Conditions: Tuberculosis
Keywords: ascending dose Pharmacokinetics GSK3036656 FTIH Safety
Allocation: RANDOMIZED | Intervention model: SINGLE_GROUP
Enrollment: 30
Healthy volunteers: yes

Brief summary:
GSK3036656 is being developed by GSK for the treatment of tuberculosis (TB). This is the FTIH study for GSK3036656 to evaluate the safety, tolerability and PK of single ascending and repeat oral doses of GSK3036656 in healthy adult subjects. 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 PK of GSK3036656. The study will be conducted in two parts: Part A (single dose) and Part B (repeat dose). Up to two cohorts will be included in Part A. 9 healthy adult subjects will be included in each cohort. Each cohort will participate in up to 4 treatment (dosing) periods including a food effect treatment period. During each treatment period, GSK3036656 will be administered to 6 subjects and placebo will be administered to 3 subjects. The starting dose in Part A will be 5 milligrams (mg), and the maximum dose will be 1500 mg. The two cohorts in Part A will be dosed sequentially (i.e., dosing in Cohort 2 starts after dosing in Cohort 1 is completed). Initially, there will be a 14 day wash out period for individual subjects between each dose level. Study progression to Part B from Part A will be based on an acceptable safety, tolerability and PK profile in Part A. Part B will comprise up to 4 cohorts (Cohorts 3, 4, 5, and 6) 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. Appropriate doses and dose regimens for Part B will be selected based on available safety, tolerability and PK data from Part A and/or any preceding repeat dose cohorts from Part B. Dividing the total daily dose into 2 or 3 smaller doses may be done in both Part A and Part B. Up to 18 subjects will be enrolled into Part A and up to 40 subjects will be enrolled into Part B. The total duration of the study for each subject recruited into Part A and Part B will be approximately 12 weeks and 8 weeks, respectively.

Detailed description:

Arms:
arm 1: During Part A (Cohort 1), Subjects will receive a single dose of GSK3036656 in the morning on Day 1 in each of the 4 treatment (dosing) periods after an overnight fast of at least 8 hours. Dosing with food may also be done in Part A once results from the food effect analysis are available. The total daily dose for the treatment (dosing) period may also be divided into 2 or 3 smaller doses administered within 24 hours on discretion of the GSK study team and the principal investigator. The starting dose in Part A will be 5 mg and will then be escalated up to a dose no higher than 1500 mg. One of the 4 dosing periods will be food effect group which will be determined based on from previous cohorts. For the food effect assessment, the selected dose will be given with a high fat meal. There will be a 2 week washout between doses initially but the washout period may be modified depending on emerging data from previous cohorts. Subjects will be followed up to 2 weeks from the last dose. arm 2: During Part A (Cohort 1), Subjects will receive a single matching placebo in morning on Day 1 in each of the 4 treatment (dosing) periods after an overnight fast of at least 8 hours. Dosing with food may also be done in Part A once results from the food effect analysis are available. Placebo for the treatment (dosing) period may also be divided into 2 or 3 smaller doses administered within 24 hours in a similar manner if divided for subjects receiving active treatment in the same period. One of the 4 dosing periods will be food effect group which will be determined based on from previous cohorts. For the food effect assessment, placebo will be given with a high fat meal. There will be a 2 week washout between doses initially but the washout period may be modified depending on emerging data from previous cohorts. Subjects will be followed up to 2 weeks from the last dose. arm 3: During Part A (Cohort 2), Subjects will receive a single dose of GSK3036656 in morning on Day 1 in each period after an overnight fast of at least 8 hours. Dosing with food may also be done once results from the food effect analysis are available. The total dose for the treatment period may also be divided into 2 or 3 smaller doses administered within 24 hours on discretion of the GSK study team and the principal investigator. The dose will be selected on basis of safety, tolerability and PK data from the previous treatment period or cohort and will then be escalated up to a dose no higher than 1500 mg. One of the 4 dosing periods will be food effect group, determined based on from previous cohorts, where the selected dose will be given with a high fat meal. There will be a 2 week washout between doses initially but the washout period may be modified depending on emerging data from previous cohorts. Subjects will be followed up to 2 weeks from the last dose. arm 4: During Part A (Cohort 2), Subjects will receive a single matching placebo in morning on Day 1 in each of the 4 treatment (dosing) periods after an overnight fast of at least 8 hours. Dosing with food may also be done once results from the food effect analysis are available. Placebo for the treatment period may also be divided into 2 or 3 smaller doses administered within 24 hours in a similar manner if divided for subjects receiving active treatment in the same period. One of the 4 dosing periods will be food effect group, determined based on from previous cohorts, where the placebo will be given with a high fat meal. There will be a 2 week washout between doses initially but the washout period may be modified depending on emerging data from previous cohorts. Subjects will be followed up to 2 weeks from the last dose. arm 5: During Part B (Cohort 3), Subjects will receive a single dose of GSK3036656 once daily in morning on Day 1 after an overnight fast of at least 8 hours. Subjects will receive repeat single dose of GSK3036656 once daily over a period of 14 days. Dosing with food may also be done if there are PK or tolerability reasons making it preferable to dose in a fed state (dose will be given with a high fat meal.). The total dose may also be divided into 2 or 3 smaller doses administered within 24 hours on discretion of the GSK study team and the principal investigator. Appropriate dose and dose regimen will be selected on available safety, tolerability and PK data from Part A. Subjects will be followed up to 2 weeks from the last dose. arm 6: During Part B (Cohort 3), Subjects will receive a single matching placebo once daily in morning on Day 1 after an overnight fast of at least 8 hours. Subjects will receive a placebo once daily over a period of 14 days. Dosing with food may also be done if the active treatment is given in a fed state (dose will be given with a high fat meal.). The total dose may also be divided into 2 or 3 smaller doses administered within 24 hours in a similar manner if divided for subjects receiving active treatment in the same cohort. Subjects will be followed up to 2 weeks from the last dose. arm 7: During Part B (Cohort 4), Subjects will receive a single dose of GSK3036656 once daily in morning on Day 1 after an overnight fast of at least 8 hours. Subjects will receive repeat single dose of GSK3036656 once daily over a period of 14 days. Dosing with food may also be done if there are PK or tolerability reasons making it preferable to dose in a fed state (dose will be given with a high fat meal.). The total dose may also be divided into 2 or 3 smaller doses administered within 24 hours on discretion of the GSK study team and the principal investigator. Appropriate dose and dose regimen will be selected on available safety, tolerability and PK data from preceding repeat dose cohorts from Part B. Subjects will be followed up to 2 weeks from the last dose. arm 8: During Part B (Cohort 4), Subjects will receive a single matching placebo once daily in morning on Day 1 after an overnight fast of at least 8 hours. Subjects will receive a placebo once daily over a period of 14 days. Dosing with food may also be done if the active treatment is given in a fed state (dose will be given with a high fat meal.). The total dose may also be divided into 2 or 3 smaller doses administered within 24 hours in a similar manner if divided for subjects receiving active treatment in the same cohort. Subjects will be followed up to 2 weeks from the last dose. arm 9: During Part B (Cohort 5), Subjects will receive a single dose of GSK3036656 once daily in morning on Day 1 after an overnight fast of at least 8 hours. Subjects will receive repeat single dose of GSK3036656 once daily over a period of 14 days. Dosing with food may also be done if there are PK or tolerability reasons making it preferable to dose in a fed state (dose will be given with a high fat meal.). The total dose may also be divided into 2 or 3 smaller doses administered within 24 hours on discretion of the GSK study team and the principal investigator. Appropriate dose and dose regimen will be selected on available safety, tolerability and PK data from preceding repeat dose cohorts from Part B. Subjects will be followed up to 2 weeks from the last dose. arm 10: During Part B (Cohort 5), Subjects will receive a single matching placebo once daily in morning on Day 1 after an overnight fast of at least 8 hours. Subjects will receive a placebo once daily over a period of 14 days. Dosing with food may also be done if the active treatment is given in a fed state (dose will be given with a high fat meal.). The total dose may also be divided into 2 or 3 smaller doses administered within 24 hours in a similar manner if divided for subjects receiving active treatment in the same cohort. Subjects will be followed up to 2 weeks from the last dose. arm 11: During Part B (Cohort 6), Subjects will receive a single dose of GSK3036656 once daily in morning on Day 1 after an overnight fast of at least 8 hours. Subjects will receive repeat single dose of GSK3036656 once daily over a period of 14 days. Dosing with food may also be done if there are PK or tolerability reasons making it preferable to dose in a fed state (dose will be given with a high fat meal.). The total dose may also be divided into 2 or 3 smaller doses administered within 24 hours on discretion of the GSK study team and the principal investigator. Appropriate dose and dose regimen will be selected on available safety, tolerability and PK data from preceding repeat dose cohorts from Part B. Subjects will be followed up to 2 weeks from the last dose. arm 12: During Part B (Cohort 6), Subjects will receive a single matching placebo once daily in morning on Day 1 after an overnight fast of at least 8 hours. Subjects will receive a placebo once daily over a period of 14 days. Dosing with food may also be done if the active treatment is given in a fed state (dose will be given with a high fat meal.). The total dose may also be divided into 2 or 3 smaller doses administered within 24 hours in a similar manner if divided for subjects receiving active treatment in the same cohort. Subjects will be followed up to 2 weeks from the last dose.

Interventions: intervention 1: GSK3036656 intervention 2: Placebo
Intervention descriptions: intervention 1: GSK3036656 is available as capsules (for oral administration) containing 5 mg, 25 mg or 100 mg of GSK3036656 as free base equivalent. intervention 2: Placebo is a matching capsule containing Avicel PH (Suitable for Pharmaceutical Use) 102, for oral administration.

Protocol document:
Prot_000.pdf: 
2014N202803_01
CONFIDENTIAL
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201040
1
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 
jeopardize the participant or may require medical or surgical intervention to prevent 


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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

SAP_001.pdf: 
CONFIDENTIAL
The GlaxoSmithKline group of companies
201040
1
Division
: Worldwide Development
Information Type     : Reporting and Analysis Plan (RAP)
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
Effective Date 
: 28-MAR-2017
Description :
The purpose of this reporting and analysis plan (RAP) is to describe:
The planned analyses and output to be included in Clinical PharmacologyStudy 
Report for Protocol 201040. This RAP is intended todescribe exploratory analysis 
requirements during the study to support dose escalation decisions as well as the 
safety, tolerability and pharmacokinetic analyses required for the study which will be 
provided to the study team members to convey the content of the reporting efforts, 
specifically Statistical Analysis Complete (SAC).
Author’s Name and Functional Area: 
Lead Statistician(Clinical Statistics)
27-MAR-2017
Principal Statistician(Clinical Statistics)
Approvedvia E-mailby.:
Director (Clinical Statistics)
28-MAR-2017
Senior Director Clinical Pharmacology(CPMS)
27-MAR-2017
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CONFIDENTIAL
201040
2
TABLE OF CONTENTS
PAGE
1. REPORTING & ANALYSISPLAN SYNPOSIS...........................................................4
2. SUMMARY OF KEY PROTOCOL INFORMATION....................................................6
2.1.
Changes to the Protocol Defined Statistical Analysis Plan....................................6
2.2.
Study Objective(s) and Endpoint(s)...................................................................7
2.3.
Study Design..................................................................................................8
2.3.1.
Part A (Single Dose).........................................................................8
2.3.2.
Part B (Repeat Dose)........................................................................8
2.4.
Statistical Hypotheses....................................................................................10
3. PLANNED ANALYSES...........................................................................................10
3.1.
Interim Analyses...........................................................................................10
3.2.
Final Analyses..............................................................................................10
4. ANALYSIS POPULATIONS....................................................................................11
4.1.
Protocol Deviations.......................................................................................11
5. CONSIDERATIONS FOR DATA ANALYSES AND DATAHANDLING 
CONVENTIONS......................................................................................................12
6. STUDY POPULATION ANALYSES.........................................................................12
6.1.
Overview of Planned Analyses.......................................................................12
7. PRIMARY STATISTICAL ANALYSES....................................................................14
7.1.
Interim Analyses...........................................................................................14
7.1.1.
Overview of Planned Bayesian Dose Escalation Analyses...................14
7.1.2.
Planned Bayesian Statistical Analyses..............................................14
7.1.3.
Overview of Planned PK Dose Escalation Analyses...........................16
7.2.
Final Analyses..............................................................................................16
7.2.1.
Pharmacokinetic Analyses...............................................................16
7.2.1.1.
Overview of Planned Pharmacokinetic Analyses...............17
7.2.1.2.
Drug Concentration Measures........................................17
7.2.1.3.
Pharmacokinetic Parameters...........................................18
7.2.1.3.1.
Deriving Pharmacokinetic Parameters.........18
7.2.1.3.2.
Statistical Analysis of 
Pharmacokinetic Parameters.......................19
8. SAFETY ANALYSES..............................................................................................24
8.1.
Overview of Planned Adverse Events Analyses................................................24
8.2.
Overview of Planned Clinical Laboratory Analyses...........................................25
8.3.
Overview of Planned Other Safety Analyses.....................................................25
9. REFERENCES.........................................................................................................27
10. APPENDICES.........................................................................................................28
10.1
Appendix 1: Protocol Deviation Management...................................................29
10.2
Appendix 2: Time & Events...........................................................................30
10.2.1
Protocol Defined Time & Events......................................................30


