A Double Blind, Placebo-controlled First Time in Human Study to Evaluate the Safety, Tolerability and Pharmacokinetics of Single and Repeat Doses of GSK3036656 in Healthy Adult Volunteers
Phase: PHASE1
Conditions: Tuberculosis
Sponsor: GlaxoSmithKline

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201040
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TITLE PAGE
Protocol Title: A double blind, placebo-controlled first time in human study to evaluate 
the safety, tolerability and pharmacokinetics of single and repeat doses of GSK3036656 
in healthy adult volunteers
Protocol Number: 201040 / Amendment 1
Short Title: A double blind, placebo-controlled first time in human study to evaluate the 
safety, tolerability and pharmacokinetics of single and repeat doses of GSK3036656 in 
healthy adult volunteers
Compound Number:
GSK3036656
Sponsor Legal Registered Address: 
GlaxoSmithKline Research & Development Limited
980 Great West Road
Brentford
Middlesex, TW8 9GS
UK
In some countries, the clinical trial sponsor may be the local GlaxoSmithKline Affiliate 
Company (or designee). If applicable, the details of the alternative Sponsor and contact 
person in the territory will be provided to the relevant regulatory authority as part of the 
clinical trial application.
Regulatory Agency Identifying Number(s): 2015-003654-41
Copyright 2017 the GlaxoSmithKline group of companies.  All rights reserved.  
Unauthorised copying or use of this information is prohibited.

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Medical Monitor Name and SAE Contact Information:
Role
Name
Day Time Phone Number 
and email address
After-hours 
Phone/Cell/
Pager Number
Site Address
Primary 
Medical 
Monitor
 
Telephone: 
Mobile: 
1250 South Collegeville 
Road (UP-4310)
Collegeville, PA 19426
USA
Secondary 
Medical 
Monitor
Telephone: 
Mobile:
 
Iron Bridge Road 
Stockley Park West 
Uxbridge
Middlesex
UB11 1BT
UK
SAE contact  
information 
Medical 
monitor as 
above 
AND cc:
Mobile: 
1250 South Collegeville 
Road (UP-4310)
Collegeville, PA 19426
USA
Approval Date: 27-FEB-2017
PPD
PPD
PPD
P
P
D
PPD
PPD
PPD
PPD
PPD
PP
D
PPD
PP
D
PPD
P
P
D
PPD
PPD

33'
33'

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PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE
Amendment 1 (27-February-2017) 
DOCUMENT HISTORY
Document
Date
2014N202803_01
27-FEB-2017
2014N202803_00
13-JAN-2017
Amendment 1 27-February-2017
Overall Rationale for the Amendment:
To address comments from the UK regulatory authority, Medicines and Healthcare 
Products Regulatory Agency (MHRA), on the initial protocol (GlaxoSmithKline 
Document Number GSK2014N202803_00).
Section # and 
Name
Description of Change
Brief Rationale
Section 1, 
Overall Design,
Treatment Arms 
and Duration
From: “The two cohorts in Part A may be dosed sequentially
(i.e., dosing in Cohort 2 starts after dosing in Cohort 1 is 
completed) or in an overlapping/interlocking fashion. The 
exact sequence of dosing will be determined together with the 
site investigator based on emerging information about the 
half-life of GSK3036656 in humans and logistical 
considerations.”
To: “The two cohorts in Part A will be dosed sequentially (i.e., 
dosing in Cohort 2 starts after dosing in Cohort 1 is 
completed). If it is considered desirable to dose Cohorts 1 and 
2 in an overlapping/interlocking fashion (for example, if the 
half-life of GSK3036656/washout period makes sequential 
dosing impractical), approval for such dosing will be sought 
from the Regulatory Agency. Dosing in an 
overlapping/interlocking fashion will only take place if such 
approval is obtained.”
To address 
the concern 
from the 
MHRA about 
the possibility 
of overlapping/
interlocking 
dosing.
Section 4.1, 
Study Design
From: The two cohorts in Part A may be dosed sequentially 
(i.e., dosing in Cohort 2 starts after dosing in Cohort 1 is 
completed) or in an overlapping/interlocking fashion. The 
exact sequence of dosing will be determined together with the 
site investigator based on emerging information about the 
half-life of GSK3036656 in humans and logistical 
considerations.”
To: The two cohorts in Part A will be dosed sequentially (i.e., 
To address 
the concern 
from the 
MHRA about 
the possibility 
of overlapping/
interlocking 
dosing.

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Section # and 
Name
Description of Change
Brief Rationale
dosing in Cohort 2 starts after dosing in Cohort 1 is 
completed). If it is considered desirable to dose Cohorts 1 and 
2 in an overlapping/interlocking fashion (for example, if the 
half-life of GSK3036656/washout period makes sequential 
dosing impractical), approval for such dosing will be sought 
from the Regulatory Agency. Dosing in an 
overlapping/interlocking fashion will only take place if such 
approval is obtained.”
Figure 1, footnote (bullet 3) updated.
From: Cohorts may be dosed in an overlapping fashion, the 
exact sequence of dosing will be determined together with the 
investigator based on emerging information about the half life 
of GSK3036656 in humans and logistical consideration
To: Cohorts 1 and 2 will be dosed sequentially. If it is 
considered desirable to dose Cohorts 1 and 2 in an 
overlapping/interlocking fashion, approval will be sought from 
the Regulatory Agency first
Section 5.1, 
Inclusion Criteria
From: “Male subjects with female partners of child bearing 
potential must comply with the following contraception 
requirements from the time of first dose of study medication 
until follow up.”
To: “Male subjects with female partners of child bearing 
potential must comply with the following contraception 
requirements from the time of first dose of study medication 
until 90 days after the last dose of study treatment (i.e. one 
sperm cycle).”
To allow the 
completion of 
one sperm 
cycle before 
possible 
pregnancy.

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TABLE OF CONTENTS
PAGE
PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE.....................................4
1.
PROTOCOL SYNOPSIS FOR STUDY [201040]......................................................9
2.
INTRODUCTION....................................................................................................13
2.1.
Study Rationale ..........................................................................................13
2.2.
Brief Background ........................................................................................13
3.
OBJECTIVE(S) AND ENDPOINT(S) ......................................................................14
4.
STUDY DESIGN ....................................................................................................15
4.1.
Part A (Single Dose)...................................................................................15
4.1.1.
Food Effect ..................................................................................16
4.2.
Part B (Repeat Dose)..................................................................................17
4.3.
Type and Number of Subjects.....................................................................18
4.4.
Design Justification.....................................................................................18
4.5.
Dose Justification........................................................................................18
4.6.
Benefit:Risk Assessment ............................................................................20
4.6.1.
Risk Assessment .........................................................................21
4.6.2.
Benefit Assessment.....................................................................24
5.
SELECTION OF STUDY POPULATION AND WITHDRAWAL CRITERIA .............24
5.1.
Inclusion Criteria.........................................................................................24
5.2.
Exclusion Criteria........................................................................................26
5.3.
Screening/Baseline/Run-in Failures............................................................27
5.4.
Individual Withdrawal/Stopping Criteria.......................................................27
5.4.1.
Liver Chemistry Stopping Criteria ................................................28
5.4.1.1.
Study Treatment Restart or Rechallenge....................29
5.4.2.
QTc Stopping Criteria ..................................................................29
5.4.3.
Haematology Stopping Criteria ....................................................29
5.4.4.
Vital Signs Stopping Criteria ........................................................29
5.4.5.
Other Dose Adjustment/Stopping Safety Criteria .........................29
5.5.
Dose Escalation Stopping Criteria ..............................................................30
5.6.
Trial stopping criteria ..................................................................................30
5.7.
Subject and Study Completion....................................................................31
6.
STUDY TREATMENT ............................................................................................31
6.1.
Investigational Product................................................................................31
6.2.
Treatment Assignment................................................................................31
6.3.
Planned Dose Escalation and Adjustments.................................................32
6.3.1.
Dose escalation in Part A.............................................................32
6.3.2.
Dose escalation in Part B.............................................................33
6.4.
Blinding.......................................................................................................33
6.5.
Packaging and Labeling..............................................................................34
6.6.
Preparation/Handling/Storage/Accountability..............................................34
6.7.
Compliance with Study Treatment Administration.......................................35
6.8.
Treatment of Study Treatment Overdose....................................................35
6.9.
Treatment after the End of the Study ..........................................................35
6.10.
Concomitant Medications and Non-Drug Therapies....................................35

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6.10.1.
Permitted Medications and Non-Drug Therapies..........................35
6.10.2.
Prohibited Medications and Non-Drug Therapies.........................36
7.
STUDY ASSESSMENTS AND PROCEDURES .....................................................36
7.1.
Time & Events Table ..................................................................................37
7.2.
Safety Assessments ...................................................................................41
7.2.1.
Physical Examinations.................................................................41
7.2.2.
Vital Signs....................................................................................41
7.2.3.
Electrocardiograms......................................................................41
7.2.4.
Cardiac Telemetry .......................................................................41
7.2.5.
Holter Monitoring .........................................................................41
7.2.6.
Echocardiography........................................................................42
7.2.7.
Clinical Safety Laboratory Assessments ......................................42
7.3.
Pharmacokinetics .......................................................................................43
7.3.1.
Blood Sample Collection..............................................................43
7.4.
Non-Pharmacokinetic Sample Collection and Processing...........................44
7.4.1.
Urine Sample Collection ..............................................................44
7.4.2.
Sample Analysis ..........................................................................44
8.
SAFETY.................................................................................................................45
8.1.
Adverse Events (AE) and Serious Adverse Events (SAEs).........................45
8.1.1.
Time period and Frequency for collecting AE and SAE 
information...................................................................................45
8.1.2.
Method of Detecting AEs and SAEs.............................................45
8.1.3.
Follow-up of AEs and SAEs.........................................................46
8.1.4.
Regulatory Reporting Requirements for SAEs .............................46
9.
DATA MANAGEMENT ...........................................................................................46
10. DATA ANALYSIS AND STATISTICAL CONSIDERATIONS...................................47
10.1.
Hypothesis and Treatment Comparisons ....................................................47
10.2.
Sample Size Considerations.......................................................................47
10.2.1.
Sample Size Re-estimation..........................................................47
10.3.
Data analysis Considerations......................................................................47
10.3.1.
Interim Analysis ...........................................................................47
10.3.2.
Final analyses..............................................................................48
10.3.2.1.
Safety Analyses..........................................................48
10.3.2.2.
Pharmacokinetic Analyses..........................................48
10.3.3.
Non-Pharmacokinetic Sample Analysis .......................................51
11. STUDY GOVERNANCE CONSIDERATIONS........................................................51
11.1.
Regulatory and Ethical Considerations .......................................................51
11.2.
Financial Disclosure....................................................................................51
11.3.
Informed Consent Process .........................................................................52
11.4.
Data Protection...........................................................................................52
11.5.
Publication Policy........................................................................................52
11.6.
Dissemination of Clinical Study Data ..........................................................53
11.6.1.
Data Quality Assurance ...............................................................53
11.6.2.
Source Documents ......................................................................53
11.7.
Study and Site Closure ...............................................................................54
12. REFERENCES.......................................................................................................55

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13. APPENDICES........................................................................................................56
13.1.
Appendix 1: Abbreviations and Trademarks................................................56
13.2.
Appendix 2: Adverse Events: Definitions and Procedures for 
Recording, Evaluating, Follow-up, and Reporting .......................................59
13.3.
Appendix 3: Contraceptive Guidance and Collection of Pregnancy 
Information..................................................................................................64
13.4.
Appendix 4: Liver Safety: Required Actions and Follow-up 
Assessments Guidelines.............................................................................67
13.5.
Appendix 5: Protocol Amendment History...................................................69

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1.
PROTOCOL SYNOPSIS FOR STUDY [201040]
Rationale
This study is the first time into human study (FTIH) for GSK3036656. The study will 
evaluate the safety, tolerability and pharmacokinetics (PK) of single ascending and repeat 
oral doses of GSK3036656 in healthy adult volunteers.
The results of this study are intended to be used to identify appropriate and well tolerated 
doses of GSK3036656 to be used in further studies. A food effect assessment will also be 
undertaken to investigate the influence of food on the pharmacokinetics of GSK3036656.
Objective(s)/Endpoint(s)
Objectives
Endpoints
Primary

To investigate the safety and 
tolerability of GSK3036656 after single 
ascending and repeat oral doses in healthy 
adult subjects

To determine the pharmacokinetics of 
single and repeat doses of GSK3036656 in 
healthy subjects

Safety and tolerability of GSK3036656: 
o
Adverse Events
o
Clinically relevant changes in safety 
parameters: 12-lead 
electrocardiogram (ECG), 
telemetry, vital signs (systolic and 
diastolic blood pressure, heart rate, 
temperature), clinical laboratory 
data (haematology, clinical 
chemistry, urinalysis)

Derived pharmacokinetic parameters for 
GSK3036656 including area under the 
plasma drug concentration versus time 
curve (AUC(0-t), AUC(0-∞), AUC(0-)), 
maximum observed plasma drug 
concentration (Cmax), time to maximum 
observed plasma drug concentration (tmax), 
and apparent terminal half-life (t1/2) as 
appropriate
Secondary

To assess the effect of food on the 
pharmacokinetics of GSK3036656 
following an oral dose in healthy subjects

To assess preliminary dose proportionality 
of GSK3036656 following single and 

Derived pharmacokinetic parameters for 
GSK3036656 including AUC(0-t), AUC(0-
∞), Cmax, tmax, and apparent terminal 
half-life (t1/2)

AUC(0-t), AUC(0-∞), and Cmax following 
single dose and AUC(0-τ) and Cmax
following repeat dose for the assessment 

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Objectives
Endpoints
repeat oral doses, as data permit

To examine the extent of accumulation and 
achievement of steady-state following 
repeat oral doses of GSK3036656, as data 
permit

To define the metabolic profile of 
GSK3036656 by identifying and quantifying, 
where possible and appropriate,  
GSK3036656-related material in plasma 
and urine following a single and repeated 
oral administration of GSK3036656
of dose proportionality

Observed accumulation ratio based on 
AUC(Ro) and Cmax (RCmax) and steady-
state ratio (Rss) following repeat dosing

Trough plasma concentrations at the end 
of the dosing interval (Cτ) to assess the 
achievement of steady-state of 
GSK3036656 following repeat oral doses

Structure and concentration of 
GSK3036656-related material in plasma 
and urine 
Overall Design
Treatment Arms and Duration
Part A:
For the single dose part, there will be up to 2 cohorts with up to 4 treatment (dosing) 
periods in each cohort (including a food effect treatment period). Initially, there will be a 
14 day wash out period for individual subjects between each dose level which is 
considered sufficient in light of the predicted half-life of GSK3036656 [on average, 
approximately 30 hours (range: 12 to 72 hours) based on the various preclinical 
extrapolation methods], however this may be revised once relevant PK data is obtained. 9 
subjects per cohort will be enrolled and randomised to ensure adequate safety, tolerability 
and PK information is gained and a balanced randomisation is achieved across all 
treatment (dosing) periods.
During each treatment (dosing) period, GSK3036656 will be administered to 6 subjects 
and placebo will be administered to 3 subjects. As this is a FTIH study, each treatment 
(dosing) period will be staggered over 2 days. On Day 1, one subject will receive 
GSK3036656 and one subject will receive placebo. The remaining subjects will be dosed 
one day later provided satisfactory safety and tolerability is demonstrated for the subjects 
dosed on Day 1. A treatment (dosing) period does not have to be staggered if the dose 
administered is equal to or lower than a dose that has been already tested and found to be 
safe and well tolerated.

