized 
Pharmacokinetic Parameters for Day 1by Treatment Group, Dosage in 
Once, and HBeAg Status (JSS)
JSS subjects enrolled in 
Japan only
PA 
4.208
[PK]
PK03
Summary of Derived ISIS 505358 Plasma Dose-Normalized 
Pharmacokinetic Parameters for Day 1 by Treatment Group, Dosage in 
Once, and HBeAg Status (JSS)
JSS subjects enrolled in 
Japan only
PA 
4.209
[PK]
PK_T1
Assessment of Dose Proportionality of GSK3389404 using Power Model 
Following a Single Dose (JSS)
JSS subjects enrolled in 
Japan only
PA 
 
 
 
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Pharmacokinetic: Tables
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
4.210
[PK]
PK_T4
Summary of Results of Dose Proportionality Assessment of GSK3389404 
using ANOVA Following a Single Dose (JSS)
JSS subjects enrolled in 
Japan only
PA 
4.211
[PK]
PK_T4
Summary of Results of Dose Proportionality Assessment of ISIS 505358 
using ANOVA Following a Single Dose (JSS)
JSS subjects enrolled in 
Japan only
PA
13.10.4.7. Pharmacokinetic Figures
Pharmacokinetic: Figures
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
4.101
[PK]
PK17
Mean (+SD) GSK3389404 Plasma Concentration-Time Plot by Treatment 
Group and HBeAg Status (Part 2) (Linear and Semi-Log)
PA / 3m FU
4.102
[PK]
PK17
Mean (+SD) ISIS 505358 Plasma Concentration-Time Plot by Treatment 
Group and HBeAg Status (Part 2) (Linear and Semi-Log)
PA / 3m FU
4.103
[PK]
PK18
Median (range) GSK3389404 Plasma Concentration-Time Plot by Treatment 
Group and HBeAg Status (Part 2) (Linear and Semi-Log)
PA / 3m FU
4.104
[PK]
PK18
Median ISIS 505358 Plasma Concentration-Time Plot by Treatment Group 
and HBeAg Status (Part 2) (Linear and Semi-Log)
PA / 3m FU
4.105
[PK]
PK16a
Individual GSK3389404 and ISIS 505358 Plasma Concentration-Time Plot 
(Part 2) (Linear and Semi-Log)
PA / 3m FU
4.206
[PK]
PK17
Mean (+SD) GSK3389404 Plasma Concentration-Time Plot for Day 1 by 
Treatment Group, Dosage in Once, and HBeAg Status (JSS) (Linear and 
Semi-Log)
JSS subjects enrolled in 
Japan only
PA
 
 
 
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Pharmacokinetic: Figures
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
4.207
[PK]
PK17
Mean (+SD) ISIS 505358 Plasma Concentration-Time Plot for Day 1 by 
Treatment Group, Dosage in Once, and HBeAg Status (JSS) (Linear and 
Semi-Log)
JSS subjects enrolled in 
Japan only
PA
4.208
[PK]
PK18
Median (range) GSK3389404 Plasma Concentration-Time Plot for Day 1 by 
Treatment Group, Dosage in Once, and HBeAg Status (JSS) (Linear and 
Semi-Log)
JSS subjects enrolled in 
Japan only
PA
4.209
[PK]
PK18
Median ISIS 505358 Plasma Concentration-Time Plot for Day 1 by 
Treatment Group, Dosage in Once, and HBeAg Status (JSS) (Linear and 
Semi-Log)
JSS subjects enrolled in 
Japan only
PA
4.210
[PK]
PK16a
Individual GSK3389404 and ISIS 505358 Plasma Concentration-Time Plot 
for Day 1 (JSS) (Linear and Semi-Log)
JSS subjects enrolled in 
Japan only
PA
4.211
[PK]
Box Plot of GSK3389404 PK Exposure Parameters versus Dosage in Once 
for Day 1 (JSS)
JSS subjects enrolled in 
Japan only
PA
 
 
 
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Pharmacokinetic: Figures
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
4.212
[PD]
Scatter Plot of Nadir versus AUC(0-inf) for GSK3389404
JSS subjects enrolled in 
Japan only
PA/3m FU
4.213
[PD]
Scatter Plot of Time to Nadir versus AUC(0-inf) for GSK3389404
JSS subjects enrolled in 
Japan only
PA/3m FU
4.214
[PD]
Scatter Plot of Log10 Change from Baseline to Nadir versus AUC(0-inf) for 
GSK3389404
JSS subjects enrolled in 
Japan only
PA/3m FU
4.215
[PD]
Scatter Plot of Nadir versus Cmax for GSK3389404
JSS subjects enrolled in 
Japan only
PA/3m FU
4.216
[PD]
Scatter Plot of Time to Nadir versus Cmax for GSK3389404
JSS subjects enrolled in 
Japan only
PA/3m FU
4.217
[PD]
Scatter Plot of Log10 Change from Baseline to Nadir versus Cmax for 
GSK3389404
JSS subjects enrolled in 
Japan only
PA/3m FU
4.218
[PK]
Box Plot of GSK3389404 PK Exposure Parameter Comparison by 
Population for Day 1 (JSS)
PA
13.10.4.8. ICH Listings
ICH: Listings
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
Deliverable
PA
3mFU
6mFU
EOS
Study Population
1
[Screened 
Population]
ES7
Listing of Reasons for Screen Failure (Part 2)
x
x
2
[ITT]
ES2
Listing of Reasons for Study Withdrawal (Part 
2)
x
x
x
x
 
 
 
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ICH: Listings
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
Deliverable
PA
3mFU
6mFU
EOS
3
[ITT]
BL1
Listing of Subjects for whom Treatment Blind 
was Broken During the Study (Part 2)
x
x
x
4
[ITT]
TA1
Listing of Randomized and Actual Treatments 
(Part 2)
x
x
x
x
5
[ITT]
DV2
Listing of Protocol Deviations (Part 2)
x
x
x
x
6
[ITT]
IE3
Listing of Subjects with Inclusion/Exclusion 
Criteria Deviations (Part 2)
x
x
x
x
7
[ITT]
SP3
Listing of Subjects Excluded from Any 
Population (Part 2)
x
x
8
[ITT]
DM2
Listing of Demographic Characteristics (Part 2)
x
x
9
[ITT]
DM9
Listing of Race (Part 2)
x
x
10
[ITT]
CM2
Listing of Prior and Concomitant Medications 
(Part 2)
x
x
x
x
11
[ITT]
CM2
Listing of Baseline Nucleos(t)ide Use (Part 2)
x
x
12
[ITT]
MH2
Listing of Medical Conditions (Part 2)
x
x
Exposure
13
[Safety]
EX3
Listing of Exposure Data (Part 2)
x
x
x
x
Adverse Events
14
[Safety]
AE8
Listing of All Adverse Events (Part 2)
HL
x
x
x
15
[Safety]
AE7
Listing of Subject Numbers for Specified 
Adverse Events (Part 2)
x
x
x
x
16
[Safety]
AE2
Listing of Relationship between System Organ 
Class and Verbatim Text (Part 2)
x
x
x
x
 
 
 
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ICH: Listings
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
Deliverable
PA
3mFU
6mFU
EOS
17
[Safety]
AE8
Listing of Non-Fatal Serious Adverse Events 
(Part 2)
x
x
x
x
18
[Safety]
AE8
Listing of Fatal Serious Adverse Events (Part 
2)
x
x
x
x
19
[Safety]
AE8
Listing of Adverse Events Leading to 
Permanent Discontinuation of Study Treatment 
or Withdrawal from Study (Part 2)
x
x
x
x
30
[Safety]
AE14
Listing of Reasons for Considering as a 
Serious Adverse Event
x
x
x
x
Lab
20
[Safety]
LB5
Listing of All Laboratory Data (Part 2)
x
x
x
x
21
[Safety]
LB5
Listing of All Laboratory Data for Subjects with 
any Grade 1 or Higher Abnormality (Part 2)
x
x
x
x
22
[Safety]
LB5
Listing of All Laboratory Data with Grade 1 or 
Higher (Part 2)
x
x
x
x
ECG
23
[Safety]
CP_EG3
Listing of All ECG Data (Part 2)
x
x
 
 
 
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ICH: Listings
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
Deliverable
PA
3mFU
6mFU
EOS
24
[Safety]
CP_EG3
Listing of All ECG Data for Subjects with Any 
Value of Potential Clinical Importance (Part 2)
x
x
25
[Safety]
Listing of All ECG Findings (Part 2)
x
x
26
[Safety]
CP_EG5
Listing of All ECG Findings for Subjects with an 
Abnormal Finding (Part 2)
x
x
Vital Signs
27
[Safety]
CP_VS4
Listing of All Vital Signs (Part 2)
x
x
28
[Safety]
CP_VS4
Listing of All Vital Signs for Subjects with Any 
Values of Potential Clinical Importance (Part 2)
x
x
Liver
29
[Safety]
LIVER5
Listing of Liver Stopping/Monitoring Event 
Reporting (Part 2)
x
x
x
x
13.10.4.9. Non-ICH Listings
Non-ICH: Listings
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming 
Notes
Deliverable
PA
3mFU
6mFU
EOS
Efficacy
1
[ITT]
RE5a
Listing of Response based on HBsAg (Part 2)
x
x
x
x
2
[ITT]
RE5a
Listing of HBsAb and Seroconversion (Part 2)
x
x
x
x
3
[ITT]
Listing of HBsAg and HBeAg
x
x
x
x
 
 
 
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Non-ICH: Listings
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming 
Notes
Deliverable
PA
3mFU
6mFU
EOS
4
[ITT]
Listing of HBV DNA Value for subject with Virologic 
Breakthrough
HL
x
x
x
5
[ITT]
Listing of HBV DNA Value
x
x
x
x
PK
106
[PK]
PK08
Listing of GSK3389404 Plasma Pharmacokinetic 
Concentration-Time Data by Treatment Group and 
Study Day (Part 2)
PA / 3m FU
107
[PK]
PK08
Listing of ISIS 505358 Plasma Pharmacokinetic 
Concentration-Time Data by Treatment Group and 
Study Day (Part 2)
PA / 3m FU
108
[PK]
Non-Standard 
PK L_1
Individual GSK3389404 Plasma Concentrations 
(ng/mL) by Scheduled Time (Part 2)
PA / 3m FU
109
[PK]
Non-Standard 
PK L_1
Individual ISIS 505358 Plasma Concentrations 
(ng/mL) by Scheduled Time (Part 2)
PA / 3m FU
210
[PK]
PK14
Listing of Derived GSK3389404 Plasma 
Pharmacokinetic Parameters for Day 1 for Each 
Treatment Group (JSS)
JSS subjects 
enrolled in Japan 
only
PA
211
[PK]
PK14
Listing of Derived ISIS 505358 Plasma 
Pharmacokinetic Parameters for Day 1 for Each 
Treatment Group (JSS)
JSS subjects 
enrolled in Japan 
only
PA
 
 
 
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Non-ICH: Listings
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming 
Notes
Deliverable
PA
3mFU
6mFU
EOS
212
[PK]
PK14
Individual GSK3389404 Plasma Lambda_z
Related Pharmacokinetic Parameters for Each 
Treatment Group (JSS)
JSS subjects 
enrolled in Japan 
only
PA
213
[PK]
PK14
Individual ISIS 505358 Plasma Lambda_z 
Related Pharmacokinetic Parameters for Each 
Treatment Group (JSS)
JSS subjects 
enrolled in Japan
only
PA
 
 
 
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13.11.
Appendix 11: Bayesian Modelling Details
13.11.1.
PROC MCMC Parameters Settings and Validation 
Parameters
Value
Seeds
1
Number of chains
2
Blocking of parameters
All-at-once; e.g. parm alpha beta gamma;
Order of priors
Alpha beta gamma
Number of burn-in
5000
Number of MCMC after burn-in
100000
Initials for chains:
-
For BLRM
Chain
Alpha
Beta
gamma
1
0
0
0
2
-1
1
1
-
For Placebo with beta prior
 
 
 
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Chain
p
1
0.5
2
0.1
-
For placebo with logistic model with single intercept
Chain
Alpha
1
0
2
1
-
For pair-wise comparison
Chain
Alpha0
Alpha30
Alpha60
Alpha120bw
Alpha120w
1
0
0
0
0
0
2
1
-1
1
-1
1
Due to the nature of MCMC, for validation purpose, criterion will be set to be dependent on the total SD. For example, the estimated 
MCMC error, for each chain, should be < 5% of its associated SD.
13.11.2.
MCMC Mixing Diagnosis 
Two sampling chains will be run, with differing starting values and each with a burn-in period of 5,000 samples, to ensure adequate 
sampling from the posterior. The starting values will be as above section.
 
 
 
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Mixing will be regarded as “each chain is independently realizing values similar to those for which the other chains have also sampled.” 
Adequate mixing will be concluded if the chains meet all of the following conditions, in conjunction with the following actions:
1. The Brooks-Gelman Ratio (BGR) (Brooks, 1998) for each parameter is in the interval (0.8, 1.2).  
2. Each chain will begin with length 100000. The chain will be doubled in length until the estimated MCMC error, for each 
chain, is less than 5% of its associated SD.  
3. If computer memory limitations impede increasing the length of a chain enough to meet the MCMC error criterion above, 
then thinning will be used to reduce the autocorrelation of the chain. The maximum thinning value acceptable will be 100.  
The thinning values will be the prime numbers less than 100 starting at two. In the end, the chains will be thinned by the 
smallest prime number less than 100 for which the autocorrelations are less than 0.10 by 10 iterations. If no such prime 
value is found then the model will be reparameterized using algebraically equivalent formulations and then rerun.
4. Each chain appears mix well, upon visual inspection of each chain’s trace plot, including assessing the mutual overlap of 
the chains for each parameter.
5. Each kernel density plot appears smooth upon visual inspection.
 
 
 
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CONFIDENTIAL
The GlaxoSmithKline group of companies
205670
1
Division
:
Worldwide Development
Information Type
:
Reporting and Analysis Plan (RAP)
Title
:
Reporting and Analysis Plan for 205670: A Double-Blind, 
Placebo-Controlled Study to Assess the Safety, Tolerability, 
Pharmacokinetics and Pharmacodynamics of Single 
Ascending Dose and Multiple Doses of GSK3389404 in 
Chronic Hepatitis B Subjects (Part 1)
Compound Number
:
GSK3389404
Effective Date 
:
28-JUN-2018
Description:

The purpose of this RAP is to describe the planned analyses and output to be 
included in the Clinical Study Report for Protocol 205670: A Double-Blind, 
Placebo-Controlled Study to Assess the Safety, Tolerability, Pharmacokinetics and 
Pharmacodynamics of Single Ascending Dose and Multiple Doses of GSK3389404 
in Chronic Hepatitis B Subjects.

The RAP was developed in 2016 - 2017 based on 2014 RAP template with a final 
draft in September 2017.  The 2014 RAP template used for the RAP was the latest 
version at the time of RAP development.
Author’s Name and Functional Area: 
22-SEP-2017
Sr. Biostatistician, PPD
22-SEP-2017
Sr. Pharmacokineticist, PPD
Approved by: 
 
05-JUN-2018
Director, Clinical Statistics, GSK
28-JUN-2018
Manager, Clinical Programming, GSK
Copyright 2018 the GlaxoSmithKline group of companies. All rights reserved.  
Unauthorised copying or use of this information is prohibited.
 
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2
TABLE OF CONTENTS
PAGE
1.
REPORTING & ANALYSIS PLAN SYNPOSIS.........................................................5
2.
SUMMARY OF KEY PROTOCOL INFORMATION ..................................................8
2.1.
Changes to the Protocol Defined Statistical Analysis Plan............................8
2.2.
Study Objective(s) and Endpoint(s)...............................................................8
2.3.
Study Design ................................................................................................9
2.4.
Statistical Hypotheses.................................................................................10
3.
PLANNED ANALYSES ..........................................................................................10
3.1.
Interim Analyses .........................................................................................10
3.2.
Final Analyses ............................................................................................11
4.
ANALYSIS POPULATIONS ...................................................................................11
4.1.
Protocol Deviations.....................................................................................12
5.
CONSIDERATIONS FOR DATA ANALYSES AND DATA HANDLING 
CONVENTIONS.....................................................................................................13
6.
STUDY POPULATION ANALYSES .......................................................................14
6.1.
Overview of Planned Analyses ...................................................................14
6.1.1.
Disposition and Withdrawals........................................................14
6.1.2.
Demographic and Baseline Characteristics..................................15
6.1.3.
Prior and Concomitant Medications .............................................15
6.1.4.
Medical History and Current Medical Conditions..........................15
6.1.5.
Treatment Exposure ....................................................................15
7.
PRIMARY STATISTICAL ANALYSES....................................................................16
7.1.
Efficacy Analyses........................................................................................16
7.2.
Safety Analyses..........................................................................................16
7.2.1.
Overview of Planned Safety Analysis...........................................16
7.2.2.
Exposure to Study Treatment ......................................................17
7.2.3.
Adverse Events............................................................................17
7.2.4.
Vital Signs....................................................................................18
7.2.5.
Physical Examinations.................................................................19
7.2.6.
Injection Site Reactions ...............................................................19
7.2.7.
12-lead electrocardiograms (ECGs).............................................19
7.2.8.
Laboratory Measurements...........................................................19
7.2.9.
Study Treatment Discontinuation .................................................20
7.3.
Pharmacokinetic Analyses (GSK3389404) .................................................20
7.3.1.
Overview of Planned Pharmacokinetic Analyses .........................20
7.3.2.
Drug Concentration Measurements .............................................21
7.3.3.
Pharmacokinetic Parameters.......................................................21
7.3.3.1.
Deriving Pharmacokinetic Parameters........................21
7.3.3.2.
Statistical Analysis of Pharmacokinetic 
Parameters.................................................................22
8.
SECONDARY STATISTICAL ANALYSES .............................................................23
8.1.
Pharmacodynamic Analyses.......................................................................23
8.1.1.
Overview of Planned Pharmacodynamic Analyses ......................23
 
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8.2.
Pharmacokinetic Analyses (ISIS 505358) ...................................................24
8.2.1.
Overview of Planned Pharmacokinetic Analyses .........................24
9.
EXPLORATORY STATISTICAL ANALYSES .........................................................25
9.1.
Pharmacodynamic Analyses.......................................................................25
9.2.
Rate of Seroconversion ..............................................................................25
10. REFERENCES.......................................................................................................26
11. APPENDICES........................................................................................................27
11.1.
Appendix 1: Treatment Phases...................................................................28
11.1.1.
Treatment Phases .......................................................................28
11.2.
Appendix 2: Data Display Standards & Handling Conventions....................29
11.2.1.
Study Treatment & Sub-group Display Descriptors......................29
11.2.2.
Baseline Definition & Derivations .................................................29
11.2.2.1.
Baseline Definitions....................................................29
11.2.2.2.
Derivations and Handling of Missing Baseline 
Data ...........................................................................30
11.2.3.
Reporting Process & Standards...................................................30
11.3.
Appendix 3: Derived and Transformed Data ...............................................32
11.3.1.
General........................................................................................32
11.3.2.
Study Population..........................................................................32
11.3.3.
Safety ..........................................................................................33
11.3.4.
Pharmacokinetic ..........................................................................34
11.3.5.
Pharmacodynamic.......................................................................35
11.4.
Appendix 4: Premature Withdrawals & Handling of Missing Data ...............36
11.4.1.
Premature Withdrawals................................................................36
11.4.2.
Handling of Missing Data.............................................................36
11.4.2.1.
Handling of Missing Dates..........................................36
11.4.2.2.
Handling of Partial Dates............................................37
11.5.
Appendix 5: Values of Potential Clinical Importance ...................................38
11.5.1.
ECG.............................................................................................38
11.5.2.
Vital Signs....................................................................................38
11.6.
Appendix 6: Model Checking and Diagnostics for Statistical 
Analyses.....................................................................................................39
11.6.1.
Statistical Analysis Assumptions..................................................39
11.7.
Appendix 7: Pharmacokinetic Analyses ......................................................40
11.7.1.
Dose Proportionality ....................................................................40
11.8.
Appendix 8: Abbreviations & Trade Marks ..................................................41
11.8.1.
Abbreviations...............................................................................41
11.8.2.
Trademarks .................................................................................42
11.9.
Appendix 9: List of Data Displays ...............................................................43
11.9.1.
Data Display Numbering..............................................................43
11.9.2.
Table of Contents of Data Display ...............................................44
11.9.2.1.
Study Population Tables.............................................44
11.9.2.2.
Safety Tables .............................................................45
11.9.2.3.
Safety Figures ............................................................46
11.9.2.4.
Pharmacokinetic Tables .............................................47
11.9.2.5.
Pharmacokinetic Figures ............................................48
11.9.2.6.
Pharmacodynamic Tables ..........................................49
11.9.2.7.
Pharmacodynamic Figures.........................................49
11.9.2.8.
ICH Listings................................................................51
 
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11.9.2.9.
Non-ICH Listings ........................................................54
11.9.3.
Mock Example Shell Referencing ................................................55
 
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1.
REPORTING & ANALYSIS PLAN SYNPOSIS
Overview
Key Elements of the RAP
Purpose

This reporting and analysis plan (RAP) details planned analyses for a clinical 
study report for study 205670 which will be used to support the regulatory 
submissions for the treatment of subjects with chronic Hepatitis B (CHB).  
Protocol

This RAP is based on the protocol amendment number 3 [(Dated: 28JUN2017) 
of study 205670 (GSK Document No.: 2016N277028_04)].
Primary 
Objectives

To assess the safety, tolerability, and PK profile of GSK3389404 in single (Part 
1) administration in subjects with CHB.
Primary 
Endpoints

Safety and Tolerability 
As measured by clinical assessments including, but not limited to

Vital signs

Physical examinations

12-lead electrocardiograms (ECGs)

Laboratory measurements (hematology, clinical chemistry, coagulation 
parameters, complement and urinalysis)

Adverse events (AEs), serious adverse events (SAEs), discontinuations

Pharmacokinetic Profile:
Derived GSK3389404 plasma PK parameters including, but not limited to 
area under the concentration-time curve (AUC), maximum observed 
concentration (Cmax), time of maximum observed concentration (tmax),
terminal half-life (t½), and apparent subcutaneous plasma clearance 
(CL/F).
Secondary 
Endpoints

Pharmacodynamic:
Correlation between GSK3389404 PK parameters and PD parameters, 
including hepatitis B virus (HBV) deoxyribonucleic acid (DNA, as 
appropriate), HBsAg, and HBeAg levels (as appropriate, HBeAg-positive
subjects).

Pharmacokinetic:
Derived ISIS 505358 plasma PK parameters including, but not limited to 
area under the concentration-time curve (AUC), maximum observed 
concentration (Cmax), time of maximum observed concentration (tmax), 
and terminal half-life (t½).
Study 
Design

Part 1 will be conducted as a randomized, double-blind, placebo-controlled, 
single ascending dose (SAD) study with 5 planned cohorts.
Cohort A (HBeAg-positive and/or HBeAg –negative subjects): 
 
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Overview
Key Elements of the RAP
GSK3389404 30 mg SC or placebo
Cohort B (HBeAg-positive and/or HBeAg –negative subjects): 
GSK3389404 60 mg SC or placebo
Cohort C (HBeAg-positive and/or HBeAg –negative subjects): 
GSK3389404 120 mg SC or placebo
Cohort C1, optional (HBeAg-positive or HBeAg-negative subjects): 
GSK3389404 120 mg SC or placebo
Cohort D (HBeAg-positive and/or HBeAg –negative subjects): 
GSK3389404 <= 240 mg SC or placebo
Within each cohort, subjects will be randomized to receive GSK3389404 or 
placebo SC in a 3:1 ratio. Cohorts A, B, C, C1, and D will be conducted in a 
sequential fashion; Cohort C1 is an optional cohort that may be dosed after 
Cohort C or in parallel with Cohort D. The decision to enrol the optional 
Cohort C1 will be made at a prior Dose Escalation Committee Meeting. Dose 
Escalation Committee meetings will be held between sequential cohorts.

Since this is the first administration of GSK3389404 in subjects with CHB, the 
study design may change based on emerging data (safety, tolerability, and PD) 
from each cohort and/or part.
Planned 
Analyses

No formal interim analysis is planned for Part 1.

A preliminary PK analysis will be performed after each dose level is completed 
and the Dose Escalation Committee will review preliminary safety tolerability, 
PK and PD data (through Day 3 for at least 3 subjects that received 
GSK3389404) prior to each dose escalation and prior to initiation of Part 2.

The final analysis and reporting of Part 1 may be conducted prior to the 
completion of Part 2.
Analysis 
Populations

All Subjects Screened Population

Safety Population

Pharmacokinetic Population

Pharmacodynamic Population

Intent-to-Treat (ITT) Population
Hypothesis

No formal hypotheses are to be tested in Part 1.
Primary 
Analyses

Safety
Safety and tolerability parameters (AEs/SAEs, physical exams, vital signs, 
12-lead ECGs, and clinical laboratory measurements) will be listed by 
subject and summarized descriptively by treatment group and HBeAg 
status in tabular or graphical formats, as appropriate.

Pharmacokinetics (GSK3389404)
 
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Overview
Key Elements of the RAP
GSK3389404 plasma concentration-time data will be listed by subject and 
summarized descriptively by treatment group and HBeAg status in tabular 
and graphical formats.
GSK3389404 PK parameters will be derived from the concentration-time 
profiles using WinNonlin. The derived PK parameters, including but not 
limited to AUC(0-8), AUC(0-24), AUC(0-∞), Cmax, tmax, t½, and CL/F, will be listed 
by subject and summarized by treatment group and HBeAg status. 
Summaries may also combine treatment groups as applicable.
Secondary 
Analyses

Pharmacodynamics
Pharmacodynamic data (HBsAg, HBeAg, and HBV DNA) will be listed by 
subject and summarized descriptively by treatment group/HBeAg status in 
tabular and graphical formats, as appropriate.
Correlations between PD data in HBeAg-positive and HBeAg-negative 
subjects will be explored graphically. Correlation between PK parameters 
and PD parameters will also be explored graphically.

Pharmacokinetics (ISIS 505358)
ISIS 505358 plasma concentration-time data will be listed by subject and 
summarized descriptively by treatment group and HBeAg status in tabular 
and graphical formats.
ISIS 505358 PK parameters will be derived from the concentration-time 
profiles using WinNonlin. The derived PK parameters, including but not 
limited to AUC(0-8), AUC(0-24), AUC(0-∞), Cmax, tmax, and t½, will be listed by 
subject and summarized by treatment group and HBeAg status. 
Summaries may also combine treatment groups as applicable.
Other
Analyses

Subject disposition, demographics, medical history, prior and concomitant 
medications, and study treatment exposure will be listed by subject and 
summarized descriptively for each part of the study separately.

Response will also be measured based on change from baseline in HBeAg 
level in HBeAg-positive subjects. Change from baseline will be summarized by 
treatment group and listed by subject and treatment group for each part of the 
study separately.
 
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2.
SUMMARY OF KEY PROTOCOL INFORMATION
2.1.
Changes to the Protocol Defined Statistical Analysis Plan
There were no changes or deviations to the planned statistical analysis specified in the 
protocol [(Dated: 28JUN2017)].
2.2.
Study Objective(s) and Endpoint(s)
Objectives
Endpoints
Primary Objectives
Primary Endpoints

To assess the safety, tolerability, and 
PK profile of GSK3389404 in single 
(Part 1) in subjects with CHB.

Safety and Tolerability 
As measured by clinical assessments including, but not 
limited to
o
Vital signs
o
Physical examinations
o
12-lead electrocardiograms (ECGs)
o
Laboratory measurements (e.g., chemistry, 
hematology)
o
Adverse events

Pharmacokinetic Profile:
Derived GSK3389404 plasma PK parameters including, 
but not limited to area under the concentration-time curve 
(AUC), maximum observed concentration (Cmax), time of 
maximum observed concentration (tmax), terminal half-life 
(t½), and apparent subcutaneous plasma clearance 
(CL/F).
Secondary Objectives
Secondary Endpoints

To assess the PD effect of 
GSK3389404 in subjects with CHB 
(Part 1).

Correlation between GSK3389404 PK parameters and PD 
parameters, including HBV DNA (as appropriate), HBsAg, and 
HBeAg levels (as appropriate, HBeAg-positive subjects).

To investigate the PK of the 
metabolite of GSK3389404, also 
known as ISIS 505358, following 
single and multiple dose 
administration of GSK3389404 (Part 
1).

Derived ISIS 505358 plasma PK parameters including, but not 
limited to AUC, Cmax, tmax, and t½.
Exploratory Objectives
Exploratory Endpoints

To assess PD differences in HBeAg-
positive and HBeAg-negative 
subjects with CHB (Part 1, if 
applicable).

Correlation between PD parameters, including HBV DNA, HBV 
RNA, HBsAg, and/or hepatitis B core related antigen (HBcrAg).
 
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2.3.
Study Design
Overview of Study Design and Key Features
This is a Phase IIa, multicenter, randomized, double-blind (sponsor un-blinded in Part 1),
placebo-controlled 2-part study to assess the safety, tolerability, PK, and PD profiles of
GSK3389404 in subjects with CHB.
Part 1 will be conducted as a SAD study with 5 planned cohorts ranging from 30 mg to a maximum 
of 240 mg GSK3389404 (Figure 1). 

Within each cohort, subjects will be randomized to receive GSK3389404 or placebo in a 3:1 
ratio. 

Cohorts A, B, C, C1, and D will be conducted in a sequential fashion; Cohort C1 is an optional 
cohort that may be dosed after Cohort C or in parallel with Cohort D. The decision to enroll the 
optional Cohort C1 will be made at a prior Dose Escalation Committee Meeting.

Dose escalation can only occur after the Dose Escalation Committee have reviewed the 
available safety, tolerability, PK, and PD results for the previous cohort and finds the safety 
profile through Day 3 supportive to proceed with the evaluation of the next higher dose level. 
Figure 1
Part 1: Single Ascending Dose, Study Design Schematic
A = 
active (GSK3389404); HBeAg = hepatitis B virus e-antigen; P = placebo.
◊ = Dose Escalation Committee meeting
1.
Cohort C1 may include HBeAg-positive or HBeAg-negative subjects and, if enrolled, may be dosed after 
Cohort C, in parallel with Cohort D (optional). 
2.
HBeAg-positive and/or HBeAg-negative subjects will be enrolled in these cohorts.
3.
Dose escalations and/or reductions will progress with modifications based on the actual human safety and PK 
data from the preceding cohort(s). Additional dose(s) may also be considered to further assess safety, 
tolerability, PK, and/or PD. Dose will not exceed 240 mg.
Dosing
Part 1, SAD:

Cohort A: GSK3389404 30 mg SC or placebo

Cohort B: GSK3389404 60 mg SC or placebo

Cohort C: GSK3389404 120 mg SC or placebo

Cohort C1 (HBeAg-positive or HBeAg-negative subjects): GSK3389404 
120 mg SC or placebo
 
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Overview of Study Design and Key Features

Cohort D: GSK3389404 <= 240 mg SC or placebo
Treatment 
Assignment
Separate randomization schedules will be generated for each part of the study
(Part 1).
Part 1:

Subjects will be assigned to a dosing cohort based on the order in which 
they are enrolled. 

Within each cohort, subjects will be randomly assigned to study treatment
(GSK3389404: placebo [3:1]).

Subjects that withdraw from Part 1 of the study may be replaced. The new 
subject will be assigned to receive the same study treatment as the subject 
being replaced.
Interim 
Analysis

No formal interim analysis is planned for Part 1.
Rules for 
Safety 
Concern
Part 1:

Dosing in each cohort is contingent on the safety, PK, and PD profiles of at 
least 4 subjects who received GSK3389404 at the previous dose level. 

Dose escalation can only occur after the Dose Escalation Committee has
reviewed the available safety, tolerability, PK, and PD results for the 
previous cohort and finds the safety profile through Day 3 supportive to 
proceed with the evaluation of the next higher dose level. 

Dose escalations and/or reductions will progress with modifications based 
on the actual human safety and PK data from the preceding cohort(s). 

Additional dose(s) may also be considered to further assess safety, 
tolerability, PK, and/or PD.
Type and 
Number of 
Subjects

Adult male and female subjects with CHB between18 and 70 years of age, 
inclusive, and not currently receiving CHB treatment are planned for 
inclusion.

Part 1 (Cohorts A, B, C and D) will enroll HBeAg-positive and/or HBeAg-
negative subjects.

Part 1 (optional Cohort C1) may enroll HBeAg-positive or HBeAg-negative 
subjects (or none at all). In Part 1, approximately 20 to 40 subjects with 
CHB are planned for randomization (30 GSK3389404 and 10 placebo 
under older protocol versions versus 15 GSK3389404 and 5 placebo under 
amendment 3). A range is provided because different countries and sites 
may be enrolling under the older versions of the protocol.
2.4.
Statistical Hypotheses
No formal hypotheses are to be tested in Part 1.
3.
PLANNED ANALYSES
3.1.
Interim Analyses
No formal interim analysis is planned for Part 1.
 
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For Part 1, however, a preliminary PK analysis will be performed after each dose level is 
completed and the Dose Escalation Committee will review preliminary safety,
tolerability, PK and PD data (through Day 3 for at least 3 subjects that received 
GSK3389404) prior to each dose escalation and prior to initiation of Part 2. Dose 
escalation can only occur after the Dose Escalation Committee has found that the safety, 
PK, and PD profiles through Day 3 are supportive to proceed with the evaluation of the 
next higher dose level.
3.2.
Final Analyses
The final planned analysis for Part 1 will be performed after the completion of the 
following sequential steps:
1.
All subjects have completed the study or been considered as lost to follow-up.
o
A completed subject in Part 1 is one who has completed Day 60 visit. An 
ongoing subject who misses the Day 60 visit will be considered as lost to 
follow-up.
o
A completed subject in Part 2 is one who has completed Day 169 visit. An 
ongoing subject who misses the Day 169 visit will be considered as lost to 
follow up.
2.
All required database cleaning activities have been completed and final database 
release and database freeze has been declared for Part 1 by Data Management.
3.
All criteria for unblinding the randomization codes have been met.
The final analysis and reporting of Part 1 will be conducted prior to the completion of 
Part 2.
4.
ANALYSIS POPULATIONS
Population
Definition / Criteria
Analyses Evaluated
All Subjects 
Screened 

The All Subjects Screened Population will 
include all subjects who consent to participate 
in the clinical trial.

The population will be defined separately for 
Part 1 and Part 2.

Screen failure 
summary.
Safety

Include all subjects who receive at least one 
dose of the study treatment (including 
placebo)

This population will be based on the 
treatment the subject actually received.

The population will be defined separately for 
Part 1 and Part 2.

Safety
Intent-To-Treat
(ITT)

Comprise of all randomized subjects.

This population will be based on the 

Efficacy

Study Population
 
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Population
Definition / Criteria
Analyses Evaluated
treatment to which the subject was 
randomized.

Any subject who receives a treatment 
randomization number will be considered to 
have been randomized.
Pharmacokinetic
(PK)

Include all subjects in the Safety population 
for whom at least one evaluable PK sample 
will be obtained and analyzed.

PK samples that may be affected by protocol 
deviations will be reviewed by the study team 
and determined whether or not the sample 
will be excluded. 

The population will be defined separately for 
Part 1 and Part 2 of the study.

PK
Pharmacodynamic
(PD)

Include all subjects in the Safety population 
who provide evaluable PD data.

PD
4.1.
Protocol Deviations

Protocol deviations will be tracked by the study team throughout the conduct of the 
study in accordance with the Protocol Deviation Management Plan.
o
Data will be reviewed prior to unblinding and freezing the database to ensure all 
important deviations and deviations which may lead to exclusion from the 
analysis are captured and categorised on the protocol deviations dataset. 
o
This dataset will be the basis for the summaries and listings of protocol 
deviations.
 
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5.
CONSIDERATIONS FOR DATA ANALYSES AND DATA 
HANDLING CONVENTIONS
Table 1 provides an overview of appendices within the RAP for outlining general 
considerations for data analyses and data handling conventions. 
Table 1
Overview of Appendices
Section
Appendix
RAP Section 5 : General Considerations for Data Analyses & Data Handling Conventions
Section 11.1
Appendix 1: Treatment Phases
Section 11.2
Appendix 2: Data Display Standards & Handling Conventions

Study Treatment & Sub-group Display Descriptors

Baseline Definitions & Derivations

Reporting Process & Standards
Section 11.3
Appendix 3: Derived and Transformed Data

General, Study Population & Safety

Efficacy

Pharmacokinetic

Pharmacodynamic 
Section 11.4
Appendix 4: Premature Withdrawals & Handling of Missing Data

Premature Withdrawals

Handling of Missing Data
Section 11.5
Appendix 5: Values of Potential Clinical Importance
Section 11.6
Appendix 6: Model Checking and Diagnostics for Statistical Analysis
Section 11.7
Appendix 7: Pharmacokinetic Analysis
Other RAP Appendices
Section 11.8
Appendix 8: Abbreviations & Trade Marks
Section 11.9
Appendix 9: List of Data Displays
 
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6.
STUDY POPULATION ANALYSES
6.1.
Overview of Planned Analyses
The study population analyses will be based on the ITT population, unless otherwise 
specified.
Table 2 provides an overview of the planned study population analyses, with full details 
of data displays being presented in Appendix 9: List of Data Displays.
Table 2
Overview of Planned Study Population Analyses
Display Type
Data Displays Generated
Table
Figure
Listing
Randomization
Randomization
Y
Subject Disposition
Number of Subjects Enrolled by Country and Site
Y
Subject Disposition
Y
Screen Failures
Y
Y
Reason for Withdrawals
Y
Important Protocol Deviations
Y
Y
Demography
Demographics 
Y
Y
Baseline Disease Characteristics
Y
Y
Race & Racial Combinations
Y
Y
Age Ranges
Y
Subjects Excluded from Study Populations
Y
Medical Condition & Concomitant Medications
Past/Current Medical Conditions
Y
Y
Concomitant Medications
Y
Y
Baseline Nucleos(t)ide Use
Y
Y
NOTES :

Y = Yes display generated.
6.1.1.
Disposition and Withdrawals
All subjects who provide informed consent will be accounted for in this study. In each 
study part, subject disposition will be tabulated for each study treatment and for all 
subjects combined with the number of subjects who complete the study, prematurely 
discontinue, and the reason (primary and secondary, if available) for early 
discontinuation. Summaries will also be provided for number of subjects enrolled by site, 
reasons for screen failure and important protocol deviations.
Listings of inclusion/exclusion criteria deviations, reasons for screen failure, early 
withdrawal, treatment randomization, important protocol deviations and study treatment 
administration will be provided for each study part.
 
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6.1.2.
Demographic and Baseline Characteristics
Individual subject demographics, race and racial combinations, age ranges and subjects 
excluded from study populations will be presented in listings for each study part.  
Demographic characteristics such as age, sex, race, ethnicity, child bearing potential, 
height, weight, and body mass index (BMI) will be summarized and tabulated by
treatment and for all subjects overall for each study part. Descriptive statistics will be 
presented for age, height, weight, and BMI. Frequency counts and percent will be 
presented for age category, sex, race, ethnicity and child bearing potential.
Other baseline characteristics include but not limited to drug/alcohol use, HIV, HDV and 
hepatitis C information at screening, quantitative HBsAg and quantitative HBV DNA, 
HBeAg status [], HBeAg level, ALT level [x ULN] and HBV viral genotype. 
6.1.3.
Prior and Concomitant Medications
Prior and Concomitant medications will be coded using GSK Drug coding dictionary, 
summarized, and listed for each study part using generic term, verbatim text, and 
indication. The summary of prior and concomitant medications will show the number and 
percentage of subjects taking prior and concomitant medications and corresponding 
Anatomical Therapeutic Chemical (ATC) classification Level 1 (Body System) 
information.
Please refer to Appendix 1 for definition of prior, concomitant and post-treatment 
medications. Handling of partial dates for medications is outlined in Appendix 4: 
Premature Withdrawals & Handling of Missing Data.
6.1.4.
Medical History and Current Medical Conditions
Medical history and current medical conditions will be summarized and display the 
number and percentage of subjects for each body system.
6.1.5.
Treatment Exposure
Summary includes duration of treatment, the number of doses administered and total 
volumes of doses. Dose administration for all subjects in Part 1 will be displayed in the 
listing.
 
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7.
PRIMARY STATISTICAL ANALYSES
The efficacy analyses will be conducted only for Part 2. Other analyses will be applied to 
both Part 1 and Part 2.
7.1.
Efficacy Analyses
The efficacy analyses will be conducted only for Part 2.
7.2.
Safety Analyses
7.2.1.
Overview of Planned Safety Analysis
The primary safety analyses will be based on the “Safety” population for each study part, 
unless otherwise specified.
Data will be listed and summarized according to GSK reporting standards, where 
applicable. Listings will be sorted by cohort, subject and time; summaries will be 
presented by treatment and time. In general, tables, figures and listings will be presented 
separately for Part 1 and Part 2. Subjects receiving placebo will be combined into one 
treatment group in the summaries within each part. 
For categorical variables, the population size (N for sample size and n for available data) 
and the percentage (of available data) for each class of variable will be presented. 
Continuous variables will be summarized using descriptive statistics, including N, mean, 
standard deviation (SD), median, minimum and maximum values. Geometric mean will 
be included for PK parameters, where applicable.
Table 3 provides an overview of the planned safety analyses for each study part, unless 
otherwise specified, with full details of data displays being presented in Appendix 9: List
of Data Displays
Table 3
Overview of Planned Safety Analyses
Endpoint
Absolute
Change from Baseline
Summary
Individual
Summary
Individual
T
F
F
L
T
F
F
L
Exposure
Exposure 
Y
Y
Adverse Events
All AE’s
Y
Y
All Drug-Related AEs
Y
Serious AEs
Y
Y
AEs Leading to 
Withdrawal/Permanent 
Discontinuation of Study 
Treatment
Y
Y
Laboratory Values 
DAIDS Grading
Y
Y
Hematology
Y
 
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Endpoint
Absolute
Change from Baseline
Summary
Individual
Summary
Individual
T
F
F
L
T
F
F
L
Chemistry
Y
Y
Urinalysis
Y
Complement Factors
Y
Serum Creatinine, 
Creatinine 
Phosphokinase, Platelet
Y
ECG’s
Potential Clinical 
Importance
Y
ECG Findings
Y
Y
ECG Values
Y
Vital Signs
Potential Clinical 
Importance
Y
Vitals Values
Y
Other
Injection Site Reactions
Y
Study Treatment 
Discontinuation
Y
NOTES:

T = Table, F = Figures, L = Listings, Y = Yes display generated.

Summary = Represents TFL related to any summaries (i.e. descriptive statistics) of the observed raw data.

Individual = Represents FL related to any displays of individual subject observed raw data.
7.2.2.
Exposure to Study Treatment
Dose administration for Part 1 will also be displayed in separate listings.
7.2.3.
Adverse Events
Adverse events will be coded using MedDRA version 18.1. The AEs will be summarized 
by frequency and percentage of the subjects in safety population and will be sorted by 
System Organ Classes (SOC) in descending order for the total group, secondly by 
Preferred Term (PT) in descending order for the total group. Adverse events will be 
summarized in various subsets, including treatment-emergent AEs (TEAEs) by maximum 
causality, by maximum intensity, leading to treatment discontinuation and SAEs.
A TEAE is defined as an AE with start date between the first dose date of the study 
medication until the follow-up visit. Any AE starting before the first dose date or after the 
follow-up visit will not be included in any summary analyses but will be displayed in the 
listings.
Adverse event severity is classified as mild (grade = 1), moderate (grade = 2), severe 
(grade = 3), potentially life threatening (grade = 4) or resulting in death (grade = 5). 
Adverse events starting after the first dose of study medication with a missing severity 
will be classified as severe. If a subject reports an adverse event more than once within 
 
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that system organ class (SOC)/ preferred term (PT), the AE with the worst case severity 
will be used in the corresponding severity summaries.
Relationship to study medication, as indicated by the Investigator, is classified as “not 
related” or “related”. Adverse events with a missing relationship to study medication will 
be regarded as “related” to study medication. If a subject reports the same AE more than 
once within that SOC/ PT, the AE with the worst case relationship to study medication 
will be used in the corresponding relationship summaries.
All AE tabulations will be performed by treatment and maximum grade and will include 
the number and percentage of subjects.  For each study part, incidence of AEs will be 
tabulated by SOC, PT and maximum grade. 
All AEs leading to withdrawal from study will be identified by using the variable 
pertaining to outcome of the Adverse Events page of the (e)CRF, and listed separately for 
each study part.
Serious adverse events (SAEs), including deaths, are those events recorded as “Serious” 
on the Adverse Events page of the (e)CRF, and will be listed separately for each study 
part.
Listing of various adverse events experienced by individual subjects and relationship 
between SOC and verbatim text will be provided for each study part.
AEs will be graded by the clinic using the DAIDS Table for Grading the Severity of 
Adult and Paediatric Adverse Events (National Institute of Allergy and Infectious 
Diseases) as defined in the following link:
Division of AIDS (DAIDS) Table for Grading the Severity of Adult and Pediatric 
Adverse Events, Version 2.0, November 2014
For completely missing or partial missing AE start date or end date, imputation rules will 
be applied following Section 11.4.2.
7.2.4.
Vital Signs
Vital signs will be measured after 5 minutes of rest in the semi-supine or supine position. 
Temperature and respiration rate will be collected as single measurements. 
Vital sign data, as well as change from baseline, will be summarized for each parameter 
by scheduled assessment.  
Vital signs (blood pressure, heart rate, temperature, and weight) will also be listed for 
each subject.  
The number and percentage of subjects with clinically relevant abnormalities will be also 
presented in a summary table.
 
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7.2.5.
Physical Examinations
Physical examination results will be listed only.
Clinically significant abnormalities observed in physical examination results occurring 
after administration of study drug will be recorded as adverse events.
7.2.6.
Injection Site Reactions
Injection site reactions will be reported as adverse events.
7.2.7.
12-lead electrocardiograms (ECGs)
The following ECG parameters will be reported for each study part (msec): PR, QRS, 
QT, QTc, QTcF and HR (bpm). All ECGs will be collected after 5 minutes of rest in the 
semi-supine or supine position. Triplicate 12-lead ECGs will be obtained at the Screening 
visit and pre-dose on Day 1. Single 12-lead ECGs will be obtained at all other time 
points. The average of these assessments will be used as the baseline per Section
11.2.2.1. Also the average will be the representative of the subject at all other time points.
Summary tables including actual values and change from Baseline values will be 
presented for each ECG results by scheduled assessment.
An ECG outlier analysis will be performed showing the proportion of subjects out of
clinical concern range. The overall interpretation of the ECG results (Normal; Abnormal; 
Not Clinically Significant; and Abnormal, Clinically Significant) will also be
summarized.
7.2.8.
Laboratory Measurements
Central laboratory results will be included in the reporting of this study for hematology, 
clinical chemistry, complement factors and urinalysis.  
Protocol-specified clinical laboratory tests will be summarized using descriptive 
statistics.  The statistics will be presented for baseline, as defined in Section 11.2.2.1, and 
change from baseline to each scheduled assessment. Presentations will use reported units, 
as provided by the labs. Based upon laboratory normal ranges, the laboratory test results 
will be categorized according to the normal range as low (below the lower limit), normal 
(within normal range) and high (above upper limit).
The protocol required parameters to be analyzed are as follows:

Hematology: Platelet count, RBC count (MCV, MCH), Hemoglobin, Hematocrit, 
Reticulocyte count, and WBC count with differential: Neutrophils, Lymphocytes, 
Monocytes, Eosinophils, Basophils.

Clinical Chemistry: BUN, Creatinine, GFR, Uric acid, Glucose, Potassium, 
Sodium, Calcium, Phosphorous, Magnesium, AST, ALT, ALP, GGT, CPK, Total 
and direct bilirubin, Total protein, Albumin, hs-CRP.

Coagulation: INR, PT, aPTT.
 
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
Complement: C3, C4, C5a, Bb
Summaries of subject shifts in grade will be provided. These summaries will display the 
number and percentage of subjects with a maximum grade during each assessment time 
based on their baseline grade.
Complement factors will be summarized using change between maximum level observed 
post-dose (considering all time points) and pre-study drug administration. Percent change 
relative to pre-study drug administration will be presented.
Clinical laboratory abnormalities will be graded based on the DAIDS Table for Grading 
the Severity of Adult and Paediatric Adverse Events (National Institute of Allergy and 
Infectious Diseases) will be applied to hematology, chemistry and urinalysis only. 
Abnormalities (DAIDS Grade 1 or higher) for individual subjects will be listed.
Separate summary tables for hematology, chemistry laboratory tests and urinalysis tests 
will be produced.
7.2.9.
Study Treatment Discontinuation
For each study part, a listing will present subjects for whom the study treatment was 
stopped together with the reason and the status of subject.
7.3.
Pharmacokinetic Analyses (GSK3389404)
7.3.1.
Overview of Planned Pharmacokinetic Analyses
The PK analyses will be based on the “Pharmacokinetic” population.
GSK3389404 plasma concentration-time data will be listed by subject and summarized 
descriptively by treatment group and HBeAg status in tabular and graphical formats.
GSK3389404 PK parameters will be derived from the concentration-time profiles using 
WinNonlin. The derived PK parameters will be listed by subject and summarized by
treatment group and HBeAg status. 
Table 4 provides an overview of the planned analyses, with full details being presented in 
Appendix 9: List of Data Displays. 
Table 4
Overview of Planned Pharmacokinetic Analyses
Endpoints
Untransformed
Log-Transformed
Stats Analysis
Summary
Individual
Stats Analysis
Summary
Individual
T
F
L
T
F
F
L
T
F
L
T
F
F
L
Plasma Drug 
Concentrations
Y
Y 
[1] 
[2]
Y 
[1]
Y
Derived PK 
Parameters
Y
Y
Y
Y
 
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NOTES :

T = Table, F = Figure, L = Listings, Y = Display generated.

Stats Analysis = Represents TFL related to any formal statistical analyses (i.e. modelling) conducted.

Summary = Represents TFL related to any summaries (i.e. descriptive statistics) of the observed raw data.

Individual = Represents FL related to any displays of individual subject observed raw data.
1.
Linear and Semi-Log plots will be created on the same display.
2.
Separate Mean (+ SD) and Median plots will be generated.    
7.3.2.
Drug Concentration Measurements
Refer to Appendix 2: Data Display Standards & Handling Conventions (Reporting 
Process & Standards).
7.3.3.
Pharmacokinetic Parameters
7.3.3.1.
Deriving Pharmacokinetic Parameters

Refer to Appendix 2: Data Display Standards & Handling Conventions (Reporting 
Process & Standards) for the treatment of concentrations below the assay’s lower 
limit of quantification (LLQ).

The PK parameters will be calculated by standard non-compartmental analysis 
according to current working practices and using Phoenix WinNonlin® (WNL) 6.4 or 
higher (Pharsight Corporation, a Certara Company, Princeton, NJ), and/or SAS®
Version 9.3 or higher. Graphics will be prepared using the same version of SAS®.

All calculations of non-compartmental parameters will be based on actual sampling 
times.

In WNL, when the terminal slope cannot be estimated using the default fit method of 
“BestFit”, consult GSK ClinPharm rep (Kelong Han). GSK ClinPharm rep will 
determine whether to exclude this subject / profile due to atypical PK profile, or will 
select the fit method of “TimeRange” with specific time points.

Pharmacokinetic parameters described in Table 5 will be determined from the plasma 
concentration-time data, as data permits, for GSK3389404 on Day 1 of Part 1:
Table 5
Derived Pharmacokinetic Parameters (Part 1)
Parameter
Parameter Description
AUC(0-t)
Area under the concentration-time curve from time zero to the time of the last quantifiable 
concentration (ng·h/mL), calculated using the linear trapezoidal rule for each incremental 
trapezoid and the log trapezoidal rule for each decremental trapezoid.
AUC(0-8)
Area under the concentration-time curve from time zero to 8 hours post-dose (ng·h/mL),
calculated using the linear trapezoidal rule for each incremental trapezoid and the log 
trapezoidal rule for each decremental trapezoid. Actual elapsed time at 8 hours post-dose 
will be used for the calculation.
AUC(0-∞)
Area under the concentration-time curve extrapolated to infinity (ng·h/mL), calculated using 
the linear trapezoidal rule for each incremental trapezoid and the log trapezoidal rule for 
 
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Parameter
Parameter Description
each decremental trapezoid (AUCINF_pred in WNL) as: 
AUC = AUC(0-t) + C(t) / z
where C(t) is the predicted concentration at the final observation time.
AUC(0-24)
Area under the concentration-time curve from time zero to 24 hours post-dose (ng·h/mL), 
calculated using the linear trapezoidal rule for each incremental trapezoid and the log 
trapezoidal rule for each decremental trapezoid.  Actual elapsed time at 24 hours post-dose 
will be used for the calculation.
%AUCex
The percentage of AUC(0-∞) obtained by extrapolation (%). %AUCex will be calculated as:
[AUC(0-∞) – AUC(0-t)] / AUC(0-∞) x 100
Cmax
Maximum observed concentration in plasma (ng/mL), determined directly from the 
concentration-time data.
tmax
Time to reach Cmax (h), determined directly from the concentration-time data.
C24
Concentration in the plasma at 24 hours after dosing (ng/mL), obtained from interpolation of 
the observed concentration versus time data.
t½
Apparent terminal half-life (h) will be calculated as: 
t½ = ln2 / z
z
Apparent terminal rate constant (1/h), determined by linear regression of the terminal points 
of the log-linear concentration-time curve.  Visual assessment will be used to identify the 
terminal linear phase of the concentration-time profile.  A minimum of 3 data points will be 
used for determination.
tlag
Lag time before observation of quantifiable concentrations in plasma (h), obtained directly 
from the observed concentration versus time data.
CL/F
Apparent subcutaneous plasma clearance after extravascular dosing (L/h), calculated as 
administered dose divided by AUC(0-∞).  No dose adjustments are needed for this 
calculation.  
NOTES:

Additional parameters may be included as required.
7.3.3.2.
Statistical Analysis of Pharmacokinetic Parameters
The following pharmacokinetic statistical analyses will only be performed, if sufficient 
data is available (i.e. if subjects have well defined plasma profiles). 
Pharmacokinetic Statistical Analyses
Endpoint(s)

All endpoints will be natural-log transformed prior to the analysis

Dose Proportionality: AUC(0-t), AUC(0-8), AUC(0-∞), and Cmax for Part 1 
Model Specification

Dose Proportionality in Part 1 will be assessed separately by means of power model: 
Y=α∙Xβ using the least-squares linear regression model: [ln(Y) = α+ β∙ln(X)], where Y
denotes the PK parameter being analyzed and X denotes dose. 
o
PK parameters will be log transformed prior to analysis
o
For single dosing, Day 1 data from Part 1 may be combined as appropriate
 
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Pharmacokinetic Statistical Analyses
o
If the power mode does not show dose proportionality then pairwise analysis of 
variance (ANOVA) may be used as an exploratory analysis to understand the dose 
where dose proportionality fails
Model Checking & Diagnostics

Refer to Appendix 6: Model Checking and Diagnostics for Statistical Analyses
Model Results Presentation

Dose Proportionality: The intercept α and the slope β with corresponding 90% CIs will be 
estimated and presented for each PK parameter
8.
SECONDARY STATISTICAL ANALYSES
8.1.
Pharmacodynamic Analyses
8.1.1.
Overview of Planned Pharmacodynamic Analyses
The pharmacodynamic analyses will be based on the “Pharmacodynamic” population.
Pharmacodynamic data (HBsAg, HBeAg, HBV DNA, HBV RNA, and HBcrAg) will be 
listed by subject and summarized descriptively by treatment group/HBeAg status in 
tabular and graphical formats, as appropriate.
PD parameters (Nadir, Time to Nadir, and Log10 Change from Baseline to Nadir) will be 
derived from the concentration-time profiles using WinNonlin or SAS. The derived PD 
parameters will be listed by subject and summarized by treatment group and HBeAg 
status. 
Correlations between PD data in HBeAg-positive and HBeAg-negative subjects will be 
explored graphically. Correlation between PK parameters (AUC(0-∞) and Cmax) and PD 
parameters (Nadir, Time to Nadir, and Log10 Change from Baseline to Nadir) will also be 
explored graphically.
Correlations between individual PD data for HbsAg and data for ALT will be explored 
graphically.
Table 6 provides an overview of the planned pharmacodynamic analyses, with full details 
of data displays being presented in Appendix 9: List of Data Displays.
 
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Table 6
Overview of Planned Pharmacodynamic Analyses
[Endpoint / Parameter/ 
Display Type]
Untransformed
Absolute
Log10 Change from Baseline
Stats 
Analysis
Summary
Individual
Stats 
Analysis
Summary
Individual
T
F
L
T
F
F
L
T
F
L
T
F
F
L
HBsAg Values
Y
Y
[1]
Y
Y
Y
[1]
Y
HBeAg Values
Y
Y
[1]
Y
Y
Y
[1]
Y
HBV DNA Values
Y
Y
[1]
Y
Y
Y
[1]
Y
HBV RNA Values
Y
Y
[1]
Y
Y
Y
[1]
Y
HbcrAg Values
Y
Y
[1]
Y
Y
Y
[1]
Y
HBsAg Parameters
Y
Y
HBeAg Parameters
Y
Y
HBV DNA Parameters
Y
Y
HBV RNA Parameters
Y
Y
HbcrAg Parameters
Y
Y
Correlations between PD in 
HBeAg-positive and HBeAg-
negative subjects
Y
Correlations between PD and 
PK Parameters
Y
Y
Correlations between HbsAg, 
HBV DNA, HbeAg, and ALT 
data
Y
Y
NOTES:

T = Table, F = Figure, L = Listing, Y = Yes display generated.

Stats Analysis = Represents TFL related to any formal statistical analyses (i.e. modelling) conducted.

Summary = Represents TFL related to any summaries (descriptive statistics) of the observed raw data.

Individual = Represents FL related to any displays of individual subject observed raw data.
1.
Separate Mean (+ SD) and Median plots will be generated.
8.2.
Pharmacokinetic Analyses (ISIS 505358)
8.2.1.
Overview of Planned Pharmacokinetic Analyses
The pharmacokinetic (PK) analyses of ISIS 505358 data will be based on the PK
population and will follow that described for GSK3389404.
 
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ISIS 505358 plasma concentration-time data will be listed by subject and summarized 
descriptively by treatment group and HbeAg status in tabular and graphical formats.
ISIS 505358 PK parameters will be derived from the concentration-time profiles using 
WinNonlin. The derived PK parameters will be listed by subject and summarized by
treatment group and HbeAg status. 
The results of dose proportionality analysis of ISIS 505358 data will be presented in 
tabular format, separately for each Part. 
9.
EXPLORATORY STATISTICAL ANALYSES
9.1.
Pharmacodynamic Analyses
Pharmacodynamic data (HbsAg, HbeAg, HBV DNA, HBV RNA, and HbcrAg) and PD 
parameters will be listed by subject and summarized separately for HbeAg-positive and 
HbeAg-negative subjects with CHB in tabular and graphical formats, as appropriate (Part 
1, if applicable).
9.2.
Rate of Seroconversion
No analysis will be performed for rate of seroconversion for Part 1.
 
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10.
REFERENCES
GSK Document Number 2016N277028_04. Study 205670 Protocol Amendment 03 
Effective 28 JUN 2017.
Neuenschwander, B., Branson, M., & Gsponer, T. (2008). Critical aspects of the 
Bayesian approach to Phase I cancer trials. Statistics in Medicine, 27:2420-39.
 
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11.
APPENDICES
Section
Appendix
RAP Section 5 : General Considerations for Data Analyses & Data Handling Conventions
Section 11.1
Appendix 1: Treatment Phases
Section 11.2
Appendix 2: Data Display Standards & Handling Conventions

Study Treatment & Sub-group Display Descriptors

Baseline Definitions & Derivations

Reporting Process & Standards
Section 11.3
Appendix 3: Derived and Transformed Data

General, Study Population & Safety

Efficacy

Pharmacokinetic

Pharmacodynamic and or Biomarkers
Section 11.4
Appendix 4: Premature Withdrawals & Handling of Missing Data

Premature Withdrawals

Handling of Missing Data
Section 11.5
Appendix 5: Values of Potential Clinical Importance
Section 11.6
Appendix 6: Model Checking and Diagnostics for Statistical Analysis
Section 11.7
Appendix 7: Pharmacokinetic Analysis
Other RAP Appendices
Section 11.8
Appendix 8: Abbreviations & Trade Marks
Section 11.9
Appendix 9: List of Data Displays
 
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11.1.
Appendix 1: Treatment Phases
11.1.1.
Treatment Phases
Part 1 is a SAD study, thus subjects will receive treatment dose on Day 1. Subjects are 
required to return to the study site for post-treatment Follow-up visits on Days 3, 8, 15, 
22, 30, and 60.
Figure 2
Part 1: Single Ascending Dose, Participation Flow
Note: Five cohorts are planned to receive a SC dose of GSK3389404 (30 mg to 240 mg) 
or placebo 
*
In-house stays are optional from Day -1 to Day 3 based on study site/subject preference. No study procedures are 
scheduled for Day 2 but subjects may remain in-house until all Day 3 assessments are completed.
 
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11.2.
Appendix 2: Data Display Standards & Handling 
Conventions
11.2.1.
Study Treatment & Sub-group Display Descriptors
Treatment Group Descriptions for Part 1
Data Displays for Reporting 
Description
Placebo
GSK3389404 30mg 
GSK3389404 120mg 
All Active
Total
Placebo (HBeAg-)
GSK3389404 30mg (HBeAg-)
GSK3389404 120mg (HBeAg-) 
All Active (HBeAg-)
Total (HBeAg-)
Placebo (HBeAg+)
GSK3389404 30mg (HBeAg+) 
GSK3389404 120mg  (HBeAg+)
All Active (HBeAg+)
Total (HBeAg+)
11.2.2.
Baseline Definition & Derivations
11.2.2.1.
Baseline Definitions
For all endpoints (expect as noted in baseline definitions) the baseline value will be the
last value/assessment before the first dose of the study treatment (Day 1 pre-dose). If 
there are multiple assessments collected at the same scheduled time (e.g., triplicate 12-
lead ECGs), the average of these assessments will be used as the baseline.
 
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11.2.2.2.
Derivations and Handling of Missing Baseline Data
Definition
Reporting Details
Change from Baseline
= Post-Dose Visit Value – Baseline
% Change from Baseline
= 100 x [(Post-Dose Visit Value – Baseline) / Baseline]
Log10 Change from Baseline
log10(Post-Dose Visit Value / Baseline)
Maximum Change from Baseline
= Calculate the change from baseline at each given timepoint 
   and determine the maximum change
Maximum Log10 Change from 
Baseline
= Calculate the log10 change from baseline at each given 
timepoint and determine the maximum log10 change
NOTES:

Unless otherwise specified, the baseline definitions specified in Section 11.2.2.1 Baseline Definitions will be used 
for derivations for endpoints / parameters and indicated on summaries and listings.

Unless otherwise stated, if baseline data is missing no derivation will be performed and will be set to missing.

The baseline definition will be footnoted on all change from baseline displays.
11.2.3.
Reporting Process & Standards
Reporting Process
Software

The currently supported versions of SAS, R, WinBUGS and WinNonLin software will be used.
Analysis Datasets 

Analysis datasets will be created according to CDISC standards (SDTM IG Version 3.2 & 
AdaM IG Version 1.0

For creation of AdaM datasets (ADCM/ADAE), the same version of dictionary datasets will be 
implemented in SDTM.
Generation of RTF Files

RTF files will be generated.
Reporting Standards
General

The current GSK Integrated Data Standards Library (IDSL) will be applied for reporting, unless 
otherwise stated:
o
4.03 to 4.23: General Principles
o
5.01 to 5.08: Principles Related to Data Listings
o
6.01 to 6.11: Principles Related to Summary Tables
o
7.01 to 7.13: Principles Related to Graphics 
Formats

All data will be reported according to the actual treatment the subject received unless 
otherwise stated.

GSK IDSL Statistical Principles (5.03 & 6.06.3) for decimal places (DP’s) will be adopted for 
 
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Reporting Standards
reporting of data based on the raw data collected.

Numeric data will be reported at the precision collected on the eCRF.

The reported precision from non eCRF sources will follow the IDSL statistical principles but 
may be adjusted to a clinically interpretable number of DP’s.
Planned and Actual Time

Reporting for tables, figures and formal statistical analyses:

Planned time relative to dosing will be used in figures, summaries, statistical analyses and 
calculation of any derived parameters, unless otherwise stated.

The impact of any major deviation from the planned assessment times and/or scheduled 
visit days on the analyses and interpretation of the results will be assessed as appropriate.

Reporting for Data Listings: 

Planned and actual time relative to study drug dosing will be shown in listings (Refer to 
IDSL Statistical Principle 5.05.1).

Unscheduled or unplanned readings will be presented within the subject’s listings. 

Visits outside the protocol defined time-windows (i.e. recorded as protocol deviations) will 
be included in listings but omitted from figures, summaries and statistical analyses.
Unscheduled Visits

Unscheduled visits will not be included in summary tables.

Unscheduled visits will not be included in figures.

All unscheduled visits will be included in listings.
Descriptive Summary Statistics
Continuous Data
sample size, mean, median, standard deviation, minimum, and maximum
Categorical Data
N, n, frequency, %
Reporting of Pharmacokinetic Concentration Data
Descriptive 
Summary Statistics
Refer to IDSL Statistical Principle 6.06.1
Assign zero to NQ values (Refer to GUI_51487 for further details)
Reporting of Pharmacokinetic Parameters
Descriptive 
Summary Statistics
(Log Transformed)
N, n, geometric mean, 95% CI of geometric mean, standard deviation (SD)
of log-transformed data and between geometric coefficient of variation
(CVb/w (%)) will be reported.
[1] CVb (%) = √(exp(SD2) – 1) * 100
(SD = SD of log transformed data)
Parameters Not 
Being Log 
Transformed
tmax, %AUCex, tlag, z, z lower, z upper, z no. of points
Listings
Interval, number of observations included in calculation of z, regression 
coefficient and percent AUC extrapolated (%AUCex)
Graphical Displays

Refer to IDSL Statistical Principals 7.01 to 7.13.
 
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11.3.
Appendix 3: Derived and Transformed Data
11.3.1.
General
Multiple Measurements at One Time Point

Mean of the measurements will be calculated and used in any derivation of summary statistics 
but if listed, all data will be presented.

If there are two values within a time window the value closest to the target day for that window 
will be used. If values are the same distance from the target then the mean will be taken.

Subjects having both High and Low values for Normal Ranges at any post-baseline visits for 
safety parameters will be counted in both the High and Low categories of “Any visit post-
baseline” row of related summary tables. This will also be applicable to relevant Potential 
Clinical Importance summary tables.
Study Day

Calculated as the number of days from randomization date:

Ref Date = Missing                       → Study Day = Missing 

Ref Date < Randomization Date   → Study Day = Ref Date – Randomization Date    

Ref Data ≥ Randomization Date   → Study Day = Ref Date – (Randomization Date) + 1    
11.3.2.
Study Population
Demographics
Age

GSK standard IDSL algorithms will be used for calculating age where birth date will be imputed 
as follows:
o
Any subject with a missing day will have this imputed as day ‘15’. 
o
Any subject with a missing date and month will have this imputed as ‘30th June’.

Birth date will be presented in listings as ‘YYYY’.
Body Mass Index (BMI)

Calculated as Weight (kg) / [Height (m)2
Extent of Exposure

Number of days of exposure to study drug will be calculated based on the formula:  
Duration of Exposure in Days = Treatment Stop Date – (Treatment Start Date) + 1

Subjects who were randomized but did not report a treatment start date will be categorised as 
having zero days of exposure. 

The cumulative dose will be based on the formula:
Cumulative Dose = Sum of (Number of Days x Total Daily Dose)

If there are any treatment breaks during the study, exposure data will be adjusted accordingly.
 
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Laboratory Parameters

If a laboratory value which is expected to have a numeric value for summary purposes, has a 
non-detectable level reported in the database, where the numeric value is missing, but typically 
a character value starting with ‘<x’ or ‘>x’ (or indicated as less than x or greater than x in the 
comment field) is present, the number of significant digits in the observed values will be used to 
determine how much to add or subtract in order to impute the corresponding numeric value. 
o
Example 1: 2 Significant Digits =  ‘< x ‘ becomes x – 0.01
o
Example 2: 1 Significant Digit   =  ‘> x’ becomes x + 0.1
o
Example 3: 0 Significant Digits = ‘< x’ becomes x – 1    
11.3.3.
Safety
ECG Parameters
RR Interval

IF RR interval (msec) is not provided directly, then RR can be derived as:
[1] If QTcB is machine read & QTcF is not provided, then:
[2] If QTcF is machine read and QTcB is not provided, then: 

If ECGs are manually read, the RR value preceding the measurement QT interval should be a 
collected value THEN do not derive.
Corrected QT Intervals

When not entered directly in the eCRF, corrected QT intervals by Bazett’s (QTcB) and 
Fredericia’s (QTcF) formulas will be calculated, in msec, depending on the availability of other 
measurements.

IF RR interval (msec) is provided then missing QTcB and/or QTcF will be derived as: 
Laboratory Parameters

If a laboratory value which is expected to have a numeric value for summary purposes, has a 
non-detectable level reported in the database, where the numeric value is missing, but typically 
a character value starting with ‘<x’ or ‘>x’ (or indicated as less than x or greater than x in the
comment field) is present, the number of significant digits in the observed values will be used to 
determine how much to add or subtract in order to impute the corresponding numeric value. 
o
Example 1: 2 Significant Digits =  ‘< x ‘ becomes x – 0.01
o
Example 2: 1 Significant Digit   =  ‘> x’ becomes x + 0.1
o
Example 3: 0 Significant Digits = ‘< x’ becomes x – 1    
 
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11.3.4.
Pharmacokinetic

Derived GSK3389404 plasma PK parameters including, but not limited to area under the 
concentration-time curve (AUC), maximum observed concentration (Cmax), time of maximum 
observed concentration (tmax), terminal half-life (t½), and apparent subcutaneous plasma 
clearance (CL/F).

Derived ISIS 505358 plasma PK parameters including, but not limited to AUC, Cmax, tmax, and t½.
PK Concentrations and Parameters

How to handle values below the quantification limit for the calculation of individual 
pharmacokinetic profiles
If one or more non-quantifiable (NQ) values occur in a profile before the first measurable 
concentration, they will be assigned a value of zero concentration. For linear plots, zero 
concentration value(s) before the first measurable concentration will be included in the plot. For 
semilogarithmic log-linear plots, zero concentration value(s) before the first measurable 
concentration will be assigned a missing value.
If a single NQ value occurs between measurable concentrations in a profile, the NQ should 
generally be omitted (set to missing) in the derivation of pharmacokinetic parameters, statistical 
analysis, and the individual subject plots.
If two or more NQ values occur in succession between measurable concentrations, the profile will 
be deemed to have terminated at the last measurable concentration prior to these NQs. For the 
purpose of individual subject plots, these NQs will be set to 0, and the subsequent measurable 
concentrations will be retained. For the derivation of pharmacokinetic parameters, these NQs and 
any subsequent measurable concentrations will be omitted (set to missing).
NQs which occur after the last measurable concentration will be omitted (set to missing) in the 
derivation of pharmacokinetic parameters and from the individual subject plots. In some 
circumstances, there may be a pharmacokinetic rationale for fluctuation resulting in non-measurable 
concentrations in the middle of the concentration-time profile (e.g., entero-hepatic recycling, erratic 
absorption from transdermal/inhaled formulations). In these cases, the NQ values could be set to 
missing or to some other values (e.g., ½ LLQ) and subsequent valid concentrations may be 
retained. A reference line indicating LLQ would then be included in plots.
For the calculation of mean or median pharmacokinetic profiles
When estimating the mean or median value for the concentration at a given time point (i.e., 
descriptive mean or median curve), the following guidelines should be considered: All NQ values 
will be set to zero except when an individual NQ falls between two quantifiable values, in which 
case it will be omitted from the calculation of mean or median profiles. Measurable concentrations 
which follow more than one consecutive mid-profile NQ will be omitted (set to missing).
The mean/median value at a time-point where one or more samples have NQ values will be 
reported (in tabular or graphical fashion) even if the mean/median value is below the LLQ of the 
assay. For linear plots, zero concentration value(s) will be included in the plot. For semilogarithmic
log-linear plots, zero concentration value(s) will be assigned a missing value. Zero mean or median
values will be included in summary tables.
In certain cases, the NQ values could be set to missing or to some other values (e.g., ½ LLQ) with 
 
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
Derived GSK3389404 plasma PK parameters including, but not limited to area under the 
concentration-time curve (AUC), maximum observed concentration (Cmax), time of maximum 
observed concentration (tmax), terminal half-life (t½), and apparent subcutaneous plasma 
clearance (CL/F).

Derived ISIS 505358 plasma PK parameters including, but not limited to AUC, Cmax, tmax, and t½.
proper scientific justification(s). A reference line indicating LLQ would then be included in plots.
It should be noted that a high proportion of NQ values may affect the standard deviation (SD); if 
more than 30% of values are imputed, then SD will not be displayed. Any table of summary 
statistics for concentration-time data will report N (number of subjects in the analysis population), n 
(number of subjects with non-missing values) and number imputed (number of subjects with 
imputed values (i.e., NQ assigned zero concentration). BQL (Below the Quantification Limit) may be 
displayed in listings by legacy systems instead of NQ; these abbreviations are interchangeable and 
mean that a sample has been received, analysed and a concentration below the LLQ of the assay 
found.
Scientific judgement and prior knowledge should always be used in applying these guidelines.
How to Handle Anomalous Concentration Values
Individual concentrations deemed to be anomalous will be excluded from the pharmacokinetic 
analysis and median and mean profiles; such anomalous values will be identified (e.g., flagged by 
an asterisk or an appropriate footnote) in the data listings of the study report. Anomalous values are 
those that are inconsistent with known or expected pharmacokinetic behaviour of the drug, and are 
not defined in a statistical outlier sense. Clear justification must be provided in the report for 
exclusion of any data. Individual plasma concentration-time profiles by actual time and 
median/mean profiles by treatment (dose) by nominal time will be plotted.  Each of the figures will 
contain one plot on the untransformed scale (i.e., a linear plot) and one plot on the loge-transformed 
scale (i.e., semilogarithmic log-linear plot). In addition, a plot showing all individual subjects for each 
treatment (dose) will be produced (both linear and semilogarithmic log-linear).
11.3.5.
Pharmacodynamic 

Correlation between GSK3389404 PK parameters and PD parameters, including HBV DNA (as 
appropriate), HbsAg, and HbeAg levels (as appropriate, HbeAg-positive subjects).

Correlation between PD parameters, including HBV DNA, HBV RNA, HbsAg, and/or hepatitis B core 
related antigen (HbcrAg).
PD Values and Parameters

HBV DNA (as appropriate), HBV RNA, HbsAg, HbeAg and HbcrAg levels that are below the LLOQ will 
be imputed as LLOQ – 1. 

In the scenario of multiple BLQ values, the Time to Nadir will be to the first BLQ value.
 
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11.4.
Appendix 4: Premature Withdrawals & Handling of Missing 
Data
11.4.1.
Premature Withdrawals
Element
Reporting Detail
General

Subject study completion (i.e. as specified in the protocol) was defined as 
below:
o
A completed subject in Part 1 is one who has completed Day 60 visit. 
An ongoing subject who misses the Day 60 visit will be considered as 
lost to follow-up.
o
A completed subject in Part 2 is one who has completed Day 169 visit. 
An ongoing subject who misses the Day 169 visit will be considered as 
lost to follow up.

Withdrawn subjects will be replaced in Part 1 but not be replaced in Part 2.

All available data from subjects who were withdrawn from the study will be listed 
and all available planned data will be included in summary tables and figures, 
unless otherwise specified.
11.4.2.
Handling of Missing Data
Element
Reporting Detail
General

Missing data occurs when any requested data is not provided, leading to blank 
fields on the collection instrument:
o
These data will be indicated by the use of a “blank” in subject listing 
displays. Unless all data for a specific visit are missing in which case the 
data is excluded from the table. 
o
Answers such as “Not applicable” and “Not evaluable” are not considered to 
be missing data and should be displayed as such.
Outliers

Any subjects excluded from the summaries and/or statistical analyses will be 
documented along with the reason for exclusion in the clinical study report.
11.4.2.1.
Handling of Missing Dates
Element
Reporting Detail
General
Partial dates will be displayed as captured in subject listing displays.
Adverse 
Events

The eCRF allows for the possibility of partial dates (i.e., only month and year) to 
be recorded for AE start and end dates; that is, the day of the month may be 
missing. In such a case, the following conventions will be applied for calculating 
the time to onset and the duration of the event:
o
Missing Start Day: First of the month will be used unless this is before the 
start date of study treatment; in this case the study treatment start date will 
be used and hence the event is considered On-treatment as per Appendix 
 
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Element
Reporting Detail
1: Treatment States and Phases.
o
Missing Stop Day: Last day of the month will be used, unless this is after the 
stop date of study treatment; in this case the study treatment stop date will 
be used.

Completely missing start or end dates will remain missing, with no imputation 
applied. Consequently, time to onset and duration of such events will be 
missing.

Start or end dates which are completely missing (i.e. no year specified) will 
remain missing, with no imputation applied.
11.4.2.2.
Handling of Partial Dates
Element
Reporting Detail
Concomitant 
Medications

Partial dates for any concomitant medications recorded in the CRF will be 
imputed using the following convention:
o
If the partial date is a start date, a ‘01’ will be used for the day and ‘Jan’ will 
be used for the month
o
If the partial date is a stop date, a ‘28/29/30/31’ will be used for the day 
(dependent on the month and year) and ‘Dec’ will be used for the month.

The recorded partial date will be displayed in listings.
Adverse 
Events

Any partial dates for adverse events will be raised to data management. If the 
full date cannot be ascertained, the following assumptions will be made:
o
If the partial date is a start date, a ‘01’ will be used for the day and ‘Jan’ will 
be used for the month. 
o
However, if these results in a date prior to Day 1 and the event could 
possibly have occurred during treatment from the partial information, then 
the Week 1 Day 1 date will be assumed to be the start date. 
o
The AE will then be considered to start on-treatment (worst case).
o
If the partial date is a stop date, a ‘28/29/30/31’ will be used for the day 
(dependent on the month and year) and ‘Dec’ will be used for the month.

The recorded partial date will be displayed in listings.
 
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11.5.
Appendix 5: Values of Potential Clinical Importance
11.5.1.
ECG
ECG Parameter
Units
Clinical Concern Range
Lower
Upper
Absolute
Absolute QTc Interval
msec
> 450
Absolute PR Interval
msec
< 110 
> 220 
Absolute QRS Interval
msec
< 75 
> 110 
Change from Baseline
Increase from Baseline QTc
msec
> 60
11.5.2.
Vital Signs
Vital Sign Parameter
(Absolute)
Units
Clinical Concern Range
Lower
Upper
Systolic Blood Pressure
mmHg
< 85
> 160
Diastolic Blood Pressure
mmHg
< 45
> 100
Heart Rate
bpm
< 40
> 110
 
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11.6.
Appendix 6: Model Checking and Diagnostics for 
Statistical Analyses
11.6.1.
Statistical Analysis Assumptions
Endpoint(s)

PK endpoints AUC and Cmax
Analysis

Mixed effects

Model assumptions will be applied, but appropriate adjustments maybe made based on the 
data.

The Kenward and Roger method for approximating the denominator degrees of freedom and 
correcting for bias in the estimated variance-covariance of the fixed effects will be used.
 
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11.7.
Appendix 7: Pharmacokinetic Analyses
11.7.1.
Dose Proportionality
Dose proportionality of GSK3389404 and ISIS 505358 following single-dose administration in Part 
1 will be studied using the power model
y = × (dose)
where y denotes the PK parameter being analyzed [AUC(0-∞), Cmax, C24 for Part 1]. 
Dose proportionality implies that β = 1 and will be assessed by estimating β along with its 90% 
confidence interval. The exponent, β, in the power model will be estimated by regressing the loge-
transformed PK parameter on loge-transformed dose.
Log(y)=log(α) + β * log(dose)
The power model will be fitted by restricted maximum likelihood (REML) using SAS Proc Mixed, 
with subject as a random effect or a fixed effect power model will be fitted. The mean slope will be 
estimated from the power model and the corresponding 90% confidence interval calculated. Point 
estimates and confidence intervals for the slope will be reported to 4 decimal places with no 
rounding.
An example of SAS code is included here for the power model approach.
ODS output solution=stat
Proc Mixed;
class subject;
model logPKvar = logdose /cl alpha=0.1 solution;
run;
If the power model does not show dose proportionality then pairwise analysis of variance (ANOVA) 
may be used as an exploratory analysis to understand the dose where dose proportionality fails. 
PK parameters will be normalized to the reference dose (30 mg for Part 1) and then log-
transformed prior to the analysis. Dose will be treated as a categorical variable. Point estimates 
and 90% confidence intervals for AUC and Cmax will be reported to 4 decimal places with no 
rounding.
An example of SAS code is also included here for the ANOVA approach.
ODS output solution=stat;
Proc Mixed;
class subject treatment; /* treatments are different dose groups 
*/
model logdnPKvar = treatment/cl alpha=0.1 solution;;
lsmeans treatment; /* assuming one ref and three test treatments 
*/
estimate ‘test1 vs ref’ treatment -1 1 0 0 /cl alpha=0.1;
estimate ‘test2 vs ref’ treatment -1 0 1 0 /cl alpha=0.1;
run;
 
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11.8.
Appendix 8: Abbreviations & Trade Marks
11.8.1.
Abbreviations
Abbreviation
Description
z
Apparent terminal rate constant
%AUCex
The percentage of AUC(0-∞) obtained by extrapolation
AdaM
Analysis Data Model
AE
Adverse Event
AIC
Akaike’s Information Criteria
AUC
Area under the concentration-time
AUC(0-t)
Area under the concentration-time curve from time zero to the time of 
the last quantifiable concentration
AUC(0-∞)
Area under the concentration-time curve extrapolated to infinity
AUC(0-24)
Area under the concentration-time curve from time zero to 24 hours 
post-dose
AUC(0-8)
Area under the concentration-time curve from time zero to 8 hours post-
dose
A&R
Analysis and Reporting 
C24
Concentration in the plasma at 24 hours after dosing
CDISC
Clinical Data Interchange Standards Consortium
Change from 
Baseline to 
Nadir
Maximum observed change from baseline pharmacodynamic value, i.e. 
minimum absolute value
CI
Confidence Interval
CL/F
Apparent subcutaneous plasma clearance after extravascular
Cmax
Maximum observed concentration in plasma
CPMS
Clinical Pharmacology Modelling & Simulation
CS
Clinical Statistics
CSR
Clinical Study Report
CTR
Clinical Trial Register
CVb / CVw
Coefficient of Variation (Between) / Coefficient of Variation (Within)
DOB
Date of Birth
DP
Decimal Places
eCRF
Electronic Case Record Form
HBeAg
Hepatitis B e-antigen
HBsAg
Hepatitis B virus surface antigen
HBV
Hepatitis B Virus
IA
Interim Analysis
ICH
International Conference on Harmonisation
IDMC
Independent Data Monitoring Committee 
IDSL
Integrated Data Standards Library
IMMS
International Modules Management System
IP
Investigational Product
ITT
Intent-To-Treat
GUI
Guidance
 
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Abbreviation
Description
LOC
Last Observation Carries Forward
MMRM
Mixed Model Repeated Measures
Nadir
Minimum observed pharmacodynamic value
PCI
Potential Clinical Importance 
PD
Pharmacodynamic
PDMP
Protocol Deviation Management Plan
PK
Pharmacokinetic
PP
Per Protocol
QC
Quality Control
QTcF
Frederica’s QT Interval Corrected for Heart Rate
QTcB
Bazett’s QT Interval Corrected for Heart Rate
RAP
Reporting & Analysis Plan
RAMOS
Randomization & Medication Ordering System 
SAC
Statistical Analysis Complete
SDTM
Study Data Tabulation Model
SOP
Standard Operation Procedure
t½
Apparent terminal half-life
TA
Therapeutic Area
Time to Nadir
Time to reach Nadir
TFL
Tables, Figures & Listings 
tlag
Lag time before observation of quantifiable concentrations in plasma
tmax
Time to reach Cmax
GSK
GlaxoSmithKline
11.8.2.
Trademarks
Trademarks of the GlaxoSmithKline 
Group of Companies
Trademarks not owned by the 
GlaxoSmithKline Group of Companies
None
SAS
WinNonlin
 
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11.9.
Appendix 9: List of Data Displays
11.9.1.
Data Display Numbering
The following numbering will be applied for RAP generated displays:
Section
Tables
Figures
Study Population (Part 1)
1.01 to 1.12
N/A
Safety (Part 1)
3.01 to 3.20
3.01 to 3.07
Pharmacokinetic (Part 1)
4.01 to 4.10
4.01 to 4.05
Pharmacodynamic (Part 1)
5.01 to 5.04
5.01 to 5.16
Section
Listings
ICH Listings
1.01 to 3.51
Other Listings
4.01 to 5.03
 
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11.9.2.
Table of Contents of Data Display
11.9.2.1.
Study Population Tables
Study Population Tables
No.
Population
IDSL / TST ID /
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
1.01
[ITT]
ES1
Summary of Subject Disposition (Part 1)
SAC [1]
1.02
[Screened 
Population]
ES6
Summary of Screening Status and Reasons for Screening Failure (Part 1)
SAC [1]
1.03
[Screened 
Population]
NS1
Summary of Enrolled Subjects by Country and Site ID (Part 1)
SAC [1]
1.04
[ITT]
DV1
Summary of Important Protocol Deviations (Part 1)
SAC [1]
1.05
[ITT]
DM1
Summary of Demographic Characteristics (Part 1)
SAC [1]
1.06
[ITT]
DM1
Summary of Baseline Disease Characteristics (Part 1)
SAC [1]
1.07
[ITT]
DM11
Summary of Age Ranges (Part 1)
SAC [1]
1.08
[ITT]
DM5
Summary of Race and Racial Combinations (Part 1)
SAC [1]
1.09
[ITT]
MH4
Summary of Medical Conditions (Part 1)
SAC [1]
1.10
[ITT]
CM1
Summary of Prior Medications (Part 1)
SAC [1]
1.11
[ITT]
CM1
Summary of Concomitant Medications (Part 1)
SAC [1]
1.12
[ITT]
CM1
Summary of Baseline Nucleocide Use (Part 1)
SAC [1]
 
 
 
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11.9.2.2.
Safety Tables
Safety: Tables
No.
Population
IDSL / TST ID /
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Adverse Events
3.01
[Safety]
AE5B
Summary of Adverse Events by System Organ Class and Preferred Term and 
Maximum Grade (Part 1)
SAC [1]
3.02
[Safety]
AE5B
Summary of All Drug-Related Adverse Events by System Organ Class and 
Preferred Term and Maximum Grade (Part 1)
SAC [1]
3.03
[Safety]
AE5B
Summary of Non-Serious Adverse Events by System Organ Class and 
Preferred Term and maximum Grade (Part 1)
SAC [1]
3.04
[Safety]
AE3
Summary of Adverse Events by Overall Frequency (Part 1)
SAC [1]
3.05
[Safety]
AE3
Summary of Grade 2-4 Adverse Events by Overall Frequency (Part 1)
SAC [1]
3.06
[Safety]
AE3
Summary of Drug-Related Grade 2-4 Adverse Events by Overall Frequency 
(Part 1)
SAC [1]
3.07
[Safety]
Overall Summary of Adverse Events and Lab Abnormalities (Part 1)
SAC [1]
Lab
3.08
[Safety]
LB1
Summary of Chemistry Changes from Baseline by Visit (Part 1)
SAC [1]
3.09
[Safety]
Summary of Chemistry Maximum Grade by Category (Part 1)
SAC [1]
3.10
[Safety]
LB1
Summary of Hematology Changes from Baseline by Visit (Part 1)
SAC [1]
3.11
[Safety]
Summary of Hematology Maximum Grade by Category (Part 1)
SAC [1]
3.12
[Safety]
LB1
Summary of Urinalysis Changes from Baseline by Visit (Part 1)
SAC [1]
3.13
[Safety]
LB2
Summary of Coagulation Lab Data (Part 1)
SAC [1]
3.14
[Safety]
Summary of Complement Product Levels after Study Drug Dose (Part 1)
SAC [1]
 
 
 
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Safety: Tables
No.
Population
IDSL / TST ID /
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
ECG
3.15
[Safety]
EG1
Summary of ECG Findings (Part 1)
SAC [1]
3.16
[Safety]
EG2
Summary of ECG Changes from Baseline by Visit (Part 1)
SAC [1]
3.17
[Safety]
CP_EG11
Summary of Maximum Emergent QTc Values by Category (Part 1)
SAC [1]
3.18
[Safety]
CP_EG12
Summary of Maximum Change from Baseline in QTc Values by Category 
(Part 1)
SAC [1]
Vital Signs
3.19
[Safety]
VS1
Summary of Vital Sign Changes from Baseline by Visit (Part 1)
SAC [1]
3.20
[Safety]
Summary of Vital Sign Values by Category (Part 1)
SAC [1]
11.9.2.3.
Safety Figures
Safety: Figures
No.
Population
IDSL / TST ID /
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Lab
3.1.
[Safety]
LIVER9
Scatter Plot of Maximum vs. Baseline for ALT (Part 1)
SAC [1]
3.2.
[Safety]
LIVER9
Scatter Plot of Maximum ALT vs. Maximum Total Bilirubin (Part 1)
SAC [1]
3.3.
[Safety]
Mean Plot of Liver Functions (Part 1)
SAC [1]
3.4.
[Safety]
Individual Line Plot of Liver Functions (Part 1)
SAC [1]
3.5.
[Safety]
Mean Plot of Coagulation Tests (Part 1)
SAC [1]
3.6.
[Safety]
Individual Line Plot of Coagulation Tests (Part 1)
SAC [1]
 
 
 
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Safety: Figures
No.
Population
IDSL / TST ID /
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
3.7.
[Safety]
Individual Line Plot of Chemistry Lab Tests (Part 1)
SAC [1]
11.9.2.4.
Pharmacokinetic Tables
Pharmacokinetic: Tables
No.
Population
IDSL / TST ID /
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
4.01
[PK]
PK01
Summary of GSK3389404 Plasma Pharmacokinetic Concentration-Time 
Data [ng/mL] by Treatment Group and HBeAg Status in Part 1
SAC [1]
4.02
[PK]
PK01
Summary of ISIS 505358 Plasma Pharmacokinetic Concentration-Time Data 
[ng/mL] by Treatment Group and HBeAg Status in Part 1
SAC [1]
4.03
[PK]
PK03
Summary of Derived GSK3389404 Plasma Pharmacokinetic Parameters by 
Treatment Group and HBeAg Status in Part 1
SAC [1]
4.04
[PK]
PK03
Summary of Derived ISIS 505358 Plasma Pharmacokinetic Parameters by 
Treatment Group and HBeAg Status in Part 1
SAC [1]
4.05
[PK]
PK05
Summary of Log-Transformed Derived GSK3389404 Plasma 
Pharmacokinetic Parameters by Treatment Group and HBeAg Status in Part 
1
SAC [1]
4.06
[PK]
PK05
Summary of Log-Transformed Derived ISIS 505358 Plasma 
Pharmacokinetic Parameters by Treatment Group and HBeAg Status in Part 
1
SAC [1]
4.07
[PK]
PK_T1
Assessment of Dose Proportionality of GSK3389404 Following Single Dose 
in Part 1
SAC [1]
4.08
[PK]
PK_T1
Assessment of Dose Proportionality of ISIS 505358 Following Single Dose in 
Part 1
SAC [1]
 
 
 
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Pharmacokinetic: Tables
No.
Population
IDSL / TST ID /
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
4.09
[PK]
PK_T4
Summary of Results of Dose Proportionality Assessment of GSK3389404 
using ANOVA Following Single Dose in Part 1
SAC [1]
4.10
[PK]
PK_T4
Summary of Results of Dose Proportionality Assessment of ISIS 505358 
using ANOVA Following Single Dose in Part 1
SAC [1]
11.9.2.5.
Pharmacokinetic Figures
Pharmacokinetic: Figures
No.
Population
IDSL / TST ID /
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
4.01
[PK]
PK17
Mean (+SD) GSK3389404   Plasma Concentration-Time Plot by Treatment 
Group and HBeAg Status - Part 1 (Linear and Semi-Log)
SAC [1]
4.02
[PK]
PK17
Mean (+SD) ISIS 505358 Plasma Concentration-Time Plot by Treatment 
Group and HBeAg Status - Part 1 (Linear and Semi-Log)
SAC [1]
4.03
[PK]
PK18
Median (range) GSK3389404 Plasma Concentration-Time Plot by Treatment 
Group and HBeAg Status - Part 1 (Linear and Semi-Log)
SAC [1]
4.04
[PK]
PK18
Median ISIS 505358 Plasma Concentration-Time Plot by Treatment Group 
and HBeAg Status - Part 1 (Linear and Semi-Log)
SAC [1]
4.05
[PK]
PK16a
Individual GSK3389404 and ISIS 505358 Plasma Concentration-Time Plot –
Part 1 (Linear and Semi-Log)
SAC [1]
 
 
 
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11.9.2.6.
Pharmacodynamic Tables
Pharmacodynamic: Tables
No.
Population
IDSL / TST ID /
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
5.01
[PD]
PK01
Summary of Pharmacodynamic Absolute Value-Time Data by Treatment 
Group and HBeAg Status
SAC [1]
5.02
[PD]
PK01
Summary of Pharmacodynamic Log10 Absolute Value-Time Data by 
Treatment Group and HBeAg Status
SAC [1]
5.03
[PD]
PK01
Summary of Pharmacodynamic Log10 Change from Baseline Value-Time
Data by Treatment Group and HBeAg Status
SAC [1]
5.04
[PD]
PK03
Summary of Nadir and Time to Nadir by Treatment Group and HBeAg Status
SAC [1]
5.05
[PD]
PK03
Summary of Log10 Change from Baseline to Nadir by Treatment Group and 
HBeAg Status
SAC [1]
11.9.2.7.
Pharmacodynamic Figures
Pharmacodynamic: Figures
No.
Population
IDSL / TST ID /
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
5.01
[PD]
PK17
Mean (+SD) Pharmacodynamic Absolute Value-Time Plot by Treatment 
Group and HBeAg Status
SAC [1]
5.02
[PD]
PK17
Mean (+SD) Pharmacodynamic Log10 Change from Baseline Value-Time
Plot by Treatment Group and HBeAg Status 
SAC [1]
5.03
[PD]
PK18
Median (range) Pharmacodynamic Absolute Value-Time Plot by Treatment
Group and HBeAg Status
SAC [1]
5.04
[PD]
PK18
Median (range) Pharmacodynamic Log10 Change from Baseline Value-Time
Plot by Treatment Group and HBeAg Status 
SAC [1]
 
 
 
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Pharmacodynamic: Figures
No.
Population
IDSL / TST ID /
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
5.05
[PD]
PK16a
Individual Pharmacodynamic Absolute Value-Time Plot (Log10 scale)
SAC [1]
5.06
[PD]
PK16a
Individual Pharmacodynamic Log10 Change from Baseline Value-Time Plot 
SAC [1]
5.07
[PD]
Mean (+SD) Pharmacodynamic Absolute Value-Time Plot by Treatment 
Group 
SAC [1]
5.08
[PD]
Mean (+SD) Pharmacodynamic Log10 Change from Baseline Value-Time
Plot by Treatment Group 
SAC [1]
5.09
[PD]
Scatter Plot of Nadir versus AUC(0-inf) for GSK3389404
SAC [1]
5.10
[PD]
Scatter Plot of Time to Nadir versus AUC(0-inf) for GSK3389404
SAC [1]
5.11
[PD]
Scatter Plot of Log10 Change from Baseline to Nadir versus AUC(0-inf) for 
GSK3389404
SAC [1]
5.12
[PD]
Scatter Plot of Nadir versus Cmax for GSK3389404
SAC [1]
5.13
[PD]
Scatter Plot of Time to Nadir versus Cmax for GSK3389404
SAC [1]
5.14
[PD]
Scatter Plot of Log10 Change from Baseline to Nadir versus Cmax for 
GSK3389404
SAC [1]
5.15
[PD]
Individual Plot of HBsAg, HBV DNA, and HBeAg Values and ALT Values
SAC [1]
5.16
[PD]
Individual Plot of HBsAg, HBV DNA, and HBeAg Log10 Change from 
Baseline Values and ALT Values
SAC [1]
 
 
 
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11.9.2.8.
ICH Listings
ICH: Listings
No.
Population
IDSL / TST ID /
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Study Population
1.01
[Screened 
Population]
ES7
Listing of Reasons for Screen Failure (Part 1)
SAC [1]
1.02
[ITT]
ES2
Listing of Reasons for Study Withdrawal (Part 1)
SAC [1]
1.03
[ITT]
BL1
Listing of Subjects for whom Treatment Blind was Broken During 
the Study (Part 1)
SAC [1]
1.04
[ITT]
TA1
Listing of Randomized and Actual Treatments (Part 1)
SAC [1]
1.05
[ITT]
DV2
Listing of Protocol Deviations (Part 1)
SAC [1]
1.06
[ITT]
IE3
Listing of Subjects with Inclusion/Exclusion Criteria Deviations 
(Part 1)
SAC [1]
1.07
[ITT]
SP3
Listing of Subjects Excluded from Any Population (Part 1)
SAC [1]
1.08
[ITT]
DM2
Listing of Demographic Characteristics (Part 1)
SAC [1]
1.09
[ITT]
DM9
Listing of Race (Part 1)
SAC [1]
1.10
[ITT]
CM2
Listing of Prior and Concomitant Medications (Part 1)
SAC [1]
1.11
[ITT]
CM2
Listing of Baseline Nucleocide Use (Part 1)
SAC [1]
1.12
[ITT]
MH2
Listing of Medical Conditions (Part 1)
SAC [1]
Exposure
3.01
[Safety]
EX3
Listing of Exposure Data (Part 1)
SAC [1]
Adverse Events
3.02
[Safety]
AE8
Listing of All Adverse Events (Part 1)
SAC [1]
 
 
 
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ICH: Listings
No.
Population
IDSL / TST ID /
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
3.03
[Safety]
AE7
Listing of Subject Numbers for Specified Adverse Events 
(Part 1)
SAC [1]
3.04
[Safety]
AE2
Listing of Relatioship between System Organ Class and 
Verbatim Text (Part 1)
SAC [1]
3.05
[Safety]
AE8
Listing of Non-Fatal Serious Adverse Events (Part 1)
SAC [1]
3.06
[Safety]
AE8
Listing of Fatal Serious Adverse Events (Part 1)
SAC [1]
3.07
[Safety]
AE8
Listing of Adverse Events Leading to Withdrawal from Study 
(Part 1)
SAC [1]
Lab
3.11
[Safety]
LB5
Listing of All Laboratory Data (Part 1)
SAC [1]
3.12
[Safety]
LB5
Listing of All Laboratory Data for Subjects with any Grade 1 
higher Abnormality (Part 1)
SAC [1]
3.13
[Safety]
LB5
Listing of All Laboratory Data with Grade 1 or Higher (Part 1)
SAC [1]
ECG
3.21
[Safety]
CP_EG3
Listing of All ECG Data (Part 1)
SAC [1]
3.22
[Safety]
CP_EG3
Listing of All ECG Data for Subjects with Any Value of Potential 
clinical Importance (Part 1)
SAC [1]
3.23
[Safety]
Listing of All ECG Findings (Part 1)
SAC [1]
3.23
[Safety]
CP_EG5
Listing of All ECG Findings for Subjects with an Abnormal 
Finding (Part 1)
SAC [1]
Vital Signs
3.31
[Safety]
CP_VS4
Listing of All Vital Signs (Part 1)
SAC [1]
3.32
[Safety]
CP_VS4
Listing of All Vital Signs for Subjects with Any Values of Potential 
Clinical Importance (Part 1)
SAC [1]
 
 
 
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ICH: Listings
No.
Population
IDSL / TST ID /
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Liver
3.41
[Safety]
LIVER5
Listing of Liver Stopping/Monitoring Event Reporting (Part 1)
SAC [1]
Death
3.51
[Safety]
Listing of Deaths (Part 1)
SAC [1]
 
 
 
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11.9.2.9.
Non-ICH Listings
Non-ICH: Listings
No.
Population
IDSL / TST ID /
Example Shell
Title
Programming Notes
Deliverable
[Priority]
PK
4.01
[PK]
PK08
Listing of GSK3389404 Plasma Pharmacokinetic Concentration-Time Data 
by Study Part, Cohort, and Study Day
SAC [1]
4.02
[PK]
PK08
Listing of ISIS 505358 Plasma Pharmacokinetic Concentration-Time Data 
by Study Part, Cohort, and Study Day
SAC [1]
4.03
[PK]
PK14
Listing of Derived GSK3389404 Plasma Pharmacokinetic Parameters for 
Each Cohort in Part 1
SAC [1]
4.04
[PK]
PK14
Listing of Derived ISIS 505358 Plasma Pharmacokinetic Parameters for 
Each Cohort in Part 1
SAC [1]
4.05
[PK]
PK14
Individual GSK3389404 Plasma Lambda_z Related Pharmacokinetic 
Parameters for Each Cohort in Part 1
SAC [1]
4.06
[PK]
PK14
Individual ISIS 505358 Plasma Lambda_z Related Pharmacokinetic 
Parameters for Each Cohort in Part 1
SAC [1]
4.07
[PK]
Non-Standard 
PK L_1
Individual GSK3389404 Plasma Concentrations (ng/mL) by Scheduled 
Time in Part 1
SAC [1]
4.08
[PK]
Non-Standard 
PK L_1
Individual ISIS 505358 Plasma Concentrations (ng/mL) by Scheduled Time 
in Part 1
SAC [1]
PD
5.01
[PD]
PK08
Listing of Pharmacodynamic Absolute, Log10 Absolute, and Log10 Change 
from Baseline Value-Time Data by Cohort and Study Day
SAC [1]
5.02
[PD]
PK14
Listing of Derived Pharmacodynamic Parameters Nadir, Time to Nadir, and 
Log10 Change from Baseline to Nadir for Each Cohort
SAC [1]
 
 
 
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11.9.3.
Mock Example Shell Referencing
Mock shell will be in a separate document. 
 
