Conditions: Amyloidosis
Keywords: GSK3039294 GSK2315698 systemic amyloidosis CPHPC dose-escalation
Allocation: NON_RANDOMIZED | Intervention model: PARALLEL
Enrollment: 23
Healthy volunteers: yes

Brief summary:
GSK3039294 has been developed in order to offer an orally available alternative to parenteral CPHPC (GSK2315698 \[metabolite of GSK3039294\]) for plasma serum amyloid P component (SAP) depletion prior to use of anti SAP monoclonal antibody (mAb) in the treatment of systemic amyloidosis. This phase 1 study is intended to study safety, tolerability and pharmacokinetic (PK) profile of GSK3039294 in humans. This study consists of three parts. Part A will evaluate safety and tolerability of single doses of GSK3039294 in healthy subjects, Part B will evaluate safety and tolerability of repeat doses of GSK3039294 in healthy subjects, and Part C will evaluate safety and tolerability of repeat doses of GSK3039294 in subjects with systemic amyloidosis. Part A is a single dose, open label, dose escalation study. Two cohorts of subjects will be enrolled to provide data from 6 subjects per cohort and up to 4 different doses (2 dose levels per cohort) of GSK3039294 will be tested. For Cohorts 1 and 2, each subject may take part in two dosing periods. Part B is repeat dose, open label, dose escalation study. Sufficient number of subjects will be enrolled in Cohort 3a to ensure 6 completers (Cohort 3b will be conducted if required) and GSK3039294 will be administered repeatedly for a total of 21 days. Each subject will take part in a single study period. In Part C a single dose level of GSK3039294 will be tested for 21 days repeat dose, in 12 subjects with systemic amyloidosis. Each subject will take part in a single study period. The total duration for Part A is approximately 8 weeks, Part B is approximately 8-9 weeks, and Part C is approximately 13 weeks.

Detailed description:

Arms:
arm 1: Subjects will receive a single dose of GSK3039294 (Dose level 1) on Day 1 and will remain in-house until Day 4. Wash-out will take place from Day 5 to Day 14. Subjects will receive Dose level 2 on Day 15 (Period 2). arm 2: Subjects will receive a single dose of GSK3039294 (Dose level 3) on Day 1 and will remain in-house until Day 4. Wash-out will take place from Day 5 to Day 14. Subjects will receive Dose level 4 on Day 15 (Period 2). arm 3: Subjects will receive repeat dosing of GSK3039294 for a total of 21 days. The dose will be escalated every week throughout the study duration. Subjects will first receive a low dose given once daily. After 7 days, if well tolerated, the total daily dose will be increased and, GSK3039294 will be given, for example, as twice daily dosing for 7 days. At the end of this 7 day period and if previous dosing was well tolerated, the dose will be increased to a maximum daily dose that will not exceed pre-clinical safety exposure limits. On Day 4 and 5 GSK3039294 will be administered under fasted and fed conditions, respectively, to investigate the food effect on the PK. arm 4: Subjects will be enrolled in Cohort 3b only if required for further investigation. Subjects will receive GSK3039294 for 21 consecutive days and more than one dose level or regimen may be investigated, for example on the first 10 days the dose may be administered thrice daily, and on the last 11 days may be administered twice daily. arm 5: Subjects will receive repeat dosing of GSK3039294 at the predicted optimal clinical dose determined from Part B for a total of 21 days.

Interventions: intervention 1: GSK3039294
Intervention descriptions: intervention 1: GSK3039294 will be provided as white, opaque capsules. A single capsule or multiple capsules (20 mg to 200 mg), depending on the dosage required, will be taken orally with water.

Protocol document:
Prot_000.pdf: 
2014N218204_03
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201664
1
TITLE PAGE
Division: Worldwide Development
Information Type: Protocol Amendment
Title:
A three-part open-label, non-randomised, dose-escalation study 
to investigate the safety and tolerability of GSK3039294 
administered as a single dose to healthy volunteers, and as repeat 
dose to healthy volunteers and patients with systemic 
amyloidosis
Compound Number:
GSK3039294
Development Phase:
I
Effective Date:
30-NOV-2016
Protocol Amendment Number:  03
Author (s):
 Clinical pharmacology
MPC: Metabolic Pathways & Cardiovascular
Clinical Pharmacology, Science and Study Operations
QSci: Clinical Statistics
QSci: Clinical Pharmacology Modelling and Simulation
MPC: Metabolic Pathways & Cardiovascular
QSci: Clinical Statistics
Copyright 2016 the GlaxoSmithKline group of companies.  All rights reserved.  
Unauthorised copying or use of this information is prohibited.
PPD


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Revision Chronology
GlaxoSmithKline 
Document Number
Date
Version
2014N218204_00
2015-AUG-06
Original
2014N218204_01
2015-OCT-07
Amendment No. 1
Section 5.5 – MHRA requested edits to stopping criteria
2014N218204_02
2016-MAR-01
Amendment No. 2
Throughout – Ethics Committee requested edits to the study design.
2014N218204_03
2016-NOV-30
Amendment No. 3
Amended to increase cardiac monitoring in Cohort 3 and Cohort 5 with supporting text


PPD
PPD


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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 
GlaxoSmithKline 
Medicines 
Research & 
Development, 
Gunnels Wood 
Road, 
Stevenage SG1 
2NY United 
Kingdom
Secondary 
Medical 
Monitor
GlaxoSmithKline
Clinical Unit 
Cambridge
Addenbrooke’s 
Hospital
Box 128, Hills 
Rd,
Cambridge CB2 
2GG
United Kingdom
Tertiary 
Medical 
Monitor
GlaxoSmithKline
5 Crescent 
Drive NY0200, 
Philadelphia, PA 
19112, United 
States
SAE 
contact  
information 
Medical 
monitor 
as above
Sponsor Legal Registered Address: 
GlaxoSmithKline Research & Development Limited
980 Great West Road
Brentford
Middlesex, TW8 9GS
UK
PPD


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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.   
Regulatory Agency Identifying Number(s):  EudraCT 2015-003088-13


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INVESTIGATOR PROTOCOL AGREEMENT PAGE
For protocol number 201664
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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TABLE OF CONTENTS
PAGE
1.
PROTOCOL SYNOPSIS FOR STUDY 201664......................................................11
2.
INTRODUCTION....................................................................................................17
2.1.
Study Rationale ..........................................................................................18
2.2.
Brief Background ........................................................................................18
3.
OBJECTIVE(S) AND ENDPOINT(S) ......................................................................19
4.
STUDY DESIGN ....................................................................................................20
4.1.
Overall Design ............................................................................................20
4.2.
Treatment Arms and Duration.....................................................................22
4.2.1.
Part A (single dose escalation in healthy volunteers) ...................22
4.2.2.
Part B (repeat dose escalation in healthy volunteers) ..................24
4.2.2.1.
Sentinel Dosing in Part B............................................24
4.2.2.2.
7 Day Repeat Dosing (Cohort 3).................................24
4.2.2.3.
21 Day Repeat Dosing (Cohort 4a).............................25
4.2.2.4.
21 Day Repeat Dosing (Cohort 4b – optional, 
only if required)...........................................................25
4.2.3.
Part C (repeat dose escalation in patients with systemic 
amyloidosis).................................................................................27
4.2.3.1.
Sentinel Dosing in Part C............................................28
4.3.
Type and Number of Subjects.....................................................................29
4.4.
Design Justification.....................................................................................29
4.5.
Dose Justification........................................................................................31
4.6.
Benefit:Risk Assessment ............................................................................33
4.6.1.
Risk Assessment .........................................................................34
4.6.2.
Benefit Assessment.....................................................................39
4.6.3.
Overall Benefit:Risk Conclusion...................................................39
5.
SELECTION OF STUDY POPULATION AND WITHDRAWAL CRITERIA .............39
5.1.
Inclusion Criteria.........................................................................................39
5.2.
Exclusion Criteria........................................................................................42
5.3.
Screening/Baseline/Run-in Failures............................................................45
5.4.
Withdrawal/Stopping Criteria.......................................................................46
5.4.1.
Cardiovascular Safety Stopping Criteria ......................................46
5.4.2.
Liver Chemistry Stopping Criteria ................................................47
5.4.2.1.
Study Treatment Restart or Rechallenge....................49
5.4.3.
QTc Stopping Criteria ..................................................................49
5.4.4.
Cardiac Arrhythmia Stopping Criteria...........................................49
5.4.5.
Renal Stopping Criteria................................................................51
5.4.6.
Stopping Criteria Based On Disease Progression in 
Systemic Amyloidosis Patients in Part C......................................52
5.5.
Stopping Criteria for the Entire Healthy Volunteer or Patient Study 
Groups........................................................................................................52
5.6.
Subject and Study Completion....................................................................52
6.
STUDY TREATMENT ............................................................................................53
6.1.
Investigational Product and Other Study Treatment....................................53


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6.2.
Treatment Assignment................................................................................53
6.3.
Planned Dose Adjustments.........................................................................53
6.4.
Blinding.......................................................................................................54
6.5.
Packaging and Labeling..............................................................................54
6.6.
Preparation/Handling/Storage/Accountability..............................................54
6.7.
Compliance with Study Treatment Administration.......................................55
6.8.
Treatment of Study Treatment Overdose....................................................55
6.9.
Treatment after the End of the Study ..........................................................55
6.10.
Lifestyle and/or Dietary Restrictions............................................................56
6.10.1.
Meals and Dietary Restrictions ....................................................56
6.10.2.
Caffeine and Alcohol, and Tobacco .............................................56
6.10.3.
Activity .........................................................................................57
6.11.
Concomitant Medications and Non-Drug Therapies....................................57
6.11.1.
Permitted Medications and Non-Drug Therapies..........................57
6.11.2.
Prohibited Medications and Non-Drug Therapies.........................57
7.
STUDY ASSESSMENTS AND PROCEDURES .....................................................57
7.1.
Time and Events Tables .............................................................................59
7.1.1.
Part A – Cohorts 1 and 2, single dose, healthy volunteer 
subjects .......................................................................................59
7.1.2.
Part B – Cohort 3, 7 day repeat dose healthy volunteer 
subjects .......................................................................................61
7.1.3.
Part B – Cohort 4, 21 day repeat dose healthy volunteer 
subjects .......................................................................................63
7.1.4.
Part B – Cohort 4, 21 day repeat dose healthy volunteer 
subjects – dose alteration (only if dose alteration is 
required) ......................................................................................66
7.1.5.
Part C – Cohort 5, repeat dose, patient subjects..........................67
7.2.
Screening and Critical Baseline Assessments ............................................70
7.3.
Safety .........................................................................................................70
7.3.1.
Adverse Events (AE) and Serious Adverse Events (SAEs)..........70
7.3.1.1.
Time period and Frequency for collecting AE 
and SAE information...................................................70
7.3.1.2.
Method of Detecting AEs and SAEs ...........................71
7.3.1.3.
Follow-up of AEs and SAEs........................................71
7.3.1.4.
Regulatory Reporting Requirements for SAEs............71
7.3.2.
Pregnancy ...................................................................................72
7.3.3.
Physical Exams ...........................................................................72
7.3.4.
Vital Signs....................................................................................72
7.3.5.
Cardiac Monitoring – Electrocardiogram (ECG), Telemetry 
& Non-Implantable Devices for Remote Monitoring......................72
7.3.5.1.
Cardiac Safety Monitoring in Cohort 3 (Part B) 
at Screening & Baseline .............................................72
7.3.5.2.
Cardiac Safety Monitoring in Cohort 5 (Part C) 
patients with known cardiac amyloid 
involvement ................................................................73
7.3.6.
Clinical Safety Laboratory Assessments ......................................73
7.3.7.
High Sensitivity Cardiac Troponin-T (hs-cTnT) Monitoring 
after a Cardiac Arrhythmia in Part B, or Part C ............................75
7.3.8.
Renal Safety Monitoring...............................................................75
7.3.8.1.
Guidance on the Clinical Approach for 
Suspected Renal Injury ..............................................76


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7.4.
Pharmacokinetics .......................................................................................76
7.4.1.
Blood Sample Collection..............................................................76
7.4.2.
Urine Collection ...........................................................................78
7.4.3.
Sample Analysis ..........................................................................78
7.5.
Biomarker(s)/Pharmacodynamic Markers ...................................................78
7.6.
Genetics .....................................................................................................80
8.
DATA MANAGEMENT ...........................................................................................80
9.
STATISTICAL CONSIDERATIONS AND DATA ANALYSES .................................80
9.1.
Hypotheses.................................................................................................80
9.2.
Sample Size Considerations.......................................................................80
9.2.1.
Sample Size Assumptions ...........................................................80
9.2.1.1.
Safety.........................................................................81
9.2.1.2.
Pharmacodynamics (Plasma SAP).............................81
9.2.2.
Sample Size Sensitivity................................................................82
9.2.2.1.
Safety.........................................................................82
9.2.2.2.
Pharmacodynamics (Plasma SAP).............................83
9.2.3.
Sample Size Re-estimation or Adjustment...................................84
9.3.
Data Analysis Considerations .....................................................................84
9.3.1.
Analysis Populations....................................................................84
9.3.2.
Interim Analysis ...........................................................................85
9.3.2.1.
Pharmacokinetics and pharmacodynamics.................85
9.4.
Key Elements of Analysis Plan ...................................................................86
9.4.1.
Primary Analyses.........................................................................86
9.4.2.
Secondary Analyses ....................................................................86
9.4.2.1.
Pharmacokinetics, pharmacodynamics and 
PK/PD model..............................................................86
10. STUDY GOVERNANCE CONSIDERATIONS........................................................87
10.1.
Posting of Information on Publicly Available Clinical Trial Registers............87
10.2.
Regulatory and Ethical Considerations, Including the Informed 
Consent Process ........................................................................................87
10.3.
Quality Control (Study Monitoring) ..............................................................87
10.4.
Quality Assurance.......................................................................................88
10.5.
Study and Site Closure ...............................................................................88
10.6.
Records Retention......................................................................................89
10.7.
Provision of Study Results to Investigators, Posting of Information 
on Publically Available Clinical Trials Registers and Publication .................89
10.7.1.
Dose Escalation Committee.........................................................90
11. REFERENCES.......................................................................................................91
12. APPENDICES........................................................................................................93
12.1.
Appendix 1 – Abbreviations and Trademarks..............................................93
12.2.
Appendix 2: Liver Safety Required Actions and Follow up 
Assessments ..............................................................................................95
12.2.1.
Healthy Volunteers: .....................................................................95
12.2.2.
Patients .......................................................................................97
12.3.
Appendix 3 - Genetic Investigation of Individuals........................................99
12.4.
Appendix 4: Definition of and Procedures for Recording, Evaluating, 
Follow-Up and Reporting of Adverse Events.............................................102


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12.4.1.
Definition of Adverse Events......................................................102
12.4.2.
Definition of Serious Adverse Events.........................................103
12.4.3.
Recording of AEs and SAEs ......................................................104
12.4.4.
Evaluating AEs and SAEs..........................................................105
12.4.5.
Reporting of SAEs to GSK.........................................................106
12.5.
Appendix 5: Protocol Amendment Changes..............................................107


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1.
PROTOCOL SYNOPSIS FOR STUDY 201664
Rationale
Objective(s)/Endpoint(s)
Part A: Single ascending dose in healthy volunteers 
Objectives
Endpoints
Primary
Evaluate safety and tolerability of single 
doses of GSK3039294
Adverse events, laboratory 
measurements, ECG, vital signs
Secondary
Evaluate pharmacokinetics of single 
doses of GSK3039294 and its 
biotransformation into GSK2315698 
(CPHPC)
PK parameters of GSK2315698 and
GSK3039294
Part B: Repeat dose in healthy volunteers
Objectives
Endpoints
Primary
Evaluate safety and tolerability of repeat 
doses of GSK3039294
Adverse events, laboratory 
measurements, ECG, vital signs and 
cardiac telemetry (where applicable)
Secondary
Evaluate pharmacokinetics of repeat 
doses of GSK3039294 and its 
biotransformation into GSK2315698 
(CPHPC)
PK parameters of GSK2315698 and 
GSK3039294
Pharmacodynamic effect of repeat doses 
of GSK3039294 on plasma SAP levels
Plasma SAP levels
Explore correlation of dose of 
GSK3039294, blood concentration of 
GSK2315698 and plasma SAP levels
PK parameters of GSK2315698 and 
GSK3039294
Plasma SAP levels
Exploratory 
Determine the effect of food on a single 
dose of GSK3039294
PK parameters of GSK2315698 and 
GSK3039294 under fasted and fed 
conditions.


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Part C: Repeat dose in patients with systemic amyloidosis
Objectives
Endpoints
Primary
Evaluate safety and tolerability of repeat 
doses of GSK3039294
Adverse events, laboratory 
measurements, ECG, vital signs and 
cardiac telemetry (where applicable).
Secondary
Evaluate pharmacokinetics of repeat 
doses of GSK3039294 and its 
biotransformation into GSK2315698 
(CPHPC)
PK parameters of GSK2315698 and 
GSK3039294
Pharmacodynamic effect of multiple 
doses of GSK3039294 on plasma SAP 
levels
Plasma SAP levels and time to repletion 
of SAP.
Explore correlation of dose of 
GSK3039294, blood concentration of 
GSK2315698 and plasma SAP levels
PK parameters of GSK2315698 and 
GSK3039294
Plasma SAP levels


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Overall Design
This is a three-part, open-label, non-randomised study. 


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Treatment Arms and Duration
Part A: Single dose escalation in healthy volunteers
Two cohorts (cohorts 1 and 2) of subjects will be enrolled to provide data from 6 subjects 
per cohort and up to 4 different doses (2 dose levels per cohort) of GSK3039294 will be 
tested.
Subjects will be admitted to the unit on Day -1, following the dose on Day 1 subjects will 
remain in-house until Day 4. Wash-out will take place from Day 5 to Day 14.
Providing a review of the data from each dose (safety data: AE, vital signs, ECG and 
laboratory safety test and PK data up to 48 h etc) is favourable, the next dose level will be 
administered. 
Part B: Repeat dose escalation in healthy volunteers
Cohort 3: In a group of healthy volunteers (preferably < 45 years of age) sufficient 
subjects will be enrolled to ensure 6 completers, the study drug will be administered 
repeatedly for a total of 7 days.  The dose will be one that is expected to be well tolerated 
based on the single dose data and not predicted to exceed exposure limits based on single 
dose PK. 
A sentinel subject will be dosed first with repeat GSK3039294 administration for 7 
consecutive days. Subsequent subjects will only be dosed after the sentinel subject has 
successfully completed the full 7 days of dosing without any clinically concerning AEs 
being reported. If the safety data from the sentinel subject is deemed to be equivocal, a
second subject can be dosed individually for 7 days at the discretion of the Investigator in 
consultation with the GSK study team. If the safety data from the second subject is also 
equivocal, at the discretion of the Investigator in consultation with the GSK study team, 
subsequent subjects can also be individually dosed with GSK3039294 for 7 days. 
The food effect exploration in Cohort 3 will only be conducted once the Investigator in 
consultation with the GSK study team is satisfied with the safety profile of repeat dose 
GSK3039294. Following this, the food effect will be conducted on Days 4 and 5, and 
GSK3039294 will be administered under fasted and then under fed conditions
(respectively).
Sufficient subjects will be enrolled to ensure a minimum of 6 subjects complete all study 
procedures, including the food effect exploration.
Providing a review of the data (safety data: AE, vital signs, ECG, telemetry, laboratory 
safety tests and PK) is overall acceptable, Cohort 4a will be initiated. The approving REC 
will be informed of the outcome of this data review.
Cohort 4a: In a group of healthy volunteers sufficient subjects will be enrolled to ensure 6 
completers, the study drug will be administered repeatedly for a total of 21 days.


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The dose level for this cohort will be determined by a review of the safety and PK data 
from cohort 3. The dose may be adjusted (up or down) during the 21 day dosing session 
based on preliminary PK collected during dosing and ongoing review of safety. If the 
dose is to be altered, this will be done no later than Day 16 in order to achieve a new 
steady-state at Day 21.
The predicted maximum daily exposure will not exceed pre-clinical safety exposure 
limits.
Cohort 4b(optional, only if required): Based on data from Cohorts 3 and 4a, dose levels 
may be selected for further investigation in a further cohort of healthy volunteers 
(recruitment to ensure 6 completers). For this purpose the compound will be dosed for 21 
consecutive days. The dose level and / or dosing regimen may be altered once during the 
21days providing a review of the data from the starting dose (safety data: AE, vital signs, 
ECG, laboratory safety tests and PK – all obtained once steady state has been achieved) is
favourable. The predicted maximum daily dose administered will not exceed pre-clinical 
safety exposure limits.
Part C: Repeat dose escalation in patients with systemic amyloidosis
A single dose level of GSK3039294 will be tested for 21 days repeat dose, in patients 
with systemic amyloidosis which may include those with cardiac amyloid involvement.
Type and Number of Subjects
In Part A, sufficient healthy volunteers will be enrolled to ensure 6 subjects per cohort 
have completed the in-patient phases.
In Part B, sufficient healthy volunteers will be enrolled to ensure 6 subjects per cohort 
have completed each of the in-patient phases.
In Part A and B of the study, if subjects prematurely discontinue, replacement subjects 
may be enrolled and assigned to the same cohort at the discretion of the Sponsor in 
consultation with the investigator. Replacement subjects do not need to have received the 
first dose for a given cohort to join the study in the second cohort.
In Part C, a minimum of 12 patients with systemic amyloidosis will be enrolled. If 
subjects prematurely discontinue, replacement subjects may be enrolled at the discretion 
of the Sponsor in consultation with the investigator.  
Additional subjects/cohorts may be enrolled to allow for further evaluation of a given 
dose or for evaluation of additional dose levels.   


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Analysis
There are no formal hypotheses to be tested as part of this study.
Interim analyses
Safety, PK and PD data will be reviewed on an ongoing basis throughout the study by the 
study team and investigator in order to inform dosing decisions for subsequent dosing 
sessions, cohorts and study parts.  
In addition, in all Parts of the study, individual profiles over time will also be presented 
graphically for selected urine and plasma laboratory parameters pertaining to the kidney. 
To inform dosing decisions for subsequent dosing sessions in Part A, individual values of 
Cmax and AUC[0-inf] will be derived by means of non-compartmental analysis.  To 
inform dosing decisions for subsequent study parts, GSK2315698 concentration data and 
plasma SAP levels will be analysed using the PK/PD model that was developed for 
GSK2315698.
Primary and secondary analyses
Safety, PK and PD data will be listed, summarised and presented graphically as 
appropriate. GSK2315698 concentration data and plasma SAP levels will be analysed 
using the PK/PD model that was developed for GSK2315698.
Cohort Safety Reviews: A safety review will be performed on completion of each Cohort 
in Part B, as well as at completion of Cohort 5 in Part C (see Section 4.2.2. & Section 
4.2.3.). Initiation of Cohort 4a will be contingent on the findings of the safety review at 
completion of Cohort 3 (see Section 4.2.2.)
Summary of Cardiac Arrhythmia Adverse Events in Part A of this study
A total of 4 separate arrhythmias in 3 male subjects over 45 year old were reported on 24-
hour Holter after single dose administration of GSK3039294 in Part A. Three episodes of 
supraventricular tachycardia (SVT), all of atrial tachycardia morphology at doses of 
GSK3039294 at 600mg and 1200mg, and one episode of a single 5-beat accelerated 
idioventricular rhythm (AIVR) at 600mg GSK3039294, were reported in these 3 separate 
subjects. Each of the events was of short duration, completely asymptomatic, and was not 
associated with hemodynamic instability. 
No prolongation of the QTcF interval was observed in any subject after administration of 
200mg, 600mg, or 1200mg of GSK3039294 in Part A.
Both SVTs and ventricular salvos of short duration are known to occur in healthy 
volunteer subjects and can be considered to be within the normal (non-pathological) 
variation of ECG parameters. In this regard, SVTs have been reported to arise in 13.9% 
of healthy volunteer subjects over 45 years of age compared to an incidence of 1.1% in 
healthy volunteer subjects 45 years or less in FIH studies (Hingorani et al, 2016). In Part 
A, none of the three affected subjects had plasma levels of GSK3039294 detectable 
approximate to the time at which each cardiac arrhythmia occurred. Moreover, the timing 


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of each of the four arrhythmic events after dosing with GSK3039294 was not associated 
with the Tmax of CPHPC including one subject whom had no detectable plasma CPHPC 
present at approximately the time of the first of their two arrhythmic events.
Therefore, at this time, given that there were also no arrhythmogenic liabilities identified 
for GSK3039294 in preclinical toxicological studies, it is unlikely that the arrhythmias 
reported after dosing with GSK3039294 in Part A are attributable to its single dose 
administration at 600 mg or 1200mg.
2.
INTRODUCTION
GSK2315698 (CPHPC), crosslinks serum amyloid P component (SAP) resulting in 
depletion of SAP from the plasma, but needs to be given parenterally. GSK3039294 is a 
pro drug of CPHPC that has been developed in order to offer the potential of an orally 
available alternative to parenteral CPHPC for plasma SAP depletion prior to use of anti 
SAP mAb in the treatment of systemic amyloidosis. 
Systemic amyloidosis is a clinical disorder caused by progressive accumulation of 
insoluble, misfolded deposits of normally soluble precursor proteins (amyloid) in the 
extracellular matrix of target organs (kidney, liver, heart, spleen). Amyloid deposition is 
responsible for progressive and usually relentless organ dysfunction, failure and almost 
always death. 
Although the nature of the misfolded culprit protein may vary with the type of systemic 
amyloidosis, (20 different proteins have been reported in the different forms of the 
disease), they all share a common cross-β structure, they are derived from normally 
soluble precursor proteins and amyloid deposits are always decorated with SAP.
SAP is a normal, non fibrillar, plasma glycoprotein circulating at 20-40 mg/L. Its 
circulating concentration is not affected in health and disease including amyloidosis. SAP 
is a normal constituent of the extracellular matrix located on the microfibrillar mantle of 
elastic fibers throughout the body and in the lamina rara interna of the glomerular 
basement membrane. However the amount of SAP in these normal tissue sites is 
extremely low compared to the fluid phase SAP. In systemic amyloidosis, SAP 
accumulates in amyloid deposits bound to fibrils and in equilibrium with fluid phase SAP 
pool. In patients with extensive systemic amyloidosis, as much as 20g of SAP may be 
bound in amyloid deposits.
CPHPC is being developed in an obligate therapeutic parternship with anti-SAP 
monoclonal antibodies. CPHPC or GSK3039294 would be used to acutely deplete plasma 
SAP to enable subsequent safe administration of an anti-SAP monoclonal antibody 
(mAb). Binding of the antibody to residual SAP on amyloid deposits triggers their 
removal [Richards, 2015].


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2.1.
Study Rationale
GSK3039294 has been developed in order to offer an orally available alternative to 
parenteral CPHPC for plasma SAP depletion prior to use of anti SAP mAb in the 
treatment of systemic amyloidosis. 
This phase 1 study is intended to study safety, tolerability and PK profile of 
GSK3039294 in humans. It is expected that GSK3039294 will, after oral administration, 
release CPHPC in the circulation and thereby reduce plasma SAP to a level considered 
sufficient for safe administration of anti-SAP mAb (currently a target of below 2mg/L 
with IV CPHPC administration).
CPHPC PK/PD has been studied in both healthy volunteers and patients. A PK/PD model 
taking into account the various compartments, the equilibrium between amyloid bound 
SAP and plasma SAP, the affinity for CPHPC and elimination rate of the complex has 
been established. This model will be used in the present study for determination and 
comparison of the PK/PD profile of the prodrug with the profile of CPHPC [Sahota, 
2015].
Past data with CPHPC have shown that the PK /PD relationship (SAP depletion) 
observed in healthy volunteers is predictive of that in patients with systemic amyloidosis. 
The Study will therefore include healthy volunteers for single and repeat ascending doses 
and determination of PK parameters of the GSK3039294. A group of patients with 
systemic amyloidosis will be included and treated with a dose predicted to be active in 
order to verify that transformation of GSK3039294 is similar in patients and healthy 
volunteers and leads to plasma SAP depletion expected with similar exposures to 
CPHPC.
2.2.
Brief Background
CPHPC has been used in humans in order to decrease circulating SAP. In previous 
academic-sponsored studies patients with systemic amyloidosis, an infusion of CPHPC at 
doses between 0.25-6 mg/kg/day resulted into a rapid and consistent depletion of 
circulating SAP in all subjects. The most common daily dose for long term use was 1 
mg/kg. The treatment was reported to be safe and well tolerated. Some patients with 
systemic amyloidosis were treated for up to 104 weeks at 1mg/kg (given in 2 daily sc 
administrations). Subcutaneous CPHPC administration sometimes led to minor local 
stinging and bruising at the injection site. 
PK/PD studies with CPHPC have been conducted by GSK in both in healthy volunteers 
and patients with systemic amyloidosis after i.v. and s.c. administration. In all cases an iv 
regimen CPHPC decreased plasma SAP concentrations to 2 mg/L. In patients with 
systemic amyloidosis the time to nadir was longer and greatly dependent on the amyloid 
load and liver involvement. The time to plasma recovery was also dependent on amyloid 
load and took longer in patients with amyloid deposits. This indicates that most of the 
newly produced SAP is distributed to amyloid deposits before repleting the circulating 
compartment. As CPHPC is renally cleared the dose is corrected for renal function


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3.
OBJECTIVE(S) AND ENDPOINT(S)
Part A: Single ascending dose in healthy volunteers 
Objectives
Endpoints
Primary
Evaluate safety and tolerability of single 
doses of GSK3039294
Adverse events, laboratory 
measurements, ECG, vital signs and 
cardiac telemetry (where applicable)
Secondary
Evaluate pharmacokinetics of single 
doses of GSK3039294 and its 
biotransformation into GSK2315698 
(CPHPC)
PK parameters of GSK2315698 and 
GSK3039294
Part B: Repeat dose in healthy volunteers
Objectives
Endpoints
Primary
Evaluate safety and tolerability of repeat 
doses of GSK3039294
Adverse events, laboratory 
measurements, ECG, vital signs and 
cardiac telemetry (where applicable)
Secondary
Evaluate pharmacokinetics of repeat 
doses of GSK3039294 and its 
biotransformation into GSK2315698 
(CPHPC)
PK parameters of GSK2315698 and 
GSK3039294
Pharmacodynamic effect of repeat doses 
of GSK3039294 on plasma SAP levels
Plasma SAP levels
Explore correlation of dose of 
GSK3039294, blood concentration of 
GSK2315698 and plasma SAP levels
PK parameters of GSK2315698 and 
GSK3039294
Plasma SAP levels
Exploratory 
Determine the effect of food on a single 
dose of GSK3039294
PK parameters of GSK2315698 and 
GSK3039294 under fasted and fed 
conditions.
Part C: Repeat dose in patients with systemic amyloidosis


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Objectives
Endpoints
Primary
Evaluate safety and tolerability of repeat 
doses of GSK3039294
Adverse events, laboratory 
measurements, ECG, vital signs
Secondary
Evaluate pharmacokinetics of repeat 
doses of GSK3039294 and its 
biotransformation into GSK2315698 
(CPHPC)
PK parameters of GSK2315698 and 
GSK3039294
Pharmacodynamic effect of multiple 
doses of GSK3039294 on plasma SAP 
levels
Plasma SAP levels and time to repletion 
of SAP.
Explore correlation of dose of 
GSK3039294, blood concentration of 
GSK2315698 and plasma SAP levels
PK parameters of GSK2315698 and
GSK3039294
Plasma SAP levels
4.
STUDY DESIGN
4.1.
Overall Design
This is a three-part, open-label, non-randomised study. 


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Figure 1
Study Schematic


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4.2.
Treatment Arms and Duration
4.2.1.
Part A (single dose escalation in healthy volunteers)
Part A is a single dose, open label, dose escalation study conducted in healthy volunteers 
and will evaluate safety, tolerability, and PK of the compound including 
biotransformation of GSK3039294 into active CPHPC.
Two cohorts of subjects will be enrolled to provide data from 6 subjects per cohort and 
up to 4 different doses (2 dose levels per cohort) of GSK3039294 will be tested.
Doses will be administered to Cohorts using a sentinel dosing approach as described 
below. Subjects will be admitted to the unit on Day -1, following the dose on Day 1 
subjects will remain in-house until Day 4. Wash-out will take place from Day 5 to Day 
14.
Providing a review of the data from each dose (safety data: AE, vital signs, ECG and 
laboratory safety test and PK data up to 48 h etc) is favourable, the next dose level will be 
administered. Cohort 1 will be used for 2 dosing periods (Doses 1 and 2), Cohort 2 will 
also be used for 2 dosing periods (Doses 3 and 4).  A review of the data will always be 
conducted prior to the administration of the next dose level.
The planned doses for Dose levels 2, 3 and 4 may be modified based on emerging safety, 
tolerability and PK data. The number of dosing periods may be reduced or extended 
depending on emerging data. Replacement subjects in either Cohort do not need to have 
received the first dose prior to receiving the second dose.
Sentinel dosing:  For all dose levels the subsequent subject will be dosed approximately 
24 hrs after the preceding subject if there are no safety or tolerability concerns. The 
remaining subjects receiving the same dose within the cohort will receive the dose 
approximately 24hrs after the subsequent subject at intervals no less than 1hr apart.


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Table 1
Cohorts 1 and 2 Study Duration
Screening
All screening assessments to be completed within 28 days 
prior to the first dose. 
Treatment 
Period
For Cohorts 1 and 2, each subject may take part in two 
dosing periods. During each study period subjects will be in-
house from the day prior to dosing until the Day 4 after dosing 
when they will be discharged after post dose assessments 
have been completed. Subjects will return to the unit as out-
patients for any post-dose assessments.
Washout Period
From Day 5 to Day 14. 
Follow-up
At least 7 days and no greater than 14 days after study drug 
administration. If warranted, additional follow-up visits may be 
scheduled.
Total Duration
Each cohort is approximately 8 weeks
Figure 2
Study Design for Healthy Volunteer Subjects Single Dose (Cohorts 1 
and 2)
All data obtained from this study will be included in the existing PK model established 
from completed studies with CPHPC [Sahota, 2015] and will inform the dose selection 
for the next cohort/dosing session. 
At the end of this single dose part, all PK data will be analysed (see Section 9.3.2) and 
reviewed together with all available safety data.
The study drug will be further evaluated in Parts B and C, unless following Part A it is 
determined that:

If the safety profile is acceptable however the calculated bioavailability would 
mean that even following dosing of GSK3039294 at a maximum dose (which 
does not exceed pre-clinical safety exposure limits), insufficient CPHPC would be 
generated to be an effective depleter of plasma SAP. 


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
If the safety profile restricts the maximum well tolerated dose level to one that 
does not generate sufficient CPHPC to be an effective depleter of plasma SAP. 
In this situation the study may be terminated.
4.2.2.
Part B (repeat dose escalation in healthy volunteers)
Part B is repeat dose, open label, dose escalation conducted in healthy volunteer subjects 
and will evaluate the safety, tolerability, PK, pharmacodynamics of repeat dosing (7 day 
in Cohort 3, 21 day in Cohort 4) of GSK3039294. In addition to PK, plasma SAP levels 
will be measured at time points as in the Time and Events table (Section 7.1.1) to 
determine the ability of GSK3039294 to decrease plasma SAP levels to aid prediction of 
the optimal clinical dose.
4.2.2.1.
Sentinel Dosing in Part B
In each individual study cohort in Part B, a sentinel subject will complete all dosing days 
up to and including Day 7. If there are no clinically concerning safety or tolerability 
issues observed, the rest of the subjects within the cohort can be dosed. 
If the safety data from the sentinel subject is deemed to be equivocal, a second (and 
subsequent) subjects will complete all dosing days individually, up to and including Day 
7, at the discretion of the Investigator in consultation with the GSK study team.
4.2.2.2.
7 Day Repeat Dosing (Cohort 3)
In a group of healthy volunteers, sufficient subjects will be enrolled to ensure a minimum 
of 6 subjects complete all study procedures (including evaluation of food-effect) 
associated with 7 days repeat dosing administration.The dose will be one that is expected 
to be well tolerated based on the single dose data and predicted to not exceed exposure 
limits based on single dose PK. 
A food effect exploration will be conducted at Days 4 and 5 of this cohort once the 
investigator is satisfied with the safety data from the sentinel subject(s). To evaluate a 
potential food effect, GSK3039294 will be administered under fasted and then under fed 
conditions (please see SRM for details of meals), and PK samples will be taken to 
investigate the food effect on the PK.
Cardiac Safety Review of Cohort 3
Given that all cardiac arrhythmic events after single dose administration of GSK3039294 
in Part A (where there were detectable levels of plasma CPHPC) were relatively acute 
and observed between approximately 4 to 7 hours after tmax of CPHPC and when no 
GSK3039294 was detectable, and given steady state is expected to be reached after 
approximately 5 days of repeat dosing, 7 day continuous cardiac telemetry in Cohort 3 is 
deemed to be of sufficient duration to detect any potential cardiac arrhythmias associated 
with repeat dosing of GSK3039294. 


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On completion, in addition to full safety review, a cardiac safety review will be 
performed where individual subject telemetry data will be reviewed in relation to the PK 
data of GSK3039294 and CPHPC.
4.2.2.3.
21 Day Repeat Dosing (Cohort 4a)
In a group of healthy volunteers sufficient subjects will be enrolled to ensure 6 
completers, the study drug will be administered repeatedly for a total of 21 days. 
The dose level and / or dosing regimen may be adjusted (up or down)  once during the 21 
days providing a review of the data from the starting dose (safety data: AE, vital signs, 
ECG, laboratory safety tests and PK – all obtained once steady state has been achieved) is 
favourable. If the dose is to be altered, this will be done no later than Day 16 in order to 
achieve a new steady-state at Day 21. The predicted maximum daily dose administered 
will not exceed pre-clinical safety exposure limits.
Initiation of Cohort 4a: Cohort 4a will only be initiated if the conclusion of the safety 
review from Cohort 3 demonstrates an acceptable safety profile associated with the repeat 
administration of GSK3039294 for 7 days. 
Individual subjects in Cohort 4a can be withdrawn from the study at the discretion of the 
Investigator in consultation with the GSK study team if individual subject safety review 
at Day 7 demonstrates any AEs which are deemed to be equivocal or clinically 
concerning. Affected subject(s) should be followed-up, at the discretion of the 
Investigator, as per local practice.
Data from cohorts 3 and 4a are expected to provide a good evaluation of the safety, 
tolerability and repeat-dose PK. The data will be evaluated using the PK/PD model to 
identify an optimal clinical dose (see Section 9.3.2.1). However, if it is determined that 
further investigation of dose levels are required before progressing to Part C (e.g. if the 
observations in cohort 4a are different from those which the PK /PD modelling 
predicted), then recruitment into Cohort 4b may be initiated.
4.2.2.4.
21 Day Repeat Dosing (Cohort 4b – optional, only if required)
In a group of healthy volunteers, sufficient subjects will be enrolled to ensure a minimum 
of 6 completers, the study drug will be administered repeatedly for a total of 21 days. 
Based on data from Cohorts 3 and 4a, dose levels will be selected for further 
investigation in a further cohort of healthy volunteers (recruitment to ensure 6 
completers). For this purpose the compound will be dosed for 21 consecutive days. The 
dose level and / or dosing regimen may be adjusted (up or down)  once during the 21 
days providing a review of the data from the starting dose (safety data: AE, vital signs, 
ECG, laboratory safety tests and PK – all obtained once steady state has been achieved) is 
favourable. If the dose is to be altered, this will be done no later than Day 16 in order to 
achieve a new steady-state at Day 21. The predicted maximum daily dose administered 
will not exceed pre-clinical safety exposure limits.


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Table 2
Cohort 3
Screening
All screening assessments (including a 48hr Holter recording) 
to be completed within 28 days prior to the first dose
Treatment 
Period
Each subject will take part in a single study period. Subjects 
will be in-patient from Day -2 (where baseline cardiac 
telemetry will be performed for 24 hours immediately prior to 
the first dose of GSK3039294) until Day 8 when they will be 
discharged.
Follow-up
At least 7 days and no greater than 14 days after last study 
drug administration
Additional follow-up visits may be scheduled, if warranted
Total Duration
Approximately 7 weeks
Table 3
Cohort 4a (and 4b if required) Study Duration
Screening
All screening assessments to be completed within 28 days 
prior to the first dose
Treatment 
Period
Each subject will take part in a single study period. Subjects 
will be in-patient from Day -1 until Day 7 when they will be 
discharged. Subjects will self-administer their assigned dose 
when not in the clinical unit. Subjects will return as outpatients 
on Day 21, and again for a follow-up appointment.
Subjects may return to the clinic after Day 7 for an adjustment 
to their dose should a review of interim PK data require this. If 
a dose adjustment is made, subjects will be in-patient until 
they have received the new dose for 7 days, when they will be 
discharged.
Follow-up
At least 7 days and no greater than 14 days after last study 
drug administration
Additional follow-up visits may be scheduled, if warranted
Total Duration
Approximately 8-9 weeks


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Figure 3
Study Design for Healthy Volunteer Subjects Repeat Dose (Cohorts 
3, 4a and 4b – doses shown are for example only)
In Cohort 4b multiple dose levels and different regimens may be investigated based on 
data from Cohort 4a. *Day of Potential Dose Alteration (no later than D16) not specified 
as this will be performed following review of safety and PK data from previous dose.
4.2.3.
Part C (repeat dose escalation in patients with systemic 
amyloidosis)
In Part C a single dose level of GSK3039294 will be tested for 21 days repeat dose, in 
patients with systemic amyloidosis, which may include those patients with known cardiac 
amyloid involvement. This will confirm the ability of GSK3039294 (given at the 
predicted optimal clinical dose determined from Part B) to decrease plasma SAP, and 
assess the ability of GSK3039294 to maintain this level over 21 days in patients with 
systemic amyloidosis.
Safety and tolerability will also be evaluated
Initiation of Cohort 5: Cohort 5 will only be initiated if the conclusion of the safety 
review from Cohort 4 demonstrates an acceptable safety profile associated with the repeat 
administration of GSK3039294 for 21 days. 