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10.3
Appendix 3: Treatment States.........................................................................34
10.3.1
Treatment States...........................................................34
10.4
Appendix 4: Data Display Standards & Handling Conventions...........................35
10.4.1
Study Treatment & Display Descriptors:...........................................35
10.4.2 
BaselineDefinition & Derivations....................................................36
10.4.2.1
Baseline Definitions......................................................36
10.4.2.2
Derivations and Handling of Missing Baseline Data..........36
10.4.3
Reporting Process & Standards........................................................36
10.5
Appendix 5: Derived and Transformed Data.....................................................39
10.5.1
General.........................................................................................39
10.5.2
Study Population............................................................................39
10.5.3 
Safety...........................................................................................40
10.5.4
Pharmacokinetic.............................................................................40
10.6
Appendix 6: Premature Withdrawals & Handling of Missing Data......................41
10.6.1
Premature Withdrawals...................................................................41
10.6.2
Handling of Missing Data...............................................................41
10.6.2.1
Handling of Missing Dates.............................................41
10.6.2.2
Handling of Partial Dates...............................................42
10.6.2.3
Handling of PK Concentration Data................................43
10.6.2.4
Handling of Missing Data for Statistical Analysis.............43
10.7
Appendix 7: Values of Potential Clinical Importance.........................................44
10.7.1
Laboratory Values..........................................................................44
10.7.2
ECG.............................................................................................45
10.7.3
Vital Signs....................................................................................45
10.8
Appendix 8: Model Checking and Diagnostics for Statistical Analyses................46
10.8.1
Statistical Analysis Assumptions......................................................46
10.9
Appendix 9 : Abbreviations & Trade Marks.....................................................47
10.9.1
Abbreviations................................................................................47
10.9.2
Trademarks...................................................................................48
10.10 Appendix 10: List of Data Displays.................................................................49
10.10.1 Data Display Numbering.................................................................49
10.10.2 Mock Example Shell Referencing....................................................49
10.10.3 Deliverable....................................................................................49
10.10.4 Study Population Tables..................................................................50
10.10.5 Pharmacokinetic Tables..................................................................52
10.10.6 Pharmacokinetic Figures.................................................................54
10.10.7 Safety Tables.................................................................................56
10.10.8 Dose Escalation Tables...................................................................59
10.10.9 Dose Escalation Figures..................................................................60
10.10.10 ICH Listings..................................................................................61
10.10.11 Non-ICH Listings...........................................................................64
10.11 Appendix 11: Example Mock Shells for Data Displays......................................66


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1.
REPORTING & ANALYSIS PLANSYNPOSIS
Overview
Key Elements of the Reporting and Analysis Plan 
Purpose
The purpose of this reporting and analysis plan (RAP) is to describe:
The planned analyses and output to be included in the Clinical 
Pharmacology Study Reportfor Protocol201040. This RAP is 
intended to describe the safety, tolerability and pharmacokinetic 
analyses required for the study which will be provided to the study 
team members to convey the content of the reporting efforts, 
specifically Statistical Analysis Complete (SAC).
Protocol

Reporting and Analysis Plan is based on amendedprotocol 
(Dated: [27-FEB-2017]) for study 201040 [GlaxoSmithKline
Document Number: 2014N202803_01and eCRF version1].
Primary 
Objective
1. To investigate the safety and tolerability of GSK3036656 after 
single ascending and repeat oral doses in healthy adult subjects.
2. To determine the pharmacokinetics of single and repeat doses of
GSK3036656 in healthy subjects.
Primary 
Endpoint
1. Safety and tolerability of GSK3036656: 
o Adverse Events
o Clinically relevant changes in safety parameters: 12-lead 
ECG, telemetry, vital signs (systolic and diastolic blood 
pressure, heart rate, temperature), clinical laboratory data 
(haematology, clinical chemistry, urinalysis)
2. 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


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Overview
Key Elements of the Reporting and Analysis Plan 
Study Design A double blind(sponsor unblind),randomised,placebo-controlled first 
time in human, dose escalationstudyenrolling healthy adult subjects. 
Part A:   Subjects will receivesingle dosesof GSK3036656 or 
matching placebo.
It will include up to two cohorts. Each cohort will participate in up to 4
treatment periods(including a food effect treatment period).
Up to 18 subjects(9 in each cohort, 6A:3P) (excluding possible 
replacements) will be recruited into the single ascending dose part of the 
study.
PartB: Subjects will receiverepeatdosesof GSK3036656or matching 
placebo.
It will include up to four cohorts. Each cohort will participate in only 
one treatment period.
Up to 40 subjects(10 in each cohort, 8A:2P) (excluding possible 
replacements) will be recruited for the repeat dose. 
The total duration of the study will be approximately 12 weeks for 
subjects recruited into Part A and approximately 8 weeks for subjects 
recruited into part B. 
Planned
Analyses
Interim Analysis
No formal interim analysis is 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 final planned analyses will be performed, as defined in this 
RAP document,after database freeze has been declared.   
Analysis 
Population

Enrolled Population:  Defined as all subjects who were 
enrolled for the trial irrespective of whether they were 
randomized or not and for whom a record existson the study 
database.

Safety Population:  Defined as all randomised subjects who 
receive at least one dose of study medication.If subjects receive 
a treatment different to their randomised treatment, they will be 
analysed according to the treatment actually received.


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Overview
Key Elements of the Reporting and Analysis Plan 

Pharmacokinetic(PK) Population: Subjects in the Safety
population who administered at least one dose of active 
treatment and have at least one evaluable PK sample.
Hypothesis
No formal hypotheses will be tested.
Interim
Analyses
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.
PK Analyses
PK concentration data and derived PK parameters will be summarised 
appropriatelyusing the PK population.
Safety 
Analyses
Safety data will be summarized descriptively, using the safety 
population, according to GSKs Integrated Data Standard Library (IDSL) 
standards. 
2.
SUMMARY OF KEY PROTOCOL INFORMATION
2.1.
Changes to the Protocol Defined Statistical Analysis Plan
Any changes from the originally planned statistical analysis specified in the protocol are 
outlined in below table. 
Changes to Protocol Defined Analysis Plan
Protocol
Reporting & Analysis Plan
Statistical Analysis Plan
Statistical Analysis Plan
Rationale for Changes
Bayesian dose escalation 
model:
y = exp(1+)·  dose2
Bayesian dose 
escalation model:
y = exp(1+ ri+)·  
dose2
Anadditional random 
effect(r
i) has been 
included in thepower 
model forthe Bayesian 
dose escalation 
analyses inStudy Part 
A to account for the 
within subject 
correlation, see Section
7.1.2


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2.2.
Study Objective(s) and Endpoint(s)
Objectives
Endpoints
Primary Objectives
Primary Endpoints

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 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 Objectives 
Secondary Endpoints 
To assess the effect offood 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
Todefine the metabolic profile of 
GSK3036656 by identifying and 
quantifying, where possible 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 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 


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Objectives
Endpoints
appropriate,  GSK3036656-related 
material in plasma and urine following a 
single andrepeated oral administration 
of GSK3036656
plasma and urine 
2.3.
Study Design
Overview of Study Design and Key Features
2.3.1.
Part A (Single Dose)
2.3.2.
Part B (Repeat Dose)
Design Features
A double blind, placebo-controlled first 
time in human studyenrolling healthy 
adult subjects. 
Part A: Subjects will receivesingle 
doses of GSK3036656 or matching 
placebo.
It will include up to two cohorts. Each 


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Overview of Study Design and Key Features
cohort will participate up to 4treatment 
periods (including a food effect 
treatment period).
Part B: Subjects will receiverepeat
doses of GSK3036656 or matching 
placebo.
It will include up to four cohorts. Each 
cohort will participate in only one 
treatment period.
Dosing
Part A(single ascending dose)
Subjects randomized on Day 1 
followed by a single dose of 
study drug administration.
2 subjects in each cohort will be 
initially randomized to receive 
GSK3036656 or placebo in 1:1 
ratio. Dosing in the remaining 7 
subjects in each cohort will occur 
at least 24 hours later after 
review of safety results from the 
initial 2 subjects in a 5:2 ratio 
(GSK3036656: placebo).
Part B(repeat dose)
Subjects randomized on Day 1 
followed by first study drug 
administration.
Subsequent daily drug 
administrationsare planned for 
up to 2 weeks.
Treatment Assignment
Part Aconsists of up to 18 subjects 
in up to 2 cohorts(excluding possible 
replacements)(6 active: 3 placeboin 
each cohort)
Part Bconsists of up to 40 subjects in 
up to 4 cohorts(excluding possible 
replacements)(8 active: 2 placebo in 
each cohort)


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Overview of Study Design and Key Features
GSK RANDALL NG will be used to 
generate randomisation schedules. 
Interim Analyses
No plannedformalinterim analysis
Blinded review of safety data, 
unblinded review of PK data at 
aggregate level and calculation of 
Bayesian predictive probabilities 
(after the third dose) of area under 
the concentration-time curve AUC[0-
24] and maximum observed plasma 
drug concentration (Cmax) will be 
used to help drive decision making 
for dose escalation in Part A (single 
dose)and Part B (repeat dose).
2.4.
Statistical Hypotheses
No formal hypotheses will be tested for this study given that this is a first time in human 
study. 
3.
PLANNED ANALYSES
3.1.
Interim Analyses
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.
3.2.
Final Analyses
The final planned primary analyses will be performed after the completion of the 
following sequential steps:
[1]All subjects have completed the study as defined in the protocol.
[2]All required database cleaning activities have been completed and final database 
release and database freezehas been declared by Data Management.
[3]All criteria for unblinding the randomisation codes have been met. 
[4]Randomisation codes have been distributed according to RandAll NG procedures.


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4.
ANALYSIS POPULATIONS
Population
Definition / Criteria
Endpoint(s) 
Evaluated
Enrolled 
Population
Defined as all subjects who were 
enrolled for the trial irrespective of 
whether they were randomized or not 
and for whom a record exists on the 
study database.
Screen Failure
Safety
Population
Defined as all randomised subjectswho 
receive at least one dose of study 
medication. If subjects receive a 
treatment different to their randomised 
treatment, they will be analysed 
according to the treatment actually 
received.
Study Population
Safety
Pharmacokinetic
(PK)Population
Subjects in the Safety population who 
administered at least one dose of active 
treatment and have at least one evaluable 
PK sample.
PK
NOTES :

Please refer to Appendix 10which details the population to be used for each display being generated.
4.1.
Protocol Deviations
Important protocol deviations (including deviations related to study 
inclusion/exclusion criteria, conduct of the trial, patient management or patient 
assessment) will be summarised and listed.
Protocol deviations will be tracked by the study team throughout the conduct of the 
study in accordance with the Protocol Deviation Management Plan.
o Data will be reviewed prior to unblinding andfreezing the database to ensure all 
important deviations and deviations which may lead to exclusion from the 
analysisare captured and categorised on the protocol deviations dataset. 
o This dataset will be the basis for the summaries and listings of protocol 
deviations.
A separate summary and listing of all inclusion/exclusion criteria deviations will also 
be provided. This summary will be based on data as recorded on the 
inclusion/exclusion page of the eCRF.


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5.
CONSIDERATIONS FOR DATA ANALYSESAND DATA 
HANDLING CONVENTIONS
Table 1provides an overview of appendices within the RAP for outlining general 
considerations for data analysesand data handling conventions. 
Table 1 
Overview of Appendices
Section Component
10.1
Appendix 1: Protocol Deviation Management 
10.2
Appendix 2: Time & Events
10.3
Appendix 3: Treatment States and Phases
10.4
Appendix 4: Data Display Standards & Handling Conventions
10.5
Appendix 55: Derived and Transformed Data
10.6
Appendix 6: Premature Withdrawals & Handling of Missing Data
10.7
Appendix 7: Values ofPotential Clinical Importance
10.8
Appendix 8: Model Checking and Diagnostics for Statistical Analyses.
10.9
Appendix 9: Abbreviations & Trade Marks
10.10
Appendix 10: List of Data Displays
10.11
Appendix 11: Example Mock Shells for Data Displays
6.
STUDY POPULATIONANALYSES
6.1.
Overview of Planned Analyses
The study population displays will be based on the “Safety”population, unless otherwise 
specified.Outputs will be presented separately for study part A and study partB. 
Table 2provides an overview of the planned study population displays,with fulldetails 
of data displays being presented in Appendix 10: List of Data Displays.


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Table 2 
Overview of Planned Study Population Analyses
Display Type
Data Displays Generated
Table
Listing
Randomisation
Planned and Actual Treatment
Y
Subject Disposition
Subject Disposition
Y
Reasons for Screening Failures[1]
Y
Y
Reasons for Study Treatment Discontinuation
Y
Y
Reasons for Withdrawals
Y
Y
Important Protocol Deviations
Y
Y
Inclusion and Exclusion Criteria Deviations
Y
Y
Demography
Demographic Characteristics
Y
Y
Race & Racial Combinations
Y
Y
Study Populations
Y
Y
Medical/Surgical History & Concomitant  Medications
Medical/Surgical History
Y
Concomitant Medication
Y
Y
Exposure and Treatment Compliance
Exposure to Study Treatment
Y
Y
Treatment compliance
Y
Y
NOTES:

Y = Yes display generated.
1.Conditional displays, if data is availabletable andlisting will be generated.
Categorical variables will be summarized by the number and percentage of subjects, and 
the continuous parameters will be summarized by n, mean, median, sample standard 
deviation, minimum and maximum unless otherwise specified.