 
 
2018N382335_00

Prot_000.pdf: 
2016N277028_08
CONFIDENTIAL
The GlaxoSmithKline group of companies
205670
1
TITLE PAGE
Division: Worldwide Development
Information Type: Protocol Amendment
Title:
A Double-Blind, Placebo-Controlled Study to Assess the 
Safety, Tolerability, Pharmacokinetics and Pharmacodynamics 
of Single Ascending Dose and Multiple Doses of GSK3389404 
in Chronic Hepatitis B Subjects
Compound Number:
GSK3389404
Development Phase:
IIA
Effective Date:
13-JUN-2018
Protocol Amendment Number: 06
Author (s):
 
 
Copyright 2018 the GlaxoSmithKline group of companies. All rights reserved.
Unauthorised copying or use of this information is prohibited.
 
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2016N277028_08
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The GlaxoSmithKline group of companies
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2
Revision Chronology
GlaxoSmithKline Document 
Number
Date
Version
2016N277028_00
2016-JUN-21
Original
2016N277028_01
2017-FEB-21
Amendment No. 1
Reasons for the Amendment: To update the subject population in Part 2 from treatment 
naïve to treatment experienced. To increase the maximum total monthly dose in Part 2 
from 240 mg to 480 mg. To reduce complexity and visit burden for subjects. To make 
minor edits for clarity.
2016N277028_02
2017-MAR-03
Amendment No. 2
Reasons for the Amendment: To include patients with ALT less than 5x upper limit of 
normal. To make minor edits for clarity. [Rationale: see Appendix 7]
2016N277028_03
2017-MAR-07
Republishing
Reasons for the Republishing: Protocol title of the published amendment did not match 
the original (2016-JUN-21) protocol title and was corrected. 
2016N277028_04
2017-JUN-28
Amendment No. 3
Reasons for the Amendment: To reduce sample size from 8 subjects (6 active:2 placebo) 
to 4 subjects (3 active:1 placebo) in Part 1. To update the subject population in Part 1 to 
allow inclusion of subjects on nucleos(t)ide therapy and hepatitis B virus e-antigen 
(HBeAg) negative patients into Cohorts A, B, C and D. To remove the requirement for a 
minimum viral load at entry for treatment naïve subjects or subjects that have had prior 
treatment with interferon or nucleosides in Part 1. To update the subject population in 
Parts 1 and 2 to include women of child bearing potential. To update the subject 
population in Parts 1 and 2 to include patients with GFR 60 mL/min after consultation 
with the GSK medical monitor. To update the overall design and types/numbers of 
subjects that will be enrolled given the addition of an optional Japanese Part 2 sub-
study. To reduce complexity and visit burden for subjects. To provide information from 
the results of the GSK3389404 first-in-human study 202007. To provide corrections to 
the statistical simulations. To provide minor edits for clarity and typographical errors.
2016N277028_05
2017-OCT-21
Amendment No. 4
To remove females of reproductive potential for Part 1 of study 205670 based on 
feedback from South Korea MFDS. To provide edits for clarity.
 
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205670
3
2016N277028_06
2018-MAR-06
Amendment No. 5
To update the protocol to include the treatments for Part 2. To include an optional 
additional 9 month off-treatment follow up period. To provide updates to the pre-
clinical and clinical data. To include management review of un-blinded data. To 
provide updates to the statistical sections. To provide edits for clarity.
2016N277028_07
2018-JUN-05
Amendment No. 6
To correct the planned study duration for subjects. To allow inclusion of subjects with 
ALT 2xULN. To add greater clarity for exclusions 4, 8g, 9, and 11. To provide next 
steps for determining follow-up visit schedules for subjects who meet treatment 
stopping criteria, but are not withdrawn from the study. To update the Time and 
EventsTable for the optional follow-up period. To update the unblinded senior 
management review. To differentiate between final follow up visits Day 169 or Day 
450 (if subjects consent to the optional extended follow-up period). To make minor 
edits for clarity
2016N277028_08
2018-JUN-13
Republishing
Reasons for the Republishing: To clarify exclusion criteria 13.
 
2018N382335_00


 
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5
MEDICAL MONITOR/SPONSOR INFORMATION PAGE
Medical Monitor/SAE Contact Information: 
Role
Name
Day Time Phone Number 
and email address
After-hours 
Phone/Cell/
Pager Number
Fax Number
Site Address
Primary 
Medical 
Monitor 
Home based
Secondary 
Medical 
Monitor
Home based
Tertiary 
Medical 
Monitor
Home based
SAE 
contact 
information 
GlaxoSmithKline, 
5 Moore Drive, 
RTP, NC 27709
Sponsor Legal Registered Address: 
GlaxoSmithKline Research & Development Limited
980 Great West Road
Brentford
Middlesex, TW8 9GS
UK
In some countries, the clinical trial sponsor may be the local GlaxoSmithKline Affiliate 
Company (or designee). If applicable, the details of the alternative Sponsor and contact 
person in the territory will be provided to the relevant regulatory authority as part of the 
clinical trial application.
 
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6
INVESTIGATOR PROTOCOL AGREEMENT PAGE
For protocol number 205670
I confirm agreement to conduct the study in compliance with the protocol, as amended by 
this protocol amendment.
I acknowledge that I am responsible for overall study conduct. I agree to personally 
conduct or supervise the described study.
I agree to ensure that all associates, colleagues and employees assisting in the conduct of 
the study are informed about their obligations. Mechanisms are in place to ensure that site 
staff receives the appropriate information throughout the study. 
Investigator Name:
Investigator Address:
Investigator Phone Number:
Investigator Signature
Date
 
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7
TABLE OF CONTENTS
PAGE
1.
PROTOCOL SYNOPSIS FOR STUDY 205670......................................................11
2.
INTRODUCTION....................................................................................................17
2.1.
Study Rationale ..........................................................................................17
2.2.
Brief Background ........................................................................................18
3.
OBJECTIVES AND ENDPOINTS...........................................................................19
4.
STUDY DESIGN ....................................................................................................20
4.1.
Overall Design ............................................................................................20
4.2.
Treatment Arms and Duration.....................................................................23
4.3.
Type and Number of Subjects.....................................................................25
4.4.
Design Justification.....................................................................................26
4.5.
Dose Justification........................................................................................26
4.5.1.
Observed Human Pharmacokinetics............................................26
4.5.2.
Safety Margin Calculations ..........................................................28
4.5.3.
In vivo Exposure-Response Relationship of GalNAc 
Conjugated and Unconjugated Compounds.................................31
4.5.4.
Dose Escalation Justification .......................................................34
4.5.5.
GSK3389404 and Nucleos(t)ides.................................................34
4.6.
Benefit:Risk Assessment ............................................................................35
4.6.1.
Risk Assessment .........................................................................35
4.6.2.
Benefit Risk Summary .................................................................42
4.6.3.
Overall Benefit:Risk Conclusion...................................................43
5.
SELECTION OF STUDY POPULATION AND WITHDRAWAL CRITERIA .............43
5.1.
Inclusion Criteria.........................................................................................44
5.2.
Exclusion Criteria........................................................................................46
5.3.
Screening/Baseline/Run-in Failures............................................................48
5.4.
Withdrawal/Stopping Criteria.......................................................................49
5.4.1.
Liver Chemistry Stopping Criteria ................................................50
5.4.1.1.
Study Treatment Restart or Rechallenge....................52
5.4.2.
QTc Stopping Criteria ..................................................................52
5.4.3.
Hematological Stopping Criteria...................................................52
5.4.4.
Renal Function Stopping Criteria .................................................52
5.4.5.
Pharmacokinetic Stopping Criteria...............................................53
5.5.
Subject and Study Completion....................................................................53
6.
STUDY TREATMENT ............................................................................................53
6.1.
Investigational Product and Other Study Treatment....................................53
6.2.
Treatment Assignment................................................................................55
6.3.
Planned Dose Adjustments.........................................................................55
6.4.
Subject Specific Dose Adjustment Criteria..................................................57
6.5.
Blinding.......................................................................................................57
6.6.
Packaging and Labeling..............................................................................58
6.7.
Preparation/Handling/Storage/Accountability..............................................58
6.8.
Compliance with Study Treatment Administration.......................................59
6.9.
Treatment of Study Treatment Overdose....................................................59
 
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8
6.10.
Treatment after the End of the Study ..........................................................60
6.11.
Lifestyle and/or Dietary Restrictions............................................................60
6.11.1.
Meals and Dietary Restrictions ....................................................60
6.11.2.
Alcohol and Tobacco ...................................................................60
6.11.3.
Activity .........................................................................................61
6.12.
Concomitant Medications and Non-Drug Therapies....................................61
6.12.1.
Permitted Medications and Non-Drug Therapies..........................61
6.12.2.
Prohibited Medications and Non-Drug Therapies.........................61
7.
STUDY ASSESSMENTS AND PROCEDURES .....................................................62
7.1.
Time and Events Tables .............................................................................62
7.2.
Screening and Critical Baseline Assessments ............................................78
7.3.
Safety .........................................................................................................78
7.3.1.
Adverse Events and Serious Adverse Events..............................78
7.3.1.1.
Time Period and Frequency for Collecting AE 
and SAE Information ..................................................78
7.3.1.2.
Method of Detecting AEs and SAEs ...........................79
7.3.1.3.
Follow-up of AEs and SAEs........................................79
7.3.1.4.
Cardiovascular and Death Events ..............................80
7.3.1.5.
Regulatory Reporting Requirements for SAEs............80
7.3.2.
Pregnancy ...................................................................................80
7.3.3.
Physical Exams ...........................................................................81
7.3.4.
Injection Site Reactions ...............................................................81
7.3.5.
Vital Signs....................................................................................82
7.3.6.
Electrocardiogram........................................................................82
7.3.7.
Clinical Safety Laboratory Assessments ......................................82
7.4.
Pharmacokinetics .......................................................................................85
7.4.1.
Blood Sample Collection..............................................................85
7.4.2.
Sample Analysis ..........................................................................85
7.5.
Efficacy.......................................................................................................85
7.6.
Biomarker(s)/Pharmacodynamic Markers ...................................................85
7.7.
Viral Genotyping and Phenotyping..............................................................86
7.7.1.
HBV Resistance Mutation Monitoring...........................................86
8.
DATA MANAGEMENT ...........................................................................................86
9.
STATISTICAL CONSIDERATIONS AND DATA ANALYSES .................................87
9.1.
Hypotheses.................................................................................................87
9.2.
Sample Size Considerations.......................................................................87
9.2.1.
Sample Size Assumptions ...........................................................87
9.2.2.
Sample Size Sensitivity................................................................88
9.2.3.
Sample Size Re-estimation or Adjustment...................................88
9.3.
Data Analysis Considerations .....................................................................88
9.3.1.
Analysis Populations....................................................................88
9.3.2.
Definition of Baseline ...................................................................89
9.3.3.
Interim Analysis and Final Analysis..............................................89
9.3.3.1.
Part 2: Primary Analysis .............................................90
9.3.3.2.
Japanese Optional Part 2 Sub-Study Analysis............90
9.3.3.3.
Part 2: 3 month follow up Analysis..............................90
9.3.3.4.
Part 2: 6 month follow up Analysis..............................90
9.3.3.5.
Part 2: End of Study Analysis .....................................90
9.4.
Key Elements of Analysis Plan ...................................................................90
 
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9
9.4.1.
Primary Analyses.........................................................................90
9.4.2.
Secondary Analyses ....................................................................92
9.4.3.
Other Analyses ............................................................................92
10. STUDY GOVERNANCE CONSIDERATIONS........................................................93
10.1.
Posting of Information on Publicly Available Clinical Trial Registers............93
10.2.
Regulatory and Ethical Considerations, Including the Informed 
Consent Process ........................................................................................93
10.3.
Quality Assurance.......................................................................................94
10.4.
Quality Control (Study Monitoring) ..............................................................94
10.5.
Study and Site Closure ...............................................................................94
10.6.
Records Retention......................................................................................95
10.7.
Provision of Study Results to Investigators, Posting of Information 
on Publically Available Clinical Trials Registers and Publication .................96
10.8.
Review Committees....................................................................................96
10.8.1.
Dose Escalation Committee.........................................................96
10.8.2.
Part 2 Safety Review ...................................................................96
10.8.2.1.
Safety Review Team ..................................................97
11. REFERENCES.......................................................................................................98
12. APPENDICES......................................................................................................102
12.1.
Appendix 1: Abbreviations and Trademarks..............................................102
12.2.
Appendix 2: Liver Safety Required Actions and Follow-up 
Assessments ............................................................................................105
12.3.
Appendix 3: Definition of and Procedures for Recording, Evaluating, 
Follow-Up and Reporting of Adverse Events.............................................107
12.3.1.
Definition of Adverse Events......................................................107
12.3.2.
Definition of Serious Adverse Events.........................................108
12.3.3.
Definition of Cardiovascular Events ...........................................109
12.3.4.
Recording of AEs and SAEs ......................................................110
12.3.5.
Evaluating AEs and SAEs..........................................................110
12.3.5.1.
Division of AIDS (DAIDS) Table for Grading 
Severity of Adult and Pediatric Adverse Events........110
12.3.5.1.1.
Total Bilirubin Table for Term and 
Preterm Neonates: ...............................145
12.3.5.2.
Causality ..................................................................147
12.3.5.3.
Toxicity Management ...............................................147
12.3.5.4.
Follow-up..................................................................152
12.3.6.
Reporting of SAEs to GSK.........................................................152
12.4.
Appendix 4: Modified List of Highly Effective Methods for Avoiding 
Pregnancy in Females of Reproductive Potential and Collection of 
Pregnancy Information..............................................................................154
12.4.1.
Modified List of Highly Effective Methods for Avoiding 
Pregnancy in Females of Reproductive Potential.......................154
12.4.2.
Collection of Pregnancy Information ..........................................154
12.5.
Appendix 5: Country Specific Requirements.............................................156
12.6.
Appendix 6: Statistical Considerations for Part 2.......................................157
12.6.1.
Introduction................................................................................157
12.6.2.
Statistical Modeling....................................................................157
12.6.3.
Success Criteria.........................................................................158
12.6.4.
Scenarios for Testing.................................................................158
 
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12.6.5.
Simulations................................................................................159
12.7.
Appendix 7: Protocol Changes..................................................................164
12.7.1.
Protocol changes for Amendment 01 (21-FEB-2017) from 
Original Protocol (21-Jun-2016).................................................164
12.7.2.
Protocol changes for Amendment 02 (07-MAR-2017) from 
Protocol Amendment 01 (21-Feb-2017).....................................215
12.7.3.
Protocol changes for Amendment 03 (28-JUNE-2017) 
from Protocol Amendment 02 (07-MAR-2017) ...........................224
12.7.4.
Protocol changes for Amendment 04 (21-OCT-2017) from 
Protocol Amendment 03 (28-JUN-2017) ....................................294
12.7.5.
Protocol changes for Amendment 05 (06-MAR-2018) from
Protocol Amendment 03 (28-JUN-2017) ....................................297
12.7.6.
Protocol changes for Amendment 06 (05-JUN-2018) from
Protocol Amendment 05 (06-MAR-2018) ...................................355
 
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1.
PROTOCOL SYNOPSIS FOR STUDY 205670
Rationale
This is a Phase IIa, 2-part study examining the first administration of GSK3389404 in 
subjects with chronic hepatitis B (CHB). This study will evaluate safety, tolerability, 
pharmacokinetic (PK), and pharmacodynamic (PD) profiles of GSK3389404 and aim to 
establish proof-of-mechanism. Part 1 will assess the safety, tolerability, PK, and PD 
profiles of single ascending subcutaneous (SC) doses of GSK3389404. Part 2 will assess 
the safety, tolerability, PK, and PD profiles of multiple doses of GSK3389404. In 
addition, Part 2 will provide an initial evaluation of efficacious dose levels and dosing 
regimens. Finally, this study may provide an initial evaluation of any differences in PD 
between hepatitis B virus (HBV) e-antigen (HBeAg)-positive and HBeAg-negative 
subjects with CHB. Data from this study will support subsequent studies by providing an 
early assessment of safety and PD in the target patient population.
Objective(s)/Endpoint(s)
Objectives
Endpoints
Primary
To assess the safety, tolerability, and PK profile of 
GSK3389404 in single (Part 1) and multiple (Part 2) 
administration in subjects with CHB.
Safety and Tolerability
As measured by clinical assessments including, but 
not limited to

Vital signs

Physical examinations

12-lead electrocardiograms (ECGs)

Laboratory measurements (e.g., chemistry, 
hematology)

Adverse events
Pharmacokinetic Profile:
Derived GSK3389404 plasma PK parameters 
including, but not limited to area under the 
concentration-time curve (AUC), maximum 
observed concentration (Cmax), time of maximum 
observed concentration (tmax), terminal half-life (t½) 
and apparent subcutaneous plasma clearance (CL/F)
To identify one or more efficacious dose(s) and 
dosing regimen(s) of GSK3389404 over a planned 
duration of 3 months (Part 2).
Efficacy
Response rate (RR) based on the proportion of 
subjects with at least a 1.5 times log 10 IU/mL 
reduction of hepatitis B surface antigen (HBsAg) 
levels from baseline anytime during the study.
Secondary
To assess the PD effect of GSK3389404 in 
subjects with CHB (Part 1 and Part 2).
Correlation between GSK3389404 PK parameters 
and PD parameters, including hepatitis B virus (HBV) 
deoxyribonucleic acid (DNA) as appropriate, HBsAg, 
and HBeAg levels (as appropriate, HBeAg-positive 
subjects).
To investigate the PK of the metabolite of 
GSK3389404, also known as ISIS 505358, 
Derived ISIS 505358 plasma PK parameters 
including, but not limited to AUC, Cmax, tmax, and t½.
 
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Objectives
Endpoints
following single and multiple dose administration of 
GSK3389404 (Part 1 and Part 2).
Exploratory
To assess PD differences in HBeAg-positive and 
HBeAg-negative subjects with CHB (Part 1 and 
Part 2, if applicable).
Correlation between PD parameters, including HBV 
DNA, HBV RNA, HBsAg, and/or hepatitis B 
core-related antigen (HBcrAg).
To describe the seroconversion of subjects, defined 
as presence of HBV surface antibody (HBsAb) 
(Part 2 only).
Rate of seroconversion. 
Overall Design
This is a Phase IIa, multicenter, randomized, double-blind (sponsor un-blinded in Part 1), 
placebo-controlled, 2-part study to the assess safety, tolerability, PK, and PD profiles of 
GSK3389404 in subjects with CHB. 
Part 1 plans to enroll subjects primarily from the Asia-Pacific region (including, but not 
limited to, Hong Kong, South Korea, and Taiwan). Part 1 will be conducted as a single 
ascending dose (SAD) study with up to 5 planned cohorts. 

Cohort A (HBeAg-positive and/or HBeAg –negative subjects): GSK3389404 
30 mg SC or placebo

Cohort B (HBeAg-positive and/or HBeAg –negative subjects): GSK3389404 
60 mg SC or placebo

Cohort C (HBeAg-positive and/or HBeAg –negative subjects): GSK3389404 
120 mg SC or placebo

Cohort C1, optional (HBeAg-positive or HBeAg-negative subjects): 
GSK3389404 120 mg SC or placebo

Cohort D (HBeAg-positive and/or HBeAg –negative subjects): GSK3389404 
240 mg SC or placebo
Within each cohort, subjects will be randomized to receive GSK3389404 or placebo SC 
in a 3:1 ratio. Cohorts A, B, C, C1, and D will be conducted in a sequential fashion; 
Cohort C1 is an optional cohort that may be dosed after Cohort C or in parallel with 
Cohort D. Dose Escalation Committee meetings will be held between sequential cohorts.
The decision to enroll the optional Cohort C1 will be made at a prior Dose Escalation 
Committee Meeting.
Part 2 will be conducted as a multiple-dose, dose-ranging study. Part 2 plans to enroll
subjects primarily from the Asia-Pacific region, including Japan. Japan may also 
participate in an optional Japanese Part 2 sub-study. Subjects will be randomized to 
different parallel dose levels and regimens or placebo. The dose levels and regimens for 
Part 2 will be selected after review of safety (at a minimum of adverse events [AEs], 
laboratory chemistry, hematology, and electrocardiogram [ECG]), PK, and PD data from 
Part 1 (through Day 3). The treatments that were selected for Part 2 based on data from 
 
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Part 1 are 60 mg GSK3389404 weekly, 120 mg GSK3389404 bi-weekly, 120 mg 
GSK3389404 weekly or placebo. 
In Part 2, safety data from a sentinel group (1 subject from each active treatment group 
and the corresponding matching placebo) will be reviewed by the GlaxoSmithKline 
(GSK) internal clinical team or Safety Review Team (SRT) in a blinded manner. 
Randomization for the remainder of subjects in Part 2 will continue after safety data from 
at least 2 weeks of exposure in the sentinel group. Safety data from all subjects will be 
reviewed by the GSK internal clinical team or SRT in a blinded manner on a regular basis 
thereafter.
Details of the optional Japanese Part 2 sub-study will be detailed in a Japan 
country-specific amendment/supplement.
Since this is the first administration of GSK3389404 in subjects with CHB, the study 
design may change based on emerging data (safety, tolerability, and PD) from each 
cohort and/or part.
Treatment Arms and Duration
In Part 1, five dosing cohorts are planned and the total study duration, including 
screening, treatment, and post-treatment follow-up, is not expected to exceed 13 weeks 
for each subject.

A 30-day screening window is planned

Eligible subjects who fall within a 45-day window (15 days exceeding the 
30-day screening window) should undergo a brief physical exam, review 
of medical history, and review of concomitant medications to confirm 
eligibility.

Dosing will take place on Day 1 with post-treatment follow-up on Day 3. 

Based on subject and study site preference, subjects have the option to be 
domiciled at the study site or present to the study site as outpatients.

Admission to the study site is optional from Day -1 to Day 2. 

Subjects admitted to the study site may be discharged on Day 1, 
Day 2, or Day 3, based on subject and study site preference. 

Subjects may present as outpatients on Day 1 and/or Day 3, based 
on subject and study site preference.
o
On Day 1, the SC dose will be administered per cohort assignment 
(Cohort A, B, C, C1, or D) and randomized treatment assignment 
(GSK3389404 or placebo).

A post-treatment follow-up period is planned where subjects will present for 
study visits on Days 3, 8, 15, 22, 30, and 60. 
In Part 2, 60 mg GSK3389404 weekly, 120 mg GSK3389404 bi-weekly, 120 mg
GSK3389404 weekly or placebo are planned and the total study duration, including 
 
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screening, dosing, and post-treatment follow-up, is not expected to exceed 71 weeks for 
each subject. 

A 30-day screening window is planned

Eligible subjects who fall within a 45-day window (15 days exceeding the 
30-day screening window) should undergo a brief physical exam, review 
of medical history, and review of concomitant medications to confirm 
eligibility.

An expected study treatment exposure of up to 85 days is planned where 
subjects will receive multiple SC doses of 60 mg GSK3389404 weekly, 
120 mg GSK3389404 bi-weekly, 120 mg GSK3389404 weekly or placebo. 
○
A sentinel group (1 subject from each active treatment group and the 
corresponding matching placebo) will be dosed first. 

Subjects enrolled in the sentinel group will be dosed and followed 
(per the Time and Events Tables). Safety data from all subjects in 
the sentinel group will be reviewed (must be at least 2 weeks of 
exposure, but may include more data).
○
Randomization for the remaining subjects will continue after the safety 
data from all subjects in the sentinel group are reviewed.
○
For all regimens, subjects will present for weekly study visits through 
Day 85 with dosing days as follows:

For once weekly dosing, subjects will be administered GSK3389404 or 
placebo as a SC dose on Days 1, 8, 15, 22, 29, 36, 43, 50, 57, 64, 71, 
and 78. 

For bi-weekly (every 2 weeks) dosing, subjects will be administered 
GSK3389404 or placebo as a SC dose on Days 1, 15, 29, 43, 57, and 
71. 

A protocol mandated post-treatment follow-up period is planned where 
subjects will present for study visits on Days 85, 92, 99, 113, 141, and 169.

An optional extended post treatment follow-up period will be offered to 
subjects with study visits on Days 270, 360, and 450.
Type and Number of Subjects
Adult male and female subjects with CHB between 18 and 70 years of age, inclusive are 
planned for inclusion. Part 1 (Cohorts A, B, C and D) will enroll HBeAg-positive and/or
HBeAg-negative subjects, and Part 1 (optional Cohort C1) may enroll HBeAg-positive or 
HBeAg-negative subjects (or none at all). For Part 2, HBeAg-positive and/or HBeAg-
negative subjects will be enrolled.
Approximately 73 subjects with CHB are planned for randomization to study treatment 
(GSK3389404 or placebo). This number assumes full enrolment in the optional Japanese 
sub-study.
 
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
In Part 1, twelve subjects were enrolled. Originally, approximately 20 to 40
subjects with CHB were planned for randomization (30 GSK3389404 and 10
placebo under older protocol versions versus 15 GSK3389404 and 5 placebo 
under amendment 3). A range was provided because different countries and 
sites may have enrolled under the older versions of the protocol.

In Part 2, approximately 39 subjects with CHB are planned for randomization 
to study treatment. There are approximately 11 subjects in each of the active 
treatment groups and approximately 6 subjects in the placebo group.

If Japan participates in the optional Japanese Part 2 sub-study, approximately 
22 subjects may be enrolled. The exact number of subjects to be enrolled may
be found in a Japanese-specific protocol amendment/supplement.
Analysis
Part 1 and Part 2
Safety and tolerability parameters (AEs/serious AEs [SAEs], physical exams, vital signs, 
12-lead ECGs, and clinical laboratory measurements) will be listed by subject and 
summarized descriptively by treatment group and HBeAg status in tabular or graphical 
formats, as appropriate.
GSK3389404 and ISIS 505358 plasma concentration-time data will be listed by subject 
and summarized descriptively by treatment group and HBeAg status in tabular and 
graphical formats. GSK3389404 and ISIS 505358 (parent compound) PK parameters, 
including but not limited to area under the concentration-time curve from time zero 
(pre-dose) to 24 hours post-dose (AUCdose) to 24 hours post-dose (AUC)), Cmax, tmax, t½, 
and CL/F (GSK3389404 only), will be listed by subject and summarized by treatment 
group and HBeAg status. 
Pharmacodynamic data (HBsAg, HBeAg, and HBV DNA) will be listed by subject and 
summarized descriptively by treatment group and HBeAg status in tabular and graphical 
formats, as appropriate. Correlations between PD data in HBeAg-positive and HBeAg-
negative subjects will be explored graphically. Correlation between PK parameters and 
PD parameters will be explored graphically.
Part 2
The primary efficacy objective is to select the efficacious dose level and dosing regimen 
of GSK3389404 as determined by the primary endpoint, response rate (RR), based on 
reduction of HBsAg level from baseline. A subject will be considered a responder if there 
is at least a 1.5 times log 10 IU/mL reduction of HBsAg levels from baseline anytime 
during the study. A model based probability inference approach in Bayesian framework 
will be used for decision-making as the primary efficacy analysis. An active treatment 
group will be declared efficacious if the posterior probability that the difference in the 
RRs between that active group and the placebo is positive, is high (at least 90%), i.e., 
P (RRACT > RRPBO) 90%, where RRACT is the RR in active group, RRPBO is the RR in 
placebo, and P is the posterior probability.
 
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A supportive analysis will also be performed using pair-wise comparison in Bayesian 
framework using the same criteria as mentioned above. 
Dose response curve for each treatment group will be estimated to determine the dose 
response of the particular treatment group. Further details will be provided in the 
Reporting and Analysis Plan (RAP). 
The RR in each of the treatment groups will also be summarized in frequentist approach 
by descriptive measures including 90% confidence intervals using exact method. 
 
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2.
INTRODUCTION
GSK3389404 is being developed for the treatment of chronic hepatitis B (CHB) virus 
infection. The development goal for GSK3389404 is the establishment of a finite 
duration treatment that results in sustained suppression of hepatitis B virus (HBV) 
replication and viral antigen production after cessation of all treatments for CHB due to 
the restoration of a functional immune response in the absence of high antigen levels. 
ISIS 505358, known as the parent molecule of GSK3389404, is a 2′-O-(2′-methoxyethyl)
(2′-MOE) chimeric second-generation antisense oligonucleotide (ASO) drug targeted to 
HBV ribonucleic acid (RNA). GSK3389404, the prodrug, was derived from ISIS 505358. 
GSK3389404 is a 2′-MOE chimeric second-generation ASO drug targeted to HBV RNA 
that is covalently bonded to triantennary N-acetyl galactosamine (GalNAc), a high 
affinity ligand for the hepatocyte-specific asialoglycoprotein receptor (ASGPR) to form 
an ASO GalNAc- conjugate to enhance delivery of GSK3389404 to hepatocytes.
Following entry into target cells the GalNAc conjugate prodrug GSK3389404 is 
metabolized within hepatocytes to release ISIS 505358. ISIS 505358 is complementary to 
sequences present in all HBV-derived RNA transcripts and its hybridization (binding) to 
the cognate RNA results in ribonuclease H-mediated degradation. It is highly specific for 
HBV RNA transcripts and is not homologous to any regions of the human transcriptome, 
including either a single nucleotide mismatch or with 17 or more consecutive nucleotide 
matches. 
ISIS 505358 has been studied in healthy volunteers at various dose levels and for 
durations up to 1 month. GSK3389404 has been administered to healthy volunteers in 
Study 202007, a recently completed study to assess the safety, tolerability and 
pharmacokinetics (PK) of single and multiple ascending doses of GSK3389404. Results 
from the completed study of ISIS 505358 and from the single ascending dose (SAD) 
portion of Study 202007 have not identified any safety findings to date that would 
preclude further clinical development. A comprehensive summary of the preclinical 
findings for GSK3389404 including pharmacology, drug metabolism and 
pharmacokinetics (DMPK) and toxicology are available in the Investigator’s Brochure 
(IB). The clinical safety findings for both GSK3389404 and ISIS 505358 are also 
summarized in the IB [GlaxoSmithKline Document Number 2015N236049_04].
2.1.
Study Rationale
This is a Phase IIa, 2-part study examining the first administration of GSK3389404 in 
subjects with CHB. This study will evaluate the safety, tolerability, PK, and 
pharmacodynamic (PD) profile of GSK3389404 and aim to establish proof-of-
mechanism. Part 1 will assess the safety, tolerability, PK and PD profiles of single 
ascending subcutaneous (SC) doses of GSK3389404. Part 2 will assess the safety, 
tolerability, PK and PD profiles of multiple doses of GSK3389404. In addition, Part 2 
will provide an initial evaluation of efficacious dose levels and dosing regimens. Finally, 
this study may provide an initial evaluation of any differences in PD between 
HBV e-antigen (HBeAg)-positive and HBeAg-negative subjects with CHB. Data from 
 
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this study will thus support subsequent clinical studies by providing an early assessment 
of safety and PD in the target patient population.
2.2.
Brief Background
Infection with HBV, especially chronic infection, is a significant worldwide medical 
problem. More than 2 billion of the world’s population has been infected. Of these, an 
estimated 240 million are chronically infected [WHO, 2015]. Every year, 650,000 people 
die from HBV-related disease complications. For those with chronic infection, 20 to 30% 
progress to liver cirrhosis or hepatocellular carcinoma (HCC) [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, HCC, and death. This goal can be achieved if HBV replication is suppressed in a 
sustained manner thereby decreasing the histological activity of CHB and reducing the 
risk of cirrhosis and HCC [Liaw, 2004; Feld, 2009]. In both HBeAg-positive and 
HBeAg-negative CHB, the ultimate treatment endpoint is loss of detectable serum 
hepatitis B surface antigen (HBsAg) [Lok, 2009; EASL, 2012]. Loss of HBsAg is 
preceded by a robust immunological response to HBV infection resulting in sustained 
suppression of serum HBV deoxyribonucleic acid (DNA) and disease resolution.
First-line therapy for CHB is treatment with a nucleoside or nucleotide (nucleos(t)ide) 
analogue. At least 6 nucleos(t)ide analogues are available for the treatment of CHB 
patients [Lok, 2009; EASL, 2012]. 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) 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 nucleos(t)ide 
analogues. Unfortunately, with both the nucleos(t)ides 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 nucleos(t)ide 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 nucleos(t)ides 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, the majority of patients on 
treatment fail to achieve a sustained off-treatment virological- response and require 
extended and often life-long therapy to suppress HBV DNA. 
The continued production of viral antigens by infected hepatocytes is thought to interfere 
with immune clearance of both the infected cells and circulating virus particles 
[Vanlandschoot, 2003]. In vitro studies with human peripheral blood mononuclear cells 
(PBMCs) have shown HBsAg impairs the functioning of dendritic cells and inhibits the 
activation of monocytes [Vanlandschoot, 2002; Op den Brouw, 2009]. Further, data 
suggest the production of vast excess of non-replication competent HBsAg (so called 
“sub-viral particles”) likely functions as a decoy for host antibody responses. Most 
 
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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, loss of HBsAg expression is rarely achieved while loss of HBeAg 
expression occurs in a higher proportion of patients. It is believed that HBsAg may be the 
main antagonist of immune clearance. 
Should 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]. 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. GSK3389404, 
an antisense inhibitor, was designed to inhibit the synthesis of HBsAg without having a 
direct effect on covalently closed circular DNA or integrated HBV DNA. GSK3389404 
is not an immune modulator. Therefore, GSK3389404 treatment permits examination of 
whether reduction of HBsAg allows resumption of a host immune response against HBV 
and infected cells and can induce HBsAg seroclearance.
3.
OBJECTIVES AND ENDPOINTS
Objectives
Endpoints
Primary
To assess the safety, tolerability, and PK profile of 
GSK3389404 in single (Part 1) and multiple (Part 2) 
administration in subjects with CHB.
Safety and Tolerability
As measured by clinical assessments including, but 
not limited to the following:

Vital signs

Physical examinations

12-lead electrocardiograms (ECGs) 

Laboratory measurements (e.g., chemistry, 
hematology)

Adverse events 
Pharmacokinetic Profile:
Derived GSK3389404 plasma PK parameters 
including, but not limited to area under the 
concentration-time curve (AUC), maximum 
observed concentration (Cmax, time of maximum 
observed concentration (tmax, terminal half-life (t½, 
and apparent subcutaneous plasma clearance
(CL/F).
To identify one or more efficacious dose(s) and 
dosing regimen(s) of GSK3389404 over a planned 
duration of 3 months (Part 2).
Efficacy
Response rate (RR) based on the proportion of 
subjects with at least a 1.5 times log 10 IU/mL 
reduction of HBsAg levels from baseline anytime 
during the study.
Secondary
To assess the PD effect of GSK3389404 in 
subjects with CHB (Part 1 and Part 2).
Correlation between GSK3389404 PK parameters 
and PD parameters, including HBV DNA as 
 
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Objectives
Endpoints
appropriate, HBsAg, and HBeAg levels (as 
appropriate, HBeAg-positive subjects).
To investigate the PK of the metabolite of 
GSK3389404, also known as ISIS 505358, 
following single and multiple dose administration of 
GSK3389404 (Part 1 and Part 2).
Derived ISIS 505358 plasma PK parameters 
including, but not limited to AUC, Cmax, tmax, and t½.
Exploratory
To assess PD differences in HBeAg-positive and 
HBeAg-negative subjects with CHB (Part 1 and 
Part 2, if applicable).
Correlation between PD parameters, including HBV 
DNA, HBV RNA, HBsAg, and/or hepatitis B 
core-related antigen (HBcrAg).
To describe the seroconversion of subjects, defined 
as presence of HBV surface antibody (HBsAb) 
(Part 2 only).
Rate of seroconversion. 
4.
STUDY DESIGN
4.1.
Overall Design
This is a Phase IIa, multicenter, randomized, double-blind (sponsor un-blinded in Part 1), 
placebo-controlled 2-part study to assess the safety, tolerability, PK, and PD profiles of 
GSK3389404 in subjects with CHB. 
Part 1 plans to enroll subjects primarily from the Asia-Pacific region (including, but not 
limited to, Hong Kong, South Korea, and Taiwan). Part 1 will be conducted as a SAD 
study with 5 planned cohorts ranging from 30 mg to a maximum of 240 mg GSK3389404 
(Figure 1). Within each cohort, subjects will be randomized to receive GSK3389404 or 
placebo in a 3:1 ratio. Cohorts A, B, C, C1, and D will be conducted in a sequential 
fashion. Cohort C1 is an optional cohort that may be dosed after Cohort C or in parallel 
with Cohort D. The decision to enroll the optional Cohort C1 will be made at a prior 
Dose Escalation Committee Meeting. Dosing in each cohort is contingent on the safety, 
PK, and PD profiles of at least 3 subjects who received GSK3389404 at the previous dose 
level. Dose escalation can only occur after the Dose Escalation Committee 
(Section 10.8.1), consisting of the principal investigator, medical monitor, GSK study 
team leader, pharmacokineticist, GSK Global Clinical Safety and Pharmacovigilance 
[GCSP] representative, GSK data manager, programmer, and statistician (or appropriate 
designees) have reviewed the available safety, tolerability, PK, and PD results for the 
previous cohort and finds the safety profile through Day 3 supportive to proceed with the 
evaluation of the next higher dose level. Dose escalations and/or reductions will progress 
with modifications based on the actual human safety and PK data from the preceding 
cohort(s). Cohorts may be expanded (additional subjects may be enrolled) to further 
evaluate safety, PK, and/or PD findings at a given dose level. Additional dose(s) may 
also be considered to further assess safety, tolerability, PK, and/or PD. Section 6.3
provides additional information on planned dose adjustments.
Study treatment and post-treatment follow-up Time and Events Tables are provided in 
Section 7.1.
 
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Figure 1
Part 1: Single Ascending Dose, Study Design Schematic
A = active (GSK3389404); HBeAg = hepatitis B virus e-antigen; P = placebo.
◊= Dose EscalationCommittee meeting
1.
Cohort C1 may include HBeAg-positive or HBeAg-negative subjects and, if enrolled, may be dosed after 
Cohort C, in parallel with Cohort D (optional). 
2.
HBeAg-positive and/or HBeAg-negative subjects will be enrolled in these cohorts.
3.
Dose escalations and/or reductions will progress with modifications based on the actual human safety and PK 
data from the preceding cohort(s). Additional dose(s) may also be considered to further assess safety, 
tolerability, PK, and/or PD. Dose will not exceed 240 mg.
Part 2 will be conducted as a multiple-dose, dose-ranging study (Figure 2). Part 2 plans to 
enroll subjects primarily from the Asia-Pacific region, including Japan. Japan may also 
participate in an optional Japanese Part 2 sub-study. Subjects will be randomized to 
different parallel dose levels and regimens or placebo. A sentinel group will be dosed 
first and a safety review conducted before the remainder of subjects are dosed. The dose 
levels and regimens for Part 2 have been selected after Part 1 safety, (at a minimum of 
adverse events [AEs], laboratory chemistry and hematology and electrocardiogram 
[ECG]), PK, and PD data (through Day 3)) were reviewed. The treatments for Part 2 are 
60 mg GSK3389404 weekly, 120 mg bi-weekly GSK3389404, 120 mg GSK3389404 
weekly or placebo. 
A sentinel group will be dosed first and followed per the Time and Events Tables 
(Section 7.1). Safety data from all subjects in the sentinel group (1 subject from each 
active treatment group and the corresponding matching placebo) will be reviewed (must 
be at least 2 weeks of exposure, but may include more data). The safety review will be 
conducted by the GSK internal clinical team or Safety Review Team (SRT) in a blinded 
manner. Randomization for the remainder of subjects in Part 2 will continue after safety 
data from at least 2 weeks of exposure in all subjects in the sentinel group are reviewed.
Study treatment and post-treatment follow-up Time and Events Tables for weekly and 
bi-weekly (every 2 weeks) dosing regimens are provided in Section 7.1.
 
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Figure 2
Part 2: Multiple Dose, Dose-Ranging, Study Design Schematic
1.
HBeAg positive and negative subjects will be enrolled
2.
Two separate randomization schedules will be used. One for the sentinel group and one to complete 
enrollment of Part 2 subjects. Randomization for the remainder of subjects in Part 2 will continue after safety 
data from at least 2 weeks of exposure in the sentinel group are reviewed. 
3.
The sentinel group will consist of at least 1 active and 1 placebo subject per each dosing level and regimen. 
Subjects enrolled in the sentinel group are dosed and followed per the Time and Events Tables. Safety data 
from all subjects in the sentinel group will be reviewed (must be at least 2 weeks of expsosure, but may 
include more data). 
4.
Matching placebo for each treatment arm (dose/regimen)
5.
An optional Japanese Part 2 sub-study is planned. The exact details may be found in a country-specific 
protocol amendment/supplement and will not be detailed here. The Japan sub-study may include more 
intensive PK monitoring and/or potential overnight/hospital stay.
Since this is the first administration of GSK3389404 in subjects with CHB, the study 
design may change based on emerging data from each cohort and/or part. Certain aspects 
of the study design may be adjusted during the course of the study, including the 
proposed doses, dosing regimen, and/or dosing duration of GSK3389404, based on 
review of the safety, tolerability, PK, and/or PD results. Section 6.3 provides additional 
information regarding planned dose adjustments. The PK sampling scheme and/or 
assessments schedule may also be adjusted during the course of the study (in case of 
unexpected PK behavior). 
The protocol may be amended to include additional part(s) to further explore the safety, 
tolerability, and PD of GSK3389404 in order to select an optimal dose level, regimen, 
and duration for subsequent evaluation in future studies.
 
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4.2.
Treatment Arms and Duration
In Part 1, five dosing cohorts are planned (Figure 1), and the total study duration, 
including screening, treatment, and post-treatment follow-up, is not expected to exceed 
13 weeks for each subject (Figure 3). 
Subjects will receive a SC dose of GSK3389404 or placebo on Day 1 with post-treatment 
follow-up on Day 3. 
Based on subject and study site preference, subjects have the option to be 
domiciled at the study site or present to the study site as outpatients.
oAdmission to the study site is optional from Day -1 to Day 2. 
oSubjects admitted to the study site may be discharged Day 1, Day 2, or 
Day 3, based on subject and study site preference. 
oSubjects may present as outpatients on Day 1 and/or Day 3, based on 
subject and study site preference.
Subjects are required to return to the study site for post-treatment Follow-up visits on 
Days 3, 8, 15, 22, 30, and 60.
Figure 3
Part 1: Single Ascending Dose, Participation Flow
Note: Five cohorts are planned to receive a SC dose of GSK3389404 (30 mg to 240 mg) or placebo
*In-house stays are optional from Day -1 to Day 3 based on study site/subject preference. No study procedures are 
scheduled for Day 2 but subjects may remain in-house until all Day 3 assessments are completed.
 
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In Part 2, the total study duration, including screening (and the 15 day window exceeding 
the normal 30 day screening window), treatment and post-treatment follow-up, is not 
expected to exceed 71 weeks for each subject (Figure 4 and Figure 5).
For once weekly dosing (Figure 4), study treatment will be administered weekly and 
subjects followed weekly in outpatient visits until the final dose (Day 78) is administered. 
After the final dose, subjects will continue post-treatment follow-up in an outpatient 
setting on Days 85, 92, 99, 113, 141, and 169. An optional extended post treatment 
follow-up period will be offered to subjects with study visits on Days 270, 360, and 450.
Figure 4
Part 2: Multiple Dose, Dose-Ranging Participation Flow (Once a 
Week Dosing)
For bi-weekly (every 2 weeks) dosing (Figure 5), study treatment will be administered 
every 2 weeks and subjects followed weekly in outpatient visits until the final dose 
(Day 71) is administered. After the final dose, subjects will continue post-treatment 
follow-up in an outpatient setting on Days 78, 85, 92, 99, 113, 141, and 169. An optional 
extended post treatment follow-up period will be offered to subjects with study visits on 
Days 270, 360, and 450.
 
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Figure 5
Part 2 Multiple Dose, Dose-Ranging Participation Flow (Bi-weekly 
Dosing)
4.3.
Type and Number of Subjects
Adult male and female subjects with CHB between 18 and 70 years of age, inclusive are 
planned for inclusion. Part 1 (Cohorts A, B, C and D) will enroll HBeAg-positive and/or
HBeAg-negative subjects and Part 1 (optional Cohort C1) may enroll HBeAg-positive or 
HBeAg-negative subjects. For Part 2, both HBeAg-positive and/or HBeAg-negative
subjects will be enrolled.
Approximately 73 subjects with CHB are planned for randomization to study treatment 
(GSK3389404 or placebo). This number assumes full enrolment in the optional Japanese 
sub-study. 

In Part 1, twelve subjects were enrolled. Originally, approximately 20 to 
40 subjects with CHB were planned for randomization (30 GSK3389404 and 
10 placebo under older protocol versions versus 15 GSK3389404 and 
5 placebo under amendment 3). A range was provided because different 
countries and sites may have enrolled under the older versions of the protocol. 

In Part 2, approximately 39 subjects with CHB are planned for randomization 
to study treatment. There are approximately 11 subjects in each of the active 
treatment groups and approximately 6 subjects in the placebo group.

If Japan participates in the optional Japanese Part 2 sub-study, approximately 
22 subjects may be enrolled. The exact number of subjects to be enrolled may
be found in a Japanese-specific protocol amendment/supplement.
 
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In Part 1, additional subjects/cohorts may be recruited to replace those who discontinue 
the study early (Section 5.4), to expand the size of selected existing cohorts, and/or to add 
intermediate cohorts (Section 6.3).
4.4.
Design Justification
This first-in-patient study will evaluate safety, tolerability, PK, and PD of GSK3389404 
across a wide range of doses projected to encompass the expected therapeutic dose range 
and for a dosing duration of up to 3 months in the target patient population (subjects with 
CHB). 
The study is designed as a 2-part, randomized, placebo-controlled, double-blind (sponsor 
unblind in Part 1) dose ranging study to distinguish the effects of active dose levels and 
regimens in an efficient and unbiased manner. The sequential nature of Part 1 ensures 
that a range of single doses are investigated before exposing subjects to the highest 
planned dose (Cohort D). Safety, PK, and PD data from Part 1 will be reviewed prior to 
initiating Part 2 to identify the dose levels and regimens in Part 2 and to identify the HBV 
population (HBeAg-positive subjects only or HBeAg-positive- and negative subjects). 
In Part 1, the planned starting dose is 30 mg. This starting dose is based on the review of 
data from the SAD portion of the recently completed clinical trial (Study 202007; at the 
time of this protocol writing, the final study report is in progress). To ensure continued 
safety in subjects with CHB, Dose Escalation Committee meetings will be incorporated 
between Part 1 cohorts (Section 10.8.1) with planned dose adjustments incorporated as 
needed (Section 6.3). Part 2 will be initiated after the PK, safety, and tolerability of the 
previous single dose level(s) are thoroughly reviewed by the GSK study team and 
principal investigator (or appropriate designee) at the Dose Escalation Committee 
meetings for Part 1. A review of safety data (of at least 2 weeks exposure) from the 
sentinel group of Part 2 has been incorporated to ensure continued safety in subjects with 
CHB (Section 10.8.2). Safety data from all subjects will be reviewed by the GSK internal 
clinical team or SRT in a blinded manner on a regular basis thereafter. Randomization for 
the remainder of subjects in Part 2 will continue after this safety data review.
4.5.
Dose Justification
The GSK3389404 dosing regimens selected for this study were based on observed human 
PK parameters, in vivo antiviral exposure-response relationship, and predicted safety
margins relative to the 13- and 39-week no observed adverse effect level (NOAEL), AUC 
and Cmax in monkeys [ISIS Study Number 712408-AS02, 2016; ISIS Study Number 
712408-AS05, 2017]. The rationale for the selection of doses is presented below in 
Section 4.5.1 through Section 4.5.4. The actual dose levels, dosing regimens, or dosing 
duration in subjects with CHB may be adjusted during the course of the study based on 
human safety data, observed human PK, toxicological coverage, and clinical antiviral 
activity (PD data) at previous dose levels.
4.5.1.
Observed Human Pharmacokinetics
GSK3389404 has been administered to healthy adult subjects in Study 202007 and in 
CHB adult subjects in Part 1 of this study (Study 205670).
 
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Study 202007 was a Phase I, first time in human, randomized, double-blind, placebo
controlled, dose escalation study to determine the safety, tolerability, and PK profile of 
GSK3389404. GSK3389404 was administered to healthy adult subjects as single SC 
doses at doses of 10 to 120 mg, or as repeated SC doses (once weekly for 4 weeks) at 
doses of 30 to 120 mg. At the time of this protocol amendment writing, the final study 
report for 202007 has been completed. The human PK parameters are presented in Table 
1. Based on PK data, GSK3389404 showed dose proportional- PK with a mean half-life
of approximately 4 to 5 hours at a dose range of 10 to 120 mg. GSK3389404 plasma 
concentrations were similar after the first and fourth weekly dose, indicating no 
accumulation in plasma concentration after multiple doses. Half-life and plasma exposure 
(AUC and Cmax) of GSK3389404 following multiple doses were consistent with those 
observed following a single dose. The observed human PK data were evaluated using 
noncompartmental analysis (NCA) in Phoenix WinNonlin- version 6.3. All ISIS50538 
(GSK3228836) plasma concentrations were below the LLOQ of 10 ng/mL.
In this study (Study 205670), GSK3389404 has been administered to CHB adult subjects 
as single SC doses at doses of 30 mg and 120 mg. At the time of this protocol amendment 
writing, CHB subjects have been administered GSK3389404 (at 30 mg and at 120 mg
single dose). Based on the preliminary PK analysis, the mean half-life was approximately 
4 to 5 hours at the dose of 30 mg and 120 mg in CHB subjects, consistent with that in 
healthy subjects. The observed human PK data were evaluated using noncompartmental 
analysis (NCA) in Phoenix WinNonlin- version 6.3.
 
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Table 1
Summary of Selected Plasma GSK3389404 Pharmacokinetic 
Parameters in Healthy Adult Subjects
Dose
(mg)
10
30
60
120
Cohort1
A
B
E
E
C
F
F
D
G
G
Day
1
1
1
22
1
1
22
1
1
22
N
6
52
6
6
6
6
6
6
6
6
Half life3
(hr)
3.8
(66)
3.7
(81)
3.0
(34)
4.1
(61)
5.1
(71)
5.0
(206)
3.1
(51)
4.1
(29)
3.7
(43)
3.4
(38)
Tmax4
(hr)
1
(1-4)
2
(1-2)
2
(1-4)
2
(1-4)
3
(1-4)
2
(2-2)
2
(1.5-4)
4
(3-4)
2
(1.5-4)
2
(2-4)
Cmax3
(ng/mL)
90
(24)
295
(69)
228
(32)
194
(20)
512
(57)
692
(35)
577
(43)
803
(49)
1167
(50)
1107
(55)
AUC(0-)3
(ng*hr/mL)
614
(27)
1969
(35)
1394
(24)
1526
(34)
4578
(30)
5875
(52)
3966
(23)
7718
(35)
8039
(36)
8640
(32)
Fold 
coverage
Cmax5
586
179
231
273
103
76
91
66
45
48
Fold 
coverage
AUC5
802
250
353
323
108
84
124
64
61
57
Fold 
coverage
Cmax6
32
10
13
15
6
4
5
4
2
3
Fold 
coverage
AUC6
22
7
10
9
3
2
3
2
2
2
1.
Cohort A – D were single dose cohorts. Cohort E – G were multiple dose cohorts (weekly dose for 4 weeks).
2.
In Cohort B (30-mg single) dose, the pharmacokinetic profile in one subject was atypical and not evaluable.
3.
Data are presented as geometric mean (geometric coefficient of variation %).
4.
Data are presented as Median (range).
5.
Fold coverage based on exposure (AUC and Cmax) at NOAEL (no observed adverse effect level) of 13-week 
monkey study: Gender averaged Cmax = 52.7 g/mL and gender averaged AUC(0-) = 492.7 gh/mL at NOAEL 
of 30 mg/kg/week.
6.
Fold coverage based on exposure (AUC and Cmax) at NOAEL (no observed adverse effect level) of 39-week 
monkey study: Gender averaged Cmax = 2.9 g/mL and gender averaged AUC(0-) = 13.5 gh/mL at NOAEL of 
2 mg/kg/week.
4.5.2.
Safety Margin Calculations
From the 13-week toxicology studies in mice and monkeys, the NOAELs were identified 
at 2 and 30 mg/kg/week, respectively [ISIS Study Number 712408-AS01, 2016; ISIS 
Study Number 712408-AS02, 2016]. The NOAELs of 26-week mouse and 39-week 
monkey studies were 6 and 2 mg/kg/week, respectively [ISIS Study Number 712408-
AS04, 2017; ISIS Study Number 712408-AS05, 2017]. In general, rodents are more 
sensitive to the class-related pro-inflammatory effects of ASOs as compared to primates 
(including humans) and therefore, not considered an appropriate species for the 
 
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calculation of systemic safety margins [Henry, 2008]. Thus, only the monkey data were 
used to calculate the safety margin.
Based on observed PK data in healthy adult subjects (Study 202007), Cmax and AUC of 
GSK3389404 at the highest dose tested (120 mg) is at least 45-fold lower than the Cmax
and AUC values at NOAEL of 13-week monkey study, and at least 2-fold lower than the 
Cmax and AUC values at NOAEL of 39-week monkey study, respectively (Table 1).
Based on the preliminary PK analysis in Part 1 of this study (Study 205670), Cmax and 
AUC of GSK3389404 at the highest dose tested (120 mg) is lower than the Cmax and 
AUC values at NOAEL of 13-week and 39-week monkey study. 
Human liver concentrations were estimated based on liver tissue concentrations from the 
13-week toxicology study in monkeys. This estimate suggests that a 30 mg dose in a 
human would yield liver concentrations 55-fold lower than the previously completed 
Phase I study with the parent compound, ISIS 505358 (Table 2). These data support the 
proposed 30 mg dose as a safe initial dose for this study. 
Table 2 shows the observed and predicted human GSK3389404 PK, the predicted liver 
concentrations, and the fold safety margins of the predicted exposures after single, SC 
administration of GSK3389404 relative to the 13- and 39-week monkey NOAELs. In 
addition, liver concentration fold coverage based on the estimated human liver 
concentration of ISIS 505358 (parent) from a previously completed Phase I clinical trial 
is presented.
In addition, Bayesian predictive probabilities of AUC(0-) and Cmax less than the 
respective 13-week monkey study mean NOAEL were calculated for the 240 mg dose 
level using a power model and using observed data at 10, 30, 60 and 120 mg dose levels 
from Study 202007. The predictive probability of AUC(0-) and Cmax crossing the 
respective threshold values of 13-week monkey study mean NOAEL are very low 
(<0.01%) and are within the acceptable range (i.e. <50%) for the 240 mg treatment 
group.
 
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Table 2
GSK3389404 Plasma Cmax and AUC and Monkey NOAEL Exposure Fold Coverage Following Single SC 
Administration of GSK3389404 in Humans
Human 
Dose 
(mg)
Observed 
GSK3389404 
Plasma Cmax
(ng/mL)1
Observed 
GSK3389404 
Plasma AUC 
(hng/mL)1
Predicted 
Parent Liver 
Concentration 
(g/g)2
Fold Coverage Plasma 
Based on 13-week 
monkey study NOAEL 3
Fold Coverage Plasma
Based on 39-week 
monkey study NOAEL 4
Fold Coverage Of 
Estimated Human 
Liver Concentration 
from Phase I 
Parent Study5
Cmax
AUC
Cmax
AUC
10
90
614
2.8
586
802
32
22
161
30
295
1968
8.2
179
250
10
7
55
60
512
4578
16.2
103
108
6
3
28
120
803
7718
31.4
66
64
4
2
14
240
17286
159926
59.0
30
31
2
0.8
8
NOAEL = no observed adverse effect level
1.
Geometric mean of GSK3389404 plasma human PK observed at 10 to 120 mg in Study 202007 and predicted for 240 mg.
2.
Liver concentration in monkeys at 1 week after a single dose was approximately 20% of that at 13 weeks (steady state) after repeated once weekly doses. Human steady 
state liver concentration of parent compound (ISIS 505358) was estimated based on 13-week monkey liver tissue concentration and assumed to be 20% that of steady 
state. Liver concentration was fit to an Emax model and then extrapolated.
3.
Fold coverage based on 13-week monkey study NOAEL; GSK3389404 gender averaged plasma Cmax= 52.7 g/mL and gender averaged plasma AUC(0-)= 492.7 
gh/mL at 30 mg/kg/week.
4.
Fold coverage based on 39-week monkey study NOAEL; GSK3389404 gender averaged plasma Cmax= 2.9 g/mL and gender averaged plasma AUC(0-)= 13.5 
gh/mL at 2 mg/kg/week.
5.
At 450 mg of ISIS 505358 (the highest dose tested in ISIS 505358 first time in human study), human liver concentration (4 weeks) = 450 g/g, based on allometric 
scaling [Geary, 2009]. Fold coverage = 450 g/g divided by the predicted liver concentration.
6.
Predicted using linear regression (zero intercept) based on observed human PK data from previous dose cohorts (10 to 120 mg) given dose proportionality.
 
 
 
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4.5.3.
In vivo Exposure-Response Relationship of GalNAc Conjugated 
and Unconjugated Compounds
The maximum planned dose in the multiple dose cohorts (total monthly dose not 
exceeding 480 mg GSK3389404) was selected based on the in vivo exposure-response 
relationship of GSK3389404. 
ISIS 505358 is the parent compound of the prodrug GSK3389404, and is currently being 
studied in HBV infected subjects. Therefore, no direct antiviral activity data with 
ISIS 505358 from humans are available for extrapolation. To establish an exposure-
response relationship, an in vivo efficacy study of GSK3389404 dosed once weekly for 
4 weeks and ASO’s liver tissue concentrations were measured in HBV transgenic mice.
GSK3389404 reduced hepatic HBV RNA and DNA in the HBV transgenic mice. 
Administration of GSK3389404 dose-dependently reduced serum HBsAg levels within 
7 days and reduced serum levels of antigen were maintained for the 4-week period of 
testing. Maximal reduction of serum HBsAg was approximately 99% (2 logs), and liver 
concentration that produces 90% of maximal effect (EC90) was 5.9 g/g and 
concentration that produces 99% of maximal effect (EC99) was 33 g/g (Figure 6).
Figure 6
Liver EC90 of ISIS 505358 from GSK3389404-Treated HBV 
Transgenic Mice
ASO = antisense oligonucleotides, EC90 = concentration that produces 90% of maximal effect
Notes: Mice were treated with vehicle, control ASO (ISIS 716837 at 10 mg/kg/week) or various doses (1, 3 or 
10 mg/kg/week) of GSK3389404 for 4 weeks. Serum HBsAg levels at the end of treatment were plotted 
against the observed liver concentration of ISIS 505358. The EC90 was calculated from log/log transformed 
values using linear regression analysis (GraphPad Prism 6), which is shown as the solid line in graph (N=8 
mice per group).
In the GSK3389404 HBV transgenic mice study, tissue analysis indicated the GalNAc 
moiety was completely removed in the liver for all oligonucleotide treatments. Only 
unconjugated parent ASO, ISIS 505358, was observed and quantified in the liver.
 
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Thus, in order to knockdown the target gene 99%, these data suggest that Study 205670 
should explore SC doses of GSK3389404 predicted to yield human liver tissue 
concentrations of ISIS 505358 that will achieve EC99 (33 g/g). Based on observed liver 
tissue concentration in the monkey, it is estimated that a 30 mg weekly SC injection of 
GSK3389404 would reach a human liver tissue concentration of 41 g/g (>EC99) after 
13 weeks, assuming the liver tissue concentration between monkey and human is similar 
on a mg/kg basis (Table 3). However, greater clinical efficacy may be achieved if HBsAg 
is reduced by >99%. 
 
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Table 3
GSK3389404 Plasma Cmax and AUC and Monkey NOAEL Exposure Fold Coverage Following Repeat Weekly or 
Bi-weekly (every 2 weeks) SC Administration of GSK3389404 for 13 Weeks in Humans
Human 
Total 
Monthly 
Dose 
(mg)
Human
Repeat
Dose 
(mg)1
Observed 
GSK3389404 Plasma 
Predicted 
Parent Liver 
Concentration 
at Week 13 
(g/g)3
Observed Fold 
Coverage 
Fold 
Coverage of 
Predicted 
Human Liver 
Concentration 
at Week 136
Observed Fold 
Coverage 
Fold Coverage of 
Predicted Human Liver 
Concentration at 
Week 136
Cmax 
(ng/mL)2
AUC 
(hng/mL)2
Plasma 
Cmax4
Plasma 
AUC4
Plasma 
Cmax5
Plasma 
AUC5
120
30 QW
194
1526
41
272
323
34
15
9
4
240
60 QW
577
3966
81
91
124
17
5
3
2
480
120 
QW
1107
8640
157
48
57
9
3
2
1
480
240 
Q2W
2200
16769
157
24
29
9
1
0.8
1
NOAEL = no observed adverse effect level
1.
QW: dose every week. Q2W: dose every 2 weeks.
2.
Geometric mean of GSK3389404 plasma human PK observed following repeat weekly SC dose of 30 to 120 mg for 4 weeks in Study 202007. The values for 240 mg were 
predicted
3.
Human liver concentration of parent compound (ISIS 505358) at Week 13 was estimated based on 13-week monkey liver tissue concentration (an average of 1404 g/g at 
30 mg/kg/week for 13 weeks). Liver concentration was fit to Emax model and then extrapolated.
4.
Fold coverage based on 13-week monkey study NOAEL (30 mg/kg/week): gender averaged plasma GSK3389404 Cmax= 52.7 g/mL and gender averaged plasma AUC(0-
)= 492.7 gh/mL. Gender averaged liver tissue concentration of parent compound (ISIS 505358) = 1404 g/g. 
5.
Fold coverage based on 39-week monkey study NOAEL (2 mg/kg/week): gender averaged plasma GSK3389404 Cmax= 2.9 g/mL and gender averaged plasma AUC(0-
)= 13.5 gh/mL. Gender averaged liver tissue concentration of parent compound (ISIS 505358) = 176 g/g.
6.
Predicted using linear regression (zero intercept) based on observed human PK data from previous dose cohorts (30 to 120 mg) given dose proportionality 
 
 
 
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4.5.4.
Dose Escalation Justification
The planned GSK3389404 doses for this study are 30, 60, 120 and 240 mg administered 
by SC injection for the single dose cohorts (Part 1). The proposed doses of GSK3389404 
may be adjusted during the course of the study as the safety, PK, and PD results are 
reviewed. Doses in Part 2 will be selected such that the predicted mean plasma exposure 
at the next dose level will not exceed the mean plasma Cmax and area under the 
concentration-time curve from time zero (pre-dose) extrapolated to infinite time 
(AUC(0-)) observed at
the NOAEL of 30 mg/kg/week in the 13-week monkey toxicity study (Cmax = 52.7
g/mL; AUC(0-) = 492.7 gh/mL) and 
the NOAEL of 2 mg/kg/week in the 39-week monkey toxicity study (gender 
averaged Cmax = 2.9 g/mL; AUC(0-) = 13.5 gh/mL). 
Escalation to the next higher single dose or to Part 2 will only proceed after the PK, 
safety, and tolerability of the previous single dose level(s) are thoroughly reviewed by the 
study team and the investigator at the Dose Escalation Committee meeting 
(Section 10.8.1) and determined to be safe, tolerable, and supportive of escalation.
4.5.5.
GSK3389404 and Nucleos(t)ides
GSK3389404 is unlikely to be a victim or perpetrator of drug-drug interactions when 
administered with nucleos(t)ides due to their divergent absorption, distribution, 
metabolism, and excretion pathways.
Victim drug-drug interactions:
GSK3389404 is taken up into the liver by target mediated endocytosis and into the 
kidney by micropinocytosis, both routes that are not inhibited by small molecule drugs 
such as tenofovir, entecavir, lamivudine, adefovir and telbivudine. Furthermore,
GSK3389404 is metabolized by endogenous endonucleases, which are not inhibited by 
these 5 drugs.
Perpetrator drug-drug interactions:
Tenofovir, entecavir, lamivudine, adefovir and telbivudine are predominantly renally 
eliminated from systemic circulation [Lamivudine, 2002; Kearney, 2004; Adefovir , 
2012; Telbivudine, 2013; Entecavir, 2015]. 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]. 
In a recent study, a model compound of 2'-O-(2-methoxyethyl) modified antisense 
oligonucleotide was shown to be neither a substrate nor an inhibitor of OAT1, OAT3, 
OCT1 and OCT2 [Yu, 2016]. Therefore, GSK3389404, or the primary tissue metabolite 
ISIS 505358 that was shown to be extensively distributed into the kidney in non-clinical 
 
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studies, is unlikely to interact with tenofovir, entecavir, lamivudine, adefovir and 
telbivudine.
4.6.
Benefit:Risk Assessment
Summaries of findings from both clinical and non-clinical studies conducted with 
GSK3389404 can be found in the IB [GlaxoSmithKline Document Number 
2015N236049_04]. This section outlines the risk assessment and mitigation strategy for 
this protocol.
4.6.1.
Risk Assessment
Based on findings in nonclinical studies of GSK3389404 and nonclinical studies of 
related compounds, the following areas of interest have been identified and appropriate 
risk mitigation strategies have been adopted as summarized in Table 4.
Additional withdrawal/stopping criteria for liver chemistry, QT interval corrected for 
heart rate (QTc), hematology, renal function, and PK are discussed in Section 5.4. 
Planned dose adjustments are outlined in Section 6.3.
 
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Table 4
Summary of Key Issues, Their Impact, and Strategy to Mitigate Risk
Potential Risk1/Summary of Data
Impact—Eligibility Criteria
Strategy—
Monitoring/Stopping Criteria
Liver Effects: In the 13-week GSK3389404 mouse study, 
doses ≥6 mg/kg/week caused increases in liver enzymes 
(9.4 X AST, 7.5 X ALT, 1.6 X ALP and/or 1.7 X bilirubin) 
with correlating histopathology changes which include 
minimal to mild hepatocellular hypertrophy, vacuolated 
macrophages and scattered single cell hepatocyte 
necrosis with evidence of reversibility following the 
13-week recovery period. The mean liver concentration 
(13.5 g/g) at the NOAEL of 2 mg/kg/week in the mouse is 
approximately 0.4- to 2.3-fold higher than the predicted 
clinical efficacious liver concentration range 
(EC90-EC99: 5.9 to 33 g/g). In the 26-week mouse study, 
liver findings (eosinophilic hepatocytes, individual 
hepatocyte necrosis, presence of macrophages with 
vacuolated/granular cytoplasm (sinusoidal macrophages) 
and/or accumulations of pigmented macrophages, and 
karyomegaly.) without clinical chemistry correlates were 
not considered adverse. Liver concentration of ISIS 
505358 (97.8 g/g) at the NOAEL of 6 mg/kg/week in male 
mice was 16.6- to 3.0-fold of predicted clinical efficacious 
liver concentrations (EC90-EC99: 5.9 to 33 g/g). The 42 to 
238-fold higher liver concentrations (gender averages 
1403 g/g) were achieved at the NOAEL of 
30 mg/kg/week in the 13-week monkey study. In the 39-
week monkey study, the liver concentration of ISIS 505358 
(176 g/g) at the NOAEL of 2 mg/kg/week was 
approximately 29.8- to 5.3-fold of predicted clinical 
efficacious liver concentration (EC90-EC99: 5.9 to 33 g/g).
In the ISIS 505358-CS1 Phase I study in healthy subjects, 
modest (1.03 to 1.41 X ULN) elevations in ALT that were 
Exclusion Criteria: Subjects with a history or active 
diagnosis of liver disease other than CHB are excluded 
(Section 5.2, exclusion criterion 1).
Subjects with liver cirrhosis or evidence of cirrhosis are 
excluded (Section 5.2, exclusion criterion 4).
Subjects with laboratory test results suggestive or 
indicative of advanced liver disease are excluded 
(Section 5.2, exclusion criterion 8).
Subjects with co-infection with HDV are excluded 
(Section 5.2, exclusion criterion 7).
Subject Assessments: Frequent assessment for clinical 
symptoms suggestive of liver dysfunction (e.g., abdominal 
pain, yellowing of eyes, changes in urine color, etc.).
Laboratory Evaluations: Frequent laboratory assessment 
of liver function including AST, ALP, GGT, bilirubin (total 
and direct), albumin, INR, PT, aPTT.
Stopping Criteria: Individual subject liver chemistry 
stopping/increased monitoring criteria have been specified 
and required assessments for subjects that meet the 
criterion are defined in the protocol (Section 5.4.1).
 
 
 
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Potential Risk1/Summary of Data
Impact—Eligibility Criteria
Strategy—
Monitoring/Stopping Criteria
transient and not associated with concurrent symptoms or 
increases in bilirubin were observed. All subjects with 
elevated ALT returned to baseline during post-treatment 
follow-up.
In the GSK3389404 Phase 1 study in healthy subjects
(Study 202007), in Part 1 single dose, two subjects
experienced mild or moderate adverse events associated 
with elevations in ALT. Both were transient, modest 
(DAIDs criteria Grade 1 (<2.5x ULN)) and not associated 
with concurrent symptoms or increases in bilirubin. In Part 
2 multiple dose, no liver-chemistry related AEs were 
reported.
Coagulation Effects: In the 13-week GSK3389404 
monkey study, acute and transient test article-related 
changes in the coagulation included slightly prolonged (up 
to 5.1 seconds higher than the baseline value) aPTT 
values at 30 mg/kg/week. The prolongation was observed 
4 hours after dosing on Days 1 and 91 and generally 
returned to baseline by 24 hours post-dose. These results 
are consistent with the aPTT results from the clinical and 
nonclinical studies of other phosphorothioate and 
MOE-modified phosphorothioate ASOs [Dorr, 2001; 
Levin, 2001; Henry, 2008; Kwoh, 2008]. 
In the ISIS 505358-CS1 Phase I study in healthy subjects, 
aPTT prolongations were observed at 3 to 5 hours post 
injection of ISIS 505358. The magnitudes of this 
prolongation were modest, not clinically significant and 
generally resolved within 12 to 24 hours after dosing. 
There was no test article-related coagulation prolongation 
in monkeys treated with GSK3389404 at doses up to 
8 mg/kg/week for 39 weeks.
In Study 202007, the GSK 3389404 Phase 1 study in 
Exclusion Criteria: Subjects with a history of bleeding 
diathesis or coagulopathy will not be enrolled (Section 5.2, 
exclusion criterion 1e). 
Subjects with platelet count <140 X 109/L are excluded 
(Section 5.2, exclusion criterion 8d).
Subject Assessments: Subjects monitored for signs and 
symptoms of bleeding, hemorrhage, or bruising.
Laboratory Evaluations: Frequent laboratory 
assessments of coagulation parameters (i.e., aPTT, PT, 
INR) and hematological function (i.e., hemoglobin, ANC, 
and platelets).
 
 
 
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Impact—Eligibility Criteria
Strategy—
Monitoring/Stopping Criteria
healthy subjects, there was no evidence of GSK3389404 
related prolongation of aPTT.
Complement Activation: In the monkey GSK3389404 
13-week study, minimal decreases in (up to 21% from 
baseline) C3 and increased complement fragment Bb (up 
to 3.6-fold over baseline) were observed in the 8 and 
30 mg/kg groups, suggesting mild activation of the 
alternative complement pathway. The significance of these 
findings remains unclear because there was also an 11% 
decrease in C3 observed in male controls. These changes 
in aPTT, C3, Bb, ALT, and IgM were not seen during the 
13-week recovery period. In the 39-week monkey study, 
there was a mild and transient increase in complement 
fragment Bb (up to 2.1-fold over baseline compared to up 
to 1.4-fold over baseline in control) and decrease in C3 
concentrations in individual animals at ≥0.5 mg/kg/week. 
These changes were not considered adverse since they 
were mild and transient.
In the ISIS 505358-CS1 Phase I study in healthy subjects, 
no effect of ISIS 505358 administration on complement 
activation was observed.
In Study 202007, the GSK 3389404 Phase 1 study in 
healthy subjects, no effect of GSK3389404 administration 
on complement (C3, C4, C5a or Bb) was observed. 
Exclusion Criteria: Subjects with history of or suspected 
vasculitis are excluded (Section 5.2, exclusion criterion 
1h).
Subjects with a history of extrahepatic disorders possibly 
related to HBV immune complexes (e.g., 
glomerulonephritis and polyarteritis nodosa) will be 
excluded (Section 5.2, exclusion criterion 1e).
Subject Assessment: Subjects monitored for signs and 
symptoms of generalized systemic inflammation, vasculitis 
and infection and evaluated immediately if an inflammatory 
event or infection is suspected.
Laboratory Evaluations: Frequent assessment of 
inflammation-related markers to provide surveillance for 
detecting inflammation and vascular effects. These include 
measurement of hs-CRP (as specified in the Time and 
Events Tables [Section 7.1]), complement factors C3 and 
C4 (as specified in the Time and Events Tables 
[Section 7.1]), and the complement split products Bb and 
C5a (reflexive testing). Further, the acute phase reactants 
albumin and platelets, (changes in which may signal an 
acute phase response) will be assessed. Should any of 
this testing yield a result suggestive of an inflammatory 
event, measurements of cytokines, chemokines and/or 
autoimmune antibodies may be performed.
Pro-inflammatory Effects/Constitutional or Flu-Like 
Symptoms: At doses of 2 mg/kg/week GSK3889404 in 
the 13-week mouse study, vacuolated macrophages and 
mixed cell leucocytes were increased in incidence and/or 
magnitude at the site of injection compared to controls. In 
the 26-week mouse study, minimal to mild 
vacuolated/granular macrophages and increased incidence 
of mixed leukocytes were noted at the injection sites and/or 
Exclusion Criteria: Subjects with history of or suspected 
vasculitis are excluded (Section 5.2, exclusion criterion 
1g).
Subjects with a history of extrahepatic disorders possible 
related to HBV immune complexes (e.g., 
glomerulonephritis and polyarteritis nodosa) will be 
excluded (Section 5.2, exclusion criterion 1e).
Subject Assessment: Subjects clinically monitored for 
influenza/constitutional symptoms (e.g., fever, chills, 
arthralgias, and respiratory symptoms).
Subjects frequently assessed for the occurrence of 
injection site reactions (ISRs) and graded for severity 
based upon DAIDS criteria including assessments of pain, 
 
 
 
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Potential Risk1/Summary of Data
Impact—Eligibility Criteria
Strategy—
Monitoring/Stopping Criteria
non-injected skin sections in both sexes at doses of 
0.5 mg/kg/week. However, these findings are considered 
to reflect the sensitivity of rodents to proinflammatory 
effects of ASOs [Henry, 2008] and evidence of reversibility 
was seen in the recovery interval. There were no 
significant injection site findings in the 13- and 39-week 
monkey studies at doses up to 30 and 8 mg/kg/week, 
respectively. 
In humans, influenza-like/constitutional symptoms such as 
fever, chills, and arthralgias have been observed following 
SC administration of other phosphorothioate and 
MOE-modified phosphorothioate ASOs. If these 
constitutional symptoms occur, they generally arise shortly 
after dosing and resolve within 24 to 48 hours.
In the ISIS 505358-CS1 Phase I study in healthy subjects, 
administration-proximal constitutional symptoms were not 
observed.
In Study 202007, the GSK3389404 Phase 1 study in 
healthy subjects, influenza-like/constitutional symptoms 
such as fever, chills and arthralgias were not observed.
Injection site reactions were the most commonly reported 
treatment-related adverse event. These AEs were mild in 
intensity, transient in nature and not related to dose or 
duration of treatment.
erythema, swelling and pruritus.
Injection site reaction events meeting SAE criteria or 
Grade 3 DAIDS severity (by any measure) will be 
documented by photography. Events meeting SAE criteria 
or Grade 3 DAIDS severity (by any measure) or persisting 
beyond 2 weeks post-dose will be considered for potential 
dermatology consultation.
Laboratory Evaluations: Hematologic profiles including 
complete blood count with total WBC counts and 
differential counts will be frequently monitored. Plasma 
levels of hs-CRP, an inflammation related marker, are 
measured frequently throughout the study and samples 
stored for cytokine analysis, if required.
Kidney Effects: No adverse kidney findings were 
observed in the mouse (up to 24 mg/kg/week) and monkey 
(up to 30 mg/kg/week) 13-week GSK3389404 studies, and 
in mice (up to 6 mg/kg/week) and monkeys (up to 
8 mg/kg/week) following 26 and 39 weeks of repeat 
dosing, respectively. The presence of basophilic granules 
in the tubular epithelium in both species and occasionally 
Exclusion Criteria: Subjects with a history or active 
diagnosis of renal disease, either primary or secondary 
(e.g. renal disease due to diabetes, hypertension, vascular 
disease, etc.) are excluded (Section 5.2, exclusion 
criterion 1d);
Subjects with serum creatinine >ULN, glomerular filtration 
Subject Assessments: Subjects assessed for clinical 
symptoms suggestive of renal dysfunction (e.g., changes 
in urine output, color and blood). Subjects will have 
frequent laboratory assessments of renal function including 
creatinine, phosphate and albumin in serum and protein, 
creatinine, blood and glucose in urine. GFR and urine ACR 
are calculated frequently.
 
 
 
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Potential Risk1/Summary of Data
Impact—Eligibility Criteria
Strategy—
Monitoring/Stopping Criteria
vacuolated/granular macrophages surrounding the pelvic 
region of kidneys in mice are considered indicative of 
cellular uptake of oligonucleotides. These findings were 
generally reversible by the end of recovery period, and 
therefore, were not considered adverse [Henry, 2000]. 
In humans administered 2ʹ-MOE ASOs, no trends in 
laboratory parameters of kidney function test have been 
identified that suggested an effect on renal function.
In the ISIS 505358-CS1 Phase I study in healthy subjects, 
no changes in serum creatinine levels or other measures 
of renal function were observed.
In Study 202007, the GSK 3389404 Phase 1 study in 
healthy subjects, no changes in the mean values from 
baseline for serum creatinine were observed.
rate (GFR) <90 mL/min (but 60 ml/min may be 
considered after consultation with the GSK medical 
monitor), or urine albumin to creatinine ratio (ACR) 
0.03 mg/mg (or 30 mg/g).are excluded (Section 5.2, 
exclusion criteria 8e, 8f, and 8g).
Subjects with a positive test for blood in urine are excluded 
if repeat testing reveals >5 RBC per HPF Section 5.2, 
exclusion criterion 9).
Stopping Criteria: If the following are observed, results 
should be confirmed and if confirmed, further evaluation 
pursued in consult with the GSK medical monitor: 

Persistent urine ACR 0.03 mg/mg (or 30 mg/g).
and without alternative cause(s) identified.

Blood in urinalysis 5 RBC per HPF confirmed by 
microscopy without alternative cause(s) identified.

Persistent elevation of serum creatinine 
(>26.52 mol/L change from baseline) without an 
alternative cause identified.
Following confirmation of the criteria above, further 
evaluation may include but not be limited to 24-hour urine 
for analysis, consultation with a nephrology specialist, 
renal ultrasound, urine microscopy, serum creatinine, 
SPEP/UPEP, and/or complement panel (C3, C4, C5a and 
Bb).
Decreased hematological parameters: No significant 
test article related changes in platelets were observed in 
the 13-week GSK3389404 mouse or monkey toxicity 
studies. In the 39-week monkey study, a marked and 
transient decrease in platelet count was noted in one male 
monkey administered GSK3389404 at 8 mg/kg/week on 
Day 184. The platelet count in this monkey returned to 
near baseline values by Day 191, despite continued 
treatment with test article. No significant test article-related 
changes in platelets were observed in the 26-week mouse 
study.
In the 39-week monkey study, one high dose male had 
severe non-regenerative and potentially haemolytic anemia 
characterized by decreased red blood cell parameters and 
accompanied by decreased neutrophil counts, 
inflammation, renal injury/proteinuria, complement 
Exclusion Criteria: Subjects with a history of bleeding 
diathesis or coagulopathy will not be enrolled (Section 5.2, 
exclusion criterion 1f). 
Subjects with platelet counts <140 x 109/L are excluded 
(Section 5.2, exclusion criterion 8d).
Subject Assessments:
Subjects monitored for signs and symptoms suggestive of 
effects on white cell, red cell, or platelet production; these 
include signs or symptoms suggesting infection, anemia, 
bleeding, hemorrhage, or bruising. Adverse events 
indicative of bleeding will be evaluated.
Laboratory Evaluations: Frequent laboratory 
assessments for WBC, hemoglobin, reticulocyte count and 
platelets. Further, RBC counts and red cell indices (e.g., 
red cell distribution width, mean corpuscular hemoglobin), 
will be followed. Laboratory values suggestive of hemolysis 
(e.g., bilirubin and lactate dehydrogenase) will be followed.
Stopping Criteria: Individual subject hematological 
stopping criteria (Section 5.4.3) will be applied as follows:

Hemoglobin 9.9 g/dL
 
 
 
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Potential Risk1/Summary of Data
Impact—Eligibility Criteria
Strategy—
Monitoring/Stopping Criteria
activation, metabolic acidosis, and decreased nutrient 
uptake. This animal was sacrificed on Day 218 (Week 32).
Since non-regenerative anemia and other associated 
findings were only noted in this one animal, and have not 
been noted in other studies with antisense oligonucleotide 
therapies, even when accompanied by complement
activation and/or proteinuria, the relationship of anemia to 
treatment in this case is unclear.
Platelet reductions have been observed in the clinical and 
preclinical studies of a few members of 2′-MOE ASO drug 
class. In the most cases, reductions in platelets have been 
mild and reversible. However, there have been reports of 
severe thrombocytopenia requiring medical intervention.
In the ISIS 505358-CS1 phase 1 study in healthy subjects, 
laboratory data did not suggest any effect on hematological 
cell counts or hemoglobin.
In Study 202007, the GSK 3389404 Phase 1 study in 
healthy subjects, the laboratory data did not suggest any 
GSK3389404 related effect on hematological cell counts or 
hemoglobin.

ANC 750/mm3

Platelets 75 X 109/L
AE = adverse event, ALP = alkaline phosphatase, ALT = alanine aminotransferase, ANC = absolute neutrophil count, aPTT = activated partial thromboplastin time, ASO = antisense 
oligonucleotides, AST = aspartate aminotransferase, C3, C4 =complement factors 3 and 4, DAIDS = Division of Acquired Immune Deficiency Syndrome, ECG = electrocardiogram, 
GFR = glomerular filtration rate, GGT = gamma glutamyl transpeptidase, hs-CRP = high-sensitivity C-reactive protein, IB = Investigator’s Brochure, INR = international normalized ratio, 
ISR = injection site reaction, MOE = methoxyethyl, NOAEL = no observed adverse effect level, PT = prothrombin time, RBC = red blood cell, SAD = single ascending dose, 
SAE = serious adverse event, SC = subcutaneous, SPEP = serum protein electrophoresis, UA = urinalysis, ULN = upper limit of normal, UPEP = urine protein electrophoresis, 
WBC = white blood cell
1.
Additional details regarding potential risks identified in nonclinical toxicity studies as well as overall guidance for the clinical investigator are provided in the ISIS 505358 Hepatitis 
B Antisense Oligonucleotide. Investigators Brochure [available on request] [ISIS 505358, 2016].
 
 
 
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4.6.2.
Benefit Risk Summary
This first-in-patient study will evaluate safety, tolerability, PK, and PD of GSK3389404 
across a range of doses projected to encompass the expected therapeutic dose range and 
for a dosing duration of up to 3 months in the target patient population (i.e., subjects with 
CHB). The intent of this study is to enable selection of an optimal dose level and regimen 
of GSK3389404 for subsequent evaluation in future studies.
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 subjects with CHB.
The study design mitigates risk to subjects through the following:
1. Inclusion/Exclusion criteria ensuring the enrollment of subjects with CHB who 
are without underlying organ dysfunction or significant co-morbidities that 
would put them at greater risk for potential drug-specific toxicities.
2. During Part 1 (SAD), dosing is sequential and subjects closely monitored for at 
least 8 hours post-dose. Subjects have extended follow-up out to 60 days 
post-dose to assess safety. A low starting dose, based on the fold coverage to 
mean NOAEL in the 13-week monkey toxicity study, was selected for the 
initial dose in Part 1.
3. In Part 1, dose escalation will be stopped or a smaller dose increment selected 
when the predicted mean AUC(0-) and Cmax of the next dose level are expected 
to exceed the NOAEL exposures observed in the 13-week monkey toxicity 
study (Section 6.3).
4. Between each dosing cohort in Part 1, escalation to the next dose-level will 
proceed only after the safety (AE listings, flagged vital signs, ECGs, laboratory 
findings [including liver function tests]) of the previous dose level, and PK 
results derived from 24-hour plasma profiles, together with available PD data)
are thoroughly reviewed by the study team and the investigator at scheduled 
Dose Escalation Committee meetings (Section 10.8.1).
5. Safety, PK, and PD data from Part 1 will be reviewed prior to initiating Part 2 
(multiple-dose) to identify the dose levels and regimens in Part 2.
6. In Part 2, safety data from a sentinel group (1 subject from each treatment 
group and the corresponding matching placebo) will be reviewed by the GSK 
internal clinical team or SRT in a blinded manner (Section 10.8.2). 
Randomization for the remainder of subjects in Part 2 will continue after safety 
data from at least 2 weeks of exposure (but may include more data) in the 
sentinel group are reviewed. Safety data from all subjects will be reviewed by 
the GSK internal clinical team or SRT in a blinded manner on a regular basis 
thereafter.
7. In Part 2, subjects are seen at the clinic on a weekly basis and safety 
assessments (AE/serious adverse event [SAE] review, physical exam, vital 
signs, ECG assessments) and comprehensive laboratory testing is performed 
 
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on a weekly or bi-weekly (every 2 weeks) basis. At the end of the 3-month 
treatment period, subjects will continue to have regular assessments during the 
post treatment follow-up period. 
8. In both Parts 1 and 2, the protocol applies comprehensive and frequent safety 
monitoring with individual subject stopping criteria (Section 5.4) specified for 
key class and potential drug specific toxicities, including liver chemistry 
stopping criteria, QTc stopping criteria, hematological stopping criteria, renal 
function stopping criteria, and PK stopping criteria (Part 1 only). In addition, 
the protocol defines criteria, based on the occurrence of AEs of Grade 3 or 
Grade 4 severity, unacceptable pharmacological effects, or SAEs, when subject 
dosing or dose escalation is to be halted until a full safety review of the study 
has been undertaken (Section 6.3).
4.6.3.
Overall Benefit:Risk Conclusion
Based upon the safety strategies and risk mitigations inherent to this protocol and the 
potential contributions to the development of an improved treatment for patients with 
CHB, it is concluded that there is a positive risk benefit to subjects for participation in 
this study.
5.
SELECTION OF STUDY POPULATION AND 
WITHDRAWAL CRITERIA
This first-in-patient study will enroll adult male and female subjects in either the immune 
tolerant or the immune active phase of HBV infection who may or may not be on a stable 
nucleos(t)ide regimen. The immune tolerant phase is characterized by the absence of 
biochemical symptoms of the disease (i.e., elevated transaminase levels). The immune 
active phase, also referred to as HBeAg-positive or HBeAg-negative chronic hepatitis, is 
characterized by elevated alanine aminotransferase (ALT) levels, evidence of active 
hepatic inflammation, and HBV DNA levels greater than or equal to 2000 IU/mL. 
Subjects who are on a stable nucleos(t)ide regimen are characterized by ALT levels less 
than or equal to the upper limit of normal (ULN) and have suppressed HBV DNA, 
defined as HBV DNA less than or equal to the lower limit of quantification (LLOQ). The 
entry criteria for this study are designed to enroll subjects with CHB who do not have 
advanced liver fibrosis or cirrhosis, other advanced concomitant liver diseases, co-
infection, or other significant co-morbidities that would confound the safety monitoring 
and/or potentially put them at greater risk for treatment-related AEs.
Specific information regarding warnings, precautions, contraindications, AEs, and other 
pertinent information on GSK3389404 or other study treatment that may impact subject 
eligibility is provided in the IB [GlaxoSmithKline Document Number 2015N236049_04]. 
Deviations from inclusion and exclusion criteria are not allowed because they can 
potentially jeopardize the scientific integrity of the study, regulatory acceptability, or 
subject safety. Therefore, adherence to the criteria as specified in this section is essential.
A subject with a clinical abnormality or laboratory parameter(s) which is/are not 
specifically listed in the inclusion or exclusion criteria and are reported as outside of the 
 
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laboratory’s reference range may be repeated and the subject included only if the 
investigator considers the finding unlikely to introduce additional risk to the subject and 
will not interfere with the study procedures. 
5.1.
Inclusion Criteria
A subject will be eligible for inclusion in this study only if all of the following 
criteria apply:
1. Subject is able to understand and is capable of giving written informed 
consent, is willing to comply with protocol requirements, instructions and 
protocol-stated restrictions, and is likely to complete the study as planned.
2. Between 18 and 70 years of age, inclusive, at the time of signing the informed 
consent form.
3. A body mass index (BMI) between 18 to 30 kg/m2, inclusive.
4. Male or female if they satisfy the following:
a.
All females must meet the following criteria:
i. Non-pregnant (as confirmed by a negative serum human chorionic 
gonadotrophin [hCG] test); AND
ii. Non-lactating at screening and prior to dosing; AND 
b. Females of reproductive potential (FRP), must agree to follow (or confirm 
that they have and are currently following) one of the options listed in the 
Modified List of Highly Effective Methods for Avoiding Pregnancy in 
FRP (see Appendix 4) from at least 28 days prior to the first dose of study 
treatment until Follow-up visit Day 169 in conjunction with partner’s use 
of male condom. The investigator is responsible for ensuring that subjects 
understand how to properly use these methods of contraception.
c.
For females of non-reproductive potential, at least one of the following 
conditions must apply:
i. Premenopausal females without reproductive potential defined by 
one of the following:
1. Documented salpingectomy; 
2. Hysterectomy;
3. Documented bilateral oophorectomy.
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iii. A blood sample for simultaneous follicle-stimulating hormone 
(FSH) and estradiol levels may be collected at the discretion of the 
investigator or site to confirm non-reproductive potential. Please 
refer to laboratory reference ranges for confirmatory levels for 
menopause.
d.
Male subjects with a female partner of child-bearing potential must agree 
to meet one of the contraception requirements from the time of first dose 
of study treatment until Follow-up visit Day 169.
i.
Vasectomy 
ii.
Male condom plus partner’s use of one of the contraceptive options 
below that meets the standard operating procedure (SOP) 
effectiveness criteria including a <1% rate of failure per year, as 
stated in the product label:
1.
Contraceptive subdermal implant
2.
Intrauterine device or intrauterine system
3.
Combined estrogen and progestogen oral contraceptive 
[Hatcher, 2011]
4.
Injectable progestogen [Hatcher, 2011]
5.
Contraceptive vaginal ring [Hatcher, 2011]
6.
Percutaneous contraceptive patches [Hatcher, 2011]
These allowed methods of contraception are only effective when used 
consistently, correctly and in accordance with the product label. The 
investigator is responsible for ensuring that subjects understand how to 
properly use these methods of contraception.
e.
Male subjects must refrain from donating sperm from the time of first dose 
of study treatment until Follow-up visit Day 169.
5. Documented chronic HBV infection ≥6 months prior to screening.
6. Subject with HBV treatment history as follows:
a.
Part 1: 
i.
Treatment naïve, -or-
ii.
Have had prior treatment with interferon (pegylated or 
non-pegylated) that must have ended at least 6 months prior to the 
Baseline visit (Day 1 pre-dose) and/or nucleos(t)ide analogue 
therapy that must have ended at least 6 months prior to the 
Baseline visit -or-
 
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iii.
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. 
b.
Part 2: Subjects with CHB 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. Subjects with prior treatment with 
interferon (pegylated or non-pegylated) must have ended treatment at least 
6 months prior to the Baseline visit (Day 1 pre-dose).
7. Plasma or serum HBV DNA concentration:
a.
Treatment naïve subjects or subjects not currently receiving treatment, 
there is no minimum HBV DNA requirement.
b.
Subjects who are receiving stable nucleos(t)ide analogue therapy must be 
adequately suppressed, defined as plasma or serum HBV DNA <LLOQ.
8. Plasma or serum HBsAg concentration >50 IU/mL.
9. Alanine aminotransferase (ALT) concentration:
a.
ALT < 5 X ULN for treatment naïve subjects and for subjects who 
are not currently receiving treatment
b.
ALT 2 X ULN for subjects who are receiving stable 
nucleos(t)ide analogue therapy
5.2.
Exclusion Criteria
A subject will not be eligible for inclusion in this study if any of the following criteria 
apply:
1.
Medical history
a.
History of or active diagnosis of moderate to severe liver disease other 
than CHB, such as autoimmune hepatitis, non-alcoholic steatohepatitis, 
hemochromatosis, or liver failure.
b.
History or other clinical evidence of significant or unstable cardiac disease 
(e.g., prolonged QT syndrome [torsade de pointes], angina, congestive 
heart failure, myocardial infarction, diastolic dysfunction, significant 
arrhythmia, coronary heart disease and/or clinically significant ECG 
abnormalities).
c.
Uncontrolled or history of difficult to control hypertension.
d.
History of, or active diagnosis of, primary or secondary renal disease (e.g., 
renal disease secondary to diabetes, hypertension, vascular disease, etc.).
e.
History of extrahepatic disorders possibly related to HBV immune 
complexes (e.g., glomerulonephritis and polyarteritis nodosa).
f.
History of bleeding diathesis or coagulopathy.
 
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g.
History of or suspected presence of vasculitis.
h.
History of Gilbert’s Syndrome.
i.
History of malignancy within the past 5 years with the exception of 
specific cancers that are cured by surgical resection (e.g., skin cancer), 
subjects under evaluation for possible malignancy are not eligible.
2.
History of/sensitivity to GSK3389404 or components thereof or a history of drug 
or other allergy that, in the opinion of the investigator or medical monitor, 
contraindicates their participation.
3.
Confirmed or suspected HCC as evidenced by:
a.
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 
randomization.
4.
Liver cirrhosis or evidence of cirrhosis as determined by any of the following:
a.
Positive liver biopsy (i.e., Metavir Score F4) within 12 months of 
screening
b.
Fibroscan >12 kPa within 12 months of screening
c.
Aspartate aminotransferase (AST)-Platelet Index (APRI) >2 and 
FibroSure result >0.7 within 12 months of screening
d.
Investigator judgement
For subjects without a test for cirrhosis in the above timeframes, APRI and 
FibroSure should be performed during the screening period to rule out cirrhosis.
5.
Hepatitis C virus (HCV) co-infection
6.
Human immunodeficiency virus (HIV) co-infection
7.
Hepatitis D virus (HDV) co-infection
8.
Laboratory results as follows:
a.
Total bilirubin concentration >1.25 X ULN
b.
Serum albumin concentration <3.5 g/dL
c.
International normalized ratio (INR) >1.25
d.
Platelet count <140 X 109/L
e.
Serum creatinine concentration greater than the ULN
f.
Glomerular filtration rate (GFR) <90 mL/min as calculated by the Chronic 
Kidney Disease Epidemiologic Collaboration (CKD-EPI) formula.
Subjects with GFR <90 mL/min but 60 mL/min may be considered after 
consultation with the GSK medical monitor.
 