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Subjects will attend the unit on Day -1 for assessments and a meal. The subjects will then 
fast overnight (at least 8 hours) and be dosed the following morning (Day 1). Dosing with 
food may also be used in Part A once results from the food effect analysis are available. 
Dividing the total dose for the treatment (dosing) period into 2 or 3 smaller doses 
administered within 24 hours may also be done. The decision to divide the total dose into 
smaller doses will be made by the GSK study team in conjunction with the Principal 
Investigator. Post-dose, subjects will undergo safety and PK assessments. All subjects 
will remain in the unit until the 72 hour PK sample has been taken since this will enable a 
better assessment of their safety and will reduce the risk of subjects not returning for their 
visits. Subjects will be released at the discretion of the investigator following completion 
of the assessments provided there are no safety concerns identified from review of the 
clinical safety data. Approximately 14 days after their last dose, subjects will return to the 
unit for a follow-up visit.
The starting dose in Part A will be 5 mg. The dose will then be escalated up to a dose (no 
higher than 1500 mg) at which PK exposures do not exceed predefined limits determined 
from preclinical safety data (individual AUC[0-24]<4.9 µg.h/ml, individual Cmax<0.443 
µg/ml). Dose escalation will only take place provided GSK3036656 is well tolerated and 
following review of all available safety, tolerability and pharmacokinetic data from the 
previous treatment (dosing) period by the Dose Escalation Committee.
The two cohorts in Part A will be dosed sequentially (i.e., dosing in Cohort 2 starts after 
dosing in Cohort 1 is completed). If it is considered desirable to dose Cohorts 1 and 2 in 
an overlapping/interlocking fashion (for example, if the half-life of 
GSK3036656/washout period makes sequential dosing impractical), approval for such 
dosing will be sought from the Regulatory Agency. Dosing in an 
overlapping/interlocking fashion will only take place if such approval is obtained. In any 
case, a wash out period of at least 4 half-lives will be required before the same group of 
subjects is dosed again.
Part A - Food Effect:
An assessment of the effect of food on the exposure to GSK3036656 will be incorporated 
into the single dose part of the study (Part A). This assessment will be done by 
administering a single dose of GSK3036656/placebo with a high fat meal provided this 
dose was well tolerated in a previous treatment (dosing) period in the same cohort when 
administered in the fasted state. The dose to be administered with food will be selected 
such that, when administered in the fasted state, it provides exposure no higher than 50% 
of the highest exposure allowed in the study, in the eventuality that the presence of food 
unexpectedly enhances absorption. 
Part B:
Part B (Cohorts 3, 4, 5, and 6) will comprise up to 4 cohorts of 10 (8 active: 2 placebo) 
healthy adult subjects to examine the safety, tolerability and PK of a repeated daily dose 
of GSK3036656 over a period of up to 14 days. Progression to Part B from Part A will be 
based on an acceptable safety, tolerability and PK profile in Part A. Appropriate doses 
and dose regimens for Part B will be selected by the Dose Escalation Committee based 

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on available safety, tolerability and PK data from Part A and/or any preceding repeat 
dose cohorts from Part B. A decision to proceed to a higher dose in Part B will be based 
on the review of safety data from at least the first week of dosing and PK data from at 
least the first 48 hours of dosing at the preceding dose.
On Day –1, subjects will report to the unit for assessments and a meal. The subjects will 
then fast overnight (at least 8 hours) and be dosed the following morning (Day 1). Dosing 
with food may also be done if there are PK or tolerability reasons making it preferable to 
dose in a fed state. Dividing the total daily dose into 2 or 3 smaller doses administered 
over 24 hours may also be done. The decision to divide the total dose into smaller doses 
will be made by the GSK study team in conjunction with the Principal Investigator. Post-
dose, subjects will undergo safety and PK assessments. Subjects will remain in the unit 
for at least 72 hours after the initial dosing. If they are released after that, it would be 
done at the discretion of the investigator following completion of the assessments on Day 
4 and provided there are no safety concerns. If released, subjects will then return to the 
clinical unit each morning to receive their daily dose and assessments for the duration of 
Part B. Dosing will be scheduled to occur at approximately the same time each day for 
each individual subject. Subjects will be required to spend at least the last 24 hours at the 
end of the dosing period in the unit in order to complete the necessary safety assessments 
and PK sampling. The subjects may then be discharged from the unit but, if discharged, 
will be required to return for additional PK sampling at 36, 48 and 72 hours post dosing. 
Approximately 14 days after their last dose, subjects will return to the unit for a follow-
up visit.
The total duration of the study for each subject recruited into Part A will be 
approximately 12 weeks. For subjects recruited into Part B the total study duration will 
be approximately 8 weeks.
Type and Number of Subjects
Up to 18 subjects (excluding possible replacements) will be recruited into the single 
ascending dose part of the study and up to 40 subjects (excluding possible replacements)
will be recruited for the repeat dose. Both males and females of non child-bearing 
potential will be included.
Analysis
The focus of this FTIH study, both single and repeat dose phases, is to evaluate the 
safety, tolerability and pharmacokinetics of GSK3036656. No formal statistical 
hypotheses will be tested.
Safety analyses 
Safety data will be presented in tabular and/or graphical format and summarized 
descriptively according to GSK’s Integrated Data Standards Library (IDSL) standards.

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Pharmacokinetic Analyses
From the plasma concentration-time data, the following pharmacokinetic parameters will 
be determined, as data permit: maximum observed plasma concentration (Cmax), time to 
Cmax (tmax), area under the plasma concentration time curve [AUC(0-t), AUC(0-τ), and 
AUC(0-∞)], and apparent terminal phase half-life (t1/2). Trough concentration (Cτ) 
samples collected on the specified days may be used to assess attainment of steady state. 
To estimate the extent of accumulation after repeat dosing, the observed accumulation 
ratio for AUC (Ro) and Cmax (RCmax) may be determined. To estimate the 
pharmacokinetic linearity, the state ratio (Rss) may be determined. From the urine 
concentration data, the following pharmacokinetic parameters will be determined, as data 
permit: urinary excretion of unchanged drug (Ae), fraction of the dose excreted in the 
urine (fe), and the renal clearance (CLr).
2.
INTRODUCTION
2.1.
Study Rationale
This study is the first time into human study (FTIH) for GSK3036656. The study will 
evaluate the safety, tolerability and pharmacokinetics (PK) of single ascending and repeat 
oral doses of GSK3036656 in healthy adult volunteers.
The results of this study are intended to be used to identify appropriate and well tolerated 
doses of GSK3036656 to be used in further studies. A food effect assessment will also be 
undertaken to investigate the influence of food on the pharmacokinetics of GSK3036656.
2.2.
Brief Background
GSK3036656 is being developed by GSK for the treatment of tuberculosis (TB) as part of 
a future combination regimen.
GSK3036656 suppresses protein synthesis in Mycobacterium tuberculosis, the causative 
agent of TB, by inhibiting the enzyme Leucyl t-RNA synthetase. It has activity not only 
against laboratory strains of M. tuberculosis, but also against a selection of drug-sensitive 
–TB (DS-TB), multi-drug-resistant (MDR-TB) and extensively drug-resistant (XDR-TB) 
clinical isolates. The compound is a selective anti-tubercular agent as it is inactive against 
a panel of common bacterial pathogens and a panel of mammalian cell lines.
Animal models of TB infection have shown that GSK3036656 is very potent in vivo, with 
doses around 1 mg/kg providing maximum anti-TB effect in acute and chronic mouse 
models of TB. The compound possesses good chemical and metabolic stability, excellent 
physicochemical properties, and a low estimated potential for drug-drug interactions. The 
toxicological profile of GSK3036656 indicates an acceptable therapeutic window.
The clinical development program will evaluate the safety and efficacy of GSK3036656 
in humans and aim for fast registration if successful. The FTIH trial described in this 
protocol is the first study where GSK3036656 will be administered to humans. A 
successful FTIH study would be followed by subsequent clinical studies investigating the 
efficacy of GSK3036656, alone as well as in combination with other compounds, in 
patients with TB.

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3.
OBJECTIVE(S) AND ENDPOINT(S)
Objectives
Endpoints
Primary

To investigate the safety and tolerability of 
GSK3036656 after single ascending and 
repeat oral doses in healthy adult subjects

To determine the pharmacokinetics of 
single and repeat doses of GSK3036656 in 
healthy subjects

Safety and tolerability of GSK3036656: 
o
Adverse Events
o
Clinically relevant changes in safety 
parameters: 12-lead 
electrocardiogram (ECG), 
telemetry, vital signs (systolic and 
diastolic blood pressure, heart rate, 
temperature), clinical laboratory 
data (haematology, clinical 
chemistry, urinalysis)

Derived pharmacokinetic parameters for 
GSK3036656 including area under the 
plasma drug concentration versus time 
curve (AUC(0-t), AUC(0-∞), AUC(0-)), 
maximum observed plasma drug 
concentration (Cmax), time to maximum 
observed plasma drug concentration (tmax), 
and apparent terminal half-life (t1/2) as 
appropriate
Secondary

To assess the effect of food on the 
pharmacokinetics of GSK3036656 
following an oral dose in healthy subjects

To assess preliminary dose proportionality 
of GSK3036656 following single and 
repeat oral doses, as data permit

To examine the extent of accumulation and 
achievement of steady-state following 
repeat oral doses of GSK3036656, as data 
permit

To define the metabolic profile of 
GSK3036656 by identifying and quantifying, 
where possible and appropriate, 

Derived pharmacokinetic parameters for 
GSK3036656 including AUC(0-t), AUC(0-
∞), Cmax, tmax, and apparent terminal 
half-life (t1/2)

AUC(0-t), AUC(0-∞), and Cmax following 
single dose and AUC(0-τ) and Cmax 
following repeat dose for the assessment 
of dose proportionality

Observed accumulation ratio based on 
AUC(Ro) and Cmax (RCmax) and steady-
state ratio (Rss) following repeat dosing

Trough plasma concentrations at the end 
of the dosing interval (Cτ) to assess the 
achievement of steady-state of 
GSK3036656 following repeat oral doses

Structure and concentration of 
GSK3036656-related material in plasma 
and urine

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Objectives
Endpoints
GSK3036656-related material in plasma 
and urine following a single and repeated 
oral administration of GSK3036656
4.
STUDY DESIGN
4.1.
Part A (Single Dose)
Figure 1
Part A Schematic
Up to two cohorts will be included in the single dose part (Part A). Each cohort will 
participate in up to 4 treatment (dosing) periods (including a food effect treatment 
period). Initially, there will be a 14 day wash out period for individual subjects between 
each dose level which is considered sufficient in light of the predicted half-life of 
GSK3036656 [on average, approximately 30 hours (range: 12 to 72 hours) based on the 
various preclinical extrapolation methods], however this may be revised once relevant PK 
data is obtained. Nine subjects per cohort will be enrolled and randomised to ensure 
adequate safety, tolerability and PK information is gained and a balanced randomisation 
is achieved across all treatment (dosing) periods.
During each treatment (dosing) period, GSK3036656 will be administered to 6 subjects 
and placebo will be administered to 3 subjects. As this is a FTIH study, each treatment 
(dosing) period will be staggered over 2 days. On Day 1 of each dose level, one subject 
will receive GSK3036656 and one subject will receive placebo. The remaining subjects 
within the dosing group will be dosed one day later provided satisfactory safety and 
tolerability is demonstrated for the subjects dosed on Day 1. A treatment (dosing) period 
does not have to be staggered if the dose administered is equal to or lower than a dose 
that has been already tested and found to be safe and well tolerated.
Subjects will attend the unit on Day -1 for assessments and a meal. The subjects will then 
fast overnight (at least 8 hours) and be dosed the following morning (Day 1). Dosing with 
food may also be done in Part A once results from the food effect analysis are available. 
Dividing the total dose for the treatment (dosing) period into 2 or 3 smaller doses 
administered within 24 hours may also be done. The decision to divide the total dose into 

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smaller doses will be made by the GSK study team in conjunction with the Principal 
Investigator. Post-dose, subjects will undergo safety and PK assessments. All subjects 
will remain in the unit until the 72 hour PK sample has been taken since this will enable a 
better assessment of their safety and will reduce the risk of subjects not returning for their 
visits. Subjects will be released at the discretion of the investigator following completion 
of the assessments provided there are no safety concerns identified from review of the 
clinical safety data. Approximately 14 days after their last dose, subjects will return to the 
unit for a follow-up visit.
The starting dose in Part A will be 5 mg. The dose will then be escalated up to a dose (no 
higher than 1500 mg) at which PK exposures do not exceed predefined limits determined 
from preclinical safety data (individual AUC[0-24] <4.9 µg.h/ml, individual Cmax 
<0.443 µg/ml). Dose escalation will only take place provided GSK3036656 is well 
tolerated and following review of all available safety, tolerability and pharmacokinetic 
data from the previous treatment (dosing) period by the Dose Escalation Committee 
(Section 6.3). 
The two cohorts in Part A will be dosed sequentially (i.e., dosing in Cohort 2 starts after 
dosing in Cohort 1 is completed). If it is considered desirable to dose Cohorts 1 and 2 in 
an overlapping/interlocking fashion (for example, if the half-life of 
GSK3036656/washout period makes sequential dosing impractical), approval for such 
dosing will be sought from the Regulatory Agency. Dosing in an 
overlapping/interlocking fashion will only take place if such approval is obtained. In any 
case, a washout period of at least 4 half-lives will be required before the same group of 
subjects is dosed again.
4.1.1.
Food Effect
An assessment of the effect of food on the exposure to GSK3036656 will be incorporated 
into Part A. This assessment will be done by administering a single dose of 
GSK3036656/placebo with a high fat meal provided this dose was well tolerated in a 
previous treatment (dosing) period in the same cohort when administered in the fasted 
state. The dose to be administered with food will be selected such that, when 
administered in the fasted state, it provides exposure no higher than 50% of the highest 
exposure allowed in the study, in the eventuality that the presence of food unexpectedly 
enhances absorption. 