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7.
PRIMARY STATISTICAL ANALYSES
7.1.
Interim Analyses
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.
7.1.1.
Overview of Planned Bayesian Dose Escalation Analyses
The Bayesian Dose Escalation analyses will be utilised to guide dose selection after 3 
doses in each part of thestudy. The analyses will be based on the PK population, unless 
otherwise specified.
During dose escalation, a Bayesian predictive probability of geometric mean AUC[0-24] 
>4.9µg.h/ml and Cmax >0.443µg/ml will be calculated for potential future dose levels 
and used together with safety and tolerability data to aid next dose selections. The 
Bayesian predictive probability will be based on Whitehead’s method (Whitehead 2001). 
7.1.2.
Planned Bayesian Statistical Analyses
Bayesian Statistical Analyses
Endpoint(s)
AUC[0-24]
Cmax 
Model Specification
To guide dose selection after 3 doses in each part of the study have been observed, 
Bayesian posterior inferences about population probability distributions of model 
parameters of PK parameters will be assessed by using the following power model:
y = exp(1+ri+)· dose2
where y denotes the PK parameter being analyzedand r the random subject effect. The 
s, s=1,2, in the power model will be estimated by linear regression of the log
e-
transformed PK parameters on log
edose levels.
log(y
ij) = 1+ 2· log(d
ij) + ri+ 
ij       (1)
where

is the observed or predicted PK variable of the j-th dose dijadministered to the 
i-th subject. In particular, it is an AUC[0-24] or a Cmax, as applicable.

are population intercept and slope, respectively.
r
iis the random effect associated with subjects, it has mean zero and variance s
2

is a random error term, with mean zero and variance 
.
Note, for part B, subjects will not receive more than one dose, therefore the random 
subject effect (r
i) will not be included in that model. 
In general, Bayesian inference seeks to quantify the probability distributions of model 
parameters such as the (
defined in Equation (1). The presentinference will 


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Bayesian Statistical Analyses
incorporate a normal prior distribution, to express the prior information about the 
parameters (
and a gamma prior distribution for (s
2, σ
2). Due to limited information 
available about the GSK3036656 compound, a non-informative prior with large variance 
will be used. For ease of parameterization for the normal distribution in computer 
programming, use 
and w = s
-2as the precision. Model parameters are assumed 
a priorito be independent.
Table 3
Prior Distributions
Model Parameter
Prior
  (intercept)
~ Normal (0, precision=0.001 )*
  (slope of log-dose)
~ Normal (0, precision=0.001)*
(random error precision)
~ Gamma (0.01, iscale=0.001)* 
w(random effectprecision)
~ Gamma (0.01, iscale=0.001)*
All model parameters are a prioiriindependent.
*SAS Version 9.3 or later or R version 3.1.1 or laterwill be used for the Bayesian 
analysis, specifying the normal distribution using mean and precision. At least twochains 
will be run for the estimation of each parameter.
Model Checking & Diagnostics
The posterior distributions of the model parameters will be estimated using the Markov 
Chain Monte Carlo (MCMC) method. 
MCMCchains will be run for as many iterations as needed until convergence is achieved. 
Convergence will primarilybe assessed using trace plots: All chains’ trace plots will be 
inspected visually, to assess the mixing of eachchain. Convergence is indicated when all 
chains appear to be mixing well and overlapping each other randomly (no chain’s 
convergence is indicated until the chains of all model parameters appear well-mixed). 
Additional convergence diagnostics, such as Monte Carlo Standard Error divided by the 
standard deviation of the posterior distribution(MCSE/SD), Gelman-Rubin statistic, 
effective sample size (ESS) and autocorrelation plots may alsobe reviewed. 
The modelling will be subject to independent quality control, the final results for the 
probability of exceeding the pre-defined thresholds for both Cmax and AUC[0-24] 
should have a percentage of difference of ≤5% to conclude agreement.
Model Results Presentation
Once the posterior distributions have been estimated, the following inferences and 
predictions will be estimated using the associated posteriors:
Predictions of PK parameters AUC[0-24] and Cmax for potential future dose 
levels: mean, median, 5
thand 95
thpercentiles. 
The Bayesian predictive probability that an individual subject will have AUC[0-
24] or Cmax values greater than 4.9 μg.h/mL and 0.443 μg/mL (a 30-fold 


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Bayesian Statistical Analyses
margin from the dog no observed adverse effect level (NOAEL) exposure), 
respectively, will be calculated for each potential future dose level in Part 1 and 
Part 2. Note, prediction in Part 2 will be independent of Part 1.
Graphical representation of the predictivedistribution for AUC[0-24] and Cmax 
via line plots and density plots.
7.1.3.
Overview of Planned PKDose Escalation Analyses
Dose escalation for the first 2 dose levels 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 
theassumption 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 population PK model will be a fit for purpose model. Candidate model selection will 
be primarily based on a significant reduction in the objective function value (≥ 3.32, χ2 
<0.05) and improvement in the fits of diagnostic scatter plots.  Inter-individual variability 
will be modelledusing an exponential error model and residual error will be described by 
a proportional, proportional plus additive, or additive error model, depending on the data. 
Model performance will be evaluated using a visual predictive check.  Simulations for 
doserecommendations will be conducted to determine the probability of an individual 
subject exceeding the defined exposure margins for AUC and Cmax.
7.2.
Final Analyses
7.2.1.
Pharmacokinetic Analyses
The reconciliation of the PK Case Report Form (CRF) and will be performed by, or under 
the direct auspices of, Clinical Pharmacology Science and Study Operations (CPSSO), 
GlaxoSmithKline. 
The merge of PK concentration data, randomisation and CRF data will be performed by, 
or under the direct auspices of QSI, GlaxoSmithKline.   
Derivation of pharmacokinetic parameters will be performed by or under the direct 
auspices of CPMS, QSci, GlaxoSmithKline.
Statistical Analysis of pharmacokinetic parameters will be performed by or under the 
direct auspices of, QSI, GlaxoSmithKline.    


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7.2.1.1.
Overview of Planned Pharmacokinetic Analyses
The pharmacokinetic (PK) analyses will be based on the “Pharmacokinetic” population, 
unless otherwise specified.
Table 4provides an overview of the planned non-compartmental pharmacokinetic 
analyses, with full details being presented in Appendix 10: List of Data Displays.
Table 4
Overview of Planned Pharmacokinetic Analyses
Display Type
Untransformed
Log-Transformed
Stats Analysis
Summary
Individual
Stats Analysis
Summary
Individual
T
F
L
T
F
F
L
T
F
L
T
F
F
L
Descriptive statistics
Plasma Drug 
Concentrations
Y Y Y Y
Y
PK Urine 
Concentrations
Y Y Y Y
Derived PK 
Parameters
Y Y 
Y
Y
PK Urine 
Parameters
Y
Statistical Analysis of Primary PK Parameters
Dose 
Proportionality
Y
Y[1]
Food Effect
Y
Y[1]
Time Invariance 
of GSK3036656
Y
Y[1]
Accumulation 
ratio
Y
Y[1]
Achievement of 
Steady State
Y
Y[1]
NOTES :

T = Table, F = Figure, L = Listings, Y = Display generated.

Stats Analysis = Represents TFL related to any formal statistical analyses (i.e. modelling) conducted.

Summary = Represents TFL related to any summaries (i.e. descriptive statistics) of the observed raw 
data.
Individual = Represents FL related to any displays of individual subject observed raw data.
1. Supportive SAS Output from Statistical Analysis 
7.2.1.2.
Drug Concentration Measures
Refer to Appendix 4: Data Display Standards & Handling Conventions (Section 10.4.3. 
Reporting Process & Standards).


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7.2.1.3.
Pharmacokinetic Parameters
7.2.1.3.1. Deriving Pharmacokinetic Parameters
Refer to Appendix 4: Data Display Standards & Handling Conventions 
(Section10.4.3. Reporting Process & Standards). 
Plasma GSK3036656concentration-time data will be analyzed by non-
compartmental methodsaccording to current working practiceswithWinNonlin 
5.2 or higher. 
Non-compartmental analysis will be performed in accordance with GSK PK 
Guidance document GUI_51487.
All calculations of non-compartmental parameters will be based on actual 
sampling times recorded during the study.
Pharmacokinetic parameters described in Table 5will be determined from plasma 
concentration-time data and urine concentration data, as data permits. 
Table 5
Derived Pharmacokinetic Parameters
Parameter
Parameter Description
AUC(0-t)
Area under the concentration-time curve from time zero to the 
time of the last quantifiable concentration (C(t)) will be calculated 
using the linear trapezoidal rule for each incremental trapezoid 
and the log trapezoidal rule for each decremental trapezoid.
AUC(0-∞)
Area under the concentration-time curve extrapolated to infinity 
calculated as: 
AUC = AUC(0-t) + C(t) / lambda_z
AUC(0-24h)
Area under the concentration-time curve from time zero to 24 
hours post-dose
AUC(0-)
AUC from time zero during a dosing interval of duration “”
AUC(Ro)
Observed accumulation ratio (Ro) for AUC will be calculated as 
follows: 
Day 14 AUC(0-τ)/Day 1 AUC(0-τ)
Ae
Urinary excretion of unchanged drug
Cmax
Maximum observed blood concentration, determined directly 
from the concentration-time data.


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Parameter
Parameter Description
Ctrough
Pre-dose observed concentration, will be obtained directly from 
the concentration-time data. 
CLr
Renal clearance
Fe
Fraction of the dose excreted in the urine
Lambda_z
The first order rate constant associated with the terminal (log-
linear) portion of the concentration-time curve.
Rss
Steady state ratio (Rss) will be calculated as follows: 
Day 14 AUC(0-τ)/Day 1 AUC(0-∞)
RCmax
Observed accumulation ratio for Cmax (RCmax) will be 
calculated as follows: 
Day 14 Cmax/Day 1 Cmax
tmax
Time to reach Cmax, determined directly from the concentration-
time data.
t½
Apparent terminal phase half-life will be calculated as: 
t½ = ln2 / Lambda_z
(NOTE: Lambda_z is the terminal phase rate constant).
7.2.1.3.2. Statistical Analysis of Pharmacokinetic Parameters
For each of the parameters AUC (AUC(0-∞), AUC (0-t), AUC(0-τ), AUC(Ro)), RCmax, 
Rss,Cτ, Ae, fe, CLrand Cmax the following summary statistics will be calculated and 
tabulatedby dose group for study Part A and Part B separately:
Untransformed Data:N, n, arithmetic mean, 95% confidence interval (CI) for the 
arithmetic mean, SD, median, minimum, maximum.
Loge-transformed Data:  Geometric mean, 95% CI for the geometric mean, SD of 
log
e-transformed data and %CVb.
For tmax, and t½ the summary statistics specified for untransformed data above will be 
generated.
The following pharmacokinetic statistical analyseswill only be performed, if sufficient 
data is available (i.e. if subjects have well defined plasma profiles). Pharmacokinetic 
analysis will be the responsibility of the Clinical Pharmacology Modeling and Simulation 
Department, (CPMS) and Statistical analyses of the pharmacokinetic parameter data will 
be the responsibility of QSIStats & Programming.


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Pharmacokinetic Statistical Analyses (Dose Proportionality -Single and Repeat 
Dose Study Phases)
Endpoint(s)
Single Dose: AUC(0-t), AUC(0-∞) and Cmax 
Repeat Dose : AUC(0-τ) and Cmax
Model Specification
Will be statistically analysed using the power model
y = α* doseβ
Where y =PK parameter being analyzed and α= subject 
Logetransformed data will be analysed by fitting the following terms in the mixed 
effect model:
Fixed effect: loge(dose)
Random effect: Subject
Model Checking & Diagnostics
Refer to Appendix 8:Model Checking and Diagnostics for Statistical Analyses.
Model Results Presentation
Estimates of the mean slopes of loge(dose) will be reported along withcorresponding 
90% confidence intervals (slope≈1 implies dose proportionality).
Pharmacokinetic Statistical Analyses (Food Effect -Single Dose StudyPhase)
Endpoint(s)
AUC(0-t), AUC(0-∞), Cmax and t1/2
Model Specification
Will be statistically analysed using a mixed model (MM).
Terms fitted in the mixed effect ANOVA model will include:
Fixed effect                     : fed/fasted
Random Effect                :Subject
Only data from the same dose level as the fed dose group will be included in this 
analysis, all other dose leveldata will be excluded. 
The Kenward and Roger method for approximating the denominator degrees of 
freedom and correcting for bias in the estimated variance-covariance of the fixed 
effects will be used.
An unstructured covariance structure for the G matrix will be used. 
o In the event that this model fails to converge, alternative covariance structures 
may be considered such as VC or CS. 
o Akaike
's Information Criteria (AIC) will be used to assist with the selection of 
covariance structure.
Model Checking & Diagnostics
Refer to Appendix 8: Model Checking and Diagnostics for Statistical Analyses.