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4.2.3.1.
Sentinel Dosing in Part C
Renal Amyloidosis Sentinel Subject: A sentinel systemic amyloidosis patient (n=1) 
with known renal involvement and an estimated GFR ≥ 60 ml / min, but with no known 
cardiac involvement, will be dosed repeatedly with GSK3039294 for the full 21-day 
period before dosing any other patients begin. Following this, dosing of other patients 
with renal involvement (with an eGFR > 50 mL / min) but with no cardiac involvement 
can be initiated, provided no concerning safety signals are detected in this sentinel 
patient.
Cardiac Amyloidosis Sentinel Subject: Once the sentinel renal patient has successfully 
completed dosing, a sentinel cardiac amyloidosis patient (n=1) with eGFR≥ 60 mL / min 
& LV Ejection Fraction (EF)  ≥ 50% will be dosed repeatedly with GSK3039294 for the 
full 21-day period. Following this, dosing of any other patients with cardiac involvement 
(NYHA ≤2) can be initiated provided no concerning safety signals are detected in the 
sentinel cardiac patient.
Table 4
Cohort 5 Study Duration
Screening
All screening assessments to be completed within 28 days 
prior to the first dose including out-patient cardiac monitoring 
for 7 continuous days (with external portable monitoring 
device) only in those patients with known cardiac amyloid 
involvement
Treatment 
Period
Each subject will take part in a single study period. Subjects 
will be in-patient from Day -1 until Day 8 when they will be 
discharged after assessments have been completed. 
In-patient cardiac telemetry will be performed from at least 
Day -1 until Day 8 only in those patients with known cardiac 
amyloid involvement.
Subjects will return to the unit as out-patients for regular 
assessments whilst continuing dosing to Day 21.
Safety Follow-up
Subjects will attend 7-14 days post last dose for a safety 
follow-up
PD Follow-up
Weekly PD assessments will be made up to 42 days after last 
study drug administration
Additional follow-up visits may be scheduled, if warranted
Total Duration
Approximately 13 weeks


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Figure 4
Illustrative Schematic of Proposed Study Design for Patient 
Subjects Repeat Dose (Cohort 5)
4.3.
Type and Number of Subjects
In Part A, sufficient healthy volunteers will be enrolled to ensure 6 subjects per cohort 
have completed the in-patient phases.
In Part B, sufficient healthy volunteers will be enrolled to ensure a minimum of 6 
subjects per cohort have completed the in-patient phases with all study procedures.
Subjects who participate in Part A will be eligible to participate in Part B at the discretion 
of the Investigator. 
In Part A and B of the study, if subjects prematurely discontinue, replacement subjects 
may be enrolled and assigned to the same cohort at the discretion of the Sponsor in 
consultation with the investigator. Replacement subjects do not need to have received the 
first dose for a given cohort to join the study in the second cohort.
In Part C, a minimum of 12 patients with systemic amyloidosis (which may include
those with known cardiac amyloid involvement) will be enrolled.  If subjects prematurely 
discontinue, replacement subjects may be enrolled at the discretion of the Sponsor in 
consultation with the investigator.  
Additional subjects/cohorts may be enrolled to allow for further evaluation of a given 
dose or for evaluation of additional dose levels. 
4.4.
Design Justification
CPHPC has had a good safety and tolerability profile in clinical studies to date.
GSK3039294 is expected to release CPHPC in the circulation. The measures of this are 
pharmacokinetic and pharmacodynamic (SAP depletion) and therefore no control group 
is included. Subjects treated with placebo are also not included because an assessment of 
the precision of causality that feasible numbers of subjects would give is poor (see 
Section 9.2). 
Previous data shows that the PK/PD of CPHPC in healthy volunteers is predictive of that 
in the target patient population, hence the inclusion of this group in the study.


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Once an effective and well-tolerated regimen has been established in healthy volunteers, 
this will be tested in patients with systemic amyloidosis to confirm that the PK PD of the 
pro drug.   
Part A will allow assessment of safety, tolerability and PK including biotransformation 
of GSK3039294 into active CPHPC of single doses of GSK3039294. If the absorption of 
GSK3039294 and subsequent biotransformation of GSK3039294 to CPHPC is sufficient 
then repeat dosing will be investigated in Part B.
Part A washout period:  In Part A of the study, subjects will receive 2 dose levels of 
GSK3039294, and the washout between doses will be appoximately 14 days.  This 
washout period will allow a thorough investigation of safety, tolerability and PK, 5 days 
is considered sufficient to eliminate any systemic exposure carryover between dosing 
periods.
Part B will allow assessment of safety, tolerability and PK including biotransformation 
of GSK3039294 into active CPHPC of repeat doses of GSK3039294 and PD (depletion 
of plasma SAP). PK and PD data will be compared within a subject following repeat 
dosing and dose escalation and regimen adjustments. If the exposure to CPHPC and the 
resulting depletion of SAP is sufficient the repeat dosing of patients with systemic 
amyloidosis will be investigated in Part C.
The duration of 7 days for Cohort 3 Part B was selected as steady state is predicted to be 
achieved in this time. The duration of 21 days for Cohorts 4a and 4b in Part B was 
selected to reflect the likely duration of treatment needed for clinical use with the anti 
SAP monoclonal antibody. 
Part C will confirm the ability of GSK3039294 (given at the predicted pharmacological 
dose determined from Part B) to decrease plasma SAP to a level suitable for mAb 
administration in subsequent studies and its ability to maintain this level over 21 days in 
patients with systemic amyloidosis. Also, safety and tolerability of the optimal clinical 
dose of GSK3039294 will be evaluated in systemic amyloidosis patients which may 
include those with known cardiac amyloid involvement.
The duration of 21 days for Part C was selected to reflect the likely duration of treatment 
needed for clinical use with the anti SAP monoclonal antibody.
Pharmacogenetics: Although human esterases can exhibit a high level of redundancy for 
specific substrates, there are particular prodrugs, such as oseltamivir which have been 
found to be preferentially metabolized by a specific esterase (i.e. carboxyesterase (CES)-
1). Therefore, in all three parts of the study, blood samples will be collected from healthy 
volunteers and patients, and stored for retrospective SNP (single nucleotide 
polymorphism) array analysis in the event of unexpected PK profile patterns for 
GSK2315698 (CPHPC) and / or plasma SAP being observed. This might be indicative of 
either slower or accelerated pro-drug CPHPC activation which might be explained by the 
presence of a germline SNP affecting a specific esterase-encoding gene(s) (see Section 
7.6 & Appendix 3).


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Companion Diagnostic Assay Development: Blood taken for PD analysis in Part B of 
this study will also be used in the development and validation of a companion diagnostic 
assay to measure SAP levels.
4.5.
Dose Justification
This study is planned to test single doses of GSK3039294 and repeat doses up to the 
maximum tolerated dose or the maximum allowable dose based on pre-clinical findings. 
The intention is to target the PK exposure of CPHPC seen in previous clinical studies 
producing the SAP depletion required for future studies with anti-SAP mAb.
Part A
The starting dose in Part A is planned to be 200mg of GSK3039294. This dose is selected 
using the PK/PD model that was developed for CPHPC (active molecule) [Sahota, 2015], 
adjusted for the oral absorption of GSK3039294 and the conversion of GSK3039294 to 
CPHPC. PK in pre-clinical species (rat and dog) show a very fast and complete 
conversion of GSK3039294 into CPHPC. Several marketed pro-drugs (viread, cerebyx, 
spectracef, hepsera) have either a fast and complete conversion into the active compound, 
or a tmax of the active compound that is within a few hours consistent with fast 
conversion.
Assuming fast and complete oral absorption of GSK3039294 and  fast and complete 
conversion of GSK3039294 into CPHPC, then both processes are described by a single 
first-order process (Ka) and high bioavailability (F). For the purposes of dose estimation 
Ka and F have been assumed to be high: 1.3/hr and 100%, as this will result in the highest 
exposures to CPHPC possible. Distribution and elimination of CPHPC is expected to be 
the same, regardless of IV administration of CPHPC or oral administration of the pro-
drug (GSK3039294). Therefore, distribution and elimination parameters, as well as 
between subject variability, were set to the estimates from the analysis of CPHPC itself.
The NOAEL for GSK3039294 in preclinical species is set to 1000 mg/kg/day, which is 
associated with CPHPC exposure of AUC[0-24] of 250 g.hr/mL and Cmax of 
22.1 g/mL. In the rat cardiovascular changes were observed at concentrations of about 
6 g/mL. These changes were not observed in studies with dogs, and are considered 
species specific, however, to confirm there are no cardiovascular changes in clinic, the 
SD dose escalation in Part A will start at a dose that is predicted to result in CPHPC 
concentrations that are lower than 6 g/mL.
Using the PK/PD model the concentration-time profiles of CPHPC after a single dose of 
GSK3039294 were simulated, and Cmax and AUC[0-inf] were derived. For a dose of 
200 mg, this resulted in a predicted AUC[0-inf] of 14.5 g.hr/mL  (95% CI of 9.5-22.4 
g.hr/mL) and a predicted Cmax of 3.4 g/mL (95% CI of 2.1-5.0 g.hr/mL).
The next doses in Part A will be determined based on the data of the preceding dosing 
sessions. All available PK data will be analysed (see Section 9.3.2.1), and the next dose 
will be such that the median Cmax will be about 6 g/mL, and the predicted 95% CI will 
not exceed preclinical Cmax and AUC limits.
The highest dose in Part A will not exceed pre-clinical safety exposure limits of 
AUC[0-24] of 250 g.hr/mL and Cmax of 22.1g/mL.


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Part B
The dose level for Cohort 3 in Part B will be determined based on the PK data obtained in 
Part A, by analysing all available PK data from Part A and subsequently predicting 
concentration-time profiles at steady state after repeat dosing. Table 5 shows examples of 
dose levels and frequencies with predicted AUC[0-24] and Cmax at steady state, using 
the PK/PD model that was developed for CPHPC (active molecule) [Sahota, 2015], 
adjusted for oral absorption and conversion of GSK3039294 into CPHPC. The PK data 
from Part A will be used to obtain estimates for Ka and F.
Table 5
Example Doses And Predicted Exposures For Part B
Dose
Ka
F
AUC[0-24h] 
(g.hr/mL) *)
Cmax (g/mL) *)
Cohort 3
300mg OD
1.3
1
23.4 (15.3-35.9)
5.20 (3.32-7.84)
300mg OD
1.3
0.5
11.4 (7.36-18.1)
2.61 (1.72-3.86)
300mg OD
0.6
1
22.8 (14.7-36.2)
3.83 (2.73-5.42)
Cohort 4a (first part)
300mg BID
1.3
1
45.7 (29.4-72.5)
5.49 (3.75-8.05)
300mg BID
1.3
0.5
22.8 (14.7-36.2)
2.74 (1.87-4.02)
300mg BID
0.6
1
45.7 (29.4-72.5)
4.09 (2.94-5.76)
Cohort 4a (last part)
600mg BID
1.3
1
91.3 (58.9-145)
11.0 (7.50-16.1)
600mg BID
1.3
0.5
45.7 (29.4-72.5)
5.49 (3.75-8.05)
600mg BID
0.6
1
91.3 (58.9-145)
8.19 (5.88-11.5)
*) Predicted AUC[0-24] and Cmax at steady state; presented are mean and 95%CI
The dose levels for subsequent cohorts in Part B will be determined based on the PK data 
from Part A (single dose), and cohort 3 in Part B (multiple dose). All available PK data 
will be analysed (see Section 9.3.2.1). The dose levels and dosing frequencies will be 
chosen such that the predicted 95% CI of Cmax and AUC at steady state will not exceed 
preclinical Cmax and AUC limits (22.1 g/mL and 250 g.hr/mL, respectively).


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Part C
GSK3039294 will be administered at the predicted optimal clinical dose for 21 days. This 
dose will be determined using the PK/PD model that was developed for CPHPC (active 
molecule) [Sahota, 2015]. Using all available PK and plasma SAP (PD) data from Parts 
A and B, the model will be adjusted for the oral absorption of GSK3039294 and the 
conversion of GSK3039294 to CPHPC. Plasma concentration-time profiles of CPHPC as 
well as the plasma SAP time course after repeat dosing with GSK3039294 will be 
predicted in order to determine the optimal clinical dose and dose frequency. The dose 
level and frequency will be chosen such that the predicted 95% CI of Cmax and AUC at 
steady state will not exceed preclinical Cmax and AUC limits (22.1 g/mL and 250 
g.hr/mL, respectively). See Section 9.3.2.1 for further details of the analysis.
4.6.
Benefit:Risk Assessment
GSK3039294 is an oral prodrug of CPHPC (GSK2315698). CPHPC has been associated 
with a good safety profile in clinical studies to date (see Investigator’s Brochure)
There is no clinical benefit to either healthy volunteer subjects or systemic amyloidosis 
patients in achieving plasma SAP depletion during any Part of the study.  
A NOAEL of 1000 mg/kg/day has been identified in Wistar rats based upon adverse 
findings as regards urine biochemistry in the absence of any identified pathological 
changes within the kidney using light microscopy techniques. Close monitoring of 
plasma and urine biochemical parameters, including renal function and proteinuria 
surveillance, will be performed in all Parts of the study including in systemic amyloidosis 
patients in Part C (see Section 7.1 & Section 7.5).
The release of CPHPC from GSK3039294 will be accompanied by the release of 2 
molecules of formaldehyde. Formaldehyde is generated by endogenous human basal 
metabolism is substantial amounts, (approximately 50g per day).  For a dose of 1.2 g per 
day (a dose not likely to be exceeded in this study), the total amount of formaldehyde
generated would be around 120mg. In addition, a number of prodrug compounds such as 
Viread, Cerebyx, Spectracef and Hepsera releasing up to 120mg/day of formaldehyde
have been described in the literature and there have been no specific human toxicology 
findings [Dhareshwar, 2008] associated with this upper level of formaldehyde release 
from their metabolism Exogenous production of formaldehyde from either food stuffs or 
licensed prodrugs is not known, to date, to cause detectable organ or physiological 
dysfunction in humans.
Summaries of findings from non-clinical studies conducted with GSK3039294 can be 
found in the Investigator’s Brochure. Summaries of findings from both clinical and non-
clinical studies conducted with GSK2315698 can be found in the Investigator’s Brochure. 
The following section outlines the risk assessment and mitigation strategy for this 
protocol:  


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4.6.1.
Risk Assessment
Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
Investigational Product (IP) [e.g., GSK3039294, GSK2315698]
Generation of formaldehyde upon 
transformation of GSK3039294 (prodrug) 
into active (GSK2315698).
Refer to Section 4.5
Maximum dose is likely to be below 1.2g, 
which releases similar amounts of 
formaldehyde as existing prodrugs releasing 
formaldehyde.
GSK2315698 - Epistaxis 
Small volume nose bleeds have been noted 
in a few patients which have been self-
limited and not associated with any 
evidence of thrombocytopenia or 
coagulopathy. 
The relationship to GSK2315698 is unclear 
but subjects are closely monitored for 
bleeding. 
Observe for incidence / severity
Monitoring of haemoglobin & platelets
Potential food effect on PK of GSK3039294 
(and subsequent GSK2315698)
Based on the physical-chemical properties 
of GSK3039294 it is not expected that the 
PK will be affected by food. However, as it 
is not feasible to give bid or tid dosing 
under fasted conditions, administration of 
GSK3039294 in Weeks 2 and 3 of Part B 
and in Part C will be without restrictions 
with respect to meal times.
A potential effect of food will be explored 
in this study (Cohort 3 of Part B). If the 
food effect exploration shows an effect of 
food on the PK of GSK3039294 (and 
subsequently GSK2315698), a formal food 
effect study will be considered.


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Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
Preclinical finding of potential 
nephrotoxicity of GSK3039294
Following 4 weeks oral dosing in rats, 
minor changes in urine composition 
comprising of low pH in males given 300 
mg/kg/day (mean pH was 5.8 and 6.4 at 
1000 mg/kg/day or control respectively) and 
females given 1000 mg/kg/day (mean pH 
was 5.6 and 5.9 at 1000 mg/kg/day or 
control respectively), an increase in total 
protein excretion in both sexes given 1000 
mg/kg/day (up to 1.48X control) and 
increased specific gravity, creatinine and 
glucose output for males given 1000 
mg/kg/day (1.02X, 1.14X and 1.22X 
control, respectively). These changes were 
considered not biochemically concerning, 
and were not associated with any renal 
pathological findings on H&E staining of rat 
kidney paraffin sections. 
Additionally, no change in any urinalysis 
parameters was observed in the dog 28 day 
toxicity study with GSK3039294 at doses 
1000 mg/kg/day.
Overall, in the absence of any renal 
pathological changes under light 
microscopy, the significance of these rat 
renal biochemical changes is unclear.
Precautions as listed in Section 7.4 to detect 
signals of potential nephrotoxicity from 
GSK3039294 in humans at the earliest time 
point possible during both single and repeat 
dose administration in both healthy 
volunteer subjects and systemic amyloidosis 
patients.


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Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
Preclinical finding of haematologic effects 
associated with GSK2315698
In toxicology studies using IV 
GSK2315698, minor reductions in red cell 
parameters were observed in female dogs 
given 200 mg/kg/day for 4 weeks. A 34% 
increase in platelet count was seen in rats 
receiving 400 mg/kg/day for 8 days. 
Some trends (haemoglobin increased; white 
cells and platelets decreased) within the 
reference range were observed in a single 
dose study in healthy volunteers 
(CPH113776). The clinical significance of 
these observations is not clear and similar 
changes were not observed in the patient 
study (CPH114527).
Therefore, at this time, it is felt to be very 
unlikely that GSK2315698 (CPHPC) has 
any haematological toxicity properties in 
human subjects.
Haematological parameters will be 
monitored in the clinic.
Dosing not to exceed the existing NOAEL.
Preclinical finding of testicular changes 
associated with GSK2315698
In one study in male rats (but not in another 
similar study), testicular changes 
(seminiferous tubular degeneration/atrophy, 
reduced spermatozoa, shedding of 
spermatogenic cells) were observed at the 
highest dose tested (400 mg/kg/day for 28 
days). No testicular changes were observed 
in a rat 26 week study (terminated at week 
The highest dose of GSK3039294 will not 
yield exposures of GSK2315698 exceeding 
a predicted mean AUC0-24 of 145 ug*h/mL 
and Cmax of 6.05 ug/mL based on the 
NOAEL in the rat 28 day IV repeat dose 
studies, and therefore the potential risk to 
humans during the proposed short term 
dosing is considered very low


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Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
21) at GSK2315698 doses ≤ 1000 
mg/kg/day.
No testicular changes were observed in rat 
28 day study with GSK3039294 at doses ≤ 
1000 mg/kg/day. In the dog no testicular 
changes have been observed with 
GSK2315698 or GSK3039294 at doses of ≤ 
200 mg/kg/day and ≤ 1000 mg/kg/day, 
respectively.
Preclinical finding of cardiovascular 
changes associated with GSK2315698.
Preclinical finding in preliminary 
cardiovascular screen (rat only) of blood 
pressure, pulse pressure, heart rate increase 
and QA interval reduction associated with 
GSK2315698 (See IB for further 
information).
No arrhythmogenic safety signals were 
detected
Cardiovascular parameters, including blood 
pressure and heart rate, will be closely 
monitored in the clinical study.
Cardiac arrhythmias identified on 24-hour 
Holter after single dose administration of 
GSK3039294 in Part A of this study.
Four (4) asymptomatic, hemodynamically 
stable arrhythmias in 3 healthy volunteer 
subjects were seen on 24-hour Holter 
monitoring after single dose administration 
of GSK3039294 in Part A. 3 / 4 events were 
atrial tachycardias, and 1 / 4 event was a 
single 3.4 second episode of a AIVR (5 
beats). All SVT (atrial) events were less 
Supraventricular or ventricular arrhythmia 
exclusion criterion. Continuous telemetry at 
in-patient dosing. 
Sentinal subject (systemic amyloidosis 
patient with known cardiac amyloid) in Part 
C for cardiac evaluation and monitoring 
prior to further recruitment.  


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Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
than < 11 seconds in duration.
One healthy volunteer subject had two 
separate arrhythmic events which consisted 
of a single episode of atrial tachycardia 10 
minutes after administration of 
GSK3039294 - when neither prodrug or 
CPHPC were detectable - followed by a 
single 5-beat episode of AIVR 
approximately 12 hours later.
Subjects will be withdrawn from the study if 
the Investigator deems any cardiac AE to be 
clinically concerning, and / or triggers the 
measurement of plasma hs-cTn to exclude 
the possibility of arrhythmia-associated 
myocardial ischemia / injury (see Section 
5.4.4. & Section 7.3.7.). 


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4.6.2.
Benefit Assessment
No medical benefit can be expected by participating in this study.
4.6.3.
Overall Benefit:Risk Conclusion
GSK3039294 is an oral prodrug of CPHPC, as such it is expected to release CPHPC after 
oral administration. Previous clinical experience with CPHPC shows it has a good safety 
and tolerability profile therefore we do not anticipate safety issues linked to the release of 
the active moiety.
At this time, although the cardiac arrhythmias reported in Part A are unlikely to be 
attributable to single dose administration of GSK3039294 at either 600mg or 1200mg, as 
a precaution, and to further assess and confirm this conclusion, the cardiac safety 
monitoring of healthy volunteer subjects during repeat dose administration of 
GSK3039294 for 7 consecutive days in Cohort 3 Part B has been enhanced (see Section 
7.3.7.), and also in systemic amyloidosis patients in Cohort 5 Part C who are known to 
have cardiac amyloid involvement (see Section 7.3.8.).
Biotransformation from prodrug into active will release 2 molecules of formaldehyde. 
There is precedent of licensed prodrugs releasing formaldehyde with no associated 
toxicity on a background that formaldehyde is physiologically metabolised very rapidly 
within the systemic circulation (EFSA Journal, 2014; 12(2):3550). 
Preclinical signs of potential nephrotoxicity were observed at very high doses which are 
unlikely to be reached in the clinic, however monitoring of renal function will be 
performed in the study in order to detect any potential changes. 
There will be no medical benefit to healthy volunteers or patients with systemic 
amyloidosis being treated with GSK3039294 alone. The design of the study, schedule of 
assessments, and oversight mean that any risks to participants are minimised including 
those which might potentially affect the kidney and heart, and therefore the clinical study 
is justified.
5.
SELECTION OF STUDY POPULATION AND 
WITHDRAWAL CRITERIA
Specific information regarding warnings, precautions, contraindications, adverse events, 
and other pertinent information on the GSK investigational product or other study 
treatment that may impact subject eligibility is provided in the IB for GSK3039294.
Deviations from inclusion and exclusion criteria are not allowed because they can 
potentially jeopardise the scientific integrity of the study, regulatory acceptability or 
subject safety. Therefore, adherence to the criteria as specified in the protocol is essential.
5.1.
Inclusion Criteria
A subject will be eligible for inclusion in this study only if all of the following criteria 
apply:


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All Subjects
[1] AGE
1. 18 to 70 years of age inclusive at the time of signing the informed consent.
[2] RELEVANT HABITS
1. Non-smokers and Smokers. Smokers (<5 /day) are permitted but must be willing 
to abstain for the duration of residential study sessions and / or dosing period 
(whichever is longer).
[3] WEIGHT
1. Body weight > 50kg and body mass index (BMI) ≥18 kg/m2 (inclusive) and 
excluding the effects of peripheral oedema.
[4] SEX
1. Male or female 
2. Female subjects are eligible to participate if they are of non-childbearing potential 
defined as premenopausal females with a documented tubal ligation or 
hysterectomy or bilateral oophorectomy; or postmenopausal defined as 12 month 
of spontaneous amenorrhea (in questionable cases a blood sample with 
simultaneous follicle stimulating hormone (FSH) > 40 MIU/ml and estradiol < 40 
pg/ml (147 pmol/l) is confirmatory
3. Male subjects with female partners of child bearing potential must comply with 
one of the following contraception requirements from the time of first dose of 
study medication until completion of the follow-up visit
a. Vasectomy with documentation of azoospermia.  
b. Male condom plus partner use of one of the contraceptive options below:

Contraceptive subdermal implant that meets the effectiveness criteria of a 
<1% rate of failure per year, as stated in the product label

Intrauterine device or intrauterine system that meets the SOP effectiveness 
criteria including a <1% rate of failure per year, as stated in the product 
label [Hatcher, 2007a]

Oral Contraceptive, either combined or progestogen alone [Hatcher, 2007a] 
Injectable progestogen [Hatcher, 2007a]

Contraceptive vaginal ring [Hatcher, 2007a]

Percutaneous contraceptive patches [Hatcher, 2007a]

Occlusive cap (female diaphragm or cervical/vault cap) with a vaginal 


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spermicide (foam, gel, cream or suppository).
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
[5] INFORMED CONSENT
1. Capable of giving signed informed consent as described in Section 10.2 which 
includes compliance with the requirements and restrictions listed in the consent 
form and in this protocol
Additional Inclusion Criteria – Healthy Volunteers
[1] TYPE OF SUBJECT
1. Healthy as determined by a responsible and experienced physician, based on a 
medical evaluation including medical history, physical examination, laboratory 
tests and cardiac monitoring. 
2. A subject with a clinical abnormality or laboratory parameter(s) which is/are not 
specifically listed in the inclusion or exclusion criteria, outside the reference range 
for the population being studied may be included only if the investigator in 
consultation with the Medical Monitor if required agree and document that the 
finding is unlikely to introduce additional risk factors and will not interfere with 
the study procedures.
3. AST, ALT, Alkaline phosphatase and bilirubin ≤1.5 ULN (isolated bilirubin >1.5 
ULN is acceptable if bilirubin is fractionated and direct bilirubin <35%)
Additional Inclusion Criteria – Patients 
[1] TYPE OF SUBJECT AND DIAGNOSIS INCLUDING DISEASE SEVERITY 
1. Subject medically diagnosed with systemic amyloidosis
2. SAP scan identifying amyloid at any anatomical site, including subset of patients 
with large amyloid load in the liver
3. Up to and including NYHA class 2 
4. For AL amyloidosis patients, ≥ 6 months post-chemotherapy with either a free 
light chain (FLC) complete response (CR) or a very good partial response 
(VGPR) 
5. eGFR > 50mL/min
6. Alanine amino transferase (ALT) ≤ 3x upper limit of normal (ULN) and bilirubin 
≤1.5x ULN (isolated bilirubin > 1.5 xULN is acceptable if bilirubin was 
fractionated and direct bilirubin <35%), irrespective of alkaline phosphatase 


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(ALP) level
7. Subject is ambulant and capable of attending the clinical unit
Further Inclusion Criteria for Patients with known cardiac amyloid involvement
8. eGFR ≥ 60 mL / min
9. Echocardiogram – LV ejection fraction ≥ 50% within 3 months of screening.
5.2.
Exclusion Criteria
A subject will not be eligible for inclusion in this study if any of the following criteria 
apply:
All Subjects
[1] CONCOMITANT MEDICATIONS
1. Use of prohibited medication (Section 6.11.2)
[2] RELEVANT HABITS
1. History of regular alcohol consumption within 6 months of the study defined as: 

For UK sites – healthy volunteers: an average weekly intake of >21 units for 
males or >14 units for females.  One unit is equivalent to 8 g of alcohol: a half-
pint (~240 mL) of beer, 1 glass (125 mL) of wine or 1 (25 mL) measure of 
spirits. 
[3]  CONTRAINDICATIONS 
1. History of sensitivity to any of the study medications, or metabolite thereof or a
history of drug or other allergy that, in the opinion of the investigator or Medical 
Monitor, contraindicates their participation
[4] DIAGNOSTIC ASSESSMENTS AND OTHER CRITERIA
1. Cohort 3 (Part B) subjects only: Cardiac arrhythmia detected on the 48hr 
screening Holter, with the exception of physiological bradycardia, first-degree 
heart block, supraventricular premature complexes and / or premature ventricular 
complexes (PVCs) less than a single 5-beat AIVR
2.
Cohort 3 (Part B) subjects only: High sensitivity Cardiac Troponin level at 
screening > ULN for the specified assay
3. Presence of hepatitis B surface antigen (HBsAg), positive hepatitis C antibody 
test result at screening or within 3 months prior to first dose of study treatment. 


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4. A positive pre-study drug/alcohol screen (unless a positive test is due to 
prescribed medications)
5. A positive test for HIV antibody
6. Where participation in the study would result in donation of blood or blood 
products in excess of 500 mL within 84 days
7. 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: 30 days, 5 half-lives or twice the duration of the biological effect of 
the investigational product (whichever is longer). Prior to Part A for subjects 
participating in Parts A and B
8. Exposure to more than four new chemical entities within 12 months prior to the 
first dosing day
9. Lactating females 
10. Poor or unsuitable venous access
Additional Exclusion Criteria – Healthy Volunteer
[1]  CONCURRENT CONDITIONS/MEDICAL HISTORY (INCLUDES LIVER 
FUNCTION AND QTc INTERVAL) 
1. Current or chronic history of liver disease, or known hepatic or biliary 
abnormalities (with the exception of Gilbert's syndrome or asymptomatic 
gallstones)
2. QTcF > 450 msec from a mean of triplicate readings triplicate readings taken 5 
minutes apart
Additional Exclusion Criteria – Patients
[1]  CONCURRENT CONDITIONS/MEDICAL HISTORY (INCLUDES LIVER 
FUNCTION AND QTc INTERVAL) 
1. Non-amyloid heart diseases (e.g. epicardial coronary artery heart disease, or non-
amyloid valvular heart disease)
2. Subject with mean QTcF of >480ms from a mean of triplicate readings
3. Cardiac Amyloidosis Patients ONLY – Within 3 months of Screening, Or at 
Screening: a). Sustained (≥ 10 beats) / symptomatic monomorphic ventricular 
tachycardia (VT), or rapid polymorphic VT; b). Complete heart block; c). Brady 
arrhythmias deemed clinically concerning in this patient population by the 
Investigator in consultation with the Medical Monitor
4. Plasma albumin < 30g/litre


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5. A syncopal episode, within 4 weeks of screening
6. Average SBP ≤ 100mmHg at Screening from triplicate readings in Part C 
systemic amyloidosis patients with known cardiac amyloid involvement Or, 
Average SBP ≤ 90mmHg at Screening from triplicate readings in systemic 
amyloidosis patients without known cardiac amyloid involvement
7. Implantable cardiac defibrillator (ICD)
8. Insertion of permanent pacemaker in last 2 months
9. Decompensated or uncontrolled heart failure in last 2 months 
10. Anaemia Hb < 9g/dL
11. Uncontrolled  hypertension in a known hypertensive patient, or fulfilling 
diagnostic criteria of essential hypertension at screening
12. Presence of any co-morbid condition (e.g. severe or unstable coronary artery 
disease; moderate to severe chronic obstructive pulmonary disease) which in the 
opinion of the investigator would increase the potential risk to the subject
13. Non-amyloidosis causes of chronic liver disease (with the exception of Gilbert’s 
syndrome or clinically asymptomatic gallstones)
14. Diabetes Mellitus
15. Glycosuria at Screening
16. Urine pH < 6.0 at screening
17. Hypoalbuminaemia (< 30nmol/L)
18. Hypophosphatemia (less than 0.8mmol/L)
19. Prothombin time >1.5xULN
20.Malabsorption syndrome of any aetiology


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[2] CONCOMITANT MEDICATIONS
1. Compassionate use of CPHPC or participation in a separate clinical trial involving 
CPHPC within 3 months of screening
2. Currently taking any of the following esterase-cleaved prodrug medications: 
cerebyx, aquavan, spectracef, hepsera, viread
3. Anticoagulation therapy within 4 weeks of Screening
4. Currently receiving or have received within 12 weeks of screening 
immunosuppressive anti-cytokine monoclonal antibodies (e.g. anti-TNF or anti-
IL-1), disease modifying drugs (e.g. methotrexate, gold or cyclophosphamide), or 
high-dose infusional steroids (e.g. methylprednisolone), with the exception of 
low-dose maintenance oral corticosteroids (e.g. ≤ 30 mg prednisolone per day)
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 enrolled. In order to ensure transparent reporting of screen failure 
subjects, meet the Consolidated Standards of Reporting Trials (CONSORT) 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 any Serious Adverse Events.


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5.4.
Withdrawal/Stopping Criteria
The following actions must be taken in relation to a subject who fails to attend the clinic 
for a required study visit:

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 to 
have withdrawn from the study with a primary reason of “Lost to Follow-up”. 
Non-compliance to the study regimen or withdrawal of consent (no reason has to be 
given by the individual subject) will lead to the removal from the study. An individual 
subject may withdraw from study treatment at any time at his/her own request, or may be 
withdrawn at any time at her own request, or at the discretion of the investigator for 
safety, behavioural or administrative reasons. 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. The entire study will be terminated if the sponsor (GSK) 
stops the study at any stage.
Individual subjects may be withdrawn at the investigator’s discretion at any time during 
the study, provided there is a valid and confirmable clinical reason. The presence of 
severe AEs predefined as stopping criteria below in Section 5.5, or SAE as defined in
Appendix 3, will lead to the withdrawal of an individual subject. Withdrawn subjects will 
be replaced by new subjects as per the guidance in Section 6.4
5.4.1.
Cardiovascular Safety Stopping Criteria
1. New onset or worsening symptoms of cardiac ischemia which is reasonably 
attributable to GSK3039294
2. Development of decompensated or uncontrolled cardiac failure which is 
reasonably attributable to GSK303294.
3. Systolic blood pressure > 170 mmHg as an average of triplicate readings taken at 
rest over 15 minutes on three consecutive days at any time after administration 
and is reasonably attributable to GSK3039294.
4. Healthy Volunteers & Amyloidosis Patients without bundle branch block:
QTcF > 500 msec, (or a change from baseline of QTcF > 60 msec on a 12-lead 


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ECG in healthy volunteers) which is reasonably attributable to GSK3039294 on 
an average from triplicate readings (see Section 5.4.3). 
5. Systemic Amyloidosis patients with bundle branch block - if baseline QTcF < 
450 msec: QTcF > 500 msec on a 12-lead ECG at any time after administration of 
GSK3039294; If baseline QTcF 450-480 msec: QTcF > 530 msec at any time 
after drug administration and is reasonably attributable to GSK3039294, as an 
average of triplicate readings (see Section 5.4.3).
6. Any cardiovascular SAE as predefined in Appendix 4 after drug administration 
and is reasonably attributable to GSK3039294
Please also see Section 5.4.4. Cardiac Arrhythmia stopping criteria
5.4.2.
Liver Chemistry Stopping Criteria
Liver chemistry stopping and increased monitoring criteria have been designed to 
assure subject safety and evaluate liver event etiology (in alignment with the FDA 
premarketing clinical liver safety guidance). 
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guid
ances/UCM174090.pdf
Study treatment will be discontinued for a healthy volunteer subject in Part A or B, or 
a systemic amyloidosis patient without liver involvement /no biochemical liver 
dysfunction in Part C with baseline liver chemistry within the normal reference range 
for ALT if they are reasonably attrituble to GSK3039294 and provided the following 
liver chemistry stopping criteria are met:


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Phase I Liver Chemistry Stopping Criteria – Liver Stopping Event Algorithm
Continue Study Treatment 
Discontinue Study Treatment 
*INR value not applicable to subjects on anticoagulants 
ALT ≥3xULN 
No
Yes
Must refer to Liver Safety Required Actions and Follow up Assessments  section in the Appendix
Report as an SAE if possible Hy’s Law case: ALT≥3xULN and  Bilirubin≥2xULN (>35% direct)  or 
INR>1.5, if measured*
In Part C, systemic amyloidosis patients will be required to return for follow-up liver 
chemistry assessments within 1 week of the changes from the baseline liver chemistry at 
Day -1 (see Table 6) being reported. Individual systemic amyloidosis patients will be 
withdrawn from the study if the following liver chemistry changes are reported from 
baseline at Day -1 (see Table 6).
Table 6
Change from baseline in liver chemistry for repeat or withdrawal
Baseline
Liver Chemistry
Repeat assessment within 
1 week
Withdrawal
x1 ULN < ALT ≤ x3 ULN
Bilirubin ≤ x1ULN
ALT > x4 ULN
Bilirubin > x 1.5 ULN
ALT > x6 ULN
Bilirubin > x 1.5 ULN
x1 ULN < ALT ≤ x3 ULN
Bilirubin ≤ x1.5 ULN
ALT > x4 ULN
Bilirubin > x 2 ULN
ALT > x6 ULN
Bilirubin > x 2 ULN
Liver Safety Required Actions and Follow up Assessments Section can be found in 
Appendix 2 (Section 12.2)


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5.4.2.1.
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.
5.4.3.
QTc Stopping Criteria
Healthy Volunteers & Amyloidosis Patients:
A healthy volunteer or patient that meets either bulleted criterion below will be 
withdrawn from the study.  

QTcF > 500 msec,

Change from baseline in healthy volunteer subjects: QTcF >60 msec
For patients with underlying bundle branch block, follow the discontinuation criteria 
listed below:
Baseline QTcF with Bundle Branch 
Block
Discontinuation QTcF with Bundle 
Branch Block
< 450 msec
> 500 msec
450 – 480 msec
≥ 530 msec
5.4.4.
Cardiac Arrhythmia Stopping Criteria
All cardiac arrhythmias in individual subjects will be reviewed by the Investigator in 
consultation with the Medical Monitor at the earliest possible opportunity after the event, 
and will also be reviewed by a cardiologist where it is deemed appropriate to do so by the 
Investigator in consultation with the Medical Monitor on a case-by-case basis.
A clinically concerning cardiac arrhythmia in this study is any type of arrhythmia or 
divergent QRS complex morphology that is deemed by the Investigator to be reasonably 
attributable to GSK3039294 - rather than within normal variation for each type of 
affected subject receiving repeat dose GSK3039294; i.e. healthy volunteer subjects in 
Part B, or systemic amyloidosis patients with known cardiac involvement Part C.
Furthermore, a clinically concerning arrhythmia is an adverse event which is deemed by 
the Investigator in consultation with the Medical Monitor to be of sufficient temporal 
duration and / or character to potentially affect subject safety. 
Detection of the following during baseline assessment or following administration of 
GSK3039294 will lead to withdrawal:
a). Sustained (≥ 10 beats) / symptomatic monomorphic ventricular tachycardia (VT), or 
rapid polymorphic VT; b). Complete heart block; c). Brady arrhythmias deemed 


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clinically concerning by the Investigator in consultation with the Medical Monitor (i.e. 
except physiological bradycardia or first degree heart block).
Additional cardiac arrhythmic events could include, but are not restricted, to: 

A sustained arrhythmia (i.e. ≥30 seconds) except physiological bradycardia.

A non-sustained wide-complex tachyarrhythmia ≥ 100 / minute that is:
o
accompanied by symptoms or other new ECG changes (e.g. new ST 
depression)
o
repetitive (e.g. repeated short salvos)
o
Greater than 10 seconds in duration
Subjects who either have a clinically concerning arrhythmic event during the study, or 
where there is electrophysiological diagnostic uncertainty on cardiac telemetry / ECG, 
must be withdrawn from the study, and should have an immediate cardiac troponin level 
evaluated using a high-sensitivity point-of-care assay as outlined in Section 7.3.7 & 
Figure 5, below. 
Affected subjects should be referred to the local cardiology service and the Medical 
Monitor should be informed as soon as possible. 


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Figure 5
Algorithm for Management of Subjects having received one or more 
doses of GSK3039294 in Parts B & C based on Arrhythmia 
Characterization
In Part C, the patient’s amyloidosis physician should be informed as soon as possible 
after any type of cardiac adverse event, by the Medical Monitor, irrespective of the 
patient’s cardiac amyloid status at Screening.
5.4.5.
Renal Stopping Criteria
The presence of any of the following which are reasonably attrituble to GSK3039294 will 
be nominally categorised as a severe adverse event and will constitute individual stopping 
criteria for subjects:
Healthy volunteers (Part A or Part B): 

Spot Urine Protein Creatinine (UPC) ratio > 0.5
Healthy volunteers (Part A or Part B) & Patients (Part C):

Increase in serum creatinine (ΔsCr) of 0.3 g/dL from baseline (or an increase of 50% 
at any time if the baseline is > 0.6 g/dL)

Detectable glycosuria in the presence of concomitant normoglycaemia


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
Hypophosphataemia (less than 0.8mmol/L)

Metabolic acidosis 
All abnormal results should be confirmed within 24 hours before individual subject 
stopping criteria are implemented.
5.4.6.
Stopping Criteria Based On Disease Progression in Systemic 
Amyloidosis Patients in Part C
In Part C, individual systemic amyloidosis patients can be withdrawn at any time during 
the study where the investigator has a reasonable level of clinical suspicion that the 
patient's underlying systemic amyloidosis is worsening (including worsening cardiac 
dysfunction in those patients known to have cardiac amyloid involvement). In this 
setting, the investigator in consultation with the Medical Monitor must refer the patient to 
their primary hospital physician for further consultation and appropriate diagnostic tests
5.5.
Stopping Criteria for the Entire Healthy Volunteer or Patient 
Study Groups

If an SAE occurs that the investigator believes is reasonably attributable to IMP, in 
any subject at any one dose level of GSK3039294, continuation of the study will be 
temporarily halted and no further subjects will be dosed until a full safety review of 
the data has taken place.

If the same severe adverse event is observed in two subjects across all study parts, 
and is reasonably attributable, in the opinion of the investigator, to GSK3039294, the 
study will be temporarily halted and no further subjects will be dosed until a full 
safety review of the study has taken place. 

If the study is temporarily halted, relevant reporting and discussion with the Medical 
Monitor, relevant GSK personnel, and with the applicable regulatory authority will 
take place prior to any resumption of dosing

Every effort will be made to take a blood sample for pharmacokinetic analysis from 
each affected individual at the time of any of the adverse events described above
5.6.
Subject and Study Completion
A completed subject is one who has completed all phases of the study including the final 
follow-up visit.
The end of the study is defined as the last subject’s last visit.