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4.2.
Part B (Repeat Dose)
Figure 2
Part B Schematic
Part B (Cohorts 3, 4, 5, and 6) will comprise up to 4 cohorts each containing 10 (8 active: 
2 placebo) healthy adult subjects to examine the safety, tolerability and PK of a repeated 
daily dose of GSK3036656 over a period of up to 14 days. Progression to Part B from 
Part A will be based on an acceptable safety, tolerability and PK profile in Part A. 
Appropriate doses and dose regimens for Part B will be selected by the Dose Escalation 
Committee based on available safety, tolerability and PK data from Part A and/or any 
preceding repeat dose cohorts from Part B (Section 6.3). A decision to proceed to a 
higher dose in Part B will be based on the review of safety data from at least the first 
week of dosing and PK data from at least the first 48 hours of dosing at the preceding 
dose.
On Day –1 of each cohort, subjects will report to the unit for assessments and a meal. The 
subjects will then fast overnight (at least 8 hours) and be dosed the following morning 
(Day 1). Dosing with food may also be done if there are PK or tolerability reasons 
making it preferable to dose in a fed state. Dividing the total daily dose into 2 or 3 
smaller doses administered over 24 hours may also be done. The decision to divide the 
total dose into smaller doses will be made by the GSK study team in conjunction with the 
Principal Investigator.  Post-dose, subjects will undergo safety and PK assessments. 
Subjects will remain in the unit for at least 72 hours after the initial dosing. If they are 
released after that, it would be done at the discretion of the investigator following 
completion of assessments on Day 4 and provided there are no safety concerns. If 
released, subjects will then return to the clinical unit each morning to receive their daily 
dose and assessments for the duration of Part B. Dosing will be scheduled to occur at 
approximately the same time each day for each individual subject. Subjects will be 
required to spend at least the last 24 hours at the end of the dosing period in the unit in 
order to complete the necessary safety assessments and PK sampling. The subjects may 
then be discharged from the unit but, if discharged, will be required to return for 
additional PK sampling at 36, 48 and 72 hours post dosing. Approximately 14 days after 
their last dose, subjects will return to the unit for a follow-up visit.
The total duration of the study for each subject recruited into Part A will be 
approximately 12 weeks. For subjects recruited into Part B the total study duration will 
be approximately 8 weeks.

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4.3.
Type and Number of Subjects
Up to 18 subjects (excluding possible replacements) will be enrolled into Part A and up 
to 40 subjects (excluding possible replacements) will be enrolled into to Part B. 
If subjects prematurely discontinue the study, replacements will be permitted for the 
single ascending dose part of the study (Part A) and will be considered on a case by case 
basis for the repeat dose (Part B) by the Sponsor in consultation with the investigator.
4.4.
Design Justification
The FTIH study with GSK3036656 will evaluate the safety of the compound in healthy 
volunteers in order to avoid confounding factors resulting from the disease or 
concomitant drugs in patients with TB that may hinder the proper evaluation of safety. 
Also, ethical considerations dictate exploration of safety and tolerability in healthy 
volunteers first as patients with TB may be more vulnerable to side effects caused by the 
compound.
A cross-over design is preferred for Part A as it would allow assessment of safety and PK 
in the same individual thus reducing the influence of inter-individual variability.
Based on the physicochemical properties of GSK3036656, no significant food effect is 
predicted. Nevertheless, the study will investigate the possibility of food effect in order to 
provide guidance for dosing in future studies. If the FTIH study with GSK3036656 is 
successful, the next study in humans is expected to be an efficacy study in patients with 
TB where the compound is dosed for up to 2 weeks. Therefore, the proposed dosing for 
up to 14 days in Part B of the FTIH study is an appropriate first step in evaluating the 
safety of GSK3036656.
4.5.
Dose Justification
Dose selection of GSK3036656 for this FTIH study was based on no observed adverse 
effect level (NOAEL) data, predicted pharmacokinetics for humans using the 
pharmacokinetic data from various preclinical species, and a targeted therapeutic 
exposure based on efficacy data from a murine model of chronic lung infection. 
GSK3036656 PK parameters and exposure values were converted from whole blood 
values to plasma values when necessary. GSK3036656 suppresses protein synthesis in 
Mycobacterium tuberculosis by inhibiting the enzyme Leucyl t-RNA synthetase which is 
not a human target; thus, the minimum anticipated biological effect level (MABEL) in 
humans for GSK3036656 could not be determined.
The in vivo PK parameters obtained in preclinical species (CD-1 mouse, SD rat, and 
beagle dog) after 1 mg/kg intravenous administration and the in vitro parameters 
(intrinsic Cl from microsomes and hepatocytes, plasma protein binding, and blood to 
plasma ratio) were used for calculations. The GlaxoSmithKline software package PK 
Predictor Pro (GUI v1.1.45 Calculation Engine v1.4.4) was used for IVIVE, LBF, GFR 
and allometric scaling and the CloePK software (Cyprotex) for the physiologically based 
pharmacokinetic (PBPK) modelling.

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Predicted human clearance values ranged from approximately 1.1 (allometric scaling 
with MLP) to 7.2 (PBPK) mL/min/kg while predicted volume of distribution ranged from 
3.5 (PBPK) to 4.5 (simple allometry) L/kg. Preclinically, oral bioavailability ranged from 
approximately 60% to greater than 100%.
The NOAEL dose in the rat (the most sensitive species) was 30 mg/kg with an average 
AUC(0-24) and Cmax of 90.5 µg.h/mL and 7.59 µg/mL, respectively; the NOAEL dose 
in the dog was 20 mg/kg with an average AUC(0-24) and Cmax of 147.0 µg.h/mL and 
13.3 µg/mL, respectively. Due to the presence of heart valvular and vascular lesions in 
dogs at higher doses, and based on discussions with the GSK Cardiovascular Safety 
panel, the maximum individual daily human exposure after single or repeat dose in the 
study will be limited to 4.9 µg.h/mL for AUC(0-24) and 0.443 µg/ml for Cmax (30-fold 
margins from the dog NOAEL exposures of 147.0 µg.h/mL and 13.3 µg/ml, 
respectively).
The minimum target therapeutic exposure to be achieved in human is a mean AUC(0-24) 
of 1.74 µg.h/mL (95% CI: 0.94 – 4.55 µg.h/mL) based on efficacy data from a murine 
model of chronic lung infection.
Maximum Recommended Starting Dose (MRSD)
Using the FDA Guidance for estimation of the maximum safe starting dose, the NOAEL 
in rats was converted to the Human Equivalent Dose (HED) based on surface body area. 
After applying an uncertainty safety factor of 10 (guideline default) to the HED, the 
maximum recommended starting dose is 31 mg.
Dose Predicted to Achieve the Therapeutic Exposure Target
Simulations were conducted to predict the dose that would provide a therapeutic exposure 
in 90% and 95% of simulated subjects (n=10,000). Based on the range of predicted 
human clearance (CL) and bioavailability values for GSK3036656, 50% CV for CL, and 
a mean efficacy target of 1.74 µg.h/mL, the human dose to achieve the therapeutic 
exposure target ranges from 12 to 170 mg.
Predicted Exposure of the Proposed Starting Dose Compared to Study Exposure 
Limits
Simulations (n=10000 subjects) were conducted to predict the probability of individual 
exposure for a starting dose of 5 mg to exceed the AUC exposure limit of 4.9 µg.h/mL. 
Based on the range of predicted human CL and bioavailability values for GSK3036656 
and 50% CV for CL, there is a very low probability (<1%) of any individual subject 
exceeding the AUC limit of 4.9 µg.h/mL for a 5 mg dose.
Based on the large predicted human volume of distribution (242 – 315 L), Cmax is 
expected to be very low following oral absorption of a 5 mg dose.

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Summary
The proposed starting dose is 5 mg which is less than the Food and Drug Administration 
(FDA) Maximum Recommended Starting Dose (MRSD) of 31 mg and has a very low 
probability of any individual subject exceeding the limits of 4.9 µg.h/mL for AUC(0-24) 
or 0.443 µg/ml for Cmax . Further dose escalation will be based on exposure, safety, and 
tolerability data from the previous dose level. The maximum dose that can be 
administered in the study is 1500 mg based on a Genotoxic Risk Assessment.
4.6.
Benefit:Risk Assessment
Consistent with GlaxoSmithKline guidance for early phase studies, GSK3036656 will be 
administered in an in-patient setting (with sufficient overnight facilities) with appropriate 
monitoring.
In order to minimise the risk of the initial human administration of GSK3036656, at the 
beginning of each treatment (dosing) period in Part A, one subject will receive 
GSK3036656 and one subject will receive placebo. The remaining subjects from that 
cohort will be dosed on the next day only if satisfactory safety and tolerability is 
demonstrated for the subjects dosed on Day 1. A treatment (dosing) period does not have 
to be staggered if the dose administered is equal to or lower than a dose that has been 
already tested and found to be safe and well tolerated.
Summaries of findings from non-clinical studies conducted with GSK3036656 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) [GSK3036656] 
Reduction in red blood cell count
In a 4-week rat study (doses 3, 10 & 30 mg/kg/d) -  
dose-dependent decline in reticulocytes (by up to 52% 
in males and 62% in females) at day 7 followed by 
normal levels by day 14 and increased levels by day 
29/30 compared to controls. Hgb levels decreased by 
10-13% compared to controls on day 14 and day 
29/30.
In a 4 week dog study (doses 5, 10 & 20 mg/kg/d) -  
mild dose-dependent decrease in Hgb on day 14 (by 
about 10% compared to controls) with recovery by 
week 4. Reticulocyte counts unaffected. Dogs not bled 
on day 7.
No histopathological changes in bone marrow or other 
relevant histopathology in the 4-week studies.
Standard safety haematology and clinical 
chemistry assessments will be performed and 
both trends and changes outside normal range 
will be monitored as part of laboratory safety 
assessments.
Subjects whose haemoglobin drops below pre-
specified limits (<110 g/L for males, <100 g/L for 
females) will be withdrawn from the study and 
followed up until levels are not clinically 
significant (Section 6.4– Individual 
Withdrawal/Stopping Criteria).
While women of non-childbearing potential are 
permitted in this study, women who are 
susceptible to periods or heavy vaginal bleeding 
or spotting will be excluded in order to minimize 
blood loss and avoid confounding effects on the 
interpretation of hematology parameters.
Reduction in white blood cell count
In the 4 week rat study, decrease of up to 37% in total 
leucocyte count on day 29/30 compared to controls.
In the 4-week dog study, no reported effects on white 
White blood cell count will be monitored as part 
of laboratory safety assessments. Any clinically
significant changes will be followed up until 
levels are not clinically significant.

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Potential Risk of Clinical Significance 
Summary of Data/Rationale for Risk
Mitigation Strategy 
blood cells.
Subjects developing neutrophil counts 
<1000/mm3 (1.0x109/L) and lymphocyte counts 
<500/mm3 (0.5x109/L) will be withdrawn from the 
study and followed up until levels are not 
clinically significant (Section 6.4 – Individual 
Withdrawal/Stopping Criteria).
Heart valvular and vascular pathology
In a 7-day dog dose range finding (DRF) study –
minimal focal subendocardial hemorrhage on the atrial 
surface of the left atrioventricular valve observed in 
both animals at the top dose of 60 mg/kg/d.
In a 10day dog investigative study at 65 mg/kg/d –
vascular lesions (including minimal focal necrosis and 
inflammatory infiltrate) in 3 out of 8 dogs.
In the 4-week dog GLP study - no heart or valve 
changes up to the top dose of 20mg/kg/day; no 
increased inflammatory markers. 
Valvular or vascular pathology not observed in rats. 
This pathological change is not commonly seen in 
animals, and its mechanism and significance to 
humans are not clear. A correlation between the 
presence of hemodynamic changes and the presence 
of this pathology is suspected, but currently unproven.
This pathology is not monitorable in humans.
To avoid risk to humans, dosing in the FTIH 
study will be limited to doses at which individual 
exposures [AUC (0-24)] do not exceed of 4.9 
µg.h/ml – 1/30 of the dog NOAEL exposure 
(from the 4-week GLP study) at which no heart 
pathology was seen.
Echocardiograms will be done at screening and 
follow up in order to exclude subjects with pre-
existing valve or other cardiac abnormalities from 
the study and detect the presence of 
abnormalities after completion of the study.
Hemodynamic changes
Hemodynamic changes in several studies at ≥100 
mg/kg in rats and ≥20 mg/kg in dogs - increased heart 
rate (rats and dogs), increased (rats) or decreased 
Vital signs monitoring and stopping criteria will 
be used.