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g.
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 subjects 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 patient 
does not have a history of diabetes, hypertension or other risk 
factors that may affect renal function and discuss with the PPD or 
GSK medical monitor, or designee
9.
Positive test for blood in urine. In the event of a positive test, the test may be 
repeated once, and if repeat is negative or if urine microscopy reveals <5 red 
blood cells (RBC) per high-power field (HPF), the subject is considered eligible.
10. Fridericia’s QT correction formula (QTcF) ≥450 msec (if single ECG at screening 
shows QTcF 450 msec, a mean of triplicate measurements should be used to 
confirm that subject meets exclusion criterion).
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. Current alcohol use as judged by investigator to potentially interfere with 
participant compliance.
13. A positive pre-study treatment screen and an unwillingness to refrain from use of 
illicit drugs (or substances with abuse potential) and adhere to other protocol-
stated restrictions while participating in the study. [The screen refers to illicit 
drugs and substances with abuse potential. Medications that are used by the 
patient as directed, whether over-the-counter or through prescription, are 
acceptable and would not meet the exclusion criteria]
14. Where participation in the study would result in donation of blood or blood 
products in excess of 500 mL within a 56-day period.
15. The subject 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 non-GSK oligonucleotide or small interfering RNA 
(siRNA) within 12 months prior to the first dosing day or prior treatment with 
GSK oligonucleotide within 3 months prior to the first dosing day.
17. Pregnant or lactating females at screening and prior to dosing
5.3.
Screening/Baseline/Run-in Failures
Screen failures are defined as subjects who consent to participate in the clinical trial but 
are never subsequently randomized. In order to ensure transparent reporting of screen 
failure subjects, meet the Consolidated Standards of Reporting Trials (CONSORT) 
 
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publishing requirements, and respond to queries from regulatory authorities, a minimal 
set of screen failure information is required including demography, screen failure details, 
eligibility criteria, and SAEs (see Section 7.3.1.5).
5.4.
Withdrawal/Stopping Criteria
A subject may withdraw from the study at any time at his/her own request, or may be 
withdrawn at any time at the discretion of the investigator for safety, behavioral or
administrative reasons. Subjects who are discontinued from study treatment will enter the 
post-treatment follow-up period (please submit an electronic protocol inquiry platform
[EPIP] query (either site or clinical research associate [CRA] may submit) to receive
post-treatment follow up dates for subjects who discontinue study treatment) unless 
consent is withdrawn. Every effort should be made to complete the early termination 
(ET) study procedures and observations if the subject does not enter post-treatment 
follow-up. 
For a subject who fails to attend the study site for a required study visit, the following 
actions must be taken:

The site must attempt to contact the subject and re-schedule the missed visit as 
soon as possible. 

The site must counsel the subject on the importance of maintaining the 
assigned visit schedule and ascertain whether or not the subject wishes to 
and/or should continue in the study. 

In cases where the subject is deemed lost to follow-up, the investigator or 
designee must make every effort to regain contact with the subject (where 
possible, 3 telephone calls and if necessary a certified letter to the subject’s last 
known mailing address or local equivalent methods). These contact attempts 
should be documented in the subject’s medical record. 

Should the subject continue to be unreachable, only then will he/she be 
considered lost to follow-up.
Subjects are not obligated to state the reason for withdrawal, but the investigator must 
make every attempt to elucidate a reason. The efforts must be documented in the source 
including efforts to locate a subject that has been deemed lost to follow-up. The reasons 
for withdrawal, or failure to provide a reason, must be documented in the case report 
form (CRF). If a subject withdraws from the study, he/she may request destruction of any 
samples taken, and the investigator must document this in the site study records.
All subjects who discontinue prematurely from the study will be asked for additional 
information to establish the reason for withdrawal. Reasons for study withdrawal may 
include:

Adverse event

Subject meets stopping criteria (as outlined in Section 5.4.1, Section 5.4.2, 
Section 5.4.3, Section 5.4.4, and Section 5.4.5)

Protocol deviation
 
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
Pregnancy

Non-compliance

Subject lost to follow-up

Subject withdraws consent

Investigator discretion

Sponsor terminates the study
Any laboratory parameter that meets the stopping criteria should be repeated once to 
confirm the value prior to withdrawal.
Subjects who are withdrawn from the study may be replaced as follows: 

In Part 1, a subject may be replaced if he/she does not complete the study 
through Day 3.
o
Replacement subjects will receive the same study treatment as the 
withdrawn subject.

In Part 2, subjects that withdraw from the study will not be replaced. 
5.4.1.
Liver Chemistry Stopping Criteria
Liver chemistry stopping and increased monitoring criteria have been designed to assure 
subject safety and evaluate liver event etiology during administration of study treatment 
and the follow-up period. 
Table 5 provides guidance for liver stopping criteria for subjects with baseline ALT less 
than or equal to the ULN and for subjects with elevated baseline ALT. 
Eligible subjects in Part 1 and Part 2 may have an elevated ALT at screening as specified
in Section 5.1. However, the screening ALT may differ from the baseline ALT. Baseline 
ALT will be measured prior to dosing on Day 1, but results will not be available from the 
laboratory until after the subject has already been dosed.
A CHB subject who meets the criteria listed in Table 5 will be permanently discontinued 
from study treatment. Every attempt must be made to have the subject return to the study 
site (within 24 hours) for repeat liver chemistries, additional testing, and close monitoring 
(a specialist or hepatology consultation is recommended). The event must be reported to 
GSK/designee within 24 hours of learning of its occurrence. Subjects must be monitored
twice weekly until liver chemistries (ALT, AST, alkaline phosphatase [ALK], bilirubin) 
resolve, stabilize, or return to within baseline (Day 1 pre-dose) values. Please submit an 
EPIP query (either site or CRA may submit) to receive post-treatment follow up dates for 
subjects who discontinue study treatment.
Refer to Appendix 2 (Section 12.2) for details of the required assessments if a subject 
meets any of the liver chemistry stopping criteria.
 
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Subjects with ALT 3 X baseline or 3 X ULN (if baseline ALT ULN) and who do not 
meet the stopping criteria outlined in Table 5 can continue with the study treatment. At 
any point, if these subjects meet the liver chemistry threshold stopping criteria or are 
unable to return for weekly liver chemistries, study treatment must be permanently 
stopped, additional testing performed, and the subject will continue safety follow-up 
procedures until liver chemistries resolve, stabilize, or return to baseline (Day 1 pre-dose) 
values. The subject must then attend the Follow-up visits specified in the Time and 
Events Table (Section 7.1). 
Subjects who meet the stopping criteria with ALT but do not meet bilirubin stopping 
criteria must be immediately discontinued from study treatment. Every attempt must be 
made to have the subject return to clinic within 24 to 72 hours for repeat liver chemistries 
and additional testing and weekly monitoring until liver chemistries (ALT, AST, ALK, 
bilirubin) resolve, stabilize, or return to within baseline (Day 1 pre-dose) values. This 
event must be reported to GSK/designee within 24 hours of learning of its occurrence.
Upon completion of the safety follow-up procedures, the subject must attend the 
Follow-up visits specified in the Time and Events Table (Section 7.1).
Table 5
Liver Stopping Criteria
Baseline Bilirubin ULN
Baseline Bilirubin >ULN
Baseline 
ALT ULN
If ALT 5 X ULN, permanently withdraw 
study treatment
If ALT 5 X ULN, permanently withdraw 
study treatment
If ALT 3 to <5 X ULN, permanently 
withdraw study treatment if any of the 
following apply:

associated with the appearance 
or worsening of hepatitis 
symptoms

bilirubin ≥1.5 X ULN (>35% direct)

increase persists ≥4 weeks
If ALT ≥3 to <5 X ULN, permanently 
withdraw study treatment if any of the 
following apply:

associated with the appearance or 
worsening of hepatitis symptoms

bilirubin ≥1.5 X baseline 
(>35% direct)

increase persists ≥4 weeks
Baseline 
ALT >ULN
If ALT 5 X baseline or 20 X ULN, 
permanently withdraw study treatment.
If ALT 5 X baseline or 20 X ULN, 
permanently withdraw study treatment.
If ALT 3 to <5 X baseline (up to 
<20 X ULN), permanently withdraw study 
treatment if any of the following apply:

associated with the appearance or 
worsening of hepatitis symptoms

bilirubin 1.5 X ULN (>35% direct)

increase persists 4 weeks
If ALT 3 to <5 X baseline (up to 
<20 X ULN), permanently withdraw study 
treatment if any of the following apply:

associated with the appearance or 
worsening of hepatitis symptoms

bilirubin 1.5 X baseline 
(>35% direct)

increase persists 4 weeks
ALT = alanine aminotransferase, ULN = upper limit of normal
Notes:

Any abnormal laboratory parameters that meet the criteria for individual treatment stop must be confirmed by 
retest of a new collection of blood samples as soon as possible. 

Any deterioration from the baseline in the liver parameters must be confirmed by retesting ALT, total bilirubin, 
and direct bilirubin. 

If 1 criterion in the list above is met and confirmed by retesting, further treatment may be stopped for the 
subject after discussion with the medical monitor. Results of retesting must be evaluated before the next 
dose is administered. 
 
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5.4.1.1.
Study Treatment Restart or Rechallenge
Study treatment restart or rechallenge after liver chemistry stopping criteria are met by 
any subject participating in this study is not allowed.
5.4.2.
QTc Stopping Criteria

For Part 1 and Part 2 of this study, QTcF will be used to determine eligibility for 
and discontinuation from study treatment.

A subject who meets either of the bulleted criteria below will be discontinued 
from study treatment:
o
QTcF >500 msec 
o
Change from baseline in QTcF >60 msec
Discontinuation of subjects will be based on average QTcF from triplicate ECGs. If a 
single ECG measurement demonstrates a prolonged QTcF interval, the ECG should be 
repeated 2 more times and the average of the 3 QTcF values used to determine whether 
the subject should be discontinued from the study treatment.
Please submit an EPIP query (either site or CRA may submit) to receive post-treatment 
follow up dates for subjects who discontinue study treatment
5.4.3.
Hematological Stopping Criteria
In Parts 1 and 2, a subject who meets any of the criteria below will be discontinued from 
study treatment:

Hemoglobin ≤9.9 g/dL

Absolute neutrophil count (ANC) 750/mm3

Platelets 75 X 109/L
Please submit an EPIP query (either site or CRA may submit) to receive post-treatment 
follow up dates for subjects who discontinue study treatment
5.4.4.
Renal Function Stopping Criteria
If any of the following are observed in Part 1 or Part 2, results should be confirmed, and 
if confirmed, further evaluation for alternative causes should be pursued in consultation 
with the medical monitor: 

Persistent urine ACR 0.03 mg/mg (30 mg/g) and without alternative cause(s) 
identified

Blood in urinalysis 5 RBC per HPF confirmed by microscopy without alternative 
cause(s) identified

Persistent elevation of serum creatinine (>26.52 mol/L change from baseline) 
without an alternative cause identified
 
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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 creatinine, serum protein electrophoresis 
(SPEP)/urine protein electrophoresis (UPEP), and/or complement panel (C3, C4, C5a and 
Bb). Further evaluation and actions should be determined by the investigator in 
consultation with the medical monitor. 
5.4.5.
Pharmacokinetic Stopping Criteria
Part 1: Doses will be escalated such that the predicted mean plasma exposure at the next 
dose level will not exceed the mean plasma AUC(0-) and Cmax observed at the NOAEL 
dose of 30 mg/kg/week in the 13-week monkey toxicity study 
(AUC(0-) = 492.7 mgh/mL and Cmax = 52.7 mg/mL).
A Bayesian predictive probability of AUC(0-) and Cmax less than 492.7 mgh/mL and 
52.7 mg /mL (mean exposures at NOAEL in the 13-week monkey study), respectively, 
will be calculated for the next dose level and used together with safety and tolerability 
data to aid next dose selection. Dose escalation may be stopped or a smaller dose 
increment selected (Section 6.3) for the next cohort if the predictive probability of 
exceeding the mean NOAEL exposure is greater than 50%.
Part 2: No interim PK analysis is planned.
5.5.
Subject and Study Completion

A completed subject in Part 1 is one who has completed Day 60 visit. An ongoing 
subject who misses the Day 60 visit will be considered as lost to follow-up.

A completed subject in Part 2 is one who has completed Day 169 visit. An 
ongoing subject who misses the Day 169 visit will be considered as lost to 
follow up.

For subjects who participate in the optional extended post treatment follow-up 
period, a completed subject in extended follow-up period is one who has 
completed the Day 450 visit. An ongoing subject who misses the Day 450 visit 
will be considered as lost to follow up for the optional extended follow-up period.
The study will be completed after all subjects complete the last study visit or are 
considered lost to follow-up. 
6.
STUDY TREATMENT
6.1.
Investigational Product and Other Study Treatment
The term ‘study treatment’ is used throughout the protocol to describe any combination 
of products received by the subject as per the protocol design. Study treatment may 
therefore refer to GSK3389404 or placebo or both. Details of the study treatment are 
provided in Table 6.
 
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Table 6
Study Treatment
Study Treatment
Product Name:
GSK3389404
Placebo
Formulation Description:
Clear colorless to slightly 
yellow solution
Clear colorless solution
Dosage Form:
Solution for injection
Solution for injection
Unit Dose Strength(s)/Dosage 
Level(s):
100 mg/mL; 1.0 mL nominal 
volume per vial (minimal
overfill per vial)
Placebo 
Route/Administration/Duration:
SC, single and multiple (once 
weekly, bi-weekly, up to 
85 days)
SC, single and multiple (once 
weekly, bi-weekly, up to 
85 days)
Dosing Instructions:
Administer SC
Administer SC
Manufacturer/Source of 
Procurement:
GSK Global Manufacturing 
and Supply, Parma (Italy)
Locally sourced normal saline
Method for Individualizing 
Dosage:
Dispensing into syringes
Dispensing into syringes
GSK = GlaxoSmithKline, SC = subcutaneous
Dosing volumes are presented in Table 7. Study treatment administration will take place 
after completion of all pre-dose study assessments as specified in the Time and Events 
Tables (Section 7.1). The site of injection will be recorded for each subject and dose. 
Sites of injection are listed in order of preference and are a guide for the clinical staff. 
Injections may be rotated within each anatomical site. Injection into areas with ongoing 
injection site reactions (ISRs) should be avoided.
1.
Abdominal quadrants
2.
Thighs
3.
Outer area of the upper arms
4.
Buttocks
Please refer to the Study Reference Manual (SRM) provided by the Sponsor or designee 
for more information about study treatment administration. 
Table 7
Study Treatment Dose and Injection Volume
Dose1
Volume to Administer2
30 mg or placebo
0.30 mL
60 mg or placebo
0.60 mL
120 mg or placebo
1.2 mL
1.
Dose may change based on safety and pharmacokinetic data from preceding cohort(s)
2.
If a change in dose is warranted, volume to administer (mL) = dose (mg)/100
 
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6.2.
Treatment Assignment
Separate randomization schedules will be generated for each part of the study. The 
randomization schedule for the optional Japanese Part 2 sub-study will be generated 
separately. The randomization schedules will be generated by an independent 
randomization team within the clinical research organization (CRO) biostatistics 
department. The randomization schedule will be generated using SAS codes developed 
by a CRO technical team.
Subjects in Part 1 will be assigned to a dosing cohort based on the order in which they are 
enrolled. Within each cohort, subjects will be randomly assigned to study treatment 
(GSK3389404:placebo [3:1]) in accordance with the randomization schedule generated 
before the start of the study. As discussed in Section 5.4, subjects that withdraw from 
Part 1 of the study may be replaced. The new subject will be assigned a replacement 
randomization number to receive the same study treatment as the subject being replaced. 
Two randomization schedules for Part 2 will be generated after dosing in Part 1 is 
completed and dose levels and regimens for Part 2 have been identified. A separate 
randomization schedule will be generated for the sentinel group. The remainder of Part 2 
subjects will be centrally randomized using a randomization schedule to receive 1 of the 
active dose levels and regimens selected in Part 2 or corresponding matching placebo.
Subjects in Part 2 will be randomized in a 1:1 ratio (active:placebo) in the sentinel group. 
Remainder of the Part 2 subjects will be randomized in an approximately 10:1 ratio 
(active:placebo). The overall randomization ratio of Part 2 will be an approximately 
11:2 ratio (active:placebo). The randomization ratio of the optional Japanese Part 2 
sub-study will be provided in a Japan country-specific protocol amendment/supplement.
Sentinel 
Remainder
Part 2
Active
Placebo
Active
Placebo
60 mg GSK3389404 weekly
1
1
10
1
120 mg GSK3389404 bi-weekly
1
1
10
1
120 mg GSK3389404 weekly
1
1
10
1
Study site personnel will be required to contact the central randomization service for 
assignment of a unique identifier (designating the subject’s randomization code) for each 
subject participating in the study. A unique treatment number will be assigned for each 
subject participating in the study.
6.3.
Planned Dose Adjustments
This protocol allows some alteration from the currently outlined dosing plan for Part 1. 

In Part 1, the decision to proceed to the next dose level of GSK3389404, to adjust 
the next dose level, or add/remove cohorts will be made by the Dose Escalation 
Committee (Section 10.8.1) based on safety, tolerability and preliminary PK 
 
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and/or PD data through Day 3 obtained in at least 3 subjects that received 
GSK3389404 at the prior dose level. 
o
Dose adjustments may involve either an increase or a decrease in the planned 
dose. However, the maximum dose will not exceed 240 mg and the maximum 
exposure will not exceed the monkey mean NOAEL exposures observed in 
the 13-week monkey toxicity study.
o
A Bayesian predictive probability of AUC(0-) and Cmax less than 492.7
gh/mL and 52.7 g/mL (mean exposures at NOAELof the 13-week monkey 
study at steady state), respectively, may be calculated with adequate data for 
the next dose levels and used together with safety and tolerability data to aid 
next dose selection.
o
In the case of undetectable or extremely low concentrations following the 
first dose (e.g., if the majority of PK samples are below LLOQ), a more than 
3-fold increase in dose may be considered for the next dose level.
o
The dosing plan may also be adjusted to expand a dosing cohort (enroll 
additional subjects) to further evaluate safety, PK, and/or PD findings at a 
given dose level, or to add cohort(s) to evaluate additional dose level(s), not 
exceeding the maximum dose as defined in Section 4.1. The study 
procedures for these additional subject(s) or cohort(s) will be the same as that 
described for other study subjects.
o
Planned cohorts may be removed depending on safety, tolerability, PK, 
and/or PD results from the previous cohorts as follows: 
If AEs, which are of Grade 3 or Grade 4 severity as defined within the 
Division of Acquired Immune Deficiency Syndrome (DAIDS) table in 
Appendix 3 (Section 12.3) and are consistent across subjects in the group, 
or if unacceptable pharmacological effects, reasonably attributable in the 
opinion of the investigator to dosing with GSK3389404 are observed in 
more than 40% of the subjects in a group, the dose escalation will be 
temporarily halted, and no further subject will be administered until a full 
safety review of the study has taken place. Relevant reporting and 
discussion with the medical monitor, relevant GSK personnel, and with 
the Independent Ethics Committee (IEC) will then take place prior to any 
resumption of dosing.
If the same SAE (i.e., similar SAE term) occurs in more than one subject, 
the dose escalation will be temporarily halted, and no further subject will 
be administered until a full safety review of the data has taken place. 
Relevant reporting and discussion with the medical monitor, relevant GSK 
personnel, and with the IEC will then take place prior to any resumption of 
dosing.

The above criteria will apply even if measured PK parameters are below the 
above-mentioned PK stopping criteria, and every effort will be made to take a 
blood sample at the time of the event for PK analysis in the presence of any of the 
above events.
This protocol allows some alteration from the currently outlined dosing plan for Part 2. 
 
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
After review of Part 1 data, adjustments may be implemented for the planned 
duration of multiple dose administration in Part 2.

In Part 2, if multiple treatment arms show similar efficacy and safety profiles, 
additional Part(s) may be added to the study protocol via a protocol amendment to 
allow for further evaluation.
6.4.
Subject Specific Dose Adjustment Criteria
Subject specific dose adjustment criteria will not be implemented in this study. Study 
treatment restart or rechallenge after the stopping criteria are met by any subject 
participating in this study is not allowed.
6.5.
Blinding
This will be a double-blind (sponsor unblinded for Part 1) study and the following will 
apply. 

Study subjects and study site staff (other than unblinded pharmacy personnel) will 
be blinded to study treatment assignment. 

The GSK study team will be unblinded at the aggregate level for decision making 
for Part 1 of the study. Where possible, GSK personnel will not have access to 
subject specific treatment assignment so as to not potentially introduce bias in 
discussions with the study site(s). The pharmacokineticist, statisticians, 
programmers and data managers, however, may need access to subject 
randomization during the course of the study for analysis purposes to support dose 
adjustment and escalations in Part 1. Other GSK/CRO staff may be included in 
discussions around dose adjustments and progression if it is deemed necessary 
and relevant by the above mentioned GSK/CRO study team members.

In Part 2, dosing regimens will not be blinded. It may also be difficult to blind 
dose levels. For example, subjects randomized to a total monthly dose of 240 mg
in a monthly dosing regimen, will be given two injections each with 120 mg; 
whereas subjects randomized to other active treatment groups will receive only 
one injection in a visit. Dose levels may also be identified by the dosing volume. 
Matching placebo injections will be prepared for each dose level and dosing 
regimen and will be administered similarly to the corresponding active treatment 
group. Therefore, the dose level and dosing regimen of a subject will be known; 
however, it will be unknown if a subject is receiving an active treatment at each 
dose level or placebo. Thus, the double-blind nature of Part 2 will be maintained.

Senior management review of unblinded efficacy data is planned for both parts of 
the study (this includes the Japanese optional sub-study). For Part 1, the review 
provides early information on potential efficacious dose and dose frequency 
including the need for dose escalation. For Part 2, the review will facilitate 
internal governance decision making on project progress and trigger further 
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
The frequency of management review in Part 2 will be synchronized with monthly 
blinded SRT review of the study as appropriate. The management review of the 
Part 2 data will occur as required for decision making.

The investigator or treating physician may unblind a subject’s treatment 
assignment only in the case of an emergency OR in the event of a serious 
medical condition when knowledge of the study treatment is essential for the 
appropriate clinical management or welfare of the subject as judged by the 
investigator. 
o
It is preferred (but not required) that the investigator first contacts the medical 
monitor or appropriate GSK study personnel to discuss options before 
unblinding the subject’s treatment assignment.
o
If the medical monitor or appropriate GSK personnel are not contacted before 
the unblinding, the investigator must notify the medical monitor or appropriate 
GSK personnel as soon as possible after unblinding, but without revealing the 
treatment assignment of the unblinded subject, unless that information is 
important for the safety of subjects currently in the study. 
o
The date and reason for the unblinding must be fully documented in the CRF 
A subject may continue in the study if that subject’s treatment assignment is unblinded. 
The primary reason for the unblinding (the event or condition which led to the 
unblinding) will be recorded in the CRF.
GlaxoSmithKline’s GCSP staff may unblind the treatment assignment for any subject 
with an SAE. If the SAE requires that an expedited regulatory report be sent to one or 
more regulatory agencies, a copy of the report, identifying the subject’s treatment 
assignment, may be sent to investigators in accordance with local regulations and/or GSK 
policy.
6.6.
Packaging and Labeling
GSK3389404 solution for injection 100 mg/mL is available in a single use 3-mL 
stoppered Type 1 glass vial containing an aliquot of the modified phosphorothioate 
oligonucleotide dissolved in a phosphate buffer. The vial contains a minimal overfill to
allow a single 1.0 mL withdraw volume. The contents of the label will be in accordance 
with all applicable regulatory requirements.
A placebo to match GSK3389404 solution for injection will be locally sourced normal 
saline solution.
6.7.
Preparation/Handling/Storage/Accountability
The unblinded pharmacist, or qualified designee, will prepare GSK3389404 and placebo 
for SC injection from bulk supply according to the central randomization schedule. The 
preparation of each dose will be confirmed by a second member of the unblinded 
pharmacy staff. Please refer to the SRM provided by the sponsor or designee for more 
detailed instructions for study treatment preparation. 
 
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
Upon receipt, the investigator or designee must confirm appropriate temperature 
conditions have been maintained during transit for all study treatment received, 
and any discrepancies are to be reported and resolved before use of the study 
treatment.

Only subjects enrolled in the study may receive study treatment, and only 
authorized site staff may supply or administer study treatment. All study 
treatments 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 treatment accountability, reconciliation, and 
record maintenance (i.e., receipt, reconciliation, and final disposition records). 

Further guidance and information for final disposition of unused study treatment 
are provided in the SRM.

Under normal conditions of handling and administration, study treatment 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) or 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.
6.8.
Compliance with Study Treatment Administration
All subjects will receive study treatment directly from the investigator or designee, under 
medical supervision. The date and time of each dose administered in the study site will be 
recorded in the source documents. The dose of study treatment and study subject 
identification will be confirmed at the time of dosing by a member of the study site staff 
other than the person administering the study treatment. 
6.9.
Treatment of Study Treatment Overdose
For this study, any dose of GSK3389404 greater than the subject’s randomized treatment 
assignment will be considered an overdose.
There is no specific antidote for overdose with GSK3389404. In the event of a suspected 
overdose, the investigator should do the following:
1.
Contact the medical monitor immediately.
2.
Closely monitor the subject for AEs/SAEs and laboratory abnormalities until 
GSK3389404 can no longer be detected systemically (at least 5 half-lives for 
GSK3389404).
 
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3.
Obtain a plasma sample for PK analysis within 2 days from the date of the last 
dose of study treatment if requested by the medical monitor (determined on a 
case-by-case basis).
4.
Document the quantity of the excess dose as well as the duration of the 
overdosing in the CRF.
Decisions regarding dose interruptions or modifications will be made by the investigator 
in consultation with the medical monitor based on the clinical evaluation of the subject.
6.10.
Treatment after the End of the Study
The investigator is responsible for ensuring that consideration has been given to the 
post-study care of the subject’s medical condition, whether or not GSK is providing 
specific post-study treatment. 
6.11.
Lifestyle and/or Dietary Restrictions
6.11.1.
Meals and Dietary Restrictions
Admission to the study site is optional. If subjects opt to stay in-house in Part 1, subjects 
will be restricted to meals and beverages provided at the study site. 

On Day 1, a snack (not full meal) will be provided after dosing and completion of 
study procedures. A meal or lunch will be provided approximately 4 hours 
post-dose. If appropriate, dinner will be provided approximately 9 hours post-dose 
and an evening snack may be available until 22:00 hours. 

On Day 2, breakfast, lunch, and dinner may be provided. 
○
Subjects may be discharged at any time on Day 2. 
○
An evening snack may be available until 22:00 hours. 

On Day 3, subjects who decide to stay in-house through Day 3 will be offered a 
meal (e.g., bagged or canteen) after completion of morning procedures/prior to 
discharge from the study site.
During Part 2 (and Part 1 outpatient visits), subjects will be offered a meal (e.g., bagged 
or canteen [or reimbursed]) after completion of all study procedures at each outpatient 
visit.
6.11.2.
Alcohol and Tobacco

During each dosing session, subjects will abstain from alcohol for 24 hours prior to 
the start of dosing until collection of the final PK and or PD sample during each 
session. 

Subjects who use tobacco products will be instructed that use of nicotine-containing 
products (including nicotine patches) will not be permitted while they are in the 
study site. 
 
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6.11.3.
Activity
Subjects will abstain from strenuous exercise for 48 hours prior to each blood collection 
for clinical laboratory tests. For the duration of the study, until final follow-up (this 
includes the optional additional follow-up period), subjects are encouraged to refrain 
from changing their activity beyond that which they normally perform. While domiciled 
in the study site, subjects may participate in light recreational activities.
6.12.
Concomitant Medications and Non-Drug Therapies
All medications taken at any time from 3 months prior to Baseline (Day 1 pre-dose) to 
the final Follow-up visit (this includes the optional additional follow-up period) will be 
recorded in the CRF. The minimum requirement is that drug name and the dates of 
administration are to be recorded.
6.12.1.
Permitted Medications and Non-Drug Therapies
In Part 1, permitted medication includes nucleos(t)ide agents such as tenofovir, entecavir, 
lamivudine, adefovir and telbivudine. Treatment naïve patients should avoid initiating
HBV therapy until completion of the final follow-up visit unless deemed medically 
necessary by the investigator.
In Part 2, required medication includes nucleos(t)ide agents such as tenofovir, entecavir, 
lamivudine, adefovir and telbivudine. 
If patients are receiving nucleos(t)ide therapy, administration of the nucleos(t)ide should 
continue unchanged unless directed by the physician. There are no requirements with 
regards to the timing of the administration of nucleos(t)ide agent in relation to the study 
medicine.
Other concomitant medications (prescription and non-prescription) should be 
administered only as medically necessary during the study (except prohibited medications 
described in Section 6.12.2).
Traditional Chinese medicine (TCM) and/or acupuncture as it relates to CHB therapy
should be avoided during the duration of the study. If subjects report use of TCM and/or 
acupuncture, then details must be recorded in the concomitant medication CRF. 
6.12.2.
Prohibited Medications and Non-Drug Therapies
The following concomitant medications are not permitted during Part 1 and Part 2 (until 
Day 169 unless indicated otherwise):

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 Exclusion Criterion 11, 
Section 5.2).
 
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
Non-GSK -oligonucleotide or siRNA from 12 months prior to Day 1 through the 
final Follow-up visit or prior treatment with a GSK oligonucleotide from 3 months 
prior to Day 1 through the final Follow-up visit (includes optional follow-up period 
if applicable; see Exclusion Criterion 16, Section 5.2).
7.
STUDY ASSESSMENTS AND PROCEDURES
This section lists the procedures and parameters of each planned study assessment. The 
exact timing of each assessment is specified in the Time and Events Tables in 
Section 7.1. Protocol waivers or exemptions are not allowed with the exception of 
immediate safety concerns. Therefore, adherence to the study design requirements, 
including those specified in the Time and Events Tables, are essential and required for 
study conduct. 
The following points must be noted: 
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.
The timing and number of planned study assessments, including safety, PK, or PD 
assessments, may be altered during the course of the study based on newly available data 
(e.g., to obtain data closer to the time of peak plasma concentrations) to ensure 
appropriate monitoring. 
The change in timing or addition of time points for any planned study assessments must 
be documented in a Note to File which is approved by the relevant GSK study team 
member and then archived in the study sponsor and site study files, but this will not 
constitute a protocol amendment. 
The IEC will be informed of any safety issues that require alteration of the safety 
monitoring scheme or amendment of the Informed Consent Form. 
No more than 500 mL of blood will be collected over a 56-day period, including any 
extra assessments that may be required.
7.1.
Time and Events Tables
Screening assessments are detailed in Table 8 for Part 1 and Part 2 of the study. 
Part 1 assessments are detailed in Table 9 (Day -1 and Day 1) and Table 10 (Day 2 to 
Day 60/ET). 
Part 2 assessments are provided in different tables based on dosing regimen. 

Once weekly dosing regimen assessments are detailed for the treatment period in 
Table 11 (Day 1 to Day 85) and for the post-treatment follow-up period in
Table 12 (Day 92 to Day 169/ET, with an optional additional follow-up on Days 
270, 360, and 450). 
 
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
Bi-weekly dosing regimen assessments are detailed for the treatment period in 
Table 13 (Day 1 to Day 85) and for the post-treatment follow-up period in
Table 14 (Day 92 to Day 169/ET, with an optional additional follow-up on Days 
270, 360, and 450). 
 
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Table 8
Time and Events Table: Screening: Single Ascending Dose (Part 1) 
and Multiple Dose (Part 2)
Assessment
Screening 
(Up to 30 days 
Prior to Day 1)*
Informed Consent (obtained any time prior to screening)
X
Inclusion and exclusion criteria
X
Demography
X
Medical history (includes substance usage1) and current medical conditions 
X
Safety Assessments
Medication history and concomitant medication review
X
Full physical exam including height and weight
X
Vital signs2
X
12-lead ECG3
X
Laboratory Assessments
Drug/Alcohol screen
X
Serum hCG pregnancy test (as appropriate)
X
FSH/Estradiol (as appropriate)
X
Hematology/Chemistry/Urinalysis4
X
Urine ACR5
X
PT, INR, aPTT
X
HIV and hepatitis C screen
X
Hepatitis B screen (HBsAg; plasma or serum)
X
Hepatitis B profile (HBV DNA, HBeAg; plasma or serum)
X
Hepatitis D screen
X
Alpha-fetoprotein (as appropriate)6
X
Test of cirrhosis (as appropriate)7
X
ACR = albumin to creatinine ratio, aPTT = activated partial thromboplastin time, ECG = electrocardiogram, 
FSH = follicle-stimulating hormone, HBeAg = hepatitis B virus e-antigen, HBsAg = hepatitis B surface antigen, 
HBV = hepatitis B virus, hCG = human chorionic gonadotropin, HIV = human immunodeficiency virus, 
INR = international normalized ratio, PT = prothrombin time
* Eligible subjects who exceed the regular 30-day screening window by 15 days (total 45 days) should undergo a brief 
physical exam, review of medical history, and review of concomitant medications to confirm eligibility
1.
Drugs, alcohol, and tobacco.
2.
Temperature and respiration rate (single measurement); blood pressure and heart rate (single measurement after 
5 minutes of rest in the semi-supine or supine position).
3.
12-lead ECGs (single measurement after 5 minutes of rest in the semi-supine or supine position).
4.
Fasting not required for Screening visit.
5.
Urine ACR at screening is not required to be first morning void. Subjects will be given a clean urine collection cup 
to take home and bring back to study site with first morning void, if required for a second measurement.
6.
For subjects with confirmed or suspected hepatocellular carcinoma.
7.
Test of cirrhosis (Fibroscan or APRI and FibroSure per exclusion criterion 4 in Section 5.2). For subjects without a 
test for cirrhosis in the specified timeframes, APRI and FibroSure should be performed during the screening 
period to rule out cirrhosis.
 
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Table 9
Time and Events Table: Day -1 and Day 1 of Single Ascending Dose 
(Part 1)
Day 
-1
Day 1
Post Dose in Hours (h)
Assessments
Pre-dose2
O h
0.5 h
1 h
1.5 h
2 h
3 h
4 h
6 h
8 h
Inclusion and exclusion criteria
X
Admission to study site1
(X)
(X)
Discharge from study site1
(X)
Randomization2
X
Study treatment dosing3
X
Meals4
X
Safety Assessments
AE/SAE review5
Continuous
Concomitant medication review
Continuous
Brief physical exam
X
Vital signs6
X
X
X
X
X
12-lead ECG7
X
X
X
X
Injection site reactions8
X
X
X
X
X
X
X
X
X
Laboratory Assessments
Pregnancy test 
(as appropriate)9
X
Hematology/Chemistry/Urinalysi
s 10,11
X
Urine ACR11,12
X
Complement (C3/C4)
X
X
X
X
PT, INR, aPTT
X
X
X
X
hs-CRP
X
PK sampling13
X
X
X
X
X
X
X
X
X
Archived serum and plasma 
samples14
X
HBsAg and HBV DNA
X
X
HBeAg15
X
X
HBV genotype/phenotype16
X
X
 
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ACR = albumin to creatinine ratio;, AE/SAE = adverse event/serious adverse event, aPTT = activated partial 
thromboplastin time, CHB = chronic hepatitis B, ECG = electrocardiogram, HBeAg = hepatitis B virus e-antigen, 
HBsAg = hepatitis B surface antigen, HBV = hepatitis B virus, hCG: human chorionic gonadotropin, HIV = human 
immunodeficiency virus, hs-CRP = high sensitivity C-reactive protein, INR = international normalized ratio, 
ISR = injection site reaction, PK = pharmacokinetics, PT = prothrombin time 
1.
Admission to the study site is optional. Subjects admitted on Day -1 may be discharged after completion of all 
protocol specified procedures on Day 1, 8-hour time point, with instructions to return for outpatient visits (Days 3, 
8, 15, 22, 30, and 60).
2.
Subjects randomized to GSK3389404 or placebo on Day 1 prior to dosing.
3.
Study treatment will be administered as subcutaneous injection(s) subsequent to laboratory assessments prior to 
dosing.
4.
On Day 1, subjects may receive a snack (not full meal) after completion of study procedures and post-dose.. A 
meal or lunch will be approximately 4 hours (1 hour) dosing. If appropriate, dinner will be provided approximately 
9 hours (1 hour) after dosing. An evening snack (optional) may be provided until 22:00 hours.
5.
Adverse events will be collected from the first dose of study treatment and until the final Follow-up visit. However, 
any SAEs assessed as related to study participation (e.g., protocol mandated procedures or invasive tests) or 
related to GSK3389404 will be recorded from the time a subject consents to participate in the study up to and 
including any Follow-up visit. All AEs and SAEs will be graded based on the DAIDS table or supplemental criteria 
as defined in Appendix 3 (Section 12.3.5.1).
6.
Temperature, respiration rate (single measurement); blood pressure and heart rate (single measurement after 
5 minutes of rest in the semi-supine or supine position).
7.
12-lead ECGs will be measured in triplicate at pre-dose on Day 1, after 5 minutes of rest in the semi-supine or 
supine position and single measurements at all other time points.
8.
Subjects will be monitored for pain/tenderness, erythema/redness, induration/swelling, and pruritus. Dermatology 
consult may be warranted (Section 7.3.4). If injection site reaction is observed, then the reaction should be 
monitored until resolution or stabilization.
9.
Female subjects at screening: serum hCG pregnancy test; all other time points: serum hCG or urine pregnancy 
test. (Confirm subject is not pregnant with either serum hCG or urine pregnancy test prior to dosing.)
10. Sample must be obtained prior to dosing.
11. The study site may collect and divide urine sample for urinalysis test and ACR (first void) assessments.
12. Collect first morning urine void sample for ACR assessment. Subjects may be given a clean urine collection cup 
and instructed to collect and bring in a first morning urine void sample on the day of their visit.
13. Plasma PK samples to be collected pre-dose (within 15 to 30 minutes prior to dosing; prefer sample as close to 
pre-dose time point as possible). Post-dose PK samples should be collected as close to the exact nominal time as 
possible. The exact time of each PK blood collection should be recorded.
14. Archived serum and plasma samples for exploratory biomarker analyses. Complement C5a and Bb as well as 
HBV RNA, HBcrAg, and/or IDO may be analyzed from the archived samples.
15. HBeAg-positive subjects only.
16. HBV genotype/phenotype sample to be stored and analyzed per sponsor’s discretion. Samples will be used to 
assess for changes in HBV genotype/phenotype from baseline, HBsAg nadir, and/or final Follow-up visit.
 
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Table 10
Time and Events Table: Day 2 to Day 60 of Single Ascending Dose (Part 1)
Day 2
DAY 3
Day 8
Day 15
Day 22
Day 30
Day 60
Post Dose in Hours (h)
(1 day)
(1 day)
(1 day)
(1 day)
(1 day)
ET
Assessment
48 h 
(8 h)
Meals1
(X)1
(X)1
Discharge from study site2
(X)
(X)
Outpatient visits
(X)
X
X
X
X
X
X
Safety Assessments
AE/SAE review3
Continuous
Concomitant medication review
Continuous
Brief physical exam
X
X
X
X
Vital signs4
X
X
X
X
12-lead ECG5
X
X
X
X
Injection site reactions6
X
X
X
X
X
X
X
Laboratory Assessments7
Pregnancy test (as appropriate) 8
X
X
X
X
Hematology/Chemistry/Urinalysis9
X
X
X
X
X
Urine ACR9,10
X
X
X
X
Complement (C3/C4)
X
X
X
X
PT, INR, aPTT
X
X
X
X
hs-CRP
X
X
X
X
PK sampling11
X
X
X
X
Archived serum and plasma samples12
X
X
X
X
HBsAg, HBV DNA
X
X
X
X
X
X
X
HBeAg13
X
X
X
X
X
X
X
HBV genotype/phenotype14
X
X
X
X
X
X
X
 
 
 
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ACR = albumin to creatinine ratio, AE/SAE = adverse event/serious adverse event, aPTT = activated partial thromboplastin time, CHB = chronic hepatitis B, ECG = electrocardiogram, 
ET = early termination, HBeAg = hepatitis B virus e-antigen, HBsAg = hepatitis B surface antigen, HBV = hepatitis B virus, HIV = human immunodeficiency virus, hCG = human 
chorionic gonadotropin, hs-CRP = high sensitivity C-reactive protein, INR = international normalized ratio, PK = pharmacokinetics, PT = prothrombin time 
1.
On Day 2, breakfast, lunch, and dinner may be provided. If subjects choose to stay in-house through Day 3, then on Day 2, lunch will also be served approximately 4 hours 
(1 hour) after the breakfast, dinner will be served approximately 9 hours (1 hour) after the breakfast, and an evening snack (optional) may be provided until 22:00 hours. If 
subjects choose to stay in-house through Day 3, they will be offered a meal (e.g., bagged or canteen [or reimbursed]) after completion of all study procedures and prior to 
discharge on Day 3.
2.
Subjects may be discharged at any time on Day 2 with instructions to return for outpatient visits (Days 3. 8, 15, 22, 30, and 60). If subjects prefer, they may stay in-house until all 
Day 3 assessments are completed.
3.
Adverse events will be collected from the time of first dose of study treatment and until the final Follow-up visit. However, any SAEs assessed as related to study participation 
(e.g., protocol-mandated procedures or invasive tests) or related to GSK3389404 will be recorded from the time a subject consents to participate in the study up to and including 
any Follow-up visit. All AEs and SAEs will be graded based on the DAIDS table or supplemental criteria as defined in Appendix 3 (Section 12.3.5.1).
4.
Temperature and respiration rate (single measurement); blood pressure and heart rate (single measurement after 5 minutes of rest in the semi-supine or supine position).
5.
Single 12-lead ECGs will be measured after 5 minutes of rest in the semi-supine or supine position.
6.
Subjects will be monitored for pain/tenderness, erythema/redness, induration/swelling, and pruritus. Dermatology consult may be warranted (Section 7.3.4). If injection site 
reaction is observed, then the reaction should be monitored until resolution or stabilization.
7.
Samples for clinical laboratory tests to be collected after vital sign and ECG assessments
8.
Female subjects: serum hCG or urine pregnancy test.
9.
The study site may collect and divide urine sample for urinalysis test and ACR (first void) assessments.
10. Collect first morning urine void sample for ACR assessment while subjects are in study site. For outpatient visits, subjects will be given a clean urine collection cup and instructed 
to collect and bring in a first morning urine void sample on the day of their outpatient visit.
11. PK samples should be collected as close to the exact nominal time as possible. The exact time of each PK blood collection should be recorded.
12. Archived serum and plasma samples for exploratory biomarker analyses. Complement C5a and Bb as well as HBV RNA, HBcrAg, and/or IDO may be analyzed from the archived 
samples.
13. HBeAg-positive subjects only.
14. HBV genotype/phenotype sample to be stored and analyzed per sponsor’s discretion. Samples will be used to assess for changes in HBV genotype/phenotype from baseline, 
HBsAg nadir, and/or final Follow-up visit.
 
 
 
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Table 11
Time and Events Table: Day 1 to Day 85 of Multiple Dose (Part 2) Once Weekly Dosing
Treatment Period
Assessment
Day 1
Day 8 
(2 day)
Day 15 
(2 day)
Day 22 
(2 day)
Day 29 
(2 day)
Day 36 
(2 day)
Day 43 
(2 day)
Day 50 
(2 day)
Day 57 
(2 day)
Day 64 
(2 day)
Day 71 
(2 day)
Day 78 
(2 day)
Day 85 
(2 day)
Outpatient visit
X
X
X
X
X
X
X
X
X
X
X
X
X
Randomization1
X
Study treatment dosing2
X
X
X
X
X
X
X
X
X
X
X
X
Safety Assessments
AE/SAE review3
Continuous
Concomitant medication 
review
Continuous
Brief physical exam
X
X
X
X
Vital signs4
X
X
X
X
X
X
X
X
X
X
X
X
X
12-lead ECG5
X
X
X
X
Injection site reactions6
X
X
X
X
X
X
X
X
X
X
X
X
X
Laboratory Assessments7
Pregnancy test 
(as appropriate)8
X
X
X
X
Hematology/Chemistry/
Urinalysis9
X
X
X
X
X
X
X
X
X
X
X
X
X
Urine ACR9,10
X
X
X
X
X
X
X
Complement (C3/C4)
X
X
X
X
X
X
X
PT, INR, aPTT
X
X
X
X
X
X
X
hs-CRP
X
X
X
X
X
X
X
PK sampling11
X11
X11
X11
Archived serum and plasma 
samples12
X
X
X
X
HBsAg and HBV DNA
X
X
X
X
X
X
X
X
X
X
X
X
X
HBeAg13
X
X
X
X
X
X
X
X
X
X
X
X
X
HBV genotype/phenotype14
X
X
X
X
X
X
X
HBsAb
X
X
Meal15
X
X
X
X
X
X
X
X
X
X
X
X
X
 
 
 
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ACR = albumin to creatinine ratio, AE/SAE = adverse event/serious adverse event, aPTT = activated partial thromboplastin time, CHB = chronic hepatitis B, ECG = electrocardiogram, 
HBeAg = hepatitis B virus e-antigen, HBsAb = hepatitis B virus surface antibody, HBsAg = hepatitis B surface antigen, HBV = hepatitis B virus, HIV = human immunodeficiency 
virus, hCG = human chorionic gonadotropin, hs-CRP = high sensitivity C-reactive protein, INR = international normalized ratio, PK = pharmacokinetics, PT = prothrombin time 
Note: Except where indicated, assessments are to be conducted pre-dose. 
1.
Subjects randomized to GSK3389404 or placebo on Day 1 prior to dosing.
2.
Study treatment will be administered as subcutaneous injection(s) subsequent to the laboratory collection and other study assessments conducted prior to dosing.
3.
Adverse events will be collected from the time of first dose of study treatment and until the final Follow-up visit. However, any SAEs, including those assessed as related to study 
participation (e.g., protocol-mandated procedures or invasive tests) or related to GSK3389404 will be recorded from the time a subject consents to participate in the study up to 
and including any Follow-up visit. All AEs and SAEs will be graded based on the DAIDS table or supplemental criteria as defined in Appendix 3 (Section 12.3.5.1).
4.
Temperature, respiration rate (single measurement); blood pressure and heart rate (single measurement after 5 minutes of rest in the semi-supine or supine position).
5.
12-lead ECGs to be measured in triplicate at pre-dose on Day 1, after 5 minutes of rest in the semi-supine or supine position and single measurements at all other time points.
6.
Subjects will be monitored for pain/tenderness, erythema/redness, induration/swelling, and pruritus. Dermatology consult may be warranted (Section 7.3.4). If injection site 
reaction is observed, then the reaction should be monitored until resolution or stabilization. 
7.
Samples for clinical laboratory tests to be collected prior to dosing (if applicable).
8.
Female subjects at screening: serum hCG pregnancy test; all other time points for females of reproductive potential: serum hCG or urine pregnancy test. (Confirm subject is not 
pregnant with either serum hCG or urine pregnancy test prior to dosing.)
9.
The study site may collect and divide urine sample for urinalysis test and ACR (first void) assessments.
10. Collect first morning urine void sample for ACR assessment. For outpatient visits, subjects will be given a clean urine collection cup and instructed to collect and bring in a first 
morning urine void sample on the day of their outpatient visit.
11. On extended PK/dosing days (Days 1, 29, and 57), PK samples will be collected pre-dose (within 15 to 120 minutes prior to dosing; prefer sample as close to pre-dose time point 
as possible) and at 1, 2, and 3 hours post-dose. PK samples should be collected as close to the exact nominal time as possible. The exact time of each PK blood collection should 
be recorded. PK sampling for the optional Japanese Part 2 sub-study may be detailed in the Japan country-specific protocol amendment/supplement.
12. Archived serum and plasma samples for exploratory biomarker analyses. Complement C5a and Bb as well as HBV RNA, HBcrAg, and/or IDO may be analyzed from the archived 
samples.
13. HBeAg-positive subjects only.
14. HBV genotype/phenotype samples to be stored and analyzed per sponsor’s discretion. Samples will be used to assess for changes in HBV genotype/phenotype from baseline, 
HBsAg nadir, and/or final Follow-up visit. 
15. Subjects will be offered a meal (e.g., bagged or canteen [or reimbursed]) after completion of all study procedures.
 
 
 
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Table 12
Time and Events Table: Day 92 to Day 169 of Multiple Dose (Part 2) Once Weekly Dosing
Post-treatment Follow-up
Assessment
Day 92(2 
days)
Day 99 
(2 days)
Day 113 
(2 days)
Day 141 
(2 days)
Day 169 
Follow-up
(2 days)
ET
Outpatient visit
X
X
X
X
X
X
Safety assessments
AE/SAE review1
Continuous
X
Concomitant medication review
Continuous
X
Brief physical exam
X
X
X
X
X
X
Vital signs2
X
X
X
X
X
X
12-lead ECG3
X
X
Injection site reactions4
X
X
X
X
X
X
Laboratory assessments5
Pregnancy test (as appropriate)6
X
X
X
X
Hematology/Chemistry/Urinalysis7
X
X
X
X
X
X
Urine ACR7,8
X
X
X
X
X
X
Complement (C3/C4)
X
X
X
X
X
X
PT, INR, aPTT
X
X
X
X
X
X
hs-CRP
X
X
X
X
X
X
PK sampling9
X
X
Archived serum and plasma samples10
X
X
X
X
HBsAg and HBV DNA
X
X
X
X
X
X
HBeAg11
X
X
X
X
X
X
HBV genotype/phenotype12
X
X
X
X
X
HBsAb
X
X
Meal13
X
X
X
X
X
X
 
 
 
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ACR = albumin to creatinine ratio, AE/SAE = adverse event/serious adverse event, aPTT = activated partial thromboplastin time, CHB = chronic hepatitis B, ECG = electrocardiogram, 
ET = early termination, HBeAg = hepatitis B virus e-antigen, HBsAb = hepatitis B virus surface antibody, HBsAg = hepatitis B surface antigen, HBV = hepatitis B virus, 
HIV = human immunodeficiency virus, hCG = human chorionic gonadotropin, hs-CRP = high sensitivity C-reactive protein, INR = international normalized ratio, 
PK = pharmacokinetics, PT = prothrombin time 
1.
Adverse events will be collected from the time of first dose of study treatment and until the final Follow-up visit. However, any SAEs, including those assessed as related to study 
participation (e.g., protocol-mandated procedures or invasive tests) or related to GSK3389404 will be recorded from the time a subject consents to participate in the study up to 
and including any Follow-up visit. All AEs and SAEs will be graded based on the DAIDS table or supplemental criteria as defined in Appendix 3 (Section 12.3.5.1). 
2.
Temperature and respiration rate (single measurement); blood pressure and heart rate (single measurement after 5 minutes of rest in the semi-supine or supine position).
3.
Single 12-lead ECGs will be measured after 5 minutes of rest in the semi-supine or supine position.
4.
Subjects will be monitored for pain/tenderness, erythema/redness, induration/swelling, and pruritus. Dermatology consult may be warranted (Section 7.3.4). If injection site 
reaction is observed, then the reaction should be monitored until resolution or stabilization. 
5.
Samples for clinical laboratory tests to be collected after vital sign and ECG assessments.
6.
Female subjects of reproductive potential: serum hCG or urine pregnancy test.
7.
The study site may collect and divide urine sample for urinalysis test and ACR (first void) assessment.
8.
Collect first morning urine void sample for ACR assessment. For outpatient visits, subjects will be given a clean urine collection cup and instructed to collect and bring in a first 
morning urine void sample on the day of their outpatient visit.
9.
On PK days (Day 169 / Early Termination), collect the PK sample after completion of vital sign assessments. The exact time of each PK blood collection should be recorded. PK 
sampling for the optional Japanese Part 2 sub-study will be detailed in the Japan country-specific protocol amendment/supplement.
10. Archived serum and plasma samples for exploratory biomarker analyses. Complement C5a and Bb as well as HBV RNA, HBcrAg, and/or IDO may be analyzed from the archived 
samples.
11. HBeAg-positive subjects only.
12. HBV genotype/phenotype samples to be stored and analyzed per sponsor’s discretion. Samples will be used to assess for changes in HBV genotype/phenotype from baseline, 
HBsAg nadir, and/or final Follow-up visit. 
13. Subjects will be offered a meal (e.g., bagged or canteen [or reimbursed]) after completion of all study procedures.
 
 
 
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Table 13
Time and Events Table: Day 1 to Day 85 of Multiple Dose (Part 2) Bi-Weekly Dosing
Treatment Period
Assessment
Day 1
Day 8 
(2 day)
Day 15 
(2 day)
Day 22 
(2 day)
Day 29 
(2 day)
Day 36 
(2 day)
Day 43 
(2 day)
Day 50 
(2 day)
Day 57 
(2 day)
Day 64 
(2 day)
Day 71 
(2 day)
Day 78 
(2 day)
Day 85 
(2 day)
Outpatient visit
X
X
X
X
X
X
X
X
X
X
X
X
X
Randomization1
X
Study treatment dosing2
X
X
X
X
X
X
Safety Assessments
AE/SAE review3
Continuous
Concomitant medication 
review
Continuous
Brief physical exam
X
X
X
X
Vital signs4
X
X
X
X
X
X
X
X
X
X
X
X
X
12-lead ECG5
X
X
X
X
Injection site reactions6
X
X
X
X
X
X
X
X
X
X
X
X
X
Laboratory Assessments7
Pregnancy test (as 
appropriate)8
X
X
X
X
Hematology/Chemistry/
Urinalysis9
X
X
X
X
X
X
X
X
X
X
X
X
X
Urine ACR9,10
X
X
X
X
X
X
X
Complement (C3/C4)
X
X
X
X
X
X
X
PT, INR, aPTT
X
X
X
X
X
X
X
hs-CRP
X
X
X
X
X
X
X
PK sampling11
X11
X11
X11
Archived serum and plasma 
samples12
X
X
X
X
HBsAg and HBV DNA
X
X
X
X
X
X
X
X
X
X
X
X
X
HBeAg13
X
X
X
X
X
X
X
X
X
X
X
X
X
HBV genotype/phenotype14
X
X
X
X
X
X
X
HBsAb
X
X
Meal15
X
X
X
X
X
X
X
X
X
X
X
X
X
 
 
 
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ACR = albumin to creatinine ratio, AE/SAE = adverse event/serious adverse event, aPTT = activated partial thromboplastin time, CHB = chronic hepatitis B, ECG = electrocardiogram, 
HBeAg = hepatitis B virus e-antigen, HBsAb = hepatitis B virus surface antibody, HBsAg = hepatitis B surface antigen, HBV = hepatitis B virus, HIV = human immunodeficiency 
virus, hCG = human chorionic gonadotropin, hs-CRP = high sensitivity C-reactive protein, INR = international normalized ratio, PK = pharmacokinetics, PT = prothrombin time 
Note: Except where indicated, assessments are to be conducted pre-dose.
1.
Subjects randomized to GSK3389404 or placebo on Day 1 prior to dosing.
2.
Study treatment will be administered as subcutaneous injection(s) subsequent to the laboratory collection and other study assessments conducted prior to dosing.
3.
Adverse events will be collected from the time of first dose of study treatment and until the final Follow-up visit. However, any SAEs, including those assessed as related to study 
participation (e.g., protocol-mandated procedures or invasive tests) or related to GSK3389404 will be recorded from the time a subject consents to participate in the study up to 
and including any Follow-up visit. All AEs and SAEs will be graded based on the DAIDS table or supplemental criteria as defined in Appendix 3 (Section 12.3.5.1). 
4.
Temperature, respiration rate (single measurement); blood pressure and heart rate (single measurement after 5 minutes of rest in the semi-supine or supine position).
5.
12-lead ECGs to be measured in triplicate at pre-dose on Day 1, after 5 minutes of rest in the semi-supine or supine position and single measurements at all other time points.
6.
Subjects will be monitored for pain/tenderness, erythema/redness, induration/swelling, and pruritus. Dermatology consult may be warranted (Section 7.3.4). If injection site 
reaction is observed, then the reaction should be monitored until resolution or stabilization.
7.
Samples for clinical laboratory tests to be collected prior to dosing (if applicable).
8.
Female subjects at screening: serum hCG pregnancy test; all other time points for females of reproductive potential: serum hCG or urine pregnancy test. (Confirm subject is not 
pregnant with either serum hCG or urine pregnancy test prior to dosing.)
9.
The study site may collect and divide urine sample for urinalysis test and ACR (first void) assessments.
10. Collect first morning urine void sample for ACR assessment. For outpatient visits, subjects will be given a clean urine collection cup and instructed to collect and bring in a first 
morning urine void sample on the day of their outpatient visit.
11. On extended PK/dosing days (Days 1, 29, and 57), PK samples will be collected at pre-dose (within 15 to 120 minutes prior to dosing; prefer sample as close to pre-dose time 
point as possible) and at 1, 2, and 3 hours post-dose. PK samples should be collected as close to the exact nominal time as possible. The exact time of each PK blood collection 
should be recorded. PK sampling for the optional Japanese Part 2 sub-study may be detailed in the Japan country-specific protocol amendment/supplement.
12. Archived serum and plasma samples for exploratory biomarker analyses. Complement C5a and Bb as well as HBV RNA, HBcrAg, and/or IDO may be analyzed from the archived 
samples.
13. HBeAg-positive subjects only.
14. HBV genotype/phenotype samples to be stored and analyzed per sponsor’s discretion. Samples will be used to assess for changes in HBV genotype/phenotype from baseline, 
HBsAg nadir, and/or final Follow-up visit. 
15. Subjects will be offered a meal (e.g., bagged or canteen [or reimbursed]) after completion of all study procedures.
 
 
 
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Table 14
Time and Events Table: Day 92 to Day 169 of Multiple Dose (Part 2) Bi-Weekly Dosing
Post-treatment Follow-up
Assessment
Day 92 
(2 days)
Day 99 
(2 days)
Day 113 
(2 days)
Day 141 
(2 days)
Day 169 
(2 days)
ET
Outpatient visit
X
X
X
X
X
X
Safety Assessments
AE/SAE review1
Continuous
X
Concomitant medication review
Continuous
X
Brief physical exam
X
X
X
X
X
X
Vital signs2
X
X
X
X
X
X
12-lead ECG3
X
X
Injection site reactions4
X
X
X
X
X
X
Laboratory Assessments5
Pregnancy test (as appropriate)6
X
X
X
X
Hematology/Chemistry/Urinalysis7
X
X
X
X
X
X
Urine ACR7,8
X
X
X
X
X
X
Complement (C3/C4)
X
X
X
X
X
X
PT, INR, aPTT
X
X
X
X
X
X
hs-CRP
X
X
X
X
X
X
PK sampling9
X
X
Archived serum and plasma samples10
X
X
X
X
HBsAg and HBV DNA
X
X
X
X
X
X
HBeAg11
X
X
X
X
X
X
HBV genotype/phenotype12
X
X
X
X
X
HBsAb
X
X
Meal13
X
X
X
X
X
X
 
 
 
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ACR = albumin to creatinine ratio, AE/SAE = adverse event/serious adverse event, aPTT = activated partial thromboplastin time, CHB = chronic hepatitis B, ECG = electrocardiogram, 
ET = early termination, HBeAg = hepatitis B virus e-antigen, HBsAb = hepatitis B virus surface antibody, HBsAg = hepatitis B surface antigen, HBV = hepatitis B virus, 
HIV = human immunodeficiency virus, hCG = human chorionic gonadotropin, hs-CRP = high sensitivity C-reactive protein, INR = international normalized ratio, 
PK = pharmacokinetics, PT = prothrombin time 
1.
Adverse events will be collected from the time of first dose of study treatment and until the final Follow-up visit. However, any SAEs, including those assessed as related to study 
participation (e.g., protocol-mandated procedures or invasive tests) or related to GSK3389404 will be recorded from the time a subject consents to participate in the study up to 
and including any Follow-up visit. All AEs and SAEs will be graded based on the DAIDS table or supplemental criteria as defined in Appendix 3 (Section 12.3.5.1).
2.
Temperature and respiration rate (single measurement); blood pressure and heart rate (single measurement after 5 minutes of rest in the semi-supine or supine position).
3.
Single 12-lead ECGs will be measured after 5 minutes of rest in the semi-supine or supine position.
4.
Subjects will be monitored for pain/tenderness, erythema/redness, induration/swelling, and pruritus. Dermatology consult may be warranted (Section 7.3.4). If injection site 
reaction is observed, then the reaction should be monitored until resolution or stabilization.
5.
Samples for clinical laboratory tests to be collected after vital sign and ECG assessments.
6.
Female subjects of reproductive potential: serum hCG or urine pregnancy test.
7.
The study site may collect and divide urine sample for urinalysis test and ACR (first void) assessment.
8.
Collect first morning urine void sample for ACR assessment. For outpatient visits, subjects will be given a clean urine collection cup and instructed to collect and bring in a first 
morning urine void sample on the day of their outpatient visit.
9.
On PK days (Day 169 / Early Termination), collect the PK sample after completion of vital sign assessments. The exact time of each PK blood collection should be recorded. PK 
sampling for the optional Japanese Part 2 sub-study will be detailed in the Japan country-specific protocol amendment/supplement.
10. Archived serum and plasma samples for exploratory biomarker analyses. Complement C5a and Bb as well as HBV RNA, HBcrAg, and/or IDO may be analyzed from the archived 
samples.
11. HBeAg-positive subjects only.
12. HBV genotype/phenotype samples to be stored and analyzed per sponsor’s discretion. Samples will be used to assess for changes in HBV genotype/phenotype from baseline, 
HBsAg nadir, and/or final Follow-up visit. 
13. Subjects will be offered a meal (e.g., bagged or canteen [or reimbursed]) after completion of all study procedures.
 
 
 
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Table 15
Time and Events Table: Optional Follow-up Period Day 270 to Day 450 for Once Weekly and Bi-weekly Dosing 
Assessment
Day 270
(7 days)
Day 360 
(7 days)
Day 450 
(7 days)
ET
Outpatient visit
X
X
X
X
Safety Assessments
AE/SAE review1
Continuous
X
Concomitant medication review
Continuous
X
Laboratory Assessments
Chemistry
X
X
X
X
PT, INR
X
X
X
X
Archived serum and plasma samples2
X
X
X
X
HBsAg and HBV DNA
X
X
X
X
HBeAg3
X
X
X
X
HBV genotype/phenotype4
X
X
X
X
HBsAb
X
X
X
X
Meal5
X
X
X
X
ACR = albumin to creatinine ratio, AE/SAE = adverse event/serious adverse event, aPTT = activated partial thromboplastin time, CHB = chronic hepatitis B, ECG = electrocardiogram, 
ET = early termination, HBeAg = hepatitis B virus e-antigen, HBsAb = hepatitis B virus surface antibody, HBsAg = hepatitis B surface antigen, HBV = hepatitis B virus, 
HIV = human immunodeficiency virus, hCG = human chorionic gonadotropin, hs-CRP = high sensitivity C-reactive protein, INR = international normalized ratio, 
PK = pharmacokinetics, PT = prothrombin time 
1.Adverse events will be collected from the time of first dose of study treatment and until the final Follow-up visit. However, any SAEs, including those assessed as related to 
study participation (e.g., protocol-mandated procedures or invasive tests) or related to GSK3389404 will be recorded from the time a subject consents to participate in the
study up to and including any Follow-up visit. All AEs and SAEs will be graded based on the DAIDS table or supplemental criteria as defined in Appendix 3
(Section 12.3.5.1).
2.Archived serum and plasma samples for exploratory biomarker analyses. Complement C5a and Bb as well as HBV RNA, HBcrAg, and/or IDO may be analyzed from the 
archived samples.
3.HBeAg-positive subjects only.
4.HBV genotype/phenotype samples to be stored and analyzed per sponsor’s discretion. Samples will be used to assess for changes in HBV genotype/phenotype from 
baseline, HBsAg nadir, and/or final Follow-up visit. 
5.Subjects will be offered a meal (e.g., bagged or canteen [or reimbursed]) after completion of all study procedures.
 
 
 
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7.2.
Screening and Critical Baseline Assessments
Eligibility criteria must be carefully assessed at the Screening visit and at the Baseline 
visit. Eligible subjects who fall out of the 30-day screening window may be rescreened at 
the discretion of the investigator/site. 

Eligible subjects who fall within a 45-day window (15 days out of the 30-day 
screening window) should undergo a brief physical exam, review of medical 
history, and review of concomitant medications to confirm eligibility. 

For any other subject who is rescreened, all required screening assessments 
(Section 7.1, Table 8) should be repeated. 
Subjects who screen failed under previous versions of the protocol may be re-screened.
Screening assessments are provided in Table 8. 

Demographic parameters (year of birth, sex, race and ethnicity) will be recorded.

Medical and medication history will be assessed as related to the 
inclusion/exclusion criteria listed in Section 5. Cardiovascular medical 
history/risk factors (as detailed in the CRF) will be assessed at screening.

Procedures conducted as part of the subject’s routine clinical management 
(HBsAg, liver biopsy, Fibroscan, APRI, or FibroSure) and obtained prior to 
signing of informed consent may be utilized for screening purposes provided the 
procedure meets the protocol-defined criteria and has been performed within the 
timeframe defined in the inclusion/exclusion criteria listed in Section 5.
Baseline assessments are provided in Table 9 for Part 1, and Table 11 and Table 13 for 
Part 2.
7.3.
Safety
Planned time points for all safety assessments are specified in the Time and Events 
Tables (Section 7.1). 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.
7.3.1.
Adverse Events and Serious Adverse Events
The definitions of an AE or SAE can be found in Appendix 3 (Section 12.3). The severity 
of an AE is graded according to the DAIDS table in Appendix 3 (Section 12.3.5.1). 
The investigator and their designees are responsible for detecting, documenting and 
reporting events that meet the definition of an AE or SAE. 
7.3.1.1.
Time Period and Frequency for Collecting AE and SAE Information

Any SAEs, including those assessed as related to study participation (e.g., 
protocol-mandated procedures, invasive tests, or change in existing therapy) or 
 
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related to a GSK product, will be recorded from the time a subject consents to 
participate in the study up to and including any follow-up contact. 

Adverse events will be collected from the time of first dose of study treatment
until the final follow-up contact (Section 7.3.1.3) as specified in the Time and 
Events Table (Section 7.1).

Medical occurrences that begin prior to the start of study treatment but after 
obtaining informed consent may be recorded on the Medical History/Current 
Medical Conditions section of the CRF.

All SAEs will be recorded and reported to GSK within 24 hours, as indicated in 
Appendix 3 (Section 12.3.6).

Investigators are not obligated to actively seek AEs or SAEs in former study 
subjects. However, if the investigator learns of any SAE, including a death, at any 
time after a subject has been discharged from the study, and he/she considers the 
event reasonably related to the study treatment or study participation, the 
investigator must promptly notify GSK.
NOTE: The method of recording, evaluating, and assessing causality of AEs and SAEs 
plus procedures for completing and transmitting SAE reports to GSK are provided in 
Appendix 3 (Section 12.3.4 and Section 12.3.5).
7.3.1.2.
Method of Detecting AEs and SAEs
Care will be taken not to introduce bias when detecting AEs and/or SAEs. Open-ended 
and non-leading verbal questioning of the subject is the preferred method to inquire about 
AE occurrence. Appropriate questions include:

“How are you feeling?” 

“Have you had any (other) medical problems since your last visit/contact?” 

“Have you taken any new medicines, other than those provided in this study, since 
your last visit/contact?” 
7.3.1.3.
Follow-up of AEs and SAEs
After the initial AE/SAE report, the investigator is required to proactively follow each 
subject at subsequent visits/contacts. All SAEs, and non-serious AEs of special interest 
(as defined in Section 4.6.1) will be followed until resolution, until the condition 
stabilizes, until the event is otherwise explained, or until the subject is lost to follow-up 
(as defined in Section 5.4). After the SAE or AE are followed until resolution or 
stabilization or event is otherwise explained, the subject will enter into the post-treatment 
follow up. The exact schedule for post-treatment follow up for those subjects who 
withdraw study treatment early should be confirmed with the GSK team. Further 
information on follow-up procedures is given in Appendix 3 (Section 12.3.5.4).
 
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7.3.1.4.
Cardiovascular and Death Events
For any cardiovascular events detailed in Appendix 3 (Section 12.3.3) and all deaths, 
whether or not they are considered SAEs, specific cardiovascular 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 cardiovascular CRFs are presented as queries in response to reporting of certain 
cardiovascular Medical Dictionary for Regulatory Activities (MedDRA) terms. The 
cardiovascular information should be recorded in the specific cardiovascular section of 
the CRF within one week of receipt of a cardiovascular event data query prompting its 
completion. 
The Death CRF is provided immediately after the occurrence or outcome of death is 
reported. Initial and follow-up reports regarding death must be completed within one 
week of when the death is reported.
7.3.1.5.
Regulatory Reporting Requirements for SAEs
Prompt notification by the investigator to GSK or designee of SAEs related to study 
treatment (even for non- interventional post-marketing studies) is essential so that legal 
obligations and ethical responsibilities towards the safety of subjects and the safety of a 
product under clinical investigation are met. 
GSK has a legal responsibility to notify both the local regulatory authority and other 
regulatory agencies about the safety of a product under clinical investigation. GSK will 
comply with country specific regulatory requirements relating to safety reporting to the 
regulatory authority, IEC and investigators.
Investigator safety reports are prepared for suspected unexpected serious adverse 
reactions according to local regulatory requirements and GSK policy and are forwarded 
to investigators as necessary.
An investigator who receives an investigator safety report describing an SAE(s) or other 
specific safety information (e.g., summary or listing of SAEs) from GSK will file it with 
the IB and will notify the IEC, if appropriate according to local requirements.
7.3.2.
Pregnancy
Females of reproductive potential are permitted in this study. Pregnancy tests will be 
conducted on all female subjects at the Screening and Baseline visits. A negative 
pregnancy test result is required to determine eligibility for study treatment 
administration. Pregnancy testing will also be conducted as specified in the Time and 
Events Tables (Section 7.1). 

Details of all pregnancies in female subjects and if indicated female partners of 
male subjects will be collected after the start of dosing and until the final specified 
Follow-up visit (includes the optional follow-up period for Part 2).
 
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
If a pregnancy is reported then the investigator should inform GSK within 
2 weeks of learning of the pregnancy and should follow the procedures outlined in 
Appendix 4 (Section 12.4.2).

Male subjects with female partners who are currently pregnant should comply 
with the acceptable contraceptive requirement as detailed in the protocol. No 
precautions are required for the male subject’s pregnant partner.
7.3.3.
Physical Exams
A complete physical exam will be conducted at the Screening visit. Brief physical exams 
will be conducted at all other time points. 

A complete physical exam will include, at a minimum, assessment of the 
dermatologic, cardiovascular, respiratory, gastrointestinal, and neurological 
systems. Height and weight will also be measured and recorded (with subject 
wearing daytime clothing with no shoes). 

A brief physical exam will include, at a minimum, assessments of the 
dermatologic, cardiovascular, respiratory, and gastrointestinal systems.

Investigators should pay special attention to clinical signs related to previous 
serious illnesses.
7.3.4.
Injection Site Reactions
Injection Site Reactions are any experiences which occur at the site of injection of the 
study treatment. Subjects will be monitored closely for the following in relation to ISRs: 

Pain or tenderness

Erythema or redness

Induration or swelling 

Pruritus
Injection site reactions will be graded according to the criteria provided in the DAIDS 
grading table (see Appendix 3, Section 12.3.5.1).
Digital photographs will be documented where possible on all subjects who have an ISR 
that meets SAE criteria OR is Grade 3 or above for injection site pain/tenderness, 
erythema/redness, induration/swelling, or pruritus per the DAIDS grading table (see 
Appendix 3, Section 12.3.5.1).
Dermatology will be consulted on all subjects who have an ISR that meets SAE criteria 
OR is Grade 3 or above for injection site pain/tenderness, erythema/redness, 
induration/swelling, or pruritus per the DAIDS grading table (see Appendix 3, 
Section 12.3.5.1) or if clinically significant and persistent beyond 14 days. Dermatology 
may also be consulted for other ISRs if the investigator or GSK medical monitor feels it 
is medically necessary.
 
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Details regarding photo collection and any other follow-up will be given by the GSK 
medical monitor at the time of assessment.
7.3.5.
Vital Signs

Vital signs will be measured after 5 minutes of rest in the semi-supine or supine 
position:
o
Systolic and diastolic blood pressure, heart rate, temperature, and respiration 
rate will be collected as single measurements.

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.
7.3.6.
Electrocardiogram

All ECGs will be collected after 5 minutes of rest in the semi-supine or supine 
position.
o
All ECGs will be conducted using an ECG machine that automatically 
calculates the heart rate and measures PR, QRS, QT, and QTcF intervals. 
o
Triplicate 12-lead ECGs will be obtained at pre-dose on Day 1. Single 12-lead 
ECGs will be obtained at all other time points. 

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. 

Refer to Section 5.4.2 for QTc withdrawal criteria and additional QTcF readings 
that may be necessary.
7.3.7.
Clinical Safety Laboratory Assessments
All protocol required laboratory assessments, as defined in Table 16, must be conducted 
in accordance with the Laboratory Manual and the Time and Events Tables in 
Section 7.1. Fasting is not required for laboratory testing. Details for blood and urine 
sampling are provided in a separate Laboratory Manual. 
Laboratory requisition forms must be completed and samples must be clearly labelled 
with the subject number, protocol number, site/center number, and visit date. Details for 
the preparation and shipment of samples are provided in a separate Laboratory Manual. 
Reference ranges for all safety parameters will be provided to the site by the central 
laboratory responsible for the assessments.
All study-required laboratory assessments will be performed by a central laboratory, apart 
from:

Hematology laboratory assessments. The results of each test must be entered into 
the CRF.
 
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
For China, urine drug screen. The results of each test must be entered into the 
CRF.
NOTE: Local laboratory results are only required in the event that the central laboratory 
results are not available in time for either a treatment and/or response evaluation to be 
performed. If a local sample is required it is important that the sample for central analysis 
is obtained at the same time. 
 
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Table 16
Protocol Required Safety Laboratory Assessments
Laboratory 
Assessments1
Parameters
Hematology
Platelet Count
RBC Indices:
WBC count with Differential:
RBC Count
MCV
Neutrophils
Hemoglobin
MCH
Lymphocytes
Hematocrit
Monocytes
Reticulocyte count
Eosinophils
Basophils
Clinical chemistry2
BUN
Potassium
AST (SGOT)
Total and direct bilirubin
Creatinine
Sodium
ALT (SGPT)
Total protein
GFR 
(CKD-EPI)
Calcium
ALP
Albumin
Uric acid
Phosphorous
GGT
hs-CRP
Glucose
Magnesium
CPK
Routine urinalysis

Specific gravity

pH, glucose, protein, blood and ketones by dipstick

Microscopic examination (if blood or protein is abnormal)
Coagulation

INR

PT

aPTT
Complement

C3, C4, C5a, Bb
Other Screening 
and/or Follow-up 
tests

Urine ACR3

HIV, HCV, HDV 

HBsAg

HBsAb

HBV DNA

Viral genotype/phenotype

HBeAg

Alpha-fetoprotein (in subjects with confirmed or suspected HCC)

Test of cirrhosis (APRI and FibroSure) performed as needed in subjects without a test 
in the necessary screening timeframe (exclusion criterion 4 in Section 5.2)

Alcohol and drug screen (to include at minimum: amphetamines, barbiturates, 
cocaine, opiates, cannabinoids and benzodiazepines)

FSH and estradiol (as needed in women of non-child bearing potential)

Serum hCG pregnancy test at Screening, serum or urine hCG pregnancy test at other 
time points4

HBV RNA, HBcrAg, and/or IDO may be analyzed from archived samples
ACR = albumin to creatinine ratio, ALP =alkaline phosphatase ALT = alanine aminotransferase, APRI = AST platelet 
index, aPTT = activated partial thromboplastin time, AST = aspartate aminotransferase, BUN = blood urea 
nitrogen, CKD-EPI = Chronic Kidney Disease Epidemiologic Collaboration, CPK = creatine phosphokinase, 
FSH = follicle-stimulating hormone, GFR = glomerular filtration rate, GGT = gamma glutamyl transpeptidase,
HBcrAg = hepatitis B core-related antigen, HBeAg = hepatitis B virus e-antigen, HBsAb = hepatitis B virus surface 
antibody, HBsAg = hepatitis B surface antigen, HBV = hepatitis B virus, HCC = hepatocellular carcinoma, 
HCV = hepatitis C virus, HDV = hepatitis D virus, hCG = human chorionic gonadotropin, HIV = human 
immunodeficiency virus, hsCRP = high sensitivity C-reactive protein, IDO = indoleamine 2,3 dioxygenase, 
INR = international normalized ratio, MCH = mean corpuscular hemoglobin, MCV = mean cell volume, 
PT = prothrombin time, RBC = red blood cell
1.
Fasting is not required for laboratory testing.
2.
Details of liver chemistry stopping criteria and required actions and follow-up assessments after a liver stopping or 
monitoring event are given in Section 5.4.1 and Appendix 2 (Section 12.2), respectively. 
3.
With the exception of the Screening visit, when first morning void is not required, urine ACR assessments will be 
conducted using the first morning void urine sample. For outpatient visits, subjects will be given a clean urine 
collection cup for the first morning void on the day of their outpatient visit. 
4.
With the exception of the Screening visit, local urine testing will be standard for the protocol unless serum testing 
 
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is required by local regulation or ethics committee.
7.4.
Pharmacokinetics
7.4.1.
Blood Sample Collection
Blood samples for PK analysis of GSK3389404 and ISIS 505358 will be collected at the 
time points specified in the Time and Events Tables in Section 7.1. The actual date and 
time of each blood sample collection will be recorded. Since this is the first 
administration of GSK3389404 to subjects with CHB, the timing of PK samples may be 
altered and/or additional PK samples may be obtained based on review of safety, 
tolerability, and PK during the study. 
At each PK time point, approximately 4 mL of blood will be collected into potassium 
ethylenediaminetetraacetic acid (K2 EDTA) tubes. Processing, storage and shipping 
procedures are provided in the SRM.
7.4.2.
Sample Analysis
Plasma analysis will be performed under the control of Platform Technology and Science 
– InVivo/ InVitro Translation PTS-IVIVT/ Third Party Resources TPR, GSK, the details 
of which will be included in the SRM. Concentrations of GSK3389404 and ISIS 505358 
will be determined from plasma samples using the currently approved bioanalytical 
methodology. Raw data will be archived at the bioanalytical site (detailed in the SRM).
Once plasma samples have been analyzed for GSK3389404 and ISIS 505358, any 
remaining plasma may be analyzed for other compound-related metabolites and the 
results reported under a separate PTS-IVIVT/TPR, GSK protocol.
7.5.
Efficacy
Blood samples for HBsAg will be collected as specified in the Time and Events Tables in 
Section 7.1. Blood collection, processing, storage, shipping, and analysis details are 
provided in the SRM. 
7.6.
Biomarker(s)/Pharmacodynamic Markers
Blood samples for HBeAg and HBV DNA will be collected as specified in the Time and 
Events Tables in Section 7.1. Blood collection, processing, storage, shipping, and 
analysis details are provided in the SRM. 
Additional blood samples for archive will be collected as specified in the Time and 
Events Tables in Section 7.1. The archive samples may be used for the purposes of 
follow-up exploration of laboratory findings and/or AEs (e.g., measurement of cytokine 
and/or chemokine levels, measurement of additional markers of kidney function, 
measurement of antibodies, etc.). The archive samples may also be used for studying 
biomarkers that may be affected by treatment, such as HBcrAg, HBV RNA or 
indoleamine 2,3 dioxygenase (IDO). Blood collection, processing, storage, and shipping 
details are provided in the SRM.
 
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7.7.
Viral Genotyping and Phenotyping
Blood samples for HBV viral genotyping and phenotyping will be collected as specified 
in the Time and Events Tables in Section 7.1. The blood samples will be stored and may 
be analyzed based on the sponsor’s discretion. Blood collection, processing, storage, and 
shipping details are provided in the SRM.
7.7.1.
HBV Resistance Mutation Monitoring
For Part 2, in subjects who are on a stable nucleos(t)ide regimen with adequate
suppression of HBV DNA, defined as HBV DNA levels below the LLOQ: 
Virologic breakthrough is defined as the occurrence of confirmed virologic breakthrough 
(e.g., HBV DNA becoming quantifiable after being below the LLOQ).
Plasma or serum HBV DNA levels for each subject will be measured throughout the 
study (see Time and Events Tables in Section 7.1). If evidence of virologic breakthrough 
is observed, subjects will be interviewed regarding treatment compliance and the 
concomitant usage of medication that might affect virus replication (e.g., corticosteroids), 
and other potentially relevant parameters.
Samples collected for viral genotyping and phenotyping may be used for HBV resistance 
mutation analysis where the viral genome will be DNA sequenced to determine whether 
mutations have occurred in the GSK3389404 binding region (and if applicable, whether 
any known nucleos(t)ide resistance mutations are present in the polymerase coding 
region).
8.
DATA MANAGEMENT

For this study, subject data will be entered into the CRO data management/capture 
system, transmitted electronically to GSK or designee and combined with data 
provided from other sources in a validated data system. 

Management of clinical data will be performed in accordance with applicable 
CRO standards and data cleaning procedures to ensure the integrity of the data, 
e.g., removing errors and inconsistencies in the data.

Adverse events and concomitant medications terms will be coded using MedDRA 
and an internal validated medication dictionary, GSKDrug. 

Case report forms (including queries and audit trails) will be retained by GSK, 
and copies will be sent to the investigator to maintain as the investigator copy. 
Subject initials will not be collected or transmitted to GSK according to GSK 
policy.
 
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9.
STATISTICAL CONSIDERATIONS AND DATA 
ANALYSES
Statistical considerations and planned analyses are summarized in this section. A detailed 
description of the statistical analyses will be documented in the study Reporting and 
Analysis Plan (RAP). 
9.1.
Hypotheses
No formal hypotheses are to be tested in Part 1. 
One of the primary objectives of Part 2 of this study is to select the efficacious dose level 
and dosing regimen of GSK3389404 as determined by the primary endpoint, response
rate (RR), based on reduction of HBsAg level from baseline. A subject will be considered 
a responder if there is at least a 1.5 times log 10 IU/mL reduction of HBsAg levels from 
baseline anytime during the study. A model based probability inference approach in 
Bayesian framework will be used for decision-making as the primary efficacy analysis. 
An active treatment group will be declared efficacious if the posterior probability that the 
difference in the RRs between that active group and the placebo is positive, is high (at 
least 90%), i.e., P (RRACT > RRPBO) 90%, where RRACT is the RR in the active group, 
RRPBO is the RR in the placebo group, and P is the posterior probability.
9.2.
Sample Size Considerations
9.2.1.
Sample Size Assumptions
Sample size is based on feasibility for Part 1 of this study. No formal calculation of 
power or sample size for Part 1 of the study will be performed. A sample size of at least 4 
HBV subjects (3 receiving active treatment: 1 placebo) in each cohort should provide 
preliminary estimates of inter subject variability for GSK3389404 PK parameters and 
initial safety and PD assessments. 
In Part 2, approximately 39 subjects with CHB are planned for randomization to study 
treatment. There are approximately 11 subjects in each of the active treatment group and 
approximately 6 subjects in the placebo group. Matching placebo injections will be 
prepared for each dose level and dosing regimen and will be administered in the similar 
way of the corresponding active treatment group. Approximately 2 subjects will be 
randomized in each placebo dose level and dosing regimen. The total sample size will 
provide sufficient power to select an efficacious treatment group using a Bayesian model 
based approach sharing common degrees of freedom across treatment arms. With the 3 
treatment groups selected for part 2, the probability of declaring success of an 
inefficacious treatment arm (with RR 5%) is less than 14%. On the other hand, if an 
active treatment arm has a 30% RR, the probability of selecting the treatment arm is 
about 80% under the model assumption. Appendix 6 (Section 12.6) details the operating 
characteristics of the design.
 
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9.2.2.
Sample Size Sensitivity
Sample size sensitivity and design operating characteristics are detailed in Appendix 6
(Section 12.6).
9.2.3.
Sample Size Re-estimation or Adjustment
There will be no sample size re-estimation.
9.3.
Data Analysis Considerations
9.3.1.
Analysis Populations
All Subjects Screened Population
The All Subjects Screened Population will include all subjects who consent to participate 
in the clinical trial. Subjects in this population will be used for screen failure summary. 
The population will be defined separately for Part 1 and Part 2. 
Safety Population
The Safety Population will include all subjects who receive at least one dose of the study 
treatment (including placebo) and will be based on the actual treatment received if this 
differs from that to which the subject was randomized. Subjects in this population will be 
used for all safety analyses. The population will be defined separately for Part 1 and 
Part 2.
Pharmacokinetic Population
The PK Population will include all subjects in the Safety population for whom at least 
one evaluable PK sample will be obtained and analyzed. Pharmacokinetic 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. All PK analyses will be based on this 
analysis population. The population will be defined separately for Part 1 and Part 2 of the 
study.
Pharmacodynamic Population
The PD population will include all subjects in the Safety population who provide 
evaluable PD data. All PD analyses will be based on this analysis population.
Intent-to-Treat Population
The Intent-to-Treat (ITT) population will comprise all randomized subjects regardless of 
whether or not treatment was administered. This population will be based on the 
treatment to which the subject was randomized and will be the primary population for 
efficacy analyses. Any subject who receives a treatment randomization number will be 
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9.3.2.
Definition of Baseline
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. 
9.3.3.
Interim Analysis and Final Analysis
Part 1:
No formal interim analysis is planned for Part 1. However, a preliminary PK analysis will 
be performed after each dose level is completed and the Dose Escalation Committee 
(Section 10.8.1) will review preliminary safety tolerability, PK and PD data (through 
Day 3 for at least 3 subjects that received GSK3389404) prior to each dose escalation and 
prior to initiation of Part 2. Dose escalation can only occur after the Dose Escalation 
Committee has found that the safety, PK, and PD profiles through Day 3 are supportive 
to proceed with the evaluation of the next higher dose level.
The relationship between dose levels, plasma GSK3389404 exposure, and associated 
variability will be characterized by a power model if 3 or more subjects’ PK data are 
available from at least 2 dose levels. The model will be updated as data become available 
throughout the study. During dose escalation, a Bayesian predictive probability of mean 
AUC(0-) and Cmax less than 492.7 gh/mL and 52.7 g /mL (mean exposures at 
NOAEL of the 13-week monkey study), respectively, will be calculated for the next dose 
level and used together with safety and tolerability data to aid the next dose selection. 
The Bayesian predictive probability will be based on Whitehead’s model [Whitehead, 
2001] using non-informative prior for model parameters.
Where yi is log-PK of i-th subject, di is the log-dose administered to i-th subject. θ1 and θ2
are population intercept and slope, respectively and i is random error of i-th subject.
The analysis and reporting of Part 1 may be conducted prior to the completion of Part 2.
Part 2 Interim Analysis:
No formal interim analysis is planned for Part 2.
However, before randomizing all subjects in Part 2, safety data from a sentinel group 
(1 subject from each treatment group and the corresponding matching placebo) will be 
reviewed by the GSK internal clinical team or SRT in a blinded manner (Section 10.8.2). 
Randomization for the remainder of subjects in Part 2 will continue after safety data from 
at least 2 weeks of exposure (but may include more data) in all subjects in the sentinel 
group are reviewed. Safety data from all subjects will be reviewed by the GSK internal 
clinical team or SRT in a blinded manner on a regular basis thereafter.
 
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9.3.3.1.
Part 2: Primary Analysis 
In Part 2, the primary analysis will be conducted once the last randomized subject in the 
sentinel group and remainder of subjects have completed the Day 85 visit. Treatment 
assignment will be unblinded for subjects included in the analysis. The results of this 
analysis will be used to characterize safety, tolerability and identify efficacious dose and 
dosing regimen of GSK3889404. 
9.3.3.2.
Japanese Optional Part 2 Sub-Study Analysis
Details of the analysis of the optional Japanese Part 2 sub-study may be found in the 
Japan country-specific protocol amendment/supplement. If applicable, the analysis of 
Japanese cohort will be conducted once the last randomized Japanese subject has 
completed the Day 85 and/or Day 169 visit. Treatment assignment for the optional 
Japanese sub-study will be unblinded. Depending on the timing of the last Japanese 
subject to finish the Day 85 visit, the analysis may or may not be reported together with 
the Primary analysis. 
9.3.3.3.
Part 2: 3 month follow up Analysis
The 3 month follow up analysis for Part 2 will be conducted once last randomized subject 
has completed the Day 169 visit. 
9.3.3.4.
Part 2: 6 month follow up Analysis
The 6 month follow up analysis for Part 2 may be conducted once last randomized 
subject has completed the Day 270 visit to support internal decision making and/or 
regulatory interaction.
9.3.3.5.
Part 2: End of Study Analysis
The end of study analysis for Part 2 will be conducted once the last subject participating
in the optional follow-up has completed the Day 450 visit.
9.4.
Key Elements of Analysis Plan
9.4.1.
Primary Analyses
Safety
Safety and tolerability parameters (AEs/SAEs, physical exams, vital signs, 12-lead ECGs, 
and clinical laboratory measurements) will be listed by subject and summarized 
descriptively by treatment group and HBeAg status in tabular or graphical formats, as 
appropriate. For continuous variables, these summaries will include sample size, mean, 
median, standard deviation, minimum, and maximum. For categorical variables, the 
summaries will include frequencies and corresponding percentages.
Adverse events will be coded using MedDRA. Adverse events will be summarized in 
various subsets, including treatment-emergent AEs (TEAEs) by maximum causality, by 
 
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maximum intensity, leading to treatment discontinuation or withdrawal from study, and 
SAEs.
Exposure to study treatment as the number of doses administered will be presented for 
each treatment group for Part 2.
Pharmacokinetics
GSK3389404 plasma concentration-time data will be listed by subject and summarized 
descriptively by treatment group and HBeAg status in tabular and graphical formats. 
GSK3389404 PK parameters will be derived from the concentration-time profiles using 
WinNonlin. The derived PK parameters, including but not limited to AUC(0-24), AUC(0-), 
Cmax, tmax, t½, and CL/F, will be listed by subject and summarized by treatment group and 
HBeAg status. Summaries may also combine treatment groups as applicable. 
Efficacy
In Part 2, the primary efficacy objective is to select an efficacious dose level and dosing 
regimen of GSK3389404 as determined by the primary endpoint RR, based on reduction 
of HBsAg level from baseline. A subject will be considered a responder if there is at least 
1.5 times log 10 IU/mL reduction of HBsAg levels from baseline anytime during the 
study.
The RR data will be analyzed using a dose-response model. The posterior mean for each 
active treatment group will be derived from the posterior distribution of the response 
rates using a 3-parameter logistic regression model using weakly informative priors for 
model parameters. Estimates for this model’s parameters will be derived using the data 
generated within each treatment arm, i.e., this model will borrow degrees of freedom 
across active dose levels and regimens therefore providing higher power compared to 
pair-wise comparisons given the small sample size of each treatment arm. 
A Bayesian logistic regression model (BLRM) [Neuenschwander, 2008] is considered to 
find an efficacious dose in this study.
For dose d and regimen R, the number of subjects with a response (Ydr) in a treatment 
arm of size ndr is binomial. Therefore, Ydr| ndr ~ Binomial (dr, ndr), with RRs
logit (dr) = + log(d/d*)+ R, 
where d is the active dose; R is the regimen (R=1 for regimen 1 and R=0 for regimen 2); 
d* is a reference dose allowing for the interpretation of as the odds of a response at d*; 
is the change in the log-odds of a response by a unit increase in log-dose; is the 
change in the log-odds of a response due to change in regimen. Since this is the first 
study of administration of GSK3389404 in subjects with CHB, weakly informative priors 
of the model parameters (~ N(0, var=100), ~ N(0, var=25), ~ N(0, var=9)) are 
assumed. To justify the prior selection, a set of 1000 observations were generated from 
each of the prior distribution. The estimate of each of the parameters centers close to 0.5, 
with ranges between (0, 1) and standard deviation approximately 0.5. Posterior 
distribution of response rates of active treatment arms will be generated using BLRM.
 
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Since it is not expected to have any responder in the placebo arm, posterior distribution of 
RRs is generated separately from a Beta distribution, i.e., Beta (0.1,0.1). Placebo 
injections will be given in different dosing regimens (according to the corresponding 
active treatment group) for the purpose of maintaining the blind. However, all placebo 
subjects across dosing regimens will be combined in 1 group for this analysis, since no 
difference in RR is expected if placebo is administered in different dosing regimens.
In Part 2, GSK3389404 treatment efficacy will be declared if the posterior probability 
that the difference in the RRs between that active group and the placebo is positive and is 
high (at least 90%), i.e., P (RRACT >RRPBO) 90%, where RRACT is the RR in active 
group, RRPBO is the RR in placebo, and P is the posterior probability. 
The primary efficacy analysis of Part 2 will be performed after all ongoing subjects in 
Part 2 complete the Day 85 visit (may or may not include the Japanese subjects from the 
optional Part 2 sub-study). At that time the database will be unblinded. Other primary 
analyses as mentioned above will also be performed. Details will be included in the RAP.
9.4.2.
Secondary Analyses
Pharmacodynamics
Pharmacodynamic data (HBsAg, HBeAg, and HBV DNA) will be listed by subject and 
summarized descriptively by treatment group/HBeAg status in tabular and graphical 
formats, as appropriate. 
Correlations between PD data in HBeAg-positive and HBeAg-negative subjects will be 
explored graphically. Correlation between PK parameters and PD parameters will also be 
explored graphically. 
Pharmacokinetics
ISIS 505358 plasma concentration-time data will be listed by subject and summarized 
descriptively by treatment group and HBeAg status in tabular and graphical formats. 
ISIS 505358 PK parameters will be derived from the concentration-time profiles using 
WinNonlin. The derived PK parameters, including but not limited to AUC(0-24), AUC(0-), 
Cmax, tmax, and t½ will be listed by subject and summarized by treatment group and 
HBeAg status. Summaries may also combine treatment groups as applicable. 
9.4.3.
Other Analyses
Subject disposition, demographics, medical history, prior and concomitant medications, 
and study treatment exposure will be listed by subject and summarized descriptively for 
each part of the study separately. 
Response will also be measured based on change from baseline in HBeAg level in 
HBeAg-positive subjects. Change from baseline will be summarized by treatment group 
and listed by subject and treatment group for each part of the study separately.
 
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10.
STUDY GOVERNANCE CONSIDERATIONS
10.1.
Posting of Information on Publicly Available Clinical Trial 
Registers
Study information from this protocol will be posted on publicly available clinical trial 
registers before enrolment of subjects begins.
10.2.
Regulatory and Ethical Considerations, Including the 
Informed Consent Process
Prior to initiation of a site, GSK will obtain favorable opinion/approval from the 
appropriate regulatory agency to conduct the study in accordance with International 
Conference on Harmonisation (ICH) Good Clinical Practice (GCP) and applicable 
country-specific regulatory requirements.
The study will be conducted in accordance with all applicable regulatory requirements, 
and with GSK policy.
The study will also be conducted in accordance with ICH GCP, all applicable subject 
privacy requirements, and the guiding principles of the current version of the Declaration 
of Helsinki. This includes, but is not limited to, the following:

IEC review and favorable opinion/approval of the study protocol and amendments 
as applicable

Obtaining signed informed consent

Investigator reporting requirements (e.g., reporting of AEs/SAEs/protocol 
deviations to IEC)

GSK will provide full details of the above procedures, either verbally, in writing, 
or both.

Signed informed consent must be obtained for each subject prior to participation 
in the study

The IEC, and where applicable the regulatory authority, approve the clinical 
protocol and all optional assessments, including genetic research. 

Optional assessments (including those in a separate protocol and/or under separate 
informed consent) and the clinical protocol should be concurrently submitted for 
approval unless regulation requires separate submission. 

Approval of the optional assessments may occur after approval is granted for the 
clinical protocol where required by regulatory authorities. In this situation, written 
approval of the clinical protocol should state that approval of optional assessments 
is being deferred and the study, with the exception of the optional assessments, 
can be initiated.
 
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10.3.
Quality Assurance

To ensure compliance with GCP and all applicable regulatory requirements, GSK 
may conduct a quality assurance assessment and/or audit of the site records, and 
the regulatory agencies may conduct a regulatory inspection at any time during or 
after completion of the study. 

In the event of an assessment, audit, or inspection, the investigator (and 
institution) must agree to grant the advisor(s), auditor(s), and inspector(s) direct 
access to all relevant documents and to allocate their time and the time of their 
staff to discuss the conduct of the study, any findings/relevant issues, and to 
implement any corrective and/or preventative actions to address any 
findings/issues identified.
10.4.
Quality Control (Study Monitoring)

In accordance with applicable regulations including GCP, and GSK procedures, 
GSK/designee monitors will contact the site prior to the start of the study to 
review with the site staff the protocol, study requirements, and their 
responsibilities to satisfy regulatory, ethical, and GSK requirements. 

When reviewing data collection procedures, the discussion will also include 
identification, agreement and documentation of data items for which the CRF will 
serve as the source document.
GSK/designee will monitor the study and site activity to verify the following:

Data are authentic, accurate, and complete.

Safety and rights of subjects are being protected.

Study is conducted in accordance with the currently approved protocol and any 
other study agreements, GCP, and all applicable regulatory requirements.
The investigator and the head of the medical institution (where applicable) agrees to 
allow the monitor direct access to all relevant documents
10.5.
Study and Site Closure

Upon completion or premature discontinuation of the study, the GSK monitor or 
designee will conduct site closure activities with the investigator or site staff, as 
appropriate, in accordance with applicable regulations including GCP, and GSK 
SOPs.

GSK reserves the right to temporarily suspend or prematurely discontinue this 
study at any time for reasons including, but not limited to, safety or ethical issues 
or severe non-compliance. For multicenter studies, this can occur at one or more 
or at all sites. 

If GSK determines such action is needed, GSK will discuss the reasons for taking 
such action with the investigator or the head of the medical institution (where 
applicable). When feasible, GSK will provide advance notification to the 
 
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investigator or the head of the medical institution, where applicable, of the 
impending action.

If the study is suspended or prematurely discontinued for safety reasons, GSK will 
promptly inform all investigators, heads of the medical institutions (where 
applicable) and/or institution(s) conducting the study. GSK will also promptly 
inform the relevant regulatory authorities of the suspension or premature 
discontinuation of the study and the reason(s) for the action. 

If required by applicable regulations, the investigator or the head of the medical 
institution (where applicable) must inform the IEC promptly and provide the 
reason for the suspension or premature discontinuation.
10.6.
Records Retention

Following closure of the study, the investigator or the head of the medical 
institution (where applicable) must maintain all site study records (except for 
those required by local regulations to be maintained elsewhere), in a safe and 
secure location. 

The records must be maintained to allow easy and timely retrieval, when needed 
(e.g., for a GSK audit or regulatory inspection) and must be available for review 
in conjunction with assessment of the facility, supporting systems, and relevant 
site staff. 

Where permitted by local laws/regulations or institutional policy, some or all of 
these records can be maintained in a format other than hard copy (e.g., microfiche, 
scanned, or electronic); however, caution needs to be exercised before such action 
is taken. 

The investigator must ensure that all reproductions are legible and are a true and 
accurate copy of the original and meet accessibility and retrieval standards, 
including re-generating a hard copy, if required. Furthermore, the investigator 
must ensure there is an acceptable back-up of these reproductions and that an 
acceptable quality control process exists for making these reproductions.

GSK/designee will inform the investigator of the time period for retaining these 
records to comply with all applicable regulatory requirements. The minimum 
retention time will meet the strictest standard applicable to that site for the study, 
as dictated by any institutional requirements or local laws or regulations, GSK 
standards/procedures, and/or institutional requirements. 

The investigator must notify GSK/designee of any changes in the archival 
arrangements, including, but not limited to, archival at an off-site facility or 
transfer of ownership of the records in the event the investigator is no longer 
associated with the site.
 