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Pharmacokinetic Statistical Analyses (Food Effect -Single Dose StudyPhase)
Model Results Presentation
Point estimates and corresponding 90% confidence intervals will be constructed for the 
comparisons of interest ofGSK3036656 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.
Endpoint(s)
Tmax
Model Specification
Wilcoxon matched pair test
Only data from the same dose level as the fed dose group will be included in this 
analysis, all other dose level data will be excluded.
Model Checking & Diagnostics
Refer to Appendix 8: Model Checking and Diagnostics for Statistical Analyses.
Model Results Presentation
Point estimate and 90% confidence interval for the median difference (fed –fasted)
Pharmacokinetic Statistical Analyses (Time Invariance of GSK3036656-Repeat 
Dose Study Phase)
Endpoint(s)
time invariance ratio 
Model Specification
Will be statistically analysed using a mixed model(MM) ANOVA.
Fixed, categoricaleffect   : day
Random Effect                 :Subject
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, using log-transformed AUC. 
The Kenward and Roger method for approximating the denominator degrees of 
freedom and correcting for bias in the estimated variance-covariance of the fixed 
effects will be used.
Anunstructured covariance structure for the G matrix will be used. 
o In the event that this model fails to converge, alternative covariance structures 
may be considered such as VC or CS. 
o Akaike
's Information Criteria (AIC) will be used to assist with the selection of 
covariance structure.
Model Checking & Diagnostics
Refer to Appendix 8: Model Checking and Diagnostics for Statistical Analyses.
Model Results Presentation
The time invariance ratio of GSK3036656will be estimated by calculating the ratio 
of the generalized least square means of AUC (0-) on Day 14 to AUC (0-inf) on 


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Pharmacokinetic Statistical Analyses (Time Invariance of GSK3036656-Repeat 
Dose Study Phase)
Day 1, along with the corresponding 90% CI at each dose level. 
Pharmacokinetic Statistical Analyses (Accumulation -Repeat Dose Study Phase)
Endpoint(s)
AUC (Ro) and Cmax (RCmax)
Model Specification
Will be statistically analysed using a mixed model (MM)using a loge-transformation.
Fixed effects                     : dose, day and dose*day
Random Effect              :Subject
The Kenward and Roger method for approximating the denominator degrees of 
freedom and correcting for bias in the estimated variance-covariance of the fixed 
effects will be used.
An unstructured covariance structure for the G matrix will be used. 
o In the event that this model fails to converge, alternative covariance structures 
may be considered such as VC or CS. 
o Akaike
's Information Criteria (AIC) will be used to assist with the selection of 
covariance structure.
Model Checking & Diagnostics
Refer to Appendix 8: Model Checking and Diagnostics for Statistical Analyses.
Model Results Presentation
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.
Pharmacokinetic Statistical Analyses (Achievement of Steady State -Repeat Dose 
Study Phase)
Endpoint(s)
Trough plasma concentrations at the end of the dosing interval (Cτ)
Model Specification
Will be statistically analysed using a mixed models (MM)using log-transformed dose 
data.
Fixed effects                     : dose, day and dose*day
Random Effect                  :Subject
The Kenward and Roger method for approximating the denominator degrees of 
freedom and correcting for bias in the estimated variance-covariance of the fixed 


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Pharmacokinetic Statistical Analyses (Achievement of Steady State -Repeat Dose 
Study Phase)
effects will be used.
An unstructured covariance structure for the G matrix will be used. 
o In the event that this model fails to converge, alternative covariance structures 
may be considered such as VC or CS. 
o Akaike
's Information Criteria (AIC) will be used to assist with the selection of 
covariance structure.
Model Checking & Diagnostics
Refer to Appendix 8: Model Checking and Diagnostics for Statistical Analyses.
Model Results Presentation
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.
Trough concentration levels collected pre-morning dose will be plotted by collection day 
and dose. 


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8.
SAFETY ANALYSES
The safety analyses will be based on the “Safety” population, unless otherwise specified.
Outputs will be presented separately for study part A and study part B.
8.1.
Overview of Planned Adverse Events Analyses
Adverse Events will becoded using Medical Dictionary for Regulatory Activities 
(MedDRA) central coding dictionaryandsummarized by dosegroup. 
Counting of AEs will be based on the number of subjects –not the number of AEs. For 
example ifa subject experiences the same AE (i.e. same preferred term) more than once, 
they are counted only once under the count for the preferred term. If a subject 
experiences more than one AE in a particular SOC, they will only be included once in the 
count forthe SOC, but will appear in the count for each appropriate preferred term within 
the SOC.  Therefore, the sum of the numbers of subjects with each preferred term event 
within a SOC may exceed the total number of subjects with at least one event. For the 
summary of AEs by maximum intensity, subjects who experience the same event several 
times with different intensity will only be counted once with the maximum intensity.
Table 6provides an overview of the planned analyses,with further details of data 
displays being presented inAppendix 10: List of Data Displays.
Table 6
Overview of Planned Adverse Event Analyses
Endpoint / Parameter/ Display Type
Absolute
Summary
Individual
T
F
L
Adverse Events (AEs)
All AE’s
Y
Y
Serious AE’s
Y
Y
Drug Related AEs
Y
Y
AE’s leading to withdrawal
Y
Y
Common (>=5% in any treatment group) Non-serious AEs by 
SOC and PT –number of subjects and occurrences
Y
Serious Adverse Events by System Organ ClassandPreferred 
Term (Number of Subjects and Occurrences)
Y
Relationship Between System Organ Class And Verbatim 
Text
Y
Subject Numbers for Individual Adverse Events
Y
NOTES:

T = Table, F = Figures, L = Listings, Y = Yes display generated

Summary = Represents TF related to any summaries (i.e. descriptive statistics) of the observed raw 
data.
Individual = Represents FL related to any displays of individual subject observed raw data.


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8.2.
Overview of Planned Clinical Laboratory Analyses
Table 7provides an overview of the planned analyses,with further details of data 
displays being presented inAppendix 10: List of Data Displays.
Table 7
Overview of Planned Clinical Laboratory Analyses
Endpoint / Parameter/ 
Display Type
Absolute
Change from BL
Summary
Individual
Summary
Individual
T
F
L
T
F
L
Chemistry
Clinical Chemistry
Y
Y 
Y
Y
Haematology
Haematology
Y
Y 
Y
Y
Urinalysis
Urinalysis
Y
Y
NOTES:

T = Table, F = Figures, L = Listings, Y = Yes display generated

Summary = Represents TFL related to any summaries (i.e. descriptive statistics) of the observed raw 
data.
Individual = Represents FL related to any displays of individual subject observed raw data.
8.3.
Overview of Planned Other Safety Analyses
Table 8provides an overview of the planned analyses,with further details of data 
displays being presented inAppendix 10: List of Data Displays.
Table 8
Overview of Planned Other Safety Analyses
Endpoint / Parameter/ 
Display Type
Absolute
Change from BL
Summary Individual Summary
Individual
T
F
L
T
F
L
ECG
ECG Findings
Y
Y
ECG Values
Y
Y 
Y
Y
ECG Values Outside the PCI Range
Y
Telemetry
Y
Vital Signs
Vitals Values
Y
Y 
Y
Y
Vital Signs Measurements Outside 
the PCI Range
Y


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NOTES:

T = Table, F = Figures, L = Listings, Y = Yes display generated, PCI = Potential Clinical Importance

Summary = Represents TFL related to any summaries (i.e. descriptive statistics) of the observed raw 
data.
Individual =Represents FL related to any displays of individual subject observed raw data.


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9.
REFERENCES
GlaxoSmithKline Document Number2014N202803_00(Original –13-JAN-
2017):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.
GUI_137354, Information for Authors: Reporting and Analysis Plan (RAP), 
Global
SOP_54838, Development, Review & Approval of Reporting & Analysis Plan 
(RAP), Global
GUI_51487, Non-Compartmental Analysis of Pharmacokinetic Data, CPMS 
Global


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10.
APPENDICES
Section
Appendix
RAP Section 4: Analysis Populations
Section 10.1
Appendix 1: Protocol Deviation Management 
RAP Section 5: General Considerations for Data Analyses & Data Handling 
Conventions
Section 10.2
Appendix 2: Time and Events
Section 10.3
Appendix 3: Treatment States & Phases
Section 10.4
Appendix 4: Data Display Standards & Handling Conventions
Study Treatment & Sub-group Display Descriptors
Baseline Definitions & Derivations
Reporting Process & Standards
Section 10.5
Appendix 5: Derived and Transformed Data
General
Study Population
Safety
Pharmacokinetic
Section 10.6
Appendix 6: Premature Withdrawals & Handling of Missing Data
Premature Withdrawals
Handling of Missing Data
o Handling of Missing Dates
o Handling of Partial Dates
Section 10.7
Appendix 7: Values of Potential Clinical Importance
Laboratory Values
ECG
Vital Signs
Section 10.8
Appendix 8: Model Checking and Diagnostics for Statistical Analyses
Other RAP Appendices
Section 10.9
Appendix 9: Abbreviations & Trade Marks
Section 10.10 Appendix 10: List of Data Displays
Section 10.11 Appendix 11: Example Mock Shells for Data Displays


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10.1
Appendix 1: Protocol Deviation Management
There are no pre-defined categories leading to exclusion from the PK population but all 
protocol deviations will be reviewed on a case-by-case basis. 
No subjects will be excluded from the safety population.


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10.2.1
Protocol Defined Time & Events
Part A
Days
–1
1 
2 
3 
4
15
In
f
ormed
 consen
t
X
Inc
lu
s
ion
/exc
lus
ion
 cr
ite
r
ia
1
X
X
Med
ical
/
surgica
l
 
h
is
tory
X
X
Admiss
io
n
X
Inpa
t
ie
n
t s
ta
y
Dose
 o
f G
SK30366562
X
Echocard
iogram
3
X
X
D
ischarge
X 
X
Outp
a
tie
nt vis
i
t
4
X 
X
X
Sa
fety assessmen
ts
Phys
ical
 
examin
a
tio
n
5
X
X 
X 
X 
X
He
igh
t &
 we
igh
t
5
X
V
i
ta
l s
ig
ns
6
X
X 
X 
X 
X 
X 
X
12-le
ad
 ECG
7
X
X 
X 
X 
X 
X
Ho
lter m
on
itor
ing
8
Tele
met
ry
9
C
lin
ica
l
 
la
boratory as
sessmen
ts
Screen
ing
 
tests
 (in
c
l
 b
lood
 FSH &
 
est
rad
io
l 
f
or 
f
ema
le
 sub
jects
 on
l
y)
X
Haemato
logy,
 b
i
ochemis
t
ry and
 
ur
ina
lysis
10
X
X 
X 
X 
X
Pregnancy te
s
t (fe
male
 on
l
y)
11
X
X
Ur
ine
 drug
 screen
,
 a
lcoho
l &
 
smokin
g
 brea
th
 
tests
X
X
PK
 samp
les
B
lood
 
for PK
 GSK3036656
12
X 
X 
X 
X
Total
 
urin
e
 co
lle
c
tio
n
13
X 
X 
X 
X
Concomi
t
an
t 
t
herapy revie
w14
Adverse even
ts
14
Part A
Follow-
up
-28 to -2
Screening
Day
1
Inc
lus
ion/exc
lus
ion cr
iter
ia w
i
l
l on
ly be assessed at Day-1 of the f
irst per
iod.
2
In the event of a d
iv
ided dose, a
lterat
ions to event t
imepo
ints may be commun
icated 
in a f
i
lenote. For the food 
effect assessment, the se
lected dose w
i
l
l be g
iven w
ith a h
igh fat mea
l.
3
Echocard
iograms may be done at a separate screen
ing v
is
it.
4
When there 
is Ho
lter mon
itor
ing at screen
ing, sub
jects w
i
l
l return after 24 h to have the Ho
lter removed.
5
Br
ief phys
ica
l examinat
ion w
i
l
l be done at adm
iss
ion (Day–1) and 
in the morn
ing on Days 2 and 4 
in each 
10.2
Appendix 2: Time & Events


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31
treatment sess
ion. Fu
l
l phys
ica
l exam
inat
ion w
i
l
l be done at screen
ing and fo
l
low
-up (to 
inc
lude he
ight and 
we
ight at screen
ing on
ly).
6
B
lood pressure, heart rate, tympan
ic temperature and resp
iratory rate. V
ita
l s
igns w
i
l
l be recorded:  at pre-dose 
and at 0.5, 1, 2, 3, 4, 6, 12, 24, 48 and 72 h after dos
ing on Day 1.
7
ECGs w
i
l
l be recorded at pre-dose and at 0.5, 1, 2, 3, 4, 6, 12, 24, 48 and 72 h after dos
ing on Day 1. Tr
ip
l
icate 
measurements (about 2-5 m
ins apart) w
i
l
l be taken at pre-dose; s
ing
le measurements w
i
l
l be taken at a
l
l 
other t
ime po
ints.
8
24 h Ho
lter mon
itor
ing at screen
ing on
ly.
9
Te
lemetry w
i
l
l be recorded from -1 h pre-dose unt
i
l 24 h post-dose
10
Haemato
logy, c
l
in
ica
l chem
istry, and ur
ina
lys
is w
i
l
l be done at Day-1 and at 24 and 72 h post-dose.
11
Pregnancy test
ing of fema
le sub
jects on
ly. At screen
ing pregnancy test w
i
l
l be done us
ing the b
lood samp
le; 
ur
ine pregnancy test w
i
l
l be done on adm
iss
ion.
12
B
lood samp
les for assay of GSK3036656 w
i
l
l 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 dos
ing on Day 1. 
13
Tota
l ur
ine co
l
lect
ions for GSK3036656 w
i
l
l be performed at the fo
l
low
ing t
ime po
ints:  pre-dose and 0-6, 6-12, 
12-24, 24-48 and 48-72 h after dos
ing on Day 1.
14
AEs and concom
itant med
icat
ions w
i
l
l be recorded co
l
lected from the start of 
informed consent unt
i
l the fo
l
low-
up contact.