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Potential Risk of Clinical Significance 
Summary of Data/Rationale for Risk
Mitigation Strategy 
(dogs) blood pressure.
Phototoxicity
As GSK3036656 absorbs light in the UVB wavelength 
range (>290 nm), there is a potential for phototoxicity 
in clinical populations. 
No pathology in the skin or eye has been observed in 
animals so far. 
Subjects with a history of photosensitivity will be 
excluded from participating in the study 
(Exclusion Criteria, Section 6.2). 
All study subjects will be instructed to minimise 
exposure to sunlight and other sources of 
ultraviolet radiation (Section 6.2).

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4.6.2.
Benefit Assessment
This is a healthy volunteer study and subjects will not stand to directly benefit from 
administration of GSK3036656.
5.
SELECTION OF STUDY POPULATION AND 
WITHDRAWAL CRITERIA
Consent for screening evaluations may be obtained using the information and consent 
form for the HMR healthy volunteer panel, which has been approved by the Health 
Research Authority’s Generic Document Review Committee.  The trial-specific 
information and consent form will be signed by the subject either before any study-
specific screening evaluation or after the investigator confirms the eligibility of the 
subject for the trial and before the subject is randomised to receive the first administration 
of study drug.
Specific information regarding warnings, precautions, contraindications, adverse events, 
and other pertinent information on the GSK investigational product that may impact 
subject eligibility is provided in the GSK3036656 Investigator’s Brochure 
[GlaxoSmithKline Document Number 2016N305393_01].
Deviations from inclusion and exclusion criteria are not allowed because they can 
potentially jeopardize the scientific integrity of the study, regulatory acceptability or 
subject safety. Therefore, adherence to the criteria as specified in 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:
[1] AGE

Between 18 and 55 years of age inclusive, at the time of signing the informed 
consent.
[2] TYPE OF SUBJECT 

Healthy as determined by the investigator or medically qualified designee based on a 
medical evaluation including medical history, physical examination, laboratory tests 
and cardiac monitoring.

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.

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[3] WEIGHT

Body weight ≥60 kg and body mass index (BMI) within the range 19 to 29.9 kg/m2 
inclusive.
[4] SEX

Male

Female subjects of non-child bearing potential are eligible to participate. Non-child 
bearing potential is defined as: 
Pre-menopausal females with one of the following:

Documented tubal ligation

Documented hysteroscopic tubal occlusion procedure with follow-up
confirmation of bilateral tubal occlusion or documented bilateral 
salpingectomy

Hysterectomy

Documented Bilateral Oophorectomy
Postmenopausal defined as 12 months of spontaneous amenorrhea. Post-
menopausal status will be confirmed by a simultaneous FSH and 
estradiol levels test. 

Male subjects with female partners of child bearing potential must comply with the 
following contraception requirements from the time of first dose of study medication 
until 90 days after the last dose of study treatment (i.e. one sperm cycle).
Vasectomy with documentation of azoospermia.  
Male condom plus partner use of one of the contraceptive options below:

Contraceptive subdermal implant 

Intrauterine device or intrauterine system 

Highly effective oral contraceptive, either combined or progestogen alone 
(provided it’s associated with inhibition of ovulation)

Injectable progestogen 

Contraceptive vaginal ring 

Percutaneous contraceptive patches 

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 
(Appendix 3).

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[5] INFORMED CONSENT

The subject is able to understand and comply with protocol requirements, instructions 
and protocol-stated restrictions.
5.2.
Exclusion Criteria
A subject will not be eligible for inclusion in this study if any of the following criteria 
apply:
[1]  CONCURRENT CONDITIONS/MEDICAL HISTORY (INCLUDES LIVER 
FUNCTION AND QTc INTERVAL) 

Alanine aminotransferase (ALT) and bilirubin >1.5xupper limit of normal (ULN) 
(isolated bilirubin >1.5xULN may be acceptable, after consultation with the GSK 
Medical Monitor, if bilirubin is fractionated and direct bilirubin <35%). 

Current or chronic history of liver disease, or known hepatic or biliary abnormalities 
(with the exception of Gilbert's syndrome or asymptomatic gallstones).

QTcF >450 msec. 

Presence of moderate or severe valve disorder or any other clinically significant 
abnormality. 

Subjects with a history of photosensitivity.

Females of non-childbearing potential who are susceptible to heavy periods or 
vaginal bleeding or spotting.

Pregnant females. A human chorionic gonadotrophin (hCG) test will be performed 
on Day-1 of each treatment (dosing) period in Part A and Part B for women for 
whom post-menopausal status has not been confirmed by follicle stimulating 
hormone (FSH)/estradiol testing. No pregnancy tests will be required for female 
subjects confirmed as post-menopausal by FSH/estradiol testing.

Lactating females.
[2] CONCOMITANT MEDICATIONS

Use of prescription or non-prescription drugs, including high-dose vitamins, herbal 
and dietary supplements (including St John’s Wort) within 7 days (or 14 days if the 
drug is a potential enzyme inducer) or 5 half-lives (whichever is longer) prior to the 
first dose of study medication, unless in the opinion of the Investigator and sponsor 
the medication will not interfere with the study procedures or compromise subject 
safety. Paracetamol for mild analgesia will be permitted.

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[3] RELEVANT HABITS

Breath carbon monoxide test indicative of smoking or history of current use of 
tobacco- or nicotine-containing products.

Current regular alcohol consumption defined as: 

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. 

Subjects must not sunbathe or use a tanning device (e.g. sunbed or solarium) whilst 
taking the study medication and until at least 2 weeks after their last dose. Subjects 
are to be advised that they should wear protective clothing (e.g. sun hat, long sleeves) 
and use a broad spectrum UVA/UVB sunscreen (SPF ≥30) when outdoors.
[4]  CONTRAINDICATIONS 

History of sensitivity to heparin or heparin-induced thrombocytopenia.

History of sensitivity to any of the study medications, or components thereof or a 
history of drug or other allergy that, in the opinion of the investigator or Medical 
Monitor, contraindicates their participation.
[5] DIAGNOSTIC ASSESSMENTS AND OTHER CRITERIA

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. 

A positive test for HIV antibody.

A positive pre-study drug/alcohol screen.

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: 3 months, 5 half-lives or twice the duration of the biological effect of the 
investigational product (whichever is longer).

Exposure to more than four new chemical entities within 12 months prior to the first 
dosing 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 randomized. 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.
5.4.
Individual 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:

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
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”. 
A subject may withdraw from study treatment at any time at his/her own request, or may 
be withdrawn at any time at the discretion of the investigator for safety, behavioural or 
administrative reasons. 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. 
5.4.1.
Liver Chemistry Stopping Criteria
Study treatment will be discontinued for a subject if liver chemistry stopping criteria are 
met:
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*
Liver Safety Required Actions and Follow up Assessments Section can be found in 
Appendix 4.

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5.4.1.1.
Study Treatment Restart or Rechallenge
Study treatment restart or rechallenge after liver chemistry stopping criteria are met by 
any subject participating in this study is not allowed.
5.4.2.
QTc Stopping Criteria
A subject that meets either bulleted criterion below will be withdrawn from the study.  

QTcF >500 msec,

Change from baseline: increase in QTcF >60 msec
Withdrawal of subjects is to be based on an average QTcF value of triplicate ECGs. If an 
ECG demonstrates a prolonged QT interval, obtain two more ECGs over a brief period of 
time and then use the averaged QTcF values of the three ECGs to determine whether the 
subject should be discontinued from the study.
5.4.3.
Haematology Stopping Criteria
Study treatment will be discontinued for a subject if the following haematology stopping 
criteria are met and subjects should be followed up until values are not clinically 
significant.

A reduction in haemoglobin to below 110 g/L in males and below 100 g/L in 
females

A reduction in neutrophil count to below 1000/mm3 (1.0x109/L)

A reduction in lymphocyte count to below 500/mm3 (0.5x109/L)
5.4.4.
Vital Signs Stopping Criteria
Study treatment will be discontinued for a subject if the following vital signs stopping 
criteria are met: 

Clinically significant and sustained increase in resting heart rate (for example, 
>120 beats/minute for more than 2 hours)

Clinically significant and sustained  change in blood pressure (for example, 
systolic blood pressure >150 mm Hg or <85 mm Hg for more than 2 hours, or 
diastolic blood pressure >95 mm Hg for more than 2 hours)
5.4.5.
Other Dose Adjustment/Stopping Safety Criteria
For an individual study participant, stopping criteria include, but are not limited to:

Severe signs or symptoms, or significant changes in any of the safety 
assessments that put the safety of the individual at risk (e.g. ECG, vital signs, 

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laboratory tests etc), as judged by the Principal Investigator, in consultation with 
the Medical Monitor if necessary.
Any unacceptable adverse event that is thought to be related to the investigational 
product and any general safety finding that, in the opinion of the Investigator, gives cause 
for concern may result in the withdrawal of subject(s) and/or the study being paused or 
terminated and/or a dose adjustment.
5.5.
Dose Escalation Stopping Criteria
Dose escalation in Part A or Part B will be stopped if any of the following occurs in a 
group/cohort:
1.
There is substantially increased incidence and/or severity of clinically significant 
adverse events or withdrawals possibly related to GSK3036656 in the active 
treatment subgroup at the last dose level administered as compared to the placebo 
subgroup. The GSK Study Team in conjunction with the study investigator will 
determine the significance of the adverse events or withdrawals and make a 
decision about whether stopping further dose escalation is necessary. 
2.
At least one subject has a plasma AUC (0-24) higher than 4.9 µg.h/mL or a plasma 
Cmax higher than 0.443 µg/mL on any day.
3.
For Part A, no meaningful increase in exposure is observed with increase in dose 
(i.e., a plateau in exposures is reached).
Note: If dose escalation is stopped due to reasons 1 or 2 above occurring at the last 
dose, dosing at a lower level (e.g., an intermediate level between the last dose and a 
previous dose where dose escalation stopping criteria were not met) could be 
allowed. The GSK Study Team in conjunction with the study investigator will 
decide whether dosing at such level could be done and will select the dose to be 
administered.
5.6.
Trial stopping criteria
The trial will be stopped if either of the following occurs:

A serious adverse event that is considered to be at least possibly related to 
GSK3036656 in one or more subjects on active treatment

Severe, clinically significant non-serious adverse events that are considered 
to be at least possibly related to GSK3036656 in 2 or more subjects on 
active treatment in the same group/cohort
If, following an internal safety review, it is appropriate to restart the trial, a substantial 
amendment will be submitted to the Medicines and Healthcare products Regulatory 
Agency (MHRA) and Independent Ethics Committee (IEC). The trial will not restart until 
the amendment has been approved by the MHRA and IEC.

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5.7.
Subject and Study Completion
A completed subject is one who has completed all phases of the study including the 
follow-up visit.
The end of the study is defined as the last subject’s last visit.
6.
STUDY TREATMENT
6.1.
Investigational Product
The term ‘study treatment’ is used throughout the protocol to describe products received 
by the subject as per the protocol design. 
Study Treatment
Product name:
GSK3036656
Placebo
Formulation description:
GSK3036656 capsules 
containing 5 mg, 25 mg or 
100 mg of GSK3036656 as 
free base equivalent 
Matching capsule 
containing Avicel PH 102
Dosage form:
Capsule
Capsule
Unit dose strength(s)/Dosage 
level(s):
5 mg, 25 mg and 100 mg 
N/A
Route of Administration
Oral
Oral
Dosing instructions:
See Study Reference Manual 
See Study Reference 
Manual 
Physical description:
Swedish Orange Size 0 
capsule with no identifying 
markings containing a white to 
slightly coloured powder
Swedish Orange Size 0 
capsule with no identifying 
markings containing a white 
to slightly coloured powder
Method for individualizing 
dosage:
Capsules packed in separate 
HDPE bottles
Capsules packed in 
separate HDPE bottles
6.2.
Treatment Assignment
Eligible subjects will receive a unique subject number which will be assigned in 
chronological order. Once a subject number has been assigned to a subject, it cannot be 
reassigned to another subject.
A randomisation schedule will be generated by Clinical Statistics, prior to the start of the 
study, using validated internal software, which will assign subjects to GSK3036656 or 
placebo during a specific period. The pharmacist would be sent a copy of the 
randomisation schedule by the GSK randomisation co-ordinator, together with 
instructions as to which subjects to dose on Days 1 and 2 in the case of sentinel dosing. 
The pharmacist will assign randomisation numbers accordingly and communicate those 
back to the site to enter in the case report form (CRF). 