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10.7.
Provision of Study Results to Investigators, Posting of 
Information on Publically Available Clinical Trials Registers 
and Publication
Where required by applicable regulatory requirements, an investigator signatory will be 
identified for the approval of the clinical study report. The investigator will be provided 
reasonable access to statistical tables, figures, and relevant reports and will have the 
opportunity to review the complete study results at a GSK site or other mutually-
agreeable location.
GSK will also provide the investigator with the full summary of the study results. The 
investigator is encouraged to share the summary results with the study subjects, as 
appropriate.
GSK will provide the investigator with the randomization codes for their site only after 
completion of the full statistical analysis.
The procedures and timing for public disclosure of the results summary and for 
development of a manuscript for publication will be in accordance with GSK Policy.
10.8.
Review Committees
10.8.1.
Dose Escalation Committee
The decision to proceed to the next dose level of GSK3389404 in each cohort and to 
initiate Part 2 of the study will be made by a Dose Escalation Committee consisting of the 
principal investigator (or appropriate designee), medical monitor, GSK study team leader, 
GSK pharmacokineticist, a GSK GCSP representative, and GSK data manager, 
programmer, and statistician (appropriate designees may attend). The GSK study team 
will remain unblinded at an aggregate level throughout Part 1 of the study as detailed in 
Section 6.5.
Dosing decisions for each subsequent dosing cohort will be based on safety, tolerability, 
PK, and PD data from the previous dose levels investigated. Dose escalation decisions 
will be based on data through Day 3 obtained from at least 3 subjects receiving 
GSK3389404 at the prior dose level. The review data set will include listings for AEs, 
flagged vital signs, ECGs, laboratory findings (including liver function tests), and PK 
results derived from 24-hour plasma profiles, together with any available PD data. A 
maximum AUC(0-) of 492.7 gh/mL or Cmax of 52.7 g/mL of GSK3389404 is not 
expected to be exceeded in any cohort.
10.8.2.
Part 2 Safety Review
In Part 2, safety data from a sentinel group (1 subject from each treatment group and the 
corresponding matching placebo) will be reviewed by the GSK internal clinical team or 
SRT in a blinded manner. The remainder of subjects in Part 2 will continue after safety 
data from at least 2 weeks of exposure (but may include more data) in the sentinel group 
are reviewed. Safety data from all subjects will be reviewed by the GSK internal clinical 
team or SRT in a blinded manner on a regular basis thereafter.
 
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The review data set will include listings for AEs, ISRs, flagged vital signs, ECGs, and 
laboratory findings (including liver function tests). All efforts will be made to maintain 
the study integrity and validity of study data.
10.8.2.1.
Safety Review Team
The SRT is an internal GSK cross-functional team reviewing all available blinded safety 
data related to the project in an ongoing manner. The SRT is an internal GSK 
requirement put in place to ensure holistic evaluation of the safety profile of an 
investigational product with systematic, periodic and documented reviews of available 
safety data, with the appropriate communication and escalation of new findings that have 
the potential to impact patient safety.
The SRT reviews will commence in Part 2 of the study, as the Dose Escalation 
Committee meetings will fulfil this purpose in Part 1.
 
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Walsh R, Locarnini S. Hepatitis B precore protein: pathogenic potential and therapeutic 
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toll-like receptor-mediated innate immune responses in murine parenchymal and 
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major drug transporters. Nucleic Acid Ther 2016;26:111-17.
 
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12.
APPENDICES
12.1.
Appendix 1: Abbreviations and Trademarks
Abbreviations
ACR
albumin to creatinine ratio
AE
adverse event
ALK
alkaline phosphatase
ALT
alanine aminotransferase
ANC
absolute neutrophil count
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
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
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
FSH
follicle stimulating hormone
GalNAc
N-acetyl galactosamine
GCP
Good Clinical Practice
GCSP
Global Clinical Safety and Pharmacovigilance
 
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GFR
glomerular filtration rate
GSK
GlaxoSmithKline
H
hours
HBcrAg
hepatitis B core-related antigen
HBeAg
hepatitis B virus e-antigen
HBsAb
hepatitis B virus surface antibody
HBsAg
hepatitis B virus surface antigen
HBV
hepatitis B virus
HCC
hepatocellular carcinoma
hCG
human chorionic gonadotropin
HCV
hepatitis C virus
HDV
hepatitis D virus
HIV
human immunodeficiency virus
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
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
LLOQ
lower limit of quantification
m2
square meters
MCMC
Markov Chain Monte Carlo
MedDRA
Medical Dictionary for Regulatory Activities
mEq
milliequivalents
Mg
milligrams
Min
minutes
mL
milliliters
mm3
cubic millimeters
MOE
methoxyethyl
Msec
milliseconds
MSDS
Material Safety Data Sheet
NCA
non-compartmental analysis
Ng
nanograms
NOAEL
no observed adverse effect level
Nucleos(t)ide
nucleoside or nucleotide
OAT
organic anion transporter
OCT
organic cation transporter
 
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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
SAE
serious adverse event
SC
subcutaneous(ly)
siRNA
small interfering ribonucleic acid
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
Trademark Information
Trademarks of the GlaxoSmithKline 
group of companies
Trademarks not owned by the 
GlaxoSmithKline group of companies
NONE
FibroSure
Fibrsoscan
MedDRA
SAS
WinNonlin
 
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12.2.
Appendix 2: Liver Safety Required Actions and Follow-up 
Assessments
The procedures listed below are to be followed if a subject meets any of the liver 
chemistry stopping criteria defined in Section 5.4.1.

Immediately withdraw the subject from study treatment. 

Notify the GSK medical monitor within 24 hours of learning of the abnormality to 
confirm the subject’s study treatment cessation and follow-up.

Complete the Liver Event case report form (CRF).

Complete the “Safety Follow-up Procedures” listed below.

Upon completion of the safety follow-up, withdraw the subject from the study unless 
further safety follow-up is required.

Do not re-challenge with study treatment
Safety Follow-up Procedures For Subjects 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.

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 
subject’s best approximation. Instructions for sample handling and shipping are 
included in the Study Reference Manual (SRM).

Serum creatine phosphokinase (CPK) and lactate dehydrogenase (LDH).

Fractionate bilirubin, if total bilirubin 1.5 X upper limit of normal (ULN)

Assess eosinophilia

Record the appearance or worsening of clinical symptoms of hepatitis (fatigue, 
nausea, vomiting, right upper quadrant pain or tenderness, fever, rash or 
eosinophilia) as relevant on the Adverse Event (AE) CRF.

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.
 
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The following are required for subjects who meet the ALT and bilirubin stopping
criteria (Table 5) 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 subjects 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.
 
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12.3.
Appendix 3: Definition of and Procedures for Recording, 
Evaluating, Follow-Up and Reporting of Adverse Events
12.3.1.
Definition of Adverse Events
Adverse Event Definition:

An AE is any untoward medical occurrence in a patient or clinical investigation 
subject, temporally associated with the use of a medicinal product, whether or not 
considered related to the medicinal product.

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 medicinal product.
Events meeting AE definition include:

Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) 
or other safety assessments (e.g., ECGs, radiological scans, vital signs 
measurements), including those that worsen from baseline, and felt to be clinically 
significant in the medical and scientific judgment of the investigator.

Exacerbation of a chronic or intermittent pre-existing condition including either an 
increase in frequency and/or intensity of the condition.

New conditions detected or diagnosed after study treatment administration even 
though it may have been present prior to the start of the study.

Signs, symptoms, or the clinical sequelae of a suspected interaction.

Signs, symptoms, or the clinical sequelae of a suspected overdose of either study 
treatment or a concomitant medication (overdose per se will not be reported as an 
AE/SAE unless this is an intentional overdose taken with possible suicidal/self-
harming intent. This 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. However, the signs and symptoms and/or clinical 
sequelae resulting from lack of efficacy will be reported if they fulfil the definition 
of an AE or SAE.
Events NOT meeting definition of an AE include:

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 subject’s condition.

The disease/disorder being studied or expected progression, signs, or symptoms of 
the disease/disorder being studied, unless more severe than expected for the subject’s 
 
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condition.

Medical or surgical procedure (e.g., endoscopy, appendectomy): the condition that 
leads to the procedure is an AE.

Situations where 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.
12.3.2.
Definition of Serious Adverse Events
If an event is not an AE per definition above, then it cannot be an SAE even if serious 
conditions are met (e.g., hospitalization for signs/symptoms of the disease under study, 
death due to progression of disease, etc.).
Serious Adverse Event (SAE) is defined as any untoward medical occurrence that, 
at any dose:
i.
Results in death
Is life-threatening
NOTE:
The term 'life-threatening' in the definition of 'serious' refers to an event in which the 
subject was at risk of death at the time of the event. It does not refer to an event, which 
hypothetically might have caused death, if it were more severe.
Requires hospitalization or prolongation of existing hospitalization
NOTE:

In general, hospitalization signifies that the subject has been detained (usually 
involving at least an overnight stay) at the hospital or emergency ward for 
observation and/or treatment that would not have been appropriate in the physician’s 
office or out-patient setting. Complications that occur during hospitalization are AEs. 
If a complication prolongs hospitalization or fulfills any other serious criteria, the 
event is serious. When in doubt as to whether “hospitalization” occurred or was 
necessary, the AE should be considered serious.

Hospitalization for elective treatment of a pre-existing condition that did not worsen 
from baseline is not considered an AE.
Results in disability/incapacity
NOTE:

The term disability means a substantial disruption of a person’s ability to conduct 
normal life functions.
 
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Serious Adverse Event (SAE) is defined as any untoward medical occurrence that, 
at any dose:

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 or prevent everyday 
life functions but do not constitute a substantial disruption
Is a congenital anomaly/birth defect
Other situations:

Medical or scientific judgment should be exercised in deciding whether reporting is 
appropriate in other situations, such as important medical events that may not be 
immediately life-threatening or result in death or hospitalization but may jeopardize 
the subject or may require medical or surgical intervention to prevent one of the 
other outcomes listed in the above definition. These should also be considered 
serious.

Examples of such events are invasive or malignant cancers, intensive treatment in an 
emergency room or at home for allergic bronchospasm, blood dyscrasias or 
convulsions that do not result in hospitalization, or development of drug dependency 
or drug abuse
12.3.3.
Definition of Cardiovascular Events
Cardiovascular Events (CV) Definition:
Investigators will be required to fill out the specific CV event page of the CRF for the 
following AEs and SAEs:

Myocardial infarction/unstable angina

Congestive heart failure

Arrhythmias

Valvulopathy

Pulmonary hypertension

Cerebrovascular events/stroke and transient ischemic attack

Peripheral arterial thromboembolism

Deep venous thrombosis/pulmonary embolism

Revascularization
 
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12.3.4.
Recording of AEs and SAEs
AEs 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) 
relative to the event.

The investigator will then record all relevant information regarding an AE/SAE in 
the CRF

It is not acceptable for the investigator to send photocopies of the subject’s medical 
records to GSK in lieu of completion of the GSK, AE/SAE CRF page.

There may be instances when copies of medical records for certain cases are 
requested by GSK. In this instance, all subject identifiers, with the exception of the 
subject number, will be blinded on the copies of the medical records prior to 
submission to GSK.

The investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information. In such cases, the diagnosis will be 
documented as the AE/SAE and not the individual signs/symptoms.
12.3.5.
Evaluating AEs and SAEs
12.3.5.1.
Division of AIDS (DAIDS) Table for Grading Severity of Adult and 
Pediatric Adverse Events
The DAIDS Table [DAIDS, 2014] will be used to grade the severity of an AE that is not 
specifically identified in the grading table. In addition, all deaths related to an AE are to 
be classified as grade 5.
Parameter
Grade 1
Mild
Grade 2 
Moderate
Grade 3 
Severe
Grade 4 
Potentially Life 
Threatening
Clinical
adverse
event NOT
identified 
elsewhere in
the
grading table
Mild symptoms
causing no or 
minimal
interference with
usual social &
functional
activities with
intervention not 
indicated
Moderate 
symptoms
causing greater
than minimal
interference with
usual social &
functional activities 
with intervention 
indicated
Severe symptoms
causing inability to 
perform usual social
& functional activities 
with
intervention or 
hospitalization
indicated
Potentially life-
threatening
symptoms causing
inability to perform
basic self-care 
functions with
intervention
indicated to prevent 
permanent
impairment, persistent
disability, or death
 
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Major Clinical Conditions Grading Table
Cardiovascular:
PARAMETER
GRADE 1
MILD
GRADE 2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY LIFE- THREATENING
Arrhythmia
(by ECG or physical
examination)
Specify type, if
applicable
No symptoms AND No
intervention indicated
No symptoms AND Non-
urgent intervention indicated
Non-life-threatening symptoms 
AND Non-urgent
intervention indicated
Life-threatening arrhythmia OR Urgent 
intervention indicated
Blood Pressure
Abnormalities1
Hypertension (with the 
lowest reading taken 
after repeat testing 
during a visit)
≥ 18 years of age
140 to <160 mmHg 
systolic
OR
90 to <100 mmHg 
160 to <180 mmHg systolic 
OR
100 to <110
mmHg diastolic
180 mmHg systolic
OR
≥ 110 mmHg diastolic
Life-threatening consequences in a 
participant not previously diagnosed 
with hypertension (e.g., malignant
hypertension) OR Hospitalization 
<18 years of age
>120/80 mmHg
95th to <99th percentile 
+5 mmHg adjusted for age, 
height, and gender (systolic 
and/or diastolic)
9th percentile
+5 mmHg adjusted for age,
height, and gender (systolic 
and/or diastolic)
Life-threatening consequences in a 
participant not previously diagnosed 
with hypertension (e.g., malignant
hypertension) OR Hospitalization 
Hypotension
No symptoms
Symptoms corrected with oral
fluid replacement
Symptoms AND IV
fluids indicated
Shock requiring use of vasopressors 
or mechanical assistance to maintain
blood pressure
Cardiac Ischemia or
Infarction
Report only one
Not 
applicable
Not applicable
New symptoms with ischemia 
(stable angina) OR New testing
consistent with ischemia
Unstable angina OR Acute myocardial 
infarction
 
 
 
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PARAMETER
GRADE 1
MILD
GRADE 2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY LIFE- THREATENING
Heart Failure
No symptoms AND
Laboratory or cardiac 
imaging abnormalities
Symptoms with mild to
moderate activity or exertion
Symptoms at rest or with
minimal activity or exertion (e.g., 
hypoxemia) OR Intervention
indicated (e.g., oxygen)
Life-threatening consequences OR
Urgent intervention indicated (e.g.,
vasoactive medications, ventricular 
assist device, heart transplant)
Haemorrhage
(with significant acute
blood loss)
Not 
applicable
Symptoms AND No 
transfusion indicated
Symptoms AND Transfusion of
2 units packed RBCs indicated
Life-threatening hypotension OR
Transfusion of >2 units packed RBCs 
(for children, packed RBCs
>10 cc/kg) indicated
Prolonged PR Interval 
or AV Block
Report only one
>16 years of age
PR interval 0.21 to <
0.25 seconds
PR interval ≥ 0.25
seconds OR Type I
2nd degree AV block
Type II 2nd degree AV block OR
Ventricular pause 3.0 seconds
Complete AV block
≤ 16 years of age
1st degree AV block
(PR interval
>normal for age and rate)
Type I 2nd degree AV
block
Type II 2nd degree AV block OR
Ventricular pause ≥ 3.0 seconds
Complete AV block
Prolonged QTc
Interval2
0.45 to 0.47 seconds
>0.47 to 0.50 seconds
>0.50 seconds OR
.06 seconds above baseline
Life-threatening consequences (e.g., 
Torsade de pointes, other associated
serious ventricular dysrhythmia)
Thrombosis or
Embolism
Report only one
Not applicable
Symptoms AND No 
intervention indicated
Symptoms AND Intervention
indicated
Life-threatening embolic event (e.g.,
pulmonary embolism, thrombus)
1.
Blood pressure norms for children <18 years of age can be found in: Expert Panel on Integrated Guidelines for Cardiovascular Health and Risk Reduction in Children and
Adolescents. Pediatrics 2011;128;S213; originally published online November 14, 2011; DOI: 10.1542/peds.2009-2107C
2.
As per Bazett’s formula
 
 
 
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Dermatologic:
PARAMETER
GRADE 1
MILD
GRADE 2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY LIFE-
THREATENING
Alopecia (scalp only)
Detectable by study 
participant, caregiver, or 
physician AND Causing no or
minimal interference with
usual social & functional
activities
Obvious on visual 
inspection AND Causing
greater than minimal
interference with usual
social & functional activities
Not applicable
Not applicable
Bruising
Localized to one area
Localized to more than one 
area
Generalized
Not applicable
Cellulitis
Not 
applicable
Non-parenteral treatment
indicated (e.g., oral
antibiotics, antifungals, 
antivirals)
IV treatment indicated (e.g., IV
antibiotics, antifungals,
antivirals)
Life-threatening consequences 
(e.g., sepsis, tissue necrosis)
Hyperpigmentation
Slight or localized causing no
or minimal interference with
usual social & functional
activities
Marked or generalized
causing greater than
minimal interference with 
usual social & functional
activities
Not applicable
Not applicable
Hypopigmentation
Slight or localized causing no
or minimal interference with
usual social & functional
activities
Marked or generalized
causing greater than
minimal interference with 
usual social & functional
activities
Not applicable
Not applicable
Petechiae
Localized to one area
Localized to more than one 
area
Generalized
Not applicable
 
 
 
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PARAMETER
GRADE 1
MILD
GRADE 2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY LIFE-
THREATENING
Pruritus1
(without skin lesions)
Itching causing no or minimal 
interference with usual social
& functional activities
Itching causing greater
than minimal interference
with usual social & 
functional activities
Itching causing inability to
perform usual social & 
functional activities
Not applicable
Rash
Specify type, if applicable
Localized rash
Diffuse rash OR Target
lesions
Diffuse rash AND Vesicles or
limited number of bullae or 
superficial ulcerations of
mucous membrane limited to
one site
Extensive or generalized 
bullous lesions OR Ulceration
of mucous membrane 
involving two or more distinct
mucosal sites OR Stevens-
Johnson syndrome OR Toxic 
epidermal necrolysis
1.
For pruritus associated with injections or infusions, see the Site Reactions to Injections and Infusions section
 
 
 
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Endocrine and Metabolic:
PARAMETER
GRADE 1
MILD
GRADE 2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY LIFE-
THREATENING
Diabetes Mellitus
Controlled without 
medication
Controlled with medication
OR Modification of current
medication regimen
Uncontrolled despite 
treatment modification OR
Hospitalization for immediate 
glucose control indicated
Life-threatening consequences 
(e.g., ketoacidosis, 
hyperosmolar non- ketotic 
coma, end organ failure)
Gynaecomastia
Detectable by study 
participant, caregiver, or 
physician AND Causing no
or
minimal interference with
usual social & functional
activities
Obvious on visual inspection
AND Causing pain with 
greater than minimal 
interference with usual social
& functional activities
Disfiguring changes AND
Symptoms requiring
intervention or causing
inability to perform usual
social
& functional activities
Not applicable
Hyperthyroidism
No symptoms AND
Abnormal laboratory value
Symptoms causing greater
than minimal interference
with usual social & functional
activities OR Thyroid 
suppression therapy 
indicated
Symptoms causing inability
to perform usual social & 
functional activities OR
Uncontrolled despite 
treatment modification
Life-threatening consequences 
(e.g., thyroid storm)
Hypothyroidism
No symptoms AND
Abnormal laboratory value
Symptoms causing greater
than minimal interference
with usual social & functional
activities OR Thyroid 
replacement therapy 
indicated
Symptoms causing inability
to perform usual social & 
functional activities OR
Uncontrolled despite 
treatment modification
Life-threatening consequences 
(e.g., myxedema coma)
 
 
 
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PARAMETER
GRADE 1
MILD
GRADE 2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY LIFE-
THREATENING
Lipoatrophy1
Detectable by study 
participant, caregiver, or 
physician AND Causing no
or
minimal interference with
usual social & functional
activities
Obvious on visual inspection
AND Causing greater than 
minimal interference with
usual social & functional
activities
Disfiguring changes
Not applicable
Lipohypertrophy2
Detectable by study 
participant, caregiver, or 
physician AND Causing no
or
minimal interference with
usual social &
functional activities
Obvious on visual inspection
AND Causing greater than 
minimal interference with
usual social & functional
activities
Disfiguring changes
Not applicable
1.
Definition: A disorder characterized by fat loss in the face, extremities, and buttocks.
2.
Definition: A disorder characterized by abnormal fat accumulation on the back of the neck, breasts, and abdomen.
 
 
 
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Gastrointestinal:
PARAMETER
GRADE 1
MILD
GRADE 2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY LIFE-
THREATENING
Anorexia
Loss of appetite without
decreased oral intake
Loss of appetite associated
with decreased oral intake 
without significant weight
loss
Loss of appetite associated
with significant weight loss
Life-threatening consequences 
OR Aggressive intervention 
indicated (e.g., tube feeding,
total parenteral nutrition)
Ascites
No symptoms
Symptoms AND
Intervention indicated (e.g.,
diuretics, therapeutic 
paracentesis)
Symptoms recur or persist
despite intervention
Life-threatening consequences
Bloating or Distension
Report only one
Symptoms causing no or
minimal interference with 
usual social & functional
activities
Symptoms causing greater
than minimal interference
with usual social & 
functional activities
Symptoms causing inability
to perform usual social & 
functional activities
Not applicable
Cholecystitis
Not applicable
Symptoms AND Medical
intervention indicated
Radiologic, endoscopic, or 
operative intervention 
indicated
Life-threatening consequences 
(e.g., sepsis, perforation)
Constipation
Not applicable
Persistent
constipation requiring 
regular use of dietary 
modifications, laxatives, or
Obstipation with manual
evacuation indicated
Life-threatening consequences 
(e.g., obstruction)
 
 
 
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PARAMETER
GRADE 1
MILD
GRADE 2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY LIFE-
THREATENING
Diarrhoea
≥ 1 year of age
Transient or intermittent
episodes of unformed stools 
OR Increase of 3 stools over
baseline per 24-hour period
Persistent episodes of 
unformed to watery stools 
OR Increase of
4 to 6 stools over baseline 
per 24-hour period
Increase of 7 stools
per 24-hour period
OR IV fluid replacement
indicated
Life-threatening consequences 
(e.g., hypotensive shock)
<1 year of age
Liquid stools (more unformed
than usual) but usual number
of stools
Liquid stools with increased
number of stools OR Mild 
dehydration
Liquid stools with moderate 
dehydration
Life-threatening consequences 
(e.g., liquid stools resulting in 
severe dehydration, 
hypotensive shock)
Dysphagia or
Odynophagia
Report only one and specify 
location
Symptoms but able to eat
usual diet
Symptoms causing altered
dietary intake with no
intervention indicated
Symptoms causing severely
altered dietary intake with 
intervention indicated
Life-threatening reduction in
oral intake
Gastrointestinal
Bleeding
Not requiring intervention
other than iron supplement
Endoscopic intervention
indicated
Transfusion indicated
Life-threatening consequences 
(e.g., hypotensive shock)
Mucositis or Stomatitis
Report only one and specify 
location
Mucosal erythema
Patchy pseudomembranes 
or ulcerations
Confluent 
pseudomembranes or 
ulcerations OR Mucosal 
bleeding with minor trauma
Life-threatening consequences 
(e.g., aspiration, choking) OR 
Tissue necrosis OR Diffuse 
spontaneous mucosal bleeding
 
 
 
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PARAMETER
GRADE 1
MILD
GRADE 2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY LIFE-
THREATENING
Nausea
Transient (<24 hours) or 
intermittent AND No or 
minimal interference with oral 
intake
Persistent nausea resulting 
in decreased oral intake for 
24 to 48 hours
Persistent nausea resulting 
in minimal oral intake for 
>48 hours OR
Rehydration indicated
(e.g., IV fluids)
Life-threatening consequences 
(e.g., hypotensive shock)
Pancreatitis
Not applicable
Symptoms with 
hospitalization not indicated
Symptoms with 
hospitalization indicated
Life-threatening consequences 
(e.g., circulatory failure, 
haemorrhage, sepsis)
Perforation
(colon or rectum)
Not applicable
Not applicable
Intervention indicated
Life-threatening consequences
Proctitis
Rectal discomfort with no 
intervention indicated
Symptoms causing greater 
than minimal interference 
with usual social & 
functional activities OR 
Medical
intervention indicated
Symptoms causing inability 
to perform usual social & 
functional activities OR 
Operative intervention 
indicated
Life-threatening consequences 
(e.g., perforation)
Rectal Discharge
Visible discharge
Discharge requiring the use 
of pads
Not applicable
Not applicable
Vomiting
Transient or intermittent AND 
No or minimal interference 
with oral intake
Frequent episodes with no 
or mild dehydration
Persistent vomiting resulting 
in orthostatic hypotension 
OR Aggressive
rehydration indicated
(e.g., IV fluids)
Life-threatening consequences 
(e.g., hypotensive shock)
 
 
 
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Musculoskeletal:
PARAMETER
GRADE 1
MILD
GRADE 2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY LIFE-
THREATENING
Arthralgia
Joint pain causing no or
minimal interference with 
usual social & functional
activities
Joint pain causing greater
than minimal interference
with usual social & 
functional activities
Joint pain causing inability to
perform usual social & 
functional activities
Disabling joint pain causing
inability to perform basic self-
care functions
Arthritis
Stiffness or joint swelling
causing no or minimal 
interference with usual social
& functional activities
Stiffness or joint swelling
causing greater than
minimal interference with 
usual social & functional
activities
Stiffness or joint swelling
causing inability to perform 
usual social & functional
activities
Disabling joint stiffness or
swelling causing inability to
perform basic self-care
functions
Myalgia (generalized)
Muscle pain causing no or
minimal interference with 
usual social & functional
activities
Muscle pain causing 
greater than minimal 
interference with usual
social & functional activities
Muscle pain causing inability to
perform usual social & 
functional activities
Disabling muscle pain causing
inability to perform basic self-
care functions
Osteonecrosis
Not applicable
No symptoms but with
radiographic findings AND
No operative intervention 
indicated
Bone pain with radiographic 
findings OR Operative 
intervention indicated
Disabling bone pain with 
radiographic findings causing
inability to perform basic self-
care functions
Osteopenia1
≥ 30 years of age
BMD t-score
-2.5 to -1
Not applicable
Not applicable
Not applicable
<30 years of age
BMD z-score
-2 to -1
Not applicable
Not applicable
Not applicable
 
 
 
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PARAMETER
GRADE 1
MILD
GRADE 2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY LIFE-
THREATENING
Osteoporosis1
≥ 30 years of age
Not applicable
BMD t-score <-2.5
Pathologic fracture (e.g.,
compression fracture causing
loss of vertebral height)
Pathologic fracture causing
life-threatening consequences
<30 years of age
Not applicable
BMD z-score <-2
Pathologic fracture (e.g.,
compression fracture 
causing loss of vertebral
height)
Pathologic fracture causing
life-threatening 
consequences
1.
Bone mineral density (BMD) t and z scores can be found in: Kanis JA on behalf of the World Health Organization Scientific Group (2007). Assessment of osteoporosis at the
primary health-care level. Technical Report. World Health Organization Collaborating Center for Metabolic Bone Diseases, University of Sheffield, UK. 2007: Printed by the
University of Sheffield.
 
 
 
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Neurologic:
PARAMETER
GRADE 1
MILD
GRADE 2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY LIFE-
THREATENING
Acute CNS Ischemia
Not applicable
Not applicable
Transient ischemic attack
Cerebral vascular accident
(e.g., stroke with neurological 
deficit)
Altered Mental Status (for
Dementia, see Cognitive,
Behavioral, or Attentional
Disturbance below)
Changes causing no or
minimal interference with 
usual social & functional
activities
Mild lethargy or somnolence 
causing greater than
minimal interference with 
usual social & functional
activities
Confusion, memory 
impairment, lethargy, or 
somnolence causing
inability to perform usual
social
Delirium OR Obtundation OR
Coma
Ataxia
Symptoms causing no or
minimal interference with 
usual social & functional
activities OR No symptoms 
with ataxia detected on
examination
Symptoms causing greater
than minimal interference
with usual social & 
functional activities
Symptoms causing inability
to perform usual social & 
functional activities
Disabling symptoms causing
inability to perform basic self-
care functions
Cognitive, Behavioural, or 
Attentional Disturbance 
(includes dementia and attention 
deficit disorder)
Specify type, if applicable
Disability causing no or
minimal interference with 
usual social & functional
activities OR Specialized 
resources not indicated
Disability causing greater
than minimal interference
with usual social & 
functional activities OR
Specialized resources on
part- time basis indicated
Disability causing inability to
perform usual social & 
functional activities OR
Specialized resources on a 
full- time basis indicated
Disability causing inability to
perform
basic self-care functions OR
Institutionalization indicated
 
 
 
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PARAMETER
GRADE 1
MILD
GRADE 2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY LIFE-
THREATENING
Developmental Delay
<18 years of age
Specify type, if applicable
Mild developmental delay,
either motor or cognitive, as 
determined by comparison
with a developmental 
screening tool appropriate for
the setting
Moderate developmental
delay, either motor or 
cognitive, as determined by 
comparison with a 
developmental screening
tool appropriate for the 
setting
Severe developmental 
delay, either motor or 
cognitive, as determined by 
comparison with a 
developmental screening
tool appropriate for the 
setting
Developmental regression,
either motor or cognitive, as 
determined by comparison with
a developmental screening tool
appropriate for the setting
Headache
Symptoms causing no or
minimal interference with 
usual social & functional
activities
Symptoms causing greater
than minimal interference
with usual social & 
functional activities
Symptoms causing inability
to perform usual social & 
functional activities
Symptoms causing inability to
perform
basic self-care functions
OR Hospitalization indicated 
OR Headache
with significant
impairment of alertness or
other neurologic
function
Neuromuscular Weakness 
(includes myopathy and 
neuropathy)
Specify type, if applicable
Minimal muscle weakness 
causing no or minimal 
interference with usual social 
& functional activities OR No 
symptoms with decreased 
strength on examination
Muscle weakness causing 
greater than minimal 
interference with usual 
social & functional activities
Muscle weakness causing 
inability to perform usual 
social & functional activities
Disabling muscle weakness 
causing inability to perform
basic self-care functions OR 
Respiratory muscle weakness 
impairing ventilation
 
 
 
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PARAMETER
GRADE 1
MILD
GRADE 2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY LIFE-
THREATENING
Neurosensory Alteration 
(includes paresthesia and 
painful neuropathy)
Specify type, if applicable
Minimal paresthesia causing 
no or minimal
interference with usual social 
& functional activities
OR No symptoms with 
sensory alteration on 
examination
Sensory alteration or 
paresthesia causing greater 
than minimal interference 
with usual social & 
functional activities
Sensory alteration or 
paresthesia causing 
inability to perform usual 
social & functional activities
Disabling sensory alteration or 
paresthesia causing inability to 
perform basic self-care 
functions
Seizures
New Onset Seizure
≥ 18 years of age
Not applicable
Not applicable
1 to 3 seizures
Prolonged and repetitive 
seizures (e.g., status 
epilepticus) OR Difficult to 
control (e.g.,
refractory epilepsy)
<18 years of age
(includes new or pre-existing 
febrile seizures)
Seizure lasting <5 minutes 
with <24 hours postictal state
Seizure lasting 5 to <20 
minutes with 
<24 hours postictal state
Seizure lasting 20 minutes 
OR >24 hours postictal 
state
Prolonged and repetitive 
seizures (e.g., status 
epilepticus) OR Difficult to 
control (e.g.,
refractory epilepsy)
 
 
 
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PARAMETER
GRADE 1
MILD
GRADE 2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY LIFE-
THREATENING
Pre-existing Seizure
Not applicable
Increased frequency from 
previous level of control 
without change in seizure 
character
Change in seizure 
character either in duration 
or quality (e.g., severity or 
focality)
Prolonged and repetitive 
seizures (e.g., status 
epilepticus) OR Difficult to 
control (e.g.,
refractory epilepsy)
Syncope
Near syncope without loss of 
consciousness (e.g., pre-
syncope)
Loss of consciousness with 
no intervention indicated
Loss of consciousness AND 
Hospitalization or 
intervention required
Not applicable
Pregnancy, Puerperium and Perinatal:
PARAMETER
GRADE 1
MILD
GRADE 2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY LIFE-
THREATENING
Foetal Death or Stillbirth 
(report using mother’s 
participant ID)
Not applicable
Not applicable
Foetal loss occurring at
20 weeks gestation
Not applicable
Preterm Delivery1 (report using
mother’s participant ID)
Delivery at 34 to
<37 weeks gestational age
Delivery at 28 to
<34 weeks gestational age
Delivery at 24 to
<28 weeks gestational age
Delivery at <24 weeks
gestational age
Spontaneous Abortion or 
Miscarriage2 (report using
mother’s participant ID)
Report only one
Chemical pregnancy
Uncomplicated 
spontaneous abortion or
miscarriage
Complicated spontaneous 
abortion or miscarriage
Not applicable
1.
Definition: A delivery of a live-born neonate occurring at ≥ 20 to <37 weeks gestational age.
2.
Definition: A clinically recognized pregnancy occurring at <20 weeks gestational age.
 
 
 
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Psychiatric: 
PARAMETER
GRADE 1
MILD
GRADE 2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY LIFE-
THREATENING
Insomnia
Mild difficulty falling asleep, 
staying asleep, or waking
up early
Moderate difficulty falling
asleep, staying asleep, or
waking up early
Severe difficulty falling
asleep, staying asleep, or
waking up early
Not applicable
Psychiatric Disorders (includes 
anxiety, depression, mania, and 
psychosis)
Specify disorder
Symptoms with 
intervention not indicated
OR Behavior causing no or
minimal interference with 
usual social & functional
Symptoms with intervention
indicated OR Behavior
causing greater than minimal 
interference with
usual social &
Symptoms with 
hospitalization indicated OR
Behavior causing inability to
perform usual social & 
functional activities
Threatens harm to self or others 
OR Acute psychosis OR
Behavior causing inability to 
perform basic self-care 
functions
Suicidal Ideation or
Attempt
Report only one
Preoccupied with thoughts 
of death AND No wish to
kill oneself
Preoccupied with thoughts 
of death AND Wish to kill 
oneself with no specific plan
or intent
Thoughts of killing oneself
with partial or complete plans 
but no attempt to do so OR
Hospitalization indicated
Suicide attempted
 
 
 
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Respiratory:
PARAMETER
GRADE 1
MILD
GRADE 2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY LIFE-
THREATENING
Acute Bronchospasm
Forced expiratory volume 
in 1 second or peak flow 
reduced to
70 to <80% OR Mild
symptoms with
intervention not
indicated
Forced expiratory volume in
1 second or peak flow 50 to
<70% OR Symptoms with
intervention
indicated OR Symptoms 
causing greater than minimal 
interference with
usual social &
Forced expiratory volume in
1 second or peak flow 25 to
<50% OR Symptoms 
causing inability to
perform usual social
& functional activities
Forced expiratory volume in 1
second or peak flow <25% OR
Life-threatening respiratory or 
hemodynamic compromise OR
Intubation
Dyspnoea or Respiratory
Distress
Report only one
Dyspnoea on exertion with
no or minimal interference
with usual social & 
functional activities OR
Wheezing OR Minimal
increase in respiratory rate
for age
Dyspnoea on exertion 
causing greater than minimal
interference with usual social
& functional activities OR
Nasal flaring OR Intercostal
retractions OR Pulse 
oximetry 90 to <95%
Dyspnoea at rest causing
inability to perform usual
social
& functional
activities OR Pulse oximetry
<90%
Respiratory failure with 
ventilator support indicated
(e.g., CPAP, BPAP, intubation)
 
 
 
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Sensory:
PARAMETER
GRADE 1
MILD
GRADE 2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY LIFE-
THREATENING
Hearing Loss
≥ 12 years of age
Not applicable
Hearing aid or intervention
not indicated
Hearing aid or intervention
indicated
Profound bilateral hearing loss 
(>80 dB at
2 kHz and above) OR Non-
serviceable hearing
(i.e., >50 dB audiogram and
<50% speech discrimination)
<12 years of age (based on a 1,
2, 3, 4, 6 and 8 kHz audiogram)
>20 dB hearing loss at 4 kHz >20 dB hearing loss at
>4 kHz
>20 dB hearing loss at ≥ 3
kHz in one ear with
additional speech language 
related services indicated 
(where available) OR
Hearing loss
sufficient to indicate 
therapeutic
intervention,
including hearing aids
Audiologic indication for 
cochlear implant and additional
speech- language related
services indicated (where 
available)
Tinnitus
Symptoms causing no or
minimal interference with 
usual social & functional
activities with intervention not 
indicated
Symptoms causing greater
than minimal interference
with usual social & 
functional activities with
intervention indicated
Symptoms causing inability
to perform usual social & 
functional activities
Not applicable
 
 
 
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PARAMETER
GRADE 1
MILD
GRADE 2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY LIFE-
THREATENING
Uveitis
No symptoms AND Detectable 
on examination
Anterior uveitis with 
symptoms OR
Medicamylasal intervention
indicated
Posterior or pan- uveitis OR
Operative intervention
indicated
Disabling visual loss in affected
eye(s)
Vertigo
Vertigo causing no or minimal 
interference with usual social
& functional activities
Vertigo causing greater
than minimal interference
with usual social & 
functional activities
Vertigo causing inability to
perform usual social & 
functional activities
Disabling vertigo causing
inability to perform basic self-
care functions
Visual Changes
(assessed from baseline)
Visual changes causing no or 
minimal interference with
usual social & functional
activities
Visual changes causing
greater than minimal
interference with usual
social & functional activities
Visual changes causing
inability to perform usual
social
& functional activities
Disabling visual loss in affected
eye(s)
 
 
 
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Systemic:
PARAMETER
GRADE 1
MILD
GRADE 2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY LIFE-
THREATENING
Acute Allergic
Reaction
Localized urticaria (wheals)
with no medical intervention 
indicated
Localized urticaria with
intervention indicated OR
Mild angioedema with no 
intervention indicated
Generalized urticaria OR
Angioedema with intervention
indicated OR Symptoms of
mild bronchospasm
Acute anaphylaxis OR Life-
threatening bronchospasm OR
Laryngeal oedema
Chills
Symptoms causing no or
minimal
interference with usual social
& functional activities
Symptoms causing greater
than minimal interference
with usual social &
functional activities
Symptoms causing inability to
perform usual social & 
functional activities
Not applicable
Cytokine Release
Syndrome1
Mild signs and symptoms
AND Therapy (i.e., antibody 
infusion) interruption not
indicated
Therapy (i.e., antibody
infusion) interruption 
indicated AND Responds
promptly to symptomatic 
treatment OR Prophylactic 
medications indicated for ≤
24 hours
Prolonged severe signs and
symptoms OR Recurrence of 
symptoms following initial
improvement
Life-threatening consequences 
(e.g., requiring pressor or 
ventilator support)
Fatigue or Malaise
Report only one
Symptoms causing no or
minimal
interference with usual social
& functional
activities
Symptoms causing greater
than minimal interference
with usual social &
functional activities
Symptoms causing inability to
perform usual social & 
functional activities
Incapacitating symptoms of
fatigue or malaise causing inability
to perform basic self-care 
functions
Fever (non-axillary 
temperatures only)
38.0 to <38.6°C or
100.4 to <101.5°F
38.6 to <39.3°C
or 101.5 to
<102.7°F
39.3 to <40.0°C or
102.7 to <104.0°F
40.0°C or 104.0°F
 
 
 
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PARAMETER
GRADE 1
MILD
GRADE 2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY LIFE-
THREATENING
Pain2 (not associated with
study agent injections and not 
specified elsewhere)
Specify location
Pain causing no or minimal
interference with usual social
& functional activities
Pain causing greater than
minimal interference with 
usual social & functional
activities
Pain causing inability to
perform usual social
& functional activities
Disabling pain causing inability to
perform basic self-care functions 
OR Hospitalization indicated
Serum Sickness3
Mild signs and symptoms
Moderate signs and 
symptoms AND
Intervention indicated
(e.g., antihistamines)
Severe signs and symptoms
AND Higher level intervention
indicated (e.g., steroids or IV 
fluids)
Life-threatening consequences 
(e.g., requiring pressor or 
ventilator support)
Underweight4
>5 to 19 years of age
Not applicable
WHO BMI z-score
<-2 to ≤ -3
WHO BMI z-score
<-3
WHO BMI z-score
<-3 with life-threatening 
consequences
2 to 5 years of age
Not applicable
WHO Weight-for- height z-
score
<-2 to ≤ -3
WHO Weight-for- height z-
score <-3
WHO Weight-for-height z-score <-
3 with life- threatening 
consequences
<2 years of age
Not applicable
WHO Weight-for- length z-
score
<-2 to -3
WHO Weight-for- length z-
score <-3
WHO Weight-for-length z-score 
<-3 with life- threatening 
consequences
 
 
 
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PARAMETER
GRADE 1
MILD
GRADE 2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY LIFE-
THREATENING
Weight Loss (excludes 
postpartum weight
loss)
Not applicable
5 to <9% loss in body 
weight from baseline
≥ 9 to <20% loss in body 
weight from baseline
≥ 20% loss in body weight from 
baseline OR Aggressive 
intervention indicated (e.g., tube 
feeding, total parenteral nutrition)
1.
Definition: A disorder characterized by nausea, headache, tachycardia, hypotension, rash, and/or shortness of breath.
2.
For pain associated with injections or infusions, see the Site Reactions to Injections and Infusions section.
3.
Definition: A disorder characterized by fever, arthralgia, myalgia, skin eruptions, lymphadenopathy, marked discomfort, and/or dyspnoea
4.
WHO reference tables may be accessed by clicking the desired age range or by accessing the following URLs: http://www.who.int/growthref/who2007_bmi_for_age/en/ for 
participants >5 to 19 years of age and http://www.who.int/childgrowth/standards/chart_catalogue/en/ for those ≤5 years of age
Urinary:
PARAMETER
GRADE 1
MILD
GRADE 2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY LIFE-
THREATENING
Urinary Tract
Obstruction
Not applicable
Signs or symptoms of 
urinary tract obstruction
without hydronephrosis or 
renal dysfunction
Signs or symptoms of 
urinary tract obstruction with 
hydronephrosis or renal
dysfunction
Obstruction causing life-
threatening
consequences
 
 
 
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Site Reactions to Injections and Infusions:
PARAMETER
GRADE 1
MILD
GRADE 2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY LIFE-
THREATENING
Injection Site Pain or
Tenderness
Report only one
Pain or tenderness causing
no or minimal limitation of
use of limb
Pain or tenderness causing
greater than minimal
limitation of use of limb
Pain or tenderness causing
inability to perform usual
social
& functional activities
Pain or tenderness causing
inability to perform basic self-
care function OR Hospitalization
indicated
Injection Site Erythema or 
Redness1
Report only one
>15 years of age
2.5 to <5 cm in diameter
OR 6.25 to
<25 cm2 surface
area AND Symptoms 
causing no or minimal 
interference with usual
social & functional activities
5 to <10 cm in diameter
OR 25 to
<100 cm2 surface
area OR Symptoms causing
greater than minimal
interference with usual social
& functional activities
10 cm in diameter OR
100 cm2 surface area OR
Ulceration OR Secondary
infection OR Phlebitis
OR Sterile abscess
OR Drainage OR Symptoms 
causing
inability to perform
Potentially life- threatening 
consequences (e.g., abscess,
exfoliative dermatitis, necrosis 
involving dermis or deeper
tissue)
≤ 15 years of age
≤ 2.5 cm in diameter
>2.5 cm in diameter with
<50% surface area of the 
extremity segment involved 
(e.g., upper arm or thigh)
50% surface area of the 
extremity segment involved
(e.g., upper arm or thigh) OR
Ulceration OR Secondary
infection OR Phlebitis OR
Sterile abscess OR Drainage
Potentially life- threatening 
consequences (e.g., abscess,
exfoliative dermatitis, necrosis 
involving dermis or deeper
tissue)
 
 
 
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PARAMETER
GRADE 1
MILD
GRADE 2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY LIFE-
THREATENING
Injection Site
Induration or Swelling
Report only one
>15 years of age
Same as for Injection Site 
Erythema or Redness,
>15 years of age
Same as for Injection Site 
Erythema or Redness,
>15 years of age
Same as for Injection Site 
Erythema or Redness,
>15 years of age
Same as for Injection Site 
Erythema or Redness,
>15 years of age
≤15 years of age
Same as for Injection Site 
Erythema or Redness, ≤ 
15 years of age
Same as for Injection Site 
Erythema or Redness, ≤ 
15 years of age
Same as for Injection Site 
Erythema or Redness, ≤ 
15 years of age
Same as for Injection Site 
Erythema or Redness, ≤ 
15 years of age
Injection Site Pruritus
Itching localized to the 
injection site that is relieved 
spontaneously or in
<48 hours of treatment
Itching beyond the injection
site that is not generalized
OR Itching localized to the 
injection site requiring
48 hours treatment
Generalized itching causing
inability to perform usual
social
& functional activities
Not applicable
1.
Injection Site Erythema or Redness should be evaluated and graded using the greatest single diameter or measured surface area.
Laboratory Values – Chemistries
PARAMETER
GRADE 1
MILD
GRADE 2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY LIFE-
THREATENING
Acidosis
Not applicable
pH 7.3 to <LLN
pH <7.3 without life-
threatening consequences
pH <7.3 with life- threatening 
consequences
Albumin, Low
(g/dL; g/L)
3.0 to <LLN
30 to <LLN
2.0 to <3.0
20 to <30
<2.0
<20
Not applicable
 
 
 
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PARAMETER
GRADE 1
MILD
GRADE 2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY LIFE-
THREATENING
Alkaline Phosphatase, High
1.25 to <2.5 x ULN
2.5 to <5.0 x ULN
5.0 to <10.0 x ULN
10.0 x ULN
Alkalosis
Not applicable
pH >ULN to ≤ 7.5
pH >7.5 without life-
threatening consequences
pH >7.5 with life- threatening 
consequences
ALT or SGPT, High
Report only one
1.25 to <2.5 x ULN
2.5 to <5.0 x ULN
5.0 to <10.0 x ULN
≥ 10.0 x ULN
Amylase (Pancreatic) or
Amylase (Total), High
Report only one
1.1 to <1.5 x ULN
1.5 to <3.0 x ULN
3.0 to <5.0 x ULN
5.0 x ULN
AST or SGOT, High
Report only one
1.25 to <2.5 x ULN
2.5 to <5.0 x ULN
5.0 to <10.0 x ULN
10.0 x ULN
Bicarbonate, Low
(mEq/L; mmol/L)
16.0 to <LLN
16.0 to <LLN
11.0 to <16.0
11.0 to <16.0
8.0 to <11.0
8.0 to <11.0
<8.0
<8.0
Bilirubin
Direct Bilirubin1, High
>28 days of age
Not applicable
Not applicable
>ULN
>ULN with life- threatening
consequences (e.g., signs
and symptoms of liver failure)
≤ 28 days of age
ULN to1 mg/dL
>1 to 1.5 mg/dL
>1.5 to 2 mg/dL
>2 mg/dL
Total Bilirubin, High
>28 days of age
1.1 to <1.6 x ULN
1.6 to <2.6 x ULN
2.6 to <5.0 x ULN
5.0 x ULN
 
 
 
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PARAMETER
GRADE 1
MILD
GRADE 2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY LIFE-
THREATENING
≤ 28 days of age
See Appendix 3
(Section 12.3.5.1.1). Total
Bilirubin for Term and Preterm 
Neonates
See Appendix 3
(Section 12.3.5.1.1). Total
Bilirubin for Term and
Preterm Neonates
See Appendix 3
(Section 12.3.5.1.1). Total
Bilirubin for Term and
Preterm Neonates
See Appendix 3
(Section 12.3.5.1.1). Total 
Bilirubin for Term and Preterm
Neonates
Calcium, High
(mg/dL; mmol/L)
≥ 7 days of age
10.6 to <11.5
2.65 to <2.88
11.5 to <12.5
2.88 to <3.13
12.5 to <13.5
3.13 to <3.38
13.5
3.38
<7 days of age
11.5 to <12.4
2.88 to <3.10
12.4 to <12.9
3.10 to <3.23
12.9 to <13.5
3.23 to <3.38
13.5
3.38
Calcium (Ionized), High
(mg/dL; mmol/L)
>ULN to <6.0
>ULN to <1.5
6.0 to <6.4
1.5 to <1.6
6.4 to <7.2
1.6 to <1.8
7.2
.8
Calcium, Low
(mg/dL; mmol/L)
≥ 7 days of age
7.8 to <8.4
1.95 to <2.10
7.0 to <7.8
1.75 to <1.95
6.1 to <7.0
1.53 to <1.75
<6.1
<1.53
<7 days of age
6.5 to <7.5
1.63 to <1.88
6.0 to <6.5
1.50 to <1.63
5.50 to <6.0
1.38 to <1.50
<5.50
<1.38
Calcium (Ionized), Low
(mg/dL; mmol/L)
<LLN to 4.0
<LLN to 1.0
3.6 to <4.0
0.9 to <1.0
3.2 to <3.6
0.8 to <0.9
<3.2
<0.8
 
 
 
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PARAMETER
GRADE 1
MILD
GRADE 2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY LIFE-
THREATENING
Cardiac Troponin I, High
Not applicable
Not applicable
Not applicable
Levels consistent with 
myocardial infarction or 
unstable angina as defined by 
the local laboratory
Creatine Kinase, High
3 to <6 x ULN
6 to <10 x ULN
10 to <20 x ULN
20 x ULN
Creatinine, High
1.1 to 1.3 x ULN
>1.3 to 1.8 x ULN OR 
Increase of
>0.3 mg/dL above
baseline
>1.8 to <3.5
x ULN OR Increase of 1.5 
to <2.0 x
above baseline
3.5 x ULN OR
Increase of 2.0 x
above baseline
Creatinine Clearance2
or eGFR, Low
Report only one
Not applicable
<90 to 60 ml/min or 
ml/min/1.73 m2
OR
10 to <30% decrease from 
baseline
<60 to 30 ml/min or 
ml/min/1.73 m2
OR
30 to <50% decrease 
from baseline
<30 ml/min or ml/min/1.73 m2
OR
50% decrease from baseline 
or dialysis needed
Glucose
(mg/dL; mmol/L)
Fasting, High
110 to 125
6.11 to <6.95
>125 to 250
6.95 to <13.89
>250 to 500
13.89 to <27.75
>500
27.75
Nonfasting, High
116 to 160
6.44 to <8.89
>160 to 250
8.89 to <13.89
>250 to 500
13.89 to <27.75
>500
27.75
 
 
 
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PARAMETER
GRADE 1
MILD
GRADE 2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY LIFE-
THREATENING
Glucose, Low
(mg/dL; mmol/L)
≥ 1 month of age
55 to 64
3.05 to 3.55
40 to <55
2.22 to <3.05
30 to <40
1.67 to <2.22
<30
<1.67
<1 month of age
50 to 54
2.78 to 3.00
40 to <50
2.22 to <2.78
30 to <40
1.67 to <2.22
<30
<1.67
Lactate, High
ULN to <2.0 x ULN without 
acidosis
≥ 2.0 x ULN without 
acidosis
Increased lactate with 
pH<7.3 without life-
threatening consequences
Increased lactate with pH<7.3 
with life- threatening 
consequences
Lipase, High
1.1 to <1.5 x ULN
1.5 to <3.0 x ULN
3.0 to <5.0 x ULN
5.0 x ULN
Lipid Disorders
(mg/dL; mmol/L)
Cholesterol, Fasting, High
≥ 18 years of age
200 to <240
5.18 to <6.19
240 to <300
6.19 to <7.77
300
7.77
Not applicable
<18 years of age
170 to <200
4.40 to <5.15
200 to <300
5.15 to <7.77
300
7.77
Not applicable
LDL, Fasting, High
≥ 18 years of age
130 to <160
3.37 to <4.12
160 to <190
4.12 to <4.90
190
4.90
Not applicable
 
 
 
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PARAMETER
GRADE 1
MILD
GRADE 2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY LIFE-
THREATENING
>2 to <18 years of age
110 to <130
2.85 to <3.34
130 to <190
3.34 to <4.90
190
4.90
Not applicable
Triglycerides, Fasting, High
150 to 300
1.71 to 3.42
>300 to 500
>3.42 to 5.7
>500 to <1,000
>5.7 to 11.4
>1,000
>11.4
Magnesium3, Low
(mEq/L; mmol/L)
1.2 to <1.4
0.60 to <0.70
0.9 to <1.2
0.45 to <0.60
0.6 to <0.9
0.30 to <0.45
<0.6
<0.30
Phosphate, Low
(mg/dL; mmol/L)
>14 years of age
2.0 to <LLN
0.81 to <LLN
1.4 to <2.0
0.65 to <0.81
1.0 to <1.4
0.32 to <0.65
<1.0
<0.32
1 to 14 years of age
3.0 to <3.5
0.97 to <1.13
2.5 to <3.0
0.81 to <0.97
1.5 to <2.5
0.48 to <0.81
<1.5
<0.48
<1 year of age
3.5 to <4.5
1.13 to <1.45
2.5 to <3.5
0.81 to <1.13
1.5 to <2.5
0.48 to <0.81
<1.5
<0.48
Potassium, High
(mEq/L; mmol/L)
5.6 to <6.0
5.6 to <6.0
6.0 to <6.5
6.0 to <6.5
6.5 to <7.0
6.5 to <7.0
7.0
7.0
Potassium, Low
(mEq/L; mmol/L)
3.0 to <3.4
3.0 to <3.4
2.5 to <3.0
2.5 to <3.0
2.0 to <2.5
2.0 to <2.5
<2.0
<2.0
Sodium, High
(mEq/L; mmol/L)
146 to <150
146 to <150
150 to <154
150 to <154
154 to <160
154 to <160
160
160
Sodium, Low
(mEq/L; mmol/L)
130 to <135
130 to <135
125 to <130
125 to <135
121 to <125
121 to <125
120
120
 
 
 
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PARAMETER
GRADE 1
MILD
GRADE 2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY LIFE-
THREATENING
Uric Acid, High
(mg/dL; mmol/L)
7.5 to <10.0
0.45 to <0.59
10.0 to <12.0
0.59 to <0.71
12.0 to <15.0
0.71 to <0.89
15.0
0.89
1.
Direct bilirubin >1.5 mg/dL in a participant <28 days of age should be graded as grade 2, if <10% of the total bilirubin
2.
Use the applicable formula (i.e., Cockroft-Gault in mL/min or Schwatrz in mL/min/1.73m2)
3.
To convert a magnesium value from mg/dL to mmol/L, laboratories should multiply by 0.4114
 
 
 
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Hematology:
PARAMETER
GRADE 1
MILD
GRADE 2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY LIFE-
THREATENING
Absolute CD4+ Count, Low
(cell/mm3; cells/L)
>5 years of age
(not HIV infected)
300 to <400
300 to <400
200 to <300
200 to <300
100 to <200
100 to <200
<100
<100
Absolute Lymphocyte
Count, Low
(cell/mm3; cells/L)
>5 years of age
(not HIV infected)
600 to <650
0.600 x 109 to
<0.650 x 109
500 to <600
0.500 x 109 to
<0.600 x 109
350 to <500
0.350 x 109 to <0.500x109
<350
<0.350x109
Absolute Neutrophil
Count (ANC), Low
(cells/mm3; cells/L)
>7 days of age
800 to 1,000
0.800 x 109 to 1.000 x 109
600 to 799
0.600 x 109 to 0.799 x 109
400 to 599
0.400 x 109 to 0.599 x 109
<400
<0.400 x 109
2 to 7 days of age
1,250 to 1,500
1.250 x 109 to 1.500 x 109
1,000 to 1,249
1.000 x 109 to 1.249 x 109
750 to 999
0.750 x 109 to 0.999 x 109
<750
<0.750 x 109
≤ 1 day of age
4,000 to 5,000
4.000 x 109to 5.000 x 109
3,000 to 3,999
3.000 x 109 to 3.999 x 109
1,500 to 2,999
1.500 x 109 to 2.999 x 109
<1,500
<1.500 x 109
 
 
 
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PARAMETER
GRADE 1
MILD
GRADE 2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY LIFE-
THREATENING
Fibrinogen, Decreased
(mg/dL; g/L)
100 to <200
1.00 to <2.00
OR
0.75 to <1.00 x LLN
75 to <100
0.75 to <1.00
OR
≥ 0.50 to <0.75 x LLN
50 to <75
0.50 to <0.75
OR
0.25 to <0.50 x LLN
<50
<0.50
OR
<0.25 x LLN
OR Associated with gross 
bleeding
Haemoglobin1, Low
(g/dL; mmol/L)2
≥ 13 years of age
(male only)
10.0 to 10.9
6.19 to 6.76
9.0 to <10.0
5.57 to <6.19
7.0 to <9.0
4.34 to <5.57
<7.0
<4.34
≥ 13 years of age
(female only)
9.5 to 10.4
5.88 to 6.48
8.5 to <9.5
5.25 to <5.88
6.5 to <8.5
4.03 to <5.25
<6.5
<4.03
57 days of age to <13 years of 
age
(male and female)
9.5 to 10.4
5.88 to 6.48
8.5 to <9.5
5.25 to <5.88
6.5 to <8.5
4.03 to <5.25
<6.5
<4.03
36 to 56 days of age
(male and female)
8.5 to 9.6
5.26 to 5.99
7.0 to <8.5
4.32 to <5.26
6.0 to <7.0
3.72 to <4.32
<6.0
<3.72
22 to 35 days of age
(male and female)
9.5 to 11.0
5.88 to 6.86
8.0 to <9.5
4.94 to <5.88
6.7 to <8.0
4.15 to <4.94
<6.7
<4.15
8 to ≤ 21 days of age
(male and female)
11.0 to 13.0
6.81 to 8.10
9.0 to <11.0
5.57 to <6.81
8.0 to <9.0
4.96 to <5.57
<8.0
<4.96
≤ 7 days of age
(male and female)
13.0 to 14.0
8.05 to 8.72
10.0 to <13.0
6.19 to <8.05
9.0 to <10.0
5.59 to <6.19
<9.0
<5.59
 
 
 
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PARAMETER
GRADE 1
MILD
GRADE 2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY LIFE-
THREATENING
INR, High
(not on anticoagulation
therapy)
1.1 to <1.5 x ULN
1.5 to <2.0 x ULN
2.0 to <3.0 x ULN
≥ 3.0 x ULN
Methaemoglobin
(% haemoglobin)
5.0 to <10.0%
10.0 to <15.0%
15.0 to <20.0%
≥ 20.0%
PTT, High
(not on anticoagulation
therapy)
1.1 to <1.66 x ULN
1.66 to <2.33 x ULN
2.33 to <3.00 x ULN
≥ 3.00 x ULN
Platelets, Decreased
(cells/mm3; cells/L)
100,000 to
<124,999
100.000 x 109 to
<124.999 x 109
50,000 to
<100,000
50.000 x 109 to
<100.000 x 109
25,000 to
<50,000
25.000 x 109 to
<50.000 x 109
<25,000
<25.000 x 109
PT, High
(not on anticoagulation
therapy
1.1 to <1.25 x ULN
1.25 to <1.50 x ULN
1.50 to <3.00 x ULN
≥ 3.00 x ULN
WBC, Decreased
(cells/mm3; cells/L)
>7 days of age
2,000 to 2,499
2.000 x 109 to 2.499 x 109
1,500 to 1,999
1.500 x 109 to 1.999 x 109
1,000 to 1,499
1.000 x 109 to 1.499 x 109
<1,000
<1.000 x 109
≤ 7 days of age
5,500 to 6,999
5.500 x 109 to 6.999 x 109
4,000 to 5,499
4.000 x 109 to 5.499 x 109
2,500 to 3,999
2.500 x 109 to 3.999 x 109
<2,500
<2.500 x 109
1.
Male and female sex is defined as sex at birth.
2.
The conversion factor used to convert g/dL to mmol/L is 0.6206 and is the most commonly used conversion factor. For grading haemoglobin results obtained by an analytic 
method with a conversion factor other than 0.6206, the result must be converted to g/dL using the appropriate conversion factor for the particular laboratory.
 
 
 
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Urinalysis:
PARAMETER
GRADE 1
MILD
GRADE 2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY LIFE-
THREATENING
Glycosuria (random collection
tested by dipstick)
Trace to 1+ or 250 mg
2+ or ˃250 to 500 mg
>2+ or >500 mg
Not applicable
Haematuria (not to be reported
based on dipstick findings or on
blood believed to be of
menstrual origin)
6 to <10 RBCs per high
power field
≥ 10 RBCs per high
power field
Gross, with or without clots 
OR With RBC casts OR
Intervention indicated
Life-threatening consequences
Proteinuria (random collection
tested by dipstick)
1+
2+
3+ or higher
Not applicable
 
 
 
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12.3.5.1.1.
Total Bilirubin Table for Term and Preterm Neonates:
PARAMETER
GRADE 1
MILD
GRADE 2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY LIFE-
THREATENING
Total Bilirubin1, High
(mg/dL; µmol/L)2
Term Neonate3
<24 hours of age
4 to <7
68.4 to <119.7
7 to <10
119.7 to <171
10 to <17
171 to <290.7
17
≥ 290.7
24 to <48 hours of age
5 to <8
85.5 to <136.8
8 to <12
136.8 to <205.2
12 to <19
205.2 to <324.9
19
324.9
48 to <72 hours of age
8.5 to <13
145.35 to <222.3
13 to <15
222.3 to <256.5
15 to <22
256.5 to <376.2
22
376.2
72 hours to <7 days of age
11 to <16
188.1 to <273.6
16 to <18
273.6 to <307.8
18 to <24
307.8 to <410.4
24
410.4
7 to 28 days of age
(breast feeding)
5 to <10
85.5 to <171
10 to <20
171 to <342
20 to <25
342 to <427.5
25
427.5
7 to 28 days of age
(not breast feeding)
1.1 to <1.6 x ULN
1.6 to <2.6 x ULN
2.6 to <5.0 x ULN
5.0 x ULN
Preterm Neonate20
35 to <37 weeks gestational age
Same as for Total Bilirubin,
High, Term Neonate (based
on days of age).
Same as for Total Bilirubin,
High, Term Neonate (based
on days of age).
Same as for Total
Bilirubin, High,
Term Neonate (based
on days of age).
Same as for Total Bilirubin,
High, Term Neonate (based
on days of age).
32 to <35 weeks gestational age 
and <7 days of age
Not applicable
Not applicable
10 to <14
171 to <239.4
14
239.4
 
 
 
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PARAMETER
GRADE 1
MILD
GRADE 2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY LIFE-
THREATENING
28 to <32 weeks gestational age 
and <7 days of age
Not applicable
Not applicable
6 to <10
102.6 to <171
10
171
<28 weeks gestational age and
<7 days of age
Not applicable
Not applicable
5 to <8
85.5 to <136.8
8
136.8
7 to 28 days of age (breast
feeding)
5 to <10
85.5 to <171
10 to <20
171 to <342
20 to <25
342 to <427.5
25
427.5
7 to 28 days of age (not breast
feeding)
1.1 to <1.6 x ULN
1.6 to <2.6 x ULN
2.6 to <5.0 x ULN
5.0 x ULN
1.
Severity grading for total bilirubin in neonates is complex because of rapidly changing total bilirubin normal ranges in the first week of life followed by the benign phenomenon of 
breast milk jaundice after the first week of life. Severity grading in this appendix corresponds approximately to cut-offs for indications for phototherapy at grade 3 and for exchange
transfusion at grade 4.
2.
A laboratory value of 1 mg/dL is equivalent to 17.1 mol/L.
3.
Definitions: Term is defined as 37 weeks gestational age; near-term, as 35 weeks gestational age; preterm, as <35weeks gestational age; and neonate, as 0 to 28 days of age.
 
 
 
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12.3.5.2.
Causality
Assessment of Causality

The investigator is obligated to assess the relationship between study treatment and 
the occurrence of each AE/SAE.

A "reasonable possibility" is meant to convey that there are facts/evidence 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 natural history of the underlying diseases, concomitant 
therapy, other risk factors, and the temporal relationship of the event to the study 
treatment will be considered and investigated.

The investigator will also consult the Investigator Brochure (IB) and/or Product 
Information, for marketed products, in the determination of 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 when 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 
prior to the initial transmission of the SAE data to GSK.

The investigator may change his/her opinion of causality in light of follow-up 
information, amending the SAE data collection tool accordingly.

The causality assessment is one of the criteria used when determining regulatory 
reporting requirements.
12.3.5.3.
Toxicity Management
ANEMIA
Grade 1 (mild) hemoglobin decrease:
Any hemoglobin decrease meeting the definition of Grade 1 must be repeated with the 
following additional tests:
1. peripheral blood smear
2. indirect bilirubin (abnormal if increased >50% from baseline)
3. haptoglobin
(abnormal if 25 mg/dL)
4. reticulocyte count (abnormal if 4%) 
If the additional tests are within the normal range, subjects may continue study treatment. 
If one or more of the additional tests is abnormal or suggestive of hemolytic anemia as 
 
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specified above, subjects will permanently discontinue study treatment and be withdrawn 
from the trial. Subjects should be followed up until resolution of anemia.
Grade 2 (moderate) hemoglobin decrease:
Any hemoglobin decrease meeting the definition of Grade 2 must be repeated with the 
following additional tests:
1. peripheral blood smear
2. indirect bilirubin
(abnormal if increased > 50% from baseline)
3. haptoglobin
(abnormal if 25 mg/dL)
4. reticulocyte count
(abnormal if 4%) 
If the additional tests are within the normal range, subjects may continue study treatment. 
If one or more of the additional tests is abnormal or suggestive of hemolytic anemia as 
specified above, subjects will permanently discontinue study treatment and be withdrawn 
from the trial. Consultation with a Hematologist should be considered. Subjects should be 
followed up until resolution of anemia.
Grade 3 (severe) or Grade 4 (potentially life threatening) hemoglobin decrease:
Any hemoglobin decrease meeting the definition of Grade 3 or 4 must be repeated with 
the following additional tests:
1. peripheral blood smear
2. indirect bilirubin
3.
haptoglobin
4.
reticulocyte count 
Subjects will permanently discontinue study treatment and be withdrawn from the trial. 
Consultation with a Hematologist should be considered. Subjects should be followed up 
until resolution of anemia.
TOTAL BILIRUBIN ELEVATION
Grade 1 (mild) bilirubin elevation (1.1 - 1.5 times ULN) or Grade 2 
(moderate) bilirubin elevation (1.6-2.5 times ULN):
Any bilirubin value above the ULN must be repeated and fractionated (direct and indirect 
bilirubin). Subjects may continue study treatment. Subjects should be followed up until 
resolution (return to baseline) of elevation.
Grade 3 (severe: 2.6-5.0 times ULN) or 4 (life-threatening: > 5.0 times ULN) 
bilirubin elevation:
Any bilirubin value above the ULN must be repeated and fractionated (direct and indirect 
bilirubin). Subjects will permanently discontinue study treatment and be withdrawn from 
 
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the trial. Subjects should be followed up until resolution (return to baseline) of bilirubin 
elevation.
AST AND ALT ELEVATION
See Appendix 2 (Section 12.2).
RASH
Grade 1 rash (Localized macular rash):
Subjects with Grade 1 rash should be evaluated by the Investigator immediately. A 
dermatologist may be consulted and a biopsy may be obtained if recommended by the 
dermatologist. The study treatment should be permanently discontinued if the following 
signs or symptoms are noted at any time:
1.
Temperature >38.5°C
2.
Lymphadenopathy
3.
Pharyngitis
4.
Any indication of internal organ involvement (hepatitis, nephritis)
In the absence of the above signs or symptoms, subjects with Grade 1 rash may continue 
the study treatment at the discretion of the Investigator. The subject should be advised to 
contact the Investigator immediately if there is any worsening of the rash, if any systemic 
signs or symptoms worsen, or if mucosal ulceration develops. If the rash is considered to 
be most likely due to concomitant illness or non-study treatment, standard management, 
including discontinuation of the likely causative agent, should be undertaken. If no other 
causative factor is found after clinical evaluation, the subject may be treated 
symptomatically until the rash resolves. Antihistamines, topical corticosteroids or 
antipruritic agents may be prescribed. The subject should remain on the study to be 
followed for safety and PK as outlined in Section 5.4.
Grade 2 rash (Diffuse macular, maculopapular, or morbilliform rash OR Target 
lesions):
Subjects with Grade 2 rash should be evaluated by the Investigator immediately. Digital 
photographs should be obtained. A dermatologist may be consulted and a biopsy may be 
obtained if recommended by the dermatologist. The study treatment should be 
permanently discontinued if the following signs or symptoms are noted at any time:
1.
Temperature >38.5°C
2.
Lymphadenopathy
3.
Pharyngitis
4.
Any indication of internal organ involvement (hepatitis, nephritis)
In the absence of the above signs or symptoms, subjects with Grade 2 rash may continue 
the study treatment at the discretion of the Investigator. It should be noted that oral 
mucosal erosions may be part of a Grade 2 rash. Any mucosal ulceration increases the 
severity of the rash to at least Grade 3. The subject should be advised to contact the 
 
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Investigator immediately if there is any worsening of the rash, if any systemic signs or 
symptoms worsen, or if mucosal ulceration develops. If the rash is considered to be most 
likely due to concomitant illness or non-study treatment, standard management, including 
discontinuation of the likely causative agent, should be undertaken. If no other causative 
factor is found after clinical evaluation, the subject may be treated symptomatically until 
the rash resolves. Antihistamines, topical corticosteroids or antipruritic agents may be 
prescribed. The subject should remain on the study to be followed for safety and PK as 
outlined in Section 5.4.
Grade 3 rash (Diffuse macular, maculopapular, or morbilliform rash with vesicles 
or limited number of bullae OR Superficial ulcerations of mucous membrane 
limited to one site):
Subjects with a Grade 3 rash will permanently discontinue the study treatment. The 
subject should be evaluated in the physician’s office immediately and should be seen in 
the physician’s office or contacted by phone every 2 days until the rash resolves. A 
dermatologist should be consulted and digital photographs and a biopsy should be 
obtained. Antihistamines, topical corticosteroids or antipruritic agents may be prescribed 
at the discretion of the Investigator. The subject should be advised to contact the 
Investigator immediately if there is any worsening of the rash, if any systemic signs or 
symptoms appear, or if mucosal involvement develops. The subject should remain on the 
study to be followed for safety and PK as outlined in Section 5.4.
Grade 4 rash (Extensive or generalized bullous lesions OR Stevens-Johnson 
syndrome OR Ulceration of mucous membrane involving two or more distinct 
mucosal sites OR Toxic epidermal necrolysis (TEN)):
Subjects with a Grade 4 rash will permanently discontinue the study treatment. A 
dermatologist should be consulted and digital photographs and a biopsy should be 
obtained. Sponsor and medical monitor should be notified of this SAE within 24 hours 
via phone or fax. The subject should be closely followed every day until resolution of the 
reaction. The subject should remain on the study to be followed for safety and PK as 
outlined in Section 5.4.
ALLERGIC REACTION
Grade 1 allergic reaction (Pruritus without rash):
Subjects with Grade 1 allergic reaction should be evaluated by the Investigator 
immediately. The study treatment should be permanently discontinued if the following 
signs or symptoms are noted at any time:
1.
Temperature >38.5°C
2.
Eosinophilia
3.
Respiratory involvement including bronchospasm, laryngospasm, or 
angioedema
4.
Any indication of internal organ involvement (hepatitis, nephritis)
 
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In the absence of the above signs or symptoms, subjects with Grade 1 allergic reaction 
may continue the study treatment at the discretion of the Investigator. The subject should 
be advised to contact the Investigator immediately if there is any worsening of the 
allergic reaction and/or if any systemic signs or symptoms worsen. If the allergic reaction 
is considered to be most likely due to concomitant illness or non-study treatment, 
standard management, including discontinuation of the likely causative agent, should be 
undertaken. If no other causative factor is found after clinical evaluation, the subject may 
be treated symptomatically until the rash resolves. Antihistamines, topical corticosteroids 
or antipruritic agents may be prescribed. The subject should remain on the study to be 
followed for safety and PK as outlined in Section 5.4.
Grade 2 allergic reaction (Localized urticaria):
Subjects with Grade 2 allergic reaction should be evaluated by the Investigator 
immediately. The study treatment should be permanently discontinued if the following 
signs or symptoms are noted at any time:
1.
Temperature > 38.5°C
2.
Eosinophilia
3.
Respiratory involvement including bronchospasm, laryngospasm, or 
angioedema
4.
Any indication of internal organ involvement (hepatitis, nephritis)
In the absence of the above signs or symptoms, subjects with Grade 2 allergic reaction 
may continue the study treatment at the discretion of the Investigator. The subject should 
be advised to contact the Investigator immediately if there is any worsening of the 
allergic reaction and/or if any systemic signs or symptoms worsen. If the allergic reaction 
is considered to be most likely due to concomitant illness or non-study treatment, 
standard management, including discontinuation of the likely causative agent, should be 
undertaken. If no other causative factor is found after clinical evaluation, the subject may 
be treated symptomatically until the rash resolves. Antihistamines, topical corticosteroids 
or antipruritic agents may be prescribed. The subject should remain on the study to be 
followed for safety and PK as outlined in Section 5.4.
Grade 3 allergic reaction (Generalized urticaria or angioedema):
Subjects will permanently discontinue the study treatment and be withdrawn from the 
trial. Subjects will be treated as clinically appropriate. Subjects should be followed up 
until resolution of the AE and standard management should be undertaken.
Grade 4 allergic reaction (Anaphylaxis):
Subjects will permanently discontinue the study treatment and be withdrawn from the 
trial. Subjects will be treated as clinically appropriate. Subjects should be followed up 
until resolution of the AE and standard management should be undertaken.
 
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Revised ACTG Toxicity Grade
Definitions
Investigator Action
Grade 1
Pruritus without rash
May continue therapy
Grade 2
Localized urticaria
May continue therapy
Grade 3
Generalized urticaria
Angioedema
Discontinue Therapy
Grade 4
Anaphylaxis
Discontinue Therapy
12.3.5.4.
Follow-up
Follow-up of AEs and SAEs

The investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as may be indicated or as requested by GSK to 
elucidate as fully as possible the nature and/or causality of the AE or SAE.

The investigator is obligated to assist. This may include additional laboratory tests or 
investigations, histopathological examinations or consultation with other health care 
professionals.

If a subject dies during participation in the study or during a recognized follow-up 
period, the investigator will provide GSK with a copy of any post-mortem findings, 
including histopathology.

New or updated information will be recorded in the originally completed CRF.

The investigator will submit any updated SAE data to GSK within the designated 
reporting time frames.
12.3.6.
Reporting of SAEs to GSK
SAE reporting to GSK via electronic data collection tool

Primary mechanism for reporting SAEs to PPD/GSK will be the electronic data 
collection tool

If the electronic system is unavailable for greater than 24 hours, the site will use the 
paper SAE data collection tool and fax it to the SAE coordinator

Site will enter the SAE data into the electronic system as soon as it becomes 
available.

The investigator will be required to confirm review of the SAE causality by ticking 
the ‘reviewed’ box at the bottom of the eCRF page within 72 hours of submission of 
the SAE.

After the study is completed at a given site, the electronic data collection tool (e.g., 
InForm system) will be taken off-line to prevent the entry of new data or changes to 
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SAE reporting to GSK via electronic data collection tool

If a site receives a report of a new SAE from a study subject or receives updated data 
on a previously reported SAE after the electronic data collection tool has been taken 
off-line, the site can report this information on a paper SAE form or to PPD Safety 
Hotline by telephone.

Contacts for SAE receipt can be found at the beginning of this protocol on the 
Sponsor/Medical Monitor Contact Information page.
 
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12.4.
Appendix 4: Modified List of Highly Effective Methods for 
Avoiding Pregnancy in Females of Reproductive Potential 
and Collection of Pregnancy Information
12.4.1.
Modified List of Highly Effective Methods for Avoiding Pregnancy 
in Females of Reproductive Potential
Contraceptive requirements for male subjects with female partners of reproductive 
potential (when applicable) and for female subjects of reproductive potential (FRP).
Male subjects with female partners of child bearing potential and female subjects of child 
bearing potential must comply with the following contraception requirements from either 
the time of first dose of study treatment (male) or from at least 28 days prior to the first 
dose of study treatment (FRP) until Follow-up visit Day 169.
This list does not apply to FRP with same sex partners or for subjects who are and will 
continue to be abstinent from penile-vaginal intercourse on a long term and persistent 
basis, when this is their preferred and usual lifestyle. Periodic abstinence (e.g. calendar, 
ovulation, symptothermal, post-ovulation methods) and withdrawal are not acceptable 
methods of contraception.
1.
Male vasectomy with documentation of azoospermia. The documentation on male 
sterility can come from the site personnel’s review of the male subject’s (or female 
subject’s male partner prior to the female subject’s entry into the study) medical 
records, medical examination and/or semen analysis, or medical history interview. 
This documentation may be provided by male subjects, by female subjects on behalf 
of their partner, or by her partner.
2.
Male condom plus partner use of one of the contraceptive options below that meets 
the SOP effectiveness criteria including a <1% rate of failure per year, as stated in 
the product label:

Contraceptive subdermal implant

Intrauterine device or intrauterine system

Combined estrogen and progestogen oral contraceptive [Hatcher, 2011] 

Injectable progestogen [Hatcher, 2011]

Contraceptive vaginal ring [Hatcher, 2011]

Percutaneous contraceptive patches [Hatcher, 2011]
These allowed methods of contraception are only effective when used consistently, 
correctly and in accordance with the product label. The investigator is responsible for 
ensuring that subjects understand how to properly use these methods of contraception.
12.4.2.
Collection of Pregnancy Information
For female subjects that becomes pregnant during the study:
 
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
Investigator will collect pregnancy information on any female subject, who 
becomes pregnant while participating in this study

Information will be recorded on the appropriate form and submitted to GSK 
within 2 weeks of learning of a subject's pregnancy.

Subject will be followed to determine the outcome of the pregnancy. The 
investigator will collect follow-up information on mother and infant, which will 
be forwarded to GSK. Generally, follow-up will not be required for longer than 6 
to 8 weeks beyond the estimated delivery date. 

Any termination of pregnancy will be reported, regardless of fetal status (presence 
or absence of anomalies) or indication for procedure.

While pregnancy itself is not considered to be an AE or SAE, any pregnancy 
complication or elective termination of a pregnancy will be reported as an AE or 
SAE.

A spontaneous abortion is always considered to be an SAE and will be reported as 
such. 

Any SAE occurring as a result of a post-study pregnancy which is considered 
reasonably related to the study treatment by the investigator, will be reported to 
GSK as described in Appendix 3. While the investigator is not obligated to 
actively seek this information in former study participants, he or she may learn of 
an SAE through spontaneous reporting.
Any female subject who becomes pregnant while participating will discontinue 
study treatment or be withdrawn from the study.
For female partners of a male study subject: 

Investigator will attempt to collect pregnancy information on any female partner 
of a male study subject who becomes pregnant while participating in this study. 
This applies only to subjects who are randomized to receive study treatment. 

After obtaining the necessary signed informed consent from the female partner 
directly, the investigator will record pregnancy information on the appropriate 
form and submit it to GSK within 2 weeks of learning of the partner’s pregnancy

Partner will also be followed to determine the outcome of the pregnancy. 
Information on the status of the mother and child will be forwarded to GSK. 

Generally, follow-up will be no longer than 6 to 8 weeks following the estimated 
delivery date. Any termination of the pregnancy will be reported regardless of 
fetal status (presence or absence of anomalies) or indication for procedure.
 
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12.5.
Appendix 5: Country Specific Requirements
If Japan conducts the optional Japanese Part 2 sub-study, Japan-specific requirements 
will be specified in a country-specific amendment or supplement protocol. 
South Korea will exclude females of reproductive potential in Part 1 only as shown in the 
country-specific protocol amendment 4.
Otherwise, no country-specific requirements exist.
 
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12.6.
Appendix 6: Statistical Considerations for Part 2
12.6.1.
Introduction
This document describes the Bayesian model based design for Part 2 of Study 205670 of 
GSK3389404 in chronic hepatitis B (CHB) subjects. The purpose of this section is to 
provide an overview of the trial design and simulation results. Analyses will be 
performed using Proc Markov Chain Monte Carlo (MCMC) procedure of SAS 9.3.
The primary efficacy objective of Part 2 of this study is to select an efficacious dose level 
and dosing regimen of GSK3389404 as determined by the primary endpoint, response 
rate (RR), based on reduction of hepatitis B surface antigen (HBsAg) level from baseline. 
A subject will be considered a responder if there is at least a 1.5 times log 10 IU/mL 
reduction of HBsAg levels from baseline anytime during the study. A model based 
probability inference approach in Bayesian framework will be used for decision-making. 
In Part 2, approximately 39 subjects with CHB are planned for randomization to study 
treatment. There are approximately 11 subjects in each of the active treatment groups and 
approximately 6 subjects in placebo. Matching placebo injections will be prepared for 
each dose level and dosing regimen and will be administered in the similar way of the 
corresponding active treatment group. Approximately 2 subjects will be randomized in 
each placebo dose level and regimen.
12.6.2.
Statistical Modeling
The RR data will be analyzed using a dose-response model. The posterior mean for each 
active treatment group will be derived from the posterior distribution of the response 
rates using a 3-parameter logistic regression model using weakly-informative priors for 
model parameters. Estimates for this model’s parameters will be derived using the data 
generated within each treatment arm, i.e., this model will borrow degrees of freedom 
across active dose levels and regimens therefore providing higher power compared to 
pair-wise comparison given the small sample size of each treatment arm and low 
expected response rate for placebo. 
A Bayesian logistic regression model (BLRM) [Neuenschwander, 2008] is considered to 
find an efficacious dose in this study.
For dose d and regimen R, the number of subjects with a response (Ydr) in a treatment 
arm of size ndr is binomial. Therefore, Ydr| ndr ~ Binomial (dr, ndr), with RRs
logit (dr) = + log(d/d*)+ R, 
where d is the active dose; R is the regimen (R=1 for regimen 1 and R=0 for regimen 2); 
d* is a reference dose allowing for the interpretation of as the odds of a response at d*; 
is the change in the log-odds of a response by a unit increase in log-dose; is the 
change in the log-odds of a response due to change in regimen. Since this is the 
first-in-patient, a weakly informative priors of the model parameters (~ N(0, var=100), 
 
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~ N(0, var=25), ~ N(0, var=9)) are assumed. To justify the prior selection, a set of 
1000 observations were generated from each of the prior distribution. The estimate of 
each of the parameters centers close to 0.5, with range between (0, 1) and standard 
deviation approximately 0.5. Posterior distribution of RRs of active treatment arms will 
be generated using BLRM.
Since it is not expected to have any responder in the placebo arm, posterior distribution of 
RRs is generated separately from a Beta distribution, i.e., Beta(0.1,0.1). Placebo 
injections will be given in different dosing regimens (according to the corresponding 
active treatment group) for the purpose of maintaining the blind. However, all placebo 
subjects across dosing regimens will be combined in 1 group for this analysis, since no 
difference in RR is expected if placebo is administered in different dosing regimens.
The difference between the posterior RRs between active treatment arm and placebo will 
be calculated to determine the probability of success (PoS) as described in Section 12.6.3.
12.6.3.
Success Criteria
An active treatment group will be declared efficacious if the posterior probability that the 
difference in the RRs between that active group and the placebo is positive, is high (at 
least 90%), i.e., P (RRACT > RRPBO) 90%, where RRACT is the RR in the active group, 
RRPBO is the RR in the placebo group, and P is the posterior probability.
A large set of posterior mean of RRs for each treatment group will be generated by using 
MCMC samples from the posterior distribution using BLRM (for active) or beta 
distribution (placebo). Then the difference between posterior mean of each active 
treatment group and placebo (active – placebo) will be calculated for each of the MCMC 
sample. The number of times the difference greater than 0 over the parameter space (i.e. 
number of MCMC samples) provides the posterior probability of the difference in RRs 
between that active group and the placebo group is positive.
12.6.4.
Scenarios for Testing
The treatments selected for Part 2 are 60 mg GSK3389404 weekly, 120 mg bi-weekly 
GSK3389404, 120 mg GSK3389404 weekly or placebo. . The description of treatment 
groups along with the sample size is provided in Table 17 A range of scenarios, as 
described in Table 18, were created to test the model performance.
Table 17
Treatment Description
Treatment Description
Treatment
Sample Size
Total monthly dose of 240 mg divided weekly (i.e., 60 mg once a week)
240W
11
Total monthly dose of 240 mg divided bi-weekly (i.e., 120 mg bi-weekly)
240BW
11
Total monthly dose of 480 mg divided weekly (i.e., 120 mg once a week)
480W
11
Matching placebo for each active treatment 
PBO
6
A RR of 5% or below is considered for placebo or no treatment effect. A 30% or more 
absolute improvement in the RRs over placebo is considered an important treatment 
effect among subjects with CHB.
 
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Table 18
Scenarios for Simulation
Scenario 
Number
Response Rate (%)
(PBO, 240W, 240BW, 480W)
Description
1
(5, 5, 5, 5)
No treatment effect
2
(5, 30, 30, 30)
All of the active treatment groups are equally effective 
(medium effect size)
3
(5, 15, 15, 35)
Larger effect in higher dose group, bi-weekly dosing is 
equally effective as weekly
4
(5, 20, 15, 35)
Larger effect in higher dose group, weekly dosing has 
small effect
BW = bi-weekly; PBO = placebo; W = weekly
12.6.5.
Simulations
Simulations are performed to calculate the operating characteristics of this model and to 
understand the model performance under each of the scenarios described in Table 18. 
Response data for 3 treatment groups are generated from binomial distributions using the 
sample size from Table 17 and response rates from Table 18. A set of 1000 datasets were 
simulated for each scenario. For each of the scenarios, average posterior means along 
with 90% credible intervals (CI), and average PoS are calculated over the sample space 
of 1000 simulations. Sensitivity of sample size is also provided using different cutoff 
points for PoS (e.g. 85%, 90%, 95% and 98%).
The above operating characteristics are also calculated for pair-wise comparison 
(i.e., without any model, based on difference in posterior distributions of individual 
treatment arm against placebo, both with Beta (0.1, 0.1) as prior distribution). In most of 
the scenarios, the decision of selecting an active treatment group is in agreement by both 
the methods. However, BLRM provided better operating characteristics (larger power 
and tighter CI). The probability of selecting an inefficacious treatment group is lower in 
BLRM compared to pair-wise method. 
Simulation results for all scenarios are summarized in Table 19 to Table 22.
A cutoff point of 90% for PoS seems to provide reasonable probability for selecting an 
efficacious dose group given the sample size of this study.
 
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Table 19
Simulation Results From Scenario 1
Scenario 1
No Treatment Effect
(PBO, 240W, 240BW, 480W): (5, 5, 5, 5)
Treatment
Posterior 
RR (%)
90% CI
Average 
PoS1
Power2
Cutoff Points
85
%
90%
95%
98%
Pairwise
PBO
6.82
(0.71,20.71)
240W
6.05
(0.81,16.59)
53.17
30
.8
30.8
8.2
1.6
240BM
5.72
(0.67,16.09)
53.05
31
.4
31.4
6.2
0.8
480W
5.46
(0.63,15.53)
51.86
28
.7
28.7
6.6
0.6
BLRM
PBO
6.95
(0.71,21.34)
240W
4.88
(0.56,14.02)
57.83
21
.9
11.0
3.1
0.3
240BW
5.3
(0.55,15.34)
58.67
31
.4
13.8
3.9
0.3
480W
5.13
(0.52,15.04)
57.84
28
.7
13.7
4.7
0.2
 
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Table 20
Simulation Results From Scenario 2
Scenario 2
All of the active treatment groups are equally 
effective 
(medium effect size)
(PBO, 240W, 240BW, 480W): (5, 30, 30, 30)
Treatment
Posterior 
RR (%)
90% CI
Average 
PoS1
Power2
Cutoff Points
Pairwise
85%
90%
95%
98%
PBO
6.82
(0.71,20.7)
240W
30.93
(12.67,53.01)
88.77
75.8
75.7
66.0
49.1
240BM
30.09
(12.01,52.13)
88.26
75.9
75.8
65.7
49.1
480W
30
(11.85,52.15)
88.6
75.8
75.8
66.2
49.2
BLRM
PBO
6.95
(0.71,21.34)
240W
30.38
(12.62,51.95)
89.53
76.2
74.1
64.9
46.7
240BW
29.88
(12.05,51.71)
88.8
75.9
75.4
65.2
47.7
480W
29.77
(11.84,51.77)
89.02
75.8
75.0
65.9
48.9
BLRM = Bayesian logistic regression model; BW = bi-weekly; CI = credible interval; PBO = placebo; 
PoS = probability of success; RR = response rate; W = weekly
1.
PoS is defined as P(RRACT >RRPBO), a dose group will be considered efficacious if the PoS is at 
least 90%, treatment group with highest PoS will be selected
2.
Power is defined as proportion of simulation samples where PoS is greater than various cutoff 
points(85,90,95,98%) over the sample space (i.e., 1000 simulations)
 
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Table 21
Simulation Results From Scenario 3
Scenario 3
Larger effect in higher dose group, bi-weekly dosing is 
equally effective as weekly
(PBO, 240W, 240BW, 480W): (5, 15, 15, 35)
Treatment
Posterior 
RR (%)
90% CI
Average
PoS1
Power2
Cutoff Points
85%
90%
95%
98%
Pairwise
PBO
6.82
(0.71,20.7)
240W
16.23
(4.27,34.07)
74.83
61.0
61.0
36.9
17.7
240BM
15.58
(3.89,33.22)
74.26
60.3
60.2
37.7
15.5
480W
34.86
(15.25,57.59)
91.23
80.5
80.4
70.9
58.3
BLRM
PBO
6.95
(0.71,21.34)
240W
16.27
(4.42,34.06)
79
61.0
56.7
35.2
15.1
240BW
15.28
(3.81,32.93)
77.24
60.3
55.0
36.8
12.1
480W
33.72
(14.57,56.2)
90.88
80.5
77.6
69.2
54.0
BLRM = Bayesian logistic regression model; BW = bi-weekly; CI = credible interval; PBO = placebo; PoS = probability 
of success; RR = response rate; W = weekly
1.
PoS is defined as P(RRACT >RRPBO), a dose group will be considered efficacious if the PoS is at least 90%, 
treatment group with highest PoS will be selected
2.
Power is defined as proportion of simulation samples where PoS is greater than various cutoff 
points(85,90,95,98%) over the sample space (i.e., 1000 simulations)
 
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Table 22
Simulation Results From Scenario 4
Scenario 4
Larger effect in higher dose group, weekly dosing small effect
(PBO, 240W, 240BW, 480W): (5, 20, 15, 35)
Treatment
Posterior 
RR (%)
90% CI
Average
PoS1
Power2
Cutoff Points
85%
90%
95%
98%
Pairwise
PBO
6.82
(0.71,20.7)
240W
20.9
(6.61,40.53)
80.33
65.9
65.9
48.5
27.8
240BM
15.58
(3.89,33.2)
74.25
60.3
60.2
37.7
15.5
480W
34.86
(15.24,57.6)
91.24
80.5
80.3
71.0
58.2
BLRM
PBO
6.95
(0.71,21.34)
240W
20.41
(6.57,39.67)
82.65
65.8
63.1
47.0
22.4
240BW
15.61
(3.95,33.45)
77.78
60.3
56.7
37.0
12.7
480W
34
(14.77,56.48)
91.03
80.5
77.8
69.2
55.0
BLRM = Bayesian logistic regression model; BW = bi-weekly; CI = credible interval; PBO = placebo; PoS = probability 
of success; RR = response rate; W = weekly
1.
PoS is defined as P(RRACT >RRPBO), a dose group will be considered efficacious if the PoS is at least 90%, 
treatment group with highest PoS will be selected
2.
Power is defined as proportion of simulation samples where PoS is greater than various cutoff points 
(85,90,95,98%) over the sample space (i.e., 1000 simulations)
 
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12.7.
Appendix 7: Protocol Changes
12.7.1.
Protocol changes for Amendment 01 (21-FEB-2017) from Original 
Protocol (21-Jun-2016)
Protocol Amendment 1 replaces the original protocol dated 21 Jun 2016 and applies to all 
study sites. 
Protocol Amendment 1 is being implemented for the following reasons:

To update the subject population in Part 2 from treatment naïve to treatment 
experienced. 
o
Rationale: Investigator feedback is that the major focus should be on 
patients currently taking nucleos(t)ide, unless there is a scientific reason 
why GSK3389404 cannot be given with nucleos(t)ides. There is low 
potential for a drug-drug interaction with the nucleos(t)ides. Changing the 
population also eliminates the concern, albeit minor, that treatment-naïve 
subjects would remain untreated during the study.

To increase the maximum total monthly dose in Part 2 from 240 mg to 480 mg. 
o
Rationale: This change provides the flexibility to explore a wider range of 
possible total monthly doses in Part 2. A maximum total monthly dose of 
480 mg is supported by the preclinical package. The increase is also 
supported by the initial safety/tolerability and PK data from the 
first-in-human Study 202007, in which healthy volunteers were 
administered up to 480 mg for 4 weeks. Review of the initial safety and 
tolerability data shows a favorable benefit-risk profile.

To reduce complexity and visit burden for subjects.
o
Rationale: Feedback from investigators suggests that the visit schedule in 
Part 1, particularly the overnight stay(s) will be too burdensome for 
subjects. The original protocol allowed for sites to admit subjects on 
Day -1 to complete Day 1 assessments, and also required subjects to stay 
overnight between Day 1 and Day 2 of the study. The amendment makes 
overnight stays optional, and eliminates the Day 2 assessments. Day 3 
assessments will remain. Based on the results of the first-in-human 
Study 202007, removal of the Day 2 assessments should not impact 
subject safety.

To make minor edits for clarity and typographical errors (these minor edits are not 
included in the list of changes). 
LIST OF CHANGES
Title Page, Author (s)
 
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Rationale for change: new clinical team member added.
Original Text
 
Amended Text
 
 
Section 1, Rationale, Paragraph 1, Last Sentence
Rationale for change: to update the subject population in Part 2 from treatment naïve to 
treatment experienced.
Original Text: 
Data from this study will support subsequent studies by providing an early assessment of 
safety and PD in the target patient population when GSK3389404 is administered as 
monotherapy. 
Amended Text: 
Data from this study will support subsequent studies by providing an early assessment of 
safety and PD in the target patient population when GSK3389404 is administered as 
monotherapy (Part 1) or adjunctive therapy (Part 2).
Section 1, Objective(s)/Endpoints(s), Exploratory, (New objective added) 
Rationale for change: addition of new exploratory endpoint to assess GSK3389404 
treatment outcomes in case seroconversion is seen in subjects with chronic hepatitis B.
Original Text:
Not applicable.
Amended Text:
To describe the seroconversion of subjects, 
defined as presence of HBV surface antibody 
(HBsAb) (Part 2 only)
Rate of seroconversion. 
 
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Section 1, Overall Design, Paragraph 4, Sentence 3
Rationale for change: to increase the maximum total monthly dose in Part 2 from 240 mg
to 480 mg
Original Text:
The dose levels and regimens for Part 2 will be selected after review of safety (at a 
minimum of adverse events [AEs], laboratory chemistry, hematology, and 
electrocardiogram [ECG]), PK, and PD (HBsAg levels and HBV DNA) data from Part 1 
(through Day 3) but will not exceed a total monthly SC dose of 240 mg.
Amended Text:
The dose levels and regimens for Part 2 will be selected after review of safety (at a 
minimum of adverse events [AEs], laboratory chemistry, hematology, and 
electrocardiogram [ECG]), PK, and PD (HBsAg levels and HBV DNA) data from Part 1 
(through Day 3) but will not exceed a total monthly SC dose of 240480 mg.
Section 1, Overall Design, Paragraph 4, (New sentence 5)
Rationale for change: to increase the maximum total monthly dose in Part 2 from 240 mg
to 480 mg
Original Text: 
Not applicable.
Amended Text:
However, the total monthly SC dose of 480 mg will only be explored in a once 
weekly or bi-weekly (every 2 weeks) dosing regimen.
Section 1, Treatment Arms and Duration, Paragraph 1, Bullet 2 (and sub-bullets) and 
Bullet 3
Rationale for change: to reduce complexity and visit burden for subjects.
Original Text:

A 2 to 4-day in-house period is planned. 
o
At most, 4-day, 3-night in-house period is planned (Day -1 to Day 3). At a 
minimum, a 2-day, 1 night in-house period is required (Day 1 to Day 2).

Day -1 admission is optional based on laboratory capabilities and study 
site/subject preference. 
 
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
An in-house stay is required from Day 1 to Day 2. 

Day 3 is an outpatient visit, but subjects may stay in-house until Day 3 
assessments are completed.
o
Dosing will take place on Day 1. The SC dose will be administered per cohort 
assignment (Cohorts A, B, C, C1, or D) and randomized treatment assignment 
(GSK3389404 or placebo).
Amended Text: 

A 2 to 4-day in-house period is planned. Dosing will take place on Day 1 with 
follow-up on Day 3.

At most, 4-day, 3-night in-house period is planned (Day -1 to Day 3). At a 
minimum, a 2-day, 1 night in-house period is required (Day 1 to Day 2).
Based on subject and study site preference, subjects have the option to be 
domiciled at the study site or present to the study site as outpatients.

Day -1 aAdmission to the study site is optional based on laboratory 
capabilities and study site/subject preference from Day -1 to Day 2. 

An in-house stay is required from Day 1 to Day 2 Subjects admitted 
to the study site may be discharged Day 1, Day 2, or Day 3, based 
on subject and study site preference. 

Day 3 is an outpatient visit, but subjects may stay in-house until Day 3 
assessments are completed Subjects may present as outpatients on 
Day 1 and/or Day 3, based on subject or study site preference.
o
Dosing will take place oOn Day 1,. Tthe SC dose will be administered per 
cohort assignment (Cohorts A, B, C, C1, or D) and randomized treatment 
assignment (GSK3389404 or placebo).
Section 1, Treatment Arms and Duration, Paragraph 2, Bullet 2 and new sub-bullet
Rationale for change: to increase the maximum total monthly dose in Part 2 from 240 mg
to 480 mg
Original Text:

An expected study treatment exposure of up to 85 days is planned where subjects 
will receive multiple SC doses of GSK3389404 (240 mg total monthly dose) or 
placebo at once weekly, bi-weekly (every 2 weeks), or monthly dosing regimens. 
Amended Text: 

An expected study treatment exposure of up to 85 days is planned where subjects 
will receive multiple SC doses of GSK3389404 (240480 mg total monthly dose) 
or placebo at once weekly, bi-weekly (every 2 weeks), or monthly dosing 
regimens. 
 
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o
The total monthly SC dose of 480 mg will only be explored in a once 
weekly or bi weekly (every 2 weeks) dosing regimen. 
Section 1, Treatment Arms and Duration, Paragraph 2, Bullet 2, last sub-bullet, sub-sub 
bullets 1, 2, and 3
Rationale for change: To make minor edits for clarity
Original Text:

For once weekly dosing, subjects will be administered as a SC dose on 
Days 1, 8, 15, 22, 29, 36, 43, 50, 57, 64, 71, and 78. 

For bi-weekly (every 2 weeks) dosing, subjects will be administered as a 
SC dose on Days 1, 15, 29, 43, 57, and 71. 