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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 the individual study treatments or the combination of those study 
treatments.
Study Treatment
Product name:
GSK3039294 Capsules
Dosage form:
Capsules 
Unit dose 
strength(s)/Dosage 
level(s):
20 to 200mg
Route of Administration
Oral 
Dosing instructions:
Swallow with water as directed in the SRM
Physical description:
White, opaque capsule
Method for 
individualising dosage:
A single capsule or multiple capsules to be taken depending on the 
dosage required
6.2.
Treatment Assignment
This is an open-label, non-randomised study with no active or placebo control.
GSK3039294 doses will be administered sequentially, as detailed in Section 4.1, and will 
be based on the review of safety, PK and PD data from previous cohorts, dosing sessions 
and study parts. 
6.3.
Planned Dose Adjustments
This protocol allows some alteration from the currently outlined dosing schedule, but the 
maximum daily dose will not exceed pre-clinical exposure limits (Cmax of 22.1 g/mL 
and AUC[0-24] of 250 g.hr/mL).
The decision to proceed to the next dose level of GSK3039294, will be made by the GSK 
Study Team and the investigator based on safety, tolerability and preliminary 
pharmacokinetic and/or pharmacodynamic data (Parts B and C) obtained in at least 6
subjects at the prior dose level (see Section 10.7.1).  The actual doses to be administered 
may be adjusted based on safety, tolerability and preliminary pharmacokinetic and/or 


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pharmacodynamic data at previous dose levels; these dose adjustments may involve 
either an increase or a decrease in the planned dose.
The dosing schedule may also be adjusted to expand a dosing cohort to further evaluate 
safety, pharmacokinetic and/or pharmacodynamic findings at a given dose level, or to add 
cohorts to evaluate additional dose levels.  The study procedures for these additional 
subject(s) or cohort(s) will be the same as that described for other study subjects.
6.4.
Blinding
This will be an open-label, non-randomised, dose-escalation study with no active or 
placebo control.
6.5.
Packaging and Labeling
The contents of the label will be in accordance with all applicable regulatory 
requirements.
6.6.
Preparation/Handling/Storage/Accountability
A description of the methods and materials required for preparation of GSK3039294 will 
be detailed in a Study Specific Technical Agreement/Memo (TTS) or Pharmacy Manual 
which will be accompanied by a Quality Agreement.

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)/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.


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6.7.
Compliance with Study Treatment Administration
When the individual dose for a subject is prepared from a bulk supply, the preparation of 
the dose will be confirmed by a second member of the study site staff. 
When subjects are dosed at the site, they will receive study treatment directly from the 
investigator or designee, under medical supervision.  The date and time of each dose 
administered in the clinic will be recorded in the source documents.  The dose of study 
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.  
Study site personnel will examine each subject’s hands and mouth to ensure that the 
study treatment was ingested.
When subjects self-administer study treatment(s) at home, compliance with GSK3039294 
will be assessed through a dosing record, querying with the subject during the site visits 
and documented in the source documents and CRF.  A record of the number of 
GSK3039294 capsules dispensed to and taken by each subject must be maintained and 
reconciled with study treatment and compliance records.  Treatment start and stop dates, 
including dates for treatment delays and/or dose reductions will also be recorded in the 
CRF.
6.8.
Treatment of Study Treatment Overdose
For this study, any dose of GSK3039294 greater than the agreed dose for a particular 
cohort, dosing session or study part will be considered an overdose.
GSK does not recommend specific treatment for an overdose.
In the event of an overdose the investigator or treating physician should:
1.
Contact the Medical Monitor immediately
2.
Closely monitor the subject for adverse events (AEs)/serious adverse events (SAEs) 
and laboratory abnormalities until GSK3039294 or GSK2315698 (CPHPC) can no 
longer be detected systemically (at least 4 days for GSK2315698 (CPHPC))
3.
Obtain a plasma sample for pharmacokinetic (PK) analysis as soon as possible, but at
least within 7 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.
6.9.
Treatment after the End of the Study
Subjects will not receive any additional treatment from GSK after completion of the 
study because the regimens investigated are not designed as study treatments but to 
investigate PK/PD kinetics of various regimens of GSK3039294 dosing.


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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.
6.10.
Lifestyle and/or Dietary Restrictions
6.10.1.
Meals and Dietary Restrictions

In Part A, and during Cohort 3 of Part B on all dosing days, subjects will be required 
to fast from midnight until 3 hours after administration of study treatment (with the 
exception of Day 5 of Cohort 3 in which subjects will be fed). At other times, snacks 
and meals will be provided by the clinical unit.  Water will be allowed as desired 
except for one hour before and after drug administration.

An investigation into a possible food effect will be conducted on Days 4 and 5 of 
Cohort 3 of Part B in this study (This will only be triggered by the Investigator in 
consultation with the Medical Monitor as per Section 4.2.2). On Day 4 subjects will 
be fasted until following the collection of the 4hr post-dose PK sample, on Day 5 
subjects will be fed prior to PK samples being taken. This investigation will inform 
possible further meal restrictions in the study (rest of Part B and Part C).

There are no meal restrictions for Cohorts 4a and 4b of Part B and all of Part C, 
unless the food effect exploration indicates significant effects on PK.
6.10.2.
Caffeine and Alcohol, and Tobacco

During each dosing session, subjects will abstain from ingesting caffeine- or 
xanthine-containing products (e.g., coffee, tea, cola drinks and chocolate) for at least 
24 hours (48 hours for Cohort 3) prior to the start of dosing until collection of the 
final pharmacokinetic and or pharmacodynamic sample during each session. 

Healthy Subjects: During each treatment period, subjects will abstain from alcohol 
for 24 hours (48 hours for Cohort 3) prior to the start of dosing until collection of the 
final PK sample for each in-house session. Subjects will also abstain from alcohol 
for 24 hours prior to screening and follow-up.  At all other times during the study, 
male subjects should have no more than 2 drinks per day and female subjects should 
have no more than 1 drink per day (1 drink is equivalent to 12 g of alcohol: 360 mL 
of beer, 150 mL of wine or 45 mL of 80 proof distilled spirits).

Patients with raised LFT’s at baseline: No alcohol is to be consumed from D-1 
until follow-up assessments are completed

During each resident dosing session, subjects will abstain from smoking for 12 hours 
prior to administration and until discharge from the clinical unit.


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6.10.3.
Activity
Subjects must abstain from strenuous exercise for at least 48 hrs before each blood 
collection for clinical laboratory tests. Subjects may participate in light recreational 
activities during studies (e.g. watch television, read).
6.11.
Concomitant Medications and Non-Drug Therapies
6.11.1.
Permitted Medications and Non-Drug Therapies
Paracetamol, at doses of 2 grams/day is permitted for use any time during the study.
Other concomitant medication may be considered on a case by case basis by the 
investigator in consultation with the Medical Monitor.
For patients only
Subjects' usual medication can be continued during this study with the exception of those
listed in Section 6.11.2
6.11.2.
Prohibited Medications and Non-Drug Therapies
All Subjects:
Subjects must abstain from taking prescription or non-prescription drugs (including 
vitamins and dietary or herbal supplements), within 14 days prior to the first dose of 
study medication until completion of the follow-up visit, unless in the opinion of the 
Investigator and sponsor the medication will not interfere with the study.
Patients:
The following medications are not permitted in the study. If use is medically required 
then the subject will be withdrawn: 

Immunosuppressive anti-cytokine monoclonal antibodies (e.g. anti-TNF or anti-
IL-1), disease modifying drugs (e.g. cyclophosphamide, methotrexate or gold), or 
high-dose infusional steroids (e.g. methylprednisolone).

Use of anti-coagulant drugs

Use of Domperidone as an antiemetic
7.
STUDY ASSESSMENTS AND PROCEDURES
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 Table, are essential and required for study conduct.
This section lists the procedures and parameters of each planned study assessment.  The 
exact timing of each assessment is listed in the Time and Events Table Section 7.1


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The following points must be noted: 

If assessments are scheduled for the same nominal time, THEN the assessments 
are recommended to occur in the following order:
1.
12-lead ECG
2.
Vital signs
3.
Blood draws.  
Note: The timing of the assessments should allow the blood draw to occur at the 
exact nominal time.

The timing and number of planned study assessments, including safety, 
pharmacokinetic, pharmacodynamic 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 IRB/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 the duration of the study, 
including any extra assessments that may be required.


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7.1.
Time and Events Tables
7.1.1.
Part A – Cohorts 1 and 2, single dose, healthy volunteer subjects
Procedure
Screening 
(within 28 
days of 
Day1)
Treatment Period
Wash 
out
Follow-up 
Day 14
Notes
Day
-1
1
2
3
4
5-13
Outpatient Visit
X
X
Outpatient visit at the end of 
second treatment.
Admission to Clinical Unit
X
X
Admission if due to start next dose 
level on the following day.
Inpatient Stay at Clinical Unit
---------------------
Informed consent
X
Inclusion and exclusion criteria
X
X
Demography
X
Full physical exam including height and weight
X
Brief Physical
X
X
Medical history (includes substance usage)
X
Past and current medical conditions 
X
Urine Drug/Alcohol Breath Test
X
X
FSH and oestradiol (women)
X
Clinical Safety Laboratory Assessments (HIV, 
Hep B and Hep C Screen at screening only1) –
except Core Urine Monitoring Asssessments
X
X
X
X
X
On dosing days, samples to be 
taken in the morning pre-dose.
1If performed within 3 months prior 
to first dose of study treatment, 
testing at screening is not 
required.
Clinical Chemistry Only
X
Core Urine Monitoring Asssessments
X
X
X
X1
X
X
On dosing days, samples to be 
taken in the morning.
124 hrs post-dose
Urine Sample (for storage)
X
24hr Urine collection
X
Collection from dose until 24hrs 
post-dose


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Procedure
Screening 
(within 28 
days of 
Day1)
Treatment Period
Wash 
out
Follow-up 
Day 14
Notes
Day
-1
1
2
3
4
5-13
12-lead ECG and Vital sign
X
X
X
X
X
X
X
Triplicate for all
Pre dose and 0.25, 0.5, 1, 2, 4, 6, 
8, 12, 24, 48 and 72hrs post-dose
24hr holter 
X
X
Continuous from 1hr predose to 
24hr post dose
Study Treatment
X
Single administration
Blood Sampling for pharmacokinetics
-------------
For sampling time points, see 
Section 7.4.1
Discharge from Clinical Unit
X
Following completion of all 
assessments
PGx Sample
-----------------------------------
Pre-dose if possible. Informed 
consent for optional genetics 
research must be obtained before 
collecting a sample
AE/SAE review
X
------------------------------------
X
Concomitant medication review
X
------------------------------------
X


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7.1.2.
Part B – Cohort 3, 7 day repeat dose healthy volunteer subjects
Procedure
Screening 
(within 28 days 
of Day 1)
Treatment Period (Days)
Follow-up
(7-14 days 
following last 
dose)
Notes
-
2
-
1
1
2
3
4
5
6
7
8
Outpatient Visit
X
X
Admission to Clinical Unit
X
Inpatient Stay at Clinical Unit
--------------------------------------------
Informed consent
X
Inclusion and exclusion criteria
X
X
Demography
X
Full physical exam incl height and 
weight
X
Brief Physical
X
X
Medical history (includes substance
usage)
X
Substances: Drugs, Alcohol, 
tobacco and caffeine
Past and current medical conditions 
X
FSH and oestradiol (women)
X
Clinical Safety Laboratory Assessments 
(HIV, Hep B and Hep C Screen at 
screening only1) – except Core Urine 
Monitoring Asssessments
X
X
X
X
X
X
On dosing days, samples to be 
taken in the morning pre-dose.
1If performed within 3 months 
prior to first dose of study 
treatment, testing at screening is 
not required.
Clinical Chemistry Only
X
X
High-sensitivity cardiac Troponin
X
X
Pre-dose
Core Urine Monitoring Asssessments
X
X
X
X
X
X
X
Samples for Urine pH to be taken 
in the morning
Urine Sample (for storage)
X
Urine Drug/Alcohol Breath Test
X
X
12-lead ECG and vital signs
X
X
X
X
X
X
X
X
X
X
X
Triplicate for all. Pre-dose and 1hr 
post-dose
48hr Holter
X


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Procedure
Screening 
(within 28 days 
of Day 1)
Treatment Period (Days)
Follow-up
(7-14 days 
following last 
dose)
Notes
-
2
-
1
1
2
3
4
5
6
7
8
Telemetry
----------------------------------------------------------------------
Temporary removal of telemetry 
(e.g. for showering) is permitted
Evaluation of Food Effect 
X
X
Fasted on Day 4, Fed on Day 5. 
Not to be performed in sentinel 
subjects.
Study Treatment
------------------------------------------
Blood Sampling (PK)
For sampling time points, see Section 7.4.1
X
For 1st dose and escalation
See Section 7.4.1. 
Blood Sampling (PD)
For sampling time points, see Section 7.5
X
Discharge from Clinical Unit
X
Following completion of all 
assessments
PGx Sample
X
Pre-dose if possible. Informed 
consent for optional genetics 
research must be obtained before 
collecting a sample
AE/SAE review
-------------------------------------------------------
X
Concomitant medication review
X
-------------------------------------------------------
X


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7.1.3.
Part B – Cohort 4, 21 day repeat dose healthy volunteer subjects
Procedure
Screening 
(within 28 
days of
Day 1)
Treatment Period (Days)
Follow-up
(7-14 days 
following 
last dose)
Notes
-
1
1
2
3
4
5
6
7
8
9 10 11 12
1
3
14
15
1
6
1
7
18
1
9
2
0
21
Outpatient Visit
X
X2
X
X
2Visit day ± 2 days 
is allowed
Admission to Clinical Unit
X
Inpatient Stay at Clinical 
Unit
-----------------------------
Informed consent
X
Inclusion and exclusion 
criteria
X
X
Demography
X
Full physical exam incl 
height and weight
X
Brief Physical
X
X
Medical history (includes 
substance usage)
X
Substances: 
[Drugs, Alcohol, 
tobacco and 
caffeine]
Past and current medical 
conditions 
X
SH and oestradiol (women)
X
X


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Procedure
Screening 
(within 28 
days of
Day 1)
Treatment Period (Days)
Follow-up
(7-14 days 
following 
last dose)
Notes
-
1
1
2
3
4
5
6
7
8
9 10 11 12
1
3
14
15
1
6
1
7
18
1
9
2
0
21
Clinical Safety Laboratory 
Assessments (HIV, Hep B 
and Hep C Screen at 
screening only1) – except 
Core Urine Monitoring 
Asssessments
X
X
X
X
X
X2
X
X
On dosing days,
samples to be 
taken in the 
morning pre-
dose.
1If performed 
within 3 months 
prior to first dose 
of study treatment, 
testing at 
screening is not 
required.
2Visit day ± 2 days 
is allowed
Clinical Chemistry Only
X
X
Core Urine Monitoring 
Asssessments
X
X
X
X
X
X
X2
X
X
Samples for Urine 
pH to be taken in 
the morning.
2Visit day ± 2 days 
is allowed
Urine Sample (for storage)
X
Urine Drug/Alcohol Breath 
Test
X
X
X
12-lead ECG and vital 
signs
X
X
X
X
X
X
X
X
X
X2
X
X
Triplicate for all.
Pre-dose and 1hr 
post-dose.
2Visit day ± 2 days 
is allowed
Home Dosing Record
-------------------------------------------------------------------


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Procedure
Screening 
(within 28 
days of
Day 1)
Treatment Period (Days)
Follow-up
(7-14 days 
following 
last dose)
Notes
-
1
1
2
3
4
5
6
7
8
9 10 11 12
1
3
14
15
1
6
1
7
18
1
9
2
0
21
Study Treatment
Cohort 4a: Dose and dosing frequency may be altered once during treatment period
------------------------------------------------------------------------------------------------------------------------------
Cohort 4b: dosing regimen will be determined based on information from Cohort 4a
D21 a.m. dosing  
only
Blood Sampling (PK)
For sampling time points, see Section 7.4.1
X
For 1st dose and 
escalation
See Section 7.4.1
Blood Sampling (PD)
For sampling time points, see Section 7.5
X
Discharge from Clinical 
Unit
X
Following 
completion of all 
assessments
PGx Sample
X
Pre-dose if 
possible. Informed 
consent for 
optional genetics 
research must be 
obtained before 
collecting a sample
AE/SAE review
--------------------------------------------------------------------------------------------------------------
X
Concomitant medication 
review
X
--------------------------------------------------------------------------------------------------------------
X


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7.1.4.
Part B – Cohort 4, 21 day repeat dose healthy volunteer subjects – dose alteration (only if dose alteration 
is required)
Should a dose alteration be required, subjects will be re-admitted to the clinical unit and the procedures be administered as stated below. 
Note: The ‘Dose Day’ relates to the first day of the adjusted dose, and not the study day.
Procedure
Dose Days
Notes
-
1
1
2
3
4
5
6
7
Admission to Clinical Unit
X
Inpatient Stay at Clinical 
Unit
-----------------------------
SH and oestradiol (women)
Clinical Safety Laboratory 
Assessments – except 
Core Urine Monitoring 
Asssessments
X
X
X
X
On dosing days, samples to be taken in the 
morning pre-dose.
Clinical Chemistry Only
X
X
Core Urine Monitoring 
Asssessments
X
X
X
X
X
Samples for Urine pH to be taken in the 
morning
Urine Drug/Alcohol Breath 
Test
X
12-lead ECG and vital 
signs
X
X
X
X
X
X
X
X
Triplicate for all. Pre-dose and 1hr post-dose
Study Treatment
------------------------------------------
Blood Sampling (PK)
For sampling time points, see Section 
7.4.1
Blood Sampling (PD)
For sampling time points, see Section 
7.5


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Procedure
Dose Days
Notes
-
1
1
2
3
4
5
6
7
Discharge from Clinical 
Unit
X
Following completion of all assessments
AE/SAE review
----------------------------------------
Concomitant medication 
review
-----------------------------------------
7.1.5.
Part C – Cohort 5, repeat dose, patient subjects
Procedure
Screening (within 28 
days of Day 1)
Treatment Period (Days)
Safety 
Follow-
up
(7-14 
days 
after last 
dose)
PD 
Follow-
up
(weekly 
up to 
D63)
-
1
1
2
3
4
5
6
7
8
9-
11
12
13+ 
14
15
16 
+ 
17
18
19 
+ 
20
21
Outpatient Visit
X
X
X
X
X
X
Admission to Clinical Unit
X
Inpatient Stay at Clinical Unit
-------------------------------------------
Informed consent
X
Inclusion and exclusion 
criteria
X
X
Demography
X
Full physical exam incl height 
and weight
X
Medical history (includes 
substance usage)1
X
Past and current medical 
conditions 
X
FSH and oestradiol (women)
X
X
X
X
X
X


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Procedure
Screening (within 28 
days of Day 1)
Treatment Period (Days)
Safety 
Follow-
up
(7-14 
days 
after last 
dose)
PD 
Follow-
up
(weekly 
up to 
D63)
-
1
1
2
3
4
5
6
7
8
9-
11
12
13+ 
14
15
16 
+ 
17
18
19 
+ 
20
21
Clinical Safety Laboratory 
Assessments2 (HIV, Hep B 
and Hep C Screen at 
screening only3) – except 
Core Urine Monitoring 
Asssessments
X
X
X
X
X
X
X
X
X
X
X
Clinical Chemistry Only
X
X
X
High-sensitivity cardiac 
Troponin3
X
X
Core Urine Monitoring 
Asssessments (except Spot 
UPC ratio)4
X
X
X
X
X
X
X
X
X
X
X
X
Urine Sample (for storage)
X
Urine Drug/Alcohol Breath 
Test
X
X
X
X
X
X
X
Echocardiogram5
X
12-lead ECG and vital signs
X
X
X
X
X
X
X
X
X
X
X
Lead II monitoring6
X8
-------------------------------------------------------------
Home Dosing Record
X
X
X
X
X
X
X
X
Study Treatment
--------------------------------------------------------------------------------------------------
Blood Sampling (PK)
For sampling time points, see Section 7.4.1
Blood Sampling (PD)
For sampling time points, see Section 7.5
X
X
Brief Physical
X
X
Discharge from Clinical Unit
X


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Procedure
Screening (within 28 
days of Day 1)
Treatment Period (Days)
Safety 
Follow-
up
(7-14 
days 
after last 
dose)
PD 
Follow-
up
(weekly 
up to 
D63)
-
1
1
2
3
4
5
6
7
8
9-
11
12
13+ 
14
15
16 
+ 
17
18
19 
+ 
20
21
PGx Sample 7
X
AE/SAE review
-------------------------------------------------------------------------------------------------------
X
X
Concomitant medication 
review
X
-------------------------------------------------------------------------------------------------------
X
1.
Substances: Drugs, Alcohol, tobacco and caffeine
2.
On dosing days, samples to be taken in the morning pre-dose.
3.
If test otherwise performed within 3 months prior to first dose of study treatment, testing at screening is not required
4.
Samples to be taken in the morning pre-dose.
5.
Patients with known cardiac amyloid involvement only. If test otherwise performed within 3 months of screening, and the patient has remained overall 
symptomatically stable during that time, then no testing at screening is required; otherwise, an echocardiogram is required at Screening
6.
Patients with known cardiac involvement only. It is permissible to temporarily remove Telemetry from the subject for activities of daily living (e.g. showering) 
during patient monitoring
7.
Informed consent for optional genetics research must be obtained before collecting a sample, sample to be collected pre-dose if possible
8.
7 day out-patient cardiac monitoring (Body Guardian or similar) only in patients with known cardiac involvement.


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7.2.
Screening and Critical Baseline Assessments
Cardiovascular medical history/risk factors (as detailed in the CRF) will be assessed at 
screening.
The following demographic parameters will be captured: year of birth, sex, race and 
ethnicity.
Medical/medication/family history will be assessed as related to the inclusion/exclusion 
criteria listed in Section 5.  
Procedures conducted as part of the subject’s routine clinical management e.g. blood 
count and obtained prior to signing of informed consent may be utilized for Screening or 
baseline purposes provided the procedure meets the protocol-defined criteria and has 
been performed in the timeframe of the study.
7.3.
Safety
Planned time points for all safety assessments are listed 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 (AE) and Serious Adverse Events (SAEs)
The definitions of an AE or SAE can be found in Appendix 4 and Section 12.4
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

AEs and SAEs will be collected from the start of Study Treatment until the follow-
up contact (see Section 7.3.1.3), at the timepoints 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.

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. 

All SAEs will be recorded and reported to GSK within 24 hours, as indicated in 
Appendix 4 .

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 


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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 4
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). Further information on follow-up procedures is given in 
Appendix 4 .
7.3.1.4.
Regulatory Reporting Requirements for SAEs
Prompt notification by the investigator to GSK of SAEs and non-serious AEs 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, Institutional Review Board (IRB)/Independent Ethics Committee 
(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 a 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 IRB/IEC, if appropriate according to local requirements.


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7.3.2.
Pregnancy

Details of all pregnancies in female partners of male subjects will be collected after 
the start of dosing and until follow-up.

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.
7.3.3.
Physical Exams

A complete physical examination will include, at a minimum, assessment of the 
Cardiovascular, Respiratory, Gastrointestinal and Neurological systems. Height and 
weight will also be measured and recorded. 

A brief physical examination will include, at a minimum assessments of the lungs, 
cardiovascular system, and abdomen (liver and spleen).

Investigators should pay special attention to clinical signs related to previous serious 
illnesses
7.3.4.
Vital Signs

Vital signs will be measured in semi-supine position after 5 minutes rest and will 
include temperature, systolic and diastolic blood pressure and pulse. 

Triplicate readings of blood pressure and pulse rate will be taken and averaged at all 
times.
7.3.5.
Cardiac Monitoring – Electrocardiogram (ECG), Telemetry & Non-
Implantable Devices for Remote Monitoring

12-lead ECGs will be measured in semi-supine position after 5 minutes rest 
(triplicate readings will be taken and averaged at all times) will be obtained at each 
timepoint during the study using an ECG machine that automatically calculates the 
heart rate and measures PR, QRS, QT, and QTcF intervals. Refer to Section 5.4.3 for 
QTcF withdrawal criteria and additional QTcF readings that may be necessary.
7.3.5.1.
Cardiac Safety Monitoring in Cohort 3 (Part B) at Screening & Baseline
This will consist of a 48 hour Holter at Screening and continuous telemetry for 24 hours 
immediately preceding the first dose of GSK303294 at baseline. 

In-Patient Dosing with GSK3039294: Continuous telemetry during repeat 7 day 
dosing of healthy volunteer subjects in Cohort 3 will be performed for up to 
approximately 24 hours after Day 7 to detect any cardiac arrhythmias potentially 
attributable to repeat dosing with GSK3039294 for 7 days in Cohort 3.


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7.3.5.2.
Cardiac Safety Monitoring in Cohort 5 (Part C) patients with known 
cardiac amyloid involvement

Screening: 7-day out-patient cardiac monitoring using an appropriate non-
implantable recording device which is acceptable to the patient – this will 
evaluate the arrhythmic background of eligible cardiac amyloidosis patients such 
that false positive attribution of arrhythmias to GSK3039294 during repeat dosing 
will be minimized.

Baseline: 24 hour in-patient telemetry immediately before the first dose of 
GSK3039294.

In-patient dosing with GSK3039294: Continuous telemetry will be performed 
for up to 24 hours after Day 7 administration of GSK3039294 to detect any 
arrhythmias in patients with known cardiac amyloidosis potentially attributable to 
repeat dosing with GSK3039294 including worsening of known patient-specific 
arrhythmias from Screening and / or Baseline assessments.

Optional cardiac monitoring after completion of in-patient dosing: At 
Investigator discretion, on a case by case basis determined by in-patient cardiac 
telemetry / ECG findings, and in consultation with the Medical Monitor, cardiac 
monitoring can be extended either as an in-patient or as an out-patient (using a 
portable non-implantable device of Investigator choosing) in patients with known 
cardiac amyloidosis.
Cardiac monitoring should continue in cardiac amyloidosis patients based on emerging 
safety data until it is deemed to be clinically appropriate for monitoring to stop after 
consultation with the Medical Monitor.
7.3.6.
Clinical Safety Laboratory Assessments
All protocol required laboratory assessments, as defined in Table 7, must be conducted in 
accordance with the Laboratory Manual, and Protocol Time and Events Schedule.
Laboratory requisition forms must be completed and samples must be clearly labelled 
with the subject number, protocol number, site/centre number, and visit date. Details for 
the preparation and shipment of samples will be provided by the laboratory and are 
detailed in the SRM. Reference ranges for all safety parameters will be provided to the 
site by the laboratory responsible for the assessments.
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 or AE or dose 
modification) the results must be recorded in the CRF.
Refer to the SRM for appropriate processing and handling of samples to avoid duplicate 
and/or additional blood draws.


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Haematology, clinical chemistry, urinalysis and additional parameters to be tested are 
listed in Table 7.
Table 7
Protocol Required Clinical Safety Laboratory Assessments
Laboratory 
Assessments
Parameters
Haematology
Platelet Count
RBC Indices:
WBC count with Differential:
RBC Count
MCV
Neutrophils
Hemoglobin
MCH
Lymphocytes
Hematocrit
Monocytes
Prothrombin Time
Eosinophils
Basophils
Clinical 
Chemistry 1
BUN
Potassium
AST (SGOT)
Total and direct 
bilirubin
Creatinine
Sodium
ALT (SGPT)
Total Protein
Glucose 
Calcium
Alkaline phosphatase
Albumin
Phosphate
Bicarbonate
Routine 
Urinalysis

Specific gravity

pH, glucose, protein, blood and ketones by dipstick

Microscopic examination (if blood or protein in healthy subjects is
abnormal)
Core Urine 
Monitoring 
Asssessments

Spot UPC ratio

Glycosuria using dipstix

Urine pH using a pH meter
Other 
Screening 
Tests

HIV

Hepatitis B (HBsAg)

Hepatitis C (Hep C antibody)

FSH and estradiol (as needed in women of non-child bearing 
potential only)

Alcohol and drug screen (to include at minimum: amphetamines, 
barbiturates, cocaine, opiates, cannabinoids and benzodiazepines)
NOTES :
1.
Details of Liver Chemistry Stopping Criteria and Required Actions and Follow-Up 
Assessments after liver stopping or monitoring event are given in Section 6 and
Appendix 2
2.
Local urine testing will be standard for the protocol unless serum testing is required 
by local regulation or ethics committee.


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7.3.7.
High Sensitivity Cardiac Troponin-T (hs-cTnT) Monitoring after a 
Cardiac Arrhythmia in Part B, or Part C
Baseline hs-cTnT: In Part B  and Part C, all subjects will have hs-cTn level for purposes 
of screening as well as to provide baseline with which to compare, in the event that a 
subject develops a clinically concerning cardiac arrhythmic event after dosing with 
GSK3039294. 
Subjects should be advised by the local study site to abstain from strenuous exercise (e.g. 
running or gym work) ≤ 24 hours before a baseline hs-cTn level is taken.
Monitoring of hs-cTnT after an Arrhythmia Event: A blood samples for hs-cTnT will 
be taken immediately at the time of onset of a cardiac arrhythmia which is deemed by the 
Investigator to be of clinical concern (see Section 5.4.4), or where there is 
electrophysiological diagnostic uncertainty. 
High-sensitivity cTn levels should be serially repeated (using the same assay) following 
local troponin monitoring protocols at the study site, and with advice from a cardiologist 
if this is deemed clinically necessary by the Investigator. 
Additional investigations, including but not restricted to serial ECGs and evaluation of 
cardiac function using echocardiogram and / or cardiac magnetic resonance (CMR) 
imaging, can be performed at the discretion of the Investigator in consultation with the 
Medical Monitor and a cardiologist.
7.3.8.
Renal Safety Monitoring
All urine studies will be performed in the early morning prior to eating in healthy 
volunteers (with the expection of the Part B, Day 4 which will be fasting) and patients. 
For all Parts of the study, a urine sample will be taken and stored from individual subjects 
at baseline for each dose level in Part A, at the beginning of week 1 for repeat dosing in 
Parts B & C, and at the beginning of week 2 in Part B only (see T&E Table).
Core renal parameters will assessed frequently as shown in the T&E Tables.
Table 8
Monitoring of Renal Functions
Subject Group
Core Renal Parameters
Assessments
Healthy Volunteers
Detection of Protinuria
Spot UPC ratio
Healthy Volunteers & Patients
Assessments of Renal 
Function
Changes in Serum Creatinine
Healthy Volunteers & Patients
Assessment of Tubule 
Function
-Glycosuria using dipstix 
-Urine pH using a pH meter


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Subject Group
Core Renal Parameters
Assessments
-Plasma phosphate levels
Healthy Volunteers & Patients
Assessment of Metabolic 
Acidosis (if required)
Whenever urine pH is 
confirmed to be < 6.0 on an 
average of three readings over 
10 minutes from the same 
urine sample additional 
assesments e.g. a venous 
bicarbonate analysis will be 
initially performed. If this is 
deemed to be low, an arterial 
blood gas (ABG) must then be 
performed to investigate 
development of metabolic 
acidosis.
7.3.8.1.
Guidance on the Clinical Approach for Suspected Renal Injury
If Renal Injury is Suspected (any subject), additional urine samples will be taken on a 
prospective basis if biochemical signatures of renal injury are detected at any time during 
the study. Urine samples will be analysed for biomarkers of renal injury (e.g. KIM-1 and 
NGAL), as well as for the presence of small molecular proteins (e.g. cystatin C & α1-
microglobulin). The Investigator should liaise with a local nephrologist as regards any 
additional investigations which may be necessary to confirm either that renal injury has 
occurred or its nature.
7.4.
Pharmacokinetics
7.4.1.
Blood Sample Collection
Blood samples for pharmacokinetic (PK) analysis of GSK3039294 (pro-drug), and 
GSK2315698 (CPHPC) will be collected at the time points indicated.  The actual date 
and time of each blood sample collection will be recorded.  The timing of PK samples 
may be altered and/or PK samples may be obtained at additional time points to ensure 
thorough PK monitoring.  
Part A (Single dose to Healthy Volunteers):
Pre-dose, and 0.25; 0.5; 0.75; 1; 1.5; 2; 3; 4; 5; 6; 8; 10; 12; 16; 24 and 48 hrs post-dose.


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Part B – Cohort 3 (7 day repeat dose to Healthy Volunteers):
Study Day
PK sampling timepoint(s)
1
Pre-dose, and 0.5, 1, 2, 3, 4, 6 hrs post-dose
2&3
Pre-dose
4*
Pre-dose, and 0.5; 1; 2; 3; 4; 6 hrs post-dose
5
Pre-dose, and 0.5; 1; 2; 3; 4; 6 hrs post-dose
Follow-up 
(7 – 14 
days post-
dose)
Single sample
*Day 4 PK samples will not be collected for sentinel subjects
Part B – Cohort 4a/b (21 day repeat dose to Healthy Volunteers):
Study Day
PK sampling timepoint(s)
1
Pre-dose, and 2hr post-dose (1st dose of the day only)
2-4
Pre-dose (before 1st dose of the day only)
5
Pre-dose, and 0.5; 1; 2; 3; 4; 6 hrs post-dose (1st dose of the 
day only)
21
Pre-dose, and 0.5; 1; 2; 3; 4; 6; 8 and 12 hrs post-dose (1st 
dose; note: 12hr post dose sample to be taken before next 
dose administration
Follow-up 
(7 – 14 
days post-
dose)
Single sample
If a dose adjustment is required within the 21 day repeat dose period, PK samples will 
also taken at timepoints indicated below. Note: The ‘Dose Day’ relates to the first day of 
the adjusted dose, and not the study day.
Dose Day
PK sampling timepoint(s)
-1
Pre-dose
1
Pre-dose, and 2hr post-dose (1st dose of the day only)
2-4
Pre-dose (before 1st dose of the day only)
5
Pre-dose, and 0.5; 1; 2; 3; 4; 6 hrs post-dose (1st dose of the 
day only)
Study Day
21
Pre-dose, and 0.5; 1; 2; 3; 4; 6; 8 and 12 hrs post-dose (1st 
dose; note: 12hr post dose sample to be taken before next 
dose administration
Follow-up 
(7 – 14 
days post-
dose)
Single sample


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Part C (Repeat dose to patients):
Study Day
PK sampling timepoint(s)
1
Pre-dose, and 0.25; 0.5; 0.75; 1; 1.5; 2; 3; 4; 5; 6; 8; 10 and 12 hrs post-dose 
(note: 12hr post-dose sample to be taken before next dose administration)
2-7
Pre-dose (before 1st dose of the day only)
8-20
Pre-dose (before 1st dose of the day only) on days that a visit is planned
21
Pre-dose, and 0.5; 1; 2; 3; 4; 6; 8 and 12 hrs post-dose (1st dose; note: 12hr 
post dose sample to be taken before next dose administration)
During Follow-up
1 sample/wk (for first 2 weeks only)
Processing, storage and shipping procedures are provided in the Study Reference Manual 
(SRM).
7.4.2.
Urine Collection
Urine samples for exploratory analysis of GSK3039294, GSK2315698 and possible 
metabolites will be collected. Details of PK urine sample collection, processing, storage 
and shipping procedures are provided in the SRM.
7.4.3.
Sample Analysis
Pharmacokinetic sample analysis will be performed under the control of PTS-DMPK, 
GlaxoSmithKline, the details of which will be included in the Study Reference Manual 
(SRM). Concentrations of GSK3039294 and GSK2315698 will be determined in blood 
and plasma samples, respectively, using the currently approved bioanalytical 
methodology. Raw data will be archived at the bioanalytical site (detailed in the SRM).
Once blood / plasma has been analyzed for GSK3039294 and GSK2315698 any 
remaining blood and plasma extracts may be analyzed for other compound-related 
metabolites and the results reported under a separate PTS-DMPK, GlaxoSmithKline 
protocol. The urine samples will be analysed for compound-related material and the 
results will be reported under a separate DMPK protocol.
7.5.
Biomarker(s)/Pharmacodynamic Markers
Blood samples for pharmacodynamic (PD) analysis will be collected at the time points 
indicated .  The actual date and time of each blood sample collection will be recorded.  
The timing of PD samples may be altered and/or PD samples may be obtained at 
additional time points to ensure thorough PD monitoring.
Sampling times for SAP samples are given in Table 9 and Table 10 The timing of SAP
samples may be altered and/or SAP samples may be obtained at additional time points to 
ensure thorough SAP monitoring. At each time point samples will be taken from all 
subjects, however, samples will be analysed on a needs basis.
Blood samples taken in Part B for PD analysis will also be used for the development and 
validation of a companion diagnostic assay for the analysis of SAP. Blood for this will be 
taken as an aliquot and stored from the sample that is already being taken for PD 
analysis.


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Table 9
Part B (repeat dose to Healthy Volunteers)
Cohort 3 (7 day repeat dose to Healthy Volunteers):
Study Day
PD sampling timepoint(s)
1
Pre-dose, and 2hr post-dose
2 and 4
Pre-dose
5
Pre-dose, and 0.5; 1; 2; 3; 4; 6 hrs post-dose
7
Pre-dose (before 1st dose of the day only)
Follow-up (7 – 14 days post-dose)
Single sample
Cohort 4a/b (21 day repeat dose to Healthy Volunteers):
Study Day
PD sampling timepoint(s)
1
Pre-dose, and 2hr post-dose (1st dose only)
2 and 4
Pre-dose (before 1st dose of the day only)
5
Pre-dose, and 2hr post-dose (1st dose of the day only)
Follow-up (7 – 14 days post-dose)
Single sample
If a dose adjustment is required within the 21 day repeat dose period (Cohort 4a/4b), PD 
samples will also taken at timepoints indicated below. Note: The ‘Dose Day’ relates to 
the first day of the adjusted dose, and not the study day.
Dose Day
PD sampling timepoint(s)
-1
Pre-dose
1
Pre-dose, and 2hr post-dose (1st dose only)
2-4
Pre-dose (before 1st dose of the day only)
5
Pre-dose, and 2hr post-dose (1st dose of the day only)
Study Day
Follow-up 
(7 – 14 
days post-
dose)
Single sample
Table 10
Part C (Repeat dose to Patients)
Study Day
PD sampling timepoint(s)
1
Pre-dose, and; 2; 4; 6; and 12 hrs post-dose (note: 12hr 
post-dose sample to be taken before next dose 
administration)
2-7
Pre-dose (before 1st dose of the day only)
8-20
Pre-dose (before 1st dose of the day only) on days that a 
visit is planned
21
Pre-dose, and 0.5; 1; 2; 3; 4; 6; 8 and 12 hrs post-dose 
(1st dose; note: 12hr post dose sample to be taken before 


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Study Day
PD sampling timepoint(s)
next dose administration)
Safety Follow-up
Single sample
PD Follow-up
1 sample/wk up to 6 weeks
7.6.
Genetics
In the event of an unexpected PK profile (i.e. increased or decreased metabolism of 
GSK3039294) being observed in an individual subject during any Part of the study, 
germline SNP analysis for recognised esterase-encoded genes which have been 
previously implicated in the dysfunctional metabolism of other esterase-cleaved 
prodrugs (e.g. CES-1 in oseltamivir), or genome-wide locus agnostic analysis, will 
be initiated from the stored blood samples of the affected individual subject(s). In 
addition, the stored blood samples of the remaining unaffected subjects within that 
particular part of the study will also undergo SNP analysis. This will facilitate 
comparative SNP data analysis of the affected subject(s) versus the rest of the study 
population.
Information regarding genetic research will be included in Appendix 3.
8.
DATA MANAGEMENT

For this study, the data collection tool will be PIMS, a validated computer software 
program. In all cases, subject initials will be collected in source documentation at the 
site but will not be transmitted to GSK sponsor team.

Subject data necessary for analysis and reporting will be entered/transmitted into a 
validated database or data system. 

Management of clinical data will be performed in accordance with applicable GSK 
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 
(Medical Dictionary for Regulatory Activities) and an internal validated medication 
dictionary, GSKDrug.  