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6.3.
Planned Dose Escalation and Adjustments
After the initial dose of GSK3036656, the decision to proceed to each subsequent dose 
level will be made by the Dose Escalation Committee (DEC) based on safety, tolerability 
and preliminary pharmacokinetic data from the prior lower dose level (Further details 
regarding dose escalation can be found in the 201040 Dose Escalation Charter). In Part 
A, safety data for at least 5 days post-dose and PK data for at least 2 days (48 hours) 
postdose from at least 4 subjects who received active treatment at the prior lower dose 
level will be reviewed before dose escalation. In Part B, safety data for at least the first 1 
week (7 days) of dosing and PK data for at least the first 2 days (48 hours) of dosing from 
at least 4 subjects who received active treatment at the prior lower dose level will be 
reviewed before dose escalation. The actual doses to be administered will be selected by 
the DEC and may involve either an increase or a decrease in the dose, or repeating the 
same dose.
The exposures (AUC, Cmax) expected with the next selected dose will be predicted by 
pharmacokinetic assessment and modelling, and by calculating Bayesian predictive 
probabilities as data permit (more details in Section 10.3.1).
In toxicology studies in dogs, heart valvular and vascular lesions have been observed at 
relatively high doses and exposures; no such lesions have been seen in rats at similar 
exposures. To avoid the risk of this adverse event in the FTIH subjects, exposures in the 
FTIH study will be limited to predefined levels. Based on discussions with the GSK 
Cardiovascular Safety panel, the study will aim to limit the maximum individual daily 
plasma AUC(0-24) and Cmax after single or repeat dose to 4.9 µg.h/mL and 0.443 µg/ml, 
respectively - a 30-fold margin from the corresponding dog NOAEL exposures of 147.0 
µg.h/mL and 13.3 µg/ml at which no valvular or vascular lesions have been detected.
Note: The term “mean” applied to group human exposure parameters (e.g., AUC) in this 
section refers to Geometric Mean of a dose cohort.
6.3.1.
Dose escalation in Part A
In Part A, bigger dose escalation steps may be allowed at lower doses and systemic 
exposures as the expected risk of adverse events at these exposures is low. At higher 
doses, smaller dose escalation steps will be used to minimize the risk of adverse events 
and gastrointestinal intolerance.
The following rules will guide dose selection in Part A:
1. No dose escalation to the next dose will be higher than 6-fold.
2. Once the dose is ≥300 mg, any further dose escalation will be no higher than 3-
fold irrespective of the observed exposures.
3. The highest dose in Part A will not exceed 1500 mg. 
4. A proposed dose will be acceptable if the predicted probability of an individual 
exceeding a Day 1 plasma AUC (0-24) of 4.9 μg.h/mL or Cmax of 0.443 μg/mL, 
as estimated by PK modeling and Bayesian analysis (if feasible), is no more than 
10%.

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5. Based on prior PK data, individual doses may be adjusted, if needed, such that a 
predicted individual Day 1 AUC (0-24) or Cmax does not exceed 4.9 μg.h/mL or 
0.443 μg/mL, respectively.
Dosing with food in Part A will be initiated after the exposures achieved with at least two 
dose levels administered in a fasted state are already known.  
6.3.2.
Dose escalation in Part B
Part B may be initiated after the safety and PK data of at least three doses from Part A are 
already known. The decision to initiate Part B will be made by the GSK Study team in 
conjunction with the investigator. 
The following rules will guide dose selection in Part B:
1.
The starting daily dose in Part B will be selected such that its expected exposure 
(mean AUC[0-24] or Cmax) on the last day of dosing is no higher than the Day 1 
exposure of a dose that has been found to be safe and well tolerated in Part A. The 
expected daily exposures during the dosing period, including on the last day of 
dosing, will be predicted based on the PK parameters for GSK3036656 established 
in Part A. As the highest exposure with repeat dosing is expected on the last day of 
dosing (as a result of accumulation), this approach would select a daily dose which 
provides systemic concentrations that, at any time during the period of dosing, are 
not likely to be higher than the ones already found to be safe and well tolerated in 
Part A. 
2.
Subsequent doses in Part B may be selected using the criteria described above for 
the starting dose in Part B. The expected daily exposures during the dosing period, 
including on the last day of dosing, will be predicted based on available PK data 
from Part A and from prior cohorts in Part B. Alternatively, a dose may also be 
selected even if it does not meet these criteria provided it is no more than 4-fold 
higher than a previous dose that has been found to be safe and well tolerated upon 
repeat dosing in Part B.
3.
The highest daily dose in Part B will not exceed the highest single dose that has 
been found to be safe and well tolerated in Part A. 
4.
A proposed dose will be acceptable if the predicted probability of an individual 
exceeding a daily plasma AUC (0-24) of 4.9 μg.h/mL or Cmax of 0.443 μg/mL on 
any day of the dosing period, as estimated by PK modeling and Bayesian analysis 
(if feasible), is no more than 10%.
6.4.
Blinding
This will be a double blind (sponsor unblind) study where neither the study subjects nor 
the investigator are aware of the treatment received. The following will apply. 

The investigator or treating physician may unblind a subject’s treatment assignment 
only in the case of an emergency OR in the event of a serious medical condition 
when knowledge of the study treatment is essential for the appropriate clinical 
management or welfare of the subject as judged by the investigator. 

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
Investigators have direct access to the subject’s individual study treatment. 

It is preferred (but not required) that the investigator first contacts the Medical 
Monitor or appropriate GSK study personnel to discuss options before unblinding 
the subject’s treatment assignment. 

If GSK personnel are not contacted before the unblinding, the investigator must 
notify GSK as soon as possible after unblinding. The date and reason for the 
unblinding must be fully documented in the CRF.
If a subject’s treatment is unblinded, subjects may continue in the study at the discretion 
of the sponsor. The primary reason for unblinding (the event or condition which led to the 
unblinding) will be recorded in the CRF.

GSK’s Global Clinical Safety and Pharmacovigilance (GCSP) staff may unblind the 
treatment assignment for any subject with an SAE. If the SAE requires that an 
expedited regulatory report be sent to one or more regulatory agencies, a copy of the 
report, identifying the subject’s treatment assignment, may be sent to investigators in 
accordance with local regulations and/or GSK policy.
6.5.
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 GSK3036656 will 
be detailed in a Study Specific Technical Agreement/Memo (TTS).

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.

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 study 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 
participant identification will be confirmed at the time of dosing by a member of the 
study site staff other than the person administering the study treatment.
6.8.
Treatment of Study Treatment Overdose
For this study, any dose of GSK3036656 greater than the dose specified for that treatment 
(dosing) period will be considered an overdose.
GSK does not recommend specific treatment for an overdose. The investigator or 
physician in charge of the subject at the time will use clinical judgment to treat any 
overdose.
In the event of an overdose the investigator or treating physician should:

contact the Medical Monitor immediately.

closely monitor the subject for adverse events (AEs)/serious adverse events 
(SAEs) and laboratory abnormalities for at least 30 days.

obtain a plasma sample for pharmacokinetic (PK) analysis, if requested by the 
Medical Monitor, within 2 days of that request (determined on a case-by-case 
basis).

document the quantity of the excess dose as well as the duration of the overdosing 
in the CRF.
In case of an overdose, 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 only healthy volunteers are eligible for study participation.
6.10.
Concomitant Medications and Non-Drug Therapies
6.10.1.
Permitted Medications and Non-Drug Therapies
Paracetamol at doses of 2 grams/day is permitted. Other concomitant medication may 
be considered on a case by case basis by the investigator in consultation with the GSK 
Medical Monitor.

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6.10.2.
Prohibited Medications and Non-Drug Therapies
Subjects must abstain from taking prescription or non-prescription drugs (including 
vitamins and dietary or herbal supplements), within 7 days (or 14 days if the drug is a 
potential enzyme inducer) or 5 half-lives (whichever is longer) 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.
7.
STUDY ASSESSMENTS AND PROCEDURES
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
The following points must be noted: 

If assessments are scheduled for the same nominal time, THEN the assessments 
should occur in the following order:
1. 12-lead ECG and vital signs
2. 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 and PK 
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. 

Part B outpatient visits: If subjects are discharged on Day 4, they will be 
required to return to the unit daily for dosing and assessments. Safety 
assessments will include daily vital signs, AE and concomitant medication 
review and laboratory assessments on days 6, 10 and 15.

The IEC and MHRA will be informed of any safety issues that require a 
protocol amendment 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 & Events Table
Table 1
Part A
Days
–1
1
2
3
4
15
Informed consent
X
Inclusion/exclusion criteria1
X
X
Medical/surgical history
X
X
Admission
X
Inpatient stay
Dose of GSK30366562
X
Echocardiogram3
X
X
Discharge
X
X
Outpatient visit4
X
X
X
Safety assessments
Physical examination5
X
X
X
X
X
Height & weight5
X
Vital signs6
X
X
X
X
X
X
X
12-lead ECG7
X
X
X
X
X
X
Holter monitoring8
Telemetry9
Clinical laboratory assessments
Screening tests (incl blood FSH & 
estradiol for female subjects only)
X
Haematology, biochemistry and 
urinalysis10
X
X
X
X
X
Pregnancy test (female only)11
X
X
Urine drug screen, alcohol & 
smoking breath tests
X
X
PK samples
Blood for PK GSK303665612
X
X
X
X
Total urine collection13
X
X
X
X
Concomitant therapy review14
Adverse events14
Part A
Follow-
up
-28 to -2
Screening
Day
1.
Inclusion/exclusion criteria will only be assessed at Day-1 of the first period.
2.
In the event of a divided dose, alterations to event timepoints may be communicated in a filenote. 
For the food effect assessment, the selected dose will be given with a high fat meal.
3.
Echocardiograms may be done at a separate screening visit.
4.
When there is Holter monitoring at screening, subjects will return after 24 h to have the Holter 
removed.
5.
Brief physical examination will be done at admission (Day–1) and in the morning on Days 2 and 4 
in each treatment session. Full physical examination will be done at screening and follow-up (to 
include height and weight at screening only).
6.
Blood pressure, heart rate, tympanic temperature and respiratory rate. Vital signs will be recorded:  
at pre-dose and at 0.5, 1, 2, 3, 4, 6, 12, 24, 48 and 72 h after dosing on Day 1.

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7.
ECGs will be recorded at pre-dose and at 0.5, 1, 2, 3, 4, 6, 12, 24, 48 and 72 h after dosing on 
Day 1. Triplicate measurements (about 2-5 mins apart) will be taken at pre-dose; single 
measurements will be taken at all other time points.
8.
24 h Holter monitoring at screening only.
9.
Telemetry will be recorded from -1 h pre-dose until 24 h post-dose
10. Haematology, clinical chemistry, and urinalysis will be done at Day-1 and at 24 and 72 h post-
dose.
11. Pregnancy testing of female subjects only. At screening pregnancy test will be done using the 
blood sample; urine pregnancy test will be done on admission.
12. Blood samples for assay of GSK3036656 will be taken:  at pre-dose and at 0.25, 0.5, 0.75, 1, 1.5, 
2, 3, 4, 6, 8, 12, 15, 24, 36, 48 and 72 h after dosing on Day 1. 
13. Total urine collections for GSK3036656 will be performed at the following time points:  pre-dose 
and 0-6, 6-12, 12-24, 24-48 and 48-72 h after dosing on Day 1.
14. AEs and concomitant medications will be recorded collected from the start of informed consent 
until the follow-up contact.

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Table 2
Part B
Days
–1
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
28
Informed consent
X
Inclusion/exclusion criteria
X
X
Medical/surgical history
X
X
Admission
X
Inpatient stay
Dose of GSK30366561
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Echocardiogram2
X
X
Discharge
X
X
Outpatient visit3
X
X
X
X
X
Safety assessments
Physical examination4
X
X
X
X
X
X
X
X
Height & weight4
X
Vital signs5
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
12-lead ECG6
X
X
X
X
X
X
X
X
X
Holter monitoring7
Telemetry8
Clinical laboratory assessments
Screening tests (incl blood FSH & 
estradiol for female subjects only)
X
Haematology, biochemistry and 
urinalysis9
X
X
X
X
X
X
X
Serum pregnancy test (female 
only)10
X
X
Urine drug screen, alcohol & 
smoking breath tests
X
X
PK samples
Blood for PK GSK303665611
X
X
X
X
X
X
X
X
X
X
Total urine collection12
X
X
X
X
Concomitant therapy review13
Adverse events13
Part B
Screening
Day
Follow-up
-28 to -2

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1.
Dosing of GSK3036656 should be at approximately the same time each day. In the event of a divided dose, alterations to event timepoints may be communicated in 
a filenote.
2.
Echocardiograms may be done at a separate screening visit.
3.
When there is Holter monitoring at screening, subjects will return after 24 h to have the Holter removed.
4.
Brief physical examination will be done on Days-1, 2, 4, 6, 10, and 15. Full physical examination will be done at screening and follow-up (to include height and 
weight at screening only).
5.
Blood pressure, heart rate, tympanic temperature and respiratory rate. Vital signs will be recorded:  at pre-dose and at 0.5, 1, 2, 3, 4, 6, 12, 24, 48 and 72 h after 
dosing on Days 1 and 14; and at pre-dose on Days 5-13.
6.
ECGs will be recorded at pre-dose and at 0.5, 1, 2, 3, 4, 6, 12, 24, 48 and 72 h after dosing on Days 1 and 14; and at pre-dose on Days 6 and 10. Triplicate 
measurements (about 2-5 mins apart) will be taken at pre-dose; single measurements will be taken at all other time points.
7.
24 h Holter monitoring at screening only.
8.
Telemetry will be recorded from -1 h pre-dose until 24 h post-dose on Day 1.
9.
Haematology, clinical chemistry and urinalysis will be done on Day-1 and in the morning (pre-dose if feasible) on Days, 4, 6, 10, and 15.
10. Pregnancy testing of female subjects only. At screening pregnancy test will be done using the blood sample; urine pregnancy test will be done on Day-1.
11. Blood samples for assay of GSK3036656 will be taken:  at pre-dose and at 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 12, 15, 24, 36, 48 and 72 h after dosing on Day 1; 
and at pre-dose and at 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 12, 15, 24, 36 48 and 72 h after dosing on Day 14. PK samples will also be taken pre-dose on Days 12 
and 13.
12. Total urine collections for GSK3036656 will be performed at the following time points: pre-dose and 0-6, 6-12 and 12-24 h after dosing on Days 1 and 14.
13. AEs and concomitant medications will be recorded collected from the start of informed consent until the follow-up contact.

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7.2.
Safety Assessments
Planned time points for all safety assessments are provided in the Time and Events table 
(Section 7.1). 
7.2.1.
Physical Examinations

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 (at screening only).

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.
7.2.2.
Vital Signs

Tympanic temperature, pulse rate, respiratory rate, and blood pressure will be 
assessed.

Blood pressure and pulse measurements will be assessed supine with a 
completely automated device. Manual techniques will be used only if an 
automated device is not available or in the case of an emergency.