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32
Part B
Days
–1
1 
2 
3 
4 
5 
6 
7 
8 
9
10
11 
12 
13
14 
15 16 
17 
28
Inf
ormed
 consen
t
X
Inc
lu
s
ion
/exc
lus
ion
 cri
t
eria
X
X
Med
ical
/
surg
ica
l
 h
is
tory
X
X
Admiss
io
n
X
Inpa
t
ie
nt s
t
ay
Dose
 o
f G
SK30366561
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X
Echocard
iogram
2
X
X
D
ischarge
X
X
Ou
tpatie
nt vis
i
t
3
X 
X
X 
X
X
Sa
fety assessments
Phys
ical
 examin
atio
n
4
X
X 
X
X
X
X
X
X
He
ight &
 we
i
gh
t
4
X
V
i
ta
l s
igns
5
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
Ho
lter mon
ito
r
ing
7
Tele
met
ry
8
C
lin
ica
l
 
labor
atory assessm
ents
Screen
ing
 
tests
 (
i
ncl
 b
lood
 F
SH
 &
 
est
rad
io
l 
f
or 
f
ema
le
 sub
jec
ts
 on
ly)
X
Haemato
logy,
 b
i
ochemis
t
ry and
 
ur
ina
lysis
9
X
X
X
X
X
X
X
Serum pregnancy te
s
t (female
 
on
ly)
10
X
X
Ur
ine
 drug
 screen
,
 a
lcoho
l &
 
smokin
g breath tests
X
X
PK
 samp
les
B
lood
 
for
 PK
 GSK303665611
X 
X 
X 
X
X 
X
X 
X 
X 
X
Tota
l
 ur
in
e
 co
lle
c
tio
n
12
X 
X
X 
X
Concomi
t
an
t 
t
herapy rev
i
ew13
Adverse
 events
13
Part B
Screening
Day
Follow
-up
-28 to -2


CONFIDENTIAL
201040
33
1
Dos
ing of GSK3036656 shou
ld be at approx
imate
ly the same t
ime each day. In the event of a d
iv
ided dose, a
lterat
ions to event t
imepo
ints may be commun
icated 
in a f
i
lenote.
2
Echocard
iograms may be done at a separate screen
ing v
is
it.
3
When there 
is Ho
lter mon
itor
ing at screen
ing, sub
jects w
i
l
l return after 24 h to have the Ho
lter removed.
4
Br
ief phys
ica
l exam
inat
ion w
i
l
l be done on Days-1, 2, 4, 6, 10, and 15. Fu
l
l phys
ica
l exam
inat
ion w
i
l
l be done at screen
ing and fo
l
low-up (to 
inc
lude he
ight and we
ight at 
screen
ing on
ly).
5
B
lood pressure, heart rate, tympan
ic temperature and resp
iratory rate. V
ita
l s
igns w
i
l
l be recorded:  at pre-dose and at 0.5, 1, 2, 3, 4, 6, 12, 24, 48 and 72 h after dos
ing on 
Days 1 and 14; and at pre-dose on Days 5-13.
6
ECGs w
i
l
l be recorded at pre-dose and at0.5, 1, 2, 3, 4, 6, 12, 24, 48 and 72 h after dos
ing on Days 1 and 14; and at pre-dose on Days 6 and 10. Tr
ip
l
icate measurements 
(about 2-5 m
ins apart) w
i
l
l be taken at pre-dose; s
ing
le measurements w
i
l
l be taken at a
l
l other t
ime po
ints.
7
24 h Ho
lter mon
itor
ing at screen
ing on
ly.
8
Te
lemetry w
i
l
l be recorded from -1 h pre-dose unt
i
l 24 h post-dose on Day 1.
9
Haemato
logy, c
l
in
ica
l chem
istry and ur
ina
lys
is w
i
l
l be done on Day-1 and 
in the morn
ing (pre-dose 
if feas
ib
le) on Days, 4, 6, 10, and 15.
10
Pregnancy test
ing of fema
le sub
jects on
ly. At screen
ing pregnancy test w
i
l
l be done us
ing the b
lood samp
le; ur
ine pregnancy test w
i
l
l be done on Day-1.
11
B
lood samp
les for assay of GSK3036656 w
i
l
l 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 dos
ing 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 dos
ing on Day 14. PK samp
les w
i
l
l a
lso be taken pre-dose on Days 12 and 13.
12
Tota
l ur
ine co
l
lect
ions for GSK3036656 w
i
l
l be performed at the fo
l
low
ing t
ime po
ints: pre-dose and 0-6, 6-12 and 12-24 h after dos
ing on Days 1 and 14.
13
AEs and concom
itant med
icat
ions w
i
l
l be recorded co
l
lected from the start of 
informed consent unt
i
l the fo
l
low-up contact.


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10.3
Appendix 3: Treatment States 
10.3.1
Treatment States
Assessments and events will be classified according to time of occurrence relative to the 
start and/or stop date and time of the study treatment.
Treatment 
State
Definition
Pre-Treatment
Dateand time< Study Treatment Start Dateand time
On-Treatment
If onset date is on or after treatment start dateand time& on or before the 
treatment stop dateand time
Study Treatment Start Date and time ≤ Dateand time≤ Study Treatment Stop 
Date and time
Post-
Treatment
If onset dateand timeis after the treatment stop dateand time
Date and time> Study Treatment Stop Dateand time
AE Onset 
Time
Since First 
Dose
(Days)
If Treatment Start Date > AE Onset Date = AE Onset Date -Treatment Start 
Date
If Treatment Start Date ≤ AE Onset Date = AE Onset Date -Treatment Start 
Date +1
Missing otherwise
AE Duration 
(Days) 
AE Resolution Date –AE Onset Date + 1
AE Drug-
related
If relationship is marked ‘YES’on eCRF or value is missing. 
NOTES: 
If the study treatment stop date is missing then the AE will be considered to be On-Treatment.


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10.4
Appendix 4: Data Display Standards & Handling Conventions
10.4.1
Study Treatment & Display Descriptors:
Treatment Group Descriptions
RandAll NG
Data Displays for Reporting 
Part
Code
Description
Description[1]
A 
P
Placebo
Placebo
A 
D1
GSK3036656 Dose 1
Dose X mg
A
D2
GSK3036656 Dose 2
Dose X mg
A
D3
GSK3036656 Dose 3
Dose X mg
A
D4
GSK3036656 Dose 4
Dose X mg
A
D5
GSK3036656 Dose 5
Dose X mg
A
D6
GSK3036656 Dose 6
Dose X mg
A
D7
GSK3036656 Dose 7
Dose X mg
A
D8
GSK3036656 Dose 8
Dose X mg
B 
P
Placebo
Placebo
B 
R1
GSK3036656 Repeat Dose 1
Repeat Dose X mg
B
R2
GSK3036656 Repeat Dose 2
Repeat Dose X mg
B
R3
GSK3036656 Repeat Dose 3
Repeat Dose X mg
B
R4
GSK3036656 Repeat Dose 4
Repeat Dose X mg
NOTES:
The decision to proceed to each subsequent dose level will be made by the Dose Escalation Committee 
(DEC)
Note, in tables, figures and listings, treatments should be presented with placebo first, then in order of 
increasing dose within each study part.
1. ‘Dose X’ to be replaced by actual dose.


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10.4.2 
Baseline Definition & Derivations
10.4.2.1
Baseline Definitions
For all endpoints the baseline value will be the latest pre-dose assessment. 
Unless otherwise stated, the mean of replicate assessments at any given time point will be 
used as the value for that time point.
If the latest pre-dose assessment is missing then the previous assessmenttime point 
would be considered as baseline where possible (i.e.if Day 1 (Pre-dose) is missing the 
Day -1 will be used). 
10.4.2.2
Derivations and Handling of Missing Baseline Data
Definition
Reporting Details
Change from Baseline
= Post-Dose Visit Value –Baseline
% Change from Baseline
= 100 x [(Post-Dose Visit Value –Baseline) / Baseline]
NOTES :

Unless otherwise specified, the baseline definitions specified in Section 10.4.2.1Baseline Definitions 
will be used for derivations for endpoints / parameters and indicated on summaries. Unless otherwise 
stated, if baseline data is missing or post-dose data is missing no derivation will be performed and (%) 
change from baseline will be set to missing.
The baseline definition will be footnoted on all change from baseline displays.
10.4.3
Reporting Process & Standards
Reporting Process
Software
The currently supported versions of SASsoftware will be used.
Reporting Area
HARP Server
: UK1SALX00175
HARP Area
: arenv/arprod/GSK3036656/201040/final
QC Spreadsheet
: arenv/arwork/GSK3036656/201040/final/documents
Analysis Datasets 
Analysis datasets will be created according to CDISC standards(SDTM IG Version 
3.1.3 & AdaM IG Version 1.0).
For creation of ADaM datasets (ADCM/ADAE), the same version of dictionary 
datasetswill be implemented for conversion from SI to SDTM.
Generation of RTF Files
RTF files will be generated forSAC.


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Reporting Standards
General
The current GSK Integrated Data Standards Library (IDSL) will be applied for 
reporting, unless otherwise stated:
o 4.03 to 4.23: General Principles
o 5.01 to 5.08: Principles Related to Data Listings
o 6.01 to6.11: Principles Related to Summary Tables
o 7.01 to 7.13: PrinciplesRelated to Graphics 
Formats
All data will be reported according to the actual treatmentthe subject received unless 
otherwise stated.
GSK IDSL Statistical Principles (5.03 & 6.06.3) for decimal places (DP’s) will be 
adopted for reporting of data based on the raw data collected.
Numeric data will be reportedat the precision collected on the eCRF.
The reported precision from non eCRF sources will follow the IDSL statistical 
principles but may be adjusted to a clinically interpretable number of DP’s.
Planned and Actual Time
Reporting for tables, figures and formal statistical analyses :
o Planned time relative to dosing will be used in figures, summaries, statistical 
analyses and calculation of any derived parameters, unless otherwise stated.
o Theimpact of any major deviation from the planned assessment times and/or 
scheduled visit days on the analyses and interpretation of the results will be 
assessed as appropriate.
Reporting for Data Listings: 
o Planned and actual time relative to study drug dosing will be shown in listings 
(Refer to IDSL Statistical Principle 5.05.1).
o Unscheduled or unplannedreadings will be presented within the subject’s listings. 
o Visitsoutside the protocol defined time-windows (i.e. recorded as protocol 
deviations) will be included in listings but omitted from figures, summaries and 
statistical analyses.
Unscheduled Visits
Unscheduled visits will not be included in summary tables.
Unscheduled visits will not be included in figures.
All unscheduled visits will be included in listings.
Descriptive Summary Statistics
Continuous Data
Refer to IDSL Statistical Principle 6.06.1
Categorical Data
N, n, frequency, %
Reporting of Pharmacokinetic Concentration Data
Descriptive 
Summary Statistics
Refer to IDSL Statistical Principle6.06.1and Standards for the 
Transfer and Reporting of PK Data using HARP. 


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Reporting Standards
ForNQ values,refer to GUI_51487.
Reporting of Pharmacokinetic Parameters
Descriptive 
Summary Statistics.                           
(Loge Transformed)   
N, n, geometric mean, 95% CI of geometric mean, standard 
deviation (SD) of logtransformeddata and between subject 
geometric coefficient of variation (CVb (%)) will be reported.
CVb (%) = √ (exp(SD2) -1) * 100
[NOTE: SD = SD of log
etransformed    data]
Parameters Not 
Being Loge
Transformed  
Tmax, t1/2
Summary Tables
Cmax, tmax, AUC(0-τ), AUC(0-t), AUC (0-∞),AUC (Ro), 
RCmax, Cτ, t1/2, Rss, Ae, fe, CLr, as data permit
Listings
Include PK Parameters Cmax, tmax, AUC(0-τ), AUC(0-t), AUC 
(0-∞),AUC (Ro), RCmax, Cτ, t1/2, Rss, Ae, fe, CLr, as data 
permit
Graphical Displays
Refer to IDSL Statistical Principles 7.01 to 7.13and Standards for the Transfer and 
Reporting of PK Data using HARP. 