CRFs (including queries and audit trails) will be retained by GSK.  Subject initials 
will not be transmitted to GSK according to GSK policy.
9.
STATISTICAL CONSIDERATIONS AND DATA 
ANALYSES
9.1.
Hypotheses
No formal hypotheses will be tested in this study.
9.2.
Sample Size Considerations
9.2.1.
Sample Size Assumptions
The sample size for this study is based primarily on feasibility.  An assessment of the 
planned sample size has been based on the level of precision the study would provide 


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around the estimated true rate of a given safety event and around the estimated SAP 
depletion levels for a given dose. 
9.2.1.1.
Safety
Table 11 presents the 95% credible interval for the true event rate of a specific AE, 
assuming various observed AE rates and a sample size of 6 and 12. Here the credible 
interval specifies with a fixed probability of 95%, a range of values for the true AE rate 
after updating some prior position on the true AE rate with the AE data observed during 
the study. In general, a larger sample size will yield a narrower 95% credible interval.
For example, if we observe one specific adverse event in a single cohort/dosing session 
with n=6, ie an observed AE rate of 17%, then there is a 95% probability that the true AE 
rate lies between 4 and 58%. This implies that a true AE rate of greater than 58% could 
occur, though with a 2.5% probability.
Similarly, if we observe one specific adverse event in a single cohort/dosing session with 
n=12, ie an observed AE rate of 8%, then there is a 95% probability that the true AE rate 
lies between 2 and 36%. This implies that a true AE rate of greater than 36% could occur, 
though with a 2.5% probability.
Table 11
95% credible intervals for observed adverse event rate
Number of 
subjects per 
cohort/dose (n)
Observed 
number subjects 
with adverse 
event
Observed 
adverse event 
rate 
95% credible interval 
for adverse event rate, 
given observed data1
6
0
0.00
(0.00, 0.41)
6
1
0.17
(0.04, 0.58)
6
2
0.33
(0.10, 0.71)
12
0
0.00
(0.00, 0.25)
12
1
0.08
(0.02, 0.36)
12
2
0.17
(0.05, 0.45)
(1) derived within a Bayesian framework with a non-informative conjugate prior distribution Beta(1,1)
9.2.1.2.
Pharmacodynamics (Plasma SAP)
The standard deviation of log-transformed post-dose plasma SAP depletion levels, based 
on completed CPHPC studies to date, is assumed to be approximately 0.3 in healthy 
volunteers and between 0.7 and 0.9 in systemic amyloidosis patients.  
With an assumed standard deviation of 0.9 for log-transformed post-dose plasma SAP 
depletion levels, and 6 subjects, the upper limit of the 95% confidence interval (CI) 
around the observed geometric mean post-dose plasma SAP level will be 2.57 times the 
observed geometric mean. Hence, if we observe a geometric mean post-dose plasma SAP 
level of 2mg/L, then the upper limit of the 95% CI around this observed geometric mean 


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will be approximately 5.1mg/L.  Similarly, if we observe a geometric mean post-dose 
plasma SAP level of 0.5mg/L, then the upper limit of the 95% CI around this observed 
geometric mean will be approximately 1.3mg/L.  
A small gain in precision is achieved with more than 6 subjects (see Section 9.2.2, 
Sample Size Sensitivity).
9.2.2.
Sample Size Sensitivity
An assessment of sample size sensitivity has been based on the level of precision the 
study would provide around the estimated true rate of a given safety event and around the 
estimated SAP depletion levels for a given dose.
9.2.2.1.
Safety
Table 12 presents the 95% credible interval for the true event rate of a given AE, 
assuming various observed AE rates and selected sample sizes between 5 and 20.  
Sample sizes of less than 6 per cohort/dosing session were not planned since this would 
mean, irrespective of the number of events for a given AE in a single cohort/dosing 
session (i.e. an observed AE rate of ≥0%) that the upper limit of the 95% credible interval 
for the true AE rate would range as high as approximately 50% or more.
Sample sizes greater than 12 per cohort/dosing session were not planned since in order to 
provide significant gains in terms of safety information, the sample size would need to be 
increased beyond feasibility.  For example, with a sample size of 20, if we observe one 
given adverse event (ie an observed AE rate of 5%) then a 95% credible interval about 
the true AE rate would still have an upper limit as high as 24%.
Table 12
95% credible intervals for observed adverse event rate
N
Observed 
number subjects 
with adverse 
event
Observed 
adverse event 
rate 
95% credible interval 
for adverse event rate, 
given observed data1
5
0
0.00
(0.00, 0.46)
5
1
0.20
(0.04, 0.64)
6
0
0.00
(0.00, 0.41)
6
1
0.17
(0.04, 0.58)
8
0
0.00
(0.00, 0.34)
8
1
0.13
(0.03, 0.48)
10
0
0.00 
(0.00, 0.28) 
10
1
0.10 
(0.02, 0.41) 


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N
Observed 
number subjects 
with adverse 
event
Observed 
adverse event 
rate 
95% credible interval 
for adverse event rate, 
given observed data1
12
0
0.00 
(0.00, 0.25) 
12
1
0.08 
(0.02, 0.36) 
14
0
0.00 
(0.00, 0.22) 
14
1
0.07 
(0.02, 0.32) 
16
0
0.00 
(0.00, 0.20) 
16
1
0.06 
(0.01, 0.29) 
18
0
0.00 
(0.00, 0.18) 
18
1
0.06 
(0.01, 0.26) 
20
0
0.00 
(0.00, 0.16) 
20
1
0.05 
(0.01, 0.24) 
(1) derived within a Bayesian framework with a non-informative conjugate prior distribution Beta(1,1)
9.2.2.2.
Pharmacodynamics (Plasma SAP)
Figure 5 shows how the precision around the observed geometric mean post-dose plasma 
SAP levels improves with decreasing standard deviation and increasing sample size (i.e. 
the factor by which the upper 95% CI is above the observed geometric mean decreases 
with decreasing standard deviation and increasing sample size). 
Given an expected post-dose depletion level for plasma SAP to less than 2mg/L, no 
significant improvement in precision would be achieved with greater than 6 subjects.  
Similarly, precision levels across the explored range of standard deviations would not 
differ significantly.


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Figure 6
Impact of standard deviation and sample size on precision
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
1.0
1.5
2.0
2.5
3.0
3.5
4.0
4.5
5.0
N per dose group
5
6
7
8
9
10
11
12
Assumed standard deviation (for log-transformed post-dose plasma SAP)
Precision Factor
Upper limit of 95% CI = (estimated post-dose plasma SAP) x (precision factor)
Lower limit of 95% CI = (estimated post-dose plasma SAP) / (precision factor)
9.2.3.
Sample Size Re-estimation or Adjustment
Additional subjects/cohorts may be enrolled to allow for further evaluation of a given 
dose or for evaluation of additional dose levels. 
9.3.
Data Analysis Considerations
9.3.1.
Analysis Populations
Safety Population:
This population is defined as all subjects who received at least one dose of study 
medication.  This will be the primary population for assessing safety.


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PK Population:
This population is defined as all subjects administered at least one dose of study 
medication and who have at least one PK sample taken and analysed.  This will be the 
primary population for assessing PK.  Subjects will be classified by the actual dose 
received.
PD Population:
This population is defined as all subjects who received at least one dose of study 
medication and who also have a baseline measurement and at least one post-treatment PD 
measure. This will be the primary population for assessing PD.  Subjects will be 
classified by the actual dose received.
PK/PD Population:
This population is defined as all subjects included in both the PK and PD populations.  
This will be the primary population for PK/PD modelling.  Subjects will be classified by 
the actual dose received.
9.3.2.
Interim Analysis
Data will be reviewed on an ongoing basis throughout the study by the study team and 
investigator in order to inform dosing decisions for subsequent dosing sessions, cohorts 
and study parts.  Dose escalation meetings will be held prior to increasing the dose. Key 
data to inform dosing decisions will include but not be limited to: safety (AEs, clinical 
laboratory data, vital signs and ECGs), PK (concentrations of GSK2315698, and if 
possible, GSK3039294 and the intermediate molecule GSK3037412), and plasma SAP 
levels (Parts B & C only).
In addition to the ongoing review of data throughout the study, at the end of Part B,
individual profiles over time will be presented graphically for selected urine and plasma 
laboratory parameters pertaining to the kidney. Individual profiles will be presented for 
both single and repeat-dose healthy volunteer data to further inform the evaluation of 
renal safety and the decision to progress to repeat dosing in systemic amyloidosis patients 
in Part C.
9.3.2.1.
Pharmacokinetics and pharmacodynamics
To inform dosing decisions for subsequent dosing sessions in Part A, individual values of 
Cmax and AUC[0-inf] will be derived by means of non-compartmental analysis. 
Assuming linear kinetics, the next dose will be such that the 95%CI of Cmax and AUC 
will not exceed preclinical safety limits (22.1 g /mL and 250 g.hr/mL, respectively).
To inform dosing decisions for subsequent study parts, GSK2315698 concentration data 
and plasma SAP levels will be analysed using the PK/PD model that was developed for 
GSK2315698 [Sahota, 2015]. Based on pre-clinical data it is expected that the 
conversion of GSK3039294 to GSK2315698 is very fast. Therefore, it can be assumed 
that this conversion will occur mainly during the absorption phase, and that the 


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distribution and elimination of GSK2315968 are not altered. Therefore, all distribution 
and elimination parameters (PK/PD) will be fixed to the reported parameter estimates, 
and only bioavailability (F) and absorption related parameters (e.g. Ka) will be estimated. 
Nominal time points will be used for this interim analysis. This updated model will be 
used to simulate concentration-time data and plasma SAP levels using different dose 
levels and dosing regimens, which will be used to inform dosing decisions for subsequent 
dosing sessions, cohorts and study parts.
9.4.
Key Elements of Analysis Plan
9.4.1.
Primary Analyses
Safety data will be listed and presented in tabular and/or graphical format, as appropriate, 
and summarized descriptively according to GSK’s Integrated Data Standards Library 
(IDSL) standards.
9.4.2.
Secondary Analyses
9.4.2.1.
Pharmacokinetics, pharmacodynamics and PK/PD model
Concentration data of GSK2315698 and GSK3039294 will be listed and presented in 
tabular and graphical format, as appropriate, and summarised descriptively. Further 
details will be described in the RAP.
Individual plasma SAP profiles over time will be listed and presented graphically.  
Plasma SAP levels will be log-transformed, or other transformation as appropriate, and 
summarised over time by cohort/dose, together with corresponding 95% confidence 
intervals.  Further details will be described in the RAP.
GSK2315698 concentration data and plasma SAP levels will be analysed using the 
PK/PD model that was developed for GSK2315698 [Sahota, 2015]. Based on pre-
clinical data it is expected that the conversion of GSK3039294 to GSK2315698 is very 
fast. Therefore, it can be assumed that this conversion will occur mainly during the 
absorption phase, and that the distribution and elimination of GSK2315698 are not 
altered. GSK3039294 and the intermediate molecule GSK3037412 do not affect plasma 
SAP levels, and therefore it can be assumed that the PK/PD relationship between 
GSK2315698 and SAP is not changed. Therefore, all distribution and elimination 
parameters and all PD parameters will be fixed to the reported parameter estimates, and 
only bioavailability (F) and absorption related parameters (e.g. Ka) will be estimated. If 
needed, the PK/PD model may be updated in a data driven fashion. Actual time points 
will be used for this final analysis. Further details will be described in the RAP.


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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 enrollment of subjects begins.
10.2.
Regulatory and Ethical Considerations, Including the 
Informed Consent Process
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 Good Clinical Practice (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:

IRB/IEC review and favorable opinion/approval of the study protocol and 
amendments as applicable

Signed informed consent  to be obtained for each subject before participation in the 
study (and for amendments as applicable)

Investigator reporting requirements (e.g. reporting of AEs/SAEs/protocol deviations 
to IRB/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/IRB, 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.
10.3.
Quality Control (Study Monitoring)

In accordance with applicable regulations including GCP, and GSK procedures, 
GSK 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.  


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
When reviewing data collection procedures, the discussion will also include 
identification, agreement and documentation of data items for which the PIMS 
record will serve as the source document.
GSK will monitor the study and site activity to verify that the:

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
10.4.
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.
10.5.
Study and Site Closure

Upon completion or premature discontinuation of the study, the GSK monitor will 
conduct site closure activities with the investigator or site staff, as appropriate, in 
accordance with applicable regulations including GCP, and GSK Standard Operating 
Procedures.

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 
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.  


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
If required by applicable regulations, the investigator or the head of the medical 
institution (where applicable) must inform the IRB/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, 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 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 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.
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.


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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.
10.7.1.
Dose Escalation Committee
The decision to proceed to the next dose level of GSK3039294 in Parts A and B, or to 
proceed to the next study part will be made by a Dose Escalation Committee (DEC) 
consisting of the Principal Investigator, Medical Monitor, GSK Study Team Leader, GSK 
Pharmacokineticist and GSK Statistician (or appropriate designee’s).
For Part A, dose escalation decisions will be based on data obtained from 6 or more 
subjects receiving GSK3039294 at the prior dose level(s). The review data set will at a
minimum consist of all available PK data, adverse events, flagged vital signs, flagged 
findings during continuous cardiac monitoring (telemetry), ECG and laboratory findings.
The decision and selection of dose to proceed to Part B as well as any dose escalation 
decisions, will be made by the DEC based on all available PK data. the listings of any 
adverse events, flagged vital signs, flagged findings during continuous cardiac 
monitoring (telemetry), ECG and laboratory findings.
The decision and selection of dose to proceed to Part C, will be made by the DEC based 
at a minimum on available PK data the listings of any adverse events, flagged vital signs, 
flagged findings during continuous cardiac monitoring (telemetry), ECG and laboratory 
findings, together with any available PD data from the dose levels investigated in Part A, 
and available PK the listings of any adverse events, flagged vital signs, flagged findings 
during continuous cardiac monitoring (telemetry), ECG and laboratory findings, together 
with any available PD data from the dose levels investigated in Part B.
For further details related to the planned PK and PK/PD analyses to support the dose 
escalations, see Section 9.3.2.1. A maximum Cmax of 22.1 g/mL and AUC[0-24] of 
250 g.hr/mL will not be exceeded in any cohort or study part.


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11.
REFERENCES
Adefovir dipivoxil (Hepsera) SPC/Label, Gilead Sciences Ltd [Internet] Available from 
http://www.medicines.org.uk/emc/medicine/12438 Accessed on 31st July 2013.
Barbhaiya CR et al, 2016. Electrophysiological assessment of conduction abnormalities 
and atrial arrhythmias associated with amyloid cardiomyopathy. Heart Rhythm; 
13(2):383-390
Boldrini M et al, 2013. Prevalence and prognostic value of conduction disturbances at the 
time of diagnosis of cardiac AL amyloidosis. Ann Noninvasive Electrocardiol; 18(4):327-
335
Cefditoren pivoxil (Spectracef) SPC/Label, Cornerstone BioPharma, Inc [Internet] 
Available from 
http://www.accessdata.fda.gov/drugsatfda_docs/label/2008/021222s012lbl.pdf Accessed 
on 31st July 2013.
Dhareshwar S., Stella V., your prodrug releases formaldehyde, should you be concerned? 
no! Journal of pharmaceutical sciences 2008, 97, 10, 418-44193
Endogenous formaldehyde turnover in humans compared with exogenous contribution 
from food sources. EFSA Journal 2014;12(2):3550
Fosphenytoin (Cerebyx) SPC/Label, Pfizer Limited [Internet] Available from 
http://www.medicines.org.uk/emc/medicine/13310 Accessed on 31st July 2013.
Gillmore JD, Tennent G., Hutchinson WL, Gallimore JR, Lachmann HJ, Goodman HJ, 
Offer M., Millar DJ, Petrie A, Hawkins PN, Pepys MB. Sustained pharmacological 
depletion of serum amyloid P component in patients with systemic amyloidosis. Br J. 
Haematol. 2010 148 (5) 760-767
GlaxoSmithKline Document Number 2012N132812_07: SAP115570: A single dose first 
in human study of GSK2398852 coadministered with GSK2315698 in patients with 
systemic amyloidosis. Effective Date 30-JUL-2014
GlaxoSmithKline Document Number 2015N242763_00: GSK3039294 Investigator's 
Brochure Effective Date 27-JUL-2015
Hatcher RA, Trussell J, Nelson AL, Cates W Jr, Stewart F, Kowal D, editors. 
Contraceptive Technology. 19th edition. New York: Ardent Media, 2007(a): 24. Table 3-
2.
Hatcher RA, Trussell J, Nelson AL, Cates W Jr, Stewart F, Kowal D, editors. 
Contraceptive Technology. 19th edition. New York: Ardent Media, 2007(b): 28.


2014N218204_03
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201664
92
Hingorani et al., Arrhythmias Seen in Baseline 24-Hour Holter ECG Recordings in 
Healthy Normal Volunteers During Phase 1 Clinical Trials., The Journal of Clinical 
Pharmacology 2016, 56(7) 885–893
James LP, Letzig L, Simpson PM, Capparelli E, Roberts DW, Hinson JA, Davern TJ, Lee 
WM. Pharmacokinetics of Acetaminophen-Adduct in Adults with Acetaminophen 
Overdose and Acute Liver Failure. Drug Metab Dispos 2009; 37:1779-1784.
Kolstoe SE, Ridha BH, Belloti V, Wang N, Robinson CV, Crutch SJ, Keir G, 
Kukkastevenhmas R, Gallimore JR, Hutchinson WL, Hawkins PN, Wood SP, Rossor 
MN, Pepys MB. Molecular dissection of alzhzeimer’s disease neuropathology by 
depletion of serum amyloid P component. Proc Natl Acad Sci USA2009; 106(18) : 7619-
7623. 
Pepys MB, Herbert J, Hutchinson WL, Tennent GA, Lachmann HJ, Gallimore JR, Lovat 
LB, Bartfai T, Alanine A, Hertel C, HoffmannT, Jakob-Roetne R, NorcrossRD, Kemp 
JA, Yamamura K, Suzuki M, TaylorGW, Murray S, Thompson D, Purvis A, Kolstoe S, 
Wood SP, Hawkins PN. Targeted pharmacological depletion of serum amyloid P 
componenet for treatment of human amyloidosis. Nature 2002; 417 (6886) : 254-259
Richards DB, Cookson LM, Berges AC, Barton SV, Lane T, Ritter JM, Fontana M, 
Moon JC, Pinzani M, Gillmore JD, Hawkins PN, Pepys MB. Therapeutic Clearance of 
Amyloid by Antibodies to Serum Amyloid P Component. N Engl J Med. 2015 Jul 15. 
[Epub ahead of print]
Sahota T, Berges A, Barton S, Cookson L, Zamuner S, Richards D. Target mediated drug 
disposition model of CPHPC in patients with systemic amyloidosis. CPT 
Pharmacometrics Syst Pharmacol 2015;4:e15
Tenofovir disoproxil (Viread) SPC/Label, Gilead Sciences Ltd. [Internet] Available from 
https://www.medicines.org.uk/emc/medicine/9008 Accessed on 31st July 2013.


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12.
APPENDICES
12.1.
Appendix 1 – Abbreviations and Trademarks
Abbreviations
g
Micrograms
AE
Adverse Event
ALT
Alanine transaminase
AST
Aspartate transaminase
AUC
Area Under the Curve
BID
Twice Dialy
BMI
Body Mass Index
CI
Confidence Interval
Cmax
Concentration (maximal)
CONSORT
Consolidated Standards of Reporting Trials
CRF
Case Report Form
DEC
Dose Escalation Committee
DMPK
Drug Metabolism and Pharmacokinetics
ECG
Echocardiogram
EDTA
Ethylenediaminetetraacetic acid
F
Bioavailability
FDA
Food and Drug Administration
FLC
Free Light Chain
FSH
Follicle-Stimulating Hormone
g
Grams
GFR
Glomerular filtration rate
GI
GastroIntestinal
GSK
GlaxoSmithKline
h(r)
Hour
i.v.
Intravenous
IDSL
Integrated Data Standards Library
IEC
Independent Ethics Committee
IRB
Institutional Review Board
kg
Kilograms
L
Litres
mAb
Monoclonal Antibody
MCH
Mean corpuscular hemoglobin
MCV
Mean corpuscular volume
MedDRA
Medical Dictionary for Regulatory Activities
mg
Milligrams
MRI
Magnetic Resonance Imaging
MSDS
Material Safety Data Sheet
msec
Millisecond
NYHA
New York Heart Association
OD
Once Dialy


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PD
Pharmacodynamic
pg
Picograms
PIMS
Phase 1 Monitoring System
PK
Pharmacokinetic
RAP
Reporting and Analysis Plan
RBC
Red Blood Cell
s.c.
Subcutaneous
SAE
Serious Adverse Event
SAP
Serum Amyloid P component
SNP
Single Nucleotide Polymorphism
SRM
Study Referene Manual
ULN
Upper Limit of Normal
UPC
Urine Protein Creatinine
Trademark Information
Trademarks of the GlaxoSmithKline 
group of companies
Trademarks not owned by the 
GlaxoSmithKline group of companies
NONE
None


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12.2.
Appendix 2: Liver Safety Required Actions and Follow up 
Assessments
Phase I Liver chemistry stopping criteria have been designed to assure subject safety and 
to evaluate liver event etiology (in alignment with the FDA premarketing clinical liver 
safety guidance).
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guid
ances/UCM174090.pdf.
12.2.1.
Healthy Volunteers:
Phase I liver chemistry stopping criteria and required follow up assessments
Liver Chemistry Stopping Criteria – Liver Stopping Event
ALT-absolute
ALT≥3xULN
If  ALT≥3xULN  AND bilirubin1,2 2xULN (>35% direct bilirubin) or  INR >1.5, 
Report as an SAE.
See additional Actions and Follow Up Assessments listed below
Required Actions and Follow up Assessments following Liver Stopping Event
Actions
Follow Up Assessments

Immediately discontinue study treatment 

Report the event to GSK within 24 hours

Complete the liver event CRF, and complete 
an SAE data collection tool if the event also 
meets the criteria for an SAE2

Perform liver event follow up assessments 

Monitor the subject until liver chemistries 
resolve, stabilise, or return to within baseline 
(see MONITORING below)
MONITORING:
If ALT≥3xULN AND bilirubin 2xULN  or INR 
>1.5

Repeat liver chemistries (include ALT, AST, 
alkaline phosphatase, bilirubin) and perform 
liver event follow up assessments within  24 
hrs

Monitor subjects twice weekly until liver 
chemistries resolve, stabilise or return to 

Viral hepatitis serology3

Blood sample for pharmacokinetic (PK) 
analysis, obtained within 48 hours of last 
dose4

Serum creatine phosphokinase (CPK) and 
lactate dehydrogenase (LDH).

Fractionate bilirubin, if total 
bilirubin2xULN

Obtain complete blood count with 
differential to assess eosinophilia

Record the appearance or worsening of 
clinical symptoms of liver injury, or 
hypersensitivity, on the AE report form

Record use of concomitant medications on 
the concomitant medications report form 
including acetaminophen, herbal remedies, 
other over the counter medications.

Record alcohol use on the liver event 


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Liver Chemistry Stopping Criteria – Liver Stopping Event
within baseline

A specialist or hepatology consultation is 
recommended
If ALT≥3xULN AND bilirubin < 2xULN  and 
INR ≤1.5:

Repeat liver chemistries (include ALT, AST, 
alkaline phosphatase, bilirubin) and perform 
liver event follow up assessments within 24-
72hrs

Monitor subjects weekly until liver 
chemistries resolve, stabilize or return to 
within baseline
alcohol intake case report form
If ALT≥3xULN AND bilirubin 2xULN  or 
INR >1.5:

Anti-nuclear antibody, anti-smooth muscle 
antibody, Type 1 anti-liver kidney 
microsomal antibodies, and quantitative 
total immunoglobulin G (IgG or gamma 
globulins).

Serum acetaminophen adduct HPLC assay 
(quantifies potential acetaminophen 
contribution to liver injury in subjects with 
definite or likely acetaminophen use in the 
preceding week [James, 2009]. NOTE: not 
required in China.

Liver imaging (ultrasound, magnetic 
resonance, or computerised tomography) 
and /or liver biopsy to evaluate liver 
disease; complete Liver Imaging and/or 
Liver Biopsy CRF forms.
1.
Serum bilirubin fractionation should be performed if testing is available. If serum bilirubin fractionation is not 
immediately available, discontinue study treatment for that subject if ALT 3xULN and bilirubin 2xULN. 
Additionally, if serum bilirubin fractionation testing is unavailable, record presence of detectable urinary 
bilirubin on dipstick, indicating direct bilirubin elevations and suggesting liver injury. 
2.
All events of ALT 3xULN and bilirubin 2xULN (>35% direct bilirubin) or ALT 3xULN and INR>1.5, if INR 
measured, which may indicate severe liver injury (possible ‘Hy’s Law’), must be reported as an SAE (excluding 
studies of hepatic impairment or cirrhosis); INR measurement is not required and the threshold value stated 
will not apply to subjects receiving anticoagulants
3.
Includes: Hepatitis A IgM antibody; Hepatitis B surface antigen and Hepatitis B Core Antibody (IgM); Hepatitis C 
RNA; Cytomegalovirus IgM antibody;  Epstein-Barr viral capsid antigen IgM antibody (or if unavailable, obtain 
heterophile antibody or monospot testing);  Hepatitis E IgM antibody 
4.
PK sample may not be required for subjects known to be receiving placebo or non-GSK comparator treatments.  
Record the date/time of the PK blood sample draw and the date/time of the last dose of study treatment prior to 
blood sample draw on the CRF. If the date or time of the last dose is unclear, provide the subject’s best 
approximation. If the date/time of the last dose cannot be approximated OR a PK sample cannot be collected in 
the time period indicated above, do not obtain a PK sample. Instructions for sample handling and shipping are in 
the SRM. 


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12.2.2.
Patients
Phase I liver chemistry stopping criteria and required follow up assessments 
Liver Chemistry Stopping Criteria – Liver Stopping Event
ALT-absolute
ALT≥3xULN
If ALT≥3xULN AND bilirubin1,2 2xULN (>35% direct bilirubin) or  INR >1.5, 
Report as an SAE.
See additional Actions and Follow Up Assessments listed below
Required Actions and Follow up Assessments following Liver Stopping Event
Actions
Follow Up Assessments

Immediately discontinue  study treatment 

Report the event to GSK within 24 hours

Complete the liver event CRF, and complete an 
SAE data collection tool if the event also meets 
the criteria for an SAE2

Perform liver event follow up assessments 

Monitor the subject until liver chemistries resolve, 
stabilise, or return to within baseline (see 
MONITORING below)

Do not restart/rechallenge subject with study 
treatment. Permanently discontinue study 
treatment and may continue subject in the study
for any protocol specified follow up assessments
MONITORING:
If ALT≥3xULN AND bilirubin 2xULN or INR 
>1.5:

Repeat liver chemistries (include ALT, AST, 
alkaline phosphatase, bilirubin) and perform liver 
event follow up assessments within  24 hrs

Monitor subjects twice weekly until liver 
chemistries resolve, stabilise or return to within 
baseline

A specialist or hepatology consultation is 
recommended
If ALT≥3xULN AND bilirubin < 2xULN and INR 
≤1.5:

Viral hepatitis serology3

Blood sample for pharmacokinetic 
(PK) analysis, obtained within 48 
hours of last dose4

Serum creatine phosphokinase (CPK) 
and lactate dehydrogenase (LDH).

Fractionate bilirubin, if total 
bilirubin2xULN

Obtain complete blood count with 
differential to assess eosinophilia

Record the appearance or worsening 
of clinical symptoms of liver injury, or 
hypersensitivity, on the AE report form

Record use of concomitant 
medications on the concomitant 
medications report formincluding 
acetaminophen, herbal remedies, 
other over the counter medications.

Record alcohol use on the liver event 
alcohol intake case report form
If ALT≥3xULN AND bilirubin 2xULN 
or INR >1.5:

Anti-nuclear antibody, anti-smooth 
muscle antibody, Type 1 anti-liver 
kidney microsomal antibodies, and 
quantitative total immunoglobulin G 
(IgG or gamma globulins).


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Liver Chemistry Stopping Criteria – Liver Stopping Event

Repeat liver chemistries (include ALT, AST, 
alkaline phosphatase, bilirubin)  and perform liver 
event follow up assessments within  24-72 hrs 

Monitor subjects weekly until liver chemistries 
resolve, stabilize or return to within baseline

Serum acetaminophen adduct HPLC 
assay (quantifies potential 
acetaminophen contribution to liver 
injury in subjects with definite or likely 
acetaminophen use in the preceding 
week [James, 2009]). NOTE: not 
required in China

Liver imaging (ultrasound, magnetic 
resonance, or computerised 
tomography) and /or liver biopsy to 
evaluate liver disease; complete Liver 
Imaging and/or Liver Biopsy CRF 
forms.
1.
Serum bilirubin fractionation should be performed if testing is available. If serum bilirubin fractionation is not 
immediately available, discontinue study treatment for that subject if ALT 3xULN and bilirubin 2xULN. 
Additionally,if serum bilirubin fractionation testing is unavailable, record presence of detectable urinary 
bilirubin on dipstick,indicating direct bilirubin elevations and suggesting liver injury. 
2.
All events of ALT 3xULN and bilirubin 2xULN (>35% direct bilirubin) or ALT 3xULN and INR>1.5, if INR 
measured, which may indicate severe liver injury (possible ‘Hy’s Law’), must be reported as an SAE 
(excludingstudies of hepatic impairment or cirrhosis); INR measurement is not required and the threshold value 
stated will not apply to subjects receiving anticoagulants
3.
Includes: Hepatitis A IgM antibody; Hepatitis B surface antigen and Hepatitis B Core Antibody (IgM); Hepatitis 
CRNA; Cytomegalovirus IgM antibody; Epstein-Barr viral capsid antigen IgM antibody (or if unavailable, obtain 
heterophile antibody or monospot testing);  Hepatitis E IgM antibody 
4.
PK sample may not be required for subjects known to be receiving placebo or non-GSK comparator treatments. 
Record the date/time of the PK blood sample draw and the date/time of the last dose of study treatment prior to 
blood sample draw on the CRF. If the date or time of the last dose is unclear, provide the subject’s best 
approximation. If the date/time of the last dose cannot be approximated OR a PK sample cannot be collected in 
the time period indicated above, do not obtain a PK sample. Instructions for sample handling and shipping are in 
the SRM


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12.3.
Appendix 3 - Genetic Investigation of Individuals
Genetic Research Objectives and Analyses
The objectives of the genetic research are to investigate the relationship between genetic 
variants and: 

Response to any treatment regimens under investigation in this study
Genetic data may be generated while the study is underway or following completion of 
the study.  Single Nucleotide Polymorphism (SNP) analysis for recognised esterase-
encoded genes which have been previously implicated in the dysfunctional metabolism of 
other esterase-cleaved prodrugs (e.g. CES-1 in oseltamivir), or genome-wide locus 
agnostic analysis, may be performed to investigate (for example) an unexpected PK or 
plasma SAP profile, and / or clinically concerning AEs being observed in an individual 
subject. Genetic analyses will utilize data collected in the study and will be limited to 
understanding the objectives highlighted above.  Analyses may be performed using data 
from multiple clinical studies to investigate these research objectives.
Appropriate descriptive and/or statistical analysis methods will be used. A detailed 
description of any planned analyses will be documented in a Reporting and Analysis Plan 
(RAP) prior to initiation of the analysis. Planned analyses and results of genetic 
investigations will be reported either as part of the clinical RAP and study report, or in a 
separate genetics RAP and report, as appropriate.
Study Population
Any subject who is enrolled in the study can participate in genetic research.  Any subject 
who has received an allogeneic bone marrow transplant must be excluded from the 
genetic research.
Study Assessments and Procedures
A key component of successful genetic research is the collection of samples during 
clinical studies.  

A 6 ml blood sample will be taken for Deoxyribonucleic acid (DNA) extraction. A 
Blood sample is collected during the study, after the subject has been randomized 
and provided informed consent for genetic research. Instructions for collection and 
shipping of the genetic sample are described in the laboratory manual. The DNA 
from the blood/saliva sample may undergo quality control analyses to confirm the 
integrity of the sample. If there are concerns regarding the quality of the sample, then 
the sample may be destroyed. The blood/saliva sample is taken on a single occasion 
unless a duplicate sample is required due to an inability to utilize the original sample.  
The genetic sample is labelled (or “coded”) with the same study specific number used to 
label other samples and data in the study.   This number can be traced or linked back to 
the subject by the investigator or site staff. Coded samples do not carry personal 
identifiers (such as name or National Insuramnce number). 


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Samples will be stored securely and may be kept for up to 15 years after the last subject 
completes the study, or GSK may destroy the samples sooner.  GSK or those working 
with GSK (for example, other researchers) will only use samples collected from the study 
for the purpose stated in this protocol and in the informed consent form.  Samples may be 
used as part of the development of a companion diagnostic to support the GSK medicinal 
product.
Subjects can request their sample to be destroyed at any time.
Informed Consent
Subjects who do not wish to participate in the genetic research may still participate in the 
study.  Genetic informed consent must be obtained prior to any blood/saliva being taken.
Subject Withdrawal from Study
If a subject who has consented to participate in genetic research withdraws from the 
clinical study for any reason other than being lost to follow-up, the subject will be given a 
choice of one of the following options concerning the genetic sample, if already 
collected:

Continue to participate in the genetic research in which case the genetic DNA sample 
is retained

Discontinue participation in the genetic research and destroy the genetic DNA 
sample 
If a subject withdraws consent for genetic research or requests sample destruction for any 
reason, the investigator must complete the appropriate documentation to request sample 
destruction within the timeframe specified by GSK and maintain the documentation in 
the site study records. 
Genotype data may be generated during the study or after completion of the study and 
may be analyzed during the study or stored for future analysis. 

If a subject withdraws consent for genetic research and genotype data has not been 
analyzed, it will not be analyzed or used for future research.  

Genetic data that has been analyzed at the time of withdrawn consent will continue 
to be stored and used, as appropriate. 
Screen and Baseline Failures
If a sample for genetic research has been collected and it is determined that the subject 
does not meet the entry criteria for participation in the study, then the investigator should 
instruct the subject that their genetic sample will be destroyed. No forms are required to 
complete this process as it will be completed as part of the consent and sample 
reconciliation process.  In this instance a sample destruction form will not be available to 
include in the site files.


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Provision of Study Results and Confidentiality of Subject’s Genetic Data
GSK may summarize the genetic research results in the clinical study report, or 
separately and may publish the results in scientific journals. 
GSK may share genetic research data with other scientists to further scientific 
understanding in alignment with the informed consent. GSK does not inform the subject, 
family members, insurers, or employers of individual genotyping results that are not 
known to be relevant to the subject’s medical care at the time of the study, unless
required by law. This is due to the fact that the information generated from genetic 
studies is generally preliminary in nature, and therefore the significance and scientific 
validity of the results are undetermined.  Further, data generated in a research laboratory 
may not meet regulatory requirements for inclusion in clinical care.


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12.4.
Appendix 4: Definition of and Procedures for Recording, 
Evaluating, Follow-Up and Reporting of Adverse Events
12.4.1.
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 judgement 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).
.
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 
condition.

Medical or surgical procedure (e.g., endoscopy, appendectomy): the condition that 
leads to the procedure is an AE.


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
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.
12.4.2.
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:
a. Results in death
b. 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.
c.
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.
d.
Results in disability/incapacity
NOTE:

The term disability means a substantial disruption of a person’s ability to conduct 
normal life functions.

This definition is not intended to include experiences of relatively minor medical 
significance such as uncomplicated headache, nausea, vomiting, diarrhea, influenza, 
and accidental trauma (e.g. sprained ankle) which may interfere or prevent everyday 
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e.
Is a congenital anomaly/birth defect
f.
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
g.
Is associated with liver injury and impaired liver function defined as:

ALT 3xULN and total bilirubin* 2xULN (>35% direct), or

ALT 3xULN and INR** > 1.5.
* Serum bilirubin fractionation should be performed if testing is available; if unavailable, 
measure urinary bilirubin via dipstick.  If fractionation is unavailable and ALT 3xULN 
and total bilirubin 2xULN, then the event is still to be reported as an SAE.
** INR testing not required per protocol and the threshold value does not apply to 
subjects receiving anticoagulants.  If INR measurement is obtained, the value is to be 
recorded on the SAE form.

Refer to Appendix 2 for the required liver chemistry follow-up instructions
12.4.3.
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 of to GSK.

The investigator will attempt to establish a diagnosis of the event based on signs, 


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symptoms, and/or other clinical information.  In such cases, the diagnosis will be 
documented as the AE/SAE and not the individual signs/symptoms.
12.4.4.
Evaluating AEs and SAEs
Assessment of Intensity
The investigator will make an assessment of intensity for each AE and SAE reported 
during the study and will assign it to one of the following categories:

Mild:  An event that is easily tolerated by the subject, causing minimal discomfort 
and not interfering with everyday activities.

Moderate:  An event that is sufficiently discomforting to interfere with normal 
everyday activities

Severe:  An event that prevents normal everyday activities. - an AE that is assessed 
as severe will not be confused with an SAE. Severity is a category utilized for rating 
the intensity of an event; and both AEs and SAEs can be assessed as severe.

An event is defined as ‘serious’ when it meets at least one of the pre-defined 
outcomes as described in the definition of an SAE.
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 


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information, amending the SAE data collection tool accordingly.

The causality assessment is one of the criteria used when determining regulatory 
reporting requirements.
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.
12.4.5.
Reporting of SAEs to GSK
SAE reporting to GSK via paper CRF

Facsimile transmission of the SAE paper CRF is the preferred method to transmit 
this information to the Medical Monitor 

In rare circumstances and in the absence of facsimile equipment, notification by 
telephone is acceptable, with a copy of the SAE data collection tool sent by 
overnight mail

Initial notification via the telephone does not replace the need for the investigator to 
complete and sign the SAE CRF pages within the designated reporting time frames.

Contacts for SAE receipt can be found at this beginning of the protocol on the 
Sponsor/Medical Monitor Contact Information page.


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12.5.
Appendix 5: Protocol Amendment Changes
AMENDMENT 1
Where the Amendment Applies
Section 5.5 and Appendix 1.
Summary of Amendment Changes with Rationale
Changes requested by MHRA – Clarification of the stopping criteria. Addition of ‘FLC’ 
and definition to the Abbreviations table.
List of Specific Changes
Section 12.1 Appendix 1 – Abbreviations and Trademarks
REVISED TEXT
Addition of “FLC – Free Light Chain”
Section 5.5 – Stopping Criteria for the Entire Healthy Volunteer or Patient 
Study Groups
PREVIOUS TEXT

If a suspected unexpected serious adverse reaction (SUSAR) is observed, as deemed 
by the investigator, in any subject at any one dose level of GSK3039294, 
continuation of the study will be temporarily halted and no further subjects will be 
dosed until a full safety review of the data has taken place.

If the same severe adverse event is observed in two subjects across all study parts, 
and is reasonably attributable, in the opinion of the investigator, to GSK3039294, the 
study will be temporarily halted and no further subjects will be dosed until a full 
safety review of the study has taken place. 

If the study is temporarily halted, relevant reporting and discussion with the Medical 
Monitor, relevant GSK personnel, and with the applicable regulatory authority will 
take place as appropriate prior to any resumption of dosing

Every effort will be made to take a blood sample for pharmacokinetic analysis from 
each affected individual at the time of any of the adverse events described above
REVISED TEXT

If a suspected unexpected serious adverse reaction (SUSAR) is observed, as deemed 
by the investigator, If an SAE occurs that the investigator believes is reasonably 
attributable to IMP, in any subject at any one dose level of GSK3039294, 
continuation of the study will be temporarily halted and no further subjects will be 
dosed until a full safety review of the data has taken place.


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
If the same severe adverse event is observed in two subjects across all study parts, 
and is reasonably attributable, in the opinion of the investigator, to GSK3039294, the 
study will be temporarily halted and no further subjects will be dosed until a full 
safety review of the study has taken place. 

If the study is temporarily halted, relevant reporting and discussion with the Medical 
Monitor, relevant GSK personnel, and with the applicable regulatory authority will 
take place as appropriate prior to any resumption of dosing

Every effort will be made to take a blood sample for pharmacokinetic analysis from 
each affected individual at the time of any of the adverse events described above
AMENDMENT 2
Where the Amendment Applies
Throughout the protocol.
Summary of Amendment Changes with Rationale
Changes requested by REC – Alteration of Part B of this study include a 7 days repeat 
dose and perform PK and safety review prior to starting 21 day repeat dose in healthy 
subjects.
List of Specific Changes
Protocol Synopsis – Treatment Arms and Duration
PREVIOUS TEXT
Two cohorts of subjects will be enrolled to provide data from 6 subjects per cohort and 
up to 4 different doses (2 dose levels per cohort) of GSK3039294 will be tested.
Subjects will be admitted to the unit on Day -1, following the dose on Day 1 subjects will 
remain in-house until Day 4. Wash-out will take place from Day 5 to Day 14.
Providing a review of the data from Dose 1 (safety data: AE, vital signs, ECG and 
laboratory safety test and PK data up to 48 h etc) is favourable, the next dose level will be 
administered. 


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Part B: Repeat dose escalation in healthy volunteers
A food effect exploration will be conducted at Days 4 and 5 of this repeat dose study 
cohort. On these days GSK3039294 will be administered under fasted and then under fed 
conditions
In a group of sufficient healthy volunteers to ensure 6 completers, the compound will be 
administered repeatedly for a total of 21 days.
the dose will be escalated every week throughout the study duration. Subjects will first 
receive a low dose given once daily. After 7 days, if well tolerated, the total daily dose 
will be increased and GSK3039294 will be given e.g. as bid dosing for 7 days. At the end 
of this 7 day period and if previous dosing was well tolerated, the dose will be increased 
to a maximum daily dose that will not exceed pre-clinical safety exposure limits.
Cohort 3b(optional, only if required): Based on data from, dose levels may be selected 
for further investigation in a further cohort of healthy volunteers (recruitment to ensure 6 
completers). For this purpose the compound will be dosed for 21 consecutive days.
REVISED TEXT
Two cohorts (cohorts 1 and 2) of subjects will be enrolled to provide data from 6 
subjects per cohort and up to 4 different doses (2 dose levels per cohort) of GSK3039294 
will be tested.
Subjects will be admitted to the unit on Day -1, following the dose on Day 1 subjects will 
remain in-house until Day 4. Wash-out will take place from Day 5 to Day 14.
Providing a review of the data from each dose Dose 1 (safety data: AE, vital signs, ECG 
and laboratory safety test and PK data up to 48 h etc) is favourable, the next dose level 
will be administered. 
Part B: Repeat dose escalation in healthy volunteers
Cohort 3: In a group of healthy volunteers sufficient subjects will be enrolled to 
ensure 6 completers, the study drug will be administered repeatedly for a total of 7 
days.  The dose will be one that is expected to be well tolerated based on the single 
dose data and not predicted to exceed exposure limits based on single dose PK. 
Providing a review of the data (safety data: AE, vital signs, ECG, laboratory safety 
tests and PK) is favourable, Cohort 4 will be initiated.
A food effect exploration will be conducted at Days 4 and 5 of this repeat dose study
cohort. On these days GSK3039294 will be administered under fasted and then under fed 
conditions
Cohort 4a: In a group of sufficient healthy volunteers sufficient subjects will be 
enrolled to ensure 6 completers, the compound study drug will be administered 
repeatedly for a total of 21 days.