Blood pressure and pulse measurements should be preceded by at least 5 
minutes of rest for the participant in a quiet setting without distractions (e.g., 
television, cell phones).

Pulse rate and blood pressure will be measured in triplicate at screening and pre-
dose. The readings should be averaged to give the measurement to be recorded 
in the CRF.
7.2.3.
Electrocardiograms

Triplicate 12-lead ECG will be obtained at screening and predose using an ECG 
machine that calculates the heart rate and measures PR, QRS, QT, and QTcF 
intervals. Refer to Section 5.4.2 for QTc withdrawal criteria and additional QTc 
readings that may be necessary.

At each time point at which triplicate ECG are required, three individual ECG 
tracings should be obtained as closely as possible in succession, but no more 
than 2 to 5 minutes apart. 
7.2.4.
Cardiac Telemetry

Continuous cardiac telemetry will be performed from approximately 1 hr pre-
dose to 24 hours post dosing in both Parts A and B. Full disclosures will be 
maintained as part of the participant’s source documents and will be reviewed in 
detail.
7.2.5.
Holter Monitoring

Holter monitoring will be performed in Parts A & B at screening for the duration 
of 24 hours.

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7.2.6.
Echocardiography

Echocardiography will be performed at screening and at follow-up in a blinded 
fashion. This assessment will be done only for subjects who have undergone all 
other screening assessments, have been found eligible for the study, and are 
willing to enrol into the study.
7.2.7.
Clinical Safety Laboratory Assessments

The tests will be performed by the local laboratory.

Additional tests may be performed at any time during the study as determined 
necessary by the investigator or required by local regulations.

The investigator must review the laboratory report, document this review, and 
record any clinically relevant changes occurring during the study in the AE 
section of the CRF. The laboratory reports must be filed with the source 
documents. Clinically significant abnormal laboratory findings are those which 
are not associated with an underlying disease, unless judged by the investigator 
to be more severe than expected for the participant's condition.

All laboratory tests with values considered clinically significantly abnormal 
during participation in the study or at follow-up should be repeated until the 
values return to normal or baseline or are no longer considered significantly 
abnormal by the investigator or medical monitor. 

If such values do not return to normal/baseline within a period of time judged 
reasonable by the investigator, the aetiology should be identified and the sponsor 
notified.

All protocol-required laboratory assessments must be conducted in accordance 
with the laboratory manual and the Time and Events table (Section 7.1).

If laboratory values from non-protocol specified laboratory assessments 
performed at the institution’s local laboratory require a change in participant 
management or are considered clinically significant by the investigator (e.g. 
SAE or AE or dose modification), then the results must be recorded in the CRF.
Table 3
Protocol Required Safety Laboratory Assessments
Laboratory 
Assessments
Parameters
Haematology
Platelet Count
RBC Indices:
WBC count with Differential:
RBC Count
MCV
Neutrophils
Hemoglobin
MCH
Lymphocytes
Hematocrit
Monocytes
Reticulocytes
Eosinophils
Basophils
Clinical 
Chemistry
BUN
Potassium
AST (SGOT)
Total and direct 
bilirubin

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Laboratory 
Assessments
Parameters
Creatinine
Sodium
ALT (SGPT)
Total Protein
Glucose 
Calcium
Alkaline phosphatise
Albumin
Cholesterol
Triglycerides
Cardiac troponin
Routine 
Urinalysis

Specific gravity

pH, glucose, protein, blood and ketones by dipstick

Microscopic examination (if blood or protein is abnormal)
Screening 
Tests

HIV

Hepatitis B (HBsAg)

Hepatitis C (Hep C antibody)

FSH and estradiol (as needed in women of non-child bearing 
potential only)

Pregnancy (hCG) – serum or urine

Urine drug screen (to include at minimum: amphetamines, 
barbiturates, cocaine, opiates, cannabinoids and benzodiazepines) 

Alcohol and smoking breath tests
NOTES :

Details of Liver Chemistry Stopping Criteria and Required Actions and Follow-
Up Assessments after liver stopping or monitoring event are given in Section 
5.4.1 and Appendix 4
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.
7.3.
Pharmacokinetics
7.3.1.
Blood Sample Collection
Blood samples for plasma PK analysis of GSK3036656 will be collected into K3 EDTA 
tubes at the time points indicated in the Time and Events Table (Section 7.1). The actual 
date and time of each blood sample collection will be recorded. In the repeat dose part of 
the study on days 12 and 13, PK samples will be taken pre-dose to assess the 
achievement of steady-state of GSK3036656 following repeat oral doses. On the last 
dosing day of the repeat dose, subjects will undergo the same assessments as on Day 1. 
Subjects may then be discharged but will be required to return for the 36, 48 and 72 hour 
PK sampling. PK samples obtained on pre-dose and 24 hours post-dose on day 14 will 
also be used as part of the assessment to see if steady-state has been achieved.
The timing of PK samples may be altered and/or PK samples may be obtained at 
additional time points to ensure thorough PK monitoring.
Details of PK blood sample collection (including volume to be collected), processing, 
storage and shipping procedures are provided in the SRM. 

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7.4.
Non-Pharmacokinetic Sample Collection and Processing
7.4.1.
Urine Sample Collection
Urine samples will be collected from each subject prior to dosing (the pre-dose sample 
can be collected up to 48 hours prior to dosing) and over the time period listed in the 
Time and Events Table to investigate any GSK3036656 related material excreted via this 
route. Details of urine sample collection, processing, storage and shipping procedures are 
provided in the Study Reference Manual (SRM).
7.4.2.
Sample Analysis
Plasma analysis will be performed under the control of Platform Technologies and 
Science (PTS), GlaxoSmithKline, the details of which will be included in the 
SRM. Concentrations of GSK3036656 will be determined in plasma samples using the 
currently approved bioanalytical methodology. Raw data will be archived at the 
bioanalytical site (detailed in the SRM).
Once the plasma has been analyzed for GSK3036656, any remaining plasma may be 
analyzed for other compound-related metabolites and the results reported under a 
separate PTS, GlaxoSmithKline protocol.
The urine samples may be analysed qualitatively and quantitatively for compound-related 
material and the results will be reported under a separate PTS, GlaxoSmithKline protocol.

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8.
SAFETY
Planned time points for all safety assessments are listed in the Time and Events Table 
(Section 7.1).  Additional time points for safety tests may be added during the course of 
the study based on newly available data to ensure appropriate safety monitoring.
8.1.
Adverse Events (AE) and Serious Adverse Events (SAEs)
The definitions of an AE or SAE can be found in Appendix 2.
The investigator and their designees are responsible for detecting, documenting and 
reporting events that meet the definition of an AE or SAE. 
8.1.1.
Time period and Frequency for collecting AE and SAE 
information

AEs and SAEs will be collected from the start of informed consent until the follow-
up contact, at the time points specified in the Time and Events Table (Section 7.1).

AEs and SAEs collected before the start of study treatment will be recorded as pre-
treatment AEs/SAEs.

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 the sponsor or designee immediately 
and under no circumstances should this exceed 24 hours, as indicated in 
Appendix 2. The investigator will submit any updated SAE data to the sponsor 
within 24 hours of it being available.

Investigators are not obligated to actively seek AEs or SAEs in former study 
subjects. However, if the investigator learns of any SAE, including a death, at any 
time after a subject has been discharged from the study, and he/she considers the 
event reasonably related to the study treatment or study participation, the investigator 
must promptly notify GSK.
NOTE: The method of recording, evaluating and assessing causality of AEs and SAEs 
plus procedures for completing and transmitting SAE reports to GSK are provided in 
Appendix 2.
8.1.2.
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?”

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
“Have you taken any new medicines, other than those provided in this study, since 
your last visit/contact?”
8.1.3.
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 
will be followed until resolution, until the condition stabilizes, until the event is otherwise 
explained, or until the subject is lost to follow-up. Further information on follow-up 
procedures is given in Appendix 2.
8.1.4.
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, 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 IEC, if appropriate according to local requirements.
9.
DATA MANAGEMENT

For this study data will be double-entered into a clinical database management system 
(ClinPlus Version 3.3).

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 Medical 
Dictionary for Regulatory Activities (MedDRA) and an internal validated medication 
dictionary, GSKDrug by GSK.
Original CRFs will be retained by GSK, while the investigator will retain a copy. Subject 
initials will not be collected or transmitted to GSK according to GSK policy.

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10.
DATA ANALYSIS AND STATISTICAL CONSIDERATIONS
10.1.
Hypothesis and Treatment Comparisons
Given this is the first time in human trial for GSK3036656, no formal statistical 
hypotheses are to be tested. Where appropriate, an estimation approach will be taken, and 
point estimates and confidence intervals (CIs) will be constructed.
10.2.
Sample Size Considerations
The planned sample size is 18 subjects for Part A of this study (9 subjects per cohort) and 
up to 40 subjects for Part B (10 subjects per cohort). Additional subjects may be recruited 
as replacement for withdrawn subjects.
No statistical techniques were used to calculate the sample size, and because this is a 
FTIH study, no information on PK variability is available to allow any precision estimate.
10.2.1.
Sample Size Re-estimation
No sample size re-estimation is currently planned for this study. 
10.3.
Data analysis Considerations
Statistical analyses will be performed by, or under the direct auspices of, Statistics, 
Programming and Data Sciences (SPDS), GlaxoSmithKline.
Complete details of the planned statistical analyses will be provided in the RAP.
10.3.1.
Interim Analysis
No formal interim analyses are planned for this study. However, safety, tolerability, and 
pharmacokinetic data will be reviewed before each dose escalation in Part A (single dose) 
and Part B (repeat dose), and prior to the investigation of the food effect.
The relationship between dose and plasma GSK3036656 exposure, and associated 
variability will be characterized by a power model once data are available from 3 dose 
levels. Prior to that, prediction of the human exposure at the next dose will be based on 
population PK modelling (if feasible) or on the assumption of dose–exposure 
proportionality (i.e., doubling the dose gives an approximate doubling of exposure). If 
prior PK results show less than proportional increase in exposure with increasing dose, 
the prediction will be based on the assumption that the fold exposure increase to fold 
dose increase ratio will be the same with the current dose escalation as it was with the 
previous one. If prior PK results show more than proportional increase in exposure with 
dose, subsequent dose escalations will not be higher than 3-fold. The power model will 
be updated as data become available throughout the study. During dose escalation, and 
once data is available from 3 doses, a Bayesian predictive probability that an individual 
will have  AUC(0-24) greater than 4.9 µg.h/mL or a Cmax greater than 0.443 µg/mL, 

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will be calculated for the next dose level and used together with safety and tolerability 
data to aid the next dose selection.
The Bayesian predictive probability will be based on Whitehead’s model [Whitehead, 
2001]:
log(yij) = 1 + 2· log(dij) + ij      
where

yij is the observed or predicted log-AUC variable (AUC[0-24]) or log-Cmax of the j-th dose dij
administered to the i-th subject 

1, 2  are population intercept and slope, respectively.

ij  is a random error term, with mean zero and variance σ2.
10.3.2.
Final analyses
10.3.2.1.
Safety Analyses
Safety data will be presented in tabular and/or graphical format and summarized 
descriptively according to GSK’s Integrated Data Standards Library (IDSL) standards.
10.3.2.2.
Pharmacokinetic Analyses
Pharmacokinetic analysis will be the responsibility of the Clinical Pharmacology 
Modeling and Simulation Department, (CPMS), GlaxoSmithKline. Plasma GSK3036656 
concentration-time data will be analyzed by non-compartmental methods with 
WinNonlin 5.2 or higher.  Calculations will be based on the actual sampling times 
recorded during the study.  
From the plasma concentration-time data, the following pharmacokinetic parameters will 
be determined, as data permit: 

maximum observed blood concentration (Cmax), 

time to Cmax (tmax), 

area under the plasma concentration-time curve [AUC(0-t), AUC(0-∞) and 
AUC(0-τ)], 

apparent terminal phase half-life (t1/2)

trough concentration (C).
AUC(0-∞) or AUC(0-τ) and Cmax following single and repeat doses may be used for 
assessment of dose proportionality. Trough concentration (C) samples collected on the 
specified days will be used to assess attainment of steady state and the steady state ratio 
(Rss) will be calculated (Day 14 AUC(0-τ)/Day 1 AUC(0-∞)). To estimate the extent of 

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accumulation after repeat dosing, the observed accumulation ratio (Ro: Day 14 AUC(0-
)/Day 1 AUC(0-); and RCmax: Day 28 Cmax/Day 1 Cmax) will be determined.
From the urine concentration data, the following pharmacokinetic parameters will be 
determined, as data permit: urinary excretion of unchanged drug (Ae), fraction of the 
dose excreted in the urine (fe), and the renal clearance (CLr).
Pharmacokinetic data will be presented in graphical and/or tabular form and will be 
summarized descriptively. 
Statistical analyses of the pharmacokinetic parameter data will be the responsibility of 
SPDS, GlaxoSmithKline. Distributional assumptions underlying the statistical analyses 
will be assessed by visual inspection of residual plots. Normality will be examined by 
normal probability plots, while homogeneity of variance will be assessed by plotting the 
residuals against the predicted values for the model. Alternative analyses of the data will 
be performed if any of the model assumptions appear to be violated. Full details on the 
statistical aspects will be detailed in the Reporting and Analysis Plan (RAP).
Dose Proportionality (Single and Repeat Dose Study Phases)
Dose proportionality will be assessed following single doses of GSK3036656 (Part A) via 
analyses of AUC(0-t), AUC(0-∞), and Cmax. Dose proportionality following repeated 
dosing (Part B) will be assessed using AUC(0-τ) and Cmax.
A statistical analysis will be performed using the power model. The analysis will be 
performed on loge-transformed data. For each of these parameters a mixed effects model 
will be fitted with loge (dose) as a fixed effect and individual subject fitted as random 
effects. Estimates of the mean slopes of loge (dose) will be reported along with 
corresponding 90% confidence intervals (slope≈1 implies dose proportionality).
Food Effect (Single Dose Study)
The effect of food on the pharmacokinetics of GSK3036656 will be examined. AUC(0-t), 
AUC(0-∞), Cmax, and t1/2 of GSK3036656 will be analysed after a loge-transformation 
of the data. An analysis of variance model will be fitted along with 90% confidence 
intervals using a mixed effects model, with fed/fasted condition as a fixed effect and 
subject as a random effect. Point estimates and corresponding 90% confidence intervals 
will be constructed for the comparisons of interest of GSK3036656 fed – GSK3036656 
fasted, using the residual variance. These will then be back-transformed to provide point 
estimates and corresponding 90% confidence intervals for the geometric mean ratios 
fed:fasted.
Tmax will be analyzed non-parametrically using a Wilcoxon matched pairs test to 
compute the point estimate and 90% confidence interval for the median difference (fed –
fasted).