For monthly dosing, subjects will be administered as a SC dose on Days 1, 
29, and 57. 
Amended Text: 

For once weekly dosing, subjects will be administered GSK3389404 or 
placebo as a SC dose on Days 1, 8, 15, 22, 29, 36, 43, 50, 57, 64, 71, and 
78. 

For bi-weekly (every 2 weeks) dosing, subjects will be administered 
GSK3389404 or placebo as a SC dose on Days 1, 15, 29, 43, 57, and 71. 

For monthly dosing, subjects will be administered GSK3389404 or 
placebo as a SC dose on Days 1, 29, and 57. 
Section 1, Type and Number of Subjects, Paragraph 1, Sentence 1
Rationale for change: To update the subject population in Part 2 from treatment naïve to 
treatment experienced
Original Text: 
Adult male and female subjects with CHB between18 and 70 years of age, inclusive, and 
not currently receiving CHB treatment are planned for inclusion.
Amended Text:
Adult male and female subjects with CHB between 18 and 70 years of age, inclusive, and 
not currently receiving CHB treatment (Part 1) or currently on a stable nucleos(t)ide 
regimen (Part 2) are planned for inclusion.
 
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Section 2.1, Study Rationale, Paragraph 1, Last Sentence
Rationale for change: To update the subject population in Part 2 from treatment naïve to 
treatment experienced
Original Text: 
Data from this study will thus support subsequent studies by providing an early 
assessment of safety and PD in the target patient population when GSK3389404 is 
administered as monotherapy. 
Amended Text: 
Data from this study will thus support subsequent studies by providing an early 
assessment of safety and PD in the target patient population when GSK3389404 is 
administered as monotherapy (Part 1) or adjunctive therapy (Part 2).
Section 3, Objectives and Endpoints, Exploratory, (New objective added) 
Rationale for change: addition of new exploratory endpoint to assess GSK3389404 
treatment outcomes in case seroconversion is seen in subjects with chronic hepatitis B 
Original Text:
Not applicable.
Amended Text:
To describe the seroconversion of subjects, 
defined as presence of HBV surface antibody 
(HBsAb) (Part 2 only)
Rate of seroconversion. 
Section 4.1, Overall Study Design, Paragraph 4, Sentence 4
Rationale for change: to increase the maximum total monthly dose in Part 2 from 240 mg
to 480 mg
Original Text: 
The dose levels and regimens for Part 2 will be selected after a review of Part 1 safety, (at 
a minimum of adverse events [AEs], laboratory chemistry and hematology and 
electrocardiogram [ECG]), PK, and PD data (HBsAg and HBV DNA) (through Day 3) 
but will not exceed a total monthly dose of 240 mg.
 
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Amended Text:
The dose levels and regimens for Part 2 will be selected after a review of Part 1 safety, (at 
a minimum of adverse events [AEs], laboratory chemistry and hematology and 
electrocardiogram [ECG]), PK, and PD data (HBsAg and HBV DNA) (through Day 3) 
but will not exceed a total monthly dose of 240480 mg.
Section 4.1, Overall Study Design, Paragraph 4, (New sentence 6)
Rationale for change: to increase the maximum total monthly dose in Part 2 from 240 mg
to 480 mg
Original Text: 
Not applicable.
Amended Text:
However, the total monthly SC dose of 480 mg will only be explored in a once 
weekly or bi-weekly (every 2 weeks) dosing regimen.
Section 4.1, Overall Study Design, Figure 2, Footnote 4
Rationale for change: to increase the maximum total monthly dose in Part 2 from 240 mg
to 480 mg
Original Text: 
1.
Total monthly dose may be divided into weekly, bi-weekly (every two weeks), and/or monthly dosing, and total 
monthly dose will not exceed 240 mg.
Amended Text: 
4.
Total monthly dose may be divided into weekly, bi-weekly (every two 2 weeks), and/or monthly dosing, and total 
monthly dose will not exceed 240480 mg. However, the total monthly SC dose of 480 mg will only be 
explored in a weekly or bi-weekly dosing regimen.
Section 4.2, Treatment Arms and Duration, Paragraph 2, Bullet 1 and Sub-bullets, 
Bullet 2 and Sub-bullets, Bullet 3, Bullet 4 and Sub-bullets, and Paragraph 3
Rationale for change: to reduce complexity and visit burden for subjects.
 
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Original Text: 
For the treatment period, a 2 to 4-day in-house stay is planned. 

Day -1 admission is optional, based on laboratory capabilities and study 
site/subject preference. 
o
The study site/subject may use Day -1 as an outpatient visit for assessments 
and blood sample collection. 
o
If the subject is willing to arrive early and the site is capable (early admission 
available and critical laboratory result turn-around is available prior to 
randomization), subjects may be admitted on Day 1 with all Day -1 
assessments conducted pre-dose.

An in-house stay is required from Day 1 to Day 2.

Subjects will receive a SC dose of GSK3389404 or placebo on Day 1. 
Subjects will remain in the study site until completion of the 
protocol-specified procedures on Day 2.

Day 3 is an outpatient visit, but subjects may stay in-house until Day 3 
assessments are completed.

All in-house period options are listed below
o
4 day, 3 night stay: Day -1 admission, Day 3 discharge
o
3 day, 2 night stay: Day -1 admission, Day 2 discharge
o
3 day, 2 night stay: Day 1 admission, Day 3 discharge
o
2 day, 1 night stay: Day 1 admission, Day 2 discharge
Amended Text:
For the treatment period, a 2 to 4-day in-house stay is planned Subjects will receive a 
SC dose of GSK3389404 or placebo on Day 1, and with post-treatment follow-up on 
Day 3. 

Day -1 admission is optional, based on laboratory capabilities and study 
site/subject preference Based on subject and study site preference, subjects 
have the option to be domiciled at the study site or present to the study site as 
outpatients. 
o
The study site/subject may use Day -1 as an outpatient visit for assessments 
and blood sample collection Admission to the study site is optional from 
Day -1 to Day 2. 
o
If the subject is willing to arrive early and the site is capable (early admission 
available and critical laboratory result turn-around is available prior to 
randomization), subjects may be admitted on Day 1 with all Day -1 
assessments conducted pre-dose Subjects admitted to the study site may be 
discharged Day 1, Day 2, or Day 3, based on subject and study site 
preference.
 
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o
Subjects may present as outpatients on Day 1 and/or Day 3, based on 
subject or study site preference.

An in-house stay is required from Day 1 to Day 2.

Subjects will receive a SC dose of GSK3389404 or placebo on Day 1. 
Subjects will remain in the study site until completion of the 
protocol-specified procedures on Day 2.

Day 3 is an outpatient visit, but subjects may stay in-house until Day 3 
assessments are completed.

All in-house period options are listed below
o
4 day, 3 night stay: Day -1 admission, Day 3 discharge
o
3 day, 2 night stay: Day -1 admission, Day 2 discharge
o
3 day, 2 night stay: Day 1 admission, Day 3 discharge
o
2 day, 1 night stay: Day 1 admission, Day 2 discharge
Section 4.2, Treatment Arms and Duration, Figure 3
Rationale for change: to reduce complexity and visit burden for subjects.
Original Text:
Note: Five cohorts are planned to received a SC dose of GSK3389404 (30 mg to 240 mg) or placebo
*
Day -1 admission is optional based on laboratory capabilities and study site/subject preference. In-house stay is 
required from Day 1 to Day 2. Day 3 is an outpatient visit, but subjects may remain in-house until all Day 3 
assessments are completed.
 
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Amended Text:
Note: Five cohorts are planned to received a SC dose of GSK3389404 (30 mg to 240 mg) or placebo
*
Day -1 admission isIn-house stays are optional from Day -1 to Day 3 based on laboratory capabilities and study 
site/subject preference. In-house stay is required from Day 1 to Day 2. Day 3 is an outpatient visit, but No study 
procedures are scheduled for Day 2 but subjects may remain in-house until all Day 3 assessments are completed.
Section 4.2, Treatment Arms and Duration, Paragraph 4, Sentence 2 and new Sentence 3
Rationale for change: to increase the maximum total monthly dose in Part 2 from 240 mg
to 480 mg
Original Text:
Subjects will receive multiple SC doses of GSK3389404 (240 mg total monthly dose) or 
placebo (Figure 2) at once weekly, bi-weekly (every 2 weeks), or monthly dosing 
regimens.
Amended Text:
Subjects will receive multiple SC doses of GSK3389404 (240480 mg total monthly 
dose) or placebo (Figure 2) at once weekly, bi-weekly (every 2 weeks), or monthly 
dosing regimens. However, the total monthly SC dose of 480 mg will only be explored 
in a once weekly or bi-weekly dosing regimen.
 
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Section 4.3, Type and Number of Subjects, Paragraph 1, Sentence 1
Rationale for change: To update the subject population in Part 2 from treatment naïve to 
treatment experienced
Original Text: 
Adult male and female subjects with CHB between18 and 70 years of age, inclusive, and 
not currently receiving CHB treatment are planned for inclusion.
Amended Text
Adult male and female subjects with CHB between 18 and 70 years of age, inclusive, and 
not currently receiving CHB treatment (Part 1) or currently on a stable nucleos(t)ide 
regimen (Part 2) are planned for inclusion.
Section 4.5.1, Observed Human Pharmacokinetics
Rationale for change: To provide supporting data to increase the maximum total monthly 
dose in Part 2 from 240 mg to 480 mg.
Original Text: 
GSK3389404 has been administered as single doses to healthy adult subjects at doses of 
10 to 120 mg in Study 202007, a Phase I, first time in human, randomized, double-blind, 
placebo-controlled, dose escalation study to determine the safety, tolerability, and PK 
profile of GSK3389404. At the time of this protocol writing, the SAD part of 
Study 202007 has been completed, and the multiple ascending dose part is ongoing. The 
preliminary human PK parameters are presented in Table 1. Based on preliminary PK 
data, GSK3389404 showed dose-proportional PK with a meant t½ of 4 to 5 hours at a 
dose range of 10 to 120 mg. The preliminary observed human PK data were evaluated 
using non-compartmental analysis (NCA) in Phoenix WinNonlin version 6.3.
Table 1
Summary of Selected Preliminary Plasma GSK3389404 
Pharmacokinetic Parameters in Humans
Dose 
(mg)
N1
Cmax2
(ng/mL)
tmax3
(h)
t½2
(h)
AUC(0-)2 
(hng/mL)
10
6
90 (24)
1 (1 - 4)
3.8 (66)
614 (27)
30
5
295 (69)
2 (1 - 2)
3.7 (81)
1968 (35)
60
6
512 (57)
3 (1 - 4)
5.1 (71)
4578 (30)
120
6
803 (49)
4 (3 - 4)
4.1 (29)
7718 (35)
1.
At the 30-mg dose, the pharmacokinetic profile in 1 subject was atypical and not evaluable.
2.
Data are presented as geometric mean (geometric coefficient of variation %)
3.
Data are presented as Median (range)
 
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Amended Text:
GSK3389404 has been administered as single doses to healthy adult subjects in 
Study 202007 as single SC doses at doses of 10 to 120 mg. or as repeated SC doses 
(once weekly for 4 weeks) at doses of 30 to 120 mg. Study 202007 was in 
Study 202007, a Phase I, first time in human, randomized, double-blind, 
placebo-controlled, dose escalation study to determine the safety, tolerability, and PK 
profile of GSK3389404. At the time of this protocol writing, the SAD part of 
Study 202007 has been completed, and the multiple ascending dose part is ongoing. The 
preliminary human PK parameters are presented in Table 1. Based on preliminary PK 
data, GSK3389404 showed dose-proportional PK with a mean half-life of 
approximately 4 to 5 hours at a dose range of 10 to 120 mg. GSK3389404 plasma 
concentrations were similar after the first and fourth weekly dose, indicating no 
accumulation in plasma concentration after multiple doses. Half-life and plasma 
exposure (AUC and Cmax) of GSK3389404 following multiple doses were consistent 
with those observed following a single dose. meant t½ of 4 to 5 hours at a dose range of 
10 to 120 mg. The preliminary observed human PK data were evaluated using non-
compartmental analysis (NCA) in Phoenix WinNonlin version 6.3. All ISIS50538 
(GSK3228836) plasma concentrations were non-quantifiable.
Table 1
Summary of Selected Preliminary Plasma GSK3389404 
Pharmacokinetic Parameters in Humans
Dose 
(mg)
N1
Cmax2
(ng/mL)
tmax3
(h)
t½2
(h)
AUC(0-)2 
(hng/mL)
10
6
90 (24)
1 (1 - 4)
3.8 (66)
614 (27)
30
5
295 (69)
2 (1 - 2)
3.7 (81)
1968 (35)
60
6
512 (57)
3 (1 - 4)
5.1 (71)
4578 (30)
120
6
803 (49)
4 (3 - 4)
4.1 (29)
7718 (35)
1.
At the 30-mg dose, the pharmacokinetic profile in 1 subject was atypical and not evaluable.
2.
Data are presented as geometric mean (geometric coefficient of variation %)
3.
Data are presented as Median (range)
Dose
(mg)
10
30
60
120
Cohort1
A
B
E
E
C
F
F
D
G
G
Day
1
1
1
22
1
1
22
1
1
22
N
6
52
6
6
6
6
6
6
6
6
Half life3
(hr)
3.8
(66)
3.7
(81)
3.0
(34)
4.1
(61)
5.1
(71)
5.0
(206)
3.1
(51)
4.1
(29)
3.7
(43)
3.4
(38)
Tmax4
(hr)
1
(1-4)
2
(1-2)
2
(1-4)
2
(1-4)
3
(1-4)
2
(2-2)
2
(1.5-4)
4
(3-4)
2
(1.5-4)
2
(2-4)
Cmax3
(ng/mL)
90
(24)
295
(69)
228
(32)
194
(20)
512
(57)
692
(35)
577
(43)
803
(49)
1167
(50)
1107
(55)
AUC(0-)3
(ng*hr/mL)
614
(27)
1969
(35)
1394
(24)
1526
(34)
4578
(30)
5875
(52)
3966
(23)
7718
(35)
8039
(36)
8640
(32)
Fold coverage
Cmax5
642
197
255
298
113
84
100
72
50
52
Fold coverage
759
237
334
305
102
79
117
60
58
54
 
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AUC5
1.
Cohort A – D were single dose cohorts. Cohort E – G were multiple dose cohorts (weekly dose for 
4 weeks).
2.
In Cohort B (30-mg single) dose, the pharmacokinetic profile in one subject was atypical and not 
evaluable.
3.
Data are presented as geometric mean (geometric coefficient of variation %).
4.
Data are presented as Median (range).
5.
Fold coverage based on monkey NOAEL (no observed adverse effect level): NOAEL 
Cmax = 57.9 g/mL and NOAEL AUC(0-) = 465.7 gh/mL at 30 mg/kg/week.
Section 4.5.2, Safety Margin Calculations, Paragraph 2
Rationale for change: To provide supporting data to increase the maximum total monthly 
dose in Part 2 from 240 mg to 480 mg.
Original Text:
Based on observed PK data in healthy adult subjects (Study 202007), Cmax and AUC of 
GSK3389404 at the highest dose tested (120 mg) is 72-fold and 60-fold lower than the 
monkey NOAEL Cmax and AUC, respectively (Table 1).
Amended Text:
Based on observed PK data in healthy adult subjects (Study 202007), Cmax and AUC of 
GSK3389404 at the highest dose tested (120 mg) is 72-fold and 60-fold at least 50-fold
lower than the monkey NOAEL Cmax and AUC, respectively (Table 1).
Section 4.5.2, Safety Margin Calculations, Table 2, Header Row
Rationale for change: To provide supporting data to increase the maximum total monthly 
dose in Part 2 from 240 mg to 480 mg.
Original Text:
Human 
Dose 
(mg)
Observed 
GSK3389404 
Cmax 
(ng/mL)1
Observed 
GSK3389404 
AUC 
(hng/mL)1
Predicted 
Parent Liver 
Concentration 
(g/g)2
Fold 
Coverage 
Cmax3
Fold 
Coverage
AUC3
Fold coverage of 
estimated human 
liver concentration 
from Phase I 
Parent Study4
Amended Text:
Human 
Dose 
(mg)
Observed 
GSK3389404 
Plasma Cmax 
(ng/mL)1
Observed 
GSK3389404 
Plasma AUC 
(hng/mL)1
Predicted 
Parent Liver 
Concentration 
(g/g)2
Fold 
Coverage 
Plasma 
Cmax3
Fold 
Coverage
Plasma 
AUC3
Fold Coverage Of 
Estimated Human 
Liver 
Concentration 
from Phase I 
Parent Study4
 
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Section 4.5.2, Safety Margin Calculations, Table 2, Last Row
Rationale for change: To provide supporting data to increase the maximum total monthly 
dose in Part 2 from 240 mg to 480 mg.
Original Text:
240
17285
159925
59.0
345
295
8
Amended Text:
240
17285
159925
59.0
345
295
8
Section 4.5.2, Safety Margin Calculations, Table 2, Footnote 3
Rationale for change: To provide supporting data to increase the maximum total monthly 
dose in Part 2 from 240 mg to 480 mg. Minor edits for clarity.
Original Text:
Fold coverage based on monkey NOAEL; GSK3389404 Cmax = 57.9 g/mL and 
AUC(0-) = 465.7 g•h/mL at 30 mg/kg/week.
Amended Text:
Fold coverage based on monkey NOAEL; GSK3389404 plasma Cmax = 57.9 g/mL and 
plasma AUC(0-) = 465.7 g•h/mL at 30 mg/kg/week.
Section 4.5.2, Safety Margin Calculations, Table 2, Footnote 5
Rationale for change: To provide supporting data to increase the maximum total monthly 
dose in Part 2 from 240 mg to 480 mg.
Original Text:
Predicted using linear regression (zero intercept) based on observed human PK data from 
previous dose cohorts (10 to 120 mg) assuming dose proportionality.
Amended Text:
Predicted using linear regression (zero intercept) based on observed human PK data from 
previous dose cohorts (10 to 120 mg) assuming given dose proportionality.
 
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Section 4.5.3, In vivo Exposure-Response Relationship of GalNAc Conjugated and 
Unconjugated Compounds, Paragraph 1
Rationale for change: To increase the maximum total monthly dose in Part 2 from 
240 mg to 480 mg.
Original Text:
The maximum planned dose in the multiple dose cohorts (total monthly dose not 
exceeding 240 mg GSK3389404) was selected based on the in vivo exposure-response 
relationship of GSK3389404. 
Amended Text:
The maximum planned dose in the multiple dose cohorts (total monthly dose not 
exceeding 240480 mg GSK3389404) was selected based on the in vivo exposure-
response relationship of GSK3389404. 
Section 4.5.3, In vivo Exposure-Response Relationship of GalNAc Conjugated and 
Unconjugated Compounds, Paragraph 5
Rationale for change: To provide supporting data to increase the maximum total monthly 
dose in Part 2 from 240 mg to 480 mg.
Original Text:
Thus, in order to knockdown the target gene 90% or 99%, these data suggest that 
Study 205670 should explore SC doses of GSK3389404 predicted to yield human liver 
tissue concentrations of ISIS 505358 between EC90 (5.9 g/g) and EC99 (33 g/g). Based 
on observed liver tissue concentration in the monkey, it is estimated that a 60 mg weekly 
SC injection of GSK3389404 over 4 weeks would reach a human liver tissue 
concentration of 40.4 g/g (>EC99), assuming the liver tissue concentration between 
monkey and human is similar on a mg/kg basis (Table 3).
Amended Text: 
Thus, in order to knockdown the target gene 90% or 99%, these data suggest that 
Study 205670 should explore SC doses of GSK3389404 predicted to yield human liver 
tissue concentrations of ISIS 505358 that will achieve between EC90 (5.9 g/g) and EC99
(33 g/g). Based on observed liver tissue concentration in the monkey, it is estimated that 
a 60 30 mg weekly SC injection of GSK3389404 over 4 weeks would reach a human 
liver tissue concentration of 4140.4 g/g (>EC99) after 13 weeks, assuming the liver 
tissue concentration between monkey and human is similar on a mg/kg basis (Table 3). 
However, greater clinical efficacy may be achieved if HBsAg is reduced by >99%. 
Thus, a total monthly dose not exceeding 480 mg GSK3389404 (weekly doses of 
120 mg or bi-weekly doses of 240 mg) may be selected for Part 2.
 
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Section 4.5.3, In vivo Exposure-Response Relationship of GalNAc Conjugated and 
Unconjugated Compounds, Table 3
Rationale for change: To provide supporting data to increase the maximum total monthly 
dose in Part 2 from 240 mg to 480 mg.
Original Text:
Table 3
GSK3389404 Plasma Cmax and AUC and Monkey NOAEL Exposure 
Fold Coverage Following Repeat Weekly SC Administration of 
GSK3389404 for 4 Weeks in Humans
Huma
n 
Dose 
(mg)
Predicted 
GSK338940
4 
Cmax
(ng/mL)1
Predicted 
GSK338940
4 
AUC 
(hng/mL)1
Predicted 
Parent Liver 
Concentratio
n 
(g/g)2
Fold 
Coverag
e Cmax3
Fold 
Coverag
e AUC3
Fold 
coverage of 
estimated 
human liver 
concentratio
n from Phase 
I 
Parent 
Study4
30
295
1968
20.5
197
237
22.0
60
512
4578
40.4
113
102
11.1
120
803
7718
78.4
72
60
5.7
240
1728
15922
147.6
34
29
3.0
NOAEL = no observed adverse effect level
1.
Predicted based on observed GSK3389404 human PK data at 10 to 120 mg in Study 202007.
2.
Liver concentration in transgenic mice at 4 weeks after repeated once weekly doses was about 50% of that at 13 
weeks (steady state) after repeated once weekly doses. Human steady state liver concentration of parent 
compound (ISIS 505358) was estimated based on 13-week monkey liver tissue concentration and assumed to be 
50% of that at steady state. Liver concentration was fit to Emax model and then extrapolated.
3.
Fold coverage based on monkey NOAEL; GSK3389404 Cmax = 57.9 g/mL and AUC(0-)= 465.75 gh/mL at 
30 mg/kg/week. 
4.
At 450 mg of ISIS 505358 (the highest dose in the ISIS 50538 first time in human study), human liver 
concentration (4 weeks) = 450 g/g, based on allometric scaling [Geary, 2009]. Fold coverage = 450 g/g divided 
by the predicted liver concentration.
Amended Text: 
Table 3
GSK3389404 Plasma Cmax and AUC and Monkey NOAEL Exposure Fold 
Coverage Following Repeat Weekly or Bi-weekly (every 2 weeks) SC 
Administration of GSK3389404 for 13 Weeks in Humans
Human 
Dose 
(mg)
Predicted 
GSK33894
04 
Cmax 
(ng/mL)1
Predicted 
GSK338940
4 
AUC 
(hng/mL)1
Predicted 
Parent Liver 
Concentratio
n 
(g/g)2
Fold 
Coverag
e Cmax3
Fold 
Coverag
e AUC3
Fold 
coverage of 
estimated 
human liver 
concentratio
n from Phase 
I 
 
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Parent Study4
30
295
1968
20.5
197
237
22.0
60
512
4578
40.4
113
102
11.1
120
803
7718
78.4
72
60
5.7
240
1728
15922
147.6
34
29
3.0
NOAEL = no observed adverse effect level
1.
Predicted based on observed GSK3389404 human PK data at 10 to 120 mg in Study 202007.
2.
Liver concentration in transgenic mice at 4 weeks after repeated once weekly doses was about 50% of that at 13 
weeks (steady state) after repeated once weekly doses. Human steady state liver concentration of parent 
compound (ISIS 505358) was estimated based on 13-week monkey liver tissue concentration and assumed to be 
50% of that at steady state. Liver concentration was fit to Emax model and then extrapolated.
3.
Fold coverage based on monkey NOAEL; GSK3389404 Cmax = 57.9 g/mL and AUC(0-)= 465.75 gh/mL at 
30 mg/kg/week. 
4.
At 450 mg of ISIS 505358 (the highest dose in the ISIS 50538 first time in human study), human liver 
concentration (4 weeks) = 450 g/g, based on allometric scaling [Geary, 2009]. Fold coverage = 450 g/g divided 
by the predicted liver concentration.
Huma
n
Total
Month
ly
Dose
(mg)
Huma
n 
Repea
t
Dose 
(mg)1
Observed
GSK33894
04 
Plasma 
Cmax
(ng/mL)2
Observed 
GSK33894
04 
Plasma 
AUC 
(hng/mL)2
Predicted 
Parent Liver 
Concentrati
on
At Week 13 
(g/g)3
Observe
d 
Fold 
Coverag
e 
Plasma 
Cmax4
Observe
d 
Fold 
Coverag
e 
Plasma 
AUC4
Fold 
Coverage 
Of 
Predicted 
Human 
Liver 
Concentrat
ion 
at Week 
135
120
30 
QW
194
1526
41
298
305
34
240
60 
QW
577
3966
81
100
117
17
480
120 
QW
1107
8640
157
52
54
9
480
240 
Q2W
2200
16769
157
26
28
9
NOAEL = no observed adverse effect level
1.
QW: dose every week. Q2W: dose every 2 weeks.
2.
Geometric mean of GSK3389404 plasma human PK observed following repeat weekly SC dose of 30 to 
120 mg for 4 weeks in Study 202007. The values for 240 mg were predicted
3.
Human liver concentration of parent compound (ISIS 505358) at week 13 was estimated based on 13-week 
monkey liver tissue concentration (an average of 1404 g/g at 30 mg/kg/week for 13 weeks). Liver 
concentration was fit to Emax model and then extrapolated.
4.
Fold coverage based on monkey NOAEL (30 mg/kg/week for 13 weeks): GSK3389404 plasma Cmax= 57.9 
g/mL and plasma AUC(0-)= 465.75 gh/mL. Liver tissue concentration of parent compound 
(ISIS 505358) = 1404 g/g.
5.
Predicted using linear regression (zero intercept) based on observed human PK data from previous dose 
cohorts (30 to 120 mg) given dose proportionality
 
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Section 4.5.4, Dose Escalation Justification, Paragraph 1, Sentence 4
Rationale for change: To make minor edits for clarity.
Original Text: 
Escalation to the next higher single or to Part 2 will only proceed after the PK, safety, and 
tolerability of the previous single dose level(s) are thoroughly reviewed by the study team 
and the investigator at the Dose Escalation Committee meeting (Section 10.8.1) and 
determined to be safe, tolerable, and supportive of escalation.
Amended Text:
Escalation to the next higher single dose or to Part 2 will only proceed after the PK, 
safety, and tolerability of the previous single dose level(s) are thoroughly reviewed by the 
study team and the investigator at the Dose Escalation Committee meeting 
(Section 10.8.1) and determined to be safe, tolerable, and supportive of escalation.
New Section 4.5.5, GSK3389404 and Nucleos(t)ides
Rationale for change: To provide supporting data to update the subject population in Part 
2 from treatment naïve to treatment experienced
Original Text: 
Not applicable
Amended Text: 
GSK3389404 is unlikely to be a victim or perpetrator of drug-drug interactions 
when administered with nucleos(t)ides due to their divergent absorption, 
distribution, metabolism, and excretion pathways.
Victim drug-drug interactions:
GSK3389404 is taken up into the liver by target mediated endocytosis and into the 
kidney by micropinocytosis, both routes that are not inhibited by small molecule 
drugs such as tenofovir, entecavir, lamivudine, adefovir and telbivudine. 
Furthermore GSK3389404 is metabolized by endogenous endonucleases, which are 
not inhibited by these 5 drugs.
Perpetrator drug-drug interactions:
Tenofovir, entecavir, lamivudine, adefovir and telbivudine are predominantly 
renally eliminated from systemic circulation [Lamivudine, 2002; Kearney, 2004; 
Adefovir, 2012; Telbivudine, 2013; Entecavir, 2015]. 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 
 
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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]. 
In a recent study, a model compound of 2'-O-(2-methoxyethyl) modified antisense 
oligonucleotide was shown to be neither a substrate nor an inhibitor of OAT1, 
OAT3, OCT1 and OCT2 [Yu, 2016]. Therefore, GSK3389404 or the primary tissue 
metabolite ISIS 505358 that was shown to be extensively distributed into the kidney 
in non-clinical studies, is unlikely to interact with tenofovir, entecavir, lamivudine, 
adefovir and telbivudine.
Section 4.6 Benefit:Risk Assessment
Rationale for change: To make minor edits for clarity
Original Text
GlaxoSmithKline Document Number 2015N236049_02
Amended Text
GlaxoSmithKline Document Number 2015N236049_02
Section 4.6.2 Benefit Risk Summary, Paragraph 3, Number 2
Rationale for change: To make minor edits for clarity.
Original Text: 
2. During Part 1 (SAD), dosing is sequential and subjects are housed in a research unit 
and closely monitored for at least 24 hours. Following discharge from the study site 
on Day 2 or 3, subjects have extended follow-up out to 60 days post-dose to assess 
safety. A low starting dose, based on the fold coverage to mean NOAEL in the 
13-week monkey toxicity study, was selected for the initial dose in Part 1.
Amended Text:
2. During Part 1 (SAD), dosing is sequential and subjects are housed in a research unit 
and closely monitored for at least 248 hours post-dose. Following discharge from the 
study site on Day 2 or 3, sSubjects have extended follow-up out to 60 days post-dose 
to assess safety. A low starting dose, based on the fold coverage to mean NOAEL in 
the 13-week monkey toxicity study, was selected for the initial dose in Part 1.
 
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Section 5, Selection of Study Population and Withdrawal Criteria, Paragraph 1, 
Sentence 1
Rationale for change: To update the subject population in Part 2 from treatment naïve to 
treatment experienced
Original Text: 
This first-in-patient study will enroll adult male and female subjects in the immune active 
phase of HBV infection who are not currently receiving HBV treatment.
Amended Text:
This first-in-patient study will enroll adult male and female subjects in the immune active 
phase of HBV infection who are not currently receiving HBV treatment (Part 1) or who 
are currently on a stable nucleos(t)ide regimen (Part 2).
Section 5, Selection of Study Population and Withdrawal Criteria, Paragraph 1, New 
Sentence 3
Rationale for change: To update the subject population in Part 2 from treatment naïve to 
treatment experienced
Original Text: 
Not applicable
Amended Text: 
Subjects who are on a stable nucleos(t)ide regimen are characterized by ALT levels 
less than or equal to the upper limit of normal (ULN) and have suppressed HBV 
DNA, defined as HBV DNA less than or equal to the lower limit of quantification 
(LLOQ).
Section 5, Selection of Study Population and Withdrawal Criteria, Paragraph 2
Rationale for change: To make minor edits for clarity
Original Text 
GlaxoSmithKline Document Number 2015N236049_02
Amended Text
GlaxoSmithKline Document Number 2015N236049_02
 
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Section 5.1, Inclusion Criteria, Number 5
Rationale for change: To make minor edits for clarity- to allow lab to use either serum or 
plasma to analyze HBsAg.
Original Text:
5.
Documented chronic HBV infection, defined as positive serum HBsAg ≥6 months 
prior to screening.
Amended Text:
5.
Documented chronic HBV infection, defined as positive plasma or serum HBsAg 
≥6 months prior to screening.
Section 5.1, Inclusion Criteria, Number 6
Rationale for change: To update the subject population in Part 2 from treatment naïve to 
treatment experienced
Original Text:
6.
Treatment naive or have had prior treatment with interferon (pegylated or 
non-pegylated) that must have ended at least 12 months prior to the Baseline visit 
(Day 1 pre-dose) and/or nucleos(t)ide analogue therapy that must have ended at 
least 6 months prior to the Baseline visit.
Amended Text:
6.
Subject with HBV treatment history as follows:
a. Part 1: Treatment naive or have had prior treatment with interferon (pegylated or 
non-pegylated) that must have ended at least 12 months prior to the Baseline visit 
(Day 1 pre-dose) and/or nucleos(t)ide analogue therapy that must have ended at 
least 6 months prior to the Baseline visit.
b. Part 2: Subjects with CHB receiving stable nucleos(t)ide analogue therapy, 
defined 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. 
 
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Section 5.1, Inclusion Criteria, Number 7
Rationale for change: To make minor edits for clarity- to allow lab to use either serum or 
plasma to analyze HBV DNA.
Original Text:
7.
Plasma HBV DNA concentration:
a.
≥20,000 IU/mL for HBeAg-positive subject
b.
≥2000 IU/mL for HBeAg-negative subjects
Amended Text:
7.
Plasma or serum HBV DNA concentration:
a.
Part 1:
i.
≥20,000 IU/mL for HBeAg-positive subject
ii.
≥2000 IU/mL for HBeAg-negative subjects
b.
Part 2: HBV DNA must be adequately suppressed, defined as plasma 
or serum HBV DNA <LLOQ.
Section 5.1, Inclusion Criteria, Number 8
Rationale for change: To make minor edits for clarity- to allow lab to use either serum or 
plasma to analyze HBsAg.
Original Text:
8.
Serum HBsAg concentration >50 IU/mL.
Amended Text:
8.
Plasma or serum HBsAg concentration >50 IU/mL.
Section 5.1, Inclusion Criteria, Number 9
Rationale for change: To update the subject population in Part 2 from treatment naïve to 
treatment experienced. To make minor edits for clarity.
 
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Original Text:
9.
Alanine aminotransferase (ALT) concentration >60 U/L for males, >38 U/L for 
females, and ≤10 X the upper limit of normal (ULN).
Amended Text:
9.
Alanine aminotransferase (ALT) concentration:
a.
Part 1: ALT >60 U/L for males, >38 U/L for females, and ≤10 X the 
upper limit of normal (ULN).
b.
Part 2: ALT ULN
Section 5.2, Exclusion Criteria, Number 1b and addition of 1c
Rationale for change: To make minor edits for clarity on the type of hypertension that 
will be excluded- the exclusion criteria was designed to exclude patients with significant 
cardiac or renal disease, not controlled hypertension.
Original text:
1.
Medical history
a.
History of or active diagnosis of liver disease other than CHB, such as 
autoimmune hepatitis, non-alcoholic fatty liver disease/non-alcoholic 
steatohepatitis, hemochromatosis, or liver failure.
b. History or other clinical evidence of hypertension, significant or unstable 
cardiac disease (e.g., prolonged QT syndrome [torsade de pointes], angina, 
congestive heart failure, myocardial infarction, diastolic dysfunction, 
significant arrhythmia, coronary heart disease and/or clinically significant 
ECG abnormalities).
c.
History of, or active diagnosis of, primary or secondary renal disease (e.g., 
renal disease secondary to diabetes, hypertension, vascular disease, etc.).
d. History of extrahepatic disorders possibly related to HBV immune 
complexes (e.g., glomerulonephritis and polyarteritis nodosa).
e.
History of bleeding diathesis or coagulopathy.
f.
History of or suspected presence of vasculitis.
g. History of Gilbert’s Syndrome.
h. History of malignancy within the past 5 years with the exception of 
specific cancers that are cured by surgical resection (e.g., skin cancer), 
subjects under evaluation for possible malignancy are not eligible.
 
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Amended text:
1.
Medical history
a.
History of or active diagnosis of liver disease other than CHB, such as 
autoimmune hepatitis, non-alcoholic fatty liver disease/non-alcoholic 
steatohepatitis, hemochromatosis, or liver failure.
b. History or other clinical evidence of hypertension, significant or unstable 
cardiac disease (e.g., prolonged QT syndrome [torsade de pointes], angina, 
congestive heart failure, myocardial infarction, diastolic dysfunction, 
significant arrhythmia, coronary heart disease and/or clinically significant 
ECG abnormalities).
c.
Uncontrolled or history of difficult to control hypertension.
d. History of, or active diagnosis of, primary or secondary renal disease (e.g., 
renal disease secondary to diabetes, hypertension, vascular disease, etc.).
e.
History of extrahepatic disorders possibly related to HBV immune 
complexes (e.g., glomerulonephritis and polyarteritis nodosa).
f.
History of bleeding diathesis or coagulopathy.
g. History of or suspected presence of vasculitis.
h. History of Gilbert’s Syndrome.
i.
History of malignancy within the past 5 years with the exception of 
specific cancers that are cured by surgical resection (e.g., skin cancer), 
subjects under evaluation for possible malignancy are not eligible.
Section 5.4.1, Liver Chemistry Stopping Criteria, Paragraph 2
Rationale for change: To make minor edits for clarity
Original Text:
Table 5 provides guidance for liver stopping criteria for subjects with baseline ALT less 
than the ULN and for subjects with elevated baseline ALT.
Amended Text:
Table 5 provides guidance for liver stopping criteria for subjects with baseline ALT less 
than or equal to the ULN and for subjects with elevated baseline ALT.
Section 5.4.1, Liver Chemistry Stopping Criteria, Paragraph 3
Rationale for change: To make minor edits for clarity. To reduce complexity and visit 
burden for subjects.
 
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Original Text:
Eligible subjects should have an elevated ALT at screening as specified in Section 5.1. 
However, the screening ALT may differ from the baseline ALT. Baseline ALT will be 
measured prior to dosing on Day 1, but results will not be available from the central 
laboratory until after the subject has already been dosed
Amended Text:
Eligible subjects in Part 1 should have an elevated ALT at screening as specified in
Section 5.1. Baseline ALT will be measured prior to dosing on Day 1, but results will not 
be available from the central laboratory until after the subject has already been dosed
Section 6.1, Investigational Product and Other Study Treatment, Table 6, Row 8
Rationale for change: To make minor edits for clarity. Normal Saline is not always 
provided by study site.
Original Text: 
Manufacturer/Source of 
Procurement:
GSK Global Manufacturing 
and Supply, Parma (Italy)
Sourced locally at study site
Amended Text: 
Manufacturer/Source of 
Procurement:
GSK Global Manufacturing 
and Supply, Parma (Italy)
Sourced locally at study site
Locally sourced normal 
saline
Section 6.1, Investigational Product and Other Study Treatment, Table 7, Row 1 and 
footnote 1and footnote 2
Rationale for change: To make minor edits for clarity
Original Text: 
Total Dose1
Total Volume to Administer2
30 mg or placebo
0.30 mL
60 mg or placebo
0.60 mL
120 mg or placebo
1.2 mL
240 mg or placebo
2.4 mL
1.
Total dose may change based on safety and pharmacokinetic data from preceding cohort(s)
2.
If a change in total dose is warranted, total volume to administer (mL) = dose (mg)/100
 
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Amended Text:
Total Dose1
Total Volume to Administer2
30 mg or placebo
0.30 mL
60 mg or placebo
0.60 mL
120 mg or placebo
1.2 mL
240 mg or placebo
2.4 mL
1.
Total d Dose may change based on safety and pharmacokinetic data from preceding cohort(s)
2.
If a change in total dose is warranted, total volume to administer (mL) = dose (mg)/100
Section 6.3, Planned Dose Adjustments, Paragraph 1, Bullet 1, Sub-bullet 3
Rationale for change: To make minor edits for clarity
Original Text:
o
In the case of undetectable or extremely low concentrations following the 
first dose (e.g., if the majority of PK samples are below the lower limit of 
quantification), a more than 3-fold increase in dose may be considered for the 
next dose level;
Amended Text
o
In the case of undetectable or extremely low concentrations following the 
first dose (e.g., if the majority of PK samples are below the lower limit of 
quantification LLOQ), a more than 3-fold increase in dose may be 
considered for the next dose level;
Section 6.6, Packaging and Labeling, Paragraph 2
Rationale for change: To make minor edits for clarity
Original Text:
A placebo to match GSK3389404 solution for injection will be site sourced normal saline 
solution.
Amended Text:
A placebo to match GSK3389404 solution for injection will be site locally sourced 
normal saline solution.
 
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Section 6.10, Treatment after the End of the Study, Paragraph 1
Rationale for change: To make minor edits for clarity. To allow for exceptional 
circumstances that may require GSK to provide treatment options for subjects.
Original Text:
Subjects will not receive any additional treatment from GSK after completion of the
study. 
Amended Text: 
Subjects will not receive any additional treatment from GSK after completion of the 
study. 
Section 6.10, Treatment after the End of the Study, Paragraph 2, Bullets 1 and 2
Rationale for change: To make minor edits for clarity. To allow for exceptional 
circumstances that may require GSK to provide treatment options for subjects.Original 
Text:

In Part 1, subjects with CHB may be evaluated by the investigator for initiation of 
standard of care therapy after the final Follow-up visit (Day 60). The study 
sponsor will not be responsible for providing standard of care. 

In Part 2, subjects with CHB may be evaluated by the investigator for initiation of 
standard of care therapy during the study as appropriate based on evidence of 
CHB exacerbation or at any time after Day 113. The study sponsor will not be 
responsible for providing standard of care.
Amended Text:

In Part 1, subjects with CHB may be evaluated by the investigator for initiation of 
standard of care therapy after the final Follow-up visit (Day 60). The study 
sponsor will not be responsible for providing standard of care. 

In Part 2, subjects with CHB may be evaluated by the investigator for initiation of 
standard of care therapy during the study as appropriate based on evidence of
CHB exacerbation or at any time after Day 113. The study sponsor will not be 
responsible for providing standard of care discuss post-study care with the 
investigator.
Section 6.11.1, Meals and Dietary Restrictions, Paragraph 2, Bullet 1, Bullet 2 and 
sub-bullet
Rationale for change: To reduce complexity and visit burden for subjects.
 
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Original Text:
During the in-house stay in Part 1, subjects will be restricted to meals and beverages 
provided at the study site. 

On Day 1, a morning snack (not full meal) will be provided after dosing and 
completion of morning study procedures. Lunch will be provided approximately 
4 hours post-dose, dinner will be provided approximately 9 hours post-dose, and 
an evening snack may be available until 22:00 hours. 

On Day 2, breakfast will be provided after completion of morning 
procedures/prior to discharge from the study site. 
o
If subjects decide to stay in-house through Day 3, lunch will be provided 
approximately 4 hours after the breakfast, dinner will be provided 
approximately 9 hours after the breakfast, and an evening snack may be 
available until 22:00 hours.
Amended Text:
Admission to the study site is optional. If subjects opt to stay During the in-house stay 
in Part 1, subjects will be restricted to meals and beverages provided at the study site. 

On Day 1, a morning snack (not full meal) will be provided after dosing and 
completion of morning study procedures. Lunch will be provided approximately 
4 hours post-dose,. If subjects are still on-site, dinner will be provided
approximately 9 hours post-dose, and an evening snack will be available until 
22:00 hours. 

On Day 2, breakfast, lunch, and dinner may will be provided after completion of 
morning procedures/prior to discharge from the study site. 
o
If subjects decide to stay in-house through Day 3, lunch will be provided 
approximately 4 hours after the breakfast, dinner will be provided 
approximately 9 hours after the breakfast, and an evening snack will be 
available until 22:00 hours Subjects may be discharged at any time on 
Day 2.
o
An evening snack will be available until 22:00 hours.
Section 6.12.1, Permitted Medications and Non-Drug Therapies, Paragraph 1, Sentence 1
Rationale for change: To update the subject population in Part 2 from treatment naïve to 
treatment experienced
Original Text: 
Concomitant medications (prescription and non-prescription) should be administered 
only as medically necessary during the study (except prohibited medications described in 
Section 6.12.2).
 
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Amended text:
In Part 2, required medication includes nucleos(t)ide agents such as tenofovir, 
entecavir, lamivudine, adefovir and telbivudine. Other concomitant medications 
(prescription and non-prescription) should be administered only as medically necessary 
during the study (except prohibited medications described in Section 6.12.2).
Section 6.12.2, Prohibited Medications and Non-Drug Therapies, Entire section
Rationale for change: To update the subject population in Part 2 from treatment naïve to 
treatment experienced and impact on concomitant medications.
Original Text: 

Interferon (pegylated or non-pegylated) from 12 months prior to Baseline (Day 1 
pre-dose) through the final Follow-up visit (see Inclusion Criterion 6, 
Section 5.1).

Nucleos(t)ide analogue therapy from 6 months prior to Baseline (Day 1 pre-dose) 
through the final Follow-up visit (see Inclusion Criterion 6, Section 5.1).

Immunosuppressing drug (e.g., prednisone) use >2 weeks duration from 3 months 
prior to Screening through the final Follow-up visit (see Exclusion Criterion 11, 
Section 5.2).

Oligonucleotide or siRNA from 12 months prior to Day 1 through the final 
Follow-up visit (see Exclusion Criterion 11, Section 5.2). 
Amended Text:
The following concomitant medications are not permitted during Part 1:

Interferon (pegylated or non-pegylated) from 12 months prior to Baseline (Day 1 
pre-dose) through the final Follow-up visit (see Inclusion Criterion 6, 
Section 5.1).

Nucleos(t)ide analogue therapy from 6 months prior to Baseline (Day 1 pre-dose) 
through the final Follow-up visit (see Inclusion Criterion 6, Section 5.1).
The following concomitant medications are not permitted during Part 1 and Part 2:

Immunosuppressing drug (e.g., prednisone) use >2 weeks duration from 3 months 
prior to Screening through the final Follow-up visit (see Exclusion Criterion 11, 
Section 5.2).

Oligonucleotide or siRNA from 12 months prior to Day 1 through the final 
Follow-up visit (see Exclusion Criterion 16, Section 5.2).
 
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Section 7.1, Table 8, Header Row
Rationale for change: To make minor edits for clarity.
Original Text: 
Assessment
Screening
Amended Text:
Assessment
Screening
(Up to 30 days 
Prior to Day 1)
Section 7.1, Table 8, Column 1, Rows 19 and 20
Rationale for change: To make minor edits for clarity
Original Text: 
Hepatitis B screen (quantitative HBsAg; plasma)
Hepatitis B profile (quantitative HBV DNA, HBeAg; plasma)
Amended Text: 
Hepatitis B screen (quantitative HBsAg; plasma or serum)
Hepatitis B profile (quantitative HBV DNA, HBeAg; plasma or serum)
Section 7.1, Table 9
Rationale for change: To reduce complexity and visit burden for subjects. To make minor 
edits for clarity- to allow for both quantitative and/or qualitative testing
Original Text (on next page): 
 
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Day-11
Day 1
Post Dose in Hours (h)
Assessments
Pre-dose1
O h
0.5 h
1 h
1.5 h
2 h
3 h
4 h
6 h
8 h
9 h
12 h
Inclusion and exclusion criteria
X
Admission to study site1
(X1)
X1
Randomization2
X
Study treatment dosing3
X
Meals4
X
X
X
Safety Assessments
AE/SAE review5
Continuous
Concomitant medication review
Continuous
Brief physical exam
X
Vital signs6
X
X
X
X
X
X
X
Holter
X
X
X
X
X
X
X
X
X
12-lead ECG7
X
X
X
X
X
Injection site reactions8
X
X
X
X
X
X
X
X
X
X
X
Laboratory Assessments
Drug/Alcohol screen9
X
Pregnancy test (as appropriate) 9,10
X
Hematology/Chemistry/Urinalysis9,11,12
X
X
Urine ACR9,12,13
X
Complement (C3/C4)
X
X
X
X
PT, INR, aPTT9
X
X
X
X
hs-CRP9
X
PK sampling14
X
X
X
X
X
X
X
X
X
X
Archived serum and plasma samples15
X
Quantitative HBsAg and HBV DNA
X
X
Quantitative HBeAg16
X
X
 
 
 
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Day-11
Day 1
Post Dose in Hours (h)
Assessments
Pre-dose1
O h
0.5 h
1 h
1.5 h
2 h
3 h
4 h
6 h
8 h
9 h
12 h
HBV genotype/phenotype17
X
X
Amended Text: 
Day-11
Day 1
Post Dose in Hours (h)
Assessments
Pre-dose12
O h
0.5 h
1 h
1.5 h
2 h
3 h
4 h
6 h
8 h
9 h
12 h
Inclusion and exclusion criteria
X
X
Admission to study site1
(X1)
(X)1
Discharge from study site1
(X)
Randomization2
X
Study treatment dosing3
X
Meals4
X
X
X
Safety Assessments
AE/SAE review5
Continuous
Concomitant medication review
Continuous
Brief physical exam
X
X
Vital signs6
X
X
X
X
X
X
X
Holter
X
X
X
X
X
X
X
X
X
12-lead ECG7
X
X
X
X
X
Injection site reactions8
X
X
X
X
X
X
X
X
X
X
X
Laboratory Assessments
Drug/Alcohol screen9
X
 
 
 
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Day-11
Day 1
Post Dose in Hours (h)
Assessments
Pre-dose12
O h
0.5 h
1 h
1.5 h
2 h
3 h
4 h
6 h
8 h
9 h
12 h
Pregnancy test (as appropriate) 9,10
X
X
Hematology/Chemistry/Urinalysis9, 10,11,12
X
X
Urine ACR9,11,12,13
X
X
Complement (C3/C4)
X
X
X
X
X
PT, INR, aPTT9
X
X
X
X
X
hs-CRP9
X
X
PK sampling1413
X
X
X
X
X
X
X
X
X
X
Archived serum and plasma samples1514
X
Quantitative HBsAg and HBV DNA
X
X
X
Quantitative HBeAg1615
X
X
X
HBV genotype/phenotype1716
X
X
X
 
 
 
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Section 7.1, Table 9, Footnotes 1, 4, 7, 9-17
Rationale for change: To reduce complexity and visit burden for subjects.
Original Text:
1.
Day -1 admission is optional based on laboratory capabilities and study 
site/subject preference. The study site/subject may use Day -1 as an outpatient 
visit for assessments and blood sample collection. If the subject is willing to 
arrive early and the site is capable (early admission available, critical laboratory 
result turn-around available prior to randomization), subjects may be admitted on 
Day 1 with all Day -1 assessments conducted pre-dose.
4.
On Day 1, subjects may receive a morning snack (not full meal) after completion 
of morning study procedures and post-dose, prior to lunch. Lunch will be 
approximately 4 hours (1 hour) dosing and dinner approximately 9 hours 
(1 hour) after dosing. An evening snack (optional) may be provided until 
22:00 hours
7.
12-lead ECGs to be measured in triplicate at pre-dose on Day 1, after 5 minutes of 
rest in the semi supine or supine position and all other ECGs to be measured in 
duplicate.
9.
Laboratory assessment results are required before randomization
10.
Female subjects at screening and pre-dose: serum hCG pregnancy test; All other 
time points: serum hCG or urine pregnancy test.
11.
Samples may be collected on Day -1 and/or pre-dose Day 1. At least one set of 
samples must be obtained after an overnight fast (at least 8 hours) and before 
breakfast.
12.
The study site may collect and divide urine sample for urinalysis test and ACR 
(first void) assessments.
13.
Collect first morning urine void sample for ACR assessment while subjects are in 
study site. 
14.
Plasma PK samples to be collected pre-dose (within 15 to 30 minutes prior to 
dosing; prefer sample as close to pre-dose time point as possible). Post-dose PK 
samples should be collected as close to the exact nominal time as possible. The 
exact time of each PK blood collection should be recorded.
15.
Archived serum and plasma samples for exploratory biomarker analyses. 
Complement C5a and Bb may be analyzed from the archived plasma sample.
16.
HBeAg-positive subjects only.
 
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17.
HBV Genotype/Phenotype sample to be stored and analyzed per sponsor’s 
discretion. Samples will be used to assess for changes in HBV 
genotype/phenotype from baseline, HBsAg nadir, and/or final Follow-up visit.
Amended Text:
1.
Day -1 admission is optional based on laboratory capabilities and study 
site/subject preference. The study site/subject may use Day -1 as an outpatient 
visit for assessments and blood sample collection. If the subject is willing to 
arrive early and the site is capable (early admission available, critical laboratory 
result turn-around available prior to randomization), subjects may be admitted on 
Day 1 with all Day -1 assessments conducted pre-dose. 1.
Admission to the 
study site is optional. Subjects admitted on Day -1 may be discharged after 
completion of all protocol specified procedures on Day 1, 8-hour time point, 
with instructions to return for outpatient visits (Days 3, 8, 15, 22, 30, and 60).
4.
On Day 1, subjects may receive a morning snack (not full meal) after completion 
of morning study procedures and post-dose, prior to lunch. Lunch will be 
approximately 4 hours (1 hour) dosing. If subjects are still on site, and dinner 
will be provided approximately 9 hours (1 hour) after dosing. An evening snack 
(optional) may be provided until 22:00 hours
7.
12-lead ECGs to be measured in triplicate at pre-dose on Day 1, after 5 minutes of 
rest in the semi supine or supine position and duplicate at all other measurement 
time pointsECGs to be measured in duplicate.
9.
Laboratory assessment results are required before randomization
10. 9. Female subjects at screening and pre-dose: serum hCG pregnancy test; All other 
time points: serum hCG or urine pregnancy test.
11.10. Samples may be collected on Day -1 and/or pre-dose Day 1. At least one set of 
samples Sample must be obtained after an overnight fast (at least 8 hours) and 
before breakfast.
12.11 The study site may collect and divide urine sample for urinalysis test and ACR 
(first void) assessments.
13.12 Collect first morning urine void sample for ACR assessment while subjects are in 
study site. 
14.13 Plasma PK samples to be collected pre-dose (within 15 to 30 minutes prior to 
dosing; prefer sample as close to pre-dose time point as possible). Post-dose PK 
samples should be collected as close to the exact nominal time as possible. The 
exact time of each PK blood collection should be recorded.
15.14 Archived serum and plasma samples for exploratory biomarker analyses. 
Complement C5a and Bb may be analyzed from the archived plasma sample.
 
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16.15 HBeAg-positive subjects only.
17.16 HBV Genotype/Phenotype sample to be stored and analyzed per sponsor’s 
discretion. Samples will be used to assess for changes in HBV 
genotype/phenotype from baseline, HBsAg nadir, and/or final Follow-up visit.
 
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Section 7.1, Table 10
Rationale for change: To reduce complexity and visit burden for subjects. To make minor edits for clarity- to allow for both quantitative 
and/or qualitative testing.
Original Text: 
Day 2
DAY 3
Day 8
Day 15
Day 22
Day 30
Day 60
Post Dose in Hours (h)
(1 day)
(1 day)
(1 day)
(1 day)
(1 day)
ET
Assessment
24 h
28 h
33 h
48 h 
(8 h)
Meals1
X
(X)1
(X)1
(X)1
Discharge from study site2
(X)2
(X)2
Outpatient visits
(X)2
X
X
X
X
X
X
Safety Assessments
AE/SAE review3
Continuous
Concomitant medication review
Continuous
Brief physical exam
X
X
X
X
Vital signs4
X
X
X
X
X
12-lead ECG5
X
X
X
X
X
Injection site reactions6
X
X
X
X
X
X
X
X
X
X
Laboratory Assessments
Pregnancy test (as appropriate)7
X
X
X
X
Hematology/Chemistry/Urinalysis8,9
X
X
X
X
X
X
Urine ACR9,10
X
X
X
X
X
Complement (C3/C4)
X
X
X
X
X
PT, INR, aPTT
X
X
X
X
X
hs-CRP
X
X
X
X
X
PK sampling11
X
X
X
X
X
Archived serum and plasma samples12
X
X
X
X
X
 
 
 
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Day 2
DAY 3
Day 8
Day 15
Day 22
Day 30
Day 60
Post Dose in Hours (h)
(1 day)
(1 day)
(1 day)
(1 day)
(1 day)
ET
Assessment
24 h
28 h
33 h
48 h 
(8 h)
Quantitative HBsAg, HBV DNA
X
X
X
X
X
X
X
X
Quantitative HBeAg13
X
X
X
X
X
X
X
X
HBV genotype/phenotype14
X
X
X
X
X
X
X
X
Amended Text: 
Day 2
DAY 3
Day 8
Day 15
Day 22
Day 30
Day 60
Post Dose in Hours (h)
(1 day)
(1 day)
(1 day)
(1 day)
(1 day)
ET
Assessment
24 h
28 h
33 h
48 h 
(8 h)
Meals1
X
(X)1
(X)1
(X)1
Discharge from study site2
(X)2
(X)2
Outpatient visits
(X)2
X
X
X
X
X
X
Safety Assessments
AE/SAE review3
Continuous
Concomitant medication review
Continuous
Brief physical exam
X
X
X
X
Vital signs4
X
X
X
X
X
12-lead ECG5
X
X
X
X
X
Injection site reactions6
X
X
X
X
X
X
X
X
X
X
Laboratory Assessments
Pregnancy test (as appropriate)7
X
X
X
X
Hematology/Chemistry/Urinalysis8,9
X
X
X
X
X
X
Urine ACR9,10
X
X
X
X
X
Complement (C3/C4)
X
X
X
X
X
PT, INR, aPTT
X
X
X
X
X
 
 
 
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Day 2
DAY 3
Day 8
Day 15
Day 22
Day 30
Day 60
Post Dose in Hours (h)
(1 day)
(1 day)
(1 day)
(1 day)
(1 day)
ET
Assessment
24 h
28 h
33 h
48 h 
(8 h)
hs-CRP
X
X
X
X
X
PK sampling11
X
X
X
X
X
Archived serum and plasma samples12
X
X
X
X
X
Quantitative HBsAg, HBV DNA
X
X
X
X
X
X
X
X
Quantitative HBeAg13
X
X
X
X
X
X
X
X
HBV genotype/phenotype14
X
X
X
X
X
X
X
X
 
 
 
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Section 7.1, Table 10, Footnotes 1 and 2
Rationale for change: To reduce complexity and visit burden for subjects.
Original Text:
1.
On Day 2, breakfast is provided after completion of morning procedures/prior to 
discharge. If subjects choose to stay in-house through Day 3, then on Day 2, lunch will 
also be served approximately 4 hours (1 hour) after the breakfast, dinner will be served 
approximately 9 hours (1 hour) after the breakfast, and an evening snack (optional) may 
be provided until 22:00 hours. If subjects choose to stay in-house through Day 3, they 
will be offered a meal (e.g., bagged or canteen) after completion of all study procedures 
and prior to discharge on Day 3.
2.
Discharge from the study site may occur after completion of all protocol specified 
procedures on Day 2 with instructions to return for outpatient visits (Days 3. 8, 15, 22, 
30, and 60). If subjects prefer, they may stay in-house until all Day 3 assessments are 
completed.
Amended Text:
1.
On Day 2, breakfast, lunch, and dinner may be is provided. after completion of 
morning procedures/prior to discharge. If subjects choose to stay in-house through Day 3, 
then on Day 2, lunch will also be served approximately 4 hours (1 hour) after the 
breakfast, dinner will be served approximately 9 hours (1 hour) after the breakfast, and 
an evening snack (optional) may be provided until 22:00 hours. If subjects choose to stay 
in-house through Day 3, they will be offered a meal (e.g., bagged or canteen) after 
completion of all study procedures and prior to discharge on Day 3.
2.
Subjects may be Ddischarged from the study site may occur after completion of 
all protocol specified procedures at any time on Day 2 with instructions to return for 
outpatient visits (Days 3. 8, 15, 22, 30, and 60). If subjects prefer, they may stay in-house 
until all Day 3 assessments are completed.
Section 7.1, Table 11, Table 13, and Table 15 Rows 20 through 25
Rationale for change: To reduce complexity and visit burden for subjects.
Original Text: 
PK sampling11,12
X11,12
X11
X11
X11
X11,12
X11
X11
X11
X11,12
X11
X11
X11
X11
Archived serum and 
plasma samples13
X
X
X
X
Quantitative HBsAg 
and HBV DNA
X
X
X
X
X
X
X
X
X
X
X
X
X
Qualitative HBeAg14
X
X
X
X
X
X
X
X
X
X
X
X
X
HBV 
genotype/phenotype15
X
X
X
X
X
X
X
Meal16
X
X
X
X
X
X
X
X
X
X
X
X
X
 
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Amended Text: 
PK sampling11,12
X11,12
X11
X11
X11
X11,12
X11
X11
X11
X11,12
X11
X11
X11
X11
Archived serum and 
plasma samples1312
X
X
X
X
Quantitative HBsAg 
and HBV DNA
X
X
X
X
X
X
X
X
X
X
X
X
X
Qualitative HBeAg1413
X
X
X
X
X
X
X
X
X
X
X
X
X
HBV 
genotype/phenotype1514
X
X
X
X
X
X
X
HBsAb
X
X
Meal1615
X
X
X
X
X
X
X
X
X
X
X
X
X
Section 7.1, Table 11, Table 13, and Table 15, New abbreviation footnote
Rationale for change: addition of new exploratory endpoint to assess GSK3389404 
treatment outcomes in case seroconversion is seen in subjects with chronic hepatitis B
Original Text:
Not applicable
Amended Text:
HBsAb = hepatitis B virus surface antibody
Section 7.1, Tables 11, 13, and 15 Footnotes 1, 2, and 5
Rationale for change: To reduce complexity and visit burden for subjects.
Original Text:
1.
Subjects randomized to GSK3389404 or placebo on Day 1 prior to dosing, but 
only after critical assessments are performed to ensure subject eligibility.
2.
Study treatment will be administered as subcutaneous injection(s) in the morning 
following an overnight fast of at least 8 hours and subsequent to the laboratory 
assessments and other study assessments conducted prior to dosing.
5.
12-lead ECGs to be measured in triplicate at pre-dose on Day 1, after 5 minutes of 
rest in the semi-supine or supine position and all other ECGs to be measured in 
duplicate.
Amended Text: 
1.
Subjects randomized to GSK3389404 or placebo on Day 1 prior to dosing, but 
only after critical assessments are performed to ensure subject eligibility.
 
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2.
Study treatment will be administered as subcutaneous injection(s) in the morning 
following an overnight fast of at least 8 hours and subsequent to the laboratory 
assessments collection and other study assessments conducted prior to dosing.
5.
12-lead ECGs to be measured in triplicate at pre-dose on Day 1, after 5 minutes of 
rest in the semi-supine or supine position and duplicate at all other ECGs to be 
measured in duplicate measurement time points.
Section 7.1, Table 11, Table 13, and Table 15, Footnotes 11 through 16
Rationale for change: To reduce complexity and visit burden for subjects.
Original Text: 
11.
Collect plasma PK samples on all days indicated. On dosing days, collect PK 
samples pre-dose (within 15 to 30 minutes prior to dosing; prefer sample as close 
to pre-dose time point as possible). On Day 85, collect the PK sample after 
completion of vital sign assessments. The exact time of each PK blood collection 
should be recorded.
12.
On extended PK/dosing days (Days 1, 29, and 57), additional PK samples will be 
collected at 1, 2, 3, and 4 hours post-dose. PK samples should be collected as 
close to the exact nominal time as possible. The exact time of each PK blood 
collection should be recorded.
13.
Archived serum and plasma samples for exploratory biomarker analyses. 
Complement C5a and Bb may be analyzed from the archived plasma sample.
14.
HBeAg-positive subjects only.
15.
HBV Genotype/Phenotype samples to be stored and analyzed per sponsor’s 
discretion. Samples will be used to assess for changes in HBV
genotype/phenotype from baseline, HBsAg nadir, and/or final Follow-up visit. 
16.
Subjects will be offered a meal (e.g., bagged or canteen) after completion of all 
study procedures.
Amended Text: 
11.
Collect plasma PK samples on all days indicated. On dosing days, collect PK 
samples pre-dose (within 15 to 30 minutes prior to dosing; prefer sample as close 
to pre-dose time point as possible). On Day 85, collect the PK sample after 
completion of vital sign assessments. The exact time of each PK blood collection 
should be recorded.
1211. On extended PK/dosing days (Days 1, 29, and 57), additional PK samples will be 
collected at pre-dose (within 15 to 30 minutes prior to dosing; prefer sample 
as close to pre-dose time point as possible) and at 1, 2, and 3, and 4 hours post-
 
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dose. PK samples should be collected as close to the exact nominal time as 
possible. The exact time of each PK blood collection should be recorded.
1312. Archived serum and plasma samples for exploratory biomarker analyses. 
Complement C5a and Bb may be analyzed from the archived plasma sample.
1413. HBeAg-positive subjects only.
1514. HBV Genotype/Phenotype samples to be stored and analyzed per sponsor’s 
discretion. Samples will be used to assess for changes in HBV 
genotype/phenotype from baseline, HBsAg nadir, and/or final Follow-up visit. 
1615. Subjects will be offered a meal (e.g., bagged or canteen) after completion of all 
study procedures.
Section 7.1, Table 12, Table 14, and Table 16, Row 18
Rationale for change: To reduce complexity and visit burden for subjects.
Original Text:
PK sampling9
X
X
X
X
X
X
Amended Text: 
PK sampling9
X
X
X
X
X
X
Section 7.1, Table 12, Table 14, and Table 16, Column 1, Rows 20 and 21
Rationale for change: To make minor edits for clarity- to allow for both quantitative 
and/or qualitative testing
Original Text:
Quantitative HBsAg and HBV DNA
Quantitative HBeAg11
Amended Text: 
Quantitative HBsAg and HBV DNA
Quantitative HBeAg11
Section 7.1, Table 12, Table 14, and Table 16, New Row 23
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Original Text:
Meal13
X
X
X
X
X
X
Amended Text:
HBsAb
X
X
Meal13
X
X
X
X
X
X
Section 7.1, Table 12, Table 14, and Table 16, New abbreviation footnote
Rationale for change: addition of new exploratory endpoint to assess GSK3389404 
treatment outcomes in case seroconversion is seen in subjects with chronic hepatitis B
Original Text:
Not applicable
Amended Text:
HBsAb = hepatitis B virus surface antibody
Section 7.1, Table 12, Table 14, and Table 16, Footnote 9
Rationale for change: To make minor edits for clarity
Original Text:
9.
The exact time of each PK blood collection should be recorded.
Amended Text: 
9.
On PK days (Day 169 / Early Termination), collect the PK sample after 
completion of vital sign assessments. The exact time of each PK blood 
collection should be recorded.
Section 7.1, Table 16, Row 10
Rationale for change: To make minor edits for clarity- to correct a clerical error in not 
including assessment
Original Text:
Injection site reactions4
 
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Amended Text: 
Injection site reactions4
X
X
X
X
X
X
Section 7.2, Screening and Critical Baseline Assessments, Paragraph 2, Bullet 3
Rationale for change: To make minor edits for clarity
Original Text:

Procedures conducted as part of the subject’s routine clinical management 
(qualitative HBsAg, liver biopsy, Fibroscan, APRI, or FibroSure) and obtained 
prior to signing of informed consent may be utilized for screening purposes 
provided the procedure meets the protocol-defined criteria and has been 
performed within the timeframe defined in the inclusion/exclusion criteria listed 
in Section 5.
Amended Text:

Procedures conducted as part of the subject’s routine clinical management 
(qualitative HBsAg, liver biopsy, Fibroscan, APRI, or FibroSure) and obtained 
prior to signing of informed consent may be utilized for screening purposes 
provided the procedure meets the protocol-defined criteria and has been 
performed within the timeframe defined in the inclusion/exclusion criteria listed 
in Section 5.
Section 7.3.8, Clinical Safety Laboratory Assessments, Paragraph 4
Rationale for change: To make minor edits for clarity- based on decision that this 
information was not needed in electronic case report form (CRF) as information would be 
provided in narratives/reports.
Original Text:
If additional non-protocol specified laboratory assessments are performed at the 
institution’s local laboratory and result in a change in subject management or are 
considered clinically significant by the investigator (e.g., SAE, AE, or dose modification) 
the results must be recorded in the CRF.
Amended Text: 
If additional non-protocol specified laboratory assessments are performed at the 
institution’s local laboratory and result in a change in subject management or are 
considered clinically significant by the investigator (e.g., SAE, AE, or dose modification) 
the results must be recorded in the CRF.
 
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Section 7.3.8, Clinical Safety Laboratory Assessments, Paragraph 5, Sentence 3
Rationale for change: To make minor edits for clarity- based on decision that this 
information was not needed in electronic case report form (CRF) as information would be 
provided in narratives/reports.
Original Text:
Additionally if the local laboratory results are used to make either a treatment or response 
evaluation, the results must be entered into the CRF.
Amended Text:
Additionally if the local laboratory results are used to make either a treatment or response 
evaluation, the results must be entered into the CRF.
Section 7.3.8, Clinical Safety Laboratory Assessments, Table 17, Row 7, Bullet 3 and 
new Bullet 4
Rationale for change: To make minor edits for clarity. Addition of new exploratory 
endpoint to assess GSK3389404 treatment outcomes in case seroconversion is seen in 
subjects with chronic hepatitis B
Original Text:

Quantitative HBsAg
Amended Text: 

Quantitative HBsAg

HBsAb
Section 7.3.8, Clinical Safety Laboratory Assessments, Table 17, New abbreviation 
footnote
Rationale for change: Addition of new exploratory endpoint to assess GSK3389404 
treatment outcomes in case seroconversion is seen in subjects with chronic hepatitis B
Original Text:
Not applicable
Amended Text:
HBsAb = hepatitis B virus surface antibody
 
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Section 7.5, Efficacy, Paragraph 1, Sentence 1
Rationale for change: To make minor edits for clarity- to allow for both quantitative 
and/or qualitative testing
Original Text:
Blood samples for quantitative HBsAg will be collected as specified in the Time and 
Events Tables in Section 7.1.
Amended Text:
Blood samples for quantitative HBsAg will be collected as specified in the Time and 
Events Tables in Section 7.1.
Section 7.6 Biomarker(s)/Pharmacydynamic Markers, Paragraph 2, Sentence 3
Rationale for change: To make minor edits for clarity- to include additional analyses for 
biomarkers
Original Text:
Blood collection, processing, storage, and shipping details are provided in the SRM.
Amended Text:
The archive samples may also be used for studying biomarkers that may be affected 
by treatment, such as hepatitis B core-related antigen (HBcrAg) or indoleamine 
2,3 dioxygenase (IDO). Blood collection, processing, storage, and shipping details are 
provided in the SRM.
New Section 7.7.1 HBV Resistance Mutation Monitoring
Rationale for change: To update the subject population in Part 2 from treatment naïve to 
treatment experienced; to define virologic breakthrough and processes should virologic 
breakthrough were to occur
Original Text:
Not applicable
Amended Text:
For Part 2, in subjects who are on a stable nucleos(t)ide regimen with adequate 
suppression of HBV DNA, defined as HBV DNA levels below the LLOQ: 
 
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Virologic breakthrough is defined as the occurrence of confirmed virologic 
breakthrough (e.g., HBV DNA becoming quantifiable after being below the LLOQ).
Plasma or serum HBV DNA levels for each subject will be measured throughout the 
study (see Time and Events Tables in Section 7.1). If evidence of virologic 
breakthrough is observed, subjects will be interviewed regarding treatment 
compliance and the concomitant usage of medication that might affect virus 
replication (e.g., corticosteroids), and other potentially relevant parameters.
Samples collected for viral genotyping and phenotyping may be used for HBV 
resistance mutation analysis where the viral genome will be DNA sequenced to 
determine whether mutations have occurred in the GSK3389404 binding region 
(and if applicable, whether any known nucleos(t)ide resistance mutations are 
present in the polymerase coding region).
Section 11 REFERENCES
Rationale for change: To make minor edits for clarity; additional references added
New references added
Baraclude (Entecavir) [package insert]. Bristol-Myers Squibb Company. Princeton (NJ); 
2015. 
Cihlar T, Ho ES, Lin DC, Mulato AS. Human renal organic anion transporter 1 (hOAT1) 
and its role in the nephrotoxicity of antiviral nucleotide analogs. Nucleosides Nucleotides 
Nucleic Acids 2001;20:641–48.
Cihlar T, Bleasby K, Roy A, Prichard J. Abstr. 44th Intersci. Conf. Antimicrob. Agents 
Che- mother., abstr. A448, 2004
Epivir (Lamivudine) [package insert]. GlaxoSmithKline. Research Triangle Park (NC); 
2002.
Hepsera (Adefovir dipivoxil) [package insert]. Gilead Sciences, Inc. Foster City (CA); 
2012.
Kearney B, Flaherty J, Shah J. Tenofovir disoproxil fumarate: clinical pharmacology and 
pharmacokinetics. Clin Pharmacokinet 2004;439:595-612
Minuesa G, Volk C, Molina-Arcas M, Gorboulev V, Erkizia I, Arndt P, et al. Transport 
of lamivudine [(-)-beta-L-2’,3’-dideoxy-3’-thiacytidine] and high-affinity interaction of 
nucleoside reverse transcriptase inhibitors with human organic cation transporters 1, 2, 
and 3. J Pharmacol Exp Ther 2009;329:252–61
Servais A, Lechat P, Zahr N, Urien S, Aymard G, Jaudon MC, et al. Tubular transporters 
and clearance of adefovir. Eur J Pharmacol 2006;540:168-74.
 
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Shemesh CS, Yu RZ, Gaus HJ, Greenlee S, Post N, Schmidt K, et al. Elucidation of the 
biotransformation pathways of a galnac3-conjugated antisense oligonucleotide in rats and 
monkeys. Mol Ther Nucleic Acids 2016;10;5:e319.
Tyzeka (Telbivudine) [package insert]. Novartis Pharmaceuticals Corporation. East 
Hanover (NJ); 2013. 
Uwai Y, Ida H, Tsuji Y, Katsura T, Inui K. Renal transport of adefovir, cidofovir, and 
tenofovir by SLC22A family members (hOAT1, hOAT3, and hOCT2). Pharm Res
2007;24:811-15.
Xu Q, Wang C, Meng Q, Liu Q, Sun H, Peng J, et al. OAT1 and OAT3: targets of 
drug-drug interaction between entecavir and JBP485. Eur J Pharm Sci 2013;48;650-57.
Yanxiao C, Ruijuan X, Jin Y, Lei C, Qian W, Xuefen Y, et al. Organic anion and cation 
transporters are possibly involved in renal excretion of entecavir in rats. Life Sci
2011;89:1–6.
Yu RZ, Warren MS, Watanabe T, Nichols B, Jahic M, Huang J. Lack of interactions 
between an antisense oligonucleotide with 2'-O-(2-methoxyethyl) modifications and 
major drug transporters. Nucleic Acid Ther 2016;26:111-17.
Section 12.1 Appendix 1: Abbreviations and Trademarks, New abbreviations
Rationale for change: To make minor edits for clarity
Original Text:
Not applicable
Amended Text:
HBsAb
hepatitis B virus surface antibody
LLOQ
lower limit of quantification
OAT
organic anion transporter
OCT
organic cation transporter
Section 12.6.1, Introduction, New Paragraph 4
Rationale for change: To increase the maximum total monthly dose in Part 2 from 
240 mg to 480 mg
Original Text:
Not applicable
 
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Amended Text: 
The dosing regimens for selected treatment groups will be identical. For example, if 
480 mg is selected for Part 2, other selected treatment groups will also be 
administered in a weekly and bi-weekly (every 2 weeks) dosing regimen.
Section 12.6.2, Statistical Modeling, Paragraph 1, Sentence 3
Rationale for change: To make minor edits for clarity.
Original Text:
Estimates for this model’s parameters will be derived using the data generated within 
each treatment arm, i.e., this model will borrow degrees of freedom across active dose 
levels and regimens therefore providing higher power compared to pair-wise comparison 
given the small sample size of each treatment arm. 
Amended Text:
Estimates for this model’s parameters will be derived using the data generated within 
each treatment arm, i.e., this model will borrow degrees of freedom across active dose 
levels and regimens therefore providing higher power compared to pair-wise comparison 
given the small sample size of each treatment arm and low expected response rate for 
placebo.
Section 12.6.4, Scenarios for Testing, Paragraph 1, Sentence 1
Rationale for change: To make minor edits for clarity. To increase the maximum total 
monthly dose in Part 2 from 240 mg to 480 mg
Original Text:
It is assumed that 3 dose levels (60, 120, and 240 mg) each at 2 regimens (weekly and 
monthly) will be selected in Part 2.
Amended Text:
It is assumed that 3 dose levels (60, 120, and 240, and 480 mg) each at 2 regimens 
(weekly and monthlybi-weekly) will be selected in Part 2.
 
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Section 12.64 and Section 12.6.5, Scenarios for Testing and Simulations, Table 18 
through Table 28
Rationale for change: To make minor edits for clarity. To increase the maximum total 
monthly dose in Part 2 from 240 mg to 480 mg
Due to the updated scenarios for testing documented in Section 12.6.4, all simulation 
tables were updated. 
 
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12.7.2.
Protocol changes for Amendment 02 (07-MAR-2017) from 
Protocol Amendment 01 (21-Feb-2017)
Protocol Amendment 2 replaces the protocol amendment 1 dated 21 Feb 2017 and 
applies to all study sites. 
Protocol Amendment 2 is being implemented for the following reasons:

To include patients with ALT less than 5X upper limit of normal (ULN) based on 
investigator feedback. Part 1 is a single dose administration to examine the safety 
and effect of viral biomarkers. Administration of a single dose of GSK3389404 is 
not considered likely to trigger a change in disease state or alter the benefit-risk 
assessment.

To make minor edits for clarity and typographical errors. 
LIST OF CHANGES
Title Page, Title
Rationale: Protocol Amendment 01 title did not match the original protocol title.
Original text:
A Double-Blind, Placebo-Controlled Study to Assess the Safety, Tolerability, 
Pharmacokinetics and Pharmacodynamics of Single Ascending and Multiple Doses of 
GSK3389404 in Chronic Hepatitis B Subjects
Amended text:
A Double-Blind, Placebo-Controlled Study to Assess the Safety, Tolerability, 
Pharmacokinetics and Pharmacodynamics of Single Ascending Dose and Multiple Doses 
of GSK3389404 in Chronic Hepatitis B Subjects
Section 4.2, Treatment Arms and Duration, Figure 3
Rationale for change: to edit figure for clarity, previous figure was unclear.
 
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Original Figure:
Amended Figure:
Section 4.5.5, GSK3389404 and Nucleos(t)ides, last paragraph
Rationale for change: Minor edit for clarity
Original text:
In a recent study, a model compound of 2'-O-(2-methoxyethyl) modified antisense 
oligonucleotide was shown to be neither a substrate nor an inhibitor of OAT1, OAT3, 
OCT1 and OCT2 [Yu, 2016]. Therefore, although GSK404 was shown to be extensively 
 
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distributed into the kidney [Shemesh, 2016], GSK3389404 is unlikely to interact with 
tenofovir, entecavir, lamivudine, adefovir and telbivudine.
Amended text:
In a recent study, a model compound of 2'-O-(2-methoxyethyl) modified antisense 
oligonucleotide was shown to be neither a substrate nor an inhibitor of OAT1, OAT3, 
OCT1 and OCT2 [Yu, 2016]. Therefore, although GSK3389404 was shown to be 
extensively distributed into the kidney [Shemesh, 2016], GSK3389404 is unlikely to 
interact with tenofovir, entecavir, lamivudine, adefovir and telbivudine.
Section 5, Selection of Study Population and Withdrawal Criteria, Paragraph 1
Rationale for change: Part 1 is a single dose administration to examine the safety and 
effect of viral biomarkers. Based on investigator feedback, the recommendation is to 
include patients with ALT less than 5X upper limit of normal. Administration of a single 
dose of GSK3389404 is not considered likely to trigger a change in disease state or alter 
the benefit-risk assessment.
Original text:
This first-in-patient study will enroll adult male and female subjects in the immune active 
phase of HBV infection who are not currently receiving HBV treatment (Part 1) or who 
are currently on a stable nucleos(t)ide regimen (Part 2). The immune active phase, also 
referred to as HBeAg-positive or HBeAg-negative chronic hepatitis, is characterized by 
elevated alanine aminotransferase (ALT) levels, evidence of active hepatic inflammation, 
and HBV DNA levels greater than or equal to 2000 IU/mL. Subjects who are on a stable 
nucleos(t)ide regimen are characterized by ALT levels less than or equal to the upper 
limit of normal (ULN) and have suppressed HBV DNA, defined as HBV DNA less than 
or equal to the lower limit of quantification (LLOQ). The entry criteria for this study are 
designed to enroll subjects with CHB who do not have advanced liver fibrosis or 
cirrhosis, other concomitant liver diseases, co-infection, or other significant 
co-morbidities that would confound the safety monitoring and/or potentially put them at 
greater risk for treatment-related AEs. The ALT eligibility criteria are generally 
consistent with the International Liver Society guidelines (e.g., Asian Pacific Association 
for the Study of the Liver [Liaw, 2012], European Association for the Study of the Liver 
[EASL, 2012], American Association for the Study of Liver Diseases [Terrault, 2016]).
Amended text:
This first-in-patient study will enroll adult male and female subjects in either the 
immune tolerant or the immune active phase of HBV infection who are not currently 
receiving HBV treatment (Part 1) or who are currently on a stable nucleos(t)ide regimen 
(Part 2). The immune tolerant phase is characterized by the absence of biochemical 
symptoms of the disease (i.e., elevated transaminase levels). The immune active phase, 
 
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also referred to as HBeAg-positive or HBeAg-negative chronic hepatitis, is characterized 
by elevated alanine aminotransferase (ALT) levels, evidence of active hepatic 
inflammation, and HBV DNA levels greater than or equal to 2000 IU/mL. Subjects who 
are on a stable nucleos(t)ide regimen are characterized by ALT levels less than or equal 
to the upper limit of normal (ULN) and have suppressed HBV DNA, defined as HBV 
DNA less than or equal to the lower limit of quantification (LLOQ). The entry criteria for 
this study are designed to enroll subjects with CHB who do not have advanced liver 
fibrosis or cirrhosis, other concomitant liver diseases, co-infection, or other significant 
co-morbidities that would confound the safety monitoring and/or potentially put them at 
greater risk for treatment-related AEs. The ALT eligibility criteria are generally 
consistent with the International Liver Society guidelines (e.g., Asian Pacific Association 
for the Study of the Liver [Liaw, 2012], European Association for the Study of the Liver 
[EASL, 2012], American Association for the Study of Liver Diseases [Terrault, 2016]).
Section 5.1, Inclusion Criteria, Number 9
Rationale for change: To expand population to include subjects with normal ALT.
Original text:
Alanine aminotransferase (ALT) concentration:
Part 1: ALT >60 U/L for males, >38 U/L for females, and 10 X ULN.
Part 2: ALT ULN
Amended text:
Alanine aminotransferase (ALT) concentration:
Part 1: ALT < 5 X ULN ALT >60 U/L for males, >38 U/L for females, and ≤10 X ULN.
Part 2: ALT ULN
Section 5.4.1, Liver Chemistry Stopping Criteria, Paragraph 3
Rationale for change: Minor edit for clarity to align with the change made to inclusion 
criteria 9 to include subjects with normal to elevated ALT < 5 X ULN.
Original text:
Eligible subjects in Part 1 should have an elevated ALT at screening as specified in 
Section 5.1
 
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Amended text:
Eligible subjects in Part 1 should may have an elevated ALT at screening as specified in 
Section 5.1
Section 7.1, Time and Events Tables, Table 10
Rationale for change: minor edit for clarity to re-order and re-number 
superscript/footnoes.
Original Table 10 and footnotes (excerpt- For review purposes, only the rows and text 
that have been changed are shown below):
Table 10 Time and Events Table: Day 2 to Day 60 of Single Ascending Dose (Part 1)
Day
2
DA
Y 3
Day
8
Day 1
5
Day 2
2
Day 3
0
Day 6
0
Post Dose 
in Hours 
(h)
(1 
day)
(1 
day)
(1 
day)
(1 
day)
(1 
day)
E
T
Laboratory Assessments
Pregnancy test (as appropriate)7
X
X
X
X
Hematology/Chemistry/Urinalysis
8,9
X
X
X
X
X
Urine ACR9,10
X
X
X
X
7. Female subjects: serum hCG or urine pregnancy test.
8. Samples for clinical laboratory tests to be collected in the morning after an overnight fast of at least 8 hours.
9. The study site may collect and divide urine sample for urinalysis test and ACR (first void) assessments.
10. Collect first morning urine void sample for ACR assessment while subjects are in study site. For outpatient visits, 
subjects will be given a clean urine collection cup and instructed to collect and bring in a first morning urine void 
sample on the day of their outpatient visit.
Amended Table 10:
Table 10 Time and Events Table: Day 2 to Day 60 of Single Ascending Dose (Part 1)
Day
2
DA
Y 3
Day
8
Day 1
5
Day 2
2
Day 3
0
Day 6
0
Post Dose 
in Hours 
(h)
(1 
day)
(1 
day)
(1 
day)
(1 
day)
(1 
day)
E
T
Laboratory Assessments7
Pregnancy test (as 
appropriate)78
X
X
X
X
Hematology/Chemistry/Urinalysis
8,9
X
X
X
X
X
Urine ACR9,10
X
X
X
X
7. Samples for clinical laboratory tests to be collected in the morning after an overnight fast of at least 8 hours
Female subjects: serum hCG or urine pregnancy test.
 
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8. Female subjects: serum hCG or urine pregnancy test Samples for clinical laboratory tests to be collected in the 
morning after an overnight fast of at least 8 hours.
9. The study site may collect and divide urine sample for urinalysis test and ACR (first void) assessments.
10. Collect first morning urine void sample for ACR assessment while subjects are in study site. For outpatient visits, 
subjects will be given a clean urine collection cup and instructed to collect and bring in a first morning urine void 
sample on the day of their outpatient visit.
Section 7.1, Time and Events Tables, Table 11
Rationale for change: minor edit for clarity to remove inappropriate superscript (does not 
apply).
Original Table 11 (excerpt- For review purposes, only the row that has been changed is 
shown below):
Table 11 Time and Events Table: Day 1 to Day 85 of Multiple Dose (Part 2) Once 
Weekly Dosing
Treatment Period
Assess
ment
Day
1
Day
8 
(1 
day
)
Day
15 
(1 
day)
Day
22 
(1 
day)
Day
29 
(1 
day)
Day
36 
(1 
day)
Day
43 
(1 
day)
Day
50 
(1 
day)
Day
57 
(1 
day)
Day
64 
(1 
day)
Day
71 
(1 
day)
Day
78 
(1 
day)
Day
85 
(1 
day)
PK 
samplin
g11
X11,
12
X11,1
2
X11, 
12
 
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Amended Table 11:
Table 11 Time and Events Table: Day 1 to Day 85 of Multiple Dose (Part 2) Once 
Weekly Dosing
Treatment Period
Assess
ment
Day
1
Day
8 
(1 
day
)
Day
15 
(1 
day)
Day
22 
(1 
day)
Day
29 
(1 
day)
Day
36 
(1 
day)
Day
43 
(1 
day)
Day
50 
(1 
day)
Day
57 
(1 
day)
Day
64 
(1 
day)
Day
71 
(1 
day)
Day
78 
(1 
day)
Day
85 
(1 
day)
PK 
samplin
g11
X11,
12
X11,1
2
X11,1
2
Section 7.1, Time and Events Tables, Table 13
Rationale for change: minor edit for clarity to remove inappropriate superscript (does not 
apply).
Original Table 13 (excerpt- For review purposes, only the row that has been changed is 
shown below):
Table 13 Time and Events Table: Day 1 to Day 85 of Multiple Dose (Part 2) Bi-
Weekly Dosing
Treatment Period
Assess
ment
Day
1
Day
8 
(1 
day
)
Day
15 
(1 
day)
Day
22 
(1 
day)
Day
29 
(1 
day)
Day
36 
(1 
day)
Day
43 
(1 
day)
Day
50 
(1 
day)
Day
57 
(1 
day)
Day
64 
(1 
day)
Day
71 
(1 
day)
Day
78 
(1 
day)
Day
85 
(1 
day)
PK 
samplin
g11
X11,
12
X11,1
2
X11, 
12
 
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Amended Table 13:
Table 13 Time and Events Table: Day 1 to Day 85 of Multiple Dose (Part 2) Bi-
Weekly Dosing
Treatment Period
Assess
ment
Day
1
Day
8 
(1 
day
)
Day
15 
(1 
day)
Day
22 
(1 
day)
Day
29 
(1 
day)
Day
36 
(1 
day)
Day
43 
(1 
day)
Day
50 
(1 
day)
Day
57 
(1 
day)
Day
64 
(1 
day)
Day
71 
(1 
day)
Day
78 
(1 
day)
Day
85 
(1
day)
PK 
samplin
g11
X11,
12
X11,1
2
X11,1
2
Section 7.1, Time and Events Tables, Table 15
Rationale for change: minor edit for clarity to remove inappropriate superscript (does not 
apply).
Original Table 15 (excerpt- For review purposes, only the row that has been changed is 
shown below):
Table 15 Time and Events Table: Day 1 to Day 85 of Multiple Dose (Part 2) Once 
Monthly Dosing
Treatment Period
Assess
ment
Day
1
Day
8 
(1 
day
)
Day
15 
(1 
day)
Day
22 
(1 
day)
Day
29 
(1 
day)
Day
36 
(1 
day)
Day
43 
(1 
day)
Day
50 
(1 
day)
Day
57 
(1 
day)
Day
64 
(1 
day)
Day
71 
(1 
day)
Day
78 
(1 
day)
Day
85 
(1 
day)
PK 
samplin
g11
X11,
12
X11,1
2
X11, 
12
 
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Amended Table 15:
Table 15 Time and Events Table: Day 1 to Day 85 of Multiple Dose (Part 2) Once 
Monthly Dosing
Treatment Period
Assess
ment
Day
1
Day
8 
(1 
day
)
Day
15 
(1 
day)
Day
22 
(1 
day)
Day
29 
(1 
day)
Day
36 
(1 
day)
Day
43 
(1 
day)
Day
50 
(1 
day)
Day
57 
(1 
day)
Day
64 
(1 
day)
Day
71 
(1 
day)
Day
78 
(1 
day)
Day
85 
(1 
day)
PK 
samplin
g11
X11,
12
X11,1
2
X11,1
2
 
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12.7.3.
Protocol changes for Amendment 03 (28-JUNE-2017) from 
Protocol Amendment 02 (07-MAR-2017)
Protocol Amendment 3 replaces the protocol amendment 2 dated 07 Mar 2017 and 
applies to all study sites. 
Protocol Amendment 3 is being implemented for the following reasons:

To reduce sample size from 8 subjects (6 active:2 placebo) to 4 subjects 
(3 active:1 placebo) in Part 1. 

Rationale: The purpose of the single dose administration in Part 1 is to examine 
target engagement (e.g., effect on viral biomarkers) and safety of GSK3389404 
in HBV patients. Safety data is already available from the first-in-human healthy 
volunteer study (202007), with no reported deaths or SAEs following single and 
multiple dose administration. Based on investigator feedback and internal 
discussion it was determined that the effect on viral biomarkers should be 
evident within a cohort of 3 active, 1 placebo. Study 205670 is not statistically 
powered and reducing the sample size of Part 1 will not affect the scientific 
integrity of the program.

To update the subject population in Part 1 to allow inclusion of subjects on 
nucleos(t)ide therapy and hepatitis B virus e-antigen (HBeAg) negative patients into
Cohorts A, B, C and D.

Rationale: The primary viral efficacy marker is the reduction of HBsAg and this
reduction can be evaluated equally well in HBeAg positive, HBeAg negative 
and in patients receiving nucleos(t)ide therapy. Based on investigator feedback, 
the sponsor would like to widen the entry criteria to i) include patients currently 
on stable nucleos(t)ide therapy and ii) allow both HBeAg negative and positive 
patients into cohorts A, B, C and D rather than restricting recruitment to HBeAg 
positive patients. 

To remove the requirement for a minimum viral load at entry for treatment naïve 
subjects or subjects that have had prior treatment with interferon or nucleosides in 
Part 1.

Rationale: The primary efficacy endpoint is reduction in HBsAg and as such 
restricting the population to a minimum HBV DNA threshold is an unnecessary 
restriction.

To update the subject population in Parts 1 and 2 to include women of child bearing 
potential 

Rationale: The risk of GSK3389404 to women of child bearing potential is 
considered to be low based upon pre-clinical embryo-fetal development studies
to date with the GSK3389404 compound and with the ASO class in general. 
Appropriate pregnancy precautions (e.g., double barrier contraceptives) will be 
implemented and pregnancy testing will be conducted before (serum at 
screening, urine prior to dosing) and during the study.
 
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
To update the subject population in Parts 1 and 2 to include patients with GFR 60 
mL/min after consultation with the GSK medical monitor. 

Rationale: In young adults, although the normal GFR number is >90 mL/min, 
many older subjects will have GFR below 90 mL/min in the absence of kidney 
disease. Consequently, the sponsor has revised the protocol to allow patients 
with a GFR number of 60 mL/min to participate in the study if after 
consultation with the GSK medical monitor the patient does not have a history 
or active diagnosis of renal disease.

To update the overall design and types/numbers of subjects that will be enrolled 
given the addition of an optional Japanese Part 2 sub-study. 

Rationale: Japan may also participate in an optional Japanese Part 2 sub-study. 
The protocol amendment 3 is updated to reflect the potential increase in number 
of subjects who may be exposed to GSK3389404.

To reduce complexity and visit burden for subjects. 

Rationale: Feedback from investigators suggests that the visit schedule in Parts 1 
and 2 remain burdensome for subjects. In particular, it was requested to remove 
mandatory fasting for all visits as this does not affect safety lab parameters 
(except fasting glucose measurement), to remove holter monitoring (supported 
by the absence of pre-clinical cardiac signals and absence of findings in the first-
in-human study 202007), to reduce routine ECG readings from duplicate or
triplicate to single assessments and to streamline/simplify visit schedules.

To provide information from the results of the GSK3389404 first-in-human Study 
202007.

Rationale: The first-in-human study 202007 was recently completed and at the 
time of this protocol writing, the study report is being finalized. Preliminary 
information from study 202007 to support changes in the study design, dose 
selection, benefit:risk, and Time and Events assessments were included.

To provide corrections to the statistical simulations

Rationale: The statistical assumptions were found to have an unintended bias, 
the simulations and decision criteria were updated appropriately

To provide minor edits for clarity and typographical errors.
LIST OF CHANGES
Title Page, Authors

Rationale: To update authors
Original Text:
Author (s):
 
 
 
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Amended Text:
Author (s):
 
Protocol Synopsis and Section 2.1, Study Rationale Last 2 Sentences

Rationale: To update the subject population in Part 1 to allow inclusion of subjects 
on nucleos(t)ide therapy and hepatitis B virus e-antigen (HBeAg) negative patients 
into Cohorts A, B, C and D. 
Original Text:
Finally, this study will provide an initial evaluation of any differences in PD between 
hepatitis B virus (HBV) e antigen (HBeAg)-positive and HBeAg-negative subjects with 
CHB. Data from this study will support subsequent studies by providing an early 
assessment of safety and PD in the target patient population when GSK3389404 is 
administered as monotherapy (Part 1) or adjunctive therapy (Part 2).
Amended Text: 
Finally, this study will may provide an initial evaluation of any differences in PD 
between hepatitis B virus (HBV) e antigen (HBeAg)-positive and HBeAg-negative 
subjects with CHB. Data from this study will support subsequent studies by providing an 
early assessment of safety and PD in the target patient population when GSK3389404 is 
administered as monotherapy (Part 1) or adjunctive therapy (Part 2).
 
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Protocol Synopsis and Section 3, Objective(s) and Endpoint(s), Primary

Rationale: To make edits for typographical error
Original text
To identify one or more efficacious dose(s) and 
dosing regimen(s) of GSK3389404 over a planned 
duration of 3 months (Part 2).
Efficacy
Response rate (RR) based on the proportion of 
subjects with at least a 1.5 times log 10 copies/mL 
reduction of hepatitis B surface antigen (HBsAg) 
levels from baseline anytime during the study.
Amended text
To identify one or more efficacious dose(s) and 
dosing regimen(s) of GSK3389404 over a planned 
duration of 3 months (Part 2).
Efficacy
Response rate (RR) based on the proportion of 
subjects with at least a 1.5 times log 10 copiesIU/mL 
reduction of hepatitis B surface antigen (HBsAg) 
levels from baseline anytime during the study.
Protocol Synopsis and Section 3, Objective(s) and Endpoint(s), Secondary

Rationale: To update the subject population in Part 1 to allow inclusion of subjects 
on nucleos(t)ide therapy and hepatitis B virus e-antigen (HBeAg) negative patients 
into Cohorts A, B, C and D.; subjects who are receiving nucleos(t)ide therapy would 
have suppressed HBV DNA levels
Original Text:
Secondary
To assess the PD effect of GSK3389404 in 
subjects with CHB (Part 1 and Part 2).
Correlation between GSK3389404 PK parameters 
and PD parameters, including hepatitis B virus (HBV) 
deoxyribonucleic acid (DNA), HBsAg, and HBeAg 
levels (as appropriate, HBeAg-positive subjects).
Amended Text: 
Secondary
To assess the PD effect of GSK3389404 in 
subjects with CHB (Part 1 and Part 2).
Correlation between GSK3389404 PK parameters 
and PD parameters, including hepatitis B virus (HBV) 
deoxyribonucleic acid (DNA) as appropriate, HBsAg, 
and HBeAg levels (as appropriate, HBeAg-positive 
subjects).
Protocol Synopsis and Section 3, Objective(s) and Endpoint(s), Exploratory

Rationale: To provide edits for clarity; to provide details regarding other PD 
parameters that may be assessed
 
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Original Text:
Exploratory
To assess PD differences in HBeAg-positive and 
HBeAg-negative subjects with CHB (Part 1 and 
Part 2, if applicable).
Correlation between PD parameters, including HBV 
DNA and HBsAg.
Amended Text: 
Exploratory
To assess PD differences in HBeAg-positive and 
HBeAg-negative subjects with CHB (Part 1 and 
Part 2, if applicable).
Correlation between PD parameters, including HBV 
DNA, HBV RNA, and HBsAg, and/or hepatitis B 
core-related antigen (HBcrAg).
Protocol Synopsis, Overall Design, Paragraph 2, Bullets 1 through 5 and Paragraph 3

Rationale: To update the subject population in Part 1 to allow inclusion of subjects 
on nucleos(t)ide therapy and hepatitis B virus e-antigen (HBeAg) negative patients 
into Cohorts A, B, C and D. 
Original Text:
Part 1 will be conducted as a single ascending dose (SAD) study with 5 planned cohorts.

Cohort A (HBeAg-positive subjects): GSK3389404 30 mg SC or placebo

Cohort B (HBeAg-positive subjects): GSK3389404 60 mg SC or placebo

Cohort C (HBeAg-positive subjects): GSK3389404 120 mg SC or placebo

Cohort C1, optional (HBeAg-negative subjects): GSK3389404 120 mg SC or 
placebo

Cohort D (HBeAg-positive subjects): GSK3389404 240 mg SC or placebo
Within each cohort, subjects will be randomized to receive GSK3389404 or placebo SC 
in a 3:1 ratio. Cohorts A, B, C, C1, and D will be conducted in a sequential fashion; 
Cohort C1 may be dosed after Cohort C or in parallel with Cohort D. Dose Escalation 
Committee meetings will be held between sequential cohorts.
Amended Text: 
Part 1 plans to enroll subjects primarily from the Asia-Pacific region (including, but 
not limited to: Hong Kong, South Korea, and Taiwan). Part 1 will be conducted as a 
single ascending dose (SAD) study with up to 5 planned cohorts.