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The dose level for this cohort will be determined by a review of the safety and PK 
data from cohort 3. The dose may be adjusted (up or down) during the 21 dosing 
session based on preliminary PK collected during dosing and ongoing review of 
safety. If the dose is to be altered, this will be done no later than Day 16 in order to 
achieve a new steady-state at Day 21.
the dose will be escalated every week throughout the study duration. Subjects will first 
receive a low dose given once daily. After 7 days, if well tolerated, the total daily dose 
will be increased and GSK3039294 will be given e.g. as bid dosing for 7 days. At the end 
of this 7 day period and if previous dosing was well tolerated, the dose will be increased 
to a The predicted maximum daily exposure dose that will not exceed pre-clinical safety 
exposure limits.
Cohort 4b(optional, only if required): Based on data from Cohorts 3 and 4a, dose levels 
may be selected for further investigation in a further cohort of healthy volunteers 
(recruitment to ensure 6 completers). For this purpose the compound will be dosed for 21 
consecutive days. and more than one The dose level and / or dosing regimen may be 
altered once during the 21days providing a review of the data from the starting dose 
(safety data: AE, vital signs, ECG, laboratory safety tests and PK – all obtained 
once steady state has been achieved) is favourable. The predicted maximum daily 
dose administered will not exceed pre-clinical safety exposure limits.
Protocol Synopsis – Type and Number of Subjects
PREVIOUS TEXT
In Part A, sufficient healthy volunteers will be enrolled to ensure a total of 6 subjects per 
cohort have completed the in-patient phases.
In Part B, sufficient healthy volunteers will be enrolled to ensure a total of 6 subjects per 
cohort have completed the in-patient phases.
In Part C, 12 patients with systemic amyloidosis will be enrolled. 
REVISED TEXT
In Part A, sufficient healthy volunteers will be enrolled to ensure a total of 6 subjects per 
cohort have completed the in-patient phases.
In Part B, sufficient healthy volunteers will be enrolled to ensure a total of 6 subjects per 
cohort have completed each of the in-patient phases.
In Part A and B of the study, if subjects prematurely discontinue, replacement 
subjects may be enrolled and assigned to the same cohort at the discretion of the 


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Sponsor in consultation with the investigator. Replacement subjects do not need to 
have received the first dose for a given cohort to join the study in the second cohort.
In Part C, 12 patients with systemic amyloidosis will be enrolled. If subjects 
prematurely discontinue, replacement subjects may be enrolled at the discretion of 
the Sponsor in consultation with the investigator.  
Additional subjects/cohorts may be enrolled to allow for further evaluation of a 
given dose or for evaluation of additional dose levels.   
Section 4.2.1 – Part A (single dose escalation in healthy volunteers)
PREVIOUS TEXT
Doses will be administered to Cohorts using a sentinel dosing approach. Subjects will be 
admitted to the unit on Day -1, following the dose on Day 1 subjects will remain in-house 
until Day 4. Wash-out will take place from Day 5 to Day 14.
Providing a review of the data from Dose 1 (safety data: AE, vital signs, ECG and 
laboratory safety test and PK data up to 48 h etc) is favourable, Dose level 2 will be 
administered. Cohort 1 will be used for 2 dosing periods (Doses 1 and 2), Cohort 2 will 
also be used for 2 dosing periods (Doses 3 and 4).  A review of the data will always be 
conducted prior to the administration of the next dose level.
The planned doses for Dose levels 2, 3 and 4 may be modified based on emerging safety, 
tolerability and PK data. The number of dosing periods may be reduced or extended 
depending on emerging data. Replacement subjects in either Cohort do not need to have 
received the first dose prior to receiving the second dose.
Sentinel dosing:  For all dose levels and if necessary (based on evaluation of the 
gathered safety data) for next dose levels, only 2 subjects will be dosed on Day 1, 
separated by at least 1 hour. If there are no safety or tolerability concerns, the rest of the 
cohort will be dosed the next day at appropriate intervals.
REVISED TEXT
Doses will be administered to Cohorts using a sentinel dosing approach as described 
below. Subjects will be admitted to the unit on Day -1, following the dose on Day 1 
subjects will remain in-house until Day 4. Wash-out will take place from Day 5 to Day 
14.
Providing a review of the data from each dose Dose 1 (safety data: AE, vital signs, ECG 
and laboratory safety test and PK data up to 48 h etc) is favourable, the next dose level
Dose level 2 will be administered. Cohort 1 will be used for 2 dosing periods (Doses 1 


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and 2), Cohort 2 will also be used for 2 dosing periods (Doses 3 and 4).  A review of the 
data will always be conducted prior to the administration of the next dose level.
The planned doses for Dose levels 2, 3 and 4 may be modified based on emerging safety, 
tolerability and PK data. The number of dosing periods may be reduced or extended 
depending on emerging data. Replacement subjects in either Cohort do not need to have 
received the first dose prior to receiving the second dose.
Sentinel dosing:  For all dose levels the subsequent subject will be dosed 
approximately 24 hrs after the preceding subject if there are no safety or tolerability 
concerns. The remaining subjects receiving the same dose within the cohort will 
receive the dose approximately 24hrs after the subsequent subject at intervals no 
less than 1hr apart. and if necessary (based on evaluation of the gathered safety data) 
for next dose levels, only 2 subjects will be dosed on Day 1, separated by at least 1 hour. 
If there are no safety or tolerability concerns, the rest of the cohort will be dosed the next 
day at appropriate intervals.
Table 1 – Cohorts 1 and 2 Study Duration
PREVIOUS TEXT
Washout Period
Up to 14 days  
REVISED TEXT
Washout Period
From Day 5 to Day 14. Up to 14 days
Section 4.2.1 – Part A (single dose escalation in healthy volunteers)
PREVIOUS TEXT
At the end of this single dose part, all PK data will be analysed (see Section 9.3.2) with
all available safety data.
REVISED TEXT
At the end of this single dose part, all PK data will be analysed (see Section 9.3.2) and 
reviewed together with all available safety data.
Section 4.2.2 – Part B (repeat dose escalation in healthy volunteers)
PREVIOUS TEXT


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A food effect exploration will be conducted at Days 4 and 5 of this repeat dose study. On 
these days GSK3039294 will be administered under fasted and then under fed conditions
(please see SRM for details of meals), and PK samples will be taken to investigate the 
food effect on the PK.
Cohort 3a: In a group of sufficient healthy volunteers to ensure 6 completers, the 
compound will be administered repeatedly for a total of 21 days.
The dose will be escalated every week throughout the study duration. Subjects will first 
receive a low dose given once daily. After 7 days, if well tolerated, the total daily dose 
will be increased and GSK3039294 will be given e.g. as bid dosing for 7 days. At the end 
of this 7 day period and if previous dosing was well tolerated, the dose will be increased 
to a maximum daily dose that will not exceed pre-clinical safety exposure limits.
Data from Cohort 3a is expected to provide a good evaluation of the safety, tolerability 
and repeat-dose PK. The data will be evaluated using the PK/PD model to identify an 
optimal clinical dose (see Section 9.3.2.1). However, if it is determined that further 
investigation of dose levels are required before progressing to Part C (e.g. if the 
observations in Cohort 3a are different from those which the PK /PD modelling 
predicted), then recruitment into Cohort 3b may be initiated.
Cohort 3b (optional, only if required): Based on data from Cohorts 2 and 3a, dose levels 
will be selected for further investigation in a further cohort of healthy volunteers 
(recruitment to ensure 6 completers). For this purpose the compound will be dosed for 21 
consecutive days.
Table 3 
Cohort 3a (and 3b if required) Study Duration
Screening
All screening assessments to be completed within 28 days 
prior to the first dose
Treatment 
Period
Each subject will take part in a single study period. Subjects 
will be in-patient from Day -1 until Day 5 when they will be 
discharged. Additional in-patient stays will be from Day 7 to 
11, and Day 14 to 18. Subjects will self-administer their 
assigned dose when not in the clinical unit. Subjects will 
return as outpatients on Day 21, and again for a follow-up 
appointment.
Follow-up
At least 7 days and no greater than 14 days after last study 
drug administration
Additional follow-up visits may be scheduled, if warranted
Total Duration
Approximately 8-9 weeks
In Cohort 4b multiple dose levels and different regimens may be investigated based on 
data from Cohort 4a.


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REVISED TEXT
Cohort 3: In a group of healthy volunteers sufficient subjects will be enrolled to 
ensure 6 completers, the study drug will be administered repeatedly for a total of 7 
days.  The dose will be one that is expected to be well tolerated based on the single 
dose data and predicted to not exceed exposure limits based on single dose PK. 
Providing a review of the data (safety data: AE, vital signs, ECG, laboratory safety 
tests and PK) is favourable, Cohort 4 will be initiated.
Sentinel dosing:  The subsequent subjects will be dosed after the first subject has 
completed all dosing days if there are no safety or tolerability concerns.
A food effect exploration will be conducted at Days 4 and 5 of this repeat dose study
cohort. On these days GSK3039294 will be administered under fasted and then under fed 
conditions (please see SRM for details of meals), and PK samples will be taken to 
investigate the food effect on the PK.
Cohort 4a: In a group of sufficient healthy volunteers sufficient subjects will be 
enrolled to ensure 6 completers, the compound study drug will be administered 
repeatedly for a total of 21 days. 
The dose level for this cohort will be determined by a review of the safety and PK 
data from cohort 3. The dose may be adjusted (up or down) during the 21 day 
dosing session based on preliminary PK collected during dosing and ongoing review 
of safety. If the dose is to be altered, this will be done no later than Day 16 in order 
to achieve a new steady-state at Day 21.
the dose will be escalated every week throughout the study duration. Subjects will first 
receive a low dose given once daily. After 7 days, if well tolerated, the total daily dose
will be increased and GSK3039294 will be given e.g. as bid dosing for 7 days. At the end 
of this 7 day period and if previous dosing was well tolerated, the dose will be increased 
to a The predicted maximum daily exposure dose that will not exceed pre-clinical safety 
exposure limits.
Data from cohorts 3 and 4a 3a are is expected to provide a good evaluation of the 
safety, tolerability and repeat-dose PK. The data will be evaluated using the PK/PD 
model to identify an optimal clinical dose (see Section 9.3.2.1). However, if it is 
determined that further investigation of dose levels are required before progressing to 
Part C (e.g. if the observations in cohort 4a 3a are different from those which the PK /PD 
modelling predicted), then recruitment into Cohort 4b3b may be initiated.
Cohort 4b (optional, only if required): Based on data from Cohorts 3 and 4a, dose 
levels will be selected for further investigation in a further cohort of healthy volunteers 
(recruitment to ensure 6 completers). For this purpose the compound will be dosed for 21 
consecutive days. and more than one The dose level and / or dosing regimen may be 
altered once during the 21 days providing a review of the data from the starting 
dose (safety data: AE, vital signs, ECG, laboratory safety tests and PK – all obtained 
once steady state has been achieved) is favourable. The predicted maximum daily 
dose administered will not exceed pre-clinical safety exposure limits.


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Table 2
Cohort 3
Screening
All screening assessments to be completed within 28 
days prior to the first dose
Treatment 
Period
Each subject will take part in a single study period. 
Subjects will be in-patient from Day -1 until Day 8 when 
they will be discharged.
Follow-up
At least 7 days and no greater than 21 days after last 
study drug administration
Additional follow-up visits may be scheduled, if 
warranted
Total Duration
Approximately 7 weeks
Table 3
Cohort 4a (and 4b if required) Study Duration
Screening
All screening assessments to be completed within 28 days 
prior to the first dose
Treatment 
Period
Each subject will take part in a single study period. Subjects 
will be in-patient from Day -1 until Day 5 Day 7 when they will 
be discharged. Additional in-patient stays will be from Day 7 
to 11, and Day 14 to 18. Subjects will self-administer their 
assigned dose when not in the clinical unit. Subjects will 
return as outpatients on Day 21, and again for a follow-up 
appointment.
Subjects may return to the clinic after Day 7 for an 
adjustment to their dose should a review of interim PK 
data require this. If a dose adjustment is made, subjects 
will be in-patient until they have received the new dose 
for 7 days, when they will be discharged.
Follow-up
At least 7 days and no greater than 14 days after last study 
drug administration
Additional follow-up visits may be scheduled, if warranted
Total Duration
Approximately 8-9 weeks


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In Cohort 4b multiple dose levels and different regimens may be investigated based on 
data from Cohort 4a. *Day of Potential Dose Alteration not specified as this will be 
performed following review of safety and PK data from previous dose.
Section 4.3 – Type and Number of Subjects
PREVIOUS TEXT
In Part A, sufficient healthy volunteers will be enrolled to ensure a total of 6 subjects per 
cohort have completed the in-patient phases.
In Part B, sufficient healthy volunteers will be enrolled to ensure a total of 6 subjects per 
cohort have completed the in-patient phases
In Part A and B of the study, if subjects prematurely discontinue, replacement subjects 
may be enrolled and assigned to the same treatment at the discretion of the Sponsor in 
consultation with the investigator.
REVISED TEXT
In Part A, sufficient healthy volunteers will be enrolled to ensure a total of 6 subjects per 
cohort have completed the in-patient phases.
In Part B, sufficient healthy volunteers will be enrolled to ensure a total of 6 subjects per 
cohort have completed the in-patient phases
In Part A and B of the study, if subjects prematurely discontinue, replacement subjects 
may be enrolled and assigned to the same treatment at the discretion of the Sponsor in 
consultation with the investigator.
In Part A and B of the study, if subjects prematurely discontinue, replacement 
subjects may be enrolled and assigned to the same cohort at the discretion of the 
Sponsor in consultation with the investigator. Replacement subjects do not need to 
have received the first dose for a given cohort to join the study in the second cohort.
Section 4.4 – Design Justification
PREVIOUS TEXT
The maximum duration of 21 days for Part B was selected to reflect the likely duration of 
treatment needed for clinical use with the anti SAP monoclonal antibody. The duration of 
7 days treatment before dose escalation was chosen as, based on the half life of CPHPC 
of approximately 18 hrs, steady state PK will be achieved by 4 days.
REVISED TEXT


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The duration of 7 days for Cohort 3 Part B was selected as steady state is predicted 
to be achieved in this time. The maximum duration of 21 days for Cohorts 4a and 4b 
in Part B was selected to reflect the likely duration of treatment needed for clinical use 
with the anti SAP monoclonal antibody. The duration of 7 days treatment before dose 
escalation was chosen as, based on the half life of CPHPC of approximately 18 hrs, 
steady state PK will be achieved by 4 days.
Section 4.5 – Dose Justification
PREVIOUS TEXT
Part B
The dose level in Part B will be determined based on the PK data obtained in Part A, by 
analysing all available PK data from Part A and subsequently predicting concentration-
time profiles at steady state after repeat dosing (see Section 9.3.2.1). The dose levels and 
dosing frequencies will be chosen such that the predicted 95% CI of Cmax and AUC at 
steady state will not exceed preclinical Cmax and AUC limits (22.1 g/mL and 
250 g.hr/mL, respectively).
REVISED TEXT
Part B
The dose level for Cohort 3 in Part B will be determined based on the PK data obtained 
in Part A, by analysing all available PK data from Part A and subsequently predicting 
concentration-time profiles at steady state after repeat dosing. Table 3 shows examples 
of dose levels and frequencies with predicted AUC[0-24] and Cmax at steady state, 
using the PK/PD model that was developed for CPHPC (active molecule) [Sahota, 
2015], adjusted for oral absorption and conversion of GSK3039294 into CPHPC. 
The PK data from Part A will be used to obtain estimates for Ka and F.
Table 5
Example Doses And Predicted Exposures For Part B
Dose
Ka
F
AUC[0-24h] 
(g.hr/mL) *)
Cmax (g/mL) *)
Cohort 3
300mg OD
1.3
1
23.4 (15.3-35.9)
5.20 (3.32-7.84)
300mg OD
1.3
0.5
11.4 (7.36-18.1)
2.61 (1.72-3.86)
300mg OD
0.6
1
22.8 (14.7-36.2)
3.83 (2.73-5.42)
Cohort 4a (first part)


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Dose
Ka
F
AUC[0-24h] 
(g.hr/mL) *)
Cmax (g/mL) *)
300mg BID
1.3
1
45.7 (29.4-72.5)
5.49 (3.75-8.05)
300mg BID
1.3
0.5
22.8 (14.7-36.2)
2.74 (1.87-4.02)
300mg BID
0.6
1
45.7 (29.4-72.5)
4.09 (2.94-5.76)
Cohort 4a (last part)
600mg BID
1.3
1
91.3 (58.9-145)
11.0 (7.50-16.1)
600mg BID
1.3
0.5
45.7 (29.4-72.5)
5.49 (3.75-8.05)
600mg BID
0.6
1
91.3 (58.9-145)
8.19 (5.88-11.5)
*) Predicted AUC[0-24] and Cmax at steady state; presented are mean and 95%CI
The dose levels for subsequent cohorts in Part B will be determined based on the PK 
data from Part A (single dose), and cohort 3 in Part B (multiple dose). All available 
PK data will be analysed (see Section 9.3.2.1). The dose levels and dosing frequencies 
will be chosen such that the predicted 95% CI of Cmax and AUC at steady state will not 
exceed preclinical Cmax and AUC limits (22.1 g/mL and 250 g.hr/mL, respectively).
Section 4.6.1 – Risk Assessment
PREVIOUS TEXT
A potential effect of food will be explored in this study (Week 1 of Part B).
REVISED TEXT
A potential effect of food will be explored in this study (Week 1 Cohort 3 of Part B).
Section 5.1 – Inclusion Criteria, All Subjects, 3 Weight
PREVIOUS TEXT
Body weight > 50kg and body mass index (BMI) within the range 18.5-32 kg/m2 
(inclusive) and excluding the effects of peripheral oedema.


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REVISED TEXT
Body weight > 50kg and body mass index (BMI) within the range ≥18.5-32 kg/m2 
(inclusive) and excluding the effects of peripheral oedema.
Section 5.1 – Additional Inclusion Criteria – Patients
PREVIOUS TEXT
SAP scan identifying amyloid at any anatomical site, including subset of patients with 
moderate-large amyloid load in the liver
Up to and including NYHA class 2 with a stable clinical cardiac status 12 weeks prior 
to screening
For AL amyloidosis patients, ≥12 months post-chemotherapy with a stable FLC ratio 
in the preceding 4 months
REVISED TEXT
SAP scan identifying amyloid at any anatomical site, including subset of patients with 
moderate-large amyloid load in the liver
Up to and including NYHA class 2 with a stable clinical cardiac status 12 weeks prior 
to screening
For AL amyloidosis patients, ≥12 6 months post-chemotherapy with a stable FLC 
ratio in the preceding 4 months
Section 5.2. – Exclusion Criteria – All Subjects
PREVIOUS TEXT
A positive pre-study drug/alcohol screen
REVISED TEXT
A positive pre-study drug/alcohol screen (unless a positive test is due to prescribed 
medications)
Section 5.2. – Additional Exclusion Criteria – Patients
PREVIOUS TEXT
First degree heart block deemed to require pacing; Second degree AV block Mobitz 
Type II; Trifasicular block; Ventricular tachyarrthymias – with the exception of 


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bundle branch block, atrial fibrillation & first degree heart block not requiring pacing, 
or second degree AV block Mobitz Type I
24 hour proteinuria 5g 
A syncopal episode, of any causation, within 4 weeks of screening
Average SBP ≤ 90 mmHg at Screening from triplicate readings
Implantable cardiac defibrillator (ICD) 
Evidence of severe cardiac dysfunction within 12 months of screening, as diagnosed 
by a cardiologist, using Echocardiography or cardiac MRI i.e. markedly impaired 
ejection fraction (EF < 50% for cardiac amyloidosis patients), or cardiac imaging 
parameters of severe diastolic dysfunction (grade 3 or 4) 
REVISED TEXT
First degree heart block deemed to require pacing; Second degree AV block Mobitz 
Type II; Trifasicular block; Ventricular tachyarrthymias – with the exception of 
bundle branch block, atrial fibrillation & first degree heart block not requiring pacing, 
or second degree AV block Mobitz Type I
24 hour proteinuria 5g Plasma albumin < 30g/litre
A syncopal episode, of any causation, within 4 weeks of screening
Average SBP ≤ 90 mmHg at Screening from triplicate readings
Implantable cardiac defibrillator (ICD) 
Insertion of permanent pacemaker in last 2 months
Evidence of severe cardiac dysfunction within 12 months of screening, as diagnosed 
by a cardiologist, using Echocardiography or cardiac MRI i.e. markedly impaired 
ejection fraction (EF < 50% for cardiac amyloidosis patients), or cardiac imaging 
parameters of severe diastolic dysfunction (grade 3 or 4) Decompensated or 
uncontrolled heart failure in last 2 months
Section 5.4.1 – Cardiovascular Safety Stopping Criteria
PREVIOUS TEXT
Chest pain at rest or exertion at any time after drug administration and is reasonably 
attrituble to GSK3039294, with proven or suspected changes of cardiac ischaemia on 
a 12-lead ECG.


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Development of pulmonary oedema or uncontrolled congestive cardiac failure which 
is reasonably attributable to GSK303294.
Systolic blood pressure > 170 mmHg as an average of triplicate readings taken at rest 
over 15 minutes on three consecutive days at any time after drug administration and is 
reasonably attributable to GSK3039294.
Healthy Volunteers & Amyloidosis Patients without bundle branch block: QTcF 
> 500 msec, (or a change from baseline of QTcF > 60 msec on a 12-lead ECG in 
healthy volunteers) at any time after drug administration and is reasonably 
attributable to GSK3039294 on an average from triplicate readings (see Section 
5.4.3). 
Systemic Amyloidosis patients with bundle branch block - if baseline QTcF < 450 
msec: QTcF > 500 msec on a 12-lead ECG at any time after administration of 
GSK3039294; If baseline QTcF 450-480 msec: QTcF > 530 msec at any time after 
drug administration and is reasonably attributable to GSK3039294, as an average of 
triplicate readings (see Section 5.4.3).
Arrhythmias which have developed from a baseline of sinus rhythm: Development of 
Atrial fibrillation, any type of tachy-arrhythmia (e.g. pulsed ventricular tachycardia or 
SVT), or any type of heart block (with the exception of transient first degree heart 
block in healthy volunteers), confirmed on a 12-lead ECG at any time after drug 
administration and is reasonably attributable to GSK3039294.
In systemic amyloidosis patients only: Development of sinus bradycardia ≤ 40 beats 
per minute (from a non-bradycardic baseline) lasting ≥ 10 minutes at any time after 
drug administration and is reasonably attributable to GSK3039294, or progression of 
first degree heart block (or second degree AV block Mobitz Type I) to any type of 
heart block requiring pacing.
REVISED TEXT
Chest pain at rest or exertion at any time after drug administration and is reasonably 
attrituble to New onset or worsening symptoms of cardiac ischemia which is 
reasonably attributable to GSK3039294, with proven or suspected changes of 
cardiac ischaemia on a 12-lead ECG.
Development of pulmonary oedema or decompensated or uncontrolled congestive
cardiac failure which is reasonably attributable to GSK303294.
Systolic blood pressure > 170 mmHg as an average of triplicate readings taken at rest 
over 15 minutes on three consecutive days at any time after drug administration and is 
reasonably attributable to GSK3039294.
Healthy Volunteers & Amyloidosis Patients without bundle branch block: QTcF 
> 500 msec, (or a change from baseline of QTcF > 60 msec on a 12-lead ECG in 
healthy volunteers) at any time after drug administration and is which is reasonably 


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attributable to GSK3039294 on an average from triplicate readings (see Section 
5.4.3). 
Systemic Amyloidosis patients with bundle branch block - if baseline QTcF < 450 
msec: QTcF > 500 msec on a 12-lead ECG at any time after administration of 
GSK3039294; If baseline QTcF 450-480 msec: QTcF > 530 msec at any time after 
drug administration and is reasonably attributable to GSK3039294, as an average of 
triplicate readings (see Section 5.4.3).
Arrhythmias Development of a new arrhythmia which have developed from a 
baseline of sinus rhythm: Development of Atrial fibrillation, any type of tachy-
arrhythmia (e.g. pulsed ventricular tachycardia or SVT), or any type of heart block 
(with the exception of transient first degree heart block in healthy volunteers), 
confirmed on a 12-lead ECG at any time after drug administration and which is 
reasonably attributable to GSK3039294.
In systemic amyloidosis patients only: Development of sinus bradycardia ≤ 40 beats 
per minute (from a non-bradycardic baseline) lasting ≥ 10 minutes at any time after 
drug administration and is reasonably attributable to GSK3039294, or progression of 
first degree heart block (or second degree AV block Mobitz Type I) to any type of 
heart block requiring pacing.
Section 6.10.1 – Meals and Dietary Restrictions
PREVIOUS TEXT

In Part A, and during Week 1 of Part B, on all dosing days, subjects will be required 
to fast from midnight until 3 hours after administration of study treatment (with the 
exception of Day 5 of Part B in which subjects will be fed). At other times, snacks 
and meals will be provided by the clinical unit.  Water will be allowed as desired 
except for one hour before and after drug administration.

An investigation into a possible food effect will be conducted on Days 4 and 5 of 
Part B in this study. On Day 4 subjects will be fasted until following the collection of 
the 4hr post-dose PK sample, on Day 5 subjects will be fed prior to PK samples 
being taken. This investigation will inform possible further meal restrictions in the 
study (rest of Part B and Part C).

There are no meal restrictions for Weeks 2 and 3 of Part B and all of Part C, unless 
the food effect exploration indicates significant effects on PK.
REVISED TEXT

In Part A, and during Cohort 3 of Part B Week 1 of Part B, on all dosing days, 
subjects will be required to fast from midnight until 3 hours after administration of 
study treatment (with the exception of Day 5 of Cohort 3 Part B in which subjects 
will be fed). At other times, snacks and meals will be provided by the clinical unit.  


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Water will be allowed as desired except for one hour before and after drug 
administration.

An investigation into a possible food effect will be conducted on Days 4 and 5 of 
Cohort 3 of Part B in this study. On Day 4 subjects will be fasted until following the 
collection of the 4hr post-dose PK sample, on Day 5 subjects will be fed prior to PK 
samples being taken. This investigation will inform possible further meal restrictions 
in the study (rest of Part B and Part C).

There are no meal restrictions for Cohorts 4a and 4b Weeks 2 and 3 of Part B and 
all of Part C, unless the food effect exploration indicates significant effects on PK.
Section 7.1 – Time and Events Tables
Multiple Changes throughout, addition of table for 7 day repeat dose, and addition of 
table for optional dose alteration in 21 day repeat dose (healthy subjects).
Section 7.3.4 – Vital Signs
PREVIOUS TEXT
Triplicate readings of blood pressure and pulse rate will be taken and averaged at 
screening and at pre-first dose for each dose level, single readings will be collected at all 
other times.
REVISED TEXT
Triplicate readings of blood pressure and pulse rate will be taken and averaged at 
screening and at pre-first dose for each dose level, single readings will be collected at all 
other times.
Section 7.3.5 – Electrocardiogram (ECG)
PREVIOUS TEXT
12-lead ECGs (triplicate readings at screening and at pre-first dose for each dose level, 
single readings will be collected at all other times)
REVISED TEXT
12-lead ECGs will be measured in semi-supine position after 5 minutes rest (triplicate 
readings at screening and at pre-first dose for each dose level, single readings will be 
collected at will be taken and averaged at all other times)
Section 7.4.1 – Blood Sample Collection
PREVIOUS TEXT


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Part A (Single dose to Healthy Volunteers):
Pre-dose, and 0.25; 0.5; 0.75; 1; 1.5; 2; 3; 4; 5; 6; 8; 10; 12; 16; 24 and 48 hrs post-dose.
REVISED TEXT
Part A (Single dose to Healthy Volunteers):
Pre-dose, and 0.25; 0.5; 0.75; 1; 1.5; 2; 3; 4; 5; 6; 8; 10; 12; 16; 24 and 48 hrs post-dose.
Part B – Cohort 3 (7 day repeat dose to Healthy Volunteers):
Study Day
PK sampling timepoint(s)
1
Pre-dose, and 2hr post-dose
2&3
Pre-dose
4
Pre-dose, and 0.5; 1; 2; 3; 4; 6 hrs post-dose
5
Pre-dose, and 0.5; 1; 2; 3; 4; 6 hrs post-dose
Follow-up 
(7 – 14 
days post-
dose)
Single sample
Part B – Cohort 4a/b (21 day repeat dose to Healthy Volunteers):
Study Day
PK sampling timepoint(s)
1
Pre-dose, and 2hr post-dose (1st dose of the day only)
2-4
Pre-dose (before 1st dose of the day only)
5
Pre-dose, and 0.5; 1; 2; 3; 4; 6 hrs post-dose (1st dose of 
the day only)
21
Pre-dose, and 0.5; 1; 2; 3; 4; 6; 8 and 12 hrs post-dose 
(1st dose; note: 12hr post dose sample to be taken before 
next dose administration
Follow-up 
(7 – 14 
days post-
dose)
Single sample
If a dose adjustment is required within the 21 day repeat dose period, PK samples 
will also taken at timepoints indicated below. Note: The ‘Dose Day’ relates to the 
first day of the adjusted dose, and not the study day. 
Dose Day
PK sampling timepoint(s)
-1
Pre-dose
1
Pre-dose, and 2hr post-dose (1st dose of the day only)
2-4
Pre-dose (before 1st dose of the day only)


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5
Pre-dose, and 0.5; 1; 2; 3; 4; 6 hrs post-dose (1st dose of 
the day only)
Study Day
21
Pre-dose, and 0.5; 1; 2; 3; 4; 6; 8 and 12 hrs post-dose 
(1st dose; note: 12hr post dose sample to be taken before 
next dose administration
Follow-up 
(7 – 14 
days post-
dose)
Single sample
Section 7.5 – Biomarker(s)/Pharmacodynamic Marker
Study Day
PD sampling timepoint(s)
1
Pre-dose, and; 2; 4; 6; and 12 hrs post-dose (note: 12hr 
post-dose sample to be taken before next dose 
administration)
2-7
Pre-dose (before 1st dose of the day only)
8-20
Pre-dose (before 1st dose of the day only) on days that a 
visit is planned
21
Pre-dose, and 0.5; 1; 2; 3; 4; 6; 8 and 12 hrs post-dose 
(1st dose; note: 12hr post dose sample to be taken before 
next dose administration)
During Follow-up
1 sample/wk up to 6 weeks
REVISED TEXT
Cohort 3 (7 day repeat dose to Healthy Volunteers):
Study Day
PD sampling timepoint(s)
1
Pre-dose, and 2hr post-dose
2 and 4
Pre-dose
5
Pre-dose, and 0.5; 1; 2; 3; 4; 6 hrs post-dose
7
Pre-dose (before 1st dose of the day only)
Follow-up (7 – 14 days post-
dose)
Single sample
Cohort 4a/b (21 day repeat dose to Healthy Volunteers):
Study Day
PD sampling timepoint(s)
1
Pre-dose, and 2hr post-dose (1st dose only)
2 and 4
Pre-dose (before 1st dose of the day only)
5
Pre-dose, and 2hr post-dose (1st dose of the day only)
Follow-up (7 – 14 days post-
dose)
Single sample


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If a dose adjustment is required within the 21 day repeat dose period (Cohort 
4a/4b), PD samples will also taken at timepoints indicated below. Note: The ‘Dose 
Day’ relates to the first day of the adjusted dose, and not the study day. 
Dose Day
PD sampling timepoint(s)
-1
Pre-dose
1
Pre-dose, and 2hr post-dose (1st dose only)
2-4
Pre-dose (before 1st dose of the day only)
5
Pre-dose, and 2hr post-dose (1st dose of the day only)
Study Day
Follow-up 
(7 – 14 
days post-
dose)
Single sample
Study Day
PD sampling timepoint(s)
1
Pre-dose, and; 2; 4; 6; and 12 hrs post-dose (note: 12hr 
post-dose sample to be taken before next dose 
administration)
2-7
Pre-dose (before 1st dose of the day only)
8-20
Pre-dose (before 1st dose of the day only) on days that a 
visit is planned
21
Pre-dose, and 0.5; 1; 2; 3; 4; 6; 8 and 12 hrs post-dose 
(1st dose; note: 12hr post dose sample to be taken before 
next dose administration)
Safety Follow-up
Single sample
PD During Follow-
up
1 sample/wk up to 6 weeks
Section 8 – Data Management
PREVIOUS TEXT
For this study, the data collection tool will be PIMS, a validated computer software 
program. In all cases, subject initials will be collected in source documentation at the site 
but will not be transmitted to GSK sponsor team
REVISED TEXT
For this study, the data collection tool will be PIMS, a validated computer software 
program. In all cases, subject initials numbers will be collected in source documentation 
at the site but will not be transmitted to GSK sponsor team


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Section 10.7.1 – Dose Escalation Committee
PREVIOUS TEXT
For Part A, dose escalation decisions will be based on data obtained from 6 or more 
subjects receiving GSK3039294 at the prior dose level(s). The review data set will at 
minimum consist of all available PK data, the listings of any adverse events, flagged vital 
signs, flagged findings during continuous cardiac monitoring (telemetry), ECG and 
laboratory findings, together with any available pharmacodynamic (PD) data.
The decision and selection of dose to proceed to Part B will be made by the DEC based 
on all available PK data. the listings of any adverse events, flagged vital signs, flagged 
findings during continuous cardiac monitoring (telemetry), ECG and laboratory findings, 
together with any available pharmacodynamic (PD) data from the dose levels 
investigated in Part A
The decision and selection of dose to proceed to Part C, will be made by the DEC 
basedon available PK data the listings of any adverse events, flagged vital signs, flagged 
findings during continuous cardiac monitoring (telemetry), ECG and laboratory findings, 
together with any available PD data from the dose levels investigated in Part A, and 
available PK the listings of any adverse events, flagged vital signs, flagged findings 
during continuous cardiac monitoring (telemetry), ECG and laboratory findings, together 
with any available PD data from the dose levels investigated in Part B.
REVISED TEXT
For Part A, dose escalation decisions will be based on data obtained from 6 or more 
subjects receiving GSK3039294 at the prior dose level(s). The review data set will at a
minimum consist of all available PK data, the listings of any adverse events, flagged vital 
signs, flagged findings during continuous cardiac monitoring (telemetry), ECG and 
laboratory findings, together with any available pharmacodynamic (PD) data.
The decision and selection of dose to proceed to Part B as well as any dose escalation 
decisions, will be made by the DEC based on all available PK data. the listings of any 
adverse events, flagged vital signs, flagged findings during continuous cardiac 
monitoring (telemetry), ECG and laboratory findings, together with any available 
pharmacodynamic (PD) data from the dose levels investigated in Part A
The decision and selection of dose to proceed to Part C, will be made by the DEC based 
at a minimum on available PK data the listings of any adverse events, flagged vital 
signs, flagged findings during continuous cardiac monitoring (telemetry), ECG and 
laboratory findings, together with any available PD data from the dose levels investigated 
in Part A, and available PK the listings of any adverse events, flagged vital signs, flagged 
findings during continuous cardiac monitoring (telemetry), ECG and laboratory findings, 
together with any available PD data from the dose levels investigated in Part B.


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AMENDMENT 2
Where the Amendment Applies
Throughout the protocol.
Summary of Amendment Changes with Rationale
Changes made are to reflect an increase in cardiac monitoring in Cohort 3 (Healthy 
subjects in Part B) and Cohort 5 (patients in Part C), in order obtain further safety data in
these groups.
List of Specific Changes
Protocol Synopsis: Objectives and Endpoints (Parts B and C)
PREVIOUS TEXT
Adverse events, laboratory measurements, ECG, vital signs
REVISED TEXT
Adverse events, laboratory measurements, ECG, vital signs and cardiac telemetry 
(where applicable)
Protocol Synopsis: Treatment Arms and Duration
PREVIOUS TEXT
Part B: Repeat dose escalation in healthy volunteers
Cohort 3: In a group of healthy volunteers sufficient subjects will be enrolled to ensure 6 
completers, the study drug will be administered repeatedly for a total of 7 days.  The dose 
will be one that is expected to be well tolerated based on the single dose data and not 
predicted to exceed exposure limits based on single dose PK. Providing a review of the 
data (safety data: AE, vital signs, ECG, laboratory safety tests and PK) is favourable, 
Cohort 4 will be initiated.
A food effect exploration will be conducted at Days 4 and 5 of this cohort. On these days 
GSK3039294 will be administered under fasted and then under fed conditions


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REVISED TEXT
Part B: Repeat dose escalation in healthy volunteers
Cohort 3: In a group of healthy volunteers (preferably < 45 years of age) sufficient 
subjects will be enrolled to ensure 6 completers, the study drug will be administered 
repeatedly for a total of 7 days.  The dose will be one that is expected to be well tolerated 
based on the single dose data and not predicted to exceed exposure limits based on single 
dose PK. Providing a review of the data (safety data: AE, vital signs, ECG, laboratory 
safety tests and PK) is favourable, Cohort 4 will be initiated.
A food effect exploration will be conducted at Days 4 and 5 of this cohort. On these days 
GSK3039294 will be administered under fasted and then under fed conditions
A sentinel subject will be dosed first with repeat GSK3039294 administration for 7 
consecutive days. Subsequent subjects will only be dosed after the sentinel subject 
has successfully completed the full 7 days of dosing without any clinically 
concerning AEs being reported. If the safety data from the sentinel subject is 
deemed to be equivocal, a second subject can be dosed individually for 7 days at the 
discretion of the Investigator in consultation with the GSK study team. If the safety 
data from the second subject is also equivocal, at the discretion of the Investigator in 
consultation with the GSK study team, subsequent subjects can also be individually 
dosed with GSK3039294 for 7 days. 
The food effect exploration in Cohort 3 will only be conducted once the Investigator 
in consultation with the GSK study team is satisfied with the safety profile of repeat 
dose GSK3039294. Following this, the food effect will be conducted on Days 4 and 5, 
and GSK3039294 will be administered under fasted and then under fed conditions 
(respectively).
Sufficient subjects will be enrolled to ensure a minimum of 6 subjects complete all 
study procedures, including the food effect exploration.
Providing a review of the data (safety data: AE, vital signs, ECG, telemetry, 
laboratory safety tests and PK) is overall acceptable, Cohort 4a will be initiated. The 
approving REC will be informed of the outcome of this data review.
Protocol Synopsis: Treatment Arms and Duration
PREVIOUS TEXT
Part C: Repeat dose escalation in patients with systemic amyloidosis


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A single dose level of GSK3039294 will be tested for 21 days repeat dose, in patients 
with systemic amyloidosis. 
REVISED TEXT
Part C: Repeat dose escalation in patients with systemic amyloidosis
A single dose level of GSK3039294 will be tested for 21 days repeat dose, in patients 
with systemic amyloidosis which may include those with cardiac amyloid 
involvement. 
Protocol Synopsis: Type and Number of Subjects
PREVIOUS TEXT
In Part C, 12 patients with systemic amyloidosis will be enrolled. If subjects prematurely 
discontinue, replacement subjects may be enrolled at the discretion of the Sponsor in 
consultation with the investigator.  
REVISED TEXT
In Part C, a minimum of 12 patients with systemic amyloidosis will be enrolled. If 
subjects prematurely discontinue, replacement subjects may be enrolled at the discretion 
of the Sponsor in consultation with the investigator.  
Protocol Synopsis: Analysis
PREVIOUS TEXT
Interim analyses
Safety, PK and PD data will be reviewed on an ongoing basis throughout the study by the 
study team and investigator in order to inform dosing decisions for subsequent dosing 
sessions, cohorts and study parts.  
At the end of Part B, individual profiles over time will also be presented graphically for 
selected urine and plasma laboratory parameters pertaining to the kidney. To inform 
dosing decisions for subsequent dosing sessions in Part A, individual values of Cmax and 
AUC[0-inf] will be derived by means of non-compartmental analysis.  To inform dosing 
decisions for subsequent study parts, GSK2315698 concentration data and plasma SAP 
levels will be analysed using the PK/PD model that was developed for GSK2315698.
Primary and secondary analyses


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Safety, PK and PD data will be listed, summarised and presented graphically as 
appropriate.  GSK2315698 concentration data and plasma SAP levels will be analysed 
using the PK/PD model that was developed for GSK2315698.
REVISED TEXT
Interim analyses
Safety, PK and PD data will be reviewed on an ongoing basis throughout the study by the 
study team and investigator in order to inform dosing decisions for subsequent dosing 
sessions, cohorts and study parts.  
In addition, in all Parts of the study, individual profiles over time will also be 
presented graphically for selected urine and plasma laboratory parameters pertaining to 
the kidney. To inform dosing decisions for subsequent dosing sessions in Part A, 
individual values of Cmax and AUC[0-inf] will be derived by means of non-
compartmental analysis.  To inform dosing decisions for subsequent study parts, 
GSK2315698 concentration data and plasma SAP levels will be analysed using the 
PK/PD model that was developed for GSK2315698.
Primary and secondary analyses
Safety, PK and PD data will be listed, summarised and presented graphically as 
appropriate.  GSK2315698 concentration data and plasma SAP levels will be analysed 
using the PK/PD model that was developed for GSK2315698.
Cohort Safety Reviews: A safety review will be performed on completion of each 
Cohort in Part B, as well as at completion of Cohort 5 in Part C (see Section 4.2.2. & 
Section 4.2.3.). Initiation of Cohort 4a will be contingent on the findings of the safety 
review at completion of Cohort 3 (see Section 4.2.2.)
Summary of Cardiac Arrhythmia Adverse Events in Part A of this study
A total of 4 separate arrhythmias in 3 male subjects over 45 year old were reported 
on 24-hour Holter after single dose administration of GSK3039294 in Part A. Three 
episodes of supraventricular tachycardia (SVT), all of atrial tachycardia 
morphology at doses of GSK3039294 at 600mg and 1200mg, and one episode of a 
single 5-beat accelerated idioventricular rhythm (AIVR) at 600mg GSK3039294, 
were reported in these 3 separate subjects. Each of the events was of short duration, 
completely asymptomatic, and was not associated with hemodynamic instability. 
No prolongation of the QTcF interval was observed in any subject after 
administration of 200mg, 600mg, or 1200mg of GSK3039294 in Part A.