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10.5
Appendix 5: Derived and Transformed Data
10.5.1
General
Multiple Measurements at One Time Point
Mean of the measurements will be calculated and used in any derivation of summary 
statistics but if listed, all data will be presented.
If there are two values within a time window the value closest to the target day for 
that window will be used. If values are the same distance from the target then the 
mean will be taken.
Subjects having both High and Low values for Normal Ranges at any post-baseline 
visits for safety parameters will be counted in both the High and Low categories of 
“Any visit post-baseline” row of related summary tables. This will also be applicable 
to relevant Potential Clinical Importance summary tables.
Study Day
Calculated as thenumber of days from Treatment start date :
Ref Date = Missing                       →Study Day = Missing 
Ref Date < Treatment start Date   →Study Day = Ref Date –Treatment start Date    
Ref Data ≥ Treatment start Date   →Study Day = (Ref Date –Treatment start 
Date) + 1    
10.5.2
Study Population
Demographics
Age
GSK standard IDSL algorithms will be used for calculating age where birth date will 
be imputed as follows:
o Any subject with a missing day will have this imputed as day ‘15’. 
o Any subject with a missing date and month will have this imputed as ‘30th June’.
Birth date will be presented in listings as ‘YYYY’.
Body Mass Index (BMI)
Calculated as Weight (kg) / [Height (m)]2
Extent of Exposure
Number of days of exposure to study drug will be calculated based on the formula:  
                  Duration of Exposure in Days = Treatment Stop Date –(Treatment Start 
Date) + 1
Subjects who were randomized but did not report a treatment start date will be 
categorised as having zero days of exposure. 
Thecumulative dose will be based on the formula:


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Cumulative Dose = Sum of (Number of Days x Total Daily Dose)
If there are any treatment breaks during the study, exposure data will be adjusted 
accordingly.
10.5.3
Safety
Laboratory Parameters
If a laboratory value which is expected to have a numeric value for summary purposes, 
has a non-detectable level reported in the database, where the numeric value is 
missing, but typically a character value starting with ‘<x’ or ‘>x’ (or indicated as less 
than x or greater than x in the comment field) is present, the number of decimal places
in the observed values will be used to determine how much to add or subtract in order 
to impute the corresponding numeric value. 
Example 1: 2 Decimal Places=  ‘< x ‘ becomes x –0.01
Example 2: 1 Decimal Places=  ‘> x’ becomesx + 0.1
Example 3: 0 Decimal Places= ‘< x’ becomes x –1
10.5.4
Pharmacokinetic
PK Parameters
The PK Population will include all subjects who undergo PK sampling and have 
evaluable PK assay results. 
See table 5 for derived Pharmacokinetic parameters


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10.6
Appendix 6: Premature Withdrawals & Handling of Missing Data
10.6.1
Premature Withdrawals
Element
Reporting Detail
General
A completed subject is one who has completed all phases of the study 
including the follow-up visit. 
Withdrawn subjects may be replaced in the study. 
All subjects who withdraw prematurely from the study/study drug will 
be documented and the reason for their withdrawal recorded in the final 
Clinical Pharmacology Study Report (CPSR).  
All available data collected up until the point of withdrawal,and the 
follow-up visits will be used in the analyses and will be listed and all 
available planned data will be included in the summaries according to 
the populations defined in Section 4unless otherwise specified.
10.6.2
Handling of Missing Data
Element
Reporting Detail
General
Missing data occurs when any requested data is not provided, leading to 
blank fields on the collection instrument :
These data will be indicated by the use of a “blank” in subject listing 
displays. Unlessall data for a specific visit are missing in which case 
the data is excluded from the table. 
Answers such as “Not applicable” and “Not evaluable” are not 
considered to be missing data and should be displayed as such.
Outliers
Any subjects excluded from the summaries and/or statistical analyses 
will be documented along with the reason for exclusion in the clinical 
study report.
10.6.2.1
Handling of Missing Dates
Element
Reporting Detail
General
Partial dates will be displayed as captured in subject listing displays.
Adverse 
Events
The eCRF allows for the possibility of partial dates (i.e., only month and 
year) to be recorded for AE start and end dates; that is, the day of the 
month may be missing. In such a case, the following conventions will be 
applied for calculating the time to onset and the duration of the event:
Missing Start Day:First of the month will be used unless this is 
before the start date of investigational product; in this case the study 
treatment start date will be used (and hence the event isconsidered 


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Element
Reporting Detail
On-treatment as per Appendix 3: Treatment States and Phases).
Missing Stop Day: Last day of the month will be used, unless this is 
after the stop date of study treatment; in this case the study treatment 
stop date will be used.
Completely missing start or end dates will remain missing, with no 
imputation applied. Consequently, time to onset and duration of such 
events will be missing.
AEs with entirely missing or unknown start dates will be assumed to be 
on-treatment for reporting. 
AEs with missing end dates are not anticipated to affect reporting. 
10.6.2.2
Handling of Partial Dates
Element
Reporting Detail
Concomitant 
Medications
Partial dates for any concomitant medications recorded in the CRF will 
be imputed using the following convention:
If the partial date is a start date, a 
'01
' will be used for the day and 
'J
an
' will be used for the month
If the partial date is a stop date, a 
'28/29/30/31
' will be used for the 
day (dependent on the month and year) and 
'Dec' 
will be used for 
the month.
The recorded partial date will be displayed in listings.
Adverse 
Events
Any partial dates for adverse events will be raised to data management. 
If the full date cannot be ascertained, the following assumptions will be 
madefor calculating the time to onset and the duration of the event:
If the partial date is a start date, a 
'01
' will be used for the day and 
'J
an
' will be used for the month,unless this is before the start date 
of investigational product; in this case the study treatment start date 
will be used (and hence the event is considered on-treatment as per 
Appendix 3: Treatment States).
If the partial date is a stop date, a 
'28/29/30/31
' will be used for the 
day (dependent on the month and year) and 
'Dec
' will be used for 
the month, unless this is after the stop date of study treatment; in 
this case the study treatment stop date will be used.
The recorded partial date will be displayed in listings.


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10.6.2.3
Handling of PK Concentration Data
Element
Reporting Detail
General
The PK Population will include all subjects who undergo PK sampling 
and have evaluable PK assay results. This population will be used for the 
concentration listing, summaries and plotting of the individual 
concentration-time profiles.
PK assay results from samples collected from a subject with vomiting 
occurring within 2 times the median Tmax will not be considered as 
evaluable for that period. 
If the pre-dose concentration is ≤ 5% of Cmax value in a subject, the 
concentration data for that subject without any adjustments will be 
included in pharmacokinetic and statistical analysis. If the pre-dose 
concentration is > 5% of Cmax value in a subject, then the 
concentration data for that subject will not be included in 
pharmacokinetic and statistical analysis and only the concentration data 
of that subject(s) will be presented
For missing and NQ values, refer to GUI_51487.
10.6.2.4
Handling of Missing Data for Statistical Analysis
Element
Reporting Detail
Imputation No imputation will be performed for missing data


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10.7
Appendix 7: Values of Potential Clinical Importance
10.7.1
Laboratory Values
Haematology
Laboratory 
Parameter
Units
Category
Clinical Concern Range
Low Flag (< x)
High Flag (>x)
Hematocrit 
Ratio of 1
Male
0.54
Female
0.54
∆ from BL
↓0.075
Hemoglobin 
g/L
Male
180
Female
180
∆ from BL
↓25
Lymphocytes 
x109/ L
0.8
Neutrophil Count 
x109/ L
1.5
Platelet Count 
x109/ L
100
550
While Blood Cell 
Count (WBC)
x109/ L
3
20
Clinical Chemistry
Laboratory 
Parameter
Units
Category
Clinical Concern Range
Low Flag (< x)
High Flag (>x)
Albumin 
mmol/L
30
Calcium
mmol/L
2
2.75
Creatinine
mmol/L
∆ from BL
↑ 44.2
Glucose
mmol/L
3
9
Potassium
mmol/L
3
5.5
Sodium
mmol/L
130
150
Liver Function
Test Analyte
Units
Category
Clinical Concern Range
ALT/SGPT 
U/L
High
2x ULN
AST/SGOT 
U/L
High
2x ULN
AlkPhos 
U/L
High
2x ULN
T Bilirubin 
µmol/L
High
1.5xULN
T. Bilirubin + ALT
µmol/L
High
1.5xULN T. Bilirubin
+
U/L
2x ULN ALT


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10.7.2
ECG
ECG Parameter
Units
Clinical Concern Range
Lower
Upper
Absolute
Absolute QTc Interval
msec
> 450
Absolute PR Interval
msec
< 110
> 220
Absolute QRS Interval
msec
< 75
> 110
Change from Baseline
Increase from Baseline 
QTc
msec
> 60
10.7.3
Vital Signs
Vital Sign Parameter
(Absolute)
Units
Clinical Concern Range
Lower
Upper
Systolic Blood Pressure
mmHg
< 85
> 160
Diastolic Blood 
Pressure
mmHg
< 45
> 100
Heart Rate
bpm
< 40
> 110


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10.8
Appendix 8: Model Checking and Diagnostics for Statistical 
Analyses
10.8.1
Statistical Analysis Assumptions
Endpoint(s) PK End points AUCand Cmax
Analysis
Mixed Model
Assumptions:
For the Mixed Model, model assumptions will be checked, andappropriate 
adjustments may be applied based on the data.
Distributional assumptions underlying the model used for analysis will be examined 
by obtaining a normal probability plot of the residuals and a plot of the residuals 
versus the fitted values (i.e. checking the normality assumption and constant variance 
assumption of the model respectively) to gain confidence that the model assumptions 
are reasonable. 
If there are any departures from the distributional assumptions, alternative 
transformations, such as data squaredor square rootof data, will be explored. 
Non-parametric analyses willbe conducted if the normality assumption does not hold.


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10.9
Appendix 9:Abbreviations & Trade Marks
10.9.1
Abbreviations
µg
Microgram
z
Terminal phase rate constant
AE
Adverse Event
Ae
Excretion of unchanged drug
AIC
Akaike
's InformationCriteria
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
CDISC
Clinical Data Interchange Standards Consortium
CI
Confidence Interval
CL
Clearance
CLr
Renal Clearance
Cmax
Maximum observed concentration 
CPMS
Clinical Pharmacology Modelling and Simulation
CPSR
Clinical Pharmacology Study Report
CPSSO
Clinical Pharmacology Sciences and Study Operations
CRF
Case Report Form
Cτ 
Trough concentration (Cτ) 
CV
Coefficient of variance
DBR
Database Release
DEC
Dose Escalation Committee
DP’s
Decimal places
ECG
Electrocardiogram
ESS
Effective sample size 
fe
Fraction of the dose excreted in urine
GSK
GlaxoSmithKline
h
Hour
HARP
Harmonized Analysis and  Reporting Process
Hg
Mercury


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ICH
International Conference on Harmonisation
IDSL
Integrated Data Standards Library
kg
Kilogram
L
Litres
MCMC
Markov Chain Monte Carlo
MCSE
Monte Carlo Standard Error
mg
Milligram
mL
Millilitre
mm
Millimetre
MM
Mixed Model
nm
Nanometer
NOAEL
No Observed Adverse Effect Level
PK
Pharmacokinetic
PTS
Platform Technologies and Science
QSI
Quantitative Sciences India
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
Rss
Steady-State Ratio
SAC
Statistical Analysis Complete
SAE
Serious adverse event(s)
SAS
Statistical Analysis System
SD
Standard Deviation
SGOT
Serum glutamic-oxaloacetic transaminase
SGPT
Serum glutamic pyruvic transaminase
SPDS
Statistics, Programming and Data Sciences
t½
Terminal phase half-life
Tmax
Time of occurrence of Cmax
TB
Tuberculosis
tmax
Time of occurrence of Cmax
ULN
Upper Limit of Normal
WBC
White blood cells
10.9.2
Trademarks
Trademarks of the GlaxoSmithKline 
group of companies
Trademarks not owned by the 
GlaxoSmithKline group of 
companies
NONE
R
SAS
WinNonlin


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10.10
Appendix 10: List of Data Displays
10.10.1
Data Display Numbering
The following numbering will be appliedfor RAP generated displays:
Section
Tables
Figures
Study Population
1.1 to 1.23
N/A
Pharmacokinetic
2.1 to 2.15
2.1 to 2.8
Safety
3.1 to 3.32
N/A
Dose Escalation
4.1to 4.2
4.1 to 4.4
Section
Listings
ICH Listings
1 to 32
Other Listings
33to 41
10.10.2
Mock Example Shell Referencing
Non IDSL specifications will be referenced as indicated and if required an example 
mock-up displays provided inAppendix 11: Example Mock Shells for Data Displays.
Section
Figure
Table
Listing
Pharmacokinetic
PK_Tn
Dose Escalation
DE_Fn
DE_Tn
NOTES: 
Non-Standard displays are indicated in the ‘IDSL / TST ID / Example Shell’ or 
‘Programming Notes’ column as ‘[Non-Standard] + Reference.’
10.10.3
Deliverable
Delivery 
Description
DE 
Dose Escalation
SAC 
Statistical Analysis Complete