Cohort A (HBeAg-positive and/or HBeAg –negative subjects): GSK3389404
30 mg SC or placebo

Cohort B (HBeAg-positive and/or HBeAg –negative subjects): GSK3389404 
60 mg SC or placebo
 
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
Cohort C (HBeAg-positive and/or HBeAg –negative subjects): GSK3389404 
120 mg SC or placebo

Cohort C1, optional (HBeAg-positive or HBeAg-negative subjects): 
GSK3389404 120 mg SC or placebo

Cohort D (HBeAg-positive and/or HBeAg –negative subjects): GSK3389404 
240 mg SC or placebo
Within each cohort, subjects will be randomized to receive GSK3389404 or placebo SC 
in a 3:1 ratio. Cohorts A, B, C, C1, and D will be conducted in a sequential fashion.;
Cohort C1 is an optional cohort that may be dosed after Cohort C or in parallel with 
Cohort D. Dose Escalation Committee meetings will be held between sequential cohorts. 
The decision to enroll the optional Cohort C1 will be made at a prior Dose 
Escalation Committee Meeting.
Protocol Synopsis, Overall Design, Paragraph 4, Inserted New Sentence 2 and 3

Rationale: To update the overall design and types/numbers of subjects that will be 
enrolled given the addition of an optional Japanese Part 2 sub-study. 
Original Text:
Not applicable
Amended Text:
Part 2 plans to enroll subjects primarily from the Asia-Pacific region. Japan may 
also participate in an optional Japanese Part 2 sub study. 
Protocol Synopsis, Overall Design, New added at Paragraph 6

Rationale: To update the overall design and types/numbers of subjects that will be 
enrolled given the addition of an optional Japanese Part 2 sub-study. 
Original Text:
Since this is the first administration of GSK3389404 in subjects with CHB, the study 
design may change based on emerging data (safety, tolerability, and PD) from each 
cohort and/or part.
Amended Text:
Details of the optional Japanese Part 2 sub-study will be detailed in a Japan 
country-specific amendment/supplement.
 
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Since this is the first administration of GSK3389404 in subjects with CHB, the study 
design may change based on emerging data (safety, tolerability, and PD) from each 
cohort and/or part.
Protocol Synopsis and Section 4.3, Type and Number of Subjects, Paragraph 1, 
Sentences 1 and 2
Rationale: To update the subject population in Part 1 to allow inclusion of subjects on 
nucleos(t)ide therapy and hepatitis B virus e-antigen (HBeAg) negative patients into 
Cohorts A, B, C and D. Original Text:
Adult male and female subjects with CHB between 18 and 70 years of age, inclusive, and 
not currently receiving CHB treatment (Part 1) or currently on a stable nucleos(t)ide 
regimen (Part 2) are planned for inclusion. Part 1 (Cohorts A, B, C and D) will enroll 
HBeAg-positive subjects, and Part 1 (Cohort C1) will enroll HBeAg-negative subjects.
Amended Text: 
Adult male and female subjects with CHB between 18 and 70 years of age, inclusive, and 
not currently receiving CHB treatment (Part 1) or currently on a stable nucleos(t)ide 
regimen (Part 2) are planned for inclusion. Part 1 (Cohorts A, B, C and D) will enroll 
HBeAg-positive and/or HBeAg-negative subjects, and Part 1 (optional Cohort C1) will
may enroll HBeAg-positive or HBeAg-negative subjects (or none at all).
Protocol Synopsis and Section 4.3, Type and Number of Subjects, Paragraph 2, Sentence 
1, Bullet 1 and new Bullet 3

Rationale: To update the overall design and types/numbers of subjects that will be 
enrolled given the addition of an optional Japanese Part 2 sub-study
Original Text:
Approximately 120 subjects with CHB are planned for randomization to study treatment 
(GSK3389404 or placebo) in Part 1 and Part 2. 

In Part 1, approximately 40 subjects with CHB are planned for randomization 
(30 GSK3389404 and 10 placebo). 

In Part 2, approximately 80 subjects with CHB are planned for randomization 
to study treatment. 
Amended Text: 
Approximately 150 subjects with CHB are planned for randomization to study treatment 
(GSK3389404 or placebo). This number assumes full enrolment in the optional 
Japanese sub-study.
 
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In Part 1, approximately 4020 to 40 subjects with CHB are planned for 
randomization (30 GSK3389404 and 10 placebo under older protocol 
versions versus 15 GSK3389404 and 5 placebo under amendment 3). A 
range is provided because different countries and sites may be enrolling 
under the older versions of the protocol.

If Japan participates in the optional Japanese Part 2 sub-study, 
approximately 22 subjects may be enrolled. The exact number of subjects 
to be enrolled may be found in a Japanese-specific protocol 
amendment/supplement.
Protocol Synopsys, Analysis, Part 2 and Section 9.1, Hypotheses and 9.4.1, Efficacy

Rationale: To provide corrections to the statistical simulations
Original Text:
An active treatment group will be declared efficacious if the posterior probability that the 
difference in the RRs between that active group and the placebo is positive, is high (at 
least 80%), i.e., P (RRACT > RRPBO) 80%, where RRACT is the RR in active group, 
RRPBO is the RR in placebo, and P is the posterior probability.
Amendend Text:
An active treatment group will be declared efficacious if the posterior probability that the 
difference in the RRs between that active group and the placebo is positive, is high (at 
least 9580%), i.e., P (RRACT > RRPBO) 9580%, where RRACT is the RR in active group, 
RRPBO is the RR in placebo, and P is the posterior probability.
Protocol Synopsis, Analysis

Rationale: To make edits for typographical error
Original text
The primary efficacy objective is to select the efficacious dose level and dosing regimen 
of GSK3389404 as determined by the primary endpoint, response rate (RR), based on 
reduction of HBsAg level from baseline. A subject will be considered a responder if there 
is at least a 1.5 times log 10 copies/mL reduction of HBsAg levels from baseline anytime 
during the study.
Amended text
The primary efficacy objective is to select the efficacious dose level and dosing regimen 
of GSK3389404 as determined by the primary endpoint, response rate (RR), based on 
reduction of HBsAg level from baseline. A subject will be considered a responder if there 
is at least a 1.5 times log 10 copies IU/mL reduction of HBsAg levels from baseline 
anytime during the study.
 
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Section 2, Introduction, Last paragraph, 1st and 2nd Sentences

Rationale: To provide minor edits for clarity
Original Text:
ISIS 505358 has been studied in healthy volunteers at various dose levels and for 
durations up to 1 month. GSK3389404 has been administered to healthy volunteers in 
Study 202007, an on-going study to assess the safety, tolerability and pharmacokinetics 
(PK) of single and multiple ascending doses of GSK3389404. Results from the 
completed study of ISIS 505358 and from the single ascending dose (SAD) portion of the 
ongoing Study 202007 have not identified any safety findings to date that would preclude 
further clinical development.
Amended Text: 
ISIS 505358 has been studied in healthy volunteers at various dose levels and for 
durations up to 1 month. GSK3389404 has been administered to healthy volunteers in 
Study 202007, a recently completed study to assess the safety, tolerability and 
pharmacokinetics (PK) of single and multiple ascending doses of GSK3389404. Results 
from the completed study of ISIS 505358 and from the single ascending dose (SAD) 
portion of Study 202007 have not identified any safety findings to date that would 
preclude further clinical development.
Section 2.1 Study Rationale, Paragraph 1, Sentence 4

Rationale: To provide minor edits for clarity
Original Text: 
Finally, this study will provide an initial evaluation of any differences in PD between 
HBV e-antigen (HBeAg)-positive and HBeAg-negative subjects with CHB.
Amended Text:
Finally, this study may provide an initial evaluation of any differences in PD between 
HBV e-antigen (HBeAg)-positive and HBeAg-negative subjects with CHB.
Section 4.1, Overall Design, Paragraph 2, New Sentence 1

Rationale: To provide minor edits for clarity 
Original Text:
Not applicable
Part 1 plans to enroll subjects primarily from the Asia-Pacific region (including, but 
not limited to, Hong Kong, South Korea, and Taiwan). 
 
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Section 4.1, Overall Design, Paragraph 2, Sentence 3 and New Sentence 4

Rationale: To update the subject population in Part 1 to allow inclusion of subjects 
on nucleos(t)ide therapy and hepatitis B virus e-antigen (HBeAg) negative patients 
into Cohorts A, B, C and D.
Original Text:
Cohorts A, B, C, C1, and D will be conducted in a sequential fashion; Cohort C1 may be 
dosed after Cohort C or in parallel with Cohort D.
Amended Text: 
Cohorts A, B, C, C1, and D will be conducted in a sequential fashion; Cohort C1 is an 
optional cohort that may be dosed after Cohort C or in parallel with Cohort D. The 
decision to enroll the optional Cohort C1 will be made at a prior Dose Escalation 
Committee Meeting.
Section 4.1, Overall Design, Paragraph 2, Sentence 4

Rationale: To reduce sample size from 8 subjects (6 active:2 placebo) to 4 
subjects (3 active:1 placebo) in Part 1
Original Text:
Dosing in each cohort is contingent on the safety, PK, and PD profiles of at least 
4 subjects who received GSK3389404 at the previous dose level.
Amended Text:
Dosing in each cohort is contingent on the safety, PK, and PD profiles of at least 
43 subjects who received GSK3389404 at the previous dose level.
Section 4.1, Overall Design, Paragraph 2, New Sentence 7

Rationale: To provide edits for clarity
Original Text:
Additional dose(s) may also be considered to further assess safety, tolerability, PK, 
and/or PD. Section 6.3 provides additional information on planned dose adjustments.
 
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Amended Text:
Cohorts may be expanded (additional subjects may be enrolled) to further evaluate 
safety, PK, and/or PD findings at a given dose level. Additional dose(s) may also be 
considered to further assess safety, tolerability, PK, and/or PD. Section 6.3 provides 
additional information on planned dose adjustments.
Section 4.1, Overall Design, Figure 1

Rationale: To reduce sample size from 8 subjects (6 active:2 placebo) to 4 subjects 
(3 active:1 placebo) in Part 1; To update the subject population in Part 1 to allow 
inclusion of subjects on nucleos(t)ide therapy and hepatitis B virus e-antigen 
(HBeAg) negative patients into Cohorts A, B, C and D. 
Original Text:
A = active (GSK3389404); HBeAg = hepatitis B virus e-antigen; P = placebo.
◊= Dose EscalationCommittee meeting
1.
Cohort C1 may be dosed after Cohort C or in parallel with Cohort D. 
2.
HBeAg-positive subjects will be enrolled in these cohorts.
3.
Dose escalations and/or reductions will progress with modifications based on the actual human safety and PK 
data from the preceding cohort(s). Additional dose(s) may also be considered to further assess safety, 
tolerability, PK, and/or PD. Dose will not exceed 240 mg.
Amended Text:
A = active (GSK3389404); HBeAg = hepatitis B virus e-antigen; P = placebo.
◊= Dose EscalationCommittee meeting
 
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1.
Cohort C1 may include HBeAg-positive or HBeAg-negative subjects and, if enrolled, may be dosed after 
Cohort C, or in parallel with Cohort D (optional). 
2.
HBeAg-positive and/or HBeAg-negative subjects will be enrolled in these cohorts.
3.
Dose escalations and/or reductions will progress with modifications based on the actual human safety and PK 
data from the preceding cohort(s). Additional dose(s) may also be considered to further assess safety, 
tolerability, PK, and/or PD. Dose will not exceed 240 mg.
Section 4.1, Overall Design, Paragraph 4, New Sentences 2 and 3

Rationale: To update the overall design and types/numbers of subjects that will be 
enrolled given the addition of an optional Japanese Part 2 sub-study. 
Original Text: 
Not Applicable
Amended Text:
Part 2 plans to enroll subjects primarily the Asia-Pacific region, including Japan. 
Japan may also participate in an optional Japanese Part 2 sub-study. 
Section 4.1, Overall Design, Figure 2

Rationale: To update the overall design and types/numbers of subjects that will be 
enrolled given the addition of an optional Japanese Part 2 sub-study. 
Original Text:
Amended Text: 
 
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Section 4.1, Overall Design, Figure 2, New Footnote 6

Rationale: To update the overall design and types/numbers of subjects that will be 
enrolled given the addition of an optional Japanese Part 2 sub-study. 
Original Text:
Not applicable
Amended Text:
6.
An optional Japanese Part 2 sub-study is planned. The exact details may be 
found in a country-specific protocol amendment/supplement and will not be 
detailed here. The optional Japanese Part 2 sub-study may include more 
intensive PK monitoring and/or potential overnight/hospital stay.
Section 4.3, Type and Number of Subjects, Paragraph 2, Bullet 2, Last Sentence and 
Bullet 3, First Sentence

Rationale: To update the overall design and types/numbers of subjects that will be 
enrolled given the addition of an optional Japanese Part 2 sub-study. 
Original Text:
 
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Enrolling approximately 80 subjects will allow for an approximate 14% overall drop-out 
rate, so that there are 10 evaluable subjects in each active treatment group and 12 subjects 
in placebo.
Amended Text: 
Enrolling approximately 80 subjects will allow ensure enough power for Part 2 with or 
without the optional Japanese Part 2 sub-study and allow for an approximate 14% 
overall drop-out rate, so that there are 10 evaluable subjects in each active treatment 
group and 12 subjects in placebo without the optional Japanese Part 2 sub-study for 
the primary analysis.
If Japan participates in the optional Japanese Part 2 sub-study, approximately 
22 subjects may be enrolled. The exact number of subjects to be enrolled may be 
found in a Japanese-specific protocol amendment/supplement.
Section 4.4, Design Justification, Paragraph 2, Sentence 2
Rationale: To update the subject population in Part 1 to allow inclusion of subjects on 
nucleos(t)ide therapy and hepatitis B virus e-antigen (HBeAg) negative patients into 
Cohorts A, B, C and D. Original Text:
The sequential nature of Part 1 ensures that a range of single doses are investigated first 
in HBeAg-positive subjects (Part 1, Cohorts A, B, C) and HBeAg-negative subjects 
(Cohort C1) before exposing HBeAg-positive subjects to the highest planned dose 
(Cohort D).
Amended Text: 
The sequential nature of Part 1 ensures that a range of single doses are investigated first 
in HBeAg-positive subjects (Part 1, Cohorts A, B, C) and HBeAg-negative subjects 
(Cohort C1) before exposing HBeAg-positive subjects to the highest planned dose 
(Cohort D).
Section 4.4, Design Justification, Paragraph 3, Sentences 2 and 4

Rationale: To provide information from the results of the GSK3389404 
first-in-human Study 202007 and clarify dose escalation
Original Text:
This starting dose is based on the review of data from the SAD portion of the ongoing 
clinical trial (Study 202007).
Part 2 will be initiated after the PK, safety, and tolerability of the previous single dose 
level(s) are thoroughly reviewed by the study team and investigator at the Dose 
Escalation Committee meetings for Part 1. 
 
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Part 2 will be initiated after the PK, safety, and tolerability of the previous single dose 
level(s) are thoroughly reviewed by the study team and investigator at the Dose 
Escalation Committee meetings for Part 1.
Amended Text:
This starting dose is based on the review of data from the SAD portion of the ongoing
recently completed clinical trial (Study 202007; at the time of this protocol writing, 
the final study report is in progress).
Part 2 will be initiated after the PK, safety, and tolerability of the previous single dose 
level(s) are thoroughly reviewed by the GSK study team and principal investigator (or 
appropriate designee) at the Dose Escalation Committee meetings for Part 1. 
.
Section 4.5.1, Observed Human Pharmacokinetics, Paragraph 1, Sentence 3, 4 and 6

Rationale: To provide information from the results of the GSK3389404 
first-in-human Study 202007.
Original Text:
At the time of this protocol writing, the SAD part of Study 202007 has been completed, 
and the multiple ascending dose part is ongoing. The preliminary human PK parameters 
are presented in Table 1. Based on preliminary PK data, GSK3389404 showed 
dose-proportional PK with a mean half-life of approximately 4 to 5 hours at a dose range 
of 10 to 120 mg. GSK3389404 plasma concentrations were similar after the first and 
fourth weekly dose, indicating no accumulation in plasma concentration after multiple 
doses. Half-life and plasma exposure (AUC and Cmax) of GSK3389404 following 
multiple doses were consistent with those observed following a single dose. The 
preliminary observed human PK data were evaluated using non-compartmental analysis 
(NCA) in Phoenix WinNonlin version 6.3. All ISIS50538 (GSK3228836) plasma 
concentrations were non-quantifiable.
Amended Text: 
At the time of this protocol amendment writing, the SAD part of Study 202007 has been 
completed, and the multiple ascending dose part is ongoing final study report is in 
progress. The preliminary human PK parameters are presented in Table 1. Based on 
preliminary PK data, GSK3389404 showed dose-proportional PK with a mean half-life of 
approximately 4 to 5 hours at a dose range of 10 to 120 mg. GSK3389404 plasma 
concentrations were similar after the first and fourth weekly dose, indicating no 
accumulation in plasma concentration after multiple doses. Half-life and plasma exposure 
(AUC and Cmax) of GSK3389404 following multiple doses were consistent with those 
observed following a single dose. The preliminary observed human PK data were 
evaluated using non-compartmental analysis (NCA) in Phoenix WinNonlin version 6.3. 
All ISIS50538 (GSK3228836) plasma concentrations were non-quantifiable.
 
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Table 1, Title
Rationale: To provide clarity that results reported are not preliminary
Original Text:
Summary of Selected Preliminary Plasma GSK3389404 Pharmacokinetic Parameters in 
Humans
Amended Text:
Summary of Selected Preliminary Plasma GSK3389404 Pharmacokinetic Parameters in 
Humans
.
Section 4.5.5 GSK3389404 and Nucleos(t)ides 4th Paragraph, Last Sentence
Rationale: To provide clarity
Original Text: 
Therefore, although GSK3389404 was shown to be extensively distributed into the 
kidney [Shemesh, 2016], GSK3389404 is unlikely to interact with tenofovir, entecavir, 
lamivudine, adefovir and telbivudine.
Amended text: 
Therefore, although GSK3389404 or the primary tissue metabolite ISIS 505358 that 
was shown to be extensively distributed into the kidney in non-clinical studies, 
GSK3389404 is unlikely to interact with tenofovir, entecavir, lamivudine, adefovir and 
telbivudine.
Section 4.6.1, Risk Assessment, Table 4, Column 1 (Potential Risk/Summary of Data), 
Liver Effects, New Paragraph 

Rationale: To provide information from the results of the GSK3389404 
first-in-human Study 202007.
Original Text:
Not applicable
Amended Text:
In the GSK 3389404 Phase 1 study in healthy subjects (Study 202007), in Part 1 
single dose, two subjects experienced mild or moderate adverse events associated 
with elevations in ALT. Both were transient, modest (DAIDs criteria Grade 1 (<2.5x 
 
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ULN))and not associated with concurrent symptoms or increases in bilirubin. In 
Part 2 multiple dose, no liver-chemistry related AEs were reported.
Section 4.6.1, Risk Assessment, Table 4, Column 1 (Potential Risk/Summary of Data), 
Coagulation Effects, New Paragraph 

Rationale: To provide information from the results of the GSK3389404 
first-in-human Study 202007.
Original Text:
Not applicable
Amended Text:
In Study 202007, the GSK 3389404 Phase 1 study in healthy subjects, there was no 
evidence of GSK3389404 related prolongation of aPPT.
Section 4.6.1, Risk Assessment, Table 4, Column 1 (Potential Risk/Summary of Data), 
Compliment Activation, New Paragraph 

Rationale: To provide information from the results of the GSK3389404 
first-in-human Study 202007.
Original Text:
Not applicable
Amended Text:
In Study 202007, the GSK 3389404 Phase 1 study in healthy subjects, no effect of 
GSK3389404 administration on complement (C3, C4, C5a or Bb) was observed.
Section 4.6.1, Risk Assessment, Table 4, Column 1 (Potential Risk/Summary of Data), 
Pro-inflammatory Effects/Constitutional or Flu-Like Symptoms, New Paragraph 

Rationale: To provide information from the results of the GSK3389404 
first-in-human Study 202007.
Original Text:
Not applicable
Amended Text:
In Study 202007, the GSK 3389404 Phase 1 study in healthy subjects, influenza-
like/constitutional symptoms such as fever, chills and arthralgias were not observed.
Injection site reactions were the most commonly reported treatment-related adverse 
 
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event. These AEs were mild in intensity, transient in nature and not related to dose 
or duration of treatment.
Section 4.6.1, Risk Assessment, Table 4, Column 1 (Potential Risk/Summary of Data), 
Kidney Effects, New Paragraph

Rationale: To provide information from the results of the GSK3389404 
first-in-human Study 202007.
Original Text:
Not applicable
Amended Text:
In Study 202007, the GSK 3389404 Phase 1 study in healthy subjects, no changes in 
the mean values from baseline were observed. 
Section 4.6.1, Risk Assessment, Table 4, Column 2 (Impact- Eligibility Criteria), Kidney 
Effects 

Rationale: To update the subject population in Parts 1 and 2 to include patients with 
GFR 60 mL/min after consultation with the GSK medical monitor. 
Original: Subjects with serum creatinine ULN, glomerular filtration rate (GFR) < 90 
mL/min
Amended text: Subjects with serum creatinine ULN, glomerular filtration rate (GFR) < 
90 mL/min (but 60 mL/min may be considered after consultation with the GSK 
Medical Monitor)
Section 4.6.1, Risk Assessment, Table 4, Column 1 (Potential Risk/Summary of Data), 
Compelment Activation 
Rationale: To provide minor edits due to typographical error
Original Text:
Complement Activation: In the monkey GSK3389404 13-week study, minimal 
decreases in (up to 21% from baseline) C3 and increased complement fragment Bb (up to 
2.6-fold over baseline) were observed in the 8 and 30 mg/kg groups, suggesting mild 
activation of the alternative complement pathway. 
Amended Text:
Complement Activation: In the monkey GSK3389404 13-week study, minimal 
decreases in (up to 21% from baseline) C3 and increased complement fragment Bb (up to 
32.6-fold over baseline) were observed in the 8 and 30 mg/kg groups, suggesting mild 
activation of the alternative complement pathway. 
 
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Section 4.6.1, Risk Assessment, Table 4, Column 1 (Potential Risk/Summary of Data), 
Decreased hematological parameters, New Paragraph 

Rationale: To provide information from the results of the GSK3389404 
first-in-human Study 202007.
Original Text:
Not applicable
Amended Text:
In Study 202007, the GSK 3389404 Phase 1 study in healthy subjects, the laboratory 
data did not suggest any GSK3389404 related effect on hematological cell counts or 
hemoglobin.
Section 4.6.2, Benefit Risk Summary, Paragraph 3, Item 4, 

Rationale: To reduce complexity and visit burden for subjects. 
Original Text:
4.
Between each dosing cohort in Part 1, escalation to the next dose-level will 
proceed only after the safety (AE listings, flagged vital signs, flagged findings 
during cardiac monitoring [Holter], ECGs, laboratory findings (including liver 
function tests) of the previous dose level, and PK results derived from 24-hour 
plasma profiles, together with available PD data (HBsAg levels and HBV DNA) 
are thoroughly reviewed by the study team and the investigator at scheduled Dose 
Escalation Committee meetings (Section 10.8.1).
Amended Text:
4.
Between each dosing cohort in Part 1, escalation to the next dose-level will 
proceed only after the safety (AE listings, flagged vital signs, flagged findings 
during cardiac monitoring [Holter], ECGs, laboratory findings ([including liver 
function tests]) of the previous dose level, and PK results derived from 24-hour 
plasma profiles, together with available PD data (HBsAg levels and HBV DNA)
are thoroughly reviewed by the study team and the investigator at scheduled Dose 
Escalation Committee meetings (Section 10.8.1).
Section 5, Selection of Study Population and Withdrawal Criteria, Paragraph 1, 
Sentence 1, Sentence 5 and Last Sentence
Rationale: To update the subject population in Part 1 to allow inclusion of subjects on 
nucleos(t)ide therapy and hepatitis B virus e-antigen (HBeAg) negative patients into 
Cohorts A, B, C and D. Original Text:
 
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This first-in-patient study will enroll adult male and female subjects in either the immune 
tolerant or the immune active phase of HBV infection who are not currently receiving 
HBV treatment (Part 1) or who are currently on a stable nucleos(t)ide regimen (Part 2).
The entry criteria for this study are designed to enroll subjects with CHB who do not 
have advanced liver fibrosis or cirrhosis, other concomitant liver diseases, co-infection, 
or other significant co-morbidities that would confound the safety monitoring and/or 
potentially put them at greater risk for treatment-related AEs. 
The ALT eligibility criteria are generally consistent with the International Liver Society 
guidelines (e.g., Asian Pacific Association for the Study of the Liver [Liaw, 2012], 
European Association for the Study of the Liver [EASL, 2012], American Association for 
the Study of Liver Diseases [Terrault, 2016]).
Amended Text: 
This first-in-patient study will enroll adult male and female subjects in either the immune 
tolerant or the immune active phase of HBV infection who may or may are not be 
currently receiving HBV treatment (Part 1) or who are currently on a stable nucleos(t)ide 
regimen (Part 2).
The entry criteria for this study are designed to enroll subjects with CHB who do not 
have advanced liver fibrosis or cirrhosis, other advanced concomitant liver diseases, co-
infection, or other significant co-morbidities that would confound the safety monitoring 
and/or potentially put them at greater risk for treatment-related AEs.The ALT eligibility
criteria are generally consistent with the International Liver Society guidelines (e.g., 
Asian Pacific Association for the Study of the Liver [Liaw, 2012], European Association 
for the Study of the Liver [EASL, 2012], American Association for the Study of Liver 
Diseases [Terrault, 2016]).
Section 5.1, Inclusion Criteria, Item 4.

Rationale: To update the subject population in Parts 1 and 2 to include women of 
child bearing potential.
Original Text:
4. Male or female if they satisfy the following:
a. Females of reproductive potential are not permitted. Eligible females must meet 
the following criteria:
i. Non-pregnant (as confirmed by a negative serum human chorionic 
gonadotrophin [hCG] test); AND
ii. Non-lactating at screening and prior to dosing; AND
iii. Non-reproductive potential as defined by at least one of the following 
conditions:
 
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1. Premenopausal females without reproductive potential defined 
by one of the following:
a. Documented salpingectomy;
b. Hysterectomy;
c. Documented bilateral oophorectomy.
2. Postmenopausal defined as 12 months of spontaneous 
amenorrhea.
3. A blood sample for simultaneous follicle-stimulating hormone 
(FSH) and estradiol levels may be collected at the discretion of the 
investigator or site to confirm non-reproductive potential. Please 
refer to laboratory reference ranges for confirmatory levels for 
menopause.
b. Male subjects with a female partner of child-bearing potential must agree to 
meet one of the contraception requirements from the time of first dose of study 
treatment until the final Follow-up visit.
i. Vasectomy
ii. Male condom plus partner’s use of one of the contraceptive options 
below that meets the standard operating procedure (SOP) effectiveness 
criteria including a <1% rate of failure per year, as stated in the product 
label:
1. Contraceptive subdermal implant
2. Intrauterine device or intrauterine system
3. Combined estrogen and progestogen oral contraceptive 
[Hatcher, 2011]
4. Injectable progestogen [Hatcher, 2011]
5. Contraceptive vaginal ring [Hatcher, 2011]
6. Percutaneous contraceptive patches [Hatcher, 2011]
These allowed methods of contraception are only effective when used 
consistently, correctly and in accordance with the product label. The investigator 
is responsible for ensuring that subjects understand how to properly use these 
methods of contraception.
Amended Text:
4. Male or female if they satisfy the following:
 
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a. All Ffemales of reproductive potential are not permitted. Eligible females must 
meet the following criteria:
i. Non-pregnant (as confirmed by a negative serum human chorionic 
gonadotrophin [hCG] test); AND
ii. Non-lactating at screening and prior to dosing; AND
b. iii. Females of Non-reproductive potential (FRP) must agree to follow (or 
confirm that they have and are currently following) one of the options listed 
in the Modified List of Highly Effective Methods for Avoiding Pregnancy in 
FRP (see Appendix 4) from at least 28 days prior to the first dose of study 
treatment until the final Follow-up visit in conjunction with partner’s use of 
male condom. The investigator is responsible for ensuring that subjects 
understand how to properly use these methods of contraception.
c. For females of non-reproductive potential, as defined by at least one of the 
following conditions must apply:
1. i. Premenopausal females without reproductive potential defined by one 
of the following:
a. 1. Documented salpingectomy;
b. 2. Hysterectomy;
c. 3. Documented bilateral oophorectomy.
2ii. Postmenopausal defined as 12 months of spontaneous amenorrhea.
3iii. A blood sample for simultaneous follicle-stimulating hormone (FSH) 
and estradiol levels may be collected at the discretion of the investigator or 
site to confirm non-reproductive potential. Please refer to laboratory 
reference ranges for confirmatory levels for menopause.
bd. Male subjects with a female partner of child-bearing potential must agree to 
meet one of the contraception requirements from the time of first dose of study 
treatment until the final Follow-up visit.
i. Vasectomy
ii. Male condom plus partner’s use of one of the contraceptive options 
below that meets the standard operating procedure (SOP) effectiveness 
criteria including a <1% rate of failure per year, as stated in the product 
label:
1. Contraceptive subdermal implant
2. Intrauterine device or intrauterine system
 
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3. Combined estrogen and progestogen oral contraceptive 
[Hatcher, 2011]
4. Injectable progestogen [Hatcher, 2011]
5. Contraceptive vaginal ring [Hatcher, 2011]
6. Percutaneous contraceptive patches [Hatcher, 2011]
These allowed methods of contraception are only effective when used 
consistently, correctly and in accordance with the product label. The investigator 
is responsible for ensuring that subjects understand how to properly use these 
methods of contraception.
e.
Male subjects must refrain from donating sperm from the time of first 
dose of study treatment until the final Follow-up visit.
Section 5.1, Inclusion Criteria, Item 5.
Rationale: To provide clarity, documentation of chronic HBV infection is sufficient, does 
not require HBsAg only.
Original Text:
5. Documented chronic HBV infection, defined as positive plasma or serum HBsAg 
≥6 months prior to screening.
Amended Text:
5. Documented chronic HBV infection, defined as positive plasma or serum HBsAg 
≥6 months prior to screening.
Section 5.1, Inclusion Criteria, Item 6.a.
Rationale: To update the subject population in Part 1 to allow inclusion of subjects on 
nucleos(t)ide therapy and hepatitis B virus e-antigen (HBeAg) negative patients into 
Cohorts A, B, C and D. Original Text:
6. Subject with HBV treatment history as follows:
a.
Part 1: Treatment naive or have had prior treatment with interferon (pegylated 
or non-pegylated) that must have ended at least 12 months prior to the 
Baseline visit (Day 1 pre-dose) and/or nucleos(t)ide analogue therapy that 
must have ended at least 6 months prior to the Baseline visit.
Amended Text: 
6. Subject with HBV treatment history as follows:
a.
Part 1: 
 
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i. Treatment naïve, -or-
ii. Hhave had prior treatment with interferon (pegylated or non-pegylated) ) 
that must have ended at least 126 months prior to the Baseline visit 
(Day 1 pre-dose) and/or nucleos(t)ide analogue therapy that must have 
ended at least 6 months prior to the Baseline visit., –or-
iii. 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. 
Section 5.1, Inclusion Criteria, Item 7.

Rationale: To remove the requirement for a minimum viral load at entry for 
treatment naïve subjects or subjects that have had prior treatment with interferon or 
nucleosides in Part 1.
Original Text:
7. Plasma or serum HBV DNA concentration:
a.
Part 1:
i.
≥20,000 IU/mL for HBeAg-positive subject
ii.
≥2000 IU/mL for HBeAg-negative subjects
b.
Part 2: HBV DNA must be adequately suppressed, defined as plasma or 
serum HBV DNA <LLOQ.
Amended Text: 
7. Plasma or serum HBV DNA concentration:
a.
Treatment naïve subjects or subjects not currently receiving treatment, there is 
no minimum HBV DNA requirement.
b. Subjects who are receiving stable nucleos(t)ide analogue therapy must be 
adequately suppressed, defined as plasma or serum HBV DNA <LLOQ.
Section 5.1, Inclusion Criteria, Item 9.
Rationale: To update the subject population in Part 1 to allow inclusion of subjects on 
nucleos(t)ide therapy and hepatitis B virus e-antigen (HBeAg) negative patients into 
Cohorts A, B, C and D. Original Text:
9.
Alanine aminotransferase (ALT) concentration:
a.
Part 1: ALT < 5 X ULN
 
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b.
Part 2: ALT ULN
Amended Text: 
9.
Alanine aminotransferase (ALT) concentration:
a.
Part 1: 
a.
ALT < 5 X ULN for treatment naïve subjects and for subjects who are 
not currently receiving treatment
b.
ALT ULN for subjects who are receiving stable nucleos(t)ide 
analogue therapy
Section 5.2, Exclusion Criteria, Item 1.a.

Rationale: To provide minor edits for clarity
Original Text:
1.
Medical history
a.
History of or active diagnosis of liver disease other than CHB, such as 
autoimmune hepatitis, non-alcoholic fatty liver disease/non-alcoholic 
steatohepatitis, hemochromatosis, or liver failure.
b. History or other clinical evidence of hypertension significant or unstable 
cardiac disease (e.g., prolonged QT syndrome [torsade de pointes], angina, 
congestive heart failure, myocardial infarction, diastolic dysfunction, 
significant arrhythmia, coronary heart disease and/or clinically significant 
ECG abnormalities).
Amended Text: 
1.
Medical history
a.
History of or active diagnosis of moderate to severe liver disease other 
than CHB, such as autoimmune hepatitis, non-alcoholic fatty liver 
disease/non-alcoholic steatohepatitis, hemochromatosis, or liver failure.
b.
History or other clinical evidence of hypertension significant or unstable 
cardiac disease (e.g., prolonged QT syndrome [torsade de pointes], angina, 
congestive heart failure, myocardial infarction, diastolic dysfunction, 
significant arrhythmia, coronary heart disease and/or clinically significant 
ECG abnormalities).
 
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Section 5.2, Exclusion Criteria, Items 5, 6, 7
Rationale: To provide minor edits for clarity
Original Text:
5.
A positive hepatitis C virus (HCV) antibody test
6.
A positive human immunodeficiency virus (HIV) antibody test
7.
Positive hepatitis D virus (HDV) antibody test
Amended Text: 
5.
A positive hHepatitis C virus (HCV) antibody test co-infection
6.
A positive hHuman immunodeficiency virus (HIV) antibody test co-infection
7.
Positive hHepatitis D virus (HDV) antibody test co-infection
Section 5.2, Exclusion Criteria, Item 8.f

Rationale: To update the subject population in Parts 1 and 2 to include patients 
with GFR 60 mL/min after consultation with the GSK medical monitor. 
Original Text:
f.
Glomerular filtration rate (GFR) <90 mL/min as calculated by the Chronic 
Kidney Disease Epidemiologic Collaboration (CKD-EPI) formula.
Subjects with GFR <90 mL/min but 80 mL/min may be considered after 
consultation with the GSK medical monitor.
Amended Text:
f.
Glomerular filtration rate (GFR) <90 mL/min as calculated by the Chronic 
Kidney Disease Epidemiologic Collaboration (CKD-EPI) formula.
Subjects with GFR <90 mL/min but 8060 mL/min may be considered 
after consultation with the GSK medical monitor.
Section 5.2, Exclusion Criteria, Item 16

Rationale: To provide edits for clarity
Original Text:
16.
Prior treatment with any oligonucleotide or small interfering RNA (siRNA) 
within 12 months prior to the first dosing day.
Amended Text:
16.
Prior treatment with any non-GSK oligonucleotide or small interfering RNA 
(siRNA) within 12 months prior to the first dosing day or prior treatment with 
GSK oligonucleotide within 3 months prior to the first dosing day.
 
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Section 5.2, Exclusion Criteria, Item 17

Rationale: To provide edits for clarity
Original Text:
Not Applicable
Amended Text: 
Pregnant or lactating females at screening and prior to dosing
Section 5.4, QTc and Hematological Stopping Criteria

Rationale: To provide minor edits for clarity. Changes in this 
section were made to clarify that subjects were not to be withdrawn from the 
study, rather the intent was to withdraw subjects from study treatment or to 
discontinue study treatment and continue with safety follow up procedures and 
visits. Excerpts are shown below.
Original Text:
QTc Stopping Criteria:
A subject who meets either of the bulleted criteria below will be withdrawn from 
the study.
Withdrawal of subjects will be based on average QTcF from triplicate ECGs. 
Hematological Stopping Criteria:
In Parts 1 and 2, a subject who meets any of the criteria below will be withdrawn 
from study treatment
Amended Text:
QTc Stopping Criteria:
A subject who meets either of the bulleted criteria below will be withdrawn
discontinued from the study treatment
Withdrawal Discontinuation of subjects will be based on average QTcF from 
triplicate ECGs. 
Hematological Stopping Criteria:
In Parts 1 and 2, a subject who meets any of the criteria below will be 
discontinuedwithdrawn from study treatment
Section 5.4.4, Renal Function Stopping Criteria, Sentence 1

Rationale: To provide minor edits for clarity 
 
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Original Text:
If the following are observed in Part 1 or Part 2, results should be confirmed, and if 
confirmed, further evaluation for alternative causes should be pursued in consultation 
with the medical monitor:
Amended Text:
If any of the following are observed in Part 1 or Part 2, results should be confirmed, and 
if confirmed, further evaluation for alternative causes should be pursued in consultation 
with the medical monitor:
Section 6.1, Investigational Produce and Other Study Treatment, Paragraph 2, Sentence 2

Rationale: To reduce complexity and visit burden for subjects. 
Original Text:
Study treatment administration will take place in the morning after a minimum 8-hour 
overnight fast and after completion of all pre-dose study assessments as specified in the 
Time and Events Tables (Section 7.1). 
Amended Text:
Study treatment administration will take place in the morning after a minimum 8-hour 
overnight fast and after completion of all pre-dose study assessments as specified in the 
Time and Events Tables (Section 7.1). 
Section 6.2, Treatment Assignment, Paragraph 1, Sentence 2

Rationale: To update the overall design and types/numbers of subjects that will be 
enrolled given the addition of an optional Japanese Part 2 sub-study. 
Original Text:
In addition, for Part 2, separate randomization schedules will be generated for the sentinel 
subjects and the remainder of Part 2 subjects.
Amended Text:
Separate randomization schedules will be generated for each part of the study. In 
addition, for Part 2, separate randomization schedules will be generated for the sentinel 
subjects and the remainder of Part 2 subjects. The randomization schedule for the 
optional Japanese Part 2 sub-study will be generated separately.
Section 6.2, Treatment Assignment, Paragraphs 3 and 4
Rationale: To provide edits for clarity 
Original Text:
Two randomization schedules for Part 2 will be generated (one for the sentinel group and 
one for the remainder of subjects to complete Part 2 enrollment) after Part 1 is completed 
 
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and dose levels and regimens for Part 2 have been identified. Two or 3 dose levels each at 
2 different dosing regimens will be explored.
A separate randomization schedule will be generated for the sentinel group (1 subject 
from each active treatment group and the corresponding matching placebo). The 
remainder of Part 2 subjects will be centrally randomized using a randomization schedule 
to receive 1 of the active dose levels and regimens selected in Part 2 or corresponding 
matching placebo.
Amended Text:
Two randomization schedules for Part 2 will be generated (one for the sentinel group and 
one for the remainder of subjects to complete Part 2 enrollment) after Part 1 is completed 
and dose levels and regimens for Part 2 have been identified. A separate randomization 
schedule will be generated for the sentinel group. The remainder of Part 2 subjects will 
be centrally randomized using a randomization schedule to receive 1 of the active 
dose levels and regimens selected in Part 2 or corresponding matching placebo. Two 
or 3 dose levels each at 2 different dosing regimens will be explored. 
A separate randomization schedule will be generated for the sentinel group (1 subject 
from each active treatment group and the corresponding matching placebo). The 
remainder of Part 2 subjects will be centrally randomized using a randomization schedule 
to receive 1 of the active dose levels and regimens selected in Part 2 or corresponding 
matching placebo.
Section 6.2, Treatment Assignment, Paragraph 5

Rationale: To update the overall design and types/numbers of subjects that will be 
enrolled given the addition of an optional Japanese Part 2 sub-study. 
Original Text:
Subjects will be randomized in a 1:1 ratio (active:placebo) in the sentinel group. 
Remainder of the Part 2 subjects will be randomized in an approximately 10:1 ratio 
(active:placebo). The overall randomization ratio of Part 2 will be an approximately 
11:2 ratio (active:placebo).
Amended Text:
Subjects in Part 2 will be randomized in a 1:1 ratio (active:placebo) in the sentinel 
group. Remainder of the Part 2 subjects will be randomized in an approximately 
10:1 ratio (active:placebo). The overall randomization ratio of Part 2 will be an 
approximately 11:2 ratio (active:placebo). The randomization ratio of the optional 
Japanese Part 2 sub study will be provided in a Japan country-specific protocol 
amendment/supplement.
Sentinel
Remainder
Part 2
Active
Placebo
Active
Placebo
Dose Level 1, Regimen 1a
1
1
10
1
Dose Level 1, Regimen 2a
1
1
10
1
Dose Level 2, Regimen 1a
1
1
10
1
Dose Level 2, Regimen 2a
1
1
10
1
 
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Dose Level 3, Regimen 1a
1
1
10
1
Dose Level 3, Regimen 2a
1
1
10
1
a.
The actual dose levels and regimens will be identified after review of data from Part 1. Up to 3 dose 
levels and 2 regimens will be studied. 
Section 6.3, Planned Dose Adjustments, Paragraph 1, Bullet 1

Rationale: To reduce sample size from 8 subjects (6 active:2 placebo) to 4 subjects 
(3 active:1 placebo) in Part 1. 
Original Text:

In Part 1, the decision to proceed to the next dose level of GSK3389404, to adjust 
the next dose level, or add/remove cohorts will be made by the Dose Escalation 
Committee (Section 10.8.1) based on safety, tolerability and preliminary PK 
and/or PD data through Day 3 obtained in at least 4 subjects that received 
GSK3389404 at the prior dose level. 
Amended Text:

In Part 1, the decision to proceed to the next dose level of GSK3389404, to adjust 
the next dose level, or add/remove cohorts will be made by the Dose Escalation 
Committee (Section 10.8.1) based on safety, tolerability and preliminary PK 
and/or PD data through Day 3 obtained in at least 43 subjects that received 
GSK3389404 at the prior dose level. 
Section 6.3, Planned Dose Adjustments, Paragraph 1, Bullet 1, Sub-bullet 2

Rationale: To reduce sample size from 8 subjects (6 active:2 placebo) to 4 subjects 
(3 active:1 placebo) in Part 1; to provide edits for clarity
Original Text:
o
A Bayesian predictive probability of AUC(0-) and Cmax less than 
465.75 gh/mL and 57.9 g/mL (mean exposures at NOAEL dose in 
monkey at steady state), respectively, will be calculated for the next dose 
levels and used together with safety and tolerability data to aid next dose 
selection.
Amended Text: 
o
A Bayesian predictive probability of AUC(0-) and Cmax less than 
465.75 gh/mL and 57.9 g/mL (mean exposures at NOAEL dose in 
monkey at steady state), respectively, will may be calculated with adequate 
data for the next dose levels and used together with safety and tolerability 
data to aid next dose selection.
Section 6.3, Planned Dose Adjustments, Paragraph 1, Bullet 1, Sub-bullet 4, Sentence 1

Rationale: To provide edits for clarity 
 
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Original Text:
o
The dosing plan may also be adjusted to expand a dosing cohort to further 
evaluate safety, PK, and/or PD findings at a given dose level, or to add a 
cohort to evaluate 1 additional dose level.
Amended Text: 
o
The dosing plan may also be adjusted to expand a dosing cohort (enroll 
additional subjects) to further evaluate safety, PK, and/or PD findings at a 
given dose level, or to add a cohort(s) to evaluate 1 additional dose level(s), 
not exceeding the maximum dose as defined in Section 4.1.
Section 6.10, Treatment after the End of the Study 

Rationale: To provide edits for clarity 
Original Text:
The investigator is responsible for ensuring that consideration has been given to the 
post-study care of the subject’s medical condition, whether or not GSK is providing 
specific post-study treatment. 

In Part 1, subjects with CHB may be evaluated by the investigator for initiation of 
standard of care therapy after the final Follow-up visit (Day 60). 

In Part 2, subjects with CHB may discuss post-study care with the investigator.
Amended Text:
The investigator is responsible for ensuring that consideration has been given to the 
post-study care of the subject’s medical condition, whether or not GSK is providing 
specific post-study treatment. 

In Part 1, subjects with CHB may be evaluated by the investigator for initiation of 
standard of care therapy after the final Follow-up visit (Day 60). 

In Part 2, subjects with CHB may discuss post-study care with the investigator.
Section 6.11.1, Meals and Dietary Restrictions, delete Paragraph 1 

Rationale: To reduce complexity and visit burden for subjects. 
Original Text:
In Part 1 and Part 2, food and drink (other than water) will be restricted for the 8 hours 
prior to each dose administration. Subjects should be instructed to come into the clinic 
fasting for all outpatient visits, except for the Screening visit.
Amended Text:
 
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In Part 1 and Part 2, food and drink (other than water) will be restricted for the 8 hours 
prior to each dose administration. Subjects should be instructed to come into the clinic 
fasting for all outpatient visits, except for the Screening visit.
Section 6.1.11, Meals and Dietary Restrictions, Paragraph 2, Bullet 1

Rationale: To reduce complexity and visit burden for subjects. 
Original Text:

On Day 1, a morning snack (not full meal) will be provided after dosing and 
completion of morning study procedures. Lunch will be provided approximately 
4 hours post-dose. If subjects are still on-site, dinner will be provided 
approximately 9 hours post-dose and an evening snack may be available until 
22:00 hours. 
Amended Text:

On Day 1, a morning snack (not full meal) will be provided after dosing and 
completion of morning study procedures. A meal or lLunch will be provided 
approximately 4 hours post-dose. If appropriate subjects are still on-site, dinner 
will be provided approximately 9 hours post-dose and an evening snack may be 
available until 22:00 hours. 
Section 6.11.1, Meals and Dietary Restrictions, Paragraph 3

Rationale: To provide minor edits for clarity 
Original Text:
During Part 2 (and Part 1 outpatient visits), subjects will be offered a meal (e.g., bagged 
or canteen) after completion of all study procedures at each outpatient visit.
Amended Text:
During Part 2 (and Part 1 outpatient visits), subjects will be offered a meal (e.g., bagged 
or canteen [or reimbursed]) after completion of all study procedures at each outpatient 
visit.
Section 6.12.1, Permitted Medications and Non-Drug Therapies, New Sentence 1
Rationale: To update the subject population in Part 1 to allow inclusion of subjects on 
nucleos(t)ide therapy and hepatitis B virus e-antigen (HBeAg) negative patients into 
Cohorts A, B, C and D. Original Text:
Not applicable
Amended Text:
In Part 1, permitted medication includes nucleos(t)ide agents such as tenofovir, 
entecavir, lamivudine, adefovir and telbivudine. Treatment naïve patients should 
 
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avoid initiating HBV therapy until completion of the final follow-up visit unless 
deemed medically necessary by the investigator.
Section 6.12.2, Permitted Medications and Non-Drug Therapies, Sentence 1 and Bullets 1 
and 2
Rationale: To update the subject population in Part 1 to allow inclusion of subjects on 
nucleos(t)ide therapy and hepatitis B virus e-antigen (HBeAg) negative patients into 
Cohorts A, B, C and D. Original Text:
The following concomitant medications are not permitted during Part 1:

Interferon (pegylated or non-pegylated) from 12 months prior to Baseline (Day 1 
pre-dose) through the final Follow-up visit (see Inclusion Criterion 6, 
Section 5.1).

Nucleos(t)ide analogue therapy from 6 months prior to Baseline (Day 1 pre-dose) 
through the final Follow-up visit (see Inclusion Criterion6, Section 5.1). 
Amended Text:
The following concomitant medications are not permitted during Part 1:

Interferon (pegylated or non-pegylated) from 12 months prior to Baseline (Day 1 
pre-dose) through the final Follow-up visit (see Inclusion Criterion 6, 
Section 5.1).

Nucleos(t)ide analogue therapy from 6 months prior to Baseline (Day 1 pre-dose) 
through the final Follow-up visit (see Inclusion Criterion6, Section 5.1). 
Section 6.12.2, Permitted Medications and Non-Drug Therapies, Sentence 2, Bullet 2

Rationale: To provide minor edits for clarity 
Original Text:

Oligonucleotide or siRNA from 12 months prior to Day 1 through the final 
Follow-up visit (see Exclusion Criterion 16, Section 5.2).
Amended Text:

Non-GSK oOligonucleotide or siRNA from 12 months prior to Day 1 through the 
final Follow-up visit or prior treatment with a GSK oligonucleotide from 
3 months prior to Day 1 through the final Follow-up visit (see Exclusion 
Criterion 16, Section 5.2).
Section 7, Study Assessments and Procedures, Paragraphs 3 and 4
 
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
Rationale: To reduce complexity and visit burden for subjects
Original Text:
If assessments are scheduled for the same nominal time, then the assessments should 
occur in the following order:
1. 12-lead ECG
2. Vital signs
3. Blood collection
Assessment timing should allow the blood collection to occur at the exact nominal time.
Amended Text:
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 the assessments should occur in 
the following order:
1. 12-lead ECG
2. Vital signs
3. Blood collection
Assessment timing should allow the blood collection to occur at the exact nominal time.
Section 7.1, Time and Events, Table 8, Footnotes 2 and 3

Rationale: To reduce complexity and visit burden for subjects
Original Text: 
2.
Temperature and respiration rate (single measurement); blood pressure and heart 
rate (after 5 minutes of rest in the semi-supine or supine position): taken in 
triplicate.
3.
12-lead ECGs to be measured in triplicate after 5 minutes of rest in the semi 
supine or supine position.
Amended Text:
2.
Temperature and respiration rate (single measurement); blood pressure and heart
rate (single measurement after 5 minutes of rest in the semi-supine or supine 
position): taken in triplicate.
3.
12-lead ECGs to be measured in triplicate (single measurement after 5 minutes 
of rest in the semi supine or supine position).
Section 7.1, Time and Events, Table 9, Footnote 3

Rationale: To reduce complexity and visit burden for subjects
 
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Original Text: 
3. 
Study treatment will be administered as subcutaneous injection(s) in the morning 
following an overnight fast of at least 8 hours and subsequent laboratory 
assessments prior to dosing.
Amended Text:
3. 
Study treatment will be administered as subcutaneous injection(s) in the morning
following an overnight fast of at least 8 hours and subsequent to laboratory 
assessments prior to dosing.
Section 7.1, Time and Events, Table 9, Footnote 4

Rationale: To reduce complexity and visit burden for subjects
Original Text: 
4.
On Day 1, subjects may receive a morning snack (not full meal) after completion 
of morning study procedures and post-dose, prior to lunch. Lunch will be 
approximately 4 hours (1 hour) dosing. If subjects are still on site, dinner will be 
provided approximately 9 hours (1 hour) after dosing. An evening snack 
(optional) may be provided until 22:00 hours.
Amended text 
4.
On Day 1, subjects may receive a morning snack (not full meal) after completion 
of morning study procedures and post-dose, prior to lunch. A meal or l Lunch 
will be approximately 4 hours (±1 hour) dosing. If appropriate subjects are still 
on site, dinner will be provided approximately 9 hours (±1 hour) after dosing. An 
evening snack (optional) may be provided until 22:00 hours
Section 7.1, Time and Events, Table 9, Footnote 5
Rationale: To provide edits for clarity 

Original Text: 
5.
Adverse events will be collected from the time of informed consent and until the 
final Follow-up visit. However, any SAEs assessed as related to study 
participation (e.g., protocol mandated procedures or invasive tests) or related to 
GSK3389404 will be recorded from the time a subject consents to participate in 
the study up to and including any Follow-up visit. All AEs and SAEs will be 
graded based on the DAIDS table or supplemental criteria as defined in Appendix 
3 (Section 12.3.5.1).
Amended Text:
5.
Adverse events will be collected from the first dose of study treatment time of 
informed consent and until the final Follow-up visit. However, any SAEs assessed 
as related to study participation (e.g., protocol mandated procedures or invasive 
tests) or related to GSK3389404 will be recorded from the time a subject consents 
to participate in the study up to and including any Follow-up visit. All AEs and 
 
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SAEs will be graded based on the DAIDS table or supplemental criteria as 
defined in Appendix 3 (Section 12.3.5.1).
Section 7.1, Time and Events, Table 9, Footnote 6

Rationale: To reduce complexity and visit burden for subjects. 
Original Text: 
6.
Temperature, respiration rate (single measurement); blood pressure and heart rate 
(after 5 minutes of rest in the semi supine or supine position): taken in triplicate 
pre-dose on Day 1 and duplicate at all other measurement time points.
Amended Text:
6.
Temperature, respiration rate (single measurement); blood pressure and heart rate 
(single measurement after 5 minutes of rest in the semi supine or supine 
position): taken in triplicate pre-dose on Day 1 and duplicate at all other 
measurement time points.
Section 7.1, Time and Events Tables, Table 9, Footnote 7

Rationale: To reduce complexity and visit burden for subjects. 
Original Text:
7.
12-lead ECGs to be measured in triplicate at pre-dose on Day 1, after 5 minutes of 
rest in the semi supine or supine position and duplicate at all other measurement 
time points.
Amended Text:
7.
12-lead ECGs to be measured in triplicate at pre-dose on Day 1, after 5 minutes of 
rest in the semi supine or supine position and duplicate single measurements at 
all other measurement time points.
Section 7.1, Time and Events, Table 9, Footnote 9

Rationale: To reduce complexity and visit burden for subjects; to update the subject 
population in Parts 1 and 2 to include women of child bearing potential.
Original Text: 
9.
Female subjects at screening and pre-dose: serum hCG pregnancy test; all other 
time points: serum hCG or urine pregnancy test.
Amended Text:
9.
Female subjects at screening and pre-dose: serum hCG pregnancy test; all other 
time points: serum hCG or urine pregnancy test. (Confirm subject is not 
pregnant with either serum hCG or urine pregnancy test prior to dosing.)
Section 7.1, Time and Events, Table 9, Footnote 10

Rationale: To reduce complexity and visit burden for subjects. 
 
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Original Text: 
10. 
Sample must be obtained after an overnight fast (at least 8 hours) and before 
breakfast.
Amended Text: 
10. 
Sample must be obtained prior to dosing after an overnight fast (at least 8 hours) 
and before breakfast.
Section 7.1, Time and Events, Table 9, Footnote 12

Rationale: To reduce complexity and visit burden for subjects. 
Original Text: 
12.
Collect first morning urine void sample for ACR assessment while subjects are in 
study site.
Amended Text:
12.
Collect first morning urine void sample for ACR assessment while subjects are in 
study site. Subjects may be given a clean urine collection cup and instructed 
to collect and bring in a first morning urine void sample on the day of their 
visit.
Section 7.1, Time and Events Tables, Table 9, Row 13 and Footnote 14

Rationale: To reduce complexity and visit burden for subjects. 
Original Text:
Holter
X
X
X
X
X
X
X
X
X
14.
Archived serum and plasma samples for exploratory biomarker analyses. 
Complement C5a and Bb may be analyzed from the archived plasma sample.
Amended Text:
Holter
X
X
X
X
X
X
X
X
X
14.
Archived serum and plasma samples for exploratory biomarker analyses. 
Complement C5a and Bb as well as HBV RNA, HBcrAg, and/or IDO may be 
analyzed from the archived plasma samples.
Section 7.1, Time and Events Tables, Table 10, Footnote 1

Rationale: To reduce complexity and visit burden for subjects. 
Original Text:
1.
On Day 2, breakfast, lunch, and dinner may be provided. If subjects choose to 
stay in-house through Day 3, then on Day 2, lunch will also be served 
approximately 4 hours (1 hour) after the breakfast, dinner will be served 
approximately 9 hours (1 hour) after the breakfast, and an evening snack 
(optional) may be provided until 22:00 hours. If subjects choose to stay in-house 
 
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through Day 3, they will be offered a meal (e.g., bagged or canteen) after 
completion of all study procedures and prior to discharge on Day 3.
Amended Text:
1.
On Day 2, breakfast, lunch, and dinner may be provided. If subjects choose to 
stay in-house through Day 3, then on Day 2, lunch will also be served 
approximately 4 hours (1 hour) after the breakfast, dinner will be served 
approximately 9 hours (1 hour) after the breakfast, and an evening snack 
(optional) may be provided until 22:00 hours. If subjects choose to stay in-house 
through Day 3, they will be offered a meal (e.g., bagged or canteen [or 
reimbursed]) after completion of all study procedures and prior to discharge on 
Day 3.
Section 7.1, Time and Events Tables, Table 10, Footnote 3, sentence 1
Rationale: To provide clarity. Adverse events are those possibly related to study 
treatment and therefore cannot occur unitl after first dose of study treatment.
Original text:
Adverse events will be collected from the time of informed consent and until the final 
Follow-up visit.
Amended text
Adverse events will be collected from the time of informed consent first dose of study 
treatment and until the final Follow-up visit.
Section 7.1, Time and Events Tables, Table 10, Footnote 4

Rationale: To reduce complexity and visit burden for subjects. 
Original Text:
4.
Temperature and respiration rate (single measurement); blood pressure and heart 
rate will be measured in duplicate after 5 minutes of rest in the semi-supine or 
supine position.
Amended Text:
4.
Temperature and respiration rate (single measurement); blood pressure and heart 
rate will be (single measurement in duplicate after 5 minutes of rest in the semi-
supine or supine position).
Section 7.1, Time and Events Tables, Table 10, Footnote 5

Rationale: To reduce complexity and visit burden for subjects. 
Original Text:
5.
12 lead ECGs to be measured in duplicate after 5 minutes of rest in the semi-
supine or supine position.
Amended Text:
 
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5.
Single 12 lead ECGs to will be measured in duplicate after 5 minutes of rest in the 
semi-supine or supine position.
Section 7.1, Time and Events Tables, Table 10, Footnote 7

Rationale: To reduce complexity and visit burden for subjects. 
Original Text:
7. 
Samples for clinical laboratory tests to be collected in the morning after an 
overnight fast of at least 8 hours.
Amended Text:
7. 
Samples for clinical laboratory tests to be collected after vital sign and ECG 
assessments in the morning after an overnight fast of at least 8 hours.
Section 7.1, Time and Events Tables, Tables 11, 13, and 15

Rationale: To reduce complexity and visit burden for subjects. To consider subjects’ 
personal schedules and provide some flexibility in visits.
Original Text:
Treatment Period
Assessm
ent
Day
1
Day
8 
(1 
day)
Day
15 
(1 
day)
Day
22 
(1 
day)
Day
29 
(1 
day)
Day
36 
(1 
day)
Day
43 
(1 
day)
Day
50 
(1 
day)
Day
57 
(1 
day)
Day
64 
(1 
day)
Day
71 
(1 
day)
Day
78 
(1 
day)
Day
85 
(1 
day)
Amended Text:
Treatment Period
Assessm
ent
Day
1
Day
8 
(1
2
day)
Day
15 
(12
day)
Day
22 
(12
day)
Day
29 
(12
day)
Day
36 
(12
day)
Day
43 
(12
day)
Day
50 
(12
day)
Day
57 
(12
day)
Day
64 
(12
day)
Day
71 
(12
day)
Day
78 
(12
day)
Day
85 
(12
day)
Section 7.1, Time and Events Tables, Tables 11, 13, and 15, Footnote 2

Rationale: To reduce complexity and visit burden for subjects. 
Original Text:
2.
Study treatment will be administered as subcutaneous injection(s) in the morning 
following an overnight fast of at least 8 hours and subsequent to the laboratory 
collection and other study assessments conducted prior to dosing.
Amended Text: 
 
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2.
Study treatment will be administered as subcutaneous injection(s) in the morning 
following an overnight fast of at least 8 hours and subsequent to the laboratory 
collection and other study assessments conducted prior to dosing.
Section 7.1, Time and Events Tables, Tables 10, 11, 13, and 15, Footnote 3

Rationale: To provide edits for clarity 
Original Text:
3.
Adverse events will be collected from the time of informed consent and until the 
final Follow-up visit. However, any SAEs assessed as related to study 
participation (e.g., protocol mandated procedures or invasive tests) or related to 
GSK3389404 will be recorded from the time a subject consents to participate in 
the study up to and including any Follow-up visit. All AEs and SAEs will be 
graded based on the DAIDS table or supplemental criteria as defined in Appendix 
3 (Section 12.3.5.1).
Amended Text:
3.
Adverse events will be collected from the first dose of study treatment time of 
informed consent and until the final Follow-up visit. However, any SAEs assessed 
as related to study participation (e.g., protocol mandated procedures or invasive 
tests) or related to GSK3389404 will be recorded from the time a subject consents 
to participate in the study up to and including any Follow-up visit. All AEs and 
SAEs will be graded based on the DAIDS table or supplemental criteria as 
defined in Appendix 3 (Section 12.3.5.1).
Section 7.1, Time and Events Tables, Tables 11, 13, and 15, Footnote 4

Rationale: To reduce complexity and visit burden for subjects. 
Original Text:
4.
Temperature, respiration rate (single measurement); blood pressure and heart rate 
(after 5 minutes of rest in the semi-supine or supine position): taken in triplicate 
pre-dose on Day 1 and duplicate at all other measurement time points.
Amended Text:
4.
Temperature, respiration rate (single measurement); blood pressure and heart rate 
(single measurement after 5 minutes of rest in the semi-supine or supine 
position): taken in triplicate pre-dose on Day 1 and duplicate at all other 
measurement time points.
Section 7.1, Time and Events Tables, Tables 11, 13, and 15, Footnote 5

Rationale: To reduce complexity and visit burden for subjects.
Original Text:
 
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5.
12-lead ECGs to be measured in triplicate at pre-dose on Day 1, after 5 minutes of 
rest in the semi-supine or supine position and duplicate at all other measurement 
time points.
Amended Text:
5.
12-lead ECGs to be measured in triplicate at pre-dose on Day 1, after 5 minutes of 
rest in the semi-supine or supine position and duplicate single measurements at 
all other measurement time points.
Section 7.1, Time and Events Tables, Tables 11, 13, and 15, Footnote 7

Rationale: To reduce complexity and visit burden for subjects. 
Original Text:
7.
Samples for clinical laboratory tests to be collected in the morning prior to 
receiving study treatment and after an overnight fast of at least 8 hours.
Amended Text:
7.
Samples for clinical laboratory tests to be collected prior to dosing (if 
applicable) in the morning prior to receiving study treatment and after an 
overnight fast of at least 8 hours.
Section 7.1, Time and Events Tables, Tables 11, 13, and 15, Footnote 8

Rationale: To reduce complexity and visit burden for subjects; to update the subject 
population in Parts 1 and 2 to include women of child bearing potential.
Original Text:
8. Female subjects at screening and pre-dose Day 1: serum hCG pregnancy test; all 
other time points: serum hCG or urine pregnancy test. 
Amended Text:
8. Female subjects at screening and pre-dose Day 1: serum hCG pregnancy test; all 
other time points: serum hCG or urine pregnancy test. (Confirm subject is not 
pregnant with either serum hCG or urine pregnancy test prior to dosing.)
Section 7.1, Time and Events Tables, Tables 11, 13, and 15, Footnote 11

Rationale: To update the overall design and types/numbers of subjects that will be 
enrolled given the addition of an optional Japanese Part 2 sub-study. 
Original Text:
11.
On extended PK/dosing days (Days 1, 29, and 57), PK samples will be collected 
at pre-dose (within 15 to 30 minutes prior to dosing; prefer sample as close to pre-
dose time point as possible) and at 1, 2, and 3 hours post-dose. PK samples should 
 
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be collected as close to the exact nominal time as possible. The exact time of each 
PK blood collection should be recorded.
Amended Text:
11.
On extended PK/dosing days (Days 1, 29, and 57), PK samples will be collected 
at pre-dose (within 15 to 30 minutes prior to dosing; prefer sample as close to pre-
dose time point as possible) and at 1, 2, and 3 hours post-dose. PK samples should 
be collected as close to the exact nominal time as possible. The exact time of each 
PK blood collection should be recorded. PK sampling for the optional Japanese
Part 2 sub-study may be detailed in the Japan country-specific protocol 
amendment/supplement.
Section 7.1, Time and Events Tables, Tables 10, 11, 13, and 15, Footnote 12

Rationale: To provide minor edits for clarity 
Original Text:
12.
Archived serum and plasma samples for exploratory biomarker analyses. 
Complement C5a and Bb may be analyzed from the archived plasma sample.
Amended Text:
12.
Archived serum and plasma samples for exploratory biomarker analyses. 
Complement C5a and Bb as well as HBV RNA, HBcrAg, and/or IDO may be 
analyzed from the archived plasma samples.
Section 7.1, Time and Events Tables, Tables 12, 14 and 16, Row 12

Rationale: To update the subject population in Parts 1 and 2 to include women of 
child bearing potential
Original Text:
Pregnancy test (as appropriate)6
X
X
Amended Text:
Pregnancy test (as appropriate)6
X
X
X
X
Section 7.1, Time and Events Tables, Tables 12, 14 and 16, Footnote 1

Rationale: To provide minor edits for clarity 
Original Text:
1.
Adverse events will be collected from the time of informed consent and until the 
final Follow-up visit. However, any SAEs assessed as related to study 
participation (e.g., protocol mandated procedures or invasive tests) or related to 
GSK3389404 will be recorded from the time a subject consents to participate in 
the study up to and including any Follow-up visit. All AEs and SAEs will be 
graded based on the DAIDS table or supplemental criteria as defined in 
Appendix 3 (Section 12.3.5.1).
 
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Amended Text:
1.
Adverse events will be collected from the first dose of study treatment time of 
informed consent and until the final Follow-up visit. However, any SAEs assessed 
as related to study participation (e.g., protocol mandated procedures or invasive 
tests) or related to GSK3389404 will be recorded from the time a subject consents 
to participate in the study up to and including any Follow-up visit. All AEs and 
SAEs will be graded based on the DAIDS table or supplemental criteria as 
defined in Appendix 3 (Section 12.3.5.1).
Section 7.1, Time and Events Tables, Tables 12, 14, and 16, Footnote 2

Rationale: To reduce complexity and visit burden for subjects. 
Original Text:
2.
Temperature and respiration rate (single measurement); blood pressure and heart 
rate (after 5 minutes of rest in the semi-supine or supine position): taken duplicate 
at all measurement time points.
Amended Text:
2.
Temperature and respiration rate (single measurement); blood pressure and heart 
rate (single measurement after 5 minutes of rest in the semi-supine or supine 
position): taken duplicate at all measurement time points.
Section 7.1, Time and Events Tables, Tables 12, 14, and 16, Footnote 3

Rationale: To reduce complexity and visit burden for subjects. 
Original Text:
3.
12 lead ECGs to be measured in duplicate after 5 minutes of rest in the semi-
supine or supine position.
Amended Text:
3.
Single 12 lead ECGs to will be measured in duplicate after 5 minutes of rest in the 
semi-supine or supine position.
Section 7.1, Time and Events Tables, Tables 12, 14 and 16, Footnote 5

Rationale: To reduce complexity and visit burden for subjects. 
Original Text:
5. 
Samples for clinical laboratory tests to be collected in the morning after an 
overnight fast of at least 8 hours.
Amended Text:
5. 
Samples for clinical laboratory tests to be collected in the morning after vital sign 
and ECG assessments an overnight fast of at least 8 hours.
 
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Section 7.1, Time and Events Tables, Tables 12, 14 and 16, Footnote 9

Rationale: To update the overall design and types/numbers of subjects that will be 
enrolled given the addition of an optional Japanese Part 2 sub-study. 
Original Text:
9.
On PK days (Day 169 / Early Termination), collect the PK sample after 
completion of vital sign assessments. The exact time of each PK blood collection 
should be recorded.
Amended Text:
9.
On PK days (Day 169 / Early Termination), collect the PK sample after 
completion of vital sign assessments. The exact time of each PK blood collection 
should be recorded. PK sampling for the optional Japanese Part 2 sub-study 
may be detailed in the Japan country-specific protocol 
amendment/supplement.
Section 7.1, Time and Events Tables, Tables 12, 14 and 16, Footnote 10

Rationale: To provide minor edits for clarity
Original Text:
10.
Archived serum and plasma samples for exploratory biomarker analyses. 
Complement C5a and Bb may be analyzed from the archived plasma sample.
Amended Text:
10.
Archived serum and plasma samples for exploratory biomarker analyses. 
Complement C5a and Bb as well as HBV RNA, HBcrAg, and/or IDO may be 
analyzed from the archived plasma samples.
Section 7.1, Time and Events Tables, Tables 12, 14, and 16 (Footnote 13) and Tables 11, 
13, and 15 (Footnote 15)

Rationale: To reduce complexity and visit burden for subjects. 
Original Text:
13. or 15.
Subjects will be offered a meal (e.g., bagged or canteen) after completion 
of all study procedures.
Amended Text:
13. or 15.
Subjects will be offered a meal (e.g., bagged or canteen [or reimbursed]) 
after completion of all study procedures.
Section 7.2, Screening and Critical Baseline Assessments, New Sentence
Original Text:
Not applicable
 
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Amended Text:
Subjects who screen failed under previous versions of the protocol may be re-
screened.
Section 7.3.1, Adverse Events and Serious Adverse Events, new Sentence 2

Rationale: To provide minor edits for clarity
Original Text:
Not applicable.
Amended Text:
The severity of an AE is graded according to the DAIDS table in Appendix 3 
(Section 12.3.5.1).
Section 7.3.1.1, Time Period and Frequency for Collecting AE and SAE Information, 
Bullet 2

Rationale: to provide minor edits for clarity
Original Text:
•
Adverse events will be collected from the time of informed consent until the final 
follow-up contact (Section 7.3.1.3) as specified in the Time and Events Table 
(Section 7.1).
Amended Text:
•
Adverse events will be collected from the time of informed consent first dose of 
study treatment until the final follow-up contact (Section 7.3.1.3) as specified in 
the Time and Events Table (Section 7.1).
Section 7.3.2, Pregnancy, Paragraph 1, Sentence 1
Rationale: To update the subject population in Parts 1 and 2 to include women of child 
bearing potential 
Original Text:
Females of reproductive potential are not permitted in this study.
Amended Text:
Females of reproductive potential are not permitted in this study.
Section 7.3.4, Injection Site Reactions, Paragraph 2

Rationale: to provide minor edits for clarity
 
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Original Text:
Injection site reactions will be graded according to the criteria provided in the Division of 
AIDS (DAIDS) grading table (see Appendix 3, Section 12.3.5.1). 
Amended Text:
Injection site reactions will be graded according to the criteria provided in the Division of 
AIDS (DAIDS) grading table (see Appendix 3, Section 12.3.5.1).
Section 7.3.5, Vital Signs, Bullet 1, Sub-bullets 1-2 2
Original Text:
o
Temperature and respiration rate will be collected as single measurements.
o
Systolic and diastolic blood pressure and heart rate will be collected in 
triplicate at the Screening visit and pre-dose on Day 1 and in duplicate at all 
other time points.
Amended Text:
o
Systolic and diastolic blood pressure, heart rate, Ttemperature, and 
respiration rate will be collected as single measurements.
o
Systolic and diastolic blood pressure and heart rate will be collected in 
triplicate at the Screening visit and pre-dose on Day 1 and in duplicate at all 
other time points.
Section 7.3.6, Electrocardiogram, Bullet 1, Sub-bullet 2

Rationale: To reduce complexity and visit burden for subjects. 
Original Text:
o
Triplicate 12-lead ECGs will be obtained at the Screening visit and pre-dose 
on Day 1. Duplicate 12-lead ECGs will be obtained at all other time points. 
Amended Text:
o
Triplicate 12-lead ECGs will be obtained at the Screening visit and pre-dose 
on Day 1. Duplicate Single 12-lead ECGs will be obtained at all other time 
points. 
Section 7.3.7, Holter, All text

Rationale: To reduce complexity and visit burden for subjects. 
Original Text:
7.3.7. Holter
Continuous cardiac telemetry (Holter monitoring) will be performed in Part 1 as specified 
in the Time and Events Table (Section 7.1, Table 9). Full disclosures will be reviewed in 
detail and the review maintained as part of the subject’s source documents.
 
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Start date and time, stop date and time, interpretation, and nature of abnormality, if any, 
will be captured in the study database. Analysis of the Holter tapes will consider the 
following:
•
Heart rate (bradycardia and tachycardia)
•
Normal and aberrant beats
•
Number of supraventricular contractions, premature atrial contractions, 
supraventricular tachycardias, premature ventricular contractions, couplets, 
triplets, and ventricular tachycardias
•
Atrioventricular conduction defects
•
Atrial fibrillation and flutter
Amended Text:
7.3.7. Holter
Continuous cardiac telemetry (Holter monitoring) will be performed in Part 1 as specified 
in the Time and Events Table (Section 7.1, Table 9). Full disclosures will be reviewed in 
detail and the review maintained as part of the subject’s source documents.
Start date and time, stop date and time, interpretation, and nature of abnormality, if any, 
will be captured in the study database. Analysis of the Holter tapes will consider the 
following:
•
Heart rate (bradycardia and tachycardia)
•
Normal and aberrant beats
•
Number of supraventricular contractions, premature atrial contractions, 
supraventricular tachycardias, premature ventricular contractions, couplets, 
triplets, and ventricular tachycardias
•
Atrioventricular conduction defects
•
Atrial fibrillation and flutter
Section 7.3.8, Clinical Safety Laboratory Assessments (new heading number)
Rationale: To provide minor edits for clarity
Original Text:
7.3.8. Clinical Safety Laboratory Assessments
Amended Text:
7.3.87. Clinical Safety Laboratory Assessments
Section 7.3.8 Clinical Safety Laboratory Assessments, Paragraph 1, Sentences 2 and 3

Rationale: To reduce complexity and visit burden for subjects. 
Original Text:
 
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Fasting is not required for laboratory testing at the Screening visit. For all other 
laboratory time points, a minimum 8-hour fast is required prior to blood and urine 
sampling for laboratory tests.
Amended Text:
Fasting is not required for laboratory testing at the Screening visit. For all other 
laboratory time points, a minimum 8-hour fast is required prior to blood and urine 
sampling for laboratory tests.
Section 7.3.8 Clinical Safety Laboratory Assessments, Table 17, Other Screening and/or 
Follow-up tests,

Rationale: To provide minor edits for clarity
Original Text:

HIV, HCV antibody, HDV antibody
Amended Text:

HIV, HCV antibody, HDV antibody
Section 7.3.8 Clinical Safety Laboratory Assessments, Table 17, Other Screening and/or 
Follow-up tests, New bullet added at end of the list

Rationale: To provide minor edits for clarity
Original Text:
Not applicable
Amended Text:
o HBV RNA, HBcrAg, and/or IDO may be analyzed from archived samples
Section 7.3.8 Clinical Safety Laboratory Assessments, Table 17, New abbreviations 
added to footnote

Rationale: To provide minor edits for clarity
Original Text:
Not applicable
Amended Text:
HBcrAg = hepatitis B core-related antigen
IDO = indoleamine 2,3 dioxygenase,
Section 7.3.8 Clinical Safety Laboratory Assessments, Table 17, Footnote 1. 

Rationale: To reduce complexity and visit burden for subjects. 
Original Text:
 
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1. 
Fasting is not required at the Screening visit. A minimum 8-hour overnight fast is 
required for all other protocols-specified laboratory assessments.
Amended Text:
1. 
Fasting is not required for laboratory testing at the Screening visit. A minimum 
8-hour overnight fast is required for all other protocols-specified laboratory 
assessments.
Section 7.6, Biomarker(s)/Pharmacodynamic Markers, Paragraph 2, Sentence 3

Rationale: To provide minor edits for clarity and addition of HBV RNA
Original Text:
The archive samples may also be used for studying biomarkers that may be affected by 
treatment, such as hepatitis B core-related antigen (HBcrAg) or indoleamine 2,3 
dioxygenase (IDO).
Amended Text:
The archive samples may also be used for studying biomarkers that may be affected by 
treatment, such as hepatitis B core-related antigen (HBcrAg), HBV RNA or indoleamine 
2,3 dioxygenase (IDO).
Section 9. 1 Hypotheses and Section 9.4.1 Primary Analysis

Rationale: To make edits for typographical error
Original text:
A subject will be considered a responder if there is at least 1.5 times log 10 copies/mL 
reduction of HBsAg levels from baseline anytime during the study.
Amended text:
A subject will be considered a responder if there is at least 1.5 times log 10 copiesIU/mL 
reduction of HBsAg levels from baseline anytime during the study.
Section 9.2.1, Sample Size Assumptions, Paragraph 2

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Original Text:
Assuming 3 dose levels and 2 dosing regimens are selected in Part 2, the probability of 
declaring success of an inefficacious treatment arm (with RR 5%) is less than 4%. On 
the other hand if an active treatment arm has a 30% RR, the probability of selecting the 
treatment arm is at least 80% under the model assumption. Appendix 6 (Section 12.6) 
details the operating characteristics of the design.
Amended text:
Assuming 3 dose levels and 2 dosing regimens are selected in Part 2, the probability of 
declaring success of an inefficacious treatment arm (with RR 5%) is less than 4%. On 
the other hand if an active treatment arm has a 30% RR, the probability of selecting the 
treatment arm is at least 9580% under the model assumption. Appendix 6 (Section 12.6) 
details the operating characteristics of the design.
Section 9.2.1, Sample Size Assumptions, Paragraph 1

Rationale: To reduce sample size from 8 subjects (6 active:2 placebo) to 4 subjects 
(3 active:1 placebo) in Part 1. 
Original Text:
A sample size of approximately 8 HBV subjects (6 active:2 placebo) in each cohort 
should be sufficient to provide useful estimates of inter subject variability for 
GSK3389404 PK parameters and initial safety and PD assessments. Although the sample 
size is not based on statistical criteria, general probabilities can be determined on the 
likelihood of observing AEs. With 6 subjects receiving each dose of active study 
treatment, if the true adverse outcome rate is 5%, the chance of seeing at least 1 adverse 
outcome at a given dose is 26%. Similarly if the true adverse outcome rate is 20%, the 
chance of seeing at least 1 adverse outcome at a given dose is 74%. This level of 
predictivity is deemed adequate within this early phase setting prior to commencing to 
Part 2 (multiple dose, dose-ranging).
Amended Text:
A sample size of approximately at least 8 4 HBV subjects (3 receiving active treatment 
(:21 placebo) in each cohort should be sufficient to provide useful preliminary estimates 
of inter subject variability for GSK3389404 PK parameters and initial safety and PD 
assessments. Although the sample size is not based on statistical criteria, general 
probabilities can be determined on the likelihood of observing AEs. With 6 subjects 
receiving each dose of active study treatment, if the true adverse outcome rate is 5%, the 
chance of seeing at least 1 adverse outcome at a given dose is 26%. Similarly if the true 
adverse outcome rate is 20%, the chance of seeing at least 1 adverse outcome at a given 
dose is 74%. This level of predictivity is deemed adequate within this early phase setting 
prior to commencing to Part 2 (multiple dose, dose-ranging).
Section 9.3.2 Definition of Baseline

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Original Text:
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 (e.g., triplicate blood pressure, heart rate, and 12-lead ECGs), the 
average of these assessments will be used as the baseline.
Amended Text:
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 (e.g., triplicate blood pressure, heart rate, and 12-lead ECGs), the 
average of these assessments will be used as the baseline.
Section 9.3.3, Interim Analysis

Rationale: To provide minor edits for clarity 
Original Text:
9.3.3
Interim Analysis
Amended Text:
9.3.3
Interim Analysis and Final Analysis
Section 9.3.3, Interim Analysis, Part 1, Paragraph 1, Sentence 2

Rationale: To reduce sample size from 8 subjects (6 active:2 placebo) to 4 subjects 
(3 active:1 placebo) in Part 1. 
Original Text:
However, a preliminary PK analysis will be performed after each dose level is completed 
and the Dose Escalation Committee (Section 10.8.1) will review preliminary safety 
tolerability, PK and PD data (through Day 3 for at least 4 subjects that received 
GSK3389404) prior to each dose escalation and prior to initiation of Part 2.
Amended Text:
However, a preliminary PK analysis will be performed after each dose level is completed 
and the Dose Escalation Committee (Section 10.8.1) will review preliminary safety 
tolerability, PK and PD data (through Day 3 for at least 43 subjects that received 
GSK3389404) prior to each dose escalation and prior to initiation of Part 2.
Section 9.3.3, Interim Analysis, Part 1, Paragraph 2, Sentence 1

Rationale: To reduce sample size from 8 subjects (6 active:2 placebo) to 4 subjects 
(3 active:1 placebo) in Part 1. 
Original Text:
 
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The relationship between dose levels, plasma GSK3389404 exposure, and associated 
variability will be characterized by a power model once PK data are available from at 
least 2 dose levels.
Amended Text:
The relationship between dose levels, plasma GSK3389404 exposure, and associated 
variability will be characterized by a power model once if 3 or more subjects’ PK data 
are available from at least 2 dose levels.
Section 9.3.3, Interim Analysis, Part 2

Rationale: To provide edits for clarity
Original Text:
Part 2
Amended Text:
Part 2 Interim Analysis
New Sections 9.3.3.1, 9.3.3.2, and 9.3.3.3
Rationale: To update the overall design and types/numbers of subjects that will be 
enrolled given the addition of an optional Japanese Part 2 sub-study. 
Original Text:
Not applicable
Amended Text:
9.3.3.1.
Part 2: Primary Analysis 
In Part 2, the primary analysis will be conducted once the last randomized subject 
in the sentinel group and remainder of subjects have completed the Day 85 visit. 
Treatment assignment will be unblinded for subjects included in the analysis. The 
results of this analysis will be used to characterize safety, tolerability and identify 
efficacious dose and dosing regimen of GSK3889404. 
9.3.3.2.
Optional Japanese Part 2 Sub-Study Analysis
Details of the analysis of the optional Japanese Part 2 sub-study may be found in the 
Japanese country-specific protocol amendment/supplement. If applicable, the 
analysis of optional Japanese Part 2 sub-study will be conducted once the last 
randomized Japanese subject has completed the Day 85 and/or Day 169 visit. 
Treatment assignment for the optional Japanese Part 2 sub-study cohorts will be 
unblinded. Depending on the timing of the last Japanese subject to finish the Day 85 
visit, the analysis may or may not be reported together with the Primary analysis. 
9.3.3.3.
Part 2: End of Study Analysis
The end of study analysis for Part 2 will be conducted once the last randomized 
subject (Sentinel, remainder of subjects, and the Japan sub-study subjects if 
applicable) has completed the Day 169 visit.
 
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Section 9.4.1, Primary Analyses, Efficacy and Section 12.6.2 Statistical Modeling

Rationale: To provide corrections to the statistical simulations
Original text:
Since it is not expected to have any responder in the placebo arm, posterior distribution of 
RRs is generated separately from a Beta distribution using uniform prior, i.e., Beta (1,1). 
Placebo injections will be given in different dosing regimens (according to the 
corresponding active treatment group) for the purpose of maintaining the blind. However, 
all placebo subjects across dosing regimens will be combined in 1 group for this analysis, 
since no difference in RR is expected if placebo is administered in different dosing 
regimens.
Amended text:
Since it is not expected to have any responder in the placebo arm, posterior distribution of 
RRs is generated separately from a Beta distribution using uniform prior, i.e., Beta 
(0.1,0.1). Placebo injections will be given in different dosing regimens (according to the 
corresponding active treatment group) for the purpose of maintaining the blind. However, 
all placebo subjects across dosing regimens will be combined in 1 group for this analysis, 
since no difference in RR is expected if placebo is administered in different dosing 
regimens.
Section 9.4.1, Primary Analyses, Last Paragraph

Rationale: To update the overall design and types/numbers of subjects that will be 
enrolled given the addition of an optional Japanese Part 2 sub-study. 
Original Text:
The primary efficacy analysis of Part 2 will be performed after all ongoing subjects in 
Part 2 complete the Day 85 visit. At that time the database will be unblinded. Other 
primary analyses as mentioned above will also be performed. The end of study analysis 
will be performed after all ongoing subjects in Part 2 complete the Day 169 visit.
Amended Text:
The primary efficacy analysis of Part 2 will be performed after all ongoing subjects in 
Part 2 complete the Day 85 visit (may or may not include the Japanese subjects from 
the optional Japanese Part 2 sub-study). At that time the database will be unblinded. 
Other primary analyses as mentioned above will also be performed. The end of study 
analysis will be performed after all ongoing subjects in Part 2 complete the Day 169 visit.
Details will be included in the RAP.
Section 10.8.1, dose Escalation Committee, Paragraph 1, Last Sentence

Rationale: To provide minor edits for clarity 
 
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Original Text:
The GSK study team will remain unblinded throughout Part 1 of the study as detailed in 
Section 6.5. 
Amended Text:
The GSK study team will remain unblinded at an aggregate level throughout Part 1 of 
the study as detailed in Section 6.5. 
Section 10.8.1, dose Escalation Committee, Paragraph 2, Sentences 2 and 3

Rationale: To reduce sample size from 8 subjects (6 active:2 placebo) to 4 subjects 
(3 active:1 placebo) in Part 1. 
Original Text:
Dose escalation decisions will be based on data through Day 3 obtained from at least 
4 subjects receiving GSK3389404 at the prior dose level. The review data set will include 
listings for AEs, flagged vital signs, flagged findings during continuous cardiac 
monitoring (Holter), ECGs, laboratory findings (including liver function tests), and PK 
results derived from 24-hour plasma profiles, together with any available PD data 
(HBsAg levels and HBV DNA).
Amended Text:
Dose escalation decisions will be based on data through Day 3 obtained from at least 
43 subjects receiving GSK3389404 at the prior dose level. The review data set will 
include listings for AEs, flagged vital signs, flagged findings during continuous cardiac 
monitoring (Holter), ECGs, laboratory findings (including liver function tests), and PK 
results derived from 24-hour plasma profiles, together with any available PD data
(HBsAg levels and HBV DNA).
Section 11, References, Delete 2 References

Rationale: To provide minor edits for clarity 
Original Text:
Liaw Y-F, Kao JH, Piratvisuth T, Chan HL, Chien RN, Liu DJ, et al. Asian-Pacific 
consensus statement on the management of chronic hepatitis B: a 2012 update. Hepatol 
Int 2012;6:531-61.
Terrault NA, Bzowej NH, Chang KM, Hwang JP, Jonas MM, Murad MH. AASLD 
Guidelines for treatment of chronic hepatitis B. Hepatology 2016; 63:261-83.
Amended Text:
Liaw Y-F, Kao JH, Piratvisuth T, Chan HL, Chien RN, Liu DJ, et al. Asian-Pacific 
consensus statement on the management of chronic hepatitis B: a 2012 update. Hepatol 
Int 2012;6:531-61.
 
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Terrault NA, Bzowej NH, Chang KM, Hwang JP, Jonas MM, Murad MH. AASLD 
Guidelines for treatment of chronic hepatitis B. Hepatology 2016; 63:261-83.
Section 12.1, Appendix 1, Abbreviations and Trademarks, DAIDS

Rationale: To provide minor edits for clarity 
Original Text:
DAIDS
Division of Autoimmune Disorders
MCMC
Proc Markov Chain Monte Carlo
Amended Text:
DAIDS
Division of Autoimmune Disorders Allergy and Infectious 
Diseases
MCMC
Markov Chain Monte Carlo
Section 12.1, Appendix 1, Abbreviations and Trademarks, 3 new abbreviations added

Rationale: To provide minor edits for clarity
Original Text:
Not applicable
Amended Text:
HBcrAg
hepatitis B core-related antigen
IDO
indoleamine 2,3 dioxygenase
Section 12.4.1 Modified List of Highly Effective Methods for Avoiding Pregnancy in 
Females of Reproductive Potential, Paragraph 1, Paragraph 2, New Paragraph 3 added, 
and Item 1. 

Rationale: To update the subject population in Parts 1 and 2 to 
include women of child bearing potential 
Original Text:
Contraceptive requirements for male subjects with female partners of reproductive 
potential (when applicable).
Male subjects with female partners of child bearing potential must comply with the 
following contraception requirements from the time of first dose of study treatment until 
[at least five half-lives of study treatment OR for a cycle of spermatogenesis following 
five terminal half-lives] after the last dose of study treatment.
1.Vasectomy with documentation of azoospermia. The documentation on male sterility 
can come from the site personnel’s: review of subject’s medical records, medical 
examination and/or semen analysis, or medical history interview.
 