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Both SVTs and ventricular salvos of short duration are known to occur in healthy 
volunteer subjects and can be considered to be within the normal (non-pathological) 
variation of ECG parameters. In this regard, SVTs have been reported to arise in 
13.9% of healthy volunteer subjects over 45 years of age compared to an incidence 
of 1.1% in healthy volunteer subjects 45 years or less in FIH studies (Hingorani et 
al, 2016). In Part A, none of the three affected subjects had plasma levels of 
GSK3039294 detectable approximate to the time at which each cardiac arrhythmia 
occurred. Moreover, the timing of each of the four arrhythmic events after dosing 
with GSK3039294 was not associated with the Tmax of CPHPC including one 
subject whom had no detectable plasma CPHPC present at approximately the time 
of the first of their two arrhythmic events.
Therefore, at this time, given that there were also no arrhythmogenic liabilities 
identified for GSK3039294 in preclinical toxicological studies, it is unlikely that the 
arrhythmias reported after dosing with GSK3039294 in Part A are attributable to 
its single dose administration at 600 mg or 1200mg.
Section 3. Objectives and Endpoints (Parts B and C)
PREVIOUS TEXT
Adverse events, laboratory measurements, ECG, vital signs
REVISED TEXT
Adverse events, laboratory measurements, ECG, vital signs and cardiac telemetry 
(where applicable)
Section 4.2.2. Part B (repeat dose escalation in healthy volunteers
PREVIOUS TEXT
Part B is repeat dose, open label, dose escalation conducted in healthy volunteer subjects
and will evaluate the safety, tolerability, PK, pharmacodynamics of repeat dosing of 
GSK3039294. In addition to PK, plasma SAP levels will be measured at time points as in 
the Time and Events table (Section 7.1.1) to determine the ability of GSK3039294 to 
decrease plasma SAP levels to aid prediction of the optimal clinical dose.
In a group of healthy volunteers sufficient subjects will be enrolled to ensure a minimum 
of 6 subjects complete all study procedures (including the food-effect part) completers, 
the study drug will be administered repeatedly for a total of 7 days.  The dose will be one 
that is expected to be well tolerated based on the single dose data and predicted to not 
exceed exposure limits based on single dose PK. Providing a review of the data (safety 


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data: AE, vital signs, ECG, laboratory safety tests and PK) is favourable, Cohort 4 will be 
initiated.
Sentinel dosing:  The subsequent subjects will be dosed after the first subject has 
completed all dosing days if there are no safety or tolerability concerns.
A food effect exploration will be conducted at Days 4 and 5 of this cohort. On these days
GSK3039294 will be administered under fasted and then under fed conditions (please see 
SRM for details of meals), and PK samples will be taken to investigate the food effect on 
the PK.
In a group of healthy volunteers sufficient subjects will be enrolled to ensure 6 
completers, the study drug will be administered repeatedly for a total of 21 days. 
The dose level for this cohort will be determined by a review of the safety and PK data 
from cohort 3. The dose may be adjusted (up or down) during the 21 day dosing session 
based on preliminary PK collected during dosing and ongoing review of safety. If the 
dose is to be altered, this will be done no later than Day 16 in order to achieve a new 
steady-state at Day 21.
The predicted maximum daily exposure dose that will not exceed pre-clinical safety 
exposure limits.
Data from cohorts 3 and 4a are expected to provide a good evaluation of the safety, 
tolerability and repeat-dose PK. The data will be evaluated using the PK/PD model to 
identify an optimal clinical dose (see Section 9.3.2.1). However, if it is determined that 
further investigation of dose levels are required before progressing to Part C (e.g. if the 
observations in cohort 4a are different from those which the PK /PD modelling 
predicted), then recruitment into Cohort 4b may be initiated.
Based on data from Cohorts 3 and 4a, dose levels will be selected for further 
investigation in a further cohort of healthy volunteers (recruitment to ensure 6
completers). For this purpose the compound will be dosed for 21 consecutive days. The 
dose level and / or dosing regimen may be altered once during the 21 days providing a 
review of the data from the starting dose (safety data: AE, vital signs, ECG, laboratory 
safety tests and PK – all obtained once steady state has been achieved) is favourable. The 
predicted maximum daily dose administered will not exceed pre-clinical safety exposure 
limits.


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Table 2
Cohort 3
Screening
All screening assessments to be completed within 28 days 
prior to the first dose
Treatment 
Period
Each subject will take part in a single study period. Subjects 
will be in-patient from Day -1 until Day 8 when they will be 
discharged.
Follow-up
At least 7 days and no greater than 21 days after last study 
drug administration
Additional follow-up visits may be scheduled, if warranted
Total Duration
Approximately 7 weeks
REVISED TEXT
Part B is repeat dose, open label, dose escalation conducted in healthy volunteer subjects
and will evaluate the safety, tolerability, PK, pharmacodynamics of repeat dosing (7 day 
in Cohort 3, 21 day in Cohort 4) of GSK3039294. In addition to PK, plasma SAP levels 
will be measured at time points as in the Time and Events table (Section 7.1.1) to 
determine the ability of GSK3039294 to decrease plasma SAP levels to aid prediction of 
the optimal clinical dose.
Sentinel Dosing in Part B
In each individual study cohort in Part B, a sentinel subject will complete all dosing 
days up to and including Day 7. If there are no clinically concerning safety or 
tolerability issues observed, the rest of the subjects within the cohort can be dosed. 
If the safety data from the sentinel subject is deemed to be equivocal, a second (and 
subsequent) subjects will complete all dosing days individually, up to and including 
Day 7, at the discretion of the Investigator in consultation with the GSK study team.
7 Day Repeat Dosing (Cohort 3)
In a group of healthy volunteers, sufficient subjects will be enrolled to ensure a 
minimum of 6 subjects complete all study procedures (including evaluation of food-
effect) associated with 7 days repeat dosing administration.In a group of healthy 
volunteers sufficient subjects will be enrolled to ensure a minimum of 6 subjects 
complete all study procedures (including the food-effect part) completers, the study drug 
will be administered repeatedly for a total of 7 days.  The dose will be one that is 
expected to be well tolerated based on the single dose data and predicted to not exceed 
exposure limits based on single dose PK. Providing a review of the data (safety data: AE, 
vital signs, ECG, laboratory safety tests and PK) is favourable, Cohort 4 will be initiated.


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Sentinel dosing:  The subsequent subjects will be dosed after the first subject has 
completed all dosing days if there are no safety or tolerability concerns.
A food effect exploration will be conducted at Days 4 and 5 of this cohort once the 
investigator is satisfied with the safety data from the sentinel subject(s). To evaluate 
a potential food effect, On these days GSK3039294 will be administered under fasted 
and then under fed conditions (please see SRM for details of meals), and PK samples will 
be taken to investigate the food effect on the PK.
Cardiac Safety Review of Cohort 3
Given that all cardiac arrhythmic events after single dose administration of 
GSK3039294 in Part A (where there were detectable levels of plasma CPHPC) were 
relatively acute and observed between approximately 4 to 7 hours after tmax of 
CPHPC and when no GSK3039294 was detectable, and given steady state is 
expected to be reached after approximately 5 days of repeat dosing, 7 day 
continuous cardiac telemetry in Cohort 3 is deemed to be of sufficient duration to 
detect any potential cardiac arrhythmias associated with repeat dosing of 
GSK3039294. 
On completion, in addition to full safety review, a cardiac safety review will be 
performed where individual subject telemetry data will be reviewed in relation to 
the PK data of GSK3039294 and CPHPC.
21 Day Repeat Dosing (Cohort 4a)
In a group of healthy volunteers sufficient subjects will be enrolled to ensure 6 
completers, the study drug will be administered repeatedly for a total of 21 days. 
The dose level for this cohort will be determined by a review of the safety and PK data
from cohort 3. The dose may be adjusted (up or down) during the 21 day dosing session 
based on preliminary PK collected during dosing and ongoing review of safety. If the 
dose is to be altered, this will be done no later than Day 16 in order to achieve a new 
steady-state at Day 21.
The predicted maximum daily exposure dose that will not exceed pre-clinical safety 
exposure limits.
The dose level and / or dosing regimen may be adjusted (up or down)  once during 
the 21 days providing a review of the data from the starting dose (safety data: AE, 
vital signs, ECG, laboratory safety tests and PK – all obtained once steady state has 
been achieved) is favourable. If the dose is to be altered, this will be done no later 
than Day 16 in order to achieve a new steady-state at Day 21. The predicted 
maximum daily dose administered will not exceed pre-clinical safety exposure 
limits.


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Initiation of Cohort 4a: Cohort 4a will only be initiated if the conclusion of the 
safety review from Cohort 3 demonstrates an acceptable safety profile associated 
with the repeat administration of GSK3039294 for 7 days. 
Individual subjects in Cohort 4a can be withdrawn from the study at the discretion 
of the Investigator in consultation with the GSK study team if individual subject 
safety review at Day 7 demonstrates any AEs which are deemed to be equivocal or 
clinically concerning. Affected subject(s) should be followed-up, at the discretion of 
the Investigator, as per local practice.
Data from cohorts 3 and 4a are expected to provide a good evaluation of the safety, 
tolerability and repeat-dose PK. The data will be evaluated using the PK/PD model to 
identify an optimal clinical dose (see Section 9.3.2.1). However, if it is determined that 
further investigation of dose levels are required before progressing to Part C (e.g. if the 
observations in cohort 4a are different from those which the PK /PD modelling 
predicted), then recruitment into Cohort 4b may be initiated.
21 Day Repeat Dosing (Cohort 4b – optional, only if required)
In a group of healthy volunteers, sufficient subjects will be enrolled to ensure a 
minimum of 6 completers, the study drug will be administered repeatedly for a total 
of 21 days. 
Based on data from Cohorts 3 and 4a, dose levels will be selected for further 
investigation in a further cohort of healthy volunteers (recruitment to ensure 6 
completers). For this purpose the compound will be dosed for 21 consecutive days. The 
dose level and / or dosing regimen may be altered adjusted (up or down)  once during 
the 21 days providing a review of the data from the starting dose (safety data: AE, vital 
signs, ECG, laboratory safety tests and PK – all obtained once steady state has been 
achieved) is favourable. If the dose is to be altered, this will be done no later than Day 
16 in order to achieve a new steady-state at Day 21. The predicted maximum daily 
dose administered will not exceed pre-clinical safety exposure limits.


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Table 2
Cohort 3
Screening
All screening assessments (including a 48hr Holter 
recording) to be completed within 28 days prior to the first 
dose
Treatment 
Period
Each subject will take part in a single study period. Subjects 
will be in-patient from Day -1 Day -2 (where baseline 
cardiac telemetry will be performed for 24 hours 
immediately prior to the first dose of GSK3039294) until 
Day 8 when they will be discharged.
Follow-up
At least 7 days and no greater than 14 21 days after last 
study drug administration
Additional follow-up visits may be scheduled, if warranted
Total Duration
Approximately 7 weeks
Section 4.2.2. Figure 3 (footnote)
PREVIOUS TEXT
In Cohort 4b multiple dose levels and different regimens may be investigated based on 
data from Cohort 4a. *Day of Potential Dose Alteration not specified as this will be 
performed following review of safety and PK data from previous dose.
REVISED TEXT
In Cohort 4b multiple dose levels and different regimens may be investigated based on 
data from Cohort 4a. *Day of Potential Dose Alteration (no later than D16) not 
specified as this will be performed following review of safety and PK data from previous 
dose.
Section 4.2.3. Part C (repeat dose escalation in patients with systemic 
amyloidosis)
PREVIOUS TEXT
In Part C a single dose level of GSK3039294 will be tested for 21 days repeat dose, in
patients with systemic amyloidosis. This will confirm the ability of GSK3039294 (given 
at the predicted optimal clinical dose determined from Part B) to decrease plasma SAP,
and assess the ability of GSK3039294 to maintain this level over 21 days in patients with 
systemic amyloidosis.
Safety and tolerability will also be evaluated


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Table 4
Cohort 5 Study Duration
Screening
All screening assessments to be completed within 28 days 
prior to the first dose
Treatment 
Period
Each subject will take part in a single study period. Subjects 
will be in-patient from Day -1 until Day 8 when they will be 
discharged after assessments have been completed. 
Subjects will return to the unit as out-patients for regular 
assessments whilst continuing dosing to Day 21.
Safety Follow-up
Subjects will attend 7-14 days post last dose for a safety 
follow-up
PD Follow-up
Weekly PD assessments will be made up to 42 days after last 
study drug administration
Additional follow-up visits may be scheduled, if warranted
Total Duration
Approximately 13 weeks
REVISED TEXT
In Part C a single dose level of GSK3039294 will be tested for 21 days repeat dose, in
patients with systemic amyloidosis, which may include those patients with known 
cardiac amyloid involvement. This will confirm the ability of GSK3039294 (given at 
the predicted optimal clinical dose determined from Part B) to decrease plasma SAP, and 
assess the ability of GSK3039294 to maintain this level over 21 days in patients with 
systemic amyloidosis.
Safety and tolerability will also be evaluated
Initiation of Cohort 5: Cohort 5 will only be initiated if the conclusion of the safety 
review from Cohort 4 demonstrates an acceptable safety profile associated with the 
repeat administration of GSK3039294 for 21 days. 
Sentinel Dosing in Part C
Renal Amyloidosis Sentinel Subject: A sentinel systemic amyloidosis patient (n=1) 
with known renal involvement and an estimated GFR ≥ 60 ml / min, but with no 
known cardiac involvement, will be dosed repeatedly with GSK3039294 for the full 
21-day period before dosing any other patients begin. Following this, dosing of other 
patients with renal involvement (with an eGFR > 50 mL / min) but with no cardiac 
involvement can be initiated, provided no concerning safety signals are detected in 
this sentinel patient.


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Cardiac Amyloidosis Sentinel Subject: Once the sentinel renal patient has 
successfully completed dosing, a sentinel cardiac amyloidosis patient (n=1) with 
eGFR≥ 60 mL / min & LV Ejection Fraction (EF)  ≥ 50% will be dosed repeatedly 
with GSK3039294 for the full 21-day period. Following this, dosing of any other 
patients with cardiac involvement (NYHA ≤2) can be initiated provided no 
concerning safety signals are detected in the sentinel cardiac patient.
Table 4
Cohort 5 Study Duration
Screening
All screening assessments to be completed within 28 days 
prior to the first dose including out-patient cardiac 
monitoring for 7 continuous days (with external portable 
monitoring device) only in those patients with known 
cardiac amyloid involvement
Treatment 
Period
Each subject will take part in a single study period. Subjects 
will be in-patient from Day -1 until Day 8 when they will be 
discharged after assessments have been completed. 
In-patient cardiac telemetry will be performed from at 
least Day -1 until Day 8 only in those patients with known 
cardiac amyloid involvement.
Subjects will return to the unit as out-patients for regular 
assessments whilst continuing dosing to Day 21.
Safety Follow-up
Subjects will attend 7-14 days post last dose for a safety 
follow-up
PD Follow-up
Weekly PD assessments will be made up to 42 days after last 
study drug administration
Additional follow-up visits may be scheduled, if warranted
Total Duration
Approximately 13 weeks
Section 4.3. Type and Number of Subjects
PREVIOUS TEXT
In Part B, sufficient healthy volunteers will be enrolled to ensure 6 subjects per cohort 
have completed the in-patient phases.
Subjects who participate in Part A will be eligible to participate in Part B at the discretion 
of the Investigator.
In Part A and B of the study, if subjects prematurely discontinue, replacement subjects 
may be enrolled and assigned to the same cohort at the discretion of the Sponsor in 


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consultation with the investigator. Replacement subjects do not need to have received the 
first dose for a given cohort to join the study in the second cohort.
In Part C, 12 patients with systemic amyloidosis will be enrolled.  If subjects 
prematurely discontinue, replacement subjects may be enrolled at the discretion of the 
Sponsor in consultation with the investigator.
REVISED TEXT
In Part B, sufficient healthy volunteers will be enrolled to ensure a minimum of 6 
subjects per cohort have completed the in-patient phases with all study procedures.
Subjects who participate in Part A will be eligible to participate in Part B at the discretion 
of the Investigator.
In Part A and B of the study, if subjects prematurely discontinue, replacement subjects 
may be enrolled and assigned to the same cohort at the discretion of the Sponsor in 
consultation with the investigator. Replacement subjects do not need to have received the 
first dose for a given cohort to join the study in the second cohort.
In Part C, a minimum of 12 patients with systemic amyloidosis (which may include 
those with known cardiac amyloid involvement) will be enrolled.  If subjects 
prematurely discontinue, replacement subjects may be enrolled at the discretion of the 
Sponsor in consultation with the investigator.
Section 4.4. Design Justification
PREVIOUS TEXT
Part C will confirm the ability of GSK3039294 (given at the predicted pharmacological 
dose determined from Part B) to decrease plasma SAP to a level suitable for mAb 
administration in subsequent studies and its ability to maintain this level over 21 days in 
patients with systemic amyloidosis. Also, safety and tolerability of the optimal clinical
dose of GSK3039294 will be evaluated in systemic amyloidosis patients.
REVISED TEXT
Part C will confirm the ability of GSK3039294 (given at the predicted pharmacological 
dose determined from Part B) to decrease plasma SAP to a level suitable for mAb 
administration in subsequent studies and its ability to maintain this level over 21 days in 
patients with systemic amyloidosis. Also, safety and tolerability of the optimal clinical
dose of GSK3039294 will be evaluated in systemic amyloidosis patients which may 
include those with known cardiac amyloid involvement.


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Section 4.6.1. Risk Assessment

Inclusion of “Monitoring of haemoglobin & platelets” as a mitigation strategy 
for “GSK2315698  - Epistaxis”

Inclusion of further information in “Summary of Data / rationale for Risk 
mitigation strategy” for “Preclinical finding of potential nephrotoxicity of 
GSK3039294”

Inclusion of “Preclinical finding of haematologic effects associated with 
GSK2315698” and associated Summary of Data and Mitigation Strategy

Inclusion of “Preclinical finding of testicular changes associated with 
GSK2315698” and associated Summary of Data and Mitigation Strategy

Inclusion of “No arrhythmogenic safety signals were detected” and 
“Cardiovascular parameters, including blood pressure and heart rate, will be 
closely monitored in the clinical study” against “Summary of Data” and 
“Mitigation Strategy” (respectively) for “Preclinical finding of cardiovascular 
changes associated with GSK2315698”.

Inclusion of “Cardiac arrhythmias identified on 24-hour Holter after single dose 
administration of GSK3039294 in Part A of this study” and associated Summary 
of Data and Mitigation Strategy
Section 4.6.3. Overall Benefit:Risk Conclusion
PREVIOUS TEXT
GSK3039294 is an oral prodrug of CPHPC, as such it is expected to release CPHPC after 
oral administration. Previous clinical experience with CPHPC shows it has a good safety 
and tolerability profile therefore we do not anticipate safety issues linked to the release of 
the active moiety.
Biotransformation from prodrug into active will release 2 molecules of formaldehyde. 
There is precedent of drugs releasing formaldehyde with no associated toxicity.
Preclinical signs of potential nephrotoxicity were observed at very high doses which are 
unlikely to be reached in the clinic, however monitoring of renal function will be 
performed in the study in order to detect any potential changes. 
There will be no medical benefit to healthy volunteers or patients with systemic 
amyloidosis being treated with GSK3039294 alone. The design of the study, schedule of 
assessments, and oversight mean that any risks to participants are minimised including 
those which might potentially affect the kidney, and therefore the clinical study is 
justified.
REVISED TEXT
GSK3039294 is an oral prodrug of CPHPC, as such it is expected to release CPHPC after 
oral administration. Previous clinical experience with CPHPC shows it has a good safety 


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and tolerability profile therefore we do not anticipate safety issues linked to the release of 
the active moiety.
At this time, although the cardiac arrhythmias reported in Part A are unlikely to be 
attributable to single dose administration of GSK3039294 at either 600mg or 
1200mg, as a precaution, and to further assess and confirm this conclusion, the 
cardiac safety monitoring of healthy volunteer subjects during repeat dose 
administration of GSK3039294 for 7 consecutive days in Cohort 3 Part B has been 
enhanced (see Section 7.3.7.), and also in systemic amyloidosis patients in Cohort 5 
Part C who are known to have cardiac amyloid involvement (see Section 7.3.8.).
Biotransformation from prodrug into active will release 2 molecules of formaldehyde. 
There is precedent of licensed prodrugs drugs releasing formaldehyde with no 
associated toxicity on a background that formaldehyde is physiologically metabolised 
very rapidly within the systemic circulation (EFSA Journal, 2014; 12(2):3550).
Preclinical signs of potential nephrotoxicity were observed at very high doses which are 
unlikely to be reached in the clinic, however monitoring of renal function will be 
performed in the study in order to detect any potential changes. 
There will be no medical benefit to healthy volunteers or patients with systemic 
amyloidosis being treated with GSK3039294 alone. The design of the study, schedule of 
assessments, and oversight mean that any risks to participants are minimised including 
those which might potentially affect the kidney and heart, and therefore the clinical 
study is justified.
Section 5.1. Inclusion Criteria (Patients)
Addition of the following inclusion criteria:

For AL amyloidosis patients, ≥ 6 months post-chemotherapy with either a 
free light chain (FLC) complete response (CR) or a very good partial 
response (VGPR) 
Further Inclusion Criteria for Patients with known cardiac amyloid involvement

eGFR ≥ 60 mL / min

Echocardiogram – LV ejection fraction ≥ 50% within 3 months of screening
Section 5.2. Exclusion Criteria
Addition of the following exclusion criteria under “Diagnostic Assessments and Other 
Criteria”

Cohort 3 (Part B) subjects only: Cardiac arrhythmia detected on the 48hr 
screening Holter, with the exception of physiological bradycardia, first-


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degree heart block, supraventricular premature complexes and / or 
premature ventricular complexes (PVCs) less than a single 5-beat AIVR

Cohort 3 (Part B) subjects only: High sensitivity Cardiac Troponin level 
at screening > ULN for the specified assay
Alterations to the following exclusion criteria under “Additional Exclusion Criteria -
Patients”

Non-amyloid heart diseases (e.g. epicardial coronary artery heart disease, 
or non-amyloid valvular heart disease)

Subject with mean QTcF of >480ms from a mean of triplicate readings 
triplicate readings

Cardiac Amyloidosis Patients ONLY – Within 3 months of Screening, Or 
at Screening: a). Sustained (≥ 10 beats) / symptomatic monomorphic 
ventricular tachycardia (VT), or rapid polymorphic VT; b). Complete 
heart block; c). Brady arrhythmias deemed clinically concerning in this 
patient population by the Investigator in consultation with the Medical 
Monitor

Average SBP ≤ 100mmHg at Screening from triplicate readings in Part C 
systemic amyloidosis patients with known cardiac amyloid involvement 
Or, Average SBP ≤ 90mmHg at Screening from triplicate readings in 
systemic amyloidosis patients without known cardiac amyloid 
involvement
Section 5.4.4. Cardiac Arrhythmia Stopping Criteria
Additional Text and Figure:
All cardiac arrhythmias in individual subjects will be reviewed by the Investigator 
in consultation with the Medical Monitor at the earliest possible opportunity after 
the event, and will also be reviewed by a cardiologist where it is deemed appropriate 
to do so by the Investigator in consultation with the Medical Monitor on a case-by-
case basis.
A clinically concerning cardiac arrhythmia in this study is any type of arrhythmia 
or divergent QRS complex morphology that is deemed by the Investigator to be 
reasonably attributable to GSK3039294 - rather than within normal variation for 
each type of affected subject receiving repeat dose GSK3039294; i.e. healthy 
volunteer subjects in Part B, or systemic amyloidosis patients with known cardiac 
involvement Part C.
Furthermore, a clinically concerning arrhythmia is an adverse event which is 
deemed by the Investigator in consultation with the Medical Monitor to be of 
sufficient temporal duration and / or character to potentially affect subject safety. 
Detection of the following during baseline assessment or following administration of 
GSK3039294 will lead to withdrawal:


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a). Sustained (≥ 10 beats) / symptomatic monomorphic ventricular tachycardia 
(VT), or rapid polymorphic VT; b). Complete heart block; c). Brady arrhythmias 
deemed clinically concerning by the Investigator in consultation with the Medical 
Monitor (i.e. except physiological bradycardia or first degree heart block).
Additional cardiac arrhythmic events could include, but are not restricted, to: 

A sustained arrhythmia (i.e. ≥30 seconds) except physiological bradycardia.

A non-sustained wide-complex tachyarrhythmia ≥ 100 / minute that is:
o
accompanied by symptoms or other new ECG changes (e.g. new ST 
depression)
o
repetitive (e.g. repeated short salvos)
o
Greater than 10 seconds in duration
Subjects who either have a clinically concerning arrhythmic event during the study, 
or where there is electrophysiological diagnostic uncertainty on cardiac telemetry / 
ECG, must be withdrawn from the study, and should have an immediate cardiac 
troponin level evaluated using a high-sensitivity point-of-care assay as outlined in 
Section 7.3.9 & Figure 5, below. 
Affected subjects should be referred to the local cardiology service and the Medical 
Monitor should be informed as soon as possible. 
Figure 5
Algorithm for Management of Subjects having received one or 
more doses of GSK3039294 in Parts B & C based on Arrhythmia 
Characterization


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In Part C, the patient’s amyloidosis physician should be informed as soon as 
possible after any type of cardiac adverse event, by the Medical Monitor, 
irrespective of the patient’s cardiac amyloid status at Screening.
Section 5.4.6. Stopping Criteria Based On Disease Progression in Systemic 
Amyloidosis Patients in Part C
PREVIOUS TEXT
In Part C, individual patients can be withdrawn at any time during the study where the 
investigator has a reasonable level of clinical suspicion that the patient's underlying 
systemic amyloidosis is worsening. In this setting, the investigator in consultation with 
the Medical Monitor must refer the patient to their primary hospital physician for further 
consultation and appropriate diagnostic tests
REVISED TEXT
In Part C, individual systemic amyloidosis patients can be withdrawn at any time during 
the study where the investigator has a reasonable level of clinical suspicion that the 
patient's underlying systemic amyloidosis is worsening (including worsening cardiac 
dysfunction in those patients known to have cardiac amyloid involvement). In this 


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setting, the investigator in consultation with the Medical Monitor must refer the patient to 
their primary hospital physician for further consultation and appropriate diagnostic tests
Section 6.10.1 Meals and Dietary Restrictions
PREVIOUS TEXT
An investigation into a possible food effect will be conducted on Days 4 and 5 of Cohort 
3 of Part B in this study. On Day 4 subjects will be fasted until following the collection of 
the 4hr post-dose PK sample, on Day 5 subjects will be fed prior to PK samples being 
taken. This investigation will inform possible further meal restrictions in the study (rest 
of Part B and Part C).
REVISED TEXT
An investigation into a possible food effect will be conducted on Days 4 and 5 of Cohort 
3 of Part B in this study (This will only be triggered by the Investigator in 
consultation with the Medical Monitor as per Section 4.2.2). On Day 4 subjects will 
be fasted until following the collection of the 4hr post-dose PK sample, on Day 5 subjects 
will be fed prior to PK samples being taken. This investigation will inform possible 
further meal restrictions in the study (rest of Part B and Part C).
Section 6.10.2. Caffeine and Alcohol, and Tobacco
PREVIOUS TEXT

During each dosing session, subjects will abstain from ingesting caffeine- or 
xanthine-containing products (e.g., coffee, tea, cola drinks and chocolate) for at least 
24 hours prior to the start of dosing until collection of the final pharmacokinetic and 
or pharmacodynamic sample during each session. 

Healthy Subjects: During each treatment period, subjects will abstain from alcohol 
for 24 hours prior to the start of dosing until collection of the final PK sample for 
each in-house session. Subjects will also abstain from alcohol for 24 hours prior to 
screening and follow-up.  At all other times during the study, male subjects should 
have no more than 2 drinks per day and female subjects should have no more than 1 
drink per day (1 drink is equivalent to 12 g of alcohol: 360 mL of beer, 150 mL of 
wine or 45 mL of 80 proof distilled spirits).
REVISED TEXT

During each dosing session, subjects will abstain from ingesting caffeine- or 
xanthine-containing products (e.g., coffee, tea, cola drinks and chocolate) for at least 
24 hours (48 hours for Cohort 3) prior to the start of dosing until collection of the 
final pharmacokinetic and or pharmacodynamic sample during each session. 


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
Healthy Subjects: During each treatment period, subjects will abstain from alcohol 
for 24 hours (48 hours for Cohort 3) prior to the start of dosing until collection of 
the final PK sample for each in-house session. Subjects will also abstain from 
alcohol for 24 hours prior to screening and follow-up.  At all other times during the 
study, male subjects should have no more than 2 drinks per day and female subjects 
should have no more than 1 drink per day (1 drink is equivalent to 12 g of alcohol: 
360 mL of beer, 150 mL of wine or 45 mL of 80 proof distilled spirits).
Section 7.1. Time and Events Tables
Changes to assessments for Cohorts 3 and 5 and associated endnotes / footnotes
Section 7.3.5. Cardiac Monitoring – Electrocardiogram (ECG), Telemetry & 
Non-Implantable Devices for Remote Monitoring
PREVIOUS TEXT

12-lead ECGs will be measured in semi-supine position after 5 minutes rest 
(triplicate readings will be taken and averaged at all times) will be obtained at each 
timepoint during the study using an ECG machine that automatically calculates the 
heart rate and measures PR, QRS, QT, and QTcF intervals. Refer to Section 5.4.3 for
QTcF withdrawal criteria and additional QTcF readings that may be necessary.

Continuous ambulatory cardiac telemetry will be performed from 12hrs pre-dose to  
72 hours post-dose of GSK3039294 in systemic amyloidosis patients with known 
cardiac involvement during Part C, and thereafter, at any time during any part of the 
study, at the investigator’s discretion. Full disclosures will be reviewed in detail and 
the review maintained as part of the subject’s source documents.
REVISED TEXT

12-lead ECGs will be measured in semi-supine position after 5 minutes rest 
(triplicate readings will be taken and averaged at all times) will be obtained at each 
timepoint during the study using an ECG machine that automatically calculates the 
heart rate and measures PR, QRS, QT, and QTcF intervals. Refer to Section 5.4.3 for
QTcF withdrawal criteria and additional QTcF readings that may be necessary.

Continuous ambulatory cardiac telemetry will be performed from 12hrs pre-dose to  
72 hours post-dose of GSK3039294 in systemic amyloidosis patients with known 
cardiac involvement during Part C, and thereafter, at any time during any part of the 
study, at the investigator’s discretion. Full disclosures will be reviewed in detail and 
the review maintained as part of the subject’s source documents.


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Cardiac Safety Monitoring in Cohort 3 (Part B) at Screening & Baseline
This will consist of a 48 hour Holter at Screening and continuous telemetry for 24 
hours immediately preceding the first dose of GSK303294 at baseline. 

In-Patient Dosing with GSK3039294: Continuous telemetry during repeat 7 
day dosing of healthy volunteer subjects in Cohort 3 will be performed for up 
to approximately 24 hours after Day 7 to detect any cardiac arrhythmias 
potentially attributable to repeat dosing with GSK3039294 for 7 days in 
Cohort 3.
Cardiac Safety Monitoring in Cohort 5 (Part C) patients with known cardiac 
amyloid involvement

Screening: 7-day out-patient cardiac monitoring using an appropriate non-
implantable recording device which is acceptable to the patient – this will 
evaluate the arrhythmic background of eligible cardiac amyloidosis patients 
such that false positive attribution of arrhythmias to GSK3039294 during 
repeat dosing will be minimized.

Baseline: 24 hour in-patient telemetry immediately before the first dose of 
GSK3039294.

In-patient dosing with GSK3039294: Continuous telemetry will be performed 
for up to 24 hours after Day 7 administration of GSK3039294 to detect any 
arrhythmias in patients with known cardiac amyloidosis potentially 
attributable to repeat dosing with GSK3039294 including worsening of 
known patient-specific arrhythmias from Screening and / or Baseline 
assessments.

Optional cardiac monitoring after completion of in-patient dosing: At 
Investigator discretion, on a case by case basis determined by in-patient 
cardiac telemetry / ECG findings, and in consultation with the Medical 
Monitor, cardiac monitoring can be extended either as an in-patient or as an 
out-patient (using a portable non-implantable device of Investigator 
choosing) in patients with known cardiac amyloidosis. 
Cardiac monitoring should continue in cardiac amyloidosis patients based on 
emerging safety data until it is deemed to be clinically appropriate for monitoring to 
stop after consultation with the Medical Monitor.
Section 7.3.7. High Sensitivity Cardiac Troponin-T (hs-cTnT) Monitoring after a 
Cardiac Arrhythmia in Part B, or Part C 
Addition of Section:


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Baseline hs-cTnT: In Part B  and Part C, all subjects will have hs-cTn level for 
purposes of screening as well as to provide baseline with which to compare, in the 
event that a subject develops a clinically concerning cardiac arrhythmic event after 
dosing with GSK3039294. 
Subjects should be advised by the local study site to abstain from strenuous exercise 
(e.g. running or gym work) ≤ 24 hours before a baseline hs-cTn level is taken.
Monitoring of hs-cTnT after an Arrhythmia Event: A blood samples for hs-cTnT 
will be taken immediately at the time of onset of a cardiac arrhythmia which is 
deemed by the Investigator to be of clinical concern (see Section 5.4.4), or where 
there is electrophysiological diagnostic uncertainty. 
High-sensitivity cTn levels should be serially repeated (using the same assay) 
following local troponin monitoring protocols at the study site, and with advice from 
a cardiologist if this is deemed clinically necessary by the Investigator. 
Additional investigations, including but not restricted to serial ECGs and evaluation 
of cardiac function using echocardiogram and / or cardiac magnetic resonance 
(CMR) imaging, can be performed at the discretion of the Investigator in 
consultation with the Medical Monitor and a cardiologist.
Section 7.4.1. Blood Sample Collection
PREVIOUS TEXT
Part B – Cohort 3 (7 day repeat dose to Healthy Volunteers):
Study Day
PK sampling timepoint(s)
1
Pre-dose, and 2hr post-dose
2&3
Pre-dose
4
Pre-dose, and 0.5; 1; 2; 3; 4; 6 hrs post-dose
5
Pre-dose, and 0.5; 1; 2; 3; 4; 6 hrs post-dose
Follow-up 
(7 – 14 
days post-
dose)
Single sample
REVISED TEXT


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Part B – Cohort 3 (7 day repeat dose to Healthy Volunteers):
Study Day
PK sampling timepoint(s)
1
Pre-dose, and 0.5, 1, 2, 3, 4, 6 hrs post-dose
2&3
Pre-dose
4*
Pre-dose, and 0.5; 1; 2; 3; 4; 6 hrs post-dose
5
Pre-dose, and 0.5; 1; 2; 3; 4; 6 hrs post-dose
Follow-up 
(7 – 14 
days post-
dose)
Single sample
*Day 4 PK samples will not be collected for sentinel subjects
SECTION 8. DATA MANAGEMENT
PREVIOUS TEXT

For this study, the data collection tool will be PIMS, a validated computer software 
program. In all cases, subject numbers will be collected in source documentation at 
the site but will not be transmitted to GSK sponsor team.
REVISED TEXT

For this study, the data collection tool will be PIMS, a validated computer software 
program. In all cases, subject numbers initials will be collected in source 
documentation at the site but will not be transmitted to GSK sponsor team.
SECTION 11. REFERENCES
Addition of the following reference:
Hingorani et al., Arrhythmias Seen in Baseline 24-Hour Holter ECG Recordings in 
Healthy Normal Volunteers During Phase 1 Clinical Trials., The Journal of Clinical 
Pharmacology 2016, 56(7) 885–893

SAP_001.pdf: 
CONFIDENTIAL
The GlaxoSmithKline group of companies
201664
1
Division
:
Worldwide Development
Information Type
:
Reporting and Analysis Plan (RAP)
Title
:
Reporting and Analysis Plan for A three-part open-label, non-
randomised, dose-escalation study to investigate the safety 
and tolerability of GSK3039294 administered as a single dose 
to healthy volunteers, and as repeat dose to healthy volunteers 
and patients with systemic amyloidosis.
Compound Number 
:
GSK3039294
Effective Date 
:
09-NOV-2017
Description:

The purpose of this RAP is to describe the planned analyses and output to be 
included in the Clinical Study Report for Protocol 2014N218204_03.

This RAP is intended to describe the safety and PK/PD analyses of GSK3039294 
administered as a single dose to healthy volunteers, and as repeat dose to healthy 
volunteers and patients with systemic amyloidosis. 

This RAP will be provided to study team members to convey the content of the 
Statistical Analysis Complete (SAC) deliverable for the interim and final analysis for 
this study.
Author’s Name and Functional Area: 
Associate Statistician, QSI
06-NOV-2017
(approval captured
electronically within 
CARS system)
Principal Statistician, Clinical Statistics
Principal Statistician, Clinical Statistics
01-NOV-2017
(approval captured
electronically within 
CARS system)
Director, Clinical Pharmacology Modelling & Simulation
Copyright 2017 the GlaxoSmithKline group of companies. All rights reserved.  
Unauthorised copying or use of this information is prohibited.
PPD
PPD
PPD
PPD


CONFIDENTIAL
The GlaxoSmithKline group of companies
201664
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Approved by: 
01-NOV-2017 
(approval captured
electronically within 
CARS system)
Director, Clinical Statistics
31-OCT-2017
(approval captured 
via email)
Programming Manager, Clinical Statistics
PPD
PPD


CONFIDENTIAL
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TABLE OF CONTENTS
PAGE
1.
REPORTING & ANALYSIS PLAN SYNPOSIS.........................................................5
2.
SUMMARY OF KEY PROTOCOL INFORMATION ..................................................8
2.1.
Clarifications to the Protocol Defined Statistical Analysis Plan......................8
2.2.
Study Objective(s) and Endpoint(s)...............................................................8
2.3.
Study Design ..............................................................................................10
2.4.
Statistical Hypotheses.................................................................................12
3.
PLANNED ANALYSES ..........................................................................................12
3.1.
Interim Analyses .........................................................................................12
3.2.
Final Analyses ............................................................................................14
4.
ANALYSIS POPULATIONS ...................................................................................14
4.1.
Protocol Deviations.....................................................................................15
5.
CONSIDERATIONS FOR DATA ANALYSES AND DATA HANDLING 
CONVENTIONS.....................................................................................................15
6.
STUDY POPULATION ANALYSES .......................................................................15
6.1.
Overview of Planned Analyses ...................................................................15
7.
PRIMARY STATISTICAL ANALYSES....................................................................16
7.1.
Safety Analyses..........................................................................................16
8.
SECONDARY STATISTICAL ANALYSES .............................................................18
8.1.
Pharmacokinetic Analyses..........................................................................18
8.1.1.
Overview of Planned Pharmacokinetic Analyses .........................18
8.1.2.
Drug Concentration Measures .....................................................19
8.1.3.
Pharmacokinetic Parameters.......................................................19
8.2.
Pharmacodynamic Analyses.......................................................................20
8.2.1.
Overview of Planned Pharmacodynamic Analyses ......................20
8.3.
Pharmacokinetic / Pharmacodynamic Analyses..........................................21
9.
REFERENCES.......................................................................................................22
10. APPENDICES........................................................................................................23
10.1.
Appendix 1: Time & Events.........................................................................24
10.1.1.
Part A – Cohorts 1 and 2, single dose, healthy volunteer 
subjects .......................................................................................24
10.1.2.
Part B – Cohort 3, 7 day repeat dose healthy volunteer 
subjects .......................................................................................26
10.1.3.
Part B – Cohort 4a and 4b, 21 day repeat dose healthy 
volunteer subjects........................................................................28
10.1.4.
Part B – Cohort 4, 21 day repeat dose healthy volunteer 
subjects – dose alteration (only if dose alteration is 
required) ......................................................................................31
10.1.5.
Part C – Cohort 5, repeat dose, patient subjects..........................32
10.2.
Appendix 2: Treatment States and Phases.................................................35
10.2.1.
Treatment Phases .......................................................................35


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10.2.2.
Treatment States .........................................................................35
10.2.2.1.
Treatment States for AE Data.....................................35
10.3.
Appendix 3: Data Display Standards & Handling Conventions....................36
10.3.1.
Study Treatment & Sub-group Display Descriptors......................36
10.3.2.
Baseline Definition & Derivations .................................................36
10.3.2.1.
Baseline Definitions....................................................36
10.3.2.2.
Derivations and Handling of Missing Baseline 
Data ...........................................................................36
10.3.3.
Reporting Process & Standards...................................................37
10.4.
Appendix 4: Derived and Transformed Data ...............................................39
10.4.1.
General........................................................................................39
10.4.2.
Study Population..........................................................................39
10.4.3.
Safety ..........................................................................................40
10.5.
Appendix 5: Premature Withdrawals & Handling of Missing Data ...............41
10.5.1.
Premature Withdrawals................................................................41
10.5.2.
Handling of Missing Data.............................................................41
10.5.2.1.
Handling of Missing/Partial Dates...............................41
10.6.
Appendix 6: Values of Potential Clinical Importance ...................................43
10.6.1.
Values of Potential Clinical Importance (Healthy 
Volunteers) ..................................................................................43
10.6.2.
Values of Potential Clinical Importance (Systemic 
Amyloidosis Patients)...................................................................45
10.7.
Appendix 7: Pharmacokinetic / Pharmacodynamic Analyses ......................47
10.7.1.
Systems.......................................................................................47
10.7.2.
Data Assembly.............................................................................47
10.7.3.
PK/PD Modelling of GSK2315698 and SAP 
Concentrations ............................................................................47
10.7.4.
Diagnostics..................................................................................48
10.7.5.
Specifications for NONMEM-specific Dataset ..............................48
10.8.
Appendix 8: Abbreviations & Trade Marks ..................................................52
10.8.1.
Abbreviations...............................................................................52
10.8.2.
Trademarks .................................................................................53
10.9.
Appendix 9: List of Data Displays ...............................................................54
10.9.1.
Data Display Numbering..............................................................54
10.9.2.
Mock Example Referencing .........................................................54
10.9.3.
Deliverables.................................................................................54
10.9.4.
Study Population Tables..............................................................55
10.9.5.
Safety Tables...............................................................................56
10.9.6.
Safety Figures .............................................................................58
10.9.7.
Pharmacokinetic Tables...............................................................58
10.9.8.
Pharmacokinetic Figures .............................................................59
10.9.9.
Pharmacodynamic Tables ...........................................................64
10.9.10. Pharmacodynamic Figures ..........................................................65
10.9.11. Pharmacokinetic / Pharmacodynamic Tables ..............................66
10.9.12. Pharmacokinetic / Pharmacodynamic Figures .............................66
10.9.13. ICH Listings .................................................................................68
10.9.14. Non-ICH Listings..........................................................................71


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1.
REPORTING & ANALYSIS PLAN SYNPOSIS
Overview
Key Elements of the Reporting and Analysis Plan 
Purpose

The purpose of this reporting and analysis plan (RAP) is to describe all 
interim and final analyses for this study.
Protocol

Reporting and Analysis Plan is based on amended protocol (Dated: 30-
NOV-2016) for study GSK3039294/RAD201664 [GlaxoSmithKline 
Document Number: 2014N218204_03].
Objectives / 
Endpoints
Part A: Single ascending dose in healthy volunteers 
Objectives
Endpoints
Primary
Evaluate safety and tolerability of 
single doses of GSK3039294
Adverse events, laboratory 
measurements, ECG, vital signs
Secondary
Evaluate pharmacokinetics of 
single doses of GSK3039294 and 
its biotransformation into 
GSK2315698 (CPHPC)
PK parameters of GSK2315698 
and GSK3039294
Part B: Repeat dose in healthy volunteers
Objectives
Endpoints
Primary
Evaluate safety and tolerability of 
repeat doses of GSK3039294
Adverse events, laboratory 
measurements, ECG, vital signs
and cardiac telemetry (where 
applicable)
Secondary
Evaluate pharmacokinetics of 
repeat doses of GSK3039294 and 
its biotransformation into 
GSK2315698 (CPHPC)
PK parameters of GSK2315698 
and GSK3039294
Pharmacodynamic effect of repeat 
doses of GSK3039294 on plasma 
SAP levels
Plasma SAP levels
Explore correlation of dose of 
GSK3039294, blood 
concentration of GSK2315698 
and plasma SAP levels
PK parameters of GSK2315698 
and GSK3039294
Plasma SAP levels
Exploratory 
Determine the effect of food on a 
single dose of GSK3039294
PK parameters of GSK2315698 
and GSK3039294 under fasted 
and fed conditions.