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Accumulation (Repeat Dose Study Phase)
The extent of accumulation of GSK3036656 will be based on AUC (Ro) and Cmax 
(RCmax). 
The focus of the statistical analysis will be to estimate the accumulation ratio, Ro, on the 
pharmacokinetics of GSK3036656. Following loge-transformation, AUC(0-) on Day 14 
and AUC(0-) on Day 1 will be analysed by a mixed effect model, fitting fixed effect 
terms for dose, day, and day by dose interaction, and fitting subject as a random effect. 
For each dose, point estimates and 90% confidence intervals for the differences “Day 14-
Day 1” will be constructed using the appropriate error term. The point estimates and 
associated 90% confidence intervals will then be exponentially back-transformed to 
provide point and 90% confidence interval estimates for the ratios “Day 14: Day 1” for 
each active dose.  If both the dose and day by dose interaction terms are not significant, a 
single point estimate and confidence interval pooled across all doses will also be 
constructed.
Similarly, the accumulation ratio, RCmax will be estimated, using Cmax calculated on 
Day 14 and on Day 1. The analysis will be analogous to that described above for the 
estimation of Ro, replacing AUC by Cmax. 
Time Invariance
The time invariance ratio will be calculated as the ratio of AUC(0-) on Day 14 over 
AUC(0-inf) on Day 1. The time invariance ratio will be listed and summarized along with 
other PK parameters. An analysis of variance (ANOVA) with subject as a random effect 
and day as a fixed, categorical effect will be conducted by dose on the log-transformed 
AUC. The time invariance of GSK3036656 will be assessed by calculating the ratio of 
the generalized least square means of AUC(0-) on Day 14 to AUC(0-inf) on Day 1, 
along with the corresponding 90% CI at each dose level. AUC(0-inf) on Day 1 will be the 
reference phase in the analysis, while AUC(0-) on Day 14 will be the test phase.
Achievement of Steady State (Repeat Dose Study Phase)
Trough concentration levels, Cτ, collected pre-morning dose will be plotted by collection 
day and dose.
To evaluate whether steady state was achieved, statistical analysis of Cwill be 
performed after a log-transformation of the dose data.  A mixed effect model will be 
fitted with dose, day and dose-by-day interaction as fixed effects (with dose as a factor 
and day as a continuous covariate) and subject as a random effect.  The coefficients of the 
slopes for the day effect for each dose, along with corresponding 90% confidence 
intervals, will be used to determine whether steady state was achieved. If the day-by-dose 
interaction were not significant, then the point estimates and 95% CIs for the individual 
dose levels will also be pooled across all doses for a single D14/D1 ratio. 

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10.3.3.
Non-Pharmacokinetic Sample Analysis
Aliquots of any remaining plasma and urine will be transferred to a separate protocol for 
metabolite profiling investigations. The results of these investigations will be reported 
separately.
11.
STUDY GOVERNANCE CONSIDERATIONS
11.1.
Regulatory and Ethical Considerations

This study will be conducted in accordance with the protocol and with:

Consensus ethical principles derived from international guidelines 
including the Declaration of Helsinki and Council for International 
Organizations of Medical Sciences (CIOMS) International Ethical 
Guidelines

Applicable ICH Good Clinical Practice (GCP) Guidelines

Applicable laws and regulations

The protocol, protocol amendments, informed consent form (ICF), Investigator 
Brochure, and other relevant documents (e.g. advertisements) must be submitted 
to an IEC by the investigator and reviewed and approved by the IEC before the 
study is initiated. 

Any amendments to the protocol will require IEC approval before 
implementation of changes made to the study design, except for changes 
necessary to eliminate an immediate hazard to study participants. 

The investigator will be responsible for the following:

Providing written summaries of the status of the study to the IEC annually 
or more frequently in accordance with the requirements, policies, and 
procedures established by the IEC

Notifying the IEC of SAE or other significant safety findings as required 
by IEC procedures

Providing oversight of the conduct of the study at the site and adherence to 
requirements of 21 Code of Federal Regulations (CFR), ICH guidelines, 
the IEC, European regulation 536/2014 for clinical studies (if applicable), 
and all other applicable local regulations
11.2.
Financial Disclosure
Investigators and sub-investigators will provide the sponsor with sufficient, accurate 
financial information as requested to allow the sponsor to submit complete and accurate 
financial certification or disclosure statements to the appropriate regulatory authorities. 
Investigators are responsible for providing information on financial interests during the 
course of the study and for 1 year after completion of the study.

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11.3.
Informed Consent Process

The investigator or his/her representative will explain the nature of the study to 
the participant or his/her legally authorized representative and answer all 
questions regarding the study. 

Participants must be informed that their participation is voluntary. Participants 
or their legally authorized representative will be required to sign a statement of 
informed consent that meets the requirements of 21 CFR 50, local regulations, 
ICH guidelines, Health Insurance Portability and Accountability Act (HIPAA) 
requirements, where applicable, and the IEC or study center. 

The medical record must include a statement that written informed consent was 
obtained before the participant was enrolled in the study and the date the written 
consent was obtained. The authorized person obtaining the informed consent 
must also sign the ICF.

Participants must be re-consented to the most current version of the ICF(s) 
during their participation in the study.

A copy of the ICF(s) must be provided to the participant or the participant’s 
legally authorized representative. 

Participants who are rescreened are required to sign a new ICF.
11.4.
Data Protection

Participants will be assigned a unique identifier by the sponsor. Any participant 
records or datasets that are transferred to the sponsor will contain the identifier 
only; participant names or any information which would make the participant 
identifiable will not be transferred. 

The participant must be informed that his/her personal study-related data will be 
used by the sponsor in accordance with local data protection law. The level of 
disclosure must also be explained to the participant. 

The participant must be informed that his/her medical records may be examined 
by Clinical Quality Assurance auditors or other authorized personnel appointed 
by the sponsor, by appropriate IEC members, and by inspectors from regulatory 
authorities.
11.5.
Publication Policy

The results of this study may be published or presented at scientific meetings. If 
this is foreseen, the investigator agrees to submit all manuscripts or abstracts to 
the sponsor before submission. This allows the sponsor to protect proprietary 
information and to provide comments.

The sponsor will comply with the requirements for publication of study results. 
In accordance with standard editorial and ethical practice, the sponsor will 
generally support publication of multicenter studies only in their entirety and not 
as individual site data. In this case, a coordinating investigator will be 
designated by mutual agreement.

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
Authorship will be determined by mutual agreement and in line with 
International Committee of Medical Journal Editors authorship requirements.
11.6.
Dissemination of Clinical Study Data
11.6.1.
Data Quality Assurance

All participant data relating to the study will be recorded on printed or electronic 
CRF unless transmitted to the sponsor or designee electronically (e.g. laboratory 
data). The investigator is responsible for verifying that data entries are accurate 
and correct by physically or electronically signing the CRF. 

The investigator must maintain accurate documentation (source data) that 
supports the information entered in the CRF. 

The investigator must permit study-related monitoring, audits, IEC review, and
regulatory agency inspections and provide direct access to source data 
documents. 

The sponsor or designee is responsible for the data management of this study 
including quality checking of the data. 

Study monitors will perform ongoing source data verification to confirm that 
data entered into the CRF by authorized site personnel are accurate, complete, 
and verifiable from source documents; that the safety and rights of participants 
are being protected; and that the study is being conducted in accordance with the 
currently approved protocol and any other study agreements, ICH GCP, and all 
applicable regulatory requirements. 

Records and documents, including signed ICF, pertaining to the conduct of this 
study must be retained by the investigator for 25 years after study completion 
unless local regulations or institutional policies require a longer retention period. 
No records may be destroyed during the retention period without the written 
approval of the sponsor. No records may be transferred to another location or 
party without written notification to the sponsor. 
11.6.2.
Source Documents

Source documents provide evidence for the existence of the participant and 
substantiate the integrity of the data collected. Source documents are filed at the 
investigator’s site.

Data reported on the CRF that are transcribed from source documents must be 
consistent with the source documents or the discrepancies must be explained. 
The investigator may need to request previous medical records or transfer 
records, depending on the study. Also, current medical records must be 
available.

Definition of what constitutes source data can be found in Source Document 
Agreement (SDA).

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11.7.
Study and Site Closure
GSK or its designee reserves the right to close the study site or terminate the study at any 
time for any reason at the sole discretion of GSK. Study sites will be closed upon study 
completion. A study site is considered closed when all required documents and study 
supplies have been collected and a study-site closure visit has been performed.
The investigator may initiate study-site closure at any time, provided there is reasonable 
cause and sufficient notice is given in advance of the intended termination.
Reasons for the early closure of a study site by the sponsor or investigator may include 
but are not limited to:

Failure of the investigator to comply with the protocol, the requirements of the IEC 
or local health authorities, the sponsor's procedures, or GCP guidelines

Inadequate recruitment of participants by the investigator

Discontinuation of further study treatment development

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12.
REFERENCES
GlaxoSmithKline Document Number 2016N305393_01, GSK3036656 Investigator’s 
Brochure, dated 03-Jan-2017
GlaxoSmithKline Document Number 2014N202803_00, A double blind, placebo-
controlled first time in human study to evaluate the safety, tolerability and 
pharmacokinetics of single and repeat doses of GSK3036656 in healthy adult volunteers, 
dated 13-Jan-2017.
Whitehead J, Patterson S, Webber D, Francis S, Zhou Y. Easy-to-implement Bayesian 
methods for dose-escalation studies in healthy volunteers. Biostatistics. 2001 
Mar;2(1):47-61

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13.
APPENDICES
13.1.
Appendix 1: Abbreviations and Trademarks
Abbreviations
µg
Microgram
AE
Adverse Event
Ae
Excretion of unchanged drug
ALT
Alanine aminotransferase (SGPT)
ANOVA
Analysis of Variance
AST
Aspartate aminotransferase (SGOT)
AUC
Area under concentration-time curve
AUC(0-)
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-)
Area under the concentration-time curve from time zero (pre-dose) during 
a dosage interval
AUC(Ro)
Observed Accumulation Ratio for AUC observed accumulation ratio for 
AUC
AUC[0-24]
Area under the concentration-time curve from time zero (pre-dose) to 24 
hours post dose
BMI
Body mass index
BUN
Blood urea nitrogen
CI
Confidence Interval
CIOMS
Council for International Organizations of Medical Sciences
CL
Clearance
CLr
Renal Clearance
Cmax
Maximum observed concentration 
CONSORT
Consolidated Standards of Reporting Trials
CPK
Creatine phosphokinase
CPMS
Clinical Pharmacology Modelling and Simulation
CPSSO
Clinical Pharmacology Sciences and Study Operations
CRF
Case Report Form
Cτ CτCτ Cτ
Trough Concentration (Cτ) Trough concentration (Cτ) Trough 
concentration (Cτ) Trough concentration (Cτ)
DEC
Dose Escalation Committee
DRF
Dose Range Finding
DS-TB
Drug-Sensitive-Tuberculosis
ECG
Electrocardiogram
EDTA
Ethylenediaminetetraacetic acid
FDA
Food and Drug Administration
fe
Fraction of the dose excreted in urine
FRP
Females of Reproductive Potential
FSH
Follicle Stimulating Hormone
FTIH
First Time In Human

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GCP
Good Clinical Practice
GCSP
Global Clinical Safety and Pharmacovigilance
GFR
Glomerular Filtration Rate
GLP
Good Laboratory Practice
GSK
GlaxoSmithKline
h
Hour
HBsAg
Hepatitis B surface antigen
hCG
Human Chorionic Gonadotrophin
HED
Human Equivalent Dose
Hep B
Hepatitis B
Hep C
Hepatitis C
Hg
Mercury
Hgb
Haemoglobin
HIV
Human Immunodeficiency Virus
HMR
Hammersmith Medicines Research
HPLC
High Performance Liquid Chromatography
HRT
Hormone Replacement Therapy
IB 
Investigator’s Brochure
ICF
Informed Consent Form
ICH
International Conference on Harmonisation
IDSL
Integrated Data Standards Library
IEC
Independent Ethics Committee
Ig
Immunoglobulin
INR
International Normalised Ratio
IUD
Intrauterine Device
IUS
Intrauterine Hormone-Releasing System
IVIVE
In vitro in vivo extrapolation
kg
Kilogram
L
Litres
LBF
Liver Blood Flow
LDH
Lactate dehydrogenase
MABEL
Minimum Anticipated Biologically Effective Level 
MCH
Mean corpuscular haemoglobin
MCV
Mean corpuscular volume
MDR-TB
Multi-Drug-Resistant-Tuberculosis
MedRA
Medical Dictionary for Regulatory Activities
mg
Milligram
MHRA
Medicines and Healthcare products Regulatory Agency
mIU/mL
Milli-international units per millilitre
mL
Millilitre
mm
Millimetre
MRSD
Maximum Recommended Starting Dose
MSDS
Material Safety Data Sheet 
nm
Nanometer
NOAEL
No Observed Adverse Effect Level
PBPK
Physiologically Based Pharmacokinetic

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PK
Pharmacokinetic
PTS
Platform Technologies and Science
QTc
Electrocardiogram QT interval corrected for heart rate 
QTcF
Electrocardiogram QT interval corrected for heart rate using Fridericia’s 
formula
RCmax
Cmax Ratio
RAP
Reporting and Analysis Plan
RBC
Red blood cells
RNA
Ribonucleic acid
Rss
Steady-State Ratio
SAE
Serious adverse event(s)
SDA
Source Document Agreement
SGOT
Serum glutamic-oxaloacetic transaminase
SGPT
Serum glutamic pyruvic transaminase
SPDS
Statistics, Programming and Data Sciences
SPF
Sun Protection Factor
SRM
Study Reference Manual
t½
Terminal phase half-life
TB
Tuberculosis
tmax
Time of occurrence of Cmax
t-RNA
Transfer-Ribonucleic acid
ULN
Upper Limit of Normal
UV
Ultraviolet
WBC
White blood cells
XDR-TB
Extensively Drug-Resistant-Tuberculosis
Trademark Information
Trademarks of the GlaxoSmithKline 
group of companies
Trademarks not owned by the 
GlaxoSmithKline group of companies
NONE
ClinPlus
CloePK
WinNonlin

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13.2.
Appendix 2: Adverse Events: Definitions and Procedures for 
Recording, Evaluating, Follow-up, and Reporting
Definition of AE
AE Definition

An AE is any untoward medical occurrence in a clinical study participant, temporally 
associated with the use of a study treatment, whether or not considered related to the 
study treatment.