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Amended Text:
Contraceptive requirements for male subjects with female partners of reproductive 
potential (when applicable) and for female subjects of reproductive potential (FRP).
Male subjects with female partners of child bearing potential and female subjects of 
child bearing potential must comply with the following contraception requirements 
from either the time of first dose of study treatment (males) or from at least 28 days 
prior to the first dose of study treatment (FRP) until the final Follow-up visit [at least 
five half-lives of study treatment OR for a cycle of spermatogenesis following five 
terminal half-lives] after the last dose of study treatment.
This list does not apply to FRP with same sex partners or for subjects who are and 
will continue to be abstinent from penile-vaginal intercourse on a long term and 
persistent basis, when this is their preferred and usual lifestyle. Periodic abstinence 
(e.g. calendar, ovulation, symptothermal, post-ovulation methods) and withdrawal 
are not acceptable methods of contraception.
1.Male vasectomy with documentation of azoospermia. The documentation on male 
sterility can come from the site personnel’s: review of male subject’s (or female 
subject’s male partner prior to the female subject’s entry into the study) medical 
records, medical examination and/or semen analysis, or medical history interview. This 
documentation may be provided by male subjects, by female subjects on behalf of 
their partner, or by her partner.
Appendix 12.5, Country Specific Requirements

Rationale: To update the overall design and types/numbers of subjects that will be 
enrolled given the addition of an optional Japanese Part 2 sub-study. 
Original Text:
No country-specific requirements exist.
Amended Text:
If Japan conducts the optional Part 2 sub-study, Japan-specific requirements will be 
specified in a country-specific amendment/supplement protocol. Otherwise, nNo 
country-specific requirements exist.
Appendix 12.6, Section 12.6.3, Success Criteria, 1st paragraph
Rationale: To provide corrections to the statistical simulations
Original Text:
An active treatment group will be declared efficacious if the posterior probability that the 
difference in the RRs between that active group and the placebo is positive, is high (at 
least 80%), i.e., P (RRACT > RRPBO) 80%, where RRACT is the RR in the active group, 
RRPBO is the RR in the placebo group, and P is the posterior probability.
Amended Text:
 
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An active treatment group will be declared efficacious if the posterior probability that the 
difference in the RRs between that active group and the placebo is positive, is high (at 
least 9580%), i.e., P (RRACT > RRPBO) 9580%, where RRACT is the RR in the active 
group, RRPBO is the RR in the placebo group, and P is the posterior probability.
Appendix 12.6, Section 12.6.4, Scenarios for Testing, Table 18, Row 7
Rationale: To provide minor edits for clarity and typographical errors
Original Text:
Total monthly dose of 240 mg divided bi-weekly (i.e., 120 mg bi-weekly)
240BW
10
Amended Text:
Total monthly dose of 2480 mg divided bi-weekly (i.e., 1240 mg bi-weekly)
2480BW
10
Appendix 12.6, Section 12.6.5, Simulations
Rationale: To provide corrections to the statistical simulations
Original Text:
Sensitivity of sample size is also provided using different cutoff points for PoS (e.g. 75%, 
80%, 85% and 90%)
The above operating characteristics are also calculated for pair-wise comparison 
(i.e., without any model, based on difference in posterior distributions of individual 
treatment arm against placebo). In most of the scenarios, the decision of selecting an 
active treatment group is in agreement by both the methods. However, BLRM provided 
better operating characteristics (larger power and tighter CI). The probability of selecting 
an inefficacious treatment group is lower in BLRM compared to pair-wise method. The 
BLRM was not able to select the efficacious treatment group under Scenario 7, 8 and 9, 
where there is no monotonic relationship between dose and response. These scenarios are 
unlikely to happen in real life.
Simulation results for all scenarios are summarized in Table 20 to Table 28.
A cutoff point of 95% for PoS seems to provide reasonable probability for selecting an 
efficacious dose group given the sample size of this study.
.Amended Text:
Sensitivity of sample size is also provided using different cutoff points for PoS (e.g. 
85%, 90%, 95%, and 98% 75%, 80%, 85% and 90%).
The above operating characteristics are also calculated for pair-wise comparison 
(i.e., without any model, based on difference in posterior distributions of individual 
 
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treatment arm against placebo, both with Beta (0.1, 0.1) as prior distribution). In most 
of the scenarios, the decision of selecting an active treatment group is in agreement by 
both the methods. However, BLRM provided better operating characteristics (larger 
power and tighter CI). The probability of selecting an inefficacious treatment group is 
lower in BLRM compared to pair-wise method. The BLRM was not able to select the 
efficacious treatment group under Scenario 7, 8 and 9, where there is no monotonic 
relationship between dose and response. These scenarios are unlikely to happen in real 
life.
Simulation results for all scenarios are summarized in Table 20 to Table 28.
A cutoff point of 9580% for PoS seems to provide reasonable probability for selecting an 
efficacious dose group given the sample size of this study.
Appendix 12.6, Section 12.6.5, Simulations, Table 20
Rationale: To provide corrections to the statistical simulations
As all contents of the table were changed, tracked changes are not provided in the below 
tables
Original:
Table 29
Simulation Results From Scenario 1
Scenario 1
No Treatment Effect
(PBO, 120W, 120BW, 240W, 240BW, 480W, 480BW): (5, 5, 5, 5, 
5, 5, 5)
Treatment
Posterior 
RR (%)
90% CI
PoS1
Decision2
(Select 
dose)
Power3
Cutoff Points
75%
80%
85%
90%
Pairwise Comparison
PBO
11.69
(2.17,27.33)
120W
12.51
(2.08,29.93)
51.75
No
25.3
15.9
4.1
3.1
120BW
12.56
(2.1,30.01)
51.75
No
25.1
16
5.3
5.1
240W
12.7
(2.14,30.25)
52.27
No
25.4
15.2
4.4
4.2
240BW
12.22
(1.97,29.52)
50.76
No
21.4
15.2
5.1
4.6
480W
12.47
(2.04,29.9)
51.71
No
25.7
17.4
4.2
3.8
480BW
12.57
(2.1,30.03)
51.86
No
24.5
16
5.3
5
BLRM
PBO
11.69
(2.17,27.34)
120W
5.6
(0.76,15.26)
0.4
No
3.3
2.2
0.8
3.3
120BW
5.57
(0.77,15.16)
0.3
No
4.5
3.5
1.5
4.5
240W
3.92
(0.72,9.76)
0
No
1.5
0.5
0
1.5
240BW
3.95
(0.78,9.72)
0.1
No
1.5
0.5
0.2
1.5
480W
5.7
(0.75,15.65)
0.4
No
3.1
2.1
1
3.1
480BW
5.73
(0.79,15.57)
0.5
No
4.8
3.6
1.2
4.8
 
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BLRM = Bayesian logistic regression model; BW = bi-weekly; CI = credible interval; PBO = placebo; PoS = probability 
of success; RR = response rate; W = weekly
1.
PoS is defined as P(RRACT >RRPBO)
2.
A dose group will be selected if the PoS is at least 80%
3.
Power is defined as percentage of time PoS >80% over the sample space (i.e., 1000 simulations)
Table 30
Simulation Results From Scenario 2
Scenario 2
All of the active treatment groups are equally effective 
(low effect size)
(PBO, 120W, 120BW, 240W, 240BW, 480W, 480BW): (5, 20, 20, 20, 20, 
20, 20)
Treatment
Posterior 
RR (%)
90% CI
PoS1
Decision2
(Select 
dose)
Power3
Cutoff Points
75%
80%
85%
90%
Pairwise Comparison
PBO
11.53
(2.09,27.11)
120W
25.26
(8.91,46.38)
77.13
No
72.6
55.3
47.4
39.4
120BW
25.27
(8.94,46.36)
77.25
No
73.4
53.9
45.2
37
240W
25.52
(9.09,46.66)
77.98
No
75.6
54.2
45.2
37.8
240BW
24.58
(8.54,45.51)
75.98
No
69.7
51.6
42.6
35.6
480W
24.87
(8.68,45.91)
76.77
No
73.1
54.2
46.5
37.3
480BW
24.84
(8.59,45.94)
77.26
No
73.9
54.4
45.1
37.5
BLRM
PBO
11.53
(2.09,27.12)
120W
20.88
(8.14,37.81)
72.07
No
55.9
48.6
38.8
29.8
120BW
20.64
(8.03,37.46)
71.62
No
54.4
45.5
36.5
26.7
240W
19.32
(9.32,31.7)
73.28
No
59.2
47.8
39.6
27.3
240BW
19.02
(9.12,31.32)
72.73
No
59.1
47
39.5
25.5
480W
20.56
(7.95,37.39)
71.86
No
55.9
46.7
37.1
27.2
480BW
20.16
(7.7,36.87)
71.39
No
54.2
46.4
37
24.8
BLRM = Bayesian logistic regression model; BW = bi-weekly; CI = credible interval; PBO = placebo; PoS = probability 
of success; RR = response rate; W = weekly
1.
PoS is defined as P(RRACT >RRPBO)
2.
A dose group will be selected if the PoS is at least 80%
3.
Power is defined as percentage of time PoS >80% over the sample space (i.e., 1000 simulations)
Table 31
Simulation Results From Scenario 3
Scenario 3
All of the active treatment groups are equally effective 
(medium effect size)
(PBO, 120W, 120BW, 240W, 240BW, 480W, 480BW): (5, 30, 30, 30, 30, 
30, 30)
Treatment
Posterior 
RR (%)
90% CI
PoS1
Decision2
(Select 
dose)
Power3
Cutoff Points
75%
80%
85%
90%
Pai
rwi
PBO
11.63
(2.12,27.28)
 
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Scenario 2
All of the active treatment groups are equally effective 
(low effect size)
(PBO, 120W, 120BW, 240W, 240BW, 480W, 480BW): (5, 20, 20, 20, 20, 
20, 20)
Treatment
Posterior 
RR (%)
90% CI
PoS1
Decision2
(Select 
dose)
Power3
Cutoff Points
120W
33.96
(14.91,56.13)
87.1
Yes
89.2
75
70.6
58.1
120BW
33.05
(14.19,55.21)
86.4
Yes
86.6
73.6
70.4
58.9
240W
32.82
(14.03,54.96)
86.07
Yes
87.2
72.8
68.7
56.6
240BW
33.63
(14.61,55.82)
86.79
Yes
88.3
74.1
71.1
59.2
480W
33.56
(14.61,55.69)
86.51
Yes
87.6
74.1
70
59.2
480BW
33.07
(14.23,55.19)
86.56
Yes
88.3
76.2
70.7
58.6
BLRM
PBO
11.64
(2.12,27.28)
120W
30.6
(15.05,48.96)
85.75
Yes
80.4
75.6
69.1
57.9
120BW
30.3
(14.76,48.72)
86.06
Yes
80.2
75
68.3
56.8
240W
29.47
(17.09,43.47)
88.04
Yes
84.7
79.6
71.3
61.4
240BW
29.27
(16.92,43.26)
88.19
Yes
85.7
80.1
74.2
62.9
480W
30.33
(14.79,48.74)
85.92
Yes
80.9
75.4
68.7
57.8
480BW
30.22
(14.77,48.54)
85.83
Yes
81.4
77
68.5
57.2
BLRM = Bayesian logistic regression model; BW = bi-weekly; CI = credible interval; PBO = placebo; PoS = probability 
of success; RR = response rate; W = weekly
1.
PoS is defined as P(RRACT >RRPBO)
2.
A dose group will be selected if the PoS is at least 80%
3.
Power is defined as percentage of time PoS >80% over the sample space (i.e., 1000 simulations)
Table 32
Simulation Results From Scenario 4
Scenario 4
Larger effect in higher dose group 
(bi-weekly dosing regimen is more efficacious than weekly)
(PBO, 120W, 120BW, 240W, 240BW, 480W, 480BW): (5, 10, 15, 20, 25, 
30, 35)
Treatment
Posterior 
RR (%)
90% CI
PoS1
Decision2
(Select 
dose)
Power3
Cutoff Points
75%
80%
85%
90%
Pairwise Comparison
PBO
11.6
(2.14,27.2)
120W
16.22
(3.79,35.04)
60.91
No
42.2
26.9
13.9
12.4
120BW
20.68
(6.17,40.8)
69.82
No
61.9
43.3
29.7
25
240W
25.23
(8.86,46.38)
77.12
No
72.7
55.7
45.7
37.6
240BW
29.57
(11.72,51.37)
82.7
Yes
82.6
64.8
59.5
49.5
480W
33.52
(14.49,55.77)
86.83
Yes
89.2
73.4
70.1
59.2
480BW
37.5
(17.52,59.93)
90.53
Yes
93.4
82.7
80.1
68.3
BLRM
PBO
11.6
(2.14,27.19)
120W
11.82
(3.6,24.34)
51.31
No
24.9
18.6
12.2
6.1
120BW
15.15
(5.12,29.57)
60.12
No
35.5
28.5
21.5
12.5
240W
18.05
(8.31,30.37)
69.86
No
53.3
44.6
35
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Scenario 4
Larger effect in higher dose group 
(bi-weekly dosing regimen is more efficacious than weekly)
(PBO, 120W, 120BW, 240W, 240BW, 480W, 480BW): (5, 10, 15, 20, 25, 
30, 35)
Treatment
Posterior 
RR (%)
90% CI
PoS1
Decision2
(Select 
dose)
Power3
Cutoff Points
240BW
22.89
(11.69,36.35)
79.36
No
70.5
61.8
51.2
40.3
480W
30.47
(14.2,49.86)
85.05
Yes
80.4
74.5
66.3
55.5
480BW
36.93
(18.95,57.08)
91.12
Yes
90.4
87
82.4
72.5
BLRM = Bayesian logistic regression model; BW = bi-weekly; CI = credible interval; PBO = placebo; PoS = probability 
of success; RR = response rate; W = weekly
1.
PoS is defined as P(RRACT >RRPBO)
2.
A dose group will be selected if the PoS is at least 80%
3.
Power is defined as percentage of time PoS >80% over the sample space (i.e., 1000 simulations)
Table 33
Simulation Results From Scenario 5
Scenario 5
Larger effect in higher dose group 
(weekly dosing regimen is more efficacious than bi-weekly)
(PBO, 120W, 120BW, 240W, 240BW, 480W, 480BW): (5, 15, 10, 25, 20, 
35, 30)
Treatment
Posterior 
RR (%)
90% CI
PoS1
Decision2
(Select 
dose)
Power3
Cutoff Points
75%
80%
85%
90%
Pairwise Comparison
PBO
11.44
(2.07,26.95)
120W
21.33
(6.5,41.66)
71.63
No
63
45.5
33.9
28.2
120BW
16.21
(3.78,35.03)
61.39
No
42.9
28.4
15
13.5
240W
29.28
(11.47,51.09)
83.02
Yes
83.7
66.7
60
49.2
240BW
24.92
(8.78,45.89)
76.38
No
70.1
53.1
44
37.8
480W
37.93
(17.84,60.38)
90.49
Yes
92.3
82.6
80.9
70.8
480BW
32.9
(14.16,54.96)
86.27
Yes
87.6
74.1
70
59.3
BLRM
PBO
11.44
(2.07,26.95)
120W
15.55
(5.28,30.22)
61.72
No
38.1
30.4
21.8
13
120BW
11.76
(3.55,24.27)
51.74
No
22.6
17.6
11
5.7
240W
23.26
(11.96,36.77)
80.14
No
72.8
65.9
56
43.2
240BW
17.83
(8.2,30.03)
69.93
No
53.1
43.6
35.7
23.7
480W
36.98
(19.03,57.09)
90.85
Yes
89.9
85.7
81.4
73.1
480BW
29.8
(13.86,48.9)
84.19
Yes
77.8
72.3
65.1
54.7
BLRM = Bayesian logistic regression model; BW = bi-weekly’ CI = credible interval; PBO = placebo; PoS = probability 
of success; RR = response rate; W = weekly
1.
PoS is defined as P(RRACT >RRPBO)
2.
A dose group will be selected if the PoS is at least 80%
3.
Power is defined as percentage of time PoS >80% over the sample space (i.e., 1000 simulations)
 
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Table 34
Simulation Results From Scenario 6
Scenario 6
Only 480 mg (highest dose) bi-weekly dosing is efficacious
(PBO, 120W, 120BW, 240W, 240BW, 480W, 480BW): (5, 10, 10, 10, 10, 
10, 30)
Treatment
Posterior 
RR (%)
90% CI
PoS1
Decision2
(Select 
dose)
Power3
Cutoff Points
75%
80%
85%
90%
Pairwise Comparison
PBO
11.53
(2.11,27.1)
120W
16.73
(4.09,35.67)
61.94
No
44.7
29.2
16.9
14.4
120BW
16.63
(4,35.58)
62.02
No
44.1
29.2
16.6
15.1
240W
17.01
(4.19,36.07)
63.07
No
47.4
30.4
17.2
14.9
240BW
16.83
(4.14,35.79)
62.19
No
43.9
30.7
18.1
15.1
480W
16.59
(4,35.51)
61.82
No
42.9
26.7
16.9
14.9
480BW
33.63
(14.64,55.8)
87.03
No
88.8
75
69.9
59.7
BLRM
PBO
11.54
(2.11,27.1)
120W
7.37
(1.61,17.36)
35.03
No
8.3
5.4
2.7
1.4
120BW
11.41
(2.94,24.88)
48.98
No
21.9
15.6
9.4
4.5
240W
9.01
(2.94,17.97)
43.42
No
15.8
8.6
5.1
1.6
240BW
14.59
(6,25.96)
61.61
No
39.6
30.4
19.2
12.2
480W
14.85
(4.38,30.45)
58.11
No
31.9
25.6
18.3
9.9
480BW
23.81
(9.3,42.65)
75.05
No
62.9
57.2
47.8
36.2
BLRM = Bayesian logistic regression model; CI = credible interval; M = monthly; PBO = placebo; PoS = probability of
success; RR = response rate; W = weekly
1.
PoS is defined as P(RRACT >RRPBO)
2.
A dose group will be selected if the PoS is at least 80%
3.
Power is defined as percentage of time PoS >80% over the sample space (i.e., 1000 simulations)
Table 35
Simulation Results From Scenario 7
Scenario 7
Only 480 mg (highest dose) is efficacious
(bi-weekly having medium effect and weekly having small effect)
(PBO, 120W, 120BW, 240W, 240BW, 480W, 480BW): (5, 10, 10, 10, 10, 
20, 30)
Treatment
Posterior 
RR (%)
90% CI
PoS1
Decision
2
(Select 
dose)
Power3
Cutoff Points
75%
80%
85%
90%
Pairwise Comparison
PBO
11.48
(2.08,27.02)
120W
16.4
(3.89,35.27)
61.56
No
43.9
27.9
16
14.5
120BW
16.83
(4.06,35.9)
62.82
No
46
30.3
17
15.5
240W
16.93
(4.16,35.97)
62.77
No
46.4
32.1
18.1
15.2
240BW
16.73
(4.01,35.76)
62.67
No
46.4
30.1
17.1
14.8
480W
25.17
(8.81,46.31)
77.7
No
73.9
52.9
44.2
36.9
480BW
33.46
(14.51,55.62)
87.03
Yes
88.8
75.2
71
60.4
 
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Scenario 7
Only 480 mg (highest dose) is efficacious
(bi-weekly having medium effect and weekly having small effect)
(PBO, 120W, 120BW, 240W, 240BW, 480W, 480BW): (5, 10, 10, 10, 10, 
20, 30)
Treatment
Posterior 
RR (%)
90% CI
PoS1
Decision
2
(Select 
dose)
Power3
Cutoff Points
BLRM
PBO
11.48
(2.08,27.02)
120W
7.92
(1.85,18.23)
37.57
No
11.4
7.3
4.3
2
120BW
9.62
(2.37,21.53)
43.8
No
15.1
11.3
7
2.9
240W
11.45
(4.22,21.6)
52.29
No
25.7
18.7
13.1
5.7
240BW
14.29
(5.79,25.63)
60.98
No
38.3
29.3
20
11.2
480W
21.2
(7.71,39.33)
72.07
No
56
47.3
35.9
26.1
480BW
26.26
(10.88,45.63)
79.38
No
69
62.7
53.7
43.6
BLRM = Bayesian logistic regression model; BW = bi-weekly; CI = credible interval; PBO = placebo; PoS = probability 
of success; RR = response rate; W = weekly
1.
PoS is defined as P(RRACT >RRPBO)
2.
A dose group will be selected if the PoS is at least 80%
3.
Power is defined as percentage of time PoS >80% over the sample space (i.e., 1000 simulations)
Table 36
Simulation Results From Scenario 8
Scenario 8
Only 240 mg (middle dose) bi-weekly dosing is efficacious
(PBO, 120W, 120BW, 240W, 240BW, 480W, 480BW): (5, 10, 10, 10, 30, 
10, 10)
Treatment
Posterior 
RR (%)
90% CI
PoS1
Decision2
(Select 
dose)
Power3
Cutoff Points
75%
80%
85%
90%
Pairwise Comparison
PBO
11.45
(2.07, 26.97)
120W
16.08
(3.7,34.87)
61.07
No
42.4
28.6
15.8
14.2
120BW
16.27
(3.82,35.1)
61.41
No
44.4
29.2
15.2
13.6
240W
16.72
(4.05,35.7)
62.25
No
45.6
30.6
18.6
17.3
240BW
34
(14.96,56.15)
86.81
Yes
87.1
75.3
71.5
61.3
480W
16.49
(3.92,35.4)
61.94
No
44.7
30.4
14.9
13.5
480BW
16.48
(3.95,35.35)
61.44
No
43.4
30.2
17.9
16.4
BLRM
PBO
11.45
(2.07, 26.97)
120W
10.18
(2.48,22.78)
45.95
No
16.1
11.2
7.1
3.4
120BW
16.85
(5.36,33.34)
63.63
No
40.6
34.5
24.7
15.9
240W
9.13
(2.93,18.26)
45.03
No
16.9
9.5
5.4
2.3
240BW
15.35
(6.57,26.77)
64.13
No
44.4
35.3
24.9
15.1
480W
10.68
(2.68,23.6)
47.18
No
18
13.9
8.8
4.8
480BW
17.26
(5.55,33.98)
64.46
No
42.6
36.6
26.1
17
 
2018N382335_00


2016N277028_08
CONFIDENTIAL
205670
287
Scenario 8
Only 240 mg (middle dose) bi-weekly dosing is efficacious
(PBO, 120W, 120BW, 240W, 240BW, 480W, 480BW): (5, 10, 10, 10, 30, 
10, 10)
Treatment
Posterior 
RR (%)
90% CI
PoS1
Decision2
(Select 
dose)
Power3
Cutoff Points
BLRM = Bayesian logistic regression model; BW = bi-weekly; CI = credible interval; PBO = placebo; PoS = probability 
of success; RR = response rate; W = weekly
1.
PoS is defined as P(RRACT >RRPBO)
2.
A dose group will be selected if the PoS is at least 80%
3.
Power is defined as percentage of time PoS >80% over the sample space (i.e., 1000 simulations)
Table 37
Simulation Results From Scenario 9
Scenario 9
Only 120 mg (lowest dose) bi-weekly dosing is efficacious
(PBO, 120W, 120BW, 240W, 240BW, 480W, 480BW): (5, 10, 30, 10, 10, 
10, 10)
Treatment
Posterior 
RR (%)
90% CI
PoS1
Decision2
(Select 
dose)
Power3
Cutoff Points
75%
80%
85%
90%
Pairwise Comparison
PBO
11.05
(1.88,26.43)
120W
16.59
(3.97,35.54)
63.25
No
45.8
31.1
17.1
15
120BW
33.39
(14.37,55.64)
87.79
Yes
88.9
77.5
74
63.6
240W
16.91
(4.19,35.89)
63.52
No
47.7
31.3
19
16.6
240BW
16.56
(3.99,35.45)
62.81
No
45.2
29.8
17.5
16
480W
16.67
(4,35.67)
63.39
No
45.8
30.9
16.6
15.1
480BW
16.83
(4.12,35.83)
63.56
No
45.4
29.8
18
15.8
BLRM
PBO
11.05
(1.88,26.43)
120W
14.53
(4.19,30.08)
59.18
No
32.7
26.6
16.5
10
120BW
23.51
(9.04,42.35)
75.75
No
64.4
58.6
49.3
37.1
240W
9
(2.91,17.98)
44.99
No
16.4
8.7
6
2.7
240BW
14.54
(6,25.87)
62.7
No
40.8
32.7
22.3
13.2
480W
7.49
(1.65,17.58)
36.46
No
8.8
6.6
3.9
1.2
480BW
11.54
(3.06,24.93)
50.19
No
23
17.2
10.7
5.8
BLRM = Bayesian logistic regression model; BW = bi-weekly; CI = credible interval; PBO = placebo; PoS = probability 
of success; RR = response rate; W = weekly
1.
PoS is defined as P(RRACT >RRPBO)
2.
A dose group will be selected if the PoS is at least 80%
3.
Power is defined as percentage of time PoS >80% over the sample space (i.e., 1000 simulations)
 
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Amended:
Table 38
Simulation Results From Scenario 1
Scenario 1
No Treatment Effect
(PBO, 120W, 120BW, 240W, 240BW, 480W, 480BW): (5, 5, 5, 5, 
5, 5, 5)
Treatment
Posterior 
RR (%)
90% CI
PoS1
Decision2
(Select 
dose)
Power3
Cutoff Points
85%
90%
95%
98%
Pairwise Comparison
PBO
5.86
(0.79,15.93)
120W
5.77
(0.68,16.43)
48.13
No
22.3
22.3
17.9
3.5
120BW
5.71
(0.73,16.13)
47.32
No
20.7
20.7
17.3
4.3
240W
6.26
(0.76,17.48)
49.78
No
22.6
22.6
18.8
4.9
240BW
5.88
(0.69,16.67)
48.44
No
21.6
21.6
17.8
3.6
480W
6.19
(0.8,17.18)
48.94
No
23.3
23.3
18.4
6.1
480BW
5.69
(0.65,16.26)
47.79
No
21.7
21.7
18.2
4.5
BLRM
PBO
5.91
(0.79,16.21)
120W
5.51
(0.74,15.07)
56.39
No
32.7
22.6
9.9
2.0
120BW
5.53
(0.78,15.01)
56.12
No
29.9
22.0
9.9
2.4
240W
3.98
(0.76,9.84)
54.55
No
32.9
20.5
7.9
0.6
240BW
3.86
(0.73,9.58)
53.92
No
31.1
19.0
7.6
0.9
480W
6.07
(0.89,16.19)
57.82
No
32.4
25.8
13.1
4.2
480BW
5.69
(0.77,15.52)
57.19
No
30.9
24.8
12.5
2.5
BLRM = Bayesian logistic regression model; BW = bi-weekly; CI = credible interval; PBO = placebo; PoS = probability 
of success; RR = response rate; W = weekly
1.
PoS is defined as P(RRACT >RRPBO)
2.
A dose group will be selected if the PoS is at least 95%
3.
Power is defined as percentage of time PoS >95% over the sample space (i.e., 1000 simulations)
Table 39
Simulation Results From Scenario 2
Scenario 2
All of the active treatment groups are equally effective 
(low effect size)
(PBO, 120W, 120BW, 240W, 240BW, 480W, 480BW): (5, 20, 20, 20, 20, 
20, 20)
Treatment
Posterior 
RR (%)
90% CI
PoS1
Decision2
(Select 
dose)
Power3
Cutoff Points
85%
90%
95%
98%
Pairwise 
Comparison
PBO
5.66
(0.77,15.46)
120W
20.54
(6,41.01)
80.5
No
60.6
60.0
50.8
35.1
120BW
20.82
(6.2,41.3)
80.81
No
61.5
61.1
51.6
34.8
240W
21.09
(6.35,41.57)
80.5
No
62.8
61.9
50.7
36.7
240BW
20.57
(6.14,40.83)
80.05
No
59.8
59.0
49.5
33.3
 
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Scenario 2
All of the active treatment groups are equally effective 
(low effect size)
(PBO, 120W, 120BW, 240W, 240BW, 480W, 480BW): (5, 20, 20, 20, 20, 
20, 20)
Treatment
Posterior 
RR (%)
90% CI
PoS1
Decision2
(Select 
dose)
Power3
Cutoff Points
480W
19.91
(5.73,39.95)
79.03
No
60.2
59.9
49.4
35.3
480BW
20.86
(6.22,41.3)
80.1
No
61.7
61.1
51.4
35.7
BLRM
PBO
5.71
(0.77,15.73)
120W
20.53
(7.97,37.3)
86.37
No
71.3
65.2
55.2
41.2
120BW
20.8
(8.09,37.69)
86.78
No
71.2
64.6
55.3
40.9
240W
18.97
(9.07,31.27)
86.79
No
70.7
64.3
56.3
44.4
240BW
19.24
(9.28,31.59)
87.13
No
72.8
64.6
55.9
45.8
480W
20.3
(7.83,36.97)
85.5
No
70.2
64.5
55.0
40.6
480BW
20.58
(8.03,37.33)
85.78
No
69.9
64.1
56.5
41.6
BLRM = Bayesian logistic regression model; BW = bi-weekly; CI = credible interval; PBO = placebo; PoS = probability 
of success; RR = response rate; W = weekly
1.
PoS is defined as P(RRACT >RRPBO)
2.
A dose group will be selected if the PoS is at least 95%
3.
Power is defined as percentage of time PoS >95% over the sample space (i.e., 1000 simulations)
Table 40
Simulation Results From Scenario 3
Scenario 3
All of the active treatment groups are equally effective 
(medium effect size)
(PBO, 120W, 120BW, 240W, 240BW, 480W, 480BW): (5, 30, 30, 30, 30, 
30, 30)
Treatment
Posterior 
RR (%)
90% CI
PoS1
Decision2
(Select 
dose)
Power3
Cutoff Points
85%
90%
95%
98%
Pairwise Comparison
PBO
5.27
(0.63,14.82)
120W
30.22
(11.56,53.18)
90.59
No
80.4
78.9
65.7
52.5
120BW
30.47
(11.77,53.41)
91.07
No
81.0
79.6
66.9
53.3
240W
30.27
(11.62,53.2)
90.09
No
78.1
77.0
65.3
53.7
240BW
30.85
(12.03,53.79)
90.43
No
79.8
78.1
66.9
53.7
480W
31.04
(12.04,54.17)
90.8
No
80.8
79.8
68.3
56.0
480BW
29.97
(11.54,52.67)
89.68
No
78.4
77.1
65.9
52.8
BLRM
PBO
5.32
(0.63,15.09)
120W
30.39
(14.88,48.75)
94.32
No
88.0
82.9
72.4
60.8
120BW
30.25
(14.75,48.63)
94.34
No
88.7
81.8
72.2
60.8
240W
29.45
(17.05,43.47)
95.32
Yes
90.9
85.1
75.2
64.1
240BW
29.41
(17.04,43.4)
95.29
Yes
89.9
85.1
76.0
63.9
480W
30.52
(14.92,48.96)
94.1
No
86.9
81.4
73.1
60.5
480BW
30.57
(15.05,48.91)
94.02
No
86.5
82.0
72.9
60.7
 
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BLRM = Bayesian logistic regression model; BW = bi-weekly; CI = credible interval; PBO = placebo; PoS = probability 
of success; RR = response rate; W = weekly
1.
PoS is defined as P(RRACT >RRPBO)
2.
A dose group will be selected if the PoS is at least 95%
3.
Power is defined as percentage of time PoS >95% over the sample space (i.e., 1000 simulations)
Table 41
Simulation Results From Scenario 4
Scenario 4
Larger effect in higher dose group 
(bi-weekly dosing regimen is more efficacious than weekly)
(PBO, 120W, 120BW, 240W, 240BW, 480W, 480BW): (5, 10, 15, 20, 25, 
30, 35)
Treatment
Posterior 
RR (%)
90% CI
PoS1
Decision2
(Select 
dose)
Power3
Cutoff Points
85%
90%
95%
98%
Pairwise Comparison
PBO
5.42
(0.73,14.94)
120W
10.49
(1.91,25.29)
62.61
No
38.1
38.1
31.7
15.7
120BW
16.37
(4.15,34.77)
74.76
No
53.9
53.6
45.0
26.8
240W
20.75
(6.16,41.14)
81.02
No
61.4
60.5
51.5
36.6
240BW
25.88
(9.04,47.74)
86.46
No
72.3
71.5
59.9
45.0
480W
31.43
(12.49,54.39)
90.2
No
79.3
78.0
68.4
54.1
480BW
34.46
(14.41,57.92)
92.55
No
84.0
82.6
72.3
60.2
BLRM
PBO
5.47
(0.73,15.21)
120W
12.24
(3.78,25.02)
77.56
No
57.9
53.5
40.5
20.1
120BW
15.55
(5.36,30.08)
81.92
No
64.3
58.2
48.7
30.1
240W
18.39
(8.52,30.8)
86.96
No
70.9
63.7
55.9
45.4
240BW
22.96
(11.79,36.35)
90.91
No
79.9
74.1
63.9
54.3
480W
30.64
(14.45,49.87)
93.16
No
84.9
78.5
70.5
58.6
480BW
36.44
(18.66,56.44)
95.71
Yes
90.1
86.7
80.1
69.2
BLRM = Bayesian logistic regression model; BW = bi-weekly; CI = credible interval; PBO = placebo; PoS = probability 
of success; RR = response rate; W = weekly
1.
PoS is defined as P(RRACT >RRPBO)
2.
A dose group will be selected if the PoS is at least 95%
3.
Power is defined as percentage of time PoS >95% over the sample space (i.e., 1000 simulations)
Table 42
Simulation Results From Scenario 5
Scenario 5
Larger effect in higher dose group 
(weekly dosing regimen is more efficacious than bi-weekly)
(PBO, 120W, 120BW, 240W, 240BW, 480W, 480BW): (5, 15, 10, 25, 20, 
35, 30)
Treatment
Posterior 
RR (%)
90% CI
PoS1
Decision2
(Select 
dose)
Power3
Cutoff Points
85%
90%
95%
98%
 
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Scenario 5
Larger effect in higher dose group 
(weekly dosing regimen is more efficacious than bi-weekly)
(PBO, 120W, 120BW, 240W, 240BW, 480W, 480BW): (5, 15, 10, 25, 20, 
35, 30)
Treatment
Posterior 
RR (%)
90% CI
PoS1
Decision2
(Select 
dose)
Power3
Cutoff Points
Pairwise Comparison
PBO
5.89
(0.79,16.01)
120W
15.35
(3.59,33.51)
71.91
No
47.6
47.5
39.4
24.8
120BW
11.1
(2.15,26.26)
62.23
No
37.0
37.0
30.4
14.5
240W
25.26
(8.64,47)
85.09
No
69.8
68.6
56.4
40.6
240BW
20.61
(6.01,41.08)
80.06
No
60.1
59.6
48.8
33.6
480W
34.72
(14.63,58.19)
92.29
No
82.2
81.0
71.5
58.2
480BW
29.63
(11.11,52.59)
89.04
No
74.8
73.5
62.9
50.5
BLRM
PBO
5.94
(0.78,16.27)
120W
15.25
(5.19,29.7)
80.12
No
59.9
54.1
43.2
26.1
120BW
12.13
(3.73,24.83)
75.49
No
54.4
48.7
36.6
17.9
240W
22.52
(11.48,35.84)
90.03
No
77.1
69.2
59.2
47.2
240BW
18.06
(8.32,30.36)
85.58
No
66.8
60.3
52.1
41.1
480W
35.7
(18.03,55.74)
95.35
Yes
90.0
85.7
77.4
66.1
480BW
29.84
(13.75,49.13)
92.59
No
83.6
76.5
66.9
57.2
BLRM = Bayesian logistic regression model; BW = bi-weekly’ CI = credible interval; PBO = placebo; PoS = probability 
of success; RR = response rate; W = weekly
1.
PoS is defined as P(RRACT >RRPBO)
2.
A dose group will be selected if the PoS is at least 95%
3.
Power is defined as percentage of time PoS >95% over the sample space (i.e., 1000 simulations)
Table 43
Simulation Results From Scenario 6
Scenario 6
Only 480 mg (highest dose) bi-weekly dosing is efficacious
(PBO, 120W, 120BW, 240W, 240BW, 480W, 480BW): (5, 10, 10, 10, 10, 10, 
30)
Treatme
nt
Posteri
or 
RR (%)
90% CI
PoS1
Decision2
(Select 
dose)
Power3
Cutoff Points
85%
90%
95%
98%
Pairwise Comparison
PBO
5.87
(0.79,15.98)
120W
10.69
(1.94,25.78)
62.31
No
37.2
37.0
30.4
12.7
120BW
11.31
(2.13,26.85)
63.39
No
38.8
38.7
31.9
16.3
240W
10.53
(1.97,25.28)
60.78
No
35.5
35.5
29.5
14.6
240BW
10.35
(1.88,25.04)
60.98
No
35.3
35.3
29.3
13.3
480W
10.53
(1.94,25.35)
61.14
No
36.8
36.8
31.0
14.1
480BW
30.59
(11.86,53.5)
89.42
No
77.5
75.8
64.7
50.6
BLRM
PBO
5.92
(0.79,16.22)
120W
7.32
(1.61,17.24)
63.74
No
42.8
34.4
19.3
5.6
120BW
11.45
(2.99,24.92)
72.63
No
51.6
45.2
32.2
15.2
 
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Scenario 6
Only 480 mg (highest dose) bi-weekly dosing is efficacious
(PBO, 120W, 120BW, 240W, 240BW, 480W, 480BW): (5, 10, 10, 10, 10, 10, 
30)
Treatme
nt
Posteri
or 
RR (%)
90% CI
PoS1
Decision2
(Select 
dose)
Power3
Cutoff Points
240W
8.71
(2.78,17.53)
69.47
No
48.7
42.0
29.4
11.5
240BW
14.46
(5.92,25.8)
80.12
No
57.4
53.1
46.3
29.5
480W
14.24
(4.08,29.58)
77.18
No
55.6
50.3
40.5
21.9
480BW
23.65
(9.2,42.41)
86.9
No
73.6
66.4
56.9
43.1
BLRM = Bayesian logistic regression model; CI = credible interval; M = monthly; PBO = placebo; PoS = probability of
success; RR = response rate; W = weekly
1.
PoS is defined as P(RRACT >RRPBO)
2.
A dose group will be selected if the PoS is at least 95%
3.
Power is defined as percentage of time PoS >95% over the sample space (i.e., 1000 simulations)
Table 44
Simulation Results From Scenario 7
Scenario 7
Only 480 mg (highest dose) is efficacious
(bi-weekly having medium effect and weekly having small effect)
(PBO, 120W, 120BW, 240W, 240BW, 480W, 480BW): (5, 10, 10, 10, 10, 
20, 30)
Treatment
Posterior 
RR (%)
90% CI
PoS1
Decision
2
(Select 
dose)
Power3
Cutoff Points
85%
90%
95%
98%
Pairwise Comparison
PBO
5.87
(0.75,16.07)
120W
10.72
(1.97,25.75)
61.57
No
36.0
35.9
29.3
14.5
120BW
11.17
(2.09,26.61)
62.83
No
37.6
37.5
31.2
16.0
240W
11.63
(2.31,27.22)
63.58
No
39.7
39.7
31.9
15.6
240BW
10.33
(1.75,25.33)
61.66
No
35.4
35.3
29.2
12.0
480W
20.8
(6.04,41.54)
80.43
No
59.3
58.8
49.4
35.5
480BW
30.47
(11.72,53.52)
89.53
No
77.1
76.1
63.1
50.7
BLRM
PBO
5.92
(0.75,16.3)
120W
8.21
(1.95,18.74)
65.9
No
45.8
36.6
21.4
7.1
120BW
9.72
(2.41,21.68)
69.54
No
48.2
41.4
26.6
11.7
240W
11.71
(4.35,21.99)
75.37
No
55.6
50.8
39.0
20.5
240BW
14.19
(5.68,25.54)
80
No
57.1
52.0
45.8
29.5
480W
21.44
(7.88,39.61)
85.58
No
67.5
62.4
54.7
40.1
480BW
25.9
(10.63,45.2)
89.37
No
76.2
70.4
59.8
46.9
BLRM = Bayesian logistic regression model; BW = bi-weekly; CI = credible interval; PBO = placebo; PoS = probability 
of success; RR = response rate; W = weekly
1.
PoS is defined as P(RRACT >RRPBO)
2.
A dose group will be selected if the PoS is at least 95%
3.
Power is defined as percentage of time PoS >95% over the sample space (i.e., 1000 simulations)
 
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Table 45
Simulation Results From Scenario 8
Scenario 8
Only 240 mg (middle dose) bi-weekly dosing is efficacious
(PBO, 120W, 120BW, 240W, 240BW, 480W, 480BW): (5, 10, 10, 10, 30, 
10, 10)
Treatment
Posterior 
RR (%)
90% CI
PoS1
Decision2
(Select 
dose)
Power3
Cutoff Points
85%
90%
95%
98%
Pairwise Comparison
PBO
5.4
(0.68,15.04)
120W
11.04
(2.04,26.4)
64.38
No
41.0
40.9
33.3
15.2
120BW
9.94
(1.76,24.3)
61.6
No
37.8
37.7
29.2
12.0
240W
11.05
(2.07,26.33)
64.22
No
41.1
41.1
34.2
16.0
240BW
31.46
(12.39,54.59)
90.34
No
78.3
77.6
67.1
56.3
480W
10.44
(1.94,25.16)
62.3
No
38.3
38.3
32.1
14.4
480BW
10.67
(1.88,25.83)
63.48
No
39.1
39.0
33.4
15.7
BLRM
PBO
5.46
(0.68,15.33)
120W
10.68
(2.74,23.46)
73.45
No
54.8
47.5
31.9
14.2
120BW
16.98
(5.46,33.5)
82.05
No
65.7
60.4
49.8
32.8
240W
9.5
(3.19,18.68)
73.12
No
55.6
46.6
34.0
15.6
240BW
15.38
(6.6,26.82)
82.64
No
64.3
58.6
51.9
36.4
480W
10.85
(2.82,23.76)
73.32
No
55.2
48.9
32.9
14.7
480BW
17.12
(5.49,33.79)
82.42
No
65.1
59.7
49.2
33.3
BLRM = Bayesian logistic regression model; BW = bi-weekly; CI = credible interval; PBO = placebo; PoS = probability 
of success; RR = response rate; W = weekly
1.
PoS is defined as P(RRACT >RRPBO)
2.
A dose group will be selected if the PoS is at least 95%
3.
Power is defined as percentage of time PoS >95% over the sample space (i.e., 1000 simulations)
Table 46
Simulation Results From Scenario 9
Scenario 9
Only 120 mg (lowest dose) bi-weekly dosing is efficacious
(PBO, 120W, 120BW, 240W, 240BW, 480W, 480BW): (5, 10, 30, 10, 10, 
10, 10)
Treatment
Posterior 
RR (%)
90% CI
PoS1
Decision2
(Select 
dose)
Power3
Cutoff Points
85%
90%
95%
98%
Pairwise Comparison
PBO
5.84
(0.79,15.87)
120W
10.47
(1.86,25.38)
61.37
No
35.4
35.4
28.2
14.3
120BW
31.02
(11.9,54.34)
90.87
No
79.1
77.5
66.3
52.1
240W
10.6
(1.86,25.73)
62.39
No
36.5
36.5
30.5
13.4
240BW
10.27
(1.82,24.96)
61.21
No
36.5
36.5
30.6
12.8
480W
11.23
(2.12,26.65)
63.35
No
38.0
38.0
30.6
15.1
480BW
10.74
(1.97,25.76)
61.98
No
37.5
37.3
30.4
15.1
B
L
PBO
5.89
(0.79,16.13)
 
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Scenario 9
Only 120 mg (lowest dose) bi-weekly dosing is efficacious
(PBO, 120W, 120BW, 240W, 240BW, 480W, 480BW): (5, 10, 30, 10, 10, 
10, 10)
Treatment
Posterior 
RR (%)
90% CI
PoS1
Decision2
(Select 
dose)
Power3
Cutoff Points
120W
14.42
(4.15,29.85)
78.21
No
56.9
51.9
38.4
23.4
120BW
23.62
(9.06,42.55)
87.68
No
74.0
67.7
57.3
44.0
240W
8.89
(2.88,17.79)
70.22
No
50.0
41.3
29.1
13.1
240BW
14.44
(5.85,25.85)
80.92
No
61.0
55.3
45.8
31.4
480W
7.49
(1.68,17.48)
64.06
No
42.2
33.1
20.1
7.6
480BW
11.39
(2.93,24.87)
73.07
No
51.7
46.0
33.1
14.8
BLRM = Bayesian logistic regression model; BW = bi-weekly; CI = credible interval; PBO = placebo; PoS = probability 
of success; RR = response rate; W = weekly
1.
PoS is defined as P(RRACT >RRPBO)
2.
A dose group will be selected if the PoS is at least 95%
3.
Power is defined as percentage of time PoS >95% over the sample space (i.e., 1000 simulations)
Section 12.1, Appendix 1 Abbreviations
Rationale: To make edits for clarity
Original Text:
DAIDS
Division of Allergy and Infectious Diseases
Amdended Text
DAIDS
Division of Allergy and Infectious Diseases Acquired Immune 
Deficiency Syndrome
12.7.4.
Protocol changes for Amendment 04 (21-OCT-2017) from 
Protocol Amendment 03 (28-JUN-2017)
Protocol Amendment 4 replaces the protocol amendment 3 dated 28 JUN 2017 and 
applies to South Korea only. 
Protocol Amendment 4 is being implemented for the following reasons:

To remove females of reproductive potential for Part 1 of study 205670 based on 
feedback from South Korea MFDS.
o
South Korea MFDS requires 3 months of contraceptive use for women of 
child-bearing potential after the last dose of investigational product. As 
Part 1 requires contraceptive use only until Day 60, women of child-
 
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bearing potential for Part 1 has been removed to comply with MFDS 
requirements.

To provide edits for clarity.
LIST OF CHANGES
Section 5.1, Inclusion Criteria 4b.
Rationale: To remove females of reproductive potential for Part 1 of study 205670 based 
on feedback from South Korea MFDS
Original text:
Females of reproductive potential (FRP), must agree to follow (or confirm that 
they have and are currently following) one of the options listed in the 
Modified List of Highly Effective Methods for Avoiding Pregnancy in FRP 
(see Appendix 4) from at least 28 days prior to the first dose of study 
treatment until the final Follow-up visit in conjunction with partner’s use of 
male condom. The investigator is responsible for ensuring that subjects 
understand how to properly use these methods of contraception.
Amended text:
For Part 2, Females of reproductive potential (FRP), must agree to follow (or 
confirm that they have and are currently following) one of the options listed in 
the Modified List of Highly Effective Methods for Avoiding Pregnancy in 
FRP (see Appendix 4) from at least 28 days prior to the first dose of study 
treatment until the final Follow-up visit in conjunction with partner’s use of 
male condom. The investigator is responsible for ensuring that subjects 
understand how to properly use these methods of contraception.
Section 5.1, Exclusion Criteria 18.
Rationale: To remove females of reproductive potential for Part 1 of study 205670 based 
on feedback from South Korea MFDS
Original text: (not applicable)
Amended text:
18. For Part 1, females of reproductive potential
 
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Section 7.1 Time and Events Table 8. Time and Events Table: Screening: Single 
Ascending Dose (Part 1) and Multiple Dose (Part 2)
Rationale: To provide edits for clarity. The informed consent is not restricted to the 30 
day screening window. The informed consent may be obtained at any time prior to 
screening of the subject.
Original text:
Assessment
Screening 
(Up to 30 days 
Prior to Day 1)
Informed Consent 
X
Amended text:
Assessment
Screening 
(Up to 30 days 
Prior to Day 1)
Informed Consent (obtained any time prior to screening)
X
Section 7.3.2 Pregnancy
Rationale: To remove females of reproductive potential for Part 1 of study 205670 based 
on feedback from South Korea MFDS. This statement does not apply for both Parts 1 and 
2 of the study.
Original text:
Females of reproductive potential are permitted in this study.
Amended text:
Females of reproductive potential are permitted in this study.
Appendix 5: Country Specific Requirements
Rationale: To provide edits for clarity. To include South Korea specific requirement
Original text:
If Japan conducts the optional Japanese Part 2 sub-study, Japan-specific requirements 
will be specified in a country-specific amendment or supplement protocol. 
Otherwise, no country-specific requirements exist.
 
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Amended text:
If Japan conducts the optional Japanese Part 2 sub-study, Japan-specific requirements 
will be specified in a country-specific amendment or supplement protocol. 
South Korea will exclude females of reproductive potential in Part 1 only as shown 
in the country-specific protocol amendment.
Otherwise, no country-specific requirements exist.
12.7.5.
Protocol changes for Amendment 05 (06-MAR-2018) from
Protocol Amendment 03 (28-JUN-2017)
Protocol Amendment 5 replaces Protocol Amendment 03 (28 JUN 2017) and applies to 
all study sites.
Protocol Amendment 05 Summary:
Protocol Amendment 5 is being implemented for the following reasons:

To update the protocol with the treatments to be studied in Part 2 
Rationale: The previous versions of the protocol included flexible language such 
that the treatments (doses and regimens) and population (HBeAg status) to be 
studied in Part 2 would be determined after the safety review of Part 1. A request 
was made that those treatments be explicitly written in a protocol amendment for 
Part 2. These changes (e.g., treatment details, subject numbers, and statistical 
sections) were made to satisfy the request from some health authorities/ethics 
committees.

To include an optional additional 9-month off-treatment follow up period
Rationale: An additional 9-month off-treatment follow up period (total 12 
months off-treatment period) was added to evaluate a longer period of safety 
review and efficacy of GSK3389404 in chronic hepatitis B patients

To provide updates to the pre-clinical and clinical data 
Rationale: Align with pre-clinical data updates (such as the 39-week monkey 
study, 26-week mouse study) made in the Investigator’s Brochure (published 
January 2018) and to update the dose rationale with preliminary data from Part 1 
to select the treatments to be studied in Part 2

To include management review of unblinded data
Rationale: Management review of unblinded efficacy data is planned for both 
Part 1 and Part 2 of the study. For part 1, the review provides early information on 
potential efficacious dose and dose frequency including the need for dose 
 
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escalation. For part 2, the review will facilitate internal governance decision 
making on project progress and trigger further studies.

To provide updates in the statistical sections
Rationale: After selecting the treatments (dose/regimen) for Part 2, the statistical 
simulations were updated and the statistical assumptions were revised based on 
the change in total subject number. The statistical sections were also changed to 
include the addition of the optional additional follow up in Part 2 and the 
analyses/study definitions as appropriate.

To provide clarity
Rationale: Additional text has been added to provide clarity after queries were 
received by investigators and/or ethics committees. These include- clarification 
that informed consent is not restricted to the 30 day screening window;
clarification on contraceptive use for males with female partners who are 
currently pregnant; clarification on the use of interferon before and during the 
study; clarification on PK collection windows based on different site practices

To make minor edits on typographical errors, formatting changes, and updates to 
references.
Note: these changes will not be included in the list of changes below unless a 
update text change would impact the overall content
LIST OF SPECIFIC CHANGES
Section 1. Protocol Synopsis for study 205670, Overall design, fourth paragraph, first 
sentence
Rationale: To make edits for clarity, to be consistent throughout protocol
Original text:
Part 2 will be conducted as a multiple-dose, dose-ranging study. Part 2 plans to enroll 
subjects primarily from the Asia-Pacific region
Amended text:
Part 2 will be conducted as a multiple-dose, dose-ranging study. Part 2 plans to enroll 
subjects primarily from the Asia-Pacific region, including Japan.
Section 1. Protocol Synopsis for study 205670, Overall design, fourth paragraph
Rationale: To update the treatments to be studied in Part 2
Original text:
 
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The dose levels and regimens for Part 2 will be selected after review of safety (at a 
minimum of adverse events [AEs], laboratory chemistry, hematology, and 
electrocardiogram [ECG]), PK, and PD data from Part 1 (through Day 3) but will not 
exceed a total monthly SC dose of 480 mg. For each dose level, the total monthly dose 
will be the same but divided into once weekly, bi-weekly (every 2 weeks), or monthly 
dosing regimens for a planned treatment duration of 3 months. However, the total 
monthly SC dose of 480 mg will only be explored in a once weekly or bi-weekly (every 2 
weeks) dosing regimen. Part 2 may explore 2 or 3 different dose levels each at 2 different 
dosing regimens.
Amended text:
The dose levels and regimens for Part 2 will be selected after review of safety (at a 
minimum of adverse events [AEs], laboratory chemistry, hematology, and 
electrocardiogram [ECG]), PK, and PD data from Part 1 (through Day 3) but will not 
exceed a total monthly SC dose of 480 mg. For each dose level, the total monthly dose 
will be the same but divided into once weekly, bi-weekly (every 2 weeks), or monthly 
dosing regimens for a planned treatment duration of 3 months. However, the total 
monthly SC dose of 480 mg will only be explored in a once weekly or bi-weekly (every 2 
weeks) dosing regimen. Part 2 may explore 2 or 3 different dose levels each at 2 different 
dosing regimens. The treatments selected are 60 mg GSK3389404 weekly, 120 mg
GSK3389404 bi-weekly, 120 mg GSK3389404 weekly or placebo.
Section 1. Protocol Synopsis for study 205670, Treatment arms and duration, 2nd
paragraph.
Rationale: To update the treatment and populations to be studied in Part 2and to update 
text to include an optional additional 9 month off-treatment follow up period
Original text:
In Part 2, two or 3 dose levels each at 2 different dosing regimens are planned and the 
total study duration, including screening, dosing, and post-treatment follow-up, is not 
expected to exceed 29 weeks for each subject. 
Amended text:
In Part 2, 60 mg GSK3389404 weekly, 120 mg GSK3389404 bi-weekly, 120 mg
GSK3389404 weekly or placebo two or 3 dose levels each at 2 different dosing 
regimens are planned and the total study duration, including screening, dosing, and post-
treatment follow-up, is not expected to exceed 29 65 weeks for each subject. 
 
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Section 1. Protocol Synopsis for study 205670, Treatment arms and duration, 2nd
paragraph, bullet 2 and 3
Rationale: To update the treatments to be studied in Part 2 
Original text:

An expected study treatment exposure of up to 85 days is planned where 
subjects will receive multiple SC doses of GSK3389404 (480 mg total 
monthly dose) or placebo at once weekly, bi-weekly (every 2 weeks), or 
monthly dosing regimens. 
o
The total monthly SC dose of 480 mg will only be explored in a once 
weekly or bi-weekly (every 2 weeks) dosing regimen. 
Amended text:

An expected study treatment exposure of up to 85 days is planned where 
subjects will receive multiple SC doses of GSK3389404 (480 mg total 
monthly dose) or placebo at once weekly, bi-weekly (every 2 weeks), or 
monthly dosing regimens. 60 mg GSK3389404 weekly, 120 mg GSK3389404 
bi-weekly, 120 mg GSK3389404 weekly.
o
The total monthly SC dose of 480 mg will only be explored in a once 
weekly or bi-weekly (every 2 weeks) dosing regimen. 
Section 1. Protocol Synopsis for study 205670, Treatment arms and duration, 2nd
paragraph, sub-bullet of bullet 3, and bullet 5
Rationale: To update the treatments to be studied in Part 2 and to update text to include 
an optional additional 9 month off-treatment follow up period
Original text:

For monthly dosing, subjects will be administered GSK3389404 or 
placebo as a SC dose on Days 1, 29, and 57. 

A post-treatment follow-up period is planned where subjects will present for 
study visits on Days 85, 92, 99, 113, 141, and 169.
Amended text:

For monthly dosing, subjects will be administered GSK3389404 or 
placebo as a SC dose on Days 1, 29, and 57. 

A post-treatment follow-up period is planned where subjects will present for 
study visits on Days 85, 92, 99, 113, 141, and 169.
 
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
An optional extended post treatment follow-up period will be offered to 
subjects with study visits on Days 270, 360, and 450.
Section 1. Protocol Synopsis for study 205670, Type and Number of subjects
Rationale: To update the treatments to be studied in Part 2 and to provide updates to the 
clinical data from Part 1 of the study
Original text:
Adult male and female subjects with CHB between 18 and 70 years of age, inclusive are 
planned for inclusion. Part 1 (Cohorts A, B, C and D) will enroll HBeAg-positive and/or 
HBeAg-negative subjects, and Part 1 (optional Cohort C1) may enroll HBeAg-positive or 
HBeAgnegative- subjects (or none at all). A decision will be made about the specific 
CHB population for enrollment in Part 2 after completion of dosing in Part 1 (after 
review of safety, tolerability, PK, and PD differences between HBeAg status).
Approximately 150 subjects with CHB are planned for randomization to study treatment 
(GSK3389404 or placebo). This number assumes full enrolment in the optional Japanese 
sub-study.

In Part 1, approximately 20 to 40 subjects with CHB are planned for 
randomization (30 GSK3389404 and 10 placebo under older protocol versions 
versus 15 GSK3389404 and 5 placebo under amendment 3). A range is 
provided because different countries and sites may be enrolling under the older 
versions of the protocol.

In Part 2, approximately 80 subjects with CHB are planned for randomization 
to study treatment. The exact number of subjects to be enrolled will be data 
driven from Part 1 (e.g., safety, tolerability, and PD effects) and will depend on 
the number of dose levels/regimens selected for Part 2. For example, if 3 dose 
levels each with 2 dosing regimens are selected in Part 2, approximately 
80 subjects will be randomized in the 7 treatment groups (6 active groups and 
1 placebo group). Enrolling approximately 80 subjects will allow for an 
approximate14% overall drop-out rate, so that there are approximately 
10 evaluable subjects in each of the active treatment group and approximately 
12 subjects in placebo.
Amended text:
Adult male and female subjects with CHB between 18 and 70 years of age, inclusive are 
planned for inclusion. Part 1 (Cohorts A, B, C and D) will enroll HBeAg-positive and/or 
HBeAg-negative subjects, and Part 1 (optional Cohort C1) may enroll HBeAg-positive or 
HBeAg- negative- subjects (or none at all). A decision will be made about the specific 
CHB population for enrollment in Part 2 after completion of dosing in Part 1 (after 
review of safety, tolerability, PK, and PD differences between HBeAg status).
 
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Approximately 150 73 subjects with CHB are planned for randomization to study 
treatment (GSK3389404 or placebo). This number assumes full enrolment in the optional 
Japanese sub-study.

In Part 1, approximately 20 to 40 subjects with CHB are were planned for 
randomization (30 GSK3389404 and 10 placebo under older protocol versions 
versus 15 GSK3389404 and 5 placebo under amendment 3). A range is was 
provided because different countries and sites may have enrolled be enrolling 
under the older versions of the protocol. Twelve subjects were enrolled for 
Part 1 and Part 1 has completed enrollment.

In Part 2, approximately 80 39 subjects with CHB are planned for 
randomization to study treatment. The exact number of subjects to be enrolled 
will be data driven from Part 1 (e.g., safety, tolerability, and PD effects) and 
will depend on the number of dose levels/regimens selected for Part 2. For 
example, if 3 dose levels each with 2 dosing regimens are selected in Part 2, 
approximately 80 subjects will be randomized in the 7 treatment groups (6 
active groups and 1 placebo group). Enrolling approximately 80 subjects will 
allow for an approximate14% overall drop-out rate, so that There are 
approximately 110 evaluable subjects in each of the active treatment groups
and approximately 612 subjects in the placebo group.
Section 1. Protocol Synopsis for study 205670, Analysis, Part 2, paragraph 1, sentence 4
Rationale: To provide updates in the statistical section due to change in total subject 
number
Original text: 
An active treatment group will be declared efficacious if the posterior probability that the 
difference in the RRs between that active group and the placebo is positive, is high (at 
least 95%), i.e., P (RRACT > RRPBO) 95%, where RRACT is the RR in active group, 
RRPBO is the RR in placebo, and P is the posterior probability.
Amended text:
An active treatment group will be declared efficacious if the posterior probability that the 
difference in the RRs between that active group and the placebo is positive, is high (at 
least 905%), i.e., P (RRACT > RRPBO) 905%, where RRACT is the RR in active group, 
RRPBO is the RR in placebo, and P is the posterior probability.
Section 4.1 Overall Design, Paragraph 4
Rationale: To update the treatments to be studied in Part 2
Original text:
 
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The dose levels and regimens for Part 2 will be selected after a review of Part 1 safety, (at 
a minimum of adverse events [AEs], laboratory chemistry and hematology and 
electrocardiogram [ECG]), PK, and PD data (through Day 3) but will not exceed a total 
monthly dose of 480 mg. For each dose level, the total monthly SC dose will be the same 
but divided into weekly, bi-weekly (every 2 weeks), or monthly dosing regimens for a 
planned treatment duration of 3 months. However, the total monthly SC dose of 480 mg
will only be explored in a once weekly or bi-weekly (every 2 weeks) dosing regimen. 
Part 2 may explore 2 or 3 different dose levels each at 2 different dosing regimens.
Amended text:
The dose levels and regimens for Part 2 will be have been selected after a review of
Part 1 safety, (at a minimum of adverse events [AEs], laboratory chemistry and 
hematology and electrocardiogram [ECG]), PK, and PD data (through Day 3) were 
reviewed but will not exceed a total monthly dose of 480 mg. For each dose level, the 
total monthly SC dose will be the same but divided into weekly, bi-weekly (every 2 
weeks), or monthly dosing regimens for a planned treatment duration of 3 months. 
However, the total monthly SC dose of 480 mg will only be explored in a once weekly or 
bi-weekly (every 2 weeks) dosing regimen. Part 2 may explore 2 or 3 different dose 
levels each at 2 different dosing regimens. The treatments for Part 2 are 60 mg
GSK3389404 weekly, 120 mg bi-weekly GSK3389404, 120 mg GSK3389404 weekly 
or placebo.
Section 4.1 Overall Design, Paragraph 6
Rationale: To update the treatment and populations to be studied in Part 2
Original text:
Study treatment and post-treatment follow-up Time and Events Tables for weekly, 
bi-weekly (every 2 weeks), or monthly dosing regimens are provided in Section 7.1.
Amended text:
Study treatment and post-treatment follow-up Time and Events Tables for weekly, and
bi-weekly (every 2 weeks), or monthly dosing regimens are provided in Section 7.1.
Section 4.1 Overall Design, Figure 2 and footnotes
Rationale: To update the treatment and populations to be studied in Part 2 (please note 
that the figure was amended to include the treatments, a ‘strike-through’ figure was not 
included in the amended text)
Original text:
 
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6.
Hepatitis B virus e-antigen status of the subject population in Part 2 will depend on safety, pharmacokinetic, 
and/or pharmacodynamic profile in Part 1.
7.
Two separate randomization schedules will be used. One for the sentinel group and one to complete 
enrollment of Part 2 subjects. Randomization for the remainder of subjects in Part 2 will continue after safety 
data from at least 2 weeks of exposure in the sentinel group are reviewed. 
8.
Efficacious and safe dose level(s) and regimen(s) with fixed duration of 3 months will be selected based on 
data from Part 1. Part 2 may explore 2 or 3 different dose levels each at 2 different dosing regimens.
9.
Total monthly dose may be divided into weekly, bi-weekly (every 2 weeks), and/or monthly dosing, and total 
monthly dose will not exceed 480 mg. However, the total monthly SC dose of 480 mg will only be explored in 
a weekly or bi-weekly dosing regimen.
10. The sentinel group will consist of at least 1 active and 1 placebo subject per each dosing level and regimen. 
Subjects enrolled in the sentinel group are dosed and followed per the Time and Events Tables. Safety data 
from all subjects in the sentinel group will be reviewed (must be at least 2 weeks of expsosure, but may 
include more data). 
11. An optional Japanese Part 2 sub-study is planned. The exact details may be found in a country-specific 
protocol amendment/supplement and will not be detailed here. The Japan sub-study may include more 
intensive PK monitoring and/or potential overnight/hospital stay.
Amended text:
 
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1.
Hepatitis B virus e-antigen status of the subject population in Part 2 will depend on safety, pharmacokinetic, 
and/or pharmacodynamic profile in Part 1. HBeAg positive and negative subjects will be enrolled
2.
Two separate randomization schedules will be used. One for the sentinel group and one to complete 
enrollment of Part 2 subjects. Randomization for the remainder of subjects in Part 2 will continue after safety 
data from at least 2 weeks of exposure in the sentinel group are reviewed. 
3.
Efficacious and safe dose level(s) and regimen(s) with fixed duration of 3 months will be selected based on 
data from Part 1. Part 2 may explore 2 or 3 different dose levels each at 2 different dosing regimens.
4.
Total monthly dose may be divided into weekly, bi-weekly (every 2 weeks), and/or monthly dosing, and total 
monthly dose will not exceed 480 mg. However, the total monthly SC dose of 480 mg will only be explored in 
a weekly or bi-weekly dosing regimen.
5. 3. The sentinel group will consist of at least 1 active and 1 placebo subject per each dosing level and 
regimen. Subjects enrolled in the sentinel group are dosed and followed per the Time and Events Tables. 
Safety data from all subjects in the sentinel group will be reviewed (must be at least 2 weeks of expsosure, 
but may include more data). 
6. 4. Matching placebo for each treatment arm (dose/regimen)
5. An optional Japanese Part 2 sub-study is planned. The exact details may be found in a country-specific 
protocol amendment/supplement and will not be detailed here. The Japan sub-study may include more 
intensive PK monitoring and/or potential overnight/hospital stay.
Section 4.2 Treatment Arms and Duration, Paragraph 4 and 5
Rationale: To update the treatments to be studied in Part 2 and to update text to include 
the optional additional 9 month follow-up period
Original text:
 
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In Part 2, the total study duration, including screening, treatment and post-treatment 
follow-up, is not expected to exceed 29 weeks for each subject (Figure 4 to Figure 
61GSK3389404 (480 mg total monthly dose) or placebo (Figure 2) at once weekly, bi-
weekly (every 2 weeks), or monthly dosing regimens. However, the total monthly SC 
dose of 480 mg will only be explored in a once weekly or bi-weekly dosing regimen. 
Two or 3 dose levels each at 2 different dosing regimens will be explored. 
For once weekly dosing (Figure 4), study treatment will be administered weekly and 
subjects followed weekly in outpatient visits until the final dose (Day 78) is administered. 
After the final dose, subjects will continue post-treatment follow-up in an outpatient 
setting on Days 85, 92, 99, 113, 141, and 169.
Amended text:
In Part 2, the total study duration, including screening, treatment and post-treatment 
follow-up, is not expected to exceed 29 65 weeks for each subject (Figure 4 and to Figure 
6 GSK3389404 (480 mg total monthly dose) or placebo (Figure 2) at once weekly, bi-
weekly (every 2 weeks), or monthly dosing regimens. However, the total monthly SC 
dose of 480 mg will only be explored in a once weekly or bi-weekly dosing regimen. 
Two or 3 dose levels each at 2 different dosing regimens will be explored. Figure 5.
For once weekly dosing (Figure 4), study treatment will be administered weekly and 
subjects followed weekly in outpatient visits until the final dose (Day 78) is administered. 
After the final dose, subjects will continue post-treatment follow-up in an outpatient 
setting on Days 85, 92, 99, 113, 141, and 169. An optional extended post treatment 
follow-up period will be offered to subjects with study visits on Days 270, 360, and 
450.
Section 4.2 Treatment Arms and Duration, Figure 4
Rationale: To update the figure to include the optional additional follow-up period 
(please note that the figure was amended, but a ‘strike-through’ figure was not included 
in the amended text)
Original text:
 
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Amended text:
Section 4.2 Treatment Arms and Duration, Paragraph 6
Rationale: To update the treatment and populations to be studied in Part 2
Original text: 
For bi-weekly (every 2 weeks) dosing (Figure 5), study treatment will be administered 
every 2 weeks and subjects followed weekly in outpatient visits until the final dose 
(Day 71) is administered. After the final dose, subjects will continue post-treatment 
follow-up in an outpatient setting on Days 78, 85, 92, 99, 113, 141, and 169.
Amended text:
For bi-weekly (every 2 weeks) dosing (Figure 5), study treatment will be administered 
every 2 weeks and subjects followed weekly in outpatient visits until the final dose 
(Day 71) is administered. After the final dose, subjects will continue post-treatment 
follow-up in an outpatient setting on Days 78, 85, 92, 99, 113, 141, and 169. An optional 
extended post treatment follow-up period will be offered to subjects with study visits 
on Days 270, 360, and 450.
 
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Section 4.2 Treatment Arms and Duration, Figure 5
Rationale: To update the figure to include the optional additional follow-up period 
(please note that the figure was amended, but a ‘strike-through’ figure was not included 
in the amended text)
Original text:
Amended text:
Section 4.2 Treatment Arms and Duration, Paragraph 7
Rationale: To update the treatments to be studied in Part 2. Since a monthly dose will not 
be included, the text and associating figure were removed (please note that the figure was 
removed, but a ‘strike-through’ figure was not included in the amended text)
 
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Original text:
For once monthly dosing (Figure 6), study treatment will be administered monthly and 
subjects followed weekly in outpatient visits until the final dose (Day 57) is administered. 
After the final dose, subjects will continue post-treatment follow-up in an outpatient 
setting on Days 64, 71, 78, 85, 92, 99, 113, 141, and 169.
Figure 6 Part 2 Multiple Dose, Dose-Ranging Participation Flow (Once 
Monthly Dosing)
Amended text:
For once monthly dosing (Figure 6), study treatment will be administered monthly and 
subjects followed weekly in outpatient visits until the final dose (Day 57) is administered. 
After the final dose, subjects will continue post-treatment follow-up in an outpatient 
setting on Days 64, 71, 78, 85, 92, 99, 113, 141, and 169.
Section 4.3 Type and Number of Subjects, Paragraph 1
Rationale: To update the treatment and populations to be studied in Part 2.
Original text:
Adult male and female subjects with CHB between 18 and 70 years of age, inclusive are 
planned for inclusion. Part 1 (Cohorts A, B, C and D) will enroll HBeAg-positive and/or 
HBeAg-negative subjects and Part 1 (optional Cohort C1) may enroll HBeAg-positive or 
HBeAgnegative- subjects. A decision will be made about the specific CHB population 
for enrollment in Part 2 after completion of dosing in Part 1 (after review of safety, 
tolerability, PD differences between HBeAg status).
 
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Amended text:
Adult male and female subjects with CHB between 18 and 70 years of age, inclusive are 
planned for inclusion. Part 1 (Cohorts A, B, C and D) will enroll HBeAg-positive and/or 
HBeAg-negative subjects and Part 1 (optional Cohort C1) may enroll HBeAg-positive or 
HBeAg negative- subjects. A decision will be made about the specific CHB population 
for enrollment in Part 2 after completion of dosing in Part 1 (after review of safety, 
tolerability, PD differences between HBeAg status). For Part 2, both HBeAg-positive 
and HBeAg- negative subjects will be enrolled.
Section 4.3 Type and Number of Subjects, Paragraph 2 and sub-bullets 1, 2, and 3
Rationale: To update the treatments to be studied in Part 2 and to provide update with 
preliminary clinical data from Part 1
Original text:
Approximately 150 subjects with CHB are planned for randomization to study treatment 
(GSK3389404 or placebo). This number assumes full enrolment in the optional Japanese 
sub-study.

In Part 1, approximately 20 to 40 subjects with CHB are planned for 
randomization (30 GSK3389404 and 10 placebo under older protocol versions 
versus 15 GSK3389404 and 5 placebo under amendment 3). A range is 
provided because different countries and sites may be enrolling under the older 
versions of the protocol. 

In Part 2, approximately 80 subjects with CHB are planned for randomization 
to study treatment. The exact number of subjects to be enrolled will be data 
driven from Part 1 (e.g., safety, tolerability, PK, and PD effects) and will 
depend on the number of dose levels/regimens selected for Part 2. For 
example, if 3 dose levels each with 2 dosing regimens are selected in Part 2, 
approximately 80 subjects will be randomized in the 7 treatment groups 
(6 active groups and 1 placebo group). Enrolling approximately 80 subjects 
will ensure enough power for Part 2 with or without the optional Japanese Part 
2 sub-study and allow for an approximate 14% overall drop-out rate, so that 
there are 10 evaluable subjects in each active treatment group and 12 subjects 
in placebo without the optional Japanese Part 2 sub-study for the primary 
analysis.

If Japan participates in the optional Japanese Part 2 sub-study, approximately
30 subjects may be enrolled. The exact number of subjects to be enrolled may 
be found in a Japanese-specific protocol amendment/supplement
Amended text:
 
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Approximately 150 73 subjects with CHB are planned for randomization to study 
treatment (GSK3389404 or placebo). This number assumes full enrolment in the optional 
Japanese sub-study.

In Part 1, approximately 20 to 40 subjects with CHB are were planned for 
randomization (30 GSK3389404 and 10 placebo under older protocol versions 
versus 15 GSK3389404 and 5 placebo under amendment 3). A range is 
provided because different countries and sites may be enrolling under the older 
versions of the protocol. Twelve subjects were enrolled for part 1 and Part 
1 has completed enrollment.

In Part 2, approximately 8039 subjects with CHB are planned for 
randomization to study treatment. The exact number of subjects to be enrolled 
will be data driven from Part 1 (e.g., safety, tolerability, PK, and PD effects) 
and will depend on the number of dose levels/regimens selected for Part 2. For 
example, if 3 dose levels each with 2 dosing regimens are selected in Part 2, 
approximately 80 subjects will be randomized in the 7 treatment groups 
(6 active groups and 1 placebo group). Enrolling approximately 80 39 subjects 
will ensure enough power for Part 2 with or without the optional Japanese Part 
2 sub-study and allow for an approximate 14% overall drop-out rate, so that 
there are 110 subjects in each active treatment group and 126 subjects in 
placebo without the optional Japanese Part 2 sub-study for the primary 
analysis.

If Japan participates in the optional Japanese Part 2 sub-study, approximately
30 22 subjects may be enrolled. The exact number of subjects to be enrolled 
may be found in a Japanese-specific protocol amendment/supplement
Section 4.5 Dose Justification
Rationale: To provide updates of the pre-clinical data
Original text:
The GSK3389404 dosing regimens selected for this study were based on observed human 
PK parameters, in vivo antiviral exposure-response relationship, and predicted safety 
margins relative to the 13-week no observed adverse effect level (NOAEL), AUC and 
Cmax in monkeys [ISIS Study Number 712408-AS02, 2016].
Amended text:
The GSK3389404 dosing regimens selected for this study were based on observed human 
PK parameters, in vivo antiviral exposure-response relationship, and predicted safety 
margins relative to the 13- and 39-week no observed adverse effect level (NOAEL), 
AUC and Cmax in monkeys [ISIS Study Number 712408-AS02, 2016; ISIS Study 
Number 712408-AS05, 2017].
Section 4.5.1 Observed Human Pharmacokinetics
 
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Rationale: To update with preliminary clinical data from Part 1 and to provide updates of 
the pre-clinical data
Original text:
GSK3389404 has been administered to healthy adult subjects in Study 202007as single 
SC doses at doses of 10 to 120 mg, or as repeated SC doses (once weekly for 4 weeks) at 
doses of 30 to 120 mg. Study 202007 was a Phase I, first time in human, randomized, 
double-blind, placebo-controlled, dose escalation study to determine the safety, 
tolerability, and PK profile of GSK3389404. At the time of this protocol amendment 
writing, Study 202007 has been completed, and the final study report is in progress. The 
human PK parameters are presented in Table 1. Based on PK data, GSK3389404 showed 
dose proportional- PK with a mean half-life of approximately 4 to 5 hours at a dose range 
of 10 to 120 mg. GSK3389404 plasma concentrations were similar after the first and 
fourth weekly dose, indicating no accumulation in plasma concentration after multiple 
doses. Half-life and plasma exposure (AUC and Cmax) of GSK3389404 following 
multiple doses were consistent with those observed following a single dose. The observed 
human PK data were evaluated using noncompartmental analysis (NCA) in Phoenix 
WinNonlin- version 6.3. All ISIS50538 (GSK3228836) plasma concentrations were non-
quantifiable.
Amended text:
GSK3389404 has been administered to healthy adult subjects in Study 202007 and in 
CHB adult patients in Part 1 of this study (Study 205670).
Study 202007 was a Phase I, first time in human, randomized, double-blind, placebo 
controlled-, dose escalation study to determine the safety, tolerability, and PK 
profile of GSK3389404. GSK3389404 was administered to healthy adult subjects as 
single SC doses at doses of 10 to 120 mg, or as repeated SC doses (once weekly for 4 
weeks) at doses of 30 to 120 mg. Study 202007 was a Phase I, first time in human, 
randomized, double-blind, placebo-controlled, dose escalation study to determine the 
safety, tolerability, and PK profile of GSK3389404. At the time of this protocol 
amendment writing, Study 202007 has been completed, and the final study report for 
study 202007 has been completed is in progress. The human PK parameters are 
presented in Table 1. Based on PK data, GSK3389404 showed dose proportional- PK 
with a mean half-life of approximately 4 to 5 hours at a dose range of 10 to 120 mg. 
GSK3389404 plasma concentrations were similar after the first and fourth weekly dose, 
indicating no accumulation in plasma concentration after multiple doses. Half-life and 
plasma exposure (AUC and Cmax) of GSK3389404 following multiple doses were 
consistent with those observed following a single dose. The observed human PK data 
were evaluated using noncompartmental analysis (NCA) in Phoenix WinNonlin-
version 6.3. All ISIS50538 (GSK3228836) plasma concentrations were non-quantifiable. 
below the LLOQ of 10 ng/mL.
In this study (Study 205670), GSK3389404 has been administered to CHB adult 
patients as single SC doses at doses of 30 mg and 120 mg. At the time of this protocol 
amendment writing, six CHB patients have been administered GSK3389404 (3 at 
30 mg and 3 at 120 mg single dose). Based on the preliminary PK analysis, the mean 
 
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half-life was approximately 4 to 5 hours at the dose of 30 mg and 120 mg in CHB 
patients, consistent with that in healthy subjects. The observed human PK data 
were evaluated using noncompartmental analysis (NCA) in Phoenix WinNonlin-
version 6.3.
Section 4.5.1 Observed Human Pharmacokinetics, Table 1
Rationale: To update with preliminary data from Part 1 and to provide updates of the pre-
clinical data
Original text:
Summary of Selected Plasma GSK3389404 Pharmacokinetic Parameters in Human
Dose
(mg)
10
30
60
120
Cohort1
A
B
E
E
C
F
F
D
G
G
Day
1
1
1
22
1
1
22
1
1
22
N
6
52
6
6
6
6
6
6
6
6
Half life3
(hr)
3.8
(66)
3.7
(81)
3.0
(34)
4.1
(61)
5.1
(71)
5.0
(206)
3.1
(51)
4.1
(29)
3.7
(43)
3.4
(38)
Tmax4
(hr)
1
(1-4)
2
(1-2)
2
(1-4)
2
(1-4)
3
(1-4)
2
(2-2)
2
(1.5-4)
4
(3-4)
2
(1.5-4)
2
(2-4)
Cmax3
(ng/mL)
90
(24)
295
(69)
228
(32)
194
(20)
512
(57)
692
(35)
577
(43)
803
(49)
1167
(50)
1107
(55)
AUC(0-)3
(ng*hr/mL)
614
(27)
1969
(35)
1394
(24)
1526
(34)
4578
(30)
5875
(52)
3966
(23)
7718
(35)
8039
(36)
8640
(32)
Fold 
coverage
Cmax5
642
197
255
298
113
84
100
72
50
52
Fold 
coverage
AUC5
759
237
334
305
102
79
117
60
58
54
7.
Cohort A – D were single dose cohorts. Cohort E – G were multiple dose cohorts (weekly dose for 4 weeks).
8.
In Cohort B (30-mg single) dose, the pharmacokinetic profile in one subject was atypical and not evaluable.
9.
Data are presented as geometric mean (geometric coefficient of variation %).
10. Data are presented as Median (range).
11. Fold coverage based on monkey NOAEL (no observed adverse effect level): NOAEL Cmax = 57.9 g/mL and 
NOAEL AUC(0-) = 465.7 gh/mL at 30 mg/kg/week.
Amended text:
Summary of Selected Plasma GSK3389404 Pharmacokinetic Parameters in Humans 
Healthy Adult Subjects
Dose
(mg)
10
30
60
120
Cohort1
A
B
E
E
C
F
F
D
G
G
 
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Day
1
1
1
22
1
1
22
1
1
22
N
6
52
6
6
6
6
6
6
6
6
Half life3
(hr)
3.8
(66)
3.7
(81)
3.0
(34)
4.1
(61)
5.1
(71)
5.0
(206)
3.1
(51)
4.1
(29)
3.7
(43)
3.4
(38)
Tmax4
(hr)
1
(1-4)
2
(1-2)
2
(1-4)
2
(1-4)
3
(1-4)
2
(2-2)
2
(1.5-4)
4
(3-4)
2
(1.5-4)
2
(2-4)
Cmax3
(ng/mL)
90
(24)
295
(69)
228
(32)
194
(20)
512
(57)
692
(35)
577
(43)
803
(49)
1167
(50)
1107
(55)
AUC(0-)3
(ng*hr/mL)
614
(27)
1969
(35)
1394
(24)
1526
(34)
4578
(30)
5875
(52)
3966
(23)
7718
(35)
8039
(36)
8640
(32)
Fold 
coverage
Cmax5
642
586
197
179
255
231
298
273
113
103
84
76
100
91
72
66
50
45
52
48
Fold 
coverage
AUC5
759
802
237
250
334
353
305
323
102
108
79
84
117
124
60
64
58
61
54
57
Fold 
coverage
Cmax6
32
10
13
15
6
4
5
4
2
3
Fold 
coverage
AUC6
22
7
10
9
3
2
3
2
2
2
1.
Cohort A – D were single dose cohorts. Cohort E – G were multiple dose cohorts (weekly dose for 4 weeks).
2.
In Cohort B (30-mg single) dose, the pharmacokinetic profile in one subject was atypical and not evaluable.
3.
Data are presented as geometric mean (geometric coefficient of variation %).
4.
Data are presented as Median (range).
5.
Fold coverage based on exposure (AUC and Cmax) at monkey NOAEL (no observed adverse effect level) of 
13-week monkey study: Gender averaged Cmax = 57.9 52.7 g/mL and gender averaged AUC(0-) = 465.7
492.7 gh/mL at NOAEL of 30 mg/kg/week.
6.
Fold coverage based on exposure (AUC and Cmax) at NOAEL (no observed adverse effect level) of 39-
week monkey study: Gender averaged Cmax = 2.9 g/mL and gender averaged AUC(0-) = 13.5 gh/mL at 
NOAEL of 2 mg/kg/week.
Section 4.5.2 Safety Margin Calculations, Paragraph 1
Rationale: To provide updates of the pre-clinical data
Original text:
From the 13-week toxicology studies in mice and monkeys, the NOAELs were identified 
at 2 and 30 mg/kg/week, respectively [ISIS Study Number 712408-AS01, 2016; ISIS 
Study Number 712408-AS02, 2016].
Amended text:
From the 13-week toxicology studies in mice and monkeys, the NOAELs were identified 
at 2 and 30 mg/kg/week, respectively [ISIS Study Number 712408-AS01, 2016; ISIS 
Study Number 712408-AS02, 2016]. The NOAELs of 26-week rabbit and 39-week 
 
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monkey studies were 6 and 2 mg/kg/week, respectively [ISIS Study Number 712408-
AS04, 2017; ISIS Study Number 712408-AS05, 2017].2
Section 4.5.2 Safety Margin Calculations, Paragraph 2 
Rationale: To provide updates of the pre-clinical data
Original text:
Based on observed PK data in healthy adult subjects (Study 202007), Cmax and AUC of 
GSK3389404 at the highest dose tested (120 mg) is at least 50-fold lower than the 
monkey NOAEL Cmax and AUC, respectively (Table 1).
Amended text:
Based on observed PK data in healthy adult subjects (Study 202007), Cmax and AUC of 
GSK3389404 at the highest dose tested (120 mg) is at least 4550-fold lower than the
monkey NOAEL Cmax and AUC values at NOAEL of 13-week monkey study, and at 
least 2-fold lower than the Cmax and AUC values at NOAEL of 39-week monkey 
study respectively (Table 1). Based on the preliminary PK analysis in Part 1 of this 
study (Study 205670), Cmax and AUC of GSK3389404 at the highest dose tested 
(120 mg) is lower than the Cmax and AUC values at NOAEL of 13-week and 39-week 
monkey study.
Section 4.5.2 Safety Margin Calculations, Paragraph 4 and 5 
Rationale: To provide updates of the pre-clinical data
Original text:
Table 2 shows the observed and predicted human GSK3389404 PK, the predicted liver 
concentrations, and the fold safety margins of the predicted exposures after single, SC 
administration of GSK3389404 relative to the 13-week monkey NOAEL. In addition, 
liver concentration fold coverage based on the estimated human liver concentration of 
ISIS 505358 (parent) from a previously completed Phase I clinical trial is presented.
In addition, Bayesian predictive probabilities of AUC(0-) and Cmax less than the 
respective mean monkey NOAEL were calculated for the 240 mg dose level using a 
power model and using observed data at 10, 30, 60 and 120 mg dose levels from 
Study 202007. The predictive probability of AUC(0-) and Cmax crossing the respective 
threshold values of mean monkey NOAEL are very low (<0.01%) and are within the 
acceptable range (i.e. <50%) for the 240 mg treatment group.
Amended text:
Table 2 shows the observed and predicted human GSK3389404 PK, the predicted liver 
concentrations, and the fold safety margins of the predicted exposures after single, SC 
 
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administration of GSK3389404 relative to the 13- and 39-week monkey NOAEL. In 
addition, liver concentration fold coverage based on the estimated human liver 
concentration of ISIS 505358 (parent) from a previously completed Phase I clinical trial 
is presented.
In addition, Bayesian predictive probabilities of AUC(0-) and Cmax less than the 
respective mean 13-week monkey study mean NOAEL were calculated for the 240 mg
dose level using a power model and using observed data at 10, 30, 60 and 120 mg dose 
levels from Study 202007. The predictive probability of AUC(0-) and Cmax crossing the 
respective threshold values of mean 13-week monkey study mean NOAEL are very low 
(<0.01%) and are within the acceptable range (i.e. <50%) for the 240 mg treatment 
group.
Section 4.5.2 Safety Margin Calculations, Table 2 and footnotes
Rationale: To provide updates of the pre-clinical data
Original text:
Human 
Dose 
(mg)
Observed 
GSK3389404 
Plasma Cmax
(ng/mL)1
Observed 
GSK3389404 
Plasma AUC 
(hng/mL)1
Predicted 
Parent Liver 
Concentration 
(g/g)2
Fold 
Coverage 
Plasma 
Cmax3
Fold 
Coverage 
Plasma 
AUC3
Fold 
Coverage Of 
Estimated 
Human Liver 
Concentration 
from Phase I 
Parent Study4
10
90
614
2.8
642
759
161
30
295
1968
8.2
197
237
55
60
512
4578
16.2
113
102
28
120
803
7718
31.4
72
60
14
240
17285
159925
59.0
34
29
8
NOAEL = no observed adverse effect level
7.
Geometric mean of GSK3389404 plasma human PK observed at 10 to 120 mg in Study 202007 and predicted for 
240 mg.
8.
Liver concentration in monkeys at 1 week after a single dose was approximately 20% of that at 13 weeks (steady 
state) after repeated once weekly doses. Human steady state liver concentration of parent compound (ISIS 505358) 
was estimated based on 13-week monkey liver tissue concentration and assumed to be 20% that of steady state.
Liver concentration was fit to an Emax model and then extrapolated.
9.
Fold coverage based on monkey NOAEL; GSK3389404 plasma Cmax= 57.9 g/mL and plasma AUC(0-)= 465.7 
gh/mL at 30 mg/kg/week. 
10. At 450 mg of ISIS 505358 (the highest dose tested in ISIS 505358 first time in human study), human liver 
concentration (4 weeks) = 450 g/g, based on allometric scaling [Geary, 2009]. Fold coverage = 450 g/g divided 
by the predicted liver concentration.
11. Predicted using linear regression (zero intercept) based on observed human PK data from previous dose cohorts 
(10 to 120 mg) given dose proportionality.
 
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Amended text:
Human 
Dose 
(mg)
Observed 
GSK3389404 
Plasma Cmax
(ng/mL)1
Observed 
GSK3389404 
Plasma AUC 
(hng/mL)1
Predicted 
Parent Liver 
Concentration 
(g/g)2
Fold Coverage 
Plasma Based 
on 13-week 
monkey study 
NOAEL
Fold 
Coverage 
Plasma 
Based on 
39-week 
monkey 
study 
NOAEL
Fold 
Coverage Of 
Estimated 
Human Liver 
Concentration 
from Phase I 
Parent 
Study45
Cmax
AUC
Cmax
AUC
10
90
614
2.8
642586
759802
32
22
161
30
295
1968
8.2
197179
237250
10
7
55
60
512
4578
16.2
113103
102108
6
3
28
120
803
7718
31.4
7266
6064
4
2
14
240
172865
1599265
59.0
3430
2931
2
0.8
8
NOAEL = no observed adverse effect level
1.
Geometric mean of GSK3389404 plasma human PK observed at 10 to 120 mg in Study 202007 and predicted for 
240 mg.
2.
Liver concentration in monkeys at 1 week after a single dose was approximately 20% of that at 13 weeks (steady 
state) after repeated once weekly doses. Human steady state liver concentration of parent compound 
(ISIS 505358) was estimated based on 13-week monkey liver tissue concentration and assumed to be 20% that of 
steady state. Liver concentration was fit to an Emax model and then extrapolated.
3.
Fold coverage based on 13-week monkey study NOAEL; GSK3389404 gender averaged plasma 
Cmax=57.9 52.7 g/mL and gender averaged plasma AUC(0-)= 465.7492.7 gh/mL at 30 mg/kg/week. 
4.
Fold coverage based on 39-week monkey study NOAEL; GSK3389404 gender averaged plasma Cmax= 2.9 
g/mL and gender averaged plasma AUC(0-)= 13.5 gh/mL at 2 mg/kg/week.
4. 5. At 450 mg of ISIS 505358 (the highest dose tested in ISIS 505358 first time in human study), human liver 
concentration (4 weeks) = 450 g/g, based on allometric scaling [Geary, 2009]. Fold coverage = 450 g/g divided 
by the predicted liver concentration.
5. 6. Predicted using linear regression (zero intercept) based on observed human PK data from previous dose 
cohorts (10 to 120 mg) given dose proportionality.
Section 4.5.3 In vivo Exposure-Response Relationship of GalNAc Conjugated and 
Unconjugated Compounds, second paragraph
Original text:
ISIS 505358 is the parent compound of the prodrug GSK3389404, and has not been 
administered to HBV infected patients. Therefore, no direct antiviral activity data with 
ISIS 505358 from humans are available for extrapolation. To establish an 
exposureresponse- relationship, an in vivo efficacy study of GSK3389404 dosed once 
weekly for 4 weeks and ASO’s liver tissue concentrations were measured in HBV 
transgenic mice.
Amended text:
ISIS 505358 is the parent compound of the prodrug GSK3389404, and has not been 
administered to is currently being studied in HBV infected patients. Therefore, no 
direct antiviral activity data with ISIS 505358 from humans are available for 
 
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extrapolation. To establish an exposure-response relationship, an in vivo efficacy study of 
GSK3389404 dosed once weekly for 4 weeks and ASO’s liver tissue concentrations were 
measured in HBV transgenic mice.
Section 4.5.3 In vivo Exposure-Response Relationship of GalNAc Conjugated and 
Unconjugated Compounds, fifth paragraph
Rationale: to update with treatments that will be studied in Part 2, total monthly doses 
will not be explored
Original text:
Thus, a total monthly dose not exceeding 480 mg GSK3389404 (weekly doses of 120 mg
or bi-weekly doses of 240 mg) may be selected for Part 2.
Amended text: 
Thus, a total monthly dose not exceeding 480 mg GSK3389404 (weekly doses of 120 mg
or bi-weekly doses of 240 mg) may be selected for Part 2.
Section 4.5.3 In vivo Exposure-Response Relationship of GalNAc Conjugated and 
Unconjugated Compounds, Table 3
Rationale: To provide updates of the pre-clinical data
Original text:
Huma
n Total 
Monthl
y Dose 
(mg)
Huma
n
Repe
at
Dose 
(mg)1
Observed 
GSK33894
04 Plasma 
Cmax 
(ng/mL)2
Observed
GSK33894
04 
Plasma 
AUC 
(hng/mL)2
Predicted 
Parent Liver 
Concentrati
on at 
Week 13 
(g/g)3
Observ
ed Fold 
Covera
ge 
Plasma 
Cmax4
Observ
ed Fold 
Covera
ge 
Plasma 
AUC4
Fold 
Coverage of 
Predicted 
Human 
Liver 
Concentrati
on at 
Week 135
120
30 
QW
194
1526
41
298
305
34
240
60 
QW
577
3966
81
100
117
17
480
120 
QW
1107
8640
157
52
54
9
480
240 
Q2W
2200
16769
157
26
28
9
NOAEL = no observed adverse effect level
7.
QW: dose every week. Q2W: dose every 2 weeks.
 
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8.
Geometric mean of GSK3389404 plasma human PK observed following repeat weekly SC dose of 30 to 120 mg
for 4 weeks in Study 202007. The values for 240 mg were predicted
9.
Human liver concentration of parent compound (ISIS 505358) at Week 13 was estimated based on 13-week 
monkey liver tissue concentration (an average of 1404 g/g at 30 mg/kg/week for 13 weeks). Liver concentration 
was fit to Emax model and then extrapolated.
10. Fold coverage based on monkey NOAEL (30 mg/kg/week for 13 weeks): plasma GSK3389404 Cmax = 57.9 g/mL 
and plasma AUC(0-)= 465.75 gh/mL. Liver tissue concentration of parent compound (ISIS 505358) = 1404 
g/g. 
Predicted using linear regression (zero intercept) based on observed human PK data from 
previous dose cohorts (30 to 120 mg) given dose proportionality
Amended text:
Huma
n 
Total 
Mont
hly 
Dose 
(mg)
Hum
an
Repe
at
Dose 
(mg)1
Observed 
GSK3389404 
Plasma 
Predicted 
Parent 
Liver 
Concentra
tion at 
Week 13 
(g/g)3
Observed 
Fold 
Coverage 
Fold 
Coverage 
of 
Predicted 
Human 
Liver 
Concentra
tion at 
Week 136
Observed 
Fold 
Coverage 
Fold 
Coverage 
of 
Predicted 
Human 
Liver 
Concentra
tion at 
Week 136
Cmax 
(ng/m
L)2
AUC 
(hng/m
L)2
Plas
ma 
Cmax4
Plas
ma 
AUC4
Plas
ma 
Cmax5
Plas
ma 
AUC5
120
30 
QW
194
1526
41
272
323
34
15
9
4
240
60 
QW
577
3966
81
91
124
17
5
3
2
480
120 
QW
1107
8640
157
48
57
9
3
2
1
480
240 
Q2W
2200
16769
157
24
29
9
1
0.8
1
NOAEL = no observed adverse effect level
1.
QW: dose every week. Q2W: dose every 2 weeks.
2.
Geometric mean of GSK3389404 plasma human PK observed following repeat weekly SC dose of 30 to 120 mg
for 4 weeks in Study 202007. The values for 240 mg were predicted
3.
Human liver concentration of parent compound (ISIS 505358) at Week 13 was estimated based on 13-week 
monkey liver tissue concentration (an average of 1404 g/g at 30 mg/kg/week for 13 weeks). Liver concentration 
was fit to Emax model and then extrapolated.
4.
Fold coverage based on 13-week monkey study NOAEL (30 mg/kg/week for 13 weeks): gender averaged 
plasma GSK3389404 Cmax= 57.952.7 g/mL and plasma AUC(0-)= 465.75 492.7 gh/mL. Gender averaged 
lLiver tissue concentration of parent compound (ISIS 505358) = 1404 g/g. 
5.
Fold coverage based on 39-week monkey study NOAEL (2 mg/kg/week): gender averaged plasma 
GSK3389404 Cmax= 2.9 g/mL and gender averaged plasma AUC(0-)= 13.5 gh/mL. Gender averaged 
liver tissue concentration of parent compound (ISIS 505358) = 176 g/g.
6.
Predicted using linear regression (zero intercept) based on observed human PK data from previous dose cohorts 
(30 to 120 mg) given dose proportionality 
Section 4.5.4 Dose Escalation Justification, Paragraph 1
Rationale: To provide updates of the pre-clinical data
Original text:
 
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The planned GSK3389404 doses for this study are 30, 60, 120 and 240 mg administered 
by SC injection for the single dose cohorts (Part 1). The proposed doses of GSK3389404 
may be adjusted during the course of the study as the safety, PK, and PD results are 
reviewed. Doses in Part 2 will be selected such that the predicted mean plasma exposure 
at the next dose level will not exceed the mean plasma Cmax and area under the 
concentration-time curve from time zero (pre-dose) extrapolated to infinite time 
(AUC(0-)) observed at the NOAEL dose of 30 mg/kg/day in the 13-week monkey 
toxicity study (Cmax = 57.9 g/mL; AUC(0-) = 465.75 gh/mL). Escalation to the next 
higher single dose or to Part 2 will only proceed after the PK, safety, and tolerability of 
the previous single dose level(s) are thoroughly reviewed by the study team and the 
investigator at the Dose Escalation Committee meeting (Section 10.8.1) and determined 
to be safe, tolerable, and supportive of escalation.
Amended text:
The planned GSK3389404 doses for this study are 30, 60, 120 and 240 mg administered 
by SC injection for the single dose cohorts (Part 1). The proposed doses of GSK3389404 
may be adjusted during the course of the study as the safety, PK, and PD results are 
reviewed. Doses in Part 2 will be selected such that the predicted mean plasma exposure 
at the next dose level will not exceed the mean plasma Cmax and area under the 
concentration-time curve from time zero (pre-dose) extrapolated to infinite time 
(AUC(0-)) observed at 

the NOAEL dose of 30 mg/kg/day in the 13-week monkey toxicity study 
(Cmax = 57.9 52.7 g/mL; AUC(0-) = 465.75 492.7gh/mL) and 

the NOAEL of 2 mg/kg/day in the 39-week monkey toxicity study 
(Cmax = 2.9 g/mL; AUC(0-) = 13.5 gh/mL).
Escalation to the next higher single dose or to Part 2 will only proceed after the PK, 
safety, and tolerability of the previous single dose level(s) are thoroughly reviewed by the 
study team and the investigator at the Dose Escalation Committee meeting 
(Section 10.8.1) and determined to be safe, tolerable, and supportive of escalation.
Section 4.6.1 Risk Assessment, Table 4, Liver Effects, Potential Risk/Summary of Data
Rationale: To provide updates of the pre-clinical data
Original text:
Liver Effects: In the 13-week GSK3389404 mouse study, doses ≥6 mg/kg/week caused increases in liver enzymes 
(9.4 X AST, 7.5 X ALT, 1.6 X ALP and/or 1.7 X bilirubin) with correlating histopathology changes which include minimal 
to mild hepatocellular hypertrophy, vacuolated macrophages and scattered single cell hepatocyte necrosis with 
evidence of reversibility following the 13-week recovery period. The mean liver concentration (13 g/g) at the NOAEL 
of 2 mg/kg/week in the mouse is approximately 0.4- to 2.3-fold higher than the predicted clinical efficacious liver 
concentration range (EC90-EC99: 5.9 to 33 g/g). The 42 to 238-fold higher liver concentrations (gender averages 
1403 g/g) were achieved at the NOAEL of 30 mg/kg/week in the 13-week monkey study.
 
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In the ISIS 505358-CS1 Phase I study in healthy subjects, modest (1.03 to 1.41 X ULN) elevations in ALT that were 
transient and not associated with concurrent symptoms or increases in bilirubin were observed. All subjects with 
elevated ALT returned to baseline during post-treatment follow-up.
Amended text:
Liver Effects: In the 13-week GSK3389404 mouse study, doses ≥6 mg/kg/week caused increases in liver enzymes 
(9.4 X AST, 7.5 X ALT, 1.6 X ALP and/or 1.7 X bilirubin) with correlating histopathology changes which include minimal 
to mild hepatocellular hypertrophy, vacuolated macrophages and scattered single cell hepatocyte necrosis with 
evidence of reversibility following the 13-week recovery period. The mean liver concentration (13.5 g/g) at the NOAEL 
of 2 mg/kg/week in the mouse is approximately 0.4- to 2.3-fold higher than the predicted clinical efficacious liver 
concentration range (EC90-EC99: 5.9 to 33 g/g). In the 26-week mouse study, liver findings (eosinophilic 
hepatocytes, individual hepatocyte necrosis, presence of macrophages with vacuolated/granular cytoplasm 
(sinusoidal macrophages) and/or accumulations of pigmented macrophases and karyomegaly) without clinical 
chemistry correlates were not considered adverse. Liver concentration of ISIS 505358 (97.8 g/g) at the 
NOAEL of 6 mg/kg/week in male mice was 16.6- to 3.0-fold of predicted clinical efficacious liver concentrations 
(EC90-EC99: 5.9 to 33 g/g). The 42 to 238-fold higher liver concentrations (gender averages 1403 g/g) were 
achieved at the NOAEL of 30 mg/kg/week in the 13-week monkey study. In the 39-week monkey study, the liver 
concentration of ISIS 505358 (176 g/g) at the NOAEL of 2 mg/kg/week was approximately 29.8- to 5.3-fold of 
predicted clinical efficacious liver concentration (EC90-EC99: 5.9 to 33 g/g).
Section 4.6.1 Risk Assessment, Table 4, Coagulation Effects, Potential Risk/Summary of 
Data
Rationale: To provide updates of the pre-clinical data
Original text:
Coagulation Effects: In the 13-week GSK3389404 monkey study, acute and transient test article-related changes in 
the coagulation included slightly prolonged (up to 4.2 seconds higher than the baseline value) aPTT values at 
30 mg/kg/week. The prolongation was observed 4 hours after dosing on Days 1 and 91 and generally returned to 
baseline by 24 hours post-dose. These results are consistent with the aPTT results from the clinical and nonclinical 
studies of other phosphorothioate and MOE-modified phosphorothioate ASOs [Dorr, 2001; Levin, 2001; Henry, 2008; 
Kwoh, 2008]. 
In the ISIS 505358-CS1 Phase I study in healthy subjects, aPTT prolongations were observed at 3 to 5 hours post 
injection of ISIS 505358. The magnitudes of this prolongation were modest, not clinically significant and generally 
resolved within 12 to 24 hours after dosing. 
Amended text:
Coagulation Effects: In the 13-week GSK3389404 monkey study, acute and transient test article-related changes in 
the coagulation included slightly prolonged (up to 4.2 5.1 seconds higher than the baseline value) aPTT values at 
30 mg/kg/week. The prolongation was observed 4 hours after dosing on Days 1 and 91 and generally returned to 
baseline by 24 hours post-dose. These results are consistent with the aPTT results from the clinical and nonclinical 
studies of other phosphorothioate and MOE-modified phosphorothioate ASOs [Dorr, 2001; Levin, 2001; Henry, 2008; 
Kwoh, 2008]. There was no test article-related coagulation prolongation in monkeys treated with GSK3389404 at 
doses up to 8 mg/kg/week for 39 weeks.
In the ISIS 505358-CS1 Phase I study in healthy subjects, aPTT prolongations were observed at 3 to 5 hours post 
injection of ISIS 505358. The magnitudes of this prolongation were modest, not clinically significant and generally 
resolved within 12 to 24 hours after dosing. There was no test article-related coagulation prolongation in 
monkeys treated with GSK3389404 at doses up to 8 mg/kg/week for 39 weeks.
 
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Section 4.6.1 Risk Assessment, Table 4, Complement Activation, Potential 
Risk/Summary of Data
Rationale: To provide updates of the pre-clinical data
Original text:
Complement Activation: In the monkey GSK3389404 13-week study, minimal decreases in (up to 21% 
from baseline) C3 and increased complement fragment Bb (up to 3.6-fold over baseline) were observed in 
the 8 and 30 mg/kg groups, suggesting mild activation of the alternative complement pathway. The 
significance of these findings remains unclear because there was also an 11% decrease in C3 observed in 
male controls. These changes in aPTT, C3, Bb, ALT, and IgM were not seen during the 13-week recovery 
period.
Amended text:
Complement Activation: In the monkey GSK3389404 13-week study, minimal decreases in (up to 21% 
from baseline) C3 and increased complement fragment Bb (up to 3.6-fold over baseline) were observed in 
the 8 and 30 mg/kg groups, suggesting mild activation of the alternative complement pathway. The 
significance of these findings remains unclear because there was also an 11% decrease in C3 observed in 
male controls. These changes in aPTT, C3, Bb, ALT, and IgM were not seen during the 13-week recovery 
period. In the 39-week monkey study, there was a mild and transient increase in complement 
fragment Bb (up to 2.1-fold over baseline compared to up to 1.4-fold over baseline in control) and 
decrease in C3 concentrations in individual animals at ≥0.5 mg/kg/week. These changes were not 
considered adverse since they were mild and transient.
Section 4.6.1 Risk Assessment, Table 4, Pro-inflammatory effects/Constitutional or flu-
like symptoms, Potential Risk/Summary of Data
Rationale: To provide updates of the pre-clinical data
Original text:
Pro-inflammatory Effects/Constitutional or Flu-Like Symptoms: At doses of 2 mg/kg/week GSK3889404 in the 
13-week mouse study, vacuolated macrophages and mixed cell leucocytes were increased in incidence and/or 
magnitude at the site of injection compared to controls. However, this finding is considered to reflect the sensitivity of 
rodents to proinflammatory effects of ASOs [Henry, 2008] and evidence of reversibility was seen in the recovery 
interval. There were no significant injection site findings in the 13-week monkey study up to 30 mg/kg/week. 
Amended text:
Pro-inflammatory Effects/Constitutional or Flu-Like Symptoms: At doses of 2 mg/kg/week GSK3889404 in the 
13-week mouse study, vacuolated macrophages and mixed cell leucocytes were increased in incidence and/or 
magnitude at the site of injection compared to controls. . In the 26-week mouse study, minimal to mild 
vacuolated/granular macrophages and increased incidence of mixed leukocytes were noted at the injection 
sites and/or non-injected skin sections in both sexes at doses of 0.5 mg/kg/week. However, this these findings
isare considered to reflect the sensitivity of rodents to proinflammatory effects of ASOs [Henry, 2008] and evidence of 
reversibility was seen in the recovery interval. There were no significant injection site findings in the 13-and 39-week 
monkey study studies at doses up to 30 and 8 mg/kg/week, respesctively. 
 
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Section 4.6.1 Risk Assessment, Table 4, Kidney Effects, Potential Risk/Summary of Data
Rationale: To provide updates of the pre-clinical data
Original text:
Kidney Effects: No adverse kidney findings were observed in the mouse (up to 24 mg/kg/week) and monkey (up to 
30 mg/kg/week) 13-week GSK3389404 studies. The presence of basophilic granules in the tubular epithelium in both 
species are considered indicative of cellular uptake of oligonucleotides and not considered adverse [Henry, 2000]. 
Following the 13-week recovery period, monkeys dosed with 30 mg/kg/week showed reversal of the basophilic 
granularity of proximal tubular epithelial cells of the kidney.
In humans administered 2ʹ-MOE ASOs, no trends in laboratory parameters have been identified that suggested an 
effect on renal function.
Amended text:
Kidney Effects: No adverse kidney findings were observed in the mouse (up to 24 mg/kg/week) and monkey (up to 
30 mg/kg/week) 13-week GSK3389404 studies and in mice (up to 6 mg/kg/week) and monkeys (up to 
8 mg/kg/week) following 26 and 39 weeks of repeat dosing, respectively.The presence of basophilic granules in 
the tubular epithelium in both species and occasionally vacuolated/granular macrophages surrounding the pelvic 
region of kidneys in mice are considered indicative of cellular uptake of oligonucleotides These findings were 
generally reversible by the end of recovery period, and therefore, were not considered adverse [Henry, 2000]. 
Following the 13-week recovery period, monkeys dosed with 30 mg/kg/week showed reversal of the basophilic 
granularity of proximal tubular epithelial cells of the kidney.
In humans administered 2ʹ-MOE ASOs, no trends in laboratory parameters of kidney function have been identified that 
suggested an effect on renal function.
Section 4.6.1 Risk Assessment, Table 4, Kidney Effects, Strategy- Monitoring/Stopping 
Criteria
Rationale: To provide updates of the pre-clinical data
Original text:
Following confirmation of the criteria above, further evaluation may include but not be limited to 24-hour urine for 
analysis, consultation with a nephrology specialist, renal ultrasound, urine microscopy, serum creatinine kinase, 
SPEP/UPEP, and/or complement panel (C3, C4, C5a and Bb).
Amended text:
Following confirmation of the criteria above, further evaluation may include but not be limited to 24-hour urine for 
analysis, consultation with a nephrology specialist, renal ultrasound, urine microscopy, serum creatinine kinase, 
SPEP/UPEP, and/or complement panel (C3, C4, C5a and Bb).
 