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Part C: Repeat dose in patients with systemic amyloidosis
Objectives
Endpoints
Primary
Evaluate safety and tolerability of 
repeat doses of GSK3039294
Adverse events, laboratory 
measurements, ECG, vital signs
and cardiac telemetry (where 
applicable)
Secondary
Evaluate pharmacokinetics of 
repeat doses of GSK3039294 and 
its biotransformation into 
GSK2315698 (CPHPC)
PK parameters of GSK2315698 
and GSK3039294
Pharmacodynamic effect of 
multiple doses of GSK3039294 
on plasma SAP levels
Plasma SAP levels and time to 
repletion of SAP.
Explore correlation of dose of 
GSK3039294, blood 
concentration of GSK2315698 
and plasma SAP levels
PK parameters of GSK2315698 
and GSK3039294
Plasma SAP levels
Study Design

This is a three-part, open-label, non-randomised study. In Part A, 
sufficient healthy volunteers will be enrolled to ensure 6 subjects per 
cohort have completed the in-patient phases. In Part B, sufficient healthy 
volunteers will be enrolled to ensure 6 subjects per cohort have 
completed each of the in-patient phases. In Part C, a minimum of 12 
patients with systemic amyloidosis will be enrolled.    
Analysis 
Population

Screened

Enrolled

Safety

PK

PD

PK/PD
Hypothesis

There are no formal hypotheses being tested in the study.
Interim 
Analyses 

Data will be reviewed on an ongoing basis throughout the study by the 
study team and investigator in order to inform dosing decisions for 
subsequent dosing sessions, cohorts and study parts.  Dose escalation 
meetings will be held prior to increasing the dose. Key data to inform 
dosing decisions will include but not be limited to: safety (AEs, clinical 
laboratory data, vital signs and ECGs), PK (concentrations of 
GSK2315698, and if possible, GSK3039294 and the intermediate 
molecule GSK3037412), and plasma SAP levels (Part B data to inform 
Part C dosing regimen only).

In addition to the ongoing review of data throughout the study, at the end 
of Part B, individual profiles over time will be presented graphically for 


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selected urine and plasma laboratory parameters pertaining to the kidney. 
Individual profiles will be presented for both single and repeat-dose 
healthy volunteer data to further inform the evaluation of renal safety 
and the decision to progress to repeat dosing in systemic amyloidosis 
patients in Part C.
Primary
Analyses

Safety data will be summarized according to GSK’s Integrated Data 
Standards Library (IDSL) standards in tabular and/or graphical format.
Secondary 
Analyses

Pharmacokinetic: Individual GSK2315698 plasma concentration-time 
profiles (by treatment and subject) will be plotted. GSK3039294 and 
GSK2315698 plasma concentration data will also be summarised and 
listed. Plasma concentration time data for GSK2315698 will be analyzed 
by non-compartmental methods using WinNonlin and derived PK 
parameters will be presented graphically, summarised and listed. No 
formal statistical analyses will be conducted.

Pharmacodynamic: Individual plasma SAP profiles over time will be 
listed and presented graphically.  Plasma SAP levels will be log-
transformed or other transformation if appropriate, and summarised over 
time by cohort/dosing regimen, together with corresponding 95% 
confidence intervals.
Exploratory 
Analyses

A food effect exploration will be conducted at Days 4 and 5 of Part B
Cohort 3. On these days GSK3039294 will be administered under fasted 
and then under fed conditions, and the food effect on the PK parameter 
will be summarised and presented graphically.


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2.
SUMMARY OF KEY PROTOCOL INFORMATION
2.1.
Clarifications to the Protocol Defined Statistical Analysis 
Plan
Clarifications to the originally planned statistical analysis specified in the protocol
(Dated: 30-NOV-2016, GSK Document Number 2014N218204_03) are as follows: 

Reviews of PK data to inform dosing decisions for subsequent dosing 
sessions/cohorts/study parts will be during Part A, at the end of Part A and on 
completion of each cohort in Part B.

A review of the SAP data to inform the Part C dosing regimen will be at the end 
of Part B only (ie not during Part B). Note: SAP data not collected in Part A.

Doses will be selected such that the upper limit of the 95% prediction interval for 
Cmax and AUC will not exceed preclinical limits.

Analysis of the intermediate molecule GSK3037412 will be reported separately 
from the Clinical Pharmacology Study Report.
2.2.
Study Objective(s) and Endpoint(s)
Part A: Single ascending dose in healthy volunteers 
Objectives
Endpoints
Primary
Evaluate safety and tolerability of single 
doses of GSK3039294
Adverse events, laboratory 
measurements, ECG, vital signs
Secondary
Evaluate pharmacokinetics of single 
doses of GSK3039294 and its 
biotransformation into GSK2315698 
(CPHPC)
PK parameters of GSK2315698 and 
GSK3039294
Part B: Repeat dose in healthy volunteers
Objectives
Endpoints
Primary
Evaluate safety and tolerability of repeat 
doses of GSK3039294
Adverse events, laboratory 
measurements, ECG, vital signs and 
cardiac telemetry (where applicable)
Secondary
Evaluate pharmacokinetics of repeat 
doses of GSK3039294 and its 
biotransformation into GSK2315698 
(CPHPC)
PK parameters of GSK2315698 and 
GSK3039294


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Objectives
Endpoints
Pharmacodynamic effect of repeat doses 
of GSK3039294 on plasma SAP levels
Plasma SAP levels
Explore correlation of dose of 
GSK3039294, blood concentration of 
GSK2315698 and plasma SAP levels
PK parameters of GSK2315698 and 
GSK3039294
Plasma SAP levels
Exploratory 
Determine the effect of food on a single 
dose of GSK3039294
PK parameters of GSK2315698 and 
GSK3039294 under fasted and fed 
conditions.
Part C: Repeat dose in patients with systemic amyloidosis
Objectives
Endpoints
Primary
Evaluate safety and tolerability of repeat 
doses of GSK3039294
Adverse events, laboratory 
measurements, ECG, vital signs and
cardiac telemetry (where applicable)
Secondary
Evaluate pharmacokinetics of repeat 
doses of GSK3039294 and its 
biotransformation into GSK2315698 
(CPHPC)
PK parameters of GSK2315698 and 
GSK3039294
Pharmacodynamic effect of multiple 
doses of GSK3039294 on plasma SAP 
levels
Plasma SAP levels and time to repletion 
of SAP.
Explore correlation of dose of 
GSK3039294, blood concentration of 
GSK2315698 and plasma SAP levels
PK parameters of GSK2315698 and 
GSK3039294
Plasma SAP levels


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2.3.
Study Design
Overall Design:
Part A: Healthy Volunteers, Single Dose (Cohorts 1 and 2):
Part B: Healthy Volunteers, Repeat Dose (Cohorts 3, 4a and 4b – doses shown are for example only):
Part C: Systemic Amyloidosis Patients, Repeat Dose (Cohort 5 - illustrative schematic):


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Design
Features
This will be a three-part open-label, non-randomised, dose-escalation 
study with no active or placebo control.
Part A will allow assessment of safety, tolerability and PK including 
biotransformation of GSK3039294 into active CPHPC of single doses 
of GSK3039294. If the absorption of GSK3039294 and subsequent 
biotransformation of GSK3039294 to CPHPC is sufficient then repeat 
dosing will be investigated in Part B.
Part B will allow assessment of safety, tolerability and PK including
evaluation of food-effect and biotransformation of GSK3039294 into 
active CPHPC of repeat doses of GSK3039294 and PD (depletion of 
plasma SAP). PK and PD data will be compared within a subject 
following repeat dosing and dose escalation and regimen adjustments. 
If the exposure to CPHPC and the resulting depletion of SAP is 
sufficient and well tolerated, then repeat dosing of patients with 
systemic amyloidosis will be investigated in Part C.
Part C will confirm the ability of GSK3039294 (dosing regimen
determined from Part B) to decrease plasma SAP to a level suitable for 
mAb administration in subsequent studies and its ability to maintain 
this level over 21 days in patients with systemic amyloidosis. Also, 
safety and tolerability of the optimal clinical dose of GSK3039294 will 
be evaluated in systemic amyloidosis patients which may include those 
with known cardiac amyloid involvement.
Dosing
This study is planned to test single doses of GSK3039294 and repeat 
doses up to the maximum tolerated dose or the maximum allowable 
dose based on pre-clinical findings. 
Part A

The starting dose in Part A is planned to be 200mg of 
GSK3039294. This dose has been selected using the PK/PD model 
that was developed for CPHPC (active molecule), adjusted for the 
oral absorption of GSK3039294 and the conversion of 
GSK3039294 to CPHPC. 

The next doses in Part A will be determined based on the data of 
the preceding dosing sessions. All available PK data will be 
analysed and the next dose will be such that the predicted median 
Cmax will be about 6 g/mL, and the upper limit of the 95% 
prediction interval will not exceed preclinical Cmax and AUC 
limits.

The highest dose in Part A will not exceed pre-clinical safety 
exposure limits of AUC[0-24] of 250 g.hr/mL and Cmax of 
22.1g/mL.
Part B

The dose levels for Cohort 3 in Part B will be determined based on 
the PK data obtained in Part A, by analysing all available PK data 


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from Part A and subsequently predicting concentration-time 
profiles at steady state after repeat dosing. 

The dose levels for subsequent cohorts in Part B will be determined 
based on the PK data from Part A (single dose) and cohort 3 in Part 
B (multiple dose). The dose levels and dosing frequencies will be 
chosen such that the upper limit of the 95% prediction interval for
Cmax and AUC at steady state will not exceed preclinical Cmax 
and AUC limits (22.1 g/mL and 250 g.hr/mL, respectively).
Part C

GSK3039294 will be administered at the predicted optimal clinical 
dose for 21 days. This dose will be determined using the PK/PD 
model that was developed for CPHPC (active molecule) and using 
all available PK and plasma SAP (PD) data from Parts A and B, the 
model will be adjusted for the oral absorption of GSK3039294 and 
the conversion of GSK3039294 to CPHPC. The dose level and 
frequency will be chosen such that the upper limit of the 95% 
prediction interval for Cmax and AUC at steady state will not 
exceed preclinical Cmax and AUC limits (22.1 g/mL and 
250 g.hr/mL, respectively).
Treatment 
Assignment

This is an open-label, non-randomised study with no active or 
placebo control.

GSK3039294 doses will be administered sequentially and will be 
based on the review of safety, PK and PD data (as applicable) from 
previous cohorts, dosing sessions and study parts. 
Interim 
Analysis

The planned protocol-defined unblinded interim analyses are: 
[1] Ongoing data reviews throughout the study
[2] Data reviews to inform dosing decisions for subsequent dosing 
sessions, cohorts and study parts
[3] At the end of Part B, interim analysis of selected renal safety 
data.
2.4.
Statistical Hypotheses
No formal hypotheses will be tested in this study.
3.
PLANNED ANALYSES
3.1.
Interim Analyses
Data will be reviewed on an ongoing basis throughout the study by the study team and 
investigator in order to inform dosing decisions for subsequent dosing sessions, cohorts 
and study parts. Dose escalation meetings will be held prior to increasing the dose. Key 
data to inform dosing decisions will include but not be limited to: safety (AEs, clinical 
laboratory data, vital signs and ECGs), PK (concentrations of GSK2315698, and if 
possible GSK3039294), and plasma SAP levels.


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Data listings direct from the PIMS (Patient Information Management System) data 
capture system will facilitate ongoing reviews of safety data.
To inform dosing decisions for subsequent dosing sessions in Part A, individual values of 
Cmax and AUC[0-inf] will be derived by means of non-compartmental analysis. 
Assuming linear kinetics, the next dose will be such that the upper limit of the 95% 
prediction interval for Cmax and AUC will not exceed preclinical safety limits (22.1 g 
/mL and 250 g.hr/mL, respectively).
To inform dosing decisions for subsequent study parts, GSK2315698 concentration data 
and plasma SAP levels will be analysed using the PK/PD model that was developed for 
GSK2315698 [Sahota, 2015].  Based on pre-clinical data it is expected that the 
conversion of GSK3039294 to GSK2315698 is very fast. Therefore, it can be assumed 
that this conversion will occur mainly during the absorption phase, and that the 
distribution and elimination of GSK2315968 are not altered. Hence, all distribution and 
elimination parameters (PK/PD) will be fixed to the reported parameter estimates, and 
only bioavailability (F) and absorption related parameters (e.g. Ka) will be estimated. 
Nominal time points will be used. This updated model will be used to simulate 
concentration-time data and plasma SAP levels using different dose levels and dosing 
regimens, which will be used to inform dosing decisions for subsequent dosing sessions, 
cohorts and study parts.
In addition to the ongoing review of data throughout the study, at the end of Part B, 
individual profiles over time will be presented graphically for selected urine and plasma 
laboratory parameters pertaining to the kidney (including, but not limited to: blood & 
urine glucose, urine protein, serum creatinine, urine protein/urine creatinine ratio, serum 
phosphate, urine pH, and arterial blood gas test results (blood pH and blood bicarbonate)
if available.  Note, an arterial blood gas test will only be performed if urine pH is 
abnormal, i.e. acidic. Individual profiles will be presented for both single (Part A) and 
repeat-dose (Part B) healthy volunteer data to further inform the evaluation of renal 
safety and the decision to progress to repeat dosing in patients in Part C.  


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3.2.
Final Analyses
The final planned analyses will be performed at the end of Part C after the completion of 
the following sequential steps:
[1] All subjects have completed the study as defined in the protocol.
[2] All required database cleaning activities have been completed and final database 
release and database freeze have been declared by Data Management.
[3] All criteria for unblinding the randomisation codes have been met. 
[4] Randomisation codes have been distributed according to RandAll NG procedures.
4.
ANALYSIS POPULATIONS
Population
Definition / Criteria
Endpoint(s)
Evaluated
Screened 

All subjects who signed the Informed Consent

Study 
Population
Enrolled

Subjects who ultimately pass screening

Study 
Population
Safety

All subjects who received at least one dose of study 
medication.  

This will be the primary population for assessing 
safety.

Study 
Population

Safety
Pharmacokinetic

All subjects administered at least one dose of study 
medication and who have at least one PK sample 
taken and analysed.  

This will be the primary population for assessing PK.  
Subjects will be classified by the actual dose received.

PK
Pharmacodynamic:

All subjects who received at least one dose of study 
medication and at least one post-treatment PD 
measure. 

This will be the primary population for assessing PD.  

Subjects will be classified by the actual dose received.

PD
PK/PD:

All subjects included in both the PK and PD 
populations.  

This will be the primary population for PK/PD 
modelling.  

Subjects will be classified by the actual dose received.

PK/PD
NOTES : 

Please refer to Appendix 9: List of Data Displays which details the population to be used for each display.


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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 freezing the database to ensure all important 
deviations (including deviations related to study inclusion/exclusion criteria, 
conduct of the trial, patient management or patient assessment) are captured and 
categorised on the protocol deviations dataset. 
o
This dataset will be the basis for the listing of protocol deviations.

A separate listing of all inclusion/exclusion criteria deviations will also be provided, 
based on data recorded on the inclusion/exclusion page of the eCRF.
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
Component
10.1
Appendix 1: Time & Events
10.2
Appendix 2: Treatment States and Phases
10.3
Appendix 3: Data Display Standards & Handling Conventions
10.4
Appendix 4: Derived and Transformed Data
10.5
Appendix 5: Premature Withdrawals & Handling of Missing Data
10.6
Appendix 6: Values of Potential Clinical Importance
10.7
Appendix 7: Pharmacokinetic / Pharmacodynamic Analyses
10.8
Appendix 8: Abbreviations & Trade Marks
10.9
Appendix 9: List of Data Displays
6.
STUDY POPULATION ANALYSES
6.1.
Overview of Planned Analyses
The study population analyses will be based on the “Safety” 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.


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Table 2
Overview of Planned Study Population Analyses
Display Type
Data Displays Generated
Table
Listing
Randomisation
Treatment Allocation
Y
Subject Disposition
Subject Disposition
Y
Reasons for Screening Failures
Y
Y
Reasons for Withdrawals
Y
Protocol Deviations
Important Protocol Deviations
Y
Y
Inclusion and Exclusion Criteria Deviations
Y
Subjects Excluded from Analysis Populations
Y
Demographic and Baseline Characteristics
Demographics Characteristics
Y
Y
Race & Racial Combinations
Y
Y
Age Ranges
Y
Prior and Concomitant  Medications
Concomitant Medication
Y
Current/Past Medical Conditions
Y
Y = Yes display generated.
7.
PRIMARY STATISTICAL ANALYSES
7.1.
Safety Analyses
Safety data will be listed and presented in tabular and/or graphical format, as appropriate, 
and summarized descriptively according to GSK’s Integrated Data Standards Library 
(IDSL) standards.  The primary safety analyses will be based on the “Safety” population, 
unless otherwise specified.
Table 3 provides an overview of the planned safety analyses with full details of data 
displays being presented in Appendix 9: List of Data Displays.


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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 and Treatment Compliance
Exposure to Study 
Treatment
Y
Y
Adverse Events
All AE’s by SOC and 
PT
Y
Y
Serious AE’s
Y
Drug Related AEs
Y
Withdrawal AE’s
Y
Relationship Between 
System Organ Class 
and Verbatim Text
    Y
Subject Numbers for 
Individual Adverse 
Events
Y
Common Non-Serious 
AEs by SOC and PT 
(Subjects & No. of 
Occurrences)
Y
Laboratory Values 
Clinical Chemistry 
Y
Y
Emergent Chemistry 
Results by PCI 
Criteria
Y
Y
Emergent Chemistry 
Results Relative to 
Normal Range
Y
Haematology
Y
Y
Emergent Hematology 
Results by PCI 
Criteria
Y
Y
Emergent Hematology 
Relative to Normal 
Range
Y
Urinalysis
Y
Y
Urinalysis Data 
Outside the PCI 
Range
Y
Renal Parameters
Y
ECG’s
Abnormal ECG 
Findings
Y
ECG Values Outside 
the PCI Range
Y


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Endpoint
Absolute
Change from Baseline
Summary
Individual
Summary
Individual
T
F
F
L
T
F
F
L
Vital Signs
Vitals Values
Y
Y
Vital Signs 
Measurements 
Outside the PCI 
Range
Y
Holter 
Telemetry 
Interpretations
Y
Telemetry 
Abnormalities
Y
NOTES:

T = Table, F = Figures, L = Listings, Y = Yes display generated.

Summary = Represents TFL related to any summaries of the observed raw data.

Individual = Represents FL related to any displays of individual subject observed raw data.    
8.
SECONDARY STATISTICAL ANALYSES
8.1.
Pharmacokinetic Analyses
The reconciliation of the PK Case Report Form (CRF) and SMS2000 data will be 
performed by, or under the direct auspices of, Clinical Pharmacology Science and Study 
Operations (CPSSO), GlaxoSmithKline.
The merge of PK concentration data, randomisation and CRF data will be performed by, 
or under the direct auspices of QSI, GlaxoSmithKline.   
Derivation of pharmacokinetic parameters will be performed by Clinical Pharmacology 
Modelling and Simulation (CPMS), QSci, GlaxoSmithKline.
8.1.1.
Overview of Planned Pharmacokinetic Analyses
The pharmacokinetic (PK) analyses will be based on the “Pharmacokinetic” population, 
unless otherwise specified.
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
Part / Endpoint
Untransformed
Log-Transformed
Summary
Individual
Summary
Individual
T
F
F
L
T
F
F
L
Part A
GSK3039294 concentrations
Y
Y
GSK2315698 concentrations
Y
Y
Y
Y
GSK3039294 parameters
Y
Y
Y


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Part / Endpoint
Untransformed
Log-Transformed
Summary
Individual
Summary
Individual
T
F
F
L
T
F
F
L
GSK2315698 parameters
Y
Y
Y
Y
Part B
GSK3039294 concentrations
Y
Y
GSK2315698 concentrations
Y
Y
Y
Y
GSK3039294 parameters
Y1
Y1
Y1
GSK2315698 parameters
Y1
Y1
Y1
Y1
Part C
GSK3039294 concentrations
Y
Y
GSK2315698 concentrations
Y
Y
Y
Y
NOTES :

T = Table, F = Figure, L = Listings, Y = Display generated.

Summary = Represents TF related to any summaries (i.e. descriptive statistics) of the observed raw 
data.

Individual = Represents FL related to any displays of individual subject observed raw data.
1
PK parameters from Part B Cohort 3 Days 4&5 (exploration of food effect) only.
8.1.2.
Drug Concentration Measures
Refer to Appendix 3: Data Display Standards & Handling Conventions (Section 10.3.3
Reporting Process & Standards).
8.1.3.
Pharmacokinetic Parameters

Refer to Appendix 3: Data Display Standards & Handling Conventions (Section 
10.3.3 Reporting Process & Standards).

The pharmacokinetic parameters (Part A, and Days 4 and 5 of Cohort 3 in Part B 
only) will be calculated by standard non-compartmental analysis according to current 
working practices and using WinNonlin version 5.0 or higher.

All calculations of non-compartmental parameters will be based on actual sampling 
times.

Pharmacokinetic parameters described in Table 5 will be determined from the blood 
(GSK3039294) or plasma (GSK2315698) concentration-time data, as data permit.
Table 5
Derived Pharmacokinetic Parameters
Parameter
Parameter Description
AUC(0-6)
Area under the concentration-time curve from time zero to 6 hours post dose
NOTE: this parameter is derived for Days 4&5 of Part B Cohort 3 only.
AUC(0-inf)
Area under the concentration-time curve extrapolated to infinity.
AUC(0-inf)/D
AUC(0-inf) corrected for dose of prodrug.
AUC(0-t)
Area under the concentration-time curve from time zero to the time of the last 
quantifiable concentration (Clast).
AUC(0-t)/D
AUC(0-t) corrected for dose of prodrug.


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Parameter
Parameter Description
Clast
Last quantifiable concentration.
Cmax
Maximum observed concentration.
Cmax/D
Cmax corrected for dose of prodrug.
t1/2
Terminal half-life.
Lambda_z
The first order rate constant associated with the terminal (log-linear) portion of the 
concentration-time curve.
Lambda_z_lower
First time point used in computing Lambda_z.
Lambda_z_upper
Last time point used in computing Lambda_z.
#pts
Number of points used in computing Lambda_z.
r-squared
R-squared of Lambda_z computation.
tlast
Time of the last quantifiable concentration.
tmax
Time to reach Cmax.
8.2.
Pharmacodynamic Analyses
8.2.1.
Overview of Planned Pharmacodynamic Analyses
The pharmacodynamic analyses will be based on the “Pharmacodynamic” population, 
unless otherwise specified. 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. Table 7 provides a list of pharmacodynamic 
parameters to be derived.
Table 6
Overview of Planned Pharmacodynamic Analyses
Endpoint 
Absolute
Summary
Individual
T
F
F
L
Parts B&C
Plasma SAP concentrations
Y[1]
Y
Y
Y
Plasma SAP parameters
Y
Y
NOTES:

T = Table, F = Figure, L = Listing, Y = Yes display generated.

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] For summary table, data will be transformed if required as appropriate.  Table will include 95% CI. 


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Table 7
Derived Pharmacodynamic Parameters
Parameter
Parameter Description
CminSAP
The first occurrence of the minimum observed plasma SAP concentration determined 
directly from the raw SAP concentration-time data; for Part B and C only; by dosing 
regimen in Part B
tminSAP
The time at which CminSAP is observed will be determined directly from the raw plasma 
SAP concentration-time data; for Part C only
TrepSAP_80%
The earliest time a subject returns to at least 80% of their baseline plasma SAP levels 
after maximum depletion has been achieved and without any subsequent decrease in 
plasma SAP levels; for Part C only
TrepSAP_90%
The earliest time a subject returns to at least 90% of their baseline plasma SAP levels 
after maximum depletion has been achieved and without any subsequent decrease in 
plasma SAP levels; for Part C only
TrepSAP_100%
The earliest time a subject returns to at least 100% of their baseline plasma SAP 
levels after maximum depletion has been achieved and without any subsequent 
decrease in plasma SAP levels; for Part C only
8.3.
Pharmacokinetic / Pharmacodynamic Analyses

The primary goal of this analysis is to recommend the dose regimen that adequately 
reduces plasma SAP levels when the active moiety, GSK2315698, is administered as 
an oral prodrug, GSK3039294, to subjects with amyloidosis.

A summary of the planned population pharmacokinetic/pharmacodynamic analyses 
is outlined below:
o GSK2315698 plasma concentration – pharmacodynamic data (plasma SAP) 
obtained from healthy volunteers and patients with systemic amyloidosis will be 
analysed using the PK/PD model that was developed for GSK2315698 [Sahota, 
2015] using the program NONMEM to develop a population PK/PD model.
o This PK/PD model will be adjusted for oral absorption of GSK3039294 and 
conversion into GSK2315698.
o Actual time points will be used for the PK/PD analysis.
o To support this analysis a NONMEM-ready dataset will be generated, for which 
dataset specifications are provided in Appendix 7: Pharmacokinetic / 
Pharmacodynamic Analyses, which also contains detailed methodology for the 
analysis.


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9.
REFERENCES

GlaxoSmithKline Document Number 2014N218204_00 (Original – 06-AUG-2015): 
A three-part open-label, non-randomised, dose-escalation study to investigate the 
safety and tolerability of GSK3039294 administered as a single dose to healthy 
volunteers, and as repeat dose to healthy volunteers and patients with systemic 
amyloidosis.

GlaxoSmithKline Document Number 2014N218204_01 (Amendment 1 – 07-OCT-
2015): A three-part open-label, non-randomised, dose-escalation study to investigate 
the safety and tolerability of GSK3039294 administered as a single dose to healthy 
volunteers, and as repeat dose to healthy volunteers and patients with systemic 
amyloidosis.

GlaxoSmithKline Document Number 2014N218204_02 (Amendment 2 – 01-MAR-
2016): A three-part open-label, non-randomised, dose-escalation study to investigate 
the safety and tolerability of GSK3039294 administered as a single dose to healthy 
volunteers, and as repeat dose to healthy volunteers and patients with systemic 
amyloidosis.

GlaxoSmithKline Document Number 2014N218204_03 (Amendment 3 – 30-NOV-
2016): A three-part open-label, non-randomised, dose-escalation study to investigate 
the safety and tolerability of GSK3039294 administered as a single dose to healthy 
volunteers, and as repeat dose to healthy volunteers and patients with systemic 
amyloidosis.

GUI_137354 (2.0, 30-JUL-2014), Information for Authors: Reporting and Analysis 
Plan (RAP), Global

GUI_51487 (4.0, 29-OCT-2014), Non-Compartmental Analysis of Pharmacokinetic 
Data, CPMS Global

Sahota T, Berges A, Barton S, Cookson L, Zamuner S, Richards D. Target mediated 
drug disposition model of CPHPC in patients with systemic amyloidosis. CPT 
Pharmacometrics Syst Pharmacol 2015;4:e15

SOP_54838 (5.0, 30-JUL-2014), Development, Review & Approval of Reporting & 
Analysis Plan (RAP), Global 


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10.
APPENDICES
Section
Appendix
RAP Section 5 : General Considerations for Data Analyses & Data Handling Conventions
Section 10.1
Appendix 1: Time & Events
Section 10.2
Appendix 2: Treatment States and Phases
Section 10.3
Appendix 3: Data Display Standards & Handling Conventions

Baseline Definitions & Derivations

Reporting Process & Standards
Section 10.4
Appendix 4: Derived and Transformed Data

General

Study Population

Safety
Section 10.5
Appendix 5: Premature Withdrawals & Handling of Missing Data

General

Study Population & Safety
Section 10.6
Appendix 6: Values of Potential Clinical Importance

Laboratory Values

ECG

Vital Signs
Section 10.7
Appendix 7: Pharmacokinetic / Pharmacodynamic Analyses
Other RAP Appendices
Section 10.8
Appendix 8: Abbreviations & Trade Marks
Section 10.9
Appendix 9: List of Data Displays


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10.1.
Appendix 1: Time & Events
10.1.1.
Part A – Cohorts 1 and 2, single dose, healthy volunteer subjects
Procedure
Screening 
(within 28 
days of 
Day1)
Treatment Period
Wash 
out
Follow-up 
Day 14
Notes
Day
-1
1
2
3
4
5-13
Outpatient Visit
X
X
Outpatient visit at the end of 
second treatment.
Admission to Clinical Unit
X
X
Admission if due to start next dose 
level on the following day.
Inpatient Stay at Clinical Unit
---------------------
Informed consent
X
Inclusion and exclusion criteria
X
X
Demography
X
Full physical exam including height and weight
X
Brief Physical
X
X
Medical history (includes substance usage)
X
Past and current medical conditions 
X
Urine Drug/Alcohol Breath Test
X
X
FSH and oestradiol (women)
X
Clinical Safety Laboratory Assessments (HIV, 
Hep B and Hep C Screen at screening only1) –
except Core Urine Monitoring Assessments
X
X
X
X
X
On dosing days, samples to be 
taken in the morning pre-dose.
1If performed within 3 months prior 
to first dose of study treatment, 
testing at screening is not 
required.
Clinical Chemistry Only
X
Core Urine Monitoring Assessments
X
X
X
X1
X
X
On dosing days, samples to be 
taken in the morning.
124 hrs post-dose
Urine Sample (for storage)
X
24hr Urine collection
X
Collection from dose until 24hrs 
post-dose


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Procedure
Screening 
(within 28 
days of 
Day1)
Treatment Period
Wash 
out
Follow-up 
Day 14
Notes
Day
-1
1
2
3
4
5-13
12-lead ECG and Vital sign
X
X
X
X
X
X
X
Triplicate for all 
Pre dose and 0.25, 0.5, 1, 2, 4, 6, 
8, 12, 24, 48 and 72hrs post-dose
24hr Holter 
X
X
Continuous from 1hr predose to 
24hr post dose
Study Treatment
X
Single administration
Blood Sampling for pharmacokinetics
-------------
For sampling time points, see 
Section 7.4.1 in protocol
Discharge from Clinical Unit
X
Following completion of all 
assessments
PGx Sample
-----------------------------------
Pre-dose if possible. Informed 
consent for optional genetics 
research must be obtained before 
collecting a sample
AE/SAE review
X
------------------------------------
X
Concomitant medication review
X
------------------------------------
X


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10.1.2.
Part B – Cohort 3, 7 day repeat dose healthy volunteer subjects
Procedure
Screening 
(within 28 days 
of Day 1)
Treatment Period (Days)
Follow-up
(7-14 days 
following last 
dose)
Notes
-
2
-
1
1
2
3
4
5
6
7
8
Outpatient Visit
X
X
Admission to Clinical Unit
X
Inpatient Stay at Clinical Unit
--------------------------------------------
Informed consent
X
Inclusion and exclusion criteria
X
X
Demography
X
Full physical exam incl height and 
weight
X
Brief Physical
X
X
Medical history (includes substance 
usage)
X
Substances: Drugs, Alcohol, 
tobacco and caffeine
Past and current medical conditions 
X
FSH and oestradiol (women)
X
Clinical Safety Laboratory 
Assessments (HIV, Hep B and Hep C 
Screen at screening only1) – except 
Core Urine Monitoring Assessments
X
X
X
X
X
X
On dosing days, samples to be 
taken in the morning pre-dose.
1If performed within 3 months prior 
to first dose of study treatment, 
testing at screening is not 
required.
Clinical Chemistry Only
X
X
High-sensitivity cardiac Troponin
X
X
Pre-dose
Core Urine Monitoring Assessments
X
X
X
X
X
X
X
Samples for Urine pH to be taken 
in the morning
Urine Sample (for storage)
X
Urine Drug/Alcohol Breath Test
X
X
12-lead ECG and vital signs
X
X
X
X
X
X
X
X
X
X
X
Triplicate for all. Pre-dose and 1hr 
post-dose
48hr Holter
X


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Procedure
Screening 
(within 28 days 
of Day 1)
Treatment Period (Days)
Follow-up
(7-14 days 
following last 
dose)
Notes
-
2
-
1
1
2
3
4
5
6
7
8
Telemetry
----------------------------------------------------------------------
Temporary removal of telemetry 
(e.g. for showering) is permitted
Evaluation of Food Effect 
X
X
Fasted on Day 4, Fed on Day 5. 
Not to be performed in sentinel 
subjects.
Study Treatment
------------------------------------------
Blood Sampling (PK)
For sampling time points, see Section 7.4.1 in 
protocol
X
For 1st dose and escalation
See Section 7.4.1 in protocol
Blood Sampling (PD)
For sampling time points, see Section 7.5 in protocol
X
Discharge from Clinical Unit
X
Following completion of all 
assessments
PGx Sample
X
Pre-dose if possible. Informed 
consent for optional genetics 
research must be obtained before 
collecting a sample
AE/SAE review
-------------------------------------------------------
X
Concomitant medication review
X
-------------------------------------------------------
X


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10.1.3.
Part B – Cohort 4a and 4b, 21 day repeat dose healthy volunteer subjects
Procedure
Screening 
(within 28 
days of 
Day 1)
Treatment Period (Days)
Follow-up
(7-14 days 
following 
last dose)
Notes
-
1
1
2
3
4
5
6
7
8
9 10 11 12
1
3
14
15
1
6
1
7
18
1
9
2
0
21
Outpatient Visit
X
X2
X
X
2Visit day ± 2 days 
is allowed
Admission to Clinical Unit
X
Inpatient Stay at Clinical 
Unit
-----------------------------
Informed consent
X
Inclusion and exclusion 
criteria
X
X
Demography
X
Full physical exam incl 
height and weight
X
Brief Physical
X
X
Medical history (includes 
substance usage)
X
Substances: 
[Drugs, Alcohol, 
tobacco and 
caffeine]
Past and current medical 
conditions 
X
SH and oestradiol (women)
X
X


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Procedure
Screening 
(within 28 
days of 
Day 1)
Treatment Period (Days)
Follow-up
(7-14 days 
following 
last dose)
Notes
-
1
1
2
3
4
5
6
7
8
9 10 11 12
1
3
14
15
1
6
1
7
18
1
9
2
0
21
Clinical Safety Laboratory 
Assessments (HIV, Hep B 
and Hep C Screen at 
screening only1) – except 
Core Urine Monitoring 
Assessments
X
X
X
X
X
X2
X
X
On dosing days, 
samples to be 
taken in the 
morning pre-
dose.
1If performed 
within 3 months 
prior to first dose 
of study treatment, 
testing at 
screening is not 
required.
2Visit day ± 2 days 
is allowed
Clinical Chemistry Only
X
X
Core Urine Monitoring 
Assessments
X
X
X
X
X
X
X2
X
X
Samples for Urine 
pH to be taken in 
the morning.
2Visit day ± 2 days 
is allowed
Urine Sample (for storage)
X
Urine Drug/Alcohol Breath 
Test
X
X
X
12-lead ECG and vital 
signs
X
X
X
X
X
X
X
X
X
X2
X
X
Triplicate for all. 
Pre-dose and 1hr 
post-dose.
2Visit day ± 2 days 
is allowed
Home Dosing Record
-------------------------------------------------------------------
Study Treatment
Cohort 4a: Dose and dosing frequency may be altered once during treatment period
------------------------------------------------------------------------------------------------------------------------------
Cohort 4b: dosing regimen will be determined based on information from Cohort 4a
D21 a.m. dosing 
only


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Procedure
Screening 
(within 28 
days of 
Day 1)
Treatment Period (Days)
Follow-up
(7-14 days 
following 
last dose)
Notes
-
1
1
2
3
4
5
6
7
8
9 10 11 12
1
3
14
15
1
6
1
7
18
1
9
2
0
21
Blood Sampling (PK)
For sampling time points, see Section 7.4.1 in protocol
X
For 1st dose and 
escalation
See Section 7.4.1 
in protocol
Blood Sampling (PD)
For sampling time points, see Section 7.5 in protocol
X
Discharge from Clinical 
Unit
X
Following 
completion of all 
assessments
PGx Sample
X
Pre-dose if 
possible. Informed 
consent for 
optional genetics 
research must be
obtained before 
collecting a sample
AE/SAE review
--------------------------------------------------------------------------------------------------------------
X
Concomitant medication 
review
X
--------------------------------------------------------------------------------------------------------------
X


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10.1.4.
Part B – Cohort 4, 21 day repeat dose healthy volunteer subjects 
– dose alteration (only if dose alteration is required)
Should a dose alteration be required, subjects will be re-admitted to the clinical unit and 
the procedures be administered as stated below. Note: The ‘Dose Day’ relates to the first 
day of the adjusted dose, and not the study day.
Procedure
Dose Days
Notes
-1
1
2
3
4
5
6
7
Admission to 
Clinical Unit
X
Inpatient Stay at 
Clinical Unit
-----------------------------
SH and 
oestradiol 
(women)
Clinical Safety 
Laboratory 
Assessments –
except Core 
Urine Monitoring 
Assessments
X
X
X
X
On dosing days, samples to be 
taken in the morning pre-dose.
Clinical 
Chemistry Only
X
X
Core Urine 
Monitoring 
Assessments
X
X
X
X
X
Samples for Urine pH to be taken 
in the morning
Urine 
Drug/Alcohol 
Breath Test
X
12-lead ECG 
and vital signs
X
X
X
X
X
X
X
X
Triplicate for all. Pre-dose and 1hr 
post-dose
Study Treatment
------------------------------------------
Blood Sampling 
(PK)
For sampling time points, see Section 7.4.1 in protocol
Blood Sampling 
(PD)
For sampling time points, see Section 7.5 in protocol
Discharge from 
Clinical Unit
X
Following completion of all 
assessments
AE/SAE review
----------------------------------------
Concomitant 
medication 
review
-----------------------------------------


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10.1.5.
Part C – Cohort 5, repeat dose, patient subjects
Procedure
Screening (within 
28 days of Day 1)
Treatment Period (Days)
Safety 
Follow-
up
(7-14 
days 
after 
last 
dose)
PD 
Follow-
up
(weekly 
up to 
D63)
-
1
1
2
3
4
5
6
7
8
9-
11
12 13+ 
14
15 16 
+ 
17
18
19 
+ 
20
21
Outpatient Visit
X
X
X
X
X
X
Admission to Clinical Unit
X
Inpatient Stay at Clinical 
Unit
-------------------------------------------
Informed consent
X
Inclusion and exclusion 
criteria
X
X
Demography
X
Full physical exam incl 
height and weight
X
Medical history (includes 
substance usage)1
X
Past and current medical 
conditions 
X
FSH and oestradiol 
(women)
X
X
X
X
X
X
Clinical Safety Laboratory 
Assessments2 (HIV, Hep 
B and Hep C Screen at 
screening only3) – except 
Core Urine Monitoring 
Assessments
X
X
X
X
X
X
X
X
X
X
X
Clinical Chemistry Only
X
X
X
High-sensitivity cardiac 
Troponin3
X
X


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Procedure
Screening (within 
28 days of Day 1)
Treatment Period (Days)
Safety 
Follow-
up
(7-14 
days 
after 
last 
dose)
PD 
Follow-
up
(weekly 
up to 
D63)
-
1
1
2
3
4
5
6
7
8
9-
11
12 13+ 
14
15 16 
+ 
17
18
19 
+ 
20
21
Core Urine Monitoring 
Assessments (except 
Spot UPC ratio)4
X
X
X
X
X
X
X
X
X
X
X
X
Urine Sample (for 
storage)
X
Urine Drug/Alcohol 
Breath Test
X
X
X
X
X
X
X
Echocardiogram5
X
12-lead ECG and vital 
signs
X
X
X
X
X
X
X
X
X
X
X
Lead II monitoring6
X8
-------------------------------------------------------------

Home Dosing Record
X
X
X
X
X
X
X
X
Study Treatment
--------------------------------------------------------------------------------------------------
Blood Sampling (PK)
For sampling time points, see Section 7.4.1 in protocol
Blood Sampling (PD)
For sampling time points, see Section 7.5 in protocol
X
X
Brief Physical
X
X
Discharge from Clinical 
Unit
X
PGx Sample 7
X
AE/SAE review
-------------------------------------------------------------------------------------------------------
X
X
Concomitant medication 
review
X
-------------------------------------------------------------------------------------------------------
X


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1.
Substances: Drugs, Alcohol, tobacco and caffeine
2.
On dosing days, samples to be taken in the morning pre-dose.
3.
If test otherwise performed within 3 months prior to first dose of study treatment, testing at screening is not required
4.
Samples to be taken in the morning pre-dose.
5.
Patients with known cardiac amyloid involvement only. If test otherwise performed within 3 months of screening, and the patient has remained overall symptomatically stable 
during that time, then no testing at screening is required; otherwise, an echocardiogram is required at Screening
6.
Patients with known cardiac involvement only. It is permissible to temporarily remove Telemetry from the subject for activities of daily living (e.g. showering) during patient 
monitoring
7.
Informed consent for optional genetics research must be obtained before collecting a sample, sample to be collected pre-dose if possible
8.
7 day out-patient cardiac monitoring (Body Guardian or similar) only in patients with known cardiac involvement.


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10.2.
Appendix 2: Treatment States and Phases
10.2.1.
Treatment Phases
Assessments and events will be classified according to the time of occurrence relative to 
dosing for the given study part. Treatment phase classifications will be by study part.
Treatment 
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 
10.2.2.
Treatment States
Assessments and events will be classified according to time of occurrence relative to the 
start and/or stop date of the study treatment for the given study part. AE summaries and 
hence the classification of treatment states for AE data will be by study part.
10.2.2.1.
Treatment States for AE Data
Treatment 
State
Definition
Onset Time
Since First 
Dose
(Days)
If Treatment Start Date > AE Onset Date = AE Onset Date - Treatment Start 
Date
If Treatment Start Date ≤ AE Onset Date = AE Onset Date - Treatment Start 
Date +1
Missing otherwise
Duration 
(Days) 
AE Resolution Date – AE Onset Date + 1
Drug-related
If relationship is marked ‘YES’ on eCRF 
NOTES: 

If the study treatment stop date is missing and study treatment start date ≤ AE start date then the AE 
will be considered to be On-Treatment.