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10.10.4
Study Population Tables
Study Population Tables
No.
Population
IDSL / TST 
ID / 
Example 
Shell
Title
Programming Notes
Deliverable 
[Priority]
Subject Disposition
1.1.
Enrolled
ES4
Summary of Subject Disposition–Part A
SAC 
1.2.
Enrolled
ES4
Summary of Subject Disposition –Part B
SAC
1.3.
Enrolled
ES6
Summary of Screening Status and Reasons for Screen 
Failure –Part A
SAC
1.4.
Enrolled
ES6
Summary of Screening Status and Reasons for Screen 
Failure –Part B
SAC
1.5.
Safety
SD1
Summary of Reasons for Study Treatment Discontinuation
–Part B
SAC
1.6.
Safety
ES1
Summary of Reasons for Study Withdrawal during the 
Study –Part A
SAC
1.7.
Safety
ES1
Summary of Reasons for Study Withdrawal during the 
Study –Part B
SAC
1.8.
Safety
IE1
Summary of Inclusion/Exclusion Criteria Deviations –Part 
A
SAC
1.9.
Safety
IE1
Summary of Inclusion/Exclusion Criteria Deviations –Part 
B
SAC


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Study Population Tables
No.
Population
IDSL / TST 
ID / 
Example 
Shell
Title
Programming Notes
Deliverable 
[Priority]
Protocol Deviation
1.10.
Safety 
DV1
Summary of Important Protocol Deviations–Part A
SAC
1.11.
Safety 
DV1
Summary of Important Protocol Deviations–Part B 
SAC
Population Analysed
1.12.
Safety 
SP1
Summary of Study Populations–Part A
SAC
1.13.
Safety 
SP1
Summary of Study Populations–Part B
SAC
Demography
1.14.
Safety 
DM1
Summary of Demographic Characteristics–Part A
Include BMI
SAC
1.15.
Safety 
DM1
Summary of Demographic Characteristics–Part B
Include BMI
SAC
1.16.
Safety 
DM5
Summary of Race and Racial Combinations–Part A
SAC
1.17.
Safety 
DM5
Summary of Race and Racial Combinations–Part B
SAC
Concomitant  Medications
1.18.
Safety 
CM1 
Summary of Concomitant Medications –Part A
SAC
1.19.
Safety 
CM1 
Summary of Concomitant Medications –Part B
SAC


CONFIDENTIAL
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52
Study Population Tables
No.
Population
IDSL / TST 
ID / 
Example 
Shell
Title
Programming Notes
Deliverable 
[Priority]
Exposure and Treatment Compliance
1.20.
Safety
EX1
Summary of Exposure to Study Drug –Part A
SAC
1.21.
Safety
EX1
Summary of Exposure to Study Drug –Part B
SAC
1.22.
Safety
COMP1
Summary of Overall Compliance Based on Exposure –Part 
A
SAC
1.23.
Safety
COMP1
Summary of Overall Compliance Based on Exposure –Part 
B
SAC
10.10.5
PharmacokineticTables
PharmacokineticTables
No.
Population
IDSL / TST 
ID / 
Example 
Shell
Title
Programming Notes
Deliverable 
[Priority]
Pharmacokinetic
2.1.
PK
PK01
Summary of Plasma GSK3036656Pharmacokinetic 
Concentration-Time data –Part A
SAC
2.2.
PK
PK01
Summary of Plasma GSK3036656 Pharmacokinetic 
Concentration-Time data –Part B
SAC


CONFIDENTIAL
201040
53
PharmacokineticTables
No.
Population
IDSL / TST 
ID / 
Example 
Shell
Title
Programming Notes
Deliverable 
[Priority]
2.3.
PK 
PK02
Summary of Pharmacokinetic Urine Excretion Rate-Time 
Data –Part A
SAC
2.4.
PK 
PK02
Summary of Pharmacokinetic Urine Excretion Rate-Time 
Data –Part B
SAC
2.5.
PK
PK03
Summary of Derived Plasma GSK3036656
Pharmacokinetic Parameters(untransformed data)–Part A
SAC
2.6.
PK
PK03
Summary of Derived Plasma GSK3036656 
Pharmacokinetic Parameters(untransformed data)–Part B
SAC
2.7.
PK
PK05
Summary of Derived Plasma GSK3036656 
Pharmacokinetic Parameters (log-transformed data)–Part A
SAC
2.8.
PK
PK05
Summary of Derived Plasma GSK3036656 
Pharmacokinetic Parameters (log-transformed data)–Part B
SAC
2.9.
PK
Non-
Standard 
PK_T1
Statistical Analysis of log transformed plasma 
GSK3036656 Pharmacokinetic Parameters Assessing Dose 
Proportionality (Power Model) –Part A
AUC(0-t), AUC(0-∞) 
and Cmax
SAC
2.10.
PK
Non-
Standard 
PK_T1
Statistical Analysis of log transformed plasma 
GSK3036656 Pharmacokinetic Parameters Assessing Dose 
Proportionality (Power Model) –Part B
AUC(0-τ) and Cmax
SAC
2.11.
PK
Non-
Standard 
PK_T2
Statistical Analysis of log transformed plasma 
GSK3036656 Pharmacokinetic Parameters Assessing Food 
Effect–Part A
Only for Single Dose 
Study Phase: AUC(0-t), 
AUC(0-∞), Cmax and
t1/2
SAC


CONFIDENTIAL
201040
54
PharmacokineticTables
No.
Population
IDSL / TST 
ID / 
Example 
Shell
Title
Programming Notes
Deliverable 
[Priority]
2.12.
PK
Non-
Standard 
PK_T3
Non-Parametric Analysis of Pharmacokinetic Parameter
Assessing Food Effect-Tmax –Part A
Only for Single Dose 
Study Phase: T-max
SAC
2.13.
PK
Non-
Standard 
PK_T4
Statistical Analysis of log transformed plasma 
GSK3036656 Pharmacokinetic Parameters Assessing Time 
Invariance–Part B
Only for Repeat Dose 
Study Phase
SAC
2.14.
PK
Non-
Standard 
PK_T5
Statistical Analysis of log transformed plasma 
GSK3036656 Pharmacokinetic Parameters Assessing 
AccumulationRatio–Part B
Only for Repeat Dose 
Study Phase; AUC(Ro) 
and RCmax
SAC
2.15.
PK
Non-
Standard 
PK_T6
Statistical Analysis of log transformed plasma 
GSK3036656 Pharmacokinetic Parameters Assessing 
Steady State–Part B
Only for Repeat Dose 
Study Phase
SAC
10.10.6 
Pharmacokinetic Figures
Pharmacokinetic Figures
No.
Population
IDSL / TST 
ID / 
Example 
Shell
Title
Programming Notes
Deliverable 
[Priority]
Pharmacokinetic
2.1.
PK
PK16a
Individual Subject Plasma GSK3036656 Concentration-
time Plot (Linear and Semi-log) by Subject
By part
SAC


CONFIDENTIAL
201040
55
Pharmacokinetic Figures
No.
Population
IDSL / TST 
ID / 
Example 
Shell
Title
Programming Notes
Deliverable 
[Priority]
2.2.
PK
PK24
Individual Subject Plasma GSK3036656 Concentration-
time Plot (Linear and Semi-log) by Treatment
By part
SAC
2.3.
PK
PK17
Mean Plasma GSK3036656 Concentration-Time Plots 
(Linear and Semi-log)by treatment
By part
SAC
2.4.
PK
PK18
Median Plasma GSK3036656Concentration-Time Plots 
(Linear and Semi-log)by treatment
By part
SAC
2.5.
PK
PK21
Individual Urine Excretion Rate-Time Plots (Linear and 
Semi-log)by subject
By part
SAC
2.6.
PK
PK22
Mean Urine Excretion Rate-Time Plots (Linear and Semi-
log)by treatment
By part
SAC
2.7.
PK
PK23
Median Urine Excretion Rate-Time Plots (Linear and Semi-
log)by treatment
By part
SAC
2.8.
PK
PK25
Comparative Plot of Individual Subject  Plasma 
GSK3036656 Pharmacokinetic  Parameter Versus 
Treatment
By part
SAC


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10.10.7
SafetyTables
SafetyTables
No.
Population
IDSL / TST 
ID / 
Example 
Shell
Title
Programming Notes
Deliverable 
[Priority]
Adverse Events
3.1.
Safety 
AE1
Summary of All Adverse Events by System Organ Class 
and Preferred Term –Part A
SAC
3.2.
Safety 
AE1
Summary of All Adverse Events by System Organ Class 
and Preferred Term–Part B
SAC
3.3.
Safety 
AE3
Summary of Serious Adverse Events –Part A
SAC
3.4.
Safety 
AE3
Summary of Serious Adverse Events –Part B
SAC
3.5.
Safety 
AE3
Summary of Drug Related Adverse Events –Part A
SAC
3.6.
Safety 
AE3
Summary of Drug Related Adverse Events –Part B
SAC
3.7.
Safety 
AE3
Summary of Adverse Events Leading Withdrawal from 
Study –Part A
SAC
3.8.
Safety 
AE3
Summary of Adverse Events Leading Withdrawal from 
Study –Part B
SAC
3.9.
Safety
AE15
Summary of Common (>=5%)Non-serious Adverse Events 
by System Organ Class and Preferred Term (Number of 
Subjects and Occurrences) -Part A
SAC


CONFIDENTIAL
201040
57
SafetyTables
No.
Population
IDSL / TST 
ID / 
Example 
Shell
Title
Programming Notes
Deliverable 
[Priority]
3.10.
Safety
AE15
Summary of Common (>=5%) Non-serious Adverse Events 
by System Organ Class and Preferred Term (Number of 
Subjects and Occurrences) -Part B
SAC
3.11.
Safety
AE16
Summary of Serious Adverse Events by System Organ 
Class and Preferred Term (Number of Subjects and 
Occurrences) –Part A
SAC
3.12.
Safety
AE16
Summary of Serious Adverse Events by System Organ 
Class and Preferred Term (Number of Subjects and 
Occurrences) –Part B
SAC
Laboratory Measurements
3.13.
Safety
LB1
Summary of Clinical Chemistry Values –Part A
SAC
3.14.
Safety
LB1
Summary of Clinical Chemistry Values –Part B
SAC
3.15.
Safety
LB1
Summary of Change from Baseline for Clinical Chemistry 
Values –Part A
SAC
3.16.
Safety
LB1
Summary of Change from Baseline for Clinical Chemistry 
Values –Part B
SAC
3.17.
Safety
LB1
Summary of Haematology Values –Part A
SAC
3.18.
Safety
LB1
Summary of Haematology Values –Part B
SAC


CONFIDENTIAL
201040
58
SafetyTables
No.
Population
IDSL / TST 
ID / 
Example 
Shell
Title
Programming Notes
Deliverable 
[Priority]
3.19.
Safety
LB1
Summary of Change from Baseline for Haematology 
Values –Part A
SAC
3.20.
Safety
LB1
Summary of Change from Baseline for Haematology 
Values –Part B
SAC
3.21.
Safety
UR3
Summary of Urinalysis Dipstick Results –Part A
SAC
3.22.
Safety
UR3
Summary of Urinalysis DipstickResults –Part B
SAC
ECG
3.23.
Safety
EG1
Summary of ECG Findings –Part A
SAC
3.24.
Safety
EG1
Summary of ECG Findings –Part B
SAC
3.25.
Safety
EG2
Summary of ECG Values –Part A
SAC
3.26.
Safety
EG2
Summary of ECG Values –Part B
SAC
3.27.
Safety
EG2
Summary of  Change from Baseline for ECG Values –Part 
A
SAC
3.28.
Safety
EG2
Summary of  Change from Baseline for ECG Values –Part 
B
SAC
Vital Signs
3.29.
Safety
VS1
Summary of Vital Signs –Part A
SAC


CONFIDENTIAL
201040
59
SafetyTables
No.
Population
IDSL / TST 
ID / 
Example 
Shell
Title
Programming Notes
Deliverable 
[Priority]
3.30.
Safety
VS1
Summary of Vital Signs –Part B
SAC
3.31.
Safety
VS1
Summary of Change from Baseline for Vital Signs –Part A
SAC
3.32.
Safety
VS1
Summary of Change from Baseline for Vital Signs –Part B
SAC
10.10.8
Dose Escalation Tables
Dose Escalation Tables
No.
Population
IDSL / TST 
ID / 
Example 
Shell
Title
Programming Notes
Deliverable 
[Priority]
Dose Escalation Meetings
4.1.
PK
Non-
Standard 
DE_T1
Summary of PK parameters for Part A –Bayesian 
Prediction
Example given for Part 
A, same outputs will be 
produced for Part B
DE
4.2.
PK
Non-
Standard 
DE_T2
Summary of PK Parameters for Part A –Bayesian 
Predictive Probability of Exceeding Threshold
Example given for Part 
A, same outputs will be 
produced for Part B
DE


CONFIDENTIAL
201040
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10.10.9
Dose Escalation Figures
Dose Escalation Figures
No.
Population
IDSL / TST 
ID / 
Example 
Shell
Title
Programming Notes
Deliverable 
[Priority]
Dose Escalation Meetings
4.1.
PK
Non-
Standard 
DE_F1
Dose Response Curve of Predictive Distributions for AUC[0-24] 
-Part A
Example given for Part 
A, same outputs will be 
produced for Part B
DE
4.2.
PK
Non-
Standard 
DE_F2
Density Plot of Predictive Distributions for AUC[0-24] -Part A
Example given for Part 
A, same outputs will be 
produced for Part B
DE
4.3.
PK
Non-
Standard 
DE_F1
Dose Response Curve of Predictive Distributions for Cmax -Part 
A
Example given for Part 
A, same outputs will be 
produced for Part B
DE
4.4.
PK
Non-
Standard 
DE_F2
Density Plot of Predictive Distributions for Cmax -Part A
Example given for Part 
A, same outputs will be 
produced for Part B
DE