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Section 4.6.1 Risk Assessment, Table 4, Decreased hematological parameters, Potential 
Risk/Summary of Data
Rationale: To provide updates of the pre-clinical data
Original text:
Decreased hematological parameters: No significant test article related changes in platelets were 
observed in the 13-week GSK3389404 mouse or monkey toxicity studies.
Amended text:
Decreased hematological parameters: No significant test article related changes in platelets were observed in the 
13-week GSK3389404 mouse or monkey toxicity studies. In the 39-week monkey study, a marked and transient 
decrease in platelet count was noted in one male monkey administered GSK3389404 at 8 mg/kg/week on Day 
184. The platelet count in this monkey returned to near baseline values by Day 191, despite continued 
treatment with test article. No significant test article-related changes in platelets were observed in the 26-week 
mouse study.
In the 39-week monkey study, one high dose male had severe non-regenerative and potentially haemolytic
anemia characterized by decreased red blood cell parameters and accompanied by decreased neutrophil 
counts, inflammation, renal injury/proteinuria, complement activation, metabolic acidosis, and decreased 
nutrient uptake. This animal was sacrificed on Day 218 (Week 32). Since non-regenerative anemia and other 
associated findings were only noted in this one animal, and have not been noted in other studies with 
antisense oligonucleotide therapies, even when accompanied by complement activation and/or proteinuria, 
the relationship of anemia to treatment in this case is unclear.
Section 4.6.2 Benefit Risk Summary, bullet point 3
Rationale: To provide updates of the pre-clinical data
Original text:
3. In Part 1, dose escalation will be stopped or a smaller dose increment selected 
when the predicted mean AUC(0-) and Cmax of the next dose level are expected to 
exceed the NOAEL exposures observed in the monkey toxicity study 
(Section 6.3).
Amended text:
1. In Part 1, dose escalation will be stopped or a smaller dose increment selected 
when the predicted mean AUC(0-) and Cmax of the next dose level are expected to 
exceed the NOAEL exposures observed in the 13-week monkey toxicity study 
(Section 6.3).
Section 4.6.2 Benefit Risk Summary, bullet point 7
 
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Rationale: To include text on an optional 9-month off treatment follow up period
Original text:
7. In Part 2, subjects are seen at the clinic on a weekly basis and safety assessments 
(AE/serious adverse event [SAE] review, physical exam, vital signs, ECG assessments) 
and comprehensive laboratory testing subjects is performed on a weekly or bi-weekly 
(every 2 weeks) basis. At the end of the 3-month treatment exposure period, subjects 
have extended follow-up to 12 weeks to assess safety.
Amended text:
7. In Part 2, subjects are seen at the clinic on a weekly basis and safety assessments 
(AE/serious adverse event [SAE] review, physical exam, vital signs, ECG assessments) 
and comprehensive laboratory testing subjects is performed on a weekly or bi-weekly 
(every 2 weeks) basis. At the end of the 3-month treatment exposure period, subjects 
have extended follow-up to 12 weeks to assess safety with an optional extended follow 
up to 48 weeks.
Section 5.1 Inclusion Criteria, 4(b)
Rationale: To include an optional 9-month off treatment follow up period. Females of 
reproductive potential will not be on mandatory contraceptive during the optional 
observational follow-up period
Original text:
Females of reproductive potential (FRP), must agree to follow (or confirm that they have 
and are currently following) one of the options listed in the Modified List of Highly 
Effective Methods for Avoiding Pregnancy in FRP (see Appendix 4) from at least 28 
days prior to the first dose of study treatment until the final Follow-up visit in 
conjunction with partner’s use of male condom. The investigator is responsible for 
ensuring that subjects understand how to properly use these methods of contraception
Amended text:
Females of reproductive potential (FRP), must agree to follow (or confirm that they have 
and are currently following) one of the options listed in the Modified List of Highly 
Effective Methods for Avoiding Pregnancy in FRP (see Appendix 4) from at least 28 
days prior to the first dose of study treatment until the final Follow-up visit Day 169 in 
conjunction with partner’s use of male condom. The investigator is responsible for 
ensuring that subjects understand how to properly use these methods of contraception
Section 5.1 Inclusion Criteria, 4(d)
Rationale: To include an optional 9-month off treatment follow up period. Males will not 
be on mandatory contraceptive during the optional observational follow-up period
 
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Original text:
Male subjects with a female partner of child-bearing potential must agree to meet one of 
the contraception requirements from the time of first dose of study treatment until the 
final Follow-up visit.
Amended text:
Male subjects with a female partner of child-bearing potential must agree to meet one of 
the contraception requirements from the time of first dose of study treatment until the 
final Follow-up visit day 169.
Section 5.1 Inclusion Criteria, 4(e)
Rationale: To include an optional 9-month off treatment follow up period. Males will not 
be on mandatory contraceptive or be asked not to donate sperm during the optional 
observational follow-up period
Original text:
Male subjects must refrain from donating sperm from the time of first dose of study 
treatment until the final Follow-up visit.
Amended text:
Male subjects must refrain from donating sperm from the time of first dose of study 
treatment until the final Follow-up visit day 169.
Section 5.1 Inclusion Criteria, 6(b)
Rationale: To provide clarity regarding the inclusion criteria in regards to prior treatment 
with interferon
Original text:
Part 2: Subjects with CHB 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.
Amended text:
Part 2: Subjects with CHB 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. Subjects with 
prior treatment with interferon (pegylated or non-pegylated) must have ended 
treatment at least 6 months prior to the Baseline visit (Day 1 pre-dose).
 
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Section 5.4.4 Renal Function Stopping Criteria, Paragraph 2
Rationale: To provide edits for clarity. Stopping criteria is based on serum creatinine, 
creatine kinase is a different laboratory marker
Original text:
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 creatinine kinase, serum protein electrophoresis 
(SPEP)/urine protein electrophoresis (UPEP), and/or complement panel (C3, C4, C5a and 
Bb). Further evaluation and actions should be determined by the investigator in 
consultation with the medical monitor.
Amended text:
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 creatinine kinase, serum protein electrophoresis 
(SPEP)/urine protein electrophoresis (UPEP), and/or complement panel (C3, C4, C5a and 
Bb). Further evaluation and actions should be determined by the investigator in 
consultation with the medical monitor.
Section 5.4.5 Pharmacokinetic Stopping Criteria
Rationale: To provide updates of the pre-clinical data
Original text:
Part 1: Doses will be escalated such that the predicted mean plasma exposure at the next 
dose level will not exceed the mean plasma AUC(0-) and Cmax observed at the NOAEL 
dose of 30 mg/kg/day in the 13-week monkey toxicity study 
(AUC(0-) = 465.75 mgh/mL and Cmax = 57.9 mg/mL).
A Bayesian predictive probability of AUC(0-) and Cmax less than 465.75 mgh/mL and 
57.9 mg /mL (mean exposures at NOAEL dose in monkey), respectively, will be 
calculated for the next dose level and used together with safety and tolerability data to aid 
next dose selection. Dose escalation may be stopped or a smaller dose increment selected 
(Section 6.3) for the next cohort if the predictive probability of exceeding the mean 
NOAEL exposure is greater than 50%.
Amended text:
Part 1: Doses will be escalated such that the predicted mean plasma exposure at the next 
dose level will not exceed the mean plasma AUC(0-) and Cmax observed at the NOAEL 
 
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dose of 30 mg/kg/day in the 13-week monkey toxicity study (AUC(0-) = 465.75
492.7 mgh/mL and Cmax = 57.9 52.7 mg/mL).
A Bayesian predictive probability of AUC(0-) and Cmax less than465.75 492.7 mgh/mL 
and 57.9 52.7 mg /mL (mean exposures at NOAEL in the 13-week monkey study), 
respectively, will be calculated for the next dose level and used together with safety and 
tolerability data to aid next dose selection. Dose escalation may be stopped or a smaller 
dose increment selected (Section 6.3) for the next cohort if the predictive probability of 
exceeding the mean NOAEL exposure is greater than 50%.
Section 5.5 Subject and Study Completion, bullet point 3
Rationale: To update text to include an optional 9-month off treatment follow up period
Original text:
None
Amended text:

For subjects who participate in the optional extended post treatment follow-
up period, a completed subject in extended follow-up period is one who has 
completed the Day 450 visit. An ongoing subject who misses the Day 450 visit 
will be considered as lost to follow up for the optional extended follow-up 
period.
Section 6.1 Investigational Product and Other study Treatment, table 6
Rationale: to update the treatments to be studied in Part 2. Since a monthly dose will not 
be included, the text has been removed
Original text:
Study Treatment
Product Name:
GSK3389404
Placebo
Formulation Description:
Clear colorless to slightly 
yellow solution
Clear colorless solution
Dosage Form:
Solution for injection
Solution for injection
Unit Dose Strength(s)/Dosage 
Level(s):
100 mg/mL; 1.0 mL nominal 
volume per vial (0.25 mL 
overfill per vial)
Placebo 
 
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Study Treatment
Product Name:
GSK3389404
Placebo
Route/Administration/Duration:
SC, single and multiple (once 
weekly, bi-weekly, or once 
monthly, up to 85 days)
SC, single and multiple (once 
weekly, bi-weekly, or once 
monthly, up to 85 days)
Dosing Instructions:
Administer SC
Administer SC
Manufacturer/Source of 
Procurement:
GSK Global Manufacturing 
and Supply, Parma (Italy)
Locally sourced normal saline
Method for Individualizing 
Dosage:
Dispensing into syringes in 
pharmacy
Dispensing into syringes in 
pharmacy
GSK = GlaxoSmithKline, SC = subcutaneous
Amended text:
Study Treatment
Product Name:
GSK3389404
Placebo
Formulation Description:
Clear colorless to slightly 
yellow solution
Clear colorless solution
Dosage Form:
Solution for injection
Solution for injection
Unit Dose Strength(s)/Dosage 
Level(s):
100 mg/mL; 1.0 mL nominal 
volume per vial (0.25 mL 
overfill per vial)
Placebo 
Route/Administration/Duration:
SC, single and multiple (once 
weekly, bi-weekly, or once 
monthly, up to 85 days)
SC, single and multiple (once 
weekly, bi-weekly, or once 
monthly, up to 85 days)
Dosing Instructions:
Administer SC
Administer SC
Manufacturer/Source of 
Procurement:
GSK Global Manufacturing 
and Supply, Parma (Italy)
Locally sourced normal saline
Method for Individualizing 
Dosage:
Dispensing into syringes in 
pharmacy
Dispensing into syringes in 
pharmacy
GSK = GlaxoSmithKline, SC = subcutaneous
Section 6.1 Investigational Product and Other study Treatment, table 7
Rationale: To update treatments to be studied in Part 2, since 240 mg GSK3389404 as a 
single injection will not be used, it has been removed from the table
Original text:
 
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Dose1
Volume to Administer2
30 mg or placebo
0.30 mL
60 mg or placebo
0.60 mL
120 mg or placebo
1.2 mL
240 mg or placebo
2.4 mL
3.
Dose may change based on safety and pharmacokinetic data from preceding cohort(s)
4.
If a change in dose is warranted, volume to administer (mL) = dose (mg)/100
Amended text:
Dose1
Volume to Administer2
30 mg or placebo
0.30 mL
60 mg or placebo
0.60 mL
120 mg or placebo
1.2 mL
240 mg or placebo
2.4 mL
1.
Dose may change based on safety and pharmacokinetic data from preceding cohort(s)
2.
If a change in dose is warranted, volume to administer (mL) = dose (mg)/100
Section 6.2 Treatment Assignment, paragraph 3
Rationale: To update the treatments to be studied in Part 2. To provide clarity on 
processes
Original text:
Two randomization schedules for Part 2 will be generated after Part 1 is completed and 
dose levels and regimens for Part 2 have been identified. A separate randomization 
schedule will be generated for the sentinel group. The remainder of Part 2 subjects will be 
centrally randomized using a randomization schedule to receive 1 of the active dose 
levels and regimens selected in Part 2 or corresponding matching placebo. Two or 3 dose 
levels each at 2 different dosing regimens will be explored.
Amended text:
Two randomization schedules for Part 2 will be generated after dosing in Part 1 is 
completed and dose levels and regimens for Part 2 have been identified. A separate 
randomization schedule will be generated for the sentinel group. The remainder of Part 2 
subjects will be centrally randomized using a randomization schedule to receive 1 of the 
active dose levels and regimens selected in Part 2 or corresponding matching placebo. 
Two or 3 dose levels each at 2 different dosing regimens will be explored.
Section 6.2 Treatment Assignment, randomization table
 
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Rationale: To update the treatments to be studied in Part 2
Original text:
Sentinel 
Remainder
Part 2
Active
Placebo
Active
Placebo
Dose Level 1, Regimen 1a
1
1
10
1
Dose Level 1, Regimen 2a
1
1
10
1
Dose Level 2, Regimen 1a
1
1
10
1
Dose Level 2, Regimen 2a
1
1
10
1
Dose Level 3, Regimen 1a
1
1
10
1
Dose Level 3, Regimen 2a
1
1
10
1
a.
The actual dose levels and regimens will be identified after review of data from Part 1. Up to 3 dose levels and 
2 regimens will be studied. 
Amended text:
Sentinel 
Remainder
Part 2
Active
Placebo
Active
Placebo
60 mg GSK3389404 weekly Dose 
Level 1, Regimen 1a
1
1
10
1
120 mg GSK3389404 bi-weekly
Dose Level 1, Regimen 2a
1
1
10
1
120 mg GSK3389404 weekly Dose 
Level 2, Regimen 1a
1
1
10
1
Dose Level 2, Regimen 2a
1
1
10
1
Dose Level 3, Regimen 1a
1
1
10
1
Dose Level 3, Regimen 2a
1
1
10
1
a.
The actual dose levels and regimens will be identified after review of data from Part 1. Up to 3 dose levels and 
2 regimens will be studied. 
Section 6.3 Planned Dose Adjustments, bullet point 1, sub-bullet point 2
Rationale: To provide updates of the pre-clinical data
Original text:
o
A Bayesian predictive probability of AUC(0-) and Cmax less than 465.75 mgh/mL 
and 57.9 mg /mL (mean exposures at NOAEL dose in monkey), respectively, will 
be calculated for the next dose level and used together with safety and tolerability 
data to aid next dose selection
Amended text:
o
A Bayesian predictive probability of AUC(0-) and Cmax less than465.75
492.7 mgh/mL and 57.9 52.7 mg /mL (mean exposures at NOAEL in the 13-
 
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week monkey study), respectively, will be calculated for the next dose level and 
used together with safety and tolerability data to aid next dose selection
Section 6.5 Blinding, Bullet points 4 and 5 
Rationale: To include management review of unblinded data
Original text:
none
Amended text:

Management review of unblinded efficacy data is planned for both parts of 
the study. For part 1, the review provides early information on potential 
efficacious dose and dose frequency including the need for dose escalation. 
For part 2, the review will facilitate internal governance decision making on 
project progress and trigger further studies. Unblinded efficacy data may be 
provided to the following management/function as required: Senior VP of 
Infectious Disease Therapy Area, Head Unit Physician, Project Statistician, 
Head of ID Statistics/Programming, Director of Clinical Pharmacology, 
Safety Evaluation and Risk Management, Global Regulatory Lead, Project 
Physician Lead, Clinical Investigator Lead, Clinical Development 
Manager,Global Marketing Director

The frequency of management review in Part 2 will be synchronized with 
monthly blinded SRT review of the study. The management review of the 
Part 1 data will occur as required for decision making.
Section 6.11.3 Activity
Rationale: To update text to include an optional 9-month off treatment follow up period 
Original text:
Subjects will abstain from strenuous exercise for 48 hours prior to each blood collection 
for clinical laboratory tests. For the duration of the study, until final follow-up, subjects 
are encouraged to refrain from changing their activity beyond that which they normally 
perform. While domiciled in the study site, subjects may participate in light recreational 
activities.
Amended text:
 
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Subjects will abstain from strenuous exercise for 48 hours prior to each blood collection 
for clinical laboratory tests. For the duration of the study, until final follow-up (this 
includes the optional additional follow-up period), subjects are encouraged to refrain 
from changing their activity beyond that which they normally perform. While domiciled 
in the study site, subjects may participate in light recreational activities.
Section 6.12 Concomitant Medications and Non-Drug Therapies
Rationale: To update text to include an optional 9-month off treatment follow up period
Original text:
All medications taken at any time from 3 months prior to Baseline (Day 1 pre-dose) to 
the final Follow-up visit will be recorded in the CRF. The minimum requirement is that 
drug name and the dates of administration are to be recorded.
Amended text:
All medications taken at any time from 3 months prior to Baseline (Day 1 pre-dose) to 
the final Follow-up visit (this includes the optional additional follow-up period) will 
be recorded in the CRF. The minimum requirement is that drug name and the dates of 
administration are to be recorded.
Section 6.12.2 Prohibited Medications and Non-Drug Therapies
Rationale: To provide clarity regarding the inclusion criteria in regards to prior treatment 
with interferon
Original text:
none
Amended text:

PEG-interferon or other immunomodulating therapies
Section 7.1 Time and Events Tables, bullet points 1-3
Rationale: To update the time and events tables to reflect treatments to be studied in Part 
2 and to include an optional 9-month off treatment follow up period
Original text:

Once weekly dosing regimen assessments are detailed for the treatment period in 
Table 11 (Day 1 to Day 85) and for the post-treatment follow-up period in
Table 12 (Day 92 to Day 169/ET). 
 
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
Bi-weekly dosing regimen assessments are detailed for the treatment period in 
Table 13 (Day 1 to Day 85) and for the post-treatment follow-up period in
Table 14 (Day 92 to Day 169/ET). 

Once monthly dosing regimen assessments are detailed for the treatment period in 
Table 15 (Day 1 to Day 85) and for the post-treatment follow-up period in Table 
16 (Day 92 to Day 169/ET).
Amended text:

Once weekly dosing regimen assessments are detailed for the treatment period in 
Table 11 (Day 1 to Day 85) and for the post-treatment follow-up period in
Table 12 (Day 92 to Day 169/ET), with an optional additional follow-up on 
Days 270, 360, and 450).

Bi-weekly dosing regimen assessments are detailed for the treatment period in 
Table 13 (Day 1 to Day 85) and for the post-treatment follow-up period in
Table 14 (Day 92 to Day 169/ET), with an optional additional follow-up on 
Days 270, 360, and 450). 

Once monthly dosing regimen assessments are detailed for the treatment period in 
Table 15 (Day 1 to Day 85) and for the post-treatment follow-up period in Table 
16 (Day 92 to Day 169/ET).
Section 7.1 Time and Events Tables, Table 8
Rationale: To clarify that informed consent may be obtained any time prior to screening 
and is not limited to the 30 day screening window. Please note- only the row/column 
where changes were made will be shown, not the whole table
Original text:
Assessment
Screening 
(Up to 30 days 
Prior to Day 1)
Informed Consent
X
Amended text:
Assessment
Screening 
(Up to 30 days 
Prior to Day 1)
Informed Consent (obtained any time prior to screening)
X
 
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Section 7.1 Time and Events Tables, Table 12 Time and Events Table: Day 92 to Day 
169 of multiple dose (part 2) once weekly dosing and Table 14 Time and Events Table: 
Day 92 to Day 169 of multiple dose (part 2) bi-weekly dosing
Rationale: to clarify that pregnancy test should be performed on females of reproductive 
potential
Original text:
Footnote 6. Female subjects: serum hCG or urine pregnancy test.
Amended text:
Footnote 6. Female subjects of reproductive potential: serum hCG or urine pregnancy test.
Section 7.1 Time and Events Tables, Table 15 Time and Events Table: Optional Follow-
up Period Day 270 to Day 450 for once weekly and bi-weekly dosing
Rationale: To update the time and events tables to include an optional 9-month off 
treatment follow up period and the assessments that will occur during the off-treatment 
follow up period
Original text:
none
Amended text:
Assessment
Day 270
(7 days)
Day 360 
(7 days)
Day 450 
(7 days)
ET
Outpatient visit
X
X
X
X
Safety Assessments
AE/SAE review1
Continuous
X
Concomitant medication review
Continuous
X
Brief physical exam
X
X
X
X
Vital signs2
X
X
X
X
Laboratory Assessments4
Pregnancy test (as appropriate)5
X
X
Hematology/Chemistry/Urinalysis6
X
X
X
X
Urine ACR5,6
X
X
X
X
Complement (C3/C4)
X
X
X
X
PT, INR, aPTT
X
X
X
X
hs-CRP
X
X
X
X
Archived serum and plasma samples7
X
X
X
X
HBsAg and HBV DNA
X
X
X
X
HBeAg8
X
X
X
X
 
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Assessment
Day 270
(7 days)
Day 360 
(7 days)
Day 450 
(7 days)
ET
HBV genotype/phenotype9
X
X
X
X
HBsAb
X
X
X
X
Meal10
X
X
X
X
ACR = albumin to creatinine ratio, AE/SAE = adverse event/serious adverse event, aPTT = activated 
partial thromboplastin time, CHB = chronic hepatitis B, ECG = electrocardiogram, ET = early termination, 
HBeAg = hepatitis B virus e-antigen, HBsAb = hepatitis B virus surface antibody, HBsAg = hepatitis B 
surface antigen, HBV = hepatitis B virus, HIV = human immunodeficiency virus, hCG = human chorionic 
gonadotropin, hs-CRP = high sensitivity C-reactive protein, INR = international normalized ratio, 
PK = pharmacokinetics, PT = prothrombin time 
1.Adverse events will be collected from the time of first dose of study treatment and until the final 
Follow-up visit. However, any SAEs assessed as related to study participation (e.g., 
protocol-mandated procedures or invasive tests) or related to GSK3389404 will be recorded 
from the time a subject consents to participate in the study up to and including any Follow-up 
visit. All AEs and SAEs will be graded based on the DAIDS table or supplemental criteria as 
defined in Appendix 3 (Section 12.3.5.1).
2.Temperature and respiration rate (single measurement); blood pressure and heart rate (single 
measurement after 5 minutes of rest in the semi-supine or supine position).
3.Samples for clinical laboratory tests to be collected after vital sign and ECG assessments.
4.Female subjects of reproductive potential: serum hCG or urine pregnancy test.
5.The study site may collect and divide urine sample for urinalysis test and ACR (first void) 
assessment.
6.Collect first morning urine void sample for ACR assessment. For outpatient visits, subjects will be 
given a clean urine collection cup and instructed to collect and bring in a first morning urine 
void sample on the day of their outpatient visit.
7.Archived serum and plasma samples for exploratory biomarker analyses. Complement C5a and Bb 
as well as HBV RNA, HBcrAg, and/or IDO may be analyzed from the archived samples.
8.HBeAg-positive subjects only.
9.HBV genotype/phenotype samples to be stored and analyzed per sponsor’s discretion. Samples 
will be used to assess for changes in HBV genotype/phenotype from baseline, HBsAg nadir, 
and/or final Follow-up visit. 
10. Subjects will be offered a meal (e.g., bagged or canteen [or reimbursed]) after completion of all 
study procedures.
Section 7.1 Time and Events Tables, old Table 15 and 16
Rationale: To update the time and events tables to reflect treatments to be studied in Part 
2. Please note- only the table number and title will be shown in the original text as these 
tables were deleted since once monthly dosing will not be studied in Part 2
Original text:
Table 15 Time and Events Table: Day 1 to Day 85 of Multiple Dose (Part 2) Once 
Monthly Dosing
 
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Table 16 Time and Events Table: Day 92 to Day 169 of Multiple Dose (Part 2) Once 
Monthly Dosing
Amended text:
Table 15 Time and Events Table: Day 1 to Day 85 of Multiple Dose (Part 2) Once 
Monthly Dosing
Table 16 Time and Events Table: Day 92 to Day 169 of Multiple Dose (Part 2) Once 
Monthly Dosing
Section 7.2 Screening and Critical Baseline Assessments, last sentence
Rationale: To update the text and Table numbers to reflect treatments to be studied in 
Part 2
Original text:
Baseline assessments are provided in Table 9 for Part 1, and Table 11, Table 13, and 
Table 15 for Part 2.
Amended text:
Baseline assessments are provided in Table 9 for Part 1, and Table 11, and Table 13, and 
Table 15 for Part 2.
Section 7.3.2 Pregnancy
Rationale: To provide clarity regarding contraceptive use in male subjects with female 
partners who are currently pregnant
Original text:
none
Amended text:

Male subjects with female partners who are currently pregnant should comply 
with the acceptable contraceptive requirement as detailed in the protocol. No 
precautions are required for the male subject’s pregnant partner.
Section 7.3.5 Vital Signs, bullet point 2
Rationale: To provide clarity on order of assessments by investigator request
Original text:
 
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During visits where a 12-lead ECG and/or blood collection is also required, vital sign 
measurements will be taken after the ECG and prior to scheduled blood collection (which 
should be drawn at the exact nominal time point).
Amended text:
During visits where a 12-lead ECG and/or blood collection is also required, vital sign 
measurements will be taken after the ECG and prior to scheduled blood collection (which 
should be drawn at the exact nominal time point).
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
Section 7.3.6 Electrocardiogram, bullet point 2
Rationale: To provide clarity on order of assessments by investigator request
Original text:
During visits where vital signs and/or blood collection is also required, vital sign 
measurements will be taken after the ECG and prior to scheduled blood collection (which 
should be drawn at the exact nominal time point).
Amended text:
During visits where vital signs and/or blood collection is also required, vital sign 
measurements will be taken after the ECG and prior to scheduled blood collection (which 
should be drawn at the exact nominal time point).
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
Section 9.1 Hypotheses, last sentence
Rationale: To provide updates in the statistical section based on the change in total 
subject number 
Original text:
An active treatment group will be declared efficacious if the posterior probability that the 
difference in the RRs between that active group and the placebo is positive, is high (at 
least 95%), i.e., P (RRACT > RRPBO) 95%, where RRACT is the RR in the active group, 
RRPBO is the RR in the placebo group, and P is the posterior probability.
 
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Amended text:
An active treatment group will be declared efficacious if the posterior probability that the 
difference in the RRs between that active group and the placebo is positive, is high (at 
least 905%), i.e., P (RRACT > RRPBO) 905%, where RRACT is the RR in the active group, 
RRPBO is the RR in the placebo group, and P is the posterior probability.
Section 9.2.1 Sample Size Assumptions, second paragraph
Rationale: To provide updates from Part 1, to update the treatment and populations to be 
studied in Part 2, and to update statistical text to support selection of treatment and 
populations to be studied in Part 2
Original text:
In Part 2, approximately 80 subjects with CHB are planned for randomization to study 
treatment. The exact number of subjects to be enrolled will be data driven from Part 1 
and will depend on the number of dose levels selected for Part 2. For example, if 3 dose 
levels each with 2 dosing regimens are selected in Part 2, approximately 80 subjects will 
be randomized in the 7 treatment groups (6 active groups and 1 placebo group). Enrolling 
approximately 80 subjects will allow for an approximate 14% overall drop-out rate, so 
that there are approximately 10 evaluable subjects in each of the active treatment group 
and approximately 12 subjects in the placebo group. Matching placebo injections will be 
prepared for each dose level and dosing regimen and will be administered in the similar 
way of the corresponding active treatment group. Approximately 2 subjects will be 
randomized in each placebo dose level and dosing regimen. The total sample size will 
provide sufficient power to select an efficacious treatment group using a Bayesian model 
based approach sharing common degrees of freedom across treatment arms. Assuming 
3 dose levels and 2 dosing regimens are selected in Part 2, the probability of declaring 
success of an inefficacious treatment arm (with RR 5%) is less than 14%. On the other 
hand if an active treatment arm has a 30% RR, the probability of selecting the treatment 
arm is about 80% under the model assumption. Appendix 6 (Section 12.6) details the 
operating characteristics of the design.
Amended text:
In Part 2, approximately 80 subjects with CHB are planned for randomization to study 
treatment. The exact number of subjects to be enrolled will be data driven from Part 1 
and will depend on the number of dose levels selected for Part 2. For example, if 3 dose 
levels each with 2 dosing regimens are selected in Part 2, approximately 80 subjects will 
be randomized in the 7 treatment groups (6 active groups and 1 placebo group). Enrolling 
approximately 80 subjects will allow for an approximate 14% overall drop-out rate, so 
that Tthere are approximately 110 evaluable subjects in each of the active treatment 
group and approximately 12 6 subjects in the placebo group. Matching placebo injections 
will be prepared for each dose level and dosing regimen and will be administered in the 
 
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similar way of the corresponding active treatment group. Approximately 2 subjects will 
be randomized in each placebo dose level and dosing regimen. The total sample size will 
provide sufficient power to select an efficacious treatment group using a Bayesian model 
based approach sharing common degrees of freedom across treatment arms. Assuming 
3 dose levels and 2 dosing regimens are selected in Part 2With the 3 treatment groups 
selected for Part 2, the probability of declaring success of an inefficacious treatment arm 
(with RR 5%) is less than 14%. On the other hand if an active treatment arm has a 30% 
RR, the probability of selecting the treatment arm is about 80% under the model 
assumption. Appendix 6 (Section 12.6) details the operating characteristics of the design.
Section 9.2.2 Sample Size Sensitivity, first sentence
Rationale: To update statistical text to provide the sample size and treatments selected for 
Part 2
Original text: 
Sample size sensitivity of Part 2 will be provided after dose levels and regimens are 
selected from Part 1.
Amended text:
Sample size sensitivity of Part 2 will be provided after dose levels and regimens are 
selected from Part 1.
Section 9.3.3 Interim Analysis and Final Analysis, second paragraph
Rationale: To provide updates of the pre-clinical data
Original text:
During Dose escalation, a Bayesian predictive probability of mean AUC(0-) and Cmax less 
than 465.75 mgh/mL and 57.9 mg /mL (mean exposures at NOAEL dose in monkey), 
respectively, will be calculated for the next dose level and used together with safety and 
tolerability data to aid next dose selection. 
Amended text:
During Dose escalation, a Bayesian predictive probability of mean AUC(0-) and Cmax less 
than 465.75 492.7 mgh/mL and 57.9 52.7 mg /mL (mean exposures at NOAEL in the 
13-week monkey study), respectively, will be calculated for the next dose level and used 
together with safety and tolerability data to aid next dose selection.
Section 9.3.3.3 Part 2: 3 month follow up analysis
 
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Rationale: To include analysis at original end of study timepoint (Day 169), as an 
optional additional follow-up period is added to Part 2
Original text:
none
Amended text:
The 3 month follow up analysis for Part 2 will be conducted once last randomized 
subject has completed the Day 169 visit. 
Section 9.3.3.4 Part 2: 6 month follow up analysis
Rationale: To include analysis at the mid-point (6 month timepoint) of the total follow-up 
period of Part 2 (total follow-up period is approx. 12 months from last dose to final 
follow-up visit of the optional additional follow up period)
Original text:
none
Amended text:
The 6 month follow up analysis for Part 2 may be conducted once last randomized 
subject has completed the Day 270 visit to support internal decision making and/or 
regulatory interaction.
Section 9.3.3.5 Part 2: End of Study Analysis
Rationale: To update definition of the end of study analysis to include data collected 
through the optional additional follow up period
Original text:
The end of study analysis for Part 2 will be conducted once the last randomized subject 
(sentinel, remainder of subjects, and the optional Japanese Part 2 sub-study subjects if 
applicable) has completed the Day 169 visit.
Amended text:
The end of study analysis for Part 2 will be conducted once the last subject participating 
in the optional follow-up randomized subject (sentinel, remainder of subjects, and the 
optional Japanese Part 2 sub-study subjects if applicable) has completed the Day 450 169
visit.
 
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Section 9.4.1 Primary Analyses, Efficacy, 11th paragraph
Rationale: To update the statistical section based on the change in total subject number 
Original text:
In Part 2, GSK3389404 treatment efficacy will be declared if the posterior probability 
that the difference in the RRs between that active group and the placebo is positive and is 
high (at least 95%), i.e., P (RRACT > RRPBO) 95%, where RRACT is the RR in the active 
group, RRPBO is the RR in the placebo group, and P is the posterior probability.
Amended text:
An active treatment group In Part 2, GSK3389404 treatment efficacy will be declared if 
the posterior probability that the difference in the RRs between that active group and the 
placebo is positive and is high (at least 905%), i.e., P (RRACT > RRPBO) 905%, where 
RRACT is the RR in the active group, RRPBO is the RR in the placebo group, and P is the 
posterior probability.
Section 10.8.1 Dose Escalation Committee, 2nd paragraph
Rationale: To provide updates of the pre-clinical data
Original text:
A maximum AUC(0-) of 465.75 gh/mL or Cmax of 57.9 g/mL of GSK3389404 is not 
expected to be exceeded in any cohort.
Amended text:
A maximum AUC(0-) of 465.75 492.7 mgh/mL or Cmax of 57.9 52.7 mg /mL of 
GSK3389404 is not expected to be exceeded in any cohort.
Section 11. References
Rationale: To update reference
Original text:
GlaxoSmithKline Document Number 2015N236049_02. Investigator’s Brochure (IB) for 
GSK3389404. 2017.
Amended text:
GlaxoSmithKline Document Number 2015N236049_024. Investigator’s Brochure (IB) 
for GSK3389404. 20168.
 
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Section 12.6.1 Introduction, paragraph 3 and 4.
Rationale: To update the number of subjects based on number of subjects enrolled for 
Part 1 and expected number of subjects in Part 2 based on estimated number of subjects 
after selecting treatment arms for Part 2
Original text:
In Part 2, approximately 80 subjects with CHB are planned for randomization to study 
treatment. The exact number of subjects to be enrolled will be data driven from Part 1 
and will depend on the number of dose levels selected for Part 2. For example, if 3 dose 
levels each with 2 dosing regimens are selected in Part 2, approximately 80 subjects will 
be randomized in the 7 treatment groups (6 active groups and 1 placebo group). Enrolling 
approximately 80 subjects will allow for an approximate 14% overall drop-out rate, so 
that there are approximately 10 evaluable subjects in each of the active treatment group 
and approximately 12 subjects in placebo. Matching placebo injections will be prepared 
for each dose level and dosing regimen and will be administered in the similar way of the 
corresponding active treatment group. Approximately 2 subjects will be randomized in 
each placebo dose level and regimen.
The dosing regimens for selected treatment groups will be identical. For example, if 
480 mg is selected for Part 2, other selected treatment groups will also be administered in 
a weekly and bi-weekly (every 2 weeks) dosing regimen.
Amended text:
In Part 2, approximately 80 subjects with CHB are planned for randomization to study 
treatment. The exact number of subjects to be enrolled will be data driven from Part 1 
and will depend on the number of dose levels selected for Part 2. For example, if 3 dose 
levels each with 2 dosing regimens are selected in Part 2, approximately 80 subjects will 
be randomized in the 7 treatment groups (6 active groups and 1 placebo group). Enrolling 
approximately 80 subjects will allow for an approximate 14% overall drop-out rate, so 
that Tthere are approximately 110 evaluable subjects in each of the active treatment 
group and approximately 12 6 subjects in placebo. Matching placebo injections will be 
prepared for each dose level and dosing regimen and will be administered in the similar 
way of the corresponding active treatment group. Approximately 2 subjects will be 
randomized in each placebo dose level and regimen.
The dosing regimens for selected treatment groups will be identical. For example, if 
480 mg is selected for Part 2, other selected treatment groups will also be administered in 
a weekly and bi-weekly (every 2 weeks) dosing regimen.
Section 12.6.3 Success Criteria paragraph 1
Rationale: to update statistical sections
Original text:
 
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An active treatment group will be declared efficacious if the posterior probability that the 
difference in the RRs between that active group and the placebo is positive, is high (at 
least 95%), i.e., P (RRACT > RRPBO) 95%, where RRACT is the RR in the active group, 
RRPBO is the RR in the placebo group, and P is the posterior probability.
Amended text:
An active treatment group will be declared efficacious if the posterior probability that the 
difference in the RRs between that active group and the placebo is positive, is high (at 
least 950%), i.e., P (RRACT > RRPBO) 950%, where RRACT is the RR in the active group, 
RRPBO is the RR in the placebo group, and P is the posterior probability.
Section 12.6.4 Scenarios for Testing
Rationale: To update the text with treatments selected for Part 2
Original text:
It is assumed that 3 dose levels (120, 240, and 480 mg) each at 2 regimens (weekly and 
biweekly) will be selected in Part 2. The description of treatment groups along with the 
sample size is provided in Table 18 A wide range of scenarios, as described in Table 19, 
were created to test the model performance.
Amended text:
The dose levels and regimens selected for Part 2 are 60 mg GSK3389404 weekly, 
120 mg bi-weekly GSK3389404, 120 mg GSK3389404 weekly or placebo. It is 
assumed that 3 dose levels (120, 240, and 480 mg) each at 2 regimens (weekly and bi-
weekly) will be selected in Part 2. The description of treatment groups along with the 
sample size is provided in Table 18 17 A wide range of scenarios, as described in Table 
19 18, were created to test the model performance.
Section 12.6.4 Scenarios for Testing, previously Table 18 and 19
Rationale: To update with treatments selected for Part 2
Original text:
 
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Table 18
Treatment Description
Treatment Description
Treatment
Sample Size
Total monthly dose of 120 mg divided weekly (i.e., 30 mg once a week)
120W
10
Total monthly dose of 120 mg divided bi-weekly (i.e., 60 mg bi-weekly)
120BW
10
Total monthly dose of 240 mg divided weekly (i.e., 60 mg once a week)
240W
10
Total monthly dose of 240 mg divided bi-weekly (i.e., 120 mg bi-weekly)
240BW
10
Total monthly dose of 480 mg divided weekly (i.e., 120 mg once a week)
480W
10
Total monthly dose of 480 mg divided bi-weekly (i.e., 240 mg bi-weekly)
480BW
10
Matching placebo for each active treatment 
PBO
12
Table 19
Scenarios for Simulation
Scenario 
Number
Response Rate (%)
(PBO, 120W, 120BW, 240W, 
240BW, 480W, 480BW)
Description
1
(5, 5, 5, 5, 5, 5, 5)
No treatment effect
2
(5, 20, 20, 20, 20, 20, 20)
All of the active treatment groups are equally effective 
(low effect size)
3
(5, 30, 30, 30, 30, 30, 30)
All of the active treatment groups are equally effective 
(medium effect size)
4
(5, 10, 15, 20, 25, 30, 35)
Larger effect in higher dose group, bi-weekly dosing 
regimen is more efficacious than weekly
5
(5, 15, 10, 25, 20, 35, 30)
Larger effect in higher dose group, weekly dosing 
regimen is more efficacious than bi-weekly y
6
(5, 10, 10, 10, 10, 10, 30)
Only 480 mg (highest dose) bi-weekly dosing is 
efficacious 
7
(5, 10, 10, 10, 10, 20, 30)
Only 480 mg (highest dose) has dose response, 
bi-weekly having medium and weekly having small 
effect
8
(5, 10, 10, 10, 30, 10, 10)
Only 240 mg (middle dose) bi-weekly dosing is 
efficacious
9
(5, 10, 30, 10, 10, 10, 10)
Only 120 mg (lowest dose) bi-weekly dosing is 
efficacious
Amended text:
Table 178
Treatment Description
Treatment Description
Treatment
Sample Size
Total monthly dose of 120 mg divided weekly (i.e., 30 mg once a week)
120W
10
Total monthly dose of 120 mg divided bi-weekly (i.e., 60 mg bi-weekly)
120BW
10
Total monthly dose of 240 mg divided weekly (i.e., 60 mg once a week)
240W
101
Total monthly dose of 240 mg divided bi-weekly (i.e., 120 mg bi-weekly)
240BW
101
Total monthly dose of 480 mg divided weekly (i.e., 120 mg once a week)
480W
101
Total monthly dose of 480 mg divided bi-weekly (i.e., 240 mg bi-weekly)
480BW
10
Matching placebo for each active treatment 
PBO
12 6
 
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Table 189
Scenarios for Simulation
Scenario 
Number
Response Rate (%)
(PBO, 120W, 120BW, 240W, 
240BW, 480W, 480BW)
Description
1
(5, 5, 5, 5, 5, 5, 5)
No treatment effect
2
(5, 20, 20, 20, 20, 20, 20)
All of the active treatment groups are equally effective 
(low effect size)
32
(5, 30, 30, 30, 30, 30, 30)
All of the active treatment groups are equally effective 
(medium effect size)
4 3
(5, 15, 15, 35, 10, 15, 20, 25, 30, 
35)
Larger effect in higher dose group, bi-weekly dosing 
regimen is equally effective asmore efficacious than
weekly
5 4
(5, 20, 15, 35, 15, 10, 25, 20, 35, 
30)
Larger effect in higher dose group, weekly dosing has 
small effect regimen is more efficacious than bi-weekly 
y
6
(5, 10, 10, 10, 10, 10, 30)
Only 480 mg (highest dose) bi-weekly dosing is 
efficacious 
7 
(5, 10, 10, 10, 10, 20, 30)
Only 480 mg (highest dose) has dose response, 
bi-weekly having medium and weekly having small 
effect
8
(5, 10, 10, 10, 30, 10, 10)
Only 240 mg (middle dose) bi-weekly dosing is 
efficacious
9
(5, 10, 30, 10, 10, 10, 10)
Only 120 mg (lowest dose) bi-weekly dosing is 
efficacious
Section 12.6.5 Simulations, paragraph 1, 2nd sentence
Rationale: To update with treatments selected for Part 2
Original text:
Response data for 7 treatment groups are generated from binomial distributions using the 
sample size from Table 18 and response rates from Table 19.
Amended text:
Response data for 7 3 treatment groups are generated from binomial distributions using 
the sample size from Table 1718 and response rates from Table 1819.
Section 12.6.5 Simulations, paragraph 1, 4th sentence
Rationale: To update with treatments selected for Part 2
Original text:
For each of the scenarios, average posterior means along with 90% credible intervals 
(CI), average PoS, and probability of selecting a dose group based on PoS are calculated 
over the sample space of 1000 simulations.
 
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Amended text:
For each of the scenarios, average posterior means along with 90% credible intervals 
(CI), and average PoS, and probability of selecting a dose group based on PoS are 
calculated over the sample space of 1000 simulations.
Section 12.6.5 Simulations, 2nd paragraph, last sentence
Rationale: To update with treatments selected for Part 2
Original text:
The BLRM was not able to select the efficacious treatment group under Scenario 7, 8 and 
9, where there is no monotonic relationship between dose and response. These scenarios 
are unlikely to happen in real life.
Amended text:
The BLRM was not able to select the efficacious treatment group under Scenario 7, 8 and 
9, where there is no monotonic relationship between dose and response. These scenarios 
are unlikely to happen in real life.
Section 12.6.5 Simulations, paragraph 3 and 4
Rationale: To update statistical section
Original text: 
A cutoff point of 90% for PoS seems to provide reasonable probability for selecting an 
efficacious dose group given the sample size of this study
Amended text:
A cutoff point of 95 90% for PoS seems to provide reasonable probability for selecting an 
efficacious dose group given the sample size of this study
Section 12.6.5 Simulations, Table 19, 20, 21, 22
Rationale: To update with treatments selected for Part 2
Original text:
none
 
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Amended text:
Table 19 Simulation Results from Scenario 1
Scenario 1
No Treatment Effect
(PBO, 240W, 240BW, 480W): (5, 5, 5, 5)
Treatment
Posterior 
RR (%)
90% CI
PoS1
Power2
Cutoff Points
85%
90%
95%
98%
Pairwise
PBO
6.82
(0.71,20.71)
240W
6.05
(0.81,16.59)
53.17
30.8
30.8
8.2
1.6
240BM
5.72
(0.67,16.09)
53.05
31.4
31.4
6.2
0.8
480W
5.46
(0.63,15.53)
51.86
28.7
28.7
6.6
0.6
BLRM
PBO
6.95
(0.71,21.34)
240W
4.88
(0.56,14.02)
57.83
21.9
11.0
3.1
0.3
240BW
5.3
(0.55,15.34)
58.67
31.4
13.8
3.9
0.3
480W
5.13
(0.52,15.04)
57.84
28.7
13.7
4.7
0.2
BLRM = Bayesian logistic regression model; BW = bi-weekly; CI = credible interval; PBO = placebo; 
PoS = probability of success; RR = response rate; W = weekly
1.
PoS is defined as P(RRACT >RRPBO), , a dose group will be considered efficacious if the PoS is at least 
90%, treatment group with highest PoS will be selected
2.
Power is defined as proportion of simulation samples where PoS is greater than various cutoff 
points(85,90,95,98%) over the sample space (i.e., 1000 simulations)
 
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Table 20 Simulation Results from Scenario 2
Scenario 2
All of the active treatment groups are equally effective 
(medium effect size)
(PBO, 240W, 240BW, 480W): (5, 30, 30, 30)
Treatment
Posterior 
RR (%)
90% CI
PoS1
Power2
Cutoff Points
85%
90%
95%
98%
Pairwise
PBO
6.82
(0.71,20.7)
240W
30.93
(12.67,53.01)
88.77
75.8
75.7
66.0
49.1
240BM
30.09
(12.01,52.13)
88.26
75.9
75.8
65.7
49.1
480W
30
(11.85,52.15)
88.6
75.8
75.8
66.2
49.2
BLRM
PBO
6.95
(0.71,21.34)
240W
30.38
(12.62,51.95)
89.53
76.2
74.1
64.9
46.7
240BW
29.88
(12.05,51.71)
88.8
75.9
75.4
65.2
47.7
480W
29.77
(11.84,51.77)
89.02
75.8
75.0
65.9
48.9
BLRM = Bayesian logistic regression model; BW = bi-weekly; CI = credible interval; PBO = placebo; 
PoS = probability of success; RR = response rate; W = weekly
1.
PoS is defined as P(RRACT >RRPBO), , a dose group will be considered efficacious if the PoS is at least 
90%, treatment group with highest PoS will be selected
2.
Power is defined as proportion of simulation samples where PoS is greater than various cutoff 
points(85,90,95,98%) over the sample space (i.e., 1000 simulations)
Table 21 Simulation Results from Scenario 3
Scenario 3
Larger effect in higher dose group, bi-weekly dosing is 
equally effective as weekly
(PBO, 240W, 240BW, 480W): (5, 15, 15, 35)
Treatment
Posterior 
RR (%)
90% CI
PoS1
Power2
Cutoff Points
85%
90%
95%
98%
Pairwise
PBO
6.82
(0.71,20.7)
240W
16.23
(4.27,34.07)
74.83
61.0
61.0
36.9
17.7
240BM
15.58
(3.89,33.22)
74.26
60.3
60.2
37.7
15.5
480W
34.86
(15.25,57.59)
91.23
80.5
80.4
70.9
58.3
BLRM
PBO
6.95
(0.71,21.34)
240W
16.27
(4.42,34.06)
79
61.0
56.7
35.2
15.1
240BW
15.28
(3.81,32.93)
77.24
60.3
55.0
36.8
12.1
480W
33.72
(14.57,56.2)
90.88
80.5
77.6
69.2
54.0
BLRM = Bayesian logistic regression model; BW = bi-weekly; CI = credible interval; PBO = placebo; 
PoS = probability of success; RR = response rate; W = weekly
1.
PoS is defined as P(RRACT >RRPBO), , a dose group will be considered efficacious if the PoS is at least 
90%, treatment group with highest PoS will be selected
2.
Power is defined as proportion of simulation samples where PoS is greater than various cutoff 
points(85,90,95,98%) over the sample space (i.e., 1000 simulations)
 
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Table 22 Simulation Results from Scenario 4
Scenario 4
Larger effect in higher dose group, weekly dosing small effect
(PBO, 240W, 240BW, 480W): (5, 20, 15, 35)
Treatment
Posterior 
RR (%)
90% CI
PoS1
Power2
Cutoff Points
85%
90%
95%
98%
Pairwise
PBO
6.82
(0.71,20.7)
240W
20.9
(6.61,40.53)
80.33
65.9
65.9
48.5
27.8
240BM
15.58
(3.89,33.2)
74.25
60.3
60.2
37.7
15.5
480W
34.86
(15.24,57.6)
91.24
80.5
80.3
71.0
58.2
BLRM
PBO
6.95
(0.71,21.34)
240W
20.41
(6.57,39.67)
82.65
65.8
63.1
47.0
22.4
240BW
15.61
(3.95,33.45)
77.78
60.3
56.7
37.0
12.7
480W
34
(14.77,56.48)
91.03
80.5
77.8
69.2
55.0
BLRM = Bayesian logistic regression model; BW = bi-weekly; CI = credible interval; PBO = placebo; 
PoS = probability of success; RR = response rate; W = weekly
1.
PoS is defined as P(RRACT >RRPBO), , a dose group will be considered efficacious if the PoS is at least 
90%, treatment group with highest PoS will be selected
2.
Power is defined as proportion of simulation samples where PoS is greater than various cutoff 
points(85,90,95,98%) over the sample space (i.e., 1000 simulations)
Section 12.6.5 Simulations, Table 24, 25, 26, 27
Rationale: To update with treatments selected for Part 2.
Original text:
Table 24
Simulation Results From Scenario 5
Scenario 5
Larger effect in higher dose group 
(weekly dosing regimen is more efficacious than bi-weekly)
(PBO, 120W, 120BW, 240W, 240BW, 480W, 480BW): (5, 15, 10, 25, 20, 
35, 30)
Treatment
Posterior 
RR (%)
90% CI
PoS1
Decision2
(Select 
dose)
Power3
Cutoff Points
85%
90%
95%
98%
Pairwise Comparison
PBO
5.89
(0.79,16.01)
120W
15.35
(3.59,33.51)
71.91
No
47.6
47.5
39.4
24.8
120BW
11.1
(2.15,26.26)
62.23
No
37.0
37.0
30.4
14.5
240W
25.26
(8.64,47)
85.09
No
69.8
68.6
56.4
40.6
240BW
20.61
(6.01,41.08)
80.06
No
60.1
59.6
48.8
33.6
480W
34.72
(14.63,58.19)
92.29
No
82.2
81.0
71.5
58.2
480BW
29.63
(11.11,52.59)
89.04
No
74.8
73.5
62.9
50.5
BL
RM
PBO
5.94
(0.78,16.27)
120W
15.25
(5.19,29.7)
80.12
No
59.9
54.1
43.2
26.1
 
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Scenario 5
Larger effect in higher dose group 
(weekly dosing regimen is more efficacious than bi-weekly)
(PBO, 120W, 120BW, 240W, 240BW, 480W, 480BW): (5, 15, 10, 25, 20, 
35, 30)
Treatment
Posterior 
RR (%)
90% CI
PoS1
Decision2
(Select 
dose)
Power3
Cutoff Points
120BW
12.13
(3.73,24.83)
75.49
No
54.4
48.7
36.6
17.9
240W
22.52
(11.48,35.84)
90.03
No
77.1
69.2
59.2
47.2
240BW
18.06
(8.32,30.36)
85.58
No
66.8
60.3
52.1
41.1
480W
35.7
(18.03,55.74)
95.35
Yes
90.0
85.7
77.4
66.1
480BW
29.84
(13.75,49.13)
92.59
No
83.6
76.5
66.9
57.2
BLRM = Bayesian logistic regression model; BW = bi-weekly’ CI = credible interval; PBO = placebo; PoS = probability 
of success; RR = response rate; W = weekly
1.
PoS is defined as P(RRACT >RRPBO)
2.
A dose group will be selected if the PoS is at least 95%
3.
Power is defined as percentage of time PoS >95% over the sample space (i.e., 1000 simulations)
Table 25
Simulation Results From Scenario 6
Scenario 6
Only 480 mg (highest dose) bi-weekly dosing is efficacious
(PBO, 120W, 120BW, 240W, 240BW, 480W, 480BW): (5, 10, 10, 10, 10, 
10, 30)
Treatment
Posterior 
RR (%)
90% CI
PoS1
Decision2
(Select 
dose)
Power3
Cutoff Points
85%
90%
95%
98%
Pairwise Comparison
PBO
5.87
(0.79,15.98)
120W
10.69
(1.94,25.78)
62.31
No
37.2
37.0
30.4
12.7
120BW
11.31
(2.13,26.85)
63.39
No
38.8
38.7
31.9
16.3
240W
10.53
(1.97,25.28)
60.78
No
35.5
35.5
29.5
14.6
240BW
10.35
(1.88,25.04)
60.98
No
35.3
35.3
29.3
13.3
480W
10.53
(1.94,25.35)
61.14
No
36.8
36.8
31.0
14.1
480BW
30.59
(11.86,53.5)
89.42
No
77.5
75.8
64.7
50.6
BLRM
PBO
5.92
(0.79,16.22)
120W
7.32
(1.61,17.24)
63.74
No
42.8
34.4
19.3
5.6
120BW
11.45
(2.99,24.92)
72.63
No
51.6
45.2
32.2
15.2
240W
8.71
(2.78,17.53)
69.47
No
48.7
42.0
29.4
11.5
240BW
14.46
(5.92,25.8)
80.12
No
57.4
53.1
46.3
29.5
480W
14.24
(4.08,29.58)
77.18
No
55.6
50.3
40.5
21.9
480BW
23.65
(9.2,42.41)
86.9
No
73.6
66.4
56.9
43.1
BLRM = Bayesian logistic regression model; CI = credible interval; M = monthly; PBO = placebo; PoS = probability of
success; RR = response rate; W = weekly
1.
PoS is defined as P(RRACT >RRPBO)
2.
A dose group will be selected if the PoS is at least 95%
3.
Power is defined as percentage of time PoS >95% over the sample space (i.e., 1000 simulations)
 
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Table 26
Simulation Results From Scenario 7
Scenario 7
Only 480 mg (highest dose) is efficacious
(bi-weekly having medium effect and weekly having small effect)
(PBO, 120W, 120BW, 240W, 240BW, 480W, 480BW): (5, 10, 10, 10, 10, 
20, 30)
Treatment
Posterior 
RR (%)
90% CI
PoS1
Decision
2
(Select 
dose)
Power3
Cutoff Points
85%
90%
95%
98%
Pairwise Comparison
PBO
5.87
(0.75,16.07)
120W
10.72
(1.97,25.75)
61.57
No
36.0
35.9
29.3
14.5
120BW
11.17
(2.09,26.61)
62.83
No
37.6
37.5
31.2
16.0
240W
11.63
(2.31,27.22)
63.58
No
39.7
39.7
31.9
15.6
240BW
10.33
(1.75,25.33)
61.66
No
35.4
35.3
29.2
12.0
480W
20.8
(6.04,41.54)
80.43
No
59.3
58.8
49.4
35.5
480BW
30.47
(11.72,53.52)
89.53
No
77.1
76.1
63.1
50.7
BLRM
PBO
5.92
(0.75,16.3)
120W
8.21
(1.95,18.74)
65.9
No
45.8
36.6
21.4
7.1
120BW
9.72
(2.41,21.68)
69.54
No
48.2
41.4
26.6
11.7
240W
11.71
(4.35,21.99)
75.37
No
55.6
50.8
39.0
20.5
240BW
14.19
(5.68,25.54)
80
No
57.1
52.0
45.8
29.5
480W
21.44
(7.88,39.61)
85.58
No
67.5
62.4
54.7
40.1
480BW
25.9
(10.63,45.2)
89.37
No
76.2
70.4
59.8
46.9
BLRM = Bayesian logistic regression model; BW = bi-weekly; CI = credible interval; PBO = placebo; PoS = probability 
of success; RR = response rate; W = weekly
1.
PoS is defined as P(RRACT >RRPBO)
2.
A dose group will be selected if the PoS is at least 95%
3.
Power is defined as percentage of time PoS >95% over the sample space (i.e., 1000 simulations)
Table 27
Simulation Results From Scenario 8
Scenario 8
Only 240 mg (middle dose) bi-weekly dosing is efficacious
(PBO, 120W, 120BW, 240W, 240BW, 480W, 480BW): (5, 10, 10, 10, 30, 
10, 10)
Treatment
Posterior 
RR (%)
90% CI
PoS1
Decision2
(Select 
dose)
Power3
Cutoff Points
85%
90%
95%
98%
Pairwise 
Comparison
PBO
5.4
(0.68,15.04)
120W
11.04
(2.04,26.4)
64.38
No
41.0
40.9
33.3
15.2
120BW
9.94
(1.76,24.3)
61.6
No
37.8
37.7
29.2
12.0
240W
11.05
(2.07,26.33)
64.22
No
41.1
41.1
34.2
16.0
240BW
31.46
(12.39,54.59)
90.34
No
78.3
77.6
67.1
56.3
480W
10.44
(1.94,25.16)
62.3
No
38.3
38.3
32.1
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Scenario 8
Only 240 mg (middle dose) bi-weekly dosing is efficacious
(PBO, 120W, 120BW, 240W, 240BW, 480W, 480BW): (5, 10, 10, 10, 30, 
10, 10)
Treatment
Posterior 
RR (%)
90% CI
PoS1
Decision2
(Select 
dose)
Power3
Cutoff Points
480BW
10.67
(1.88,25.83)
63.48
No
39.1
39.0
33.4
15.7
BLRM
PBO
5.46
(0.68,15.33)
120W
10.68
(2.74,23.46)
73.45
No
54.8
47.5
31.9
14.2
120BW
16.98
(5.46,33.5)
82.05
No
65.7
60.4
49.8
32.8
240W
9.5
(3.19,18.68)
73.12
No
55.6
46.6
34.0
15.6
240BW
15.38
(6.6,26.82)
82.64
No
64.3
58.6
51.9
36.4
480W
10.85
(2.82,23.76)
73.32
No
55.2
48.9
32.9
14.7
480BW
17.12
(5.49,33.79)
82.42
No
65.1
59.7
49.2
33.3
BLRM = Bayesian logistic regression model; BW = bi-weekly; CI = credible interval; PBO = placebo; PoS = probability 
of success; RR = response rate; W = weekly
1.
PoS is defined as P(RRACT >RRPBO)
2.
A dose group will be selected if the PoS is at least 95%
3.
Power is defined as percentage of time PoS >95% over the sample space (i.e., 1000 simulations)
Table 28
Simulation Results From Scenario 9
Scenario 9
Only 120 mg (lowest dose) bi-weekly dosing is efficacious
(PBO, 120W, 120BW, 240W, 240BW, 480W, 480BW): (5, 10, 30, 10, 10, 
10, 10)
Treatment
Posterior 
RR (%)
90% CI
PoS1
Decision2
(Select 
dose)
Power3
Cutoff Points
85%
90%
95%
98%
Pairwise Comparison
PBO
5.84
(0.79,15.87)
120W
10.47
(1.86,25.38)
61.37
No
35.4
35.4
28.2
14.3
120BW
31.02
(11.9,54.34)
90.87
No
79.1
77.5
66.3
52.1
240W
10.6
(1.86,25.73)
62.39
No
36.5
36.5
30.5
13.4
240BW
10.27
(1.82,24.96)
61.21
No
36.5
36.5
30.6
12.8
480W
11.23
(2.12,26.65)
63.35
No
38.0
38.0
30.6
15.1
480BW
10.74
(1.97,25.76)
61.98
No
37.5
37.3
30.4
15.1
BLRM
PBO
5.89
(0.79,16.13)
120W
14.42
(4.15,29.85)
78.21
No
56.9
51.9
38.4
23.4
120BW
23.62
(9.06,42.55)
87.68
No
74.0
67.7
57.3
44.0
240W
8.89
(2.88,17.79)
70.22
No
50.0
41.3
29.1
13.1
240BW
14.44
(5.85,25.85)
80.92
No
61.0
55.3
45.8
31.4
480W
7.49
(1.68,17.48)
64.06
No
42.2
33.1
20.1
7.6
480BW
11.39
(2.93,24.87)
73.07
No
51.7
46.0
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Scenario 9
Only 120 mg (lowest dose) bi-weekly dosing is efficacious
(PBO, 120W, 120BW, 240W, 240BW, 480W, 480BW): (5, 10, 30, 10, 10, 
10, 10)
Treatment
Posterior 
RR (%)
90% CI
PoS1
Decision2
(Select 
dose)
Power3
Cutoff Points
BLRM = Bayesian logistic regression model; BW = bi-weekly; CI = credible interval; PBO = placebo; PoS = probability 
of success; RR = response rate; W = weekly
2.
PoS is defined as P(RRACT >RRPBO)
3.
A dose group will be selected if the PoS is at least 95%
4.
Power is defined as percentage of time PoS >95% over the sample space (i.e., 1000 simulations)
Amended text:
Deleted tables
 
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12.7.6.
Protocol changes for Amendment 06 (05-JUN-2018) from
Protocol Amendment 05 (06-MAR-2018)
Protocol Amendment 6 replaces Protocol Amendment 05 (06-MAR-2018) and applies to 
all study sites.
Protocol Amendment 06 Summary:
Protocol Amendment 6 is being implemented for the following reasons:
To correct the planned study duration for subjects
-
Rationale: The planned study duration was incorrect as it did not include the 
screening window period of 30 days (+15 days exceeding the 30 day screening 
window where subjects may still be considered eligible after undergoing a brief 
physical exam, review of medical history, and review of concomitant medications 
to confirm eligibility). As Part 1 is complete, changes to Part 1 figure and wording 
has not been changed.
To allow inclusion of subjects with ALT 2 X ULN
-
Rationale: After feedback from investigators, inclusion criterion 9b was changed 
to allow ALT 2XULN. This change was supported by feedback that factors other 
than HBV may contribute to slightly elevated ALT levels in subjects. 
To add greater clarity for exclusion 4,8g, 9, and 11.
-
Rationale: After feedback from investigators, exclusion criterion 4 was edited to 
include exclusion of subjects who the investigator believes may have liver 
cirrhosis without requiring a positive liver biopsy, Fibroscan, and/or 
APRI/Fibrosure result to exclude the subject.
-
It was noted that sites may use an online calculator that converts the ACR to 
mg/g instead of mg/mg. The exclusion criterion 8g now includes the ACR cut-off 
in mg/mg and mg/g. It was also noted that in some cases, subjects have both low 
urine albumin and low urine creatinine resulting in a high ACR calculation. 
Wording was added that the investigator should confirm that the patient does 
not have risk factors that may affect renal function and discuss eligibility with the 
PPD or GSK medical monitor, or designee since the high ACR may not be clinically 
relevant in all situations.
-
Exclusion criterion 9 indicated that subjects should be excluded based on a mean 
of triplicate measurements with Fridericia’s QT correction formula (QTcF) 450 
msec, however the Time and Events Table 8 for screening indicate that ECG at 
screening should be single, not triplicate. It has been clarified that if the single 
ECG at screening shows QTcF 450 msec, a mean of triplicate measurements 
should be used to confirm that subject meets exclusion criterion.
-
Investigators pointed out that some subjects use topical or inhaled 
corticosteroids, which would not result in the immunosuppressing effects. 
 
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Therefore, the exclusion criterion 11 has been clarified to allow for 
topical/inhaled steroid use.
To provide next steps for determining follow-up visit schedules for subjects who meet 
treatment stopping criteria, but are not withdrawn from the study
-
Rationale: It was not clear how investigators were to determine follow-up visit 
schedules for subjects who stop treatment (GSK3389404 or placebo), but who 
are not withdrawn from the study.
To update the Time and Events Table for the optional follow-up period
-
Rationale: The primary purpose of the optional follow-up period is to assess 
long-term efficacy of GSK3389404 and not safety. Therefore, extensive safety 
assessments were removed from the follow-up period. 
To update the unblinded senior management review
-
Rationale: as internal GSK roles/title names may change, the wording was 
changed to clarify that senior management may review the data
To differentiate between final follow up visits Day 169 or Day 450 (if subjects consent to 
the optional extended follow-up period).
-
Rationale: Some assessments/requirements were specified to end with the final 
follow up visit, which in previous versions of the protocol was Day 169. For each 
case, the final follow-up has been clarified to be Day 169 or Day 450 (if subjects 
consent to the optional extended follow-up period).
To make edits for clarity
o
Rationale: Edits were made to the NOAEL- the units for the NOAEL in the 
13-week monkey toxicity study were incorrectly written as the NOAEL of 
30 mg/kg/day, when it should be mg/kg/week. This does not affect the 
Cmax/AUC calculations for the NOAEL. Edits were made to better clarify 
that treatment selections were made for Part 2 based on data from Part 
1. Edits were made to make clear that 12 subjects were enrolled for the 
completed Part 1 of study 205670. Edits were made to remove the word 
“pharmacy” for dispensing investigational product (IP; GSK3389404 or 
placebo), as not all sites use a formal pharmacy to dispense IP. Edits were 
made to make clear that only subjects of reproductive potential should 
undergo pregnancy testing. Edits were made to ensure that the 
superscripts/footnote numbers were appropriately matched. Edits were 
made to clarify that China may also use local laboratory result (urine drug 
test) for screening as it is not available at the China central laboratory. 
Edits were made to clarify that there were no requirements to Ip and 
nucleos(t)ide dosing order. Edits were made to correct the table 
numbering. Edits were made to correct Table 20, as it was missing a 
column. Edits were made to correct typos.
 
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List of Changes
Overall Design, 5th paragraph
Rationale: To make edits for clarity- to better clarify that treatment selections were 
made for Part 2 based on data from Part 1
Original text:
Part 1 (through Day 3). The treatments selected are 60 mg GSK3389404 weekly, 120 mg 
GSK3389404 bi-weekly, 120 mg GSK3389404 weekly or placebo.
Amended text: 
Part 1 (through Day 3). The treatments that were selected for Part 2 based on data 
from Part 1 are 60 mg GSK3389404 weekly, 120 mg GSK3389404 bi-weekly, 120 mg 
GSK3389404 weekly or placebo.
Treatment Arms and Duration, Part 1, 1st bullet
Rationale: To correct the planned study duration
Original text:

A 30-day screening window is planned
Amended text: 

A 30-day screening window is planned
o
Eligible subjects who fall within a 45-day window (15 days exceeding 
the 30-day screening window) should undergo a brief physical exam, 
review of medical history, and review of concomitant medications to 
confirm eligibility.
Treatment Arms and Duration, Part 2, 1st sentence
Rationale: To correct the planned study duration
Original text:
In Part 2, 60 mg GSK3389404 weekly, 120 mg GSK3389404 bi-weekly, 120 mg 
GSK3389404 weekly or placebo are planned and the total study duration, including 
screening, dosing, and post-treatment follow-up, is not expected to exceed 65 weeks for 
each subject. 
Amended text: 
In Part 2, 60 mg GSK3389404 weekly, 120 mg GSK3389404 bi-weekly, 120 mg 
GSK3389404 weekly or placebo are planned and the total study duration, including 
screening, dosing, and post-treatment follow-up, is not expected to exceed 6571 weeks 
for each subject. 
Treatment Arms and Duration, Part 2, 1st bullet
Rationale: To correct the planned study duration
 
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Original text:

A 30-day screening window is planned
Amended text: 

A 30-day screening window is planned
o
Eligible subjects who fall within a 45-day window (15 days exceeding 
the 30-day screening window) should undergo a brief physical exam, 
review of medical history, and review of concomitant medications to 
confirm eligibility.
Treatment Arms and Duration, Part 2, 3rd bullet
Rationale: To differentiate between final follow up visits Day 169 or Day 450 (if subjects 
consent to the optional extended follow-up period)
Original text:

A post-treatment follow-up period is planned where subjects will present for 
study visits on Days 85, 92, 99, 113, 141, and 169.
Amended text: 

A protocol mandated post-treatment follow-up period is planned where 
subjects will present for study visits on Days 85, 92, 99, 113, 141, and 169.
Type and Number of Subjects, 1st paragraph, last sentence
Rationale: To provide clarity- to allow for possibility that sites may not be able to recruit 
HBeAg-positive or negative subjects
Original text:
For Part 2, both HBeAg-positive and HBeAg-negative subjects will be enrolled.
Amended text: 
For Part 2, both HBeAg-positive and/or HBeAg-negative subjects will be enrolled.
Type and Number of Subjects, 1st bullet point
Rationale: To make edits for clarity- to make clear that 12 subjects were enrolled for the 
completed Part 1 of study 205670
Original text:

In Part 1, approximately 20 to 40 subjects with CHB were planned for 
randomization (30 GSK3389404 and 10 placebo under older protocol versions 
versus 15 GSK3389404 and 5 placebo under amendment 3). A range was 
provided because different countries and sites may have enrolled under the 
older versions of the protocol. Twelve subjects were enrolled for part 1 and 
Part 1 has completed enrollment.
Amended text: 

In Part 1, twelve subjects were enrolled. Originally approximately 20 to 
 
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40 subjects with CHB were planned for randomization (30 GSK3389404 and 
10 placebo under older protocol versions versus 15 GSK3389404 and 
5 placebo under amendment 3). A range was provided because different 
countries and sites may have enrolled under the older versions of the protocol. 
Twelve subjects were enrolled for part 1 and Part 1 has completed enrollment.
Section 4.2 Treatment Arms and Duration, 4th paragraph
Rationale: To correct the planned study duration
Original text:
In Part 2, the total study duration, including screening, treatment and post-treatment 
follow-up, is not expected to exceed 65 weeks for each subject (Figure 4 and Figure 5).
Amended text: 
In Part 2, the total study duration, including screening, (and the 15 day window 
exceeding the normal 30 day screening window), treatment and post-treatment follow-
up, is not expected to exceed 6571 weeks for each subject (Figure 4 and Figure 5).
Section 4.2 Treatment Arms and Duration, Figure 4
Rationale: To correct the planned study duration (please note that the figure was 
amended, but a ‘strike-through’ figure was not included in the amended text)
Original text:
Amended text: 
 
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Section 4.2 Treatment Arms and Duration, Figure 5
Rationale: To correct the planned study duration (please note that the figure was 
amended, but a ‘strike-through’ figure was not included in the amended text)
Original text:
Amended text: 
 
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Section 4.3 Type and Number of Subjects, 1st paragraph, last sentence
Rationale: To provide clarity- to allow for possibility that sites may not be able to recruit 
HBeAg-positive or negative subjects
Original text:
For Part 2, both HBeAg-positive and HBeAg-negative subjects will be enrolled.
Amended text: 
For Part 2, both HBeAg-positive and/or HBeAg-negative subjects will be enrolled.
Section 4.3 Type and Number of Subjects, 2nd paragraph, 1st bullet
Rationale: To make edits for clarity- to make clear that 12 subjects were enrolled for the 
completed Part 1 of study 205670
Original text:

In Part 1, approximately 20 to 40 subjects with CHB were planned for 
randomization (30 GSK3389404 and 10 placebo under older protocol versions 
versus 15 GSK3389404 and 5 placebo under amendment 3). A range was 
provided because different countries and sites may have enrolled under the 
older versions of the protocol. Twelve subjects were enrolled for part 1 and 
Part 1 has completed enrollment.
Amended text: 

In Part 1, twelve subjects were enrolled. Originally approximately 20 to 
40 subjects with CHB were planned for randomization (30 GSK3389404 and 
10 placebo under older protocol versions versus 15 GSK3389404 and 
5 placebo under amendment 3). A range was provided because different 
countries and sites may have enrolled under the older versions of the protocol. 
Twelve subjects were enrolled for part 1 and Part 1 has completed enrollment.
 
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Section 4.3 Type and Number of Subjects, 2nd paragraph, 2nd bullet
Rationale: To make edits for clarity- the deleted section was a clerical error that should 
have been deleted in the previous amendment
Original text:

In Part 2, approximately 39 subjects with CHB are planned for randomization
to study treatment. Enrolling approximately 39 subjects will ensure enough 
power for Part 2 with or without the optional Japanese Part 2 sub-study and 
allow for an approximate a overall drop-out rate, so that there are 11 subjects in 
each active treatment group and 6 subjects in placebo without the optional 
Japanese Part 2 sub-study for the primary analysis.
Amended text: 

In Part 2, approximately 39 subjects with CHB are planned for randomization 
to study treatment. There are approximately 11 subjects in each of the active 
treatment groups and approximately 6 subjects in the placebo group.


In Part 2, approximately 39 subjects with CHB are planned for randomization 
to study treatment. Enrolling approximately 39 subjects will ensure enough 
power for Part 2 with or without the optional Japanese Part 2 sub-study and 
allow for an approximate a overall drop-out rate, so that tThere are 
approximately 11 subjects in each active of the active treatment groups and 
6 subjects in placebo without the optional Japanese Part 2 sub-study for the 
primary analysis.
Section 4.5.4 Dose Escalation Justification, 1st paragraph
Rationale: To make edits for clarity- to correct the units of the NOAEL in the 13- and 39-
week monkey toxicity study. This does not affect the Cmax/AUC calculations for the 
NOAEL
Original text:
the NOAEL of 30 mg/kg/day in the 13-week monkey toxicity study (Cmax = 52.7
g/mL; AUC(0-) = 492.7 gh/mL) and 
the NOAEL of 2 mg/kg/day in the 39-week monkey toxicity study 
(Cmax = 2.9 g/mL; AUC(0-) = 13.5 gh/mL). 
Amended text: 
the NOAEL of 30 mg/kg/dayweek in the 13-week monkey toxicity study 
(Cmax = 52.7 g/mL; AUC(0-) = 492.7 gh/mL) and 
the NOAEL of 2 mg/kg/ dayweek in the 39-week monkey toxicity study (gender 
averaged; Cmax = 2.9 g/mL; AUC(0-) = 13.5 gh/mL).
Section 4.6.1 Risk Assessment, Table 4, Liver Effects, Impact-eligibility criteria, 2nd
paragraph
Rationale: To make edits for clarity
 
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Original text:
Subjects with liver cirrhosis or evidence of cirrhosis (Section 5.2, exclusion criterion 4
Amended text: 
Subjects with liver cirrhosis or evidence of cirrhosis are excluded (Section 5.2, exclusion 
criterion 4
Section 4.6.1 Risk Assessment, Table 4, Coagulation Effects, Potential 
Risk/Summary of Data, last paragraph
Rationale: To make edits for clarity- typo
Original text:
In Study 202007, the GSK 3389404 Phase 1 study in healthy subjects, there was no 
evidence of GSK3389404 related prolongation of aPPT.
Amended text: 
In Study 202007, the GSK 3389404 Phase 1 study in healthy subjects, there was no 
evidence of GSK3389404 related prolongation of aPPTaPTT.
Section 4.6.1 Risk Assessment, Table 4, Kidney Effects, Impact- Eligibility Criteria 
2nd paragraph, last sentence
Rationale: To add greater clarity for exclusion criteria- ACR unit
Original text:
Subjects with serum creatinine >ULN, glomerular filtration rate (GFR) <90 mL/min (but 
60 ml/min may be considered after consultation with the GSK medical monitor), or 
urine albumin to creatinine ratio (ACR) 0.03 mg/mg are excluded (Section 5.2, 
exclusion criteria 8e, 8f, and 8g).
Amended text: 
Subjects with serum creatinine >ULN, glomerular filtration rate (GFR) <90 mL/min (but 
60 ml/min may be considered after consultation with the GSK medical monitor), or 
urine albumin to creatinine ratio (ACR) 0.03 mg/mg (or 30 mg/g) are excluded 
(Section 5.2, exclusion criteria 8e, 8f, and 8g).
Section 4.6.1 Risk Assessment, Table 4, Kidney Effects, Strategy, Stopping Criteria, 
1st bullet point
Rationale: To add greater clarity for exclusion criteria- ACR unit
Original text:
Persistent urine ACR 0.03 mg/mg (or 30 mg/g). and without alternative cause(s) 
identified.
Amended text: 
 
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•
Persistent urine ACR 0.03 mg/mg (or 30 mg/g). and without alternative 
cause(s) identified.
Section 4.6.2 Benefit Risk Summary, #7
Rationale: To differentiate between final follow up visits Day 169 or Day 450 (if subjects 
consent to the optional extended follow-up period)
Original text:
7. In Part 2, subjects are seen at the clinic on a weekly basis and safety assessments 
(AE/serious adverse event [SAE] review, physical exam, vital signs, ECG 
assessments) and comprehensive laboratory testing subjects is performed on a weekly 
or bi-weekly (every 2 weeks) basis. At the end of the 3-month treatment exposure 
period, subjects have follow-up to 12 weeks to assess safety with an optional 
extended follow up to 48 weeks. 
Amended text: 
7. In Part 2, subjects are seen at the clinic on a weekly basis and safety assessments 
(AE/serious adverse event [SAE] review, physical exam, vital signs, ECG 
assessments) and comprehensive laboratory testing subjects is performed on a 
weekly or bi-weekly (every 2 weeks) basis. At the end of the 3-month treatment 
exposure period, subjects will continue to have regular assessments during the 
post treatment follow-up period to 12 weeks to assess safety with an optional 
extended follow up to 48 weeks. 
Section 5.1 Inclusion Criteria, #9b
Rationale: After feedback from investigators, the inclusion criterion 9b was changed to 
allow ALT 2XULN. This change was supported by feedback that factors other than 
HBV may contribute to slightly elevated ALT levels in subjects
Original text:
b.
ALT ULN for subjects who are receiving stable nucleos(t)ide analogue therapy
Amended text: 
b.
ALT 2 X ULN for subjects who are receiving stable nucleos(t)ide analogue 
therapy
Section 5.2 Exclusion Criteria, #4d
Rationale: to add greater clarity- after feedback from investigators, the exclusion criterion 
4 was edited to include exclusion of subjects who the investigator believes may have liver 
cirrhosis without requiring a positive liver biopsy, Fibroscan, and/or APRI/Fibrosure 
result to exclude the subject
Original text:
N/A
Amended text: 
 
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d. investigator judgmenet
Section 5.2 Exclusion Criteria, #8g
Rationale: to add greater clarity- sites may use an online calculator that converts the ACR 
to mg/g instead of mg/mg and to clarify situations where subjects have both low urine 
albumin and low urine creatinine
Original text:
g. Urine albumin to creatinine ratio (ACR) ≥0.03 mg/mg. In the event of an ACR 
above this threshold, eligibility may be confirmed by a second measurement 
Amended text: 
g. 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 subjects 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 
patient does not have a history of diabetes, hypertension or 
other risk factors that may affect renal function and discuss 
with the PPD or GSK medical monitor, or designee
Section 5.2 Exclusion Criteria, #10
Rationale: to add greater clarity
Original text:
10.Fridericia’s QT correction formula (QTcF) ≥450 msec (mean of triplicate 
measurements).
Amended text: 
10. Fridericia’s QT correction formula (QTcF) ≥450 msec (if single ECG at screening 
shows QTcF 450 msec, a mean of triplicate measurements should be used to 
confirm that subject meets exclusion criterion).
Section 5.2 Exclusion Criteria, #11
Rationale: to add greater clarity- some subjects use topical or inhaled corticosteroids, 
which would not result in the immunosuppressing effects
Original text:
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)
Amended text: 
 
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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
Section 5.2 Exclusion Criteria, #13
Rationale: to make clear that this exclusion criteria is in reference to illicit drug/substance 
dependency
Original text:
13. A positive pre-study treatment screen or an unwillingness to refrain from use of the 
illicit drugs and adhere to other protocol-stated restrictions while participating in the 
study. 
Amended text:
13. A positive pre-study treatment screen and or an unwillingness to refrain from use of 
the illicit drugs (or substances with abuse potential) and adhere to other protocol-stated 
restrictions while participating in the study. [The screen refers to illicit drugs and 
substances with abuse potential. Medications that are used by the patient as 
directed, whether over-the-counter or through prescription, are acceptable and 
would not meet the exclusion criteria]
Section 5.4 Withdrawal/Stopping Criteria, 1st paragraph
Rationale: To provide next steps for determining follow-up visit schedules for subjects 
who meet treatment stopping criteria, but are not withdrawn from the study
Original text:
Subjects who are discontinued from study treatment will enter the post-treatment follow-
up period unless consent is withdrawn.
Amended text: 
Subjects who are discontinued from study treatment will enter the post-treatment follow-
up period (please submit an electronic protocol inquiry platform [EPIP] query 
(either site or clinical research associate [CRA] may submit) to receive post-
treatment follow up dates for subjects who discontinue study treatment) unless 
consent is withdrawn.
Section 5.4.1 Liver Chemistry Stoping Criteria, 3rd paragraph, 1st sentence
Rationale: For clarity, to align with changes in ALT criteria
Original text:
Eligible subjects in Part 1 may have an elevated ALT at screening as specified in Section 
5.1.
 
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Amended text: 
Eligible subjects in Part 1 and Part 2 may have an elevated ALT at screening as 
specified in Section 5.1.
Section 5.4.1 Liver Chemistry Stoping Criteria, 4th paragraph, last sentence
Rationale: To provide next steps for determining follow-up visit schedules for subjects 
who meet treatment stopping criteria, but are not withdrawn from the study
Original text:
The subject must then attend the Follow-up visits specified in the Time and Events Table
Amended text: 
The subject must then attend the Follow-up visits specified in the Time and Events Table
Please submit an EPIP query (either site or CRA may submit) to receive post-treatment 
follow up dates for subjects who discontinue study treatment
Section 5.4.2 QTc Stopping criteria, last sentence
Rationale: To provide next steps for determining follow-up visit schedules for subjects 
who meet treatment stopping criteria, but are not withdrawn from the study
Original text:
If a single ECG measurement demonstrates a prolonged QTcF interval, the ECG should 
be repeated 2 more times and the average of the 3 QTcF values used to determine 
whether the subject should be discontinued from the study.
Amended text: 
Discontinuation of subjects will be based on average QTcF from triplicate ECGs. If a 
single ECG measurement demonstrates a prolonged QTcF interval, the ECG should be 
repeated 2 more times and the average of the 3 QTcF values used to determine whether 
the subject should be discontinued from the study treatment. Please submit an EPIP 
query (either site or CRA may submit) to receive post-treatment follow up dates for 
subjects who discontinue study treatment
Section 5.4.3 Hematological Stopping Criteria last sentence
Rationale: To provide next steps for determining follow-up visit schedules for subjects 
who meet treatment stopping criteria, but are not withdrawn from the study
Original text:
N/A
Amended text: 
Please submit an EPIP query (either site or CRA may submit) to receive post-
treatment follow up dates for subjects who discontinue study treatment
Section 5.4.4 Renal Stopping Criteria, 1st bullet point
Rationale: To provide greater clarity on exclusion criteria- ACR units
 
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Original text:
•
Persistent urine ACR 0.03 mg/mg and without alternative cause(s) identified
Amended text: 
•
Persistent urine ACR 0.03 mg/mg (30 mg/g) and without alternative cause(s) 
identified
Section 5.4.5 Pharmacokinetic Stopping Criteria, 1st paragraph
Rationale: to make edits for clarity- to correct the units of the NOAEL in the 13-week 
monkey toxicity study were written as the NOAEL of 30 mg/kg/day, when it should be 
mg/kg/week
Original text:
Part 1: Doses will be escalated such that the predicted mean plasma exposure at the next 
dose level will not exceed the mean plasma AUC(0-∞) and Cmax observed at the 
NOAEL dose of 30 mg/kg/day in the 13 week monkey toxicity study (AUC(0 ∞) = 492.7 
mg•h/mL and Cmax = 52.7 mg/mL).
Amended text: 
Part 1: Doses will be escalated such that the predicted mean plasma exposure at the next 
dose level will not exceed the mean plasma AUC(0-∞) and Cmax observed at the 
NOAEL dose of 30 mg/kg/dayweek in the 13 week monkey toxicity study (AUC(0-∞) = 
492.7 mg•h/mL and Cmax = 52.7 mg/mL).
Section 6.1 Investigational Product and Other Study Treatment, Table 6
Rationale: To make edits for clarity- for consistency with other sections/source document 
wording
Original text:
Unit Dose Strength(s)/Dosage 
Level(s):
100 mg/mL; 1.0 mL nominal 
volume per vial (0.25 mL 
overfill per vial)
Placebo 
Amended text:
Unit Dose Strength(s)/Dosage 
Level(s):
100 mg/mL; 1.0 mL nominal 
volume per vial (0.25mL 
minimal overfill per vial)
Placebo 
Section 6.1 Investigational Product and Other Study Treatment, Table 6
Rationale: to make edits for clarity- to remove the word “pharmacy” for dispensing 
investigational product (IP; GSK3389404 or placebo), not all sites use a formal pharmacy 
to dispense IP
Original text:
 
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Method for Individualizing 
Dosage:
Dispensing into syringes in 
pharmacy
Dispensing into syringes in 
pharmacy
Amended text: 
Method for Individualizing 
Dosage:
Dispensing into syringes in 
pharmacy
Dispensing into syringes in 
pharmacy
Section 6.5 Blinding, 4th bullet
Rationale: To update the unblinded senior management review
Original text:

Management review of unblinded efficacy data is planned for both parts of the 
study. For part 1, the review provides early information on potential efficacious 
dose and dose frequency including the need for dose escalation. For part 2, the 
review will facilitate internal governance decision making on project progress and 
trigger futher studies. Unblinded efficacy data may be provided to the following 
management/function as required: Senior VP of Infectious Disease Therapy Area, 
Head Unit Physician, Project Statistician, Head of ID Statistics/Programming, 
Director of Clinical Pharmacology, Safety Evaluation and Risk Management, 
Global Regulatory Lead, Project Physician Lead, Clinical Investigator Lead,
Clinical Development Manager,Global Marketing Director
Amended text: 

Senior management review of unblinded efficacy data is planned for both parts of 
the study (this includes the Japanese optional sub-study). For part 1, the review 
provides early information on potential efficacious dose and dose frequency 
including the need for dose escalation. For part 2, the review will facilitate 
internal governance decision making on project progress and trigger futher 
studies. Unblinded efficacy data may be provided to the following 
management/function as required: Senior VP of Infectious Disease Therapy Area, 
Head Unit Physician, Project Statistician, Head of ID Statistics/Programming, 
Director of Clinical Pharmacology, Safety Evaluation and Risk Management, 
Global Regulatory Lead, Project Physician Lead, Clinical Investigator Lead,
Clinical Development Manager,Global Marketing Director
Section 6.5 Blinding, 5th bullet
Rationale: To update the unblinded senior management review
Original text:
•
The frequency of management review in Part 2 will be synchronized with 
monthly blinded SRT review of the study. The management review of the Part 1 data will 
occur as required for decision making.
Amended text: 

The frequency of management review in Part 2 will be synchronized with monthly 
blinded SRT review of the study as appropriate. The management review of the 
Part 12 data will occur as required for decision making.
 
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Section 6.12.1 Permitted Medications and Non-Drug Therapies, 3rd paragraph
Rationale: To make edits for clarity
Original text: 
N/A
Amended text:
If patients are receiving nucleos(t)ide therapy, administration of the nucleos(t)ide 
should continue unchanged unless directed by the physician. There are no 
requirements with regards to the timing of the administration of nucleos(t)ide agent 
in relation to the study medicine.
Section 6.12.1 Permitted Medications and Non-Drug Therapies, 5th paragraph
Rationale: To make edits for clarity
Original text:
Traditional Chinese medicine (TCM) and/or acupuncture should be avoided during the 
duration of the study. However, if subjects report use of TCM and/or acupuncture, then 
details must be recorded in the concomitant medication CRF. 
Amended text: 
Traditional Chinese medicine (TCM) and/or acupuncture as it relates to CHB therapy
should be avoided during the duration of the study. However, If subjects report use of 
TCM and/or acupuncture, then details must be recorded in the concomitant medication 
CRF. 
Section 6.12.2 Prohibited Medications and Non-Drug Therapies, 1st sentence
Rationale: To make edits for clarity
Original text:
The following concomitant medications are not permitted during Part 1 and Part 2
Amended text: 
The following concomitant medications are not permitted during Part 1 and Part 2 (until 
Day 169 unless indicated otherwise)
Section 6.12.2 Prohibited Medications and Non-Drug Therapies, 3rd bullet
Rationale: To make edits for clarity
Original text:

Non-GSK -oligonucleotide or siRNA from 12 months prior to Day 1 through the 
final Follow-up visit or prior treatment with a GSK oligonucleotide from 3 months 
 
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prior to Day 1 through the final Follow-up visit (see Exclusion Criterion 16, 
Section 5.2).
Amended text:

Non-GSK -oligonucleotide or siRNA from 12 months prior to Day 1 through the 
final Follow-up visit or prior treatment with a GSK oligonucleotide from 3 months 
prior to Day 1 through the final Follow-up visit (includes optional follow-up period 
if applicable; see Exclusion Criterion 16, Section 5.2).
Section 7.1 Time and Events Table, Table 8
Rationale: To correct the planned study duration for the subjects- it did not include the 
screening window period of 30 days (+15 days exceeding the 30 day screening window)
; (please note for table, only sections effected will be shown, not the whole table)
Original text:
Assessment
Screening 
(Up to 30 days 
Prior to Day 1)
Amended text: 
Assessment
Screening 
(Up to 30 days 
Prior to Day 1)*
* Eligible subjects who exceed the regular 30-day screening window by 15 days (total 45 days) should undergo 
a brief physical exam, review of medical history, and review of concomitant medications to confirm eligibility
Section 7.1 Time and Events Table, Footnote 3 (Table 11 and 13) or Footnote 1 
(Table 12, 14, and 15)
Rationale: To provide clarity
Original text:
Footnote. Adverse events will be collected from the time of first dose of study treatment 
and until the final Follow-up visit. However, any SAEs assessed as related to study 
participation (e.g., protocol mandated procedures or invasive tests) or related to 
GSK3389404 will be recorded from the time a subject consents to participate in the study 
up to and including any Follow-up visit. All AEs and SAEs will be graded based on the 
DAIDS table or supplemental criteria as defined in Appendix 3 (Section 12.3.5.1).
Amended text:
Footnote. Adverse events will be collected from the time of first dose of study treatment 
and until the final Follow-up visit. However, any SAEs, including those assessed as 
related to study participation (e.g., protocol mandated procedures or invasive tests) or 
related to GSK3389404 will be recorded from the time a subject consents to participate in 
the study up to and including any Follow-up visit. All AEs and SAEs will be graded 
based on the DAIDS table or supplemental criteria as defined in Appendix 3 (Section 
12.3.5.1).
Section 7.1 Time and Events Table, Table 11 and Table 13
 
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Rationale: To make edits for clarity- to make clear that only subjects of reproductive 
potential should undergo pregnancy testing; (please note for table, only sections effected 
will be shown, not the whole table)
Original text:
Footnote 8. Female subjects at screening: serum hCG pregnancy test; all other time points 
serum hCG or urine pregnancy test. (Confirm subject is not pregnant with either serum 
hCG or urine pregnancy test prior to dosing.)
Amended text:
Footnote 8. Female subjects at screening: serum hCG pregnancy test; all other time points 
for females of reproductive potential: serum hCG or urine pregnancy test. (Confirm 
subject is not pregnant with either serum hCG or urine pregnancy test prior to dosing.)
Section 7.1 Time and Events Table, Table 15
Rationale: to update the Time and Events Table for the optional follow-up period
Original text:
Day 270
(7 days)
Day 360 
(7 days)
Day 450 
(7 days)
ET
Outpatient visit
X
X
X
X
Safety Assessments
AE/SAE review1
Continuous
X
Concomitant medication review
Continuous
X
Brief physical exam
X
X
X
X
Vital signs2
X
X
X
X
Laboratory Assessments4
Pregnancy test (as appropriate)5
X
X
Hematology/Chemistry/Urinalysis6
X
X
X
X
Urine ACR5,6
X
X
X
X
Complement (C3/C4)
X
X
X
X
PT, INR, aPTT
X
X
X
X
hs-CRP
X
X
X
X
Archived serum and plasma samples7
X
X
X
X
HBsAg and HBV DNA
X
X
X
X
HBeAg8
X
X
X
X
HBV genotype/phenotype9
X
X
X
X
HBsAb
X
X
X
X
Meal10
X
X
X
X
1.Adverse events will be collected from the time of first dose of study treatment and until the final Follow-up 
visit. However, any SAEs assessed as related to study participation (e.g., protocol-mandated procedures 
or invasive tests) or related to GSK3389404 will be recorded from the time a subject consents to 
participate in the study up to and including any Follow-up visit. All AEs and SAEs will be graded based on 
the DAIDS table or supplemental criteria as defined in Appendix 3 (Section 12.3.5.1).
2.Temperature and respiration rate (single measurement); blood pressure and heart rate (single measurement 
after 5 minutes of rest in the semi-supine or supine position).
3.Samples for clinical laboratory tests to be collected after vital sign and ECG assessments.
4.Female subjects of reproductive potential: serum hCG or urine pregnancy test.
5.The study site may collect and divide urine sample for urinalysis test and ACR (first void) assessment.
 
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6.Collect first morning urine void sample for ACR assessment. For outpatient visits, subjects will be given a 
clean urine collection cup and instructed to collect and bring in a first morning urine void sample on the 
day of their outpatient visit.
7.Archived serum and plasma samples for exploratory biomarker analyses. Complement C5a and Bb as well 
as HBV RNA, HBcrAg, and/or IDO may be analyzed from the archived samples.
8.HBeAg-positive subjects only.
9.HBV genotype/phenotype samples to be stored and analyzed per sponsor’s discretion. Samples will be used 
to assess for changes in HBV genotype/phenotype from baseline, HBsAg nadir, and/or final Follow-up 
visit. 
10. Subjects will be offered a meal (e.g., bagged or canteen [or reimbursed]) after completion of all study 
procedures.
Amended text: 
Day 270
(7 days)
Day 360 
(7 days)
Day 450 
(7 days)
ET
Outpatient visit
X
X
X
X
Safety Assessments
AE/SAE review1
Continuous
X
Concomitant medication review
Continuous
X
Brief physical exam
X
X
X
X
Vital signs2
X
X
X
X
Laboratory Assessments4
Pregnancy test (as appropriate)5
X
X
Hematology/Chemistry/Urinalysis6
X
X
X
X
Urine ACR5,6
X
X
X
X
Complement (C3/C4)
X
X
X
X
PT, INR, aPTT
X
X
X
X
hs-CRP
X
X
X
X
Archived serum and plasma samples72
X
X
X
X
HBsAg and HBV DNA
X
X
X
X
HBeAg83
X
X
X
X
HBV genotype/phenotype94
X
X
X
X
HBsAb
X
X
X
X
Meal105
X
X
X
X
1.Adverse events will be collected from the time of first dose of study treatment and until the final Follow-up 
visit. However, any SAEs assessed as related to study participation (e.g., protocol-mandated procedures 
or invasive tests) or related to GSK3389404 will be recorded from the time a subject consents to 
participate in the study up to and including any Follow-up visit. All AEs and SAEs will be graded based on 
the DAIDS table or supplemental criteria as defined in Appendix 3 (Section 12.3.5.1).
2.Temperature and respiration rate (single measurement); blood pressure and heart rate (single measurement 
after 5 minutes of rest in the semi-supine or supine position).
3.Samples for clinical laboratory tests to be collected after vital sign and ECG assessments.
4.Female subjects of reproductive potential: serum hCG or urine pregnancy test.
5.The study site may collect and divide urine sample for urinalysis test and ACR (first void) assessment.
6.Collect first morning urine void sample for ACR assessment. For outpatient visits, subjects will be given a 
clean urine collection cup and instructed to collect and bring in a first morning urine void sample on the 
day of their outpatient visit.
72.Archived serum and plasma samples for exploratory biomarker analyses. Complement C5a and Bb as 
well as HBV RNA, HBcrAg, and/or IDO may be analyzed from the archived samples.
83.HBeAg-positive subjects only.
 
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94. HBV genotype/phenotype samples to be stored and analyzed per sponsor’s discretion. Samples will 
be used to assess for changes in HBV genotype/phenotype from baseline, HBsAg nadir, and/or final 
Follow-up visit. 
105.Subjects will be offered a meal (e.g., bagged or canteen [or reimbursed]) after completion of all study 
procedures.
Section 7.3.1.1 Time Period and Frequency for Collecting AE and SAE information, 
1st bullet
Rationale: To provide clarity
Original text:
•
Any SAEs assessed as related to study participation (e.g., protocol-mandated 
procedures, invasive tests, or change in existing therapy) or related to a GSK product, 
will be recorded from the time a subject consents to participate in the study up to and 
including any follow-up contact.
Amended text: 
•
Any SAEs, including those assessed as related to study participation (e.g., 
protocol-mandated procedures, invasive tests, or change in existing therapy) or related to 
a GSK product, will be recorded from the time a subject consents to participate in the 
study up to and including any follow-up contact.
Section 7.3.1.3 Follow-up of AEs and SAEs
Rationale: To provide next steps for determining follow-up visit schedules for subjects 
who meet treatment stopping criteria, but are not withdrawn from the study
Original text:
After the initial AE/SAE report, the investigator is required to proactively follow each 
subject at subsequent visits/contacts. All SAEs, and non-serious AEs of special interest 
(as defined in Section 4.6.1) will be followed until resolution, until the condition 
stabilizes, until the event is otherwise explained, or until the subject is lost to follow-up 
(as defined in Section 5.4). Further information on follow-up procedures is given in 
Appendix 3 (Section 12.3.5.4).
Amended text: 
After the initial AE/SAE report, the investigator is required to proactively follow each 
subject at subsequent visits/contacts. All SAEs, and non-serious AEs of special interest 
(as defined in Section 4.6.1) will be followed until resolution, until the condition 
stabilizes, until the event is otherwise explained, or until the subject is lost to follow-up 
(as defined in Section 5.4). After the SAE or AE are followed until resolution or 
stabilization or event is otherwise explained, the subject will enter into the post-
treatment follow up. The exact schedule for post-treatment follow up for those 
subjects who withdraw study treatment early should be confirmed with the GSK 
team. Further information on follow-up procedures is given in Appendix 3 (Section 
12.3.5.4).
Section 7.3.2 Pregnancy, 1st bullet
 
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Rationale: To provide clarity- To differentiate between final follow up visits Day 169 or 
Day 450 (if subjects consent to the optional extended follow-up period)
Original text:
Details of all pregnancies in female subjects and if indicated female partners of 
male subjects will be collected after the start of dosing and until the final 
specified Follow-up visit
Amended text: 

Details of all pregnancies in female subjects and if indicated female partners of 
male subjects will be collected after the start of dosing and until the final specified 
Follow-up visit (includes the optional follow-up period for Part 2).
Section 7.3.7 Clinical Safety Laboratory Assessments, 2nd bullet
Rationale: to clarify that China may also use local laboratory result (urine drug test) for 
screening as it is not available at the China central laboratory
Original text:
N/A
Amended text: 

For China, urine drug screen. The results of each test must be entered into 
the CRF.
Section 7.3.7 Protocol Required Safety Laboratory Assessments, Table 16, Other 
screening and/or follow-up tests
Rationale: To provide edits for clarity- genotype/phenotype testing is separate from 
HBeAg testing
Original text:

Viral genotype HBeAg positive or HBeAg negative
Amended text: 

Viral genotype/phenotype

HBeAg positive or HBeAg negative)
Section 12.1 Appendix 1 Abbreviations
Rationale: To make edits for clarity
Original text:
N/A
Amended text: 
CRA
Clinical Research Associate
EPIP
Electronic Protocol Inquiry Platform
Section 12.3.5.3 Toxicity Management, Anemia, Grade 2
Rationale: Edits for clarity-
 
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Original text:
1. peripheral blood smear
10. indirect bilirubin
(abnormal if increased > 50% from baseline)
11. haptoglobin
(abnormal if 25 mg/dL)
12. reticulocyte count
(abnormal if 4%) 
Amended text:
1. peripheral blood smear
102. indirect bilirubin
(abnormal if increased > 50% from baseline)
113. haptoglobin
(abnormal if 25 mg/dL)
124. reticulocyte count
(abnormal if 4%) 
Section 12.4.1, 1st paragraph, last sentence
Rationale: To differentiate between final follow up visits Day 169 or Day 450 (if subjects 
consent to the optional extended follow-up period)
Original text:
Male subjects with female partners of child bearing potential and female subjects of child 
bearing potential must comply with the following contraception requirements from either 
the time of first dose of study treatment (male) or from at least 28 days prior to the first 
dose of study treatment (FRP) until the final Follow-up visit.
Amended text: 
Male subjects with female partners of child bearing potential and female subjects of child 
bearing potential must comply with the following contraception requirements from either 
the time of first dose of study treatment (male) or from at least 28 days prior to the first 
dose of study treatment (FRP) until the final Follow-up visit Day 169.
Section 12.6.5 Simulations, 3rd paragraph
Rationale: To make edits for clarity
Original text:
Simulation results for all scenarios are summarized in Table 19 toTable 27
Amended text: 
Simulation results for all scenarios are summarized in Table 19 to Table 2722
Section 12.6.5 Simulations, Table 20
Rationale: To make edits for clarity
Original text:
Scenario 2
 
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Amended text: 
Treatment
Posterior 
RR (%)
PBO
6.82
240W
30.93
240BM
30.09
480W
30
PBO
6.95
240W
30.38
240BW
29.88
480W
29.77
Scenario 2
Treatment
Posterior 
RR (%)
Pairwise
PBO
6.82
240W
30.93
240BM
30.09
480W
30
BLRM
PBO
6.95
240W
30.38
240BW
29.88
480W
29.77
 
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