Treatment start/stop dates relate to the start/end of treatment for a given study part.


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10.3.
Appendix 3: Data Display Standards & Handling 
Conventions
10.3.1.
Study Treatment & Sub-group Display Descriptors
Treatment Group Descriptions
RandAll NG 
Data Displays for Reporting 
Part 
Cohort
Code
Description
Description
A
1
A
Regimen A
GSK3039294 xxx mg
A
1
B
Regimen B
GSK3039294 xxx mg
A
2
C
Regimen C
GSK3039294 xxx mg
A
2
D
Regimen D
GSK3039294 xxx mg
B
3
E
Regimen E
GSK3039294 xxx mg XX
B
4a
F
Regimen F
GSK3039294 xxx mg XX
B
4a
G
Regimen G
GSK3039294 xxx mg XX
B
4b
H
Regimen H
GSK3039294 xxx mg XX
B
4b
I
Regimen I
GSK3039294 xxx mg XX
C
5
J
Regimen J
GSK3039294 xxx mg XX
xxx to be imputed with dose level
XX to be imputed with dosing frequency
The decision to proceed to each subsequent dose level will be made by the Dose Escalation Committee (DEC)
10.3.2.
Baseline Definition & Derivations
10.3.2.1.
Baseline Definitions
For all endpoints, the baseline value will be the latest pre-dose assessment within a given 
study part, i.e. Day 1 (pre-dose) if available, or Day -1 if Day 1 (pre-dose) not available, 
or Screening if Day -1 and Day 1 (pre-dose) not available.
10.3.2.2.
Derivations and Handling of Missing Baseline Data
Change from Study Part Baseline = Post-Dose Visit Value – Study Part Baseline.
If baseline data is missing no derivation will be performed and it will be set to missing.


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10.3.3.
Reporting Process & Standards
Reporting Process
Software

The currently supported versions of SAS software will be used.
Reporting Area
HARP Server
: UK1SALX00175
HARP Area
: \ARPROD\GSK3039294\RAD201664\Final_01
QC Spreadsheet
: \ARWORK\ GSK3039294\RAD201664\Final_01\Documents
Analysis Datasets 

Analysis datasets will be created according to legacy GSK A&R dataset standards
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 
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:
o
Planned time relative to dosing will be used in summary figures and tables.
o
Actual time relative to dosing will be used in individual profile plots over time.  
o
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: 
o
Planned and actual time relative to study drug dosing will be shown in listings (Refer to 
IDSL Statistical Principle 5.05.1).
o
Unscheduled or unplanned results will be presented within the subject’s listings. 


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Reporting Standards
Unscheduled Visits

Unscheduled visits will not be included in summary tables.

All unscheduled visits will be included in listings and figures of individual profiles over time.
Descriptive Summary Statistics
Continuous Data
Refer to IDSL Statistical Principle 6.06.1
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 logged data and between geometric coefficient of variation (CVb 
(%)) will be reported.
CVb (%) = √(exp(SD2) - 1) * 100 [NOTE: SD = SD of log transformed data]
Parameters Not Being 
Log Transformed  
tmax (note: tmax will be summarised).
Parameters Not Being 
Summarised
Clast, Lambda_z, Lambda_z_lower, Lambda_z_upper, #pts, r-squared, 
tlast.
Listings
All PK parameters (see Table 5).
Graphical Displays

Refer to IDSL Statistical Principles 7.01 to 7.13.


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10.4.
Appendix 4: Derived and Transformed Data
10.4.1.
General
’Any Visit Post-Baseline’ Timepoint for Summaries

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 Part Day

Calculated as the number of days from randomisation date for given study part:

Ref Date = Missing
→ Study Part Day = Missing

Ref Date < Randomisation Date → Study Part Day = Ref Date – Randomisation Date

Ref Data ≥ Randomisation Date → Study Part Day = Ref Date –(Randomisation Date)+1
10.4.2.
Study Population
Demographics
Age

GSK standard IDSL algorithms will be used for calculating age where birth date is imputed as:

Any subject with a missing day will have this imputed as day ‘15’. 

Any subject with a missing day 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

Exposure will be calculated/presented by study part.

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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10.4.3.
Safety
ECG Parameters
Corrected QT an RR Intervals

QTcB will be provided directly in the eCRF.

QTcF and RR will not be derived or provided directly in the eCRF.
Non-Quantifiable Laboratory and Biomarker Parameters
For laboratory values < lower limit of quantification:

the character value (‘<x’) will be listed;

the numeric value will be imputed as half the limit of quantification (x/2) for figures and tables.
For laboratory values > upper limit of quantification:

the character value (‘>x’) will be listed;

the numeric value will be imputed as the limit of quantification (x) for figures and tables.


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10.5.
Appendix 5: Premature Withdrawals & Handling of Missing 
Data
10.5.1.
Premature Withdrawals
Element
Reporting Detail
General

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.
10.5.2.
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:

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. 

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.
10.5.2.1.
Handling of Missing/Partial Dates
Element
Reporting Detail
General
Partial dates will be displayed as captured in subject listing displays.
Adverse 
Events

The eCRF allows for the possibility of partial dates (i.e., only month and year) to 
be recorded for AE start and end dates; that is, the day of the month may be 
missing. In such a case, the following conventions will be applied for calculating 
the time to onset and the duration of the event:

Missing Start Day: First of the month will be used unless this is before the 
start date of investigational product; in this case the study treatment start 
date will be used (and hence the event is considered On-treatment as per 
Appendix 2: Treatment States and Phases).

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.


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Element
Reporting Detail
Concomitant 
Medications

Partial dates for any concomitant medications recorded in the CRF will be 
imputed using the following convention:

If the partial date is a start date, a '01' will be used for the day and 'Jan' will 
be used for the month

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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10.6.
Appendix 6: Values of Potential Clinical Importance
10.6.1.
Values of Potential Clinical Importance (Healthy Volunteers)
Laboratory Values of Potential Clinical Importance (Healthy Volunteers)
Hematology Analyte
Effect
Relative – Low
(Multipliers of LLN)
Relative – High
(Multipliers of ULN)
White Blood Cell Count 
0.67
1.82
Neutrophil Count
0.83
Hemoglobin
Male
1.03
Female
1.13
Hematocrit
Male
1.02
Female
1.17
Platelet Count
0.67
1.57
Lymphocytes
0.81
Chemistry Analyte
Low
High
Relative – Low
(Multipliers of LLN)
Relative – High
(Multipliers of ULN)
Albumin (g/L)
30
0.86
Calcium (mmol/L)
2
2.75
0.91
1.06
Glucose (mmol/L)
3
9
0.71
1.41
Magnesium (mmol/L)
0.5
1.23
0.63
1.03
Phosphorus (mmol/L)
0.8
1.6
0.80
1.14
Potassium (mmol/L)
3
5.5
0.86
1.10
Sodium (mmol/L)
130
150
0.96
1.03
Total CO2 (mmol/L)
18
32
0.86
1.14
Creatinine (µmol/L)
44.2


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Liver Function Test Values of Potential Clinical Importance (Healthy Volunteers)
Liver Function Test Analyte
Effect
Potential Clinical Importance (PCI) Range
Unit
ALT/SGPT
High
≥ 2x ULN
U/L
AST/SGOT
High
≥ 2x ULN
U/L
AlkPhos
High
≥ 2x ULN
U/L
T. Bilirubin
High
≥ 1.5x ULN
mol/L
T. Bilirubin + ALT
High
≥ 1.5x ULN T.Bilirubin
+
≥ 2x ULN ALT
mol/L
U/L
ECG Values of Potential Clinical Importance (Healthy Volunteers)
ECG Parameter
Potential Clinical Importance Range (PCI)
Unit
Absolute QTc Interval
>450
msec
Increase from Baseline QTc
>60
msec
PR Interval
<110 and >220
msec
QRS Interval
<75 and >110
msec
Vital Sign Values of Potential Clinical Importance (Healthy Volunteers)
VS Parameter
Potential Clinical Importance Range (PCI)
Unit
Systolic Blood Pressure
<85 and >160
mmHg
Diastolic Blood Pressure
<45 and >100
mmHg
Heart Rate
<40 and >110
bpm
Systolic Blood Pressure 
(Change from Baseline)
Decrease ≥20 and ≥40
mmHg
Increase ≥20 and ≥40
mmHg
Diastolic Blood Pressure 
(Change from Baseline)
Decrease ≥10 and ≥20
mmHg
Increase ≥10 and ≥20
mmHg
Heart Rate (Change from 
Baseline)
Decrease ≥15 and ≥30
bpm
Increase ≥15 and ≥30
bpm


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10.6.2.
Values of Potential Clinical Importance (Systemic Amyloidosis 
Patients)
Laboratory Values of Potential Clinical Importance (Systemic Amyloidosis 
Patients)
Haematology Analyte
Effect
Relative – Low
(Multipliers of LLN)
Relative – High
(Multipliers of ULN)
White Blood Cell Count 
0.60
1.82
Neutrophil Count
0.60
Haemoglobin
Male
0.75
1.2
Female
0.70
1.2
Haematocrit
Male
1.2
Female
1.2
Platelet Count
0.60
1.50
Lymphocytes
0.60
Chemistry Analyte
Relative – Low
(Multipliers of LLN)
Relative – High
(Multipliers of ULN)
Albumin (g/L)
0.70
Calcium (mmol/L)
0.80
1.20
Glucose (mmol/L)
0.60
2.00
Magnesium (mmol/L)
0.60
1.20
Phosphorus (mmol/L)
0.60
1.30
Potassium (mmol/L)
0.86
1.10
Sodium (mmol/L)
0.92
1.10
Total CO2 (mmol/L)
0.75
1.30
Liver Function Test Values of Potential Clinical Importance (Systemic Amyloidosis 
Patients)
Liver Function Test Analyte
Effect
Potential Clinical Importance (PCI) Range
Unit
ALT/SGPT
High
>3x ULN
U/L
AST/SGOT
High
>3x ULN
U/L
AlkPhos
High
>3x ULN
U/L
T. Bilirubin
High
>2x ULN
mol/L
T. Bilirubin + ALT
High
> 1.5x ULN T.Billirubin
+
> 3x ULN ALT 
mol/L
U/L


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ECG Values of Potential Clinical Importance (Systemic Amyloidosis Patients)
ECG Parameter
Potential Clinical Importance Range (PCI)
Unit
Absolute QTc Interval
>500
msec
Increase from Baseline QTc
>60
msec
PR Interval
<110 and >220
msec
QRS Interval
<75 and >110
msec
Vital Sign Values of Potential Clinical Importance (Systemic Amyloidosis Patients)
VS Parameter
Potential Clinical Importance Range (PCI)
Unit
Systolic Blood Pressure 
<100 and > 180 
mmHg
Diastolic Blood Pressure 
<30 and > 110 
mmHg
Heart Rate 
<35 and > 140 
Bpm
Systolic Blood Pressure 
(Change from Baseline)
Increase >30 
mmHg
Decrease < 30 
mmHg
Diastolic Blood Pressure 
(Change from Baseline)
Increase > 30 
mmHg
Decrease < 30 
mmHg
Heart Rate (Change from 
Baseline)
Increase > 50 
bpm
Decrease < 50 
bpm


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10.7.
Appendix 7: Pharmacokinetic / Pharmacodynamic Analyses
10.7.1.
Systems
All non-linear mixed effects modelling will be performed using NONMEM (ICON 
Solutions) and PsN (Perl Speaks NONMEM). R (The R Foundation for Statistical 
Computing) will be used for exploratory graphical analysis, graphical model diagnostics 
and, if needed, modifications of the dataset. The analysis will be performed by, or under 
the direct auspices of, CPMS, GlaxoSmithKline in the GSK modelling environment PME 
(Predictive Modelling Environment) using the currently supported versions of all 
software packages.
10.7.2.
Data Assembly
The merge of PK, PD, regimen and CRF data together with the creation of the 
NONMEM-specific dataset will be performed by, or under the direct auspices of, Clinical 
Statistics (Programmer), GlaxoSmithKline. This dataset programming will be conducted 
in the GSK Harmonisation for Analysis and Reporting Program (HARP) environment 
using the currently supported version of SAS. The dataset will be consistent with the 
specifications summarised in Section 10.7.5.
10.7.3.
PK/PD Modelling of GSK2315698 and SAP Concentrations
An exploratory graphical analysis of the data will be performed by generating the plots as 
presented in Appendix 9: List of Data Displays.
A PK/PD model for GSK2315698 and its effect on plasma SAP levels was developed 
previously [Sahota, 2015]. Covariates in this model are creatinine clearance (affecting 
GSK2315698 clearance), subject gender (affecting SAP baseline), and baseline amyloid 
load (affecting SAP distribution). Because of the target mediated drug disposition 
(TMDD) of GSK2315698, PK and PD will be analysed simultaneously, or parameters of 
either PK or PD will be fixed to reported estimates while exploring PD or PK, 
respectively.
As a first step the oral absorption of GSK3039294 and conversion into GSK2315968 will 
be added to the model. To that end, all available plasma GSK2315968 data will be 
analysed using the PK/PD model, extended with first order absorption and oral 
bioavailability. Based on preclinical data it is expected that the conversion of 
GSK3039294 to GSK2315698 is very fast. Therefore, it will be assumed that this 
conversion will occur mainly during the absorption phase, and that the distribution and 
elimination of GSK2315698 are not altered. GSK3039294 and the intermediate molecule 
GSK3037412 do not affect plasma SAP levels, and therefore it will be assumed that the 
PK/PD relationship between GSK2315698 and SAP is not changed.
Summarising, this means that for the first step all distribution and elimination parameters 
and all PD parameters will be fixed to the reported parameter estimates, and only 
bioavailability (F) and absorption related parameters (e.g. Ka) will be estimated. If a 
simple first order process for oral absorption and conversion is not sufficient to describe 


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the data (e.g. in case the conversion does not occur very fast), the part of the PK/PD 
model describing the absorption and conversion into GSK2315698 will be developed in a 
data driven fashion.
Subsequently, using the PK/PD model updated for oral absorption of GSK3039294 and 
conversion into GSK2315698, visual predictive checks (VPCs) will be conducted to 
assess graphically whether simulations from the PK/PD model are able to reproduce both 
the central trend and variability in the observed SAP concentrations from the current 
study as a function of time.
This VPC will be based on 1000 simulations with the model and the design structure of 
the observed data (i.e. dose level and time, time of SAP sampling and individual values 
of model covariates). The median and the 5th and 95th percentiles (or 10th and 90th, 
dependent on the size of the final dataset) will be compared to the observed data. 
Applicable stratification, such as dose level of GSK3039294 and baseline amyloid load, 
will be used.
If the VPC shows a difference between the simulated and observed PK, it will be 
investigated if the population PK/PD model can be adjusted with the current PK and SAP 
data. This process will be data driven.
10.7.4.
Diagnostics
Model acceptability will be judged by convergence, covariance estimation and standard 
goodness-of-fit plots that may include, but are not limited to:

Population and individual predictions versus observations

Conditional weighted residuals versus population predictions and time.
For the final PK/PD model, visual predictive checks (VPCs) will be conducted as 
described in Section 10.7.3.
10.7.5.
Specifications for NONMEM-specific Dataset
The concentration dataset will be a comma delimited text file, named 
“NM_GSK2315698_201664_PKPD_v1.csv”. The version number will be updated each 
time a new version is created and issued.
This file will include events of dosing, GSK3039294, GSK2315698 or SAP 
concentration as rows, with the variables in the table below as columns. Rows will be in 
increasing order of unique subject identification number; and all events in the same 
subject must be consecutive and in chronological order, ending with the last 
GSK3039294 / GSK2315698 / SAP concentration event (i.e. dosing events that occur 
after the last quantifiable concentration in a subject will not be included in the data file).
Non-numerical concentration values (such as missing samples, not assayed samples, non-
quantifiable samples or non-reportable samples) will not be included. Subjects with no 
quantifiable concentration values will not be included.


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Name
Implicit 
Unit
Description 
Programming Notes
Format
ID
-
Unique subject identification number
numeric
TRFD
h
Event time from start of first dose of GSK3039294 for each subject
numeric
DV
mg/L
For concentration events: plasma concentration of GSK3039294 or 
GSK2315698 or SAP
For dosing events: 0
numeric
AMT
mg
For dosing events: dose of GSK3039294
For concentration events: 0
numeric
MDV
-
For concentration events: 0
For dosing events: 1
Numeric
CMT
-
Compartment:
For dosing events: 1
For GSK3039294 concentration events: 2
For GSK2315698 concentration events: 3
For SAP concentration events: 5
Numeric
NOMT
h
Planned sample time for GSK3039294/GSK2315698/SAP
For dosing events: 0
For pre-dose concentration events: 0
Numeric
TRLD
h
Event time from most recent dose of GSK3039294
For dosing events: 0
Numeric
PERD
-
Study period (part):
PART A COHORT 1 DOSE 1 =1
PART A COHORT 1 DOSE 2=2
PART A COHORT 2 DOSE 1=3
PART A COHORT 2 DOSE 2=4
PART B COHORT 3=5
PART B COHORT 4=6
PARTB COHORT 4 ALT=7
PART C COHORT 5=8
Numeric
DOSE
mg
Total daily dose of GSK3009294 in mg (for all events)
Numeric


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Name
Implicit 
Unit
Description 
Programming Notes
Format
STUD
-
Numeric part of study identifier (i.e. 201664)
Numeric
FED
-
Fed/fasted status:
Part A and Week 1 of Part B (except for Day 5): 0
All other: 1
Numeric
POP
-
Study population:
Healthy volunteers (Parts A&B): 0
Patients (Part C): 1
Numeric
AGE
Years
Age at study baseline
Numeric
WT
Kg
Weight at event date, or nearest available previous value in same 
subject
Numeric
BMI
kg/m^2
Body mass index at event date, or nearest available previous value 
in same subject
Numeric
SEX
-
Subject gender:
Male=0
Female=1
Numeric
CRCL
mL/min
Creatinine clearance at session baseline (from MDRD 
measurement at screening visit)
Numeric
AMLOAD
-
Overall amyloid load at session baseline:
None=0
Small=1
Moderate=2
Large=3
Numeric


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Name
Implicit 
Unit
Description 
Programming Notes
Format
AMLOC
-
Liver involvement =1
No liver involvement =0
Numeric


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10.8.
Appendix 8: Abbreviations & Trade Marks
10.8.1.
Abbreviations
Abbreviation
Description
AE
Adverse Event
AUC(0-inf)
Area under the concentration-time curve from time zero (pre-dose) 
extrapolated to infinite time
AUC(0-t)
Area under the concentration-time curve from time zero (pre-dose) to 
last time of quantifiable concentration within a subject across all 
treatments
AUC(0-6)
Area under the concentration-time curve from time zero (pre-dose) to 6 
hours
AUC(0-24)
Area under the concentration-time curve from time zero (pre-dose) to 24 
hours
BMI
Body mass index
BP
Blood pressure
bpm
Beats per minute 
CI
Confidence Interval
Cmax
Maximum observed concentration 
CminSAP
The first occurrence of the minimum observed plasma SAP 
concentration determined directly from the raw SAP concentration-time 
data
CPHPC
R-1-[6-[R-2-carboxy-pyrrolidin-1-yl]-6-oxo-hexanoyl] pyrrolidine-2-
carboxylic acid
CPMS
Clinical Pharmacology Modelling and Simulation
CPSSO
Clinical Pharmacology Science and Study Operations
CV
Coefficient of variance
DEC
Dose Escalation Committee
ECG
Electrocardiogram
eCRF
Electronic Case Report Form
GSK
GlaxoSmithKline
HARP
Harmonisation of Analysis & Reporting Program
hrs
Hours
IDSL
Integrated Data Standards Library
PD
Pharmacodynamic
PK
Pharmacokinetic
PCI
Potentially Clinically Important 
PIMS
Patient Information Management System
QSI
Quantitative Sciences India
RAP
Reporting and Analysis Plan
SAE
Serious Adverse Event(s)
SAP
Serum Amyloid P component
SAS
Statistical Analysis Software
SD
Standard Deviation


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10.8.2.
Trademarks
Trademarks of the GlaxoSmithKline 
Group of Companies
Trademarks not owned by the 
GlaxoSmithKline Group of Companies
NONE
SAS
SAS/STAT
WinNonlin


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10.9.
Appendix 9: List of Data Displays
10.9.1.
Data Display Numbering
The following numbering will be applied for RAP generated displays. Each display will 
be repeated for each part (where applicable) with part information included in the title 
and will be identified in the numbering by the prefix x:

x=1: Part A Healthy Volunteers, Single Dose

x=2: Part B Healthy Volunteers, Repeat Dose

x=3: Part C Systemic Amyloidosis Patients, Repeat Dose
Section
Tables
Figures
Study Population
1.x01 to 1.x08
N/A
Safety
2.x01 to 2.x16
2.x01 
Pharmacokinetic
3.x01 to 3.x04
3.x01 to 3.x06
Pharmacodynamic 
4.x01 to 4.x02
4.301 to 4.302
PK/PD
5.x01 to 5.x05
5.x01 to 5.x10
Section
Listings
ICH Listings
1 to 27
Other Listings
28 to 34
10.9.2.
Mock Example Referencing
Non IDSL specifications will be referenced as indicated, as applicable.
Section
Figure
Table
Listing
Study Population
POP_Fn
POP_Tn
POP_Ln
Safety
SAFE_Fn
SAFE_Tn
SAFE_Ln
Pharmacokinetic
PK_Fn
PK_Tn
PK_Ln
Pharmacodynamic and Biomarker
PD_Fn
PD_Tn
PD_Ln
10.9.3.
Deliverables
Deliverables
Description
IA
Renal safety interim analysis at end of Part B
SAC 
Final SAC analysis at end of Part C


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10.9.4.
Study Population Tables
Study Population Tables
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
Deliverable 
Subject Disposition 
1.x01
Safety
CP_ES1 (XO)
Summary of Subject Disposition
Add part information in the title, repeat for all 
parts.
SAC
1.x02
Screened
ES6
Summary of Reasons for Screen Failures
Add part information in the title, repeat for all 
parts
SAC
Protocol Deviation
1.x03
Safety
DV1
Summary of Important Protocol Deviations
Add part information in the title, repeat for all 
parts.
SAC
Demographics and Baseline Characteristics
1.x04
Safety
DM3 (XO)
Summary of Demographic characteristics
Include BMI 
Add part information in the title, repeat for all 
parts.
SAC
1.x05
Safety
DM5
Summary of Race and Racial Combinations
Add part information in the title, repeat for all 
parts.
SAC
1.x06
Safety
DM6
Summary of Race and Racial Combinations 
Details
Add part information in the title, repeat for all 
parts.
SAC
1.x07
Enrolled
DM11
Summary of Age Ranges
Add part information in the title, repeat for all 
parts.
SAC
Prior and Concomitant Medications
1.x08
Safety
MH1
Summary of Current/Past Medical Conditions
Add part information in the title, repeat for all 
parts.
SAC


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10.9.5.
Safety Tables
Safety Tables
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
Deliverable 
Exposure
2.x01
Safety
EX1
Summary of Exposure to Study Treatment
Add part information in the title, 
repeat for all parts
SAC
Adverse Events
2.x02
Safety
CP_AE1x (xo)
Summary of All Adverse Events by System Organ 
Class and Preferred Term
Add part information in the title, 
repeat for all parts.
SAC
2.x03
Safety
CP_AE1x (xo)
Summary of Drug-Related Adverse Events
Add part information in the title, 
repeat for all parts.
SAC
2.x04
Safety
AE15
Summary of Common (>=X%) Non-serious Adverse 
Events by System Organ Class and Preferred Term 
(Number of Subjects and Occurrences)
Add part information in the title, 
repeat for all parts.
SAC
Labs
2.x05
Safety
LB1
Summary of Chemistry Changes from Baseline
Add part information in the title, 
repeat for all parts.
SAC
2.x06
Safety
LB17
Summary of Emergent Laboratory Results by 
Potential Clinical Importance (PCI) Criteria
Add part information in the title, 
repeat for all parts.
SAC
2.x07
Safety
LB15
Summary of Emergent Laboratory Results Relative to 
Normal Range
Add part information in the title, 
repeat for all parts.
SAC
2.x08
Safety
LB1
Summary of Haematology Changes From Baseline
Add part information in the title, 
repeat for all parts.
SAC


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Safety Tables
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
Deliverable 
2.x09
Safety
LB17
Summary of Emergent Hematology Results by 
Potential Clinical Importance (PCI) Criteria
Add part information in the title, 
repeat for all parts.
SAC
2.x10
Safety
LB15
Summary of Emergent Hematology Results Relative 
to Normal Range
Add part information in the title, 
repeat for all parts.
SAC
2.x11
Safety
UR3
Summary of Urinalysis Dipstick Results 
Add part information in the title, 
repeat for all parts.
SAC
2.x12
Safety
LB1
Summary of Urine Concentration Changes from Baseline
Add part information in the title, 
repeat for all parts.
SAC
Vital Signs 
2.x13
Safety
VS1
Summary of Vital Signs 
Add part information in the title, 
repeat for all parts.
SAC
2.x14
Safety
VS1
Summary of Change From Baseline for Vital Signs 
Add part information in the title, 
repeat for all parts.
SAC
Telemetry 
2.x15
Safety
HM1
Summary of Telemetry Interpretations 
Part B Cohort 3 and Part C 
patients with known cardiac 
amyloid involvement only 
SAC
2.x16
Safety
HM2
Summary of Telemetry Abnormalities
Part B Cohort 3 and Part C 
patients with known cardiac 
amyloid involvement only
SAC


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10.9.6.
Safety Figures
Safety Figures
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
Deliverable
2.x01
Safety
pkcf1x
Individual Profiles Over Time for Renal 
Parameters by Parameter 
IA at the end of Part B - Add part information 
in the title, repeat for Part A and B.
SAC – Part C only.
IA/SAC
10.9.7.
Pharmacokinetic Tables
These tables are the responsibility of Clinical Statistics.
Pharmacokinetic : Tables
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
Deliverable 
PK Concentration Data
3.x01
PK
PKCT1
Summary of Plasma GSK2315698 Pharmacokinetic  
Concentration-Time Data by Dose Level
Add part information in the title, 
repeat for all parts.
SAC
3.x02
PK
PKCT1
Summary of Plasma GSK3039294 Pharmacokinetic  
Concentration-Time Data by Dose Level
Add part information in the title, 
repeat for all parts.
SAC
PK Parameters
3.103
PK
PKPT1
Summary of Plasma GSK2315698 Pharmacokinetic 
Parameters by Dose Level - Part A Healthy Volunteers, 
Single Dose 
SAC


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Pharmacokinetic : Tables
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
Deliverable 
3.203
PK
PKPT1
Summary of Plasma GSK2315698 Pharmacokinetic 
Parameters - Part B Healthy Volunteers, Repeat Dose, 
Cohort 3 Day 4 and 5 (Food Effect Exploration)
Page by Day
SAC
3.104
PK
PKPT1
Summary of Plasma GSK3039294 Pharmacokinetic 
Parameters by Dose Level - Part A Healthy Volunteers, 
Single Dose
SAC
3.204
PK
PKPT1
Summary of Plasma GSK3039294 Pharmacokinetic 
Parameters - Part B Healthy Volunteers, Repeat Dose,
Cohort 3 Day 4 and 5 only (Food Effect Exploration)
Page by Day
SAC
10.9.8.
Pharmacokinetic Figures
. Pharmacokinetic : Figures - These figures are the responsibility of Clinical Statistics
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
Deliverable
PK
3.101
PK
pkcf6
Individual Plasma GSK2315698 Concentration-Time Plot by 
Dose (Linear and Semi-Log)
Part A Healthy Volunteers, Single Dose
Page By: NA
Panel By: Dose level
X-Axis: Time Post Dose (h)
Y-Axis: Result
Legend: Symbols/ lines distinguish 
subject IDs
SAC


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60
. Pharmacokinetic : Figures - These figures are the responsibility of Clinical Statistics
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
Deliverable
3.202
PK
pkcf1x
Individual Plasma GSK2315698 Concentration-Time Plot by 
Subject (Linear and Semi-Log)
Part B Healthy Volunteers, Single Dose, Cohort 3 Days 4 and 5 
only (Food Effect Exploration)
Page By: Scale – linear and semi-
log
Panel By: Subject ID
X-Axis: Time Post Most Recent 
Dose (h)
Y-Axis: Result
Legend: Symbols/ lines distinguish 
Day 4 (fasted) vs Day 5 (fed)
SAC
3.203
PK
pkcf6
Individual Plasma GSK2315698 Concentration-Time Plot by Day 
(Linear and Semi-Log)
Part B Healthy Volunteers, Single Dose, Cohort 3 Days 4 and 5 
only (Food Effect Exploration)
Page By: NA
Panel By: Fed / Fasted
X-Axis: Time Post Most Recent 
Dose (h)
Y-Axis: Result
Legend: Symbols/ lines distinguish 
subject IDs
Note: Fed is Day5, Fasted is Day 4
SAC
3.201
PK
pkcf6
Individual Plasma GSK2315698 Concentration-Time Plot of Pre-
Dose Samples (Semi-Log)
Part B Healthy Volunteers, Single Dose
Page By: NA
Panel By: Cohort
X-Axis: Time Post First Dose (day)
Y-Axis: Result
Legend: Symbols/ lines distinguish 
dose levels
See protocol Section 7.4.1 for days 
on which pre-dose samples are 
planned
SAC


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201664
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. Pharmacokinetic : Figures - These figures are the responsibility of Clinical Statistics
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
Deliverable
3.301
PK
pkcf6
Individual Plasma GSK2315698 Concentration-Time Plot of Pre-
Dose Samples (Semi-Log)
Part C Systemic Amyloidosis Patients, Repeat Dose
Page By: NA
Panel By: NA
X-Axis: Time Post First Dose (day)
Y-Axis: Result
Legend: Symbols/ lines distinguish 
dose levels
See protocol Section 7.4.1 for days 
on which pre-dose samples are 
planned
SAC
Median Concentration-Time Plots
3.102
PK
Pkcf5
Median Plasma GSK2315698 Concentration-Time Plot (Linear 
and Semi-Log)
Part A Healthy Volunteers, Single Dose
Page By: NA
Panel By: Scale – linear and semi-
log
X-Axis: Time Post Dose (day)
Y-Axis: Result
Legend: Symbols/ lines distinguish 
dose level
SAC
3.205
PK
Pkcf5
Median Plasma GSK2315698 Concentration-Time Plot (Linear 
and Semi-Log)
Part B Healthy Volunteers, Single Dose Cohort 3 Days 4 and 5 
only
Page By: NA
Panel By: Scale – linear and semi-
log
X-Axis: Time Post Most Recent 
Dose (h)
Y-Axis: Result
Legend: Symbols/ lines distinguish 
Day 4 (fasted) vs Day 5 (fed)
SAC


CONFIDENTIAL
201664
62
. Pharmacokinetic : Figures - These figures are the responsibility of Clinical Statistics
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
Deliverable
3.204
PK
Pkcf5
Median Plasma GSK2315698 Concentration-Time Plot of Pre-
Dose Samples (Semi-Log)
Part B Healthy Volunteers, Single Dose
Page By: NA
Panel By: NA
X-Axis: Time Post First Dose (day)
Y-Axis: Result
Legend: Symbols/ lines distinguish 
dose levels
See protocol Section 7.4.1 for days 
on which pre-dose samples are 
planned
SAC
3.302
PK
Pkcf5
Median Plasma GSK2315698 Concentration-Time Plot of Pre-
Dose Samples (Semi-Log)
Part C Systemic Amyloidosis Patients, Repeat Dose
Page By: NA
Panel By: NA
X-Axis: Time Post First Dose (day)
Y-Axis: Result
Legend: Symbols/ lines distinguish 
dose levels
See protocol Section 7.4.1 for days 
on which pre-dose samples are 
planned
SAC


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201664
63
. Pharmacokinetic : Figures - These figures are the responsibility of Clinical Statistics
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
Deliverable
PK Parameters
3.103
PK
Dose-normalised GSK2315698 PK Parameters versus Dose 
Level
Part A Healthy Volunteers, Single Dose
Page By: Parameter
Panel By: NA
X-Axis: Dose level (mg)
Y-Axis: PK parameter (unit)
Legend: NA
Note: Only plot AUC(0-inf)/D, 
AUC(0-t)/D and Cmax/D
SAC
3.206
PK
GSK2315698 PK Parameters versus Fed/Fasted Status
Part B Healthy Volunteers, Single Dose Cohort 3 Days 4 and 5 
only
Page By: Parameter
Panel By: NA
X-Axis: Fed / Fasted
Y-Axis: PK parameter (unit)
Legend: NA
Note: Only plot AUC(0-6) and 
Cmax; Fed is Day5, Fasted is Day 4
SAC


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10.9.9.
Pharmacodynamic Tables
These tables are the responsibility of Clinical Statistics.
Pharmacodynamic: Tables
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
Deliverable 
Plasma SAP Concentrations
4.x01
PD
PD1/PD2
Summary of Absolute Plasma SAP Concentration Data
Add part information in the title, 
repeat for parts B and C. Part B by 
dosing regimen. Data 
transformation as required.
Include 95% CI 
SAC
4.x02
PD
PD4
Summary of Plasma SAP parameters 
Add part information in the title, 
repeat for parts B and C. CminSAP
(Part B & C). Part B by dosing 
regimen.  Part C by baseline total 
body amyloid load (large/non-large) 
and overall.
tminSAP, TrepSAP_80%, TrepSAP_90%, 
TrepSAP_100%. Part C only.  By 
baseline total body amyloid load 
(large/non-large) and overall.
SAC


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201664
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10.9.10.
Pharmacodynamic Figures
These figures are the responsibility of Clinical Statistics.
Pharmacodynamic: Figures
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
Deliverable 
Individual Plasma SAP Concentrations
4.301.
PD
pkcf6?
Individual Plasma SAP Concentration-Time Plot of Pre-Dose 
Samples by Amyloid Load (Linear and Semi-Log)
Part C Systemic Amyloidosis Patients, Repeat Dose
Page By: Scale – linear and semi-
log
Panel By: Amyloid load category 
(HV=none; 
patients=low/moderate/high)
X-Axis: Time Post First Dose (day) 
Y-Axis: Result
Legend: Symbols/ lines distinguish 
dose levels
SAC
4.302.
PD
pkcf6?
Individual Plasma SAP Concentration-Time Plot At Day 21 by 
Amyloid Load (Semi-Log)
Part C Systemic Amyloidosis Patients, Repeat Dose
Page By: NA
Panel By: Amyloid load category 
(HV=none; 
patients=low/moderate/high)
X-Axis: Time Post Most Recent 
Dose (h) 
Y-Axis: Result
Legend: Symbols/ lines distinguish 
subject IDs
SAC


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201664
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10.9.11.
Pharmacokinetic / Pharmacodynamic Tables
These tables are the responsibility of Clinical Pharmacology Modelling and Simulation.
Pharmacokinetic / Pharmacodynamic : Tables
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
Deliverable 
Population PK/PD Analysis
5.1.
PK/PD
Summary Table of Parameter Estimates of Base Model
SAC
5.2.
PK/PD
Summary Table of Parameter Estimates of Final Model
SAC
5.3.
PK/PD
Summary Table of Models Tested
SAC
5.4.
PK/PD
NONMEM Output File of Base Model (with Control File)
SAC
5.5.
PK/PD
NONMEM Output File of Final Model (with Control File)
SAC
10.9.12.
Pharmacokinetic / Pharmacodynamic Figures
Pharmacokinetic / Pharmacodynamic: Figures - Figures 5.01 to 5.06 are the responsibility of CPMS; Figures 5.07 to 5.10 are the responsibility of CS 
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
Deliverable]
Population PK/PD Analysis
5.01
PK/PD
Goodness of Fit Plots of Base Model (GSK2315698 
Concentration Data)
SAC
5.02
PK/PD
Goodness of Fit Plots of Final Model (GSK2315698 
Concentration Data)
SAC
5.03
PK/PD
Goodness of Fit Plots of Base Model (SAP Concentration Data)
SAC
5.04
PK/PD
Goodness of Fit Plots of Final Model (SAP Concentration Data)
SAC


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Pharmacokinetic / Pharmacodynamic: Figures - Figures 5.01 to 5.06 are the responsibility of CPMS; Figures 5.07 to 5.10 are the responsibility of CS 
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
Deliverable]
5.05
PK/PD
Visual Predictive Check of Final Model (GSK2315698 
Concentration Data)
SAC
5.06
PK/PD
Visual Predictive Check of Final Model (SAP Concentration 
Data)
SAC
5.07/
5.08
PK/PD
Scatter Plot of CminSAP versus GSK2315698 (CPHPC) AUC[0-
24]
Add part information in the title, 
repeat for parts B and C.
X-Axis: GSK2315698 AUC[0-24]
Y-Axis: CminSAP
For both parts B and C. Panel by 
dosing regimen for Part B.  Use a 
different plotting character for large 
and non-large amyloid load patients
for Part C. Include a legend to 
highlight this
SAC
5.09/
5.10
PK/PD
Scatter Plot of CminSAP versus GSK3039294 (pro-drug) dose
Add part information in the title, 
repeat for parts B and C.
X-Axis: GSK3039294 dosage
Y-Axis: CminSAP
For both parts B and C. Panel by 
dosing regimen for Part B.  Use a 
different plotting character for large 
and non-large amyloid load patients 
for Part C. Include a legend to 
highlight this
SAC


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10.9.13.
ICH Listings
ICH Listings
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
Deliverable 
Randomisation
1
Safety
CP_TA1
Listing of Randomised and Actual Treatments
Page by study part 
SAC
Subject Disposition
2
Safety
ES2
Listing of Reasons for Study Withdrawal
Page by study part
SAC
3
Screened
ES7
Listing of Reasons for Screening Failure
Page by study part
SAC
Populations Analysed
4
Screened
SA3a
Listing of Subjects Excluded from Any Populations
Page by study part
SAC
Protocol Deviations
5
Safety
DV2
Listing of Important Protocol Deviations
Page by study part
SAC
6
Safety 
IE3
Listing of Subjects with Inclusion/Exclusion Criteria 
Deviations
Page by study part
SAC
Demographics
7
Safety
DM2
Listing of Demographic Characteristics
Page by study part
SAC
8
Safety
DM9
Listing of Race
Page by study part
SAC
Concomitant Medications
9
Safety 
CP_CM3
Listing of Concomitant Medications
Page by study part
SAC


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ICH Listings
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
Deliverable 
Exposure
10
Safety
EX3
Listing of Exposure
Page by study part
SAC
Adverse Events
11
Safety
AE7
Listing of Subject Numbers for Individual Adverse 
Events
Page by study part
SAC
12
Safety
CP_AE9
Listing of All Adverse Events
Page by study part
SAC
13
Safety
CP_AE9
Listing of Serious Adverse Events (Fatal and Non-
Fatal)
Page by study part. Include column to flag if 
event is drug related
SAC
14
Safety
CP_AE9
Listing of Adverse Events Leading to Withdrawal from 
Study / Permanent Discontinuation of Study 
Treatment
Page by study part
SAC
15
Safety
AE2
Listing of Relationship between System Organ Class 
and Verbatim Text 
Page by study part
SAC
LABS
16
Safety
CP_LB6
Listing of Haematology Laboratory Data for Subjects 
with Abnormalities of Potential Clinical Importance
Page by study part
SAC
17
Safety
CP_LB6
Listing of Haematology Laboratory Data of Potential 
Clinical Importance
Page by study part
SAC
18
Safety
CP_LB6
Listing of Clinical Chemistry Laboratory Data for 
Subjects With Abnormalities of Potential Clinical 
Importance
Page by study part
SAC


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ICH Listings
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
Deliverable 
19
Safety
CP_LB6
Listing of Clinical Chemistry Laboratory Data of 
Potential Clinical Importance
Page by study part
SAC
20
Safety
UR2b
Listing of Urinalysis Data
Include Microscopy and dipsticks
Page by study part
SAC
21
Safety
UR2b
Listing of Urinalysis Data for Subjects with 
Abnormalities of Potential Clinical Importance
Include Microscopy and dipsticks
Page by study part
SAC
22
Safety
UR2b
Listing of Urinalysis Data of Potential Clinical 
Importance
Include Microscopy and dipsticks
Page by study part
SAC
ECGs
23
Safety
CP_EG4
Listing of All ECG Values for Subjects with 
Abnormalities of Potential Clinical Importance
Page by study part
SAC
24
Safety
CP_EG4
Listing of ECG Values of Potential Clinical Importance
Page by study part
SAC
25
Safety
CP_EG6
Listing of Abnormal ECG Findings 
Page by study part
SAC
Vital Signs
26
Safety
CP_VS4
Listing of Vital Signs for Subjects with Abnormalities 
of Potential Clinical Importance
Page by study part
SAC
27
Safety
CP_VS4
Listing of Vital Signs of Potential Clinical Importance
Page by study part, flag high/low 
increase/decrease as per PCI 
SAC


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10.9.14.
Non-ICH Listings
Non-ICH : Listings
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
Deliverable 
PK
28
PK
pkcl1x
Listing of GSK3039294 Plasma Concentration-time Data
Page by study part
SAC
29
PK
pkpl1x
Listing of GSK3039294 Plasma Pharmacokinetic Parameters
Page by study part (
Part A and Part B Cohort 3 Days 4 
and 5)
SAC
30
PK
pkcl1x
Listing of GSK2315698 Plasma Concentration-time Data
Page by study part
SAC
31
PK
pkpl1x
Listing of GSK2315698 Plasma Pharmacokinetic Parameters
Page by study part (
Part A and Part B Cohort 3 Days 4 
and 5)
SAC
SAP
32
PD
Listing of Plasma SAP concentrations
Page by study part (Part B & C only)
SAC
33
PD
Listing of Plasma SAP parameters 
CminSAP (Part B & C). Part B by 
dosing regimen.  
tminSAP, TrepSAP_80%, TrepSAP_90%, 
TrepSAP_100%. (Part C only).  
Page by study part (Part B & C only)
SAC


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72
Non-ICH : Listings
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
Deliverable 
Other
34
Safety
CP_ML1p
Listing of Dosing Times, Meal Start and End Times on Fed 
Treatment Days
Part B Cohort 3 Day (4 and) 5 only
SAC