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201040
61
10.10.10 ICH Listings
ICH : Listings
No.
Population
IDSL / TST 
ID / 
Example 
Shell
Title
Programming Notes
Deliverable
Randomization
1.
Safety
CP_TA1
Listing of Randomized and Actual Treatments
By part
SAC
Subject Disposition
2.
Safety
SD2
Listing of reasons for study treatment 
discontinuation
Only for Part B
SAC
3.
Safety
ES2
Listing of Reasons for Study Withdrawal
By part
SAC
4.
Enrolled
ES7
Listing of Reasons for Screening Failure
By part
SAC
5.
Safety
DV2
Listing of Important Protocol Deviations
By part
SAC
6.
Safety
IE3
Listing of Subjects with Inclusion/Exclusion Criteria 
Deviations
By part
SAC
Demography
7.
Safety
DM2
Listing of Demographic Characteristics 
By part
SAC
8.
Safety
DM9
Listing of Race
By part
SAC
9.
Safety
SP3
Listing of Subjects Excluded from Any Population
By part
SAC
Medical/Surgical History & Concomitant  Medications
10. 
Safety
SP1
Listing of Medical/Surgical Procedures
By part
SAC
11.
Safety
CM3
Listing of Concomitant Medications
By part
SAC


CONFIDENTIAL
201040
62
ICH : Listings
No.
Population
IDSL / TST 
ID / 
Example 
Shell
Title
Programming Notes
Deliverable
Exposure and Treatment Compliance
12.
Safety
EX3
Listing of Exposure Data
By part
SAC
13.
Safety
COMP2
Listing of Overall Compliance
By part
SAC
Adverse Events
14.
Safety
AE7
Listing of Subject Numbers for Individual Adverse 
Events
By part
SAC
15.
Safety
AE8
Listing of All Adverse Events
By part
SAC
16.
Safety
AE8
Listing of Serious Adverse Events
By part
SAC
17.
Safety
AE8
Listing of Drug-Related Adverse Events
By part
SAC
18.
Safety
AE8
Listing of Adverse Events Leading to Withdrawal 
from Study
By part
SAC
19.
Safety
AE2
Listing of Relationship Between Adverse Event 
System Organ Classes, Preferred Terms, and 
Verbatim Text
SAC
Laboratory Measurements
20.
Safety
LB5
Listing of Clinical Chemistry Values
By part
SAC
21.
Safety
LB5
Listing of Change from Baseline for Clinical 
Chemistry Values
By part
SAC
22.
Safety
LB5
Listing of Haematology Values
By part
SAC


CONFIDENTIAL
201040
63
ICH : Listings
No.
Population
IDSL / TST 
ID / 
Example 
Shell
Title
Programming Notes
Deliverable
23.
Safety
LB5
Listing ofChange from Baseline for Haematology 
Values
By part
SAC
24.
Safety
UR2b
Listing of Urinalysis Data
By part
SAC
ECGs
25.
Safety
EG5
Listing of ECG Findings
By part
SAC
26.
Safety
EG3
Listing of ECG Values
By part
SAC
27.
Safety
EG3
Listing of Change from Baseline for ECG Values
By part
SAC
28.
Safety
CP_EG4
Listing of ECG Values OfPotential Clinical 
Importance 
By part
SAC
29.
Safety
CP_EG6
Listing of Telemetry
By part
SAC
Vital Signs
30.
Safety
CP_VS5
Listing of Vital Signs
By part
SAC
31.
Safety
CP_VS5
Listing of Change from Baseline for Vital Signs
By part
SAC
32.
Safety
CP_VS5
Listing of Vital SignValues ofPotential Clinical 
Importance 
By part
SAC


CONFIDENTIAL
201040
64
10.10.11 Non-ICH Listings
ICH : Listings
No.
Population
IDSL / TST 
ID / 
Example 
Shell
Title
Programming Notes
Deliverable
Pharmacokinetic
33.
PK
PK07
Listing of Plasma Pharmacokinetic Concentration-
Time Data
By part
SAC
34.
PK
PK09 
Listing of Urine Sample Collections
By part
SAC
35.
PK 
PK11
Listing of Urine Excretion Rate Data
By part
SAC
36.
PK
PK13
Listing of Derived Plasma Pharmacokinetic 
Parameters
By part
SAC
37.
PK
N/A
RAW SAS Output from Summary of Statistical 
Analysis of log transformed plasma GSK3036656 
Pharmacokinetic Parameters Assessing Dose 
Proportionality (Power Model) 
By part
SAC
38.
PK
N/A
RAW SAS Output from Summary of Statistical 
Analysis of log transformed plasma GSK3036656 
Pharmacokinetic Parameters Assessing Food Effect
By part
SAC
39.
PK
N/A
RAW SAS Output from Summary of Statistical 
Analysis of log transformed plasma GSK3036656 
Pharmacokinetic Parameters Assessing 
Accumulation
By part
SAC


CONFIDENTIAL
201040
65
ICH : Listings
No.
Population
IDSL / TST 
ID / 
Example 
Shell
Title
Programming Notes
Deliverable
40.
PK
N/A
RAW SAS Output from Summary of Statistical 
Analysis of log transformed plasma GSK3036656 
Pharmacokinetic Parameters Assessing Steady State
By part
SAC
41.
PK
N/A
RAW SAS Output from Non-Parametric Analysis of 
Pharmacokinetic Parameter-Tmax 
By part
SAC


CONFIDENTIAL
201040
66
10.11
Appendix 11: Example Mock Shells for Data Displays
Example 
: DE_T1
Page 1 of n
Protocol
: GSK3036656
Population
: Pharmacokinetic 
Table DE_T1
Summary of PK Parameters for Part A – Bayesian Prediction
PK Parameter
  Statistics
XX mg
XX mg
XX mg
XX mg
XX mg
XX mg
AUC[0-24] (µg.h/mL)
  N
      X
      X
      X
      NA
      NA
      NA
  Observed Mean
     X.XX
     X.XX
     X.XX
      NA
      NA
      NA
  Predictive Distribution
    Mean
     X.XX
     X.XX
     X.XX
     X.XX
     X.XX
     X.XX
    5th Percentile
     X.XX
     X.XX
     X.XX
     X.XX
     X.XX
     X.XX
    Median
     X.XX
     X.XX
     X.XX
     X.XX
     X.XX
     X.XX
    95th Percentile
     X.XX
     X.XX
     X.XX
     X.XX
     X.XX
     X.XX
Cmax (µg/mL)
  N
      X
      X
      X
      NA
      NA
      NA
  Observed Mean
     X.XX
     X.XX
     X.XX
      NA
      NA
      NA
  Predictive Distribution
    Mean
     X.XX
     X.XX
     X.XX
     X.XX
     X.XX
     X.XX
    5th Percentile
     X.XX
     X.XX
     X.XX
     X.XX
     X.XX
     X.XX
    Median
     X.XX
     X.XX
     X.XX
     X.XX
     X.XX
     X.XX
    95th Percentile
     X.XX
     X.XX
     X.XX
     X.XX
     X.XX
     X.XX


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201040
67
Example 
: DE_T2
Page 2of n
Protocol
: GSK3036656
Population
: Pharmacokinetic 
Table DE_T2
Summary of PK Parameters for Part A – Bayesian Predictive Probability of Exceeding Threshold
PK Parameter
Threshold
Probability (greater than threshold | observed data)
XX mg
XX mg
XX mg
XX mg
XX mg
XX mg
AUC[0-24] (µg.h/mL)
4.9
0.XX
0.XX
0.XX
0.XX
0.XX
0.XX
Cmax (µg/mL)
0.443
0.XX
0.XX
0.XX
0.XX
0.XX
0.XX


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201040
68
Example 
: DE_F1
Page3of n
Protocol
: GSK3036656
Population
: Pharmacokinetic 
Table DE_F1
Dose Response Curve of Predictive Distributions for AUC[0-24] Part A


CONFIDENTIAL
201040
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Example 
: DE_F2
Page 4of n
Protocol
: GSK3036656
Population
: Pharmacokinetic 
Table DE_F2
Density Plot of Predictive Distributions for AUC[0-24] Part A


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Example 
: PK_T1
Page 5of n
Protocol
: GSK3036656
Population
: Pharmacokinetic 
Table PK_T1
Statistical Analysis of log transformed plasma GSK3036656 Pharmacokinetic Parameters Assessing Dose Proportionality (PowerModel)
Part A/ Part B
   
                            
Slope                   
   90% CI
   Parameter (units)               
  Log Parameter vs Log Dose       
  of theSlope
   -----------------------------------------------------------------------------------------------------------------------------------------
   AUC(0-t) (µg.h/mL)
x.xx                   
(x.xxx, x.xxx)
   
     
  AUC(0-∞) (µg.h/mL)
  
x.xx                     
(x.xxx, x.xxx)
      
         AUC(0-τ)(µg.h/mL)
x.xx                     
(x.xxx, x.xxx)
     
  Cmax (µg/mL)
  x.xx                    
(x.xxx, x.xxx)


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Example 
: PK_T2
Page 6of n
Protocol
: GSK3036656
Population
: Pharmacokinetic 
                                                                                       
                            Table PK_T2
Statistical Analysis of log transformed plasma GSK3036656 Pharmacokinetic Parameters Assessing Food EffectPart A
        
      Parameter(units)       Treatment        Comparison          
Geom.LsMean                
Ratio                    90% 
                                                                                                       ------------------------------                                     Confidence Interval
                                                                                                              n        Test            n       Ref
  --------------------------------------------------------------------------------------------------------
AUC(0-t)(µg.h/mL)   XXmg   Fed vs Fasted     xx   x.xxx    xx x.xxx   x.xxx    (x.xxx,  x.xxx)
AUC(0-∞)(µg.h/mL)      XXmg    Fed vs Fasted     xx   x.xxx    xx x.xxx   x.xxx    (x.xxx,  x.xxx)
Cmax (µg/mL)
     XXmg    Fed vs Fasted     xx   x.xxx    xx x.xxx   x.xxx    (x.xxx,  x.xxx)
T1/2 (µg/mL)
     XXmg    Fed vs Fasted     xx   x.xxx    xx x.xxx   x.xxx    (x.xxx,  x.xxx)


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201040
72
Example 
: PK_T3
Page 7of n
Protocol
: GSK3036656
Population
: Pharmacokinetic 
                            Table PK_T3
                           Non-Parametric Analysis of Pharmacokinetic ParameterAssessing Food Effect-Tmax Part A
        
      Parameter(units)       Treatment        Comparison           
         Median               
Diff                   90% 
                                                                                                                  ------------------------------                               Confidence Interval
                                                                                                              n        Test            n      Ref
  --------------------------------------------------------------------------------------------------------
Tmax (µg/mL)
  XXmg    Fed vs Fasted     xx   x.xxx    xx x.xxx   x.xxx    (x.xxx, x.xxx)


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Example 
: PK_T4
Page8of n
Protocol
: GSK3036656
Population
: Pharmacokinetic 
                                                                                       
                            Table PK_T4
Statistical Analysis of log transformed plasma GSK3036656 Pharmacokinetic Parameters Assessing Time Invariance Part B
        
      Parameter(units)      
Treatment        Comparison          Ratio                    90% 
                                                                                                                                 
Confidence Interval
  --------------------------------------------------------------------------------------------------------
AUC(0-)(µg.h/mL) Vs AUC(0-inf)(µg.h/mL)
  XXmg    Day 14 vs Day   x.xxx     (x.xxx,  x.xxx)
   


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Example 
: PK_T5
Page 9of n
Protocol
: GSK3036656
Population
: Pharmacokinetic 
                            Table PK_T5
Statistical Analysis of log transformed plasma GSK3036656 Pharmacokinetic ParametersAssessing AccumulationRatioPart B
   
        Parameter (units)      Treatment            Comparison                        Geom.LsMean               Ratio                               90% 
                                                                                                                ------------------------------                                  Confidence Interval
                                                                                                                 n      Test              n    Ref
  --------------------------------------------------------------------------------------------------
AUC(Ro)(µg.h/mL)    XXmg     Day 14 vs Day 1      XX  x.xxx    xx x.xxx   x.xxx    ( x.xxx,  x.xxx )
Cmax(RCmax)(µg/mL)  XXmg     Day 14 vs Day 1      XX  x.xxx    xx x.xxx   x.xxx    ( x.xxx,  x.xxx )


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Example 
: PK_T6
Page 10of n
Protocol
: GSK3036656
Population
: Pharmacokinetic 
                                                                                       
                            Table PK_T6
                           Statistical Analysis of log transformed plasma GSK3036656 Pharmacokinetic Parameters Assessing Steady State Part B
     Parameter 
Treatment         Day            Back-Transformed Slope            90% Confidence Interval
        -----------------------------------------------------------------------------------------------------------------------------------------------------
                   Ctrough                            xxmg      1-14        x.xxx              
(x.xxx, x.xxx )