NOTE: An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally 
associated with the use of a study treatment.
Events Meeting the AE Definition 

Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) 
or other safety assessments (e.g., ECG, radiological scans, vital signs 
measurements), including those that worsen from baseline, considered clinically 
significant in the medical and scientific judgment of the investigator (i.e., not related 
to progression of underlying disease).

Exacerbation of a chronic or intermittent pre-existing condition including either an 
increase in frequency and/or intensity of the condition.

New conditions detected or diagnosed after study treatment administration even 
though it may have been present before the start of the study.

Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction.

Signs, symptoms, or the clinical sequelae of a suspected overdose of either study 
treatment or a concomitant medication. Overdose per se will not be reported as an 
AE/SAE unless it is an intentional overdose taken with possible suicidal/self-
harming intent. Such overdoses should be reported regardless of sequelae.
Events NOT Meeting the AE Definition 

Any clinically significant abnormal laboratory findings or other abnormal safety 
assessments which are associated with the underlying disease, unless judged by the 
investigator to be more severe than expected for the participant’s condition.

The disease/disorder being studied or expected progression, signs, or symptoms of 
the disease/disorder being studied, unless more severe than expected for the 
participant’s condition.

Medical or surgical procedure (e.g., endoscopy, appendectomy): the condition that 
leads to the procedure is the AE.

Situations in which an untoward medical occurrence did not occur (social and/or 

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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.
Definition of SAE
If an event is not an AE per definition above, then it cannot be an SAE even if serious 
conditions are met (e.g. hospitalization for signs/symptoms of the disease under study, 
death due to progression of disease).
A SAE is defined as any untoward medical occurrence that, at any dose:
a.
Results in death
b.
Is life-threatening
The term 'life-threatening' in the definition of 'serious' refers to an event in which the 
participant was at risk of death at the time of the event. It does not refer to an event, 
which hypothetically might have caused death, if it were more severe.
c.
Requires inpatient hospitalization or prolongation of existing hospitalization
In general, hospitalization signifies that the participant has been detained (usually 
involving at least an overnight stay) at the hospital or emergency ward for observation 
and/or treatment that would not have been appropriate in the physician’s office or 
outpatient setting. Complications that occur during hospitalization are AE. If a 
complication prolongs hospitalization or fulfills any other serious criteria, the event is 
serious. When in doubt as to whether “hospitalization” occurred or was necessary, the AE 
should be considered serious.
Hospitalization for elective treatment of a pre-existing condition that did not worsen from 
baseline is not considered an AE.
d.
Results in persistent disability/incapacity

The term disability means a substantial disruption of a person’s ability to conduct 
normal life functions.

This definition is not intended to include experiences of relatively minor medical 
significance such as uncomplicated headache, nausea, vomiting, diarrhea, influenza, 
and accidental trauma (e.g. sprained ankle) which may interfere with or prevent 
everyday life functions but do not constitute a substantial disruption.
e.
Is a congenital anomaly/birth defect
f.
Other situations:

Medical or scientific judgment should be exercised in deciding whether SAE 
reporting is appropriate in other situations such as important medical events that may 
not be immediately life-threatening or result in death or hospitalization but may 
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one of the other outcomes listed in the above definition. These events should usually 
be considered serious.
Examples of such events include invasive or malignant cancers, intensive treatment 
in an emergency room or at home for allergic bronchospasm, blood dyscrasias or 
convulsions that do not result in hospitalization, or development of drug dependency 
or drug abuse.

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Recording AE and SAE
AE and SAE Recording

When an AE/SAE occurs, it is the responsibility of the investigator to review all 
documentation (e.g. hospital progress notes, laboratory, and diagnostics reports) 
related to the event.

The investigator will then record all relevant AE/SAE information in the CRF.

It is not acceptable for the investigator to send photocopies of the participant’s 
medical records to GSK in lieu of completion of the GSK /AE/SAE CRF page.

There may be instances when copies of medical records for certain cases are 
requested by GSK. In this case, all participant identifiers, with the exception of the 
participant number, will be redacted on the copies of the medical records before 
submission to GSK.

The investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information. Whenever possible, the diagnosis (not 
the individual signs/symptoms) will be documented as the AE/SAE.
Assessment of Intensity
The investigator will make an assessment of intensity for each AE and SAE reported 
during the study and assign it to 1 of the following categories: 

Mild: An event that is easily tolerated by the participant, causing minimal discomfort 
and not interfering with everyday activities.

Moderate: An event that causes sufficiently discomfort and interferes with normal 
everyday activities.

Severe: An event that prevents normal everyday activities. An AE that is assessed as 
severe should not be confused with an SAE. Severe is a category utilized for rating 
the intensity of an event; and both AE and SAE can be assessed as severe.
An event is defined as ‘serious’ when it meets at least 1 of the predefined outcomes 
as described in the definition of an SAE, NOT when it is rated as severe.
Assessment of Causality

The investigator is obligated to assess the relationship between study treatment and 
each occurrence of each AE/SAE.

A "reasonable possibility" of a relationship conveys that there are facts, evidence, 
and/or arguments to suggest a causal relationship, rather than a relationship cannot 
be ruled out.

The investigator will use clinical judgment to determine the relationship.

Alternative causes, such as underlying disease(s), concomitant therapy, and other 
risk factors, as well as the temporal relationship of the event to study treatment

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administration will be considered and investigated.

The investigator will also consult the Investigator’s Brochure (IB) and/or Product 
Information, for marketed products, in his/her assessment.

For each AE/SAE, the investigator must document in the medical notes that he/she 
has reviewed the AE/SAE and has provided an assessment of causality.

There may be situations in which an SAE has occurred and the investigator has 
minimal information to include in the initial report to GSK. However, it is very 
important that the investigator always make an assessment of causality for 
every event before the initial transmission of the SAE data to GSK.

The investigator may change his/her opinion of causality in light of follow-up 
information and send an SAE follow-up report with the updated causality 
assessment.

The causality assessment is one of the criteria used when determining regulatory 
reporting requirements.
Follow-up of AE and SAE

The investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as medically indicated or as requested by GSK to 
elucidate the nature and/or causality of the AE or SAE as fully as possible. This may 
include additional laboratory tests or investigations, histopathological examinations, 
or consultation with other health care professionals.

If a participant dies during participation in the study or during a recognized follow-
up period, the investigator will provide GSK with a copy of any post-mortem 
findings including histopathology.

New or updated information will be recorded in the originally completed CRF.

The investigator will submit any updated SAE data to GSK within 24 hours of 
receipt of the information.
Reporting of SAE to GSK
SAE Reporting to GSK 

The SAE CRF should be transmitted to the SAE coordinator by e-mail.

In rare circumstances and in the absence of other options, notification by telephone is 
acceptable with a copy of the SAE data collection tool sent by overnight mail or 
courier service.

Initial notification via telephone does not replace the need for the investigator to 
complete and sign the SAE CRF pages within the designated reporting time frames.

Contacts for SAE reporting can be found at the beginning of this protocol on the 
Sponsor/Medical Monitor Contact Information page, and in the SRM.

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13.3.
Appendix 3: Contraceptive Guidance and Collection of 
Pregnancy Information
Definitions
Females of Reproductive Potential (FRP)
A woman is considered fertile following menarche and until becoming post-menopausal 
unless permanently sterile (see below).
Women in the following categories are not considered FRP
Premenarchal
Premenopausal female with ONE of the following:

Documented hysterectomy

Documented bilateral salpingectomy

Documented bilateral oophorectomy
Note: Documentation can come from the site personnel’s: review of participant’s 
medical records, medical examination, or medical history interview.
Postmenopausal female

A postmenopausal state is defined as no menses for 12 months without an 
alternative medical cause. A high follicle stimulating hormone (FSH) level in 
the postmenopausal range may be used to confirm a postmenopausal state in 
women not using hormonal contraception or hormonal replacement therapy 
(HRT). However, in the absence of 12 months of amenorrhea, a single FSH 
measurement is insufficient. 

Females on HRT and whose menopausal status is in doubt will be required to 
use one of the non-hormonal highly effective contraception methods if they wish 
to continue their HRT during the study. Otherwise, they must discontinue HRT 
to allow confirmation of postmenopausal status before study enrollment.
Contraception Guidance
Male participants
Male participants with female partners of child-bearing potential are eligible to 
participate if they agree to ONE of the following: 
Are abstinent from penile-vaginal intercourse as their usual and preferred lifestyle 
(abstinent on a long term and persistent basis) and agree to remain abstinent 

Agree to use a male condom plus an additional method of contraception with a 
failure rate of <1% per year as described in the table below when having penile-
vaginal intercourse with a female reproductive potential. 

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
Men with a pregnant or breastfeeding partner must agree to remain abstinent 
from penile-vaginal intercourse or use a male condom during each episode of 
penile penetration during the protocol-defined time frame. 

Refrain from donating sperm for duration of study and for 5 half-lives + 90 days 
after the last dose of drug.
Highly Effective Contraceptive Methods
Highly Effective Contraceptive Methods That Are User Dependent a
Failure rate of <1% per year when used consistently and correctly. 
Combined (estrogen- and progestogen-containing ) hormonal contraception associated with 
inhibition of ovulation 

oral

intravaginal 

transdermal 
Progestogen-only hormonal contraception associated with inhibition of ovulation 

injectable 
Highly Effective Methods That Are User Independent 

Implantable progestogen-only hormonal contraception associated with inhibition of 
ovulation

Intrauterine device (IUD)

Intrauterine hormone-releasing system (IUS)

bilateral tubal occlusion
Vasectomized partner 
(A vasectomized partner is a highly effective contraception method provided that the partner is 
the sole male sexual partner of the FRP and the absence of sperm has been confirmed. If not, 
an additional highly effective method of contraception should be used). 
Sexual abstinence 
(Sexual abstinence is considered a highly effective method only if defined as refraining from 
heterosexual intercourse during the entire period of risk associated with the study drug. The 
reliability of sexual abstinence needs to be evaluated in relation to the duration of the study and 
the preferred and usual lifestyle of the participant).
NOTES: 
a.
Typical use failure rates may differ from those when used consistently and correctly. Use should be consistent 
with local regulations regarding the use of contraceptive methods for participants in clinical studies. 
Pregnancy Testing

Pregnancy testing, with a sensitivity of 25 mIU/mL will be performed and assayed in 
a certified laboratory in accordance with instructions provided in its package insert.

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Collection of Pregnancy Information
Male participants with partners who become pregnant

Investigator will attempt to collect pregnancy information on any male participant’s 
female partner of a male study participant who becomes pregnant while participating 
in this study. This applies only to participants who receive study treatment.

After obtaining the necessary signed informed consent from the pregnant female 
partner directly, the investigator will record pregnancy information on the 
appropriate form and submit it to GSK within 24 hours of learning of the partner’s 
pregnancy. 

Partner will also be followed to determine the outcome of the pregnancy. 
Information on the status of the mother and child will be forwarded to GSK

Generally, follow-up will be no longer than 6 to 8 weeks following the estimated 
delivery date. Any termination of the pregnancy will be reported regardless of fetal 
status (presence or absence of anomalies) or indication for procedure. 

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13.4.
Appendix 4: Liver Safety: Required Actions and Follow-up 
Assessments Guidelines
Phase I liver chemistry stopping criteria and required follow up assessments
Liver Chemistry Stopping Criteria 
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 
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 participant 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 participants 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:

Repeat liver chemistries (include ALT, AST, 
alkaline phosphatase, bilirubin) and perform 

Viral hepatitis serology3

Obtain INR and recheck with each liver 
chemistry assessment until the 
transaminases values show downward 
trend

Obtain blood sample for pharmacokinetic 
(PK) analysis, obtained within 3 days 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 
alcohol intake case report form
If ALT≥3xULN AND bilirubin 2xULN or INR 
>1.5:

Anti-nuclear antibody, anti-smooth muscle 

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Liver Chemistry Stopping Criteria 
liver event follow up assessments within 24-
72 hrs

Monitor participants weekly until liver 
chemistries resolve, stabilize or return to 
within baseline
antibody, Type 1 anti-liver kidney 
microsomal antibodies, and quantitative 
total immunoglobulin G (IgG) or gamma 
globulins.

Serum acetaminophen adduct high 
performance liquid chromatography 
(HPLC) assay (quantifies potential 
acetaminophen contribution to liver injury 
in participants with definite or likely 
acetaminophen use in the preceding week 
[James, 2009]. 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 participant 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 participants 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 participants 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 PK blood sample draw on the CRF. If the date or time of the last dose is unclear, provide the 
participant’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. 
References
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.

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13.5.
Appendix 5: Protocol Amendment History
Not Applicable